WO2013100018A1 - Composé hétérocyclique - Google Patents

Composé hétérocyclique Download PDF

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Publication number
WO2013100018A1
WO2013100018A1 PCT/JP2012/083804 JP2012083804W WO2013100018A1 WO 2013100018 A1 WO2013100018 A1 WO 2013100018A1 JP 2012083804 W JP2012083804 W JP 2012083804W WO 2013100018 A1 WO2013100018 A1 WO 2013100018A1
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compound
reaction
alkyl
optionally
salt
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PCT/JP2012/083804
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English (en)
Japanese (ja)
Inventor
孝治 平山
浩 坂野
正格 岡庭
広行 筧
智康 石川
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武田薬品工業株式会社
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Publication of WO2013100018A1 publication Critical patent/WO2013100018A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a heterocyclic compound having CENP-E inhibitory activity and useful for prevention or treatment of cancer and the use thereof.
  • Centromere-associated protein-E also referred to herein as “CENP-E”
  • CENP-E is one of the motor proteins belonging to the kinesin superfamily
  • Non-patent Document 1 is one of the motor proteins belonging to the kinesin superfamily
  • Non-Patent Document 2 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 3 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 (Non-patent Document 3). . Since the anticancer effect is obtained by lowering the CENP-E function, it has been suggested that the inhibition of the function of CENP-E is one of effective methods for cancer treatment (Non-patent Document 4).
  • 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 that may have 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.
  • a compound represented by (5) The antitumor compound disclosed in Patent Document 5, the formula:
  • R 1 represents a group of the formula R 9 —X 2 — (R 9 represents 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 represents 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.
  • 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.
  • a compound represented by (7) A formula that is a PI3 kinase inhibitor disclosed in Patent Document 7 and useful for the treatment of cancer and the like:
  • Z is O, S, or NR A ;
  • (U, V) represents (nitrogen atom, carbon atom) or (carbon atom, nitrogen atom);
  • (X, Y) represents (nitrogen atom or CR 4 , CR 5 or nitrogen atom) and the like;
  • R 1 represents H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, NR 1 ⁇ R 2 ⁇ , etc. (“oxo” is not described).
  • KCNQ2, KCNQ3 modulators disclosed in Patent Document 8, and are 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 is 0-6;
  • R 5 represents H, optionally substituted C 1-7 alkyl or the like;
  • 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 is an optionally substituted C 1-9 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C 3-9 cyclo
  • 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.
  • X a , X b and X c are the same or different and represent CH or N; Y a represents CH 2 , CO, O, NR 5 , S, SO or SO 2 ; Y b represents a bond, CO, O, NR 6 , S, SO or SO 2 ; R 1 represents a substituent, R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are the same or different and represent a hydrogen atom or a substituent, and R 7 and R 8 are bonded to each other.
  • R 4 represents an optionally substituted C 1-6 alkyl group
  • Ar ring represents an optionally substituted aromatic ring
  • n represents an integer of 1 to 3.
  • 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.
  • X a , X b and X c are the same or different and represent CH or N; Y a represents CH 2 , CO, O, NR 5 , S, SO or SO 2 ; Y b represents a bond, CO, O, NR 6 , S, SO or SO 2 ; R 1 represents a substituent, R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are the same or different and represent a hydrogen atom or a substituent, and R 7 and R 8 are bonded to each other.
  • R 4 represents an optionally substituted C 1-6 alkyl group
  • Ar ring represents an optionally substituted aromatic ring
  • n represents an integer of 1 to 3.
  • X a , X b and X c are CH; Y a is O or SO 2 ; Y b is a bond; R 7 and R 8 are hydrogen atoms; R 9 and R 10 are the same or different, (1) a halogen atom, (2) cyano, or (3) C 1-6 alkyl optionally having 1 to 3 halogen atoms; The compound or a salt thereof according to the above [1], wherein n is 1.
  • R 4 is (1) amino having 1 or 2 C 1-6 alkyl, and 1 selected from (2) (i) C 1-6 alkyl, and (ii) a 4- to 12-membered non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from hydroxy
  • Ar ring is (1) a halogen atom, and (2) The compound or the salt thereof according to any one of the above [1] to [6], which is benzene optionally having 1 to 3 substituents selected from C 1-6 alkyl.
  • R 1 is C 1-6 alkoxy optionally having 1 to 3 halogen atoms
  • R 2 is a hydrogen atom
  • R 3 is (1) a hydrogen atom, or (2) a halogen atom
  • Ar ring is (1) a halogen atom, and (2) benzene optionally having 1 to 3 substituents selected from C 1-6 alkyl
  • R 4 is (1) (i) a 5- to 12-membered aromatic heterocycle, (ii) C 1-6 alkoxy, and (iii) amino having 1 or 2 C 1-6 alkyl optionally having 1 to 3 substituents selected from hydroxy, and (2) (i) C 1-6 alkyl optionally having hydroxy, and (ii) 4 to 12 membered non-aromatic optionally having 1 to 3 substituents selected from hydroxy
  • R 5 is (1) hydrogen atom, (2) C 1-6 alkyl-carbonyl, (3) C 1-6 al
  • a method for inhibiting CENP-E in a mammal comprising administering an effective amount of the compound or salt thereof according to any one of [1] to [11] above to a mammal.
  • a method for preventing or treating cancer in a mammal comprising administering an effective amount of the compound or salt thereof according to any one of [1] to [11] to a mammal.
  • halogen atom refers to 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.
  • 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.
  • 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.
  • 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 refers to, for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl. Of these, C 6-10 aryl is preferable.
  • 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 which “carbonyl” may have include a substituent selected from the following 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
  • heterocyclic group in the “optionally substituted heterocyclic group” refers to an aromatic heterocyclic group and a non-aromatic heterocyclic group.
  • aromatic heterocyclic group means 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 (
  • 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 such as 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 (e
  • 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 means a monocyclic non-aromatic heterocyclic group and a condensed non-aromatic heterocyclic group.
  • Examples of 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, thiazolidine
  • 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 fused 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 thereof 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 Examples include -10 cycloalkenylthio, C 6-14 arylthio, C 7-13 aralkylthio, C 8-13 arylalkenylthio, C 1-6 alkyl-carbonylthio, and 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 is 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.
  • nitrogen-containing aromatic heterocycle examples 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, 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), tetrahydropyrimidine (eg, 1,2,5,6-tetrahydropyrimidine).
  • dihydropyridine eg, 1,2-dihydropyridine
  • tetrahydropyridine eg, 1,2,5,6-tetrahydropyrimidine
  • 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)
  • 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.
  • aromatic heterocycle refers to a ring corresponding to “aromatic heterocyclic group”.
  • 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.
  • non-aromatic ring in the “optionally substituted non-aromatic ring” refers to a non-aromatic hydrocarbon or a non-aromatic heterocyclic ring.
  • non-aromatic hydrocarbon means “C 3-10 cycloalkane”, “C 3-10 cycloalkene” or “C 4-10 cycloalkadiene”, C 3-10 cycloalkyl "refers to a ring which corresponds to the" C 3-10 cycloalkenyl “or” C 4-10 cycloalkadienyl ".
  • C 3-10 cycloalkyl means, C 3-10 cycloalkane respectively, C 3-10 cycloalkene or C 4- A spiro ring group may be formed with 10 cycloalkadiene.
  • non-aromatic heterocyclic ring refers to a ring corresponding to “non-aromatic heterocyclic group”.
  • a monocyclic non-aromatic heterocycle is preferable, and a 5- or 6-membered monocyclic non-aromatic heterocycle is particularly preferable.
  • the “non-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 group in the "optionally substituted C 1-6 alkyl group” include methyl, ethyl, propyl and the like.
  • the C 1-6 alkyl group 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.
  • X a , X b and X c are the same or different and represent CH or N.
  • Y a represents CH 2 , CO, O, NR 5 , S, SO or SO 2 .
  • Y b represents a bond, CO, O, NR 6 , S, SO or SO 2 .
  • R 1 represents a substituent
  • R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are the same or different and represent a hydrogen atom or a substituent, and R 7 and R 8 are bonded to each other. These may form a ring together with adjacent carbon atoms.
  • N represents an integer of 1 to 3.
  • R 1 represents a substituent
  • R 2 represents a hydrogen atom or a substituent.
  • R 3 represents a hydrogen atom or a substituent.
  • R 1 is preferably optionally substituted C 1-6 alkoxy.
  • R 1 is more preferably C 1-6 alkoxy (eg, methoxy) optionally having 1 to 3 halogen atoms (eg, fluorine atom), Above all, C 1-6 alkoxy (eg methoxy) is preferred.
  • R 2 is more preferably a hydrogen atom.
  • R 3 is preferably (1) a hydrogen atom, or (2) A halogen atom (eg, fluorine atom).
  • R 3 is more 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).
  • the Ar ring is (1) halogen atoms (eg, fluorine atoms), and (2) C 1-6 alkyl (eg, methyl) C 6-10 aromatic hydrocarbon optionally having 1 to 3 substituents selected from (eg, benzene) It is.
  • halogen atoms eg, fluorine atoms
  • C 1-6 alkyl eg, methyl
  • C 6-10 aromatic hydrocarbon optionally having 1 to 3 substituents selected from (eg, benzene) It is.
  • the compound of the present invention having such an Ar ring has strong CENP-E enzyme inhibitory activity 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 more preferably (1) halogen atoms (eg, fluorine atoms), and (2) C 1-6 alkyl (eg, methyl) It is benzene which may have 1 to 3 substituents selected from
  • R 4 represents an optionally substituted C 1-6 alkyl.
