WO2012008508A1 - Composé hétérocyclique - Google Patents

Composé hétérocyclique Download PDF

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Publication number
WO2012008508A1
WO2012008508A1 PCT/JP2011/066022 JP2011066022W WO2012008508A1 WO 2012008508 A1 WO2012008508 A1 WO 2012008508A1 JP 2011066022 W JP2011066022 W JP 2011066022W WO 2012008508 A1 WO2012008508 A1 WO 2012008508A1
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compound
optionally
alkyl
methyl
ethyl
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PCT/JP2011/066022
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English (en)
Japanese (ja)
Inventor
孝治 平山
智康 石川
正格 岡庭
広行 筧
浩 坂野
彰宏 横田
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武田薬品工業株式会社
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Publication of WO2012008508A1 publication Critical patent/WO2012008508A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a heterocyclic compound having CENP-E inhibitory activity and useful for the prevention or treatment of cancer and the use thereof.
  • Centromere-associated protein-E (also referred to herein as “CENP-E”) is one of the motor proteins belonging to the kinesin superfamily (Non-patent Document 1).
  • CENP-E is a factor necessary for normal mitotic chromosome alignment, and it is known that mitotic chromosomal misalignment occurs in cells lacking CENP-E function.
  • Non-Patent Document 2 When CENP-E function is inhibited, chromosome alignment does not occur, and a spindle assembly checkpoint (also referred to as SAC) is activated and cell death is induced.
  • SAC spindle assembly checkpoint
  • the inhibition of the function of CENP-E is one of effective methods for cancer treatment (Non-patent Document 4).
  • R 1 represents optionally substituted aryl or the like;
  • X represents —CO or —SO 2 — or the like;
  • R 2 represents hydrogen or optionally substituted lower alkyl or the like;
  • W represents —CR 4 —, —CH 2 CR 4 —, or N;
  • R 3 represents —CO—R 7 , hydrogen, optionally substituted alkyl, etc .;
  • R 4 is hydrogen or optionally substituted alkyl;
  • R 5 represents hydrogen, hydroxyl, optionally substituted amino, etc .;
  • R 6 represents hydrogen, optionally substituted alkyl, or the like;
  • R 7 represents an optionally substituted lower alkyl or the like.
  • Patent Document 1 specifically discloses the following compounds and the like:
  • GSK-923295 is also disclosed in Non-Patent Document 5 and Non-Patent Document 6.
  • R 1 represents an optionally substituted cycloalkyl or the like;
  • X represents —CO or —SO 2 —;
  • R 2 represents hydrogen or optionally substituted lower alkyl;
  • W represents —CR 8 —, —CH 2 CR 8 — or N;
  • R 3 represents —CO—R 7 , hydrogen, optionally substituted alkyl, etc .;
  • R 4 represents halo, optionally substituted alkyl or the like;
  • R 5 represents halo, hydroxy, optionally substituted amino and the like;
  • R 6 represents an optionally substituted alkyl or the like;
  • R 7 represents an optionally substituted lower alkyl or the like;
  • R 8 represents hydrogen or optionally substituted alkyl; or R 4 and R 5 together with the carbon to which they are attached represent an oxo group; or
  • R 5 represents hydrogen or an optionally substituted lower alkyl
  • R 1 is hydrogen, optionally substituted alkyl, etc .
  • R 2 represents an optionally substituted alkyl or the like
  • n is 0, 1, 2, or 3
  • R 3 is halo, cyano, carboxy, nitro, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, etc .
  • R 1 and R 2 are the nitrogen to which they are attached
  • Taken together represent an optionally substituted 4- to 7-membered ring; or R 3 located in the ortho position of the —NR 1 R 2 group is R 1 or R 2 and the atom to which they are attached. Together with, forms an optionally substituted 5- to 7-membered ring.
  • R 1 represents an optionally substituted cycloalkyl or the like
  • X represents — (CR 10 R 11 ) m , — (CR 10 R 11 ) n C (R 13 ) ⁇ C (R 14 ), —O (CR 10 R 11 ) p —, or NR 8 —
  • Y represents a direct bond connecting X and Z, —C (O) —, or —C ( ⁇ N—R 9 ) —
  • R 8 represents —CO—R 7 , hydrogen, alkoxy, optionally substituted alkyl, etc .
  • R 9 represents hydrogen, alkoxy, optionally substituted alkyl or the like
  • R 10 and R 11 are independently hydrogen, hydroxy, optionally substituted alkyl, optionally substitute
  • Non-Patent Document 8 is also disclosed in Non-Patent Document 8.
  • K represents CH, N, —C (optionally substituted alkyl) — or the like;
  • L represents CH or N;
  • Q A represents H, alkyl, unsubstituted heteroaryl, substituted heteroaryl, etc .;
  • Q B represents H, alkyl, aryl or the like;
  • Q C is, H, -CON (R 12) 2, -N (R 12) 2, -NH 2, and -NH-alkyl or the like;
  • Q D represents H or alkyl.
  • KCNQ2, KCNQ3 modulator disclosed in Patent Document 6 and useful for treating migraine, brain tumors, and the like:
  • Q, W and Z are all carbon atoms, or any one is a nitrogen atom and the other is a carbon atom;
  • X represents a carbon atom or a nitrogen atom;
  • Y represents — (CH 2 ) n —CO—NR 5 —, — (CH 2 ) n —NR 5 —CO—, — (CH 2 ) n —SO 2 —NR 5 — and the like
  • n 0 to 6 represents R 5 : H, optionally substituted C 1-7 alkyl, etc.
  • R 1 and R 2 are each H, optionally substituted C 1-7 alkyl, CN, CF 3 and the like;
  • R 3 represents CF 3 , optionally substituted C 1-9 alkyl, optionally substituted aryl, etc .;
  • R 4 represents an optionally substituted C 1-9 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and the like;
  • R 11 and R 12 are each H,
  • R 1 to R 3 each represents a group via H, C, a group via N, a group via O or a group via S; Ring A: A ring optionally having a substituent other than R 3 is shown.
  • R 1 ⁇ R 5 are each H, halo, optionally substituted C 1-10 alkyl, carbamoyl which may be substituted, or optionally substituted N- and (C 1-10 alkyl) carbamoyl ;
  • R 6 is, H, halo, optionally substituted C 1-10 alkyl, carbamoyl which may be substituted, or optionally substituted N- and (C 1-10 alkyl) carbamoyl;
  • X is phenyl or 5- or 6-membered heteroaryl;
  • R 7 represents a substituent;
  • n is 0 to 4;
  • R 8 represents H, aryl, heteroaryl or the like;
  • R 9 represents H, alkyl, haloalkyl, aryl, heteroaryl or the like.
  • R 1 is a group of the formula R 9 —X 2 — (R 9 is H, an alkyl group having 1 to 6 carbon atoms, 1 to 3 substituted alkyl group having 1 to 6 carbon atoms, etc., and X 2 is A single bond, a carbonyl group, a sulfonyl group, etc.); R 2 represents H; R 3 to R 8 are each halo, cyano, nitro, or R 10 -X 3 (R 10 is H, an alkyl group having 1 to 6 carbon atoms, 1 to 3 carbon atoms having 1 to 6 carbon atoms substituted) An alkyl group or the like, X 3 represents a single bond, an oxygen atom (—O—), a sulfur atom (—S—) or the like); X 1 represents an oxygen atom, a sulfur atom or NH. ] A compound represented by
  • R 1 represents —C (X) NR 5 R 6 , —C ( ⁇ NCN) NR 5 NR 6 and the like
  • R 2 represents H, optionally substituted C 1-8 alkyl, optionally substituted aryl, etc .
  • A represents a bond, an optionally substituted C 1-8 alkylene, or a C 2-12 group having at least one alkylene
  • a represents 0 to 8
  • One of R 3 and R 4 is the following (iii), the other is (iv) (iii): H, -ZR 9 , halo, an optionally substituted heterocycle, etc.
  • W 1 , W 3 , W 4 , W 6 , W 8 and W 9 are each C or N;
  • R 2 is halo, optionally substituted alkyl, optionally substituted alkenyl, —CONR 10 R 11 , —COR 12 or the like;
  • R 5 represents halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and the like;
  • R 7 represents halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl and the like.
  • R 1 and R 2 are each H, halo, C 1-10 alkyl, C 1-8 alkoxy and the like together or together with C 3-5 alkylene; R 3 to R 7 are each H, halo, C 1-10 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy and the like; A represents —CH ⁇ CH—CH ⁇ CH— or — (CH 2 ) 4 —; B represents —NH— or —CH 2 —N (R 8 ) — (R 8 represents H, C 1-10 alkyl or C 7-10 aralkyl).
  • R 1 is H, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl, an optionally substituted C 3-10 cycloalkyl, an optionally substituted C 6-10 aryl, etc .
  • R 2 represents an optionally substituted C 6-10 aryl, or an optionally substituted C 6-10 heteroalkyl
  • R 3 to R 5 are each H, halo, optionally substituted C 1-6 alkyl and the like
  • R 6 represents H, halo, optionally substituted C 1-6 alkyl or the like.
  • R 1 represents a substituent
  • R 2 represents a hydrogen atom or a substituent
  • R 3 represents a hydrogen atom or a substituent
  • Ar ring represents an optionally substituted aromatic ring
  • R 4 and R 5 are the same or different and each represents an optionally substituted C 1-6 alkyl.
  • the compound represented by the formula [hereinafter sometimes referred to as compound (I)] or a salt thereof has an excellent CENP-E inhibitory action, is useful for the prevention and treatment of cancer and the like, and has an excellent medicinal effect. Found for the first time to have. Based on this knowledge, the present inventors have conducted intensive studies and completed the present invention. That is, the present invention is as follows. [1] Formula:
  • R 1 represents a substituent
  • R 2 represents a hydrogen atom or a substituent
  • R 3 represents a hydrogen atom or a substituent
  • Ar ring represents an optionally substituted aromatic ring
  • R 4 and R 5 are the same or different and each represents an optionally substituted C 1-6 alkyl.
  • Compound (I) or a salt thereof has an excellent CENP-E inhibitory action, is useful for the prevention and treatment of cancer and the like, and has an excellent medicinal effect.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • hydrocarbon group in “optionally substituted hydrocarbon group” means, for example, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cyclo Alkyl, C 3-10 cycloalkenyl, C 4-10 cycloalkadienyl, C 6-14 aryl, C 7-13 aralkyl, C 8-13 arylalkenyl are shown.
  • C 1-10 alkyl means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl are shown. Of these, C 1-6 alkyl is preferable.
  • C 1-6 alkyl means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl are shown.
  • C 2-10 alkenyl means, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl -2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl . Of these, C 2-6 alkenyl is preferable.
  • C 2-6 alkenyl means, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl And -2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
  • C 2-10 alkynyl means, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl. 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl. Of these, C 2-6 alkynyl is preferred.
  • C 2-6 alkynyl means, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl.
  • C 3-10 cycloalkyl refers to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Of these, C 3-8 cycloalkyl is preferable. In the present specification, “C 3-8 cycloalkyl” refers to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • C 3-10 cycloalkenyl refers to, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, and 3-cyclohexen-1-yl. Show. Of these, C 3-6 cycloalkenyl is preferable. In the present specification, “C 3-6 cycloalkenyl” means, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl. Show.
  • C 4-10 cycloalkadienyl means, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadiene-1 -Indicates il. Of these, C 4-6 cycloalkadienyl is preferable. In the present specification, “C 4-6 cycloalkadienyl” means, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadiene-1 -Indicates il.
  • C 3-10 cycloalkyl may each be condensed with a benzene ring to form a condensed ring group.
  • fused ring groups include, for example, indanyl, dihydronaphthyl, tetrahydronaphthyl, and fluorenyl.
  • C 3-10 cycloalkyl may be a bridged condensed ring group.
  • bridged fused ring groups include bicyclo [2.2.1] heptyl (norbornyl), bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3 2.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, and adamantyl.
  • C 3-10 cycloalkyl C 3-10 cycloalkenyl” and “C 4-10 cycloalkadienyl” are C 3-10 cycloalkane, C 3-10 cycloalkene or A spiro ring group may be formed with C 4-10 cycloalkadiene.
  • C 3-10 cycloalkane C 3-10 cycloalkene and C 4-10 cycloalkadiene
  • C 3-10 cycloalkyl C 3-10 cycloalkenyl” and “C 4-10 ”
  • a ring corresponding to "cycloalkadienyl An example of such a spiro ring group is spiro [4.5] decan-8-yl.
  • C 6-14 aryl represents, for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl. Of these, C 6-10 aryl is preferable. In the present specification, “C 6-10 aryl” means, for example, phenyl, 1-naphthyl, 2-naphthyl.
  • C 7-13 aralkyl refers to, for example, benzyl, phenethyl, naphthylmethyl, biphenylylmethyl.
  • C 8-13 arylalkenyl refers to, for example, styryl.
  • C 1-6 alkoxy means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy.
  • C 1-6 alkyl-carbonyl means, for example, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, hexyl. Indicates carbonyl.
  • C 1-6 alkoxy-carbonyl refers to, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl.
  • C 1-10 alkyl C 2-10 alkenyl
  • C 2-10 alkynyl C 1-6 alkyl
  • C 2-6 alkynyl C 1-6 alkyl
  • substituent group A The number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.
  • Substituent group A (1) a halogen atom; (2) Cyano; (3) Nitro; (4) hydroxy; (5) carboxy; (6) (a) a halogen atom, (b) hydroxy, (c) C 1-6 alkyl optionally having 1 to 3 halogen atoms, (d) C 1-6 alkoxy optionally having 1 to 3 halogen atoms, and (e) C 3-8 cyclo optionally having 1 to 3 substituents selected from oxo Alkyl; (7) (a) a halogen atom, (b) hydroxy, (c) cyano, (d) C 1-6 alkyl optionally having 1 to 3 halogen atoms, (e) C 1-6 alkoxy optionally having 1 to 3 halogen atoms, (f) 4 to 12-membered non-aromatic heterocyclic group (eg, pyrrolidinyl), and (g) 1 to 5 selected from sulfanyl optionally having 1 to 5 halogen atoms (
  • C 6-10 aryl optionally having 3 substituents (8) (a) a halogen atom, (b) hydroxy, 1 selected from (c) C 1-6 alkyl optionally having 1 to 3 halogen atoms, and (d) C 1-6 alkoxy optionally having 1 to 3 halogen atoms.
  • a 5- to 12-membered aromatic heterocyclic group optionally having 3 substituents; (9) (a) a halogen atom, (b) hydroxy, (c) C 1-6 alkyl optionally having 1 to 3 halogen atoms, (d) C 1-6 alkoxy optionally having 1 to 3 halogen atoms, (e) C 1-6 alkoxy-carbonyl optionally having 1 to 3 C 6-10 aryl (eg, phenyl), (f) oxo, and (g) C 7-13 aralkyloxy-carbonyl (eg, benzyloxycarbonyl)
  • a 4- to 12-membered non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from: (10) (a) (i) hydroxy, (ii) (A) a 5- to 12-membered aromatic heterocyclic group (eg, imidazolyl), (B) an amino optionally having 1 or 2 C 1-6 alkyl (eg, methyl), (C)
  • a 5- to 12-membered aromatic heterocyclic group optionally having 3 substituents, (h) (i) a halogen atom, (ii) hydroxy, (iii) C 1-6 alkyl optionally having 1 to 3 halogen atoms, (iv) C 1-6 alkoxy optionally having 1 to 3 halogen atoms, and (v) 4 to 12 membered optionally having 1 to 3 substituents selected from oxo A non-aromatic heterocyclic group, and (i) C 1-6 alkoxy optionally having 1 to 3 substituents selected from hydroxy; (20) C 2-6 alkenyloxy optionally having 1 to 3 halogen atoms (eg, ethenyloxy); (21) C 3-8 cycloalkyloxy (eg, cyclopropoxy, cyclopentyloxy) optionally having 1 to 3 substituents selected from (a) a halogen atom, and (b) C 1-6 alkoxy ); (22) C 6-10 aryl
  • substituent which “C 6-14 aryl”, “C 7-13 aralkyl” and “C 8-13 arylalkenyl” may have is selected from the following substituent group B: A substituent is mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.
