WO2012002502A1 - Dérivé de dihydropyrimidinone et son utilisation pharmaceutique - Google Patents

Dérivé de dihydropyrimidinone et son utilisation pharmaceutique Download PDF

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WO2012002502A1
WO2012002502A1 PCT/JP2011/065077 JP2011065077W WO2012002502A1 WO 2012002502 A1 WO2012002502 A1 WO 2012002502A1 JP 2011065077 W JP2011065077 W JP 2011065077W WO 2012002502 A1 WO2012002502 A1 WO 2012002502A1
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halogen atom
hydroxyl group
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alkyl
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智也 城
克巳 久保田
洋輔 ▲高▼梨
智昭 中村
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大日本住友製薬株式会社
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Definitions

  • the present invention relates to a novel dihydropyrimidinone derivative useful as a medicine having elastase inhibitory activity. More specifically, the present invention relates to a novel dihydropyrimidinone derivative useful as a prophylactic and / or therapeutic agent for diseases involving elastase such as inflammatory diseases.
  • elastase Human neutrophil elastase (hereinafter sometimes simply referred to as elastase) is a kind of serine protease having a molecular weight of about 30 KDa and is stored in azurophilic granules of neutrophils. In the physiological state, elastase plays a role in rapidly digesting and degrading phagocytosed bacteria and foreign substances in neutrophils, and in vivo, connective tissues such as lung, cartilage, blood vessel wall, and skin outside neutrophils. It degrades elastin, collagen (type III, type IV), proteoglycan, fibronectin, etc. that make up the stroma, and helps maintain tissue homeostasis.
  • collagen type III, type IV
  • proteoglycan proteoglycan
  • fibronectin etc.
  • Non-Patent Document 1 When there is an imbalance between endogenous elastase-inhibiting protein and elastase, or when excessive elastase is released due to a pathological condition caused by inflammation, etc., elastase actively promotes normal tissues. It is thought to induce various pathological conditions by destroying it.
  • elastase Diseases that have been suggested to be involved in the pathogenesis of elastase include, for example, chronic obstructive pulmonary disease (COPD), cystic pulmonary fibrosis, emphysema, adult respiratory distress syndrome (ARDS), acute lung injury (ALI), idiopathic Pulmonary fibrosis (IIP), chronic interstitial pneumonia, chronic bronchitis, chronic respiratory tract infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, rheumatoid arthritis, arthrosclerosis, Osteoarthritis, psoriasis, periodontitis, atherosclerosis, organ transplant rejection, early water rupture, blistering, shock, sepsis, systemic lupus erythematosus (SLE), Crohn's disease, disseminated intravascular coagulation (DIC), tissue damage during ischemia-reperfusion, formation of cornea
  • Patent Documents 1, 2, and 3 disclose 2-dihydropyrimidinone derivatives as neutrophil elastase inhibitors.
  • A-1 general formula (A-1) (formula I in the same publication) is described.
  • the 2-dihydropyrimidinone derivative has an aryl or heteroaryl ring at the 4-position, it is clearly structurally different from the compounds of the present invention described later.
  • the 2-dihydropyrimidinone derivatives described in Patent Documents 2 and 3 are also structurally different from the compounds of the present invention described later.
  • Patent Document 4 As a compound having a p38 MAP kinase inhibitory action, the first term in the claims of Patent Document 4 and Patent Document 5 is represented by the following general formula (A-2) (formula I in the same publication): Compounds are described.
  • ring A represents an optionally substituted 5-membered monocyclic heterocyclic ring containing 1 to 3 atoms selected from an oxygen atom, a nitrogen atom or a sulfur atom as a hetero atom.
  • Ring B represents a heterocyclic ring containing at least one nitrogen atom which may have a substituent
  • ring D represents a cyclic group which may have a substituent
  • ring E represents a substituent.
  • R 1 represents a substituent containing a basic nitrogen atom]
  • Patent Document 4 represents a 5-membered monocyclic heterocycle containing 1 to 3 atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, which may further have a substituent
  • B represents a heterocyclic ring which may have a substituent and may contain 1 to 3 atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom in addition to the above-described nitrogen atom
  • ring D Represents a cyclic group which may have a substituent
  • ring E represents a cyclic group which may have a substituent
  • R 1 is a neutral group containing an oxygen atom and / or a sulfur atom.
  • Patent Document 5 Represents a neutral group or acidic group containing an oxygen atom and / or a sulfur atom representing a group or acidic group]
  • the position of the substituent R 1 substituting for the 5-membered ring A is the 4th position in order from the position bonded to the ring B and the ring D.
  • ring A (L in formula (I) ′ in the present specification) is unsubstituted, and the position of the substituent in ring A (L in formula (I) in the present specification).
  • the structure is different in that it is in the fifth position.
  • the problem to be solved by the present invention is to provide a therapeutic agent for various inflammatory diseases involving elastase.
  • R 0 is —C ( ⁇ O) NR a —, —S ( ⁇ O) 2 NR a —, —C ( ⁇ O) O—, —C ( ⁇ O) —, —S ( ⁇ O) 2 —.
  • R 1 may contain 1 to 2 heteroatoms selected from the group consisting of a hydrogen atom, C 1-10 alkyl, C 2-6 alkene, N, O and S 3-6 membered saturation Or a 4- to 6-membered unsaturated aliphatic ring group, or a 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S Show
  • the alkyl and the alkene in R 1 are in substitutable positions
  • R 3 and R 4 each independently represents a hydrogen atom or C 1-3 alkyl (the alkyl may be substituted with a hydroxyl group or a halogen atom);
  • Ar 1 is a 5- to 6-membered aromatic ring group that may contain 1 to 3 heteroatoms selected from the group consisting of N, O, and S (the aromatic ring group is a substitutable position).
  • C 1-6 alkyl optionally substituted with a hydroxyl group or a halogen atom
  • C 1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro, phenyl, —NR a C ( ⁇ O) R h , —NR a S ( ⁇ O) m R h , —NR a C ( ⁇ O) NR c R d , —C ( ⁇ O) NR c R d , —C ( ⁇ O ) OR a , —C ( ⁇ O) R a , —S ( ⁇ O) m NR c R d , —S ( ⁇ O) n R h, or —NR c R d ).
  • Show L is —S ( ⁇ O) q —, a 6-membered aromatic ring group optionally containing 1 to 4 nitrogen atoms, the
  • bond 1 represents a bond to a dihydropyrimidinone ring
  • bond 2 represents a bond to Ar 2
  • Z 1 , Z 2 and Z 3 are each independently C which may be substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, —NR c R d , —C ( ⁇ O) NR c R d and —C ( ⁇ O) OR a 1-6 alkyl or C 2-6 alkene, halogen, —C ( ⁇ O) NR c R d , —C ( ⁇ O) OR a , hydroxyl group, —NR c R d or hydrogen atom)
  • L is a 6-membered aromatic ring group
  • a halogen atom a hydroxyl group, —NR c R d , —C ( ⁇ O) NR c R d and —C ( ⁇ O ) C 1-6 alkyl or C 2
  • C 1-6 alkyl optionally substituted with a hydroxyl group, cyano, or a halogen atom
  • Indicate Re is Hydrogen atom, C 1-6 alkyl (the alkyl may be substituted with a hydroxyl group,
  • R 0 is —C ( ⁇ O) NR a —, —S ( ⁇ O) 2 NR a —, —C ( ⁇ O) O—, —C ( ⁇ O) —, —S ( ⁇ O) 2 —
  • R 1 may contain 1 to 2 heteroatoms selected from the group consisting of a hydrogen atom, C 1-10 alkyl, C 2-6 alkene, N, O and S 3-6 membered saturation Or a 4- to 6-membered unsaturated aliphatic ring group, or a 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S Show The alkyl and the alkene in R 1 are in substitutable positions, Substituent list 4: (1) hydroxyl group, (2) a halogen atom, (3) cyano, (4) C 1-6 alkoxy (wherein the alkoxy is substitutable, Hydroxyl group, A halogen atom,
  • C 1-3 alkoxy optionally substituted with an atom, hydroxyl group, halogen atom, cyano, nitro, phenyl, —NR a C ( ⁇ O) R h , —NR a S ( ⁇ O) m R h , —NR a C ( ⁇ O) NR c R d , —C ( ⁇ O) NR c R d , —C ( ⁇ O) OR a , —C ( ⁇ O) R a , —S ( ⁇ O) m NR c R d , —S ( ⁇ O) n R h or —NR c R d or more).
  • L is a 6-membered aromatic ring group optionally containing 1 to 4 nitrogen atoms, the following formula Pyr-1, the following formula Tri-1 or the following formula Imi-1:
  • bond 1 represents a bond to a dihydropyrimidinone ring
  • bond 2 represents a bond to Ar 2
  • Z 1 , Z 2 and Z 3 are each independently C which may be substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, —NR c R d , —C ( ⁇ O) NR c R d and —C ( ⁇ O) OR a 1-6 alkyl or C 2-6 alkene, halogen, —C ( ⁇ O) NR c R d , —C ( ⁇ O) OR a , hydroxyl group, —NR c R d or hydrogen atom)
  • L is a 6-membered aromatic ring group
  • a halogen atom a hydroxyl group, —NR c R d , —C ( ⁇ O) NR c R d and —C ( ⁇ O ) C
  • R 1 is C 1-10 alkyl (the group may be substituted by one or more substituents described in substituent list 4), C 2-6 alkene (the group is described in substituent list 4).
  • Optionally substituted by one or more substituents may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S 3-6 membered saturated or 4-6 membered 1 to 4 selected from the group consisting of N, O and S, or an unsaturated aliphatic ring group (which may be substituted with one or more substituents described in Substituent List 5)
  • Item 1 or Item 2 which represents a 5- to 6-membered aromatic ring group (which may be substituted with one or more substituents described in Substituent List 6), which may contain the following heteroatoms: Or a physiologically acceptable salt thereof.
  • Ar 1 is a benzene ring or a pyridine ring (the benzene ring and the pyridine ring are each independently substituted with one or more substituents selected from the group consisting of a hydroxyl group and a halogen atom at substitutable positions.
  • C 1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, hydroxyl group and halogen atom, hydroxyl group, halogen atom, cyano, nitro, phenyl , —C ( ⁇ O) NR c R d , —C ( ⁇ O) OR a , —C ( ⁇ O) R a , —S ( ⁇ O) n R h, and —NR c R d
  • the compound or a physiologically acceptable salt thereof according to any one of items 1 to 4, wherein the compound is substituted with 1 to 3 substituents which are the same or different.
  • Ar 1 is represented by the following formula Ar 1 -1:
  • K 1 , K 2 , K 3 and K 4 all represent a carbon atom in the case of a benzene ring, only one nitrogen atom in the case of a pyridine ring, the other represents a carbon atom, and X represents a hydroxyl group.
  • Ar 2 is a benzene ring or a pyridine ring (the benzene ring or pyridine ring is each independently substituted with one or more substituents selected from the group consisting of a hydroxyl group and a halogen atom at substitutable positions.
  • C 1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, hydroxyl group and halogen atom, hydroxyl group, halogen atom, cyano, nitro,- Selected from the group consisting of C ( ⁇ O) NR c R d , —C ( ⁇ O) OR a , —C ( ⁇ O) R a , —S ( ⁇ O) n R h and —NR c R d
  • the compound or the physiologically acceptable salt thereof according to any one of items 1 to 6, wherein the compound is substituted with 1 to 3 substituents which are the same or different.
  • Ar 2 is represented by the following formula Ar 2 -1:
  • L 1 , L 2 , L 3 and L 4 all represent a carbon atom in the case of a benzene ring, only one nitrogen atom in the case of a pyridine ring, the other represents a carbon atom, and Y represents a hydroxyl group.
  • L represents a benzene ring or a pyridine ring,
  • the position where the ring and the dihydropyrimidinone ring are bonded is the ortho position of the position where the ring and Ar 2 are bonded;
  • the benzene ring and pyridine ring are each independently a substitutable position, C which may be substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, —NR c R d , —C ( ⁇ O) NR c R d and —C ( ⁇ O) OR a 1-6 alkyl, halogen, —C ( ⁇ O) NR c R d , —C ( ⁇ O) OR a , —NR c R d , nitro and —NR a C ( ⁇ O) R b
  • Item 9 The compound according to any one of Items 1 to 8, or a physiologically acceptable salt thereof, represented by:
  • Item 10 The compound according to any one of Items 1 to 9, or a physiologically acceptable salt thereof, wherein L is an unsubstituted benzene ring or pyridine ring.
  • Item 9 The compound according to any one of Items 1 to 8, or a physiologically acceptable salt thereof, wherein L represents Pyr-1, Tri-1 or Imi-1, and Z 1 , Z 2 and Z 3 represent a hydrogen atom Salt.
  • L represents Pyr-1, Tri-1 or Imi-1
  • Z 1 , Z 2 and Z 3 are each independently one or more selected from the group consisting of —NR c R d and a halogen atom Item 9.
  • the compound or the physiologically acceptable salt thereof according to any one of Items 1 to 8, which represents C 1-6 alkyl, —NR c R d, or a halogen atom, which may be substituted with the above substituent.
  • L represents Pyr-1, Tri-1 or Imi-1, and Z 1 , Z 2 and Z 3 may each independently be substituted with —C ( ⁇ O) NR c R d Item 9.
  • L represents Pyr-1, Tri-1 or Imi-1
  • Z 1 , Z 2 and Z 3 are each independently selected from the group consisting of a hydroxyl group and —C ( ⁇ O) OR a Or a compound according to any one of Items 1 to 8, which represents C 1-6 alkyl, hydroxyl group or —C ( ⁇ O) OR a optionally substituted with a plurality of substituents, or a physiologically acceptable product thereof Salt.
  • R 1 is C 1-10 alkyl optionally substituted by one or more substituents described in Substituent List 4 at substitutable positions, or described in Substituent List 5 at substitutable positions.
  • a 3- to 6-membered saturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S which may be substituted by one or more substituents of Item 15.
  • R 1 is C 1-10 alkyl (wherein the alkyl is a substitutable position, Substituent list 7: (1) hydroxyl group, (2) a halogen atom, (3) cyano, (4) C 1-6 alkoxy (wherein the alkoxy is Hydroxyl group, A halogen atom, 3- to 6-membered saturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of cyano and N, O and S (the aliphatic ring group is a substitutable position) And one or more substituents selected from the group consisting of C 1-3 alkyl, hydroxyl group and halogen atom optionally substituted with one or more substituents selected from the group consisting of hydroxyl groups and halogen atoms C 1-3 alkoxy optionally substituted with, hydroxyl group, halogen atom, cyano, —NR a C ( ⁇ O) R b , —NR a S ( ⁇ O) m R
  • R 1 represents 1 to 2 heteroatoms selected from the group consisting of N, O and S which may be substituted with one or more substituents described in Substituent List 5 at substitutable positions.
  • Item 16 The compound or the physiologically acceptable salt thereof according to any one of Items 1 to 15, which represents a 3- to 6-membered saturated aliphatic cyclic group which may be contained.
  • R 1 may contain 1 to 2 heteroatoms selected from the group consisting of N, O, and S.
  • the 3- to 6-membered saturated aliphatic ring group (the aliphatic ring group may be substituted) In position, Substituent list 9: (1) hydroxyl group, (2) a halogen atom, (3) cyano, (4) C 1-6 alkyl (wherein the alkyl is a substitutable position, Hydroxyl group, A halogen atom, Cyano, A 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a hydroxyl group at a substitutable position) And optionally substituted with one or more substituents selected from the group consisting of C 1-3 alkyl, hydroxyl group and halogen atom optionally substituted with one or more substituents selected from the group consisting of halogen atoms C 1-3 alkoxy, hydroxyl group, halogen
  • substituents selected from the group consisting of: (5) C 1-6 alkoxy (wherein the alkoxy is Hydroxyl group, A halogen atom, Cyano, A 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a hydroxyl group at a substitutable position) And optionally substituted with one or more substituents selected from the group consisting of C 1-3 alkyl, hydroxyl group and halogen atom optionally substituted with one or more substituents selected from the group consisting of halogen atoms C 1-3 alkoxy, hydroxyl group, halogen atom, cyano, —NR a C ( ⁇ O) R b , —NR a S ( ⁇ O) m R b , —C ( ⁇ O) OR b , —C ( ⁇ O) NR c R d
  • R 1 may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S which may be substituted with one or more substituents described in the substituent list 9.
  • Item 1 to Item 6 is a 6-membered saturated aliphatic cyclic group, and the aliphatic cyclic group is a C 3-6 saturated carbocyclic ring, aziridine, azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, theorahydropyran, morpholine or piperazine.
  • Item 15 The compound according to any one of Items 18, 18 and 19, or a physiologically acceptable salt thereof.
  • R a represents a hydrogen atom, or C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of a hydroxyl group and a fluorine atom
  • R b represents C 1-6 alkyl which may be substituted with one or more substituents selected from the group consisting of a hydroxyl group and a fluorine atom
  • R c and R d each independently represents a hydrogen atom, or C 1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of a hydroxyl group and a fluorine atom, or 4 to 6-membered saturated aliphatic ring group containing N bonded together (the aliphatic ring group is one or more selected from the group consisting of a hydroxyl group and a fluorine atom at a substitutable position) Which may be substituted with a substituent of R e is C 1-6 alkyl (the alkyl is substituted with one or more substituents selected
  • R f is a hydroxyl group, C 1-3 alkyl (the alkyl may be substituted with one or more substituents selected from the group consisting of a hydroxyl group, cyano, a fluorine atom, and —NR c R d ), or -NR a R i , R g is a hydroxyl group, C 1-3 alkyl (which may be substituted with one or more substituents selected from the group consisting of a hydroxyl group, cyano, a fluorine atom and —NR c R d ), or -NR a R i , R g is a hydroxyl group, C 1-3 alkyl (which may be substituted with one or more substituents selected from the group consisting of a hydroxyl group, cyano, a fluorine atom and ——NR c R d ), or -NR a R i , R g is a hydroxyl group, C 1-3 alkyl (
  • m represents 1 or 2; Item 21.
  • Item 21 The compound according to any one of Items 1 to 20, or a physiologically acceptable salt thereof.
  • R 1 represents —C ( ⁇ O) NR a —, —S ( ⁇ O) 2 NR a —, —C ( ⁇ O) —, —S ( ⁇ O) 2 —, or a single bond, Item 22.
  • R 1 is C 1-10 alkyl (wherein the alkyl is a substitutable position, (1) hydroxyl group, (2) a halogen atom, (4) C 1-6 alkoxy (wherein the alkoxy is Hydroxyl group, A halogen atom, A 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O
  • Item 1 The compound according to Item 1 or a physiologically acceptable salt thereof selected from the following group: 4- (4- (3-Isopropyl-6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -4H-1 , 2,4-triazol-3-yl) benzonitrile, (R) -4- (4- (3- (1-hydroxypropan-2-yl) -6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3, 4-tetrahydropyrimidin-5-yl) -4H-1,2,4-triazol-3-yl) benzonitrile, 4- (4- (3-Isopropyl-6-methyl-2-oxo-1-m-tolyl-1,2,3,4-tetrahydropyrimidin-5-yl) -4H-1,2,4-triazole- 3-yl)
  • [Claim 26] 26 A pharmaceutical composition comprising the compound according to any one of Items 1 to 25 as an active ingredient or a physiologically acceptable salt thereof and a pharmaceutical carrier.
  • Item 26 A therapeutic or prophylactic agent for inflammatory diseases comprising the compound according to any one of Items 1 to 25 or a physiologically acceptable salt thereof.
