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WO2008038841A1 - Dérivé de thiadiazolone et utilisation de celui-ci - Google Patents

Dérivé de thiadiazolone et utilisation de celui-ci Download PDF

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Publication number
WO2008038841A1
WO2008038841A1 PCT/JP2007/069519 JP2007069519W WO2008038841A1 WO 2008038841 A1 WO2008038841 A1 WO 2008038841A1 JP 2007069519 W JP2007069519 W JP 2007069519W WO 2008038841 A1 WO2008038841 A1 WO 2008038841A1
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Prior art keywords
methyl
oxo
dihydro
ylmethoxy
thiadiazole
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PCT/JP2007/069519
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English (en)
Japanese (ja)
Inventor
Shinichi Kikuchi
Takuya Matsui
Teruhiko Inoue
Masakazu Terashita
Tomoya Miura
Takayuki Mimura
Kenji Fukui
Akihiko Takahashi
Original Assignee
Japan Tobacco Inc.
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Publication of WO2008038841A1 publication Critical patent/WO2008038841A1/fr

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    • 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
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/13—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound having an excellent inhibitory action of tumor necrosis factor (TNF) ⁇ -converting enzyme (TNF-a 1 phaconvertingenzyme, hereinafter abbreviated as TACE), and a pharmaceutical composition comprising the same, and Regarding its use.
  • TNF tumor necrosis factor
  • TACE tumor necrosis factor ⁇ -converting enzyme
  • the present invention also relates to a compound useful as a therapeutic agent for inflammatory diseases including rheumatoid arthritis, a pharmaceutical composition comprising the same, and use thereof.
  • Metalloproteases can be found in the literature (DF Sealseta 1 (200 3) Genes & Develo pme nt 1 7: 7—30, GC Joneseta 1 (2005) Ar thritis Research & T herapy 7: 1 60— 169, R. V isseeta 1 (2003) Circulation Research 92: 827- 83 9), based on structural and functional considerations, the MMP (Matrix 'Metaloprotease) family, ADAM ( The AD isintegrin nd Me talloprotease) family, ADAMT S (AD isintegrin nd Me tall. Oprotease with Thrombo Spondin mo tif) family and other metallopothesis.
  • MMP Microx 'Metaloprotease
  • ADAM The AD isintegrin nd Me talloprotease
  • ADAMT S AD isintegrin nd Me tall.
  • Oprotease with Thrombo Spondin mo tif family and other metallopothesis.
  • the ADAM family (ADAM10, ADA Ml7, etc.), one of the meta-oral proteases, is a protein having a disintegrin domain and a meta-oral protease domain.
  • Various proteins such as cytokines, cytokine receptors, and growth factors And has the ability to disrupt 'release the aggregating peptide. Due to this action, ADAM 'is known to induce cell connection, migration, growth and differentiation and play an important role in skeletal muscle formation, neurogenesis, fertilization, inflammation, tumor growth, invasion, metastasis ing.
  • TACE also referred to as ADAM 17
  • ADAM 17 disrupts pro-TNF_a, a 26 kDa membrane-bound protein, and is soluble in 17 kDa biologically active soluble T It has the role of releasing NF_ ⁇ (RA ⁇ 1 acketa 1 (1 99 7) ature 38 5: 729-73 3, ML Mo sseta 1 (1 997) Nature 385: 733— 736).
  • NF_ ⁇ RA ⁇ 1 acketa 1 (1 99 7) ature 38 5: 729-73 3, ML Mo sseta 1 (1 997) Nature 385: 733— 736.
  • TACE is found in most tissues, it is known that TNF- ⁇ is mainly produced by activated monocytes, macrophages and vaginal lymphocytes.
  • TNF- ⁇ produces a wide range of pro-inflammatory biological processes, such as induction of adhesion molecules and chemokines to promote cell transport, induction of inflammatory site force-in, induction of matrix degrading enzymes, prostaglandins It is involved in the activation of fibroblasts and the activation of the immune system (EHS Choyeta 1 (200 1) NE ngl J Med 344: 9 7-9 9 6). Clinical use of anti-TNF- ⁇ biologics has shown that TNF-a has an important role in inflammatory diseases such as rheumatoid arthritis and Crohn's disease (NJ O 1 seneta 1 (2004) NE ngl J Me d 3 50: 2 16 7—21 79).
  • TACE has a central role in TNF- ⁇ production, and selective TACE inhibitors are more equal than strategies that directly neutralize TNF- ⁇ in a collagen-induced arthritis model It has also been shown to have a stronger efficacy (RC Ne wtoneta 1 (20 01) An nRheum D is 60:; iii25-iii32).
  • TACE inhibitors are therefore all diseases involving TNF- ⁇ , such as, but not limited to, inflammatory diseases (eg rheumatoid arthritis, systemic idiopathic arthritis, gout, osteoarthritis, nephritis, Inflammatory bowel disease (ulcerative colitis and Crohn's disease), COPD, hepatitis, vaginitis, cystitis, myelitis), autoimmune disease (eg systemic lupus erythematosus, psoriasis, multiple sclerosis, Behcet's disease), allergy Sex diseases (eg asthma, allergic rhinitis, conjunctivitis), atopic diseases (eg atopic dermatitis), transplant rejection, graft-versus-host disease, cardiovascular disease, reperfusion injury, infectious diseases (eg AIDS, malaria, sepsis), osteoporosis, diabetes, hyperlipidemia, Alzheimer's disease, neuropathy, organ fibrosis and malignant tumor Wait.
  • TACE activity is also increased by TGF—o ;, HB—EGF, amp hiregulin, ⁇ TNF receptor 1 & 11, IL-1 receptor II, IL-6 receptor, L-selectin, Notch, RANKL, fractalkine, Pref-1 and amyloid precursor protein . Therefore, TACE inhibitors are expected to be effective in chronic kidney disease, malignant tumors, asthma, hyperlipidemia, and Alzheimer type 1 dementia (ML Mo sseta 1 (2001) Drug Drug is Toy 41 7—426, RA B lack (2002) Int JB iochem Cell B iol 34: 1—5, BH S haheta 1 (2006) Trends Pharmacol S ci 27: 23 5—23 7).
  • matrix and meta-oral proteases play important roles in growth, differentiation, various septic lesions, fibrosis, tumor growth, invasion, and metastasis. This is based on the ability of the meta-oral protease to cleave a wide range of matrix materials such as collagen, proteoglycans and fibronectin. Matritus metametaprotease is associated with many disease symptoms, and its inhibitors are expected to be used for clinical applications such as cancer transfer suppression.
  • mice lacking MMP 14 may show similar symptoms. It is known (Z. Z houeta 1 (2000) Proc. Nat 1. Ac ad. Sci. USA 97: 405 2-4057). Therefore, a compound that selectively inhibits TACE, particularly a selective TACE inhibitor that has no inhibitory activity on MMP 14, is expected as a therapeutic agent for the above-mentioned diseases with few side effects.
  • TNF- ⁇ such as rheumatism is involved Is to provide a preventive or therapeutic drug for the disease.
  • the present invention is as follows.
  • R aa 1 and R aa 2 each independently represents a hydrogen atom or a C _ 4 alkyl group
  • 1 & represents an integer of 0, 1 or 2;
  • R ab 5 and R ab 6 each independently represents a hydrogen atom or a C, i — 4 alkyl group.
  • R ab ⁇ R ab 2 , R ab 3 and R ab 4 are each independently
  • (iii) may be substituted with the same or different 1 to 5 substituents selected from group A — 4 alkyl groups, (iv) the same or different 1 to 5 substituents which may be substituted with a substituent C 3 _ 1 2 carbocyclic group selected from group A or,
  • a heterocyclic group which may be substituted with the same or different 1 to 5 substituents selected from group A (wherein the heterocyclic group includes a nitrogen atom, 1 to 4 heteroatoms selected from an oxygen atom and a sulfur atom)
  • a saturated monocyclic hetero ring optionally substituted with 1 to 5 identical or different substituents selected from group A ('wherein the saturated monocyclic hetero ring is, in addition to the carbon atom, , 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom.) Or
  • a non-aromatic C 3 8 carbocyclic ring which may be substituted with the same or different 1 to 5 substituents selected from group C;
  • n c 0 or 1.
  • Ring J 2 is a saturated monocyclic hetero ring optionally substituted with 1 to 5 identical or different substituents selected from group A (wherein the saturated monocyclic hetero ring is In addition to carbon atoms, 1 to 4 atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms Has a terror atom. Or
  • a non-aromatic C 3 8 carbocycle which may be substituted with the same or different 1 to 5 substituents selected from Group C.
  • Ring J 3 is a saturated monocyclic hetero ring optionally substituted by 1 to 5 substituents selected from group A (wherein the saturated monocyclic hetero ring is carbon In addition to atoms, it has 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom.) Or
  • the ring L c is, (1) the same or different selected from the group C, and a C 3 12 carbocyclic ring optionally substituted with 1 to 5 substituents, or
  • an unsaturated monocyclic heterocycle optionally substituted with the same or different 1 to 5 substituents selected from group C (wherein the unsaturated monocyclic heterocycle is carbon In addition to atoms, it has 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms.)
  • R ba R ba 2 , R ba 3 , R ba 4 and R ba 5 are each independently
  • R ba ⁇ Rb a 2 , R ba 3 , R ba 4 or R ba 5 is R ab ⁇ R ab 2 when L ab 1 is a divalent group represented by the general formula [la] R ab 3 or
  • R ab 4 may be connected to each other to form a heterocycle together with the atoms to which they are bonded.
  • R ba 1 N R ba 2 , R ba 3 , R ba 4 or R ba 5 may be linked to a substituent on the ring L c to form a heterocycle with the atoms to which they are bonded, Or
  • R ba 2 or R ba 4 is the same as R ab 5 or R ab 6 when L ab 1 is a divalent group represented by one C (R ab 5 ) (R ab 6 ) — Connected to form a morpholine ring with the atoms to which they are attached,
  • L ba ⁇ L ba 2 , L ba 3 , L ba L ba 5 and L ba 6 are independent
  • a divalent group selected from the group consisting of; L d is
  • X d a and X d b are each independently
  • n d 1 and n d 2 each independently represent 0, 1 or 2
  • L d 1 and L d 2 each independently represent a hydrogen atom or a C i- 4 alkyl group. ).
  • an unsaturated monocyclic heterocyclic group optionally substituted with the same or different 1 to 5 substituents selected from group D (where “the unsaturated monocyclic heterocyclic group Has 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms.
