WO2013100018A1

WO2013100018A1 - Heterocyclic compound

Info

Publication number: WO2013100018A1
Application number: PCT/JP2012/083804
Authority: WO
Inventors: 孝治平山; 浩坂野; 正格岡庭; 広行筧; 智康石川
Original assignee: 武田薬品工業株式会社
Priority date: 2011-12-28
Filing date: 2012-12-27
Publication date: 2013-07-04
Also published as: JPWO2013100018A1

Abstract

Provided is a compound heterocyclic ring derivative that has a CENP-E inhibition activity, is useful for the prevention and treatment of cancer, etc., and has excellent pharmacological efficacy. [Solution] This invention pertains to a compound indicated by formula [in formula, each symbol is as defined in the Description] or a salt thereof.

Description

Heterocyclic compounds

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.
[Background of the invention]
Centromere-associated protein-E (also referred to herein as “CENP-E”) is one of the motor proteins belonging to the kinesin superfamily (Non-patent Document 1). CENP-E is a factor necessary for normal mitotic chromosome alignment, and it is known that mitotic chromosomal misalignment occurs in cells lacking CENP-E function. (Non-Patent Document 2). When CENP-E function is inhibited, chromosome alignment does not occur, and a spindle assembly checkpoint (also referred to as SAC) is activated and cell death is induced (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).

As known imidazopyridine derivatives, compounds described in the following documents are known.
(1) A formula that is a JNK1 and ERK inhibitor disclosed in Patent Document 1 and is useful for treating cancer and the like:

[Where:
K represents CH, N, —C (optionally substituted alkyl) — or the like;
L represents CH or N;
Q ^A represents H, alkyl, unsubstituted heteroaryl, substituted heteroaryl, etc .;
Q ^B represents H, alkyl, aryl or the like;
Q ^C ^{_{^{is, H, -CON (R 12)}}} 2, -N (R 12) 2, -NH 2, and -NH-alkyl or the like;
Q ^D represents H or alkyl. ]
A compound represented by
(2) A voltage-dependent K ⁺ channel (KCNQ2, KCNQ3) modulator disclosed in Patent Document 2 and useful for the treatment of migraine, brain tumors and the like:

[Where:
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 (where 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, halo, C _1-8 alkyl, C _1-8 alkoxy and the like;
Z ¹ is ═N—OR═C (R ¹⁶ ) —, Z ² is ═N—OR═C (R ¹⁷ ) — (where R ¹⁶ and R ¹⁷ are H, C _1-8 alkyl, respectively) , -CN, etc.). ]
A compound represented by
(3) A GnRH antagonist disclosed in Patent Document 3, which is useful for the treatment of testicular cancer, breast cancer and the like:

[Where:
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. ]
A compound represented by
(4) HDAC inhibitor and CDK inhibitor disclosed in Patent Document 4 and useful for the treatment of cancer and the like:

[Where:
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:

[Where:
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. ]
A compound represented by
(6) Formula useful for treatment of HCV, HIV, etc. disclosed in Patent Document 6:

[Where:
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:

[Where:
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). ]
A compound represented by
(8) Formulas that are potential-dependent K ⁺ channel (KCNQ2, KCNQ3) modulators disclosed in Patent Document 8, and are useful for treating migraine, brain tumors, and the like:

[Where:
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 or bicycloalkyl, or — (CH ₂ ) _p CF ₃ ;
R ⁵ represents H, an _optionally substituted C _1-7 alkyl, an _optionally substituted aryl, an optionally substituted arylalkyl;
R ¹¹ and R ¹² are each H, halo, C _1-8 alkyl, C _1-8 alkoxy and the like;
Z ¹ represents ═N— or ═C (R ¹⁶ ) —;
Z ² represents ═N— or ═C (R ¹⁷ ) —;
R ¹⁶ and R ¹⁷ each represent H, C _1-8 alkyl, —CN and the like. ]
A compound represented by
(9) A formula having a CENP-E inhibitory action disclosed in Patent Document 9 and effective for treating cancer and the like:

[Where:
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. ]
A compound represented by

International Publication No. 2008/082490 Pamphlet International Publication No. 2009/026254 Pamphlet International Publication No. 2002/0666477 Pamphlet International Publication No. 2009/002534 Pamphlet JP 2004-2826 A International Publication No. 2009/023179 Pamphlet International Publication No. 2011/075643 Pamphlet International Publication No. 2011/102964 Pamphlet International Publication No. 2012/008508 Pamphlet

Development of a novel compound having CENP-E inhibitory activity, useful for the prevention and treatment of cancer and the like and having excellent medicinal effects is desired.

As a result of intensive studies to solve the above problems, the present inventors have obtained the following formula:

[Where
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 with adjacent carbon atoms,
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.

That is, the present invention is as follows.
[1] Formula:

[Where
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 with adjacent carbon atoms,
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. ]
Or a salt thereof.
[2] 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.
[3] The compound or a salt thereof according to the above [1] or [2], wherein R ¹ is C _1-6 alkoxy.
[4] The compound or salt thereof according to any one of [1] to [3] above, wherein R ² is a hydrogen atom.
[5] The compound or a salt thereof according to any one of the above [1] to [4], wherein R ³ is a hydrogen atom.
[6] 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 The compound or a salt thereof according to any one of the above [1] to [5], which is C _1-6 alkyl optionally having 3 to 3 substituents.
[7] 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.
[8] 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 A C _1-6 alkyl _optionally having 1 to 3 substituents selected from the group consisting of heterocyclic groups;
R ⁵ is
(1) hydrogen atom,
(2) C _1-6 alkyl-carbonyl,
(3) C _1-6 alkoxy-carbonyl, or
(4) carbamoyl optionally having 1 or 2 C _1-6 alkyl;
R ⁷ and R ⁸ are the same or different,
(1) a hydrogen atom, or
(2) C _1-6 alkyl;
R ⁹ and R ¹⁰ are the same or different,
(1) hydrogen atom,
(2) a halogen atom,
(3) cyano, or
(4) C _1-6 alkyl _optionally having 1 to 3 halogen atoms;
X ^a and X ^b are the same or different and are each CH or N;
X ^c is CH;
Y ^a is CH ₂ , O, NR ⁵ (R ⁵ is as defined above), S, or SO ₂ ;
Y ^b is a bond;
The compound or a salt thereof according to the above [1], wherein n is an integer of 1 to 3.
[9] (+)-N- (6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro- 3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide or a salt thereof.
[10] (+)-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 or a salt thereof.
[11] (+)-N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- ( Dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide or a salt thereof.
[12] A medicament comprising the compound or salt thereof according to any one of [1] to [11] above.
[13] The medicament according to [12] above, which is a CENP-E inhibitor.
[14] The medicament according to the above [12], which is a preventive or therapeutic agent for cancer.
[15] 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.
[16] 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.
[17] Use of the compound or a salt thereof according to any one of the above [1] to [11] for producing a prophylactic / therapeutic agent for cancer.
[18] The compound or salt thereof according to any one of [1] to [11] above for use in the prevention / treatment of cancer,
Etc.

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.
(Detailed description of the invention)
In the present specification, “halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

In the present specification, “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.

In the present specification, “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.

In the present specification, “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.

In the present specification, “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.

In the present specification, “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.

In the present specification, “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.

In the present specification, “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.

In the present specification, “C _3-10 cycloalkyl” refers to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Of these, C _3-8 cycloalkyl is preferable.

In the present specification, “C _3-8 cycloalkyl” refers to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

In the present specification, “C _3-10 cycloalkenyl” refers to, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, and 3-cyclohexen-1-yl. Show. Of these, C _3-6 cycloalkenyl is preferable.

In the present specification, “C _3-6 cycloalkenyl” means, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl. Show.

In the present specification, “C _4-10 cycloalkadienyl” means, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadiene-1 -Indicates il. Of these, C _4-6 cycloalkadienyl is preferable.

In the present specification, “C _4-6 cycloalkadienyl” means, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadiene-1 -Indicates il.

In the present specification, “C _3-10 cycloalkyl”, “C _3-10 cycloalkenyl” and “C _4-10 cycloalkadienyl” may each be condensed with a benzene ring to form a condensed ring group. Often, such fused ring groups include, for example, indanyl, dihydronaphthyl, tetrahydronaphthyl, and fluorenyl.

In the present specification, “C _3-10 cycloalkyl”, “C _3-10 cycloalkenyl” and “C _4-10 cycloalkadienyl” may be a bridged condensed ring group. Examples of such 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.

In the present specification, “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. Here, as 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.

In the present specification, “C _6-14 aryl” refers to, for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl. Of these, C _6-10 aryl is preferable.

In the present specification, “C _6-10 aryl” means, for example, phenyl, 1-naphthyl, 2-naphthyl.

In the present specification, “C _7-13 aralkyl” refers to, for example, benzyl, phenethyl, naphthylmethyl, biphenylylmethyl.

In the present specification, “C _8-13 arylalkenyl” refers to, for example, styryl.

In the present specification, “C _1-6 alkoxy” means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy.

In the present specification, “C _1-6 alkyl-carbonyl” means, for example, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, hexyl. Indicates carbonyl.

In the present specification, “C _1-6 alkoxy-carbonyl” refers to, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl.

In the present specification, “C _1-10 alkyl”, “C _2-10 alkenyl”, “C _2-10 alkynyl”, “C _1-6 alkyl”, “C _2-6 alkynyl”, “C _1-6 alkyl” Examples of the 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 (eg, fluorine atom). 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) hydroxy,
(D) C _1-3 alkylenedioxy (eg, methylenedioxy), and (E) C _1-6 alkyl (eg, fluorine atom) optionally having 1 to 3 halogen atoms (eg, fluorine atom) Methyl)
C _6-10 aryl (eg, phenyl, naphthyl) optionally having 1 to 3 substituents selected from
(iii) (A) C _1-6 alkyl _optionally having 1 to 3 hydroxys (eg, methyl, ethyl, propyl),
(B) C _1-6 alkoxy (eg, methoxy),
(C) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl), and (D) C _6-10 arylsulfonyl (which may have 1 to 3 C _1-6 alkyl (eg, methyl) ( Example: phenylsulfonyl)
5- to 12-membered aromatic heterocyclic group optionally having 1 to 3 substituents selected from (eg, imidazolyl, indolyl, furyl, pyridyl, thiazolyl, pyrazolyl, pyrrolyl, indazolyl, pyrrolopyridyl, pyra Zolopyridyl, imidazopyridyl),
(iv) a 4- to 12-membered non-aromatic heterocyclic group (eg, dihydropyridyl) optionally having oxo;
(v) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl),
(vi) cyano,
(vii) a halogen atom (eg, fluorine atom),
(viii) carbamoyl,
(ix) C _1-6 alkylsulfanyl (eg, methylsulfanyl),
(x) C _3-10 cycloalkyl (eg, cyclopropyl) optionally having 1 to 3 C _1-6 alkoxy-carbonyl (eg, ethoxycarbonyl), and (xi) (A) C _{1 -6} alkoxy-carbonyl (eg tert-butoxycarbonyl),
(B) C _1-6 alkylsulfonyl (eg, methylsulfonyl),
(C) 1 or 2 C _1-6 alkoxy (eg, methoxy), 4- to 12-membered non-aromatic heterocyclic group (eg, piperidyl, morpholinyl), C _1-6 alkyl (eg, methyl) C _1-6 alkyl-carbonyl (eg, acetyl, propanoyl, pivaloyl) optionally having 1 to 3 substituents selected from amino optionally selected from hydroxy,
(D) 5- to 12-membered aromatic heterocyclic carbonyl (eg, pyridazinylcarbonyl, pyrazolylcarbonyl), and (E) 4- to 12-membered non-aromatic heterocyclic carbonyl optionally having oxo ( Example: pyrrolidinylcarbonyl)
C _1-6 alkyl optionally having 1 to 3 substituents selected from amino optionally having 1 or 2 substituents selected from
(b) (i) hydroxy,
(ii) cyano,
(iii) halogen atoms (eg, fluorine atoms),
(iv) C _1-6 alkoxy (eg, methoxy, ethoxy),
(v) C _1-6 alkylsulfonyl (eg, methylsulfonyl),
(vi) (A) C _1-6 alkyl (eg, methyl, ethyl), and (B) C _1-6 alkyl-carbonyl (eg, acetyl)
An amino optionally having 1 or 2 substituents selected from:
(vii) carbamoyl,
(viii) Ureid,
(ix) (A) a halogen atom (eg, fluorine atom), and (B) an amino optionally having 1 or 2 C _1-6 alkyl (eg, methyl),
C _6-10 aryl (eg, phenyl) _optionally having 1 to 3 substituents selected from:
(x) 5- to 12-membered aromatic heterocyclic group (eg, imidazolyl, tetrazolyl, pyridyl, indolyl), and (xi) 4- to 12-membered non-aromatic heterocyclic group (eg, pyrrolidinyl, piperidyl)
C _1-6 alkyl-carbonyl _optionally having 1 to 3 substituents selected from
(c) (i) a halogen atom, and (ii) C _1-6 alkoxy-carbonyl optionally having 1 to 3 substituents selected from C _6-10 aryl (eg, tert-butoxycarbonyl) ,
(d) C _3-10 cycloalkyl-carbonyl (eg, cyclopropylcarbonyl),
(e) C _6-10 aryl-carbonyl (eg, benzoyl, biphenylylcarbonyl) optionally having 1 to 3 halogen atoms (eg, fluorine atom),
(f) carboxy,
(g) (i) a halogen atom, and (ii) a C _1-6 alkylsulfonyl optionally having 1 to 3 substituents selected from C _6-10 aryl (eg, methylsulfonyl, ethylsulfonyl) ,
(h) C _6-10 arylsulfonyl (eg, phenylsulfonyl) _optionally having 1 to 3 halogen atoms (eg, fluorine atom),
(i) carbamoyl optionally having 1 or 2 C _1-6 alkyl optionally having 1 to 3 substituents selected from (i) a halogen atom, and (ii) hydroxy,
(j) (i) C _1-6 alkyl _optionally having 1 to 3 halogen atoms,
(ii) hydroxy,
(iii) C _1-6 alkoxy optionally having 1 to 3 halogen atoms, and (iv) 5 to 12 members optionally having 1 to 3 substituents selected from halogen atoms An aromatic heterocyclic group (eg, pyridyl, pyrimidinyl) and (k) (i) C _1-6 alkyl optionally having 1 to 3 halogen atoms,
(ii) hydroxy,
(iii) C _1-6 alkoxy optionally having 1 to 3 halogen atoms,
(iv) a halogen atom,
(v) a 4- to 12-membered non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from oxo;
(l) (a) C _1-6 alkyl (eg, methyl), and (b) a 5- to 12-membered aromatic heterocyclic carbonyl optionally having 1 to 3 substituents selected from hydroxy ( Examples, thienylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl, pyridylcarbonyl, indolylcarbonyl), and (m) a 4- to 12-membered non-aromatic heterocyclic carbonyl optionally having oxo (eg, tetrahydrofurylcarbonyl, pyrrole) Dinylcarbonyl, thiazolidinylcarbonyl, dihydroindolylcarbonyl)
An amino optionally having 1 or 2 substituents selected from:
(11) Imino;
(12) C _1-6 alkyl-carbonyl _optionally having 1 to 3 halogen atoms;
(13) (a) a halogen atom,
(b) C _1-6 alkoxy,
(c) C _6-10 aryl,
(d) (i) C _1-6 alkyl _optionally having 1 to 3 halogen atoms,
(ii) hydroxy,
(iii) C _1-6 alkoxy optionally having 1 to 3 halogen atoms, and (iv) 5 to 12 members optionally having 1 to 3 substituents selected from halogen atoms An aromatic heterocyclic group, and (e) (i) C _1-6 alkyl _optionally having 1 to 3 halogen atoms,
(ii) hydroxy,
(iii) C _1-6 alkoxy optionally having 1 to 3 halogen atoms,
1 to 3 substituents selected from (iv) a halogen atom, and (v) 4 to 12-membered non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from oxo C _1-6 alkoxy-carbonyl optionally having;
(14) C _1-6 alkylsulfonyl which may have 1 to 3 halogen atoms (eg, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl);
(15) C _6-10 arylsulfonyl (eg, phenylsulfonyl);
(16) (a) (i) a halogen atom,
(ii) amino optionally having 1 or 2 C _1-6 alkyl (eg, methyl, ethyl) optionally having 1 to 3 hydroxy,
(iii) hydroxy,
(iv) C _1-6 alkoxy optionally having 1 to 3 hydroxy (eg, methoxy, ethoxy, isopropoxy),
(v) C _6-10 aryl (eg, phenyl),
(vi) a 5- to 12-membered aromatic heterocyclic group (eg, pyridyl, imidazolyl, oxazolyl, indolyl) optionally having 1 to 3 C _1-6 alkyl (eg, methyl),
(vii) a 4- to 12-membered non-aromatic heterocyclic group (eg, morpholinyl, tetrahydrofuryl), and (viii) a C _1-6 alkyl _optionally having 1 to 3 substituents selected from carbamoyl (Eg, methyl, ethyl, propyl, tert-butyl),
(b) C _3-10 cycloalkyl (eg, cyclopropyl, cyclopentyl), and
(c) C _6-10 aryl (eg, phenyl)
A carbamoyl optionally having 1 or 2 substituents selected from:
(17) Thiocarbamoyl optionally having 1 or 2 C _1-6 alkyl optionally having 1 to 3 halogen atoms;
(18) Sulfamoyl optionally having 1 or 2 C _1-6 alkyl optionally having 1 to 3 halogen atoms;
(19) (a) a halogen atom,
(b) carboxy,
(c) C _1-6 alkoxy,
(d) C _1-6 alkoxy-carbonyl optionally having 1 to 3 C _6-10 aryl,
(e) an amino optionally having 1 or 2 substituents selected from C _1-6 alkyl and C _1-6 alkoxy-carbonyl;
(f) C _3-8 cycloalkyl,
(g) (i) a halogen atom,
(ii) hydroxy,
1 selected from (iii) C _1-6 alkyl optionally having 1 to 3 halogen atoms, and (iv) C _1-6 alkoxy optionally having 1 to 3 halogen atoms. 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 aryloxy (eg, phenyloxy, naphthyloxy);
(23) C _7-13 aralkyloxy (eg, benzyloxy);
(24) C _1-6 alkyl-carbonyloxy (eg, acetyloxy, tert-butylcarbonyloxy);
(25) (a) a halogen atom, and (b) optionally having 1 to 3 substituents selected from C _1-6 alkyl _optionally having 1 to 3 halogen atoms _6-10 aryl-carbonyl (eg, benzoyl, 1-naphthoyl, 2-naphthoyl);
(26) (a) a halogen atom,
(b) (i) a halogen atom,
(ii) hydroxy, and (iii) a 4- to 12-membered non-aromatic heterocyclic group (eg, pyrrolidinyl)
C _1-6 alkyl _optionally having 1 to 3 substituents selected from
(c) hydroxy, and (d) a 4-12 membered non-aromatic heterocyclic group (eg, pyrrolidinyl)
5- to 12-membered aromatic heterocyclic carbonyl optionally having 1 to 3 substituents selected from (eg, thienylcarbonyl, pyrazolylcarbonyl, pyrazinylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl, Thiazolylcarbonyl, pyrrolidinylcarbonyl, piperidylcarbonyl, morpholinylcarbonyl, piperazinylcarbonyl, tetrahydropyrazolopyridylcarbonyl);
(27) optionally having 1 to 3 substituents selected from (a) a halogen atom, and (b) C _1-6 alkyl _optionally having 1 to 3 halogen atoms To 12-membered non-aromatic heterocyclic carbonyl (eg, pyrrolidinylcarbonyl, morpholinylcarbonyl);
(28) C _7-13 aralkyloxy-carbonyl (eg, benzyloxycarbonyl);
(29) Mercapto;
(30) (a) a halogen atom, and (b) C _1-6 alkoxy - 1 to 3 substituents substituted C _1-6 alkylthio selected from carbonyl (e.g., methylthio, ethylthio);
(31) C _7-13 aralkylthio (eg, benzylthio);
(32) C _6-10 arylthio (eg, phenylthio, naphthylthio); and
(33) C _7-10 bridged cycloalkyl (eg adamantyl).

In the present specification, the 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 _7-13 aralkyl; and
(5) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) cyano,
(c) C _1-6 alkyl _optionally having 1 to 3 hydroxy (eg, methyl, ethyl),
(d) C _1-6 alkoxy (eg, methoxy), and (e) C _2-6 alkynyl (eg, ethynyl)
C _2-6 alkynyl (eg, ethynyl) optionally having 1 to 3 substituents selected from

In the present specification, _{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 C _1-6 alkoxy _7-13 aralkyl; and
(5) Oxo.

In the present specification, the “heterocyclic group” in the “optionally substituted heterocyclic group” refers to an aromatic heterocyclic group and a non-aromatic heterocyclic group.

In the present specification, “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 (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazole) Lyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (eg, 3-isothiazolyl, 4-isothiazolyl, 5 -Isothiazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (eg, 1,2,4-oxazil) Azol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (eg, 1,3,4-thiadiazol-2-yl), triazolyl (eg, 1,2,4-triazole-) 1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazole 1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (eg, tetrazol-1-yl, tetrazol-5-yl), triazinyl (eg, 1,2,4-triazin-3-yl, 1,2,4-triazin-6-yl).

Examples of the condensed aromatic heterocyclic group 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 (eg, 2-benzothienyl, 3-benzothiyl) Enyl), benzoxazolyl (eg, 2-benzoxazolyl), benzisoxazolyl (eg, 3-benzisoxazolyl), benzothiazolyl (eg, 2-benzothiazolyl), benzoisothiazolyl (eg 3-benzisothiazolyl), benzimidazolyl (eg, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzotriazolyl (eg, 1H-1,2,3) -Benzotriazol-5-yl), indolyl (eg, indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), indazolyl (eg, 1H-indazol-3-yl) Pyrrolopyrazinyl (eg, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyrazine 6-yl), imidazopyridinyl (eg, 1H-imidazo [4,5-b] pyridin-2-yl, 1H-imidazo [4,5-c] pyridin-2-yl, 2H-imidazo [1, 2-a] pyridin-3-yl), thienopyridinyl (eg, thieno [2,3-b] pyridin-3-yl), imidazopyrazinyl (eg, 1H-imidazo [4,5-b] pyrazine-2 -Yl), pyrazolopyridinyl (eg, 1H-pyrazolo [4,3-c] pyridin-3-yl), pyrazolothienyl (eg, 2H-pyrazolo [3,4-b] thiophen-2-yl), And pyrazolotriazinyl (eg, pyrazolo [5,1-c] [1,2,4] triazin-3-yl).

In the present specification, 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.

In the present specification, “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. 4 to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group, such as 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) 2-yl), imidazolidinyl (eg, imidazolidin-2-yl, imidazolidin-3-yl), oxazolinyl (eg, oxazolin-2-yl), thiazolinyl (eg, thiazolin-2-yl), imidazolinyl (eg, Imidazolin-2-yl, imidazolin-3-yl), dioxolyl (eg, 1,3-dioxol-4-yl), dioxolanyl (eg, 1,3-dioxolan-4-yl), dihydrooxadiazolyl (eg, 4,5-dihydro-1,2,4-oxadiazol-3-yl), pyranyl (eg, 2-pyranyl, 4-pyranyl), tetrahydropyranyl (eg, 2-tetrahydropyranyl, 3-tetrahydropyrani) , 4-tetrahydropyranyl), thiopyranyl (eg, 4-thiopyranyl), dihydrothiopyranyl (eg, dihydro Opiran-3-yl, dihydrothiopyran-4-yl), tetrahydrothiopyranyl (eg, 2-tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl, 4-tetrahydrothiopyranyl), 1-oxidetetrahydrothiopyrani (Eg, 1-oxidetetrahydrothiopyran-4-yl), 1,1-dioxidetetrahydrothiopyranyl (eg, 1,1-dioxidetetrahydrothiopyran-4-yl), tetrahydrofuryl (eg, tetrahydrofuran) -3-yl, tetrahydrofuran-2-yl), pyrazolidinyl (eg, pyrazolidin-1-yl, pyrazolidin-3-yl), pyrazolinyl (eg, pyrazolin-1-yl), tetrahydropyrimidinyl (eg, tetrahydropyrimidine-1- Yl), dihydrotriazolyl (eg 2,3-di) Hydro-1H-1,2,3-triazol-1-yl), tetrahydrotriazolyl (eg, 2,3,4,5-tetrahydro-1H-1,2,3-triazol-1-yl), azepanyl (Eg, 1-azepanyl, 2-azepanyl, 3-azepanyl, 4-azepanyl), dihydropyridyl (eg, dihydropyridin-1-yl, dihydropyridin-2-yl, dihydropyridin-3-yl, dihydropyridin-4-yl), And dihydropyridyl (eg, 1,6-dihydropyridin-1-yl, 1,6-dihydropyridin-2-yl, 1,6-dihydropyridin-3-yl, 1,6-dihydropyridin-4-yl).

Examples of the fused non-aromatic heterocyclic group 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. And 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 A group derived from a condensed ring formed as above; a ring corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group and a ring corresponding to the 5- to 7-membered monocyclic aromatic heterocyclic group Groups derived from fused rings formed by condensation with; groups obtained by partial saturation of these groups, such as dihydroindolyl (eg 2,3-dihydro-1H-indol-1-yl), dihydro Isoindolyl (eg, 1,3-dihydro-2H-isoindole -2-yl), dihydrobenzofuranyl (eg, 2,3-dihydro-1-benzofuran-5-yl), tetrahydrobenzofuranyl (eg, 4,5,6,7-tetrahydro-1-benzofuran- 3-yl), dihydrobenzodioxinyl (eg, 2,3-dihydro-1,4-benzodioxinyl), dihydrobenzodioxepinyl (eg, 3,4-dihydro-2H-1,5- Benzodioxepinyl), chromenyl (eg, 4H-chromen-2-yl, 2H-chromen-3-yl), dihydrochromenyl (eg, 3,4-dihydro-2H-chromen-2-yl), dihydro Quinolinyl (eg, 1,2-dihydroquinolin-4-yl), tetrahydroquinolinyl (eg, 1,2,3,4-tetrahydroquinolin-4-yl), dihydroisoquinolinyl (eg, 1 , -Dihydroisoquinolin-4-yl), tetrahydroisoquinolinyl (eg 1,2,3,4-tetrahydroisoquinolin-4-yl), dihydrophthalazinyl (eg 1,4-dihydrophthalazine-4-yl) ) And azabicyclohexyl (eg, 2-azabicyclo [3.1.0] hexane-3-yl).

In the present specification, 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.

In the present specification, 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. When 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.

In the present specification, the "which may hydroxy also be substituted", for example, 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.

Specific examples of the “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.

In the present specification, the "which may mercapto also be substituted", for example, 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.

Specific examples of the “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.

In the present specification, "to an amino optionally substituted", for example, 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;

Specific examples of the “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.

In the present specification, “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].

In the present specification, 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.

Examples of the nitrogen-containing aromatic heterocycle include 5- to 7-membered (preferably 5- or 6-membered) monocyclic nitrogen-containing aromatic heterocycle and 8- to 12-membered condensed nitrogen-containing aromatic heterocycle. It is done.

Specific examples of the 5- to 7-membered (preferably 5- or 6-membered) monocyclic nitrogen-containing aromatic heterocycle 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.

Specific examples of the 8- to 12-membered condensed nitrogen-containing aromatic heterocycle 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.

Examples of the nitrogen-containing non-aromatic heterocycle 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.

Specific examples of 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).

Specific examples of the 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).

In the present specification, 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.

As preferable examples of “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) thiocarbamoyl;
(12) an aromatic heterocyclic carbonyl optionally having 1 to 3 substituents selected from C _1-6 alkyl _optionally having 1 to 3 halogen atoms; and
(13) a non-aromatic heterocyclic carbonyl optionally having 1 to 3 substituents selected from C _1-6 alkyl _optionally having 1 to 3 halogen atoms;
Is mentioned.

In the present specification, the “aromatic ring” in the “optionally substituted aromatic ring” refers to a C _6-14 aromatic hydrocarbon or an aromatic heterocyclic ring.

In the present specification, “C _6-14 aromatic hydrocarbon” represents a ring corresponding to “C _6-14 aryl”. As the C _6-14 aromatic hydrocarbon, a ring corresponding to “C _6-10 aryl” is preferable, and benzene is particularly preferable.

In the present specification, “aromatic heterocycle” refers to a ring corresponding to “aromatic heterocyclic group”. Among these, monocyclic aromatic heterocycles are preferable, and 5- or 6-membered monocyclic aromatic heterocycles are particularly preferable.

In the present specification, 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.

In the present specification, the “non-aromatic ring” in the “optionally substituted non-aromatic ring” refers to a non-aromatic hydrocarbon or a non-aromatic heterocyclic ring.

In the present specification, “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 ". Further, _{"C 3-10} cycloalkyl", _{"C 3-10} cycloalkenyl" and _{"C 4-10} cycloalkadienyl" means, _{C 3-10} cycloalkane _{respectively, C 3-10} cycloalkene or _{C 4- A} spiro ring group may be formed with ₁₀ cycloalkadiene.

In the present specification, “non-aromatic heterocyclic ring” refers to a ring corresponding to “non-aromatic heterocyclic group”. Among them, a monocyclic non-aromatic heterocycle is preferable, and a 5- or 6-membered monocyclic non-aromatic heterocycle is particularly preferable.

In the present specification, 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.

In the present specification, preferred examples of 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.

Hereinafter, the compound (I) will be described.

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.

As the “substituent” represented by R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ or R ¹⁰ , “an optionally substituted hydrocarbon group”, “substituted” Optionally substituted heterocyclic group ”,“ optionally substituted hydroxy ”,“ optionally substituted mercapto ”,“ optionally substituted amino ”,“ cyano ”,“ nitro ”,“ acyl ” ”,“ Halogen atom ”and the like.

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).

More preferably, 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.

Since 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.

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
In particular, 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.

As the compound (I), the following compounds are suitable.
[Compound A-1-p]
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)
Benzene optionally having 1 to 3 substituents selected from:
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 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 ⁵ is
(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 the same or different,
(1) a hydrogen atom, or
(2) C _1-6 alkyl (eg, methyl);
R ⁹ and R ¹⁰ are 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);
X ^a and X ^b are the same or different and are each CH or N;
X ^c is CH;
Y ^a is CH ₂ , O, NR ⁵ (R ⁵ is as defined above), S, or SO ₂ ;
Y ^b is a bond;
Compound (I), wherein n is an integer of 1 to 3.
[Compound A-1]
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, propyl, butyl) optionally having 1 to 3 substituents selected from:
R ⁵ is
(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 the same or different,
(1) a hydrogen atom, or
(2) C _1-6 alkyl (eg, methyl);
R ⁹ and R ¹⁰ are 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);
X ^a and X ^b are the same or different and are each CH or N;
X ^c is CH;
Y ^a is CH ₂ , O, NR ⁵ (R ⁵ is as defined above), S, or SO ₂ ;
Y ^b is a bond;
Compound (I), wherein n is an integer of 1 to 3.
[Compound A-2]
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, or
(3) C _1-6 alkyl (eg, methyl) _optionally having 1 to 3 halogen atoms (eg, fluorine atom);
X ^a , X ^b and X ^c are CH;
Y ^a is O or SO ₂ ;
Y ^b is a bond;
Compound (I), wherein n is 1.
[Compound A-3]
(+)-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 (Example 5a);
(+)-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 (Example 30b);
(+)-N- [7-cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (dimethylamino) Ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (Example 52b),
Or their salts.

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. Preferable examples of 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. Preferable examples of 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. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned.

Of these, 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.

Next, a method for producing compound (I) or a salt thereof will be described.

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.

In the following reactions, examples of alcohols used as a reaction solvent include methanol, ethanol, propanol, isopropanol (2-propanol), butanol, and tert-butanol.

In the following reaction, examples of ethers used as a reaction solvent include dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, and ethylene glycol-dimethyl ether.

In the following reaction, examples of esters used as a reaction solvent include ethyl formate, ethyl acetate, and n-butyl acetate.

In the following reaction, examples of the halogenated hydrocarbon used as a reaction solvent include dichloromethane, chloroform, carbon tetrachloride, and trichloroethylene.

In the following reaction, examples of hydrocarbons used as a reaction solvent include hexane, benzene, and toluene.

In the following reaction, examples of amides used as a reaction solvent include formamide, N, N-dimethylformamide, and N, N-dimethylacetamide.

In the following reaction, examples of nitriles used as a reaction solvent include acetonitrile and propionitrile.

In the following reaction, examples of the sulfoxide used as a reaction solvent include dimethyl sulfoxide.

In the following reaction, examples of aromatic hydrocarbons used as a reaction solvent include benzene and toluene.

In the following reaction, examples of ketones used as a reaction solvent include acetone, methyl ethyl ketone, and methyl isobutyl ketone.

In the following reaction, 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.

In the following reaction, 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.

In the following reaction, lithium, sodium, potassium, cesium or the like is used as the alkali metal.

In the following reaction, magnesium, calcium or the like is used as the alkaline earth metal.

In the following reaction, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide or the like is used as the alkali metal hydroxide.

In the following reaction, magnesium hydroxide, calcium hydroxide or the like is used as the alkaline earth metal hydroxide.

In the following reaction, as the 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.

In the following reaction, the raw material compound and the production intermediate may be a salt. Examples of such a salt include the same salts as the aforementioned compound (I).

In addition, the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but from the reaction mixture according to a conventional method (for example, separation means such as recrystallization, distillation, chromatography, etc.). It may be isolated.

The production method of compound (I) is described below.

Compound (I) can be produced, for example, by the method shown in the following Reaction Scheme 1 or a method analogous thereto.
Reaction formula 1

[The symbols in the formula are as defined above. ]
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).

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. Examples of the condensing agent include carbodiimide condensation reagents (eg, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide ジ (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)).

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. Examples of 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. Examples of such 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.

Compound (IB) can also be produced by the methods described in the following reaction schemes 4 to 8.
Reaction formula 2

[Wherein, 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, and 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. 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 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy) and 1 to 3 substituents selected from nitro _Preferable examples include C _6-14 arylsulfonyloxy, and specific examples include benzenesulfonyloxy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy, naphthylsulfonyloxy.

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).

The “amino protecting group” represented by P ¹ may be any group that can be removed after the cyclization reaction. For example, 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. As the “optionally substituted 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).

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)).

Specifically, 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. Examples of such 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. Examples of such solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof may be mentioned.

This reaction can be carried out in the presence of a base or an ammonium salt.

The amount of the base or ammonium salt to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IA- (b)).

This reaction can be carried out in the presence of a metal complex such as palladium or copper or a phosphine ligand.

Examples of the metal complex 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.

Examples of the phosphine ligand include 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), triphenylphosphine, tris ( 2-methylphenyl) phosphine, bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene.

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)).

Moreover, 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)).

For example, 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.

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. An example of the 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. Examples of 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)).

The reaction time is usually 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 12 hours.

Moreover, 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 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.

Moreover, 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 also be produced by the method shown in the following reaction scheme 3 or a method analogous thereto.
Reaction formula 3

[The symbols in the formula are as defined above. ]
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 can be carried out at room temperature or under heating (usually about 20 to 200 ° C., preferably about 20 to 160 ° C.).

Moreover, this reaction may be performed under microwave irradiation.

In addition, 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.

For example, when R ^{1 of} the compound (IA- (a)) is a leaving group (eg, bromine atom), an organometallic reagent (eg, tributyl (ethynyl) stannane, copper cyanide) is allowed to act on the R 1 Another compound (IA- (a)) in which ¹ is ethynyl, cyano and the like can be produced.

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. Examples of such 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.

Examples of the metal complex 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.

Examples of the phosphine ligand include 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), triphenylphosphine, tris ( 2-methylphenyl) phosphine, bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos) 挙げ.

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.

Moreover, 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. Examples of such 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.

Moreover, 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) React certain compounds with organometallic reagents (eg, tetramethylstannane, tributyl (ethynyl) stannane, trimethyl [(tributylstannanyl) ethynyl] silane, copper cyanide, zinc cyanide), as appropriate It can be manufactured by post-processing.

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.

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.

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.

Moreover, this reaction may be performed under microwave irradiation.

Further, for example, 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 ) And a substrate may be subjected to a coupling reaction in the presence of a metal complex or a phosphine ligand.

Examples of the substrate include amines (eg, diphenylmethanimine) and 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. .

Moreover, 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. In this reaction, 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)). In the reaction for obtaining compound (IA- (a)) from compound (IA- (e)) in the next step, 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).

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.

The progress of this reaction can be confirmed by observing the reduction rate of compound (I-C2) or the production rate of compound (IA- (f)) by ¹ H NMR or LC / MS.

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.

Of the compounds (IB) used in the above reaction scheme 1, 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

[Wherein, 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).

Specifically, it 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 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).

Further, the acid may be used as a solvent.

This reaction can also be performed in the presence of a Lewis acid. Such Lewis acids include titanium (IV) isopropoxide.

The amount of Lewis acid used is usually 1 to 5 equivalents per 1 equivalent of compound (IF).

In addition, Lewis acid may be used as a solvent.

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), the compound 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).

Specifically, 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. Examples of such 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.

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)).

Moreover, 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.

Specifically, among the compounds (I-B1- (a)), 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. Examples of such 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.

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)).

Moreover, this reaction may be performed under microwave irradiation.

In the compound (I-B1- (a)), a compound in which X ⁴ is —Cl to —Br is reacted with a chlorinating agent or brominating agent to the compound (I-B1- (b)). Can be manufactured.

Examples of the chlorinating agent include thionyl chloride, phosphoric acid trichloride, phosphoric acid pentachloride, and hydrogen chloride.

Examples of the brominating agent 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. Examples of such 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.

Moreover, 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. Examples of common reducing agents include sodium borohydride, lithium aluminum hydride, borane-dimethylsulfide complex, and borane-tetrahydrofuran complex.

Compound (I-B1) can also be produced by the following method (Scheme 5) or a method analogous thereto (Route C).
Reaction formula 5

[Wherein 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.

Examples of the “amino protecting group” for P ³ 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.

As the above condensation reaction, conditions known per se can be used, and the conditions shown in Reaction Scheme 1 can also be used.

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)).

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 | subjecting to reaction.

Examples of the hydroxyamine derivative (formula: R ¹¹ —O—NH ₂ ) used in the oximation reaction include hydroxyamine, O-methylhydroxyamine, and O-benzylhydroxyamine.

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. Examples of such 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.