  • R 4 is preferably (1) (i) a 5- to 12-membered aromatic heterocycle (eg, indolyl), (ii) C 1-6 alkoxy (eg, methoxy), and (iii) C 1-6 alkyl (eg, methyl, ethyl) optionally having 1 to 3 substituents selected from hydroxy 1 or 2 aminos, and (2) (i) an optionally substituted C 1-6 alkyl (eg, methyl, ethyl, propyl), and (ii) having 1 to 3 substituents selected from hydroxy 4- to 12-membered non-aromatic heterocyclic group (eg, morpholinyl, pyrrolidinyl, azetidinyl) C 1-6 alkyl (eg, ethyl, propyl, butyl) optionally having 1 to 3 substituents selected from
  • R 4 is more preferably (1) an amino optionally having 1 or 2 C 1-6 alkyl (eg, methyl) optionally substituted with a 5- to 12-membered aromatic heterocyclic group (eg, indolyl), and (2) (i) hydroxy, and (ii) C 1-6 alkyl optionally having 1 to 3 hydroxy (eg, methyl, ethyl, propyl) 4- to 12-membered non-aromatic heterocyclic group (eg, morpholinyl, pyrrolidinyl, azetidinyl) optionally having 1 to 3 substituents selected from C 1-6 alkyl optionally having 1 to 3 substituents selected from (eg, ethyl, propyl, butyl) It is.
  • an amino optionally having 1 or 2 C 1-6 alkyl (eg, methyl) optionally substituted with a 5- to 12-membered aromatic heterocyclic group (eg, indolyl), and (2) (i) hydroxy, and (ii
  • the compound of the present invention having such R 4 is particularly excellent in CENP-E enzyme inhibitory activity, pharmacokinetics and safety in vitro and in cancer cells.
  • R 4 is more preferably (1) amino having 1 or 2 C 1-6 alkyl (eg, methyl), and (2) 4- to 12-membered non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from (i) C 1-6 alkyl (eg, methyl), and (ii) hydroxy (Eg, azetidinyl) C 1-6 alkyl optionally having 1 to 3 substituents selected from (eg, ethyl, propyl) And
  • N, N-dimethylaminopropyl group, N-methylazetidin-2-yl-ethyl group, and N, N-dimethylaminoethyl group are preferable.
  • R 5 and R 6 are preferably the same or different, (1) a hydrogen atom, or (2) Acyl.
  • R 5 and R 6 are more preferably the same or different, (1) hydrogen atom, (2) C 1-6 alkyl-carbonyl (eg, acetyl), (3) C 1-6 alkoxy-carbonyl (eg, ethoxycarbonyl), or (4) Carbamoyl optionally having 1 or 2 C 1-6 alkyl (eg, ethyl).
  • R 7 and R 8 are preferably the same or different, (1) a hydrogen atom, or (2) C 1-6 alkyl which may be substituted.
  • R 7 and R 8 are more preferably the same or different, (1) a hydrogen atom, or (2) C 1-6 alkyl (eg, methyl) And More preferably, it is a hydrogen atom.
  • R 7 and R 8 may be bonded to each other to form a ring together with adjacent carbon atoms.
  • Examples of the ring that R 7 and R 8 are bonded to each other to form together with the adjacent carbon atom include “an optionally substituted aromatic ring” and “an optionally substituted non-aromatic ring”.
  • R 9 and R 10 are preferably the same or different, (1) hydrogen atom, (2) halogen atoms (eg, fluorine atoms, chlorine atoms), (3) cyano, or (4) C 1-6 alkyl which may be substituted.
  • R 9 and R 10 are more preferably the same or different, (1) hydrogen atom, (2) halogen atoms (eg, fluorine atoms, chlorine atoms), (3) cyano, or (4) C 1-6 alkyl (eg, methyl) optionally having 1 to 3 halogen atoms (eg, fluorine atom) It is.
  • R 9 and R 10 are more preferably the same or different, (1) Halogen atoms (eg, fluorine atoms, chlorine atoms), (2) cyano, or (3) C 1-6 alkyl (eg, methyl) optionally having 1 to 3 halogen atoms (eg, fluorine atom) It is.
  • X a and X b are preferably the same or different and each is CH or N; More preferably, it is CH.
  • Xc is preferably CH.
  • Y a is preferably CH 2 , O, NR 5 (R 5 is as defined above), S, or SO 2 , More preferably, O, or SO 2.
  • Y b is preferably a bond.
  • N is more preferably 1.
  • R 1 is C 1-6 alkoxy (eg, methoxy) optionally having 1 to 3 halogen atoms (eg, fluorine atom);
  • R 2 is a hydrogen atom;
  • R 3 is (1) a hydrogen atom, or (2) a halogen atom (eg, a fluorine atom);
  • Ar ring is (1) halogen atoms (eg, fluorine atoms), and (2) C 1-6 alkyl (eg, methyl)
  • R 4 is (1) (i) a 5- to 12-membered aromatic heterocycle (eg, indolyl), (ii) C 1-6 alkoxy (eg, methoxy), and (iii) C 1-6 alkyl (eg, methyl, ethyl) optionally having 1 to 3 substituents selected from hydroxy 1 or 2 aminos, and (2) (i) an optionally substituted C 1-6
  • R 1 is C 1-6 alkoxy (eg, methoxy) optionally having 1 to 3 halogen atoms (eg, fluorine atom); R 2 and R 3 are hydrogen atoms; Ar ring is (1) halogen atoms (eg, fluorine atoms), and (2) C 1-6 alkyl (eg, methyl) Benzene optionally having 1 to 3 substituents selected from: R 4 is (1) an amino having 1 or 2 C 1-6 alkyl (eg, methyl) optionally substituted with a 5- to 12-membered aromatic heterocycle (eg, indolyl), and (2) (i) C 1-6 alkyl optionally having hydroxy (eg, methyl), and (ii) 1 to 3 substituents optionally selected from hydroxy 12-membered non-aromatic heterocyclic group (eg, morpholinyl, pyrrolidinyl, azetidinyl) C 1-6 alkyl (eg, ethyl, prop
  • R 1 is C 1-6 alkoxy (eg, methoxy); R 2 and R 3 are hydrogen atoms; Ar ring is (1) halogen atoms (eg, fluorine atoms), and (2) C 1-6 alkyl (eg, methyl) Benzene optionally having 1 to 3 substituents selected from: R 4 is (1) amino having 1 or 2 C 1-6 alkyl (eg, methyl), and (2) a 4- to 12-membered non-aromatic heterocycle optionally having 1 to 3 substituents selected from (i) C 1-6 alkyl (eg, methyl), and (ii) hydroxy Group (eg, azetidinyl) C 1-6 alkyl (eg, ethyl, propyl) optionally having 1 to 3 substituents selected from: R 7 and R 8 are hydrogen atoms; R 9 and R 10 are the same or different, (1) Halogen atoms (eg, fluorine atoms, chlorine atoms), (2) cyano,
  • 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; and aluminum salt.
  • the salt with an 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 And 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.
  • pharmaceutically acceptable salts are preferred.
  • examples of 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. ) And the like, and when the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid, or 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.
  • an alkali metal salt eg, sodium salt, potassium salt
  • an alkaline earth metal salt eg, calcium salt, magnesium salt
  • an inorganic acid such as hydrochloric acid, hydrobro
  • Compound (I) or a salt thereof can be produced according to a method known per se, for example, the method described in detail below or a method analogous thereto.
  • examples of alcohols used as a reaction solvent include methanol, ethanol, propanol, isopropanol (2-propanol), butanol, and tert-butanol.
  • examples of ethers used as a reaction solvent include dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, and ethylene glycol-dimethyl ether.
  • 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 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 sulfoxide used as a reaction solvent include dimethyl sulfoxide.
  • examples of aromatic hydrocarbons used as a reaction solvent include benzene and toluene.
  • 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, potassium hydrogen carbonate, etc .; alkali metals C 1-6 such as sodium methoxide, sodium ethoxide, potassium tert-butoxide (2-methylpropan-2-olate), etc.
  • Alkoxides trimethylamine, triethylamine, diisopropylethylamine (N-ethyl-N-isopropylpropan-2-amine), pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, N, N-dimethylaniline, 1,5-diazabicyclo [ 4.3.0] -5-Nonene, 1,4-diazabicyclo [2.2.2] octa , Organic bases such as 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), tetramethylguanidine; organolithiums such as methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium And lithium amides such as lithium diisopropylamide.
  • organolithiums such as methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium
  • 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, or ammonium phosphate, or organic acid ammonium such as ammonium acetate, ammonium formate, or ammonium citrate is used.
  • the raw material compound and the production intermediate may be a salt.
  • a salt examples include the same salts as 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.
  • a conventional method for example, separation means such as recrystallization, distillation, chromatography, etc.
  • 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) or a reactive derivative thereof (eg, acid halide, acid anhydride, active ester, acid imidazolide) with compound (IB).
  • a reactive derivative thereof eg, acid halide, acid anhydride, active ester, acid imidazolide
  • the amount of compound (IB) to be used is generally 0.8 to 10 equivalents relative to 1 equivalent of compound (IA) or a reactive derivative thereof.
  • This reaction can be performed in the presence of a base.
  • the amount of the base used is usually 1 to 10 equivalents relative to 1 equivalent of compound (IA) or a reactive derivative thereof.