  • an unsaturated condensed heterocyclic group which may be substituted with the same or different 1 to 5 substituents selected from group D (wherein the unsaturated condensed heterocyclic group is a carbon atom; In addition, 1 to 4 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom Has a terror atom. ), Or
  • R f is a hydrogen atom or CI_ 4 alkyl group
  • (AA4) Heterocyclic group optionally substituted by 1 to 5 substituents selected from group C (wherein the heterocyclic group includes a nitrogen atom in addition to a carbon atom) , Oxygen atom, and 1 to 4 heteroatoms selected from sulfur atoms)), or
  • Ci 4 alkyl group which may be substituted with the same or different 1 to 5 substituents selected from group B;
  • substituents C 6 - 12 7 may be substituted by aryl group 7 Arukanoi Honoré one Okishi group,
  • (D13) Heterocyclic group which may be substituted with the same or different 1 to 5 substituents selected from Group C (wherein the heterocyclic group includes a nitrogen atom in addition to a carbon atom) 1 to 4 heteroatoms selected from a child, an oxygen atom, and a sulfur atom)
  • 11 & 3 1 and 1 3 a 2 each independently represents a hydrogen atom or an alkyl group
  • n a 0, 1 or 2;
  • R ab ⁇ R ab 2 , R ab 3 and R ab 4 are each independently
  • Saturated monocyclic heterocycle optionally substituted with 1 to 5 substituents selected from group A (wherein the saturated monocyclic heterocycle includes, in addition to carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom.) Or
  • a non-aromatic C 3 8 carbocyclic ring which may be substituted with the same or different 1 to 5 substituents selected from group C;
  • n c 0 or 1.
  • Ring J 2 is a saturated monocyclic hetero ring optionally substituted with the same or different 1 to 5 substituents selected from group A (wherein the saturated monocyclic hetero ring is carbon In addition to atoms, it has 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom.) Or
  • a non-aromatic C 3 8 carbocycle which may be substituted with the same or different 1 to 5 substituents selected from group C.
  • Ring J 3 are the same or different ivy 1 to 5 amino saturated may be substituted with a substituent monocyclic heterocycle (wherein selected from group A, said heterocycle saturated monocyclic are carbon In addition to atoms, it has 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom.) Or
  • an unsaturated monocyclic heterocycle optionally substituted by 1 to 5 substituents selected from group C, wherein the unsaturated monocyclic heterocycle is In addition to carbon atom, it has 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, and sulfur atom.
  • R ba X Rb a 2 , Rb a 3 , R ba 4 and R ba 5 are each independently
  • C 6 - 12 Ariru may be substituted by a group - 7 Arukanoiru group (4) C 7 - u7 Royle group or,
  • R ba ⁇ Rb a 2 , Rb a 3 , R ba 4 or R ba 5 is R ab R ab 2 when L ab 1 is a divalent group represented by the general formula [la], R ab 3 or
  • R ab 4 may be connected to each other to form a heterocycle with the atoms to which they are bonded, or
  • R ba ⁇ R ba 2 , Rb a 3 , R ba 4 or R ba 5 may be linked to a substituent on ring L c to form a heterocycle with the atoms to which they are bonded, L ba L ba 2 , L ba 3 , L ba 4 and L ba 5 are each independently
  • a divalent group selected from the group consisting of;
  • X d a and X d b are each independently
  • R d is a hydrogen atom, a Ci- 4 alkyl group, a d-7 alkanoyl group optionally substituted by 1 to 5 Ce- i 2 aryl groups or CT—indicates an iaroyl group.
  • n d 1 and n d 2 each independently represent 0, 1 or 2.
  • an unsaturated monocyclic heterocyclic group which may be substituted with the same or different 1 to 5 substituents selected from group D (wherein the unsaturated monocyclic heterocyclic group is In addition to the carbon atom, it has 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom.)
  • an unsaturated condensed heterocyclic group which may be substituted with the same or different 1 to 5 substituents selected from group D (wherein the unsaturated condensed heterocyclic group is a carbon atom; In addition, it has 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom.
  • R f is a hydrogen atom or — 4 alkyl group
  • R al 0, R all, R al 2, R al 3, R a l4, R al 5, R al 6, R al 7, R al 8 and R a 19 is independently
  • (AA2) may be substituted with the same or different 1 to 5 substituents selected from group B—.
  • (AA3) Cs-i 2 carbocyclic group which may be substituted with the same or different 1 to 5 substituents selected from group C;
  • (AA4) Heterocyclic group which may be substituted with the same or different 1 to 5 substituents selected from Group C (wherein the heterocyclic group includes a nitrogen atom in addition to a carbon atom) 1 to 4 heteroatoms selected from an oxygen atom and a sulfur atom), or
  • (A21) group which may be substituted by the same or different 1 to 5 substituents selected from C C 3 - 12 carbocycle one - 4 alkyl group,
  • (B21) Heterocyclic monocarbonyl group which may be substituted with the same or different 1 to 5 substituents selected from Group C (wherein the heterocycle moiety is a nitrogen atom in addition to a carbon atom) 1 to 4 heteroatoms selected from atoms, oxygen atoms, and sulfur atoms.
  • R ab 1 and R ab 2 are each independently
  • a heterocyclic group which may be substituted with the same or different 1 to 5 substituents selected from group A (wherein the heterocyclic group includes a nitrogen atom, An oxygen atom and 1 to 4 heteroatoms selected from sulfur atoms).
  • R a b. 3 and R ab 4 are each independently
  • a heterocyclic group which may be substituted with the same or different 1 to 5 substituents selected from group A 1 (wherein the heterocyclic group includes a nitrogen atom in addition to a carbon atom); 1 to 4 heteroatoms selected from a child, an oxygen atom, and a sulfur atom.
  • Ring J 2 ′ is a saturated monocyclic hetero ring optionally substituted with 1 to 5 substituents selected from group A (wherein the saturated monocyclic hetero ring is In addition to the carbon atom, it has 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • a non-aromatic C 3 8 carbocycle which may be substituted.
  • Ring J 3 ′ is a saturated monocyclic hetero ring optionally substituted with 1 to 5 substituents selected from group A (wherein the saturated monocyclic hetero ring is carbon In addition to atoms, it has 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms. Or
  • Rb a ⁇ Rb a 2 , Rb a 3 , R ba 4 and R ba 5 are each independently
  • R ba ⁇ Rb a 2 , R ba 3 , R ba 4 or R ba 5 is R ab ⁇ R ab 2 when L ab 1 is a divalent group represented by the general formula [la] R ab 3 or
  • R ab 4 may be connected to form an unsubstituted heterocycle with the atoms to which they are bonded
  • R ba ⁇ R ba 2 , R ba 3 , R ba 4 or R ba 5 may be linked to a substituent on ring L c to form a heterocycle with the atoms to which they are bonded, is there Yes
  • R ba 2 or R ba 4 is the same as R ab 5 or R ab 6 when L ab 1 is a divalent group represented by one C (R ab 5 ) (R ab 6 ) — Connected to form an unsubstituted morpholine ring with the atoms to which they are attached,
  • L ba L ba 2 , L ba 3 , L ba 4 , L ba 5 and L ba 6 are each independently
  • Ci- 3 alkylene group which may be substituted with the same or different 1 to 5 substituents selected from Group B.
  • a divalent group selected from the group consisting of;
  • R al 5 , R al 6 , R al 7 , R al 8 and R al 9 are each independently (AA1) hydrogen atom,
  • (AA4) Heterocyclic group optionally substituted by 1 to 5 substituents selected from group C (wherein the heterocyclic group includes a nitrogen atom in addition to a carbon atom) 1 to 4 heteroatoms selected from an oxygen atom and a sulfur atom), or
  • (AA6) may be replacement by the same or different 1 to 5 substituents selected from group B C 2 - 6 alkynyl group
  • L ba ⁇ L ba 2 and L ba 6 are each independently a bond, the compound according to the above [4], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R ab 1 , R ab 2 , R ab 3 and R ab 4 are each independently
  • Ring J 1 is synonymous with [1] above. )
  • Ring 2 is as defined in [1] above. ) A divalent group represented by
  • Ring J 3 has the same meaning as [1] above.
  • Ring L c is as defined in [1] above;
  • R ba 2 is linked to R ab ⁇ R ab 2 , R ab 3 or R ab 4 when L ab 2 is a divalent group represented by the general formula [II a] May form a heterocycle with the atom to which
  • Rb a 2 may be linked to a substituent on the ring L c to form a heterocycle with the atoms to which they are attached;
  • L d, U e, R f, Group A, Group B, Group C, and Group D are synonymous with [1] above. Or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • R ab 1 and R ab 2 are each independently
  • (V) a hetero ring group which may be substituted with the same or different 1 to 5 substituents selected from group A (wherein the hetero ring group includes a nitrogen atom, 1 to 4 heteroatoms selected from an oxygen atom and a sulfur atom)
  • Ring L c is as defined above [1];
  • R ab 3 and R ab 4 are each independently
  • Ring j 1 is synonymous with [1] above. )
  • Ring J 2 ′ is a saturated monocyclic hetero ring optionally substituted with 1 to 5 substituents selected from group A (wherein the saturated monocyclic hetero ring is In addition to the carbon atom, it has 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom.) Or, with the same or different 1 to 5 substituents selected from the group C substituted showing a non-aromatic C 3 _ 8 carbocycle may have. ) A divalent group represented by
  • Ring J 3 ′ is a saturated monocyclic hetero ring optionally substituted with 1 to 5 substituents selected from group A (wherein the saturated monocyclic hetero ring is carbon In addition to atoms, it has 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms. Or
  • nonaromatic C 3 _ 8 carbocycle may be substituted with a group selected from group C.
  • Ci- 4 alkyl group which may be substituted with the same or different 1 to 5 substituents selected from group B;
  • R ba 2 is connected to R ab R ab 2 , R ab 3 or R a.b 4 when L ab 2 is a divalent group represented by the general formula [II a], They may form an unsubstituted heterocycle with the atoms to which they are attached, or
  • R ba 2 may be linked to a substituent on ring L c to form a heterocycle with the atoms to which they are attached;
  • Group A 1 is synonymous with [3] above;
  • L d, U e, R f, Group B, Group C, and Group D are synonymous with [1] above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • L d is 1 O—CH 2 —, or a compound or pharmaceutical according to the above [7] Acceptable salt thereof or a solvate thereof c,
  • R ab 1 Q is a hydrogen atom or a substituent selected from group E.
  • R c represents the same or different substituent selected from group C;
  • n c is an integer from 0 to 4.
  • X e 1 and X e 2 each independently represent a carbon atom or a nitrogen atom
  • X e 3 and X e 4 each independently represent a carbon atom, a nitrogen atom or an oxygen atom
  • n e 1 and n e 2 each independently represents an integer of 0 to 4,
  • R e 1 and R e 2 are each independently selected from group D,
  • n e 3 represents an integer of 0 to 2.
  • R el , Re 2 , Re 3 , Re 4 , Re 5 , Re 6 , Re 7 and Re 8 are each independently
  • (EE3) C 3 1 j 2 carbocyclic group optionally substituted with 1 to 5 identical or different substituents selected from group C; (EE4) Heterocyclic group optionally substituted by 1 to 5 substituents selected from Group C (wherein the heterocyclic group includes a nitrogen atom in addition to a carbon atom) , Oxygen atom, and 1 to 4 heteroatoms selected from sulfur atoms), or
  • (EE6) may be replacement by the same or different 1 to 5 substituents selected from group B C 2 - 6 alkynyl group
  • (El 1) may be substituted by the same or different 1 to 5 substituents selected from group B C 2 - 6 alkynyl group,
  • R f, Group B, Group C, and Group D are each synonymous with [1] above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R ab 1 Q is a hydrogen atom or a substituent selected from group E.