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).

Moreover, this reaction may be performed under microwave irradiation.

As a reduction condition used for the reduction reaction, a hydrogenation method known per se or a reduction method known per se is used.

Specifically, 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. Examples of such 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.

Further, 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.).

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. Examples of such solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof may be mentioned.

This reaction can 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. Examples of such solvents include halogenated hydrocarbons, aromatic hydrocarbons, alcohols, ethers, ketones, nitriles, esters, amides, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Hexamethylphosphoramide, water or a mixed solvent thereof may be mentioned.

Compound (I-B1) can also be produced by a reductive amination reaction using compound (I-B1- (d)) and compound (IE3).

As the above reductive amination reaction, not only the conditions known per se can be used, but also the conditions indicated by Route IV in Reaction Scheme 4 can be used.

Compound (IE3) can be produced using a commercially available reagent or by a reaction known per se.

Further, 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)).

Specifically, 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)).

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)).

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)).

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)).

Moreover, 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.

Among the compounds (IB) used in the above reaction scheme 1, Y ^a is SO ₂ , Y ^b is a bond, and n is 1 (hereinafter referred to as Compound (IB2)) ) Can also be produced by the following method (Scheme 6) or a method analogous thereto (Route D).
Reaction formula 6

[The symbols in the formula are as defined above. ]
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)).

Moreover, 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.

Examples of the oxidizing agent include m-chloroperbenzoic acid (mCPBA), monoperphthalic acid or a salt thereof, hydrogen peroxide solution, percarbonate, peracetic acid or a salt thereof, and 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)).

Further, when the oxidizing agent 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. Examples of such 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.

Compound (I-B2- (b)) is commercially available, or can be produced by a reaction known per se.

In addition, 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)).

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.

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. Examples of such 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.

Of the compounds (IB) used in the above Reaction Scheme 1, Y ^a is SO ₂ or CO, Y ^b is a bond, and n is 1 (hereinafter referred to as Compound (IB3) )) Can also be produced by the following method (Scheme 7) or a method analogous thereto.
Reaction formula 7

[The symbols in the formula are as defined above. ]
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).

In the intramolecular cyclization reaction, an intermediate imine (I-B3- (a)) or an imine equivalent (eg, hemiaminal) may be isolated if it is chemically stable. In this reaction, 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.

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).

Compound (IG) may be a commercially available product, or can be produced by a method known per se.

Further, 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 . After obtaining (I-B3- (b)), the compound (I-B3- (b)) can be reacted with the compound (I-E1) (Route F).

Specifically, for example, 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)).

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)).

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)).

Moreover, 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.

Specifically, for example, in the compound (I-B3- (b)), 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)). Alternatively, 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)).

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)).

Moreover, this reaction may be performed under microwave irradiation.

In the compound (I-B3- (b)), a compound in which X ⁴ is —Cl to —Br is reacted with a chlorinating agent or brominating agent to the compound (I-B3- (c)). Can be manufactured.

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)).

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)).

The reaction time is usually 1 to 30 hours, preferably 1 to 20 hours.

Moreover, 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).

Intramolecular cyclization reaction described above, relative to the compound (I-G), with the addition of suitable activators, it can proceed by activating methyl group adjacent to Y ^a.

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).

Of the compounds (IB) used in the above Reaction Scheme 1, Y ^a is S or O, Y ^b is a bond, and n is 1 (hereinafter referred to as Compound (IB4)) Can also be produced by the following method (Scheme 8) or a method analogous thereto (Route G).
Reaction formula 8

[The symbols in the formula are as defined above. ]
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.

In the above 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. Followed by intramolecular nucleophilic reaction to produce compound (I-B4).

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).

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. Examples of such 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.

Compound (IH) and compound (I-E1) may be commercially available, or can be produced by a reaction known per se.

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

[The symbols in the formula are as defined above. ]
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.

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.

When the carboxylic acid (II) is derivatized into an acid halide, 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. Examples of such a solvent include halogenated hydrocarbons, aromatic hydrocarbons, ethers, acetonitrile, or a mixed solvent thereof.

If 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. .

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. Examples of such a solvent include halogenated hydrocarbons, aromatic hydrocarbons, ethers, or a mixed solvent thereof.

Compound (II) may be a commercially available product, or can be produced by a reaction known per se.

Compound (IF) used in the above reaction schemes 4 to 6 can also be produced by the following method (reaction scheme 10) or a method analogous thereto.
Reaction formula 10

[Wherein, 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 β-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).

Compound (IJ) is commercially available, or can be produced by a reaction known per se.

The β-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)). In the examples shown below, 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.

The decarboxylation (decarboxylation) reaction of the β-ketoester equivalent (IF- (a)) can be carried out under reaction conditions known per se.

When the β-ketoester equivalent (IF- (a)) is an ester (P ⁵ is not a hydrogen atom), the carboxy protecting group P ⁵ is deprotected to form a carboxylic acid (P ⁵ is a hydrogen atom). Conversion can also accelerate the progress of decarboxylation.

For the deprotection reaction of the protecting group P ⁵ , known deprotection conditions (for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980)) can be used.

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)).

Further, 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. Examples of such 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)).

Of the compounds (IF) used in the above reaction scheme 4 or 5, Y ^a is SO ₂ or CO, Y ^b is a bond, and n is 1 (in the present specification, Compound (I-F1)) can also be produced by the following method (Scheme 11) or a method analogous thereto.
Reaction formula 11

[The symbols in the formula are as defined above. ]
Compound (I-F1) can be produced by an intramolecular cyclization reaction of a methyl group adjacent to Y ^a of compound (IK).

Intramolecular cyclization reaction described above, relative to the compound (I-K), with the addition of suitable activators, it can proceed by activating methyl group adjacent to Y ^a.

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).

Compound (IK) may be commercially available or can be produced by a reaction known per se.

Of the compounds (IF) used in the reaction scheme 4 or 5, a compound in which Y ^a is NR ⁵ and Y ^b is a bond (hereinafter referred to as compound (IF2)) is It can also be produced by the following method (Scheme 12) or a method analogous thereto.
Reaction formula 12

[The symbols in the formula are as defined above. ]
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)).

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.

Examples of the oxidizing agent used in this reaction include m-chloroperbenzoic acid (mCPBA), 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)).

In addition, when the oxidizing agent is a liquid, 10 equivalents or more may be used as a solvent with respect to the compound (IF2- (b)).

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).

Compound (IL) is commercially available, or can be produced by a reaction known per se.

In addition, for the substituent conversion (that is, introduction of a substituent or functional group conversion) for the compound (I), a known general method is used. For example, 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.

When introducing a substituent or converting a functional group, if there is a reactive site where a reaction other than the target occurs, 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.

For example, when 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. In this case, the target compound can be obtained by removing the protecting group as necessary after the reaction.

Examples of the amino-protecting group include those exemplified as P ¹ above.

As the protective groups of carboxy, for example, those exemplified as P ² 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.

Depending on the type of the substituent of the raw material compound, 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. .

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.

When compound (I) or a salt thereof has an isomer such as an optical isomer, a stereoisomer, or a positional isomer, any one of the isomers and a mixture are included in compound (I) or a salt thereof. . For example, when 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. Here, 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.

Furthermore, 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. Is a compound that changes to compound (I) or a salt thereof, and a compound that undergoes hydrolysis or the like by gastric acid or the like to change to compound (I) or a salt thereof. Examples of 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 (I) is esterified, amidated Compound (eg, carboxy of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compound). These compounds can be produced from compound (I) or a salt thereof by a method known per se.

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.

In addition, 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.).

Therefore, the compound of the present invention can be safely administered to mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human).

Accordingly, the compound of the present invention 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 duct cancer), thyroid cancer (eg, medullary thyroid cancer), kidney cancer (eg, renal cell carcinoma, renal pelvis and Transitional cell carcinoma of the ureter), uterine cancer, brain tumor (eg, pineal astrocytoma, ciliary astrocytoma, diffuse astrocytoma, regression) Astrocytoma), melanoma (eg, melanoma), sarcoma, bladder cancer, blood cancer (eg, multiple myeloma)] prevention or treatment agent; cancer growth inhibitor; cancer metastasis inhibitor; It is used as a medicine such as an agent.

In particular, 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.

As 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 Examples include oral preparations (including soft capsules and microcapsules), syrups, 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). In addition, 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.

As a method for producing the medicament of the present invention, a known production method generally used in the field (for example, a method described in Japanese Pharmacopoeia) can be applied. Further, when producing the medicament of the present invention, if necessary, excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, ordinarily used in the pharmaceutical field, An appropriate amount of an additive such as an emulsifier can be appropriately added.

For example, when producing tablets containing the compound of the present invention, excipients, binders, disintegrants, lubricants and the like can be used. When producing pills and granules, excipients are used. , Binders, disintegrants and the like can be used. In the case of producing powders and capsules, 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.

Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, and calcium sulfate.

Examples of the binder 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.

Examples of disintegrants include starch and calcium carbonate.

Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, and purified talc.

Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, and simple syrup.

Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl 40 stearate.

Examples of the suspending agent include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, and bentonite.

Examples of emulsifiers include gum arabic, tragacanth, gelatin, and polysorbate 80.

Furthermore, when producing the medicament of the present invention, 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. .

Examples of the injection 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). Examples of the oily liquid include sesame oil and soybean oil. 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. The prepared injection solution is usually filled in an ampoule.

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. For example, in the case of oral administration to a patient for the purpose of cancer treatment, 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.

When the compound of the present invention is administered parenterally, it is usually administered in the form of a liquid (for example, an injection). The single dose varies depending on the administration subject, target organ, symptom, administration method, and the like. For example, in the form of an injection, 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. Specifically, 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. Hereinafter, a drug that can be used in combination with the compound of the present invention is abbreviated as “concomitant drug”.

Examples of the `` hormone therapeutic agent '' 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, fadrozole hydrochloride, anastrozole, reso Rozole, exemestane, borozole, formestane), antiandrogens (eg, flutamide, bicalutamide, nilutamide), 5α-reductase inhibitors (eg, finasteride, epristeride), corticosteroids (eg, dexamethasone, prednisolone, betamethasone, triamcinolone) ), Androgen synthesis inhibitors (eg, abiraterone), drugs that retard the metabolism of retinoids and retinoids (eg, riarosol), thyroid hormones, and their DDS (Drug Delivery System) formulations.

As the “chemotherapeutic agent”, for example, alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents are used.

Examples of the “alkylating agent” 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, adozelesin, cystemustine, Bizereshin, and their DDS (Drug Delivery System) formulation is used.

Examples of the “antimetabolite” 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.

Examples of the “anticancer antibiotic” 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.

As the “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.

Examples of the “immunotherapeutic agent” 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, TGFα inhibitor, harregulin inhibitor, insulin inhibitor, IGF inhibitor, FGF inhibitor, KGF inhibitor, CSF inhibition Agent, EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGFβ 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, ERK inhibitors and the like are used. More specifically, examples of such 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) -5- [3- [4- (1 -Pyrrolidinyl) butyl] ureido] isothiazole-4-carboxamide (CP-547632), Axitinib, N- (3,3-dimethyl-2,3-dihydro-1H-indol-6-yl) -2- (pyridine- 4-ylmethylamino) pyridine-3-carboxamide (AMG-706), Nilotinib, 6- [4- (4-ethylpipera N-1-ylmethyl) phenyl] -N- [1 (R) -phenylethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (AEE-788), Vandetanib, Temsirolimus, Everolimus, Enzastaurin, N- [4- [4- (4-Methylpiperazin-1-yl) -6- (3-methyl-1H-pyrazol-5-ylamino) pyrimidin-2-ylsulfanyl] phenyl] cyclopropanecarboxamide (VX-680 ), 2- [N- [3- [4- [5- [N- (3-fluorophenyl) carbamoylmethyl] -1H-pyrazol-3-ylamino] quinazolin-7-yloxy] propyl] -N-phosphate Ethylamino] ethyl ester (AZD-1152), 4- [9-chloro-7- (2,6-difluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2-ylamino] benzoic acid (MLN-8054), N- [2-methoxy-5-[(E) -2- (2,4,6-trimethoxyphenyl) vinylsulfonylmethyl] phenyl] glycine sodium salt (ON-1910Na), 4- [8-Cyclopentyl-7 (R) -ethyl-5-methyl-6-oxy So-5,6,7,8-tetrahydropteridin-2-ylamino] -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide (BI-2536), 5- (4-bromo-2- Chlorophenylamino) -4-fluoro-1-methyl-1H-benzimidazole-6-carbohydroxamic acid 2-hydroxyethyl ester (AZD-6244), N- [2 (R), 3-dihydroxypropoxy] -3,4 -Difluoro-2- (2-fluoro-4-iodophenylamino) benzamide (PD-0325901) and everolimus (RAD001) are used.

In addition to the above drugs, L-asparaginase, acegraton, procarbazine hydrochloride, protoporphyrin / cobalt complex, mercury hematoporphyrin / sodium, topoisomerase I inhibitor (eg, irinotecan, topotecan), topoisomerase II inhibitor (eg, sobuzoxane), Differentiation inducer (eg, retinoid, vitamin D), other angiogenesis inhibitors (eg, fumagillin, shark extract, COX-2 inhibitor), α-blocker (eg, tamsulosin hydrochloride), bisphosphonic acid (eg, Pamidronate, zoledronate), thalidomide, 5-azacytidine, decitabine, proteasome inhibitors (eg, bortezomib), apoptosis inducers (eg, TRAIL receptor agonists, anti-TRAIL antibodies, Bcl-2 inhibitors), antitumor antibodies ( Eg, anti-CD20 antibody), toxin-labeled antibody, etc. It can be used as the object.

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;

When the compound of the present invention and a concomitant drug are used in combination, 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. When administered at a time difference, 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. When the compound of the present invention is administered first, there is a method in which 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.

As 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.

Furthermore, the compound of the present invention can be used in combination with non-drug therapy. Specifically, 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;

For example, by using the compound of the present invention before or after the above-mentioned non-drug therapy, effects such as prevention of resistance development, prolongation of disease-free (Disease-Free Survival), suppression of cancer metastasis or recurrence, life prolongation, etc. are obtained. .

In addition, treatment with the compound of the present invention and supportive therapy [(i) administration of antibiotics (for example, β-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.].

Before or after the aforementioned non-drug therapy, 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.

When the compound of the present invention is 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. Thus, by administering the compound of the present invention before the above-described non-drug therapy, for example, cancer tissue can be reduced, so that the above-described non-drug therapy is facilitated.

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. Thus, by administering the compound of the present invention after the aforementioned non-drug therapy, the effect of the aforementioned non-drug therapy can be enhanced.

Hereinafter, the present invention will be described in more detail with reference to Examples, Formulation Examples, and Test Examples. However, the present invention is not limited thereto and may be changed without departing from the scope of the present invention. Good.

“Room 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.

In the 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.

The abbreviations in the following examples and test examples follow the examples currently used in the present technical field, and have the following meanings, for example.
¹ H NMR: proton nuclear magnetic resonance spectrum
HPLC: High performance liquid chromatography
SFC: Supercritical fluid chromatography
MS: Mass spectrum
LC / MS: Liquid chromatograph mass spectrometer
ESI method: Electrospray ionization method
APCI method: atmospheric pressure chemical ionization method
HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate
BINAP: 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl
DBU: 2,3,4,6,7,8,9,10-octahydropyrimido [1,2-a] azepine (1,8-diazabicyclo [5.4.0] -7-undecene)
EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
mCPBA: m-chloroperbenzoic acid
Xantphos: 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene
DMSO: Dimethyl sulfoxide
EGTA: Ethylene glycol bis-2-aminoethyl ether tetraacetic acid
BSA: Bovine serum albumin ¹ H NMR was measured by Fourier transform NMR. For analysis, ACD / SpecManager (trade name) was used. Peaks with very gentle protons such as hydroxyl groups and amino groups are not described.

MS was measured by LC / MS. As the ionization method, ESI method, APCI method, or simultaneous ESI / APCI multi method was used. The data is the actual measurement (found). Usually, 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. There is also. In the case of a compound having a hydroxyl group (—OH), a peak from which H ₂ O is eliminated may be observed as a fragment ion. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.