  • Substituent group B (1) a substituent selected from the substituent group A; (2) (a) a halogen atom, (b) hydroxy, (c) carboxy, (d) C 1-6 alkoxy, (e) may have 1 to 3 substituents selected from C 1-6 alkoxy-carbonyl, and (f) amino optionally having 1 or 2 C 1-6 alkyl C 1-6 alkyl; (3) (a) a halogen atom, (b) hydroxy, (c) carboxy, (d) C 1-6 alkoxy, (e) C 1-6 alkoxy-carbonyl, and (f) C 1-6 alkyl optionally having 1 to 3 substituents selected from amino optionally having 1 or 2 C 1-6 alkyl 2-6 alkenyl; (4) (a) a halogen atom, (b) hydroxy, (c) C 1-6 alkyl optionally having 1 to 3 halogen atoms, and (d) C 1-6 optionally having a substituent selected from C 1-6 alkoxy
  • examples of the substituent that the “C 3-10 cycloalkyl”, “C 3-10 cycloalkenyl” and “C 4-10 cycloalkadienyl” may have include the following substituents C And substituents selected from the group.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.
  • Substituent group C (1) a substituent selected from the substituent group A; (2) (a) a halogen atom, (b) hydroxy, (c) carboxy, (d) C 1-6 alkoxy, (e) C 1-6 alkoxy-carbonyl, and (f) C 1-6 alkyl optionally having 1 to 3 substituents selected from amino optionally having 1 or 2 C 1-6 alkyl 1-6 alkyl; (3) (a) a halogen atom, (b) hydroxy, (c) carboxy, (d) C 1-6 alkoxy, (e) C 1-6 alkoxy-carbonyl, and (f) C 1-6 alkyl optionally having 1 to 3 substituents selected from amino optionally having 1 or 2 C 1-6 alkyl 2-6 alkenyl; (4) (a) a halogen atom, (b) hydroxy, (c) C 1-6 alkyl optionally having 1 to 3 halogen atoms, and (d) C 1-6 optionally having a substituent selected from
  • the “heterocyclic group” in the “optionally substituted heterocyclic group” refers to an aromatic heterocyclic group and a non-aromatic heterocyclic group.
  • the “aromatic heterocyclic group” refers to a monocyclic aromatic heterocyclic group and a condensed aromatic heterocyclic group. Examples of the monocyclic aromatic heterocyclic group include 5 to 7 members (preferably containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom).
  • 5- or 6-membered monocyclic aromatic heterocyclic groups such as furyl (eg 2-furyl, 3-furyl), thienyl (eg 2-thienyl, 3-thienyl), pyridyl (eg 2- Pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), Pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl) ), Pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazo
  • condensed aromatic heterocyclic group examples include an 8- to 12-membered condensed aromatic heterocyclic group, specifically, a ring corresponding to the 5- to 7-membered monocyclic aromatic heterocyclic group and C 6.
  • a group derived from a condensed ring formed by condensation with -10 arene (eg, benzene, naphthalene); formed by condensation of rings corresponding to the 5- to 7-membered monocyclic aromatic heterocyclic group
  • Groups derived from fused rings for example, quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolyl (eg, 3-isoquinolyl), quinazolyl (eg, 2-quinazolyl, 4-quinolyl) Quinazolyl), quinoxalyl (eg, 2-quinoxalyl, 6-quinoxalyl), benzofuranyl (eg, 2-benzofuranyl, 3-benzofuranyl), benzothienyl (
  • the “5- to 12-membered aromatic heterocyclic group” refers to the 5- to 7-membered monocyclic aromatic heterocyclic group and the 8- to 12-membered condensed aromatic heterocyclic group.
  • non-aromatic heterocyclic group refers to a monocyclic non-aromatic heterocyclic group and a condensed non-aromatic heterocyclic group.
  • the monocyclic non-aromatic heterocyclic group include a hetero atom selected from an oxygen atom, a sulfur atom (the sulfur atom may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring-constituting atom.
  • azetidinyl eg, 1-azetidinyl, 2-azetidinyl
  • pyrrolidinyl eg, 1 -Pyrrolidinyl, 2-pyrrolidinyl
  • piperidyl eg, piperidino, 2-piperidyl, 3-piperidyl
  • morpholinyl eg, morpholino
  • thiomorpholinyl eg, thiomorpholino
  • piperazinyl eg, 1-piperazinyl, 2-piperazinyl) 3-piperazinyl
  • oxazolidinyl eg, oxazolidin-2-yl
  • thiazolidinyl eg, thiazolidin- -Yl
  • imidazolidinyl eg, imidazolidin-2-yl, imidazolidin-3-
  • fused non-aromatic heterocyclic group examples include, for example, an 8- to 12-membered fused non-aromatic heterocyclic group, specifically, a ring corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group.
  • a group derived from a condensed ring formed by the condensation of C 6-10 arene (eg, benzene, naphthalene); the rings corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group are condensed together
  • the “4- to 12-membered non-aromatic heterocyclic group” refers to the 4- to 7-membered monocyclic non-aromatic heterocyclic group and the 8- to 12-membered condensed non-aromatic heterocyclic group. Show.
  • the aromatic heterocyclic group when the “heterocyclic group” in the “optionally substituted heterocyclic group” is an “aromatic heterocyclic group”, the aromatic heterocyclic group may have a substituent Examples of the group include a substituent selected from the above-mentioned substituent group B.
  • the “heterocyclic group” in the “optionally substituted heterocyclic group” is a “non-aromatic heterocyclic group”
  • the non-aromatic heterocyclic group may have The substituent chosen from the said substituent C group is mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.
  • the "which may hydroxy also be substituted" may be substituted respectively, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 And hydroxy which may have a substituent selected from cycloalkenyl, C 6-14 aryl, C 7-13 aralkyl, C 8-13 arylalkenyl, C 1-6 alkyl-carbonyl, and heterocyclic group.
  • optionally substituted hydroxy include, for example, hydroxy; each optionally substituted C 1-10 alkoxy, C 2-10 alkenyloxy, C 3-10 cycloalkyloxy, C Examples include 3-10 cycloalkenyloxy, C 6-14 aryloxy, C 7-13 aralkyloxy, C 8-13 arylalkenyloxy, C 1-6 alkyl-carbonyloxy, and heterocyclic oxy.
  • the "which may mercapto also be substituted" may be substituted respectively, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 And mercapto which may have a substituent selected from cycloalkenyl, C 6-14 aryl, C 7-13 aralkyl, C 8-13 arylalkenyl, C 1-6 alkyl-carbonyl, and heterocyclic group.
  • optionally substituted mercapto include, for example, mercapto; each optionally substituted C 1-10 alkylthio, C 2-10 alkenylthio, C 3-10 cycloalkylthio, C 3 -10 cycloalkenylthio, C 6-14 arylthio, C 7-13 aralkylthio, C 8-13 arylalkenylthio, C 1-6 alkyl-carbonylthio, heterocyclic thio.
  • amino optionally substituted may be substituted respectively, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 aryl, C 7-13 aralkyl, C 8-13 arylalkenyl, heterocyclic group; amino optionally having 1 to 2 substituents selected from acyl;
  • optionally substituted amino include, for example, amino; mono- or di-C 1-10 alkyl-amino, mono- or di-C 2-10 each optionally substituted. Alkenyl-amino, mono- or di-C 3-10 cycloalkyl-amino, mono- or di-C 3-10 cycloalkenyl-amino, mono- or di-C 6-14 aryl-amino, mono- or di- C 7-13 aralkyl-amino, mono- or di-C 8-13 arylalkenyl-amino, mono- or di-heterocycle-amino; mono- or di-acyl-amino.
  • acyl refers to, for example, the formula: —COR A , —CO—OR A , —SO 3 R A , —S (O) 2 R A , —SOR A , —CO—NR A ′ R B ′, —CS—NR A ′ R B ′, —S (O) 2 NR A ′ R B ′ [wherein R A represents a hydrogen atom, an optionally substituted hydrocarbon group, or a substituted group; An optionally substituted heterocyclic group is shown.
  • R A ′ and R B ′ are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or R A ′ and R B ′ are And a nitrogen-containing heterocyclic ring which may be substituted together with the adjacent nitrogen atom].
  • the “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” means a nitrogen-containing aromatic heterocycle having at least one nitrogen atom as a ring-constituting atom and a nitrogen-containing non-ring.
  • An aromatic heterocycle is shown.
  • the nitrogen-containing aromatic heterocycle include 5- to 7-membered (preferably 5- or 6-membered) monocyclic nitrogen-containing aromatic heterocycle and 8- to 12-membered condensed nitrogen-containing aromatic heterocycle. It is done.
  • 5- to 7-membered (preferably 5- or 6-membered) monocyclic nitrogen-containing aromatic heterocycle examples include pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, Examples include isoxazole, oxadiazole, thiadiazole, triazole (eg, 1,2,3-triazole, 1,2,4-triazole), tetrazole and triazine.
  • 8- to 12-membered condensed nitrogen-containing aromatic heterocycle examples include quinoline, isoquinoline, quinazoline, quinoxaline, benzoxazole, benzisoxazole, benzothiazole, benzimidazole (eg, 1H-benzimidazole), benzotriazole ( Examples: 1H-1,2,3-benzotriazole), indole, indazole, pyrrolopyrazine, imidazopyridine (eg, 1H-imidazo [4,5-b] pyridine, 1H-imidazo [4,5-c] pyridine) , Thienopyridinine, imidazopyrazine, pyrazolopyridine, pyrazolothiophene, and pyrazolotriazine.
  • nitrogen-containing non-aromatic heterocycle examples include 4- to 7-membered (preferably 5- or 6-membered) monocyclic nitrogen-containing non-aromatic heterocycle and 6- to 12-membered condensed nitrogen-containing non-aromatic heterocycle. A ring is mentioned.
  • 4- to 7-membered (preferably 5- or 6-membered) monocyclic nitrogen-containing non-aromatic heterocycle include azetidine, pyrrolidine, piperidine, morpholine, piperazine, oxazolidine, thiazolidine, imidazolidine, oxazoline, thiazoline Imidazoline, pyrazolidine, pyrazoline, dihydropyridine (eg, 1,2-dihydropyridine), tetrahydropyridine (eg, 1,2,3,4-tetrahydropyridine, 1,2,5,6-tetrahydropyridine), dihydropyrimidine (eg, 1,2-dihydropyrimidine) and tetrahydropyrimidine (eg, 1,2,5,6-tetrahydropyrimidine).
  • dihydropyridine eg, 1,2-dihydropyridine
  • tetrahydropyridine eg, 1,2,3,4-tetrahydropyridine
  • 6 to 12-membered condensed nitrogen-containing non-aromatic heterocycle include dihydroindole (eg, indoline), dihydroisoindole (eg, isoindoline), dihydroquinoline (eg, 1,2-dihydroquinoline), Tetrahydroquinoline (eg, 1,2,3,4-tetrahydroquinoline), dihydroisoquinoline (eg, 1,2-dihydroisoquinoline), tetrahydroisoquinoline (eg, 1,2,3,4-tetrahydroisoquinoline), dihydrophthalazine (Eg, 1,2-dihydrophthalazine), azabicyclohexane (eg, 2-azabicyclo [3.1.0] hexane).
  • dihydroindole eg, indoline
  • dihydroisoindole eg, isoindoline
  • dihydroquinoline eg, 1,2-dihydroquino
  • nitrogen-containing heterocycle when “nitrogen-containing heterocycle” is “nitrogen-containing aromatic heterocycle”, it may have a substituent selected from the above-mentioned substituent group B at a substitutable position. Further, when the “nitrogen-containing heterocycle” is a “nitrogen-containing non-aromatic heterocycle”, it may have a substituent selected from the above-mentioned substituent group C.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.
  • acyl (1) formyl; (2) carboxy; (3) C 1-6 alkyl-carbonyl optionally having 1 to 3 halogen atoms; (4) C 1-6 alkoxy-carbonyl optionally having 1 to 3 halogen atoms; (5) C 3-10 cycloalkyl-carbonyl; (6) C 6-14 aryl-carbonyl optionally having 1 to 3 halogen atoms; (7) (a) a halogen atom, C 1-6 alkoxy, C 1-6 alkoxy - 1 selected from carbonyl and carboxy to 3 substituents substituted C 1-6 alkyl, and (b ) A carbamoyl optionally having 1 or 2 substituents selected from amino optionally having 1 or 2 C 1-6 alkoxy-carbonyl; (8) C 1-6 alkylsulfonyl optionally having 1 to 3 halogen atoms; (9) C 6-14 arylsulfonyl; (10) sulfamoyl; (11)
  • the “aromatic ring” in the “optionally substituted aromatic ring” refers to a C 6-14 aromatic hydrocarbon or an aromatic heterocyclic ring.
  • C 6-14 aromatic hydrocarbon represents a ring corresponding to “C 6-14 aryl”.
  • a ring corresponding to “C 6-10 aryl” is preferable, and benzene is particularly preferable.
  • the “aromatic heterocyclic ring” refers to a ring corresponding to the “aromatic heterocyclic group”. Among these, monocyclic aromatic heterocycles are preferable, and 5- or 6-membered monocyclic aromatic heterocycles are particularly preferable.
  • the “aromatic ring” may have a substituent selected from the above-mentioned substituent group B at a substitutable position.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.
  • C 1-6 alkyl in the "optionally substituted C 1-6 alkyl", methyl, ethyl, propyl and the like.
  • the C 1-6 alkyl may have a substituent selected from the above substituent group A at a substitutable position.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.
  • R 1 represents a substituent.
  • R 2 represents a hydrogen atom or a substituent.
  • R 3 represents a hydrogen atom or a substituent.
  • the “substituent” represented by R 1 , R 2 or R 3 include “optionally substituted hydrocarbon group”, “optionally substituted heterocyclic group”, and “optionally substituted hydroxy”. ”,“ Optionally substituted mercapto ”,“ optionally substituted amino ”,“ cyano ”,“ nitro ”,“ acyl ”,“ halogen atom ”and the like.
  • R 1 is preferably a halogen atom, an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, C 1-6 Amino or cyano optionally having 1 or 2 alkyls, C 1-6 alkoxy-carbonyl which may be substituted, or C 3-10 cycloalkyl which may be substituted.
  • R 1 is more preferably (1) halogen atom (eg, chlorine atom, bromine atom), (2) (a) a halogen atom (eg, fluorine atom), and (b) C 1-6 alkyl (eg, methyl) optionally having 1 to 3 substituents selected from hydroxy, (3) C 2-6 alkynyl (eg, ethynyl, 1-propynyl), (4) (a) a halogen atom (eg, fluorine atom), and (b) a C 1-6 alkoxy (eg, methoxy, ethoxy) optionally having 1 to 3 substituents selected from hydroxy, (5) amino optionally having 1 or 2 C 1-6 alkyl (eg, methyl, ethyl), (6) Cyano, (7) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl), or (8) C 3-10 cycloalkyl (eg, cyclopropyl) It is.
  • R 1 is Even more preferably, (1) a halogen atom (e.g., bromine atom), (2) C 2-6 alkynyl (eg, ethynyl), (3) C 1-6 alkoxy (eg, methoxy, ethoxy), or (4) amino optionally having 1 or 2 C 1-6 alkyl (eg, methyl, ethyl), Above all, C 1-6 alkoxy (eg methoxy) is preferred.
  • a halogen atom e.g., bromine atom
  • C 2-6 alkynyl eg, ethynyl
  • C 1-6 alkoxy eg, methoxy, ethoxy
  • amino optionally having 1 or 2 C 1-6 alkyl eg, methyl, ethyl
  • C 1-6 alkoxy eg methoxy
  • R 2 is preferably a hydrogen atom.
  • R 3 is preferably a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl, cyano, C 2-6 alkynyl, or an optionally substituted amino.
  • R 3 is more preferably (1) hydrogen atom, (2) halogen atoms (eg, bromine atoms), (3) C 1-6 alkyl (eg, methyl), (4) cyano, (5) C 2-6 alkynyl (eg, ethynyl), or (6) Amino optionally having 1 or 2 C 1-6 alkyl-carbonyl (eg, acetylacetyl).
  • halogen atoms eg, bromine atoms
  • C 1-6 alkyl eg, methyl
  • cyano (5) C 2-6 alkynyl (eg, ethynyl)
  • Amino optionally having 1 or 2 C 1-6 alkyl-carbonyl (eg, acetylacetyl).
  • R 3 is even more preferably (1) hydrogen atom, (2) a halogen atom (eg bromine atom), or (3) C 1-6 alkyl (eg, methyl) It is.