  • Item 26 A therapeutic or prophylactic agent for a disease requiring an inhibitory activity on elastase, comprising the compound according to any one of Items 1 to 25 or a physiologically acceptable salt thereof.
  • the present application also provides the following aspects.
  • Item 26 Use of the compound according to any one of Items 1 to 25 or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of inflammatory diseases.
  • Item 26 The compound according to any one of Items 1 to 25 or a physiologically acceptable salt thereof, or a pharmaceutical composition containing the same as an active ingredient for use in the treatment or prevention of inflammatory diseases.
  • R 0 is —C ( ⁇ O) NR a1 —, —S ( ⁇ O) 2 NR a2 —, —C ( ⁇ O) O—, —C ( ⁇ O) —, —S ( ⁇ O) 2 —.
  • L represents a 5- to 6-membered unsubstituted aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S, or —S ( ⁇ O) q —.
  • Show Ar 2 is a 5- to 6-membered aromatic ring group that may contain 1 to 3 heteroatoms selected from the group consisting of N, O, and S (the aromatic ring group is a substitutable position).
  • C 1-6 alkyl optionally substituted with a hydroxyl group, cyano, or a halogen atom
  • C 1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro,- S ( ⁇ O) n R h or —NR c36 R d36 or more).
  • R 0 is —C ( ⁇ O) NR a1 —, —S ( ⁇ O) 2 NR a2 —, —C ( ⁇ O) O—, —C ( ⁇ O) — or —S ( The compound or a physiologically acceptable salt thereof according to Item 1 ′, wherein ⁇ O) 2 —.
  • Ar 1 is the following Ar 1 -1 ′ or Ar 1 -2 ′
  • G 1 , G 2 and G 3 each independently represent a carbon atom or a heteroatom selected from the group consisting of N, O and S, and X is substituted with a hydroxyl group or a halogen atom C 1-6 alkyl which may be substituted, C 1-3 alkoxy which may be substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro or —NR c35 R d35 , and E 1 , E 2 , E 3 , E 4 , G 1 , G 2 or G 3 may be substituted with a C 1-6 alkyl, hydroxyl group or halogen atom which may be further substituted with a hydroxyl group or a halogen
  • Ar 2 is represented by Ar 2 -1' or Ar 2 -2 'shown below:
  • K 1 , K 2 , K 3 and K 4 each independently represent a carbon atom or a nitrogen atom (provided that K 1 , K 2 , K 3 and K 4 all simultaneously represent a nitrogen atom)
  • R d36 represents C 1- which may be further substituted with a hydroxyl group, cyano or halogen atom at a substitutable position of K 1 , K 2 , K 3 , K 4 , L 1 , L 2 or L 3.
  • L is a 5- to 6-membered unsubstituted aromatic ring group that may contain 1 to 4 heteroatoms selected from the group consisting of N, O, and S.
  • I ')' is a 5- to 6-membered unsubstituted aromatic ring group that may contain 1 to 4 heteroatoms selected from the group consisting of N, O, and S.
  • R 1 is a hydrogen atom, C 1-10 alkyl (wherein the alkyl may be substituted with the same substituent as defined in item 1 ′) or N, O and A 3- to 6-membered saturated or unsaturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of S (wherein the aliphatic ring group is a substitutable position, The compound or a physiologically acceptable salt thereof according to any one of Items 1 ′ to 8 ′, which may be substituted with the same substituent as defined in “1.
  • R 1 is a hydrogen atom or C 1-10 alkyl (wherein the alkyl may be substituted with the same substituent as defined in Item 1 ′ at a substitutable position);
  • a and A ′′ are each independently substituted, from the group consisting of phenyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl Selected from the group consisting of selected aromatic ring groups or optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrrolinyl, dihydropyridinyl and
  • R c17, R c18, R c19 , R c21, R c22, R c24, R c25, R c38, R d17, R d18, R d19, R d21, R d22, R d24, R d25 and R d38 are each Independently represents a hydrogen atom, or C 1-3 alkyl optionally substituted with a hydroxyl group or a fluorine atom, or together, 1-2 heteroaryl selected from the group consisting of N and O
  • a 4- to 6-membered saturated aliphatic cyclic group containing atoms (the saturated aliphatic cyclic group may be substituted with a hydroxyl group or a fluorine atom at a substitutable position), R c20, R c23, R c27 , R c37, R c40
  • Ar 1 is the following Ar 1 -1 ′′:
  • E 1 , E 2 and E 3 each independently represents a carbon atom or a nitrogen atom, and X represents a C 1-3 alkyl, hydroxyl group or hydroxyl group which may be substituted with a hydroxyl group or a fluorine atom.
  • K 1 , K 2 , K 3 and K 4 each independently represent a carbon atom or a nitrogen atom (provided that K 1 , K 2 , K 3 and K 4 are all simultaneously nitrogen atoms) except where indicated)
  • Y represents a halogen atom, a cyano or nitro, a substitutable position of K 1, K 2, K 3 or K 4, which may be substituted by a hydroxyl group or a fluorine atom
  • C 1- 3 may have a substituent selected from alkyl, hydroxyl group, or C 1-3 alkoxy optionally substituted with a fluorine atom, hydroxyl group, halogen atom, cyano and —NR c36 R d36
  • L ′ represents a benzene ring group, a thiophene ring group, a furan ring group, a pyrrole ring group, an imidazole ring group, a pyridine ring group, a pyrazine ring group, an isoxazole ring group, a pyrazole ring group, an isothiazole ring group,
  • the following formula (I ′′) ′ which is a pyrimidine ring group, pyridazine ring group, oxazole ring group, thiazole ring group, triazole ring group or tetrazole ring group:
  • L ′ represents a benzene ring group, an imidazole ring group, a pyridine ring group, a pyrazine ring group, an isoxazole ring group, a pyrazole ring group, a pyrimidine ring group, an oxazole ring group, a triazole ring group, or a tetrazole ring group.
  • a pharmaceutical composition comprising the compound according to any one of items 1' to 15 'as an active ingredient or a physiologically acceptable salt thereof and a pharmaceutical carrier as active ingredients.
  • a therapeutic or prophylactic agent for inflammatory diseases comprising the compound according to any one of items 1' to 15 'or a physiologically acceptable salt thereof.
  • a therapeutic or prophylactic agent for a disease requiring an elastase inhibitory activity comprising the compound according to any one of items 1' to 15 'or a physiologically acceptable salt thereof.
  • a therapeutic or prophylactic agent for diseases involving elastase such as inflammatory diseases can be provided.
  • Diseases that have been suggested to be involved in the pathogenesis of elastase include, for example, chronic obstructive pulmonary disease (COPD), cystic pulmonary fibrosis, emphysema, adult respiratory distress syndrome (ARDS), acute lung injury (ALI), idiopathic Pulmonary fibrosis (IIP), chronic interstitial pneumonia, chronic bronchitis, chronic respiratory tract infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, rheumatoid arthritis, arthrosclerosis, Osteoarthritis, psoriasis, periodontitis, atherosclerosis, organ transplant rejection, early water rupture, blistering, shock, sepsis, systemic lupus
  • COPD chronic obstructive pulmonary disease
  • physiologically acceptable salts of the compounds represented by formula (I) and formula (I) ′ are those of formula (I) and formula (I) ′ having a group capable of forming an acid addition salt in the structure.
  • the acid addition salt include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate, and other inorganic acid salts, oxalate, malonate, Maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfone
  • Organic acid salts such as acid salts, and amino acid salts such as glutamate and aspartate.
  • salts with bases include alkali metal or alkaline earth metal salts such as sodium salt, potassium salt or calcium salt, salts with organic bases such as pyridine salt and triethylamine salt, and lysine, arginine and the like.
  • examples include salts with amino acids.
  • the compounds of formula (I) and formula (I) ′ and their salts may exist in the form of hydrates and / or solvates, these hydrates and / or solvates may also be present. Included in the compounds of the present invention. That is, the “compound of the present invention” includes, in addition to the compounds represented by the above formulas (I) and (I) ′ and physiologically acceptable salts thereof, hydrates and / or solvents thereof. Japanese products are included.
  • the compounds of formula (I) and formula (I) ′ may have one or more asymmetric carbon atoms and may cause geometric isomerism and axial chirality, so It can exist as an isomer.
  • these stereoisomers, mixtures thereof and racemates are included in the compounds represented by formula (I) and formula (I) 'of the present invention.
  • Alkyl means a linear or branched saturated hydrocarbon group, and “C 1-3 alkyl”, “C 1-6 alkyl” and “C 1-10 alkyl” It means groups having 1 to 3, 1 to 6 and 1 to 10 carbon atoms.
  • C 1-3 alkyl such as methyl, ethyl, propyl, isopropyl and the like
  • C 1-6 alkyl includes, in addition to the above, butyl, isobutyl, sec-butyl, tert- Butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
  • C 1-10 alkyl includes, in addition to the above, octyl, nonyl, decyl, etc.
  • the alkyl may be linear or branched. It may be a shape.
  • C 1-3 alkyl is methyl, ethyl, propyl, and isopropyl
  • C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl
  • Hexyl as “C 1-10 alkyl” includes methyl, ethyl, propyl, isopropyl, butyl, pentyl, and hexyl.
  • alkyl part of “alkylthio” has the same meaning as the above “alkyl”, and specific examples of “alkylthio” include methylthio, ethylthio, propylthio, isopropylthio, tert-butylthio and the like, preferably methylthio, and ethylthio Is mentioned.
  • alkyl part of “alkylcarbonyl” has the same meaning as the above “alkyl”, and specific examples of “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, tert-butylcarbonyl (pivaloyl) And preferably include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, and tert-butylcarbonyl.
  • Cycloalkyl means a cyclic hydrocarbon group, preferably a cyclic saturated hydrocarbon group.
  • C 3-6 cycloalkyl means cyclopropane, cyclobutane, cyclopentane, And cyclohexane.
  • cyclopropane, cyclobutane, and cyclopentane are used.
  • “Saturated carbocycle” means a cyclic saturated hydrocarbon group.
  • “C 3-6 saturated carbocycle” includes cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
  • cyclopropane, cyclobutane, and cyclopentane are used.
  • Alkene means a linear or branched unsaturated hydrocarbon group.
  • C 2-6 alkene has 2 to 6 carbon atoms and contains an unsaturated bond. Means group. Specific examples include ethene, 1-propylene, 2-propylene, 1-butene, 2-butene, 3-butene, 1-pentene, 2-pentene, 3-pentene, 4-pentene, 1-hexene and 2-hexene. , 3-hexene, 4-hexene, 5-hexene, 2-methyl-3-butene, 2-methyl-2-pentene, 3-methyl-2-pentene and the like. Among them, ethene, 2-propylene, and 2-butene are preferable.
  • Halogen atom includes fluorine atom, chlorine atom, bromine atom and iodine atom.
  • a fluorine atom, a chlorine atom, and a bromine atom are mentioned.
  • Alkoxy is a group in which alkyl is bonded to an oxygen atom, and the “alkyl” moiety is as defined above for “alkyl”.
  • C 1-3 alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy and the like
  • C 1-6 alkoxy includes n-butoxy, isobutoxy, sec- Examples include butoxy, tert-butoxy, pentyloxy, hexyloxy groups and the like.
  • methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy are mentioned.
  • Alkoxycarbonyl is a group in which alkoxy is bonded to carbonyl, and the “alkoxy” part has the same meaning as the above “alkoxy”.
  • Specific examples of “alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, propoxycarbo Onyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and the like can be mentioned, and methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl are preferred.
  • Examples of the “5- to 6-membered aromatic ring group optionally containing 1 to 3 heteroatoms selected from the group consisting of N, O and S” include phenyl, nitrogen, oxygen and sulfur It means 1 to 3 heteroatoms selected from the group consisting of atoms and monocyclic 5 to 6-membered aromatic heterocyclic groups consisting of carbon atoms.
  • Examples of the “5- to 6-membered aromatic ring group optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S” include phenyl, nitrogen, oxygen and sulfur Means 1 to 4 heteroatoms selected from the group consisting of atoms and monocyclic 5 to 6-membered aromatic heterocyclic groups consisting of carbon atoms, selected from the group consisting of “N, O and S”
  • phenyl, pyridyl, pyrazinyl, and triazolyl are examples of the “5- to 6-membered aromatic ring group optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S”.
  • the “5-membered aromatic ring group optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S” is selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms
  • imidazolyl, pyrazolyl, and triazolyl are included.
  • Examples of the “6-membered aromatic ring group which may contain 1 to 4 nitrogen atoms” include phenyl and monocyclic 6-membered aromatic heterocycles composed of 1 to 4 nitrogen atoms and carbon atoms. It means a cyclic group, and specific examples include phenyl, pyridyl, pyrimidinyl, triazinyl, tetrazinyl and the like. Preferably, phenyl and pyridyl are mentioned.
  • the “3- to 6-membered saturated aliphatic cyclic group optionally containing 1 to 2 heteroatoms selected from the group consisting of N, O and S” is a monocyclic ring having 3 to 6 carbon atoms.
  • the nitrogen atom, oxygen atom and sulfur atom are all atoms constituting a ring.
  • the “4- to 6-membered saturated aliphatic cyclic group containing 1 to 2 heteroatoms selected from the group consisting of N and O” include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolidinyl And oxazolidinyl. Preferred are azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and oxazolidinyl.
  • the “4- to 6-membered unsaturated aliphatic cyclic group which may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S” is a single atom having 4 to 6 carbon atoms.
  • the nitrogen atom, oxygen atom and sulfur atom are all atoms constituting a ring.
  • cyclobutenyl examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, dihydropyranyl, dihydrofuranyl, pyrrolinyl, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, dihydropyridinyl, tetrahydropyridinyl and the like.
  • the “4- to 6-membered unsaturated aliphatic cyclic group containing 1 to 2 heteroatoms selected from the group consisting of N and O” is the same or different 1 to 6 selected from nitrogen atoms and oxygen atoms Examples thereof include 4 to 6-membered monocyclic unsaturated heteroaliphatic cyclic groups having 2 atoms. Both the nitrogen atom and the oxygen atom are atoms constituting a ring. Specific examples include dihydropyranyl, dihydrofuranyl, pyrrolinyl, imidazolinyl, pyrazolinyl, oxazolinyl, dihydropyridinyl, tetrahydropyridinyl and the like. Preferably, dihydropyranyl and tetrahydropyridyl are mentioned.
  • the “4- to 6-membered saturated aliphatic cyclic group containing 1 or 2 N” includes a 4- to 6-membered saturated heteroaliphatic cyclic group having 1 or 2 nitrogen atoms.
  • the nitrogen atom is an atom constituting a ring.
  • Specific examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl and the like. Preferred are azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and imidazolidinyl.
  • a 4-6 membered saturated or unsaturated aliphatic ring group which together contains N bonded together and may further contain 1 to 2 heteroatoms selected from the group consisting of N, O and S
  • a 4- to 6-membered saturated or unsaturated heteroaliphatic cyclic group containing one nitrogen atom and further containing 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • Specific examples include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyridyl, dihydropyrrolyl and the like.
  • Preferred are azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and tetrahydropyridyl.
  • the “3- to 6-membered saturated aliphatic cyclic group optionally containing 1 to 2 heteroatoms selected from the group consisting of N and O” is monocyclic saturated having 3 to 6 carbon atoms. Examples thereof include a hydrocarbon aliphatic cyclic group and a 3- to 6-membered saturated heteroaliphatic cyclic group having 1 to 2 heteroatoms selected from a nitrogen atom and an oxygen atom.
  • cyclopropyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and the like.
  • Preferred are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.
  • Alkyl substituted with halogen atom means one or more (for example, 1 to 5, preferably 1 to 3) hydrogen atoms of the above alkyl substituted with halogen atoms.
  • Alkoxy substituted with a halogen atom means one or more (for example, 1 to 5, preferably 1 to 3) hydrogen atoms of the above alkoxy substituted with halogen atoms.
  • Preferred examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, and 1,1-difluoroethoxy.
  • Alkylthio substituted with a halogen atom means one or more (for example, 1 to 5, preferably 1 to 3) hydrogen atoms of the above alkylthio substituted with halogen atoms. Specific examples include trifluoromethylthio, 2,2,2-trifluoroethylthio, 2-fluoroethylthio, 3-fluoropropylthio, 3,3,3-trifluoropropylthio, and preferably Examples include trifluoromethylthio and 2,2,2-trifluoroethylthio.
  • Alkylcarbonyl substituted with a halogen atom means one in which one or more (for example, 1 to 5, preferably 1 to 3) hydrogen atoms of the above alkylcarbonyl are substituted with a halogen atom.
  • Specific examples include trifluoromethylcarbonyl, 2-fluoroethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, 3,3,3-trifluoropropylcarbonyl, etc., preferably trifluoromethylcarbonyl, Examples include 2-fluoroethylcarbonyl and 2,2,2-trifluoroethylcarbonyl.
  • Alkoxycarbonyl substituted with a halogen atom refers to a compound in which one or more (eg, 1 to 5, preferably 1 to 3) hydrogen atoms of the above alkoxycarbonyl are substituted with a halogen atom.
  • Specific examples include trifluoromethoxycarbonyl, 2-fluoroethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 3,3,3-trifluoropropoxycarbonyl, etc., preferably trifluoromethoxycarbonyl, Examples include 2-fluoroethoxycarbonyl and 2,2,2-trifluoroethoxycarbonyl.
  • Aromatic ring group substituted with halogen atom means the above aromatic ring group substituted with 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom or iodine atom Means.
  • the “saturated aliphatic cyclic group substituted with a halogen atom” is a monocyclic 3 substituted with 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • Means a 6-membered saturated aliphatic cyclic group include fluorocyclopropyl, difluorocyclopropyl, fluorocyclobutyl, difluorocyclobutyl, chlorocyclobutyl, dichlorocyclobutyl, fluorocyclopentyl, difluorocyclopentyl, chlorocyclopentyl, fluorocyclohexyl, difluorocyclohexyl and the like.
  • the “unsaturated aliphatic ring group substituted with a halogen atom” is a monocyclic group substituted with 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. It means a 4-6 membered unsaturated aliphatic cyclic group.
  • fluorocyclobutenyl difluorocyclobutenyl, chlorocyclobutenyl, dichlorocyclobutenyl, fluorocyclopentenyl, difluorocyclopentenyl, chlorocyclopentenyl, fluorocyclohexenyl, difluorocyclohexenyl and the like.
  • fluorocyclobutenyl, difluorocyclobutenyl, and difluorocyclopentenyl are used.
  • Alkyl substituted with a hydroxyl group means one or more (for example, 1 to 5, preferably 1 to 2) hydrogen atoms of the alkyl substituted with a hydroxyl group. Specifically, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxy Butyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, 2,4-dihydroxybutyl, 2-hydroxypentyl, 3-hydroxypentyl, 4-hydroxypentyl, 5-hydroxypentyl, 2,5-hydroxypentyl, 3,5-hydroxypentyl, 2-hydroxyhexyl, 3-hydroxyhexyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 6-hydroxyhexyl, 2,6-dihydroxyhexyl, 3,6-dihydroxyhexyl, 4,6- Dihydroxy hex 2-
  • Alkoxy substituted with a hydroxyl group means one or more (eg, 1 to 5, preferably 1 to 2) hydrogen atoms of the alkoxy substituted with a hydroxyl group.
  • Alkylthio substituted with a hydroxyl group means one or more (for example, 1 to 5, preferably 1 to 2) hydrogen atoms of the above alkylthio substituted with a hydroxyl group.