  • This reaction can also be performed in the presence of a condensing agent.
  • the condensing agent include carbodiimide condensation reagents (eg, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide ⁇ (EDC) and its hydrochloride (EDC ⁇ HCl)), phosphoric acid condensation reagents (Eg, diethyl cyanophosphate, diphenylphosphoryl azide), N, N'-carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolium tetrafluoroborate, O- (7-azabenzotriazol-1-yl ) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU)).
  • carbodiimide condensation reagents eg, dicyclohexyl
  • the amount of the condensing agent to be used is generally 0.1 to 10 equivalents per 1 equivalent of compound (IA) or a reactive derivative thereof.
  • This reaction can also be performed 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 with respect to 1 equivalent of compound (IA) 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 by using a commercially available reagent, a reaction known per se, a method represented by the following Reaction Scheme 2, or a method analogous thereto.
  • Compound (IB) can be produced using a commercially available reagent or by a reaction known per se.
  • X 1 represents a leaving group
  • X 2 represents a leaving group
  • X 3 represents a leaving group
  • P 1 represents a hydrogen atom or an amino protecting group
  • P 2 represents a carboxy protection group.
  • Group is shown, and other symbols are as defined above.
  • Examples of the “leaving group” represented by X 1 include acyloxy (eg, acetyloxy, benzoyloxy), halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), halogenated Good C 1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy [triflate]), and optionally substituted C 6-14 arylsulfonyloxy may be mentioned.
  • acyloxy eg, acetyloxy, benzoyloxy
  • halogen atom eg, fluorine atom, chlorine atom, bromine atom, iodine atom
  • halogenated Good C 1-6 alkylsulfonyloxy eg, methanesulf
  • Examples of the “ optionally substituted C 6-14 arylsulfonyloxy” include C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl).
  • 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
  • substituents selected from nitro Preferable examples include C 6-14 arylsulfonyloxy, and specific examples include benzenesulfonyloxy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy, naphthylsulfonyloxy.
  • the "leaving group” represented by X 2 include the same as those exemplified as the “leaving group” represented by X 1.
  • Examples of the “leaving group” represented by X 3 include a dihydroxyboranyl group (—B (OH) 2 ) and a dialkoxyboranyl group (preferably 4,4,5,5-tetramethyl-1,3 , 2-dioxaboran-2-yl) and tri-C 1-6 alkylstannyl groups (preferably trimethylstannyl group and n-tributylstannyl group).
  • 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 groups preferably trimethylstannyl group and n-tributylstannyl group.
  • the “amino protecting group” represented by P 1 may be any group that can be removed after the cyclization reaction.
  • C 1-6 alkyl- which may be substituted with a halogen atom (eg, fluorine atom).
  • Carbonyl preferably acetyl, trifluoroacetyl
  • optionally substituted C 1-6 alkyl-oxycarbonyl preferably tert-butyloxycarbonyl
  • C 7-13 aralkyl-oxycarbonyl preferably benzyl Oxycarbonyl
  • C 1-3 alkylsulfonyloxy preferably trifluoromethanesulfonyloxy [triflate], etc.
  • optionally substituted with a halogen atom eg, fluorine atom
  • C 6-14 optionally substituted Arylsulfonyl 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 “carboxy protecting group” represented by P 2 include C 1-6 alkyl (eg, methyl, ethyl, tert-butyl), C 7-11 aralkyl (eg, benzyl), phenyl, trityl, substituted silyl (Eg, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl (eg, 1-allyl).
  • C 1-6 alkyl eg, methyl, ethyl, tert-butyl
  • C 7-11 aralkyl eg, benzyl
  • phenyl trityl
  • substituted silyl Eg, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylphenyl
  • Compound (IA) can be produced by subjecting compound (IA- (a)) 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, John Wiley and Sons edited (1999)).
  • compound (IA) can be produced by reacting compound (IA- (a)) 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 (IA).
  • This reaction is preferably performed in a solvent inert to the reaction.
  • a solvent include alcohols, ethers, halogenated hydrocarbons, hydrocarbons, amides, nitriles, sulfoxides, sulfolane, hexamethylphosphoramide, water, or a mixed solvent thereof. Can be mentioned.
  • This reaction can be 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.
  • the compound (IA- (a)) used in this reaction can be produced by subjecting the compound (IA- (b)) to a coupling reaction with the compound (I-C1).
  • the amount of compound (I-C1) used in the above coupling reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IA- (b)).
  • 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, relative to 1 equivalent of compound (IA- (b)).
  • This reaction can 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 (tri Examples thereof include phenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), copper (I) iodide, and copper (I) oxide.
  • phosphine ligand examples 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.
  • 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 (IA- (b)).
  • 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 (IA- (b)).
  • This reaction can be 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 (I-C1) can be produced using a commercially available reagent or a reaction known per se.
  • Compound (IA- (b)) can be produced from compound (IA- (c)).
  • the compound (IA- (b)) in which X 2 is a halogen atom is obtained by adding a halogenating agent (eg, iodine, bromine, chlorine, N-iodosuccinimide) to the compound (IA- (c)), N-bromosuccinimide, N-chlorosuccinimide) can be used for the production.
  • a halogenating agent eg, iodine, bromine, chlorine, N-iodosuccinimide
  • N-bromosuccinimide, N-chlorosuccinimide can be used for the production.
  • the amount of the halogenating agent to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IA- (c)).
  • This reaction can also be performed in the presence of a radical initiator.
  • a radical initiator is 2,2'-azobis (2-methylpropionitrile).
  • the amount of the radical initiator used is usually 0.05 to 1 equivalent, preferably 0.1 to 0.5 equivalent, relative to 1 equivalent of compound (IA- (c)).
  • This reaction can be performed in the presence of an acid.
  • the acid include acetic acid and trifluoroacetic acid.
  • the amount of acid used is usually 0.1 to 1000 equivalents, preferably 1 to 100 equivalents, relative to 1 equivalent of compound (IA- (c)).
  • 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 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, and more preferably 1 to 12 hours.
  • this reaction may be performed under microwave irradiation.
  • Compound (IA- (c)) can be produced by reacting compound (IA- (d)) with compound (ID) and then intramolecular cyclization.
  • the amount of compound (IA- (d)) to be used is generally 1-5 equivalents, preferably 1-2 equivalents, relative to 1 equivalent of compound (ID).
  • 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 also be performed 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 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, and more preferably 1 to 12 hours.
  • this reaction may be performed under microwave irradiation.
  • Compound (IA- (d)) and compound (ID) can be produced using commercially available reagents or by a reaction known per se.
  • Compound (IA- (a)) can be produced by reacting compound (IA- (e)) with compound (ID) and then cyclizing within the molecule.
  • the amount of compound (IA- (e)) to be used is generally 1-5 equivalents, preferably 1-2 equivalents, relative to 1 equivalent of compound (ID).
  • 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 also be performed 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, and more preferably 1 to 12 hours.
  • this reaction may be performed under microwave irradiation.
  • compound (IA- (a)) is further subjected to substituent conversion (substituent introduction or functional group conversion) by applying a method known per se, and compound (IA- (a)) Other compounds represented can also be made.
  • R 1 of the compound (IA- (a)) is a leaving group (eg, bromine atom)
  • an organometallic reagent eg, tributyl (ethynyl) stannane, copper cyanide
  • 1 is ethynyl, cyano and the like
  • the amount of the organometallic reagent used in such a reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents per 1 equivalent of the compound (IA- (a)).
  • This reaction is preferably performed in a solvent inert to the reaction.
  • a solvent 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 (IA- (a)).
  • 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.
  • metal complex examples include [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, dichloromethane complex, tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, tetrakis (triphenyl Examples include phosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), copper (I) iodide, and copper (I) oxide.
  • phosphine ligand examples 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 (IA- (a)).
  • 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 (IA- (a)).
  • 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 (I-A- (a)) and R 3 is a bromine atom in the the compound (I-A- (a)) and R 3 is a hydrogen atom and brominating agent (e.g., N- It can be produced by reacting bromosuccinimide).
  • the amount of brominating agent used in such a reaction is usually 1 to 3 equivalents, preferably 1 to 3 equivalents relative to 1 equivalent of the compound (IA- (a)) wherein R 3 is a hydrogen atom. 2 equivalents.
  • 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, Examples include hexamethylphosphoramide, acetic acid, water, or a mixed solvent thereof.
  • This reaction can be 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 (I-A- (a)) and R 3 is methyl, ethynyl or cyano is a compound (I-A- (a)) R 3 of a leaving group (e.g., bromine atom)
  • a leaving group e.g., bromine atom
  • organometallic reagents eg, tetramethylstannane, tributyl (ethynyl) stannane, trimethyl [(tributylstannanyl) ethynyl] silane, copper cyanide, zinc cyanide
  • organometallic reagents 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 5 equivalents, preferably 1 equivalent of the compound (IA- (a)) in which R 3 is a leaving group. 1-2 equivalents.
  • 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 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 (IA- (a)) in which R 3 is a leaving group. It is.
  • 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.
  • metal complex examples include [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, dichloromethane complex, tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, tetrakis (triphenyl Examples include phosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), copper (I) iodide, and copper (I) oxide.
  • phosphine ligand examples 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 (IA- (a)) 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 (IA- (a)) in which R 3 is a leaving group. is there.
  • This reaction can be 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 (I-A- (a)) and R 3 is amino or cyclopropyl or the like of the compound (I-A- (a)) R 3 is a leaving group (eg, a bromine atom )
  • a substrate may be subjected to a coupling reaction in the presence of a metal complex or a phosphine ligand.