  • R 3 is particularly preferably a hydrogen atom.
  • Ar ring represents an optionally substituted aromatic ring.
  • the Ar ring is preferably an optionally substituted C 6-10 aromatic hydrocarbon (eg, benzene) or an optionally substituted 5 or 6 membered monocyclic aromatic heterocycle (eg, pyridine). It is.
  • the Ar ring is more preferably (1) (a) Halogen atom (eg, fluorine atom, chlorine atom), (b) cyano, (c) C 1-6 alkyl optionally having 1 to 3 hydroxy (eg, methyl, ethyl), (d) C 1-6 alkoxy (eg, methoxy), and (e) C 2-6 alkynyl (eg, ethynyl)
  • a C 6-10 aromatic hydrocarbon eg, benzene
  • substituents selected from: (2) 5- or 6-membered monocyclic aromatic heterocycle (eg, pyridine) It is.
  • the Ar ring is preferably an optionally substituted benzene. Since the compound of the present invention having such an Ar ring has high CENP-E selectivity and can obtain a medicinal effect at a low dose, it is an excellent preventive / therapeutic agent for cancer and the like with reduced side effects.
  • the Ar ring is (a) a halogen atom (e.g., fluorine atom), (b) C 1-6 alkyl (eg, methyl), (c) C 1-6 alkoxy (eg, methoxy), and (d) C 2-6 alkynyl (eg, ethynyl)
  • Benzene optionally having 1 to 3 substituents selected from: Particularly preferably, (a) a halogen atom (eg, fluorine atom), and (b) C 1-6 alkyl (eg, methyl) It is benzene which may have 1 to 3 substituents selected from
  • R 4 and R 5 are the same or different and each represents an optionally substituted C 1-6 alkyl.
  • R 4 and R 5 are preferably the same or different, (1) hydroxy, (2) (i) (a) hydroxy, (b) (A) a 5- to 12-membered aromatic heterocyclic group (eg, imidazolyl), (B) an amino optionally having 1 or 2 C 1-6 alkyl (eg, methyl), (C) hydroxy, (D) C 1-3 alkylenedioxy (eg, methylenedioxy), and (E) C 1-6 alkyl (eg, fluorine atom) optionally having 1 to 3 halogen atoms (eg, fluorine atom) Methyl) C 6-10 aryl (eg, phenyl, naphthyl) optionally having 1 to 3 substituents selected from (c) (A) C 1-6 alkyl (eg, methyl, ethyl, propyl) optionally having 1 to 3 hydroxys, (B) C 1-6 alkoxy (eg, methoxy), (C) C 1-6 alkoxy-carbon
  • C 6-10 aryl eg, phenyl
  • C 6-10 aryloxy eg, phenoxy
  • a 4- to 12-membered non-aromatic heterocyclic group eg, piperidyl, morpholinyl, pyrrolidinyl
  • R 4 is (1) hydroxy, (2) (i) (a) hydroxy, (b) (A) a 5- to 12-membered aromatic heterocyclic group (eg, imidazolyl), (B) an amino optionally having 1 or 2 C 1-6 alkyl (eg, methyl), (C) hydroxy, (D) C 1-3 alkylenedioxy (eg, methylenedioxy), and (E) C 1-6 alkyl (eg, fluorine atom) optionally having 1 to 3 halogen atoms (eg, fluorine atom) Methyl) C 6-10 aryl (eg, phenyl, naphthyl) optionally having 1 to 3 substituents selected from (c) (A) C 1-6 alkyl (eg, methyl, ethyl, propyl) optionally having 1 to 3 hydroxys, (B) C 1-6 alkoxy (eg, methoxy), (C) C 1-6 alkoxy-carbonyl (eg, me
  • An amino optionally having 1 or 2 substituents selected from: (3) (i) a C 1-6 alkyl (eg, methyl), and (ii) a 4- to 12-membered non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from hydroxy (Eg, morpholinyl, pyrrolidinyl), and (4) Halogen atoms (eg, fluorine atoms) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isopentyl, hexyl) optionally having 1 to 3 substituents selected from R 5 and (1) hydroxy, (2) (i) C 1-6 alkyl (eg, methyl) optionally having 1 to 3 5- to 12-membered aromatic heterocyclic groups (eg, indolyl), (ii) (a) hydroxy, (b) cyano, (c) a halogen atom (eg, fluorine atom), (d) C
  • C 6-10 aryl eg, phenyl
  • C 6-10 aryloxy eg, phenoxy
  • R 4 is more preferably (1) (i) (a) hydroxy, (b) (A) a 5- to 12-membered aromatic heterocyclic group (eg, imidazolyl), (B) an amino optionally having 1 or 2 C 1-6 alkyl (eg, methyl), (C) hydroxy, (D) C 1-3 alkylenedioxy (eg, methylenedioxy), and (E) C 1-6 alkyl (eg, fluorine atom) optionally having 1 to 3 halogen atoms (eg, fluorine atom) Methyl) C 6-10 aryl (eg, phenyl, naphthyl) optionally having 1 to 3 substituents selected from (c) (A) C 1-6 alkyl (eg, methyl, ethyl, propyl) optionally having 1 to 3 hydroxys, (B) C 1-6 alkoxy (eg, methoxy), (C) C 1-6 alkoxy-carbonyl (eg, methoxycarbony
  • the compound of the present invention having such R 4 is particularly excellent in CENP-E enzyme inhibitory activity in vitro and in cancer cells.
  • R 4 is even more preferably (i) amino optionally having 1 or 2 C 1-6 alkyl (eg, methyl, propyl) optionally having 1 to 3 hydroxy, and (ii) 1 to 3 4- to 12-membered non-aromatic heterocyclic group (eg, pyrrolidinyl) optionally having C 1-6 alkyl (eg, methyl) C 1-6 alkyl (eg, ethyl, butyl) having 1 to 3 substituents selected from Particularly preferred is C 1-6 alkyl (eg, ethyl, butyl) having 1 to 3 aminos optionally having 1 or 2 C 1-6 alkyl (eg, methyl).
  • C 1-6 alkyl eg, ethyl, butyl
  • R 5 is even more preferably (i) a halogen atom (eg, chlorine atom), and (ii) C 1-6 alkyl (eg, methyl) optionally having 1 to 3 halogen atoms (eg, fluorine atom), A phenyl group which may have 1 to 3 substituents selected from: C 1-6 alkyl (eg, methyl, ethyl) which may further have 1 to 3 hydroxy groups.
  • a halogen atom eg, chlorine atom
  • C 1-6 alkyl eg, methyl
  • halogen atoms eg, fluorine atom
  • a halogen atom eg, chlorine atom
  • C 1-6 alkyl eg, methyl
  • substituents for example, methyl, ethyl
  • R 1 is a halogen atom, an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, a C 1-6 alkyl 1 Or optionally 2 amino, cyano, optionally substituted C 1-6 alkoxy-carbonyl, or optionally substituted C 3-10 cycloalkyl;
  • R 2 is a hydrogen atom;
  • R 3 is (1) hydrogen atom, (2) halogen atoms (eg, bromine atoms), (3) C 1-6 alkyl (eg, methyl), (4) cyano, (5) C 2-6 alkynyl (eg, ethynyl), or (6) Amino optionally having 1 or 2 C 1-6 alkyl-carbonyl (eg, acetyl);
  • the Ar ring is an optionally substituted C 6-10 aromatic hydrocarbon (preferably benzene) or an optionally substituted 5 or 6 membere
  • R 1 is (1) halogen atom (eg, chlorine atom, bromine atom), (2) (a) a halogen atom (eg, fluorine atom), and (b) C 1-6 alkyl (eg, methyl) optionally having 1 to 3 substituents selected from hydroxy, (3) C 2-6 alkynyl (eg, ethynyl, 1-propynyl), (4) (a) a halogen atom (eg, fluorine atom), and (b) a C 1-6 alkoxy (eg, methoxy, ethoxy) optionally having 1 to 3 substituents selected from hydroxy, (5) amino optionally having 1 or 2 C 1-6 alkyl (eg, methyl, ethyl), (6) Cyano, (7) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl), or (8) C 3-10 cycloalkyl (eg, cyclopropyl) Is; R 2 is (1) halogen
  • C 6-10 aryl eg, phenyl
  • C 6-10 aryloxy eg, phenoxy
  • (5) (i) a halogen atom (eg, a chlorine atom), and (ii) a C 1-6 alkyl (eg, methyl) optionally having 1 to 3 halogen atoms (eg, a fluorine atom) 5- to 12-membered aromatic heterocyclic group (eg, pyridyl, indolyl, benzothienyl, imidazolyl) optionally having 1 to 3 substituents selected from (6) (i) C 1-6 alkyl (eg, methyl) (ii) hydroxy, and (iii) C 7-13 aralkyloxy-carbonyl (eg, benzyloxycarbonyl)
  • a 4- to 12-membered non-aromatic heterocyclic group eg, piperidyl, morpholinyl, pyrrolidinyl
  • An amino optionally having 1 or 2 substituents selected from: (3) (i) a C 1-6 alkyl (eg, methyl), and (ii) a 4- to 12-membered non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from hydroxy (Eg, morpholinyl, pyrrolidinyl), and (4) Halogen atoms (eg, fluorine atoms) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isopentyl, hexyl) optionally having 1 to 3 substituents selected from R 5 and (1) hydroxy, (2) (i) C 1-6 alkyl (eg, methyl) optionally having 1 to 3 5- to 12-membered aromatic heterocyclic groups (eg, indolyl), (ii) (a) hydroxy, (b) cyano, (c) a halogen atom (eg, fluorine atom), (d) C
  • C 6-10 aryl eg, phenyl
  • C 6-10 aryloxy eg, phenoxy
  • (5) (i) a halogen atom (eg, chlorine atom), and (ii) C 1-6 alkyl (eg, methyl) optionally having 1 or 3 halogen atoms (eg, fluorine atom) 5- to 12-membered aromatic heterocyclic group (eg, pyridyl, indolyl, benzothienyl, imidazolyl) optionally having 1 to 3 substituents selected from (6) a 4- to 12-membered non-aromatic heterocyclic group (eg, piperidyl) optionally having 1 to 3 C 7-13 aralkyloxy-carbonyl (eg, benzyloxycarbonyl), (7) C 1-6 alkoxy-carbonyl (eg, ethoxycarbonyl), (8) (i) (a) amino optionally having 1 or 2 C 1-6 al
  • R 1 is a halogen atom, an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, a C 1-6 alkyl 1 Or an amino, cyano or optionally substituted C 1-6 alkoxy-carbonyl which may have two;
  • R 2 is a hydrogen atom;
  • R 3 is a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl;
  • the Ar ring is an optionally substituted C 6-10 aromatic hydrocarbon (preferably benzene) or an optionally substituted 5 or 6 membered monocyclic aromatic heterocycle (preferably pyridine). Yes; and
  • R 4 and R 5 are the same or different and each is an optionally substituted C 1-6 alkyl compound (I).
  • R 1 is (1) a halogen atom (preferably a chlorine atom or a bromine atom), (2) (a) a halogen atom (preferably a fluorine atom), and (b) C 1-6 alkyl (preferably methyl) optionally having 1 to 3 substituents selected from hydroxy, (3) C 2-6 alkynyl (preferably ethynyl, 1-propynyl), (4) (a) a halogen atom (preferably a fluorine atom), and (b) a C 1-6 alkoxy optionally having 1 to 3 substituents selected from hydroxy (preferably methoxy, ethoxy ), (5) amino optionally having 1 or 2 C 1-6 alkyl (preferably methyl, ethyl), (6) cyano, or (7) C 1-6 alkoxy-carbonyl (preferably methoxycarbonyl) Is; R 2 is a hydrogen atom; R 3 is a hydrogen atom; Ar ring is (1) (a) a) a halogen atom
  • R 1 is (1) a halogen atom (e.g., bromine atom), (2) C 2-6 alkynyl (eg, ethynyl), (3) C 1-6 alkoxy (eg, methoxy, ethoxy), or (4) amino optionally having one or two C 1-6 alkyl (eg, methyl, ethyl);
  • R 2 is a hydrogen atom;
  • R 3 is a hydrogen atom;
  • Ar ring is (a) a halogen atom (e.g., fluorine atom), (b) C 1-6 alkyl (eg, methyl), (c) C 1-6 alkoxy (eg, methoxy), and (d) C 2-6 alkynyl (eg, ethynyl) Benzene optionally substituted with 1 to 3 substituents selected from:
  • R 4 is (i) amino optionally having 1 or 2 C 1-6 alkyl (eg, methyl, propyl) optionally having 1 to
  • R 1 is C 1-6 alkoxy (eg, methoxy);
  • R 2 is a hydrogen atom;
  • R 3 is a hydrogen atom;
  • Ar ring is (a) a halogen atom (eg, fluorine atom), and (b) C 1-6 alkyl (eg, methyl) Benzene optionally substituted with 1 to 3 substituents selected from:
  • R 4 is C 1-6 alkyl (eg ethyl, butyl) having 1 to 3 aminos optionally having 1 or 2 C 1-6 alkyl (eg methyl)
  • R 5 is (i) a halogen atom (eg, chlorine atom), and (ii) C 1-6 alkyl (eg, methyl) optionally having 1 to 3 halogen atoms (eg, fluorine atom) C 1-6 alkyl having phenyl optionally having 1 to 3 substituents selected from (eg, methyl, ethyl) Compound (I).
  • Examples of the salt of compound (I) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • the salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • the pharmaceutically acceptable salt include an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt) when the compound has an acidic functional group.
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid
  • examples thereof include salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
  • a salt with an inorganic acid is preferable, and a salt with hydrochloric acid is particularly preferable.
  • Alcohols used as a reaction solvent include, for example, methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol.
  • ethers used as a reaction solvent in the following reaction include dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, and ethylene glycol-dimethyl ether.
  • examples of esters used as a reaction solvent include ethyl formate, ethyl acetate, and n-butyl acetate.
  • examples of the halogenated hydrocarbon used as a reaction solvent include dichloromethane, chloroform, carbon tetrachloride, and trichloroethylene.
  • examples of hydrocarbons used as a reaction solvent include n-hexane, benzene, and toluene.
  • examples of amides used as a reaction solvent include formamide, N, N-dimethylformamide, and N, N-dimethylacetamide.
  • examples of nitriles used as a reaction solvent include acetonitrile and propionitrile.
  • examples of the sulfoxides used as a reaction solvent include dimethyl sulfoxide.
  • examples of aromatic hydrocarbons used as a reaction solvent include benzene and toluene.
  • examples of ketones used as a reaction solvent include acetone, methyl ethyl ketone, and methyl isobutyl ketone.
  • examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metals such as magnesium hydroxide and calcium hydroxide; sodium carbonate and potassium carbonate Alkali metal carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal C 1-6 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; trimethylamine, triethylamine, diisopropylethylamine, pyridine , Picoline, N-methylpyrrolidine, N-methylmorpholine, N, N-dimethylaniline, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane 1,8-diazabi Organic bases such as cyclo [5.4.0] -7-undecene and tetramethylguanidine; organic lithiums such as methyllithium,
  • examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid; methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid And sulfonic acids such as formic acid, acetic acid, propionic acid, and trifluoroacetic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid
  • methanesulfonic acid ethanesulfonic acid
  • benzenesulfonic acid benzenesulfonic acid
  • toluenesulfonic acid camphorsulfonic acid
  • sulfonic acids such as formic acid, acetic acid, propionic acid, and trifluoroacetic acid.
  • lithium, sodium, potassium, cesium, or the like is used as the alkali metal.
  • magnesium, calcium or the like is used as the alkaline earth metal.
  • lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, or the like is used as the alkali metal hydroxide.
  • magnesium hydroxide, calcium hydroxide, or the like is used as the alkaline earth metal hydroxide.
  • ammonium salt inorganic acid ammonium such as ammonium chloride, ammonium sulfate, and ammonium phosphate, or organic acid ammonium such as ammonium acetate, ammonium formate, and ammonium citrate are used.
  • the raw material compound and the production intermediate may be a salt.
  • a salt examples include the same salts as those of the aforementioned compound (I).
  • the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but from the reaction mixture according to a conventional method (for example, separation means such as recrystallization, distillation, chromatography, etc.). It may be isolated.
  • the “amino-protecting group” for P 1 may be any group that can be removed after the cyclization reaction.