Specific rotation was measured using a polarimeter (light source: sodium D line, wavelength: 589 nm). Data are measured temperature (unit: ° C), sample concentration c (unit: g / 100 mL), measurement solvent (eg, CHCl) _Three ), And the average value (unit: °) of the specific rotation measured multiple times under the conditions on the left.
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
A) 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). The reaction mixture was stirred at 40 ° C. for 14 hours and diluted with ethyl acetate / hexane (2: 1) (450 mL). The resulting solution was washed with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, and the resulting organic layer was filtered through a pad of basic silica gel. The filtrate was concentrated under reduced pressure, and the precipitated solid was collected by adding hexane to give the title compound (11 g).
MS (ESI +): [M + H] + 221.0.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.32 (3H, t, J = 7.1 Hz), 4.11 (3H, s), 4.31 (2H, q, J = 7.2 Hz), 6.45 (1H, d, J = 7.0 Hz), 7.26 (1H, d , J = 9.1 Hz), 7.41 (1H, dd, J = 9.1, 7.6 Hz), 8.22 (1H, s).
B) Ethyl 3-bromo-5-methoxyimidazo [1,2-a] pyridine-2-carboxylate
N-bromosuccinimide (4.0 g) was added to a solution of ethyl 5-methoxyimidazo [1,2-a] pyridine-2-carboxylate (5.0 g) in N, N-dimethylformamide (150 mL) at 4 ° C. added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. Water (100 mL) was added to the concentrated oily substance, and the mixture was stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration and washed with water (100 mL) to give the title compound (6.5 g).
MS (ESI +): [M + H] + 299.0.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.32 (3H, t, J = 7.1 Hz), 4.04 (3H, s), 4.31 (2H, q, J = 7.1 Hz), 6.42 (1H, dd, J = 7.6, 0.9 Hz), 7.14-7.32 (1H, m), 7.32-7.55 (1H, m).
C) Ethyl 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylate
Ethyl 3-bromo-5-methoxyimidazo [1,2-a] pyridine-2-carboxylate (5.8 g), (4-fluoro-3-methylphenyl) boronic acid (4.6 g), cesium carbonate (20 g) , [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1.6 g), water (30 mL) and 1,2-dimethoxyethane (150 mL) under a nitrogen atmosphere. The mixture was stirred at 90 ° C for 1.5 hours. The reaction mixture was cooled to room temperature, suspended in ethyl acetate (300 mL), and washed with saturated brine (150 mL). The aqueous layer was extracted with ethyl acetate (100 mL), and the combined organic layers were dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (5.8 g).
MS (ESI +): [M + H] + 329.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.06 (3H, t, J = 7.2 Hz), 2.27 (3H, d, J = 1.5 Hz), 3.67 (3H, s), 3.99-4.18 (2H, m), 6.32 (1H, dd, J = 7.5, 0.8 Hz), 7.03-7.18 (1H, m), 7.19-7.29 (2H, m), 7.29-7.41 (2H, m).
D) 3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid
Ethyl 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylate (5.7 g), 2 N aqueous sodium hydroxide solution (18 mL), methanol (10 mL) and tetrahydrofuran (10 mL) were stirred at room temperature for 8 hours. The pH of the mixture was adjusted from 4 to 5 at 0 ° C. with 6 N hydrochloric acid and 1 N hydrochloric acid, and the resulting solution was extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with saturated brine (50 mL) 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 (3.9 g).
MS (ESI +): [M + H] + 301.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.26 (3H, d, J = 1.3 Hz), 3.66 (3H, s), 6.35 (1H, d, J = 7.6 Hz), 7.02-7.19 (1H, m), 7.20-7.36 (3H, m) , 7.36-7.49 (1H, m).
E) (±) -N '-(7,8-Dichloro-3,4-dihydro-2H-chromen-4-yl) -N, N-dimethylethane-1,2-diamine
To a solution of 7,8-dichlorochroman-4-one (500 mg) in methanol (7.3 mL) and acetic acid (0.73 mL) at room temperature, N, N-dimethylethane-1,2-diamine (240 mg) and 2- Methylpyridine borane complex (320 mg) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (10 mL) and hexane (10 mL), 2N hydrochloric acid (20 mL) was added, and the mixture was stirred for 30 min. The obtained aqueous layer was made alkaline by adding 8 N aqueous sodium hydroxide solution (5 mL) and 2 N aqueous sodium hydroxide solution (2 mL), and then extracted with ethyl acetate. And then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (390 mg).
MS (ESI +): [M + H] + 289.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.97-2.04 (2H, m), 2.23 (6H, s), 2.40-2.47 (2H, m), 2.66-2.84 (2H, m), 3.77 (1H, t, J = 4.3 Hz), 4.31- 4.51 (2H, m), 6.95-7.00 (1H, m), 7.06-7.11 (1H, m).
F) (±) -N- (7,8-Dichloro-3,4-dihydro-2H-chromen-4-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3 -Methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
To a solution of 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (150 mg) in N, N-dimethylformamide (3 mL), (± ) -N '-(7,8-dichloro-3,4-dihydro-2H-chromen-4-yl) -N, N-dimethylethane-1,2-diamine (150 mg), HATU (210 mg) and Diisopropylethylamine (160 mg) was added and stirred at room temperature for 3 hours. The reaction mixture was suspended in ethyl acetate (20 mL), and washed with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (190 mg).
MS (ESI +): [M + H] + 571.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.85-2.43 (12H, m), 2.52-3.02 (2H, m), 3.20-3.66 (1H, m), 3.73-3.81 (3H, m), 3.92-4.33 (1H, m), 4.36-4.52 (1H, m), 5.05-5.91 (1H, m), 6.00-6.08 (1H, m), 6.24-6.62 (1H, m), 6.71-6.89 (1H, m), 6.99-7.12 (1H, m) , 7.18-7.26 (2H, m), 7.27-7.40 (2H, m).
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.
MS (ESI +): [M + H] + 273.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.22 (6H, s), 2.36-2.82 (7H, m), 2.90-3.00 (1H, m), 4.20 (1H, t, J = 6.8 Hz), 7.29 (1H, s), 7.41 (1H, s).
B) (±) -N- (5,6-Dichloro-2,3-dihydro-1H-inden-1-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3 -Methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
Step of Example 1 using (±) -N ′-(5,6-dichloro-2,3-dihydro-1H-inden-1-yl) -N, N-dimethylethane-1,2-diamine In the same manner as in F, the title compound (200 mg) was obtained.
MS (ESI +): [M + H] + 555.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.89-2.15 (7H, m), 2.17-2.28 (1H, m), 2.33 (3H, s), 2.38-2.53 (2H, m), 2.54-2.67 (1H, m), 2.80-3.04 (2H , m), 3.12-3.40 (1H, m), 3.75-3.79 (3H, m), 5.23-5.97 (1H, m), 6.04 (1H, d, J = 7.2 Hz), 6.52-6.73 (1H, m ), 7.01-7.11 (1H, m), 7.19-7.25 (2H, m), 7.27-7.40 (3H, m).
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.
MS (ESI +): [M + H] + 273.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.81-1.97 (1H, m), 2.28 (6H, s), 2.44-2.54 (4H, m), 2.76-3.13 (4H, m), 4.30 (1H, t, J = 6.8 Hz), 7.31 ( 1H, d, J = 7.9 Hz), 7.46 (1H, d, J = 7.9 Hz), 7.60 (1H, s).
B) (±) -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
Example 1 using (±) -N, N-dimethyl-N ′-[6- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] ethane-1,2-diamine By the same method as in Step F, the title compound (220 mg) was obtained.
MS (ESI +): [M + H] + 555.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.80-2.19 (8H, m), 2.28-2.41 (4H, m), 2.43-2.59 (1H, m), 2.63-2.82 (1H, m), 2.86-3.14 (2H, m), 3.18-3.32 (1H, m), 3.72-3.80 (3H, m), 5.43 (1H, t, J = 8.1 Hz), 6.01-6.06 (1H, m), 6.87-7.11 (2H, m), 7.18-7.25 (2H , m), 7.27-7.47 (4H, m).
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.
MS (ESI +): [M + H] + 273.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.84-1.99 (1H, m), 2.24 (6H, s), 2.36-2.58 (4H, m), 2.76-2.81 (2H, m), 2.89-3.26 (2H, m), 4.28 (1H, t , J = 6.6 Hz), 7.26-7.32 (1H, m), 7.47 (1H, d, J = 7.6 Hz), 7.53 (1H, d, J = 7.6 Hz).
B) (±) -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
Example 1 using (±) -N, N-dimethyl-N ′-[4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] ethane-1,2-diamine By the same method as in Step F, the title compound (210 mg) was obtained.
MS (ESI +): [M + H] + 555.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.82-2.16 (8H, m), 2.25-2.35 (3H, m), 2.39-2.56 (2H, m), 2.67-3.50 (4H, m), 3.75-3.80 (3H, m), 5.30-6.10 (2H, m), 6.90-7.09 (2H, m), 7.17-7.25 (2H, m), 7.27-7.48 (4H, m).
Example 5
(±) -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
A) (±) -N '-(6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -N, N-dimethylethane-1,2-diamine
To a solution of 6,7-dichloro-1-benzofuran-3 (2H) -one (1.0 g) in tetrahydrofuran (15 mL), methanol (5.0 mL) and acetic acid (2.0 mL) at room temperature, 2-methylpyridine borane complex ( 800 mg) and N, N-dimethylethane-1,2-diamine (650 mg) were added, and the mixture was stirred at room temperature for 23 hours. 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. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (820 mg).
MS (ESI +): [M + H] + 274.9.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.18 (6H, s), 2.35-2.44 (2H, m), 2.53-2.65 (2H, m), 2.68-2.81 (1H, m), 4.49-4.59 (2H, m), 4.63-4.75 (1H , m), 7.00 (1H, d, J = 7.9 Hz), 7.15 (1H, d, J = 7.9 Hz).
B) (±) -N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3 -Methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
To a solution of 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (450 mg) in N, N-dimethylformamide (8 mL), (± ) -N '-(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) -N, N-dimethylethane-1,2-diamine (460 mg), HATU (630 mg) and Diisopropylethylamine (490 mg) was added, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was suspended in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (680 mg).
MS (ESI +): [M + H] +557.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.78-1.88 (3H, m), 2.04-2.12 (4H, m), 2.33 (3H, s), 2.40-2.63 (1H, m), 3.02-3.46 (2H, m), 3.77 (3H, s ), 4.41-4.87 (2H, m), 5.71-6.25 (2H, m), 6.82-7.09 (3H, m), 7.19-7.26 (2H, m), 7.27-7.35 (2H, m).
Example 5a
(+)-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 / ethanol = 500/500), and the fraction with the shorter retention time containing the desired product was concentrated under reduced pressure to give the title compound (320 mg).
Optical purity:> 99.9% ee, Retention time: 14.20 min (CHIRALPAK ADH (KD137), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500)
Specific rotation: [α] 25. D. +101.0 (c 0.231, CHCl _Three )
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 / ethanol = 500/500), and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to give the title compound (320 mg).
Optical purity:> 99.9% ee, Retention time: 18.82 min (CHIRALPAK ADH (KD137), 4.6 mm ID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500)
Specific rotation: [α] 25. D. -97.4 (c 0.231, CHCl _Three )
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. (220 mg) was obtained.
MS (ESI +): [M + H] + 375.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.34-1.70 (12H, m), 1.83-2.12 (1H, m), 2.74-2.95 (5H, m), 3.22-3.49 (2H, m), 4.30-4.49 (1H, m), 6.97 (1H , d, J = 8.3 Hz), 7.05-7.19 (1H, m).
B) (±) -tert-butyl {2-[(7,8-dichloro-3,4-dihydro-2H-chromen-4-yl) {[3- (4-fluoro-3-methylphenyl) -5 -Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate
Using (±) -tert-butyl {2-[(7,8-dichloro-3,4-dihydro-2H-chromen-4-yl) amino] ethyl} methylcarbamate and step F of Example 1 In the same manner, the title compound (140 mg) was obtained.
MS (ESI +): [M + H] + 657.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.21-1.45 (9H, m), 1.58-1.69 (2H, m), 1.91-2.26 (1H, m), 2.28-2.36 (3H, m), 2.62-2.94 (3H, m), 3.09-3.64 (3H, m), 3.74-3.75 (3H, m), 3.94-4.32 (1H, m), 4.35-4.59 (1H, m), 5.07-6.01 (1H, m), 6.01-6.09 (1H, m) , 6.17-6.62 (1H, m), 6.69-6.93 (1H, m), 6.96-7.12 (1H, m), 7.19-7.26 (3H, m), 7.27-7.40 (1H, m).
C) (±) -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
(±) -tert-butyl {2-[(7,8-dichloro-3,4-dihydro-2H-chromen-4-yl) {[3- (4-fluoro-3-methylphenyl) -5-methoxy Imidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate (130 mg) was dissolved in trifluoroacetic acid (1 mL) at 0 ° C. and stirred at room temperature for 0.5 hour. The reaction mixture was diluted with diethyl ether (15 mL), 2N aqueous sodium hydroxide solution was added to the residue (pH> 11), and the mixture was extracted twice with diethyl ether. 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 to give the title compound (100 mg).
MS (ESI +): [M + H] + 557.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.85-2.40 (10H, m), 2.63-2.90 (2H, m), 3.18-3.63 (1H, m), 3.76 (3H, s), 3.92-4.32 (1H, m), 4.35-4.53 (1H , m), 5.08-5.92 (1H, m), 6.05 (1H, d, J = 6.8 Hz), 6.25-6.61 (1H, m), 6.70-6.89 (1H, m), 6.95-7.25 (3H, m ), 7.28-7.39 (2H, m).
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-methylphenyl) -5-methoxy-N- [2- To a solution of (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (100 mg) in methanol (2.3 mL) and acetic acid (0.23 mL) at room temperature, 1H-indole-3-carbaldehyde (130 mg) and 2-methylpyridine borane complex (45 mg) were added, and the mixture was stirred at room temperature for 25 hours. To the reaction mixture were further added 1H-indole-3-carbaldehyde (26 mg) and 2-methylpyridine borane complex (26 mg) at room temperature, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, 1 N hydrochloric acid (15 mL) was added to the residue, and the mixture was washed successively with ethyl acetate (7.5 mL) and hexane (7.5 mL). The resulting aqueous layer was made alkaline (pH 8) by adding a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (73 mg).
MS (ESI +): [M + H] + 686.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.85-2.46 (11H, m), 2.55-3.13 (2H, m), 3.38 (1H, d, J = 3.4 Hz), 3.74 (3H, d, J = 1.5 Hz), 3.78-4.30 (2H, m), 4.91-5.86 (1H, m), 5.98-6.09 (1H, m), 6.13-6.53 (1H, m), 6.63-7.24 (9H, m), 7.27-7.47 (2H, m), 7.60- 8.04 (1H, m).
B) (-)-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-methylphenyl) -N- {2-[(1H- Indol-3-ylmethyl) (methyl) amino] ethyl} -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (67 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL, Daicel Fractions were collected using a chemical industry, mobile phase: methanol), and the fraction having a shorter retention time containing the target compound was concentrated under reduced pressure to obtain the title compound (34 mg).
Optical purity:> 99.9% ee, Retention time: 10.19 min (CHIRALCEL OD (HD070), 4.6 mmID × 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: methanol)
Specific rotation: [α] 25. D. -97.3 (c 0.150, CHCl _Three )
Example 7b
(+)-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-methylphenyl) -N- {2-[(1H- Indol-3-ylmethyl) (methyl) amino] ethyl} -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (67 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL, Daicel The fraction was collected with a chemical industry, mobile phase: methanol), and the fraction having the longer retention time containing the target compound was concentrated under reduced pressure to obtain the title compound (33 mg).
Optical purity: 99.4% ee, Retention time: 14.63 min (CHIRALCEL OD (HD070), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: methanol)
Specific rotation: [α] 25. D. +90.3 (c 0.150, CHCl _Three )
Example 8
(±) -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
A) tert-butyl {2-[(1H-indol-3-ylmethyl) (methyl) amino] ethyl} carbamate
To a solution of tert-butyl [2- (methylamino) ethyl] carbamate hydrochloride (2.11 g) in methanol (70 mL) at room temperature, sodium acetate (0.82 g), acetic acid (7 mL), 1H-indole-3-carbamate Rudehydr (2.90 g) and 2-methylpyridine borane complex (1.07 g) were added, and the mixture was stirred at room temperature overnight. To this mixture was further added 2-methylpyridine borane complex (1.07 g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 10% aqueous sodium carbonate solution was added to the residue (pH> 9), and the mixture was 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 successively by silica gel column chromatography (methanol / ethyl acetate) and (NH, ethyl acetate / hexane) to give the title compound (1.99 g).
MS (ESI +): [M + H] + 304.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.42 (9H, s), 2.24 (3H, s), 2.52 (2H, t, J = 5.9 Hz), 3.23 (2H, q, J = 5.5 Hz), 3.71 (2H, s), 5.01 (1H , brs), 7.07-7.24 (3H, m), 7.37 (1H, d, J = 7.9 Hz), 7.71 (1H, d, J = 7.6 Hz), 8.04 (1H, brs).
B) N- (1H-Indol-3-ylmethyl) -N-methylethane-1,2-diamine
Tert-butyl {2-[(1H-indol-3-ylmethyl) (methyl) amino] ethyl} carbamate (1.98 g) was dissolved in trifluoroacetic acid (8 mL) with stirring under ice cooling, and the reaction mixture was dissolved. The mixture was stirred for 30 minutes under ice cooling. 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.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.24 (2H, s), 2.29 (3H, s), 2.52 (2H, t, J = 5.9 Hz), 2.79 (2H, t, J = 5.9 Hz), 3.76 (2H, s), 7.05-7.23 (3H, m), 7.36 (1H, d, J = 7.7 Hz), 7.69 (1H, d, J = 7.6 Hz), 8.21 (1H, brs).
C) (±) -N '-(6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -N- (1H-indol-3-ylmethyl) -N-methylethane-1,2 -Diamine
The title compound (130 mg) was obtained in the same manner as in Step A of Example 5 using N- (1H-indol-3-ylmethyl) -N-methylethane-1,2-diamine.
MS (ESI +): [M + H] + 390.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.22 (3H, d, J = 5.1 Hz), 2.49-2.81 (4H, m), 3.67 (2H, d, J = 4.5 Hz), 4.29-4.45 (2H, m), 4.50-4.63 (1H, m), 6.89-7.00 (2H, m), 7.01-7.11 (2H, m), 7.13-7.22 (1H, m), 7.29-7.37 (1H, m), 7.58-7.67 (1H, m), 8.08 ( 1H, brs).
D) (±) -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) -N- (1H-indol-3-ylmethyl) -N-methylethane-1,2-diamine Was used to give the title compound (170 mg) in the same manner as in Step F of Example 1.
MS (ESI +): [M + H] + 672.0.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.06-2.69 (8H, m), 2.98-3.64 (4H, m), 3.73-3.78 (3H, m), 4.30-4.78 (2H, m), 5.68-6.28 (2H, m), 6.64-6.74 (1H, m), 6.78-7.25 (8H, m), 7.27-7.45 (3H, m), 7.54-8.06 (1H, m).
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 to obtain the title compound (39 mg).
Optical purity:> 99.9% ee, Retention time: 8.63 min (CHIRALPAK AY-H (NA006), 4.6 mmID × 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: ethanol)
Specific rotation: [α] 25. D. +55.0 (c 0.150, CHCl _Three )
Example 9a
(+)-N- (6,7-Dichloro-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
A) (±) -tert-butyl {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} methylcarbamate
To a solution of 6,7-dichloro-1-benzofuran-3 (2H) -one (1030 mg) in tetrahydrofuran (10 mL), methanol (14 mL) and acetic acid (1.4 mL) at room temperature, tert-butyl (2-amino Ethyl) methylcarbamate (1060 mg) was added, and the mixture was stirred at 40 ° C. for 3 hr. 2-Methylpyridine borane complex (710 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 46 hours. The reaction mixture was concentrated under reduced pressure, 0.5 N hydrochloric acid (30 mL), ethyl acetate (10 mL) and hexane (10 mL) were added to the residue, and the mixture was stirred for 20 min under ice cooling. The mixture was washed with ethyl acetate (10 mL) and hexane (10 mL), and then the aqueous layer obtained was made alkaline with 2 N aqueous sodium hydroxide solution (8 mL). The obtained aqueous layer was extracted with ethyl acetate, and the 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, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (47 mg).
MS (ESI +): [M + H] + 361.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.43-1.45 (9H, m), 1.56-1.81 (1H, m), 2.68-2.83 (2H, m), 2.85 (3H, s), 3.20-3.48 (2H, m), 4.44-4.51 (1H , m), 4.52-4.60 (1H, m), 4.63-4.74 (1H, m), 6.99-7.03 (1H, m), 7.13 (1H, d, J = 7.9 Hz).
B) (±) -tert-butyl {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5 -Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate
Using (±) -tert-butyl {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} methylcarbamate and step F of Example 1 In a similar manner, the title compound (210 mg) was obtained.
MS (ESI +): [M + H] + 643.3.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.16-1.41 (9H, m), 2.28-2.44 (4H, m), 2.76 (2H, s), 2.97-3.50 (4H, m), 3.75-3.79 (3H, m), 4.26-4.88 (2H , m), 5.74-6.43 (2H, m), 6.79-7.12 (3H, m), 7.19-7.25 (1H, m), 7.27-7.34 (3H, m).
C) (±) -N- (6,7-Dichloro-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
(±) -tert-butyl {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5-methoxy The title compound (190 mg) was obtained in the same manner as in Step C of Example 6 using imidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate.
MS (ESI +): [M + H] + 543.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.25-2.63 (9H, m), 3.16-3.47 (2H, m), 3.77 (3H, s), 4.36-4.93 (2H, m), 5.66-6.37 (2H, m), 6.87-7.09 (3H , m), 7.20-7.25 (1H, m), 7.27-7.32 (3H, m).
D) (+)-N- (6,7-Dichloro-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- (6,7-Dichloro-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 (190 mg) was HPLC (CHIRALPAK AD (AK001), 50 mm ID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = (300/700), and the fraction with the shorter retention time containing the desired product was concentrated under reduced pressure to give the title compound (83 mg).
Optical purity: 97.7% ee, Retention time: 11.54 min (CHIRALPAK AD (KF051), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 300/700)
Specific rotation: [α] 25. D. +83.3 (c 0.160, CHCl _Three )
Example 9b
(-)-N- (6,7-Dichloro-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- (6,7-Dichloro-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 (190 mg) was HPLC (CHIRALPAK AD (AK001), 50 mm ID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = (300/700), and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to give the title compound (77 mg).
Optical purity:> 99.9% ee, Retention time: 14.64 min (CHIRALPAK AD (KF051), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 300/700)
Specific rotation: [α] 25. D. -103.4 (c 0.150, CHCl _Three )
Example 10
(±) -N- (4,5-Dichloro-2,3-dihydro-1H-inden-1-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2- (Methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
A) (±) -tert-butyl {2-[(4,5-dichloro-2,3-dihydro-1H-inden-1-yl) amino] ethyl} methylcarbamate
To a solution of 4,5-dichloroindan-1-one (500 mg) in tetrahydrofuran (10 mL) and methanol (2 mL) at room temperature, tert-butyl (2-aminoethyl) methylcarbamate (570 mg), 2- Methylpyridine borane complex (400 mg) and acetic acid (1.2 mL) were added, and the mixture was stirred at room temperature for 66 hours. The reaction mixture was concentrated under reduced pressure, 0.5 N hydrochloric acid (20 mL) was added to the residue under ice cooling, and the mixture was stirred at room temperature for 30 min. The mixture was extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (570 mg).
MS (ESI +): [M + H] + 359.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.45 (9H, s), 1.77-1.91 (1H, m), 2.38-2.52 (1H, m), 2.75-2.87 (3H, m), 2.88 (3H, s), 3.00-3.13 (1H, m ), 3.23-3.48 (2H, m), 4.29 (1H, t, J = 6.7 Hz), 7.15 (1H, d, J = 7.9 Hz), 7.27-7.31 (1H, m).
B) (±) -tert-butyl {2-[(4,5-dichloro-2,3-dihydro-1H-inden-1-yl) {[3- (4-fluoro-3-methylphenyl) -5 -Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate
Using (±) -tert-butyl {2-[(4,5-dichloro-2,3-dihydro-1H-inden-1-yl) amino] ethyl} methylcarbamate and step F of Example 1 In a similar manner, the title compound (340 mg) was obtained.
MS (ESI +): [M + H] + 641.3.
C) (±) -N- (4,5-Dichloro-2,3-dihydro-1H-inden-1-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [ 2- (Methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -tert-butyl {2-[(4,5-dichloro-2,3-dihydro-1H-inden-1-yl) {[3- (4-fluoro-3-methylphenyl) -5-methoxy The title compound (270 mg) was obtained in the same manner as in Step C of Example 6 using imidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate.
MS (ESI +): [M + H] + 541.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.03-2.34 (8H, m), 2.45-2.71 (3H, m), 2.92-3.14 (2H, m), 3.22-3.46 (1H, m), 3.77 (3H, s), 5.34-6.00 (1H , m), 6.04 (1H, dd, J = 7.2, 1.1 Hz), 6.53-6.63 (1H, m), 6.95-7.09 (1H, m), 7.16-7.25 (3H, m), 7.28-7.36 (2H , m).
Example 10a
(-)-N- (4,5-Dichloro-2,3-dihydro-1H-inden-1-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2- (Methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -N- (4,5-Dichloro-2,3-dihydro-1H-inden-1-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2- (Methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (228 mg) was HPLC (CHIRALCEL OD (CG002), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = (700/300), and the fraction with the shorter retention time containing the desired product was concentrated under reduced pressure to give the title compound (114 mg).
Optical purity:> 99.9% ee, Retention time: 5.09 min (CHIRALCEL OD (HD070), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 700/300)
Specific rotation: [α] 25. D. -126.2 (c 0.150, CHCl _Three )
Example 10b
(+)-N- (4,5-Dichloro-2,3-dihydro-1H-inden-1-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2- (Methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -N- (4,5-Dichloro-2,3-dihydro-1H-inden-1-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2- (Methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (228 mg) was HPLC (CHIRALCEL OD (CG002), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = The fraction having a longer retention time containing the target compound was concentrated under reduced pressure to obtain the title compound (112 mg).
Optical purity: 99.7% ee, Retention time: 8.70 min (CHIRALCEL OD (HD070), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 700/300)
Specific rotation: [α] 25. D. +120.9 (c 0.150, CHCl _Three )
Example 11a
(+)-trans-N- (6,7-Dichloro-2-methyl-2,3-dihydro-1-benzofuran-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-methyl-2,3-dihydro-1-benzofuran-3-yl) -N, N-dimethylethane-1,2-diamine (trans: cis = 4: 1 mixture)
Using 6,7-dichloro-2-methyl-1-benzofuran-3 (2H) -one in the same manner as in Step A of Example 5, N ′-(6,7-dichloro-2-methyl- 2,3-Dihydro-1-benzofuran-3-yl) -N, N-dimethylethane-1,2-diamine (trans: cis = 1: 1 mixture) was obtained. Obtained N '-(6,7-dichloro-2-methyl-2,3-dihydro-1-benzofuran-3-yl) -N, N-dimethylethane-1,2-diamine (trans: cis = 1 : 1 mixture) was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to give the title compound (54 mg).
MS (ESI +): [M + H] + 289.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.40-1.48 (2.4H, m), 1.51-1.58 (0.6H, m), 2.12-2.25 (6H, m), 2.32-2.46 (2H, m), 2.53-2.66 (2H, m), 2.67 -2.78 (1H, m), 4.06-4.12 (0.8H, m), 4.17-4.23 (0.2H, m), 4.70-4.79 (0.8H, m), 4.80-4.88 (0.2H, m), 6.93- 7.04 (1H, m), 7.07-7.17 (1H, m).
B) (±) -trans-N- (6,7-Dichloro-2-methyl-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-methyl-2,3-dihydro-1-benzofuran-3-yl) -N, N-dimethylethane-1,2-diamine (trans: cis = 4: 1 mixture ) Was used to give the title compound (63 mg) in the same manner as in Step F of Example 1.
MS (ESI +): [M + H] + 571.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.41-1.53 (3H, m), 1.79-2.09 (7H, m), 2.32 (3H, s), 2.39-2.65 (1H, m), 2.97-3.40 (2H, m), 3.78 (3H, d , J = 1.9 Hz), 4.68-5.02 (1H, m), 5.19-5.90 (1H, m), 6.00-6.11 (1H, m), 6.55-7.23 (4H, m), 7.27-7.42 (3H, m ).
C) (+)-trans-N- (6,7-Dichloro-2-methyl-2,3-dihydro-1-benzofuran-3-yl) -N- [2- (dimethylamino) ethyl] -3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -trans-N- (6,7-Dichloro-2-methyl-2,3-dihydro-1-benzofuran-3-yl) -N- [2- (dimethylamino) ethyl] -3- (4 -Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (56 mg) by HPLC (CHIRALPAK AD (LF001), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, Ltd. Phase: hexane / 2-propanol = 600/400), and the fraction with the shorter retention time containing the desired product was concentrated under reduced pressure to give the title compound (30 mg).
Optical purity:> 99.9% ee, Retention time: 12.26 min (CHIRALPAK AD (MF012), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol = 600/400)
Specific rotation: [α] 25. D. +89.8 (c 0.155, CHCl _Three )
Example 11b
(-)-trans-N- (6,7-Dichloro-2-methyl-2,3-dihydro-1-benzofuran-3-yl) -N- [2- (dimethylamino) ethyl] -3- (4 -Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -trans-N- (6,7-Dichloro-2-methyl-2,3-dihydro-1-benzofuran-3-yl) -N- [2- (dimethylamino) ethyl] -3- (4 -Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (56 mg) by HPLC (CHIRALPAK AD (LF001), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, Ltd. Phase: hexane / 2-propanol = 600/400), and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to give the title compound (25 mg).
Optical purity:> 99.9% ee, Retention time: 19.53 min (CHIRALPAK AD (MF012), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol = 600/400)
Specific rotation: [α] 25. D. -94.5 (c 0.150, CHCl _Three )
Example 12
(±) -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
A) 6,7-Dichloro-2,2-dimethyl-1-benzofuran-3 (2H) -one
To a solution of 6,7-dichloro-1-benzofuran-3 (2H) -one (1090 mg) in tetrahydrofuran (40 mL) at −30 ° C., iodomethane (2290 mg), then sodium hydride (oily, 60% ) (650 mg) was added and the mixture was stirred at −30 ° C. for 30 minutes under a nitrogen atmosphere. The reaction mixture was warmed to 0 ° C., stirred for 30 minutes, further warmed to room temperature, and stirred for 30 minutes. To the reaction mixture was added 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (330 mg).
¹ H NMR (300 MHz, CDCl _Three ) δ 1.53 (6H, s), 7.19 (1H, dd, J = 8.2, 0.8 Hz), 7.51 (1H, dd, J = 8.2, 0.8 Hz).
B) (±) -6,7-Dichloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-3-ol
To a solution of 6,7-dichloro-2,2-dimethyl-1-benzofuran-3 (2H) -one (430 mg) in tetrahydrofuran (8 mL) and methanol (3 mL) at room temperature, sodium borohydride (170 mg) was added and the mixture was stirred at room temperature for 5.5 hours. To the reaction mixture was added 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (350 mg).
¹ H NMR (300 MHz, CDCl _Three ) δ 1.41 (3H, s), 1.56 (3H, s), 1.73 (1H, dd, J = 8.3, 1.5 Hz), 4.82 (1H, d, J = 8.3 Hz), 7.03 (1H, dd, J = 8.0, 1.7 Hz), 7.23 (1H, dd, J = 8.0, 1.0 Hz).
C) (±) -N '-(6,7-Dichloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-3-yl) -N, N-dimethylethane-1,2-diamine
To a solution of (±) -6,7-dichloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-3-ol (290 mg) and triethylamine (690 μL) in tetrahydrofuran (6 mL) at 0 ° C Then, methanesulfonyl chloride (190 μL) was added and stirred at 0 ° C. for 30 minutes. N, N-dimethylethane-1,2-diamine (670 μL) 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. And then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (85 mg).
MS (ESI +): [M + H] + 303.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.46 (3H, s), 1.50 (3H, s), 2.20 (6H, s), 2.38-2.44 (2H, m), 2.54-2.87 (3H, m), 3.97 (1H, s), 6.96 ( 1H, d, J = 7.9 Hz), 7.11 (1H, d, J = 7.9 Hz).
D) (±) -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
Using (±) -N '-(6,7-dichloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-3-yl) -N, N-dimethylethane-1,2-diamine By the same method as in Step F of Example 1, the title compound (160 mg) was obtained.
MS (ESI +): [M + H] + 585.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.53-1.61 (6H, m), 1.64-1.98 (7H, m), 2.28-2.36 (3H, m), 2.38-2.66 (1H, m), 2.83-3.33 (1H, m), 3.73-3.81 (3H, m), 3.81-3.94 (1H, m), 4.98-5.85 (1H, m), 5.98-6.12 (1H, m), 6.49-7.26 (5H, m), 7.27-7.38 (2H, m) .
Example 12a
(+)-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: hexane / 2-propanol = 700/300), and the fraction with the shorter retention time containing the desired product was concentrated under reduced pressure to give the title compound (57 mg).
Optical purity:> 99.9% ee, Retention time: 5.27 min (CHIRALPAK AD (MF012), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol = 700/300)
Specific rotation: [α] 25. D. +21.8 (c 0.222, CHCl _Three )
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: hexane / 2-propanol = 700/300), and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to give the title compound (55 mg).
Optical purity:> 99.9% ee, Retention time: 12.00 min (CHIRALPAK AD (MF012), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol = 700/300)
Specific rotation: [α] 25. D. -21.9 (c 0.150, CHCl _Three )
Example 13
(±) -N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N- [2- (dimethylamino) ethyl] -3- ( 4-Fluoro-3-methylphenyl) -5- (trifluoromethoxy) imidazo [1,2-a] pyridine-2-carboxamide
A) 2-Chloro-6- (trichloromethoxy) pyridine
6-Chloropyridin-2-ol (5.0 g) is dissolved in 5% aqueous sodium hydroxide solution (34 mL), and thiophosgene (3.0 mL) in chloroform (24 mL) is slowly added to the mixture at 0 ° C. Was stirred at 0 ° C. for 2 hours. The reaction mixture was extracted with chloroform, and the obtained organic layer was washed successively with 1 N hydrochloric acid and water, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was saturated with chlorine gas and stirred at room temperature for 2 hours. An excess amount of chlorine gas was added until the color of the reaction mixture changed to yellow, and the mixture was stirred at room temperature for 24 hours. Excess chlorine gas was removed under a nitrogen stream, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-pentane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (4.3 g).
¹ H NMR (400 MHz, CDCl _Three ) δ 7.15 (1H, d, J = 8.0 Hz), 7.31 (1H, d, J = 7.6 Hz), 7.82 (1H, t, J = 8.0 Hz).
B) 2-Chloro-6- (trifluoromethoxy) pyridine
To a mixture of antimony trifluoride (64 g) and antimony pentachloride (7.3 g) was added 2-chloro-6- (trichloromethoxy) pyridine (43 g) at 120 ° C, and the reaction mixture was stirred at 140 ° C for 4 hours. did. The reaction mixture was cooled to 0 ° C., diluted with dichloromethane (400 mL), and neutralized with saturated aqueous sodium hydrogen carbonate solution (700 mL) and 20% aqueous potassium fluoride solution (300 mL). The insoluble material was filtered off, the filtrate was extracted with dichloromethane, and the resulting organic layer was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue was distilled to give the title compound (30 g).
¹ H NMR (400 MHz, CDCl _Three ) δ 6.96 (1H, d, J = 8.2 Hz), 7.27 (1H, d, J = 7.8 Hz), 7.76 (1H, t, J = 8.0 Hz).
C) 2-Bromo-6- (trifluoromethoxy) pyridine
A mixture of 2-chloro-6- (trifluoromethoxy) pyridine (14 g) and 33% hydrogen bromide / acetic acid solution (150 mL) was stirred at 100 ° C. for 5 days. The reaction mixture was cooled to 0 ° C. and neutralized by adding saturated aqueous sodium hydrogen carbonate solution (500 mL). The mixture was extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (6.5 g).
¹ H NMR (400 MHz, CDCl _Three ) δ 7.03 (1H, d, J = 8.0 Hz), 7.46 (1H, d, J = 8.0 Hz), 7.69 (1H, t, J = 8.0 Hz).
D) 2,2-Dimethyl-N- [6- (trifluoromethoxy) pyridin-2-yl] propanamide
To a toluene (20 mL) solution of 2-bromo-6- (trifluoromethoxy) pyridine (2.0 g), pivalamide (1.1 g), tripotassium phosphate (3.9 g), Xantphos (840 mg) and tris (dibenzylidene) Acetone) dipalladium (0) (660 mg) was added, and the reaction mixture was stirred at 110 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / n-pentane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (1.8 g).
¹ H NMR (400 MHz, CDCl _Three ) δ 1.25 (9H, s), 6.68 (1H, d, J = 7.8 Hz), 7.46 (1H, t, J = 8.0 Hz), 7.86 (1H, brs), 8.10 (1H, d, J = 8.0 Hz) ).
E) 6- (Trifluoromethoxy) pyridin-2-amine
To a solution of 2,2-dimethyl-N- [6- (trifluoromethoxy) pyridin-2-yl] propanamide (2.5 g) in ethanol (10 mL), add 9 N hydrochloric acid (20 mL), and under nitrogen atmosphere. The reaction mixture was heated to reflux with stirring overnight. The reaction mixture was concentrated under reduced pressure, the residue was diluted with methanol (20 mL), potassium carbonate (2.0 g) was added, and the mixture was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane (50 mL). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.5 g).
¹ H NMR (400 MHz, CDCl _Three ) δ 4.57 (2H, brs), 6.34-6.38 (2H, m), 7.48 (1H, t, J = 8.0 Hz).
F) Ethyl 5- (trifluoromethoxy) imidazo [1,2-a] pyridine-2-carboxylate
The title compound (680 mg) was obtained in the same manner as in Step A of Example 1 using 6- (trifluoromethoxy) pyridin-2-amine.
¹ H NMR (400 MHz, CDCl _Three ) δ 1.38 (3H, t, J = 7.6 Hz), 4.41 (2H, q, J = 7.6 Hz), 6.76-6.78 (1H, m), 7.31 (1H, t, J = 8.4 Hz), 7.65 (1H , d, J = 8.8 Hz), 8.29 (1H, s).
G) Ethyl 3-bromo-5- (trifluoromethoxy) imidazo [1,2-a] pyridine-2-carboxylate
The title compound (780 mg) was obtained in the same manner as in Step B of Example 1 using ethyl 5- (trifluoromethoxy) imidazo [1,2-a] pyridine-2-carboxylate.
¹ H NMR (400 MHz, CDCl _Three ) δ 1.46 (3H, t, J = 6.8 Hz), 4.49 (2H, q, J = 6.8 Hz), 6.80-6.82 (1H, m), 7.28-7.32 (1H, m), 7.68-7.70 (1H, m).
H) Ethyl 3- (4-fluoro-3-methylphenyl) -5- (trifluoromethoxy) imidazo [1,2-a] pyridine-2-carboxylate
The title compound (810 mg) was obtained in the same manner as in Step C of Example 1 using ethyl 3-bromo-5- (trifluoromethoxy) imidazo [1,2-a] pyridine-2-carboxylate. It was.
¹ H NMR (400 MHz, CDCl _Three ) δ 1.25 (3H, t, J = 7.2 Hz), 2.32 (3H, s), 4.30 (2H, q, J = 7.2 Hz), 6.69 (1H, dd, J = 6.4, 0.8 Hz), 7.08 (1H , t, J = 9.2 Hz), 7.19-7.31 (3H, m), 7.71 (1H, d, J = 9.2 Hz).
I) 3- (4-Fluoro-3-methylphenyl) -5- (trifluoromethoxy) imidazo [1,2-a] pyridine-2-carboxylic acid
3- (4-Fluoro-3-methylphenyl) -5- (trifluoromethoxy) imidazo [1,2-a] pyridine-2-carboxylate (850 mg) in methanol (16 mL), tetrahydrofuran (16 mL ) And water (8 mL) solution was added lithium hydroxide monohydrate (550 mg) and the mixture was stirred at room temperature for 30 minutes. Methanol and tetrahydrofuran were distilled off under reduced pressure, the residue was diluted with water, and then the pH of the mixture was adjusted to 4 to 5 using 1 N hydrochloric acid. The precipitated solid was collected by filtration and washed with water. The filtrate was extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to obtain a solid. The obtained solids were combined and washed with ethyl acetate / n-pentane (1:10) to obtain the title compound (680 mg).
MS (ESI +): [M + H] + 355.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.26 (3H, s), 6.99 (1H, d, J = 7.2 Hz), 7.16 (1H, t, J = 9.2 Hz), 7.28-7.32 (1H, m), 7.37-7.43 (2H, m) , 7.68 (1H, d, J = 9.2 Hz).
J) [(2,3-Dichlorophenyl) sulfanyl] acetic acid
Dissolve 2,3-dichlorobenzenethiol (20 g) in 2 N aqueous sodium hydroxide solution (560 mL), add chloroacetic acid (26.38 g) and sodium hydroxide (14.5 g) to this solution at 25 ° C, and add 100 Stir at 1 ° C. for 1 hour. The reaction mixture was cooled to 0 ° C. and the pH was adjusted to 3 using 2 N hydrochloric acid (10 mL). The precipitate was collected by filtration and washed with ice-cold water to give the title compound (24 g).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.97 (2H, s), 7.29 (1H, d, J = 7.8 Hz), 7.35 (1H, t, J = 8.0 Hz), 7.42-7.46 (1H, m), 13.04 (1H, brs).