  • the substrate examples include amines (eg, diphenylmethanimine) and boronic acids (eg, cyclopropylboronic acid).
  • amines eg, diphenylmethanimine
  • boronic acids eg, cyclopropylboronic acid
  • the amount of the substrate used is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (IA- (a)) 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 may be mentioned.
  • 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 (IA- (a)) in which R 3 is a leaving group. It is.
  • 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.
  • metal complex examples include [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, dichloromethane complex, tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, tetrakis (triphenyl Examples include phosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), copper (I) iodide, and copper (I) oxide.
  • phosphine ligand examples 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 (IA- (a)) 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 (IA- (a)) in which R 3 is a leaving group. is there.
  • This reaction can be 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 (IA- (e)) is obtained by subjecting Compound (IA- (g)) to an aldol addition reaction with Compound (I-C2), which is an aromatic aldehyde, to Compound (IA- ( After preparing f)), it can be produced by opening the oxirane.
  • the compound (IA- (f)) has different chemical stability depending on the type of Ar ring and may be isolated as the compound (IA- (f)). In some cases, it can be isolated as A- (e)). In many cases, the compound (IA- (e)) is obtained as a mixture with the compound (IA- (f)).
  • compound (IA- (f)) is compound (IA- (e)). Therefore, even if compound (IA- (f)) is mixed in compound (IA- (e)), it can be used as it is in the next step.
  • the amount of compound (IA- (g)) to be used is generally 1-5 equivalents, preferably 1-2 equivalents, relative to 1 equivalent of compound (IC-2).
  • 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 also be performed 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 (IA- (g)).
  • 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.
  • Compound (IA- (f)) can be converted to compound (IA- (e)) by extending the reaction time as it is in the same reaction system. If the conversion is slow, the conversion to the compound (IA- (e)) can be accelerated by raising the reaction temperature. In addition, when the compound (IA- (f)) is sufficiently stable with respect to the liquid separation operation, the compound (IA- (f)) is isolated as the compound (IA- (f)) and then gradually removed during storage. A- (e)) can also be converted.
  • This conversion reaction can be performed 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 (IA- (g)) and compound (I-C2) can be produced using commercially available reagents or by a reaction known per se.
  • reaction formula 4 a compound in which a hydrogen atom is added to a ring-constituting carbon atom bonded to N (hereinafter referred to as compound (IB1)) is represented by the following reaction scheme. It can also be produced by the method shown in 4 or a method analogous thereto. Reaction formula 4
  • X 4 represents a leaving group, and other symbols are as defined above.
  • Examples of the “leaving group” represented by X 4 include the same as those exemplified as the “leaving group” represented by X 1 .
  • Compound (I-B1) can be produced by subjecting compound (IF) and compound (IE1) to a reductive amination reaction (Route A).
  • the reaction system can be produced by reacting a hemiaminal or imine generated in the reaction system by mixing the compound (IF) and the compound (IE1) with an appropriate reducing agent.
  • the amount of compound (I-E1) to be used is generally 1-10 equivalents, preferably 1-2 equivalents, relative to 1 equivalent of compound (IF).
  • a general reducing agent is widely used as the reducing agent.
  • Examples of common reducing agents include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and 2-methylpyridine borane complex.
  • the amount of the reducing agent to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IF).
  • 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 also be carried out in the presence of an acid.
  • An example of such an acid is acetic acid.
  • the amount of acid used is usually 1 to 5 equivalents relative to 1 equivalent of compound (IF).
  • the acid may be used as a solvent.
  • This reaction can also be performed in the presence of a Lewis acid.
  • Lewis acids include titanium (IV) isopropoxide.
  • the amount of Lewis acid used is usually 1 to 5 equivalents per 1 equivalent of compound (IF).
  • Lewis acid may be used as a solvent.
  • This reaction can be 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 (IE1) and compound (IF) can be produced using commercially available reagents or by a reaction known per se.
  • Compound (IF) can also be produced by the methods described in the following reaction formulas 9 to 12.
  • the compound (I-B1) was reduced (I-F) carbonyl, the obtained compound (I-B1- (b)) of hydroxy compound converted to a leaving group X 4 in (I- It can also be produced by reacting B1- (a)) with compound (IE1) (Route B).
  • the compound (I-B1) is different from the compound (I-B1- (a)) in which, for example, X 4 is —O—SO 2 Me, —Cl or —Br. It can be produced by reacting E1).
  • the amount of compound (I-E1) to be used is generally 1-5 equivalents, preferably 1-2 equivalents, relative to 1 equivalent of compound (I-B1- (a)).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, water, or a mixed solvent thereof.
  • 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 (I-B1- (a)).
  • This reaction can also be carried out in the presence of additives such as potassium iodide or sodium iodide.
  • the amount of the additive to be used is generally 0.01 to 5 equivalents, preferably 0.1 to 1 equivalent, relative to 1 equivalent of compound (I-B1- (a)).
  • This reaction can be 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 (I-B1- (a)) is commercially available, or can be produced by a reaction known per se.
  • the compound (I-B1- (a)) can also be produced by subjecting the compound (I-B1- (b)) to a conversion reaction known per se.
  • a compound in which X 4 is —O—SO 2 Me is methanesulfonyl chloride or methane with respect to the compound (I-B1- (b)). It can be produced by reacting a sulfonic anhydride.
  • the amount of methanesulfonyl chloride or methanesulfonic anhydride used in this reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (I-B1- (b)).
  • This reaction is preferably carried out in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, pyridine, water, or a mixed solvent thereof.
  • 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 (I-B1- (b)).
  • This reaction can be 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.
  • chlorinating agent examples include thionyl chloride, phosphoric acid trichloride, phosphoric acid pentachloride, and hydrogen chloride.
  • brominating agent examples include phosphoric acid tribromide, hydrogen bromide, bromine, and N-bromosuccinimide.
  • the amount of the chlorinating agent or brominating agent used in this reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (I-B1- (b)).
  • This reaction may be carried out in the presence of a radical initiator such as 2,2′-azobis (2-methylpropionitrile).
  • the amount of the radical initiator to be used is generally 0.05 to 10 equivalents, preferably 0.05 to 2 equivalents, relative to 1 equivalent of compound (I-B1- (b)).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, pyridine, acetic acid, water, or a mixed solvent thereof.
  • 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 (I-B1- (b)).
  • This reaction can be carried out at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.).
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours.
  • this reaction may be performed under microwave irradiation.
  • Compound (I-B1- (b)) is commercially available, or can be produced by a reaction known per se.
  • Compound (I-B1- (b)) can also be produced by reacting compound (IF) with a reducing agent.
  • a general reducing agent is widely used as the reducing agent.
  • common reducing agents include sodium borohydride, lithium aluminum hydride, borane-dimethylsulfide complex, and borane-tetrahydrofuran complex.
  • the amount of the reducing agent to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IF).
  • 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 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 (I-B1) can also be produced by the following method (Scheme 5) or a method analogous thereto (Route C). Reaction formula 5
  • R 11 represents a hydrogen atom or an alcohol substituent
  • R 12 represents a partial structure when R 4 is represented as R 12 —CH 2 —.
  • P 3 represents an amino protecting group
  • X 5 represents a leaving group, Other symbols are as defined above.
  • the “alcohol substituent” represented by R 11 includes, for example, a C 1-6 alkyl group (eg, methyl, benzyl) optionally substituted with a C 6-10 aryl group.
  • amino protecting group examples include those exemplified as the “amino protecting group” for P 1 .
  • Examples of the “leaving group” represented by X 5 include the same as those exemplified as the “leaving group” represented by X 1 .
  • Compound (I-B1) is obtained by subjecting compound (I-B1- (d)) and compound (IE-2) to a condensation reaction to derivatize compound (I-B1- (c)). It can be produced by an amide reduction reaction.
  • Examples of the reducing agent used in the amide reduction reaction of the compound (I-B1- (c)) include lithium aluminum hydride, aluminum hydride, borane-tetrahydrofuran complex, and borane-dimethylsulfide complex.
  • the amount of the reducing agent to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (I-B1- (c)).
  • 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 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 (I-B1- (d)) and compound (IE2) may be commercially available products, or can be produced by a method known per se.
  • Compound (I-B1- (d)) is obtained by subjecting compound (IF) to an oximation reaction to derivatize compound (I-B1- (e)), and then reducing the obtained oxime. It can manufacture by attaching
  • the amount of the hydroxyamine derivative to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IF).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, pyridine, water, or a mixed solvent thereof.
  • 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 (IF).
  • This reaction can be 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.
  • this reduction reaction can be performed by, for example, a hydrogenation method using palladium-carbon, Raney nickel or the like as a catalyst.
  • the amount of the catalyst used is usually 5 to 50% w / w%, preferably 10 to 20% w / w% with respect to the compound (I-B1- (e)).
  • This reduction reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, pyridine, acetic acid, water, or a mixed solvent thereof.
  • this reduction reaction can also be carried out in the presence of a solvent containing ammonia.
  • the pressure of hydrogen gas used for this reduction reaction is usually 1 to 10 atmospheres, preferably 1 to 3 atmospheres.
  • This reduction reaction can be performed at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.).
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours, more preferably 1 to 10 hours.
  • This reduction reaction can also be performed using, for example, a borane-tetrahydrofuran complex or a borane-dimethylsulfide complex as a reducing agent.
  • the amount of the reducing agent to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (I-B1- (e)).