  • R c is a halogen atom
  • n c is an integer from 0 to 1;
  • Xe 1 and X e 2 each independently represent a carbon atom or a nitrogen atom
  • X e 3 and X e 4 each independently represent a carbon atom, a nitrogen atom or an oxygen atom
  • n e l and n e 2 each independently represents an integer of 1 to 2,
  • R e 1 and R e 2 are each independently
  • (D6) identical are selected from the group C or different 1 to 5 substituents in optionally substituted CI_ 4 alkoxy groups, and
  • n e 3 represents an integer of 1.
  • Group E is synonymous with [1 1] above;
  • R f and Group C are as defined above [1]. Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • L ab 3 is represented by the general formulas [III a], [III c,] and [III e ′].
  • R ab 10 is a substituent selected from a hydrogen atom, a Ci 4 alkyl group, and a formyl group.
  • R c is a halogen atom
  • n c is an integer from 0 to 1;
  • X e 1 and X e 2 each independently represent a carbon atom or a nitrogen atom
  • X e 3 and X e 4 each independently represent a carbon atom, a nitrogen atom or an oxygen atom
  • n e l and n e 2 each independently represents an integer of 1 to 2,
  • R e 1 and R e 2 are each independently
  • n e 3 represents an integer of 1.
  • n e 3 represents an integer of 1.
  • Group E is synonymous with [1 1] above;
  • R f is synonymous with [1] above. Or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • U e may be substituted with the same or different 1 to 5 substituents selected from group D, quinolyl group, 5, 6, 7, 8-tetrahydroquinolyl group or 1, 2 , 3, 4-tetrahydroquinolyl group, the compound according to [7] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a pharmaceutical composition comprising the compound according to any one of [1] to [13] or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier. ..
  • Systemic idiopathic arthritis gout, osteoarthritis, nephritis, inflammatory bowel disease (ulcerative colitis and Crohn's disease), COPD, hepatitis, knee inflammation, cystitis, myelitis), autoimmune diseases (eg systemic) Lupus erythematosus, psoriasis, multiple sclerosis, Behcet's disease), allergic diseases (eg asthma, allergic rhinitis, conjunctivitis), atopic diseases (eg atopic dermatitis), transplant rejection, graft Anti-host disease, cardiovascular disease, reperfusion injury, infectious disease (eg AIDS, malaria, sepsis), osteoporosis, diabetes, hyperlipidemia, Alzheimer's disease, neuropathy, organ fibrosis and evil Therapeutic or prophylactic agent of the tumor.
  • infectious disease eg AIDS, malaria, sepsis
  • osteoporosis diabetes, hyperlipidemia, Alzheimer's disease, neuropathy, organ fibrosis and evil Therapeutic
  • Rheumatoid arthritis treatment comprising as an active ingredient the compound according to any one of [1] to [13], or a pharmaceutically acceptable salt thereof, or a solvate thereof. Medication or prophylactic.
  • [1 7] Treatment of inflammatory bowel disease (IBD) comprising the compound according to any one of [1] to [1 3] above or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient Drug or preventive drug.
  • IBD inflammatory bowel disease
  • a therapeutic or prophylactic agent for nephritis comprising the compound according to any one of [1] to [13] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
  • a TACE inhibitor comprising as an active ingredient the compound according to any one of [1] to [13] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • [20] comprising administering to a mammal a pharmaceutically effective amount of the compound according to any one of [1] to [13] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof. , T AC E inhibition method.
  • a pharmaceutically effective amount of the compound according to any one of the above [1] to [13] or a pharmaceutically acceptable salt thereof, or a solvate thereof is administered to a mammal. Including pathological onset / excessive TNF-o; a method of reducing production.
  • a pharmaceutically effective amount of the compound according to any one of the above [1] to [13] or a pharmaceutically acceptable salt or solvate thereof is administered to a mammal.
  • a method for treating or preventing rheumatoid arthritis is provided.
  • [22] comprising administering to a mammal a pharmaceutically effective amount of the compound according to any one of [1] to [13] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • [23] comprising administering to a mammal a pharmaceutically effective amount of the compound according to any one of [1] to [13] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • [28] (a) comprising the compound according to any one of [1] to [13] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and (b) another therapeutic agent for rheumatoid arthritis.
  • a therapeutic or prophylactic agent for rheumatoid arthritis comprising a combination of at least one selected from the group.
  • R ab 10 is a substituent selected from a hydrogen atom or a group E,) in selected from divalent groups represented;
  • PX represents a hydrogen atom or an amine protecting group (eg, tert-butoxycarbonyl group (Boc), penzinoreoxycarboenole group (Z), 9-funolerenorenotoxycanoxyreponyl group (Fmo c), trifluoro Loacetyl group (TF A) etc .; 'Group E is
  • R el, R e 2, R e 3, R e 4, R e 5, R e 6, 1 67 Oyopi 1 ⁇ 68 are each independently,
  • (EE4) Heterocyclic group which may be substituted with 1 to 5 identical or different substituents selected from Group C (wherein the heterocyclic group is a nitrogen atom in addition to a carbon atom) 1 to 4 heteroatoms selected from an oxygen atom and a sulfur atom), or
  • (EE5) may be replacement by the same or different 1 to 5 substituents selected from group C C 6 - 12 Ariru one 4 alkyl group, or,
  • (E9) Heterocyclic group which may be substituted with 1 to 5 identical or different substituents selected from Group C (wherein the heterocyclic group includes a nitrogen atom in addition to a carbon atom) Or 1 to 4 heteroatoms selected from a child atom, an oxygen atom, and a sulfur atom.), (E10) may be substituted with the same or different 1 to 5 substituents selected from group C Good C 3 — 12 carbocycle — alkyl group, and
  • (El 1) may be substituted by the same or different 1 to 5 substituents selected from group B C 2 - 6 alkynyl group, Selected from the group consisting of:
  • R f, Group B, and Group C are synonymous with [1] above. ] The compound represented by this.
  • R c represents the same or different substituent selected from group C.
  • n c is an integer from 0 to 4.
  • X e 1 represents a carbon atom or a nitrogen atom
  • X e 3 and X e 4 each independently represent a carbon atom, a nitrogen atom or an oxygen atom,
  • n e l and n e 2 each independently represents an integer of 0 to 4,
  • R e 1 and R e 2 are each independently selected from group D, or when two or more exist, they are the same or different selected from group C in combination with each other. May form a ring optionally substituted with 1 to 5 substituents,
  • n e 3 represents an integer of 0 to 2.
  • P y represents a hydroxyl group, a halogen atom or a mono-O-carboxyl protecting group (eg, a lower alkyl group such as methyl, ethyl, tert-ptyl, benzyl, etc.);
  • Group C and Group D are as defined above [1] It is. ] The compound represented by this.
  • the compound of the present invention exhibits an excellent T A C E inhibitory action and also has a high selectivity for other meta-oral proteases such as MMP14.
  • the compound of the present invention is effective in preventing or treating diseases associated with TNF- ⁇ such as rheumatoid arthritis, inflammatory bowel disease (IBD), nephritis, etc. by suppressing the production of TNF- ⁇ based on TACE inhibitory activity.
  • the compound of the present invention does not show inhibitory activity against other meta-oral proteases, particularly MMP 14, it can be a drug with few side effects such as musculoskeletal myalgia.
  • the compound of the present invention has high membrane permeability, solubility, etc., excellent physical properties as a pharmaceutical, and can be a pharmaceutical with excellent pharmacokinetics such as oral absorption.
  • each substituent and each site used in the present specification are as follows.
  • the term “which may be substituted” includes both the case where the substitutable position of the target group is substituted and the case where it is not substituted (unsubstituted).
  • “unsubstituted” means that all substitutable positions of the target group are hydrogen atoms.
  • Halogen atom and “halogeno” are fluorine atom, chlorine atom, bromine atom ′ or iodine atom.
  • Ji- 4 alkyl group is a linear or branched alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isoptinole group, a sec-butinole group. Tert-Putinole group and the like.
  • Alkyl group means a linear or branched alkyl group having 1 to 1 carbon atoms. For example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutinole group, a sec-butinole group, a tert-butinole group, a pentinole group, an isopentyl group, a tert-pentyl group, a 1-ethylpropyl group, Neopentyl group, hexyl group, heptyl group, 1-propylpropyl group, octyl group, nonyl group, decyl group and the like.
  • C 3 _ 12 carbocyclic group is a cyclic hydrocarbon group having 3 to 1 2 saturated or unsaturated carbon, specifically, C 6 - 12 Ariru group, C 3 - 10 cycloalkyl group, C 3 _ i. It means a cycloalkenyl group or a condensed carbocyclic group in which two or more of the rings constituting them are condensed.
  • C 6 _12 aryl group means an aryl group having 6 to 12 carbon atoms, such as phenyl group, naphthyl group (eg, naphthalene-2-yl, naphthalene-1-yl, etc.), azulenyl group, Examples include a pentalenyl group.
  • Cycloalkyl group means a cycloalkyl group having 3 to 10 carbon atoms, such as a cyclopropyl group, a cyclopentinole group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group. Groups and the like.
  • the “cycloalkenyl group” is a cycloalkenyl group having 3 to 10 carbon atoms and contains at least 1, preferably 1 or 2, double bonds. , For example, cyclo.propenino group, cyclobutyr group, cyclopentenino group, cyclopentadienyl group, cyclohexenino group, cyclohexagenino group (2,4-cyclohexagen-1-1-inole group, 2,5- Cyclohexagen-1-inore group, etc.), cycloheptyl group, cyclootatul group and the like.
  • C 6 - 12 Ariru group - As the "C 3 10 cycloalkyl group”, fused carbocyclic group or two fused rings comprising the "C 3 one 10 consequent Roarukeyuru group”, if example embodiment, Indul group, Indanyl group (eg, Indan-1-yl), Fluorenyl group, Dihydranaphthyl group, Tetrahydranaphthyl group (eg, 1, 2, 3, 4-Tetradronaphthalene 2-yl, 5,6,7,8-tetrahydronaphthalene-2-yl, etc., perhydrodronaphtyl group, tetrahydrobenzocycloheptyl group (eg, 6, 7, 8, 9-tetrahydro 5H-benzocyclo) Heptul, etc.).
  • Indul group Indanyl group (eg, Indan-1-yl), Fluorenyl group, Dihydranaphthyl group, Tetrahydranap
  • C 3 _ 12 carbocycle is a cyclic hydrocarbons, saturated or unsaturated 3 to 1 2 carbon atoms, specifically, C 6 _ 12 aromatic hydrocarbons, C 3 _ 10 cycloalkane , C 3 _ i. It means cycloalkylene or a condensed carbocyclic ring in which two or more of the rings constituting it are condensed.
  • the - "C 6 12 aromatic hydrocarbon” is an aromatic hydrocarbon having a carbon number of 6 to 1 2, for example, benzene, naphthalene, Azuren, pentalene, and the like.