  • Specific examples include 2-hydroxyethylthio, 2-hydroxy-1-propylthio, 3-hydroxy-1-propylthio, 1-hydroxy-2-propylthio and the like, preferably 2-hydroxyethylthio, 3-hydroxy Examples include hydroxy-1-propylthio and 1-hydroxy-2-propylthio.
  • Alkylcarbonyl substituted with a hydroxyl group means one or more (eg, 1 to 5, preferably 1 to 2) hydrogen atoms of the above alkylcarbonyl substituted with a hydroxyl group. Specific examples include hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, hydroxyisopropylcarbonyl, hydroxybutylcarbonyl, and the like, and preferably hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, and hydroxybutylcarbonyl. It is done.
  • Alkoxycarbonyl substituted with a hydroxyl group means one or more (for example, 1 to 5, preferably 1 to 2) hydrogen atoms of the above alkoxycarbonyl substituted with a hydroxyl group. Specific examples include hydroxyethoxycarbonyl, hydroxypropoxycarbonyl, hydroxyisopropoxycarbonyl, hydroxybutoxycarbonyl, and the like, and preferably hydroxyethoxycarbonyl, hydroxypropoxycarbonyl, and hydroxyisopropoxycarbonyl. It is done.
  • “Aromatic ring group substituted with a hydroxyl group” refers to a group in which one or more (for example, 1 to 2) hydrogen atoms of the aromatic ring group are substituted with a hydroxyl group.
  • the “saturated aliphatic ring group substituted with a hydroxyl group” means a group in which one or more (for example, 1 to 2) hydrogen atoms of the saturated aliphatic ring group are substituted with a hydroxyl group.
  • Specific examples include hydroxycyclopropyl, hydroxycyclobutyl, hydroxycyclopentyl, hydroxycyclohexyl and the like.
  • hydroxycyclopropyl, hydroxycyclobutyl, and hydroxycyclopentyl are used.
  • the “unsaturated aliphatic ring group substituted with a hydroxyl group” means a group in which one or more (for example, 1 to 2) hydrogen atoms of the unsaturated aliphatic ring group are substituted with a hydroxyl group.
  • Specific examples include hydroxycyclobutenyl, hydroxycyclopentenyl, hydroxycyclohexenyl and the like.
  • Preferred examples include hydroxycyclopentenyl and hydroxycyclohexenyl.
  • aromatic ring group substituted with alkyl means one in which one or more (for example, 1 to 2) hydrogen atoms of the aromatic ring group are substituted with alkyl.
  • “Aromatic ring group substituted with cyano” means one or more (for example, 1 to 2) hydrogen atoms of the above aromatic ring group substituted with cyano.
  • Alkyl substituted with cyano refers to one or more (eg, 1 to 2) hydrogen atoms of the above alkyl substituted with cyano. Specific examples include cyanomethyl, cyanoethyl, cyanopropyl, cyanoisopropyl, cyanobutyl, cyanoisobutyl, cyanopentyl, cyanohexyl, cyanooctyl, cyanononyl, cyanodecyl and the like. More preferred are cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 1-cyano-2-propyl, and 4-cyanobutyl.
  • Alkoxy substituted with cyano refers to one or more (for example, 1 to 2) hydrogen atoms of the above alkoxy substituted with cyano.
  • Specific examples include cyanomethoxy, cyanoethoxy, cyanopropoxy, cyanoisopropoxy, cyanobutoxy, cyanopentyloxy, cyanohexyloxy, cyanooctyloxy, cyanononoxy, cyanodecyloxy and the like. More preferred are cyanomethoxy, 2-cyanoethoxy, 3-cyanopropoxy, 1-cyano-2-propoxy, and 4-cyanobutoxy.
  • Alkylcarbonyl substituted with cyano means one or more (for example, 1 to 2) hydrogen atoms of the above alkylcarbonyl substituted with cyano. Specific examples include cyanomethylcarbonyl, cyanoethylcarbonyl, cyanopropylcarbonyl, cyanoisopropylcarbonyl, cyanobutylcarbonyl, cyanopentylcarbonyl, cyanohexylcarbonyl, etc., preferably cyanomethylcarbonyl, cyanoethylcarbonyl, cyanopropylcarbonyl, Examples include cyanoisopropylcarbonyl and cyanobutylcarbonyl.
  • saturated aliphatic ring group substituted with cyano refers to a group in which one or more (eg, 1 to 2) hydrogen atoms of the saturated aliphatic ring group are substituted with cyano.
  • Specific examples include cyanocyclobutyl, cyanocyclopentyl, cyanocyclohexyl, cyanopyrrolidinyl, cyanopiperidinyl, cyanopiperazinyl, cyanomorpholinyl, cyanotetrahydrofuranyl and the like. More preferred are cyanocyclobutyl, cyanocyclopentyl, cyanocyclohexyl, cyanopyrrolidinyl, and cyanopiperidinyl.
  • “Unsaturated alicyclic group substituted with cyano” means one or more (for example, 1 to 2) hydrogen atoms of the above unsaturated alicyclic group substituted with cyano.
  • Specific examples include cyanocyclobutenyl, cyanocyclopentenyl, cyanocyclohexenyl, cyanodihydropyranyl, cyanodihydrofuranyl, cyanodihydropyridyl, cyanotetrahydropyridyl, and the like.
  • cyanocyclopentenyl, cyanocyclohexenyl, cyanodihydropyridyl, and cyanotetrahydropyridyl are mentioned.
  • Alkyl substituted with alkoxy means one or more (for example, 1 to 3) hydrogen atoms of the alkyl substituted with the alkoxy.
  • “Aromatic group substituted with alkoxy” means one or more (for example, 1 to 3) hydrogen atoms of the aromatic group substituted with the alkoxy.
  • Alkylcarbonyl substituted with alkoxy means one or more (for example, 1 to 3) hydrogen atoms of the above alkylcarbonyl substituted with the above alkoxy.
  • Specific examples include methoxymethylcarbonyl, ethoxymethylcarbonyl, methoxyethylcarbonyl, ethoxyethylcarbonyl, methoxypropylcarbonyl, methoxyisopropylcarbonyl and the like.
  • methoxymethylcarbonyl, ethoxymethylcarbonyl, methoxyethylcarbonyl, and ethoxyethylcarbonyl are mentioned.
  • the “saturated aliphatic ring group substituted with alkoxy” refers to a group in which one or more (for example, 1 to 3) hydrogen atoms of the saturated aliphatic ring group are substituted with the alkoxy.
  • Specific examples include methoxycyclopropyl, ethoxycyclopropyl, methoxycyclobutyl, ethoxycyclobutyl, methoxycyclopentyl, methoxycyclohexyl, methoxytetrahydropyranyl, methoxypyrrolidinyl, methoxypiperidinyl, methoxytetrahydrofuranyl and the like.
  • methoxycyclopropyl ethoxycyclopropyl
  • methoxycyclobutyl methoxycyclobutyl
  • methoxycyclopentyl methoxycyclohexyl
  • the “unsaturated aliphatic ring group substituted with alkoxy” refers to a group in which one or more (eg, 1 to 3) hydrogen atoms of the unsaturated aliphatic ring group are substituted with the alkoxy.
  • Specific examples include methoxycyclobutenyl, methoxycyclopentenyl, methoxycyclohexenyl, ethoxycyclobutenyl, ethoxycyclopentenyl, ethoxycyclohexenyl, methoxydihydropyranyl, methoxydihydrofuranyl, methoxytetrahydropyridinyl and the like.
  • Alkyl substituted with an optionally substituted aromatic ring group means that one or more hydrogen atoms of the above alkyl are substituted with an “optionally substituted aromatic ring group”. Say. Specifically, it is an alkyl in which any hydrogen atom of an alkyl having 1 to 6 carbon atoms is substituted with an aromatic ring group such as phenyl, pyridyl, oxazolyl, thiazolyl, pyrazolyl and the like which may be substituted. Specific examples of the substituent of the aromatic ring group that may be used include methoxy, methanesulfonyl, dimethylamino, cyano and the like.
  • alkoxy substituted with an optionally substituted aromatic ring group is a group in which the above “alkyl substituted with an optionally substituted aromatic ring group” is bonded to an oxygen atom.
  • alkylthio substituted by an optionally substituted aromatic ring group is a group in which the above “alkyl substituted by an optionally substituted aromatic ring group” is bonded to a sulfur atom.
  • saturated aliphatic ring group substituted with oxo examples include those in which the hydrogen atom of the saturated aliphatic ring group is substituted with 1 to 2 oxo groups, such as 2-oxocyclopentyl, 3-oxocyclopentyl, 2-oxocyclohexyl, 3-oxocyclohexyl, 4-oxocyclohexyl, 2-oxopyrrolidinyl, 3-oxopyrrolidinyl, 2,5-dioxopyrrolidinyl, 2-oxopiperidinyl, 3-oxopi Peridinyl, 4-oxopiperidinyl, 2,6-dioxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, 2-oxomorpholinyl, 2-oxothiomorpholinyl, oxoimidazo Lysinyl, dioxoimidazolidinyl, oxooxazolid
  • the unsaturated aliphatic ring group substituted with oxo refers to one in which the hydrogen atom of the unsaturated aliphatic ring group is substituted with 1 to 2 oxo groups, for example, oxocyclopentenyl, oxocyclohexenyl, Examples include oxopyrrolinyl, oxoimidazolinyl, oxooxazolinyl, oxothiazolinyl, oxodihydropyridinyl, oxotetrahydropyridinyl and the like. Preferred examples include oxopyrrolinyl, oxoimidazolinyl, oxodihydropyridinyl, and oxotetrahydropyridinyl.
  • an aliphatic cyclic group means an alicyclic group.
  • (aromatic) heterocyclic group and “(aromatic) heterocyclic group” are synonymous.
  • R a represents a hydrogen atom or C 1-6 alkyl optionally substituted with a hydroxyl group or a halogen atom, Preferably, it represents a hydrogen atom or a C 1-3 alkyl optionally substituted with a hydroxyl group or a fluorine atom, More preferably, it represents a hydrogen atom, methyl, ethyl, trifluoromethyl, difluoromethyl, hydroxymethyl, or hydroxyethyl.
  • R b is a hydrogen atom, a hydroxyl group or a C 1-6 alkyl optionally substituted with a halogen atom, a benzyl optionally substituted with methoxy or nitro, or a C 3 ⁇ optionally substituted with a hydroxyl group or a halogen atom.
  • R c and R d each independently represent a hydrogen atom, or C 1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom, or together contain N bonded thereto; 4 to 6-membered saturated or unsaturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of O, S, and the aliphatic ring group at a substitutable position , C 1-6 alkyl, hydroxyl group, halogen atom or oxo may be substituted)
  • R c and R d each independently represent a hydrogen atom, C 1-3 alkyl optionally substituted with a hydroxyl group or a fluorine atom, or together, N and O
  • C 1-6 alkyl the alkyl may be substituted with a hydroxyl group, cyano, a fluoride
  • R f represents a hydrogen atom, a hydroxyl group, C 1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano, a halogen atom, C 1-3 alkoxy or —NR c R d ), C 1-3 Alkoxy (the alkoxy may be substituted with phenyl, hydroxyl group, cyano, halogen atom, C 1-3 alkoxy or —NR c R d optionally substituted with methoxy or nitro), —A or —NR a Ri represents Preferably, it represents a hydrogen atom, a hydroxyl group, C 1-3 alkyl, C 1-3 alkoxy, —A or —NR a R i .
  • R g is a hydroxyl group, C 1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano, a halogen atom, C 1-3 alkoxy or —NR c R d ), —A or —NR a R i
  • it represents C 1-6 alkyl (which may be substituted with a hydroxyl group, cyano or fluorine atom), —A or —NR a R i
  • R h represents C 1-6 alkyl which may be substituted with a hydroxyl group or a halogen atom, and preferably represents methyl, ethyl, or trifluoromethyl.
  • R i represents a hydrogen atom, C 1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano, a halogen atom, C 1-3 alkoxy, C 3-6 cycloalkyl or —NR c R d ) , —A, —C ( ⁇ O) R b , —C ( ⁇ O) A ′, or C 1-6 alkylcarbonyl (the alkyl part of the group is a hydroxyl group, a halogen atom, cyano, C 1-3 alkoxy, or -NR c R d may be substituted by) it represents, Preferably, a hydrogen atom, C 1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano, fluorine atom, C 1-3 alkoxy, C 3-6 cycloalkyl, or —NR c R d ) Or -A '.
  • A is a 5- to 6-membered aromatic ring group that may contain 1 to 4 heteroatoms selected from the group consisting of N, O, and S (the aromatic ring group is located at a substitutable position).
  • C 1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom
  • C 1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, —C ( ⁇ O) OH
  • optionally substituted with —NR c R d or may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S 3-6 membered saturated or 4-6
  • a membered unsaturated aliphatic ring group (the aliphatic ring group is substituted with a C 1-3 alkyl, hydroxyl group or halogen atom which may be substituted with a hydroxyl group or a halogen atom at a substitutable position).
  • an optionally substituted aromatic ring group selected from the group consisting of phenyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl, or Represents an optionally substituted saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrrol
  • a ′ is a 5- to 6-membered aromatic ring group that may contain 1 to 4 heteroatoms selected from the group consisting of N, O, and S (the aromatic ring group is a substitutable position).
  • a C 1-3 alkyl which may be substituted with a hydroxyl group or a halogen atom, a C 1-3 alkoxy which may be substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, —C ( ⁇ O)
  • an optionally substituted aromatic ring group selected from the group consisting of phenyl, imidazolyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl and isothiazolyl, or optionally substituted cyclopropyl, cyclobutyl,
  • R 0 is —C ( ⁇ O) NR a —, —S ( ⁇ O) 2 NR a —, —C ( ⁇ O) O—, —C ( ⁇ O) —, —S ( ⁇ O) 2 —.
  • R 0 represents —C ( ⁇ O) NR a —, —S ( ⁇ O) 2 NR a —, —C ( ⁇ O) O— or a single bond, More preferably, it represents —C ( ⁇ O) NR a —, —S ( ⁇ O) 2 NR a — or a single bond, Even more preferably, it represents —C ( ⁇ O) NH— or a single bond.
  • R 1 is preferably C 1-10 alkyl or 3-6 membered saturated or 4-6 membered optionally containing 1-2 heteroatoms selected from the group consisting of N, O and S An unsaturated aliphatic cyclic group,
  • the alkyl may be substituted at a substitutable position with one or three or more substituents selected from the group consisting of (1) to (13) in the substituent list 1.
  • the saturated or unsaturated aliphatic cyclic group is selected from the group consisting of (1) to (20) in the substituent list 2 at a substitutable position, and a plurality of 1 or 3 or less May be substituted with a substituent of R 1 is more preferably C 1-10 alkyl or a 3- to 6-membered saturated aliphatic cyclic group which may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S
  • the alkyl is one or a plurality of substituents of 1 or 3 or less selected from the group consisting of (1) to (4) and (6) to (10) in substituent list 1 at substitutable positions.
  • the saturated aliphatic cyclic group is 1 or 3 or less selected from the group consisting of (1) to (4) and (7) to (10) in the substituent list 2 at substitutable positions. It may be substituted with a plurality of substituents.
  • R 2 is a hydrogen atom, a halogen atom, cyano or C 1-3 alkyl (the alkyl is substituted with a hydroxyl group, a halogen atom, —NR c R d , —OR a , or —OC ( ⁇ O) R a. May be) And preferably a hydrogen atom or C 1-3 alkyl (the alkyl may be substituted with a hydroxyl group, a halogen atom, —NR c R d , —OR a , or —OC ( ⁇ O) R a ) Represents More preferably, it represents a hydrogen atom, methyl or hydroxymethyl.
  • R 3 and R 4 each independently represents a hydrogen atom or C 1-3 alkyl (the alkyl may be substituted with a hydroxyl group or a halogen atom); Preferably, each independently represents a hydrogen atom or unsubstituted C 1-3 alkyl, More preferably, each independently represents a hydrogen atom or methyl.
  • M represents an integer of 1 or 2, preferably 2.
  • N represents an integer of 0 to 2, preferably 2.
  • L is —S ( ⁇ O) q — (q represents an integer of 0 to 2, preferably 1 or 2), a 6-membered aromatic ring optionally containing 1 to 4 nitrogen atoms
  • a group (the group is selected from the group consisting of a halogen atom, a hydroxyl group, —NR c R d , —C ( ⁇ O) NR c R d, and —C ( ⁇ O) OR a at a substitutable position; C 1-6 alkyl or C 2-6 alkene optionally substituted with one or more substituents, halogen, —C ( ⁇ O) NR c R d , —C ( ⁇ O) OR a , hydroxyl group, —NR c R d , optionally substituted with one or more substituents selected from the group consisting of nitro and —NR a C ( ⁇ O) R b ), the following formula Pyr-1, the following formula Tri-1 or The following formula Imi-1: (In each group
  • L is preferably a benzene ring group, a pyridine ring group, or a formula Pyr-1, a formula Tri-1, or a formula Imi-1. More preferably, L is a benzene ring group, a pyridine ring group, the formula Pyr-1, or the formula Tri-1.
  • Ar 1 is a 5- to 6-membered aromatic ring group that may contain 1 to 3 heteroatoms selected from the group consisting of N, O, and S (the aromatic ring group is a substitutable position).
  • C 1-6 alkyl optionally substituted with a hydroxyl group or a halogen atom
  • C 1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro, phenyl, —NR a C ( ⁇ O) R h , —NR a S ( ⁇ O) m R h , —NR a C ( ⁇ O) NR c R d , —C ( ⁇ O) NR c R d , —C ( ⁇ O ) OR a , —C ( ⁇ O) R a , —S ( ⁇ O) m NR c R d , —S ( ⁇ O) n R h
  • a benzene ring or pyridine ring represented by the following formula Ar 1 -1: (In the group, K 1 , K 2 , K 3 and K 4 all represent a carbon atom in the case of a benzene ring, only one nitrogen atom in the case of a pyridine ring, the other represents a carbon atom, and X represents a hydroxyl group.
  • X represents C 1-3 alkyl optionally substituted with 1 to 3 fluorine atoms, chlorine atom, cyano or nitro).
  • Ar 2 is a 5- to 6-membered aromatic ring group which may contain 1 to 3 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a substitutable position)
  • C 1-6 alkyl optionally substituted with a hydroxyl group, cyano, or a halogen atom
  • (Y represents a cyano group, a chloro atom, or a nitro group).
  • R a1 to R a31 each independently represent a hydrogen atom, or C 1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom;
  • R a1 to R a17 and R a25 to R a29 each independently represent a hydrogen atom or methyl
  • R a18 to R a24 and R a30 to R a31 each independently represent a hydrogen atom, a hydroxyl group
  • R a21 to R a23 and R a30 to R a31 each independently represent a hydrogen atom or methyl.
  • R b1, R b4, R b8 , R b9, R b12, R b16, R b19, R b23, R b26, R b30 and R b34 each independently represent a hydrogen atom, substituted by a hydroxyl group or halogen atom Represents optionally substituted C 1-6 alkyl, or benzyl optionally substituted by methoxy or nitro,
  • R b1, R b4, R b8, R b9, R b12, R b16, R b19, R b23, R b26, R b30 and R b34 are each independently, C 1 hydrogen atom or an unsubstituted Represents -6 alkyl.
  • R b2, R b3, R b5 , R b6, R b7, R b10, R b11, R b13, R b14, R b15, R b17, R b18, R b20, R b21, R b22, R b24, R b25 , R b27 , R b28 , R b29 , R b31 , R b32 , R b33 , R b35 , R b36 , R b37 and R b38 are each independently C 1 which may be substituted with a hydroxyl group or a halogen atom.
