WO2006006490A1 - Composé spirocyclique - Google Patents

Composé spirocyclique Download PDF

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Publication number
WO2006006490A1
WO2006006490A1 PCT/JP2005/012569 JP2005012569W WO2006006490A1 WO 2006006490 A1 WO2006006490 A1 WO 2006006490A1 JP 2005012569 W JP2005012569 W JP 2005012569W WO 2006006490 A1 WO2006006490 A1 WO 2006006490A1
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Prior art keywords
group
substituent
diazaspiro
ring
general formula
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PCT/JP2005/012569
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English (en)
Japanese (ja)
Inventor
Kazuhiko Torisu
Yoshihiko Nakai
Hiromu Egashira
Masaru Sakai
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Ono Pharmaceutical Co., Ltd.
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Publication of WO2006006490A1 publication Critical patent/WO2006006490A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • the present invention relates to a spiro compound.
  • general formula (I) For details, refer to general formula (I)
  • the blood coagulation reaction is one of the ecological defense reactions triggered in response to stimulation of endotoxin and other foreign substances as well as vascular damage. This reaction also acts as a cascading mechanism that proceeds on the membrane of platelets or damaged endothelial cells that aggregate at the site of injury and in the presence of calcium ions.
  • the blood clotting system is also composed of various serine protease precursors, protein cofactors and fibrous tampa fibrinogen. Thrombin generated in the coagulation cascade converts soluble fibrinogen to insoluble fibrin, causing blood clotting.
  • the blood coagulation cascade is roughly divided into two types, an extrinsic system and an intrinsic system.
  • the extrinsic system begins with the formation of a complex with the activation of blood coagulation factor VII by the tissue factor exposed by vascular disruption and endotoxin stimulation, and activates factor X.
  • the endogenous system leads to the activation of factor X through a multi-stage enzymatic reaction after the activation of the contact factor.
  • These extrinsic systems and intrinsic systems merge at Factor X, and activated Factor X (blood coagulation factor Xa, hereinafter abbreviated as FXa) activates prothrombin to thrombin to produce soluble fibrinogen.
  • activated Factor X blood coagulation factor Xa, hereinafter abbreviated as FXa
  • FXa which is located at the confluence of extrinsic and intrinsic systems, is upstream of thrombin, and FXa inhibition is more efficient and specific than thrombin inhibition and may be an anticoagulant.
  • an anticoagulant sulfarin and thrombin inhibitors are used.
  • thrombin inhibitors heparin and the like have side effects such as bleeding because of their low specificity for enzymes.
  • selective thrombin inhibitors also suppress platelet aggregation by thrombin and the production of protein C, a coagulation regulator, so the divergence from bleeding is narrow and likely.
  • FXa inhibitors can be effective anticoagulants because they inhibit the confluence of extrinsic and intrinsic systems.
  • FXa selective inhibitors that do not have thrombin inhibitory activity should not have direct platelet aggregation inhibitory activity or protein C production inhibitory activity, and therefore have a greater discrepancy between anticoagulant action and bleeding action than thrombin inhibitor. It can be an ideal anticoagulant that can be expected
  • Non-patent Document 1 (Wherein, X A represents a nitrogen atom or —CH—) is known to have GPIIb-II la antagonist action (Non-patent Document 1, Non-patent Document 2) ).
  • a 3 , AA and A 6 together with the two carbons to which they are attached form a substituted benzene, where A 3 is CR 3b and A 4 is CR 4b Yes, A 5 is CR 5b , A 6 is CR 6b , where R 3b is hydrogen, methyl, methoxy, fluoro, black mouth, or force noreoxy, and one of R 4b and R 5b is hydrogen, C1 4 anorequinole, halo, etc.
  • R 4b and R 5b are hydrogen
  • R 6b is hydrogen, methyl, fluoro, black mouth, or methoxy
  • R 3b , R 4b , and R 6b are each hydrogen
  • L 1 is CO—NH 2
  • 1 L 1 —Q 1 is 1 CO—NH—Q 1
  • Q 1 has a methyl, methoxy, methylthio, fluoro, or black-and-back substituent at the 5th position.
  • R 2b is one L 2 —Q 2 , where L 2 is NH—CO 2, etc.
  • Q 2 is Q 2A , Q 2B , Q 2C , Q 2D , Q 2 E or Q 2E , where X 2 is a single bond or methylene, and L 2 and Q 2 are sometimes chosen as NH—CO—X 2 —Q 2A isotropic , Where Q 2A (showing L 2 to which it is attached) is
  • Patent Document 1 International Publication No. 00Z39118 pamphlet.
  • Non-Patent Document 1 Bioorganic & Medicinal Chemistry Letters (11), 1289 (2001)
  • Non-Patent Document 2 Bioorganic & Medicinal Chemistry Letters (11), p. 1293 (2001)
  • Thrombotic diseases with activated blood clotting mechanisms such as thrombus associated with cardiovascular disease Thrombosis, thrombosis associated with cerebrovascular disease, embolism, thrombosis associated with venous vascular disease, embolism, and Z or systemic and Z or peripheral thrombus, embolism prevention and Z or treatment
  • thrombus associated with cardiovascular disease Thrombosis thrombosis associated with cerebrovascular disease
  • embolism thrombosis associated with venous vascular disease
  • embolism embolism
  • Z or systemic and Z or peripheral thrombus embolism prevention and Z or treatment
  • the present invention provides:
  • R 1 represents a hydrogen atom or a substituent
  • R 2 represents a substituent
  • R 3 represents a hydrogen atom or a substituent
  • R 1 and R 2 together are substituted by a substituent.
  • Ring A which may form an optional ring, represents a single ring that is substituted with R 1 and R 2 and may be further substituted with a substituent
  • ring B is substituted with R 3
  • X represents a carbon atom or a nitrogen atom
  • W represents a carbon atom or a nitrogen atom.
  • ring 1 represents an optionally substituted cyclic group
  • R 4 represents a hydrogen atom or a substituent
  • R 1 and R 4 are joined together by a bond or a substituent. It may be substituted or may form a ring Y may be substituted by a bond or a substituent, and may represent a spacer having 1 to 5 atoms in the main chain, and Z is a bond
  • [1] which represents a spacer having 1 to 5 atoms in the main chain which may be substituted by a hand or a substituent, and other symbols have the same meaning as in the above [1].
  • R 5 represents a hydrogen atom or a substituent, and other symbols have the same meanings as defined in [1] and [7] above),
  • ring2 and ring3 each independently represent a cyclic group which may have a substituent, and U and V are each independently substituted by a bond or a substituent!
  • the main chain represents a spacer having 1 to 5 atoms in the main chain, and the other symbols have the same meaning as in the above [1].
  • a pharmaceutical composition comprising as an active ingredient a compound represented by the general formula (I) according to [1], a salt thereof, an N-oxide, a solvate thereof or a prodrug thereof , [25]
  • the compound of the present invention represented by the general formula (I) potently inhibited FXa.
  • the compound of the present invention represented by the general formula (I) is a compound excellent in selectivity that specifically inhibits FXa and has a weak inhibitory effect on other enzymes (for example, thrombin).
  • the compound of the present invention is a compound having excellent solubility and absorbability.
  • the compound of the present invention is a compound having a very weak inhibitory action on drug metabolizing enzymes. These are medicines It has the physical, chemical, and pharmacological properties that are most required for development. & Co. out; 3 ⁇ 4 ".
  • the spiro ring represented by the general formula (I) in this specification forms a monocyclic ring A and a monocyclic ring B force via the carbon atom (C). That is, ring A is a single ring that forms a spiro ring with ring B, and ring B is a single ring that forms a spiro ring with ring A.
  • the “monocycle” in the monocycle represented by ring A and which may be further substituted with a substituent is a C3-15 monocyclic carbocycle, or an oxygen atom, a nitrogen atom, and Z Or sulfur nuclear means a 3-15 membered monocyclic bicyclic ring containing 1 to 5 selected heteroatoms.
  • the C3-15 monocyclic carbocycle represented by ring A includes all saturated rings and partially unsaturated rings.
  • the 3- to 15-membered monocyclic heterocycle containing 1 to 5 heteroatoms selected from the oxygen atom, nitrogen atom and Z or sulfur atom represented by ring A is an all-saturated ring. And rings that are partially unsaturated.
  • examples of the “substituent” in the monocyclic ring which may be further substituted with a substituent represented by ring A include (1) an alkyl group which may have a substituent, (2 ) An optionally substituted alkenyl group, (3) an optionally substituted alkyl group, (4) an optionally substituted carbocyclic group, (5 ) An optionally substituted heterocyclic group, (6) an optionally protected hydroxyl group, (7) an optionally protected thiol group, (8) an optionally protected amino group (9) A rubamoyl group which may have a substituent, (10) a sulfamoyl group which may have a substituent, (11) a carboxyl group, (12) an alkoxycarbo group (for example, , Methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc. Cl-6 alkoxy carbonyl groups, etc.), (13) sulfo group (one SO H) , (14)
  • alkyl group in the “optionally substituted alkyl group” as a substituent examples include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl , Pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or icosyl
  • the substituent of the alkyl group includes a hydroxyl group, an amino group, a carboxyl group, a nitro group, an azido group, a mono- or di-Cl-6 alkylamino group (for example, methylamino, ethylamino, propylamino-containing dimethylamino-containing ketylamino, etc.) , N aromatic ring amino group (for example, N-phenylamino), N aromatic ring N-alkylamino group (for example, N-phenyl-N-methylamido N-phenyl-N ethylamine-containing N-phenol) Lou N Puropiruami input N- Hue - Lou N butylamine input N Hue - Lou N - Penchiruami input N - Hue - Lou N - to Kishiruamino etc.), Ashiruamino group, N
  • the acyl group in the acyl group and the N-acyl-N-alkylamino group as the substituent of the alkyl group are "may be protected as a hydroxyl group", " It represents the same meaning as the acyl group as the protective group in “protected and may be a thiol group” and “protected and may be an amino group”.
  • alkyl group in the N-acyl-N-alkylamino group examples include, for example, methyl, ethyl, n-propyl, isopropylinole, n-butinole, isobutinole, sec-butinole, tert-butinole, pentinore, hexinole, Examples include linear or branched Cl-20 alkyl groups such as ptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or icosyl group.
  • Examples of the carbocycle as the substituent of the alkyl group include a C3-15 monocyclic, bicyclic or tricyclic aromatic carbocyclic ring which may be partially or wholly saturated.
  • the C3-15 monocyclic, bicyclic or tricyclic aromatic carbocyclic ring which may be partially or fully saturated includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, Cyclooctane, Cyclononane, Cyclodecane, Cycloundecane, Cyclododecane, Cyclotridodecane, Cyclotetradecane, Cyclopentadecane, Cyclopentene, Cyclohexene, Cycloheptene, Cyclopentene, Cyclopentagen, Cyclohexagen, Cyclohexadiene, Cyclohexane Octagen, benzene, pentalene, par
  • a C3-15 monocyclic, bicyclic or tricyclic aromatic carbocyclic ring which may be partially or fully saturated may include a spiro-bonded bicyclic carbocyclic ring and a bridged bicyclic carbocyclic ring.
  • the substituent of the carbocyclic ring as the substituent of the alkyl group includes a Cl to 8 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- Butyl, pentyl, hexyl, heptyl, octyl, etc.), hydroxyl group, amino group, carboxyl group, nitro group, mono- or di-Cl-6 alkylamino group (for example, methylamino, ethylamino, propylamino-containing dimethylamino-containing ketylamino, etc.) Cl-6 alkoxy group (for example, methoxy, ethoxy, propoxy, hexyloxy, etc.), Cl-6 alkoxy carbo group (for example, methoxycarbol, ethoxycarbol, tert-butoxycarbol
  • the heterocycle as a substituent of the alkyl group is, for example, partially or fully saturated containing 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom or a sulfur atom.
  • Examples thereof include a 3- to 15-membered monocyclic, bicyclic or tricyclic aromatic heterocycle.