  • C 1-6 alkyl-carbonyl optionally substituted with a halogen atom eg, fluorine
  • a halogen atom eg, fluorine
  • C 1-6 alkyl-oxycarbonyl preferably tert-butyloxycarbonyl
  • C 7-13 aralkyl-oxycarbonyl preferably benzyloxy Carbonyl
  • C 1-3 alkylsulfonyloxy optionally substituted with a halogen atom (eg, fluorine) (preferably trifluoromethanesulfonyloxy [triflate] etc.)
  • C 6-14 arylsulfonyl optionally substituted Is mentioned.
  • C 6-14 arylsulfonyl for example, C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) , C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy) and 1 to 3 substituents selected from nitro
  • Examples thereof include C 6-14 arylsulfonyl, and specific examples include benzenesulfonyl and p-toluenesulfonyl.
  • Examples of the “leaving group” represented by X 1 include acyloxy (eg, acetyloxy, benzoyloxy), halogen atom (eg, fluorine, chlorine, bromine, iodine), optionally halogenated C 1- Examples include 6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy [triflate]), and optionally substituted C 6-14 arylsulfonyloxy.
  • acyloxy eg, acetyloxy, benzoyloxy
  • halogen atom eg, fluorine, chlorine, bromine, iodine
  • optionally halogenated C 1- Examples include 6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfon
  • C 6-14 arylsulfonyloxy for example, C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) ), C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy) and 1 to 3 substituents selected from nitro
  • Preferable examples include C 6-14 arylsulfonyloxy, and specific examples include benzenesulfonyloxy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy, naphthylsulfonyloxy.
  • Examples of the “carboxy protecting group” represented by R 6 include C 1-6 alkyl, C 7-11 aralkyl (eg, benzyl), phenyl, trityl, substituted silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl). , Tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl (eg, 1-allyl).
  • C 1-6 alkyl C 7-11 aralkyl (eg, benzyl), phenyl, trityl, substituted silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl). , Tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl (eg, 1-allyl).
  • Compound (I) can be produced by subjecting compound (IA) and compound (IB) to a condensation reaction.
  • the condensation reaction can be carried out by reacting compound (IA) with compound (IB) or a reactive derivative thereof (for example, acid halide, acid anhydride, active ester, acid imidazolide).
  • the amount of compound (IA) to be used is generally 0.8 to 10 equivalents relative to 1 equivalent of compound (IB) or a reactive derivative thereof.
  • This reaction can be carried out in the presence of a base.
  • the amount of the base to be used is generally 1-10 equivalents relative to 1 equivalent of compound (IB) or a reactive derivative thereof.
  • This reaction can be carried out in the presence of a condensing agent.
  • condensing agent examples include carbodiimide condensing reagents (eg, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide and its hydrochloride), phosphoric acid condensing reagents (eg, diethyl cyanophosphate, azide).
  • carbodiimide condensing reagents eg, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide and its hydrochloride
  • phosphoric acid condensing reagents eg, diethyl cyanophosphate, azide
  • Diphenylphosphoryl N, N′-carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolium tetrafluoroborate, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N'-tetramethyluronium hexafluorophosphate).
  • the amount of the condensing agent to be used is generally 0.1 to 10 equivalents relative to 1 equivalent of compound (IB) or a reactive derivative thereof.
  • This reaction can be carried out in the presence of a condensation accelerator.
  • the condensation accelerator include 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, and N-hydroxyphthalimide.
  • the amount of the condensation accelerator used is usually 0.1 to 10 equivalents relative to 1 equivalent of compound (IB) or a reactive derivative thereof.
  • This reaction is preferably performed in a solvent inert to the reaction.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, ethers, nitriles, esters, amides, 1-methyl-2-pyrrolidone, pyridine, dimethyl sulfoxide, hexamethyl phosphor Amides are mentioned.
  • the reaction temperature is usually ⁇ 30 to 120 ° C., preferably 0 to 100 ° C.
  • the reaction time is usually 0.1 to 30 hours.
  • Compound (IA) can be produced using a commercially available reagent or by a reaction known per se.
  • Compound (IB) can be produced by subjecting compound (IC) to a hydrolysis reaction.
  • the hydrolysis reaction can be carried out according to a method known per se (for example, the method described in Comprehensive Organic Transformations, edited by John Wiley and Sons (1999)).
  • compound (IB) can be produced by reacting compound (IC) with an alkali metal hydroxide or an alkaline earth metal hydroxide.
  • the amount of alkali metal hydroxide or alkaline earth metal hydroxide to be used is generally 1-1000 equivalents, preferably 1-20 equivalents, relative to 1 equivalent of compound (IC). This reaction is preferably performed in a solvent inert to the reaction.
  • solvents examples include alcohols, ethers, halogenated hydrocarbons, hydrocarbons, amides, nitriles, sulfoxides, sulfolane, hexamethylphosphoramide, water, and mixed solvents thereof.
  • This reaction is carried out under cooling (usually about ⁇ 78 to 20 ° C., preferably about ⁇ 10 to 10 ° C.), at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.). it can.
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours, more preferably 1 to 10 hours.
  • Compound (IC) can be produced by reacting compound (IE) with compound (ID) and then cyclizing within the molecule.
  • the amount of compound (IE) to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (ID).
  • This reaction is preferably performed in a solvent inert to the reaction. Examples of such solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof may be mentioned.
  • This reaction can be carried out in the presence of a base or an ammonium salt.
  • the amount of the base or ammonium salt to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (ID).
  • This reaction can be carried out at room temperature or under heating (usually about 20 to 200 ° C., preferably about 20 to 160 ° C.).
  • the reaction time is usually 1 to 48 hours, preferably 1 to 24 hours, more preferably 1 to 12 hours.
  • This reaction may be performed under microwave irradiation.
  • Compound (ID) can be produced using a commercially available reagent or by a reaction known per se.
  • compound (IC) can be converted into another different compound (IC) by a reaction known per se.
  • R 1 of compound (IC) is a leaving group (eg, bromine atom)
  • a different R 1 eg, Ethynyl, cyano
  • the amount of the organometallic reagent used in such a reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IC).
  • This reaction is preferably performed in a solvent inert to the reaction.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof is used.
  • This reaction can also be carried out in the presence of a base or an ammonium salt.
  • the amount of the base or ammonium salt to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IC).
  • This reaction can also be carried out in the presence of a metal complex such as palladium or copper or a phosphine ligand.
  • metal complex examples include [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, tetrakis (triphenyl) Phosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II).
  • Examples of the phosphine ligand include 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), triphenylphosphine, tris ( 2-methylphenyl) phosphine, bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos).
  • the amount of the metal complex to be used is generally 0.05 to 10 equivalents, preferably 0.05 to 2 equivalents, relative to 1 equivalent of compound (IC).
  • the amount of the phosphine ligand to be used is generally 0.1-20 equivalents, preferably 0.1-4 equivalents, per 1 equivalent of compound (IC).
  • This reaction is carried out under cooling (usually about ⁇ 78 to 20 ° C., preferably about ⁇ 10 to 10 ° C.), at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.). it can.
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours, more preferably 1 to 10 hours. This reaction may be performed under microwave irradiation.
  • the compound (IC) in which R 3 is a bromine atom is obtained by reacting the compound (IC) in which R 3 is a hydrogen atom with a brominating agent (eg, N-bromosuccinimide). Can be manufactured.
  • a brominating agent eg, N-bromosuccinimide
  • the amount of brominating agent used in such a reaction is usually 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (IC) in which R 3 is a hydrogen atom. is there. This reaction is preferably performed in a solvent inert to the reaction.
  • solvents examples include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof is used.
  • This reaction is carried out under cooling (usually about ⁇ 78 to 20 ° C., preferably about ⁇ 10 to 10 ° C.), at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.). it can.
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours, more preferably 1 to 10 hours.
  • This reaction may be performed under microwave irradiation.
  • a compound in which R 3 is methyl, ethynyl or cyano is a compound in which R 3 is a leaving group (eg, bromine atom) in the compound (IC) and an organometallic reagent.
  • R 3 is a leaving group (eg, bromine atom) in the compound (IC) and an organometallic reagent.
  • the amount of the organometallic reagent used in such a reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (IC) in which R 3 is a leaving group. It is.
  • This reaction is preferably performed in a solvent inert to the reaction. Examples of such solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof is used.
  • This reaction can also be carried out in the presence of a base or an ammonium salt.
  • the amount of the base or ammonium salt to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (IC) in which R 3 is a leaving group.
  • This reaction can also be carried out in the presence of a metal complex such as palladium or copper or a phosphine ligand.
  • metal complex examples include [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, tetrakis (triphenyl) Phosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II).
  • Examples of the phosphine ligand include 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), triphenylphosphine, tris ( 2-methylphenyl) phosphine, bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos).
  • the amount of the metal complex to be used is generally 0.05 to 10 equivalents, preferably 0.05 to 2 equivalents, relative to 1 equivalent of the compound (IC) in which R 3 is a leaving group.
  • the amount of the phosphine ligand used is usually 0.1 to 20 equivalents, preferably 0.1 to 4 equivalents, relative to 1 equivalent of the compound (IC) in which R 3 is a leaving group. is there.
  • This reaction is carried out under cooling (usually about ⁇ 78 to 20 ° C., preferably about ⁇ 10 to 10 ° C.), at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.). it can.
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours, more preferably 1 to 10 hours. This reaction may be performed under microwave irradiation.
  • a compound in which R 3 is amino, cyclopropyl, or the like is obtained by combining the compound (IC) with a compound in which R 3 is a leaving group (eg, bromine atom). It can be produced by subjecting a metal catalyst to a coupling reaction.
  • the coupling substrate used in such a reaction include amines (eg, diphenylmethanimine) and boronic acids (eg, cyclopropylboronic acid).
  • the amount of the substrate to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (IC) in which R 3 is a leaving group. This reaction is preferably performed in a solvent inert to the reaction.
  • solvents examples include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof is used.
  • This reaction can also be carried out in the presence of a base or an ammonium salt.
  • the amount of the base or ammonium salt to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (IC) in which R 3 is a leaving group.
  • This reaction can also be carried out in the presence of a metal complex such as palladium or copper or a phosphine ligand.
  • metal complex examples include [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, tetrakis (triphenyl) Phosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II).
  • Examples of the phosphine ligand include 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), triphenylphosphine, tris ( 2-methylphenyl) phosphine, bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos).
  • the amount of the metal complex to be used is generally 0.05 to 10 equivalents, preferably 0.05 to 2 equivalents, relative to 1 equivalent of the compound (IC) in which R 3 is a leaving group.
  • the amount of the phosphine ligand used is usually 0.1 to 20 equivalents, preferably 0.1 to 4 equivalents, relative to 1 equivalent of the compound (IC) in which R 3 is a leaving group. is there.
  • This reaction is carried out under cooling (usually about ⁇ 78 to 20 ° C., preferably about ⁇ 10 to 10 ° C.), at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.). it can.
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours, more preferably 1 to 10 hours. This reaction may be performed under microwave irradiation.
  • Compound (IE) is prepared by subjecting Compound (IG) to an aldol addition reaction with Compound (IFA), which is an aromatic aldehyde, to prepare Compound (IF). It can be produced by opening the ring.
  • compound (IF) has different chemical stability depending on the type of Ar, and may be isolated as compound (IF) or may be isolated as compound (IE). .
  • compound (IE) is obtained as a mixture with compound (IF).
  • the compound (IF) functions as an equivalent of the compound (IE). Therefore, the compound (IE) is converted into the compound (IE). Even if (IF) is mixed, it can be used as it is in the next step.
  • the amount of compound (IG) to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IFA).
  • This reaction is preferably performed in a solvent inert to the reaction.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof may be mentioned.
  • This reaction can be carried out in the presence of a base or an ammonium salt.
  • the amount of the base or ammonium salt to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, per 1 equivalent of compound (IG).
  • This reaction can be carried out under cooling (usually about ⁇ 78 to 20 ° C.) or at room temperature (usually about 20 to 40 ° C.).
  • the reaction time is usually 1 to 24 hours, preferably 1 to 12 hours, and more preferably 1 to 6 hours.
  • the progress of this reaction can be confirmed by observing the reduction rate of compound (IFA) or the production rate of compound (IF) by 1 H NMR, LC-MS, or the like.
  • Compound (IF) can be converted to compound (IE) by extending the reaction time as it is in the same reaction system. When the conversion is slow, the conversion to the compound (IE) can be accelerated by raising the reaction temperature. In addition, when compound (IF) is sufficiently stable for liquid separation operation, it can be isolated as compound (IF) and gradually converted to compound (IE) during storage. This conversion reaction can be carried out at room temperature (usually about 20 to 40 ° C.) or under heating (usually about 40 to 120 ° C., preferably about 40 to 80 ° C.). The reaction time is usually 1 to 72 hours, preferably 1 to 48 hours, more preferably 1 to 24 hours. Compound (IG) can be produced using a commercially available reagent, or a reaction known per se.
  • Examples of the “leaving group” represented by X 2 include the same as those exemplified as the “leaving group” represented by X 1 .
  • compound (I) is produced by reacting compound (IH) with R 5 -X 2 .
  • the amount of R 5 —X 2 to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IH).
  • This reaction is preferably performed in a solvent inert to the reaction. Examples of such solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof may be mentioned.
  • This reaction can be carried out in the presence of a base or an ammonium salt.
  • the amount of the base or ammonium salt to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, per 1 equivalent of compound (IH).
  • This reaction can be carried out in the presence of a metal complex such as palladium or copper or a phosphine ligand.
  • a metal complex such as palladium or copper or a phosphine ligand.
  • the metal complex include [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate.
  • Examples of the phosphine ligand include 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), and triphenylphosphine. It is done.
  • the amount of the metal complex to be used is generally 0.05 to 10 equivalents, preferably 0.05 to 2 equivalents, relative to 1 equivalent of compound (IH).
  • the amount of the phosphine ligand to be used is generally 0.1-20 equivalents, preferably 0.1-4 equivalents, per 1 equivalent of compound (IH).
  • This reaction is carried out under cooling (usually about ⁇ 78 to 20 ° C., preferably about ⁇ 10 to 10 ° C.), at room temperature or under heating (usually about 20 to 200 ° C., preferably about 20 to 160 ° C.). it can.
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours, more preferably 1 to 10 hours.
  • This reaction may be performed under microwave irradiation.
  • Compound (IH) can be produced by subjecting compound (IB) and compound (II) to a condensation reaction.
  • the condensation reaction can be carried out by reacting compound (II) with compound (IB) or a reactive derivative thereof (eg, acid halide, acid anhydride, active ester, acid imidazolide).
  • the amount of compound (II) to be used is generally 0.8 to 10 equivalents relative to 1 equivalent of compound (IB) or a reactive derivative thereof.
  • This reaction can be performed in the presence of a base.
  • the amount of the base to be used is generally 1 to 10 equivalents relative to 1 equivalent of compound (IB) or a reactive derivative thereof.
  • This reaction can be carried out in the presence of a condensing agent.
  • condensing agents examples include carbodiimide condensing reagents (eg, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide and its hydrochloride), phosphoric acid condensing reagents (eg, diethyl cyanophosphate).
  • carbodiimide condensing reagents eg, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide and its hydrochloride
  • phosphoric acid condensing reagents eg, diethyl cyanophosphate
  • the amount of the condensing agent to be used is generally 0.1 to 10 equivalents relative to 1 equivalent of compound (IB) or a reactive derivative thereof. This reaction can be carried out in the presence of a condensation accelerator.
  • condensation accelerators examples include 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, and N-hydroxyphthalimide.
  • the amount of the condensation accelerator used is usually 0.1 to 10 equivalents relative to 1 equivalent of compound (IB) or a reactive derivative thereof.
  • This reaction is preferably performed in a solvent inert to the reaction.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, ethers, nitriles, esters, amides, 1-methyl-2-pyrrolidone, pyridine, dimethyl sulfoxide, hexamethyl phosphor Amides are mentioned.
  • the reaction temperature is usually ⁇ 30 to 120 ° C., preferably 0 to 100 ° C.
  • the reaction time is usually 0.1 to 30 hours.
  • Compound (II) can be produced using a commercially available reagent, or a reaction known per se.
  • Examples of the “leaving group” represented by X 3 include the same as those exemplified as the “leaving group” represented by X 1 .