  • R b2, R b3, R b5, R b6, R b7, R b10, R b11, R b13, R b14, R b15, R b17, R b18, R b20, R b21, R b22, R b24 , R b25, R b27, R b28, R b29, R b31, R b32, R b33, R b35, R b36, R b37 and R b38 are each independently be substituted with a hydroxyl group or a fluorine atom Good C 1-6 alkyl, or C 3-6 cycloalkyl optionally substituted with a hydroxyl group or a fluorine atom,
  • R c5, R c13, R c16 , R c20, R c23, R c27, R c30, R c34, R c37, R c40, R c41, R c42, R c43, R d5, R d13, R d16, R d20 , R d23, R d27, R d30, R d34, R d37, R d40, R d41, R d42 and R d43 are each independently hydrogen atom or a hydroxyl group or a halogen atom which may be substituted in C, and 4-6 membered saturated or substituted with 1 to 2 heteroatoms, selected from the group consisting of N and O, together with substituents attached to the same nitrogen atom, representing 1-3 alkyl Represents an unsaturated heteroaliphatic ring group (which may be substituted with a hydroxyl group, a halogen atom or oxo at a substitutable position);
  • R c35 , R c36 , R d35 and R d36 each independently represent a hydrogen atom, C 1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom, or a substituent bonded to the same nitrogen atom Together, the 4- or 6-membered saturated heteroaliphatic ring group containing one or two nitrogen atoms (the aliphatic ring group is substituted with a hydroxyl group or a halogen atom at substitutable positions).
  • R c35 , R c36 , R d35 and R d36 each independently represent a hydrogen atom or a C 1-3 alkyl optionally substituted with a hydroxyl group or a fluorine atom, More preferably, R c35 , R c36 , R d35 and R d36 each independently represent a hydrogen atom, methyl or ethyl.
  • R e is a hydrogen atom, C 1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano, a halogen atom, C 1-3 alkoxy, or —NR c37 R d37 ), —A, —C ( ⁇ O) —A ′, C 1-6 alkylcarbonyl (the alkyl part of the alkylcarbonyl may be substituted with a hydroxyl group or a halogen atom), C 1-6 alkoxycarbonyl (the alkyl part of the alkoxycarbonyl is a hydroxyl group) Or optionally substituted with a halogen atom), —C ( ⁇ O) NR c38 R d38 or —S ( ⁇ O) m R b37 , Preferably, C 1-6 alkyl (which may be substituted with a hydroxyl group, cyano, a fluorine atom, C 1-3 alkoxy, or —NR c37 R
  • R e ′ represents —A ′′ or —C ( ⁇ O) NR c39 R d39 , and preferably represents —A ′′.
  • R f is a hydrogen atom, a hydroxyl group, C 1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano or a halogen atom), C 1-3 alkoxy (the alkoxy is substituted with methoxy or nitro)
  • R g represents a hydroxyl group, C 1-6 alkyl (which may be substituted with a hydroxyl group, cyano or a halogen atom), —D or —NR a31 R i ′ ; Preferably, it represents a hydroxyl group, C 1-6 alkyl (which may be substituted with a hydroxyl group, cyano or a fluorine atom), —D or —NR a31 R i ′ ; More preferably, it represents C 1-6 alkyl (which may be substituted with a hydroxyl group, cyano or a fluorine atom), —D or —NR a31 R i ′ .
  • R h represents C 1-6 alkyl which may be substituted with a hydroxyl group or a halogen atom, and preferably represents methyl.
  • hydrogen atom, C 1-6 alkyl (said alkyl, hydroxyl, cyano, fluorine atom, C 1-3 alkoxy, optionally substituted C 3-6 cycloalkyl, or with -NR c40 R d40) Or represents -B '.
  • R i ′ is a hydrogen atom, C 1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano, a halogen atom, C 1-3 alkoxy, C 3-6 cycloalkyl, or —NR c41 R d41. ) Or -D '
  • a hydrogen atom, C 1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano, a fluorine atom, C 1-3 alkoxy, C 3-6 cycloalkyl, or —NR c41 R d41 )
  • A is a 5- to 6-membered aromatic ring group that may contain 1 to 4 heteroatoms selected from the group consisting of N, O, and S (the aromatic ring group is located at a substitutable position).
  • C 1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom, C 1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, —C ( ⁇ O) OH Or optionally substituted with —NR c42 R d42 ) or may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S 3-6 membered saturated or unsaturated aliphatic Hajime Tamaki (the aliphatic ring group may be at substitutable position, a hydroxyl group or a halogen atom which may be substituted C 1-3 alkyl, optionally substituted by a hydroxyl group or halogen atom C 1- 3 al
  • a ′ is a 5- to 6-membered aromatic ring group that may contain 1 to 4 heteroatoms selected from the group consisting of N, O, and S (the aromatic ring group is a substitutable position).
  • a C 1-3 alkyl which may be substituted with a hydroxyl group or a halogen atom, a C 1-3 alkoxy which may be substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, —C ( ⁇ O)
  • a ′′ is the same as the definition of A, preferably the same as the preferable definition of A, and more preferably the same as the more preferable definition of A.
  • B is a 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is at a substitutable position).
  • C 1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom, C 1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, —C ( ⁇ O) OH Or optionally substituted with —NR c42 R d42 ) or may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S 3-6 membered saturated or unsaturated aliphatic Hajime Tamaki (the aliphatic ring group may be at substitutable position, a hydroxyl group or a halogen atom which may be substituted C 1-3 alkyl, optionally substituted by a hydroxyl group or halogen atom C 1- 3 alkoxy
  • B ′ is a 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a substitutable position).
  • a C 1-3 alkyl which may be substituted with a hydroxyl group or a halogen atom, a C 1-3 alkoxy which may be substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, —C ( ⁇ O)
  • D ′ is the same as the definition of B ′, preferably the same as the preferable definition of B ′; More preferably, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, aromatic Hajime Tamaki selected from the group consisting of thiazolyl and isothiazolyl (hetero groups to the aromatic is hydroxyl or fluorine may be substituted with atoms C 1 -3 alkyl, hydroxyl group or C 1-3 alkoxy optionally substituted with a hydroxyl atom or fluorine atom, optionally substituted with hydroxyl group, fluorine atom, cyano, —C ( ⁇ O) OH or —NR c42 R d42 ) or Saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and pyranyl (the aliphatic ring group is a C 1-3 al
  • R 0 is —C ( ⁇ O) NR a1 —, —S ( ⁇ O) 2 NR a2 —, —C ( ⁇ O) O—, —C ( ⁇ O) —, —S ( ⁇ O 2 ) represents a single bond or More preferably, —C ( ⁇ O) NR a1 —, —S ( ⁇ O) 2 NR a2 —, —C ( ⁇ O) O—, —C ( ⁇ O) — or —S ( ⁇ O) 2 — Represents Even more preferably, —C ( ⁇ O) NH— or —
  • R 1 is preferably a hydrogen atom, C 1-10 alkyl or 3-6 membered saturated or unsaturated which may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S
  • the alkyl may be substituted with one or three or more substituents selected from the group consisting of the above (1) to (13),
  • the saturated or unsaturated aliphatic ring group is a hydroxyl group, a halogen atom, cyano, nitro, C 1-6 alkyl at a substitutable position (the alkyl is a hydroxyl group, a halogen atom at a substitutable position).
  • R 2 represents C 1-3 alkyl (the alkyl may be substituted with a hydroxyl group or a halogen atom), and preferably represents methyl.
  • R 3 and R 4 each independently represents a hydrogen atom or C 1-3 alkyl (the alkyl may be substituted with a hydroxyl group or a halogen atom); Preferably, each independently represents a hydrogen atom or unsubstituted C 1-3 alkyl, More preferably, each independently represents a hydrogen atom or methyl.
  • M represents an integer of 1 or 2, preferably 2.
  • N represents an integer of 0 to 2, preferably 2.
  • L is a 5- to 6-membered unsubstituted aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S, or —S ( ⁇ O) q — ( q represents an integer of 0 to 2, and
  • L represents a 5- to 6-membered unsubstituted aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S;
  • a preferable bonding position of the aromatic ring is the following formula (I ′) ′:
  • L is preferably a benzene ring group, a thiophene ring group, a furan ring group, a pyrrole ring group, an imidazole ring group, a pyridine ring group, a pyrazine ring group, an isoxazole ring group, a pyrazole ring group, an isothiazole ring group, or a pyrimidine ring group.
  • Ar 1 is a 5- to 6-membered aromatic ring group that may contain 1 to 3 heteroatoms selected from the group consisting of N, O, and S (the aromatic ring group is a substitutable position).
  • C 1-6 alkyl optionally substituted with a hydroxyl group or a halogen atom
  • C 1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro or —NR c35 R d35 or more are substituted
  • E 1 , E 2 , E 3 and E 4 each independently represent a carbon atom or a nitrogen atom (provided that E 1 , E 2 , E 3 and E 4 all represent a nitrogen atom at the same time).
  • G 1 , G 2 and G 3 each independently represent a carbon atom or a heteroatom selected from the group consisting of N, O and S, and X is substituted with a hydroxyl group or a halogen atom C 1-6 alkyl which may be substituted, C 1-3 alkoxy which may be substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro or —NR c35 R d35 , E 1 , E 2 , E 3 , E 4 , G 1 , G 2 or G 3 may be further substituted with a C 1-6 alkyl, hydroxyl group or halogen atom which may be further substituted with a hydroxyl group or
  • E 1 , E 2 and E 3 each independently represents a carbon atom or a nitrogen atom, and X represents a C 1-3 alkyl which may be substituted with a hydroxyl group or a fluorine atom, a hydroxyl group or a fluorine atom.
  • X represents C 1-3 alkyl optionally substituted with 1 to 3 fluorine atoms, chlorine atom, cyano or nitro).
  • Ar 2 is a 5- to 6-membered aromatic ring group which may contain 1 to 3 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a substitutable position)
  • the aromatic ring group is a substitutable position
  • C 1-6 alkyl optionally substituted with a hydroxyl group, cyano, or a halogen atom
  • C 1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro,- S ( ⁇ O) n R h or —NR c36 R d36 or more
  • Ar 2 -1 ′ or Ar 2 -2 ′ shown below:
  • K 1 , K 2 , K 3 and K 4 each independently represent a carbon atom or a nitrogen atom (provided that K 1 , K 2 , K 3 and K 4 all simultaneously represent a nitrogen atom)
  • L 1 , L 2 and L 3 each independently represents a carbon atom or a heteroatom selected from the group consisting of N, O and S
  • K 1 , K 2 , K 3, and K 4 each independently represent a carbon atom or a nitrogen atom (except when K 1 , K 2 , K 3, and K 4 all represent a nitrogen atom at the same time)
  • Y represents a halogen atom, cyano or nitro
  • C 1 , K 2 , K 3 or K 4 may be substituted with a hydroxyl group or a fluorine atom or a C 1-3 alkyl, hydroxyl group Or a substituent selected from C 1-3 alkoxy optionally substituted with a fluorine atom, a hydroxyl group, a halogen atom, cyano and —NR c36 R d36 ),
  • Ar 2 -1 ′ ′′ the following Ar 2 -1 ′ ′′:
  • the compound of the present invention represented by the formulas (I) and (I) ′ can be produced by the following production methods A to P.
  • the compounds represented by the formula (I) and the formula (I) ′ or physiologically acceptable salts thereof are novel compounds, for example, according to the production methods described below, examples described later or known methods. It can be manufactured by a method.
  • Ar 1 , Ar 2 , L, R 0 , R 1 , R 2 are the same as defined in item 1, and R 3a , R 4a both represent a hydrogen atom or are Represents a carbon atom that becomes methylene.
  • Step 1 When R 3a and R 4a of Compound 1 both represent a hydrogen atom, Compound 3 can be produced by subjecting Compound 1 and Compound 2 to an addition reaction according to a conventional method. For example, in this reaction, compound 1 and compound 2 are converted into aldehyde reagents such as formaldehyde and paraformaldehyde, Lewis acids such as titanium tetrachloride and boron trifluoride / diethyl ether complex, copper chloride in a suitable solvent or without solvent.
  • aldehyde reagents such as formaldehyde and paraformaldehyde
  • Lewis acids such as titanium tetrachloride and boron trifluoride / diethyl ether complex
  • copper chloride in a suitable solvent or without solvent.
  • this reaction is carried out in an acid reagent solvent such as hydrochloric acid or acetic acid, or under a condition where an appropriate amount of an acid reagent such as hydrochloric acid or acetic acid is added.
  • an acid reagent solvent such as hydrochloric acid or acetic acid
  • Compound 3 can be produced by subjecting Compound 1 and Compound 2 to an addition reaction according to a conventional method.
  • this reaction can be achieved by reacting compound 1 and compound 2 in the presence of a Lewis acid such as boron trifluoride / diethyl ether complex, or a copper reagent such as copper chloride in an appropriate solvent or without solvent. Is done.
  • this reaction is performed in an acid reagent such as hydrochloric acid or acetic acid, or in the presence of the above reagent and an acid reagent such as hydrochloric acid or acetic acid.
  • Step 2 Compound 4 can be produced by subjecting compound 3 to a cyclization reaction according to a conventional method.
  • this reaction can be achieved by reacting compound 3 in the presence of an acid reagent such as acetic acid or paratoluenesulfonic acid in a suitable solvent or without solvent.
  • an acid reagent such as acetic acid or paratoluenesulfonic acid
  • Step 3 When R 3a and R 4a of Compound 1 both represent a hydrogen atom, Compound 4 can be produced by subjecting Compound 1 and Compound 2 to a cyclization reaction according to a conventional method.
  • compound 1 and compound 2 are converted into aldehyde reagents such as formaldehyde and paraformaldehyde, Lewis acids such as titanium tetrachloride and boron trifluoride / diethyl ether complex, copper chloride in a suitable solvent or without solvent.
  • aldehyde reagents such as formaldehyde and paraformaldehyde
  • Lewis acids such as titanium tetrachloride and boron trifluoride / diethyl ether complex
  • copper chloride in a suitable solvent or without solvent.
  • this reaction is performed in an acid reagent such as hydrochloric acid or acetic acid, or in the presence of the above reagent and an acid reagent such as hydrochloric acid or acetic acid.
  • Compound 4 can be produced by subjecting Compound 1 and Compound 2 to a cyclization reaction according to a conventional method. It can.
  • this reaction can be achieved by reacting compound 1 and compound 2 in the presence of a Lewis acid such as boron trifluoride / diethyl ether complex, or a copper reagent such as copper chloride in an appropriate solvent or without solvent. Is done.
  • this reaction is performed in an acid reagent such as hydrochloric acid or acetic acid, or in the presence of the above reagent and an acid reagent such as hydrochloric acid or acetic acid. (See Examples 1, 2, 3, 109-120)
  • the solvent in each reaction of the production method A should be selected according to the kind of the raw material compound, etc., but for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, acetonitrile, toluene, Examples thereof include alcohols such as ethyl acetate, acetic acid or methanol, ethanol, and isopropanol, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • L represents a 5- to 6-membered aromatic ring group (L a ) optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S; 3 and R 4 both represent a hydrogen atom [compound of the following formula 7] is also produced by the following production method.
  • L represents a group described in item 1 (excluding —S ( ⁇ O) q —), it is also produced by the following production method.
  • Ar 1, Ar 2, R 0, R 1, R 2 are the same as defined in claim 1, 1 to 4 heteroatoms which L a is selected from the group consisting of N, O and S Represents a 5- to 6-membered aromatic ring group which may contain an atom, R 3a and R 4a are the same as defined above, W 1 represents a hydrogen atom, an amino group or a halogen atom, and Z 1 represents A substituent on Ar 2 , which represents a metal substituent such as boronic acid, boronic acid ester, organotin, zinc halide, magnesium halide, organosilicon, lithium, etc., Z 2 is on a carbon atom in the ring of Ar 2 And represents a halogen atom.
  • Step 1 Compound 6 can be produced by subjecting Compound 5 and Compound 2 to a cyclization reaction according to the same method as Production Method A. (See Reference Example 17)
  • Step 2 Production method B-1: When W 1 in compound 6 represents a halogen atom, compound 7 is produced by performing a coupling reaction between compound 6 and Z 1 -Ar 2 (Z 1 is as defined above) according to a conventional method. Can do. For example, in this reaction, in an appropriate solvent or in the absence of a solvent, compound 6 and Z 1 -Ar 2 are converted into a palladium catalyst typified by tetrakistriphenylphosphine palladium, a copper catalyst typified by copper iodide, nickel chloride.
  • a nickel catalyst typified by a 1,2-bis (diphenylphosphino) ethane complex
  • a zinc reagent and an iron chelating reagent in some cases, 2,2′-bis (diphenylphosphino) -1,1
  • 2,2′-bis (diphenylphosphino) -1,1 This is achieved by adding a phosphorus ligand typified by -binaphthalene, 2- (di-t-butyl) phosphinobiphenyl and the like, and carrying out a cross-coupling reaction.
  • alkali metal carbonates eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • alkali metal phosphates eg, potassium phosphate
  • organic bases triethylamine, diisopropylethylamine, etc.
  • alkali metal halides lithium chloride, cesium fluoride, etc.
  • alkali metal hydroxides sodium hydroxide, etc.
  • metal alkoxides t-butoxypotassium, etc.
  • Production method B-2 Further, W 1 in the compound 6, if a hydrogen atom, compound 7, the L a group of the compound 6 After halogenation can be produced by performing a coupling reaction with Z 1 -Ar 2 .
  • this halogenation reaction can be achieved by reacting compound 6 with a halogenating agent such as N-iodosuccinimide, N-bromosuccinimide, iodine, bromine or the like in a suitable solvent or without a solvent. Is achieved according to the same method as in production method B-1.
  • Production method B-3 When W 1 in Compound 6 represents a halogen atom, Compound 7 converts W 1 of Compound 6 into a coupling reagent such as a boride, zinc halide, magnesium halide, and the like.
  • 2- Ar 2 (Z 2 is as defined above) can be produced by performing a coupling reaction according to a conventional method. For example, this reaction is prepared by reacting compound 6 with a boron reagent typified by bis (pinacolato) diboron reagent and a palladium catalyst typified by tetrakistriphenylphosphine palladium in a suitable solvent or without solvent.
  • a coupling reagent such as a boron halide, a zinc halide prepared by reacting compound 3 with zinc powder, or a magnesium halide prepared by reacting compound 6 with magnesium powder, and Z 2 -Ar 2 , a palladium catalyst typified by tetrakistriphenylphosphine palladium, a copper catalyst typified by copper iodide, a nickel catalyst typified by nickel chloride-1,2-bis (diphenylphosphino) ethane complex, a zinc reagent, In some cases, 2,2′-bis (diphenyl The phosphorous ligand represented by ruphosphino) -1,1-binaphthalene, 2- (di-t-butyl) phosphinobiphenyl, or a ligand compound such as organic arsenic is added to carry out a cross-coupling reaction.
  • a palladium catalyst typified by tetrakistriphenylphosphin
  • alkali metal carbonates eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • alkali metal phosphates eg, potassium phosphate
  • organic bases triethylamine, diisopropylethylamine, etc.
  • alkali metal halides lithium chloride, cesium fluoride, etc.
  • alkali metal hydroxides sodium hydroxide, etc.
  • metal alkoxides t-butoxypotassium, etc.