K) 6,7-Dichloro-1-benzothiophene-3 (2H) -one
Phosphorous acid trichloride (23.1 mL) was slowly added to a solution of [(2,3-dichlorophenyl) sulfanyl] acetic acid (12 g) in chlorobenzene (100 mL) at 25 ° C., and the mixture was stirred at 70 ° C. for 2 hours. The 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).
¹ H NMR (400 MHz, DMSO-d ₆ ) Keto-enol mixture δ 4.15 (1H, s), 6.65 (0.5H, s), 7.53-7.73 (2H, m), 10.48 (0.5H, s).
L) 6,7-Dichloro-N-hydroxy-1-benzothiophene-3 (2H) -imine
Add hydroxylamine hydrochloride (18.5 g) and sodium acetate (25.6 g) to a solution of 6,7-dichloro-1-benzothiophene-3 (2H) -one (11.0 g) in methanol (440 mL) at room temperature, Heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted 4 times 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 to give the title compound (11 g).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.26 (2H, s), 7.39 (1H, d, J = 8.3 Hz), 7.52 (1H, d, J = 8.3 Hz), 11.77 (1H, s).
M) (±) -6,7-Dichloro-2,3-dihydro-1-benzothiophen-3-amine
Zinc dust (27.94 g) was added to a solution of 6,7-dichloro-N-hydroxy-1-benzothiophene-3 (2H) -imine (4.0 g) in methanol (1300 mL) at 60 ° C. Subsequently, 6 N hydrochloric acid (127 mL) was slowly added over 30 minutes at the same temperature, and the mixture was further stirred for 30 minutes. The reaction mixture was cooled to room temperature and then filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted 4 times with ethyl acetate. The obtained organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a residue containing the title compound. 6,7-Dichloro-N-hydroxy-1-benzothiophene-3 (2H) -imine (4 × 5 g, 4 g, 2 g) was used to combine the residues obtained by the above method and silica gel column The product was purified by chromatography (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure. The residue was washed with pentane to obtain the title compound (5.1 g).
MS (ESI +): [M + H] + 220.1.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.27 (2H, brs), 3.10-3.16 (1H, m), 3.53-3.58 (1H, m), 4.59 (1H, t, J = 8.3 Hz), 7.24 (1H, d, J = 7.9 Hz) , 7.34 (1H, d, J = 8.0 Hz).
N) (±) -tert-butyl (6,7-dichloro-2,3-dihydro-1-benzothiophen-3-yl) carbamate
Di-tert-butyl dicarbonate (1.02 mL) was added to a solution of (±) -6,7-dichloro-2,3-dihydro-1-benzothiophen-3-amine (0.88 g) in tetrahydrofuran (10 mL) at room temperature. The mixture was further stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.27 g).
¹ H NMR (300 MHz, CDCl _Three ) δ 1.42 (9H, s), 3.26 (1H, dd, J = 11.1, 9.3 Hz), 3.64 (1H, dd, J = 11.2, 8.1 Hz), 5.37 (1H, q, J = 8.5 Hz), 7.07 (1H, d, J = 8.0 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.68 (1H, d, J = 8.2 Hz).
O) (±) -tert-butyl (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) carbamate
To a solution of (±) -tert-butyl (6,7-dichloro-2,3-dihydro-1-benzothiophen-3-yl) carbamate (1.10 g) in ethyl acetate (20 mL) at room temperature, mCPBA (1.86 g ) Was added and stirred at room temperature overnight. To the reaction mixture was added 1 N aqueous sodium hydroxide solution, and the mixture was 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 to give the title compound (1.20 g).
MS (ESI-): [MH] ^- 350.0.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.42 (9H, s), 3.54 (1H, dd, J = 13.5, 7.0 Hz), 4.17 (1H, dd, J = 13.5, 7.9 Hz), 5.24-5.38 (1H, m), 7.49 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 7.9 Hz), 7.98 (1H, d, J = 8.3 Hz).
P) (±) -6,7-Dichloro-2,3-dihydro-1-benzothiophen-3-amine 1,1-dioxide
(±) -tert-butyl (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) carbamate (1.05 g) was stirred at room temperature with trifluoroacetic acid ( 5 mL) and stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate while stirring under ice-cooling, and 8 N aqueous sodium hydroxide solution (8 mL), water and 10% aqueous sodium carbonate solution were added. This 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 to give the title compound (751 mg).
MS (ESI +): [M + H] + 252.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.41 (1H, dd, J = 13.3, 7.1 Hz), 4.01 (1H, dd, J = 13.3, 7.3 Hz), 4.55 (1H, t, J = 7.1 Hz), 7.75 (1H, d, J = 8.4 Hz), 7.98 (1H, d, J = 8.3 Hz).
Q) (±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N ² , N ² -Dimethylglycinamide
(±) -6,7-Dichloro-2,3-dihydro-1-benzothiophen-3-amine 1,1-dioxide (725 mg), N, N-dimethylglycine (445 mg), EDC / HCl (827 mg), 1H-benzotriazol-1-ol (583 mg) and N, N-dimethylformamide (15 mL) were stirred at room temperature overnight. The reaction mixture was diluted with water and 10% aqueous sodium carbonate 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 collected by filtration and washed with ethyl acetate and diisopropyl ether to give the title compound (905 mg).
MS (ESI +): [M + H] + 337.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.22 (6H, s), 2.98 (2H, s), 3.74 (1H, dd, J = 13.4, 7.0 Hz), 4.12 (1H, dd, J = 13.4, 7.8 Hz), 5.61 (1H, q, J = 7.7 Hz), 7.46 (1H, d, J = 8.2 Hz), 7.97 (1H, d, J = 8.3 Hz), 8.64 (1H, d, J = 8.3 Hz).
R) (±) -N '-(6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N, N-dimethylethane-1,2-diamine
(±) -N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N ² , N ² To a solution of -dimethylglycinamide (337 mg) in tetrahydrofuran (10 mL) was added a 1 M borane tetrahydrofuran complex tetrahydrofuran solution (10 mL) at room temperature in an argon atmosphere, and the mixture was stirred at 60 ° C overnight. The reaction mixture was cooled to room temperature, methanol (10 mL) was added, and the mixture was concentrated under reduced pressure. The residue was dissolved in methanol (10 mL), 6 N hydrochloric acid (10 mL) was added, and the mixture was stirred at 60 ° C. for 3 hr. The reaction mixture was made alkaline (pH 9) by adding aqueous ammonia, and then 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 to give the title compound (328 mg).
MS (ESI +): [M + H] + 323.2.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.13 (6H, s), 2.24-2.41 (2H, m), 2.55-2.71 (2H, m), 3.56 (1H, dd, J = 13.5, 5.6 Hz), 4.07 (1H, dd, J = 13.4 , 7.3 Hz), 4.56-4.66 (1H, m), 7.69 (1H, d, J = 8.2 Hz), 7.96 (1H, d, J = 8.3 Hz).
S) (±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N- [2- (dimethylamino) ethyl] -3 -(4-Fluoro-3-methylphenyl) -5- (trifluoromethoxy) imidazo [1,2-a] pyridine-2-carboxamide
3- (4-Fluoro-3-methylphenyl) -5- (trifluoromethoxy) imidazo [1,2-a] pyridine-2-carboxylic acid, and (±) -N ′-(6,7-dichloro- 1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N, N-dimethylethane-1,2-diamine by a method similar to step F of Example 1, The title compound (93 mg) was obtained.
MS (ESI +): [M + H] + 659.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.99-2.13 (6H, m), 2.17-2.72 (6H, m), 3.35-4.23 (3H, m), 4.61-6.05 (1H, m), 6.74 (1H, d, J = 7.4 Hz), 6.96-7.25 (2H, m), 7.27-7.39 (3H, m), 7.48-7.71 (2H, m).
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. for 2 hours. To the reaction mixture was added 2-methylpyridine borane complex (278 mg) at room temperature, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. To the reaction mixture, 2 N hydrochloric acid (10 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added 8 N aqueous sodium hydroxide solution (3 mL) and 10% aqueous sodium carbonate solution (10 mL) at 0 ° C, 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 (NH, ethyl acetate / hexane) to give the title compound (103 mg).
MS (ESI +): [M + H] + 207.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.18 (6H, s), 2.40 (2H, td, J = 6.0, 1.4 Hz), 2.58-2.69 (1H, m), 2.73-2.84 (1H, m), 4.35-4.42 (1H, m), 4.44-4.60 (2H, m), 6.83 (1H, d, J = 8.1 Hz), 6.89 (1H, td, J = 7.5, 0.9 Hz), 7.19 (1H, td, J = 7.7, 1.3 Hz), 7.31 -7.36 (1H, m).
B) (±) -N- (2,3-Dihydro-1-benzofuran-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 (89 mg) and (±) -N '-(2,3-dihydro-1 To a solution of -benzofuran-3-yl) -N, N-dimethylethane-1,2-diamine (130 mg) in tetrahydrofuran (5 mL) and pyridine (1 mL) at room temperature was added HATU (197 mg). Stir for 2 hours at ° C. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified successively by silica gel column chromatography (methanol / ethyl acetate) and (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure. The residue was crystallized from diethyl ether / hexane to give the title compound (96 mg).
MS (ESI +): [M + H] + 489.3.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.69-2.62 (11H, m), 3.01-3.42 (2H, m), 3.74-3.81 (3H, m), 4.24-4.74 (2H, m), 5.56-6.24 (2H, m), 6.73-7.40 (9H, m).
Example 15
(±) -N- (8,9-Dichloro-2,3,4,5-tetrahydro-1-benzooxepin-5-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro -3-Methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
A) (±) -N '-(8,9-Dichloro-2,3,4,5-tetrahydro-1-benzooxepin-5-yl) -N, N-dimethylethane-1,2-diamine
Of 8,9-dichloro-3,4-dihydro-1-benzooxepin-5 (2H) -one (100 mg), N, N-dimethylethane-1,2-diamine (114 mg) and acetic acid (0.2 mL) To a solution of tetrahydrofuran (0.4 mL) and methanol (2 mL) was added 2-methylpyridine borane complex (93 mg) at room temperature, and the mixture was stirred at room temperature for 2 hours and at 60 ° C. for 4 hours. 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. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (109 mg).
MS (ESI +): [M + H] + 303.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.74-2.64 (14H, m), 3.78 (1H, dd, J = 6.8, 2.3 Hz), 3.90 (1H, ddd, J = 11.9, 9.4, 2.4 Hz), 4.18-4.29 (1H, m), 7.04-7.11 (1H, m), 7.11-7.18 (1H, m).
B) (±) -N- (8,9-Dichloro-2,3,4,5-tetrahydro-1-benzooxepin-5-yl) -N- [2- (dimethylamino) ethyl] -3- (4 -Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
Performed with (±) -N ′-(8,9-dichloro-2,3,4,5-tetrahydro-1-benzooxepin-5-yl) -N, N-dimethylethane-1,2-diamine In the same manner as in Step B of Example 14, the title compound (156 mg) was obtained.
MS (ESI +): [M + H] + 585.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.76-2.55 (14H, m), 2.57-3.14 (1H, m), 3.17-4.41 (7H, m), 5.07-5.31 (1H, m), 5.96-6.10 (1H, m), 6.54-6.75 (1H, m), 6.80-7.47 (6H, m).
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 at room temperature overnight. 1 N Hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added 10% aqueous sodium carbonate solution, and the mixture was 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 (147 mg).
MS (ESI +): [M + H] + 327.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.44 (9H, s), 2.65-2.94 (5H, m), 3.18-3.48 (2H, m), 4.32-4.41 (1H, m), 4.41-4.51 (1H, m), 4.51-4.63 (1H , m), 6.79-6.92 (2H, m), 7.21 (1H, d, J = 7.9 Hz).
B) (±) -tert-butyl {2-[(6-chloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5-methoxy Imidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate
Similar to Step B of Example 14, using (±) -tert-butyl {2-[(6-chloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} methylcarbamate By the method, the title compound (232 mg) was obtained.
MS (ESI +): [M + H] + 609.3.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.09-1.44 (9H, m), 2.23-2.79 (6H, m), 2.79-3.50 (4H, m), 3.70-3.82 (3H, m), 4.17-4.77 (2H, m), 5.60-6.34 (2H, m), 6.74-7.13 (4H, m), 7.16-7.38 (4H, m).
C) (±) -N- (6-Chloro-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
(±) -tert-butyl {2-[(6-chloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [ 1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate (227 mg) was dissolved in trifluoroacetic acid (1 mL) with stirring under ice cooling, and stirred at room temperature for 1 hour. . The reaction mixture was diluted with ethyl acetate while stirring under ice-cooling, and 2N aqueous sodium hydroxide solution (6 mL) and 10% aqueous sodium carbonate solution (10 mL) were added. 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 to give the title compound (186 mg).
MS (ESI +): [M + H] + 509.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.01-2.78 (8H, m), 3.06-3.48 (2H, m), 3.78 (3H, s), 4.27-4.80 (2H, m), 5.57-6.27 (2H, m), 6.74-7.14 (4H , m), 7.18-7.38 (4H, m).
Example 16a
(+)-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
(±) -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 (110 mg) was HPLC (CHIRALPAK AD (AK001), 50 mm ID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol = 500/500), and the fraction with a shorter retention time containing the desired product was concentrated under reduced pressure to obtain the title compound (54 mg).
Optical purity:> 99.9% ee, Retention time: 11.06 min (CHIRALPAK AD (KF051), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol / diethylamine = 500/500/1)
Specific rotation: [α] 25. D. +109.4 (c 0.400, CHCl _Three )
Example 16b
(-)-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
(±) -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 (110 mg) was HPLC (CHIRALPAK AD (AK001), 50 mm ID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol = The fraction with a longer retention time containing the desired product was concentrated under reduced pressure to obtain the title compound (51 mg).
Optical purity:> 99.9% ee, Retention time: 19.75 min (CHIRALPAK AD (KF051), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol / diethylamine = 500/500/1)
Specific rotation: [α] 25. D. -106.2 (c 0.407, CHCl _Three )
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.
MS (ESI +): [M + H] + 327.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.44 (9H, s), 2.67-2.90 (5H, m), 3.20-3.45 (2H, m), 4.39-4.49 (1H, m), 4.51-4.71 (2H, m), 6.80-6.90 (1H , m), 7.17-7.24 (2H, m).
B) (±) -tert-butyl {2-[(7-chloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5-methoxy Imidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate
Similar to Step B of Example 14, using (±) -tert-butyl {2-[(7-chloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} methylcarbamate By the method, the title compound (226 mg) was obtained.
MS (ESI +): [M + H] + 609.3.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.06-1.49 (9H, m), 2.24-2.78 (6H, m), 2.82-3.51 (4H, m), 3.71-3.81 (3H, m), 4.19-4.84 (2H, m), 5.74-6.45 (2H, m), 6.76-7.13 (3H, m), 7.14-7.39 (5H, m).
C) (±) -N- (7-Chloro-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
(±) -tert-butyl {2-[(7-chloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [ The title compound (162 mg) was obtained in the same manner as in Step C of Example 16 using 1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate.
MS (ESI +): [M + H] + 509.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.97-2.77 (8H, m), 3.04-3.43 (2H, m), 3.72-3.83 (3H, m), 4.36-4.84 (2H, m), 5.70-6.36 (2H, m), 6.73-7.12 (3H, m), 7.15-7.38 (5H, m).
Example 18
(±) -3- (4-Fluoro-3-methylphenyl) -5-methoxy-N- [2- (methylamino) ethyl] -N- [6- (trifluoromethyl) -2,3-dihydro- 1-Benzofuran-3-yl] imidazo [1,2-a] pyridine-2-carboxamide
A) Methyl 2-hydroxy-4- (trifluoromethyl) benzoate
To a solution of 2-hydroxy-4- (trifluoromethyl) benzoic acid (6.18 g) in methanol (20 mL) was added sulfuric acid (1.3 mL) dropwise at room temperature, and the mixture was refluxed for 2 days. 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).
¹ H NMR (300 MHz, CDCl _Three ) δ 3.99 (3H, s), 7.12 (1H, dd, J = 8.3, 1.3 Hz), 7.25 (1H, s), 7.95 (1H, d, J = 8.3 Hz), 10.88 (1H, s).
B) Methyl 2- (2-ethoxy-2-oxoethoxy) -4- (trifluoromethyl) benzoate
To a solution of methyl 2-hydroxy-4- (trifluoromethyl) benzoate (5.85 g) in acetone (30 mL) was added potassium carbonate (5.51 g) at room temperature. Subsequently, ethyl bromoacetate (4.42 mL) was added dropwise, and the mixture was stirred at 55 ° C. for 2 hours. The reaction mixture was filtered 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 (8.18 g).
MS (ESI +): [M + H] + 307.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.30 (3H, t, J = 7.2 Hz), 3.94 (3H, s), 4.28 (2H, q, J = 7.2 Hz), 4.75 (2H, s), 7.10 (1H, s), 7.28-7.35 (1H, m), 7.91 (1H, d, J = 8.1 Hz).
C) 2- (Carboxymethoxy) -4- (trifluoromethyl) benzoic acid
To a solution of methyl 2- (2-ethoxy-2-oxoethoxy) -4- (trifluoromethyl) benzoate (4.90 g) in methanol (60 mL) was added 2 N aqueous sodium hydroxide solution (32 mL) at room temperature. And stirred at room temperature for 3 days. The reaction mixture was acidified with 6 N hydrochloric acid (12 mL) and concentrated under reduced pressure. The precipitate was collected by filtration and washed with water to give the title compound (3.77 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.93 (2H, s), 7.33 (1H, s), 7.38 (1H, d, J = 8.1 Hz), 7.80 (1H, d, J = 7.9 Hz), 13.18 (2H, brs).
D) 6- (Trifluoromethyl) -1-benzofuran-3-yl acetate
A mixture of 2- (carboxymethoxy) -4- (trifluoromethyl) benzoic acid (3.70 g), acetic anhydride (13.2 mL), acetic acid (1.92 mL) and sodium acetate (1.38 g) was stirred at 120 ° C. overnight. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. Water was added to the residue, and the mixture was 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 (2.20 g).
¹ H NMR (300 MHz, CDCl _Three ) δ 2.40 (3H, s), 7.53 (1H, d, J = 8.1 Hz), 7.67 (1H, d, J = 8.1 Hz), 7.75 (1H, s), 8.16 (1H, s).
E) 6- (Trifluoromethyl) -1-benzofuran-3 (2H) -one
To a solution of 6- (trifluoromethyl) -1-benzofuran-3-yl acetate (2.15 g) in methanol (24 mL) was added 1 N hydrochloric acid (6 mL) at room temperature, and the mixture was refluxed overnight. Methanol was distilled off under reduced pressure. Water was added to the residue, and the mixture was 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 (965 mg).
¹ H NMR (300 MHz, CDCl _Three ) δ 4.72 (2H, s), 7.35 (1H, d, J = 8.1 Hz), 7.43 (1H, s), 7.80 (1H, d, J = 7.9 Hz).
F) (±) -tert-Butyl methyl (2-{[6- (trifluoromethyl) -2,3-dihydro-1-benzofuran-3-yl] amino} ethyl) carbamate
To a solution of 6- (trifluoromethyl) -1-benzofuran-3 (2H) -one (404 mg) and acetic acid (0.8 mL) in ethanol (8 mL) at room temperature, tert-butyl (2-aminoethyl) methylcarba Mart (523 mg) and 2-methylpyridine borane complex (428 mg) were added, and the mixture was stirred at room temperature for 2 days. 1 N Hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added 10% aqueous sodium carbonate solution, and the mixture was 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 (197 mg).
MS (ESI +): [M + H] + 361.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.44 (9H, s), 2.68-2.95 (5H, m), 3.19-3.47 (2H, m), 4.37-4.46 (1H, m), 4.50-4.66 (2H, m), 7.06 (1H, s ), 7.16 (1H, d, J = 7.7 Hz), 7.41 (1H, d, J = 7.6 Hz).
G) (±) -tert-butyl [2-({[3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} [6- (Trifluoromethyl) -2,3-dihydro-1-benzofuran-3-yl] amino) ethyl] methylcarbamate
Step B of Example 14 using (±) -tert-butylmethyl (2-{[6- (trifluoromethyl) -2,3-dihydro-1-benzofuran-3-yl] amino} ethyl) carbamate The title compound (235 mg) was obtained by a method similar to that described above.
MS (ESI +): [M + H] + 643.3.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.09-1.49 (9H, m), 2.27-2.78 (6H, m), 2.82-3.53 (4H, m), 3.71-3.81 (3H, m), 4.22-4.79 (2H, m), 5.77-6.41 (2H, m), 6.98-7.37 (8H, m).
H) (±) -3- (4-Fluoro-3-methylphenyl) -5-methoxy-N- [2- (methylamino) ethyl] -N- [6- (trifluoromethyl) -2,3- Dihydro-1-benzofuran-3-yl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -tert-butyl [2-({[3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} [6- (tri Fluoromethyl) -2,3-dihydro-1-benzofuran-3-yl] amino) ethyl] methylcarbamate was used in the same manner as in Step C of Example 16, to obtain the title compound (169 mg). .
MS (ESI +): [M + H] + 543.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.98-2.80 (8H, m), 3.03-3.55 (2H, m), 3.70-3.84 (3H, m), 4.34-4.82 (2H, m), 5.71-6.30 (2H, m), 6.97-7.40 (8H, m).
Example 18a
(+)-3- (4-Fluoro-3-methylphenyl) -5-methoxy-N- [2- (methylamino) ethyl] -N- [6- (trifluoromethyl) -2,3-dihydro- 1-Benzofuran-3-yl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -3- (4-Fluoro-3-methylphenyl) -5-methoxy-N- [2- (methylamino) ethyl] -N- [6- (trifluoromethyl) -2,3-dihydro- 1-Benzofuran-3-yl] imidazo [1,2-a] pyridine-2-carboxamide (120 mg) was analyzed by HPLC (CHIRALPAK AD (AF003), 50 mm ID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / (Ethanol = 500/500), and the fraction with a shorter retention time containing the desired product was concentrated under reduced pressure to obtain the title compound (80 mg).
Optical purity:> 99.9% ee, Retention time: 11.03 min (CHIRALPAK ADH (DJ153), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500)
Specific rotation: [α] 25. D. +94.4 (c 0.400, CHCl _Three )
Example 18b
(-)-3- (4-Fluoro-3-methylphenyl) -5-methoxy-N- [2- (methylamino) ethyl] -N- [6- (trifluoromethyl) -2,3-dihydro- 1-Benzofuran-3-yl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -3- (4-Fluoro-3-methylphenyl) -5-methoxy-N- [2- (methylamino) ethyl] -N- [6- (trifluoromethyl) -2,3-dihydro- 1-Benzofuran-3-yl] imidazo [1,2-a] pyridine-2-carboxamide (120 mg) was analyzed by HPLC (CHIRALPAK AD (AF003), 50 mm ID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / (Ethanol = 500/500), and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to obtain the title compound (80 mg).
Optical purity:> 99.9% ee, Retention time: 17.90 min (CHIRALPAK ADH (DJ153), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500)
Specific rotation: [α] 25. D. -94.1 (c 0.400, CHCl _Three )
Example 19
(±) -N- (5-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-[(5-chloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} methylcarbamate
The title compound (176 mg) was obtained in the same manner as in Step 16 of Example 16 using 5-chloro-1-benzofuran-3 (2H) -one.
MS (ESI +): [M + H] + 327.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.45 (9H, s), 2.61-2.92 (5H, m), 3.21-3.48 (2H, m), 4.31-4.39 (1H, m), 4.42-4.61 (2H, m), 6.75 (1H, d , J = 8.5 Hz), 7.15 (1H, dd, J = 8.5, 2.3 Hz), 7.27 (1H, d, J = 2.3 Hz).
B) (±) -tert-butyl {2-[(5-chloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5-methoxy Imidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate
(±) -tert-butyl {2-[(5-chloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} methyl carbamate By the method, the title compound (247 mg) was obtained.
MS (ESI +): [M + H] + 609.3.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.07-1.49 (9H, m), 2.24-2.81 (6H, m), 2.81-3.51 (4H, m), 3.69-3.83 (3H, m), 4.21-4.75 (2H, m), 5.63-6.38 (2H, m), 6.65-7.39 (8H, m).
C) (±) -N- (5-Chloro-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
(±) -tert-butyl {2-[(5-chloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [ The title compound (164 mg) was obtained in the same manner as in Step C of Example 16 using 1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate.
MS (ESI +): [M + H] + 509.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.00-2.79 (8H, m), 3.03-3.54 (2H, m), 3.71-3.85 (3H, m), 4.31-4.78 (2H, m), 5.59-6.27 (2H, m), 6.64-7.42 (8H, m).
Example 20
(±) -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
A) 2- [2-Chloro-3- (trifluoromethyl) phenoxy] tetrahydro-2H-pyran
To a solution of 2-chloro-3- (trifluoromethyl) phenol (1.97 g) and 3,4-dihydro-2H-pyran (1.83 mL) in toluene (10 mL) at room temperature, pyridinium 4-methylbenzenesulfonate (251 mg) was added and stirred at room temperature overnight. To the reaction mixture was added 10% aqueous sodium carbonate solution, and the mixture was 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 (2.29 g).
¹ H NMR (300 MHz, CDCl _Three ) δ 1.57-2.20 (6H, m), 3.57-3.69 (1H, m), 3.87 (1H, td, J = 10.9, 3.1 Hz), 5.54 (1H, t, J = 2.7 Hz), 7.23-7.42 ( 3H, m).
B) Methyl 3-chloro-2-hydroxy-4- (trifluoromethyl) benzoate
To a solution of N, N, N ', N'-tetramethylethane-1,2-diamine (0.905 mL) in tetrahydrofuran (4 mL) under nitrogen atmosphere at -15 ° C, 1.6 M butyllithium in hexane (3.75 mL) ) Was added and stirred at the same temperature for 10 minutes. A solution of 2- [2-chloro-3- (trifluoromethyl) phenoxy] tetrahydro-2H-pyran (1.12 g) in tetrahydrofuran (2 mL) was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 1 hour. An excess amount of crushed dry ice was added at the same temperature, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 1 hour. The reaction mixture was acidified with 2N hydrochloric acid, and extracted twice with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate), and a crude product containing 3-chloro-2- (tetrahydro-2H-pyran-2-yloxy) -4- (trifluoromethyl) benzoic acid (1.27 g) was obtained. To a solution of this crude product (1.21 g) in methanol (5 mL), sulfuric acid (0.20 mL) was added dropwise at room temperature, and the mixture was refluxed for 2 hours. Sulfuric acid (0.50 mL) was added and refluxed overnight. 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).
¹ H NMR (300 MHz, CDCl _Three ) δ 4.03 (3H, s), 7.24 (1H, d, J = 8.5 Hz), 7.87 (1H, d, J = 8.5 Hz), 11.52 (1H, s).
C) Methyl 3-chloro-2- (2-ethoxy-2-oxoethoxy) -4- (trifluoromethyl) benzoate
The title compound (5.24 g) was obtained by a method similar to that in Step B of Example 18 using methyl 3-chloro-2-hydroxy-4- (trifluoromethyl) benzoate.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.33 (3H, t, J = 7.2 Hz), 3.93 (3H, s), 4.31 (2H, q, J = 7.2 Hz), 4.72 (2H, s), 7.56 (1H, d, J = 8.3 Hz) ), 7.78 (1H, dd, J = 8.3, 0.8 Hz).
D) 2- (Carboxymethoxy) -3-chloro-4- (trifluoromethyl) benzoic acid
The title compound (4.35 g) was prepared in the same manner as in Step C of Example 18, using methyl 3-chloro-2- (2-ethoxy-2-oxoethoxy) -4- (trifluoromethyl) benzoate. Obtained.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.64 (2H, s), 7.73 (1H, d, J = 8.3 Hz), 7.84 (1H, d, J = 8.1 Hz).
E) 7-Chloro-6- (trifluoromethyl) -1-benzofuran-3-yl acetate
The title compound (3.47 g) was obtained by a method similar to that in Step D of Example 18 using 2- (carboxymethoxy) -3-chloro-4- (trifluoromethyl) benzoic acid.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.40 (3H, s), 7.52-7.58 (1H, m), 7.58-7.64 (1H, m), 8.23 (1H, s).
F) 7-Chloro-6- (trifluoromethyl) -1-benzofuran-3 (2H) -one
The title compound (625 mg) was obtained in the same manner as in Step E of Example 18 using 7-chloro-6- (trifluoromethyl) -1-benzofuran-3-yl acetate.
¹ H NMR (300 MHz, CDCl _Three ) δ 4.83 (2H, s), 7.46 (1H, d, J = 8.1 Hz), 7.68 (1H, dd, J = 7.9, 0.8 Hz).
G) (±) -tert-butyl (2-{[7-chloro-6- (trifluoromethyl) -2,3-dihydro-1-benzofuran-3-yl] amino} ethyl) methylcarbamate
Using 7-chloro-6- (trifluoromethyl) -1-benzofuran-3 (2H) -one (600 mg), the title compound (144 mg) was obtained in the same manner as in Step F of Example 18. It was.
MS (ESI +): [M + H] + 395.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.44 (9H, s), 2.60-2.93 (5H, m), 3.19-3.47 (2H, m), 4.49 (1H, dd, J = 9.3, 3.7 Hz), 4.57-4.67 (1H, m), 4.67-4.76 (1H, m), 7.21-7.32 (2H, m).
H) (±) -tert-butyl (2-{[7-chloro-6- (trifluoromethyl) -2,3-dihydro-1-benzofuran-3-yl] {[3- (4-fluoro-3 -Methylphenyl) -5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino} ethyl) methylcarbamate
Performed with (±) -tert-butyl (2-{[7-chloro-6- (trifluoromethyl) -2,3-dihydro-1-benzofuran-3-yl] amino} ethyl) methylcarbamate In the same manner as in Step B of Example 14, the title compound (209 mg) was obtained.
MS (ESI +): [M + H] + 677.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.11-1.46 (9H, m), 2.27-2.82 (6H, m), 2.84-3.55 (4H, m), 3.73-3.79 (3H, m), 4.33-4.89 (2H, m), 5.90-6.49 (2H, m), 6.95-7.38 (7H, m).
I) (±) -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
(±) -tert-butyl (2-{[7-chloro-6- (trifluoromethyl) -2,3-dihydro-1-benzofuran-3-yl] {[3- (4-fluoro-3-methyl Phenyl) -5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino} ethyl) methylcarbamate was used in the same manner as in Example 16, Step C to give the title compound (153 mg )
MS (ESI +): [M + H] + 577.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.01-2.83 (8H, m), 2.98-3.56 (2H, m), 3.77 (3H, s), 4.46-4.92 (2H, m), 5.84-6.37 (2H, m), 6.94-7.41 (7H , m).
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. Phase: hexane / ethanol = 700/300), and the fraction with the shorter retention time containing the desired product was concentrated under reduced pressure to give the title compound (57 mg).
Optical purity:> 99.9% ee, Retention time: 10.26 min (CHIRALPAK AD-H (MB053), 4.6 mm ID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 700/300)
Specific rotation: [α] 25. D. +115.2 (c 0.205, CHCl _Three )
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. Phase: hexane / ethanol = 700/300), and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to give the title compound (60 mg).
Optical purity:> 99.9% ee, Retention time: 13.37 min (CHIRALPAK AD-H (MB053), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 700/300)
Specific rotation: [α] 25. D. -115.3 (c 0.205, CHCl _Three )
Example 21
(±) -N- (6-Fluoro-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-fluoro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} methylcarbamate
The title compound (28 mg) was obtained in the same manner as in Step F of Example 18 using 6-fluoro-1-benzofuran-3 (2H) -one.
MS (ESI +): [M + H] + 311.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.44 (9H, s), 2.67-2.92 (5H, m), 3.19-3.45 (2H, m), 4.34-4.50 (2H, m), 4.53-4.63 (1H, m), 6.50-6.64 (2H , m), 7.18-7.28 (1H, m).
B) (±) -tert-butyl {2-[(6-fluoro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5-methoxy Imidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate
Similar to step 14 of Example 14 using (±) -tert-butyl {2-[(6-fluoro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} methylcarbamate By the method, the title compound (62 mg) was obtained.
MS (ESI +): [M + H] + 593.3.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.05-1.52 (9H, m), 2.26-2.79 (6H, m), 2.84-3.49 (4H, m), 3.72-3.81 (3H, m), 4.18-4.78 (2H, m), 5.60-6.31 (2H, m), 6.44-6.67 (2H, m), 6.85-7.37 (6H, m).
C) (±) -N- (6-Fluoro-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
(±) -tert-butyl {2-[(6-fluoro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [ The title compound (27 mg) was obtained in the same manner as in Step C of Example 16 using 1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate.
MS (ESI +): [M + H] + 493.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.97-2.79 (8H, m), 3.02-3.56 (2H, m), 3.71-3.82 (3H, m), 4.25-4.80 (2H, m), 5.55-6.23 (2H, m), 6.43-6.67 (2H, m), 6.83-7.37 (6H, m).
Example 22
(±) -N- (1-acetyl-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
A) 6,7-Dichloro-1H-indole
To a solution of 1,2-dichloro-3-nitrobenzene (9.60 g) in tetrahydrofuran (500 mL) was added dropwise 1 M bromo (vinyl) magnesium tetrahydrofuran solution (100 mL) at −45 ° C. under a nitrogen atmosphere. The mixture was stirred at -40 to -40 ° C for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture at the same temperature, and the resulting mixture was warmed to room temperature 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 (6.14 g).
¹ H NMR (300 MHz, CDCl _Three ) δ 6.57 (1H, dd, J = 3.0, 2.3 Hz), 7.18 (1H, d, J = 8.5 Hz), 7.23-7.28 (1H, m), 7.46 (1H, d, J = 8.5 Hz), 8.37 (1H, brs).
B) 6,7-Dichloro-1H-indole-3-carbaldehyde
To N, N-dimethylformamide (20 mL) was added dropwise trichloride phosphate (4.78 mL) at 0 ° C. in a nitrogen atmosphere, and the mixture was stirred at 0 ° C. for 30 min. To the reaction mixture, a solution of 6,7-dichloro-1H-indole (6.13 g) in N, N-dimethylformamide (30 mL) was added at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was added to ice-cold water, made alkaline (pH> 11) using 8 N aqueous sodium hydroxide solution, and stirred at 60 ° C. for 1 hour. The reaction mixture was acidified with 6 N hydrochloric acid (pH After <2), the precipitate was collected by filtration and washed with water and diisopropyl ether to give the title compound (5.73 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.43 (1H, d, J = 8.3 Hz), 8.04 (1H, d, J = 8.5 Hz), 8.43 (1H, s), 9.97 (1H, s), 12.70 (1H, brs).
C) tert-butyl 6,7-dichloro-3-formyl-1H-indole-1-carboxylate
To a mixture of 6,7-dichloro-1H-indole-3-carbaldehyde (3.21 g) and tetrahydrofuran (50 mL) at room temperature, di-tert-butyl dicarbonate (3.83 mL) and N, N-dimethylpyridine-4- Amine (92 mg) was added and stirred at room temperature for 1 hour. To the reaction mixture was added 0.1 N hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with diisopropyl ether to give the title compound (4.03 g).
¹ H NMR (300 MHz, CDCl _Three ) δ 1.69 (9H, s), 7.50 (1H, d, J = 8.5 Hz), 8.14 (1H, s), 8.18 (1H, d, J = 8.5 Hz), 10.06 (1H, s).
D) tert-butyl 6,7-dichloro-3- (formyloxy) -1H-indole-1-carboxylate
To a toluene (150 mL) solution of tert-butyl 6,7-dichloro-3-formyl-1H-indole-1-carboxylate (5.40 g) was added mCPBA (5.08 g) at room temperature, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.78 g).
¹ H NMR (300 MHz, CDCl _Three ) δ 1.65 (9H, s), 7.35-7.45 (2H, m), 7.81 (1H, s), 8.34 (1H, s).
E) tert-Butyl 6,7-dichloro-3-oxoindoline-1-carboxylate
Sodium sulfite (1.39 g) in water (33 mL) at room temperature to a solution of tert-butyl 6,7-dichloro-3- (formyloxy) -1H-indole-1-carboxylate (3.67 g) in tetrahydrofuran (50 mL) ) The solution was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.09 g).
¹ H NMR (300 MHz, CDCl _Three ) δ 1.56 (9H, s), 4.34 (2H, s), 7.36 (1H, d, J = 8.1 Hz), 7.56 (1H, d, J = 8.1 Hz).
F) (±) -tert-Butyl 6,7-dichloro-3-{[2- (dimethylamino) ethyl] amino} indoline-1-carboxylate
To a solution of tert-butyl 6,7-dichloro-3-oxoindoline-1-carboxylate (1.2 g) and acetic acid (4 mL) in tetrahydrofuran (20 mL) and ethanol (20 mL) at room temperature, N, N-dimethylethane 1,2-diamine (700 mg) and 2-methylpyridine borane complex (850 mg) were added, and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added 2 N hydrochloric acid (10 mL) at 0 ° C, and the mixture was stirred at 0 ° C for 1 hr. The reaction mixture was concentrated under reduced pressure to half volume, 2N aqueous sodium hydroxide solution (40 mL) and 10% aqueous sodium carbonate solution (40 mL) were added, and the mixture was 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 (NH, ethyl acetate / hexane) to give the title compound (885 mg).
MS (ESI +): [M + H] + 374.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.53 (9H, s), 2.18 (6H, s), 2.28-2.50 (2H, m), 2.59-2.70 (2H, m), 3.96-4.05 (1H, m), 4.06-4.16 (1H, m ), 4.19-4.25 (1H, m), 7.12-7.18 (1H, m), 7.18-7.23 (1H, m).
G) (±) -tert-butyl 6,7-dichloro-3-{[2- (dimethylamino) ethyl] {[3- (3-fluoro-4-methylphenyl) -5-methoxyimidazo [1,2 -a] pyridin-2-yl] carbonyl} amino} indoline-1-carboxylate
3- (3-Fluoro-4-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (698 mg) and (±) -tert-butyl 6,7-dichloro-3- Add HATU (1.06 g) at room temperature to a solution of {[2- (dimethylamino) ethyl] amino} indoline-1-carboxylate (870 mg) in tetrahydrofuran (20 mL) and pyridine (4 mL) at room temperature overnight. Stir. 3- (3-Fluoro-4-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (140 mg) and HATU (177 mg) were added, and 1 hour at room temperature, 50 ° C For 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified successively by silica gel column chromatography (methanol / ethyl acetate) and (NH, ethyl acetate / hexane) to give the title compound (1.08 g).
MS (ESI +): [M + H] + 656.3.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.47-1.55 (9H, m), 1.74-2.62 (11H, m), 3.06-3.39 (2H, m), 3.80 (3H, s), 3.91-4.31 (2H, m), 5.40-5.86 (1H) , m), 6.00-6.13 (1H, m), 6.74-7.02 (1H, m), 7.07-7.35 (6H, m).
H) (±) -N- (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
(±) -tert-butyl 6,7-dichloro-3-{[2- (dimethylamino) ethyl] {[3- (3-fluoro-4-methylphenyl) -5-methoxyimidazo [1,2-a ] Pyridin-2-yl] carbonyl} amino} indoline-1-carboxylate (1.00 g) dissolved in trifluoroacetic acid (5 mL) with stirring under ice-cooling, 30 minutes at 0 ° C., 30 minutes at room temperature Stir. The 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.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.78-2.65 (11H, m), 3.09-3.99 (7H, m), 3.99-4.23 (1H, m), 5.51-6.25 (2H, m), 6.60-6.88 (2H, m), 7.08-7.34 (5H, m).
I) (±) -N- (1-acetyl-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) and acetic anhydride (1 mL) was stirred at 80 ° C. for 8 hours. 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 (NH, ethyl acetate / hexane, then methanol / ethyl acetate) to give the title compound (55 mg).
MS (ESI +): [M + H] + 598.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.76-2.60 (14H, m), 2.83-3.53 (2H, m), 3.80 (3H, s), 4.01-4.41 (2H, m), 5.51-5.73 (1H, m), 6.08 (1H, t , J = 5.6 Hz), 6.72-7.03 (1H, m), 7.07-7.34 (6H, m).
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. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then methanol / ethyl acetate) to give the title compound (64 mg).
MS (ESI +): [M + H] + 628.3.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.33 (3H, t, J = 7.1 Hz), 1.76-2.56 (11H, m), 2.93-3.44 (2H, m), 3.80 (3H, s), 3.97-4.34 (4H, m), 5.46- 5.84 (1H, m), 6.03-6.11 (1H, m), 6.76-6.99 (1H, m, J = 7.9 Hz), 7.05-7.35 (6H, m).
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. Stir for hours. Isocyanatoethane (0.1 mL) was added, and the mixture was stirred at 60 ° C. overnight. Methanol (2 mL) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (69 mg).
MS (ESI +): [M + H] + 627.3.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.15-1.24 (3H, m), 1.79-2.58 (11H, m), 2.99-3.53 (4H, m), 3.80 (3H, s), 3.96-4.40 (2H, m), 4.72-4.88 (1H , m), 5.48-5.82 (1H, m), 6.01-6.13 (1H, m), 6.73-7.00 (1H, m), 7.05-7.33 (6H, m).
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. did. The reaction mixture was diluted with ethyl acetate, and 8 N aqueous sodium hydroxide solution (4 mL) and 10% aqueous sodium carbonate solution (10 mL) were added. 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 (53 mg).
MS (ESI +): [M + H] + 599.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.79-2.62 (11H, m), 2.94-3.55 (2H, m), 3.80 (3H, s), 4.05-4.42 (2H, m), 4.89 (2H, brs), 5.53-5.81 (1H, m ), 6.02-6.13 (1H, m), 6.75-7.03 (1H, m), 7.06-7.36 (6H, m).
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 the title compound (66 mg).
Optical purity: 99.3% ee, Retention time: 8.61 min (CHIRALCEL OD (OG015), 4.6 mmID × 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: methanol)
Specific rotation: [α] 25. D. -135.7 (c 0.400, CHCl _Three )
Example 26b
(+)-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 longer retention time containing the target compound was concentrated under reduced pressure to obtain the title compound (58 mg).
Optical purity: 99.7% ee, Retention time: 9.51 min (CHIRALCEL OD (OG015), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: methanol)
Specific rotation: [α] 25. D. +144.4 (c 0.200, CHCl _Three )
Example 27
(±) -N- [2- (Dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [6- (trifluoromethyl) -2,3-dihydrofuro [ 2,3-b] pyridin-3-yl] imidazo [1,2-a] pyridine-2-carboxamide