  • Oxygen atom, nitrogen atom or sulfur nuclear power may also be selected Partially or fully saturated containing 1 to 5 heteroatoms 3-15 membered monocyclic, bicyclic or tricyclic aromatic Among the aromatic heterocycles, oxygen atoms, nitrogen atoms or sulfur nuclear powers include 3 to 15-membered monocyclic, bicyclic or tricyclic aromatic heterocycles containing 1 to 5 heteroatoms selected.
  • Rings include aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, virazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydrovirazine, tetrahydrovirazine, piperazine , Dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine Tetrahydropyridazine, perhydro pyridazine, dihydr
  • a Cl to 8 alkyl group for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- Butyl, pentyl, hexyl, heptyl, octyl, etc.
  • hydroxyl group amino group, carboxyl group, nitro group, mono- or di-Cl-6 alkylamino group (for example, methylamino, ethylamino, propylamino-containing dimethylamino-containing ketylamino, etc.)
  • Cl-6 alkoxy group for example, methoxy, ethoxy, propoxy, hexyloxy, etc.
  • Cl-6 alkoxy carbo group for example, methoxycarbol, ethoxycarbol, tert-butoxycarbol, etc.
  • alkenyl group in the "having a alkenyl group having a substituent" as a substituent examples include, for example, ethyl, probe, butenyl, pentyl, and hepar. Examples thereof include linear or branched C2-20 alkenyl groups such as xylene.
  • the substituent of the alkenyl group has the same meaning as the substituent in the aforementioned “alkyl group optionally having substituent (s)”.
  • alkyl group in "having a substituent, which may be an alkyl group" as a substituent include, for example, ethynyl, probule, butyur, pentyl, and hexul. Examples thereof include a linear or branched C2-20 alkynyl group.
  • the substituent of the alkynyl group is the same as the substituent in the aforementioned “alkyl group optionally having substituent (s)”. Represents meaning.
  • carbocycle in the "having a substituent, or carbocyclic group" as a substituent for example, a part or all of which may be saturated C3-15 monocyclic, bicyclic Examples thereof include a ring or a tricyclic aromatic carbocyclic ring.
  • Examples of the C3-15 monocyclic, bicyclic or tricyclic aromatic carbocyclic ring which may be partially or fully saturated include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, Cyclooctane, Cyclononane, Cyclodecane, Cycloundecane, Cyclododecane, Cyclotridodecane, Cyclotetradecane, Cyclopentadecane, Cyclopentene, Cyclohexene, Cycloheptene, Cyclopentene, Cyclopentagen, Cyclohexagen, Cyclohexadiene, Cyclooctagen, benzene, pentalene, nohydropentalene, azulene, nohydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthal
  • a C3-15 monocyclic, bicyclic or tricyclic aromatic carbocyclic ring which may be partially or fully saturated may be a spiro-bonded bicyclic carbocyclic ring or a bridged bicyclic carbon. Rings are also included, for example, spiro [4. 4] nonan, spiro [4. 5] decane, spiro [5. 5] undecane, bicyclo [2.2.1] heptane, bicycl mouth [2.2.1] Hepter-2, Bicyclo [3. 1. 1] Heptane, Bicyclo [3. 1. 1] Hepta-2-ene, Bicyclo [2. 2. 2] Octane, Bicyclo [2.2.2] Otter 2— For example, a ring, adamantane or noradamantan ring.
  • examples of the substituent on the carbocyclic ring include Cl to 4 alkyl groups (for example, methyl, ethyl, propyl, butyl, etc.), C2 to 4 alkenyl groups (for example, ethyl, probe, butyl).
  • C2-4 alkyl groups eg, etul, probule, pentyl, etc.
  • hydroxyl groups Cl-4 alkoxy groups (eg, methoxy, ethoxy, propoxy, butoxy, etc.), Cl— 6 alkoxycarbonyl groups (for example, methoxycarbon, ethoxycarbol, tert-butoxycarbonyl, etc.), thiol groups, Cl-4 alkylthio groups (for example, methylthio, ethylthio, propylthio, butylthio, etc.), amino groups, Mono- or di-Cl-4 alkylamino groups (e.g.
  • Ethylamino etc. amino-Cl-4 alkyl group (eg aminomethyl etc.), mono- or di-Cl-4 alkylamino-Cl-4 alkyl group (eg dimethylaminomethyl, methylaminomethyl etc.), imino group, imino group Alkyl groups (e.g., ethanimidyl), oxo groups, halogen atoms (fluorine, chlorine, bromine, iodine), torino, romethyl groups (e.g., trifluoromethyl, etc.), torino, romethoxy groups (e.g., , Trifluoromethoxy, etc.), torino, romethylthio group (eg, trifluoromethylthio, etc.), dihalomethylthio group (eg, difluoromethylthio, etc.), an optionally substituted cyclic group, cyano Group, Cl-4 alkylsulfol group (for example, methyl
  • the cyclic group may have a substituent as a substituent of a carbocyclic ring in the "having a substituent, or may be a carbocyclic group" as a substituent.
  • substituent it may have a substituent as a substituent of a carbocyclic ring in “having a substituent! / ⁇ may! / ⁇ carbocyclic group”! / ⁇
  • the substituent of the cyclic group has the same meaning as the substituent of the carbocycle as the substituent of the “optionally substituted alkyl group” as the substituent, and these optional substituents can be substituted. You can replace 1 and 4 in the correct position.
  • Examples of the heterocycle in the "having a substituent, which may have a substituent" as the substituent include, for example, an oxygen atom, a nitrogen atom, or a sulfur atom, and 1 to 5 heteroatoms selected. And 3- to 15-membered monocyclic, bicyclic or tricyclic aromatic heterocycles which may be partially or fully saturated. Oxygen atom, nitrogen atom or sulfur nuclear power selected 1!
  • Oxygen atom, nitrogen atom or sulfur nuclear power 1 to 5 heteroatoms selected may be partially or fully saturated 3 to 15 membered monocyclic, bicyclic or tricyclic aromatic Among heterocycles, oxygen atom, nitrogen atom or sulfur nuclear power 3 to 15-membered monocyclic, bicyclic or tricyclic heterocyclic ring partially or fully saturated containing 1 to 5 selected heteroatoms
  • the substituent of the heterocyclic ring has the same meaning as the substituent in the aforementioned “having a substituent, and may be a carbocyclic group”, and these optional substituents are substitutable positions. One or four of them may be replaced.
  • Examples of the protecting group in the “protected ! may be a hydroxyl group”, “protected, may be a thiol group” and “optionally protected amino group” as a substituent include, for example, It may have a substituent, or may be an alkyl group (which has the same meaning as the above-mentioned “having a substituent, may be an alkyl group”), and a carbocycle which may have a substituent.
  • Alkylsulfonyl group for example, Cl to 4 alkylsulfol groups such as methylsulfol and ethylsulfol
  • aromatic ring sulfol group for example, C6-10 aromatic ring sulfo group such as furol sulfol
  • an acyl group for example,
  • acyl group (1) may have a substituent, an alkyl carbo group, and (2) have a substituent! /, May! /, An alkenyl group. (3) an optionally substituted alkylcarbonyl group, (4) an optionally substituted carbocyclic group, or (5) an optionally substituted group; Alternatively, a heterocyclic carbonyl group may be mentioned, and these optional substituents may be substituted at 1 or 4 positions at substitutable positions.
  • Alkyl may have the above-mentioned “With a substituent. And the same meaning as “alkyl group”. It may have a substituent in “Alkalcarporo group” or may have a substituent! /, Or Alkal may have the above-mentioned “Substituent”. This means the same meaning as “alkenyl group”. It has a substituent in "Alkyl carbonyl group which may have a substituent”! In addition, alkyl represents the same meaning as the above-mentioned “alkyl group having a substituent”.
  • The! / ⁇ may be! / ⁇ carbocycle has the same meaning as the above-mentioned “may be substituted with a carbocycle”.
  • the heterocyclic ring may have a substituent in “having a substituent or may be a heterocyclic carbonyl group”, and the heterocyclic ring may have the above-mentioned “having a substituent or a heterocyclic group”. Means the same as
  • substituent having a substituent, but a strong rubamoyl group
  • an unsubstituted strong rubamoyl group for example, an N-mono-Cl-4 alkyl rubamoyl group (for example, N-methyl) Rucarbamoyl, N-ethylcarbamoyl, N-propyl-powered rubamoyl, N-isopropyl-powered rubamoyl, N-butylcarbamoyl, etc.), N, N-diCl-4 alkyl-powered rubamoyl (eg, N, N-dimethylcarbamoyl N, N-Jetylcarbamoyl, N, N-dipropyl-powered rubamoyl, N, N-dibutylcarbamoyl, etc.) or 1-piveridylcarbonyl group.
  • N-mono-Cl-4 alkyl rubamoyl group for example, N-methyl
  • the "sulfamoyl group which may have a substituent" as the substituent includes, for example, an unsubstituted sulfamoyl group, N-mono-Cl-4 alkylsulfamoyl (for example, N-methyls).
  • N-ethylsulfamoyl N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.
  • N, N-diCl-4 alkylsulfamoyl for example, N, N-dimethylsulfamoyl, N, N-jetylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, etc.
  • the "monocycle" in the monocycle represented by ring B and further substituted with a substituent is a C3-15 monocyclic carbocycle, oxygen atom, nitrogen Atom and Z or Sulfur Nuclear A 3-15 membered monocyclic bicyclic ring containing 1-5 heteroatoms selected.
  • the C3-15 monocyclic carbocycle represented by ring B includes all saturated rings and partially unsaturated rings.
  • the 3- to 15-membered monocyclic heterocycle containing 1 to 5 heteroatoms selected from the oxygen atom, nitrogen atom and Z or sulfur atom represented by ring B includes all saturated rings.
  • rings that are partially unsaturated For example, aziridine, azetidine, azepine, imidazolidine, imidazoline, oxazidine, oxazine, oxathian, oxetane, diazepine, dioxane, dioxolan, dithiane, dithiolane, dihydroazepine, dihydroisoxazole, dihydroisothiazole, dihydroxodiazine, Oxaziazepine, dihydrooxadiazole, dihydrooxazine, dihydrooxazepine, dihydrooxazole, dihydrooxazole, dihydrooxepin, dihydrodiazepine, dihydrothiadiazine, dihydrothiadiazepine, dihydrothiadia Zonole, dihydrothiazine, dihydrothiazepine, dihydrothiazole, dihydrochepine, dihydr
  • the "substituent" in the monocyclic heterocycle which may be further substituted with a substituent represented by ring B is further substituted with a substituent represented by ring A. Represents the same meaning as the substituent in a good monocycle.
  • examples of the substituent represented by R 1 include (1) an alkyl group which may have a substituent, and (2) an alkyl which may have a substituent. Group, (3) an alkynyl group which may have a substituent, (4) a carbocyclic group which may have a substituent, and (5) a heterocyclic group which may have a substituent.
  • Alkyl sulfier groups for example, Cl to 4 alkyl sulfier groups such as methyl sulfiel and ethyl sulfile
  • Aromatic ring sulfiel groups for example, C6 such as fursulfur groups) 10 aromatic ring sulfiel groups
  • alkylsulfol groups eg, Cl to 4 alkylsulfol groups such as methylsulfol and ethylsulfol groups
  • aromatic ring sulfo groups for example, C6-10 aromatic ring sulfol group such as phenylsulfol
  • Acyl group for example, C1-6 alkanoyl group such as formyl, acetyl, propanol, bivaloyl, etc., for example, benzoyl etc.
  • R 1 which may have a substituent alkyl group
  • (2) may have a substituent Aruke - group
  • substituents (4) a carbocyclic group that may have a substituent
  • (5) a heterocyclic group that may have a substituent
  • (6) a protected group.
  • the sulfamoyl group which may have a substituent represents the same meaning as those of the “substituent” in a single ring, which may be further substituted by a substituent represented by ring A.
  • examples of the substituent represented by R 2 include (1) optionally having a substituent.
  • An alkyl group (2) an optionally substituted alkenyl group, (3) an optionally substituted alkynyl group, and (4) an optionally substituted carbocyclic ring.