  • Cycloalkane is a cycloalkane having 3 to 10 carbon atoms, and examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and cyclononane.
  • Cycloalkene is a cycloalkene having 3 to 10 carbon atoms, and contains at least one, preferably 1 or 2, double bonds.
  • cyclopropene, cyclobutene, cyclopentene, cyclopentagen, cyclohexene, cyclohexagen, cycloheptene, cyclootaten and the like can be mentioned.
  • non-aromatic C 3 _ 8 carbocycle among the “C 3 ._ 12 carbocycle”, is of 3 to 8 carbon atoms, excluding the aromatic hydrocarbons, e.g., cyclopropane, cyclobutane , Cyclopentane, cyclohexane, cyclohexane heptane, cyclooctane, cyclopentane pen, cyclobutane, cyclopentane, cyclopentane, cyclohexane, cyclohexene, cycloheptene, cyclooctene, etc. .
  • aromatic hydrocarbons e.g., cyclopropane, cyclobutane , Cyclopentane, cyclohexane, cyclohexane heptane, cyclooctane, cyclopentane pen, cyclobutane, cyclopentane,
  • Heterocyclic group refers to atoms having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, Including 3 to 14 atoms, including saturated and unsaturated rings, monocyclic rings and condensed rings.
  • hetero ring groups include those in which 1 to 3 ring atoms are oxoated.
  • “Unsaturated monocyclic heterocyclic group” includes, for example, a chenyl group (eg,
  • dihydrothenyl group eg, furyl group (eg, furan 3-yl), dihydrofuryl group, pyrrolyl group (eg, 2-pyrroline 1-11yl, 3— Pyrrolin-1-yl, etc.), pyrrolinyl group, oxopyrrolinyl group (eg 2-oxo-1-pyrroline-11-yl, 2-oxo-1-pyrroline-3-yl, etc.), dioxopyrrolinyl Groups (eg, 2,5-dioxo-3-pyrroline-1-yl, etc.), imidazolyl groups (eg, imidazole-1-yl, 1 H-imidazole-2-yl, 1 H-imidazole) —4-yl, etc.), imidazolinyl groups (eg, 2-imidazoline-2-yl, etc.), pyrazolyl groups (eg, pyrazole 1-l, 1 H-pyrazo
  • 6-membered heterocycles Groups unsaturated 7-membered heterocyclic groups such as azepinyl group, chebule group, oxebuyl group, diazepinyl group, thiazebuyl group, oxazebuyl group, triazepinyl group, thiadiazebuyl group, oxadiazepinyl group and the like.
  • the position of the hetero atom in the ring of these heterocyclic groups, the position of the bond, and the position of the substituent when having a substituent are not particularly limited as long as they are chemically acceptable.
  • saturated monocyclic heterocyclic group examples include saturated three-membered heterocyclic groups such as oxylael group, thiylyl group, and aziridinyl group; oxetanyl group, chetanyl group, azetidinyl group (eg, azetidine 1- Saturated 4-membered heterocyclic groups such as tetrahydrofurfuryl, tetrahydrochenyl, pyrrolidinyl (eg, pyrrolidine-1-yl), oxopyrrolidinyl (eg, 2-oxopyrrolidine-1-) , 2-oxopyrrolidine-1-yl, etc.), dioxopyrrolidinyl group (eg, 2,5-dioxopyrrolidine-1-3-tyl), imidazolidinyl group, virazolidinyl group, thiazolidinyl group, isothiyl Azolidinyl group, oxazo
  • Examples of the “unsaturated condensed heterocyclic group” include a quinolyl group (eg, quinoline monoyl), a dihydroquinolyl group, a tetrahydroquinolyl group (eg, 1, 2, 3, 4 —tetrahydroquinoline mono 7— , 5, 6, 7, 8-tetrahydroquinoline 4-yl, etc.), isoquinolyl group, dihydroisoquinolyl group, tetrahydroisoquinol group Noryl group (eg, 1, 2, 3, 4—tetrahydroquinoline 1-5— ⁇ T, etc.), quinazolinyl group, dihydroquinazolinyl group, tetrahydroquinazolinyl group, quinoxalyl group, dihydroquinoxalyl group, tetrahydroquinoxalyl group, phthalajuryl Group, dihydrophthaladyl group, tetrahydrophthaladuryl group, cinn
  • “Saturated monocyclic heterocycle” is a ring having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, Is a saturated monocyclic ring having 3 to 14 atoms (4 to 14 in the case of ring J 3 ). Also included are heterocycles in which 1 to 3 ring atoms are oxoated.
  • saturated 3-membered heterocycles such as oxilan, thiirane, and aziridine
  • saturated 4-membered heterocycles such as oxetane, chetan, and azetidine
  • tetrahydrofuran, tetrahydrodrthiophene pyrrolidine, oxopyrrolidine Oxopyrrolidine, etc.
  • dioxopyrrolidine eg, 2,5-dixopyrrolidine, etc.
  • Piperidine morpholine, thiomorpholine, piperazine, tetrahydropyran, tetrahydrothiopyran, etc.
  • Unsaturated monocyclic heterocycle means having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom as an atom constituting the ring, An unsaturated monocyclic ring having 3 to 14 atoms constituting the ring.
  • heterocycles in which 1 to 3 ring atoms are oxolated are also included.
  • R ba R ba 2 , R ba 3 , R ba 4, or R ba 5 are R ab R ab 2 , R ab 3 when L ab 1 is a divalent group represented by the general formula [I a]
  • the heterocycle formed by connecting to R ab 4 and the atoms to which they are bonded is, for example, at least one ring-constituting atom such as pyrrolidine, piperidine, morpholine, thiomorpholine, or piperazine.
  • a saturated monocyclic heterocyclic ring containing a nitrogen atom is mentioned.
  • the aspect of a following formula is mentioned.
  • heterocyclic ring is unsubstituted.
  • unsubstituted means that there are no substituents other than those specified in the formulas [I], [I I], etc. (the same applies hereinafter).
  • a heterocycle formed by Rb a ⁇ Rb a 2 , Rb a 3 , Rb & 4 or 1 a 5 connecting to a substituent on ring L c together with the atom to which they are bonded is ring L c It is a condensed heterocycle included as a constituent ring.
  • the condensed heterocycle include indoline, Soindoline, 2-oxoindoline, 1-oxoisoindoline, 3, 4-dihydrodraw 2 H-isoquinoline 1-one, 3, 4-dihydroline 1 H-quinoline 1
  • Examples thereof include an unsaturated condensed heterocyclic ring containing at least one nitrogen atom as a ring-constituting atom such as 2-one.
  • an unsaturated condensed heterocyclic ring containing at least one nitrogen atom as a ring-constituting atom such as 2-one.
  • the aspect of a following formula is mentioned.
  • the ring L c moiety may be further substituted with the same or different 1 to 5 substituents selected from group C.
  • the constituent rings other than the ring L c are preferably unsubstituted.
  • R ba 2 or R ba 4 is linked to R ab 5 or R ab 6 when L ab 1 is a divalent group represented by one C (R ab 5 ) (R ab 6 )
  • Examples of the morpholine ring formed together with the atoms to which they are bonded include the following embodiments.
  • the morpholine ring is preferably a non-substituted embodiment other than that specified in the formula [I].
  • “7-alkanoyl group” means a straight-chain or branched-chain alkanol group having 1 to 7 carbon atoms.
  • the “C 7 -aroyl group” represents a linear or branched alloy group having 7 to 11 carbon atoms, and examples thereof include a benzoyl group, a 1-naphthoyl group, and a 2-naphthoyl group.
  • the - "0 3 alkylene” represents an alkylene having 1 to 3 carbon atoms, for example main styrene, ethylene and trimethylene.
  • halogeno C 4 alkyl group is intended to "Ji 4 alkyl group” defined above is 1-9 amino substituted with "halogen atom” defined above, e.g., Furuorome methyl group, Jifuruoromechiru group, Torifuruo Examples include romethyl clog, promomethyl group, black methyl group, 1,2-dichloroethyl group, 2,2-dichloroethynole group, 2,2,2-trifluoroethyl group and the like.
  • the "human Dorokishi d_ 4 alkyl group” which has been 1-4 substituents in the above definition of ICi- 4 alkyl group "Gahi Dorokishi group, for example, human Dorokishimechiru group, 1 over human Dorokishechinore group, 2- Examples thereof include a hydroxychetinole group, a 3-hydroxypropyl group, and a 4-hydroxybutyl group.
  • C 2 —, 6 alkynyl group means a straight or branched alkynyl group having 1 to 7 carbon atoms, such as an ethur group, a 2-propynyl group, a 1-ptulyl group, a 2-butynino group, Examples include a 3-petitinole group, 2_pentininole group, 3-pentyninole group, 2-pentynyl group, 2-penturyl group, and 3-hexyl group.
  • C 3 12 carbocycle one Ji 4 alkyl group is its gamma C i_ 4 alkyl group in the alkyl portion is as defined above, "C 3 - 12 carbocycle site of the above defined” C 3 _ 12 carbon a carbocycle primary alkyl group is a ring group "," C 6 - 12 Ariru one C - 4 alkyl group "includes such” C 3- i cycloalkyl one C Bok 4 alkyl group "..
  • Ji ⁇ alkoxy group is an alkyl one Okishi group is "Ji 4 alkyl Le group” of the alkyl moiety is as defined above, for example, main butoxy group, an ethoxy group, flop port epoxy group, an isopropyl O alkoxy group , Butoxy group, isobutoxy group, tert-butoxy group and the like.
  • the "C bets 4 alkylamino group" is a Arukiruamino group is as defined above ⁇ alkyl group ", for example, Mechiruamino group, Echiru amino group, propylamino group, isopropylamino group, Buchiruamino group, isobutylene A tyramino group, a sec-ptylamino group, a tert-ptylamino group, and the like.
  • the "di (d _ 4 alkyl) amino group" the alkyl portion is " ⁇ defined above - is 4 dialkyl
  • one Amino groups are Anorekiru group J, for example, Jimechiruamino group, Jechiruamino group, dipropylamino group, Diisopropylamino group, dibutylamino group, disobutylamino group, di-sec-butylamino group, di-tert-butylamino group, N-ethyl-N-methylamino group, N-methyl-1-N-propylamino group, N -Petitlou N-methylamino group, etc.
  • ⁇ ⁇ —4 alkylamino-carbonyloxy group means an alkyl monoamino-carbonyloxy group whose alkyl moiety is “. ⁇ 4 alkyl group” as defined above, for example, methylamino-carbonyl Oxy group, ethylamino-carbonyloxy group, propylamino-carbonyloxy group, isopropylamino-carbonyloxy group, butylamino-carbonyloxy group, isobutylamino-carbonyloxy group, sec-butylamino-carbonyloxy group Tert-butyl amino-carbonyloxy group and the like.