A) Ethyl 2-chloro-6- (trifluoromethyl) nicotinate
To a solution of 2-chloro-6- (trifluoromethyl) nicotinic acid (5 g) in ethanol (20 mL), sulfuric acid (1.18 mL) was added dropwise at room temperature, and the mixture was stirred at 70 ° C. overnight. 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 to give the title compound (5.27 g).
MS (ESI +): [M + H] + 254.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.35 (3H, t, J = 7.1 Hz), 4.40 (2H, q, J = 7.1 Hz), 8.10 (1H, d, J = 7.9 Hz), 8.50-8.58 (1H, m).
B) Ethyl 3-hydroxy-6- (trifluoromethyl) furo [2,3-b] pyridine-2-carboxylate
Ethyl glycolate (3.88 mL) was added to a suspension of sodium hydride (oil, 60%) (1.80 g) in 1,2-dimethoxyethane (40 mL) at 0 ° C., and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added a solution of ethyl 2-chloro-6- (trifluoromethyl) nicotinate (5.20 g) in 1,2-dimethoxyethane (10 mL) at room temperature, and the mixture was stirred at 70 ° C. overnight. The reaction mixture was acidified with acetic acid (3 mL), water was added, and the mixture was 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 collected by filtration and washed with diisopropyl ether to give the title compound (3.58 g).
MS (ESI +): [M + H] + 276.2.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.33 (3H, t, J = 7.1 Hz), 4.35 (2H, q, J = 7.1 Hz), 7.92 (1H, d, J = 8.0 Hz), 8.65 (1H, d, J = 8.1 Hz), 11.65 (1H, brs).
C) 6- (Trifluoromethyl) furo [2,3-b] pyridin-3 (2H) -one
Ethyl 3-hydroxy-6- (trifluoromethyl) furo [2,3-b] pyridine-2-carboxylate (1.45 g), lithium hydroxide monohydrate (1.11 g), DMSO (26 mL) and water (26 mL) was stirred at 80 ° C. for 1 hour. Ice-cold water and 1 N hydrochloric acid (28 mL) were added to the reaction mixture, and the mixture was 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 recrystallized from diisopropyl ether / hexane to give the title compound (710 mg).
MS (ESI-): [MH] -202.4.
¹ H NMR (300 MHz, CDCl _Three ) δ 4.86 (2H, s), 7.53 (1H, d, J = 7.6 Hz), 8.23 (1H, d, J = 7.6 Hz).
D) (±) -N- [2- (Dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [6- (trifluoromethyl) -2,3- Dihydrofuro [2,3-b] pyridin-3-yl] imidazo [1,2-a] pyridine-2-carboxamide
6- (Trifluoromethyl) furo [2,3-b] pyridin-3 (2H) -one (609 mg) and 2-methylpyridine borane complex (481 mg) in tetrahydrofuran (9 mL) and methanol (3 mL) Acetic acid (1.2 mL) and N, N-dimethylethane-1,2-diamine (397 mg) were added to the solution at room temperature, and the mixture was stirred at room temperature overnight. 2 N hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 10% aqueous sodium carbonate solution, and the mixture was 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 (NH, ethyl acetate / hexane), and (±) -N, N-dimethyl-N '-[6- (trifluoromethyl) -2,3-dihydrofuro [2,3- A product (144 mg) containing b] pyridin-3-yl] ethane-1,2-diamine was obtained. Using this product, the title compound (163 mg) was obtained in the same manner as in Step B of Example 14.
MS (ESI +): [M + H] + 558.3.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.71-2.42 (11H, m), 3.00-3.67 (2H, m), 3.78 (3H, s), 4.36-4.93 (2H, m), 5.34-5.91 (1H, m), 6.29-6.46 (1H , m), 7.04-7.94 (7H, m).
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.
MS (ESI +): [M + H] + 305.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.22 (6H, s), 2.95 (2H, s), 3.40 (1H, dd, J = 11.2, 8.5 Hz), 3.64 (1H, dd, J = 11.2, 8.1 Hz), 5.61-5.75 (1H, m), 7.08 (1H, dd, J = 8.1, 1.0 Hz), 7.35 (1H, d, J = 8.1 Hz), 8.45 (1H, d, J = 8.4 Hz).
B) (±) -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
(±) -N- (6,7-Dichloro-2,3-dihydro-1-benzothiophen-3-yl) -N ² , N ² (±) -N ′-(6,7-dichloro-2,3-dihydro-1-benzothiophen-3-yl)-by using the same method as in Step R of Example 13, using -dimethylglycinamide A product (363 mg) containing N, N-dimethylethane-1,2-diamine was obtained. Using this product (363 mg), the title compound (139 mg) was obtained in the same manner as in Step B of Example 14.
MS (ESI +): [M + H] + 573.2.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.81-2.40 (11H, m), 2.95-3.83 (7H, m), 5.68-5.86 (1H, m), 6.33-6.43 (1H, m), 6.75-7.05 (1H, m), 7.10-7.45 (6H, m).
Example 28a
(-)-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
(±) -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 (100 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2 -Propanol = 600/400), and the fraction with a shorter retention time containing the desired product was concentrated under reduced pressure to obtain the title compound (54 mg).
Optical purity:> 99.9% ee, Retention time: 7.07 min (CHIRALCEL OD (DB195), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol = 600/400)
Specific rotation: [α] 25. D. -117.2 (c 0.202, CHCl _Three )
Example 28b
(+)-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
(±) -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 (100 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2 -Propanol = 600/400), and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to give the title compound (56 mg).
Optical purity: 99.8% ee, Retention time: 12.17 min (CHIRALCEL OD (DB195), 4.6 mm ID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol = 600/400)
Specific rotation: [α] 25. D. +101.8 (c 0.207, CHCl _Three )
Example 29
(±) -N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [3- (Pyrrolidin-1-yl) propyl] imidazo [1,2-a] pyridine-2-carboxamide
A) (±) -6,7-Dichloro-N- [3- (pyrrolidin-1-yl) propyl] -2,3-dihydro-1-benzofuran-3-amine
To a solution of 3,4-dichloro-2-hydroxybenzaldehyde (96 mg) in ethanol (3 mL), add 3- (pyrrolidin-1-yl) propan-1-amine (64 mg) at room temperature, and add 1 at 60 ° C. Stir for hours. The reaction mixture was concentrated under reduced pressure to give the imine intermediate. To a solution of trimethylsulfoxonium iodide (220 mg) in DMSO (3 mL) was added sodium hydride (oily, 60%) (40 mg) at room temperature, and the mixture was stirred at room temperature for 30 minutes. A DMSO (3 mL) solution of the imine intermediate synthesized above was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (45 mg).
MS (ESI +): [M + H] + 315.2.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.45-1.73 (6H, m), 2.28-2.64 (8H, m), 4.36-4.45 (1H, m), 4.47-4.56 (1H, m), 4.63-4.72 (1H, m), 7.12 (1H , d, J = 7.9 Hz), 7.29 (1H, d, J = 7.9 Hz).
B) (±) -N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [ 3- (Pyrrolidin-1-yl) propyl] imidazo [1,2-a] pyridine-2-carboxamide
Similar to Step B of Example 14 using (±) -6,7-dichloro-N- [3- (pyrrolidin-1-yl) propyl] -2,3-dihydro-1-benzofuran-3-amine By the method, the title compound (74 mg) was obtained.
MS (ESI +): [M + H] + 597.2.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.94-1.73 (6H, m), 1.89-2.35 (9H, m), 2.82-3.26 (2H, m), 3.79 (3H, s), 4.33-4.93 (2H, m), 5.63-5.93 (1H , m), 6.35-6.43 (1H, m), 7.00-7.44 (7H, m).
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 was stirred overnight at room temperature, and further stirred at 60 ° C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure. The residue was crystallized from ethyl acetate / hexane to give the title compound (153 mg).
MS (ESI +): [M + H] + 605.0.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.95 (6H, s), 2.22-2.45 (5H, m), 3.67-4.26 (7H, m), 5.38-6.01 (1H, m), 6.38 (1H, d, J = 7.4 Hz), 7.10- 7.59 (6H, m), 7.82-8.09 (1H, m).
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: hexane / ethanol = 600/400), and the fraction with the shorter retention time containing the desired product was concentrated under reduced pressure to obtain the title compound (70 mg).
Optical purity:> 99.9% ee, Retention time: 5.50 min (CHIRALCEL OD (OG015), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 600/400)
Specific rotation: [α] 25. D. -100.7 (c 0.205, CHCl _Three )
Example 30b
(+)-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, (Mobile phase: hexane / ethanol = 600/400), and the fraction having the longer retention time containing the target compound was concentrated under reduced pressure to obtain the title compound (66 mg).
Optical purity: 99.9% ee, Retention time: 9.36 min (CHIRALCEL OD (OG015), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 600/400)
Specific rotation: [α] 25. D. +98.1 (c 0.113, CHCl _Three )
Example 31
(±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -5- Methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
A) (±) -tert-butyl {2-[(6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) amino] -2-oxoethyl} methylcarba Mart
The title compound (795 mg) was obtained in the same manner as in Step Q of Example 13 using N- (tert-butoxycarbonyl) -N-methylglycine.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.28-1.48 (9H, m), 2.75-2.90 (3H, m), 3.50-3.65 (1H, m), 3.77-3.89 (2H, m), 4.10-4.25 (1H, m), 5.55-5.68 (1H, m), 7.43-7.55 (1H, m), 7.94-8.07 (1H, m), 8.65-8.80 (1H, m).
B) (±) -tert-butyl {2-[(6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) amino] ethyl} methylcarbamate
(±) -tert-butyl {2-[(6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) amino] -2-oxoethyl} methylcarbamate ( To a solution of 212 mg) in tetrahydrofuran (5 mL) was added a tetrahydrofuran solution (5 mL) of 1 M tetrahydrofuran borane complex at room temperature under an argon atmosphere, and the mixture was stirred at 60 ° C. for 3 hr. The reaction mixture was cooled to room temperature, methanol (5 mL) was carefully added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 10% aqueous sodium carbonate solution was added to the residue, and the mixture was 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 (139 mg).
MS (ESI +): [M + H] + 409.2.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.26-1.49 (9H, m), 2.56-2.74 (3H, m), 2.80 (3H, brs), 3.11-3.38 (2H, m), 3.50 (1H, dd, J = 13.4, 6.0 Hz), 4.11 (1H, dd, J = 13.5, 7.3 Hz), 4.56-4.69 (1H, m), 7.66 (1H, d, J = 8.2 Hz), 7.97 (1H, d, J = 8.3 Hz).
C) (±) -tert-butyl {2-[(6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) {[3- (4-fluoro- 3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate
3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (137 mg) and (±) -tert-butyl {2-[(6,7 -Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) amino] ethyl} methylcarbamate (156 mg) in N, N-dimethylformamide (5 mL) at room temperature Were added HATU (217 mg) and diisopropylethylamine (0.20 mL), and the mixture was stirred at room temperature overnight, at 60 ° C. for 10 hours, and at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (222 mg).
MS (ESI +): [M + H] + 691.2.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.94-1.46 (9H, m), 2.21-2.32 (3H, m), 2.57-2.67 (3H, m), 2.68-4.39 (9H, m), 5.41-6.14 (1H, m), 6.38 (1H , d, J = 7.4 Hz), 7.07-8.10 (7H, m).
D) (±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl)- 5-Methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -tert-butyl {2-[(6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) {[3- (4-fluoro-3- The title compound (119) was prepared in the same manner as in Step C of Example 16, using (methylphenyl) -5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate. mg).
MS (ESI +): [M + H] + 591.2.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.52-2.39 (7H, m), 2.52-2.63 (2H, m), 3.48-3.92 (6H, m), 4.16 (1H, dd, J = 12.9, 8.2 Hz), 5.41-5.99 (1H, m ), 6.38 (1H, d, J = 7.5 Hz), 7.09-7.52 (6H, m), 7.79-8.09 (1H, m).
Example 31a
(-)-N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -5- Methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -5- Methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (93 mg) was analyzed by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, (Mobile phase: hexane / ethanol = 700/300), and the fraction with a shorter retention time containing the desired product was concentrated under reduced pressure to obtain the title compound (43 mg).
Optical purity:> 99.9% ee, Retention time: 15.89 min (CHIRALCEL OD (OG015), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 700/300)
Specific rotation: [α] 25. D. -111.4 (c 0.105, CHCl _Three )
Example 31b
(+)-N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -5- Methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -5- Methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (93 mg) was analyzed by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, (Mobile phase: hexane / ethanol = 700/300), and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to give the title compound (42 mg).
Optical purity:> 99.9% ee, Retention time: 20.91 min (CHIRALCEL OD (OG015), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 700/300)
Specific rotation: [α] 25. D. +104.9 (c 0.111, CHCl _Three )
Example 32
(±) -N- (7,8-Dichloro-1,2,3,4-tetrahydroquinolin-4-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3- Methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
A) 3-[(2,3-Dichlorophenyl) amino] propanenitrile
To a solution of 2,3-dichloroaniline (9.7 g) in acetic acid (30 mL), add acrylonitrile (32 g) and copper (I) iodide (250 mg), and stir at 100 ° C. for 3 hours with a reflux apparatus attached. did. To the reaction mixture was further added copper (I) iodide (1.2 g), and the mixture was further stirred at 100 ° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with 28% aqueous ammonia (150 mL), and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was washed with diethyl ether and hexane, the insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.0 g). .
¹ H NMR (300 MHz, DMSO-d ₆ ) δ2.78 (2H, t, J = 6.6 Hz), 3,41-3.58 (2H, m), 5.99-6.03 (1H, m), 6.74-6.93 (2H, m), 7.04-7.34 (1H, m).
B) N- (2,3-Dichlorophenyl) -β-alanine
To a reaction vessel containing 3-[(2,3-dichlorophenyl) amino] propanenitrile (1.7 g) was added 10% aqueous sodium hydroxide solution (14 mL), and the mixture was stirred at 100 ° C. for 6 hr. The reaction mixture was cooled to room temperature, neutralized with 1 N hydrochloric acid (36 mL), the aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.5 g).
MS (ESI +): [M + H] + 234.0.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.55 (2H, t, J = 6.9 Hz), 3.27-3.45 (2H, m), 5.45-5.86 (1H, m), 6.72 (1H, dd, J = 8.3, 1.3 Hz), 6.80 (1H, dd, J = 7.9, 1.3 Hz), 7.15 (1H, dd, J = 8.3, 7.9 Hz), 12.30 (1H, brs).
C) 7,8-Dichloro-2,3-dihydroquinolin-4 (1H) -one
To a reaction vessel containing N- (2,3-dichlorophenyl) -β-alanine (2.2 g), add phosphorous oxide (V) -methanesulfonic acid mixture (Eaton's reagent) (25 mL), and continue at 70 ° C for 3 hours. Stir. The reaction mixture was added to ice water (100 mL), and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.6 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.55-2.63 (2H, m), 3.54 (2H, td, J = 7.2, 2.5 Hz), 6.83 (1H, d, J = 8.5 Hz), 6.97 (1H, brs), 7.58 (1H, d, J = 8.5 Hz).
D) 7,8-Dichloro-1- (trifluoroacetyl) -2,3-dihydroquinolin-4 (1H) -one
To a solution of 7,8-dichloro-2,3-dihydroquinolin-4 (1H) -one (550 mg) in pyridine (13 mL) was added trifluoroacetic anhydride (0.61 mL) at 0 ° C, and 2 Stir for hours. The reaction mixture was added to ice water (50 mL), and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (0.77 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.71-2.89 (1H, m), 3.08-3.28 (1H, m), 4.07-4.48 (2H, m), 7.77-8.00 (2H, m).
E) (±) -N '-(7,8-Dichloro-1,2,3,4-tetrahydroquinolin-4-yl) -N, N-dimethylethane-1,2-diamine
To a mixed solution (3.3 mL) of 7,8-dichloro-1- (trifluoroacetyl) -2,3-dihydroquinolin-4 (1H) -one (310 mg) in methanol and acetic acid (10: 1) was added N, N-dimethylethane-1,2-diamine (180 mg) and 2-methylpyridine borane complex (320 mg) were added, and the mixture was stirred at room temperature for 24 hours. 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 insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then methanol / ethyl acetate) to give the title compound (160 mg).
MS (ESI +): [M + H] + 288.1
¹ H NMR (300 MHz, DMSO-d ₆ ) δ2.12 (6H, s), 2.28-2.34 (2H, m), 2.54-2.74 (2H, m), 3.19-3.52 (4H, m), 3.63 (1H, t, J = 3.8 Hz), 5.93 -6.09 (1H, m), 6.66 (1H, d, J = 8.1 Hz), 7.00 (1H, d, J = 8.1 Hz).
F) (±) -N- (7,8-Dichloro-1,2,3,4-tetrahydroquinolin-4-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro- 3-Methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N '-(7,8-Dichloro-1,2,3,4-tetrahydroquinolin-4-yl) -N, N-dimethylethane-1,2-diamine (160 mg) in tetrahydrofuran (4 mL) To the solution was added 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (170 mg), HATU (300 mg) and diisopropylethylamine (0.20). mL) was added and stirred at room temperature for 20 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (30 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, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated. The residue was purified by preparative HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% trifluoroacetic acid)), and the obtained fraction was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (50 mg).
MS (ESI +): [M + H] + 570.2.
¹ H NMR (300 MHz, CDCl _Three ) δ1.65-1.81 (1H, m), 1.86-2.45 (12H, m), 2.57-3.70 (4H, m), 3.71-3.85 (3H, m), 4.29-4.70 (1H, m), 4.74- 5.93 (1H, m), 6.04 (1H, s), 6.17-6.46 (1H, m), 6.57 (1H, d, J = 8.5 Hz), 6.90-7.11 (1H, m), 7.16-7.42 (4H, m).
Example 33
(±) -N- (7,8-Dichloro-1,2,3,4-tetrahydroquinolin-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-1,2,3,4-tetrahydroquinolin-4-yl) amino] ethyl} methylcarbamate
To a mixture of 7,8-dichloro-1- (trifluoroacetyl) -2,3-dihydroquinolin-4 (1H) -one (920 mg) in methanol and acetic acid (10: 1) (9.9 mL) was added tert- Butyl (2-aminoethyl) methylcarbamate (0.70 mL) and 2-methylpyridine borane complex (630 mg) were added, and the mixture was stirred at room temperature for 24 hours. 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).
MS (ESI +): [M + H] + 374.3.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.19-1.29 (1H, m), 1.44 (9H, s), 1.73-1.98 (2H, m), 2.74-2.95 (5H, m), 3.25-3.44 (3H, m), 3.44-3.59 (1H , m), 3.71-3.83 (1H, m), 4.58-4.81 (1H, m), 6.67 (1H, d, J = 8.1 Hz), 6.97 (1H, d, J = 8.1 Hz).
B) (±) -tert-butyl {2-[(7,8-dichloro-1,2,3,4-tetrahydroquinolin-4-yl) {[3- (4-fluoro-3-methylphenyl)- 5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate
Tetrahydrofuran of (±) -tert-butyl {2-[(7,8-dichloro-1,2,3,4-tetrahydroquinolin-4-yl) amino] ethyl} methylcarbamate (148 mg) (4 mL) To the solution, add 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (125 mg), HATU (226 mg) and diisopropylethylamine (0.21 mL). And stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (30 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, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (220 mg).
MS (ESI +): [M + H] + 656.3.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.19-1.47 (10H, m), 1.60 (2H, s), 1.68-1.94 (1H, m), 2.04 (1H, s), 2.25-2.41 (4H, m), 2.62-2.97 (1H, m ), 3.08-3.68 (4H, m), 3.70-3.85 (3H, m), 4.47-4.69 (1H, m), 4.89-6.64 (4H, m), 6.89-7.12 (4H, m), 7.12-7.46 (1H, m).
C) (±) -N- (7,8-Dichloro-1,2,3,4-tetrahydroquinolin-4-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2- (Methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -tert-butyl {2-[(7,8-dichloro-1,2,3,4-tetrahydroquinolin-4-yl) {[3- (4-fluoro-3-methylphenyl) -5- Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} methylcarbamate (60 mg) was dissolved in trifluoroacetic acid (1.0 mL) and stirred at room temperature for 2 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (20 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, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then methanol / ethyl acetate) to give the title compound (33 mg).
MS (ESI +): [M + H] + 556.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.64-1.81 (1H, m), 1.88-2.15 (2H, m), 2.27-2.34 (3H, m), 2.35-2.40 (2H, m), 2.44-3.09 (3H, m), 3.13-3.29 (1H, m), 3.30-3.68 (2H, m), 3.70-3.82 (3H, m), 4.46-4.70 (1H, m), 4.87-5.91 (1H, m), 5.93-6.10 (1H, m) , 6.16-6.68 (2H, m), 6.94-7.11 (1H, m), 7.14-7.43 (4H, m).
Example 33a
(+)-N- (7,8-Dichloro-1,2,3,4-tetrahydroquinolin-4-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2 -(Methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -N- (7,8-Dichloro-1,2,3,4-tetrahydroquinolin-4-yl) -3- (4-fluoro-3-methylphenyl) produced by the same method as in Example 33 ) -5-methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (113 mg) by HPLC (CHIRALPAK AD (AK001), 50 mmID × 500 mmL, Daicel) Fractionated by chemical industry, mobile phase: hexane / 2-propanol / diethylamine = 700/300/1), and the fraction having a shorter retention time containing the target product was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then methanol / ethyl acetate) to give the title compound (22 mg).
Optical purity:> 99.9% ee, Retention time: 16.03 min (CHIRALPAK ADH (CG075), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol / diethylamine = 700/300/1)
Specific rotation: [α] 25. D. +86.2 (c 0.313, CHCl _Three )
Example 33b
(-)-N- (7,8-Dichloro-1,2,3,4-tetrahydroquinolin-4-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2 -(Methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -N- (7,8-Dichloro-1,2,3,4-tetrahydroquinolin-4-yl) -3- (4-fluoro-3-methylphenyl) -5- prepared in Example 33a Methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (113 mg) was analyzed by HPLC (CHIRALPAK AD (AK001), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, The fraction was collected with a mobile phase: hexane / 2-propanol / diethylamine = 700/300/1), and the fraction having the longer retention time containing the target product was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then methanol / ethyl acetate) to give the title compound (20 mg).
Optical purity:> 99.9% ee, Retention time: 24.31 min (CHIRALPAK ADH (CG075), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol / diethylamine = 700/300/1)
Specific rotation: [α] 25. D. -101.1 (c 0.333, CHCl _Three )
Example 34a
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-((2S) -Pyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (Diastereomer A)
A) tert-butyl (2S) -2- {2- [methoxy (methyl) amino] -2-oxoethyl} pyrrolidine-1-carboxylate
To a solution of [(2S) -1- (tert-butoxycarbonyl) pyrrolidin-2-yl] acetic acid (1.0 g) in N, N-dimethylformamide (20 mL), N-methoxymethanamine hydrochloride (470 mg), Diisopropylethylamine (1.9 mL), 1H-benzotriazol-1-ol (650 mg) and EDC · HCl (920 mg) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (30 mL), and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with 0.1 N aqueous sodium hydroxide solution and 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 (1.2 g).
MS (ESI +): [M + H] + 273.2.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.39 (9H, s), 1.57-2.01 (4H, m), 2.32-2.48 (1H, m), 2.66-2.88 (1H, m), 3.08 (3H, s), 3.17-3.30 (2H, m ), 3.65 (3H, s), 3.94-4.07 (1H, m).
B) tert-Butyl (2S) -2- (2-oxoethyl) pyrrolidine-1-carboxylate
1 M hydrogenation of tert-butyl (2S) -2- {2- [methoxy (methyl) amino] -2-oxoethyl} pyrrolidine-1-carboxylate (590 mg) in tetrahydrofuran (10 mL) at 0 ° C Diisobutylaluminum / toluene solution (3.0 mL) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with 0.1 N hydrochloric acid (20 mL), and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (230 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.38 (9H, s), 1.51-1.67 (1H, m), 1.72-1.91 (2H, m), 1.94-2.08 (1H, m), 2.52-2.78 (2H, m), 3.23 (2H, t, J = 7.0 Hz), 4.04-4.16 (1H, m), 9.65 (1H, brs).
C) tert-butyl (2S) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} pyrrolidine-1-carboxylate (diastereomers blend)
To a mixed solution (8.0 mL) of tert-butyl (2S) -2- (2-oxoethyl) pyrrolidine-1-carboxylate (300 mg) in methanol / tetrahydrofuran (1: 1), acetic acid (1.0 mL), (±) -6,7-dichloro-2,3-dihydro-1-benzofuran-3-amine hydrochloride (260 mg) and 2-methylpyridine borane complex (170 mg) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 1 N hydrochloric acid (20 mL) and diethyl ether (20 mL), and the organic layer was extracted with 1 N hydrochloric acid (20 mL). The combined aqueous layer was made alkaline with 8 N aqueous sodium hydroxide solution (7.0 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, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (130 mg).
MS (ESI +): [M + H] + 401.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.37-1.69 (11H, m), 1.70-2.02 (5H, m), 2.45-2.80 (2H, m), 3.23-3.50 (2H, m), 3.74-4.03 (1H, m), 4.37-4.81 (3H, m), 6.87-7.08 (1H, m), 7.06-7.25 (1H, m).
D) tert-butyl (2S) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5-Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} pyrrolidine-1-carboxylate (diastereomeric mixture)
tert-Butyl (2S) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} pyrrolidine-1-carboxylate (diastereomeric mixture) Was used to give the title compound (290 mg) in the same manner as in Step B of Example 33.
MS (ESI +): [M + H] + 683.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.00-1.63 (13H, m), 1.65-1.95 (2H, m), 2.32 (3H, s), 2.75-3.64 (5H, m), 3.69-3.84 (3H, m), 4.20-5.04 (2H) m), 5.62-6.41 (2H, m), 6.71-7.13 (3H, m), 7.14-7.37 (4H, m).
E) N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-(( 2S) -Pyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomeric mixture)
tert-butyl (2S) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5 -Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} pyrrolidine-1-carboxylate (diastereomer mixture) (290 mg) was dissolved in trifluoroacetic acid (3.0 mL), Stir at room temperature for 2 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (30 mL), and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a mixture (280 mg) containing the title compound.
MS (ESI +): [M + H] + 583.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.04 (6H, s), 2.21-2.49 (3H, m), 2.69-3.68 (5H, m), 3.72-3.93 (3H, m), 4.20-4.90 (2H, m), 5.63-6.32 (1H) , m), 6.32-6.84 (1H, m), 6.91-7.18 (2H, m), 7.30-7.96 (5H, m), 8.55-11.08 (1H, m).
F) N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-(( 2S) -Pyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (Diastereomer A)
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-((2S) -Pyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomeric mixture) (280 mg) was mixed with SFC (column: CHIRALPAK IC (MB001), 20 mmID × 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide / methanol / diethylamine = 660/340/3), and the fraction with the shorter retention time containing the desired product was concentrated under reduced pressure to give the title compound (97 mg) was obtained.
Optical purity:> 99.9% de, Retention time: 12.35 min (CHIRALPAK IC (LH119), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 500/500/1)
Specific rotation: [α] 25. D. -98.8 (c 0.333, CHCl _Three )
MS (ESI +): [M + H] + 583.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 0.63-1.83 (6H, m), 2.32 (3H, d, J = 1.5 Hz), 2.47-3.02 (3H, m), 3.07-3.29 (2H, m), 3.72-3.83 (3H, m), 4.27-4.90 (2H, m), 5.66-6.39 (2H, m), 6.74-6.92 (1H, m), 6.91-7.12 (2H, m), 7.18-7.37 (4H, m).
Example 34b
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-((2S) -Pyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (Diastereomer B)
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-((2S) -Pyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomeric mixture) (280 mg) was mixed with SFC (column: CHIRALPAK IC (MB001), 20 mmID × 250 Fractionated fractions with mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide / methanol / diethylamine = 660/340/3), and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to give the title compound (100 mg) was obtained.
Optical purity:> 99.9% de, Retention time: 16.65 min (CHIRALPAK IC (LH119), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 500/500/1)
Specific rotation: [α] 25. D. +106.1 (c 0.333, CHCl _Three )
MS (ESI +): [M + H] + 583.2.
¹ H NMR (300 MHz, CDCl _Three ) 0.70-1.39 (3H, m), 1.41-1.82 (3H, m), 2.23-2.39 (3H, m), 2.40-2.96 (3H, m), 2.98-3.43 (2H, m), 3.66-3.86 (3H, m), 4.25-4.89 (2H, m), 6.05 (2H, s), 6.75-7.13 (3H, m), 7.16-7.41 (4H, m).
Example 35a
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-((2S) -1-methylpyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomer A) dihydrochloride
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-((2S) -Pyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomer A) (56 mg) in formic acid (0.50 mL) was mixed with 37% aqueous formaldehyde (0.25 mL). In addition, the mixture was heated to reflux for 4 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then methanol / ethyl acetate). The fraction containing the desired product was concentrated under reduced pressure, the residue was dissolved in diethyl ether (1.0 mL), 4 N hydrogen chloride / ethyl acetate solution (0.10 mL) was added, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the residue was washed with diethyl ether to give the title compound (31 mg).
Specific rotation: [α] 25. D. -137.3 (c 0.433, CHCl _Three )
MS (ESI +): [M + H] + 597.2.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.14-2.18 (8H, m), 2.24-2.33 (3H, m), 2.64-2.78 (3H, m), 2.86-3.15 (3H, m), 3.80 (3H, s), 4.26-4.98 (2H , m), 5.67-5.94 (1H, m), 6.36-6.60 (1H, m), 6.94-7.69 (7H, m), 9.34-10.39 (1H, m).
Example 35b
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-((2S) -1-methylpyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomer B) dihydrochloride
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-((2S) -Pyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (Diastereomer B) was used to give the title compound (44 mg) in the same manner as in Example 35a. .
Specific rotation: [α] 25. D. +83.3 (c 0.387, CHCl _Three )
MS (ESI +): [M + H] + 597.2
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.21-2.05 (6H, m), 2.22-2.35 (3H, m), 2.57-2.72 (3H, m), 2.84-3.22 (3H, m), 3.27-3.52 (2H, m), 3.81 (3H , brs), 4.30-4.95 (2H, m), 5.59-5.93 (1H, m), 6.43-6.65 (1H, m), 6.84-7.76 (7H, m), 9.88-10.65 (1H, m).
Example 36
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (3-fluoro-4-methylphenyl) -5-methoxy-N- [2-((3R) -Morpholin-3-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (mixture of diastereomers)
A) tert-butyl (3R) -3- {2- [methoxy (methyl) amino] -2-oxoethyl} morpholine-4-carboxylate
The title compound (2.2 g) was obtained in the same manner as in Step A of Example 34a using [(3R) -4- (tert-butoxycarbonyl) morpholin-3-yl] acetic acid.
MS (ESI +): [M + H] + 289.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.38 (9H, s), 2.34-2.49 (1H, m), 2.89 (1H, s), 2.98-3.20 (4H, m), 3.32 (1H, s), 3.41-3.49 (1H, m), 3.55-3.70 (5H, m), 3.73-3.83 (1H, m), 4.17-4.30 (1H, m).
B) tert-butyl (3R) -3- (2-oxoethyl) morpholine-4-carboxylate
To a solution of tert-butyl (3R) -3- {2- [methoxy (methyl) amino] -2-oxoethyl} morpholine-4-carboxylate (2.2 g) in tetrahydrofuran (37 mL) at −78 ° C., 1.5 M hydrogen Diisobutylaluminum fluoride / toluene solution (7.5 mL) was added, and the mixture was stirred at the same temperature for 1 hour. Sodium sulfate decahydrate (11 g) was added to the reaction mixture, the temperature was raised to room temperature, and the mixture was further stirred for 18 hours. To the reaction mixture was added anhydrous magnesium sulfate, the insoluble material was filtered off, and the insoluble material was washed with tetrahydrofuran (50 mL). The combined filtrate and washings were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.59 g).
¹ H NMR (300 MHz, CDCl _Three ) δ 1.46 (9H, s), 2.68-2.82 (1H, m), 2.85-2.99 (1H, m), 3.02-3.22 (1H, m), 3.39-3.51 (1H, m), 3.57-3.66 (1H , m), 3.70-3.92 (3H, m), 4.41-4.56 (1H, m), 9.80 (1H, t, J = 2.0 Hz).
C) (±) -6,7-Dichloro-2,3-dihydro-1-benzofuran-3-amine
Commercially available (±) -6,7-dichloro-2,3-dihydro-1-benzofuran-3-amine hydrochloride (750 mg) was suspended in saturated aqueous sodium bicarbonate (30 mL), and ethyl acetate (30 mL) was suspended. ). The 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 (500 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.20 (2H, brs), 4.18 (1H, dd, J = 9.1, 5.7 Hz), 4.55-4.66 (1H, m), 4.69-4.80 (1H, m), 7.12 (1H, d, J = 7.9 Hz), 7.29 (1H, dd, J = 7.9, 0.8 Hz).
D) tert-butyl (3R) -3- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} morpholine-4-carboxylate (diastereomer blend)
To a reaction vessel containing (±) -6,7-dichloro-2,3-dihydro-1-benzofuran-3-amine (500 mg), tert-butyl (3R) -3- (2-oxoethyl) morpholine- A mixed solution (8.0 mL) of 4-carboxylate (720 mg) in methanol / acetic acid (10: 1) and 2-methylpyridine borane complex (500 mg) were added, and the mixture was stirred at room temperature for 16 hours. 1N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was washed with diethyl ether (30 mL), and the washing was extracted twice with 1 N hydrochloric acid (30 mL) again. The combined aqueous layer was made alkaline by adding 8 N aqueous sodium hydroxide solution (15 mL), and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (270 mg).
MS (ESI +): [M + H] + 417.1
¹ H NMR (300 MHz, CDCl _Three ) δ 1.36-1.49 (9H, m), 1.62-1.84 (2H, m), 1.95-2.23 (1H, m), 2.43-2.72 (2H, m), 2.97-3.18 (1H, m), 3.32-3.51 (1H, m), 3.52-3.63 (1H, m), 3.63-3.86 (3H, m), 3.94-4.06 (1H, m), 4.42-4.75 (3H, m), 6.90-7.05 (1H, m) , 7.08-7.20 (1H, m).
E) tert-butyl (3R) -3- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (3-fluoro-4-methylphenyl) -5-Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} morpholine-4-carboxylate (mixture of diastereomers)
tert-butyl (3R) -3- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} morpholine-4-carboxylate (mixture of diastereomers) To a solution of (270 mg) in tetrahydrofuran (3.3 mL) was added 3- (3-fluoro-4-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (260 mg), diisopropylethylamine. (0.23 mL) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (410 mg).
MS (ESI +): [M + H] + 699.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.09-1.49 (9H, m), 1.59 (4H, s), 1.65-2.19 (1H, m), 2.37 (3H, brs), 2.73-3.69 (6H, m), 3.71-3.96 (3H, m ), 4.21-4.98 (2H, m), 5.63-6.54 (2H, m), 6.85-7.34 (7H, m).
F) N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (3-fluoro-4-methylphenyl) -5-methoxy-N- [2-(( 3R) -Morpholin-3-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomeric mixture)
tert-butyl (3R) -3- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (3-fluoro-4-methylphenyl) -5 -Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} morpholine-4-carboxylate (mixture of diastereomers) by a method similar to step C of Example 33, The title compound (270 mg) was obtained.
MS (ESI +): [M + H] + 599.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.01-1.53 (2H, m), 2.28-2.42 (3H, m), 2.46-2.88 (3H, m), 2.90-3.76 (6H, m), 3.81 (3H, s), 4.29-5.02 (2H , m), 5.54-6.51 (2H, m), 6.84-7.36 (7H, m).
Example 37
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (3-fluoro-4-methylphenyl) -5-methoxy-N- [2-((3R) -4-Methylmorpholin-3-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomeric mixture)
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (3-fluoro-4-methylphenyl) -5-methoxy-N- [2-((3R) To a solution of (morpholin-3-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomer mixture) (140 mg) in formic acid (1.0 mL), add 37% aqueous formaldehyde (0.50 mL). The mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution (60 mL) was added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated. The residue was purified by preparative HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% trifluoroacetic acid)), and the fraction containing the desired product was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (78 mg).
MS (ESI +): [M + H] + 613.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 0.64-1.53 (2H, m), 1.70-2.27 (5H, m), 2.37 (3H, s), 2.40-2.62 (1H, m), 2.66-3.75 (6H, m), 3.77-3.86 (3H , m), 4.17-4.92 (2H, m), 6.08 (2H, s), 6.84-7.35 (7H, m).
Example 38
N- (6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (3-fluoro-4-methylphenyl) -N- {2-[(2S) -1- ( 2-Hydroxyethyl) pyrrolidin-2-yl] ethyl} -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (diastereomeric mixture)
A) tert-butyl (2S) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (3-fluoro-4-methylphenyl) -5-Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} pyrrolidine-1-carboxylate (diastereomeric mixture)
tert-Butyl (2S) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} pyrrolidine-1-carboxylate (diastereomeric mixture) Was used in the same manner as in Step E of Example 36 to give the title compound (5.2 g).
MS (ESI +): [M + H] + 683.3.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.91-1.83 (15H, m), 2.32 (3H, s), 2.74-3.20 (4H, m), 3.34-3.62 (1H, m), 3.75-3.88 (3H, m), 4.27-4.98 (2H , m), 5.50-6.13 (1H, m), 6.41 (1H, d, J = 7.6 Hz), 6.94-7.48 (7H, m).
B) N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (3-fluoro-4-methylphenyl) -5-methoxy-N- [2-(( 2S) -Pyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomeric mixture)
tert-butyl (2S) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (3-fluoro-4-methylphenyl) -5 -Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} pyrrolidine-1-carboxylate (a mixture of diastereomers) by a method similar to step E of Example 34a, The title compound (4.5 g) was obtained.
MS (ESI +): [M + H] + 583.3.
¹ H NMR (300 MHz, CDCl _Three ) δ 0.69-1.80 (6H, m), 2.36 (3H, s), 2.43-2.98 (3H, m), 2.99-3.45 (2H, m), 3.81 (3H, s), 4.26-4.94 (2H, m ), 5.66-6.39 (2H, m), 6.82-7.40 (7H, m).
C) Ethyl ((2S) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (3-fluoro-4-methylphenyl)- 5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} pyrrolidin-1-yl) acetate (diastereomeric mixture)
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (3-fluoro-4-methylphenyl) -5-methoxy-N- [2-((2S) -Pyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomer mixture) (410 mg) in methanol / acetic acid (10: 1) mixture (6.9 mL) A% ethyl glyoxylate / toluene solution (300 mg) and 2-methylpyridine borane complex (150 mg) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 1 N hydrochloric acid (20 mL) and stirred at room temperature for 1 hour. The reaction mixture was made alkaline by adding 1 N aqueous sodium hydroxide solution (20 mL) and saturated aqueous sodium hydrogen carbonate solution (20 mL), and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (370 mg).
MS (ESI +): [M + H] + 669.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 0.74-1.39 (5H, m), 1.42-1.78 (2H, m), 1.95-2.17 (1H, m), 2.19-2.30 (1H, m), 2.36 (3H, s), 2.61-3.52 (5H , m), 3.56-3.88 (5H, m), 3.95-4.91 (4H, m), 5.49-6.60 (2H, m), 6.79-7.44 (7H, m).
D) N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (3-fluoro-4-methylphenyl) -N- {2-[(2S) -1 -(2-Hydroxyethyl) pyrrolidin-2-yl] ethyl} -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (mixture of diastereomers)