  • Examples of the “leaving group” represented by G 1 include a dihydroxyboranyl group (—B (OH) 2 ) and a dialkoxyboranyl group (preferably 4,4,5,5-tetramethyl-1,3 , 2-dioxaboran-2-yl), a tri-C 1-6 alkylstannyl group (preferably a trimethylstannyl group or an n-tributylstannyl group).
  • compound (IC) is produced by subjecting compound (IJ) to a coupling reaction with compound (ICA).
  • the amount of compound (ICA) to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IJ).
  • This reaction is preferably performed in a solvent inert to the reaction. Examples of such solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof may be mentioned.
  • This reaction can be carried out in the presence of a base or an ammonium salt.
  • the amount of the base or ammonium salt to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IJ).
  • This reaction can be carried out in the presence of a metal complex such as palladium or copper or a phosphine ligand.
  • a metal complex such as palladium or copper or a phosphine ligand.
  • the metal complex include [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, tetrakis (tri Phenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II).
  • Examples of the phosphine ligand include 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), triphenylphosphine, tris ( 2-methylphenyl) phosphine, bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos).
  • the amount of the metal complex to be used is generally 0.05 to 10 equivalents, preferably 0.05 to 2 equivalents, relative to 1 equivalent of compound (IJ).
  • the amount of the phosphine ligand to be used is generally 0.1-20 equivalents, preferably 0.1-4 equivalents, relative to 1 equivalent of compound (IJ).
  • This reaction is carried out under cooling (usually about ⁇ 78 to 20 ° C., preferably about ⁇ 10 to 10 ° C.), at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.). it can.
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours, more preferably 1 to 10 hours. This reaction may be performed under microwave irradiation.
  • Compound (IJ) can be produced from compound (IK).
  • the compound (IJ) in which X 3 is a halogen atom is obtained by adding a halogenating agent (eg, iodine, bromine, chlorine, N-iodosuccinimide, N-bromosuccinimide, N— It can be produced by reacting chlorosuccinimide).
  • a halogenating agent eg, iodine, bromine, chlorine, N-iodosuccinimide, N-bromosuccinimide, N— It can be produced by reacting chlorosuccinimide).
  • the amount of the halogenating agent to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, per 1 equivalent of compound (IK).
  • This reaction can be carried out in the presence of a radical initiator.
  • An example of the radical initiator is 2,2′-azobis (2-methylpropionitrile).
  • the amount of the radical initiator to be used is generally 0.05 to 1 equivalent, preferably 0.1 to 0.5 equivalent, relative to 1 equivalent of compound (IK).
  • This reaction can be carried out in the presence of an acid.
  • the acid include acetic acid and trifluoroacetic acid.
  • the amount of the acid to be used is generally 0.1-1000 equivalents, preferably 1-100 equivalents, relative to 1 equivalent of compound (IK). This reaction is preferably performed in a solvent inert to the reaction.
  • solvents examples include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof may be mentioned.
  • This reaction is carried out under cooling (usually about ⁇ 78 to 20 ° C., preferably about ⁇ 10 to 10 ° C.), at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.). it can.
  • the reaction time is usually 1 to 48 hours, preferably 1 to 24 hours, more preferably 1 to 12 hours.
  • This reaction may be performed under microwave irradiation.
  • Compound (IK) can be produced by reacting compound (IL) with compound (ID) and then intramolecular cyclization.
  • the amount of compound (IL) to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (ID).
  • This reaction is preferably performed in a solvent inert to the reaction. Examples of such solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof may be mentioned.
  • This reaction can be carried out in the presence of a base or an ammonium salt.
  • the amount of the base or ammonium salt to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (ID).
  • This reaction is carried out under cooling (usually about ⁇ 78 to 20 ° C., preferably about ⁇ 10 to 10 ° C.), at room temperature or under heating (usually about 20 to 200 ° C., preferably about 20 to 160 ° C.). it can.
  • the reaction time is usually 1 to 48 hours, preferably 1 to 24 hours, more preferably 1 to 12 hours.
  • This reaction may be performed under microwave irradiation.
  • Compound (IL) can be produced using a commercially available reagent or by a reaction known per se.
  • Q 1 represents a leaving group or hydroxy
  • G 2 represents a hydrogen atom, a leaving group, hydroxy or a metal atom, and other symbols are as defined above.
  • R 1 moiety of the compound (I) is a compound (IM) that functions as Q 1 capable of functional group conversion, it has another R 1 by acting R 1 -G 2 It can be converted to compound (I).
  • Examples of the “leaving group” represented by Q 1 include the same as those exemplified as the “leaving group” represented by X 1 .
  • Preferred examples of Q 1 include a halogen atom and hydroxy.
  • Examples of the “leaving group” represented by G 2 include a halogen atom, a dihydroxyboranyl group (—B (OH) 2 ), a dialkoxyboranyl group (preferably 4,4,5,5-tetramethyl- 1,3,2-dioxaboran-2-yl), tri-C 1-6 alkylstannyl group (preferably trimethylstannyl group, n-tributylstannyl group), and magnesium halide.
  • Examples of the “metal atom” represented by G 2 include Na, K, and Cu.
  • G 2 includes a hydrogen atom, a dihydroxyboranyl group (—B (OH) 2 ), a dialkoxyboranyl group (preferably 4,4,5,5-tetramethyl-1 , 3,2-dioxaboran-2-yl), tri-C 1-6 alkylstannyl group (preferably trimethylstannyl group, n-tributylstannyl group), Na, K and Cu are preferred.
  • G 2 is preferably a halogen atom.
  • compound (I) is produced by reacting compound (IM) with R 1 -G 2 .
  • R 1 is C 1-10 alkoxy
  • compound (IM) in which Q 1 is a halogen atom with the corresponding alcohol (G 2 H).
  • the amount of R 1 -G 2 to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IM).
  • This reaction is preferably performed in a solvent inert to the reaction.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof is used.
  • This reaction can also be carried out in the presence of a base or an ammonium salt.
  • the amount of the base or ammonium salt to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, per 1 equivalent of compound (IM).
  • This reaction can also be carried out in the presence of a metal complex such as palladium or copper or a phosphine ligand.
  • a metal complex such as palladium or copper or a phosphine ligand.
  • the metal complex include [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, tetrakis (triphenyl) Phosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II).
  • Examples of the phosphine ligand include 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), triphenylphosphine, tris ( 2-methylphenyl) phosphine, bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos).
  • the amount of the metal complex to be used is generally 0.05 to 10 equivalents, preferably 0.05 to 2 equivalents, per 1 equivalent of compound (IM).
  • the amount of the phosphine ligand to be used is generally 0.1-20 equivalents, preferably 0.1-4 equivalents, per 1 equivalent of compound (IM).
  • This reaction is carried out under cooling (usually about ⁇ 78 to 20 ° C., preferably about ⁇ 10 to 10 ° C.), at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.). it can.
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours, more preferably 1 to 10 hours. This reaction may be performed under microwave irradiation.
  • a compound within the scope of the present invention can also be produced by applying a method known per se to compound (I) and further carrying out substituent conversion (introduction of a substituent or functional group conversion).
  • a compound in which R 3 is methyl, ethynyl, cyano, etc. is a compound in which R 3 is a leaving group (eg, bromine atom, etc.) in compound (I) and an organometallic reagent (eg, , Tetramethylstannane, tributyl (ethynyl) stannane, trimethyl [(tributylstannanyl) ethynyl] silane, copper cyanide, zinc cyanide), and by performing an appropriate post-treatment as necessary can do.
  • organometallic reagent eg, Tetramethylstannane, tributyl (ethynyl) stannane, trimethyl [(tributylstannanyl) ethynyl] silane, copper cyanide, zinc cyanide
  • the amount of the organometallic reagent used in such a reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (I) in which R 3 is a leaving group. .
  • This reaction is preferably performed in a solvent inert to the reaction.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof is used.
  • This reaction can also be carried out in the presence of a base or an ammonium salt.
  • the amount of the base or ammonium salt used is usually 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (I) in which R 3 is a leaving group.
  • This reaction can also be carried out in the presence of a metal complex such as palladium or copper or a phosphine ligand.
  • metal complex examples include [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, tetrakis (triphenyl) Phosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II).
  • Examples of the phosphine ligand include 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), triphenylphosphine, tris ( 2-methylphenyl) phosphine, bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos).
  • the amount of the metal complex to be used is generally 0.05 to 10 equivalents, preferably 0.05 to 2 equivalents, relative to 1 equivalent of the compound (I) in which R 3 is a leaving group.
  • the amount of the phosphine ligand used is usually 0.1 to 20 equivalents, preferably 0.1 to 4 equivalents, relative to 1 equivalent of the compound (I) in which R 3 is a leaving group.
  • This reaction is carried out under cooling (usually about ⁇ 78 to 20 ° C., preferably about ⁇ 10 to 10 ° C.), at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.). it can.
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours, more preferably 1 to 10 hours. This reaction may be performed under microwave irradiation.
  • a compound in which R 3 is amino, cyclopropyl, or the like includes a compound in which R 3 is a leaving group (eg, bromine atom) in the compound (I) and an organometallic catalyst. It can manufacture by attaching
  • the coupling substrate used in such a reaction include amines (eg, diphenylmethanimine) and boronic acids (eg, cyclopropylboronic acid).
  • the amount of the substrate to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (I) in which R 3 is a leaving group.
  • This reaction is preferably performed in a solvent inert to the reaction.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof is used.
  • This reaction can also be carried out in the presence of a base or an ammonium salt.
  • the amount of the base or ammonium salt used is usually 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (I) in which R 3 is a leaving group.
  • This reaction can also be carried out in the presence of a metal complex such as palladium or copper or a phosphine ligand.
  • a metal complex such as palladium or copper or a phosphine ligand.
  • the metal complex include [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, tetrakis (triphenyl) Phosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II).
  • Examples of the phosphine ligand include 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), triphenylphosphine, tris ( 2-methylphenyl) phosphine, bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos).
  • the amount of the metal complex to be used is generally 0.05 to 10 equivalents, preferably 0.05 to 2 equivalents, relative to 1 equivalent of the compound (I) in which R 3 is a leaving group.
  • the amount of the phosphine ligand used is usually 0.1 to 20 equivalents, preferably 0.1 to 4 equivalents, relative to 1 equivalent of the compound (I) in which R 3 is a leaving group.
  • This reaction is carried out under cooling (usually about ⁇ 78 to 20 ° C., preferably about ⁇ 10 to 10 ° C.), at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.). it can.
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours, more preferably 1 to 10 hours.
  • This reaction may be performed under microwave irradiation.
  • substituent conversion that is, introduction of a substituent or functional group conversion
  • a known general method is used for the substituent conversion (that is, introduction of a substituent or functional group conversion) for the compound (I).
  • conversion to carboxy by hydrolysis of an ester, or amidation of carboxy Conversion to carbamoyl, conversion to carboxy by reduction of carboxy, conversion to alcohol by reduction of carbonyl or addition of alkyl to carbonyl, reductive amination of carbonyl, oximation of carbonyl, acylation of amino, Amino urealation, amino sulfonylation, amino alkylation, substitution or amination of active halogens with amines, hydroxy alkylation, hydroxy substitution or amination are used.
  • a protective group is introduced into the reactive site in advance by a known method, if necessary, After carrying out the desired reaction, the protecting group can be removed by means known per se to produce compounds within the scope of the present invention.
  • the raw material compound or intermediate has amino, carboxy or hydroxy as a substituent, these groups may be protected with a protecting group generally used in peptide chemistry or the like.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • the amino-protecting group include those exemplified as P 1 above.
  • the protecting group for carboxy include those exemplified as R 6 above.
  • Examples of the protecting group for hydroxy include C 1-6 alkyl, phenyl, trityl, C 7-10 aralkyl (eg, benzyl), formyl, C 1-6 alkyl-carbonyl, benzoyl, C 7-10 aralkyl-carbonyl ( Examples, benzylcarbonyl), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, substituted silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl ( Examples include 1-allyl).
  • the above-described protecting group may have 1 to 3 substituents selected from a halogen atom, C 1-6 alkyl, C 1-6 alkoxy or nitro.
  • the above-described removal of the protecting group includes a method known per se, for example, the method described in Protective Groups in Organic Synthesis, edited by John Wiley and Sons (1980). Specifically, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide), etc. are used. It is carried out by the method of reducing or reducing.
  • a raw material compound having a different substituent can be produced by the above substituent conversion, using the compound produced by the above production method as a raw material.
  • Compound (I) or a salt thereof, which is a product in this reaction may be produced as a single compound or as a mixture.
  • Compound (I) or a salt thereof thus obtained can be isolated and purified by a separation means known per se, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc. .
  • a separation means known per se for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc.
  • compound (I) When compound (I) is obtained in a free form, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely, when it is obtained as a salt, a method known per se Alternatively, it can be converted into a free form or other desired salt by a method equivalent thereto.
  • any one of the isomers and a mixture are included in compound (I) or a salt thereof.
  • compound (I) or a salt thereof has an optical isomer
  • the optical isomer resolved from the racemate is also encompassed in compound (I) or a salt thereof.
  • Each of these isomers can be obtained as a single product by a known synthesis method and separation method (eg, concentration, solvent extraction, column chromatography, recrystallization).
  • Compound (I) or a salt thereof may be in the form of a crystal, and is included in compound (I) or a salt thereof regardless of whether the crystal form is single or a crystal form mixture.
  • the crystal can be produced by crystallization by applying a crystallization method known per se.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • a co-crystal or co-crystal salt is composed of two or more unique solids at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity and stability). Means crystalline material.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • Compound (I) or a salt thereof may be a hydrate, a non-hydrate, a solvate, or a non-solvate.
  • Compound (I) or a salt thereof may also be labeled with an isotope (eg, 3 H, 14 C, 35 S, 125 I) and the like. Further, compound (I) or a salt thereof may be a deuterium converter.
  • a prodrug of compound (I) or a salt thereof is a compound that is converted into compound (I) or a salt thereof by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, hydrolyzed, etc. It refers to a compound that changes to compound (I) or a salt thereof, or a compound that changes to compound (I) or a salt thereof by causing hydrolysis or the like with gastric acid or the like.
  • prodrugs of compound (I) or salts thereof include compounds in which amino of compound (I) is acylated, alkylated, and phosphorylated (eg, amino of compound (I) is eicosanoylated, alanylated, pentyl Aminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidinylmethylated, pivaloyloxymethylated, tert-butylated Compound); Compound in which hydroxy of compound (I) is acylated, alkylated, phosphorylated, borated (eg, hydroxy of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumaryl , Alanylated, dimethylaminomethylcarbonylated compound); carboxy of compound (I)
  • Compound (I) or a salt thereof, or a prodrug thereof (hereinafter, sometimes abbreviated as “the compound of the present invention”) has CENP-E inhibitory activity and is clinically useful for prevention or treatment of cancer. It is useful as an agent, a cancer growth inhibitor, a cancer metastasis inhibitor, an apoptosis promoter, and the like.
  • the compounds of the present invention can also be used for the prevention or treatment of CENP-E related diseases in mammals. Since the compound of the present invention is excellent in membrane permeability and can have a medicinal effect at a low dose, it becomes an excellent preventive / therapeutic agent for cancer and the like with reduced side effects.
  • the compound of the present invention exhibits strong inhibitory activity against CENP-E.
  • the compound of the present invention has a medicinal effect, pharmacokinetics (absorbability, distribution, metabolism, excretion, etc.), solubility (water solubility, etc.), interaction with other pharmaceuticals, safety (acute toxicity, chronic toxicity, genetics) It is also useful as a pharmaceutical because it is excellent in terms of toxicity (low toxicity such as toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and stability (chemical stability, stability to enzymes, etc.).
  • the compound of the present invention can be safely administered to mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human). Accordingly, the compound of the present invention can be used for CENP-E-related diseases such as cancer [eg, colon cancer (eg, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor), lung cancer (eg, non-small cell).
  • cancer eg, colon cancer (eg, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor)
  • lung cancer eg, non-small cell.