  • Alkyl sulfiel groups for example, Cl to 4 alkyl sulfier groups such as methyl sulfiel and ethyl sulfile
  • Aromatic ring sulfiel groups for example, C6 such as fursulfur groups) 10 aromatic ring sulfiel groups
  • alkylsulfol groups eg, Cl to 4 alkylsulfol groups such as methylsulfol and ethylsulfol groups
  • aromatic ring sulfo groups for example, C6-10 aromatic ring sulfol group such as furolsulfol
  • Acyl group for example, C1-6 alkanoyl group such as formyl, acetyl, propanoyl, bivaloyl, such as benzoyl
  • C6-10 aromatic ring carbo group etc. oxo group
  • (28) thixo group 29) (Cl-6
  • ring 1 represents a cyclic group which may have a substituent
  • R 4 represents a hydrogen atom or a substituent
  • Y is substituted by a bond or a substituent.
  • Z represents a spacer having 1 to 5 atoms in the main chain which may be substituted by a bond or a substituent.
  • ring2 and ring3 each independently represent a cyclic group which may have a substituent, and U and V each independently may be substituted by a bond or a substituent. (Represents a spacer with 1 to 5 atoms in the main chain.), And (32) [1— (3 amino 1, 2 benzisoxazol 5 yl) 3— (trifluoromethyl) 1H— Villazol-5-yl] carbol group and the like.
  • R 2 (1) alkyl which may have a substituent, (2) may have a substituent Aruke - group, (3) substituents (4) a carbocyclic group that may have a substituent, (5) a heterocyclic group that may have a substituent, and (6) a protected group.
  • the sulfamoyl group which may have a substituent represents the same meaning as those of the “substituent” in a single ring, which may be further substituted by a substituent represented by ring A.
  • examples of the “cyclic group” in the “cyclic group optionally having substituent (s)” represented by ringl include, for example, (1) part or all of which may be saturated. ⁇ 15 monocyclic, bicyclic, or tricyclic aromatic carbocycles, or (2) selected from oxygen, nitrogen, or sulfur atoms, 1 and containing 5 heteroatoms, Examples thereof include a 3- to 15-membered monocyclic, bicyclic, or tricyclic aromatic heterocyclic ring that may be partially or fully saturated.
  • a “substituent may be substituted or may be a cyclic group” represented by ringl “a cyclic group” represented by “a part or all of which may be saturated C3-15 monocyclic, bicyclic
  • a cyclic group represented by “a part or all of which may be saturated C3-15 monocyclic, bicyclic
  • Examples of the ⁇ ring or tricyclic aromatic carbocycle '' include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, and cyclotridodecane.
  • a C3-15 monocyclic, bicyclic or tricyclic aromatic carbocyclic ring which may be partially or fully saturated may include a spiro-bonded bicyclic carbocyclic ring and a bridged bicyclic carbocyclic ring.
  • examples of the substituent on the carbocycle include Cl to 4 alkyl groups (for example, methyl, ethyl, propyl, butyl, etc.), C2 to 4 alkenyl groups (for example, ethyl, probe, butyl).
  • C2-4 alkyl groups eg, etul, probule, pentyl, etc.
  • hydroxyl groups Cl-4 alkoxy groups (eg, methoxy, ethoxy, propoxy, butoxy, etc.), Cl— 6 alkoxycarbonyl groups (for example, methoxycarbon, ethoxycarbol, tert-butoxycarbonyl, etc.), thiol groups, Cl-4 alkylthio groups (for example, methylthio, ethylthio, propylthio, butylthio, etc.), amino groups, Mono- or di-Cl-4 alkylamino group (for example, methylamino, ethylamino-containing propylamino-containing dimethylamino-containing diethylamino, etc.), halogen atom (fluorine, chlorine, bromine, Iodine), torino, romethyl group (eg, trifluoromethyl, etc.),
  • Oxygen atom, nitrogen atom, or sulfur nuclear atom represented by “Cyclic group” in “Can be substituted with a cyclic group” represented by ringl 1 to 5 hetero selected Among 3 to 15-membered monocyclic, bicyclic, or tricyclic aromatic heterocycles containing atoms, which may be partially or fully saturated, selected from oxygen, nitrogen, or sulfur atoms.
  • 3- to 15-membered monocyclic, bicyclic, or tricyclic aromatic bicyclic rings containing 1 to 5 heteroatoms include, for example, pyrrole, imidazole, triazole, tetrazole, pyrazonole, pyridine, Pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, chepin, oxazonole, isoxazonole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepinepine, oxazazepine, oxazazepine , Thiazine, thiadiazine, thiazepine, thiazepine, indole, isoindole, indolizine, benzo
  • cyclic group in “with cyclic group” represented by ringl Selected from an oxygen atom, a nitrogen atom, or a sulfur atom among the 3 to 15-membered monocyclic, bicyclic, or tricyclic aromatic heterocycles which may be partially or fully saturated.
  • Partially or fully saturated monocyclic, bicyclic or tricyclic heterocycles containing 5 heteroatoms include aziridines, azetidines, pyrrolines, pyrrolidines, imidazolines, imidazolidines, Triazoline, Triazolidine, Tetrazoline, Tetrazolidine, Virazolin, Virazolidine, Dihydropyridine, Tetrahydropyridine, Piperidine, Dihydrovirazine, Tetrahydrovirazine, Perazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine , Talented xylan, talented xetane, dihydrofuran
  • the substituent of the heterocyclic ring is partially saturated or partially saturated with "cyclic group” in “having a substituent, which may have a substituent,” represented by ringl. However, it represents the same meaning as the substituent in the “C3-15 monocyclic, bicyclic, or tricyclic aromatic carbocycle”, and these optional substituents have 1 at the substitutable position. You can replace them.
  • examples of the substituent represented by R 4 include (1) an alkyl group which may have a substituent, and (2) an alkyl which may have a substituent. Group, (3) an alkynyl group which may have a substituent, (4) a carbocyclic group which may have a substituent, and (5) a heterocyclic group which may have a substituent. , (6) an optionally protected hydroxyl group, (7) an optionally protected thiol group, (8) an optionally protected amino group, (9) an optionally substituted rubamoyl Group, (1
  • an optionally substituted sulfamoyl group (11) a carboxyl group, (12) an alkoxy carbo group (for example, Cl such as methoxycarbol, ethoxycarbol, tert-butoxycarbol, etc.) ⁇ 6 alkoxy carbo group etc.), (13) sulfo group (one SO H), (14) sul
  • Phino group (15) phosphono group, (16) -tro group, (17) cyano group, (18) amidino group, (19) (C1-67 alkoximino) methyl group (for example, (methoxyimino) methyl group, etc.), (20) — B (OH) group, (2
  • Halogen atom for example, fluorine, chlorine, bromine, iodine, etc.
  • Alkylsulfinyl group for example, Cl to 4 alkylsulfur groups such as methylsulfyl, ethylsulfur, etc.
  • Aromatic sulfiel groups for example, C6-10 aromatic sulfiel groups such as fursulfiel
  • Alkylsulfol groups for example, Cl-4 alkylsulfol such as methylsulfol, ethylsulfol, etc.
  • aromatic ring sulfol group for example, C6-10 aromatic ring sulfol group such as phenol sulfol
  • acyl group for example, formyl, acetyl, Cl-6 alkanoyl groups such as propanoyl and bivalloyl
  • C6-10 aromatic ring carbo group such as
  • R 4 (1) may have a substituent, may be an alkyl group, (2) an alkenyl group which may have a substituent, (3) An alkyl group which may have a substituent, (4) a carbocyclic group which may have a substituent, (5) a heterocyclic group which may have a substituent, (6) protection An optionally protected hydroxyl group, (7) an optionally protected thiol group, (8) an optionally protected amino group, (9) an optionally substituted rubamoyl group, and (10)
  • the sulfamoyl group which may have a substituent has the same meaning as that of the “substituent” in the monocyclic ring, which may be further substituted by a substituent represented by ring A.
  • R 1 and R 4 are together a connexion represented, substituted It is formed by a spacer having 1 to 5 atoms in the main chain which may be substituted by a group, a nitrogen atom to which R 4 is bonded, Z, and a part of ring A.
  • R 1 and R 4 may be substituted by a substituent represented by V together, “the number of main chain atoms” in a spacer having 1 to 5 main chain atoms.
  • “Spacer of 1 to 5” means the interval between the main chain and up to 5 nuclear power.
  • the “number of atoms in the main chain” is counted so that the atoms in the main chain are minimized.
  • Examples of the “spacer having 1 to 5 atoms in the main chain” include, for example, a methylene group (one CH ⁇ which may have 1 or 2 substituents).
  • Optionally substituted nitrogen atom (—NH—), —CO—, —O—, —S—, —SO—, —SO— forces are also selected 1 to 5 divalent groups Etc.
  • the substituent of the group and the substituent of the nitrogen atom have the same meaning as the “substituent” in the monocyclic ring which may be further substituted by the substituent represented by the ring A.
  • substituent represented by the ring A for example, — CR 101 R 102 —, — NR 103 —, —CO—, — O—, — S—, —SO—,
  • R 1Cn and R 1C> 2 representing the same meaning as a “substituent” in a hydrogen atom or a single ring represented by ring A, which may be further substituted by a substituent.
  • R 1Cn and R 1C> 2 representing the same meaning as a “substituent” in a hydrogen atom or a single ring represented by ring A, which may be further substituted by a substituent.
  • R 1Cn and R 1C> 2 representing the same meaning as a “substituent” in a hydrogen atom or a single ring represented by ring A, which may be further substituted by a substituent.
  • the C2-5 alkylene group which may be replaced with one oxygen atom, nitrogen atom or sulfur atom includes C2-5 linear or branched alkylene such as ethylene, propylene, isopropylene, butylene, isobutylene and pentylene groups. Or a C2-5 alkylene group in which one carbon atom in the ethylene, propylene, isopropylene, butylene, isoprene, or pentylene group is replaced with an oxygen atom, a nitrogen atom, or a sulfur atom.
  • the remaining bonds of the nitrogen atom are a hydrogen atom, a C16 alkyl group, a C2-6 acyl group, or a C16 alkoxycarbonyl group (for example, methoxycarbon, ethoxycarbo, tertbutoxycarbonyl, etc.) Combine with.
  • the C2-5 alkylene group may be substituted with a substituent.
  • substituents include a C1-8 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl).
  • C2-5 alkylene group examples include one (CH) —, — (CH) one, (CH
  • Examples of the C1-6 alkylidene group in the “optionally C16 alkylidene group” include methylidene, ethylidene, propylidene, butylidene, pentylidene, and hexylidene.
  • a hydroxyl group an amino group, a carboxyl group, a nitro group, an azide group, a mono- or di-C1-6 alkylamino group (for example, , Methylamino, ethylamino, propylamino-containing dimethylamino, jetylamino, etc., N aromatic ring amino groups (eg, N-phenylamino, etc.), N aromatic rings—N alkylamino groups (eg, N-phenyl-N-containing N-methylamino) --Fu-Lu N ethylamine-containing N-Fu-Lu N Propylami-containing N-Fu-Lu N Butylami-containing N-Fu-Lu N Pentylami-containing N-Fu-Lu N Hexylamino etc.), C1-6 alkoxy group (for example, Methoxy
  • a spacer having 1 to 5 atoms in the main chain in a spacer having 1 to 5 atoms in the main chain which may be substituted by the substituent represented by Y Represents the same meaning as “the spacer having 1 to 5 atoms in the main chain” represented by the above R 1 and R 4 together.
  • the “spacer having 1 to 5 atoms in the main chain” in the spacer having 1 to 5 atoms in the main chain may be substituted with a substituent represented by Z.
  • R 1 and R 4 represent the same meaning as “a spacer having 1 to 5 atoms in the main chain”.
  • R 1 and R 2 are together a connexion represented, substituted It may be substituted by a group, but is formed by a spacer and a part of ring A.
  • R 1 and R 2 are represented together, and may be substituted by a substituent.
  • the “spacer” in a spacer is defined as 1 to Means an interval of 15 lines.