  • Production method B-4 When W 1 of Compound 6 represents an amino group, Compound 7 converts W 1 to a halogen atom such as bromine or iodine by a Sandmeyer reaction according to a conventional method, and then converts this to Z 1 -Ar 2 . It can also be produced by a coupling reaction according to the same method as Production Method B-1. For example, in the Sandmeyer reaction, compound 6 is reacted with nitrite typified by sodium nitrite and copper halide typified by copper bromide or copper iodide in an appropriate solvent or without solvent. To be achieved.
  • a halogen atom such as bromine or iodine
  • Production method B-5 Also, if the L a Compound 6 has an NH group in the ring, i.e., if they contain NH groups in group constituting L a, compound 7, compound 6 and Z 2 -Ar 2 (Z 2 is the The same as the definition) or Z 3 -Ar 2 (Z 3 is a substituent on a carbon atom in the ring of Ar 2 and represents boronic acid or boronic acid ester), or a substitution reaction or coupling according to a conventional method It can manufacture by performing reaction.
  • an alkali metal carbonate e.g., sodium carbonate, potassium carbonate, etc. cesium carbonate
  • phosphoric acid React in the presence of alkali metal potassium carbonate etc.
  • organic base triethylamine, diisopropylethylamine etc.
  • alkali metal halide lithium chloride, cesium fluoride etc.
  • alkali hydroxide metal sodium hydroxide etc.
  • the ring L a and Z 3 -Ar 2 having an NH group in the ring a palladium catalyst represented by tetrakistriphenylphosphine palladium or palladium acetate, copper catalysts typified by copper iodide, or zinc reagent and iron
  • a chelating reagent in some cases, a phosphorus catalyst typified by 2,2′-bis (diphenylphosphino) -1,1-binaphthalene, 2- (di-t-butyl) phosphinobiphenyl, It can also be achieved by adding a diamine reagent typified by 2-diaminocyclohexane or the like and carrying out a cross-coupling reaction.
  • alkali metal carbonates eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • alkali metal phosphates eg, potassium phosphate
  • organic bases triethylamine, diisopropylethylamine, etc.
  • Alkali metal halides such as lithium chloride and cesium fluoride
  • alkali metal hydroxides such as sodium hydroxide
  • metal alkoxides such as potassium t-butoxy
  • Z 1 -Ar 2 represents, according to a conventional method, Z 4 -Ar 2 (Z 4 is a substituent on a carbon atom in the ring of Ar 2 and represents a halogen atom or a hydrogen atom) as various metal atoms. It can be manufactured by substitution.
  • a boron reagent such as bis (pinacolato) diboron reagent and a palladium catalyst typified by tetrakistriphenylphosphine palladium in a suitable solvent or in the absence of a solvent
  • a boron reagent can be produced by reacting a trialkoxy borane reagent such as a trimethyl borate reagent.
  • An organotin reagent can be produced by reacting Z 4 -Ar 2 with an alkyllithium reagent such as butyllithium in an appropriate solvent or in the absence of a solvent, and then reacting an alkyltin reagent such as tributyltin chloride. .
  • a zinc halide reagent can be produced by reacting Z 4 —Ar 2 with zinc powder in a suitable solvent or without a solvent.
  • a magnesium halide reagent can be produced by reacting Z 4 —Ar 2 with magnesium powder in a suitable solvent or without a solvent.
  • An organosilicon reagent is produced by reacting Z 4 -Ar 2 with an alkyllithium reagent such as butyllithium in an appropriate solvent or in the absence of a solvent and then reacting with an alkylsilicon reagent such as trialkylsilicon chloride. Can do.
  • An organolithium reagent can be produced by reacting Z 4 —Ar 2 with an alkyllithium reagent such as butyllithium in a suitable solvent or without a solvent.
  • each reaction of production method B should be selected according to the type of raw material compound and the like.
  • Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • L represents a group described in item 1 (excluding —S ( ⁇ O) q —), it is also produced by the following production method.
  • Step 1 Compound 9 can be produced by subjecting compound 8 to a cyclization reaction according to a conventional method.
  • this reaction can be achieved by reacting compound 8 in the presence of an acid reagent such as acetic acid or paratoluenesulfonic acid in a suitable solvent or in the absence of a solvent.
  • an acid reagent such as acetic acid or paratoluenesulfonic acid
  • Step 2 Compound 10 can be produced by halogenating compound 9 according to a conventional method.
  • this reaction can be carried out by reacting compound 9 with a halogenating agent such as N-iodosuccinimide, N-bromosuccinimide, potassium iodide and cerium ammonium nitrate, iodine, bromine or the like in a suitable solvent or without solvent. Achieved.
  • the alkyl group of R 2 may be halogenated, but by reacting a reducing agent such as sodium borohydride, the halogen atom substituted by R 2 is selectively converted to a hydrogen atom. can do. (See Reference Examples 29, 30, 33, and 34)
  • Step 3 Compound 11 is produced by subjecting compound 10 and Z 1 -L a -Ar 2 (Z 1 is the same as defined above) to a coupling reaction according to the method of Production Method B-1. Can do. (See Example 7)
  • Compound 11 is prepared by converting X 1 in Compound 10 into a coupling reagent such as a boride, zinc halide, magnesium halide, etc. according to the method of Production Method B-3, and then converting the compound and Z 2 -L a -Ar 2 (Z 2 are as defined above) can be prepared by carrying out the coupling reaction with.
  • a coupling reagent such as a boride, zinc halide, magnesium halide, etc.
  • Z 1 -L a -Ar 2 is obtained by substituting various metal atoms for Z 4 -L a -Ar 2 (Z 4 is the same as defined above) according to the production method B-6.
  • Z 4 -L a -Ar 2 is a known compound, or a production method using Z 4 -L a -Z 1 and Ar 2 -Z 2 or Z 4 -L a -Z 2 and Ar 2 -Z 1 also carrying out the coupling reaction of an aromatic ring L a and Ar 2 in B-1 and the same methods can be produced.
  • Z 4 -L a -Ar 2 where the binding of the aromatic ring L a and Ar 2 is a C-N bond can be produced by performing a substitution reaction.
  • Ar 2 having an NH group in the ring and Z 2 -L a -Z 4 or Z 3 -L a -Z 4 can be produced in a suitable solvent or without solvent in the production method B- This can be achieved by carrying out the reaction according to the method of 5.
  • the solvent in each reaction of the production method C should be selected according to the kind of the raw material compound and the like.
  • Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • R 0 is a single bond
  • L is a 5- to 6-membered aromatic ring group (L) optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S
  • the compound representing the a ) [compound of the following formula 11] is also produced by the following production method.
  • L represents a group described in item 1 (excluding —S ( ⁇ O) q —), it is also produced by the following production method.
  • Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 are the same as defined in item 1, and La , Z 1 , Z 2 , W 1 , X 1 are defined as above. Same.
  • Step 1 Compound 12 is produced by performing a coupling reaction between Compound 10 and Z 1 -L a -W 1 (Z 1 is the same as defined above) according to the production method B-1. be able to.
  • compound 12 is obtained according to the process of Preparation B-3, the X 1 in compound 10, boron embodying, zinc halide body, after converting the coupling reagent magnesium halide and the like, the compound and Z 2 -L a 2 -W 1 (Z 2 is the same as defined above) can be produced by performing a coupling reaction.
  • Step 2 When W 1 in Compound 12 represents a halogen atom, Compound 11 is a cup of Compound 12 and Z 1 —Ar 2 (Z 1 is as defined above) according to the method of Production Method B-1. It can be produced by carrying out a ring reaction.
  • W 1 in Compound 12 represents a halogen atom
  • Compound 11 is prepared by using W 1 of Compound 12 as a coupling reagent such as a boride, zinc halide, or magnesium halide according to the method of Production Method B-3. After the conversion, the compound can be produced by performing a coupling reaction between the compound and Z 2 —Ar 2 (Z 2 is as defined above).
  • W 1 of compound 12 is, if an amino group, compound 11, after which according to the method of Preparation B-4, was converted to W 1 to halogen atoms of bromine or iodine by Sandmeyer reaction, this and Z 1- Ar 2 can also be produced by a coupling reaction according to the same method as Production Method B-1.
  • L a compound 12 having a NH group in the ring i.e., if they contain NH groups in group constituting L a
  • compound 11 is obtained according to the process of Preparation B-5
  • compound 12 and Z 2- Ar 2 (Z 2 is the same as defined above) or Z 3 -Ar 2 (Z 3 is defined as defined above) can be produced by performing a substitution reaction or a coupling reaction.
  • the solvent in each reaction of Production Method D should be selected according to the type of the raw material compound and the like.
  • Examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, and alcohols such as methanol, ethanol, and isopropanol, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • Ar 1 , Ar 2 , L, R 2 , R 3 , and R 4 are the same as defined in item 1, and W 0 is a protecting group such as a benzyl group that may be substituted with methoxy or nitro. Represents.
  • Compound 14 can be produced by subjecting compound 13 to a reduction reaction according to a conventional method.
  • this reaction may be carried out by reacting compound 13 with a catalytic reducing reagent such as palladium carbon or palladium hydroxide in a hydrogenated state or in the presence of ammonium formate, or in a suitable solvent or without solvent, or trifluoroacetic acid or the like.
  • the reaction is carried out in the presence of an acid, or in the presence of an oxidizing agent such as 2,3-dichloro-5,6-dicyano-para-benzoquinone.
  • each reaction of production method E should be selected according to the type of the raw material compound and the like.
  • examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • R 0 is a single bond
  • R 1 is optionally substituted, C 1-10 alkyl, C 2-6 alkene, or 1-2 selected from the group consisting of N, O and S
  • a compound [compound of the following formula 15] representing a 3- to 6-membered saturated or 4- to 6-membered unsaturated aliphatic ring group (R 1a ), which may contain a heteroatom, is also produced by the following production method. Is done.
  • R 1a is defined as above (optionally substituted, C 1-10 alkyl, C 2-6 alkene, 3-6 membered saturated or 4-6 membered unsaturated aliphatic ring group optionally containing 1-2 heteroatoms selected from the group consisting of N, O and S X 2 represents a leaving group typified by a halogen atom or triflate.)
  • Compound 15 can be produced by subjecting compound 14 to an alkylation reaction according to a conventional method.
  • compound 14 is converted into a metal hydride reagent such as sodium hydride, an alkali metal reagent such as potassium carbonate, an alkali metal phosphate reagent such as potassium phosphate, in a suitable solvent or without solvent.
  • an organic base reagent such as triethylamine
  • an alkali metal halide reagent such as lithium chloride
  • an alkali metal hydroxide such as sodium hydroxide
  • a metal alkoxide such as potassium t-butoxy
  • each reaction of production method F should be selected according to the type of the raw material compound and the like.
  • examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate and the like, and they can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • R 0a represents the above definition (—C ( ⁇ O) O—, — The same as C ( ⁇ O) — and —S ( ⁇ O) 2 —).
  • Compound 16 can be produced by subjecting compound 14 to carbamation, acetylation or sulfonation according to a conventional method.
  • this reaction may be carried out in an appropriate solvent or in the absence of a solvent, such as a metal hydride reagent such as sodium hydride, an alkali metal reagent such as potassium carbonate, an alkali metal phosphate reagent such as potassium phosphate, or an organic compound such as triethylamine.
  • a metal hydride reagent such as sodium hydride
  • an alkali metal reagent such as potassium carbonate
  • an alkali metal phosphate reagent such as potassium phosphate
  • organic compound such as triethylamine
  • an alkali metal halide reagent such as lithium chloride, an alkali metal hydroxide (sodium hydroxide, etc.), a metal alkoxide (t-butoxypotassium, etc.), compound 14 is converted to the carboxylic acid derivative of R 1 and sulfone.
  • active esters derived from acid derivatives, acid anhydrides of R 1 is accomplished by reacting an acid halide of R 1 and the like.
  • the active ester examples include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, N-hydroxypiperidine ester 2-pyridylthiol ester, N-methylimidazole ester and the like.
  • the acid anhydride a symmetric acid anhydride or a mixed acid anhydride is used.
  • the mixed acid anhydride include mixed acid anhydrides with ethyl chlorocarbonate, isovaleric acid and the like. (See Examples 31, 32, and 33)
  • each reaction of production method G should be selected according to the type of raw material compound and the like.
  • examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate and the like, and they can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • Ar 1 , Ar 2 , L, R 1 , R 2 , R 3 , R 4 are the same as defined in Item 1, and R L is optionally substituted C 1-10 alkyl, or substituted. Represents an optionally substituted phenyl group.
  • Compound 17 can be produced by urea compound 14 according to a conventional method.
  • this reaction may be carried out in an appropriate solvent or in the absence of a solvent, such as a metal hydride reagent such as sodium hydride, an alkali metal reagent such as potassium carbonate, an alkali metal phosphate reagent such as potassium phosphate, or an organic compound such as triethylamine.
  • a metal hydride reagent such as sodium hydride
  • an alkali metal reagent such as potassium carbonate
  • an alkali metal phosphate reagent such as potassium phosphate
  • organic compound such as triethylamine.
  • the solvent in each reaction of the production method H should be selected according to the kind of the raw material compound and the like.
  • examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate and the like, and they can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • Step 1 Compound 18 or 19 is prepared by subjecting a metal hydride reagent such as sodium hydride, an alkali metal reagent such as potassium carbonate, phosphorus such as potassium phosphate, etc.
  • a metal hydride reagent such as sodium hydride, an alkali metal reagent such as potassium carbonate, phosphorus such as potassium phosphate, etc.
  • an organic base reagent such as triethylamine
  • an alkali metal halide reagent such as lithium chloride
  • an alkali metal hydroxide such as sodium hydroxide
  • a metal alkoxide such as t-butoxypotassium
  • Step 2 Compound 20 is prepared according to a conventional method, using a metal hydride reagent such as sodium hydride, an alkali metal reagent such as potassium carbonate, an alkali metal phosphate reagent such as potassium phosphate, an organic base reagent such as triethylamine, By reacting compound 18 or 19 with R 1 R a NH in the presence of an alkali metal halide reagent such as lithium chloride, alkali metal hydroxide (such as sodium hydroxide), metal alkoxide (such as t-butoxypotassium), etc. Can be manufactured. In some cases, for example, according to the method described in J. Org. Chem. 2003, 68, 115-119. Or the like, a compound 18 is reacted with a trifluoroacetate such as methyl trifluoroacetate. Then, it can be produced by reacting R 1 R a NH.
  • a metal hydride reagent such as sodium hydride
  • the solvent in each reaction of Production Method I should be selected according to the type of raw material compound and the like.
  • examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, and alcohols such as methanol, ethanol, and isopropanol, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • R 1 R a NH is a known compound, or in some cases, for example, can be produced according to the method described in J. Med. Chem. 2010, 53, 3517-3531, etc., or a method analogous thereto. it can.
  • Ar 1 , Ar 2 , L, R 1 , R 2 , R 3 , R 4 , and R a are the same as defined in Item 1, and W 2 represents phenyl, p-nitrophenyl, and the like.
  • Compound 22 is prepared by a conventional method, such as a metal hydride reagent such as sodium hydride, an alkali metal reagent such as potassium carbonate, an alkali metal phosphate reagent such as potassium phosphate, an organic base reagent such as triethylamine, or a halogen such as lithium chloride.
  • alkali metal reagent, an alkali metal hydroxide such as sodium hydroxide, in the presence of a metal alkoxide) such as t- butoxy potassium can be prepared by reacting a compound 21 with R 1 R a NH.
  • each reaction of Production Method J should be selected according to the type of raw material compound and the like.
  • examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene and ethyl acetate, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • R 1 is C 1-10 alkyl or C 2-6 alkene substituted with —C ( ⁇ O) OH or —S ( ⁇ O) 2 OH, —C ( ⁇ O) OH
  • R 1 is —C ( ⁇ O) NR a R i , —S ( ⁇ O) 2 NR a R i or —C ( ⁇ O) OR b
  • Step 1 Compound 24 can be produced by subjecting compound 23 to hydrolysis according to a conventional method.
  • this reaction can be achieved by performing a hydrolysis reaction in an appropriate solvent or in the absence of a solvent under alkaline conditions such as an aqueous sodium hydroxide solution or acidic conditions such as hydrochloric acid. (See Examples 80 and 98)
  • Compound 24 can be produced by carrying out a reduction reaction of Compound 23 according to a conventional method.
  • this reaction may be performed by reacting a catalytic reduction reagent such as palladium carbon or palladium hydroxide in a hydrogenated state or in the presence of ammonium formate, or in the presence of an acid such as trifluoroacetic acid, in a suitable solvent or in the absence of a solvent.
  • a catalytic reduction reagent such as palladium carbon or palladium hydroxide in a hydrogenated state or in the presence of ammonium formate, or in the presence of an acid such as trifluoroacetic acid, in a suitable solvent or in the absence of a solvent.
  • an oxidant such as 2,3-dichloro-5,6-dicyano-para-benzoquinone.
  • Step 2 Compound 25 can be produced by subjecting compound 24 to amidation or esterification according to a conventional method.
  • compound 24 is converted into a reactive derivative (for example, active ester, acid anhydride, acid halide, etc.) in an appropriate solvent or without solvent, and reacted with various amines or various alcohols.
  • active ester include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, N-hydroxypiperidine ester 2-pyridylthiol ester, N-methylimidazole ester and the like.
  • the acid anhydride a symmetric acid anhydride or a mixed acid anhydride is used.
  • the mixed acid anhydride include mixed acid anhydrides with ethyl chlorocarbonate, isovaleric acid and the like.
  • Compound 25 can also be produced by reacting compound 24 with various amines and various alcohols in the presence of a condensing agent according to a conventional method.
  • a condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride, N, N′-carbonyldiimidazole, dimethylaminosulfonic acid chloride, Examples include 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, benzotriazol-1-yl-oxytris (pyrrolidino) phosphonium-hexafluorophosphate, and the like.
  • These condensing agents can be used alone or in combination with these condensing agents and peptide synthesis reagents such as N-hydroxysuccinimide and N-hydroxybenzotriazole. (See Example 85)
  • each reaction of production method K should be selected according to the type of raw material compound and the like.
  • Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • R 1 consists of C 1-10 alkyl, C 2-6 alkene, N, O and S substituted with sulfo (SO 3 H), sulfonyl (SO 2 R), sulfoxide (SOR) Selected from the group consisting of 3-6 membered saturated or 4-6 membered unsaturated aliphatic ring groups or N, O and S which may contain 1 to 2 heteroatoms selected from the group
  • a compound [compound of the following formula 27] representing a 5- to 6-membered aromatic ring group (R 1f ) optionally containing 1 to 4 heteroatoms is produced by the following production method.
  • Ar 1 , Ar 2 , L, R 0 , R 2 , R 3 , R 4 are the same as defined in item 1, and R 1e is C 1 -substituted with thiol, alkylthio, or sulfoxide.
  • R 1f represents sulfo (SO 1 to 2 heteroatoms selected from the group consisting of 3 H), sulfoxide (SOR), C 1-10 alkyl substituted with sulfonyl (SO 2 R), C 2-6 alkene, N, O and S 3-6 membered saturated or 4-6 membered unsaturated
  • Compound 27 can be produced by oxidizing compound 26 according to a conventional method. For example, this reaction can be achieved by reacting compound 26 with a peroxidant such as metachloroperbenzoic acid, hydrogen peroxide, oxone, sodium perborate or the like in a suitable solvent.
  • a peroxidant such as metachloroperbenzoic acid, hydrogen peroxide, oxone, sodium perborate or the like in a suitable solvent.
  • each reaction of Production Method L should be selected according to the type of raw material compound and the like.
  • dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, toluene, ethyl acetate And acetic acid and the like can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • R 1 contains 1 to 2 heteroatoms selected from the group consisting of C 1-10 alkyl substituted with oxo, C 2-6 alkene, or N, O and S
  • a compound representing a 3- to 6-membered saturated or 4- to 6-membered unsaturated aliphatic ring group (R 1h ) [compound of the following formula 29] may be produced by the following production method.
  • R 1g is a C 1-10 alkyl substituted with a hydroxyl group, C 1 A 2-6 alkene, or a 3-6 membered saturated or 4-6 membered unsaturated aliphatic ring group which may contain 1-2 heteroatoms selected from the group consisting of N, O and S
  • R 1h contains 1 to 2 heteroatoms selected from the group consisting of C 1-10 alkyl substituted with an oxo group, C 2-6 alkene, or substituted N, O and S Represents a 3- to 6-membered saturated or 4- to 6-membered unsaturated aliphatic ring group which may be
  • Compound 29 can be produced by oxidizing compound 28 according to a conventional method.
  • this reaction can be achieved by reacting Compound 28 with an oxidizing agent such as Dess-Martin reagent, potassium dichromate, sodium hypochlorite, Jones reagent, pyridinium dichromate in an appropriate solvent or without solvent. Is done.
  • an oxidizing agent such as Dess-Martin reagent, potassium dichromate, sodium hypochlorite, Jones reagent, pyridinium dichromate in an appropriate solvent or without solvent. Is done.
  • the solvent in each reaction of the production method M should be selected according to the kind of the raw material compound and the like.
  • examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid and the like, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • R 1i is an acetal group (CH (OR h ) 2 , R h are as defined in claim 1. represents C 1-10 alkyl or C 2-6 alkene substituted with)
  • R 1j is, C 1-10 alkyl or C 2-6 alkene substituted with aldehyde
  • R 1k represents C 1-10 alkyl or C 2-6 alkene substituted with CH 2 NR c R d (the definitions of R c and R d are the same as in item 1).
  • Step 1 Compound 31 can be produced by deprotecting the acetal group of compound 30 according to a conventional method.
  • this reaction can be achieved by reacting compound 30 with an acid reagent such as p-toluenesulfonic acid, trifluoroacetic acid, hydrochloric acid or the like in a suitable solvent or without a solvent.
  • an acid reagent such as p-toluenesulfonic acid, trifluoroacetic acid, hydrochloric acid or the like in a suitable solvent or without a solvent.
  • Step 2 Compound 32 can be produced by subjecting compound 31 to a reductive amination reaction according to a conventional method.
  • compound 31 and NR a R e are mixed with a hydride reagent such as sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or the like in an appropriate solvent or in the absence of a solvent. This is achieved by reacting in the presence of an acid such as acetic acid or hydrochloric acid.
  • a hydride reagent such as sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or the like
  • each reaction of Production Method N should be selected according to the type of raw material compound, etc., but for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, toluene, ethyl acetate , Acetic acid or alcohols such as methanol, ethanol, and isopropanol, and the like.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • R 1 is 1-2 substituents selected C 1-10 alkyl or C 2-6 alkene substituted with NHR a, N substituted with NHR a, from the group consisting of O and S Selected from the group consisting of N, O and S substituted with 3-6-membered saturated or 4-6-membered unsaturated aliphatic ring groups which may contain any heteroatoms, or NHR a
  • a compound that is a 5- to 6-membered aromatic ring group (R 1m ) optionally containing 4 heteroatoms [compound of the following formula 34]
  • R 1l is substituted with NR a C ( ⁇ O) OR b .
  • Step 1 Compound 34 can be produced by deprotecting the carbamate group by hydrolysis or reduction of compound 33 according to a conventional method. For example, this reaction is achieved according to the same method as [Step 1] of production method K. (See Examples 100 and 101)
  • Step 2 Compound 35 can be produced by subjecting compound 34 to an amidation reaction according to a conventional method.
  • this reaction can be achieved by reacting compound 34 with various active esters derived from carboxylic acid derivatives and sulfonic acid derivatives, various acid anhydrides or various acid halides in a suitable solvent or without solvent.
  • the active ester include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, N-hydroxypiperidine ester 2-pyridylthiol ester, N-methylimidazole ester and the like.
  • the acid anhydride a symmetric acid anhydride or a mixed acid anhydride is used.
  • Specific examples of the mixed acid anhydride include mixed acid anhydrides with ethyl chlorocarbonate, isovaleric acid and the like. (See Examples 102-104)
  • Compound 35 can also be produced by reacting compound 34 with various carboxylic acids and sulfonic acids in the presence of a condensing agent according to a conventional method.
  • a condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride, N, N′-carbonyldiimidazole, dimethylaminosulfonic acid chloride, Examples include 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, benzotriazol-1-yl-oxytris (pyrrolidino) phosphonium-hexafluorophosphate, and the like.
  • These condensing agents can be used alone or in combination with these condensing agents and peptide synthesis reagents such as N-hydroxysuccinimide and N-hydroxybenzotriazole.
  • compound 35 can be produced by urea formation of compound 34 according to a conventional method.
  • this reaction can be produced by reacting compound 34 with various substituted isocyanate compounds in a suitable solvent or without a solvent.
  • Compound 35 can also be produced by converting compound 34 to a reactive derivative (eg, active carbamate) and reacting with various amines according to a conventional method.
  • this reaction can be achieved by reacting compound 34 with phenyl chloroformate, carbodiimidazole, or the like in an appropriate solvent or without a solvent, and then reacting various amines.
  • these urealation reactions may be performed by metal hydride reagents such as sodium hydride and potassium hydride, inorganic bases such as potassium carbonate and sodium hydrogen carbonate, or triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine, It may be carried out in the presence of an organic base such as 4-dimethylaminopyridine.
  • metal hydride reagents such as sodium hydride and potassium hydride
  • inorganic bases such as potassium carbonate and sodium hydrogen carbonate
  • triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine it may be carried out in the presence of an organic base such as 4-dimethylaminopyridine.
  • each reaction of production method O should be selected according to the type of the raw material compound and the like.
  • Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • Compound 37 can be produced by oxidizing compound 36 according to a conventional method. For example, this reaction can be achieved by reacting compound 35 with a peroxidant such as metachloroperbenzoic acid, hydrogen peroxide, oxone, sodium perborate or the like in a suitable solvent. (See Example 106)
  • a peroxidant such as metachloroperbenzoic acid, hydrogen peroxide, oxone, sodium perborate or the like in a suitable solvent.
  • each reaction of production method P should be selected according to the type of the raw material compound and the like.
  • dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, toluene, ethyl acetate And acetic acid and the like can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • Compound 38 is a known compound, or can be produced according to a known compound production method. For example, it can be produced according to the method described in Journal of Fluorine Chemistry, 2007, 128, 1255-1259, or the like, or a method analogous thereto.
  • Step 1 Compound 39 can be produced by performing an addition reaction of a propargyl dialkyl acetal compound to compound 38 according to a conventional method.
  • this reaction can be achieved by reacting a propargyl dialkyl acetal compound with an alkyl metal reagent such as butyl lithium in a suitable solvent or without solvent, and then reacting with compound 38.
  • This addition reaction may be performed in the presence of hexamethylphosphoric triamide, iodine or the like.
  • This reaction can also be achieved, for example, according to the method described in J. Am. Chem. Soc. 2003, 125, 14702-14703, or a method analogous thereto. (See Reference Example 1)
  • Step 2 Compounds 41, 42 and 43 are produced by reacting compound 39 with a compound (Ar 2 —NHNH 2 ) in which a carbon atom in the ring of Ar 2 is substituted with hydrazine in an appropriate solvent according to a conventional method.
  • Ar 2 —NHNH 2 in this reaction may be a hydrochloride, and in some cases, it may be carried out in the presence of an acid such as hydrochloric acid, sulfuric acid or acetic acid. (See Reference Examples 2, 3, 4, and 5)
  • Step 3 Compounds 42 and 43 are produced by subjecting compound 41 to a cyclization reaction in the presence of an acid such as hydrochloric acid or acetic acid or a Lewis acid such as gold trichloride in an appropriate solvent or without a solvent according to a conventional method. can do. (See Reference Example 6)
  • Step 4 Compounds 44 and 45 can be produced by subjecting compounds 42 and 43 to an oxidation reaction according to a conventional method.
  • this reaction is achieved by reacting compounds 42 and 43 with an oxidizing agent such as Dess Martin reagent, Jones reagent, pyridinium dichromate, or performing an oxidation reaction such as swan oxidation in an appropriate solvent or in the absence of a solvent. Is done. (See Reference Example 7)
  • each reaction of production method Q should be selected according to the kind of the raw material compound and the like.
  • Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • Compound 46 is a known compound, or can be produced according to a known compound production method. For example, it can be produced according to the method described in J. Org. Chem. 2009, 74, 6410-6413.
  • Step 1 Compound 48 can be produced by subjecting compound 46 and compound 47 to a cyclization reaction according to a conventional method. For example, this reaction is achieved by reacting compound 46 and compound 47 with N, N-dimethylformamide dimethyl acetal in the presence of acetic acid in a suitable solvent or without solvent. For example, it can be produced according to the method described in Org. Lett. 2004, 17 (6), 2969-2971. (See Reference Examples 8, 43, and 44)
  • Compound 47 is a known compound, or can be produced according to a known compound production method. For example, it can be produced according to the method described in WO2008122767 or the like, or a method analogous thereto.
  • Step 2 Compound 49 can be produced by subjecting compound 48 to an oxidation reaction according to a conventional method. For example, this reaction is achieved according to the same method as [Step 4] of production method Q. (See Reference Examples 9, 45, and 46)
  • the solvent in each reaction of the production method R should be selected according to the kind of the raw material compound and the like.
  • Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • Compound 50 is a known compound, or can be produced according to a known method for producing a compound. For example, by performing a reduction reaction of Ar 2 —CO 2 R 7 (R 7 represents C 1-6 alkyl or a hydrogen atom), an oxidation reaction of Ar 2 —CH 2 OH, a formylation reaction of Ar 2 , etc. Can be manufactured.
  • Step 1 Compound 51 can be produced by reacting compound 47 with compound 50 according to a conventional method.
  • this reaction can be achieved by reacting Compound 47 and Compound 50 in the presence of an acid catalyst such as paratoluenesulfonic acid in a suitable solvent or in the absence of a solvent.
  • This reaction can also be produced according to the method described in J. Med. Chem. 2003, 46, 3463-3475, or a method analogous thereto.
  • Step 2 Compound 53 can be produced by subjecting compound 51 and compound 52 (tosylmethyl isocyanide) to a cyclization reaction in a suitable solvent or in the absence of a solvent according to a conventional method. This reaction can also be achieved, for example, according to the method described in J. Med. Chem. 2003, 46, 3463-3475, or a method analogous thereto.
  • Step 3 Compound 54 can be produced by subjecting compound 53 to an oxidation reaction according to a conventional method. For example, this reaction is achieved according to the same method as [Step 4] of production method Q.
  • each reaction of production method S should be selected according to the type of the raw material compound and the like.
  • Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • a raw material compound representing a 5- to 6-membered aromatic ring group (L a ) optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S is prepared by the following production method. Is also manufactured. Similarly, when L represents a group described in item 1 (excluding —S ( ⁇ O) q —), it is also produced by the following production method.
  • L a is, N, may contain 1-4 heteroatoms selected from the group consisting of O and S 5 Represents a 6-membered aromatic ring group, and X 1 represents a halogen atom.
  • Compound 55 is a known compound, or can be produced according to a known compound production method. For example, it can be produced by performing an oxidation reaction of Ar 2 —CHOHCH 3 , an acetylation reaction of Ar 2 or the like.
  • Step 1 Compound 56 can be produced by carrying out addition reaction of compound 55 to compound 38 according to a conventional method.
  • this reaction can be achieved by reacting Compound 55 with a metal reagent such as lithium bistriethylsilylamide or lithium diisopropylamide and then reacting with Compound 38 in a suitable solvent or without solvent.
  • This reaction can also be achieved, for example, according to the method described in Tetrahedron Letters, 1991, 32, 7583-7586.
  • Step 2 Compound 58 can be produced by carrying out addition reaction of compound 57 to compound 38 according to a conventional method.
  • this reaction is achieved by reacting compound 57 with an alkyl metal reagent such as butyl lithium in a suitable solvent or without solvent, and then reacting with compound 38.
  • This addition reaction may be performed in the presence of hexamethylphosphoric triamide, iodine or the like.
  • This reaction can also be achieved, for example, according to the method described in J. Am. Chem. Soc. 2003, 125, 14702-14703, or a method analogous thereto.
  • Compound 57 is a known compound or can be produced by reacting Ar 2 with an acetylene reagent according to the method described in J. Med. Chem. 2010, 53, 699-714.
  • Step 3 Compound 56 can be produced by subjecting compound 58 to water addition reaction according to a conventional method.
  • this reaction can be achieved by reacting Compound 58 with trimethylsilyl triflate or formic acid in a suitable solvent or without solvent.
  • This reaction can also be achieved, for example, according to the method described in Eur. J. Org. Chem. 2008, 5461-5469.
  • Step 4 Compound 59 can be produced by halogenating compound 56 according to a conventional method.
  • this reaction may be carried out by reacting compound 56 with a halogenating agent such as N-iodosuccinimide, N-bromosuccinimide, potassium iodide and cerium ammonium nitrate, iodine or bromine in a suitable solvent or without solvent.
  • a halogenating agent such as N-iodosuccinimide, N-bromosuccinimide, potassium iodide and cerium ammonium nitrate, iodine or bromine.
  • Step 5 Compound 60 can be produced by subjecting compound 59 to a cyclization reaction according to a conventional method.
  • this reaction can be achieved by reacting compound 59 with methanethioamide, formamide, methanimidamide, or the like in a suitable solvent or without solvent.
  • These cyclization reactions are carried out by alkali metal carbonates (for example, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal phosphates (potassium phosphate, etc.), organic bases (triethylamine, diisopropylethylamine, etc.), alkali metal halides (chloride chloride).
  • Lithium, cesium fluoride, etc.), alkali metal hydroxide (sodium hydroxide, etc.), metal alkoxide (t-butoxypotassium, etc.), ammonium acetate, etc. may be used.
  • This reaction can also be achieved, for example, according to the method described in WO2006137658, Bioorganic & Medicinal® Chemistry® Letters, 2007, 17, 5115-5120.
  • Step 6 Compound 61 can be produced by subjecting compound 60 to an oxidation reaction according to a conventional method. For example, this reaction is achieved according to the same method as [Step 4] of production method Q. (See Reference Example 150)
  • the solvent in each reaction of the production method T should be selected according to the type of the raw material compound and the like.
  • Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • a raw material compound representing a 5- to 6-membered aromatic ring group (L a ) optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S is prepared by the following production method. Is also manufactured. Similarly, when L represents a group described in item 1 (excluding —S ( ⁇ O) q —), it is also produced by the following production method.
  • W 1 -L a -M 2 is a known compound, or can be produced according to a known production method. For example, it can be produced by reacting W 1 -L a -Z 4 (Z 4 is the same as defined above) with an alkyl lithium reagent such as butyl lithium according to a conventional method.
  • Z 4 represents halogen
  • Z 4 can be substituted with magnesium halide by reacting Z 4 with an alkyl magnesium halide reagent such as methyl magnesium bromide according to a conventional method. by reacting the powder or alkyl zinc halide reagent and the like, it can be substituted for Z 4 zinc halide.
  • W 1 represents an amino group, it is protected with t-butoxycarbonyl or the like.
  • Step 1 Compound 62 can be produced by carrying out addition reaction of W 1 -L a -M 2 to compound 38 in a suitable solvent or without solvent according to a conventional method. This addition reaction may be performed in the presence of hexamethylphosphoric triamide, iodine or the like. These reactions can also be achieved, for example, according to the method described in Bioorganic & Medicinal Chemistry Letters, 2009, 19, 1559-1563.
  • Step 2 In the case where W 1 in Compound 62 represents a halogen atom, Compound 60 is a cup of Compound 62 and Z 1 -Ar 2 (Z 1 is as defined above) according to the method of Production Method B-1. It can manufacture by performing a ring reaction.
  • compound 60 is prepared by using W 1 of compound 62 as a coupling reagent such as a boride, zinc halide, or magnesium halide according to the method of production method B-3. After the conversion, the compound can be produced by performing a coupling reaction between the compound and Z 2 —Ar 2 (Z 2 is as defined above).
  • W 1 of Compound 62 represents an amino group protected with t-butoxycarbonyl or the like
  • Compound 60 performs deprotection of the amino group, and halogen atoms such as bromine and iodine are subjected to Sandmeyer reaction according to a conventional method. Then, it can also be produced by subjecting it and Z 1 -Ar 2 to a coupling reaction according to the same method as Production Method B-1.
  • L a compound 62 having a NH group in the ring i.e., if they contain NH groups in group constituting L a
  • compound 60 is obtained according to the process of Preparation B-5, compound 62 and Z 2- Ar 2 (Z 2 is as defined above) or Z 3 -Ar 2 (Z 3 is as defined above) can be produced by performing a substitution reaction or a coupling reaction.
  • Step 3 Compound 61 can be produced by subjecting compound 60 to an oxidation reaction according to a conventional method. For example, this reaction is achieved according to the same method as [Step 4] of production method Q.
  • each reaction of Production Method U should be selected according to the type of raw material compound and the like.
  • Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • a raw material compound representing a 5- to 6-membered aromatic ring group (L a ) optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S is prepared by the following production method. Is also manufactured. Similarly, when L represents a group described in item 1 (excluding —S ( ⁇ O) q —), it is also produced by the following production method.
  • Ar 2 -L a -M 2 is a known compound, or can be produced using Ar 2 -L a -Z 4 according to the synthesis method of W 1 -L a -M 2 in Production Method U. it can.
  • Step 1 Compound 60 can be produced by an addition reaction of Ar 2 -L a -M 2 to compound 38 in a suitable solvent or without solvent according to a conventional method.
  • This addition reaction may be performed in the presence of hexamethylphosphoric triamide, iodine or the like.
  • This reaction can also be achieved, for example, according to the method described in Bioorganic & Medicinal Chemistry Letters, 2009, 19, 1559-1563.
  • Step 2 Compound 61 can be produced by subjecting compound 60 to an oxidation reaction according to a conventional method. For example, this reaction is achieved according to the same method as [Step 4] of production method Q.
  • each reaction of Production Method V should be selected according to the type of raw material compound and the like.
  • examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid and the like, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • Compound 64 can be produced by subjecting compound 63 to exomethyleneation according to a conventional method. For example, this reaction is accomplished by reacting Compound 63 with an aqueous formaldehyde solution or paraformaldehyde in the presence of an acid such as acetic acid or hydrochloric acid and an amine reagent such as piperidine or dimethylamine in an appropriate solvent or without a solvent. Is done. (See Reference Examples 16, 17, 47, 48, 51)
  • Compound 64 can also be produced by reacting Compound 63 with N, N, N, N-tetramethyldiaminomethane in the presence of acetic anhydride in an appropriate solvent or without solvent according to a conventional method. It can. This reaction can also be achieved according to the method described in J. Med. Chem. 1987, 30, 1497-1502. (See Reference Example 13)
  • each reaction of production method W should be selected according to the type of the raw material compound and the like.
  • Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • Ar 2 , L and R 2 are the same as defined in item 1, and R c and R d each independently represent C 1-3 alkyl, or together, represent azetidine. Represents pyrrolidine, piperidine, piperazine.