  • This reduction 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 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 can also be carried out by a method using zinc powder as a reducing agent in an acidic solvent.
  • the amount of zinc powder used is usually 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (I-B1- (e)).
  • This reaction can also be carried out in the presence of an acid.
  • the amount of the acid to be used is generally 1-1000 equivalents, preferably 1-100 equivalents, relative to 1 equivalent of compound (I-B1- (e)). Moreover, you may use an acid as a solvent.
  • This reaction can be 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 at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.).
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours, more preferably 1 to 10 hours.
  • Compound (I-B1) can also be produced by a reductive amination reaction using compound (I-B1- (d)) and compound (IE3).
  • Compound (IE3) can be produced using a commercially available reagent or by a reaction known per se.
  • the compound (I-B1) is obtained by introducing the compound (I-B1- (g)) obtained by introducing an amino protecting group P 3 into the amino group of the compound (I-B1- (d)). It can be produced by subjecting it to an alkylation reaction using compound (I-E4) and removing P 3 from the obtained compound (I-B1- (f)).
  • compound (I-B1- (g)) is compound (I-B1- (d)), which is a reaction for introducing a protecting group known per se (for example, Protective Groups In Organic Synthesis, John Wiley and Sons) (The method described in (1980)).
  • a protecting group known per se for example, Protective Groups In Organic Synthesis, John Wiley and Sons
  • Compound (I-B1- (f)) can be produced by reacting compound (I-B1- (g)) with compound (I-E4).
  • the amount of compound (I-E4) used in this reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (I-B1- (g)).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, water, or a mixed solvent thereof.
  • 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 (IB- (g)).
  • This reaction can also be carried out in the presence of additives such as potassium iodide or sodium iodide.
  • the amount of the additive to be used is generally 0.01 to 5 equivalents, preferably 0.1 to 1 equivalents, relative to 1 equivalent of the compound (I-B1- (g)).
  • This reaction can be 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 (I-E4) can be produced using a commercially available reagent or a reaction known per se.
  • Compound (I-B1) is obtained by subjecting compound (I-B1- (f)) to a known deprotection reaction (for example, the method described in Protective Groups In Organic Synthesis, John Wiley and Sons (1980)). Can be manufactured by.
  • Compound (I-B2) can be produced by reacting compound (I-B2- (a)) with compound (I-E1).
  • the amount of compound (I-E1) used in this reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (I-B2- (a)).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, pyridine, acetic acid, water, or a mixed solvent thereof.
  • This reaction can be carried out at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.).
  • 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 (I-B2- (a)) may be a commercially available product, or can be produced by a method known per se.
  • Compound (I-B2- (a)) can be produced by subjecting compound (I-B2- (b)) to an oxidation reaction in the presence of an oxidizing agent.
  • oxidizing agent examples include m-chloroperbenzoic acid (mCPBA), monoperphthalic acid or a salt thereof, hydrogen peroxide solution, percarbonate, peracetic acid or a salt thereof, and potassium peroxymonosulfate.
  • mCPBA m-chloroperbenzoic acid
  • monoperphthalic acid or a salt thereof hydrogen peroxide solution
  • percarbonate percarbonate
  • peracetic acid or a salt thereof potassium peroxymonosulfate
  • the amount of the oxidizing agent to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (I-B2- (b)).
  • the oxidizing agent when it is a liquid, it may be used as a solvent.
  • This reaction can also be carried out in the presence of a catalyst.
  • Examples of the catalyst used in this reaction include sodium tungstate and its hydrate.
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, acetic acid, water, or a mixed solvent thereof.
  • This reaction can be 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 (I-B2- (b)) is commercially available, or can be produced by a reaction known per se.
  • compound (I-B2- (b)) can be produced by subjecting compound (I-B2- (c)) to a dehydration reaction.
  • the dehydration reaction can be performed in the presence of an acid.
  • Examples of the acid used in this reaction include 4-methylbenzenesulfonic acid, hydrochloric acid, formic acid, boron trifluoride, and titanium trichloride.
  • the amount of acid used is usually 0.1 to 10 equivalents, preferably 0.5 to 2 equivalents, relative to 1 equivalent of compound (I-B2- (c)).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, pyridine, acetic acid, water, or a mixed solvent thereof.
  • This reaction can be 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 (I-B2- (c)) may be a commercially available product, or can be produced by a method known per se.
  • Compound (I-B2- (c)) can also be produced by reacting compound (I-F1) with a reducing agent.
  • a general reducing agent is widely used as the reducing agent.
  • common reducing agents include sodium borohydride, lithium aluminum hydride, borane-dimethylsulfide complex, and borane-tetrahydrofuran complex.
  • the amount of the reducing agent to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IF-1).
  • 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, Examples include hexamethylphosphoramide, pyridine, acetic acid, water, or a mixed solvent thereof.
  • This reaction can be 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 (I-B3) is obtained by reacting compound (IG) with compound (IE1) to give an imine (I-B3- (a)) or an equivalent of imine (eg, hemiaminal), it can be prepared by intramolecular cyclization of the methyl groups adjacent to Y a (Route E).
  • an intermediate imine (I-B3- (a)) or an imine equivalent (eg, hemiaminal) may be isolated if it is chemically stable.
  • the subsequent intramolecular cyclization reaction can be carried out without isolating the intermediate.
  • This intramolecular cyclization reaction is carried out by imine (IB-3 (a)) or an imine equivalent (eg, hemiaminal) produced in the reaction system by mixing compound (IG) and compound (IE1). respect, with the addition of suitable activators, can proceed by activating methyl group adjacent to Y a.
  • imine (IB-3 (a)) or an imine equivalent (eg, hemiaminal) produced in the reaction system by mixing compound (IG) and compound (IE1).
  • the amount of compound (IE1) to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IG).
  • the active agent of the methyl group adjacent to Y a to be used in the reaction base is used.
  • the amount of base used is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, per equivalent of imine (IB-3 (a)) or an equivalent of imine (eg, hemiaminal).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, pyridine, acetic acid, water, or a mixed solvent thereof.
  • This reaction can be 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 (IG) may be a commercially available product, or can be produced by a method known per se.
  • the compound (I-B3) is obtained by converting the hydroxy group of the compound (I-B3- (c)) obtained by intramolecular cyclization of the compound (IG) into a leaving group X 4 .
  • the compound (I-B3- (b)) can be reacted with the compound (I-E1) (Route F).
  • the compound (I-B3) is different from the compound (I-B3- (b)) in which X 4 is —O—SO 2 Me, —Cl or —Br. It can be produced by reacting (I-E1).
  • the amount of compound (I-E1) to be used is generally 1-5 equivalents, preferably 1-2 equivalents, relative to 1 equivalent of compound (I-B3- (b)).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, pyridine, water, or a mixed solvent thereof.
  • 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 (IB3- (b)).
  • This reaction can also be carried out in the presence of additives such as potassium iodide or sodium iodide.
  • the amount of the additive to be used is generally 0.1-5 equivalents, preferably 0.1-1 equivalent, relative to 1 equivalent of compound (IB-3 (b)).
  • This reaction can be 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 (I-B3- (b)) may be commercially available, or can be produced by a reaction known per se.
  • Compound (I-B3- (b)) can also be produced by subjecting compound (I-B3- (c)) to a reaction known per se.
  • a compound in which X 4 is —O—SO 2 Me is obtained by reacting methanesulfonyl chloride with respect to the compound (I-B3- (c)).
  • it can be produced by reacting methanesulfonic anhydride or the like.
  • the amount of methanesulfonyl chloride or methanesulfonic anhydride used in this reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IB-3 (c)).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, pyridine, water, or a mixed solvent thereof.
  • 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 (IB3- (c)).
  • This reaction can be 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.
  • chlorinating agent examples include thionyl chloride, phosphoric acid trichloride, phosphoric acid pentachloride, and hydrogen chloride.
  • brominating agent examples include phosphoric acid tribromide, hydrogen bromide, bromine, and N-bromosuccinimide.
  • the amount of the chlorinating agent or brominating agent used in this reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (I-B3- (c)).
  • This reaction may be carried out in the presence of a radical initiator such as 2,2′-azobis (2-methylpropionitrile).
  • the amount of the radical initiator used is usually 0.05 to 10 equivalents, preferably 0.05 to 2 equivalents, relative to 1 equivalent of the compound (I-B3- (c)).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, pyridine, water, or a mixed solvent thereof.
  • 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 (IB3- (c)).
  • This reaction can be carried out at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.).
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours.
  • this reaction may be performed under microwave irradiation.
  • Compound (I-B3- (c)) is commercially available, or can be produced by a method known per se.
  • Compound (I-B3- (c)) can be produced by intramolecular cyclization of compound (IG).
  • the active agent of the methyl group adjacent to Y a to be used in the reaction base is used.
  • the amount of the base to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IG).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, water, or a mixed solvent thereof.
  • This reaction can be 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 (I-B4) is obtained by reacting compound (IH) with compound (I-E1) to give imine (I-B4- (a)) and then subjecting it to Corey-Chaykovsky conditions using ylide. against aziridine caused by the anion of Y a can be prepared by intramolecular nucleophilic reaction.
  • the intermediate imine (I-B4- (a)) may be isolated if it is chemically stable, but in this reaction, the ylide is isolated without isolating the intermediate.
  • the ylide is isolated without isolating the intermediate.
  • the amount of compound (I-E1) to be used is generally 1-5 equivalents, preferably 1-2 equivalents, relative to 1 equivalent of compound (IH).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, acetic acid, water, or a mixed solvent thereof.