  • “the number of atoms in the main chain” is counted so that the atoms in the main chain are minimized.
  • Examples of the “spacer having 1 to 15 atoms in the main chain” include, for example, a methylene group (one CH—) which may have one or two substituents, and a substituent.
  • a good nitrogen atom one
  • the substituent of the methylene group and the substituent of the nitrogen atom have the same meaning as the “substituent” in the monocyclic ring which may be further substituted by the substituent represented by the ring A.
  • Specific examples include those described as “spacer having 1 to 5 atoms in the main chain” in which R 1 and R 4 are represented together.
  • R 3 represents a hydrogen atom or a substituent.
  • substituent represented by R 3 include (1) an alkyl group which may have a substituent, (2) an alkenyl group which may have a substituent, and (3) a substituent.
  • An alkyl group that may be substituted (4) a carbocyclic group that may have a substituent, (5) a heterocyclic group that may have a substituent, and (6) a protected group. May have a hydroxyl group, (7) an optionally protected thiol group, (8) an optionally protected amino group, (9) a substituent, and a rubamoyl group, (10 ) With substituents! /, May!
  • alkyl sulfier groups for example, Cl to 4 alkyl sulfier groups such as methyl sulfiel and ethyl sulfile
  • aromatic sulfiel groups for example, sulfulyl
  • Alkylsulfol group eg, Cl-4 alkylsulfol group, such as methylsulfol, ethylsulfol, etc.
  • Alkylsulfol group eg, Cl-4 alkylsulfol group, such as methylsulfol, ethylsulfol, etc.
  • Has substituent An aromatic ring sulfo group for example, C6-10 aromatic ring group such as phenol sulfone, or 5- to 10-membered heterocyclic sulfonyl group such as pyridinyl sulfol), or the like
  • an optionally substituted acyl group e.g., Cl-6 alkanol group such as formyl, acetyl, propanol, bivaloyl, etc., for example, C6-10 aromatic ring carbo group such as benzoyl, for example, , Pyridine carbo, etc. 5 or the
  • R 3 (1) which may have a substituent alkyl group, (2) may have a substituent Aruke - group, (3) substituents (4) a carbocyclic group that may have a substituent, (5) a heterocyclic group that may have a substituent, and (6) a protected group.
  • the sulfamoyl group which may have a substituent represents the same meaning as those of the “substituent” in a single ring, which may be further substituted by a substituent represented by ring A.
  • the “substituent” in the aromatic ring sulfo group and the optionally substituted acyl group may have a substituent represented by R 3 .
  • R 3 a substituent represented by R 3 .
  • Cl-4 alkyl group for example, methyl, ethyl, propyl, butyl, etc.
  • C2-4 alkyl group for example, etul, probe, butyr, etc.
  • C2-4 alkyl group etc.
  • examples of the substituent represented by R 5 include (1) an alkyl group which may have a substituent, (2) an alkyl group which may have a substituent, ( 3) an alkynyl group which may have a substituent, (4) a carbocyclic group which may have a substituent, (5) a heterocyclic group which may have a substituent, (6 ) An optionally protected hydroxyl group, (7) an optionally protected thiol group, (8) an optionally protected amino group, (9) an optionally substituted rubamoyl group, ( 10) an optionally substituted sulfamoyl group, (11) a carboxyl group, (12) an alkoxy carbo group (for example, methoxycarbol, ethoxycarbol, tert-butoxycarbol, etc.) Cl to 6 alkoxy carbonyl groups, etc.), (13) sulfo group (one SO H), (14) sulfur
  • Alkyl sulfier groups for example, Cl to 4 alkyl sulfier groups such as methyl sulfiel and ethyl sulfile
  • Aromatic ring sulfiel groups for example, C6 such as fursulfur groups) 10 aromatic ring sulfiel groups
  • alkylsulfol groups eg, Cl to 4 alkylsulfol groups such as methylsulfol and ethylsulfol groups
  • aromatic ring sulfo groups for example, C6-10 aromatic ring sulfol group such as phenyl sulfone
  • Acyl group eg C1-6 alkanoyl group such as formyl, acetyl, propanol, bivaloyl etc., eg, benzoyl etc. C6-10 aromatic ring carbo group etc.
  • oxo group formyl, acetyl, propanol, bivaloyl
  • R 5 (1) an alkyl group which may have a substituent, (2) an alkyl group which may have a substituent, (3) a substituent (4) a carbocyclic group that may have a substituent, (5) a heterocyclic group that may have a substituent, and (6) a protected group.
  • the sulfamoyl group which may have a substituent represents the same meaning as those of the “substituent” in the monocycle, which may be further substituted by a substituent represented by ring A.
  • ring 2 and ring 3 each independently represent the same meaning as ring 1, and U and V each independently represent the same meaning as Y or Z.
  • ring A is preferably a 3- to 15-membered monocyclic heterocycle containing 1 to 5 heteroatoms selected from oxygen atom, nitrogen atom and Z or sulfur atomic force. More preferably a 3- to 8-membered monocyclic heterocycle containing 1 to 5 heteroatoms selected from oxygen, nitrogen and Z or sulfur atoms, more preferably oxygen and nitrogen atoms.
  • Z or sulfur nuclear power is a 4 to 7-membered monocyclic heterocycle containing 1 to 5 selected heteroatoms, particularly preferably aziridine, azetidine, azepine, imidazolidine, imidazoline, oxaziazine, oxazine, Oxathian, Oxetane, Diazepine, Dioxane, Dioxolane, Dithiane, Dithiolane, Dihydroazepine, Dihydroisoxazole, Dihydroisothiazole, Dihydro Sadiadine, dihydrooxadiazepine, dihydrooxadiazole, dihydrooxazine, dihydrooxazepine, dihydroxazolone, dihydrooxepin, dihydrodiazepine, dihydrothiadiazine, dihydrothiadiazepine, Dihydrothiadiazole, dihydrothiazine, dihydrothiazepine, dihydrothi
  • W is preferably a nitrogen atom.
  • R 1 is preferably a hydrogen atom, having a substituent! /, An alkyl group, an optionally substituted carbocyclic group, or a substituted group.
  • a heterocyclic group which may have a group, a hydroxyl group which may be protected, an amino group which may be protected, a carboxyl group, an alkoxycarbonyl group, a nitro group, a cyano group, a halogen atom, an acyl group, Or an oxo group, more preferably a hydrogen atom, an optionally substituted alkyl group, a halogen atom, or an oxo group.
  • R 2 is preferably represented by the formula (I-la)
  • the group represented by the formula (I 4a) is preferably
  • R 3 is preferably a hydrogen atom, a basic group, a hydrogen-accepting group, or a cyclic group. Specifically, R 3 is preferably a hydrogen atom, [1, 3] oxazolo [5, 4-c] pyridine-2-yl, [1, 3] thiazolo [5, 4-c] pyridine-2- 1, 2, 4-oxadiazol-3-yl, 1, 3, 4-oxadiazol-2-yl, 1,3-oxazole-2-yl, 1,3-oxazole-4-yl, 1, 3- Oxazol 5-yl, 1, 3 thiazole- 2-yl, 1, 3 thiazole- 4-yl, 1, 3-thiazole-5-yl, 1, 3 benzoxazole- 2-yl, 1, 3 Benzothiazo 1L 2-yl, 1H-imidazole 1-yl, 1H-imidazole 2-yl, 1H-imidazole 4-yl, 1H-imidazole 5-yl, 1H pyr
  • ring 1 is preferably a bicyclic aromatic carbocyclic ring which may be partially or fully saturated, or an oxygen atom, a nitrogen atom or a sulfur nuclear power.
  • a bicyclic aromatic heterocyclic ring which is partially or fully saturated and contains one hetero atom is more preferably an indole or naphthalene ring.
  • the "cyclic group" in the "cyclic group” which may have a substituent represented by ring2 is preferably (1) partly or entirely saturated, However, a monocyclic aromatic carbocyclic ring, (2) —a bicyclic aromatic carbocyclic ring which may be partially or fully saturated, (3) an oxygen atom, a nitrogen atom, and a sulfur nuclear power are selected.
  • bicyclic aromatic heterocycles more preferably benzene, pyridine, indole, thiophene, thiazole, or naphthalene ring.
  • a part or all of the "cyclic group" in the "cyclic group” having a substituent represented by ring3 is (1) partially or fully saturated.
  • a monocyclic aromatic carbocycle or (2) an oxygen atom, a nitrogen atom, and 1 to 3 heteroatoms, which are also selected, may be partially or fully saturated.
  • a monocyclic aromatic heterocyclic ring more preferably (1) a part or all of which may be saturated C5-6 monocyclic
  • a 6-membered monocyclic aromatic heterocycle and more preferably a cyclopentane, cyclohexane, benzene, pyridine, pyrrolidine, piperazine, pyrazine, thiophene, benzofuran or benzothiophene ring.
  • a benzene, pyridine, pyrazine, thiophene, benzofuran or benzothiophene ring particularly preferably a benzene, pyridine, pyrazine, thiophene, benzofuran or benzothiophene ring.
  • R 4 is preferably a hydrogen atom.
  • U and V are preferably each independently CR 1G1 R 1C) 2 —, 1 NR 103 , 1 CO, 1 SO —, 1 CONR 103 , 1 NR 103 CO, 1 NR 103 COC
  • R 101 R 102 -, one CONR 103 CR 101 R 102 -, one C (R 101) C ( R 102) -, one C ⁇ C one one C R101R1.2 co -, -COCR 101 R 102 -, — NR 103 — SO—, —SO— NR 103 —, — CR 1
  • R 5 preferably has a substituent! /, May have an alkyl group, an optionally substituted alkenyl group, or a substituent.
  • Optionally substituted alkyl group substituted A carbocyclic group that may have a group, a heterocyclic group that may have a substituent, an acyl group, or an oxo group, more preferably an alkyl group that may have a substituent.
  • it may be a carbocyclic group, more preferably a carbocyclic group, and more preferably a carbocyclic group.
  • R 1 and R 2 are substituted by a substituent represented together, and as a spacer, it is preferably substituted by a substituent. But it is a spacer with 1-5 atoms in the main chain.
  • the general formula (I) is preferably the general formula (1-1) and the general formula (1-4), more preferably the general formula (I 1). — 1) and general formula (I 2— 2), more preferably general formula (I 4), more preferably general formula (I 4 1), general formula (I 4 2), and general formula (1—4— 3).
  • general formula (IA) and general formula (IB) are also preferred as general formula (I).
  • the general formula (IA) is preferably the general formula (1-1) and the general formula (1-5), more preferably the general formula (I 2-1) or the general formula (I 2— 2).
  • the general formula (IB) is preferably the general formula (I 4) and the general formula (1-6), more preferably the general formula (I 4 1) and the general formula (I 4 2), general formula (I 4 3), general formula (I 6-1) or general formula (1-6-2).
  • preferred compounds represented by the general formula (I) include the compounds described in Examples, 5- [5-[8- (4-pyridyl) -2,8 diazaspiro [4. 5] deca-2-yl]-3- (trifluoromethyl) 1H pyrazole- 1il] —1, 2 benzisoxazo 1 lou 3 ammine, 2— [1— (3 amino-1, 2, benzisoxazo leu 5— 1) Pyrazole-5-yl] -8- (4 Pyridyl) -2, 8 Diazaspiro [4.5] Decane 1-one, 2- [1- (3 —Amino-1, 2 Benzisoxazole 5 yl) 3 (Trifluoromethyl) 1 H Pyrazole 5 yl] 8 — (4 Pyridyl) 1 2, 8 Diazaspiro [4.5] Decan 1 3-one, 8 — [(6 Chromium 2-Naphtyl) sulfonyl] -2- ⁇ 2-
  • Deca-2-yl] carbol ⁇ propyl) propanamide 5— [2— (4-aminophenol) —2, 6 diazaspiro [3 6] Deca-6—yl] —4— ⁇ [2— (4 Kuroguchi Fe) 1) 2-Methylpropanoyl] amino ⁇ 2—Methyl 5—Oxopentanoic acid, 2— (Aminomethyl) N— [2— [7 — (3—aminophenol) 1 2, 7 diazaspiro [4. 4] Nona 2—yl] —1— (3—black mouth) 2—oxoxetyl] aline, N— [2— [7— (2 aminophenol) 2, 7 — bedroomsspiro [4.