  • Step 1 Compound 65 can be produced by reacting compound 63 with an aqueous formaldehyde solution, paraformaldehyde, or the like, with an amine reagent such as piperidine or dimethylamine, in an appropriate solvent or without a solvent, according to a conventional method. it can. In some cases, this reaction is carried out in the presence of an acid such as acetic acid or hydrochloric acid. Alternatively, it can be produced by reacting a commercially available Eschenmoser salt (Me 2 CN ⁇ CH 2 I ⁇ ) or the like with the compound 63.
  • an amine reagent such as piperidine or dimethylamine
  • Step 2 Compound 64 is prepared by reacting compound 65 with an alkyl halide such as methyl iodide in a suitable solvent or without solvent in the usual manner, and then a metal hydride reagent such as sodium hydride, potassium carbonate Reacting alkali metal carbonate reagents such as potassium phosphate, alkali metal phosphate reagents such as potassium phosphate, organic base reagents such as triethylamine, alkali metal hydroxides (such as sodium hydroxide), metal alkoxides (such as potassium t-butoxy), etc. Can be manufactured. This reaction can also be achieved according to the method described in Tetrahedron Asymmetry, 1212000, 1217-1225. Or a method analogous thereto.
  • the solvent in each reaction of the production method X should be selected according to the kind of the raw material compound.
  • Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • Compound 66 is a known compound, or can be produced according to a known compound production method. For example, it can be produced according to the method described in ResearchReon Chemical Intermediates, 2009, 35, 137-144.
  • Steps 1 and 2 Compounds 67 and 68 can be produced according to known methods for producing compounds. For example, it can be produced according to the method described in J. Org. Chem. 1993, 56, -4 4098-4112.
  • the starting compound of production method C can also be produced by the following production method.
  • Compound 69 is a known compound, or can be produced according to a known compound production method.
  • Step 1 Compound 70 is a known compound, or can be produced using compound 69 and R 1 —NH 2 according to a known method for producing a compound. For example, it can be produced according to the method described in WO2008 / 8518 or the like, or a method analogous thereto.
  • Step 2 Compound 8 can be produced by urea-converting compound 70 according to a conventional method.
  • Compound 8 can also be produced by converting compound 70 into a reactive derivative (eg, active carbamate) and reacting with Ar 1 —NH 2 according to a conventional method. (See Reference Example 27)
  • each reaction of production method Z should be selected according to the kind of the raw material compound and the like.
  • examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid or alcohols such as methanol, ethanol and isopropanol, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • Ar 1 , Ar 2 , L, R 0 , R 1 , R 3 , R 4 are the same as defined in item 1;
  • R 2a represents an unsubstituted C 1-3 alkyl group;
  • 2b represents a C 1-3 alkyl group substituted with a halogen atom,
  • R 2c represents a hydroxyl group, —NR c R d , —OR a and —OC ( ⁇ O) R a (R c , R d , and R a represents the same as the C 1-3 alkyl group substituted with the same as in item 1.)
  • Step 1 Compound 72 can be produced by halogenating compound 71 according to a conventional method.
  • this reaction can be achieved by reacting a halogenating reagent such as bromine, N-bromosuccinimide, or iodine in a suitable solvent or in the absence of a solvent. (See Examples 128 and 129)
  • Step 2 Compound 73 is prepared according to a conventional method in the presence of a compound 72, a metal hydroxide such as sodium hydroxide, sodium methoxide or the like in a suitable solvent or without solvent, in the presence or absence of a base. It can be produced by reacting with a metal alkoxide, a salt of a carboxylic acid such as potassium acetate, or an amine such as dimethylamine. (See Examples 130-133)
  • the solvent in each reaction of the production method X should be selected according to the kind of the raw material compound.
  • examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, and alcohols such as methanol, ethanol, and isopropanol, and these can be used alone or as a mixed solvent.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .
  • halogen atoms when two or more halogen atoms are present in the structure of the compound of the present invention represented by formula (I), an intermediate thereof, or a reaction compound, the difference in the reaction activity of the halogen atom at the bonding position It is possible to specify the halogen atom to be reacted and control the reaction position by changing the type of halogen atom and the type of halogen atom bonded thereto.
  • the compound of the present invention having a substituent on L in formula (I) can also be produced by using a raw material or an intermediate having a substituent on L. (See Example 119)
  • the compound of formula (I) produced by each of the above production methods can be isolated and purified by conventional methods such as chromatography, recrystallization and reprecipitation.
  • the compound of the formula (I) or a pharmaceutically acceptable salt thereof may have axial asymmetry or may have a substituent having an asymmetric carbon.
  • the compounds of the present invention include mixtures of these isomers and isolated ones. Examples of a method for purely obtaining such optical isomers include an optical resolution method by chromatography using an optically active column, a preferential crystallization method, a diastereomer method, and an optical resolution method.
  • the compound of the present invention or an intermediate thereof has a basic functional group
  • an inert solvent for example, an alcohol solvent such as methanol, ethanol or 2-propanol, an ether solvent such as diethyl ether.
  • Solvents can also be formed into salts.
  • ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene, acetonitrile and the like, and mixed solvents thereof
  • optically active acids for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, and lactic acid
  • camphorsulfonic acid and bromocamphorsulfonic acid can also be formed into salts.
  • an optically active amine for example, organic amines such as ⁇ -phenethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine
  • a salt can also be formed.
  • the temperature at which the salt is formed include a range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. Before the collected salt is collected by filtration, it can be cooled as necessary to improve the yield.
  • the amount of the optically active acid or amine used is suitably in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate.
  • Crystals in an inert solvent as required for example, alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene, It can also be recrystallized with acetonitrile or a mixed solvent thereof to obtain a highly pure optically active salt. If necessary, the obtained salt can be treated with an acid or a base by a conventional method to obtain a free form.
  • the compound of the formula (I) can be obtained in the form of a free base or an acid addition salt depending on the type of functional group present in the structural formula, the selection of the raw material compound, and the reaction treatment conditions. Can be converted to compounds. On the other hand, the compound of formula (I) can be converted to an acid addition salt by treating with various acids according to a conventional method.
  • the administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of compound, administration method, patient symptom / age and the like.
  • oral administration usually about 0.01 to 3000 mg, more preferably about 0.1 to 500 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses.
  • parenteral administration such as intravenous injection, usually, for example, about 0.01 mg to 500 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses.
  • the compound of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier when used for pharmaceutical use as described above.
  • a pharmaceutical carrier a non-toxic substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used.
  • citric acid glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized starch, sucrose, methyl paraoxybenzoate, propyl paraoxybenzoate, and aluminum metasilicate
  • Magnesium sulfate, synthetic aluminum silicate crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose , Polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate Light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, bee gum, carboxyvinyl polymer, titanium
  • Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, coatings, patches, inhalants and the like. These preparations can be prepared according to a conventional method. In the case of a liquid preparation, it may be dissolved or suspended in water or other appropriate medium at the time of use. Tablets and granules may be coated by a known method. In addition, these formulations may contain other therapeutically valuable ingredients.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation containing the compound of the present invention comprises: It may be administered in combination with a therapeutic or prophylactic agent.
  • Examples of the short-term or long-term muscarinic receptor (subtype M1, M2 and M3) antagonist include ipratropium bromide, tiotropium bromide and the like, and short-term or long-term ⁇ receptor ( Examples of the subtype ⁇ 1, ⁇ 2, ⁇ 3, and ⁇ 4) agonist include fenoterol hydrobromide, salbutamol sulfate, salmeterol xinafoic acid, formoterol fumarate, etc., and as inhaled or oral steroids, fluticasone Propionate, beclomethasone propionate, budesonide, etc.
  • Examples of the combination of ⁇ receptor agonist and inhaled steroid include, for example, a combination of salmeterol xinafoate and fluticasone propionate, phosphodiesterase ( PDE Examples of the inhibitor include PDE4 inhibitors such as theophylline and aminoxylline containing methylxanthanine. Examples of the expectorants include carbocysteine. Examples of the antibiotics include erythromycin and clarithromycin. Mycin etc. are mentioned.
  • Me represents a methyl group
  • Et represents an ethyl group
  • Ph represents a phenyl group
  • CN represents a cyano group
  • NO 2 represents a nitro group.
  • the symbols used in NMR are as follows: s is a single line, d is a double line, dd is a double double line, t is a triple line, td is a triple line double line, q is a quadruple line, quin is A quintet, sextet is a hex, m is a multiple, br is broad, brs is a wide single, brd is a wide double, brt is a wide triple, and J is a coupling constant.
  • the NMR measurement conditions are as follows. Measurement condition 1: 300 MHz, CDCl 3 Measurement condition 2: 300 MHz, DMSO-d 6 Measurement condition 3: 300 MHz, CD 3 OD Measurement condition 4: 400 MHz, CDCl 3 Measurement condition 5: 400 MHz, DMSO-d 6 Measurement condition 6: 400 MHz, CD 3 OD High-performance liquid chromatograph mass spectrometer; LCMS measurement conditions are as follows (measurement conditions 7 and 8), the observed mass spectrometry value [MS (m / z)] is MH +, and the retention time is Rt ( In minutes).
  • Measurement condition 8 MS detection device: Waters micromass ZQ HPLC: Waters2790 separations module Column: Impact Cadenza CD-C18 2.0mm x 20mm Flow rate: 1.0 ml / min Measurement wavelength: 254 nm
  • Step 2 Reference examples 2, 3 4-Cyanophenylhydrazine hydrochloride (4.0 g) was added to a solution of 6,6-diethoxy-4-hexyne-2-ol (4.00 g) obtained in step 1 in ethanol (30 mL). And stirred for 8 hours under reflux. Water (100 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (twice with 300 ml). The organic layer was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Reference Example 14 The corresponding compounds were used and reacted in the same manner as in the method described in Reference Example 13 to obtain the compounds shown below.
  • a saturated aqueous sodium hydrogen carbonate solution (30 ml) and a saturated aqueous sodium thiosulfate solution (30 ml) were added to the reaction mixture, followed by extraction with chloroform (twice with 30 ml).
  • the organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 5-bromo-6- (dibromomethyl) -4,4-dimethyl-1- [3- (trifluoromethyl) phenyl.
  • Example 1 4- [5- (6-Methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -1H-pyrazole -1-yl] benzonitrile
  • Example 2 4- [4- (3,6-dimethyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -4H -1,2,4-triazol-3-yl] benzonitrile
  • Example 4-6 The corresponding starting materials were used and reacted and treated in the same manner as described in Example 3 to obtain the compounds shown in Table 3.
  • Example 4 5- (4-Fluorophenylthio) -3,6-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one
  • Example 5 5- (4-Fluorophenylthio) -6-methyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one
  • Example 6 5- (4-Bromophenylthio) -6-methyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one
  • Example 7 4- [5- (4,4,6-trimethyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -1H-pyrazol-1-yl] benzonitrile
  • Example 8 2 ′-[6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile
  • Examples 9-18 The corresponding starting materials were used and reacted and treated in the same manner as described in Example 8 to obtain the compounds shown in Table 4.
  • Example 9 5- (4′-Chlorobiphenyl-2-yl) -6-methyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one
  • Example 10 6-Methyl-5- (4′-nitrobiphenyl-2-yl) -1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one
  • Example 11 6-Methyl-5- [4 ′-(methylsulfonyl) biphenyl-2-yl] -1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one
  • Example 12 6-Methyl-5- [4 ′-(trifluoromethyl) biphenyl-2-
  • Example 20-21 The corresponding starting materials were used and reacted and treated in the same manner as in Example 19 to give the compounds shown in Table 5.
  • Example 20 5- (4′-Chlorobiphenyl-2-yl) -3,6-dimethyl-1- (3-chlorophenyl) -3,4-dihydropyrimidin-2 (1H) -one
  • Example 21 5- (4′-Chlorobiphenyl-2-yl) -3,6-dimethyl-1- (3-methoxyphenyl) -3,4-dihydropyrimidin-2 (1H) -one
  • Example 22 2 ′-[6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile
  • Example 8 2 ′-[6-Methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4 obtained in Example 8 -Sodium hydride (0.7 mg) was added to a solution of carbonitrile (6.0 mg) in tetrahydrofuran (0.5 ml) under ice-cooling, stirred for 5 minutes, methyl iodide (2 ⁇ l) was added, and the mixture was stirred at room temperature. Stir for 1.5 hours. Saturated aqueous ammonium chloride solution (10 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (twice with 10 ml).
  • Examples 24-28 The corresponding starting materials were used and reacted and treated in the same manner as in Example 23 to give the compounds shown in Table 6.
  • Example 24 2- [5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -2,3-dihydropyrimidine-1 (6H)- Yl] acetamide
  • Example 25 2 '-[3-Butyl-6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile
  • Example 26 2 '-[6-Methyl-2-oxo-3- (4,4,4-trifluorobutyl) -1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidine- 5-yl] biphenyl-4-carbonitrile
  • Examples 29-30 The corresponding starting materials were used and reacted and treated in the same manner as described in Example 1 to obtain the compounds shown in Table 7.
  • Example 29 4- [5- (3,6-Dimethyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -1H-pyrazole-1 -Yl] benzonitrile
  • Example 30 4- [5- (3,4,4,6-tetramethyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl)- 1H-pyrazol-1-yl] benzonitrile
  • Example 31 2 ′-[3-acetyl-6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl- 4-carbonitrile
  • Example 8 2 ′-[6-Methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4 obtained in Example 8 -Sodium hydride (0.7 mg) was added to a solution of carbonitrile (6.0 mg) in tetrahydrofuran (0.5 ml) under ice-cooling, stirred for 5 minutes, acetyl chloride (2 ⁇ l) was added, and the mixture was stirred at room temperature for 3 minutes. Stir for hours.
  • Examples 32-35 The corresponding starting materials were used and reacted and treated in the same manner as described in Example 31 to give the compounds shown in Table 8.
  • Example 32 5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxylic acid phenyl Ester
  • Example 33 5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxylic acid 4 -Nitrophenyl ester
  • Example 34 5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide
  • Example 36 2 '-[3-Formyl-6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile
  • Examples 37-38 The corresponding starting materials were used and reacted and treated in the same manner as described in Example 1 to obtain the compounds shown in Table 9.
  • Example 37 5- [1- (4-Cyanophenyl) -1H-pyrazol-5-yl] -4,6,6-trimethyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3- Dihydropyrimidine-1 (6H) -carboxylic acid phenyl ester
  • Example 38 5- [1- (4-Cyanophenyl) -1H-pyrazol-5-yl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxylic acid phenyl ester
  • Example 39 4- [5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3,6- Tetrahydropyrimidine-1-carboxamide] butanoic acid ethyl ester
  • Example 8 2 ′-[6-Methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4 obtained in Example 8 -Sodium hydride (24.0 mg) was added to a solution of carbonitrile (200.0 mg) in N, N-dimethylformamide (5.0 ml) under ice-cooling, and the mixture was stirred for 5 minutes. Ethyl 4-isocyanatobutyrate (135 ⁇ l) was added and stirred for 2 hours.
  • Examples 40-44 The corresponding starting materials were used and reacted and treated in the same manner as in Example 39 to give the compounds shown in Table 10.
  • Example 40 5- (4′-cyanobiphenyl-2-yl) -N-ethyl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) Carboxamide
  • Example 41 5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-N-propyl-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) Carboxamide
  • Example 42 N-butyl-5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) Carboxamide
  • Example 43 2- [5- (4′-
  • Examples 45-46 The corresponding starting materials were used and reacted and treated in the same manner as described in Example 39 to give the compounds shown in Table 11.
  • Example 45 5- [1- (4-Cyanophenyl) -1H-pyrazol-5-yl] -N-ethyl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3- Dihydropyrimidine-1 (6H) -carboxamide
  • Example 46 2- [5- (1- (4-Cyanophenyl) -1H-pyrazol-5-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3 , 6-Tetrahydropyrimidine-1-carboxamide] acetic acid ethyl ester
  • Examples 48-77 The corresponding starting materials were used and reacted and treated in the same manner as in Example 47 to give the compounds shown in Table 12.
  • Example 48 5- (4′-cyanobiphenyl-2-yl) -N, 4-dimethyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide
  • Example 49 5- (4′-cyanobiphenyl-2-yl) -N-isopropyl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) Carboxamide
  • Example 50 5- (4′-cyanobiphenyl-2-yl) -N-cyclohexyl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) Carboxamide
  • Example 51 N-benzyl
  • Examples 78-79 The corresponding starting materials were used and reacted and treated in the same manner as in Example 47 to give the compounds shown in Table 13.
  • Example 78 5- [1- (4-cyanophenyl) -1H-pyrazol-5-yl] -4-methyl-2-oxo-N- (3- (pyrrolidin-1-yl) propyl) -3- [3- (Trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide
  • Example 79 5- [1- (4-Cyanophenyl) -1H-pyrazol-5-yl] -4 -Methyl-2-oxo-N- (3- (2-oxopyrrolidin-1-yl) propyl) -3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H)- Carboxamide
  • Example 80 4- [5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3,6- Tetrahydropyrimidine-1-carboxamide] butanoic acid
  • Examples 81-84 The corresponding starting materials were used and reacted and treated in the same manner as described in Example 80 to give the compounds shown in Table 14.
  • Example 81 2- [5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3,6-tetrahydropyrimidine-1 -Carboxamide] acetic acid
  • Example 82 3- [5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3,6-tetrahydropyrimidine-1 -Carboxamide] propanoic acid
  • Example 83 5- [5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3,6-tetrahydropyrimidine-1 -Carboxamide
  • Examples 86-96 The corresponding starting materials were used and reacted and treated in the same manner as described in Example 85 to give the compounds shown in Table 15.
  • Example 86 N- (2-Amino-2-oxoethyl) -5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3 -Dihydropyrimidine-1 (6H) -carboxamide
  • Example 87 5- (4′-cyanobiphenyl-2-yl) -N- [2- (methylamino) -2-oxoethyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl]- 2,3-Dihydropyrimidine-1 (6H) -carboxamide
  • Example 88 5- (4′-cyanobiphenyl-2-yl) -N- [2- (dimethylamino) -2-oxoethyl]
  • Example 28 4- [5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -2,3-dihydro obtained in Example 28
  • a solution of pyrimidine-1 (6H) -yl] butanoic acid ethyl ester (20.7 mg) in tetrahydrofuran (1.0 mL) was ice-cooled, 5N aqueous sodium hydroxide solution (10 ⁇ L) was added, and then at room temperature for 2 hours. Stir. Thereafter, an aqueous sodium hydroxide solution (5 N, 25 ⁇ L) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes.
  • Example 101 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in the method described in Example 100 to obtain the compounds shown below.
  • Example 102 N- (3-acetamidopropyl) -5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2, 3-Dihydropyrimidine-1 (6H) -carboxamide
  • Examples 103-104 The corresponding starting materials were used and reacted and treated in the same manner as described in Example 102 to give the compounds shown in Table 16.
  • Example 103 5- (4′-cyanobiphenyl-2-yl) -4-methyl-N- [3- (methylsulfonamido) propyl] -2-oxo-3- [3- (trifluoromethyl) phenyl] -2, 3-Dihydropyrimidine-1 (6H) -carboxamide
  • Example 104 (R) -N-[(1-acetylpyrrolidin-3-yl) methyl] -5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoro Methyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide
  • Example 105 2 ′-[3- (1H-imidazol-1-ylsulfonyl) -6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4 Tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile
  • Example 8 2 ′-[6-Methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4 obtained in Example 8 -Sodium hydride (6.1 mg) was added to a solution of carbonitrile (50.0 mg) in N, N-dimethylformamide (1.5 ml) under ice cooling, and the mixture was stirred for 5 minutes. Imidazole (34.3 mg) was added and stirred for 1 hour. Saturated aqueous ammonium chloride solution (10 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (twice with 10 ml).