  • Lung cancer small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (eg, pancreatic duct cancer), gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), breast cancer (eg, invasive milk) Duct cancer, noninvasive ductal carcinoma, inflammatory breast cancer), ovarian cancer (eg, epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low grade tumor), prostate cancer (eg, hormone) Dependent prostate cancer, hormone-independent prostate cancer), liver cancer (eg, primary liver cancer, extrahepatic bile duct cancer), thyroid cancer (eg, medullary thyroid cancer), kidney cancer (eg, renal cell carcinoma, renal pelvis and Transitional cell carcinoma of the ureter), uterine cancer, brain tumor (eg, pineal astrocytoma, ciliary a
  • the compound of the present invention may be administered orally or parenterally as it is or in combination with a pharmacologically acceptable carrier as a medicament (sometimes referred to as “the medicament of the present invention”).
  • a dosage form when the compound of the present invention is orally administered for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, buccal tablets, intraoral quick-disintegrating tablets), pills, granules, powders, capsules
  • oral preparations including soft capsules and microcapsules
  • syrups emulsions, suspensions, and film preparations (eg, oral mucosa adhesive film).
  • Examples of the dosage form when the compound of the present invention is administered parenterally include injections, infusions, drops, suppositories, and transdermal agents (including iontophoretic transdermal agents).
  • the compound of the present invention may be prepared by using a suitable base (eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, a mixture of butyric acid polymer and glycolic acid polymer, polyglycerol fatty acid) It is also effective to form a sustained-release preparation in combination with an ester.
  • a suitable base eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, a mixture of butyric acid polymer and glycolic acid polymer, polyglycerol fatty acid
  • a method for producing the compound of the present invention into the above-mentioned dosage form a known production method generally used in the art (for example, a method described in the Japanese Pharmacopoeia) can be applied.
  • An appropriate amount of additives such as an activator, a suspending agent, and an emulsifier can be appropriately contained.
  • excipients when producing tablets containing the compound of the present invention, excipients, binders, disintegrants, lubricants and the like can be used.
  • binders, disintegrants and the like can be used.
  • excipients, etc. in the case of producing syrups, sweeteners, etc., in the case of producing emulsions or suspensions, suspending agents, surfactants.
  • An emulsifier or the like can be used.
  • excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, and calcium sulfate.
  • binders include 5-10 wt% starch paste, 10-20 wt% gum arabic or gelatin solution, 1-5 wt% tragacanth solution, carboxymethylcellulose solution, sodium alginate solution, glycerin.
  • disintegrant include starch and calcium carbonate.
  • lubricants include magnesium stearate, stearic acid, calcium stearate, and purified talc.
  • sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, and simple syrup.
  • surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl 40 stearate.
  • suspending agent include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, and bentonite.
  • emulsifiers include gum arabic, tragacanth, gelatin, and polysorbate 80.
  • injections examples include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, infusions, and the like.
  • Such an injection is prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound of the present invention in a sterile aqueous or oily liquid.
  • Aqueous solutions for injection include isotonic solutions (eg, D-sorbitol, D-mannitol, sodium chloride) containing physiological saline, glucose and other adjuvants, and suitable solubilizers such as You may use together with alcohol (for example, ethanol), polyalcohol (for example, propylene glycol, polyethylene glycol), and a nonionic surfactant (for example, polysorbate 80, HCO-50).
  • alcohol for example, ethanol
  • polyalcohol for example, propylene glycol, polyethylene glycol
  • a nonionic surfactant for example, polysorbate 80, HCO-50.
  • examples of the oily liquid include sesame oil and soybean oil.
  • benzyl benzoate As a solubilizing agent, benzyl benzoate, benzyl alcohol and the like may be used in combination. Buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride), stabilizers (eg, human serum albumin, polyethylene glycol), preservatives (eg, , Benzyl alcohol, phenol) and the like.
  • Buffers eg, phosphate buffer, sodium acetate buffer
  • soothing agents eg, benzalkonium chloride, procaine hydrochloride
  • stabilizers eg, human serum albumin, polyethylene glycol
  • preservatives eg, , Benzyl alcohol, phenol
  • the content of the compound of the present invention in the medicament of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight based on the whole preparation. , Preferably about 2 to 85% by weight, more preferably about 5 to 70% by weight.
  • the content of a pharmacologically acceptable carrier (for example, the above-mentioned additive) in the medicament of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.9 with respect to the whole preparation. % By weight, preferably about 10 to 90% by weight.
  • the compound of the present invention can be used safely with stable, low toxicity.
  • the daily dose varies depending on the patient's condition and body weight, the type of compound, the route of administration, etc.
  • the daily dose for an adult (body weight of about 60 kg) Is about 1 to 2000 mg, preferably about 3 to 1000 mg, more preferably about 10 to 250 mg as the active ingredient (the compound of the present invention), and these can be administered once or divided into 2 to 3 times.
  • the compound of the present invention When the compound of the present invention is administered parenterally, it is usually administered in the form of a liquid (for example, an injection).
  • a liquid for example, an injection
  • the single dose varies depending on the administration subject, target organ, symptom, administration method, and the like.
  • it is usually about 0.01 to about 40 mg per kg body weight, preferably about 0.05. It is convenient to administer from about 20 mg, more preferably from about 0.1 to about 5 mg by intravenous injection or infusion.
  • the compound of the present invention can be used in combination with other drugs.
  • the compound of the present invention can be used in combination with drugs such as hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents or cell growth factors and drugs that inhibit the action of the receptors.
  • drugs such as hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents or cell growth factors and drugs that inhibit the action of the receptors.
  • a drug that can be used in combination with the compound of the present invention is abbreviated as “concomitant drug”.
  • ⁇ hormone therapeutic agent '' examples include phosfestol, diethylstilbestrol, chlorotrianicene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, Raloxifene, olmeroxifene, levormeroxifene, antiestrogens (eg, tamoxifen citrate, toremifene citrate), pill formulations, mepithiostan, testrolactone, aminoglutethimide, LH-RH agonists (eg, goserelin acetate, buserelin acetate) Leuprorelin acetate), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitor (eg, fadrozo
  • chemotherapeutic agent for example, alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents are used.
  • alkylating agent examples include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitoblonitol, Faran, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambermuthine, dibrospine hydrochloride, fotemustine hydrochloride Predonimustine, pumitepa, ribomustine, temozolomide, treosulphane, trophosphamide Zinostatin Lamar, ado
  • Examples of the “antimetabolite” include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enositabine, cytarabine, cytarabine okphosphat, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, doxyfluridine, carmofur, galocitabine, emiteful, capecitabine), aminopterin, nerzarabine, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbpyramide, pendant Idoxyuridine, mitoguazone, thiazofurin, ambamustine, bendamustine, and them DDS formulation is used.
  • 5-FU drugs eg, fluorouracil, tegafur, UFT, doxy
  • anticancer antibiotics examples include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride , Neocartinostatin, misramycin, sarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and their DDS formulations.
  • plant-derived anticancer agent for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine, and their DDS preparations are used.
  • immunotherapeutic agent examples include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacterium parvum , Levamisole, polysaccharide K, procodazole, and anti-CTLA4 antibody are used.
  • Examples of the “drug that inhibits the action of cell growth factor and its receptor” include, for example, EGF inhibitor, TGF ⁇ inhibitor, harregulin inhibitor, insulin inhibitor, IGF inhibitor, FGF inhibitor, KGF inhibitor, CSF inhibition Agent, EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGF ⁇ inhibitor, HGF inhibitor, VEGF inhibitor, angiopoietin inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER4 inhibitor, Insulin receptor inhibitor, IGF-1 receptor inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2 inhibitor, FGF receptor-3 inhibitor, FGF receptor- 4 inhibitor, VEGF receptor inhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Abl inhibitor, Raf inhibitor, FLT3 inhibitor, c-Ki t inhibitor, Src inhibitor, PKC inhibitor, Trk inhibitor, Ret inhibitor, mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK (MEK1 / 2) inhibitor, MET inhibitor, CDK inhibitor, Akt Inhibitors, ER
  • agents include anti-VEGF antibodies (eg, Bevacizumab), anti-HER2 antibodies (eg, Trastuzumab, Pertuzumab), anti-EGFR antibodies (eg, Cetuximab, Panitumumab, Matuzumab, Nimotuzumab), anti-VEGFR Antibody, anti-HGF antibody, Imatinib mesylate, Erlotinib, Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, 4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxy-7- [ 3- (1-Pyrrolidinyl) propoxy] quinazoline (AZD-2171), Lestaurtinib, Pazopanib, Canertinib, Tandutinib, 3- (4-Bromo-2,6-difluorobenzyloxy)
  • topoisomerase I inhibitor eg
  • the compound of the present invention By combining the compound of the present invention and a concomitant drug, (1) The dose can be reduced compared to the case where the compound of the present invention or the concomitant drug is administered alone; (2) A drug to be used in combination with the compound of the present invention can be selected according to the patient's symptoms (mild, severe, etc.); (3) The treatment period can be set longer; (4) The therapeutic effect can be sustained; (5) By using the compound of the present invention in combination with a concomitant drug, a synergistic effect can be obtained;
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to the administration subject, with a time difference. May be administered.
  • the time difference varies depending on the active ingredient to be administered, dosage form, and administration method. For example, when administering the concomitant drug first, within 1 minute to 3 days after administering the concomitant drug, preferably Examples include a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour.
  • the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after administering the compound of the present invention.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • an administration form when the compound of the present invention is used in combination with a concomitant drug (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug; (2) Simultaneous administration of the two compounds obtained by separately formulating the compound of the present invention and the concomitant drug by the same administration route; (3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time difference; (4) Simultaneous administration by different administration routes of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug; (5) Administration of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention and then the concomitant drug, Or administration in reverse order); Etc.
  • the dose of the concomitant drug can be appropriately selected on the basis of the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
  • the compound of the present invention can be used in combination with non-drug therapy.
  • the compound of the present invention includes, for example, (1) surgery; (2) pressor chemotherapy using angiotensin II or the like; (3) gene therapy; (4) thermotherapy; (5) cryotherapy; (6) It can also be combined with non-drug therapies such as laser ablation; (7) radiation therapy;
  • treatment with the compound of the present invention and supportive therapy [(i) administration of antibiotics (for example, ⁇ -lactams such as pansporin, macrolides such as clarithromycin) for the co-occurrence of various infectious diseases; (ii) nutrition Administration of high-calorie infusions, amino acid preparations and multivitamins to improve disability; (iii) Morphine administration for pain relief; (iv) Nausea, vomiting, loss of appetite, diarrhea, leukopenia, thrombocytopenia, decreased hemoglobin concentration , Hair loss, hepatic disorder, renal disorder, DIC, administration of a drug that improves side effects such as fever, and (v) administration of a drug for suppressing multidrug resistance of cancer; etc.].
  • antibiotics for example, ⁇ -lactams such as pansporin, macrolides such as clarithromycin
  • the compound of the present invention is administered orally (including sustained release), intravenously (including bolus, infusion, inclusion body), subcutaneous administration and intramuscular injection. It is preferable to administer (including bolus, infusion, sustained release), transdermal administration, intratumoral administration, proximal administration, and the like.
  • the compound of the present invention when administered before the aforementioned non-drug therapy, for example, it can be administered once about 30 minutes to 24 hours before the aforementioned non-drug therapy, or about 3 times of the aforementioned non-drug therapy.
  • the administration can be divided into 1 to 3 cycles a month to 6 months ago.
  • cancer tissue can be reduced, so that the aforementioned non-drug therapy is facilitated.
  • the compound of the present invention When the compound of the present invention is administered after the aforementioned non-drug therapy, it can be repeatedly administered, for example, in units of several weeks to 3 months, about 30 minutes to 24 hours after the aforementioned non-drug therapy.
  • the effect of the aforementioned non-drug therapy can be enhanced.
  • NMR proton nuclear magnetic resonance spectrum
  • MS Mass spectrum LC / MS: Liquid chromatograph mass spectrometer
  • ESI method Electrospray ionization method
  • APCI method atmospheric pressure chemical ionization method
  • HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate
  • DBU 2,3,4,6,7,8,9,10-octahydropyrimido [1,2-a] azepine (1,8-diazabicyclo [5.4.0] -7-undecene)
  • EGTA ethylene glycol bis-2-aminoethyl ether tetraacetic acid
  • BSA bovine serum albumin
  • DMSO dimethyl sulfoxide
  • Example 5 3- (3-Cyanophenyl) -N- (3,4-dichlorobenzyl) -N- [2- (dimethylamino) ethyl] -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
  • Ethyl 5-bromoimidazo [1,2-a] pyridine-2-carboxylate To a solution of 6-bromopyridin-2-amine (5.0 g) in ethanol (40 mL), ethyl 3-bromo-2-oxopropa Noate (7.6 g) was added, and the mixture was heated to reflux with stirring for 13 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure.
  • the residue was suspended in ethyl acetate, and the precipitated solid was collected by filtration and washed with ethyl acetate.
  • the obtained solid was suspended in ethyl acetate and tetrahydrofuran, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
  • the residue was suspended in a mixed solvent of ethyl acetate and n-hexane (10: 1), and the precipitated solid was collected by filtration to give the title compound (7.2 g).
  • the obtained aqueous solution was concentrated under reduced pressure, the residue was suspended in a mixed solvent of methanol and tetrahydrofuran (2: 1), insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure.
  • the residue was suspended in N, N-dimethylformamide (25 mL), and N '-(3,4-dichlorobenzyl) -N, N-dimethylethane-1,2-diamine (740 mg), HATU ( 1.3 g) and N-ethyldiisopropylamine (1.2 g) were added, and the mixture was stirred at room temperature for 13.5 hours.
  • the reaction mixture was suspended in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (NH, ethyl acetate / n-hexane) to obtain the title compound (650 mg).
  • the reaction mixture was suspended in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (NH, ethyl acetate / n-hexane) to give the title compound (510 mg).
  • Example 10 N- (2-aminoethyl) -5-bromo-N- (3,4-dichlorobenzyl) -3- (3,4-difluorophenyl) imidazo [1,2-a] pyridine-2-carboxamide hydrochloride tert
  • the title compound (110 mg) was obtained in the same manner as in Example 8 using -butyl (2-aminoethyl) carbamate.
  • Example 12 5-Bromo-N- (3,4-dichlorobenzyl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3-methoxyphenyl) imidazo [1,2-a] pyridine-2 -Carboxamide hydrochloride A) Methyl 5-bromo-3- (4-fluoro-3-methoxyphenyl) imidazo [1,2-a] pyridine-2-carboxylate 4-fluoro-3-methoxybenzaldehyde (1.5 g) in tetrahydrofuran (20 mL ) To the solution was added methyl dichloroacetate (1.5 g) and the resulting mixture was cooled to -30 ° C.
  • the reaction mixture was diluted with tetrahydrofuran (5.0 mL), methanol (3.0 mL) and water (5.0 mL), 1N aqueous sodium hydroxide solution (5.0 mL) was added to the mixture, and the mixture was stirred at room temperature for 1 hr.
  • the reaction mixture was suspended in ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / n-hexane) to give the title compound (47 mg).
  • Example 17 N- (3,4-dichlorobenzyl) -N- [2- (dimethylamino) ethyl] -5-ethynyl-3- (4-fluoro-3-methylphenyl) imidazo [1,2-a] pyridine-2 -Carboxamide dihydrochloride A) Methyl 5-ethynyl-3- (4-fluoro-3-methylphenyl) imidazo [1,2-a] pyridine-2-carboxylate methyl 5-bromo-3- (4-fluoro-3-methylphenyl) To a mixed solution (3.0 mL) of imidazo [1,2-a] pyridine-2-carboxylate (184 mg) with 1,2-dimethoxyethane and water (5: 1), add [1,1-bis (diphenylphosphine).
  • the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) and further fractionated by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% trifluoroacetic acid)). The obtained fraction was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (28 mg).
  • reaction mixture was neutralized by adding 1N hydrochloric acid (0.9 mL), and the resulting solution was fractionated by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% trifluoroacetic acid)), The minute was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (63 mg).
  • Example 22 N- [1- (3,4-dichlorophenyl) ethyl] -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a ] Pyridine-2-carboxamide hydrochloride A) Step A of Example 21 using N ′-[1- (3,4-dichlorophenyl) ethyl] -N, N-dimethylethane-1,2-diamine 1- (3,4-dichlorophenyl) ethanone The title compound (5.6 g) was obtained by a method similar to that described above.
  • Example 23 N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -N- (2-hydroxyethyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide A) Add 2-aminoethanol (6.3 g) and acetic acid (5.0 mL) to a solution of 2-[(3,4-dichlorobenzyl) amino] ethanol 3,4-dichlorobenzaldehyde (15 g) in tetrahydrofuran (150 mL). The mixture was further stirred at room temperature for 2 hours. To the reaction mixture was added anhydrous magnesium sulfate (20 g), and the mixture was further stirred at room temperature for 1 hour.