  • the "di (d-4 alkyl) amino chromatography carbonyl O alkoxy group" the alkyl portion position is dialkylamino primary amino chromatography carbonyl O alkoxy group is "Ji 4 alkyl group" defined above, e.g., dimethylamino chromatography Carbonyloxy group, Jetylamino Lonely sulfonyloxy group, Dipropylamino-carbonyloxy group, Diisopropylaminocarbonyloxy group, Dibutylamino-carbonyloxy group, Diiso Butinoleamino-force ruponinoreoxy group, di-sec-butinoleamino-carbonunoleoxy group, di-tert-butylamino-carbonyloxy group, N-ethyl-1-N-methylamino-carbonyloxy group, N-methyl-N-propylamino group Examples thereof include a carbonyloxy group, an N-butyl-1-N-methyla
  • “Ji alkylamino over force Ruponiruamino group” and is its alkyl moiety is "Ji bets 4 alkyl group” above Symbol Definition Arukiruamino one carbonyl ⁇ amino group, e.g., methylamino chromatography carbonyl ⁇ amino group, Echiru Amino-carbonyl amino group, propylamino-carbonylamino group, isopropylamino monocarbonylamino group, ptylamino monool sulfonylamino group, isoptylamino carbonylamino group, sec-butinoreaminocarbonylcarbonylamino group, tert-butyl An amino-carbonylamino group and the like.
  • “Di (C i -4 alkyl) amino-carbonylamino group” means a dialkylamino-carbonylamino group whose alkyl moiety is “. — 4 alkyl group” as defined above.
  • dimethylamino 1-carbonylamino group Jetylamino-carbonylamino group, Dipropylamino-force sulfonylamino group, Diisopropylamino-carbolamamino group, Dibutylamino-1-carbonylamino group, Diisoptylaminocarbonylcarbonylamino group, Di-s.ec-Butylamino group
  • Carbonylamino group, G-tert-butylamino-carbonylamino group N-ethyl-N-methylamino-carbonylamino group, N-methyl-1-N-propylamino group, L-phenylamino group, N-Pitreux N-methylamino-carbonylamin
  • Tri (. 4 alkyl) may be substituted with a silyl C - 4 alkoxy group of the "tri (C - C4 alkyl) silyl” refers to the alkyl moiety has the above defined “C '- 4 alkyl group” And tri (C ⁇ 4 alkyl) silyl. Examples thereof include a trimethylsilyl group, a triethylsilyl group, a triprovirsilyl group, a triisopropylpropylsilyl group, and a tert-butyldimethylsilyl group.
  • Examples of the “tri-4-alkyl) silyl-substituted alkoxy group” include trimethylolylsilyl methoxy group, 2- (trimethylolylsilyl) ethoxy group, and the like.
  • the 7 alk noisy Lou O alkoxy group ", the Arukanoiru sites are Arukanoiru one Okishi group is the above r C i-7 Arukanoiru group as defined", for example, formyl Ruokishi group, Asechiruokishi group, a propionyloxy Ruo alkoxy group, Puchiriruokishi group , Isobutyryloxy group, pentanoyloxy group, isopentanoyloxy group, 2-methylbutylyloxy group, hexanoyloxy group, isohexanoyloxy group, 2-methylpentanoyloxy group, 3-methylpentanoyl group Roxy group, 2-ethylpropylyloxy group, hept
  • the “C 7 -aroyloxy group” is an allylooxy group in which the aroyl moiety is the “diaroyl group” defined above, and examples thereof include a benzoyloxy group, a 1-naphthooxy group, a 2-naphthooxy group, and the like.
  • “7- alkanoyl-amino group” means an alkanoyl-amino group whose alkanoyl moiety is “7-alkanoyl group” as defined above.
  • formylamino group, acetylamino group, propionylamino group, propyllylamino group isoptyrylamino group, penta Nylamino group, Isopentanoylamino group, 2-Methylpropylylamino group, Hexanoylamino group, Isohexanoylamino group, 2-Methylpentanoylamino group, 3-Methylpentanoylamino group, 2- Ethyl butylylamino group, heptanoylamino group, isoheptanoylamino group, 2-methylhexanoylamino group, 3-methylhexanoylamino group, 4-methylhexanoylamino group, 2-e
  • C 7 — Struktur alloyluamino group is an alloy group whose aroyl moiety is the same as the above definition, such as benzoylamino group, 1-naphthoylamino group, 2-naphthoylamino group, etc. It is done.
  • “0 ⁇ 4 alkoxy one-strand sulfonyl group” is an alkoxy one-strand sulfonyl group whose alkoxy moiety is the r C i- 4 alkoxy group defined above, for example, a methoxy carbonyl group, ethoxy Carbonyl group, propoxycarbonyl group, isopropyl Examples include pyroxycarbonyl group, butoxycarbonyl group, isobutyloxycarbonyl group, tert-butoxycarbonyl group and the like.
  • C i- 4 alkoxy-1-carbonylamino group means an alkoxy monocarbonylamino group whose alkoxy moiety is “. — Alkoxy group” as defined above, for example, methoxycarbonylamino group, ethoxycarbonyl Examples include an amino group, a propyloxycarbonylamino group, an isopropyloxy group, a carbonylamino group, a butoxy-powered sulfonylamino group, an isobutyloxycarbonylamino group, and a tert-butoxycarbonylamino group.
  • —4 alkylamino-carbonyl group means an alkylamino-carbonyl group whose alkylamino moiety is “-4 alkylamino group” as defined above. For example, a methylaminocarbonyl group, Tyraminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, butylaminocarbonyl group, isoptylaminocarbonyl group, sec-ptylaminocarbonyl group, tert-petite And a luaminocarbonyl group.
  • "1 to 5 substituents C 6 - 1 2 may be substituted with ⁇ Li Lumpur group - 4 alkylaminocarbonyl chromatography carbonyl group” include, and the like benzyl ⁇ amino carbonyl group.
  • di (C Bok 4 alkyl) Amino one carbonyl group J, its dialkyl ⁇ amino sites dialkylamino chromatography carbonyl group is a" di alkyl) amino group "defined above, e.g., dimethyl ⁇ amino carbonitrile Interview Le Group, jetylamino force, carbonyl group, dipropylaminocarbonyl group, diisopropylaminocarbonyl group, diptylaminocarbonyl group, diisobutylaminocarbonyl group, 'g sec-peptinoreaminocanolepinore group, gee Examples thereof include tert-butynoleamino canoleponole group, N-ethyl-N-methylaminocarbonyl group, N-methyl-one-N-propylaminocarbonyl group, N-ptyluo N-methylaminocarbonyl group and the like.
  • C 6 _ 1 2 ⁇ arylamino chromatography carbonyl group the Ariru site defined above - C 6 is "C 6 1 2 Ariru group” - a 1 2 Ariru primary amino one Karuponiru group, for example, Examples include phenylamino-carbonyl group, 2-naphthylamino monocarbonyl group, and the like.
  • heterocyclic monocarbonyl group means that the heterocyclic ring moiety is the above-defined “heterocyclic ring”.
  • a heterocycle-carbonyl group which is a ring constituting the group J, for example, a pyrrolidinyl carbonyl group (eg, pyrrolidine-1-ylcarbonyl), a piperidinylcarbonyl group (eg, piperidine-1 f-luconyl, etc.) And morpholinylcarbonyl group (eg, morpholine-4-ylcarbonyl, etc.).
  • C 3 _ 1 2 carbocyclic-oxy group means a c 3 — 1 2 carbocyclic monooxy group whose carbocyclic moiety is the ring constituting “C 3 — 12 carbon ring group” as defined above
  • c 6 _ 1 2 aryloxy group eg, phenoxy group, naphthalene-2-r roxy group, etc.
  • c 3 — 1 0 cycloalkyl monooxy group eg, cyclopropyloxy group, cycloptyloxy group
  • Group cyclopentyloxy group, cyclohexyloxy group, etc.
  • c 3 — 1 0 cyclonokenenoreoxy group eg, cyclopropeninoreoxy group, cyclopteninoreoxy group, cyclopentenoxy group, cyclopentagenoxy group
  • cyclohexenyloxy group etc.
  • substituents selected from Group D When two or more substituents selected from Group D are present, they may be substituted with the same or different 1 to 5 substituents selected from Group C, which may be bonded to each other 4 to 7 membered ring is a ring fused to the U e, C 4 saturated or unsaturated cyclic hydrocarbon having 4 to 7 carbon atoms (e.g., cyclobutane, cyclopentane, cyclohexane cyclohexane, etc. cycloheptane - 7 cycloalkyl Anore cans ;.
  • Examples of the condensed ring that the ring forms with U e include the following formula.
  • Ci 7 Arukanoiru groups have been g conversion of five C 6 _ 12 Ariru group" and the above definition of ". ⁇ 7 Arukanoiru J is 1 to 5 substituents as defined above C 6 _ 12
  • the aryl group may be substituted, and examples thereof include acetyl and phenylacetyl.
  • Ci 7 alkanoyl —oxy group optionally substituted with 1 to 5 C 6 12 aryl groups is defined as “1 to 5 ⁇ 6 — 12 aryl groups as defined above”.
  • Good — 7 alkanoyl group ”and an oxygen atom for example, acetyloxy, phenylacetyloxy and the like.
  • C 4 alkyl group which may be substituted with the same or different 1 to 5 substituents selected from group A means “. ⁇ 4 alkyl group” as defined above having 1 to 5 substituents. And may contain an unsubstituted Ci 4 alkyl group. 'The substituent is selected from group A.
  • 2-methylphenyl group ' 2-methyl-1-4-propylphenyl group, 4-isopropylphenyl 2-methylphenyl group, 4-cyclopropyl-2-methylphenyl group, 3,4-dichlorophenyl group, 2, 4 —Dichlorophage phenolic group, 3,5-Dichlorophage phenolic group, 4-Promo 2—Chronic mouth phenolic group, 2—Chromatic mouthpiece 4—Propinolevenolinole group, 2-Fluoro-4-isopropylphenol ⁇ Group, 2,4-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 4-bromo-1-furesole mouth phenol group, 4-promo 3-funoleolophenol group, 3-ethynole group 1 4-Methoxypheninole group,
  • Heterocyclic group optionally substituted with 1 to 5 substituents which are the same or different from group A means that “heterocyclic group” as defined above is substituted with 1 to 5 substituents. Including an unsubstituted heterocyclic group. The substituent is selected from group A.
  • Alkyl group means “the same i. Alkyl group” defined above is 1 to 5 Unsubstituted Ci, which may be substituted with a substituent. Contains an alkyl group. The substituent is selected from group B.
  • Heterocyclic group which may be substituted with the same or different 1 to 5 substituents selected from group C means that “heterocyclic group” as defined above is substituted with 1 to 5 substituents. Including an unsubstituted heterocyclic group. The substituent is selected from dulop C.
  • azetidine 1-1yl group pyridine lysine 1-1yl group, 2 -oxo-pyrrolidine-1-1-1ole group, piperidine-1-1-1ole group, monorephorin-1-4-1ole group, 4-methylbiperazine 1-1 -Yl group, 1-methyl-1H-pyrazole-4-yl group, furan-1-yl group, 1,2,3-thiadiazole-4f group, 2H-tetrazole-5-yl group, pyridine _ 3- 1-yl group, 1-yl group, 4-hydroxypyridine 1-yl group, 4-chloropyrazole 1-yl group, 1-yl group, 5-hydroxymethylisoxazole 1-yl group Group, 1-methyl group, 4-yl group and the like.