  • This reaction can be 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.
  • Examples of the ylide used in the above reaction include dimethylsulfonium-methylide or dimethylsulfoxonium-methylide.
  • the ylide can be produced by a method known per se, for example, a method reported in E. J. Corey, Michael Chaykovsky, Journal of American Chemical Society, 1965, 87 (6), 1353-1364.
  • the intramolecular nucleophilic reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, water, or a mixed solvent thereof.
  • This reaction can be 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 (IH) and compound (I-E1) may be commercially available, or can be produced by a reaction known per se.
  • reaction scheme 9 Compound (IF) used in the above reaction schemes 4 to 6 can also be produced by the following method (reaction scheme 9) or a method analogous thereto. Reaction formula 9
  • Compound (IF) is an intramolecular ring in the presence of a carboxylic acid (II) or a reactive derivative derived from carboxylic acid (II) (eg, acid halide, acid anhydride) and an acid. It can manufacture by performing a chemical reaction.
  • a carboxylic acid (II) or a reactive derivative derived from carboxylic acid (II) eg, acid halide, acid anhydride
  • Examples of the acid used for the intramolecular cyclization reaction of carboxylic acid (II) include sulfuric acid, polyphosphoric acid, phosphorous oxide (V) -methanesulfonic acid mixture (Eaton's reagent).
  • the amount of acid used for this reaction is usually 10 equivalents or more based on the carboxylic acid (II).
  • the acid used in this reaction can also be used as a solvent.
  • This reaction can be carried out at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.).
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours, more preferably 1 to 10 hours.
  • examples of the reagent used for preparing the acid halide include thionyl chloride, oxalyl chloride, and phosphorous acid trichloride.
  • the amount of the reagent used for the preparation of the acid halide is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (II).
  • This reaction is preferably performed in a solvent.
  • a solvent include halogenated hydrocarbons, aromatic hydrocarbons, ethers, acetonitrile, or a mixed solvent thereof.
  • This reaction can be 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.
  • the acid halide obtained by the above reaction is chemically stable, it can be isolated and used, but this reaction can also be used for the next intramolecular Friedel-Crafts reaction without isolating the acid halide. .
  • a general Lewis acid In the intramolecular Friedel-Crafts reaction, a general Lewis acid is widely used.
  • Examples of the general Lewis acid include aluminum trichloride.
  • the amount of Lewis acid used in this reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (II).
  • This reaction is preferably performed in a solvent.
  • a solvent include halogenated hydrocarbons, aromatic hydrocarbons, ethers, or a mixed solvent thereof.
  • This reaction can be carried out at room temperature or under heating (usually about 40 to 200 ° C., preferably about 40 to 160 ° C.).
  • the reaction time is usually 1 to 30 hours, preferably 1 to 20 hours, more preferably 1 to 10 hours.
  • Compound (II) may be a commercially available product, or can be produced by a reaction known per se.
  • P 4 and P 5 are the same or different and each represents a hydrogen atom or a carboxy protecting group, and other symbols are as defined above].
  • Examples of the “carboxy protecting group” represented by P 4 to P 5 include, for example, C 1-6 alkyl (methyl, ethyl, tert-butyl), C 7-11 aralkyl (eg, benzyl), phenyl, trityl, substituted Examples include silyl (eg, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl (eg, 1-allyl).
  • Compound (IF) is converted to ⁇ -ketoester equivalent (IF- (a)) by Dieckmann condensation reaction of dicarboxylic acid derivative (IJ), and then subjected to decarboxylation (decarboxylation) reaction. Can be manufactured.
  • the above Dieckmann condensation reaction can be carried out in the presence of a base.
  • the amount of the base used in this reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IJ).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, pyridine, water, or a mixed solvent thereof.
  • This reaction can be 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 (IJ) is commercially available, or can be produced by a reaction known per se.
  • the ⁇ -ketoester equivalent (IF- (a)) obtained by the above Dieckmann condensation reaction may be observed in the keto form depending on the 1 H NMR measurement solvent, or the enol form (IF- ( It may be observed in a)).
  • IF- (a) The ⁇ -ketoester equivalent obtained by the above Dieckmann condensation reaction
  • the keto form depending on the 1 H NMR measurement solvent
  • the enol form IF- ( It may be observed in a)
  • either the keto body or the enol body is described according to the assignment of 1 H NMR, but both are equivalent in the subsequent reaction.
  • decarboxylation reaction of the ⁇ -ketoester equivalent (IF- (a)) can be carried out under reaction conditions known per se.
  • the above decarboxylation (decarboxylation) reaction can be carried out in the presence of an acid.
  • the amount of the acid to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IF- (a)).
  • the acid may be used as a solvent.
  • the decarboxylation (decarboxylation) reaction can also be performed in the presence of a base.
  • the amount of base used is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IF- (a)).
  • the above decarboxylation (decarboxylation) reaction can also be performed in the presence of an additive.
  • additives include sodium chloride.
  • the amount of the additive used is usually 0.1 to 5 equivalents, preferably 0.5 to 2 equivalents, relative to 1 equivalent of compound (IF- (a)).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, pyridine, acetic acid, water, or a mixed solvent thereof.
  • This reaction can be 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 (I-F1) can be produced by an intramolecular cyclization reaction of a methyl group adjacent to Y a of compound (IK).
  • the active agent of the methyl group adjacent to Y a to be used in the reaction base is used.
  • the amount of the base to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IK).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, pyridine, water, or a mixed solvent thereof.
  • This reaction can be 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 (IK) may be commercially available or can be produced by a reaction known per se.
  • Compound (IF2) is an O-formyl obtained by subjecting compound (IL) to a formylation reaction to a compound (IF2- (b)) obtained by subjecting it to a Baeyer-Villiger oxidation reaction. It can be produced by removing the formyl group from the compound (I-F2- (a)).
  • Compound (IF2) can be produced by removing the formyl group of compound (IF2- (a)) by a known deprotection reaction of formyl group.
  • This reaction can also be performed in the presence of a base.
  • the amount of the base used is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (IF2- (a)).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, acetic acid, water, or a mixed solvent thereof.
  • This reaction can be 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 (I-F2- (a)) is commercially available, or can be produced by a method known per se.
  • Compound (I-F2- (a)) can be produced by subjecting compound (I-F2- (b)) to Baeyer-Villiger oxidation reaction in the presence of an oxidizing agent.
  • oxidizing agent used in this reaction examples include m-chloroperbenzoic acid (mCPBA), hydrogen peroxide solution, percarbonate, peracetic acid or a salt thereof.
  • mCPBA m-chloroperbenzoic acid
  • hydrogen peroxide solution percarbonate, peracetic acid or a salt thereof.
  • the amount of the oxidizing agent to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IF2- (b)).
  • the oxidizing agent when the oxidizing agent is a liquid, 10 equivalents or more may be used as a solvent with respect to the compound (IF2- (b)).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, acetic acid, water, or a mixed solvent thereof.
  • This reaction can be 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 (I-F2- (b)) is commercially available, or can be produced by a method known per se.
  • Compound (IF2- (b)) can be produced by subjecting compound (IL) to a formylation reaction known per se.
  • Examples of the formylating agent used in this reaction include (chloromethylene) dimethyliminium chloride (Vilsmeier reagent).
  • the amount of the formylating agent to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IL).
  • This reaction is preferably performed in a solvent.
  • solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-
  • examples thereof include methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, acetic acid, water, or a mixed solvent thereof.
  • This reaction can be 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 (IL) is commercially available, or can be produced by a reaction known per se.
  • substituent conversion that is, introduction of a substituent or functional group conversion
  • 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.
  • amino-protecting group examples include those exemplified as P 1 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 ( Example, benzylcarbonyl), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, substituted silyl (eg, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2 -6 alkenyl (eg, 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 may be a method known per se, for example, the method described in Protective Groups in Organic Synthesis, John 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 performed by the method of performing or a reduction method.
  • 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 that is a product in this reaction may be produced as a single compound or as a mixture.
  • the thus obtained compound (I) or a salt thereof 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. .
  • 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 to 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 synthesis method and a separation method known per se (eg, concentration, solvent extraction, column chromatography, recrystallization).
  • Compound (I) or a salt thereof may be a crystal, and it is included in compound (I) or a salt thereof regardless of whether the crystal form is single or a mixture of crystal forms.
  • 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.
  • an isotope eg, 3 H, 14 C, 35 S, 125 I
  • compound (I) or a salt thereof may be a deuterium converter.
  • 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 compound of the present invention can also be used for the prevention or treatment of CENP-E related diseases in mammals.
  • the compound of the present invention is excellent in membrane permeability and can have a medicinal effect at a low dose, so that it becomes an excellent preventive / therapeutic agent for cancer and the like with reduced side effects.
  • a prodrug of compound (I) or a salt thereof is a compound that is converted to 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.
  • 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); Compounds in which the hydroxy of compound (I) is acylated, alkylated, phosphorylated, borated (eg, hydroxy of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumaryl Compound, alanylated, dimethylaminomethylcarbonylated); carboxy of compound (
  • the prodrug of compound (I) or a salt thereof changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Pharmaceutical Development”, Volume 7, Molecular Design, pages 163 to 198. You may do.
  • 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 medicine because it is excellent in terms of toxicity (low toxicity such as toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, etc.) 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).
  • mammals eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human.