Ethyl ((2S) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (3-fluoro-4-methylphenyl) -5- To a tetrahydrofuran / methanol mixed solution (3.5 mL) of methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} pyrrolidin-1-yl) acetate (diastereomer mixture) (320 mg) Lithium borohydride (21 mg) was added, and the mixture was stirred at 60 ° C. for 3 hr. The reaction mixture was cooled to room temperature, diluted with 1 N hydrochloric acid (40 mL), and stirred at room temperature for 16 hours. The reaction mixture was made alkaline by adding 8 N aqueous sodium hydroxide solution (6.0 mL), and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then methanol / ethyl acetate) to give the title compound (134 mg).
MS (ESI +): [M + H] + 627.2.
¹ H NMR (300 MHz, CDCl _Three ) 0.70-1.36 (2H, m), 1.38-1.80 (4H, m), 1.80-2.10 (2H, m), 2.13-2.42 (5H, m), 2.60-3.67 (6H, m), 3.81 (3H , s), 4.23-4.97 (2H, m), 5.59-6.51 (2H, m), 6.80-7.08 (2H, m), 7.08-7.38 (5H, m).
Example 39
N- (6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (3-fluoro-4-methylphenyl) -N- {2-[(2S) -1- ( 3-hydroxypropyl) pyrrolidin-2-yl] ethyl} -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (mixture of diastereomers)
A) Methyl 3-((2S) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (3-fluoro-4-methylphenyl ) -5-Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} pyrrolidin-1-yl) propanoate (diastereomeric mixture)
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (3-fluoro-4-methylphenyl) -5-methoxy-N- [2-((2S) -Pyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomer mixture) (410 mg) in tetrahydrofuran (6.0 mL) was added methyl acrylate (0.63 mL) and sodium methoxide. (45 mg) was added and stirred at 60 ° C. for 18 hours. Methanol (10 mL) was added to the reaction mixture to dissolve insoluble matters, and the mixture was further stirred at 60 ° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (330 mg).
MS (ESI +): [M + H] + 669.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 0.64-1.59 (5H, m), 1.62-2.19 (4H, m), 2.21-2.32 (1H, m), 2.33-2.48 (4H, m), 2.53-3.43 (4H, m), 3.58-3.70 (3H, m), 3.74-3.84 (3H, m), 4.22-5.01 (2H, m), 5.60-6.54 (2H, m), 6.80-7.41 (7H, m).
B) N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (3-fluoro-4-methylphenyl) -N- {2-[(2S) -1 -(3-Hydroxypropyl) pyrrolidin-2-yl] ethyl} -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (mixture of diastereomers)
Methyl 3-((2S) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (3-fluoro-4-methylphenyl)- 5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} pyrrolidin-1-yl) propanoate (mixture of diastereomers) using a method similar to step D of Example 38 Gave the title compound (95 mg).
MS (ESI +): [M + H] + 641.3.
¹ H NMR (300 MHz, CDCl _Three ) δ 0.53-1.18 (1H, m), 1.25-1.39 (2H, m), 1.40-1.89 (7H, m), 1.90-2.17 (2H, m), 2.21-2.51 (4H, m), 2.67-3.43 (4H, m), 3.54-4.92 (7H, m), 5.63-6.52 (1H, m), 6.83-7.41 (7H, m).
Example 40
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-((2R) -Pyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomeric mixture)
A) tert-butyl (2R) -2- {2- [methoxy (methyl) amino] -2-oxoethyl} pyrrolidine-1-carboxylate
The title compound (3.8 g) was obtained in the same manner as in Step A of Example 34a using ((2R) -1- (tert-butoxycarbonyl) pyrrolidin-2-yl) acetic acid.
MS (ESI +): [M + H] + 272.8.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ1.30-1.45 (9H, m), 1.55-1.68 (1H, m), 1.72-1.81 (2H, m), 1.91-1.93 (1H, m), 2.40-2.48 (1H, m), 2.76- 2.79 (1H, m), 3.07 (3H, brs), 3.15-3.28 (2H, m), 3.65 (3H, s), 3.98-4.00 (1H, m).
B) tert-butyl (2R) -2- (2-oxoethyl) pyrrolidine-1-carboxylate
In a similar manner to Example 34a, Step B using tert-butyl (2R) -2- {2- [methoxy (methyl) amino] -2-oxoethyl} pyrrolidine-1-carboxylate, the title compound (1.2 g) was obtained.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ1.39 (9H, s), 1.59 (1H, brs), 1.73-1.79 (3H, m), 2.52-2.67 (2H, m), 3.22 (2H, brs), 4.10 (1H, brs), 9.64 (1H, brs).
C) tert-butyl (2R) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} pyrrolidine-1-carboxylate (diastereomers blend)
The title compound (1.8 g) was obtained by a method similar to Step C of Example 34a using tert-butyl (2R) -2- (2-oxoethyl) pyrrolidine-1-carboxylate.
MS (ESI +): [M + H] + 401.2.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.27-1.44 (11H, m), 1.52-1.92 (5H, m), 2.25-2.46 (2H, m), 3.11-3.26 (2H, m), 3.63-3.79 (1H, m), 4.32-4.78 (3H, m), 7.12 (1H, d, J = 7.9 Hz), 7.29 (1H, d, J = 8.0 Hz).
D) tert-butyl (2R) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5-Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} pyrrolidine-1-carboxylate (diastereomeric mixture)
Using tert-butyl (2R) -2- (2-oxoethyl) pyrrolidine-1-carboxylate (diastereomer mixture) in the same manner as in Step B of Example 33, the title compound (570 mg) was obtained. It was.
MS (ESI +): [M + H] + 683.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.99-1.41 (11H, m), 1.47-1.82 (4H, m), 2.27 (3H, s), 2.69-3.28 (4H, m), 3.35-3.57 (1H, m), 3.79 (3H, s ), 4.22-4.97 (2H, m), 5.63-6.03 (1H, m), 6.36-6.43 (1H, m), 6.97-7.45 (7H, m).
E) N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-(( 2R) -Pyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomeric mixture)
tert-butyl (2R) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5 -Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} pyrrolidine-1-carboxylate (a mixture of diastereomers) by a method similar to step E of Example 34a, The title compound (390 mg) was obtained.
MS (ESI +): [M + H] + 583.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 0.70-1.82 (6H, m), 2.31-2.34 (3H, m), 2.45-2.98 (3H, m), 3.05-3.41 (2H, m), 3.75-3.80 (3H, m), 4.28-4.88 (2H, m), 5.70-6.33 (2H, m), 6.79-7.10 (3H, m), 7.15-7.36 (4H, m).
Example 41
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-((2R) -1-Methylpyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (mixture of diastereomers)
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-((2R) -Pyrrolidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomer mixture) was used to give the title compound (57 mg) in the same manner as in Example 35a. .
MS (ESI +): [M + H] + 597.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 0.69-1.52 (5H, m), 1.64-2.07 (4H, m), 2.10-2.16 (2H, m), 2.28-2.36 (3H, m), 2.78-3.48 (3H, m), 3.72-3.82 (3H, m), 4.25-4.88 (2H, m), 5.67-6.39 (2H, m), 6.80-7.10 (3H, m), 7.17-7.35 (4H, m).
Example 42
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [3- (methylamino) Butyl] imidazo [1,2-a] pyridine-2-carboxamide (mixture of diastereomers)
A) (±) -3-[(tert-Butoxycarbonyl) amino] butanoic acid
To a solution of (±) -3-aminobutanoic acid (7.2 g) in tetrahydrofuran (70 mL), add di-tert-butyl dicarbonate (15.3 g) and 1 N aqueous sodium hydroxide solution (70 mL), and stir at room temperature for 16 hours. did. The reaction mixture was concentrated under reduced pressure, and the residue was acidified with 1N hydrochloric acid (80 mL), and extracted with ethyl acetate. The organic layer was extracted twice with 1 N aqueous sodium hydroxide solution (75 mL), and the combined aqueous layer was neutralized with 6 N hydrochloric acid (25 mL). The aqueous layer was extracted with ethyl acetate, and the organic layer was washed 3 times with water, then 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 (12 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.04 (3H, d, J = 6.6 Hz), 1.37 (9H, s), 2.15-2.26 (1H, m), 2.33-2.45 (1H, m), 3.69-3.89 (1H, m), 6.45- 6.96 (1H, m), 11.81-12.34 (1H, m).
B) (±) -3-[(tert-Butoxycarbonyl) (methyl) amino] butanoic acid
To a solution of (±) -3-[(tert-butoxycarbonyl) amino] butanoic acid (5.8 g) in tetrahydrofuran (190 mL) was added sodium hydride (oil, 60%) (3.4 g) at 0 ° C. Stir at warm for 30 minutes. To the reaction mixture was added iodomethane (21 mL) at 0 ° C., and then the mixture was warmed to room temperature and further stirred for 16 hours. The reaction mixture was diluted with water (75 mL), and the organic solvent was distilled off under reduced pressure. The remaining aqueous layer was washed twice with ethyl acetate (75 mL), acidified with 1 N hydrochloric acid (40 mL), and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (4.2 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.08 (3H, d, J = 6.7 Hz), 1.38 (9H, s), 2.29-2.45 (2H, m), 2.64 (3H, s), 4.23-4.50 (1H, m), 12.10 (1H, s).
C) (±) -tert-butyl {4- [methoxy (methyl) amino] -4-oxobutan-2-yl} methylcarbamate
The title compound (3.2 g) was obtained in the same manner as in Step A of Example 34a using (±) -3-[(tert-butoxycarbonyl) (methyl) amino] butanoic acid.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.09 (3H, d, J = 6.7 Hz), 1.38 (9H, s), 2.51-2.58 (2H, m), 2.65 (3H, s), 3.07 (3H, s), 3.66 (3H, s) , 4.26-4.50 (1H, m).
D) (±) -tert-Butyl methyl (4-oxobutan-2-yl) carbamate
(±) -tert-butyl {4- [Methoxy (methyl) amino] -4-oxobutan-2-yl} methylcarbamate was used in the same manner as in Example 36, step B to give the title compound (1.6 g )
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.09 (3H, d, J = 6.8 Hz), 1.38 (9H, s), 2.61-2.65 (3H, m), 3.34-3.42 (2H, m), 4.38-4.80 (1H, m), 9.50- 9.68 (1H, m).
E) tert-butyl {4-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) amino] butan-2-yl} methylcarbamate (diastereomeric mixture)
The title compound (410 mg) was obtained by a method similar to that in Step C of Example 34a using (±) -tert-butylmethyl (4-oxobutan-2-yl) carbamate.
MS (ESI +): [M + H] + 389.2.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.95-1.06 (3H, m), 1.24-1.74 (11H, m), 2.23-2.45 (2H, m), 2.53-2.61 (3H, m), 3.96-4.26 (1H, m), 4.34-4.45 (1H, m), 4.45-4.60 (1H, m), 4.60-4.75 (1H, m), 7.12 (1H, d, J = 7.9 Hz), 7.26 (1H, d, J = 7.9 Hz).
F) tert-butyl {4-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [ 1,2-a] pyridin-2-yl] carbonyl} amino] butan-2-yl} methylcarbamate (mixture of diastereomers)
tert-butyl {4-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) amino] butan-2-yl} methylcarbamate (mixture of diastereomers) In the same manner as in Step B of Example 33, the title compound (470 mg) was obtained.
MS (ESI +): [M + H] + 671.2.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.76-0.99 (3H, m), 1.08-1.76 (11H, m), 2.02-2.46 (7H, m), 2.79-3.51 (2H, m), 3.79 (3H, s), 4.17-5.03 (2H , m), 5.53-6.02 (1H, m), 6.29-6.52 (1H, m), 6.85-7.56 (7H, m).
G) N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [3- (methyl Amino) butyl] imidazo [1,2-a] pyridine-2-carboxamide (mixture of diastereomers)
tert-butyl {4-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1, 2-a] pyridin-2-yl] carbonyl} amino] butan-2-yl} methylcarbamate (mixture of diastereomers) and in a manner similar to Example 33, Step C, the title compound (380 mg )
MS (ESI +): [M + H] + 571.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 0.52-0.93 (3H, m), 1.10-1.81 (2H, m), 1.96-2.46 (7H, m), 3.03-3.33 (2H, m), 3.72-3.84 (3H, m), 4.26-4.88 (2H, m), 5.69-6.37 (2H, m), 6.77-7.08 (3H, m), 7.14-7.39 (4H, m).
Example 42a
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [3- (methylamino) Butyl] imidazo [1,2-a] pyridine-2-carboxamide (Diastereomer A)
N- (7,8-Dichloro-3,4-dihydro-2H-chromen-4-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3) prepared in Example 42 -Methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (diastereomer mixture) (310 mg) by HPLC (CHIRALPAK AD (NF001), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries) , Mobile phase: hexane / 2-propanol / diethylamine = 700/300/1), and the fraction with the first retention time containing the desired product was concentrated under reduced pressure to give the title compound (69 mg) Obtained.
Optical purity:> 99.9% de, Retention time: 9.41 min (CHIRALPAK AD (KF051), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol / diethylamine = 700/300/1)
Specific rotation: [α] 25. D. +137.3 (c 0.200, DMSO)
MS (ESI +): [M + H] + 571.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 0.58-1.00 (3H, m), 1.17-1.52 (2H, m), 2.02-2.50 (7H, m), 3.02-3.43 (2H, m), 3.77 (3H, s), 4.27-4.92 (2H m), 5.69-6.40 (2H, m), 6.84-7.11 (3H, m), 7.17-7.35 (4H, m).
Example 42b
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [3- (methylamino) Butyl] imidazo [1,2-a] pyridine-2-carboxamide (Diastereomer B)
N- (7,8-Dichloro-3,4-dihydro-2H-chromen-4-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3) prepared in Example 42 -Methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (diastereomer mixture) (310 mg) by HPLC (CHIRALPAK AD (NF001), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries) , Mobile phase: hexane / 2-propanol / diethylamine = 700/300/1), and the fraction with the second smallest retention time containing the desired product was concentrated under reduced pressure to give the title compound (70 mg) Obtained.
Optical purity: 99.2% de, Retention time: 10.64 min (CHIRALPAK AD (KF051), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol / diethylamine = 700/300/1)
Specific rotation: [α] 25. D. -150.9 (c 0.200, DMSO)
MS (ESI +): [M + H] + 571.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 0.62-0.94 (3H, m), 1.06-1.49 (2H, m), 2.07-2.53 (7H, m), 3.06-3.41 (2H, m), 3.77 (3H, s), 4.28-4.92 (2H m), 5.69-6.41 (2H, m), 6.79-7.15 (3H, m), 7.18-7.39 (4H, m).
Example 42c
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [3- (methylamino) Butyl] imidazo [1,2-a] pyridine-2-carboxamide (Diastereomer C)
N- (7,8-Dichloro-3,4-dihydro-2H-chromen-4-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3) prepared in Example 42 -Methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (diastereomer mixture) (310 mg) by HPLC (CHIRALPAK AD (NF001), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries) , Mobile phase: hexane / 2-propanol / diethylamine = 700/300/1) Obtained.
Optical purity: 98.4% de, Retention time: 12.71 min (CHIRALPAK AD (KF051), 4.6 mmID × 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol / diethylamine = 700/300/1)
Specific rotation: [α] 25. D. +109.9 (c 0.150, DMSO)
MS (ESI +): [M + H] + 571.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 0.65-1.00 (3H, m), 1.06-1.36 (2H, m), 2.08-2.59 (7H, m), 3.05-3.49 (2H, m), 3.77 (3H, s), 4.30-4.93 (2H , m), 5.71-6.37 (2H, m), 6.79-7.13 (3H, m), 7.19-7.35 (4H, m).
Example 42d
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [3- (methylamino) Butyl] imidazo [1,2-a] pyridine-2-carboxamide (Diastereomer D)
N- (7,8-Dichloro-3,4-dihydro-2H-chromen-4-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3) prepared in Example 42 -Methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (310 mg) (mixed diastereomer) by HPLC (CHIRALPAK AD (NF001), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries) , Mobile phase: hexane / 2-propanol / diethylamine = 700/300/1), and the fraction with the fourth smallest retention time containing the desired product was concentrated under reduced pressure to give the title compound (66 mg) Obtained.
Optical purity:> 99.9% de, Retention time: 17.26 min (CHIRALPAK AD (KF051), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / 2-propanol / diethylamine = 700/300/1)
Specific rotation: [α] 25. D. -138.8 (c 0.200, DMSO)
MS (ESI +): [M + H] + 571.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 0.63-1.03 (3H, m), 1.17-1.39 (2H, m), 2.09-2.58 (7H, m), 3.00-3.56 (2H, m), 3.77 (3H, s), 4.31-4.88 (2H m), 5.75-6.44 (2H, m), 6.88-7.13 (3H, m), 7.18-7.37 (4H, m).
Example 43
N- [2-((2S) -azetidin-2-yl) ethyl] -N- (6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro- 3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (mixture of diastereomers)
A) 1-tert-butyl 2-methyl (2S) -azetidine-1,2-dicarboxylate
To a solution of (2S) -1- (tert-butoxycarbonyl) azetidine-2-carboxylic acid (5.5 g) in methanol (140 mL) at 0 ° C was added 2 M (diazomethyl) trimethylsilane / diethyl ether solution (20 mL). In addition, the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 2 M (diazomethyl) trimethylsilane / diethyl ether solution (20 mL), and the mixture was further stirred at 0 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (5.8 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.34 (9H, s), 1.97-2.14 (1H, m), 2.39-2.57 (1H, m), 3.68 (3H, s), 3.73-3.95 (2H, m), 4.56 (1H, dd, J = 9.2, 5.2 Hz).
B) tert-Butyl (2S) -2- (hydroxymethyl) azetidine-1-carboxylate
To a solution of 1-tert-butyl 2-methyl (2S) -azetidine-1,2-dicarboxylate (5.8 g) in tetrahydrofuran (140 mL) was added lithium borohydride (1.2 g) at 0 ° C, and at room temperature. Stir for 4 hours. The reaction mixture was added to ice-cooled saturated aqueous ammonium chloride solution (100 mL), and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (4.9 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.37 (9H, s), 1.98-2.24 (2H, m), 3.43-3.54 (1H, m), 3.55-3.76 (3H, m), 4.06-4.17 (1H, m), 4.72 (1H, t, J = 5.6 Hz).
C) tert-butyl (2S) -2-{[(methylsulfonyl) oxy] methyl} azetidine-1-carboxylate
Add triethylamine (2.9 mL) and methanesulfonyl chloride (1.2 mL) to a solution of tert-butyl (2S) -2- (hydroxymethyl) azetidine-1-carboxylate (2.6 g) in tetrahydrofuran (34 mL) at 0 ° C. And stirred at room temperature for 2 hours. The reaction mixture was diluted with water (150 mL) and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (3.3 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.38 (9H, s), 2.00-2.13 (1H, m), 2.18-2.34 (1H, m), 3.21 (3H, s), 3.58-3.82 (2H, m), 4.23-4.31 (1H, m ), 4.34-4.46 (2H, m).
D) tert-butyl (2S) -2- (cyanomethyl) azetidine-1-carboxylate
To a solution of tert-butyl (2S) -2-{[((methylsulfonyl) oxy] methyl} azetidine-1-carboxylate (2.6 g) in N, N-dimethylformamide (66 mL) at room temperature, trimethylsilanecarbonitrile ( 1.8 mL) and 1 MN, N, N-tributylbutane-1-aminium fluoride / tetrahydrofuran solution (13 mL) were added, the temperature was raised to 50 ° C., and the mixture was stirred for 18 hours. The reaction mixture was cooled to room temperature, diluted with water (150 mL), and extracted twice with a mixed solvent of ethyl acetate / hexane (1: 1). The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.6 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.39 (9H, s), 1.89-2.08 (1H, m), 2.25-2.43 (1H, m), 2.80-3.02 (2H, m), 3.56-3.86 (2H, m), 4.26-4.42 (1H , m).
E) tert-Butyl (2S) -2- (2-oxoethyl) azetidine-1-carboxylate
To a solution of tert-butyl (2S) -2- (cyanomethyl) azetidine-1-carboxylate (420 mg) in toluene (13 mL) was added 1.5 M diisobutylaluminum hydride / toluene solution (3.0 mL) at -60 ° C. The mixture was stirred at the same temperature for 45 minutes. The reaction mixture was diluted with 2 M aqueous tartaric acid solution (30 mL) and diethyl ether (20 mL), warmed to room temperature, and stirred vigorously for 2 hours. The reaction mixture was extracted twice with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (120 mg).
¹ H NMR (300 MHz, CDCl _Three ) δ 1.43 (9H, s), 1.88-2.03 (1H, m), 2.34-2.49 (1H, m), 2.67-2.84 (1H, m), 2.93-3.09 (1H, m), 3.78-3.95 (2H , m), 4.57-4.73 (1H, m), 9.81 (1H, s).
F) tert-butyl (2R) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} azetidine-1-carboxylate (diastereomers blend)
To a solution of tert-butyl (2S) -2- (2-oxoethyl) azetidine-1-carboxylate (65 mg) in methanol (2 mL) was added (±) -6,7-dichloro-2,3-dihydro-1 -Benzofuran-3-amine hydrochloride (110 mg), 2-methylpyridine borane complex (70 mg) and acetic acid (0.20 mL) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (61 mg).
MS (ESI +): [M + H] + 387.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.38-1.49 (9H, m), 1.70-1.89 (2H, m), 1.90-2.07 (1H, m), 2.22-2.39 (1H, m), 2.53-2.86 (2H, m), 3.75-3.86 (2H, m), 4.21-4.31 (1H, m), 4.47-4.57 (2H, m), 4.63-4.73 (1H, m), 6.95-7.04 (1H, m), 7.09-7.18 (1H, m) .
G) tert-butyl (2R) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5-Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} azetidine-1-carboxylate (mixture of diastereomers)
tert-Butyl (2R) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) amino] ethyl} azetidine-1-carboxylate (diastereomeric mixture) (61 mg) in tetrahydrofuran (1.1 mL) was added to 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (52 mg), HATU ( 90 mg) and diisopropylethylamine (83 μL) were added, and the mixture was stirred at room temperature for 60 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (91 mg).
MS (ESI +): [M + H] + 669.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.13-1.46 (10H, m), 1.66-2.24 (3H, m), 2.33 (3H, s), 2.96-3.37 (2H, m), 3.59-4.08 (6H, m), 4.26-4.91 (2H , m), 5.70-6.37 (2H, m), 6.74-7.13 (3H, m), 7.19-7.37 (4H, m).
H) N- [2-((2S) -azetidin-2-yl) ethyl] -N- (6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4- Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (diastereomeric mixture)
tert-butyl (2R) -2- {2-[(6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) {[3- (4-fluoro-3-methylphenyl) -5 -Methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} azetidine-1-carboxylate (diastereomer mixture) (89 mg) was dissolved in trifluoroacetic acid (1.0 mL), Stir at room temperature for 30 minutes. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (57 mg).
MS (ESI +): [M + H] + 569.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.32-1.59 (2H, m), 1.72-2.18 (2H, m), 2.33 (3H, s), 2.99-3.73 (5H, m), 3.77 (3H, s), 4.30-4.91 (2H, m ), 5.66-6.33 (2H, m), 6.71-7.12 (3H, m), 7.18-7.38 (4H, m).
Example 44
N- (6,7-Dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-((2S) -1-methylazetidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (mixture of diastereomers)
N- [2-((2S) -azetidin-2-yl) ethyl] -N- (6,7-dichloro-2,3-dihydro-1-benzofuran-3-yl) -3- (4-fluoro- 3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (diastereomer mixture) (46 mg) in acetonitrile (2.0 mL) in 37% aqueous formaldehyde (0.36 mL), And sodium triacetoxyborohydride (86 mg) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (21 mg).
MS (ESI +): [M + H] + 583.1.
¹ H NMR (300 MHz, CDCl _Three ) δ1.38-1.89 (4H, m), 1.90-1.99 (1H, m), 2.07-2.18 (2H, m), 2.33 (3H, s), 2.39-3.34 (5H, m), 3.78 (3H, s), 4.26-4.91 (2H, m), 5.66-6.40 (2H, m), 6.76-7.16 (3H, m), 7.20-7.35 (4H, m).
Example 45
N- [2-((2S) -azetidin-2-yl) ethyl] -N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl)- 3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (diastereomeric mixture)
A) tert-butyl (2R) -2- {2-[(6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) amino] ethyl} azetidine-1 -Carboxylate (mixture of diastereomers)
To a solution of tert-butyl (2S) -2- (2-oxoethyl) azetidine-1-carboxylate (540 mg) in methanol (13 mL) was added 6,7-dichloro-2,3-dihydro-1-benzothiophene- 3-Amine 1,1-dioxide (550 mg), sodium triacetoxyborohydride (800 mg) and acetic acid (1.3 mL) were added and the reaction mixture was stirred for 4 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified twice by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (170 mg).
MS (ESI +): [M + H] + 435.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.35-1.47 (9H, m), 1.74-2.07 (4H, m), 2.25-2.42 (1H, m), 2.58-2.87 (2H, m), 3.42-3.58 (1H, m), 3.71-3.90 (3H, m), 4.21-4.37 (1H, m), 4.45-4.67 (1H, m), 7.48-7.61 (1H, m), 7.61-7.73 (1H, m).
B) tert-butyl (2R) -2- {2-[(6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) {[3- (4- Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} azetidine-1-carboxylate (diastereomeric mixture)
tert-butyl (2R) -2- {2-[(6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) amino] ethyl} azetidine-1-carboxy 3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid was added to a solution of Lato (diastereomer mixture) (170 mg) in tetrahydrofuran (4.0 mL). (170 mg), HATU (230 mg) and diisopropylethylamine (0.21 mL) were added, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was further added 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (25 mg), HATU (75 mg) and diisopropylethylamine ( 0.10 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was heated to 50 ° C. and stirred at the same temperature for 16 hours. To the reaction mixture was further added 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (25 mg), and the mixture was stirred at 50 ° C. for 2 hours. . The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (240 mg).
MS (ESI +): [M + H] + 717.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.22-1.38 (9H, m), 1.70-2.26 (4H, m), 2.27-2.36 (3H, m), 2.82-4.02 (10H, m), 5.81-6.18 (2H, m), 6.90-7.33 (6H, m), 7.45-7.67 (1H, m).
C) N- [2-((2S) -azetidin-2-yl) ethyl] -N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl ) -3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (diastereomeric mixture)
tert-butyl (2R) -2- {2-[(6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) {[3- (4-fluoro- 3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino] ethyl} azetidine-1-carboxylate (mixture of diastereomers) (245 mg) in trifluoroacetic acid ( 3.0 mL) and stirred at room temperature for 30 minutes. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (200 mL) and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then methanol / ethyl acetate) to give the title compound (140 mg).
MS (ESI +): [M + H] + 617.0.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.57-2.02 (3H, m), 2.09-2.25 (1H, m), 2.33 (3H, s), 2.52-3.31 (2H, m), 3.34-4.06 (8H, m), 5.59-6.17 (2H , m), 6.80-7.18 (2H, m), 7.19-7.33 (4H, m), 7.42-7.65 (1H, m).
Example 46
N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-((2S) -1-Methylazetidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (mixture of diastereomers)
N- [2-((2S) -azetidin-2-yl) ethyl] -N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl)- To a solution of 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (diastereomer mixture) (130 mg) in acetonitrile (5.6 mL), 37% An aqueous formaldehyde solution (1.0 mL) and sodium triacetoxyborohydride (230 mg) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (50 mL) and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then methanol / ethyl acetate) to give the title compound (120 mg).
MS (ESI +): [M + H] + 631.1.
¹ H NMR (300 MHz, CDCl _Three ) δ1.46-1.97 (4H, m), 2.01-2.23 (3H, m), 2.33 (3H, s), 2.50-3.35 (4H, m), 3.39-3.57 (2H, m), 3.63-3.96 ( 4H, m), 5.89-6.14 (2H, m), 6.90-7.33 (6H, m), 7.46-7.66 (1H, m).
Example 46a
N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-((2S) -1-Methylazetidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (Diastereomer A)
N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl)-prepared in Example 46 5-methoxy-N- [2-((2S) -1-methylazetidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomer mixture) (110 mg) Fractionation with HPLC (CHIRALPAK IC (ME001), 50 mmID x 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 300/700/1) Concentration under reduced pressure gave the title compound (39 mg).
Optical purity:> 99.9% de, Retention time: 16.42 min (CHIRALPAK IC (LG009), 4.6 mmID × 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 300/700/1)
Specific rotation: [α] 25. D. -115.1 (c 0.205, DMSO)
MS (ESI +): [M + H] + 631.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.45-1.98 (4H, m), 2.02-2.21 (3H, m), 2.34 (3H, s), 2.58-3.10 (3H, m), 3.16-3.36 (2H, m), 3.42-3.92 (5H , m), 5.91-6.16 (2H, m), 6.98-7.37 (6H, m), 7.51-7.69 (1H, m).
Example 46b
N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -5-methoxy-N- [2-((2S) -1-Methylazetidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (Diastereomer B)
N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl)-prepared in Example 46 5-methoxy-N- [2-((2S) -1-methylazetidin-2-yl) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (diastereomer mixture) (110 mg) Fractionation with HPLC (CHIRALPAK IC (ME001), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 300/700/1) Concentration under reduced pressure gave the title compound (59 mg).
Optical purity: 99.3% de, Retention time: 21.81 min (CHIRALPAK IC (LG009), 4.6 mm ID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 300/700/1)
Specific rotation: [α] 25. D. +75.4 (c 0.200, DMSO)
MS (ESI +): [M + H] + 631.1.
¹ H NMR (300 MHz, CDCl _Three ) δ1.46-1.97 (4H, m), 2.01-2.23 (3H, m), 2.33 (3H, s), 2.50-3.35 (4H, m), 3.39-3.57 (2H, m), 3.63-3.96 ( 4H, m), 5.89-6.14 (2H, m), 6.90-7.33 (6H, m), 7.46-7.66 (1H, m).
Example 47
(±) -N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N- [4- (dimethylamino) butyl] -3- ( 4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
A) (±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -4- (dimethylamino) butanamide
To a solution of (±) -6,7-dichloro-2,3-dihydro-1-benzothiophen-3-amine 1,1-dioxide (180 mg) in N, N-dimethylformamide (5.0 mL), add 4- ( Dimethylamino) butanoic acid hydrochloride (180 mg), 1H-benzotriazol-1-ol (150 mg), EDC (0.19 mL), and triethylamine (0.20 mL) were added, and the mixture was stirred at room temperature for 21 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then methanol / ethyl acetate) to give the title compound (230 mg).
MS (ESI +): [M + H] + 365.0.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.74 (2H, dd, J = 10.5, 5.6 Hz), 2.03 (6H, s), 2.27-2.45 (4H, m), 3.42 (1H, dd, J = 14.0, 2.9 Hz), 3.89 (1H, dd, J = 14.0, 7.8 Hz), 5.76 (1H, td, J = 7.8, 3.1 Hz), 7.42 (1H, d, J = 8.2 Hz), 7.69 (1H, d, J = 8.2 Hz), 9.45- 9.57 (1H, m).
B) (±) -N '-(6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N, N-dimethylbutane-1,4-diamine
(±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -4- (dimethylamino) butanamide (230 mg) in tetrahydrofuran (7.2 To the solution, 1.0 M borane / tetrahydrofuran solution (6.2 mL) was added at room temperature, and the mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with methanol (10 mL), and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (10 mL) and 6 N hydrochloric acid (10 mL) and stirred at 60 ° C. for 3 hours. The reaction mixture was cooled to 0 ° C., made alkaline by adding 28% aqueous ammonia (20 mL), and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (210 mg).
MS (ESI +): [M + H] + 351.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.49-1.58 (4H, m), 2.22 (6H, s), 2.24-2.32 (2H, m), 2.61-2.73 (2H, m), 3.44 (1H, dd, J = 13.5, 5.0 Hz), 3.81 (1H, dd, J = 13.4 7.3 Hz), 4.55 (1H, dd, J = 7.0, 5.1 Hz), 7.50 (1H, d, J = 8.2 Hz), 7.67 (1H, d, J = 8.2 Hz) .
C) (±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N- [4- (dimethylamino) butyl] -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, N-dimethylbutane-1,4-diamine (110 mg) in tetrahydrofuran (2.0 mL) was added 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (120 mg), HATU (190 mg ) And diisopropylethylamine (0.16 mL) were added, and the mixture was stirred at 50 ° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium hydrogen carbonate solution (30 mL), and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then methanol / ethyl acetate) to give the title compound (98 mg).
MS (ESI +): [M + H] + 633.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.11-1.47 (4H, m), 1.87-2.26 (8H, m), 2.34 (3H, s), 2.76-2.94 (1H, m), 3.08-3.60 (3H, m), 3.78 (3H, s ), 5.85-6.14 (2H, m), 6.89-7.20 (2H, m), 7.28 (4H, s), 7.49-7.69 (1H, m).
Example 48
(±) -N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N- [3- (dimethylamino) propyl] -3- ( 4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
A) (±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N ^Three , N ^Three -Dimethyl-β-alaninamide
To a solution of (±) -6,7-dichloro-2,3-dihydro-1-benzothiophen-3-amine 1,1-dioxide (370 mg) in N, N-dimethylformamide (7.5 mL), add N, N -Dimethyl-β-alanine (260 mg) 1H-benzotriazol-1-ol (300 mg), EDC (0.39 mL) and triethylamine (0.41 mL) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (50 mL) and extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then methanol / ethyl acetate) to give the title compound (400 mg).
MS (ESI +): [M + H] + 351.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ2.13 (6H, s), 2.25-2.33 (2H, m), 2.40-2.49 (2H, m), 3.54 (1H, dd, J = 13.7, 6.0 Hz), 4.15 (1H, dd, J = 13.7, 7.9 Hz), 5.52-5.62 (1H, m), 7.54 (1H, d, J = 8.3 Hz), 7.99 (1H, d, J = 8.3 Hz), 8.76 (1H, d, J = 7.8 Hz) .
B) (±) -N '-(6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N, N-dimethylpropane-1,3-diamine
(±) -N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N ^Three , N ^Three To a solution of -dimethyl-β-alaninamide (390 mg) in tetrahydrofuran (14 mL) was added 1.0 M borane / tetrahydrofuran solution (11 mL), and the mixture was stirred at 60 ° C. for 3 hr. The reaction mixture was cooled to room temperature, diluted with methanol (10 mL), and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (10 mL) and 6 N hydrochloric acid (10 mL) and stirred at 60 ° C. for 2.5 hours. The reaction mixture was cooled to room temperature, made alkaline by adding 28% aqueous ammonia (10 mL), and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (390 mg).
MS (ESI +): [M + H] + 337.2.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.48-1.61 (2H, m), 2.04-2.18 (6H, m), 2.25 (2H, t, J = 7.1 Hz), 2.52-2.60 (2H, m), 2.62-2.84 (1H, m) , 3.50 (1H, dd, J = 13.5, 5.9 Hz), 4.04-4.15 (1H, m), 4.49-4.65 (1H, m), 7.69 (1H, d, J = 8.3 Hz), 7.96 (1H, d , J = 8.2 Hz).
C) (±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N- [3- (dimethylamino) propyl] -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, N-dimethylpropane-1,3-diamine (160 mg) in tetrahydrofuran (4 mL) was added 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (190 mg), HATU (280 mg ) And diisopropylethylamine (0.24 mL) were added, and the mixture was stirred at 50 ° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium hydrogen carbonate solution (40 mL), and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then methanol / ethyl acetate) to give the title compound (150 mg).
MS (ESI +): [M + H] + 619.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.51-2.24 (10H, m), 2.34 (3H, s), 2.75-3.58 (3H, m), 3.70-3.96 (4H, m), 5.82-6.15 (2H, m), 6.92-7.16 (2H , m), 7.19-7.37 (4H, m), 7.51-7.67 (1H, m).
Example 48a
(-)-N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N- [3- (dimethylamino) propyl] -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- [3- (dimethylamino) prepared in Example 48 Propyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (100 mg) was added to SFC (column: CHIRALPAK IA (MB001), 20 mmID × 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide / methanol / diethylamine = 660/340/1), and the fraction containing the target product with the shorter retention time was concentrated under reduced pressure. Compound (30 mg) was obtained.
Optical purity:> 99.9% ee, Retention time: 3.65 min (CHIRALPAK IA (LG021), 4.6 mmID x 150 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 660/340/1)
Specific rotation: [α] 25. D. -103.0 (c 0.240, CHCl _Three )
MS (ESI +): [M + H] + 619.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.54-1.81 (2H, m), 1.93-2.18 (8H, m), 2.32 (3H, brs), 2.73-3.59 (3H, m), 3.67-3.98 (4H, m), 5.77-6.12 (2H m), 6.88-7.14 (2H, m), 7.18-7.38 (4H, m), 7.45-7.69 (1H, m).
Example 48b
(+)-N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N- [3- (dimethylamino) propyl] -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- [3- (dimethylamino) prepared in Example 48 Propyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (100 mg) was added to SFC (column: CHIRALPAK IA (MB001), 20 mmID × 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide / methanol / diethylamine = 660/340/1), and the fraction containing the target product with the longer retention time was concentrated under reduced pressure. Compound (36 mg) was obtained.
Optical purity:> 99.9% ee, Retention time: 6.01 min (CHIRALPAK IA (LG021), 4.6 mmID × 150 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 660/340/1)
Specific rotation: [α] 25. D. +103.9 (c 0.230, CHCl _Three )
MS (ESI +): [M + H] + 619.1.
¹ H NMR (300 MHz, CDCl _Three ) δ1.48-1.80 (2H, m), 1.91-2.19 (8H, m), 2.32 (3H, brs), 2.73-3.56 (3H, m), 3.67-3.96 (4H, m), 5.75-6.16 ( 2H, m), 6.89-7.15 (2H, m), 7.18-7.34 (4H, m), 7.46-7.65 (1H, m).
Example 49
(±) -N- (1-acetyl-7,8-dichloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl) -3- (4-fluoro-3-methylphenyl) ) -5-Methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
A) Methyl 2-amino-4,5-dichlorobenzoate
To a solution of 2-amino-4,5-dichlorobenzoic acid (18.0 g) in methanol (300 mL), sulfuric acid (50.0 mL) was added dropwise at room temperature and refluxed overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was neutralized with 2N aqueous sodium hydroxide solution (pH 7). The resulting mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (17.8 g).
¹ H NMR (400 MHz, CDCl _Three ) δ 3.87 (3H, s), 5.77 (2H, br s), 6.79 (1H, s), 7.92 (1H, s).
B) Methyl 4,5-dichloro-2-{[(4-methylphenyl) sulfonyl] amino} benzoate
(4-Methylphenyl) sulfonyl chloride (21.7 g) was added to a solution of methyl 2-amino-4,5-dichlorobenzoate (20.0 g) in pyridine (500 mL), and the mixture was stirred at 50 ° C. overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water and then neutralized with 2 N hydrochloric acid (pH 7). The resulting mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (20.0 g).
¹ H NMR (400 MHz, CDCl _Three ) δ 2.39 (3H, s), 3.90 (3H, s), 7.27 (2H, d, J = 8.0 Hz), 7.75 (2H, d, J = 8.0 Hz), 7.87 (1H, s), 7.99 (1H , s), 10.57 (1H, s).
C) Methyl 4,5-dichloro-2-{(4-ethoxy-4-oxobutyl) [(4-methylphenyl) sulfonyl] amino} benzoate
To a solution of methyl 4,5-dichloro-2-{[(4-methylphenyl) sulfonyl] amino} benzoate (26.0 g) in 2-butanone (400 mL), add cesium carbonate (45 g), and then add ethyl 4 -Bromobutyrate (16.2 g) was added dropwise at room temperature and the mixture was stirred at 80 ° C. for 72 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (30.0 g).
¹ H NMR (400 MHz, CDCl _Three ) δ 1.15-1.30 (3H, m), 1.82-1.89 (2H, m), 2.39-2.46 (5H, m), 3.49 (1H, br s), 3.73 (1H, br s), 3.89 (3H, s ), 4.08-4.15 (2H, m), 6.99 (1H, s), 7.27 (2H, d, J = 8.0 Hz), 7.46 (2H, d, J = 8.0 Hz), 7.98 (1H, s).
D) Ethyl 7,8-dichloro-1-[(4-methylphenyl) sulfonyl] -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate and methyl 7,7 Mixture of 8-dichloro-1-[(4-methylphenyl) sulfonyl] -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate
Potassium tert-butoxide (15.3 g) was dissolved in toluene (136 mL), and methyl 4,5-dichloro-2-{(4-ethoxy-4-oxobutyl) [(4-methylphenyl) sulfonyl] at 70 ° C. A solution of amino} benzoate (30 g) in toluene (450 mL) was added dropwise. The reaction mixture was cooled to room temperature and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were concentrated under reduced pressure to obtain a mixture (28 g) containing the title compound. A small sample was purified by silica gel column chromatography and ethyl 7,8-dichloro-1-[(4-methylphenyl) sulfonyl] -5-oxo-2,3,4,5-tetrahydro-1H-1-benzo Azepine-4-carboxylate and methyl 7,8-dichloro-1-[(4-methylphenyl) sulfonyl] -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxy Isolate Lat, ¹ Confirmed using 1 H NMR.