  • C 3 _ 1 2 carbocyclic or 4 alkyl group optionally substituted with 1 to 5 identical or different substituents selected from group C means “C 3 _ 1 2 carbocyclic ring” as defined above. Kiichi C alkyl group "is intended may be substituted with 1 to 5 substituents, and includes unsubstituted C 3 _ 1 2 carbocyclic group. The substituent is selected from group C.
  • benzyl group 4-cyclopentyl group, 4-cyanobenzyl group, cyclopropylmethyl / le group, 1-hydroxymethylcycloprop ⁇ / methinole group, cyclopentylmethyl group, and cyclopentayl.
  • a xylmethyl group etc. are mentioned.
  • C 3 _ 1 2 carbocyclic monooxy group which may be substituted with the same or different 1 to 5 substituents selected from group C” means “C 3 _ 1 2 carbocyclic group as defined above” over O key. Shi group "is intended may be substituted with 1 to 5 substituents, and includes unsubstituted C 3 one 2 carbocyclic group. The substituent is selected from group C.
  • Specific examples include a phenoxy group, a 4-chlorophenoxy group, a 4-cyanophenoxy group, a cyclopropyloxy group, a 1-hydroxymethylcyclopropyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group. It is done.
  • Specific examples include an ethur group, a 3-hydroxyl-1-probule group, a 3-methoxy-1-probule group, and the like.
  • “Saturated monocyclic hetero ring optionally substituted with 1 to 5 substituents selected from group A” may be substituted with 1 to 5 “saturated monocyclic hetero ring” as defined above. It may be substituted with 5 substituents and includes an unsubstituted saturated monocyclic heterocycle. The substituent is selected from group A.
  • tetrahydropyran tetrahydrofuran, pyrrolidine, 2-oxopyrrolidine, 1-methinorepyrrolidine, 1-ethinorepyrrolidine, 1-propyl pyrrolidine, 1- (2-hydroxychetyl) pyrrolidine, 11 (2-Methoxystil) pyrrolidine, 1 (2-dimethylaminoethyl) pyrrolidine, 1— (3— Dimethylaminopropyl) pyrrolidine, 1- (2,2,2-trifluoroethyl) pyrrolidine, 1-propanolegrepyrrolidine, 1-isopropizolepyrrolidine, 1-cyclopropylpyrrolidine, 1-isoptylpyrrolidine, 1-cyclopropylmethylpyrrolidine, 1- (dimethylaminocarbonylmethyl) pyrrolidine, 1-benzylpyrrolidine, 1-formylpyrrolidine, 1-acetylethylpyrrolidine, 1- (hydroxyacetyl) pyrrolidine, 1-
  • 2-trifunoleolethanesulfonyl) pyrrolidine 1 (Isopropinoles / Lephonyl) pyrrolidine, 1 (Benzenesulfonyl) pyrrolidine, 1 (aminosulfonyl) pyrrolidine, 1- (dimethylaminosulfonyl) pyrrolidine, 1 1 (Pyrrolysine 1-ylsulfonyl) Pyrrolidine, 1 1 (Cyclopentylaminosulfo 2 / Le) Pyrrolysine, 1- (Mono-Rephorin 1 4-Inoles / Lephoninore) Pyrrolysine, 1- 1 (4-Methylthiazole 1- 2-yl ) Pyrrolidine, 1 (2-Isopropoxy 1,3,4-Dioxocyclobuta 1-enyl) Pyrrolidine, 1— (2-Amino-3, 4.—Dioxocyclobuter 1-enyl) Pyrrolidine
  • Non-aromatic may be substituted by the same or different 1 to 5 substituents selected from group C C 3 - 8 carbocycle" and, of the above defined “non-aromatic C 3 - 8 carbocycle "is intended may be substituted with 1 to 5 substituents, including non-aromatic C 3 _ 8 carbocycle unsubstituted.
  • the substituent is selected from group C.
  • cyclopropane cyclopentane
  • cyclobutane cyclohexane
  • cyclohexene cyclohexene
  • hydroxycyclopentane cyclopentane
  • ethizoleaminocanoleponinoreoxy cyclopentane
  • C 3 _ 1 2 carbocycle optionally substituted with 1 to 5 identical or different substituents selected from group C means that “C 3 _ 1 2 carbocycle” defined above is 1 to five are those which may be substituted with a substituent, C 3 unsubstituted - containing 8 carbocycle.
  • the substituent is selected from group C. Specific examples include benzene, black benzene, methoxy benzene, funoleo benzene, methino benzene, and cycl hexane, with benzene and fluorobenzene being preferred.
  • “Unsaturated monocyclic hetero ring optionally substituted by 1 to 5 substituents selected from group C” means “unsaturated monocyclic hetero ring” as defined above. It may be substituted with 1 to 5 substituents and includes an unsubstituted unsaturated monocyclic heterocycle. The substituent is selected from group C.
  • Embodiments in which two bonds of the divalent group represented by ring J ring J 2 or ring J 3 are bonded to the ring are chemically acceptable. It does not specifically limit as long as it is, and all aspects are included in this invention.
  • R ab 10 has the same meaning as described above.
  • R ab 1 0 are the same as defined above.). It is.
  • C 3 — 1 2 carbocyclic group optionally substituted with the same or different 1 to 5 substituents selected from group D means “C 3 — 1 2 carbocyclic group” as defined above. May be substituted with 1 to 5 substituents, including unsubstituted C s—i 2 carbocyclic groups. The substituent is selected from group D.
  • phenyl group 3-hydroxy-5-methylphenyl group, 3,5-dimethoxyphenyl group, 3-aminophenyl group, 3-amino-1-methyl-phenyl group, 2- (methylamino) phenyl A group, 2- (ethylamino) phenyl group,
  • “Unsaturated monocyclic heterocyclic group which may be substituted with the same or different 1 to 5 substituents selected from group D” means “unsaturated monocyclic heterocyclic group as defined above” Are optionally substituted with 1 to 5 substituents, including unsubstituted unsaturated monocyclic heterocyclic groups. The substituent is selected from group D.
  • “Unsaturated fused heterocyclic group optionally substituted by 1 to 5 substituents selected from group D” means “unsaturated fused heterocyclic group” defined above is 1 to It may be substituted with 5 substituents and includes an unsubstituted unsaturated condensed heterocyclic group. The substituent is selected from 'Group D.
  • R aa 1 and R aa 2 are preferable. Each independently represents a hydrogen atom or a methyl group.
  • L ab 1 is preferably a divalent group represented by the formula [I a] or a divalent group represented by the formula [I c], more preferably 2 represented by the formula [I c].
  • a divalent group more preferably a divalent group represented by the formula [I c '].
  • L b is preferably
  • L ba 6 is preferably a single bond.
  • Ring L c is preferably a benzene ring or a pyridine ring, each of which may be substituted with the same or different 1 to 5 substituents selected from group C, and more preferably the same selected from group C. Alternatively, it is a benzene ring optionally substituted with 1 to 5 different substituents.
  • L d is preferably 0—CH 2 —.
  • U e is preferably an unsaturated monocyclic heterocyclic group or an unsaturated condensed heterocyclic group, each of which may be substituted with the same or different 1 to 5 substituents selected from Group D. More preferably, it is an unsaturated condensed heterocyclic group which may be substituted with the same or different 1 to 5 substituents selected from Group D, and more preferably the same or different selected from Group D.
  • R ba 2 is preferably a hydrogen atom
  • Ring L c is preferably a benzene ring or a pyridine ring, each of which may be substituted with the same or different 1 to 5 substituents selected from group C.
  • L d is preferably 1 O—CH 2 —
  • U e is preferably a quinolyl group, 5, 6, 7, 8-tetrahydroquinolyl group or 1, 2, 3 which may be substituted with the same or different 1 to 5 substituents selected from group D. 4-tetrahydroquinolyl group.
  • R ab 1 ( ⁇ is a hydrogen atom or a substituent selected from group E).
  • R c represents the same or different substituent selected from group C;
  • n c is an integer from 0 to 4.
  • X e 1 and X e 2 each independently represent a carbon atom or a nitrogen atom
  • X e 3 and X e 4 each independently represent a carbon atom, a nitrogen atom or an oxygen atom.
  • n e l and n e 2 each independently represents an integer of 0 to 4,
  • R e 1 and R e 2 are each independently selected from group D, or when two or more exist, they are the same or different 1-room 5 substituents selected from group C in combination with each other. May form an optionally substituted ring,
  • n e 3 represents an integer of 0 to 2.
  • R el, R e 2, R e 3, R e 4, R e 5, R e 6, 1 67 Oyopishaku 68 are each independently,
  • (EE2) may be substituted with the same or different 1 to 5 substituents selected from group B; An alkyl group,.
  • (EE4) Heterocyclic group optionally substituted by 1 to 5 substituents selected from Group C (wherein the heterocyclic group includes a nitrogen atom in addition to a carbon atom) , Oxygen atom, and 1 to 4 heteroatoms selected from sulfur atoms), or
  • (EE6) may be replacement by the same or different 1 to 5 substituents selected from group B C 2 - 6 alkynyl group
  • (E9) Heterocyclic group which may be substituted with 1 to 5 identical or different substituents selected from group C (wherein the heterocyclic group includes nitrogen atom in addition to carbon atom) , Oxygen atom, and 1 to 4 heteroatoms selected from sulfur atoms.), (E10) may be substituted with the same or different 1 to 5 substituents selected from group C Good C 3 12 carbocycle — a C 4 alkyl group, and
  • R f, group B, group C and group D are as defined above.
  • the group represented by the formula [Ue 1] includes, for example, the following formulas [Ue 1 a] to [U e l d]
  • the pharmaceutically acceptable salt of the compound represented may be any salt as long as it forms a non-toxic salt with the compound of the present invention. Salts with organic acids, salts with inorganic bases, salts with organic bases, salts with amino acids, and the like.
  • salts with inorganic acids include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like.
  • salts with organic acids include oxalic acid, maleic acid, citrate, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, darconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid And salts with medalamic acid such as p-toluenesulfonic acid.
  • salts with inorganic bases include sodium salt, potassium salt, calcium salt, Examples include magnesium salts and ammonium salts.
  • organic bases and salts include methylamine, jetylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, trietanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, dicyclohexylamine, ⁇ , ⁇ -dibenzylethylenedi Salts with amamine, guanidine, pyridine, picoline, choline, cinchonine, meglumine, etc.
  • salts with amino acids include salts with lysine, arginine, aspartic acid, glutamic acid and the like.
  • each salt can be obtained by reacting the compound of the present invention with an inorganic base, an organic base, an inorganic acid, an organic acid, or an amino acid.
  • the “solvate” is a compound in which a solvent molecule is coordinated to the compound of the present invention or a pharmaceutically acceptable salt thereof, and includes a hydrate (also referred to as a hydrate).
  • the solvate is preferably a pharmaceutically acceptable solvate.