  • the compound of the present invention is used for CENP-E related diseases such as cancer [eg, colon cancer (eg, familial colon cancer, hereditary nonpolyposis colon 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, non-invasive breast cancer, 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
  • cancer
  • the compound of the present invention is effective against breast cancer, ovarian cancer, pancreatic cancer, lung cancer, blood cancer and the like.
  • 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 medicine (sometimes referred to herein as “the medicine of the present invention”). Can do.
  • 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 including soft capsules and microcapsules
  • emulsions suspensions
  • films eg, oral mucosal 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 compounds of the present invention can 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 known production method generally used in the field for example, a method described in Japanese Pharmacopoeia
  • excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents for example, an emulsifier
  • An appropriate amount of an additive such as an emulsifier can be appropriately added.
  • 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.
  • binder examples include 5 to 10% by weight starch paste solution, 10 to 20% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, and glycerin.
  • disintegrants examples include starch and calcium carbonate.
  • lubricants examples include magnesium stearate, stearic acid, calcium stearate, and purified talc.
  • sweeteners examples include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, and simple syrup.
  • surfactant examples include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl 40 stearate.
  • suspending agent examples include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, and bentonite.
  • emulsifiers examples include gum arabic, tragacanth, gelatin, and polysorbate 80.
  • an appropriate amount of coloring agents, preservatives, fragrances, flavoring agents, stabilizers, thickeners and the like that are usually used in the pharmaceutical field can be appropriately added as desired.
  • 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, preferably about 2 to 85% by weight, based on the whole preparation, Preferably it is 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
  • antimetabolite examples include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enositabine, cytarabine, cytarabine okphosphatate, 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, doxyfluridine
  • anticancer antibiotic 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)
  • 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. Can be mentioned.
  • the dose of the concomitant drug may be in accordance with the clinically used dose, 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 and a concomitant drug are used in combination (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug; (2) Simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and a 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 of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes; (5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a 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 based on 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 is, for example, (1) surgery; (2) pressor chemotherapy using angiotensin II or the like; (3) gene therapy; (4) hyperthermia; (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 orally administered (including sustained release), intravenously administered (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 above-described 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.
  • Root temperature in the following examples usually indicates about 10 ° C. to about 35 ° C.
  • the ratio shown in the mixed solvent is a volume ratio unless otherwise specified. % Indicates% by weight unless otherwise specified.
  • silica gel column chromatography when described as NH, aminopropylsilane-bonded silica gel was used. In the case of C18 on HPLC (high performance liquid chromatography), octadecyl bonded silica gel was used.
  • the ratio of the mixed solvent indicates a volume ratio unless otherwise specified.
  • MS was measured by LC / MS.
  • ESI method ESI method, APCI method, or simultaneous ESI / APCI multi method was used.
  • the data is the actual measurement (found).
  • a molecular ion peak is observed, but in the case of a compound having a tert-butoxycarbonyl group (-Boc), a peak in which the tert-butoxycarbonyl group or tert-butyl group is eliminated as a fragment ion is observed.
  • a peak from which H 2 O is eliminated may be observed as a fragment ion.
  • a salt a free molecular ion peak or a fragment ion peak is usually observed.
  • Example 1 ( ⁇ ) -N- (7,8-Dichloro-3,4-dihydro-2H-chromen-4-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3-methyl Phenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
  • Ethyl 5-methoxyimidazo [1,2-a] pyridine-2-carboxylate Ethyl 3-bromo-2-oxopropanoate (21 g) was added dropwise at 40 ° C. over 30 minutes to a solution of 6-methoxypyridin-2-amine (10 g) in ethanol (150 mL).
  • Example 2 ( ⁇ ) -N- (5,6-Dichloro-2,3-dihydro-1H-inden-1-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3-methyl Phenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide A) ( ⁇ ) -N '-(5,6-Dichloro-2,3-dihydro-1H-inden-1-yl) -N, N-dimethylethane-1,2-diamine The title compound (420 mg) was obtained in the same manner as in Step E of Example 1 using 5,6-dichloroindan-1-one.
  • Example 3 ( ⁇ ) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [6- (trifluoromethyl) -2,3-dihydro- 1H-Inden-1-yl] imidazo [1,2-a] pyridine-2-carboxamide A) ( ⁇ ) -N, N-dimethyl-N '-[6- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] ethane-1,2-diamine The title compound (630 mg) was obtained in the same manner as in Step E of Example 1 using 6- (trifluoromethyl) indan-1-one.
  • Example 4 ( ⁇ ) -N- [2- (Dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [4- (trifluoromethyl) -2,3-dihydro- 1H-Inden-1-yl] imidazo [1,2-a] pyridine-2-carboxamide A) ( ⁇ ) -N, N-dimethyl-N '-[4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] ethane-1,2-diamine The title compound (560 mg) was obtained in the same manner as in Step E of Example 1 using 4- (trifluoromethyl) indan-1-one.
  • the reaction mixture was concentrated under reduced pressure, 2 N hydrochloric acid (40 mL) was added to the residue, and the mixture was stirred for 1 hr. Insoluble material was filtered off, and the filtrate was washed with ethyl acetate (30 mL) and hexane (50 mL). The obtained aqueous layer was made alkaline by adding 8 N aqueous sodium hydroxide solution (10 mL) and 2 N aqueous sodium hydroxide solution (3 mL), and then extracted with ethyl acetate. The resulting organic layer was washed with saturated brine. And then dried over anhydrous sodium sulfate.
  • Example 5b (-)-N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3-methyl Phenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide ( ⁇ ) -N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -N- [2- (dimethylamino) ethyl] -3- (4) prepared in Example 5 -Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (670 mg) by HPLC (CHIRALPAK AD (NF001), 50 mmID ⁇ 500 mmL, manufactured by Daicel Chemical Industries, transfer Phase: hexane /
  • Example 6 ( ⁇ ) -N- (7,8-Dichloro-3,4-dihydro-2H-chromen-4-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2- (Methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide A) ( ⁇ ) -tert-butyl ⁇ 2-[(7,8-dichloro-3,4-dihydro-2H-chromen-4-yl) amino] ethyl ⁇ methylcarbamate The title compound was prepared in a manner similar to Step E of Example 1 using 7,8-dichloro-2,3-dihydro-4H-chromen-4-one and tert-butyl (2-aminoethyl) methylcarbamate.
  • Example 7a (-)-N- (7,8-Dichloro-3,4-dihydro-2H-chromen-4-yl) -3- (4-fluoro-3-methylphenyl) -N- ⁇ 2-[(1H- Indol-3-ylmethyl) (methyl) amino] ethyl ⁇ -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide A) ( ⁇ ) -N- (7,8-Dichloro-3,4-dihydro-2H-chromen-4-yl) -3- (4-fluoro-3-methylphenyl) -N- ⁇ 2-[( 1H-Indol-3-ylmethyl) (methyl) amino] ethyl ⁇ -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide ( ⁇ ) -N- (7,8-Dichloro-3,4-dihydro-2H-chromen-4-yl) -3- (4-fluoro-3-methylpheny
  • Trifluoroacetic acid was distilled off under reduced pressure, and the residue was diluted with ethyl acetate while stirring under ice-cooling, and made alkaline (aqueous layer pH> 11) by adding 2 N aqueous sodium hydroxide solution, then 10% Dilute with aqueous sodium carbonate. The obtained 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 to give the title compound (1.21 g). MS (ESI +): [M + H] + 204.1.
  • Example 8a (+)-N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -N- ⁇ 2-[(1H- Indol-3-ylmethyl) (methyl) amino] ethyl ⁇ -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide ( ⁇ ) -N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -N- ⁇ 2-[(1H- Indol-3-ylmethyl) (methyl) amino] ethyl ⁇ -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (100 mg) by HPLC (CHIRALPAK AY-H (OC006), 20 mmID ⁇ 250 mmL And fractions with a shorter retention time including the target compound were concentrated under reduced pressure
  • N, N-dimethylethane-1,2-diamine (670 ⁇ L) was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours.
  • the reaction mixture was concentrated under reduced pressure, 2 N hydrochloric acid (20 mL) was added to the residue, and the mixture was stirred for 10 min.
  • the reaction mixture was washed with ethyl acetate (5 mL) and hexane (25 mL).
  • the obtained aqueous layer was made alkaline by adding 8 N aqueous sodium hydroxide solution (5 mL) and 1 N aqueous sodium hydroxide solution (2 mL), and then extracted with diethyl ether, and the resulting organic layer was saturated with brine.
  • Example 12b (-)-N- (6,7-Dichloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-3-yl) -N- [2- (dimethylamino) ethyl] -3- (4 -Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide ( ⁇ ) -N- (6,7-Dichloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-3-yl) -N- [2- (dimethylamino) ethyl] -3- (4 -Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (116 mg) by HPLC (CHIRALPAK AD (NF001), 50 mmID ⁇ 500 mmL, manufactured by Daicel Chemical Industries, Mobile Phase:
  • reaction mixture was cooled to room temperature, aluminum trichloride (23.7 g) was added in small portions over 30 minutes, and the mixture was further stirred at 60 ° C. for 3 hours.
  • the reaction mixture was cooled, added to ice, and extracted twice with ethyl acetate.
  • the obtained organic layer was washed with saturated brine and dried over anhydrous sodium 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 / hexane) to give the title compound (6.0 g).