  • Example 24 N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- (2- (morpholin-4-yl) ethyl) imidazo [1,2-a] Pyridine-2-carboxamide dihydrochloride A) N- (3,4-dichlorobenzyl) -2- (morpholin-4-yl) ethanamine Using 2- (morpholin-4-yl) ethanamine in a manner similar to Example 1, Step A, Compound (10.5 g) was obtained.
  • Example 26 N- (3-Chloro-4- (trifluoromethyl) benzyl) -N- (2- (dimethylamino) ethyl) -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2 -a] pyridine-2-carboxamide dihydrochloride A) Examples using N ′-[3-chloro-4- (trifluoromethyl) benzyl] -N, N-dimethylethane-1,2-diamine 3-chloro-4- (trifluoromethyl) benzaldehyde The title compound (1.1 g) was obtained by a method similar to that in Step 1 of 1.
  • Example 31 Ethyl 3- (3,4-dichlorophenyl) -3-([2- (dimethylamino) ethyl] ⁇ [3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine -2-yl] carbonyl ⁇ amino) propanoate
  • Ethyl 3- (3,4-dichlorophenyl) -3- ⁇ [2- (dimethylamino) ethyl] amino ⁇ propanoate Conducted using ethyl 3- (3,4-dichlorophenyl) -3-oxopropanoate In the same manner as in Step A of Example 29, the title compound (84 mg) was obtained.
  • reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethanol (12 mL), and anhydrous magnesium sulfate (2.6 g) and methylamine 40% methanol solution (3.5 g) were added.
  • the reaction mixture was stirred at room temperature for 7 hours and at 80 ° C. for 13.5 hours.
  • Insoluble material was filtered off, sodium borohydride (250 mg) was added to the filtrate at 0 ° C., and the reaction mixture was stirred at room temperature for 24 hr.
  • the reaction mixture was concentrated under reduced pressure, and the resulting residue was suspended in 2N hydrochloric acid (15 mL) and stirred vigorously at room temperature.
  • the residue was purified by silica gel column chromatography (NH, ethyl acetate / n-hexane), and further fractionated by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% trifluoroacetic acid)). The obtained fraction was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1.0 mL), 4N hydrogen chloride / ethyl acetate solution (1.0 mL) was added, and the mixture was stirred at room temperature for 30 min.
  • the reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine and then over anhydrous magnesium sulfate. Dried. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / n-hexane), and the fraction containing the desired product was concentrated under reduced pressure.
  • Example 36 N- [1- (3,4-Dichlorophenyl) -3- (dimethylamino) propyl] -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxy Imidazo [1,2-a] pyridine-2-carboxamide trihydrochloride A) 1-(3,4-dichlorophenyl) -N 1 - [2- (dimethylamino) ethyl] -N 3, N 3 - dimethylpropane-1,3-diamine N, N-dimethyl-1,2 The title compound (490 mg) was obtained in the same manner as in Step C of Example 35 using diamine.
  • Example 38 N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -N- ⁇ 2-[(2-hydroxyethyl) (methyl) amino] ethyl ⁇ -5-methoxyimidazo [1 , 2-a] pyridine-2-carboxamide hydrochloride N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2- (methylamino) ethyl ] To a solution of imidazo [1,2-a] pyridine-2-carboxamide hydrochloride (300 mg) in tetrahydrofuran (6.0 mL) was added 2-bromoethanol (0.24 mL) and triethylamine (0.40 mL).
  • the mixture was stirred for an hour and then at room temperature for 2 days.
  • the reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate), and further fractionated by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% trifluoroacetic acid)).
  • the obtained fraction was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate.
  • Example 39 N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -N- ⁇ 2-[(1H-imidazol-4-ylmethyl) (methyl) amino] ethyl ⁇ -5-methoxy Imidazo [1,2-a] pyridine-2-carboxamide dihydrochloride N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2- ( To a solution of (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide hydrochloride (55 mg) in tetrahydrofuran (3.0 mL), add 1H-imidazole-4-carbaldehyde (18 mL) and acetic acid (0.30 mL).
  • Example 40 N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -N- (2- ⁇ [3- (1H-imidazol-1-yl) benzyl] (methyl) amino ⁇ ethyl ) -5-Methoxyimidazo [1,2-a] pyridine-2-carboxamide dihydrochloride
  • the title compound (26) was prepared in the same manner as in Example 39 using 3- (1H-imidazol-1-yl) benzaldehyde. mg).
  • the residue was separated by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% trifluoroacetic acid)), the obtained fraction was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue. Extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in diethyl ether (10 mL), 4N hydrogen chloride / ethyl acetate solution (0.5 mL) was added, and the mixture was stirred.
  • Example 42 N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- (2- ⁇ methyl [(2-methyl-1H-imidazol-4-yl) methyl ] Amino ⁇ ethyl) imidazo [1,2-a] pyridine-2-carboxamide dihydrochloride N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N To a solution of-[2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (40 mg) in tetrahydrofuran (3.0 mL) was added 2-methyl-1H-imidazole-4-carbaldehyde (17 mg) and acetic acid (0.30 mL) were added, and the mixture was stirred at room temperature for 30 min.
  • Example 44 N- ⁇ 2-[(2-cyanoethyl) (methyl) amino] ethyl ⁇ -N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1, 2-a] pyridine-2-carboxamide hydrochloride In the same manner as in Example 43 using 2-propenenitrile, the title compound (46 mg) was obtained. MS (ESI +): [M + H] + 568.2.
  • the reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with diethyl ether (10 mL), and the resulting solid was collected by filtration.
  • the obtained solid was suspended in a saturated aqueous solution of sodium bicarbonate and extracted twice with ethyl acetate.
  • the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (162 mg).
  • the obtained solid was dissolved in methanol / tetrahydrofuran (1: 1) mixed solvent (4 mL), 2N aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred with heating at 60 ° C. for 1 hr.
  • the reaction mixture was cooled to room temperature, and diluted with ethyl acetate (30 mL) and water (30 mL).
  • the obtained aqueous layer was washed with ethyl acetate, and 2N hydrochloric acid (2 mL) was added to adjust the pH to 4.
  • the mixture was extracted twice with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • Examples 54-63 Similar to the method described in Example 53, using 0.16 MN, N-dimethylformamide solution of 5-bromo-3- (4-fluorophenyl) imidazo [1,2-a] pyridine-2-carboxylic acid and various amines. And synthesized.
  • a condensation reaction was performed using an amine protected with a tert-butyloxycarbonyl (Boc) group to obtain a target Boc protected product, and then treated with trifluoroacetic acid. The Boc group was removed, and the resulting residue was purified by preparative HPLC to obtain the desired product.
  • Boc tert-butyloxycarbonyl
  • Example 64 N- [1- (3,4-Dichlorophenyl) -3-hydroxypropyl] -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1 , 2-a] pyridine-2-carboxamide ethyl 3- (3,4-dichlorophenyl) -3-([2- (dimethylamino) ethyl] ⁇ [3- (4-fluoro-3-methylphenyl) -5-
  • the title compound (10 mg) was obtained in the same manner as in Example 30 using methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl ⁇ amino) propanoate.
  • Example 65 N- (3,4-dichlorobenzyl) -N- ⁇ 2-[(2,3-dihydroxypropyl) (methyl) amino] ethyl ⁇ -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- ⁇ 2- (methylamino) ethyl ⁇ Imidazo [1,2-a] pyridine-2-carboxamide (52 mg) in tetrahydrofuran (1 mL) was added to DL-glyceraldehyde (18 mg), and acetic acid (0.1 mL) was added to the solution.
  • Example 83 N- (3,4-dichlorobenzyl) -N- ⁇ 2-[(N, N-dimethyl-beta-alanyl) (methyl) amino] ethyl ⁇ -3- (4-fluoro-3-methylphenyl) -5 -Methoxyimidazo [1,2-a] pyridine-2-carboxamide dihydrochloride N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2 N, N-dimethyl-beta-alanine (17 mg), HATU (45 mg) mg) and pyridine (17 ⁇ L) were added, and the mixture was stirred at 70 ° C. for 1 hour.
  • the reaction mixture was suspended in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate), and the fraction containing the desired product was concentrated under reduced pressure.
  • the residue was suspended in diethyl ether, 4N hydrogen chloride / ethyl acetate solution (0.5 mL) was added, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration and washed with diethyl ether to obtain the title compound (39 mg).
  • Example 84 N- (3,4-dichlorobenzyl) -N- (2- ⁇ [4- (dimethylamino) butanoyl] (methyl) amino ⁇ ethyl) -3- (4-fluoro-3-methylphenyl) -5-methoxy Imidazo [1,2-a] pyridine-2-carboxamide dihydrochloride 4- (dimethylamino) butanoic acid
  • the title compound (41 mg) was obtained in the same manner as in Example 83 using hydrochloride and triethylamine. .
  • Example 85 N- (3,4-dichlorobenzyl) -N- ⁇ 2-[(N, N-diethyl-beta-alanyl) (methyl) amino] ethyl ⁇ -3- (4-fluoro-3-methylphenyl) -5 -Methoxyimidazo [1,2-a] pyridine-2-carboxamide dihydrochloride N, N-diethyl-beta-alanine In the same manner as in Example 83 using hydrochloride and triethylamine, the title compound (54 mg) Got. MS (ESI +): [M + H] + 642.2.
  • Example 87 N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -N- ⁇ 2-[(1H-indol-3-ylmethyl) amino] ethyl ⁇ -5-methoxyimidazo [1 , 2-a] pyridine-2-carboxamide dihydrochloride N- (2-aminoethyl) -N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo The title compound (17 mg) was obtained in the same manner as in Example 39 using [1,2-a] pyridine-2-carboxamide and 1H-indole-3-carbaldehyde.
  • the combined solution of the filtrate and the washing solution was concentrated under reduced pressure.
  • the obtained residue was suspended in methanol (15 mL), and sodium borohydride (0.54 g) was added at 4 ° C.
  • the reaction mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure.
  • the obtained residue was suspended in 2N hydrochloric acid (20 mL) and stirred at room temperature.
  • the obtained aqueous suspension was washed with n-hexane, and 2N aqueous sodium hydroxide solution (30 mL) was added to adjust the pH to 14.
  • the mixture was extracted twice with ethyl acetate (50 mL), and the combined organic layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate.
  • Example 91 N- (3-Chloro-4-pyrrolidin-1-ylbenzyl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2- a] pyridine-2-carboxamide trihydrochloride
  • Example 88 using 3-chloro-4-pyrrolidin-1-ylbenzaldehyde In the same manner as in Step E, the title compound was obtained as a mixture (0.92 g) containing 3-chloro-4-pyrrolidin-1-ylbenzaldehyde.
  • Example 92 N- (3,4-dichlorobenzyl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3,5-dimethylphenyl) -5-methoxyimidazo [1,2-a] pyridine -2-Carboxamide dihydrochloride A) Methyl 3- (4-fluoro-3,5-dimethylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylate 4-fluoro-3,5-dimethylbenzaldehyde and 6-methoxypyridine The title compound (180 mg) was obtained in the same manner as in Step B of Example 8 using -2-amine.
  • Example 95 N- ⁇ 2-[(3-amino-3-oxopropyl) (methyl) amino] ethyl ⁇ -N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -5- Methoxyimidazo [1,2-a] pyridine-2-carboxamide hydrochloride N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2- ( A solution of (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (67 mg) and prop-2-enamide (0.5 g) in methanol (1 mL) was stirred at room temperature for 3 days.
  • Example 96 N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- (2- ⁇ methyl [(1-methyl-1H-indol-3-yl) methyl ] Amino ⁇ ethyl) imidazo [1,2-a] pyridine-2-carboxamide hydrochloride N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- To a solution of [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (52 mg) in tetrahydrofuran (3 mL) at room temperature, 1-methyl-1H-indole-3-carbaldehyde ( 32 mg) and acetic acid (0.3 mL) were added, and the mixture was stirred at room temperature for 30 min.
  • 1H-pyrrolo [2,3-b] pyridine-3-carbaldehyde (15 mg) and 2-methylpyridine borane complex (11 mg) were added, and the mixture was stirred at room temperature for 6 hours.
  • 1H-pyrrolo [2,3-b] pyridine-3-carbaldehyde (15 mg) and 2-methylpyridine borane complex (11 mg) were added, and the mixture was stirred at room temperature overnight.
  • 1H-pyrrolo [2,3-b] pyridine-3-carbaldehyde (15 mg) and 2-methylpyridine borane complex (11 mg) were added, and the mixture was stirred at room temperature for 6 hours.
  • Example 98 N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -N- ⁇ 2-[(1H-indazol-3-ylmethyl) (methyl) amino] ethyl ⁇ -5-methoxy
  • the title compound (54 mg) was obtained in the same manner as in Example 97 using imidazo [1,2-a] pyridine-2-carboxamide hydrochloride 1H-indazole-3-carbaldehyde.
  • Methyl 3-formyl-1H-indole-6-carboxylate (61 mg), 2-methylpyridine borane complex (16 mg), methanol (2 mL) and acetic acid (0.2 mL) were added, and the mixture was stirred at room temperature overnight.
  • Methyl 3-formyl-1H-indole-6-carboxylate (61 mg) and 2-methylpyridine borane complex (16 mg) were added, and the mixture was stirred at room temperature overnight.
  • 2-Methylpyridine borane complex (16 mg) was added and stirred at room temperature for 6 hours.
  • 2-Methylpyridine borane complex (16 mg) was added, and the mixture was stirred at room temperature overnight.
  • Example 101 N- [3-Chloro-4- (trifluoromethyl) benzyl] -3- (4-fluoro-3-methylphenyl) -N- ⁇ 2-[(1H-indol-3-ylmethyl) (methyl) amino] Ethyl ⁇ -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide dihydrochloride N- [3-chloro-4- (trifluoromethyl) benzyl] -3- (4-fluoro-3-methylphenyl) ) -5-Methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (110 mg) in methanol (5 mL) and acetic acid (0.5 mL) at room temperature 1H-indole-3-carbaldehyde (145 mg) and 2-methylpyridine borane complex (43 mg) were added and stirred at room temperature for 3 days.
  • Example 102 N- [3-Chloro-4- (trifluoromethyl) benzyl] -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- (2- ⁇ [(7-methoxy-1H-indole- 3-yl) methyl] (methyl) amino ⁇ ethyl) imidazo [1,2-a] pyridine-2-carboxamide dihydrochloride 7-methoxy-1H-indole-3-carbaldehyde similar to Example 101 By the method, the title compound (38 mg) was obtained. MS (ESI +): [M + H] + 708.2.
  • Example 106 N- [3-Chloro-4- (trifluoromethyl) benzyl] -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- ⁇ 2- [methyl (pyrazolo [1,5-a] Pyridin-3-ylmethyl) amino] ethyl ⁇ imidazo [1,2-a] pyridine-2-carboxamide trihydrochloride Similar to Example 101 using pyrazolo [1,5-a] pyridine-3-carbaldehyde By the method, the title compound (46 mg) was obtained. MS (ESI +): [M + H] + 679.2.
  • Example 110 tert-butyl (2- ⁇ [2-([3-chloro-4- (trifluoromethyl) benzyl] ⁇ [3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a ] Pyridin-2-yl] carbonyl ⁇ amino) ethyl] (methyl) amino ⁇ ethyl) carbamate
  • N- (2-aminoethyl) -N-methylethane-1,2-diamine (5.86 g) in tetrahydrofuran (30 mL )
  • a solution of di-tert-butyl dicarbonate (5.46 g) in tetrahydrofuran (30 mL) was added to the solution at 0 ° C., and the mixture was stirred at room temperature overnight.
  • the reaction mixture was concentrated under reduced pressure, 10% aqueous sodium carbonate solution was added to the resulting residue, and the mixture was extracted with ethyl acetate.
  • the obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
  • the residue was purified successively by silica gel column chromatography (NH, ethyl acetate / n-hexane) and (methanol / ethyl acetate) to give the title compound (813 mg).