  • Nona—2-yl] carbol ⁇ 1—Methylpropyl) methanesulfonamide, 3— (Aminomethyl) 4 N- [2— [2 — (1H—Imidazole 4— 2,7 diazaspiro [3.5] nona 7-yl] —2 —oxo— 1— (1H— 1, 2, 4 triazole— 1-ylmethyl) ethyl] aline, 6—black mouth — N— [2— [7— (1H—imidazole-5-yl) -2, 7 diazaspiro [4.
  • N 1 (4 Black Mole) 1
  • Methyl N 3 (1— ⁇ [2— (4, 5, 6, 7-Tetrahydro [1, 3] thiazolo [5, 4-c] pyridine 1-2-yl) 2, 6 diazaspiro [3.6] deca-6-yl] carbol ⁇ cyclopropyl) 1,3 benzenediamin, N— (5-crodiyl 2-piridyl)-?
  • Methyl 4 ( ⁇ [1 (4-chlorophenyl) ethyl] sulfol ⁇ amino) 5— [9 1 (1 Methyl 3 pyrrolidyl) 1 2, 9 Diazaspiro [5.6] —Yl] —5—oxopentanoate, 4-one ( ⁇ [1 (4) cyclopropyl] sulfol ⁇ amino) —5—oxo 5— [3— (4— Pyveridyl) 1, 3, 8—Diazaspiro [5.
  • an alkyl group, an alkyl group, an alkyl group, an alkoxy group, an alkylthio group, an alkylene group, an alkylene group or an alkylene group includes a straight chain group and a branched chain group.
  • isomers in double bonds, rings and condensed rings (E, Z, cis, trans isomers), isomers due to the presence of asymmetric carbon (R, S isomer, ⁇ ,
  • Optically active isomers with optical activity (D, L, d, 1), tautomers, polar bodies by chromatographic separation (high polarity, low polarity), equilibrium compounds, rotamers Any of these All ratio mixtures, or racemic mixtures, are included in the present invention.
  • the compound represented by the general formula (I) is converted into a salt by a known method.
  • the salt is preferably a pharmaceutically acceptable salt.
  • the salt examples include alkali metal salts, alkaline earth metal salts, ammonium salts, amine salts, and acid addition salts.
  • the salt is preferably water-soluble. Suitable salts include salts of alkali metals (potassium, sodium, etc.), alkaline earth metals (calcium, magnesium, etc.), ammonium salts, or pharmaceutically acceptable organic amines (tetramethylammonium). -Um, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl D glucamine, etc. ).
  • the acid addition salt is preferably water-soluble.
  • Suitable acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, Organic acid salts such as benzoates, citrates, methanesulfonates, ethanesulfonates, trifluoroacetates, benzenesulfonates, toluenesulfonates, isethionates, glucuronates or dalconates Is mentioned.
  • the solvate is preferably non-toxic and water-soluble.
  • Suitable solvates include, for example, solvates such as water or alcohol solvents (eg ethanol).
  • the prodrug of the compound represented by the general formula (I) is a compound that is converted into a compound represented by the general formula (I) by a reaction with an enzyme, gastric acid, or the like in a living body.
  • a prodrug of the compound represented by the general formula (I) when the compound represented by the general formula (I) has an amino group, the amino group is acylated, alkylated, or phosphorylated.
  • Compound for example, the amino group of the compound represented by the general formula (I) is converted to eicosanolation, alanylation, pentylaminocarbolation, (5-methyl-2-oxo-1,3-dioxolene-4-yl) methoxymethoxy Rubonylation, tetrahydrofuranylation, pyrrolidylmethylation, bivalyloxymethylation, acetomethylation, tert-butylated compounds, etc.); compounds represented by general formula (I) have a hydroxyl group In this case, the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, the hydroxyl group of the compound represented by the general formula (I) is acetylated, palmitoylated, propanoylated, bivalylated, succinylated.
  • [Chemical 55] Represents an ⁇ configuration, a ⁇ configuration, or a mixture thereof.
  • the compound of the present invention represented by the general formula (I) can be produced, for example, according to the method shown below, a method analogous thereto or the method shown in Examples.
  • the raw material mixture may be used as a salt.
  • a salt it may be used as a pharmaceutically acceptable salt of the general formula (I) described later.
  • ring A ring, R 1 _1 and R 3_1 represent the same meaning as ring A, ring B, R 1 and R 3 group represented by force ring A ring, R 1 1 and R 3 1 1 A carboxyl group, a hydroxyl group, an amino group, or a thiol group contained in is protected when necessary, and a compound represented by the general formula (III)
  • a method using an acid group or a ride includes, for example, a method in which a carboxylic acid is used in an organic solvent (such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, dimethoxyethane, etc.) or in an insoluble solvent.
  • an organic solvent such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, dimethoxyethane, etc.
  • an insoluble solvent such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, dimethoxyethane, etc.
  • reaction is carried out in an organic solvent (such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, acetonitrile, ethyl acetate) at a temperature of about 0 to 40 ° C.
  • organic solvent such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, acetonitrile, ethyl acetate
  • organic solvent such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, acetonitrile, ethyl acetate
  • phase transfer catalyst tetraptyl ammonium chloride, triethylbenzyl ammonium chloride, tri n-octylmethyl ammonium chloride, trimethyl in an organic solvent (dioxane, tetrahydrofuran, dichloromethane, etc.).
  • quaternary ammonium salts such as tetramethyl ammonium bromide
  • an aqueous alkaline solution such as aqueous sodium bicarbonate or sodium hydroxide solution
  • a method using a mixed acid anhydride is, for example, a method in which a carboxylic acid is used in an organic solvent (such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, etc.) or without a solvent, and a base (pyridine, triethylamine) is used.
  • an organic solvent such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, etc.
  • a base pyridine, triethylamine
  • a method using a condensing agent is performed by, for example, using a carboxylic acid and an amine in an organic solvent (such as chloroform, dichloromethane, dimethylformamide, jetyl ether, tetrahydrofuran, etc.) or without solvent in a base (pyridine , Triethylamine, dimethylamine, dimethylaminopyridine, etc.) in the presence or absence of condensing agent (1,3-dicyclohexylenorenoreimide (DCC), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide (EDC), 1, 1, -carbodidiimidazole (CDI), 2-cropone- 1-methylpyridi-mu iodine, 1-propinorephosphonic acid cyclic anhydride (1-propanephosphonic acid cyclic anhydride ⁇ PPA, etc.) And 1-hydroxybenztriazole (HOBt)
  • the reactions (1), (2) and (3) are all preferably carried out under an inert gas (argon, nitrogen, etc.) atmosphere and under anhydrous conditions.
  • an inert gas argon, nitrogen, etc.
  • the deprotection reaction by alkali hydrolysis is carried out, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.) in an alkali metal hydroxide (sodium hydroxide, sodium hydroxide, lithium hydroxide, lithium hydroxide). Etc.), alkaline earth metal hydroxides (barium hydroxide, hydroxide power, etc.), carbonates (sodium carbonate, potassium carbonate, etc.), aqueous solutions thereof, or mixtures thereof. Performed at a temperature of ⁇ 40 ° C.
  • the deprotection reaction under acid conditions can be carried out, for example, by using an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosyl) in an organic solvent (dichloromethane, chloroform, dioxane, ethyl acetate, azole, etc.). Acid), or inorganic acids (hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (hydrogen bromide, Z acetic acid, etc.) in the presence or absence of 2, 2, 2-trifluoroethanol, about 0-100 ° Performed at a temperature of C.
  • organic acid acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosyl
  • organic solvent diichloromethane, chloroform, dioxane, ethyl acetate, azole, etc.
  • Acid or inorganic acids (hydrochloric acid, sulfuric acid, etc.) or mixture
  • Deprotection reaction by hydrogenolysis includes, for example, solvents (ether type (tetrahydrofuran, dioxane, dimethoxyethane, jetyl ether, etc.), alcohol type (methanol, ethanol, etc.), benzene type (benzene, toluene, etc.) ), Ketones (acetone, methyl ethyl ketone, etc.), nitriles (acetonitrile, etc.), amides (dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixture of two or more thereof, catalyst (palladium) (Carbon, nodular black, palladium hydroxide, carbon oxide, platinum oxide, Raney nickel, etc.) in a hydrogen atmosphere under normal pressure or under pressure, or in the presence of ammonium formate, about 0 to 200 ° C At a temperature of solvents (ether type (tetrahydrofuran, dioxane, dimethoxye
  • the deprotection reaction of the silyl group is carried out, for example, using tetraptyl ammonium fluoride in an organic solvent miscible with water (tetrahydrofuran, acetonitrile). Performed at temperature.
  • the deprotection reaction using a metal is, for example, powdered zinc in an acidic solvent (acetic acid, a buffer solution having a pH of about 4.2 to 7.2 or a mixture thereof with an organic solvent such as tetrahydrofuran). In the presence of water, it is carried out at a temperature of about 0 to 40 ° C. while applying ultrasonic waves if necessary.
  • an acidic solvent acetic acid, a buffer solution having a pH of about 4.2 to 7.2 or a mixture thereof with an organic solvent such as tetrahydrofuran.
  • the deprotection reaction using a metal complex is carried out, for example, by using a trap reagent (tryptyltin hydride, hydrogenated in an organic solvent (dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a mixed solvent thereof.
  • a trap reagent tryptyltin hydride, hydrogenated in an organic solvent (dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a mixed solvent thereof.
  • the deprotection reaction can be performed by the method described in, for example, T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.
  • Examples of the protecting group for the carboxyl group include a methyl group, an ethyl group, an aryl group, a t-propyl group, a trichlorodiethyl group, a benzyl (Bn) group, a phenacyl group, a methoxybenzyl group, a trityl group, 2 —A solid phase carrier to which a black mouth trityl group or a structure thereof is bound.
  • Examples of the hydroxyl protecting group include a methyl group, a trityl group, a methoxymethyl (MOM) group, a 1-ethoxyethyl (EE) group, a methoxyethoxymethyl (MEM) group, and 2-tetrahydrovinyl (THP).
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TDMS t-butyldimethylsilyl
  • TDPS t-butyldiphenylsilyl
  • acetyl (Ac) group pivaloyl group
  • benzoyl group benzyl (Bn) group
  • examples thereof include a methoxybenzyl group, an aryloxycarbonyl (Alloc) group, and a 2,2,2-trichloro-ethoxy group (Troc) group.
  • Examples of the protecting group for the amino group include a benzyloxycarbol group, a t-butoxycarbol group (boc), an aryloxycarboro (Alloc) group, 1 methyl 1- (4 (Biphenyl) ethoxycarbol (Bpoc) group, trifluoroacetyl group, 9 fluoromethoxycarbol group, benzyl (Bn) group, methoxybenzyl group, benzyloxymethyl (BOM) group or 2- ( And a trimethylsilyl) ethoxymethyl (SEM) group.
  • a benzyloxycarbol group a t-butoxycarbol group (boc)
  • An aryloxycarboro (Alloc) group 1 methyl 1- (4 (Biphenyl) ethoxycarbol (Bpoc) group, trifluoroacetyl group, 9 fluoromethoxycarbol group, benzyl (Bn) group, methoxybenzyl group, benzyloxymethyl (B
  • thiol protecting groups include benzyl (Bn), methoxybenzyl, methoxymethyl (MOM), 2-tetrahydrovinyl (THP), diphenylmethyl or acetyl (Ac). Groups.
  • the protecting group for the carboxyl group, hydroxyl group, amino group, or thiol group is not particularly limited as long as it is a group that can be easily and selectively removed other than the above.
  • T for example, T.
  • the objective compound of the present invention can be easily produced by using and separating these deprotection reactions.
  • the compound represented by the general formula (II) can be produced by the method represented by the reaction process formula 1.
  • PN represents an amino-protecting group, and other symbols have the same meaning as described above.