Ethyl 7,8-dichloro-1-[(4-methylphenyl) sulfonyl] -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate:
¹ H NMR (400 MHz, CDCl _Three ) δ 1.31 (3H, t, J = 7.2 Hz), 2.30 (2H, t, J = 6.8 Hz), 2.40 (3H, s), 4.07 (2H, t, J = 6.8 Hz), 4.17 (2H, q , J = 7.2 Hz), 7.18 (2H, d, J = 8.4 Hz), 7.39 (2H, d, J = 8.4 Hz), 7.60 (1H, s), 7.70 (1H, s), 11.94 (1H, s ).
Methyl 7,8-dichloro-1-[(4-methylphenyl) sulfonyl] -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate:
¹ H NMR (400 MHz, CDCl _Three ) δ 2.30 (2H, t, J = 6.4 Hz), 2.41 (3H, s), 3.73 (3H, s), 4.07 (2H, t, J = 6.4 Hz), 7.18 (2H, d, J = 8.0 Hz) ), 7.39 (2H, d, J = 8.0 Hz), 7.60 (1H, s), 7.69 (1H, s), 11.84 (1H, s).
E) 7,8-Dichloro-1-[(4-methylphenyl) sulfonyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-5-one
Ethyl 7,8-dichloro-1-[(4-methylphenyl) sulfonyl] -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate and methyl 7,8- A mixture of dichloro-1-[(4-methylphenyl) sulfonyl] -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate (28.0 g) of acetic acid (150 To the solution, hydrochloric acid (44 mL) was added, and the mixture was stirred at 80 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was neutralized with 2N aqueous sodium hydroxide solution (pH 7). The mixture was extracted with ethyl acetate and dried over anhydrous sodium 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 (petroleum ether / ethyl acetate) to obtain the title compound (23.0 g).
¹ H NMR (400 MHz, CDCl _Three ) δ 1.97-2.02 (2H, m), 2.38-2.43 (2H, m), 2.45 (3H, s), 3.84 (2H, t, J = 6.4 Hz), 7.31 (2H, d, J = 8.4 Hz) , 7.61-7.64 (3H, m), 7.80 (1H, s).
F) 7,8-Dichloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one
7,8-Dichloro-1-[(4-methylphenyl) sulfonyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-5-one (23.0 g) in polyphosphoric acid (50 mL) Suspended and the mixture was stirred at 80 ° C. overnight. The reaction mixture was cooled to room temperature and neutralized with 2N aqueous sodium hydroxide (pH 7). The resulting mixture was diluted with water and ethyl acetate, and the organic layer was dried over anhydrous sodium 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 (petroleum ether / ethyl acetate) to obtain the title compound (12.0 g).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.06-2.11 (2H, m), 2.66 (2H, t, J = 7.6 Hz), 3.08-3.13 (2H, m), 7.16 (1H, s), 7.19 (1H, s), 7.54 (1H, s).
G) 1-acetyl-7,8-dichloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one
To a solution of 7,8-dichloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one (8.0 g) in acetic acid (50 mL) was added acetic anhydride (150 mL), and the mixture was Stir at 85 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was neutralized with 2N aqueous sodium hydroxide solution (pH 7). The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium 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 (petroleum ether / ethyl acetate) to obtain the title compound (5.0 g).
¹ H NMR (400 MHz, CDCl _Three ) δ 1.84 (1H, br s), 2.09 (3H, s), 2.12-3.17 (4H, m), 4.78 (1H, br s), 7.37 (1H, s), 7.98 (1H, s).
H) (±) -tert-butyl {2-[(1-acetyl-7,8-dichloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl) amino] ethyl} methyl Carbamate
1-acetyl-7,8-dichloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one (777 mg) and tert-butyl (2-aminoethyl) methylcarbamate (545 mg) ) Was added titanium (IV) isopropoxide (1.03 g), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethanol (10 mL), sodium borohydride (330 mg) was added, and the mixture was further stirred at room temperature for 2 hr. 1N Aqueous sodium hydroxide solution (2 mL) was added to the reaction mixture, the insoluble material was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium 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 (petroleum ether / ethyl acetate) to give the title compound (750 mg).
¹ H NMR (400 MHz, CDCl _Three ) δ 1.44 (4H, s), 1.48 (5H, s), 1.61 (2H, br s), 1.86-1.92 (3H, m), 1.95-2.28 (2H, m), 2.53-2.76 (3H, m) , 2.82-2.91 (3H, m), 3.19-3.43 (2H, m), 3.67-3.85 (1H, m), 4.45-4.66 (1H, m), 7.24-7.25 (1H, m), 7.34-7.68 ( 1H, m).
I) (±) -N- (1-acetyl-7,8-dichloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl) -3- (4-fluoro-3- Methylphenyl) -5-methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
To a solution of 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (142 mg) in pyridine (2 mL), (±) -tert-butyl {2-[(1-Acetyl-7,8-dichloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl) amino] ethyl} methylcarbamate (200 mg) and HATU ( 269 mg) was added, and the mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was cooled to room temperature, suspended in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure. The obtained residue was suspended in trifluoroacetic acid (2 mL) at 4 ° C. and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The 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, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (35 mg).
MS (ESI +): [M + H] + 612.2.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.60-1.40 (4H, m), 1.50-2.50 (14H, m), 2.75-3.00 (1H, m), 3.74 (3H, m), 3.95-4.30 (1H, m), 4.35-5.05 (1H , m), 6.37 (1H, br s), 6.75-7.80 (7H, m).
Example 50a
(-)-N- (6,7-Dichloro-1,1-dioxide-2,3-dihydrothieno [3,2-c] pyridin-3-yl) -N- [2- (dimethylamino) ethyl]- 3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
A) 5,6-Dichloro-4- (methylsulfanyl) nicotinic acid
To a solution of 2,2,6,6-tetramethylpiperidine (2650 mg) in tetrahydrofuran (10 mL), slowly add a 1.6 M n-butyllithium / hexane solution (11 mL) at −50 ° C. under a nitrogen atmosphere. The mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, a solution of 5,6-dichloronicotinic acid (1500 mg) in tetrahydrofuran (6 mL) was slowly added at the same temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, a solution of dimethyl disulfide (2.5 mL) in tetrahydrofuran (2 mL) was slowly added at the same temperature under a nitrogen atmosphere, the temperature was raised to −10 ° C., and the mixture was stirred for 100 minutes. To the reaction mixture, 2N hydrochloric acid was added under ice cooling to adjust the pH of the mixture to 2. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and the obtained organic layer was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (1210 mg).
MS (ESI +): [M + H] + 238.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.55 (3H, s), 8.50 (1H, s), 14.06 (1H, brs).
B) Methyl 5,6-dichloro-4- (methylsulfanyl) nicotinate
To a solution of 5,6-dichloro-4- (methylsulfanyl) nicotinic acid (490 mg) in tetrahydrofuran (6 mL) and methanol (3 mL), add 2 M (diazomethyl) trimethylsilane / hexane solution (3 mL), Stir at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and the obtained organic layer was 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), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (410 mg).
MS (ESI +): [M + H] + 252.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.51 (3H, s), 3.97 (3H, s), 8.45 (1H, s).
C) [5,6-Dichloro-4- (methylsulfanyl) pyridin-3-yl] methanol
To a solution of methyl 5,6-dichloro-4- (methylsulfanyl) nicotinate (260 mg) in ethanol (10 mL) and tetrahydrofuran (5 mL) was added calcium chloride (230 mg), and then sodium borohydride (160 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes, and further stirred at 40 ° C. for 30 minutes. 2 N hydrochloric acid was added to the reaction mixture at 0 ° C. to adjust the pH of the mixture from 1 to 2. The resulting aqueous suspension was made alkaline (pH 8) by adding saturated aqueous sodium hydrogen carbonate solution, and then the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, and then anhydrous sulfuric acid Dried over sodium. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (230 mg).
MS (ESI +): [M + H] + 224.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.52 (3H, s), 4.87 (2H, d, J = 5.8 Hz), 8.34 (1H, s).
D) [5,6-Dichloro-4- (methylsulfonyl) pyridin-3-yl] methanol
To a solution of [5,6-dichloro-4- (methylsulfanyl) pyridin-3-yl] methanol (590 mg) in methanol (20 mL) and acetic acid (10 mL), sodium tungstate dihydrate (260 mg) And then 35% aqueous hydrogen peroxide (10 mL) was added. The reaction mixture was stirred at room temperature for 20 minutes, and further stirred at 65 ° C. for 2.5 hours. Methanol and acetic acid were distilled off under reduced pressure, and the residue was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the obtained organic layer was washed successively with saturated aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (610 mg).
MS (ESI +): [M + H] + 256.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 3.13 (1H, t, J = 7.4 Hz), 3.40 (3H, s), 5.01 (2H, d, J = 7.4 Hz), 8.56 (1H, s).
E) 5,6-Dichloro-4- (methylsulfonyl) nicotinaldehyde
Manganese dioxide (2430 mg) was added to a solution of [5,6-dichloro-4- (methylsulfonyl) pyridin-3-yl] methanol (610 mg) in tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 15.5 hours. To the reaction mixture, manganese dioxide (1220 mg) was further added and stirred at room temperature for 24 hours. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with a mixed solvent of ethyl acetate and hexane to obtain the title compound (230 mg).
¹ H NMR (300 MHz, CDCl _Three ) δ 3.45 (3H, s), 8.68 (1H, s), 10.68 (1H, s).
F) (±) -N '-(6,7-Dichloro-1,1-dioxide-2,3-dihydrothieno [3,2-c] pyridin-3-yl) -N, N-dimethylethane-1, 2-diamine
Acetic acid (48 μL) and N, N-dimethylethane-1,2-diamine (55 μL) were added to a solution of 5,6-dichloro-4- (methylsulfonyl) nicotinaldehyde (110 mg) in tetrahydrofuran (2.5 mL). In addition, the reaction mixture was stirred at room temperature for 40 minutes. After the reaction mixture was diluted with tetrahydrofuran (2.5 mL), a suspension of potassium tert-butoxide (200 mg) in tetrahydrofuran (2.5 mL) was added to the mixture at 0 ° C., and the mixture was stirred at the same temperature for 20 min. The reaction mixture was suspended in water, the obtained aqueous suspension was extracted with ethyl acetate, and 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 (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (40 mg).
MS (ESI +): [M + H] + 324.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.21 (6H, s), 2.39-2.51 (2H, m), 2.69-2.82 (2H, m), 3.44-3.52 (1H, m), 3.82-3.91 (1H, m), 4.68-4.77 (1H , m), 8.66 (1H, s).
G) (±) -N- (6,7-dichloro-1,1-dioxide-2,3-dihydrothieno [3,2-c] pyridin-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-dihydrothieno [3,2-c] pyridin-3-yl) -N, N-dimethylethane-1,2- The title compound (53 mg) was obtained in the same manner as in Step F of Example 1 using diamine.
MS (ESI +): [M + H] + 606.2.
H) (-)-N- (6,7-Dichloro-1,1-dioxide-2,3-dihydrothieno [3,2-c] pyridin-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-dihydrothieno [3,2-c] pyridin-3-yl) -N- [2- (dimethylamino) ethyl]- 3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (53 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL, Daicel Chemical Fractions were collected by Kogyo Kogyo Co., Ltd., mobile phase: methanol), and fractions with a shorter retention time containing the desired product were concentrated under reduced pressure to obtain the title compound (27 mg).
MS (ESI +): [M + H] + 606.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.03-2.11 (6H, m), 2.29-2.85 (5H, m), 3.53-3.98 (6H, m), 4.16-4.80 (1H, m), 5.36-6.39 (2H, m), 7.00-7.25 (3H, m), 7.27-7.31 (2H, m), 8.20-8.43 (1H, m).
Optical purity:> 99.9% ee, Retention time: 8.96 min (CHIRALCEL OD (DB195), 4.6 mmID × 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: methanol)
Specific rotation: [α] 25. D. -62.9 (c 0.158, CHCl _Three )
Example 50b
(+)-N- (6,7-Dichloro-1,1-dioxide-2,3-dihydrothieno [3,2-c] pyridin-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-dihydrothieno [3,2-c] pyridin-3-yl) -N- [2- (dimethylamino) ethyl]- 3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (53 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL, Daicel Chemical The fraction with a longer retention time containing the target compound was concentrated under reduced pressure to obtain the title compound (25 mg).
MS (ESI +): [M + H] + 606.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.04-2.09 (6H, m), 2.29-2.84 (5H, m), 3.53-3.88 (6H, m), 4.15-4.78 (1H, m), 5.39-6.38 (2H, m), 6.99-7.24 (3H, m), 7.27-7.32 (2H, m), 8.19-8.40 (1H, m).
Optical purity: 99.5% ee, Retention time: 15.82 min (CHIRALCEL OD (DB195), 4.6 mmID × 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: methanol)
Specific rotation: [α] 25. D. +65.1 (c 0.161, CHCl _Three )
Example 51
(±) -N- [3- (Dimethylamino) propyl] -N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-3- Yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
A) Methyl 3-fluoro-2- (methylsulfanyl) -4- (trifluoromethyl) benzoate
To a solution of 2,2,6,6-tetramethylpiperidine (4070 mg) in tetrahydrofuran (15 mL), slowly add a 1.6 M n-butyllithium / hexane solution (16.6 mL) at −40 ° C. under a nitrogen atmosphere. The mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, a solution of 3-fluoro-4- (trifluoromethyl) benzoic acid (2500 mg) in tetrahydrofuran (9 mL) was slowly added at the same temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, a solution of dimethyl disulfide (4.2 mL) in tetrahydrofuran (3 mL) was slowly added at the same temperature under a nitrogen atmosphere, the temperature was raised to 0 ° C., and the mixture was stirred for 85 minutes. To the reaction mixture, 2N hydrochloric acid was added under ice cooling to adjust the pH of the mixture to 2. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and the obtained organic layer was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with ethyl acetate. The obtained residue was dissolved in tetrahydrofuran (40 mL) and methanol (20 mL), 2 M (diazomethyl) trimethylsilane / hexane solution (12 mL) was added to the mixture, and the mixture was stirred at room temperature for 40 min. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and the obtained organic layer was 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), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (2830 mg).
MS (ESI +): [M + H] + 269.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.52 (3H, d, J = 2.1 Hz), 3.96 (3H, s), 7.47-7.59 (2H, m).
B) [3-Fluoro-2- (methylsulfanyl) -4- (trifluoromethyl) phenyl] methanol
To a solution of methyl 3-fluoro-2- (methylsulfanyl) -4- (trifluoromethyl) benzoate (2830 mg) in ethanol (60 mL) and tetrahydrofuran (30 mL) was added calcium chloride (2360 mg), then Sodium borohydride (1600 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes, and further stirred at 45 ° C. for 30 minutes. 2N hydrochloric acid was added to the reaction mixture at 0 ° C. to adjust the pH of the mixture from 2 to 3. The mixture was extracted with ethyl acetate, and the obtained organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (1750 mg).
¹ H NMR (300 MHz, CDCl _Three ) δ 2.28 (1H, t, J = 6.2 Hz), 2.47 (3H, d, J = 0.8 Hz), 4.89 (2H, d, J = 5.8 Hz), 7.38 (1H, d, J = 8.0 Hz), 7.51-7.59 (1H, m).
C) [3-Fluoro-2- (methylsulfonyl) -4- (trifluoromethyl) phenyl] methanol
To a solution of [3-fluoro-2- (methylsulfanyl) -4- (trifluoromethyl) phenyl] methanol (2490 mg) in methanol (80 mL) and acetic acid (40 mL), sodium tungstate dihydrate (1030 mg) was added, followed by 35% aqueous hydrogen peroxide (39 mL). The reaction mixture was stirred at room temperature for 30 minutes, and further stirred at 60 ° C. for 1.5 hours. Methanol and acetic acid were distilled off under reduced pressure, and the residue was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the obtained organic layer was washed successively with saturated aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with hexane to give the title compound (2820 mg).
¹ H NMR (300 MHz, CDCl _Three ) δ 3.09 (1H, brs), 3.36 (3H, d, J = 1.9 Hz), 5.06 (2H, d, J = 3.9 Hz), 7.54-7.59 (1H, m), 7.86 (1H, t, J = (7.6 Hz).
D) 3-Fluoro-2- (methylsulfonyl) -4- (trifluoromethyl) benzaldehyde
To a solution of [3-fluoro-2- (methylsulfonyl) -4- (trifluoromethyl) phenyl] methanol (2820 mg) in acetonitrile (50 mL) was added manganese dioxide (5300 mg), and the mixture was stirred at room temperature for 3 hours. . To the reaction mixture, manganese dioxide (5300 mg) was further added and stirred at room temperature for 14 hours. To the reaction mixture was further added manganese dioxide (1570 mg), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture, manganese dioxide (1060 mg) was further added and stirred at room temperature for 4 hours. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with a mixed solvent of ethyl acetate and hexane to give the title compound (1600 mg).
¹ H NMR (300 MHz, CDCl _Three ) δ 3.43 (3H, d, J = 1.6 Hz), 7.77 (1H, d, J = 8.1 Hz), 7.97-8.05 (1H, m), 10.83 (1H, s).
E) (±) -N '-[7-Fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N, N-dimethylpropane 1,3-diamine
To a solution of 3-fluoro-2- (methylsulfonyl) -4- (trifluoromethyl) benzaldehyde (300 mg) in tetrahydrofuran (5 mL), acetic acid (126 μL) and N, N-dimethylpropane-1,3-diamine (152 μL) was added and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with tetrahydrofuran (5 mL), 1.11 M lithium diisopropylamide / hexane and tetrahydrofuran mixed solution (4.0 mL) was slowly added to the mixture at 0 ° C., and the mixture was stirred at the same temperature for 30 min under nitrogen atmosphere. 2N Hydrochloric acid (30 mL) was added to the mixture, and the mixture was washed successively with ethyl acetate (30 mL) and hexane (30 mL). The obtained aqueous layer was made alkaline (pH 8) by adding 2 N aqueous sodium hydroxide solution (30 mL) and saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate. The obtained organic layer was washed with saturated brine. After washing, it was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (140 mg).
MS (ESI +): [M + H] + 355.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.71 (2H, t, J = 6.6 Hz), 2.26 (6H, s), 2.42 (2H, t, J = 6.7 Hz), 2.75 (2H, t, J = 6.4 Hz), 3.48 (1H, dd , J = 13.3, 5.5 Hz), 3.84 (1H, dd, J = 13.4, 7.1 Hz), 4.68 (1H, t, J = 6.3 Hz), 7.57 (1H, d, J = 8.0 Hz), 7.86 (1H , t, J = 7.2 Hz).
F) (±) -N- [3- (Dimethylamino) propyl] -N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene- 3-yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
To a solution of 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (145 mg) in N, N-dimethylformamide (4 mL) at room temperature , (±) -N ′-[7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N, N-dimethylpropane- 1,3-diamine (143 mg), HATU (230 mg) and diisopropylethylamine (156 mg) were added and the mixture was stirred at 50 ° C. for 6 hours. The mixture was suspended in ethyl acetate (20 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate, and the obtained organic layer was washed successively with water and 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 (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (150 mg).
MS (ESI +): [M + H] + 637.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.66-1.80 (2H, m), 2.02-2.13 (8H, m), 2.27-2.35 (3H, m), 2.67-2.85 (1H, m), 3.51-4.12 (6H, m), 5.99-6.13 (2H, m), 6.90-7.25 (5H, m), 7.27-7.31 (1H, m), 7.59-7.82 (1H, m).
Example 51a
(-)-N- [3- (Dimethylamino) propyl] -N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-3- Yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [3- (Dimethylamino) propyl] -N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1 prepared in Example 51 -Benzothiophen-3-yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (150 mg) by HPLC (CHIRALCEL OD (CA002) , 50 mmID x 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 800/200/1), and the fraction containing the target product with the shorter retention time is concentrated under reduced pressure. The title compound (65 mg) was obtained.
Optical purity: 99.0% ee, Retention time: 8.60 min (CHIRALCEL OD (CG017), 4.6 mm ID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 800/200/1)
Specific rotation: [α] 25. D. -86.5 (c 0.220, CHCl _Three )
Example 51b
(+)-N- [3- (Dimethylamino) propyl] -N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-3- Yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [3- (Dimethylamino) propyl] -N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1 prepared in Example 51 -Benzothiophen-3-yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (150 mg) by HPLC (CHIRALCEL OD (CA002) , 50 mmID x 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 800/200/1), and the fraction containing the target product with the longer retention time was concentrated under reduced pressure. To give the title compound (68 mg).
Optical purity: 97.2% ee, Retention time: 11.78 min (CHIRALCEL OD (CG017), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 800/200/1)
Specific rotation: [α] 25. D. +81.9 (c 0.201, CHCl _Three )
Example 52
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -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) 2-Fluoro-3-formyl-6- (trifluoromethyl) benzonitrile
To a solution of 2,2,6,6-tetramethylpiperidine (980 mg) in tetrahydrofuran (6.5 mL), slowly add a 1.6 M n-butyllithium / hexane solution (4.0 mL) at −50 ° C. under a nitrogen atmosphere. The mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, a solution of 2-fluoro-6- (trifluoromethyl) benzonitrile (1005 mg) in tetrahydrofuran (3 mL) was slowly added at −60 ° C. under a nitrogen atmosphere, and the mixture was stirred at −50 ° C. for 30 minutes. To the reaction mixture was slowly added a solution of N, N-dimethylformamide (1170 mg) in tetrahydrofuran (1 mL) at the same temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 15 minutes. Stir for 20 minutes. Acetic acid (1 mL) and water were sequentially added to the reaction mixture at the same temperature, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then over anhydrous sodium sulfate. And dried. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1130 mg).
¹ H NMR (300 MHz, CDCl _Three ) δ 7.77 (1H, d, J = 8.1 Hz), 8.25 (1H, t, J = 7.4 Hz), 10.42 (1H, s).
B) 3-Formyl-2- (methylsulfonyl) -6- (trifluoromethyl) benzonitrile
Sodium methanesulfinate (630 mg) was added to a solution of 2-fluoro-3-formyl-6- (trifluoromethyl) benzonitrile (1090 mg) in DMSO (13 mL), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was suspended in ethyl acetate (30 mL), and washed with water (30 mL). The aqueous layer was extracted with ethyl acetate, and the obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with a mixed solvent of ethyl acetate and hexane to obtain the title compound (890 mg).
¹ H NMR (300 MHz, CDCl _Three ) δ 3.51 (3H, s), 8.12-8.17 (1H, m), 8.19-8.23 (1H, m), 10.73 (1H, s).
C) (±) -3-{[2- (Dimethylamino) ethyl] amino} -6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-7-carbonitrile 1,1-dioxide
Add N, N-dimethylethane-1,2-diamine (290 μL) to a solution of 3-formyl-2- (methylsulfonyl) -6- (trifluoromethyl) benzonitrile (570 mg) in tetrahydrofuran (25 mL). In addition, the reaction mixture was stirred at room temperature for 2 hours. To the mixture was slowly added 1.11 M lithium diisopropylamide / hexane and tetrahydrofuran mixed solution (3720 μL) at 0 ° C., and the mixture was stirred at the same temperature for 50 minutes under a nitrogen atmosphere. The reaction mixture was suspended in ethyl acetate (30 mL), and washed with water (30 mL). The aqueous layer was extracted with ethyl acetate, and 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 (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (116 mg).
MS (ESI +): [M + H] + 348.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.19-2.24 (6H, m), 2.36-2.55 (2H, m), 2.65-2.80 (2H, m), 3.49 (1H, dd, J = 13.4, 5.9 Hz), 3.93 (1H, dd, J = 13.5, 7.2 Hz), 4.70-4.81 (1H, m), 7.99-8.05 (1H, m), 8.06-8.12 (1H, m).
D) (±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (dimethyl Amino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
To a solution of 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (120 mg) in N, N-dimethylformamide (4 mL) at room temperature , (±) -3-{[2- (dimethylamino) ethyl] amino} -6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-7-carbonitrile 1,1-dioxide (116 mg), HATU (190 mg) and diisopropylethylamine (130 mg) were added and the mixture was stirred at 50 ° C. for 6 hours. The mixture was suspended in ethyl acetate (20 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate, and the obtained organic layer was washed successively with water and 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 (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure. The obtained solid was washed with a mixed solvent of ethyl acetate and hexane to obtain the title compound (140 mg).
MS (ESI +): [M + H] + 630.3.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.07 (6H, s), 2.23-2.35 (3H, m), 2.37-2.64 (2H, m), 3.55-3.92 (6H, m), 4.18-4.81 (1H, m), 5.33-6.30 (2H , m), 6.90-7.24 (3H, m), 7.28 (2H, d, J = 4.2 Hz), 7.51-8.02 (2H, m).
Example 52a
(-)-N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -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- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [prepared in Example 52 2- (Dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (132 mg) was converted to SFC (CHIRALCEL ODH (KC003) , 20 mmID × 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide / 2-propanol / acetonitrile = 800/100/100). Concentration afforded the title compound (63 mg).
Optical purity:> 99.9% ee, Retention time: 1.71 min (CHIRALCEL ODH (LD029), 4.6 mmID x 150 mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide / 2-propanol / acetonitrile = 800/100/100)
Specific rotation: [α] 25. D. -76.9 (c 0.208, CHCl _Three )
Example 52b
(+)-N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -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- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [prepared in Example 52 2- (Dimethylamino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (132 mg) was converted to SFC (CHIRALCEL ODH (KC003) , 20 mmID × 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide / 2-propanol / acetonitrile = 800/100/100). Concentration afforded the title compound (61 mg).
Optical purity: 99.8% ee, Retention time: 3.15 min (CHIRALCEL ODH (LD029), 4.6 mmID x 150 mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide / 2-propanol / acetonitrile = 800/100/100)
Specific rotation: [α] 25. D. +74.3 (c 0.231, CHCl _Three )
Example 53
(±) -N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -N- [3- (3-Hydroxyazetidin-1-yl) propyl] -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
A) 6,7-Dichloro-2,3-dihydro-1-benzothiophen-3-ol
To a solution of 6,7-dichloro-1-benzothiophene-3 (2H) -one (700 mg) in methanol (35 mL) was added sodium borohydride (245 mg) at 4 ° C, and the mixture was stirred at room temperature for 4 hours. Stir for hours. The reaction mixture was concentrated under reduced pressure, 2 N hydrochloric acid (20 mL) was added to the resulting residue, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed twice with saturated brine and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (695 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.22 (1H, dd, J = 11.7, 5.9 Hz), 3.64 (1H, dd, J = 11.7, 7.0 Hz), 5.39 (1H, q, J = 6.2 Hz), 5.95 (1H, d, J = 5.9 Hz), 7.19-7.30 (1H, m), 7.31-7.41 (1H, m).
B) 6,7-Dichloro-1-benzothiophene
To a solution of 6,7-dichloro-2,3-dihydro-1-benzothiophen-3-ol (695 mg) in acetic acid (8 mL) at 4 ° C, boron trifluoride diethyl ether complex (2 mL) was added, The mixture was stirred at room temperature for 15 minutes and then stirred at 120 ° C. for an additional 15 minutes. The reaction mixture was cooled to room temperature, and 2N aqueous sodium hydroxide solution (about 20 mL) was added to adjust to pH 8. The obtained mixture was extracted twice with ethyl acetate, and the combined organic layer was washed twice 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 (526 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.58 (1H, d, J = 5.5 Hz), 7.64 (1H, d, J = 8.5 Hz), 7.79-8.09 (2H, m).
C) 6,7-Dichloro-1-benzothiophene 1,1-dioxide
MCPBA (70%, 243 mg) was added to a solution of 6,7-dichloro-1-benzothiophene (80 mg) in ethyl acetate (3 mL), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and 1 N aqueous sodium hydroxide solution (10 mL), and the separated 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 (76 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.53 (1H, d, J = 6.8 Hz), 7.59 (1H, d, J = 7.9 Hz), 7.67 (1H, d, J = 6.9 Hz), 7.98 (1H, d, J = 8.0 Hz).
D) (±) -1- {3-[(6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) amino] propyl} azetidin-3-ol
To a solution of 6,7-dichloro-1-benzothiophene 1,1-dioxide (100 mg) in 2-propanol (4 mL), add 1- (3-aminopropyl) azetidin-3-ol (111 mg), The mixture was stirred at 70 ° C. for 24 hours. Furthermore, 1- (3-aminopropyl) azetidin-3-ol (55 mg) was added, and the mixture was stirred at 70 ° C. for 3 days. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (48.6 mg).
MS (ESI +): [M + H] + 365.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.50-1.58 (2H, m), 2.52 (2H, t, J = 6.7 Hz), 2.68 (2H, t, J = 6.5 Hz), 2.84 (2H, br s), 3.46 (1H, dd, J = 13.5, 4.9 Hz), 3.61 (2H, t, J = 6.7 Hz), 3.80 (1H, dd, J = 13.7, 7.1 Hz), 4.34-4.47 (1H, m), 4.51 (1H, t, J = 5.9 Hz), 7.49 (1H, d, J = 8.2 Hz), 7.68 (1H, d, J = 8.3 Hz).
E) (±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl)- N- [3- (3-Hydroxyazetidin-1-yl) propyl] -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
To a solution of 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (44 mg) in tetrahydrofuran (2 mL), pyridine (0.5 mL), ( ±) -1- {3-[(6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) amino] propyl} azetidin-3-ol (45 mg) And HATU (56 mg) were added and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was suspended in 20% tetrahydrofuran / ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (45 mg).
MS (ESI +): [M + H] + 647.2.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.32-1.92 (2H, m), 2.10-2.47 (5H, m), 2.58-3.02 (4H, m), 3.32-3.71 (4H, m), 3.76 (3H, s), 4.21-4.42 (1H , m), 5.83 (1H, t, J = 7.1 Hz), 6.02-6.21 (1H, m), 6.80-7.13 (2H, m), 7.21-7.38 (4H, m), 7.39-7.71 (1H, m ).
Example 53a
N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -N- [3- ( 3-Hydroxyazetidin-1-yl) propyl] -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (Enantiomer A)
(±) -N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -N- [3- (3-Hydroxyazetidin-1-yl) propyl] -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (67 mg) was analyzed by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 Fractionated fractions with mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 600/400), and the fraction with the shorter retention time containing the desired product was concentrated under reduced pressure to give the title compound (33 mg). It was.
Optical purity:> 99.9% ee, Retention time: 10.60 min (CHIRALCEL OD-3 (NL002), 4.6 mID × 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 600/400/1)
Example 53b
N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -N- [3- ( 3-Hydroxyazetidin-1-yl) propyl] -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (Enantiomer B)
(±) -N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -N- [3- (3-Hydroxyazetidin-1-yl) propyl] -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (67 mg) was analyzed by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 fractions with mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 600/400), and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to give the title compound (33 mg) It was.
Optical purity: 99.6% ee, Retention time: 16.43 min (CHIRALCEL OD-3 (NL002), 4.6 mID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 600/400/1)
Example 54a
(-)-N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -5- Methoxy-N- [3- (morpholin-4-yl) propyl] imidazo [1,2-a] pyridine-2-carboxamide
A) (±) -6,7-Dichloro-N- [3- (morpholin-4-yl) propyl] -2,3-dihydro-1-benzothiophen-3-amine 1,1-dioxide
To a solution of 6,7-dichloro-1-benzothiophene 1,1-dioxide (100 mg) in 2-propanol (4 mL), add 3-morpholinopropan-1-amine (123 mg), and continue at 70 ° C for 24 hours. Stir. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (153 mg).
MS (ESI +): [M + H] + 379.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.70 (2H, quin, J = 6.6 Hz), 1.87 (1H, br s), 2.29-2.51 (6H, m), 2.72 (2H, t, J = 6.4 Hz), 3.47 (1H, dd, J = 13.4, 4.6 Hz), 3.68 (4H, t, J = 4.4 Hz), 3.80 (1H, dd, J = 13.3, 7.2 Hz), 4.53 (1H, t, J = 5.9 Hz), 7.49 (1H, d , J = 8.0 Hz), 7.68 (1H, d, J = 8.2 Hz).
B) (±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl)- 5-Methoxy-N- [3- (morpholin-4-yl) propyl] imidazo [1,2-a] pyridine-2-carboxamide
To a solution of 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (119 mg) in tetrahydrofuran (3 mL), pyridine (1 mL), ( ±) -6,7-dichloro-N- [3- (morpholin-4-yl) propyl] -2,3-dihydro-1-benzothiophen-3-amine 1,1-dioxide (150 mg) and HATU ( 165 mg) was added, and the mixture was stirred at 60 ° C. for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (158 mg).
MS (ESI +): [M + H] + 661.1.
C) (-)-N- (6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl)- 5-Methoxy-N- [3- (morpholin-4-yl) propyl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -5- Methoxy-N- [3- (morpholin-4-yl) propyl] imidazo [1,2-a] pyridine-2-carboxamide (158 mg) was HPLC (CHIRALCEL OD (NL001), 50 mmID × 500 mmL, Daicel Chemical) The fraction was collected with a mobile phase (hexane / ethanol = 800/200) manufactured by Kogyo, and the fraction with a shorter retention time containing the target product was concentrated under reduced pressure to obtain the title compound (61 mg).
Optical purity:> 99.9% ee, Retention time: 16.10 min (CHIRALCEL OD (DL068), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 800/200)
Specific rotation: [α] 25. D. -77.5 (c 0.110, CHCl _Three )
¹ H NMR (300 MHz, CDCl _Three ) δ 1.26 (2 H, br s), 1.42-1.92 (4H, m), 1.97-2.52 (7 H, m), 2.66-3.31 (1 H, m), 3.32-4.09 (8 H, m), 5.65-6.36 (2 H, m), 6.81-7.32 (6 H, m), 7.43-7.72 (1 H, m).
Example 54b
(+)-N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -5- Methoxy-N- [3- (morpholin-4-yl) propyl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -3- (4-fluoro-3-methylphenyl) -5- Methoxy-N- [3- (morpholin-4-yl) propyl] imidazo [1,2-a] pyridine-2-carboxamide (158 mg) was HPLC (CHIRALCEL OD (NL001), 50 mmID × 500 mmL, Daicel Chemical) Fractions were collected by Kogyo Co., mobile phase: hexane / ethanol = 800/200), and the fraction having the longer retention time containing the target compound was concentrated under reduced pressure to obtain the title compound (62 mg).
Optical purity:> 99.9% ee, Retention time: 20.97 min (CHIRALCEL OD (DL068), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 800/200)
Specific rotation: [α] 25. D. +97.7 (c 0.114, CHCl _Three )
¹ H NMR (300 MHz, CDCl _Three ) δ 1.26 (2H, br s), 1.41-1.93 (4H, m), 1.96-2.45 (7H, m), 2.62-3.31 (1H, m), 3.34-4.10 (8H, m), 5.61-6.32 ( 2H, m), 6.70-7.43 (6H, m), 7.46-7.73 (1H, m).
Example 55
(±) -N- [7-Chloro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [3- (dimethylamino) Propyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
A) Methyl 3-chloro-4- (trifluoromethyl) -2-{[(trifluoromethyl) sulfonyl] oxy} benzoate
To a solution of ice-cooled methyl 3-chloro-2-hydroxy-4- (trifluoromethyl) benzoate (2.33 g) and pyridine (3.70 mL) in tetrahydrofuran (20 mL) at 0 ° C is trifluoromethanesulfonic anhydride ( 2.32 mL) was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour. Trifluoromethanesulfonic anhydride (0.77 mL) was added dropwise and stirred at 0 ° C. for 1 hour. The reaction mixture is diluted with ethyl acetate and water and acidified with 1 N hydrochloric acid (pH <2) and extracted twice with ethyl acetate. The obtained organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.42 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.94 (3H, s), 8.13-8.21 (2H, m).
B) Methyl 3-chloro-2-[(2-ethoxy-2-oxoethyl) sulfanyl] -4- (trifluoromethyl) benzoate
To a solution of methyl 3-chloro-4- (trifluoromethyl) -2-{[(trifluoromethyl) sulfonyl] oxy} benzoate (3.00 g) in toluene (40 mL) at room temperature under an argon atmosphere at room temperature. Tart (1.02 mL), diisopropylethylamine (1.63 mL), 1,1'-bis (diphenylphosphino) ferrocene (172 mg), tris (dibenzylideneacetone) dipalladium (0) (142 mg), and 100 Stir at 1 ° C. for 1 hour. The reaction mixture was cooled to room temperature, then filtered through a pad of silica gel and eluted with 50% ethyl acetate / hexane. The eluate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.75 g).
MS (ESI +): [M + H] + 356.8.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.02 (3H, t, J = 7.1 Hz), 3.71 (2H, s), 3.88 (3H, s), 3.95 (2H, q, J = 7.1 Hz), 7.76 (1H, d, J = 8.1 Hz) ), 8.03 (1H, d, J = 8.1 Hz).
C) 7-Chloro-3-hydroxy-6- (trifluoromethyl) -1-benzothiophene-2-carboxylic acid
To a solution of methyl 3-chloro-2-[(2-ethoxy-2-oxoethyl) sulfanyl] -4- (trifluoromethyl) benzoate (754 mg) in methanol (12 mL) at room temperature, 8 N aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 2 days and at 70 ° C. for 3 hours. Water (4 mL) was added to the reaction mixture, and the mixture was stirred at 70 ° C. for 2 hr. The reaction mixture was acidified with 6 N hydrochloric acid (pH <2), diluted with water, 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 to give the title compound (606 mg).
MS (ESI-): [MH]-295.0.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.90 (1H, d, J = 8.6 Hz), 8.08 (1H, d, J = 8.3 Hz).
D) 7-Chloro-6- (trifluoromethyl) -1-benzothiophen-3-ol
7-chloro-3-hydroxy-6- (trifluoromethyl) -1-benzothiophene-2-carboxylic acid (606 mg), 6 N hydrochloric acid (7 mL) and acetic acid (14 mL) were stirred at 80 ° C. for 7 hours. did. Water was added to the reaction mixture, and the mixture was 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 (411 mg).
MS (ESI-): [MH] -251.0.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.88 (1H, s), 7.77-7.85 (1H, m), 7.86-7.94 (1H, m), 10.67 (1H, s).
E) (±) -7-Chloro-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-ol
To a solution of 7-chloro-6- (trifluoromethyl) -1-benzothiophen-3-ol (500 mg) in methanol (15 mL) was added sodium borohydride (150 mg) in small portions at 0 ° C. Stir at 1 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was 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 to give the title compound (494 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.25 (1H, dd, J = 11.6, 6.6 Hz), 3.66 (1H, dd, J = 11.6, 7.1 Hz), 5.47 (1H, q, J = 6.3 Hz), 6.12 (1H, d, J = 6.0 Hz), 7.43 (1H, d, J = 7.8 Hz), 7.60 (1H, d, J = 7.8 Hz).
F) 7-Chloro-6- (trifluoromethyl) -1-benzothiophene
(±) -7-Chloro-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-ol (490 mg) in acetic acid (5 mL) solution at room temperature with boron trifluoride diethyl ether The complex (0.5 mL) was added, and the mixture was stirred at 100 ° C. for 20 minutes. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give the title compound (365 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.71 (1H, d, J = 5.5 Hz), 7.85 (1H, d, J = 8.3 Hz), 8.09 (1H, d, J = 8.4 Hz), 8.16 (1H, d, J = 5.5 Hz).
G) 7-Chloro-6- (trifluoromethyl) -1-benzothiophene 1,1-dioxide
To a solution of 7-chloro-6- (trifluoromethyl) -1-benzothiophene (348 mg) in acetic acid (5 mL), add 35% aqueous hydrogen peroxide (2.5 mL) at room temperature, and stir at 80 ° C for 3 hours. did. The reaction mixture was diluted with ethyl acetate and water, made alkaline with 8 N aqueous sodium hydroxide solution (12 mL) at 0 ° C., and extracted twice with ethyl acetate. The obtained organic layer was washed successively with 10% aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (382 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.66-7.73 (1H, m), 7.77 (2H, d, J = 7.2 Hz), 8.19 (1H, d, J = 7.9 Hz).
H) (±) -N '-[7-Chloro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N, N-dimethylpropane 1,3-diamine
7-Chloro-6- (trifluoromethyl) -1-benzothiophene 1,1-dioxide (180 mg), N, N-dimethylpropane-1,3-diamine (0.17 mL) and 2-propanol (5 mL) The mixture was stirred at 80 ° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (118 mg).
MS (ESI +): [M + H] + 370.9.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.45-1.63 (2H, m), 2.10 (6H, s), 2.24 (2H, t, J = 7.1 Hz), 2.51-2.76 (3H, m), 3.54 (1H, dd, J = 13.4, 6.3 Hz), 4.15 (1H, dd, J = 13.4, 7.5 Hz), 4.59-4.72 (1H, m), 7.88 (1H, d, J = 8.0 Hz), 8.18 (1H, d, J = 8.1 Hz).
I) (±) -N- [7-Chloro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [3- (dimethyl Amino) propyl] -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 (140 mg) and (±) -N '-[7-chloro-1,1 -Dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N, N-dimethylpropane-1,3-diamine (115 mg) in N, N-dimethylformamide (5 mL) To the solution were added HATU (236 mg) and diisopropylethylamine (0.16 mL) at room temperature, and the mixture was stirred at 60 ° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (150 mg).
MS (ESI +): [M + H] + 653.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.27-2.17 (10H, m), 2.19-2.32 (3H, m), 2.80-3.57 (2H, m), 3.70-4.38 (5H, m), 5.48-6.11 (1H, m), 6.39 (1H , d, J = 7.6 Hz), 7.09-7.75 (6H, m), 7.99-8.30 (1H, m).
Example 55a
(-)-N- [7-Chloro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [3- (dimethylamino) Propyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [7-Chloro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [3- (dimethylamino) Propyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (131 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL , Manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 800/200), and the fraction with the shorter retention time containing the target compound was concentrated under reduced pressure to obtain the title compound (52 mg). .
Optical purity:> 99.9% ee, Retention time: 8.27 min (CHIRALCEL OD (OG017), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 800/200/1)
Specific rotation: [α] 25. D. -73.8 (c 0.214, CHCl _Three )
Example 55b
(+)-N- [7-Chloro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [3- (dimethylamino) Propyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [7-Chloro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [3- (dimethylamino) Propyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (131 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL , Manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 800/200), and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to obtain the title compound (48 mg). .
Optical purity: 99.0% ee, Retention time: 12.02 min (CHIRALCEL OD (OG017), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 800/200/1)
Specific rotation: [α] 25. D. +79.8 (c 0.209, CHCl _Three )
Example 56
(±) -N- [7-Chloro-1,1-dioxide-6- (trifluoromethyl) -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 '-[7-Chloro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N, N-dimethylethane 1,2-diamine
7-chloro-6- (trifluoromethyl) -1-benzothiophene 1,1-dioxide (160 mg), N, N-dimethylethane-1,2-diamine (0.098 mL) and 2-propanol (5 mL) The mixture was stirred at 60 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (132 mg).
MS (ESI +): [M + H] + 356.9.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.12 (6H, s), 2.22-2.42 (2H, m), 2.50-2.76 (3H, m), 3.60 (1H, dd, J = 13.5, 6.1 Hz), 4.14 (1H, dd, J = 13.5 , 7.3 Hz), 4.62-4.75 (1H, m), 7.87 (1H, d, J = 8.0 Hz), 8.17 (1H, d, J = 8.1 Hz).
B) (±) -N- [7-Chloro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (dimethyl Amino) 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 (160 mg) and (±) -N '-[7-chloro-1,1 -Dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N, N-dimethylethane-1,2-diamine (127 mg) in N, N-dimethylformamide (5 mL) To the solution were added HATU (271 mg) and diisopropylethylamine (0.19 mL) at room temperature, and the mixture was stirred at 60 ° C. for 3 hr. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the fraction containing the desired product was concentrated under reduced pressure. The residue was collected by filtration and washed with acetone / hexane to give the title compound (182 mg).
MS (ESI +): [M + H] + 639.0.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.90-2.02 (6H, m), 2.21-2.31 (3H, m), 2.37-2.48 (2H, m), 3.70-4.34 (7H, m), 5.41-6.14 (1H, m), 6.39 (1H , d, J = 7.4 Hz), 7.09-7.81 (6H, m), 8.00-8.32 (1H, m).
Example 56a
(-)-N- [7-Chloro-1,1-dioxide-6- (trifluoromethyl) -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- [7-Chloro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (dimethylamino) Ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (158 mg) by HPLC (CHIRALCEL OD (NL001), 50 mmID × 500 mmL , Manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 700/300), and fractions having a shorter retention time including the target compound were concentrated under reduced pressure to obtain the title compound (77 mg). .
Optical purity:> 99.9% ee, Retention time: 5.77 min (CHIRALCEL OD (OG015), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 700/300)
Specific rotation: [α] 25. D. -80.2 (c 0.210, CHCl _Three )
Example 56b
(+)-N- [7-Chloro-1,1-dioxide-6- (trifluoromethyl) -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- [7-Chloro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (dimethylamino) Ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (158 mg) by HPLC (CHIRALCEL OD (NL001), 50 mmID × 500 mmL , Manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 700/300), and the fraction having the longer retention time containing the target compound was concentrated under reduced pressure to obtain the title compound (80 mg). .
Optical purity: 99.6% ee, Retention time: 10.42 min (CHIRALCEL OD (OG015), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 700/300)
Specific rotation: [α] 25. D. +73.9 (c 0.221, CHCl _Three )
Example 57
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [3- (dimethylamino) Propyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
A) (±) -3-Hydroxy-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-7-carbonitrile 1,1-dioxide
Example 52 To a solution of 3-formyl-2- (methylsulfonyl) -6- (trifluoromethyl) benzonitrile (3.84 g) prepared in Step B in ethanol (380 mL) was added sodium ethoxide (1.26) under ice-cooling. A solution of g) in ethanol (50 mL) was added, the temperature was raised to room temperature, and the mixture was stirred for 40 minutes. Acetic acid (1 mL) was added to the reaction mixture, the solvent was evaporated under reduced pressure, the residue was diluted with ethyl acetate (150 mL) and water (150 mL), and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.61 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.63 (1H, dd, J = 13.8, 4.9 Hz), 4.25 (1H, dd, J = 13.8, 7.1 Hz), 5.53 (1H, br s), 6.71 (1H, br s), 8.23 (1H, d, J = 8.2 Hz), 8.38 (1H, d, J = 8.2 Hz).
B) (±) -3-{[3- (Dimethylamino) propyl] amino} -6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-7-carbonitrile 1,1-dioxide
To a solution of (±) -3-hydroxy-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-7-carbonitrile 1,1-dioxide (511 mg) in pyridine (8.0 mL), 60 Methanesulfonyl chloride (215 μL) was added at 0 ° C., and the reaction mixture was stirred at the same temperature for 1 hour and 45 minutes. The reaction mixture was cooled to 0 ° C., N, N-dimethylpropane-1,3-diamine (1.16 mL) was added, the temperature was raised to room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (30 mL) and water (30 mL), and the aqueous layer was extracted four times with ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (324 mg).
MS (ESI +): [M + H] + 361.9.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.69 (2H, t, J = 6.6 Hz), 2.20 (6H, s), 2.35 (2H, t, J = 6.6 Hz), 2.70-2.78 (2H, m), 3.51 (1H, dd, J = 13.4, 5.8 Hz), 3.90 (1H, dd, J = 13.4, 7.2 Hz), 4.67 (1H, t, J = 6.4 Hz), 7.98-8.09 (2H, m).
C) (±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [3- (dimethyl Amino) propyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -3-{[3- (Dimethylamino) propyl] amino} -6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-7-carbonitrile with 1,1-dioxide In the same manner as in Step F of Example 1, the title compound (189 mg) was obtained.
MS (ESI +): [M + H] + 644.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.66-1.88 (2H, m), 2.06-2.19 (8H, m), 2.26-2.35 (3H, m), 2.66-3.80 (6H, m), 4.02-4.21 (1H, m), 5.38-6.23 (2H, m), 6.90-7.25 (4H, m), 7.28-7.32 (1H, m), 7.41-8.01 (2H, m).
Example 57a
N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [3- (dimethylamino) propyl] -3 -(4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (Enantiomer A)
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [3- (dimethylamino) Propyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (166 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL , Manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 800/200), and the fraction with the shorter retention time containing the target compound was concentrated under reduced pressure to obtain the title compound (86 mg). .
Optical purity: 99.0% ee, Retention time: 10.96 min (CHIRALCEL OD-3 (NL002), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 800/200/1)
Example 57b
N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [3- (dimethylamino) propyl] -3 -(4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (Enantiomer B)
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [3- (dimethylamino) Propyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (166 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL , Manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 800/200), and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to obtain the title compound (83 mg). .
Optical purity: 99.5% ee, Retention time: 16.17 min (CHIRALCEL OD-3 (NL002), 4.6 mm ID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 800/200/1)
Example 58
(±) -N- [2- (Dimethylamino) ethyl] -8-fluoro-N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzo Thiophen-3-yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
A) Ethyl 8-bromo-3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylate
Example 1 Ethyl 3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylate (2.51 g) prepared in Step C in tetrahydrofuran (40 mL) Under ice cooling, a solution of N-bromosuccinimide (1.54 g) in tetrahydrofuran (20 mL) was added, and the mixture was warmed to room temperature under a nitrogen atmosphere and stirred at the same temperature for 4 hours 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.80 g).
MS (ESI +): [M + H] + 407.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.24 (3H, t, J = 7.1 Hz), 2.32 (3H, d, J = 1.8 Hz), 3.67 (3H, s), 4.28 (2H, q, J = 7.1 Hz), 5.90 (1H, d , J = 7.9 Hz), 6.98-7.06 (1H, m), 7.12-7.22 (2H, m), 7.47 (1H, d, J = 7.9 Hz).
B) Ethyl 3- (4-fluoro-3-methylphenyl) -5-methoxy-8- (tributylstannyl) imidazo [1,2-a] pyridine-2-carboxylate
Ethyl 8-bromo-3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylate (3.10 g) in toluene (50 mL) at room temperature , Hexabutyldystannane (1.11 g), lithium chloride (1.62 g) and tetrakis (triphenylphosphine) palladium (0) (0.890 g) were added, and the reaction mixture was stirred at 110 ° C. for 23 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 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 (2.38 g).
MS (ESI +): [M + H] + 618.8.
¹ H NMR (300 MHz, CDCl _Three ) δ 0.85-0.93 (9H, m), 1.10-1.25 (9H, m), 1.32-1.42 (6H, m), 1.54-1.66 (6H, m), 2.30 (3H, s), 3.64 (3H, s ), 4.21 (2H, q, J = 7.1 Hz), 5.96 (1H, d, J = 7.0 Hz), 6.94-7.03 (1H, m), 7.12-7.24 (3H, m).
C) Ethyl 8-fluoro-3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylate
Ethyl 3- (4-fluoro-3-methylphenyl) -5-methoxy-8- (tributylstannyl) imidazo [1,2-a] pyridine-2-carboxylate (2380 mg) in acetone (40 mL) Sodium bicarbonate (981 mg), 1- (chloromethyl) -4-fluoro-1,4-diazoniabicyclo [2.2.2] octanebis (tetrafluoroborate) (2320 mg) and trifluoromethanesulfone Acid silver salt (98.0 mg) was added, and the reaction mixture was stirred at room temperature for 4 hours. 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 (121 mg).
MS (ESI +): [M + H] + 347.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.26 (3H, t, J = 7.1 Hz), 2.32 (3H, d, J = 1.9 Hz), 3.65 (3H, s), 4.30 (2H, q, J = 7.1 Hz), 5.83 (1H, dd , J = 8.3, 3.2 Hz), 6.93 (1H, dd, J = 9.4, 8.2 Hz), 6.98-7.07 (1H, m), 7.14-7.24 (2H, m).
D) 8-Fluoro-3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid
Ethyl 8-fluoro-3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylate by a method similar to step D of Example 1. To give the title compound (124 mg).
MS (ESI +): [M + H] + 318.9.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.32 (3H, d, J = 1.8 Hz), 3.68 (3H, s), 5.89 (1H, dd, J = 8.4, 3.3 Hz), 6.96-7.07 (2H, m), 7.16-7.25 (2H, m).
E) (±) -N '-[7-Fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N, N-dimethylethane 1,2-diamine
Example 51 To a solution of 3-fluoro-2- (methylsulfonyl) -4- (trifluoromethyl) benzaldehyde (1.02 g) prepared in Step D in tetrahydrofuran (15 mL), acetic acid (432 μL) and N, N- Dimethylethane-1,2-diamine (474 μL) was added and the reaction mixture was stirred at room temperature for 40 minutes. The reaction mixture was diluted with tetrahydrofuran (10 mL), 1.11 M lithium diisopropylamide / hexane (13.6 mL) was slowly added to the mixture at 0 ° C., and the mixture was stirred at the same temperature for 40 min under nitrogen atmosphere. 2 N hydrochloric acid (15 mL) was added to the mixture, and then the mixture was made alkaline (pH 8) by adding saturated aqueous sodium hydrogen carbonate solution, and then extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, Dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (310 mg).
MS (ESI +): [M + H] + 341.0.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.21 (6H, s), 2.35-2.55 (2H, m), 2.63-2.80 (2H, m), 3.46 (1H, dd, J = 13.4, 5.8 Hz), 3.87 (1H, dd, J = 13.4 , 7.2 Hz), 4.68-4.80 (1H, m), 7.58 (1H, d, J = 8.1 Hz), 7.82-7.89 (1H, m).
F) (±) -N- [2- (Dimethylamino) ethyl] -8-fluoro-N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1 -Benzothiophen-3-yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
8-Fluoro-3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid (123 mg) in N, N-dimethylformamide (5 mL) (±) -N '-[7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N, N-dimethylethane 1,2-diamine (120 mg), HATU (174 mg) and diisopropylethylamine (145 mg) were added, and the mixture was stirred at room temperature for 30 minutes, and then stirred at 50 ° C. for 6 hours and 20 minutes. The reaction mixture was suspended in ethyl acetate (30 mL), and washed with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and 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 (NH, ethyl acetate / hexane) to give the title compound (162 mg).
MS (ESI +): [M + H] + 641.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.06-2.12 (6H, m), 2.18-2.70 (6H, m), 3.49-3.89 (6H, m), 4.17-4.76 (1H, m), 5.87-5.95 (1H, m), 5.99-7.25 (5H, m), 7.60-7.84 (1H, m).
Example 58a
(-)-N- [2- (Dimethylamino) ethyl] -8-fluoro-N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzo Thiophen-3-yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [2- (Dimethylamino) ethyl] -8-fluoro-N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzo Thiophen-3-yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (149 mg) was prepared by HPLC (CHIRALCEL OD (CA002), 50 Fractions were collected with mmID x 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 700/300), and the fraction with the shorter retention time containing the desired product was concentrated under reduced pressure to give the title compound (77 mg )
Optical purity:> 99.9% ee, Retention time: 5.45 min (CHIRALCEL OD (DB195), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 700/300)
Specific rotation: [α] 25. D. -63.1 (c 0.164, CHCl _Three )
Example 58b
(+)-N- [2- (Dimethylamino) ethyl] -8-fluoro-N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzo Thiophen-3-yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [2- (Dimethylamino) ethyl] -8-fluoro-N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzo Thiophen-3-yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (149 mg) was prepared by HPLC (CHIRALCEL OD (CA002), 50 Fractions were collected with mmID x 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 700/300, and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to give the title compound (80 mg )
Optical purity: 98.0% ee, Retention time: 6.97 min (CHIRALCEL OD (DB195), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 700/300)
Specific rotation: [α] 25. D. +63.5 (c 0.186, CHCl _Three )
Example 59
(±) -N- [2- (Dimethylamino) ethyl] -N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-3- Yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
Example 58 (±) -N ′-[7-Fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl]-prepared in Step E The title compound (256 mg) was obtained in the same manner as in Step F of Example 1 using N, N-dimethylethane-1,2-diamine.
MS (ESI +): [M + H] + 623.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.05-2.12 (6H, m), 2.20-2.69 (6H, m), 3.44-3.86 (6H, m), 4.18-4.74 (1H, m), 6.04-6.09 (1H, m), 6.09-7.26 (4H, m), 7.27-7.34 (2H, m), 7.59-7.84 (1H, m).
Example 59a
(-)-N- [2- (Dimethylamino) ethyl] -N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-3- Yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [2- (Dimethylamino) ethyl] -N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-3- IL] -3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (243 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL , Manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500), and fractions with a shorter retention time containing the desired product were concentrated under reduced pressure to obtain the title compound (116 mg). .
Optical purity: 99.9% ee, Retention time: 8.48 min (CHIRALCEL OD (DB195), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500)
Specific rotation: [α] 25. D. -77.7 (c 0.166, CHCl _Three )
Example 59b
(+)-N- [2- (Dimethylamino) ethyl] -N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-3- Yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [2- (Dimethylamino) ethyl] -N- [7-fluoro-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-3- IL] -3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (243 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL , Manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500), and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to obtain the title compound (120 mg). .
Optical purity: 99.5% ee, Retention time: 11.75 min (CHIRALCEL OD (DB195), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500)
Specific rotation: [α] 25. D. +74.4 (c 0.184, CHCl _Three )
Example 60
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3- Methylphenyl) -5-methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
A) 6- (Trifluoromethyl) -1-benzothiophene-7-carbonitrile 1,1-dioxide
Example 57 (±) -3-Hydroxy-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-7-carbonitrile 1,1-dioxide (1.98 g) and triethylamine prepared in Step A To a solution of (2.49 mL) in tetrahydrofuran (20 mL), methanesulfonyl chloride (0.66 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure to give the title compound (1.80 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.80-7.85 (1H, m), 7.85-7.90 (1H, m), 8.15 (1H, d, J = 8.1 Hz), 8.36 (1H, d, J = 7.9 Hz).
B) (±) -tert-butyl (2-{[7-cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] amino} ethyl ) Methyl carbamate
Of 6- (trifluoromethyl) -1-benzothiophene-7-carbonitrile 1,1-dioxide (1.5 g), tert-butyl (2-aminoethyl) methylcarbamate (2.07 mL) and ethanol (40 mL) The mixture was stirred at 70 ° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.51 g).
MS (ESI +): [M-Boc + 2H] + 333.9.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.25-1.49 (9H, m), 2.63-2.88 (6H, m), 3.12-3.40 (2H, m), 3.62 (1H, dd, J = 13.5, 6.3 Hz), 4.28 (1H, dd, J = 13.5, 7.3 Hz), 4.80 (1H, q, J = 7.2 Hz), 8.21 (1H, d, J = 8.3 Hz), 8.35 (1H, d, J = 8.3 Hz).
C) (±) -tert-butyl (2-{[7-cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] {[3 -(4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino} ethyl) methylcarbamate
(±) -tert-butyl (2-{[7-cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] amino} ethyl) methyl The title compound (1.36 g) was obtained in the same manner as in Step I of Example 55 using carbamate.
MS (ESI +): [M + H] + 716.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.96-1.47 (9H, m), 2.18-2.34 (3H, m), 2.55-4.58 (12H, m), 5.54-6.35 (1H, m), 6.38 (1H, d, J = 7.6 Hz), 7.05-8.54 (7H, m).
D) (±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro- 3-Methylphenyl) -5-methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -tert-butyl (2-{[7-cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] {[3- ( 4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino} ethyl) methyl carbamate using a method similar to step C of Example 16. Gave the title compound (882 mg).
MS (ESI +): [M + H] + 616.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.53-2.34 (7H, m), 2.57-2.75 (2H, m), 3.59-3.93 (6H, m), 4.35 (1H, dd, J = 13.1, 8.2 Hz), 5.52-6.25 (1H, m ), 6.38 (1H, d, J = 7.0 Hz), 7.07-7.45 (5H, m), 7.92-8.14 (1H, m), 8.17-8.47 (1H, m).
Example 60a
(-)-N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3- Methylphenyl) -5-methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3- Methylphenyl) -5-methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (850 mg) by HPLC (CHIRALPAK AD (AF003), 50 mmID × 500 mmL , Manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 300/700), and fractions having a shorter retention time including the target compound were concentrated under reduced pressure to obtain the title compound (394 mg). .
Optical purity: 99.0% ee, Retention time: 4.76 min (CHIRALPAK ADH (OL006), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 300/700/1)
Specific rotation: [α] 25. D. -74.2 (c 0.206, CHCl _Three )
Example 60b
(+)-N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3- Methylphenyl) -5-methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3- Methylphenyl) -5-methoxy-N- [2- (methylamino) ethyl] imidazo [1,2-a] pyridine-2-carboxamide (850 mg) by HPLC (CHIRALPAK AD (AF003), 50 mmID × 500 mmL , Manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 300/700), and the fraction having the longer retention time containing the target compound was concentrated under reduced pressure to obtain the title compound (413 mg). .
Optical purity: 93.8% ee, Retention time: 12.42 min (CHIRALPAK ADH (OL006), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 300/700/1)
Specific rotation: [α] 25. D. +66.6 (c 0.203, CHCl _Three )
Example 61
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3- Methylphenyl) -5-methoxy-N- {2-[(2-methoxyethyl) (methyl) amino] ethyl} imidazo [1,2-a] pyridine-2-carboxamide
A) (±) -3-({2-[(2-methoxyethyl) (methyl) amino] ethyl} amino) -6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-7- Carbonitrile 1,1-dioxide
The title compound (324 mg) was obtained in the same manner as in Step B of Example 60 using N- (2-methoxyethyl) -N-methylethane-1,2-diamine.
MS (ESI +): [M + H] + 392.0.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.17 (3H, s), 2.41-2.51 (4H, m), 2.57-2.75 (3H, m), 3.21 (3H, s), 3.38 (2H, t, J = 5.9 Hz), 3.67 (1H, dd, J = 13.5, 6.1 Hz), 4.25 (1H, dd, J = 13.6, 7.2 Hz), 4.79 (1H, q, J = 6.3 Hz), 8.20-8.28 (1H, m), 8.31-8.38 (1H , m).
B) (±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro- 3-methylphenyl) -5-methoxy-N- {2-[(2-methoxyethyl) (methyl) amino] ethyl} imidazo [1,2-a] pyridine-2-carboxamide
(±) -3-({2-[(2-methoxyethyl) (methyl) amino] ethyl} amino) -6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-7-carbonitrile The title compound (329 mg) was obtained in the same manner as in Step 55 of Example 55 using 1,1-dioxide.
MS (ESI +): [M + H] + 674.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.94-2.09 (3H, m), 2.19-2.32 (3H, m), 2.41 (2H, t, J = 5.5 Hz), 2.47-2.60 (2H, m), 3.09-3.19 (3H, m), 3.28 (2H, t, J = 5.6 Hz), 3.68-4.47 (7H, m), 5.52-6.28 (1H, m), 6.39 (1H, d, J = 7.2 Hz), 7.08-7.46 (5H, m) , 7.79-8.51 (2H, m).
Example 61a
(-)-N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3- Methylphenyl) -5-methoxy-N- {2-[(2-methoxyethyl) (methyl) amino] ethyl} imidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3- Methylphenyl) -5-methoxy-N- {2-[(2-methoxyethyl) (methyl) amino] ethyl} imidazo [1,2-a] pyridine-2-carboxamide (269 mg) was analyzed by HPLC (CHIRALCEL OD ( CA002), 50 mmID x 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500), and fractions containing the target product and having a shorter retention time are concentrated under reduced pressure. Compound (126 mg) was obtained.
Optical purity: 98.4% ee, Retention time: 8.81 min (CHIRALCEL OD (DL068), 4.6 mm ID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500)
Specific rotation: [α] 25. D. -57.8 (c 0.337, CHCl _Three )
Example 61b
(+)-N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3- Methylphenyl) -5-methoxy-N- {2-[(2-methoxyethyl) (methyl) amino] ethyl} imidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3- Methylphenyl) -5-methoxy-N- {2-[(2-methoxyethyl) (methyl) amino] ethyl} imidazo [1,2-a] pyridine-2-carboxamide (269 mg) was analyzed by HPLC (CHIRALCEL OD ( CA002), 50 mmID x 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500), and the fraction with the longer retention time containing the desired product is concentrated under reduced pressure. Compound (134 mg) was obtained.
Optical purity: 99.2% ee, Retention time: 12.20 min (CHIRALCEL OD (DL068), 4.6 mm ID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500)
Specific rotation: [α] 25. D. +58.8 (c 0.331, CHCl _Three )
Example 62
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (ethylamino) Ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
A) tert-butyl ethyl (2-hydroxyethyl) carbamate
To a tetrahydrofuran (30 mL) solution of 2- (ethylamino) ethanol (3.28 mL) was added di-tert-butyl dicarbonate (7.81 mL) at room temperature, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure to give the title compound (6.47 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.01 (3H, t, J = 6.4 Hz), 1.38 (9H, s), 3.11-3.25 (4H, m), 3.44 (2H, q, J = 6.0 Hz), 4.64 (1H, t, J = 5.3 Hz).
B) tert-Butyl (2-azidoethyl) ethylcarbamate
To a solution of tert-butyl ethyl (2-hydroxyethyl) carbamate (1.37 g) and triphenylphosphine (3.33 g) in tetrahydrofuran (40 mL) under a nitrogen atmosphere at 0 ° C, a 40% toluene solution of diisopropyl azodicarboxylate (8.72 g) was added dropwise followed by diphenylphosphoric acid azide (2.91 g). The mixture was stirred at room temperature for 3 days under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.04 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.04 (3H, t, J = 6.7 Hz), 1.40 (9H, s), 3.20 (2H, q, J = 7.0 Hz), 3.29-3.44 (4H, m).
C) tert-butyl (2-aminoethyl) ethylcarbamate
To a solution of tert-butyl (2-azidoethyl) ethylcarbamate (1.01 g) in tetrahydrofuran (10 mL) were added triphenylphosphine (2.47 g) and water (0.51 g) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was sequentially purified by silica gel column chromatography (NH, ethyl acetate / hexane, then methanol / ethyl acetate) and (ethyl acetate, then 28% aqueous ammonia / methanol / ethyl acetate), The title compound (276 mg) was obtained.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.01 (3H, t, J = 7.0 Hz), 1.38 (9H, s), 2.60 (2H, t, J = 7.0 Hz), 3.08 (2H, t, J = 7.0 Hz), 3.16 (2H, q , J = 7.0 Hz).
D) (±) -tert-butyl (2-{[7-cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] amino} ethyl ) Ethyl carbamate
The title compound (460 mg) was obtained in the same manner as in Step B of Example 60 using tert-butyl (2-aminoethyl) ethylcarbamate.
MS (ESI +): [M + H] + 448.3.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.96-1.09 (3H, m), 1.37 (9H, brs), 2.60-2.84 (3H, m), 3.11-3.28 (4H, m), 3.62 (1H, dd, J = 13.6, 6.2 Hz), 4.27 (1H, dd, J = 13.5, 7.3 Hz), 4.80 (1H, q, J = 7.2 Hz), 8.18-8.26 (1H, m), 8.36 (1H, d, J = 8.3 Hz).
E) (±) -tert-butyl (2-{[7-cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] {[3 -(4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino} ethyl) ethylcarbamate
(±) -tert-butyl (2-{[7-cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] amino} ethyl) ethyl The title compound (440 mg) was obtained in the same manner as in Step I of Example 55 using carbamate.
MS (ESI +): [M + H] + 730.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.83-1.00 (3H, m), 1.00-1.45 (9H, m), 2.19-2.33 (3H, m), 2.81-3.24 (3H, m), 3.35-4.56 (8H, m), 5.52-6.35 (1H, m), 6.39 (1H, d, J = 7.3 Hz), 7.05-8.58 (7H, m).
F) (±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (ethyl Amino) ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -tert-butyl (2-{[7-cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] {[3- ( 4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridin-2-yl] carbonyl} amino} ethyl) ethyl carbamate using a method similar to step C of Example 16. Gave the title compound (363 mg).
MS (ESI +): [M + H] + 630.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.84-1.01 (3H, m), 2.18-2.31 (3H, m), 2.42 (2H, q, J = 6.8 Hz), 2.64-2.77 (2H, m), 3.58-4.57 (7H, m), 5.55-6.25 (1H, m), 6.39 (1H, d, J = 7.2 Hz), 7.09-7.44 (5H, m), 7.97-8.16 (1H, m), 8.19-8.49 (1H, m).
Example 62a
(-)-N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (ethylamino) Ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (ethylamino) Ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (300 mg) was analyzed by HPLC (CHIRALPAK AD (AF003), 50 mmID × 500 mmL , Manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 200/800), and the fraction with the shorter retention time containing the desired product was concentrated under reduced pressure to obtain the title compound (140 mg). .
Optical purity: 99.3% ee, Retention time: 6.39 min (CHIRALCEL OD3 (NL002), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 700/300/1)
Specific rotation: [α] 25. D. -75.7 (c 0.237, CHCl _Three )
Example 62b
(+)-N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (ethylamino) Ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (ethylamino) Ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (300 mg) was analyzed by HPLC (CHIRALPAK AD (AF003), 50 mmID × 500 mmL , Manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 200/800), and the fraction having the longer retention time containing the target compound was concentrated under reduced pressure to obtain the title compound (152 mg). .
Optical purity: 98.7% ee, Retention time: 8.15 min (CHIRALCEL OD3 (NL002), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 700/300/1)
Specific rotation: [α] 25. D. +73.1 (c 0.241, CHCl _Three )
Example 63
(±) -N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N- [2- (dimethylamino) ethyl] -8-fluoro -3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
Using (±) -N '-(6,7-dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N, N-dimethylethane-1,2-diamine In the same manner as in Step F of Example 58, the title compound (128 mg) was obtained.
MS (ESI +): [M + H] + 623.0.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.90-2.02 (6H, m), 2.22-2.31 (3H, m), 2.36-2.46 (2H, m), 3.62-4.30 (7H, m), 5.36-6.01 (1H, m), 6.28 (1H , dd, J = 8.5, 3.4 Hz), 7.11-7.58 (5H, m), 7.82-8.13 (1H, m).
Example 63a
(-)-N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N- [2- (dimethylamino) ethyl] -8-fluoro -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] -8-fluoro -3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (110 mg) by HPLC (CHIRALCEL OD (NL001), 50 mmID × 500 mmL, Daicel The fraction was collected with a chemical industry, mobile phase: hexane / ethanol = 700/300), and the fraction having a shorter retention time containing the target compound was concentrated under reduced pressure to obtain the title compound (58 mg).
Optical purity: 99.9% ee, Retention time: 4.72 min (CHIRALCEL OD3 (NL002), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 600/400/1)
Specific rotation: [α] 25. D. -92.7 (c 0.261, CHCl _Three )
Example 63b
(+)-N- (6,7-Dichloro-1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -N- [2- (dimethylamino) ethyl] -8-fluoro -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] -8-fluoro -3- (4-Fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (110 mg) by HPLC (CHIRALCEL OD (NL001), 50 mmID × 500 mmL, Daicel The fraction was collected with a chemical industry, mobile phase: hexane / ethanol = 700/300), and the fraction having the longer retention time containing the target compound was concentrated under reduced pressure to obtain the title compound (50 mg).
Optical purity: 99.9% ee, Retention time: 6.10 min (CHIRALCEL OD3 (NL002), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol / diethylamine = 600/400/1)
Specific rotation: [α] 25. D. +93.7 (c 0.285, CHCl _Three )
Example 64
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3- Methylphenyl) -N- {2-[(2-hydroxyethyl) (methyl) amino] ethyl} -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
A) (±) -3-({2-[(2-hydroxyethyl) (methyl) amino] ethyl} amino) -6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-7- Carbonitrile 1,1-dioxide
The title compound (395 mg) was obtained in the same manner as in Step B of Example 60 using 2-[(2-aminoethyl) (methyl) amino] ethanol.
MS (ESI +): [M + H] + 377.9.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.17 (3H, s), 2.31-2.48 (4H, m), 2.59-2.80 (3H, m), 3.44 (2H, q, J = 5.9 Hz), 3.65 (1H, dd, J = 13.4, 6.2 Hz), 4.26 (1H, dd, J = 13.5, 7.3 Hz), 4.33 (1H, t, J = 5.5 Hz), 4.73-4.84 (1H, m), 8.23-8.29 (1H, m), 8.31-8.37 (1H, m).
B) (±) -3-({2-[(2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) (methyl) amino] ethyl} amino) -6- (trifluoromethyl) -2, 3-Dihydro-1-benzothiophene-7-carbonitrile 1,1-dioxide
(±) -3-({2-[(2-hydroxyethyl) (methyl) amino] ethyl} amino) -6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-7-carbonitrile To a solution of 1,1-dioxide (171 mg) and triethylamine (0.32 mL) in acetonitrile (5 mL) was added dropwise a solution of tert-butyl (chloro) dimethylsilane (0.17 mL) in acetonitrile (0.5 mL) at room temperature. For 30 minutes and at 60 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (188 mg).
MS (ESI +): [M + H] + 492.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.00 (6H, s), 0.82 (9H, s), 2.19 (3H, s), 2.34-2.76 (7H, m), 3.57-3.71 (3H, m), 4.24 (1H, dd, J = 13.5 , 7.3 Hz), 4.79 (1H, q, J = 6.7 Hz), 8.20-8.27 (1H, m), 8.31-8.37 (1H, m).
C) (±) -N- (2-[(2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) (methyl) amino] ethyl) -N- [7-cyano-1,1-dioxide- 6- (Trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine- 2-carboxamide
(±) -3-({2-[(2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) (methyl) amino] ethyl} amino) -6- (trifluoromethyl) -2,3- The title compound (146 mg) was obtained in the same manner as in Step I of Example 55 using dihydro-1-benzothiophene-7-carbonitrile 1,1-dioxide.
MS (ESI +): [M + H] + 774.2.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ -0.09-0.02 (6H, m), 0.75-0.85 (9H, m), 1.98-2.12 (3H, m), 2.20-2.31 (3H, m), 2.37 (2H, t, J = 5.9 Hz) , 2.54-2.66 (2H, m), 3.52 (2H, t, J = 6.0 Hz), 3.69-4.46 (7H, m), 5.49-6.27 (1H, m), 6.39 (1H, d, J = 7.0 Hz ), 7.08-7.47 (5H, m), 7.76-8.49 (2H, m).
D) (±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro- 3-methylphenyl) -N- {2-[(2-hydroxyethyl) (methyl) amino] ethyl} -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N- {2-[(2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) (methyl) amino] ethyl} -N- [7-cyano-1,1-dioxide-6- (Trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2- A mixture of carboxamide (140 mg), trifluoroacetic acid (1 mL) and water (0.2 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate while stirring under ice-cooling, 2N aqueous sodium hydroxide solution (6 mL) and 10% aqueous sodium carbonate solution (10 mL) were added, and the mixture was stirred for 10 min. 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, ethyl acetate / hexane, then methanol / ethyl acetate) to give the title compound (108 mg).
MS (ESI +): [M + H] + 660.1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.92-2.04 (3H, m), 2.19-2.69 (7H, m), 3.43 (2H, q, J = 5.7 Hz), 3.67-4.47 (7H, m), 4.50 (1H, t, J = 5.1 Hz), 5.54-6.24 (1H, m), 6.39 (1H, d, J = 6.9 Hz), 7.08-7.46 (5H, m), 7.89-8.47 (2H, m).
Example 64a
(-)-N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3- Methylphenyl) -N- {2-[(2-hydroxyethyl) (methyl) amino] ethyl} -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3- Methylphenyl) -N- {2-[(2-hydroxyethyl) (methyl) amino] ethyl} -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (98 mg) was purified by HPLC (CHIRALCEL OD ( CA002), 50 mmID x 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500), and fractions containing the desired product and having a shorter retention time are concentrated under reduced pressure. Compound (48 mg) was obtained.
Optical purity:> 99.9% ee, Retention time: 7.86 min (CHIRALCEL OD (MC071), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500)
Specific rotation: [α] 25. D. -23.2 (c 0.325, CHCl _Three )
Example 64b
(+)-N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3- Methylphenyl) -N- {2-[(2-hydroxyethyl) (methyl) amino] ethyl} -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -3- (4-fluoro-3- Methylphenyl) -N- {2-[(2-hydroxyethyl) (methyl) amino] ethyl} -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (98 mg) was analyzed by HPLC (CHIRALCEL OD ( CA002), 50 mmID x 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500), and the fraction with the longer retention time containing the target product was concentrated under reduced pressure. Compound (48 mg) was obtained.
Optical purity: 97.9% ee, Retention time: 10.77 min (CHIRALCEL OD (MC071), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500)
Specific rotation: [α] 25. D. +23.9 (c 0.260, CHCl _Three )
Example 65
(±) -N- (6-Chloro-7-cyano-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
A) 6-Chloro-2-fluoro-3-formylbenzonitrile
The title compound (5.38 g) was obtained in the same manner as in Step A of Example 52 using 2-chloro-6-fluorobenzonitrile.
¹ H NMR (300 MHz, CDCl _Three ) δ 7.50 (1H, dt, J = 8.5, 0.9 Hz), 8.07 (1H, dd, J = 8.5, 7.4 Hz), 10.32 (1H, d, J = 0.5 Hz).
B) 6-Chloro-3-formyl-2- (methylsulfonyl) benzonitrile
The title compound (4.54 g) was obtained in the same manner as in Step B of Example 52 using 6-chloro-2-fluoro-3-formylbenzonitrile.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.69 (3H, s), 8.07 (1H, d, J = 8.5 Hz), 8.28 (1H, dd, J = 8.5, 0.6 Hz), 10.52 (1H, d, J = 0.6 Hz).
C) (±) -6-Chloro-3-hydroxy-2,3-dihydro-1-benzothiophene-7-carbonitrile 1,1-dioxide
The title compound (4.22 g) was obtained in the same manner as in Step 57 of Example 57 using 6-chloro-3-formyl-2- (methylsulfonyl) benzonitrile.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.48-3.60 (1H, m), 4.19 (1H, dd, J = 13.8, 7.0 Hz), 5.44 (1H, br s), 6.62 (1H, br s), 7.99-8.04 (1H, m), 8.09-8.14 (1H, m).
D) 6-Chloro-1-benzothiophene-7-carbonitrile 1,1-dioxide
Triethylamine in (±) -6-chloro-3-hydroxy-2,3-dihydro-1-benzothiophene-7-carbonitrile 1,1-dioxide (4.22 g) in tetrahydrofuran (45 mL) at 0 ° C (6.05 mL) and methanesulfonyl chloride (1.62 mL) were added, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and water (100 mL), and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution and 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 washed with a mixed solvent of ethyl acetate and hexane, and the obtained solid was recrystallized from ethanol / tetrahydrofuran to give the title compound (1.47 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.63-7.68 (1H, m), 7.73-7.79 (1H, m), 7.95 (1H, d, J = 8.2 Hz), 8.09 (1H, d, J = 8.2 Hz).
E) (±) -6-Chloro-3-{[2- (dimethylamino) ethyl] amino} -2,3-dihydro-1-benzothiophene-7-carbonitrile 1,1-dioxide
To a solution of 6-chloro-1-benzothiophene-7-carbonitrile 1,1-dioxide (312 mg) in ethanol (20 mL), add N, N-dimethylethane-1,2-diamine (378 μL), The reaction mixture was stirred at 70 ° C. for 4 hours 30 minutes. The solvent was evaporated under reduced pressure, 2 N hydrochloric acid (20 mL) was added to the residue, and the mixture was washed successively with ethyl acetate (15 mL) and hexane (15 mL). The obtained aqueous layer was made alkaline (pH 8) by adding 8 N aqueous sodium hydroxide solution (5 mL) and saturated aqueous sodium hydrogen carbonate solution, and then extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine. After washing, it was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (315 mg).
MS (ESI +): [M + H] + 313.9.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.21 (6H, s), 2.35-2.54 (2H, m), 2.61-2.78 (2H, m), 3.45 (1H, dd, J = 13.4, 5.6 Hz), 3.88 (1H, dd, J = 13.4 , 7.2 Hz), 4.67 (1H, t, J = 6.3 Hz), 7.71-7.77 (1H, m), 7.88 (1H, dd, J = 8.4, 0.8 Hz).
F) (±) -N- (6-Chloro-7-cyano-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
Example 1 using (±) -6-chloro-3-{[2- (dimethylamino) ethyl] amino} -2,3-dihydro-1-benzothiophene-7-carbonitrile 1,1-dioxide In the same manner as in Step F, the title compound (222 mg) was obtained.
MS (ESI +): [M + H] + 596.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.02-2.10 (6H, m), 2.23-2.35 (4H, m), 2.53-2.67 (1H, m), 3.44-3.89 (6H, m), 4.14-4.74 (1H, m), 5.25-6.13 (2H, m), 6.91-7.26 (3H, m), 7.27-7.72 (4H, m).
Example 65a
(-)-N- (6-Chloro-7-cyano-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-Chloro-7-cyano-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 (213 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL, Daicel Chemical Industries) Product, mobile phase: hexane / ethanol = 500/500), and the fraction with the shorter retention time containing the desired product was concentrated under reduced pressure to give the title compound (100 mg).
Optical purity: 99.8% ee, Retention time: 10.42 min (CHIRALCEL OD (OG019), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500)
Specific rotation: [α] 25. D. -99.1 (c 0.222, CHCl _Three )
Example 65b
(+)-N- (6-Chloro-7-cyano-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-Chloro-7-cyano-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 (213 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL, Daicel Chemical Industries) Product, mobile phase: hexane / ethanol = 500/500), and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to give the title compound (105 mg).
Optical purity: 99.7% ee, Retention time: 16.25 min (CHIRALCEL OD (OG019), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500)
Specific rotation: [α] 25. D. +94.9 (c 0.247, CHCl _Three )
Example 66
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (dimethylamino) Ethyl] -8-fluoro-3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
Example 52 (±) -3-{[2- (Dimethylamino) ethyl] amino} -6- (trifluoromethyl) -2,3-dihydro-1-benzothiophene-7-carbonitrile prepared in Step C The title compound (143 mg) was obtained in the same manner as in Step F of Example 58 using 1,1-dioxide.
MS (ESI +): [M + H] + 648.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 2.05-2.13 (6H, m), 2.26-2.36 (3H, m), 2.40-2.71 (2H, m), 3.66-3.93 (6H, m), 4.16-4.82 (1H, m), 5.23-6.25 (2H, m), 6.94-7.25 (4H, m), 7.55-8.04 (2H, m).
Example 66a
(-)-N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (dimethylamino) Ethyl] -8-fluoro-3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (dimethylamino) Ethyl] -8-fluoro-3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (137 mg) was prepared by HPLC (CHIRALCEL OD (CA002), 50 Fractions were collected with mmID x 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 600/400, and the fraction with the shorter retention time containing the desired product was concentrated under reduced pressure to give the title compound (67 mg )
Optical purity: 98.9% ee, Retention time: 8.97 min (CHIRALCEL ODH (MC071), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 600/400)
Specific rotation: [α] 25. D. -66.0 (c 0.230, CHCl _Three )
Example 66b
(+)-N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (dimethylamino) Ethyl] -8-fluoro-3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
(±) -N- [7-Cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (dimethylamino) Ethyl] -8-fluoro-3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide (137 mg) was prepared by HPLC (CHIRALCEL OD (CA002), 50 Fractions were collected with mmID x 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 600/400, and the fraction with the longer retention time containing the desired product was concentrated under reduced pressure to give the title compound (66 mg )
Optical purity: 96.4% ee, Retention time: 11.47 min (CHIRALCEL ODH (MC071), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 600/400)
Specific rotation: [α] 25. D. +68.9 (c 0.210, CHCl _Three )
Example 67
(±) -N- (4,5-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 '-(4,5-Dichloro-2,3-dihydro-1H-inden-1-yl) -N, N-dimethylethane-1,2-diamine
The title compound (384 mg) was obtained in the same manner as in Step E of Example 1 using 4,5-dichloroindan-1-one.
MS (ESI +): [M + H] + 272.9.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.84-1.97 (2H, m), 2.21 (6H, s), 2.36-2.50 (3H, m), 2.70-2.75 (2H, m), 2.79-2.91 (1H, m), 3.01-3.14 (1H , m), 4.29 (1H, t, J = 6.7 Hz), 7.17 (1H, d, J = 8.0 Hz), 7.27-7.31 (1H, m).
B) (±) -N- (4,5-Dichloro-2,3-dihydro-1H-inden-1-yl) -N- [2- (dimethylamino) ethyl] -3- (4-fluoro-3 -Methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide
Step of Example 1 using (±) -N ′-(4,5-dichloro-2,3-dihydro-1H-inden-1-yl) -N, N-dimethylethane-1,2-diamine In the same manner as in F, the title compound (299 mg) was obtained.
MS (ESI +): [M + H] + 555.1.
¹ H NMR (300 MHz, CDCl _Three ) δ 1.87-2.16 (7H, m), 2.31 (3H, br s), 2.37-2.53 (2H, m), 2.58-2.74 (1H, m), 2.88-3.07 (2H, m), 3.34-3.53 ( 1H, m), 3.71-3.80 (4H, m), 5.31-6.02 (1H, m), 6.02-6.07 (1H, m), 6.54-6.64 (1H, m), 6.98-7.25 (4H, m), 7.27-7.39 (2H, m).
Example 67a
(-)-N- (4,5-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
(±) -N- (4,5-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 (253 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500), and the fraction with a shorter retention time containing the desired product was concentrated under reduced pressure to obtain the title compound (114 mg).
Optical purity:> 99.9% ee, Retention time: 8.58 min (CHIRALCEL OD (OG017), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500)
Specific rotation: [α] 25. D. -117.2 (c 0.215, CHCl _Three )
Example 67b
(+)-N- (4,5-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
(±) -N- (4,5-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 (253 mg) by HPLC (CHIRALCEL OD (CA002), 50 mmID × 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = The fraction with a longer retention time containing the desired product was concentrated under reduced pressure to obtain the title compound (112 mg).
Optical purity: 98.6% ee, Retention time: 19.32 min (CHIRALCEL OD (OG017), 4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 500/500)
Specific rotation: [α] 25. D. +121.0 (c 0.200, CHCl _Three )
The structural formulas of the compounds described in Examples 1 to 67b are shown below.