  • the solvate can be obtained according to a method known per se.
  • it is a compound represented by the formula [I] or a pharmaceutically acceptable salt of the present invention. .
  • the compound of the present invention may be labeled with an isotope (eg, 3 H, 14 C, 35 S, etc.).
  • an isotope eg, 3 H, 14 C, 35 S, etc.
  • prodrugs of the compounds of the present invention can also be useful drugs.
  • a “prodrug” has a group that can be chemically or metabolically decomposed and, after administration to a living body, for example, hydrolysis, solvolysis, or decomposition under physiological conditions.
  • a complex of a compound of the present invention which shows an original medicinal effect by restoring to the original compound, and a complex and a salt not based on a covalent bond are also conceivable.
  • Prodrugs are used, for example, to improve absorption in oral administration or to target sites.
  • modified site examples include highly reactive functional groups such as a hydroxyl group, a carboxyl group, an amino group, and a thiol group in the compound of the present invention.
  • hydroxyl-modifying groups include acetyl, propionyl, isobutylyl, bivaloyl, palmitoyl, benzoyl, 4-methylbenzoyl, dimethylcarbamoyl, dimethylaminomethylcarbonyl, sulfo, Nyl group, fumaryl group, etc. are mentioned.
  • sodium chloride 3-force l-poxy benzoyl group, 2-carboxyethyl carbonyl group, etc. are mentioned.
  • the modifying group of the carboxyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a bivalyloxymethyl group, a carboxymethyl group, a dimethylaminomethyl group, and a single group.
  • modification group of the amino group examples include tert-butyl group, docosanoyl group, pivaloylolemethyloxy group, valanyl group, hexylcarbamoyl group, pentylcarbamoyl group, 3-methylthio 1-11 (acetylylamino) propylcarbonyl 1-sulfo 1 1 (3-ethoxy-4-hydroxyphenyl) methyl group, (5-methyl 1-2-oxo 1, 3-dioyl 1-yl) methyl group, (5-methyl 1 2 — Oxo-1,3-dioyl-4-yl) methoxycarbonyl group, tetrahydrobrael group, pyrrolidylmethyl group and the like.
  • Examples of the “pharmaceutical composition” include tablets, capsules, granules, powders, troches, syrups, emulsions, suspensions and other oral preparations, or external preparations, suppositories, injections, eye drops, transdermal Examples include parenteral agents such as nasal and pulmonary agents.
  • the pharmaceutical composition of the present invention is prepared by the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof according to a method known per se in the technical field of pharmaceutical preparations. Then, it is manufactured by mixing the appropriate amount.
  • the content of the compound of the present invention or a pharmaceutically acceptable salt thereof or a solvate thereof in the pharmaceutical composition varies depending on the dosage form, dosage, etc. For example, 0.1 to 10 of the entire composition. % By weight.
  • “pharmaceutically acceptable carrier” examples include various organic or organic carrier substances commonly used as pharmaceutical materials.
  • excipients examples include solvents, solubilizers, solubilizers, suspending agents, tonicity agents, buffers, soothing agents, etc.
  • additives such as preservatives, antioxidants, colorants, sweeteners and the like are used as necessary.
  • Excipients include, for example, lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, canolemellose, force / remellose canoleum, canolevo Examples include xymethinolestatina sodium, low-substituted hydroxypropyl cellulose, and gum arabic.
  • carmellose for example, carmellose, carmellose calcium, mu, carmellose sodium, force / repoxymethinole starch sodium, cross force noremelose sodium, crospovidone, low-substituted hydroxypropylcellulose, Examples include droxypropyl methyl cell mouthpiece and crystalline cellulose.
  • binder examples include hydroxypropylcellulose, hydroxypropyl oral methylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, gelatin, carmellose sodium, gum arabic and the like.
  • fluidizing agent examples include light anhydrous caustic acid, magnesium stearate ′ and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc and the like.
  • solvent examples include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • solvent examples include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • solvent examples include propylene glycolole, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium thioate and the like.
  • suspending agent examples include benzalkonium chloride, carmellose, hydroxypropinoresenorelose, propylene glycolanol, povidone, methinoresenorose, glyceryl monostearate and the like.
  • Examples of the “isotonic agent” include pudou sugar, D-sorbitol, sodium chloride, D-mannitol and the like.
  • buffering agent examples include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like.
  • Examples of the ⁇ soothing agent include benzyl alcohol.
  • preservative examples include ethoxyl parabenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.
  • antioxidant examples include sodium sulfite, ascorbic acid and the like.
  • colorant examples include food coloring (eg, food red No. 2 or 3, food yellow No. 4 or 5, etc.), ⁇ -carotene and the like. ,
  • sweetening agent examples include saccharin sodium, dipotassium glycyrrhizinate, aspartame and the like.
  • the pharmaceutical composition of the present invention can be used not only for humans, but also for mammals other than humans (eg, mice, rats, hamsters, mono-remotes, rabbits, cats, innu, peta, sushi, horses, hidges, monkeys). Etc.) can also be administered orally or parenterally (eg, topical, rectal, intravenous, etc.).
  • the dose varies depending on the subject of administration, disease, symptoms, dosage form, administration route, etc.
  • the dose for oral administration to adults to patients is the active ingredient.
  • it is usually in the range of about 1 mg to 1 g per day.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof effectively suppresses the production of TNF- ⁇ in vivo by exhibiting an excellent TACE inhibitory action. 69519 can. Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof or a solvate thereof is used for diseases involving TNF- ⁇ , such as inflammatory diseases (for example, rheumatoid arthritis, systemic idiopathic arthritis, gout, deformity).
  • diseases involving TNF- ⁇ such as inflammatory diseases (for example, rheumatoid arthritis, systemic idiopathic arthritis, gout, deformity).
  • infectious diseases eg AI DS, malaria, sepsis
  • osteoporosis diabetes, hyperlipidemia, Alzheimer's disease, neuropathy, organ fibrosis and mal
  • a medicament containing the compound of the present invention is expected as a therapeutic agent for rheumatoid arthritis, inflammatory bowel disease (IBD), and nephritis.
  • IBD inflammatory bowel disease
  • inhibiting TACE means to specifically inhibit the function of TACE to lose or attenuate its activity. For example, based on the conditions of Test Example 1 described later, It means specifically inhibiting the function of TACE.
  • the “inhibiting TA CE” is preferably “inhibiting human TACE”.
  • the “TACE inhibitor” is preferably a “human TACE inhibitor”.
  • TNF-a production suppression means to reduce TNF-a production in vivo, and preferably to reduce excessive TNF- a production due to the onset of disease pathology.
  • some compounds of the present invention have high selectivity for TACE inhibitory action and low inhibitory activity against other meta-oral proteases such as MMP 14, so there are few side effects such as musculoskeletal myalgia based on MMP 14 Can be a drug.
  • the compound of the present invention is excellent in physical properties (membrane permeability, etc.) as a pharmaceutical product and excellent in oral absorbability. Furthermore, the compound of the present invention has a weak inhibitory action of the proposed metabolizing enzymes (CYPs etc.) and hardly causes drug-drug interactions.
  • CYPs etc. the proposed metabolizing enzymes
  • the compound of the present invention or a pharmaceutically acceptable salt thereof or a solvate thereof is combined with one or more other drugs (hereinafter also referred to as concomitant drugs) by a general method practiced in the pharmaceutical field.
  • concomitant drugs drugs
  • Can be used hereinafter also referred to as combined use.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a concomitant drug The administration time of the agent is not limited, and these may be administered to the administration subject as a combination drug, or both preparations may be administered simultaneously or at regular intervals. Further, it may be used as a medicine characterized by being a kit comprising the pharmaceutical composition of the present invention and a concomitant drug.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, disease, symptom, dosage form, administration route, administration time, combination, and the like.
  • the administration form of the concomitant drug is not particularly limited, as long as the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof and the concomitant drug are combined.
  • Concomitant medications include: (1) other rheumatoid arthritis drugs, (2) TACE inhibitors, etc. (3) other inflammatory diseases (eg rheumatoid arthritis, systemic idiopathic arthritis, gout, osteoarthritis, nephritis) , Inflammatory bowel disease (ulcerative colitis and Crohn's disease), COPD, hepatitis, vaginitis, cystitis, myelitis), autoimmune disease (eg systemic lupus erythematosus, psoriasis, multiple sclerosis, Behcet's disease) , Allergic diseases (eg asthma, allergic rhinitis, conjunctivitis), phototopic diseases (eg, atopic dermatitis), transplant rejection, graft-versus-host disease, cardiovascular disease, reperfusion injury, infectious disease ( For example, AIDS, malaria, sepsis), osteoporosis, diabetes, hyperlipidemia, Alzheimer's disease, neuropathy, organ fibro
  • rheumatoid arthritis drugs that can be expected to have synergistic or additive effects include, for example:
  • Non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen, naproxen, diclofenac, actactite, C O X-2 inhibitors (eg, celecoxib, oral fuecoxib, valdecoxib, etc.);
  • Gold preparations Slow-acting antirheumatic drugs such as gold sodium thiomalate, penicillamine, hydroxycloquine, sulfasalazine, etc .;
  • Conoleticosteroid drugs such as prednisolone
  • Immunosuppressive drugs such as methotrexate, refnorenimide, azathioprine, cyclophosphamide, cyclosporine, tacrolimus;
  • Biological preparations such as etanercebut, infliximap, tocilizumap, BMS-1 8866 7;
  • TACE inhibitors that can be expected to have synergistic or additive effects include, for example, DPC—A 3808 8, GI— 1 55 704 A, I DDB 1 1 609, apratast at, BMS—56 1 3 92, GW3 333, etc.
  • the production method of the compound of the present invention is not limited to these.
  • the order of the reaction can be appropriately changed.
  • the reaction may be performed from a process or substitution site that seems reasonable.
  • the production may be efficiently carried out by introducing a protective group into the functional group as necessary and performing deprotection in a later step, or changing the order of each production method and step.
  • post-reaction treatment may be carried out by a commonly used method, and a commonly used method such as isolation and purification, crystallization, recrystallization, silica gel chromatography, preparative HP LC, etc. is appropriately selected and combined. Just do it. In some cases, it is possible to proceed to the next step without isolation and purification.
  • Compound [I] is produced by the following production method 1.
  • L b 1 and L b 2 represent a group having a functional group capable of reacting with each other to form L b, and other symbols are as defined above.
  • a group containing a sulfonamide bond such as
  • one is a sulfonyl halide group, and the other is an amino group
  • One Lb a 3 — Each symbol has the same meaning as defined above.)
  • a group containing carbonyl such as
  • L b 1 is a group containing a strong sulfonyl group or a cyano group
  • L b 2 is a group containing a nucleophilic substituent
  • L b 1 is a group containing a carbonyl group
  • L b 2 is a hydrogen atom
  • L b is a group containing an amino bond such as (7) —N (R ba 5 ) -L ba 5- (where each symbol is as defined above), L b 1 contains an amino group A group, L b 2 is a formyl group;
  • Compound [I] can be obtained by condensing compound [I-1] and compound [1-2] in a solvent in the presence of a condensing agent and a base.