  • reaction from the compound represented by the general formula (IV) to the compound represented by the general formula (V) is a substituent introduction reaction.
  • R 3_1 when R 3_1 is an aromatic ring, it can be produced by the following method. That is, an aromatic halide (such as bromopyridine) or an aromatic triflate and a compound represented by the general formula (IV) are mixed with an organic solvent (benzene, toluene, dimethylformamide, dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxy ester).
  • an aromatic halide such as bromopyridine
  • an organic solvent benzene, toluene, dimethylformamide, dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxy ester.
  • R 3_1 is an alkyl group, a cycloalkyl group, or a saturated heterocyclic group
  • it can be produced by the following reductive amination reaction. That is, a carbonyl compound corresponding to R 3_1 (for example, acetone, cyclohexanone, 1-methylpiperidin-4-one, etc.) and a compound represented by the general formula (IV) are mixed with an organic solvent (dichroic acid).
  • R 3_1 is an alkyl group, a cycloalkyl group, or a saturated heterocyclic group
  • R 3_1 when R 3_1 is an alkyl group, a cycloalkyl group, or a saturated heterocyclic group, it can also be produced by the alkylation reaction shown below. That is, a compound having a leaving group corresponding to R 3_1 (for example, methyl iodide and the like) and a compound represented by the general formula (IV) are converted into, for example, an organic solvent (for example, an aromatic hydrocarbon such as benzene, toluene and xylene).
  • an organic solvent for example, an aromatic hydrocarbon such as benzene, toluene and xylene
  • halogenated hydrocarbons such as dichloromethane and chloroform
  • saturated hydrocarbons such as hexane, heptane and cyclohexane
  • ethers such as jetyl ether, tetrahydrofuran and dioxane, such as acetone, methyl ether, etc.
  • Ketones such as tilketone, -tolyls such as acetonitrile
  • sulfoxides such as dimethyl sulfoxide
  • acid amides such as N, N-dimethylformamide, dimethylacetamide, 1,3 dimethyl-2-imidazolidinone, etc.
  • esters such as ethyl acetate are used.
  • Alkali metal hydrides such as sodium hydride and potassium hydride or alkaline earth metal hydrides, such as butyl lithium, sec butyl lithium, t-butyl lithium
  • Alkyllithiums such as sodium, alkoxides of alkali metals such as sodium methoxide and sodium ethoxide
  • inorganic bases such as alkali metals such as sodium metal and potassium, such as cesium carbonate, sodium carbonate and potassium carbonate
  • Carbonates such as triethylamine, tributylamine, N, N diisopropylethylamine
  • alkylamines such as N-methylmorpholine, such as N, N dimethylamine, pyridine, lutidine, collidine, 4 (dimethylamino) pyridine
  • Aromatic amines such as DBU (1,8 diazabicyclo [5,4,0] undecene
  • reaction from the compound represented by the general formula (V) to the compound represented by the general formula ( ⁇ ) is a deprotection reaction of the protecting group of the amino group.
  • protecting groups for amino groups include benzyloxycarbonyl group, t-butoxycarbonyl group, aryloxycarbol (Alloc) group, 1-methyl-11- (4-biphenyl) ethoxycarbol. (Bpoc) group, trifluoroacetyl group, 9 fluoromethoxycarbonyl group, benzyl (Bn) group, methoxybenzyl group, benzyloxymethyl (BOM) group or 2- (trimethylsilyl) ethoxymethyl ( SEM) group and the like.
  • thiol protecting groups include benzyl (Bn), methoxybenzyl, methoxymethyl (MOM), 2-tetrahydrovinyl (THP), diphenylmethyl, or acetyl (Ac). Groups.
  • the deprotection reaction of the protecting group of the amino group can be carried out by the same method as described above.
  • amidy reaction or sulfonamid reaction can be carried out by the same method as the amidy reaction.
  • the compound represented by the general formula (VI) can be produced by the method represented by the reaction process formula 2.
  • reaction scheme 2 all symbols have the same meaning as described above.
  • reaction from the compound represented by the general formula (VIII) to the compound represented by the general formula (VI) is a deprotection reaction of the protecting group of the amino group.
  • protecting groups for amino groups include benzyloxycarbonyl group, t-butoxycarbonyl group, aryloxycarbol (Alloc) group, 1-methyl-11- (4-biphenyl) ethoxycarbol. (Bpoc) group, trifluoroacetyl group, 9 fluoromethoxycarbonyl group, benzyl (Bn) group, methoxybenzyl group, benzyloxymethyl (BOM) group or 2- (trimethylsilyl) ethoxymethyl ( SEM) group and the like.
  • Examples of protecting groups for thiol groups include benzyl (Bn), methoxybenzyl, methoxymethyl (MOM), 2-tetrahydrovinyl (THP), diphenylmethyl or acetyl (Ac). Groups.
  • ring And R 103 — 1 is a force ring that has the same meaning as ring A, ring B, ring 3 , R 1 , R 3 , and R 1C> 3 , respectively.
  • ringS 1 and R 1C 3_1 (—may be the same as or different from R 103 — 1 in general formula (X)) is a force that represents the same meaning as ring2 and R 1G3 And a carboxyl group, a hydroxyl group, an amino group or a thiol group contained in the group represented by R 1G3 — 1 shall be protected when protection is required. ) Is subjected to an amidation reaction and, if necessary, further to a deprotection reaction of a protecting group.
  • the amidy reaction can be performed by the same method as the amidy reaction.
  • the compound represented by the general formula (X) can be produced by the method represented by the reaction process scheme 3.
  • P M represents a protecting group of carboxyl group
  • E is a halogen atom and the other symbols have the same meanings as described above.
  • the reaction from the compound represented by the general formula ( ⁇ ) to the compound represented by the general formula ( ⁇ ) is a urea reaction, for example, journal of Organic Chemistry, Vol.68, No. .l9, p.7289-7297 (2003) "
  • reaction from the compound represented by the general formula ( ⁇ ) to the compound represented by the general formula (X) is a deprotection reaction of a protecting group for a carboxyl group, and the same method as described above. Can be done.
  • Examples of the protecting group for the carboxyl group include a methyl group, an ethyl group, an aryl group, a tert-butyl group, a trichlorodiethyl group, a benzyl (Bn) group, a phenacyl group, a methoxybenzyl group, a trityl group, or Examples thereof include 2-trimethyl trityl group.
  • ring A 1 ring, R 1 _1 , and R 3_1 are ring A, ring B, And R 3 , but the carboxyl group, hydroxyl group, amino group or thiol group contained in the group represented by ring A ring, R 1_1 , and R 3_1 is protected when protection is required. It is assumed that ) Can be produced by subjecting it to an amidation reaction and, if necessary, subjecting it to a deprotection reaction of a protecting group.
  • the amidy reaction can be performed by the same method as the amidy reaction.
  • the compound represented by the general formula (XIV) can be produced by the method shown in Reaction Scheme 4.
  • reaction scheme 4 all symbols have the same meaning as described above.
  • reaction from the compound represented by the general formula (XVI) to the compound represented by the general formula (XVII) is an amidation reaction.
  • amidy reaction between the compound represented by the general formula (XVI) and the compound represented by the general formula (XVII) can be carried out by the same method as described above.
  • reaction from the compound represented by the general formula (XVII) to the compound represented by the general formula (XIV) is a deprotection reaction of the protecting group of the amino group.
  • protecting groups for amino groups include benzyloxycarbonyl group, t-butoxycarbonyl group, aryloxycarbonyl (Alloc) group, 1-methyl-11- (4-biphenyl) eth Xylcarbol (Bpoc) group, trifluoroacetyl group, 9-fluoromethoxycarbonyl group, benzyl (Bn) group, methoxybenzyl group, benzyloxymethyl (BOM) group or 2- (trimethylsilyl) group An ethoxymethyl (SEM) group etc. are mentioned.
  • Examples of protecting groups for thiol groups include benzyl (Bn), methoxybenzyl, methoxymethyl (MOM), 2-tetrahydrovinyl (THP), diphenylmethyl or acetyl (Ac). Groups.
  • the deprotection reaction of the protecting group of the amino group can be carried out by the same method as described above.
  • tert-butyl 2,8 diazaspiro [4.5] decane-2 carboxylate hydrochloride catalog number: WXPT-SA-004
  • tert-butyl 2, 8 diazaspiro [4.5] decane 1 8-carboxylate hydrochloride catalog number: WXPT-SA-003
  • tert butyl 2, 7 diazaspiro [3.5] nonane 2—force ruboxylate hydrochloride catalog number
  • WXPT-SA-006 tert-butyl 3,9 diazaspiro [5.5] undecano-3-carboxylate hydrochloride
  • Nonane 1-Carboxylate hydrochloride (catalog number: WXPT-SA-001) can be purchased from WuXi Pharma Tech Co., Ltd. Further, 2,8 diazaspiro [4.5] decan-1-one hydrochloride (catalog number: AR02105), which is a synthetic raw material in Example 19, can also be purchased by ARCH company.
  • reaction involving heating can be carried out using a water bath, an oil bath, a sand bath or a microwave, as will be apparent to those skilled in the art.
  • a solid-phase-supported reagent supported on a high-molecular polymer for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
  • a high-molecular polymer for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
  • the reaction product is obtained by a conventional purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion It can be purified by exchange resin, scavenger resin, column chromatography, washing or recrystallization. Purification may be performed for each reaction or after completion of several reactions.
  • a conventional purification means for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion It can be purified by exchange resin, scavenger resin, column chromatography, washing or recrystallization. Purification may be performed for each reaction or after completion of several reactions.
  • the toxicity of the compound represented by the general formula (I) is very low and is sufficiently safe for use as a medicine.
  • the compound of the present invention represented by the general formula (I) has an FXa inhibitory action and suppresses the coagulation cascade of the extrinsic system and the endogenous system, and therefore, a thrombotic disease in which the blood coagulation mechanism is activated, that is, a thrombus Useful as a preventive and Z or therapeutic agent for embolism.
  • thromboembolism means thrombosis and Z or thromboembolism.
  • examples of thromboembolism include thrombosis associated with cardiovascular disease, 'thrombosis associated with cerebrovascular disease' embolism, thrombosis associated with vascular disease 'embolism, and Z or systemic and Z Or peripheral thrombosis / embolism and the like.
  • thromboembolism associated with cardiovascular diseases includes, for example, stable exertion angina, variant angina, unstable angina and other angina, acute myocardial infarction, Myocardial infarction, asymptomatic myocardial ischemia, coronary thrombosis, reocclusion and restenosis after coronary artery bypass surgery, transcutaneous transluminal coronary angioplasty 'stent placement and reocclusion and resuscitation after Z or coronary thrombolysis Examples include stenosis.
  • Thrombus associated with cerebrovascular disease For example, lacunar infarction, atherothrombotic cerebral infarction, cerebral artery embolism, cerebral thrombosis, cerebrovascular disorder, disease associated with stroke, percutaneous transluminal angioplasty 'stent placement and Z or arterial thrombolysis Cerebral infarction such as asymptomatic cerebral infarction and restenosis, suppression of recurrence after cerebral infarction, transient ischemic attack including basilar / vertebral artery syndrome, basilar / vertebral artery syndrome, cerebral embolism Cardiogenic and Z or non-cardiogenic cerebral embolism and the like.
  • Thrombus associated with vascular vascular disease examples include deep vein thrombosis, pulmonary thromboembolism, pulmonary infarction, intraoperative and postoperative venous thromboembolism, rheumatic heart disease and atrial fibrillation Thromboembolism, valvular and Z or non-valvular atrial fibrillation associated with cerebral embolism and systemic embolism, recurrent venous thromboembolism, congenital antithrombin (AT) Examples include deficiency, cerebral vein occlusion, and the like.
  • Examples of systemic and Z or peripheral thromboembolism include limb arteriosclerosis, obstructive arteriosclerosis, peripheral arterial occlusion, Birja's disease, obstructive thromboangiitis, chronic arterial occlusion, chronic Arterial occlusion and ischemic symptoms such as ulcers based on Z or obstructive thromboangiitis, pain and coldness, intermittent claudication, generalized intravascular coagulation syndrome, sepsis, perfusion during extracorporeal circulation Prevention of blood coagulation (Hemodialysis), vascular transplantation Various accompanying vascular disorders are included.