  • Example 111 N- ⁇ 2-[(2-aminoethyl) (methyl) amino] ethyl ⁇ -N- [3-chloro-4- (trifluoromethyl) benzyl] -3- (4-fluoro-3-methylphenyl)- 5-methoxyimidazo [1,2-a] pyridine-2-carboxamide tert-butyl (2- ⁇ [2-([3-chloro-4- (trifluoromethyl) benzyl] ⁇ [3- (4-fluoro- Similar to Step C of Example 100, using 3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl ⁇ amino) ethyl] (methyl) amino ⁇ ethyl) carbamate By the method, the title compound (1.03 g) was obtained.
  • Example 112 N- [3-Chloro-4- (trifluoromethyl) benzyl] -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2- (methyl ⁇ 2-[(methylsulfonyl) amino ] Ethyl ⁇ amino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide dihydrochloride N- ⁇ 2-[(2-aminoethyl) (methyl) amino] ethyl ⁇ -N- [3-chloro- 4- (Trifluoromethyl) benzyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (59 mg) in ethyl acetate (5 mL) To the solution were added 10% aqueous sodium carbonate solution (2 mL) and methanesulfonyl chloride (0.016 mL) at room temperature, and the mixture
  • the organic layer was separated and the aqueous layer was extracted with ethyl acetate.
  • the obtained organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate), and the obtained fraction was concentrated under reduced pressure.
  • the residue was dissolved in diethyl ether (5 mL) and ethyl acetate (0.5 mL), and 4N hydrogen chloride / ethyl acetate solution (0.1 mL) was added.
  • Example 113 N- [3-Chloro-4- (trifluoromethyl) benzyl] -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- ⁇ 2- [methyl (methylsulfonyl) amino] ethyl ⁇ imidazo [1,2-a] pyridine-2-carboxamide hydrochloride N- [3-chloro-4- (trifluoromethyl) benzyl] -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- To a solution of [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (60 mg) in tetrahydrofuran (1 mL) at room temperature, pyridine (18 ⁇ L), triethylamine (31 ⁇ L), And methanesulfonyl chloride (9.3 ⁇ L) was added and stirred for 1 hour.
  • Example 114 N- [3-Chloro-4- (trifluoromethyl) benzyl] -N- ⁇ 2-[(2,3-dihydroxypropyl) amino] ethyl ⁇ -3- (4-fluoro-3-methylphenyl) -5 - methoxy imidazo [1,2-a] pyridine-2-carboxamide dihydrochloride
  • A) tert-butyl (2- ⁇ [3-chloro-4- (trifluoromethyl) benzyl] amino ⁇ ethyl) carbamate Similar to step A of Example 100 using tert-butyl (2-aminoethyl) carbamate the method to obtain the title compound (1.22 g).
  • Example 116 N- ⁇ 1- (3,4-dichlorophenyl) -2-[(N, N-dimethylglycyl) amino] ethyl ⁇ -3- (4-fluoro-3-methylphenyl) -5-methoxy-N-methyl Imidazo [1,2-a] pyridine-2-carboxamide
  • HATU (8.9 g) and N-ethyldiisopropylamine (8.8 g) were added, and the mixture was stirred at room temperature for 19.5 hours.
  • the reaction mixture was diluted with water and diethyl ether, and the insoluble material was filtered off.
  • the filtrate was suspended in 2N hydrochloric acid (20 mL) and stirred at room temperature.
  • the obtained aqueous suspension was washed with ethyl acetate, and 8N aqueous sodium hydroxide solution (6 mL) was added to adjust the pH to 14.
  • the mixture was extracted twice with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
  • Example 119 3- (3,4-dichlorophenyl) -3-([2- (dimethylamino) ethyl] ⁇ [3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine- 2-yl] carbonyl ⁇ amino) propanoic acid ethyl 3- (3,4-dichlorophenyl) -3-([2- (dimethylamino) ethyl] ⁇ [3- (4-fluoro-3-methylphenyl) -5- Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl ⁇ amino) propanoate (2.3 g) in tetrahydrofuran (3.5 mL) and methanol (3.5 mL) at 0 ° C.
  • Example 120 N- ⁇ 1- (3,4-dichlorophenyl) -3-[(2-hydroxyethyl) amino] -3-oxopropyl ⁇ -N- [2- (dimethylamino) ethyl] -3- (4-fluoro- 3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide 3- (3,4-dichlorophenyl) -3-([2- (dimethylamino) ethyl] ⁇ [3- (4 -Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl ⁇ amino) propanoic acid (150 mg) to a solution of N, N-dimethylformamide (1.5 mL) Add 2-aminoethanol (19 mg), 1-hydroxybenzotriazole (42 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodi
  • 2-Methylpyridine borane complex (340 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in 2N hydrochloric acid (20 mL). The obtained aqueous suspension was washed with ethyl acetate / n-hexane (1/1), then 8N aqueous sodium hydroxide solution (5.0 mL) and 2N aqueous sodium hydroxide solution (3.0 mL) were added to adjust the pH to 14. did. The mixture was extracted three times with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
  • the obtained oil was diluted with tetrahydrofuran (6 mL) and methanol (6.0 mL), 2N aqueous sodium hydroxide solution (8.0 mL) was added at 60 ° C., and the mixture was stirred at the same temperature for 40 min.
  • the organic solvent was distilled off under reduced pressure, and 6N hydrochloric acid (2.0 mL) and 2N hydrochloric acid (2.0 mL) were added to the resulting aqueous residue at 0 ° C. to adjust the pH to 7.
  • the precipitated solid was collected by filtration and washed with water to give the title compound (1.2 g).
  • Example 129 N-[(5-Chloro-1H-indol-2-yl) methyl] -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1 , 2-a] pyridine-2-carboxamide A) N '-[(5-Chloro-1H-indol-2-yl) methyl] -N, N-dimethylethane-1,2-diamine with 5-chloro-1H-indole-2-carbaldehyde In the same manner as in Step B of Example 117, the title compound (690 mg) was obtained.
  • Example 130 N- [2- (Dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- ⁇ [6- (trifluoromethyl) -1-benzothiophen-2-yl] Methyl ⁇ imidazo [1,2-a] pyridine-2-carboxamide A) N, N-dimethyl-N '- ⁇ [6- (trifluoromethyl) -1-benzothiophen-2-yl] methyl ⁇ ethane-1,2-diamine 6- (trifluoromethyl) -1-benzo The title compound (560 mg) was obtained in the same manner as in Step B of Example 117 using thiophene-2-carbaldehyde.
  • Example 132 N-[(3,4-dichlorophenyl) (1H-imidazol-2-yl) methyl] -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxy Imidazo [1,2-a] pyridine-2-carboxamide dihydrochloride A) To a solution of (3,4-dichlorophenyl) (1H-imidazol-2-yl) methanone 3,4-dichlorobenzoyl chloride (1.2 g) in pyridine (5.0 mL) at 0 ° C, 1H-imidazole (170 mg) and Triethylamine (0.7 mL) was added, and the mixture was stirred at the same temperature for 15 minutes.
  • reaction mixture was warmed to room temperature and stirred for an additional 45 minutes.
  • 4N aqueous sodium hydroxide solution 5.0 mL
  • the reaction mixture was cooled to room temperature, water (50 mL) was added and the mixture was extracted twice with ethyl acetate.
  • the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (370 mg).
  • N, N-dimethylethane-1,2-diamine (0.27 mL) and titanium (IV) isopropoxide (0.27 mL) were added to the reaction mixture, and the mixture was further stirred at room temperature for 18 hours.
  • Sodium cyanoborohydride (60 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr.
  • Sodium borohydride (110 mg) was added to the reaction mixture, and the mixture was stirred at 40 ° C. for 8 hr.
  • the reaction mixture was cooled to room temperature, water (1.0 mL) was added, and the resulting insoluble material was filtered off and washed with ethyl acetate.
  • the reaction mixture was cooled to room temperature and the resulting insoluble material was filtered off.
  • the filtrate was diluted with water (500 mL), and ethanol was distilled off under reduced pressure.
  • the obtained aqueous mixture was washed with diethyl ether (500 mL), and the diethyl ether layer was extracted with 1N hydrochloric acid (500 mL).
  • the combined aqueous layer was adjusted to pH 10 with 8N aqueous sodium hydroxide solution (50 mL).
  • the aqueous layer was extracted twice with diethyl ether, and the combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
  • Example 135 N- [3-amino-1- (3,4-dichlorophenyl) propyl] -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1 , 2-a] pyridine-2-carboxamide tert-butyl [3- (3,4-dichlorophenyl) -3-([2- (dimethylamino) ethyl] ⁇ [3- (4-fluoro-3-methylphenyl) To a solution of -5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl ⁇ amino) propyl] carbamate (1.9 g) in toluene (15 mL) was added trifluoroacetic acid (5.0 mL) at room temperature.
  • Example 138 N- ⁇ 1- (3,4-dichlorophenyl) -3-[(ethylcarbamoyl) amino] propyl ⁇ -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl)- 5-methoxyimidazo [1,2-a] pyridine-2-carboxamide dihydrochloride N- [3-amino-1- (3,4-dichlorophenyl) propyl] -N- [2- (dimethylamino) ethyl]- Add isocyanatoethane (24 ⁇ L) to a solution of 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (75 mg) in pyridine (1.0 mL).
  • the mixture was further stirred at room temperature for 14 hours.
  • the solvent was evaporated under reduced pressure, and the resulting residue was suspended in a saturated aqueous sodium hydrogen carbonate solution and extracted twice with ethyl acetate.
  • the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (NH, ethyl acetate / n-hexane), and the fraction containing the desired product was concentrated under reduced pressure.
  • Example 139 N- ⁇ 1- (3,4-dichlorophenyl) -3-[(1H-indol-2-ylmethyl) amino] propyl ⁇ -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3 -Methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide N- [3-amino-1- (3,4-dichlorophenyl) propyl] -N- [2- (dimethylamino) ethyl ] -3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (240 mg) in methanol (1.2 mL) in acetic acid (0.12 mL), 1H -Indole-2-carbaldehyde (73 mg) and 2-methylpyridine borane complex (58 mg) were added,
  • Example 140 N- (3,4-dichlorobenzyl) -N- [2- (diethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2- Carboxamide N '-(3,4-dichlorobenzyl) -N, N-diethylethane-1,2-diamine was used in the same manner as in Step G of Example 134 to obtain the title compound (36 mg). . MS (ESI +): [M + H] + 557.2.
  • Example 141 N- (3-aminopropyl) -N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
  • Example 144 N- (3,4-dichlorobenzyl) -N- ⁇ 3-[(2,3-dihydroxypropyl) amino] propyl ⁇ -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1, 2-a] pyridine-2-carboxamide dihydrochloride N- (3-aminopropyl) -N- (3,4-dichlorobenzyl) -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [ 1,2-a] pyridine-2-carboxamide (61 mg) in methanol (0.4 mL) in acetic acid (40 ⁇ L), 2,3-dihydroxypropanal (13 mg) and 2-methylpyridine borane complex (16 mg ) was added and stirred at room temperature for 6 hours.
  • a saturated aqueous sodium carbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / n-hexane), the fraction containing the desired product was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (0.4 mL). Ethyl solution (0.4 mL) was added, and the mixture was stirred at room temperature.
  • the reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid (50 mL) and citric acid (10 g) were added to the obtained residue, and the resulting acidic suspension was extracted twice with ethyl acetate (75 mL). .
  • the combined organic layers were extracted twice with 1N aqueous sodium hydroxide solution (75 mL) and once with 2N aqueous sodium hydroxide solution (75 mL) .
  • the combined aqueous layer was diluted with 6N hydrochloric acid (40 mL). Acidified.
  • the aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the reaction mixture was cooled to 0 ° C., and water (1.4 mL), 1N aqueous sodium hydroxide solution (1.4 mL) and water (4.2 mL) were sequentially added.
  • the resulting insoluble material was filtered off using celite and washed with ethyl acetate.
  • the combined filtrate and washings were concentrated under reduced pressure.
  • the residue was dissolved in ethyl acetate (75 mL), and the organic layer was extracted with 0.1 N hydrochloric acid (75 mL).
  • the aqueous layer was neutralized with 8N aqueous sodium hydroxide solution (1.0 mL) and extracted twice with ethyl acetate.
  • Example 146 5-cyclopropyl-N- (3,4-dichlorobenzyl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) imidazo [1,2-a] pyridine- 2-Carboxamide dihydrochloride Similar to Step D of Example 133, using 5-cyclopropyl-3- (4-fluoro-3-methylphenyl) imidazo [1,2-a] pyridine-2-carboxylic acid By the method, the title compound (83 mg) was obtained. MS (ESI +): [M + H] + 539.2.
  • the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / n-hexane, then methanol / ethyl acetate), and the fraction containing the desired product was concentrated under reduced pressure.
  • Example 148 N- [3-Chloro-4- (trifluoromethyl) benzyl] -3- (4-fluoro-3-methylphenyl) -N- ⁇ 3-[(1H-indol-3-ylmethyl) amino] butyl ⁇ - 5-methoxyimidazo [1,2-a] pyridine-2-carboxamide N- (3-aminobutyl) -N- [3-chloro-4- (trifluoromethyl) benzyl] -3- (4-fluoro-3
  • the title compound (67 mg) was prepared in the same manner as in Example 139 using -methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide and 1H-indole-3-carbaldehyde.
  • Example 150 N- (3,4-dichlorobenzyl) -N- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -5-methylimidazo [1,2-a] pyridine-2-carboxamide 5- Bromo-N- (3,4-dichlorobenzyl) -N- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) imidazo [1,2-a] pyridine-2-carboxamide (73 mg) To a mixed solution of 1,2-dimethoxyethane (12 mL) and water (0.13 mL), trimethylboroxine (45 ⁇ L), [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (21 mg) and cesium carbonate (170 mg) were added, and the mixture was stirred at 100 ° C.
  • Example 151 N- (6-Aminohexyl) -N- [3-chloro-4- (trifluoromethyl) benzyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] Pyridine-2-carboxamide
  • Step B of Example 145 the title compound (1.5 g) was obtained.

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Abstract

La présente invention concerne un dérivé hétérocyclique d'un composé présentant une activité inhibitrice de CENP-E, utile dans le traitement prophylactique ou thérapeutique du cancer, ou similaire, et présentant une excellente efficacité pharmacologique. La présente invention concerne spécifiquement un composé de formule (I) [où chaque symbole est tel que défini dans la description] ou l'un de ses sels.
PCT/JP2011/066022 2010-07-14 2011-07-13 Composé hétérocyclique WO2012008508A1 (fr)

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WO2013100018A1 (fr) * 2011-12-28 2013-07-04 武田薬品工業株式会社 Composé hétérocyclique
CN103373969A (zh) * 2012-04-27 2013-10-30 中国科学院上海有机化学研究所 苯基唑环取代酰胺类化合物及其制备方法和用途
CN104447416A (zh) * 2014-11-13 2015-03-25 吉林大学 一种3-叔丁氧酰胺基-4,4,4-三氟丁酸甲酯的制备方法

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WO2009023179A2 (fr) * 2007-08-10 2009-02-19 Genelabs Technologies, Inc. Entités chimiques bicycliques azotées pour traiter les infections virales
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JP2002255964A (ja) * 2000-10-24 2002-09-11 Sankyo Co Ltd イミダゾピリジン誘導体
JP2003313126A (ja) * 2002-04-23 2003-11-06 Sankyo Co Ltd イミダゾピリジン誘導体を有効成分とする医薬
JP2010513495A (ja) * 2006-12-20 2010-04-30 シェーリング コーポレイション 新規なｊｎｋ阻害剤
WO2009023179A2 (fr) * 2007-08-10 2009-02-19 Genelabs Technologies, Inc. Entités chimiques bicycliques azotées pour traiter les infections virales

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Publication number Priority date Publication date Assignee Title
WO2013100018A1 (fr) * 2011-12-28 2013-07-04 武田薬品工業株式会社 Composé hétérocyclique
CN103373969A (zh) * 2012-04-27 2013-10-30 中国科学院上海有机化学研究所 苯基唑环取代酰胺类化合物及其制备方法和用途
CN103373969B (zh) * 2012-04-27 2015-09-16 中国科学院上海有机化学研究所 苯基唑环取代酰胺类化合物及其制备方法和用途
CN104447416A (zh) * 2014-11-13 2015-03-25 吉林大学 一种3-叔丁氧酰胺基-4,4,4-三氟丁酸甲酯的制备方法

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