  • Example 14 ( ⁇ ) -N- (2,3-Dihydro-1-benzofuran-3-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxy Imidazo [1,2-a] pyridine-2-carboxamide A) ( ⁇ ) -N '-(2,3-Dihydro-1-benzofuran-3-yl) -N, N-dimethylethane-1,2-diamine To a solution of 1-benzofuran-3 (2H) -one (268 mg) in acetic acid (0.8 mL), tetrahydrofuran (2 mL) and methanol (6 mL) at room temperature under a nitrogen atmosphere, N, N-dimethylethane-1, 2-Diamine (229 mg) was added and stirred at 50 ° C.
  • N, N-dimethylethane-1,2-diamine (76 mg) and 2-methylpyridine borane complex (46 mg) were added, and the mixture was stirred at 60 ° C. overnight.
  • 2 N hydrochloric acid (4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr.
  • the reaction mixture was diluted with water and washed with diethyl ether.
  • the aqueous layer was made alkaline (pH> 11) by adding 8 N aqueous sodium hydroxide solution, diluted with 10% aqueous sodium carbonate solution, and extracted twice with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate.
  • Example 16 ( ⁇ ) -N- (6-Chloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2- (methyl Amino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide A) ( ⁇ ) -tert-butyl ⁇ 2-[(6-chloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl ⁇ methylcarbamate To a solution of 6-chloro-1-benzofuran-3 (2H) -one (506 mg) and acetic acid (1 mL) in tetrahydrofuran (5 mL) and ethanol (5 mL) at room temperature, tert-butyl (2-aminoethyl) Methyl carbamate (784 mg) and 2-methylpyridine borane complex (481 mg) were added, and the mixture was stirred
  • Example 17 ( ⁇ ) -N- (7-Chloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2- (methyl Amino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide A) ( ⁇ ) -tert-butyl ⁇ 2-[(7-chloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl ⁇ methylcarbamate The title compound (90 mg) was obtained in the same manner as in Step A of Example 16 using 7-chloro-1-benzofuran-3 (2H) -one.
  • the reaction mixture was made alkaline (pH 8) by adding saturated aqueous sodium hydrogen carbonate solution, and extracted twice 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 by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (5.92 g).
  • the reaction mixture was made alkaline (pH 8) by adding a saturated aqueous sodium hydrogen carbonate solution, extracted twice with ethyl acetate, and the resulting 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 by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (755 mg).
  • Example 20a (+)-N- [7-Chloro-6- (trifluoromethyl) -2,3-dihydro-1-benzofuran-3-yl] -3- (4-fluoro-3-methylphenyl) -5-methoxy -N- [2- (Methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide ( ⁇ ) -N- [7-Chloro-6- (trifluoromethyl) -2,3-dihydro-1-benzofuran-3-yl] -3- (4-fluoro-3-methylphenyl) -5-methoxy -N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (121 mg) by HPLC (CHIRALPAK AD (LF001), 50 mmID ⁇ 500 mmL, manufactured by Daicel Chemical Industries, Ltd.
  • Example 20b (-)-N- [7-Chloro-6- (trifluoromethyl) -2,3-dihydro-1-benzofuran-3-yl] -3- (4-fluoro-3-methylphenyl) -5-methoxy -N- [2- (Methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide ( ⁇ ) -N- [7-Chloro-6- (trifluoromethyl) -2,3-dihydro-1-benzofuran-3-yl] -3- (4-fluoro-3-methylphenyl) -5-methoxy -N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (121 mg) by HPLC (CHIRALPAK AD (LF001), 50 mmID ⁇ 500 mmL, manufactured by Daicel Chemical Industries, Ltd.
  • reaction mixture was diluted with ethyl acetate while stirring under ice-cooling, and 8 N aqueous sodium hydroxide solution (8 mL) and 10% aqueous sodium carbonate solution (20 mL) were added. After 10 minutes, the reaction mixture was extracted twice with ethyl acetate, and 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 by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (760 mg). MS (ESI +): [M + H] + 556.2.
  • Example 23 ( ⁇ ) -ethyl 6,7-dichloro-3- ⁇ [2- (dimethylamino) ethyl] ⁇ [3- (3-fluoro-4-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine -2-yl] carbonyl ⁇ amino ⁇ indoline-1-carboxylate ( ⁇ ) -N- (6,7-Dichloro-2,3-dihydro-1H-indol-3-yl) -N- [2- (dimethylamino) ethyl] -3- (3-fluoro-4-methyl
  • a mixture of (phenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (65 mg) and diethyl dicarbonate (2 mL) was stirred at 100 ° C.
  • Example 24 ( ⁇ ) -N- [6,7-Dichloro-1- (ethylcarbamoyl) -2,3-dihydro-1H-indol-3-yl] -N- [2- (dimethylamino) ethyl] -3- ( 3-Fluoro-4-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide ( ⁇ ) -N- (6,7-Dichloro-2,3-dihydro-1H-indol-3-yl) -N- [2- (dimethylamino) ethyl] -3- (3-fluoro-4-methyl Phenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (65 mg), isocyanatoethane (0.1 mL), pyridine (0.1 mL) and acetonitrile (1 mL) at 60 ° C.
  • Example 25 ( ⁇ ) -N- (1-carbamoyl-6,7-dichloro-2,3-dihydro-1H-indol-3-yl) -N- [2- (dimethylamino) ethyl] -3- (3-fluoro -4-Methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide ( ⁇ ) -N- (6,7-Dichloro-2,3-dihydro-1H-indol-3-yl) -N- [2- (dimethylamino) ethyl] -3- (3-fluoro-4-methyl A mixture of (phenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (65 mg), potassium cyanate (95 mg), acetic acid (2 mL) and water (1 mL) at room temperature overnight.
  • Example 26a (-)-N- (6,7-Dichloro-2,3-dihydro-1H-indol-3-yl) -N- [2- (dimethylamino) ethyl] -3- (3-fluoro-4-methyl Phenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide ( ⁇ ) -N- (6,7-Dichloro-2,3-dihydro-1H-indol-3-yl) -N- [2- (dimethylamino) ethyl] -3 prepared in Step H of Example 22 -(3-Fluoro-4-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (140 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID ⁇ 500 mmL, Daicel Chemical Industries) The fraction having a shorter retention time containing the target compound was concentrated under reduced pressure to obtain
  • Example 28 ( ⁇ ) -N- (6,7-Dichloro-2,3-dihydro-1-benzothiophen-3-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3- Methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
  • A) ( ⁇ ) -N- (6,7-Dichloro-2,3-dihydro-1-benzothiophen-3-yl) -N 2 , N 2 -Dimethylglycinamide
  • the title compound (660 mg) was obtained in the same manner as in Step Q of Example 13 using ( ⁇ ) -6,7-dichloro-2,3-dihydro-1-benzothiophen-3-amine.
  • Example 30 ( ⁇ ) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N- [2- (dimethylamino) ethyl] -3- ( 4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide 3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (123 mg) and ( ⁇ ) -N '-(6,7-dichloro-1 , 1-Dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N, N-dimethylethane-1,2-diamine (120 mg) in tetrahydrofuran (5 mL) and pyridine (1 mL) HATU (212 mg) was added at room temperature, and the mixture
  • Example 30a (-)-N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N- [2- (dimethylamino) ethyl] -3- ( 4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide ( ⁇ ) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N- [2- (dimethylamino) ethyl] -3- ( 4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (123 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID ⁇ 500 mmL, manufactured by Daicel Chemical Industries, The fraction was collected with a mobile phase:
  • the reaction mixture was diluted with 1 N hydrochloric acid (30 mL) and stirred at room temperature for 30 minutes.
  • the reaction mixture was washed with diethyl ether (30 mL), 8 N aqueous sodium hydroxide solution (4 mL) was added to the aqueous layer to make it alkaline, 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 reaction mixture was diluted with 1 N hydrochloric acid (20 mL) and stirred at room temperature for 30 minutes.
  • the reaction mixture was washed with diethyl ether (30 mL), made aqueous with 8 N aqueous sodium hydroxide solution (5 mL), and 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 obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (150 mg).

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Composé de type dérivé de cycle hétérocyclique ou sel de celui-ci, ayant une activité d'inhibition de CENP-E, utile pour prévenir et traiter le cancer, etc., et ayant une excellente efficacité pharmacologique, ledit composé étant représenté par la formule [où chaque symbole est tel que défini dans la description].
PCT/JP2012/083804 2011-12-28 2012-12-27 Composé hétérocyclique WO2013100018A1 (fr)

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CN104496884A (zh) * 2014-12-09 2015-04-08 大连理工大学 一种3-氧代吲哚啉类化合物的制备方法

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JP2009524689A (ja) * 2006-01-25 2009-07-02 スミスクライン ビーチャム コーポレーション 化合物
JP2010535773A (ja) * 2007-08-10 2010-11-25 グラクソスミスクライン エルエルシー ウイルス感染を治療するための窒素含有二環式化学物質
WO2012008508A1 (fr) * 2010-07-14 2012-01-19 武田薬品工業株式会社 Composé hétérocyclique

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Publication number Priority date Publication date Assignee Title
JP2009524689A (ja) * 2006-01-25 2009-07-02 スミスクライン ビーチャム コーポレーション 化合物
JP2010535773A (ja) * 2007-08-10 2010-11-25 グラクソスミスクライン エルエルシー ウイルス感染を治療するための窒素含有二環式化学物質
WO2012008508A1 (fr) * 2010-07-14 2012-01-19 武田薬品工業株式会社 Composé hétérocyclique

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DATABASE RN 4 November 2011 (2011-11-04), accession no. 340784-23-7 *

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