  • the Ki value is calculated by a known method.
  • the method for calculating the Ki value is, for example, “Enzyme Experimental Method I”.
  • the compound of the present invention represented by the general formula (I) comprises 1) supplementation and Z or enhancement of the preventive and Z or therapeutic effects of the compound, 2) kinetics / absorption improvement of the compound, dose reduction, and Z or 3) In order to reduce the side effects of the compound, it may be administered in combination with other drugs.
  • the combination of the compound of the present invention represented by the general formula (I) and another drug may be administered in the form of a combination drug containing both components in one drug product, or may be a separate drug product. The dosage form may be taken. When administered as separate formulations, simultaneous administration and administration by time difference are included.
  • administration with a time difference may be carried out by administering the compound of the present invention represented by the general formula (I) first, followed by other drugs, or administering other drugs first, and the general formula (I)
  • the compound of the present invention represented by may be administered later.
  • Each administration method may be the same or different.
  • Other drugs for preventing and / or supplementing and / or enhancing Z or therapeutic effect of thrombotic diseases in which the blood coagulation mechanism of the compound of the present invention represented by the general formula (I) is activated include: , Antihypertensive, antiplatelet, anticoagulant, thrombolytic, vasodilator, brain function improver, antidementia, antitumor, hypoglycemic, and antiobesity Etc.
  • Examples of the blood pressure lowering agent include enalapril maleate, benazepril hydrochloride, arasepril, cilazapril, trandolapril, lisinopril, imidapril hydrochloride, quinapril hydrochloride, temocapril hydrochloride, delapril hydrochloride, captopril, and perindopril elpmin Hexamethonium bromide, hydralazine hydrochloride, hydrazinophthalazine hydrochloride, labetalol hydrochloride, cripine hydrochloride, candesartan cilexetil (TCV-116), candesartan (CV-11974), methyldono, oral sultan potassium, oral sultan, valsartan , Eprosartan, eposartan, irbesartan, tasosartan,
  • Antihyperlipidemic drugs include HMG- CoA reductase inhibitors (for example, pravastatin). Or its sodium salt, simpastatin, flupastatin, ripanstat, cerivastatin, cerivastatin sodium, itapastatin, atorvastatin or its calcium hydrate, oral pastatin, ZD-4522, or a salt thereof), fibrate (eg, beclobrate, Vinifibrate, ciprofibrate, symfibrate, clofibrate, clofibrate aluminum, clofibric acid, bezafibrate, clinofibrate, ethofibrate, gemfib mouth gill, pilifibrate, nicofibrate, lonifibrate, simfibrate, teufibrate Ibrato, fenofibric acid, etc.), anion-exchange rosin (eg,
  • LDL receptor increasing drugs such as ezetimibe
  • MTP inhibitors such as ezetimibe
  • MTP inhibitors such as ezetimibe
  • ileal bile acid transporter inhibitors such as SCAP ligands
  • FXR ligands such as SCAP ligands
  • antiplatelet drugs include cycloxygenase inhibitors, thromboxane synthase inhibitors, thromboxane receptor antagonists, adenosine 2-phosphate receptor antagonists, serotonin receptor antagonists, phosphodiesterase inhibitors Drugs, prostaglandins or G PllbZlIIa antagonists.
  • aspirin ticlopidine hydrochloride, clopidogrel sulfate, CS-747, AZD6140, YM337, YM028, dipyridamole, cilostazol, beraprost sodium, sarpodallate hydrochloride, ozadalixate And lithium, abciximab, tirofiban or eptifibatide.
  • anticoagulant examples include henolines (for example, heno ⁇ phosphorus sodium, dalteparin sodium, heparin calcium, parnaparin sodium, leviparin sodium, etc.), heparin analogues (for example, danaparoid sodium). , Enoxaparin, nadronoline, bemiparin, leviparin, tinzaparin and other small molecular heparins, fondaperinutus, etc.
  • henolines for example, heno ⁇ phosphorus sodium, dalteparin sodium, heparin calcium, parnaparin sodium, leviparin sodium, etc.
  • heparin analogues for example, danaparoid sodium.
  • Active ⁇ Protein C formulation active form of drotecodine alpha, anti Thrombin III preparations, gabexate mesylate, nafamostat mesylate, tissue factor pathway inhibitors (eg, rNAPc2, Sunol—cH3 6, Ro—678698, PHA—798), other anticoagulants (eg, BMS—56138 9, BMS-562247, BAY 59— 7939, YM150, LY517717, KFA— 1982, K FA— 1829, DU— 176b, CS— 3030, 813893, EMR61518, EMD495235, EMD503982, AVE6324, AVE3247, Idranino Rinutas, DPC—423 , DPC—602, DPC—A52350, DX—9065a, Otamixaban, HMR2096, FXV—673, RPR—130673, MCM16, MCM17, JTV—803, TC
  • thrombolytic drug examples include tPA (tissue type plasminogen activity factor), urokinase, prolokinase, thisokinase, anoleteplase, natepase, Monteplase, pamitepase, streptokinase, and the like.
  • vasodilator examples include alprostadil alpha detas, alprostadil, limaprostanolefadetas, limaprostat, epoprostenol sodium, hep mouth-cart, isotaspurin hydrochloride, trazoline hydrochloride , Dipyridamole or dipyridamole sustained-release agent.
  • Examples of the brain function improving drug include astrocyte function improving drug (for example, (2R) -2-propylpyruocanoic acid, etc.), brain function stimulating drug (for example, aracetam, -sergoline, etc.), Drugs that improve cerebral circulation metabolism (e.g., idebenone, amantadine hydrochloride, meclofenoxate hydrochloride, dihydroergotoxine mesylate, pyrithoxine hydrochloride, ⁇ -aminobutyric acid, bifumelan hydrochloride, lisuride maleate, indeloxazine hydrochloride,- Sergoline, propentophilin, ifenprodil tartrate, cytochrome C, cardiochrome, citicoline, disodium adenosine triphosphate, fasudyl hydrate, fumaric acid-zofunonone, etc.), dopamine receptor agonists (for example, L
  • antidementia drug examples include donepezil hydrochloride.
  • Antitumor agents include, for example, alkylating agents (nitridene mustard N oxide, cyclophosphamide, ifosfamide, melphalan, thiotepa, carbocon, busulfan, etc.), nitrosourea derivatives (dimustine hydrochloride, ranimustine, etc.), Antimetabolites (methotrexate, mercaptopurine, 6-mercapropurine boside, fluorouracil, tegafur, UFT, carmofur, doxyfluridine, cytarabine, enocitabine, etc.), anticancer antibiotics (actinomycin D, mitomycin C, hydrochloric acid) Daunorubicin, doxorubicin hydrochloride, aclarubicin hydrochloride, neocalcinostatin, pirarubicin, epilubicin,
  • hypoglycemic drugs include insulin preparations (for example, animal insulin preparations extracted from sushi and swine spleen; human insulin preparations genetically engineered using E. coli and yeast; ⁇ ; insulin fragments or derivatives (eg INS-1 etc.), insulin sensitivity improvers (eg pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570, JTT 501, MCC-555, YM-440, KRP-297, CS-011, FK-614, etc., a-Dalcosidase inhibitor (for example, voglibose, akanolevose, miglitonore, emidalitate, etc.), biguanide agent (for example, phenhonolemin, methonoremin, buhonoremin, etc.), Insulin secretion, stimulant (sulfonylurea (eg, , Tolptamide, dar
  • Anti-obesity drugs include, for example, central anti-obesity drugs (for example, dexfenfluramine, fenfuneramine, fuentenoremine, sibutramine, amphepramone, dexamphetamine, mazindol, phenolpropanolamine, Benzolex, etc.), spleen lipase inhibitors (eg, orlistat), ⁇ 3 agonist (eg, CL 316243, SR—58611—A, UL—TG—307, SB—226552, AJ—9677, BMS— 196085), peptidic appetite suppressants (eg, lebutin, CNTF (ciliary neurotrophic factor), etc.) or cholecysto-ghosts (eg, lynchtrypto, FPL-15849, etc.).
  • central anti-obesity drugs for example, dexfenfluramine, fenfuneramine, fuentenoremine, sibutramine,
  • Other drugs may be administered in combination of any two or more.
  • the dose varies depending on age, body weight, symptoms, therapeutic effects, administration method, treatment time, etc., but is usually in the range of about lmg to lOOOmg per adult, once to several times a day. Orally administered once, or parenterally several times a day (preferably nasal drops, eye drops or ointments) in the range of about 0.1 mg to 10 mg per adult per person Forces given intravenously in the range of 1 to 24 hours per day, or once a day, force is also injected subcutaneously in the range of 5 times.
  • the dosage varies depending on various conditions, and therefore, an amount smaller than the above dosage may be sufficient, or may be necessary beyond the range.
  • a solid preparation for internal use for oral administration It is used as a solution for internal use and as an injection, an external preparation, a suppository, an eye drop and an inhaler for parenteral administration.
  • Solid preparations for internal use for oral administration include tablets, pills, capsules, powders, granules and the like.
  • Capsules include hard capsules and soft capsules.
  • Tablets include sublingual tablets, buccal adhesive tablets and buccal quick disintegrating tablets.
  • one or more of the active substances may be used as they are, as force or excipients (latatose, mannitol, glucose, microcrystalline cellulose, denpun etc.), binders (hydroxylpropyl). Cellulose, polypyrrole pyrrolidone, magnesium metasilicate aluminate, etc.), disintegrating agents (calcium glycol glycolate, etc.), lubricants (magnesium stearate etc.), stabilizers or solubilizers (glutamic acid, aspartic acid, etc.) Etc., and formulated into a conventional method for use.
  • force or excipients lactatose, mannitol, glucose, microcrystalline cellulose, denpun etc.
  • binders hydroxylpropyl
  • disintegrating agents calcium glycol glycolate, etc.
  • lubricants magnesium stearate etc.
  • a coating agent sucrose, gelatin, hydroxylpropylcellulose, hydroxylpropylmethylcellulose phthalate, etc.
  • a coating agent sucrose, gelatin, hydroxylpropylcellulose, hydroxylpropylmethylcellulose phthalate, etc.
  • capsules of absorbable substances such as gelatin.
  • Liquid preparations for internal use for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs.
  • one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (such as purified water, ethanol or a mixture thereof).
  • this liquid agent may contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.
  • External dosage forms for parenteral administration include, for example, ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, eye drops, And nasal drops. These contain one or more active substances and are produced and prepared by known methods or commonly used formulations.
  • Sprays, inhalants, and sprays, other than commonly used diluents are buffers that provide isotonicity with stabilizers such as sodium hydrogen sulfite, such as sodium chloride salt, It may contain isotonic agents such as sodium or citrate. Spray This manufacturing method is described in detail, for example, in US Pat. Nos. 2,868,691 and 3,095,355. Moreover, it does not matter as an aerosol.
  • Injectables for parenteral administration include solutions, suspensions, emulsions and solid injections used by dissolving or suspending in a solvent at the time of use.
  • An injection is used by dissolving, suspending or emulsifying one or more active substances in a solvent.
  • the solvent for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used.
  • this injection may contain stabilizers, solubilizers (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), suspending agents, emulsifiers, soothing agents, buffers, preservatives, etc. Good.
  • a sterile solid preparation such as a lyophilized product can be produced and used by dissolving it in sterilized or sterile distilled water for injection or other solvent before use.
  • compositions for parenteral administration include one or more active substances, suppositories for rectal administration prescribed in the usual manner, and pessaries for intravaginal administration, etc. Is included.
  • the chromatographic separation site and the solvent in the coconut shell indicated by TLC indicate the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
  • Solvent in the box shown in the NMR section indicates the solvent used for the measurement.
  • the nomenclature used in this specification is ACDZName® (version 6.00, Advanced Chemistry Development Inc. ).