  • the carboxylic acid is acid halide derived from thionyl chloride, oxalyl chloride, etc. (At this time, a catalytic amount of dimethylformamide may be added), or a mixed acid derived from chloroethyl carbonate, etc.
  • the compound [I] can also be obtained by making it a reactive derivative of carboxylic acid by a method such as anhydride, and then reacting with amine in the presence of a base.
  • Examples of the solvent include dimethylformamide (DMF), acetonitrile, tetrahydrofuran (THF), chlorophenol, ethyl acetate, methylene chloride, toluene and the like, and dimethylformamide is preferred.
  • Examples of the condensing agent include dicyclohexyl carpositimide, 1-ethyl-1-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC), and diphenyl phosphoryl azide (DPPA). If necessary, N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOB t), etc. may be added.
  • Examples of the base include potassium carbonate, triethylamine, pyridine, 41- (dimethylamino) pyridine, N-methylmorpholine, diisopropylethylamine and the like, and preferably triethylamine.
  • Px represents a hydrogen atom or an amine protecting group (eg, tert-hydroxycarbonyl group (Boc), benzyloxycarbonyl group (Z), 9-fluorenylmethoxycarbonyl group (Fmo c), trifluoro)
  • Py represents a hydroxyl group, a halogen atom or a mono-O-carboxyl protecting group (eg, a lower alkyl group such as methyl, ethyl, tert-ptyl, benzyl, etc.); other The symbols are as defined above.)
  • Compound [I] can be obtained by condensing compound [I-1] and compound [I-1] in the presence of a base in a solvent.
  • Solvents include dimethylformamide, aceto-tolyl, THF, Or a mixed solvent such as dimethyl acetate, methylene chloride, toluene, etc., preferably dimethylformamide.
  • Examples of the base include potassium carbonate, triethylamine, pyridine, 41- (dimethylamino) pyridine, N-methylmorpholine, diisopropylethylamine and the like, and preferably triethylamine.
  • Compound [I] can be obtained by subjecting compound [I-1] and compound [1-2] to a nucleophilic substitution reaction or an electrophilic substitution reaction in a solvent.
  • the nucleophilic substitution reaction can be performed by a Grignard type reaction or the like.
  • L b 1 includes a group containing a chlorocarbonyl group, N-methoxy-I N-methylcarbamoyl group, cyano group, etc.
  • L b 2 includes a group containing an organic metal such as magnesium or lithium.
  • the solvent include dimethylformamide, acetonitrile, THF, black mouth form, ethyl acetate, methylene chloride, toluene and the like, preferably THF.
  • the electrophilic substitution reaction can be performed by Friedel-Crafts type reaction using a Lewis acid.
  • L b 1 include groups containing a black carbonyl group, an acid anhydride, and the like.
  • the Lewis acid include an anolenium chloride, tin chloride, and boron trifluoride, and preferably aluminum chloride.
  • the solvent include dimethylformamide, acetonitrile, THF, chloroformate, ethyl acetate, methylene chloride, toluene and the like, and preferably chloroformate.
  • the compound [1-1] and the compound [I-12] can be condensed in a solvent in the presence of a base to form a thioether, and then oxidized to obtain a compound [I].
  • Examples of the solvent used for the condensation include dimethylformamide, acetonitrile, THF, chloroformate, ethyl acetate, methylene chloride, toluene and the like, and dimethylformamide is preferred.
  • Bases used for condensation include potassium carbonate, triethylamine, pyridine, 4 One (dimethylamino) pyridine, N-methylmorpholine, diisopropylethylamine and the like can be mentioned, and triethylamine is preferred.
  • solvent used for the oxidation examples include acetonitrile, THF, chloroformate, ethyl acetate, methylene chloride, toluene and the like, and preferably chlorofosrem.
  • oxidizing agent examples include m-chloroperbenzoic acid and oxone (registered trademark).
  • Compound [I] can be obtained by subjecting compound [I-1] and compound [I-1] to a reductive amination reaction in a solvent.
  • Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, triacetoxy boron sodium hydride, and the like, and preferably triacetoxy boron sodium hydride.
  • solvent examples include dimethylformamide, acetonitrile, THF, chloroformate, ethyl acetate, methylene chloride, toluene and the like, preferably THF and chloroformate.
  • Compound [I-1] can be produced by the method shown in the following production method 2.
  • P 1 is a protecting group for a hydroxyl group such as methyl, ethyl, tert-butyl, benzyl, etc.
  • P 2 is a tert-butoxycarbonyl group (B oc), a benzyloxycarbonyl group (Z), 9-fluorenoreme Protecting groups for amino groups such as toxoxycarbonyl group (Fmo c) and trifluoroacetyl group (TFA)
  • P 3 is a protecting group for thiol groups such as methyl, ethyl, tert-butyl, and benzyl
  • R f ' Ci- 4 Alkyl and other symbols are as defined above.
  • Compound 2 can be obtained by amidating the carboxyl group of Compound 1 by a conventional method.
  • a preferable condition in this step is that compound 1 is treated with thionyl chloride, oxalyl chloride, or the like alone or in a mixed solvent such as black mouth form, methylene chloride, and THF. After acid chloride (a catalytic amount of dimethylformamide may be added at this time), it is treated with aqueous ammonia.
  • dicyclohexyl carpositimide 1-ethyl 3- (3-dimethylaminopropyl) carpoimide imido hydrochloride (WS C), diphenyl phosphoryl azide (DP PA), etc. are used as required.
  • WS C 1-ethyl 3- (3-dimethylaminopropyl) carpoimide imido hydrochloride
  • DP PA diphenyl phosphoryl azide
  • N-hydroxysuccinimide 1-hydroxybenzotriazole (HOB t), etc.
  • Compound 3 can be obtained by reacting Compound 2 with an alkylating agent in a solvent and then reacting with Compound 10.
  • the solvent examples include black mouth form, methylene chloride, ethyl acetate, toluene, dioxane, THF, methanol, ethanol, isopropanol, and the like. Preferred is black mouth form or methylene chloride.
  • a solvent such as ethanol or methanol may be added.
  • alkylating agent examples include dimethyl sulfate, methyl triflate, trimethinoreoxo ditetrafluoroborate, methyl iodide and the like, and trimethyloxysonte tetroborate is preferred.
  • Compound [I 1 1] in which R f is a hydrogen atom can be obtained by reacting compound 3 with an acid in a solvent.
  • Solvents include ethyl acetate, THF, toluene, dioxane, methanol, and ethanol. Examples thereof include a single solvent or a mixed solvent such as diol, isopropanol, and water, and preferably ethyl acetate.
  • Examples of the acid include hydrogen chloride, acetyl chloride, p-toluenesulfonic acid, sulfuric acid, phosphoric acid, hydrogen bromide, methanesulfonic acid and the like, preferably hydrogen chloride.
  • Compound 4 can be obtained by amidating the carboxyl group of Compound 1 with Compound 10 by a conventional method.
  • Compound 4 can be obtained by condensing Compound 1 and Compound 10 in a solvent using a condensing agent and, if necessary, in the presence of a base.
  • Compound 1 is an acid halide derived from thionyl chloride, oxalyl chloride, etc. (a catalytic amount of dimethylformamide may be added), or a mixed acid derived from chloroethyl carbonate, etc.
  • Compound 4 can also be obtained by making it a reactive derivative of carboxylic acid by a method such as an anhydride, and then reacting with compound 10 in the presence of a base if necessary.
  • solvent examples include dimethylformamide, acetonitrile, T H F, black mouth form, ethyl acetate, methylene chloride, toluene and the like, and preferably dimethylformamide.
  • condensing agent examples include dicyclohexyl carpositimide, 1-ethyl-3- (3-dimethylaminopropyl) carpositimide hydrochloride (WSC), diphenylphosphoryl azide (DPPA), and the like. If necessary, N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBt), etc. may be added.
  • a method using W S C and H O B t in combination is preferred.
  • Examples of the base include potassium carbonate, triethylamine, pyridine, 4- (dimethylamino) pyridine, N-methylmorpholine, disopropylethylamine, and preferably triethylamine.
  • Compound [I 1 1] in which R f is a hydrogen atom can be obtained by reacting compound 4 with an acid in a solvent.
  • Solvents include ethyl acetate, THF, toluene, chloroform, methylene chloride, etc. Or a solvent mixture thereof, preferably THF or solvent-free.

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Abstract

L'invention concerne un composé représenté par la formule générale [I], un sel pharmaceutiquement acceptable de celui-ci ou un solvate du composé ou du sel. Le composé a une excellente activité d'inhibition sélective de TACE. Par conséquent, une composition pharmaceutique comprenant le composé peut être utilisée comme agent pharmaceutique efficace pour la prévention ou le traitement d'une maladie associée à TNF-α, telle que la polyarthrite rhumatoïde et les infections inflammatoires du tube digestif (IBD). [I] formule dans laquelle chaque symbole est tel que défini dans la description.
PCT/JP2007/069519 2006-09-30 2007-09-28 Dérivé de thiadiazolone et utilisation de celui-ci WO2008038841A1 (fr)

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WO2008103277A3 (fr) * 2007-02-16 2009-04-16 Amgen Inc Cétones d'hétérocyclyle contenant de l'azote et procédés d'utilisation
WO2010042925A3 (fr) * 2008-10-10 2010-07-29 Vm Discovery Inc. Compositions et méthodes pour traiter les troubles liés à la consommation d'alcool, la douleur et d'autres maladies
WO2012005229A1 (fr) 2010-07-08 2012-01-12 科研製薬株式会社 Dérivé de n-hydroxyformamide et produit pharmaceutique le contenant
EP2336105A4 (fr) * 2008-09-19 2012-03-28 Takeda Pharmaceutical Composé hétérocyclique contenant de l'azote et son utilisation
US20120088888A1 (en) * 2009-03-10 2012-04-12 Nissan Chemical Industries, Ltd. Polyimide precursor, polyimide, and liquid crystal aligning agent
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JP2015519381A (ja) * 2012-06-11 2015-07-09 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ−アルファ調節ベンゾイミダゾール
WO2015124934A1 (fr) * 2014-02-20 2015-08-27 Takeda Cambridge Limited Pyrrolidines, térahydrofuranes et cyclopentanes substitués utiles en tant qu'antagonistes des récepteurs des orexines
WO2015124932A1 (fr) * 2014-02-20 2015-08-27 Takeda Cambridge Limited Cyclopentanes substitués en 1,2 utilisés comme antagonistes du récepteur d'orexine
US9227930B2 (en) 2010-08-13 2016-01-05 Abbvie Inc. Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
US9238619B2 (en) 2010-08-13 2016-01-19 AbbVie Deutschland GmbH & Co. KG Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9309200B2 (en) 2011-05-12 2016-04-12 AbbVie Deutschland GmbH & Co. KG Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy
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JPWO2016171142A1 (ja) * 2015-04-20 2018-02-15 武田薬品工業株式会社 複素環化合物
WO2018074461A1 (fr) 2016-10-18 2018-04-26 武田薬品工業株式会社 Composé hétérocyclique
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