  • Examples 107-108 The corresponding starting materials were used and reacted and treated in the same manner as described in Example 106 to give the compounds shown in Table 17.
  • Example 107 5- (4-Chlorophenylsulfinyl) -3,6-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one
  • Example 108 4- [3,6-Dimethyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-ylsulfonyl] benzonitrile
  • the urea derivatives used in Reference Examples 10, 20-24, Examples 1-3, and 109-120 can be synthesized by the following method.
  • urea derivatives used in Reference Examples 10, 20-24, Examples 1-3, and 109-120 can also be synthesized by the following method.
  • Reference examples 8, 9, and 26 can also be synthesized by the following method.
  • Reference Example 44 The following compounds (Reference Example 44) were synthesized by reacting and treating in the same manner as described in Reference Example 43 using the corresponding raw material compounds.
  • Reference Example 46 The following compounds (Reference Example 46) were synthesized by reacting and treating in the same manner as described in Reference Example 45 using the corresponding raw material compounds.
  • Reference Example 48 The following compounds (Reference Example 48) were synthesized by reacting and treating in the same manner as described in Reference Example 47 using the corresponding raw material compounds.
  • Reference Example 49 Bromine (0.40 mL) was added to a solution of 4- (5- (2-hydroxypropyl) -1H-pyrazol-1-yl) benzonitrile (1.18 g) obtained in Reference Example 6b in acetic acid (10 mL). ) was added dropwise at room temperature, followed by stirring at room temperature for 10 minutes. A 10% aqueous sodium thiosulfate solution (20 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes.
  • the reaction mixture was diluted with ethyl acetate (150 mL), washed with water (50 mL), saturated aqueous sodium hydrogen carbonate (3 ⁇ 50 mL), and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 4- (4-bromo-5- (2-hydroxypropyl) -1H-pyrazol-1-ylbenzonitrile (1. 41 g) was obtained.
  • Reference Example 50 The following compounds (Reference Example 50) were synthesized by reacting and treating in the same manner as described in Reference Example 7 using the corresponding raw material compounds.
  • Reference Example 51 The following compounds (Reference Example 51) were synthesized by reacting and treating in the same manner as in the method described in Reference Example 47 using the corresponding raw material compounds.
  • Example 109 4- (4- (3-Isopropyl-6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -4H-1,2,4-triazol-3-yl) benzonitrile
  • Examples 110 to 120 were synthesized by reacting and treating in the same manner as described in Example 109 using the corresponding starting compounds.
  • Example 110 (R) -4- (4- (3- (1-hydroxypropan-2-yl) -6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1, 2,3,4-tetrahydropyrimidin-5-yl) -4H-1,2,4-triazol-3-yl) benzonitrile
  • Example 111 4- (4- (6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -4H-1 , 2,4-Triazol-3-yl) benzonitrile
  • Example 112 4- (4- (6-Methyl-2-oxo-1-m-tolyl-1,2,3,4-tetrahydropyrimidin-5-yl) -4H-1,2,4-triazole- 3-yl) benzonitrile
  • 1 H-NMR 400 MHz, CDCl 3 , ⁇ ppm
  • 1.36 s, 3H
  • 2.39 s, 3H
  • 4.13 brs, 1H
  • 4.28 brs, 1H
  • 6.99 s, 1H
  • Example 113 4- (4- (3-ethyl-6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -4H-1,2,4-triazol-3-yl) benzonitrile
  • 1 H-NMR 400 MHz, CDCl 3 , ⁇ ppm
  • Example 114 4- (4- (3-Isopropyl-6-methyl-2-oxo-1-m-tolyl-1,2,3,4-tetrahydropyrimidin-5-yl) -4H-1,2, 4-Triazol-3-yl) benzonitrile
  • Example 115 4- (4- (3-isobutyl-6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -4H-1,2,4-triazol-3-yl) benzonitrile
  • 1 H-NMR 400 MHz, DMSO-d 6 , ⁇ ppm
  • Example 116 4- (4- (6-Ethyl-3-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -4H-1,2,4-triazol-3-yl) benzonitrile
  • Example 117 4- (4- (3,6-diethyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -4H -1,2,4-triazol-3-yl) benzonitrile
  • Example 118 4- (4- (1- (3- (difluoromethyl) phenyl) -3,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidin-5-yl) -4H- 1,2,4-triazol-3-yl) benzonitrile
  • Example 119 4- (4-bromo-5- (3-isopropyl-6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidine- 5-yl) -1H-pyrazol-1-yl) benzonitrile
  • Example 120 4- (5- (3-Isopropyl-6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -1H-pyrazol-1-yl) benzonitrile
  • Example 121 5- (3- (4-cyanophenyl) -4H-1,2,4-triazol-4-yl) -N, 4-dimethyl-2-oxo-3- (3- (trifluoromethyl ) Phenyl) -2,3-dihydropyrimidine-1 (6H) -carboxamide
  • Example 122-127 were synthesized by reacting and treating in the same manner as in Example 121 using the corresponding starting compounds.
  • Example 122 5- (3- (4-cyanophenyl) -4H-1,2,4-triazol-4-yl) -N, 4-dimethyl-2-oxo-3-m-tolyl-2,3 -Dihydropyrimidine-1 (6H) -carboxamide
  • Example 123 5- (3- (4-cyanophenyl) -4H-1,2,4-triazol-4-yl) -N- (2-methoxyethyl) -4-methyl-2-oxo-3- m-Tolyl-2,3-dihydropyrimidine-1 (6H) -carboxamide
  • Example 124 5- (3- (4-cyanophenyl) -4H-1,2,4-triazol-4-yl) -4-methyl-2-oxo-N- (pyridin-2-ylmethyl) -3 -M-Tolyl-2,3-dihydropyrimidine-1 (6H) -carboxamide
  • Example 125 5- (3- (4-cyanophenyl) -4H-1,2,4-triazol-4-yl) -4-methyl-2-oxo-N- (pyridin-3-ylmethyl) -3 -M-Tolyl-2,3-dihydropyrimidine-1 (6H) -carboxamide
  • Example 126 5- (3- (4-cyanophenyl) -4H-1,2,4-triazol-4-yl) -4-methyl-2-oxo-N- (pyridin-4-ylmethyl) -3 -M-Tolyl-2,3-dihydropyrimidine-1 (6H) -carboxamide
  • Example 127 5- (3- (4-cyanophenyl) -4H-1,2,4-triazol-4-yl) -N-ethyl-4-methyl-2-oxo-3- (3- (tri Fluoromethyl) phenyl) -2,3-dihydropyrimidine-1 (6H) -carboxamide
  • 1 H-NMR 400 MHz, DMSO-d 6 , ⁇ ppm
  • the carbamate used in Examples 122-126 was synthesized by the following method.
  • Example 128 4- [4- (6-Bromomethyl) -3-isopropyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl ) -4H-1,2,4-triazol-3-yl] benzonitrile
  • Example 129 4- [4- (6-Dibromomethyl) -3-isopropyl-2-oxo-1- (3- (trifluoro Methyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -4H-1,2,4-triazol-3-yl] benzonitrile
  • Example 130 4- [4- (6-((dimethylamino) methyl) -3-isopropyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydro Pyrimidin-5-yl) -4H-1,2,4-triazol-3-yl] benzonitrile
  • Example 131 4- [4- (6-((ethylamino) methyl) -3-isopropyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydro Pyrimidin-5-yl) -4H-1,2,4-triazol-3-yl] benzonitrile
  • Example 132 4- [4- (3-Isopropyl-6- (methoxymethyl) -2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidine-5 -Yl) -4H-1,2,4-triazol-3-yl] benzonitrile
  • Example 133 (5- (3- (4-cyanophenyl) -4H-1,2,4-triazol-4-yl) -1-isopropyl-2-oxo-3- (3- (trifluoromethyl) Phenyl) -1,2,3,6-tetrahydropyrimidin-4-yl) methyl acetate
  • Example 134 4- [4- (6- (hydroxymethyl) -3-isopropyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidine-5 -Yl) -4H-1,2,4-triazol-3-yl] benzonitrile
  • Examples 135-141 were synthesized by reacting and treating in the same manner as in Example 47 using the corresponding starting compounds.
  • Example 135 N-((1H-tetrazol-5-yl) methyl) -5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl ) Phenyl) -2,3-dihydropyrimidine-1 (6H) -carboxamide
  • Example 136 5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-N- (3- (3-oxopiperazin-1-yl) propyl) -3- (3- ( Trifluoromethyl) phenyl) -2,3-dihydropyrimidine-1 (6H) -carboxamide
  • Example 137 5- (4′-cyanobiphenyl-2-yl) -N- (2,2-difluoroethyl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -2,3-dihydropyrimidine-1 (6H) -carboxamide
  • Example 138 benzyl 2- (5- (1- (4-cyanophenyl) -1H-pyrazol-5-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl)- 1,2,3,6-tetrahydropyrimidine-1-carboxamide) acetate
  • Example 139 Tertiary butyl 4- (5- (1- (4-cyanophenyl) -1H-pyrazol-5-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl ) -1,2,3,6-tetrahydropyrimidine-1-carboxamide) butanoate
  • Example 140 N-((1H-tetrazol-5-yl) methyl) -5- (1- (4-cyanophenyl) -1H-pyrazol-5-yl) -4-methyl-2-oxo-3- (3- (Trifluoromethyl) phenyl) -2,3-dihydropyrimidine-1 (6H) -carboxamide
  • 1 H-NMR (CD 3 OD: 300 MHz) ⁇ : 1.31 (s, 3H), 4.48 (s, 2H), 4.67 (s, 2H), 6.59 (d, 1H, J 1.8 Hz), 7.56-7.72 ( m, 4H), 7.76-7.79 (m, 3H), 7.87-7.90 (m, 2H).
  • Example 141 5- (1- (4-cyanophenyl) -1H-pyrazol-5-yl) -N, 4-dimethyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -2, 3-Dihydropyrimidine-1 (6H) -carboxamide
  • Example 142 to 1408 were synthesized by reacting and treating in the same manner as in Example 23 using the corresponding starting compounds.
  • Example 142 tertiary butyl 2- (5- (1- (4-cyanophenyl) -1H-pyrazol-5-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl ) -2,3-Dihydropyrimidin-1 (6H) -yl) propanoate
  • Example 143 ethyl 2- (5- (1- (4-cyanophenyl) -1H-pyrazol-5-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl)- 2,3-Dihydropyrimidin-1 (6H) -yl) propanoate
  • Example 144 Ethyl 2- (5- (3- (4-cyanophenyl) -4H-1,2,4-triazol-4-yl) -4-methyl-2-oxo-3- (3- (tri Fluoromethyl) phenyl) -2,3-dihydropyrimidin-1 (6H) -yl) propanoate
  • Example 145 2- (5- (3- (4-cyanophenyl) -4H-1,2,4-triazol-4-yl) -4-methyl-2-oxo-3- (3- (trifluoro Methyl) phenyl) -2,3-dihydropyrimidin-1 (6H) -yl) propanamide
  • Example 146 2- (5- (3- (4-cyanophenyl) -4H-1,2,4-triazol-4-yl) -4-methyl-2-oxo-3- (3- (trifluoro Methyl) phenyl) -2,3-dihydropyrimidin-1 (6H) -yl) ethyl acetate
  • Example 147 4- (4- (6-methyl-2-oxo-3- (pyridin-2-ylmethyl) -1- (3-((trifluoromethyl) phenyl) -1,2,3,4- Tetrahydropyrimidin-5-yl) -4H-1,2,4-triazol-3-yl) benzonitrile
  • Example 148 4- (4- (3- (2-methoxyethyl) -6-methyl-2-oxo-1- (3-((trifluoromethyl) phenyl) -1,2,3,4-tetrahydro Pyrimidin-5-yl) -4H-1,2,4-triazol-3-yl) benzonitrile
  • 1 H-NMR (CDCl 3 : 300 MHz) ⁇ : 1.22 (s, 2H), 1.27 (s, 1H), 2.90 (s, 1H), 3.22 (s, 2H), 3.47-3.57 (m, 4H), 4.11 -4.28 (m, 2H), 7.33 (d, 1H, J 7.7 Hz), 7.40 (s, 1H), 7.47-7.52 (m, 1H), 7.56-7.59 (m, 1H), 7.76-7.80 (m , 2H), 7.97-8.02 (m, 2H), 8.17 (s, 0.7H), 8.19 (s, 0.3H).
  • Example 149-150 The corresponding compounds (Examples 149-150) were synthesized by reacting and treating in the same manner as described in Example 80 using the corresponding starting compounds.
  • Example 151 4- (5- (1- (4-cyanophenyl) -1H-pyrazol-5-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1 , 2,3,6-Tetrahydropyrimidine-1-carboxamide) butanoic acid
  • Example 152 The corresponding compound (Example 152) was synthesized by reacting and treating in the same manner as described in Example 134 using the corresponding starting material compound.
  • Example 152 4- (4- (3- (2-hydroxyethyl) -6-methyl-2-oxo-1- (3-((trifluoromethyl) phenyl) -1,2,3,4-tetrahydro Pyrimidin-5-yl) -4H-1,2,4-triazol-3-yl) benzonitrile
  • Example 153 N- (4-amino-4-oxobutyl) -5- (1- (4-cyanophenyl) -1H-pyrazol-5-yl) -4-methyl-2-oxo-3- (3- (Trifluoromethyl) phenyl) -2,3-dihydropyrimidine-1 (6H) -carboxamide
  • Example 154 N- (2-amino-2-oxoethyl) -5- (1- (4-cyanophenyl) -1H-pyrazol-5-yl) -4-methyl-2-oxo-3- (3- (Trifluoromethyl) phenyl) -2,3-dihydropyrimidine-1 (6H) -carboxamide
  • Example 155 1- (4-cyanophenyl) -5- (3-isopropyl-6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydro Pyrimidin-5-yl) -1H-pyrazole-4-carboxylic acid
  • Test Example 1 Inhibitory Action on Human Neutrophil Elastase
  • pharmacological test results of representative compounds of the present invention will be shown, but the present invention is not limited to these test examples.
  • Assay buffer (0.4 unit / ml HNE (human neutrophil elastase, Elastin Products), 200 mM HEPES [N- (2-hydroxyethyl) piperazine-N '-(2-ethanesulfonic acid)], pH 7.5 , 2M NaCl, 0.002% Brij-35) 100 ⁇ l, water for injection 40 ⁇ l, DMSO (dimethyl sulfoxide) solution 20 ⁇ l of the compound of the present invention was mixed in a 96-well plate, and the mixed solution was preincubated at 37 ° C. for 5 minutes.
  • MeOSuc-AAPV-AMC methoxysuccinyl-alanyl-alanyl-prolyl-valyl-aminomethylcoumalide (Sigma-Aldrich)
  • a fluorescent substrate dissolved in 10% DMSO solution to 0.5 mM.
  • the reaction was started, incubated at 37 ° C. for 5 minutes, and the fluorescence intensity of AMC was measured at an excitation wavelength of 380 nM and a fluorescence wavelength of 460 nm to determine the inhibition rate.
  • Table 18 shows the IC 50 value ( ⁇ M), which is the concentration of the compound necessary for inhibiting human neutrophil elastase by 50%, or the inhibition rate (%) at 10 ⁇ M for the example compounds.
  • Test Example 2 Inhibitory action 2 on human neutrophil elastase Although the pharmacological test result in the typical compound of this invention is shown below, this invention is not limited to these test examples.
  • Assay buffer (0.4 unit / ml HNE (human neutrophil elastase, Elastin Products), 200 mM HEPES [N- (2-hydroxyethyl) piperazine-N '-(2-ethanesulfonic acid)], pH 7.5 , 400 mM NaCl, 0.2 mg / ml BSA (bovine serum albumin) 100 ⁇ l, water for injection 40 ⁇ l, 1% DMSO (dimethyl sulfoxide) solution of this compound 20 ⁇ l Preincubation.
  • MeOSuc-AAPV-AMC methoxysuccinyl-alanyl-alanyl-prolyl-valyl-aminomethylcoumalide (Sigma-Aldrich)
  • a fluorescent substrate dissolved in 0.5% DMSO solution to 0.5 mM
  • the reaction was started, incubated at 37 ° C. for 5 minutes, and the fluorescence intensity of AMC was measured at an excitation wavelength of 380 nM and a fluorescence wavelength of 460 nm to determine the inhibition rate.
  • Table 19 shows the IC 50 value (nM), which is the concentration of the compound required to inhibit human neutrophil elastase by 50% for the Example compounds.
  • the compound of the present invention is useful as a therapeutic or prophylactic agent for diseases involving elastase such as inflammatory diseases.
  • Diseases that have been suggested to be involved in the pathogenesis of elastase include, for example, chronic obstructive pulmonary disease (COPD), cystic pulmonary fibrosis, emphysema, adult respiratory distress syndrome (ARDS), acute lung injury (ALI), idiopathic Pulmonary fibrosis (IIP), chronic interstitial pneumonia, chronic bronchitis, chronic respiratory tract infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, rheumatoid arthritis, arthrosclerosis, Osteoarthritis, psoriasis, periodontitis, atherosclerosis, organ transplant rejection, early water rupture, blistering, shock, sepsis, systemic lupus erythematosus (SLE), Crohn's

Abstract

L'invention concerne le produit chimique représenté par la formule générale (I) ci-dessous ou un de ses sels physiologiquement acceptables (dans la formule : R0 représente -C(=O)NRa-, -S(=O)2NRa-, -C(=O)O-, une liaison simple ou analogue ; R1 représente un atome d'hydrogène, un alkyle, un alcène, un groupe cyclique alicyclique saturé de 3 à 6 éléments ou insaturé de 4 à 6 éléments qui peut contenir un hétéroatome, un groupe cyclique aromatique de 5 à 6 éléments qui peut contenir un hétéroatome ou analogue ; R2 représente un atome d'hydrogène, un alkyle ou analogue ; R3 et R4 représentent chacun indépendamment un atome d'hydrogène, un groupe alkyle ou analogue ; L représente un groupe cyclique aromatique de 5 à 6 éléments ou -S(=O)q- ; et Ar1 et Ar2 représentent chacun indépendamment un groupe cyclique aromatique de 5 à 6 éléments qui est substitué à un ou plusieurs sites et qui peut contenir un hétéroatome), et un agent de traitement ou de prévention qui contient ledit composé en tant qu'ingrédient actif et qui est approprié pour divers troubles inflammatoires dans lesquels l'élastase est impliquée.
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WO2014135414A1 (fr) 2013-03-04 2014-09-12 Boehringer Ingelheim International Gmbh Dihydropyrimidinones bicycliques substituées et leur utilisation en tant qu'inhibiteurs de l'activité élastase de neutrophiles
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US9458113B2 (en) 2014-07-31 2016-10-04 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
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WO2014122160A1 (fr) 2013-02-06 2014-08-14 Boehringer Ingelheim International Gmbh Dihydropyrimidinones bicycliques substituées et leur utilisation à titre d'inhibiteurs de l'activité élastase neutrophile
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US9440930B2 (en) 2014-07-31 2016-09-13 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9458113B2 (en) 2014-07-31 2016-10-04 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9475779B2 (en) 2014-07-31 2016-10-25 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9657015B2 (en) 2014-07-31 2017-05-23 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
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