  • Example 2 The compound prepared in Example 1 was dissolved in dioxane (5 mL) under an argon atmosphere. To the mixture was added 4N salt hydrohydrogen Z dioxane solution (10 mL) at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure and azeotroped twice with toluene to give the title compound having the following physical properties.
  • Example 2 tert Butyl 2,8 diazaspiro [4.5] decane-2 carboxylate
  • RS spirocyclic compound instead of hydrochloride
  • Sat Using the corresponding amino acid in place of 2-phenylphenylicin methyl ester, the same operation as in Example 4 ⁇ Example 5 ⁇ Example 6 was performed to obtain the compound of the present invention having the following physical property values. .
  • reaction solution was tert butyl 2,8 diazaspiro [4.5] decane 8 carboxylate hydrochloride (253 mg), triethinoleamine (382 / z L), 1-hydroxybenzotriazole hydrate (185 mg ) And 1- (3 dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (263 mg) were added and stirred overnight. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • Example 7 The compound (325 mg) prepared in Example 7 was dissolved in dioxane (4 mL). Under an argon atmosphere, add 4N salt dihydrohydrogen di-Z dioxane solution (3 mL) to the reaction solution at room temperature for 2 hours. Stir. The reaction solution was concentrated under reduced pressure and azeotroped twice with toluene to give the title compound (330 mg) having the following physical properties.
  • Example 10 The compound (150 mg) prepared in Example 10 was dissolved in dioxane (1 mL). Under an argon atmosphere, the mixture was charged with a 4N hydrochloric acid-Z dioxane solution (2 mL) at room temperature and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure and azeotroped twice with toluene to give the title compound having the following physical properties.
  • the reaction solution was concentrated under reduced pressure and azeotroped with toluene.
  • the residue obtained was dissolved in acetonitrile (1.5 mL) under argon atmosphere.
  • a solution of the compound prepared in Example 2 (103 mg) and triethylamine (410 L) in acetonitrile (3.5 mL) was added at room temperature and stirred for 1.5 hours.
  • the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine.
  • the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off.
  • the obtained residue was recrystallized from a mixed solvent of hexane and ethyl acetate.
  • the obtained crystals were dissolved in a mixed solvent of hexane and ethyl acetate and washed with water and saturated brine.
  • the organic layer was dried over anhydrous sodium sulfate, and the solid obtained by distilling off the solvent was washed with a mixed solvent of hexane and ethyl acetate to obtain a product having the following physical properties.
  • the invention compound (49 mg) was obtained.
  • Methyl 5 Black Mouth 2— ( ⁇ [8— (4—Pyridyl) 1, 2, 8-Diazaspiro [4.5] Deca 2 —yl] carbol ⁇ amino) Benzoate
  • methyl 2-amino-5-chlorobenzoate 300 mg is dissolved in methylene chloride (6 mL), and triethylamine (452 ⁇ L) and triphosgene (168 mg) are dissolved at room temperature and stirred for 2 hours.
  • methylene chloride was prepared.
  • the compound (206 mg) prepared in Example 2 was dissolved in methylene chloride (5 mL), and triethylamine (439 ⁇ L) and the previously prepared isocyanate in methylene chloride were dissolved at room temperature. The mixture was further stirred at room temperature for 2 hours. Ice water was added to the reaction mixture, and the mixture was extracted with methylene chloride.
  • Example 15 The compound (293 mg) prepared in Example 15 was dissolved in methanol (2.5 mL). To the reaction mixture was added 2N aqueous sodium hydroxide solution (473 ⁇ L) at room temperature, and the mixture was stirred overnight. To the reaction mixture was added 2% hydrochloric acid (488 ⁇ L), and then tert-butyl methyl ether (2 mL) was added and stirred for 10 minutes. The precipitated solid was collected by filtration and washed with tert-butyl methyl ether to give the title compound (243 mg).
  • Example 16 In an argon atmosphere, the compound prepared in Example 16 (77 mg) was dissolved in methylene chloride (2 mL), and oxalyl chloride (24 L) and N, N-dimethylformamide (catalytic amount) were added at room temperature. And stirred for 2 hours. The reaction mixture was basified with 1N aqueous sodium hydroxide solution and extracted with methylene chloride. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (73 mg) having the following physical data.
  • Example 1 was carried out using the corresponding spirocyclic compound in place of the compound prepared in Example 2. 5 ⁇
  • the spiro-ring protecting group (ter butoxycarbonyl group (boc)) in the compound produced by the same operation method as in Example 18 was prepared by deprotection by the same operation method as in Example 2.
  • Acetone against N— (4 chloro-2- ⁇ [(5 chloro-2-pyridyl) amino] carbol ⁇ phenol) — 2,8 diazaspiro [4.5] decane-2-carboxamide)
  • a compound of the present invention having the following physical properties was obtained.
  • Example 18 (6) Using 1 methylbiperidin 4one instead of paraformaldehyde, the same operation method as in Example 18 (6) was carried out to obtain the compound of the present invention having the following physical property values.
  • Example 18 (6) The same operation method as in Example 18 (6) was performed using acetone to obtain the compound of the present invention having the following physical property values.
  • the spiro-ring protecting group (ter butoxycarbonyl group (boc)) in the compound produced by the same operation method as in Example 18 was prepared by deprotection by the same operation method as in Example 2.
  • Acetone N— (4 chloro-2- ⁇ [(5 chloro-2-pyridyl) amino] carbol ⁇ phenol) -1,2,7 diazaspiro [3.5] nonane-7-carboxamide)
  • a compound of the present invention having the following physical properties was obtained.
  • Example 18 (4—Black mouth— 2— ⁇ [(5—Black mouth—2-Pyridyl) amino] Carol ⁇ F) 2—Methinore 2, 8 Diazaspiro [4.5]
  • One decane 8 Canoleboxamide
  • the compound of Example 18 (10) was treated in the same manner as in Example 18 (9) to give the compound of the present invention having the following physical data.
  • Example 18 (12) was treated in the same manner as in Example 18 (9) to give the compound of the present invention having the following physical data.
  • Example 18 (4—Black mouth— 2— ⁇ [(5—Black mouth— 2—Pyridyl) amino] Carol ⁇ F) 9-Methinore 3, 9—Diazaspiro [5.5] Undecane 1 3-Canoleboxamide
  • the compound of Example 18 (14) was treated in the same manner as in Example 18 (9) to give the compound of the present invention having the following physical data.
  • the spiro-ring protecting group (ter butoxycarbonyl group (boc)) in the compound produced by the same operation method as in Example 18 was prepared by deprotection by the same operation method as in Example 2.
  • N— (4 chloro-2- ⁇ [(5 chloro-2-pyridyl) amino] carbol ⁇ phenol) -1,9 diazaspiro [5.5] undecane-2-carboxamide) In the same manner as in Example 9 using paraformaldehyde in place of, the compound of the present invention having the following physical properties was obtained.
  • Example 18 (17) was treated in the same manner as in Example 18 (9) to give the compound of the present invention having the following physical data.
  • TLC: Rf 0.45 (methylene chloride: methanol 5: 1);
  • Example 18 (19) was treated in the same manner as in Example 18 (9) to give the compound of the present invention having the following physical data.
  • Example 18 The compound of Example 18 (22) was treated in the same manner as in Example 18 (9) to give the compound of the present invention having the following physical data.
  • Example 18 (4—Black mouth— 2— ⁇ [(5—Black mouth— 2—Pyridyl) Amino] Carbon ⁇ F) 4) -Methyl 1-Oxa 4, 9 Diazaspiro [5.5] Undecane 9-carboxamide
  • the compound of Example 18 (24) was treated in the same manner as in Example 18 (9) to give the compound of the present invention having the following physical data.
  • Example 20 The compound (615 mg) produced in Example 20 was dissolved in dioxane (3 mL) under an argon atmosphere. 4N Hydrochloric acid Z dioxane solution (3 mL) was added to the reaction mixture at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure and azeotroped twice with toluene to give the title compound having the following physical properties.
  • Example 21 Under an argon atmosphere, the compound (513 mg) produced in Example 21 was suspended in toluene (15 mL). To the reaction mixture was added 4 bromopyridine hydrochloride (369 mg), tert butoxy sodium (516 mg), (S) -2,2,1bis (diphenylphosphino) 1,1, -binaphthyl (61.5 mg) and Tris (dibenzylideneacetone) dipalladium (0) (36.2 mg) was added, and the mixture was stirred at 95 ° C. overnight. The reaction mixture was ice-cooled, tert-butyl methyl ether and aqueous sodium hydroxide solution were added, and the mixture was filtered through Celite (registered trademark).
  • Celite registered trademark
  • Example 22 The compound (599 mg) prepared in Example 22 was dissolved in methanol (6 mL). Under an argon atmosphere, 5% palladium Z carbon (60 mg) was added to the reaction solution at room temperature. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. 20% palladium hydroxide Z carbon (containing 50% water) (60 mg) was added to the reaction mixture, and the mixture was stirred under a hydrogen atmosphere for 1 hr. 4N Hydrochloric acid Z dioxane solution (3 mL) was added to the reaction mixture, and the mixture was stirred under a hydrogen atmosphere for 1 hr. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure to give the title compound (414 mg) having the following physical data. H-NMR (CD OD): ⁇ 1.62— 1.74, 1.86— 2.00, 2.14, 3.44— 3.59, 3.68, 4.
  • Example 23 Under an argon atmosphere, the compound prepared in Example 23 (204 mg) was dissolved in methylene chloride (5 mL). To the reaction mixture was added triethylamine (352 ⁇ L) and mesyl chloride (74 at 0 ° C, and the mixture was stirred for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, and the mesyl compound (230 mg) obtained by distilling off the solvent was dissolved in N, N dimethylformamide (3 mL). At room temperature, sodium azide (220 mg) was added, and the mixture was stirred for 3 hours at 70 ° C. Ice water was added to the reaction mixture, and the mixture was extracted with sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound (140 mg) having the following physical data was obtained.
  • Example 25 The compound prepared in Example 25 (57 mg) was dissolved in methylene chloride (2 mL) under an argon atmosphere. To the mixture was added triethylamine (38 L) and 6-chloronaphthalene-2-sulfonyl chloride (60 mg) at 0 ° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated.
  • triethylamine 38 L
  • 6-chloronaphthalene-2-sulfonyl chloride 60 mg
  • Iron powder (268 mg) was added to an acetic acid solution (9 mL) of the compound (300 mg) prepared in Example 27 and stirred at 80 ° C. for 3 hours.
  • the reaction mixture was cooled to room temperature and then filtered through Celite (registered trademark). Toluene was added to the filtrate and concentrated under reduced pressure (twice). The obtained residue was dissolved in ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (270 mg) having the following physical data.

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Abstract

Composé représenté par la formule générale (I) (dans laquelle le noyau A représente un monocycle substitué par R1 et R2 et éventuellement en outre substitué par un substituant ; le noyau B représente un monocycle substitué par R3 et éventuellement en outre substitué par un substituant ; X représente un atome de carbone ou d’azote ; W représente un atome de carbone ou d’azote ; R1 représente un atome d’hydrogène ou un substituant et R2 représente un substituant, à condition que R1 et R2 en combinaison puissent former un noyau éventuellement substitué par un substituant ; et R3 représente un atome d’hydrogène ou un substituant). Le composé est utile en vue de la prévention et/ou du traitement des maladies thrombotiques imputables à l’activation du mécanisme de coagulation du sang, telles que, par exemple, une thrombose/embolie associée aux maladies cardiovasculaires, une thrombose/embolie associée aux maladies cérébrovasculaires et une thrombose/embolie associée aux maladies vasculaires veineuses.
PCT/JP2005/012569 2004-07-08 2005-07-07 Composé spirocyclique WO2006006490A1 (fr)

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WO2011141728A1 (fr) 2010-05-10 2011-11-17 Convergence Pharmaceuticals Limited Dérivés spirocycliques présentant une affinité pour les canaux calciques
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JP5245827B2 (ja) * 2006-07-31 2013-07-24 小野薬品工業株式会社 スピロ結合した環状基を含有する化合物およびその用途
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