Formulation Example 1
A medicament containing the compound of the present invention as an active ingredient can be produced, for example, according to the following formulation.
1. Capsule (1) 40 mg of the compound obtained in Example 1
(2) Lactose 70mg
(3) Microcrystalline cellulose 9mg
(4) Magnesium stearate 1mg
1 capsule 120mg
After mixing 1/2 of (1), (2), (3) and (4), granulate. The remaining (4) is added to this and the whole is enclosed in a gelatin capsule.
2. Tablet (1) Compound obtained in Example 1 40 mg
(2) Lactose 58mg
(3) Corn starch 18mg
(4) Microcrystalline cellulose 3.5mg
(5) Magnesium stearate 0.5mg
1 tablet 120mg
After mixing 2/3 of (1), (2), (3), (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.
Formulation Example 2
After dissolving 50 mg of the compound obtained in the example in 50 mL of JP injection distilled water, JP distilled water for injection is added to make 100 mL. The solution is filtered under sterile conditions, then 1 mL of this solution is taken, filled into injection vials under sterile conditions, lyophilized and sealed.
Test Example 1 Measurement of CENP-E inhibitory activity (ADP-Glo method)
N-terminal GST-tagged CENP-E motor domain protein (1-395 a. A.) And Microtubule were purchased from Cytoskeleton (Denver, Colorado, USA). ADP-Glo (Promega, USA) was used to detect CENP-E enzyme activity. Reaction solution (20 mM PIPES-KOH (pH 6.8), 3 mM magnesium chloride, 3 mM potassium chloride, 1 mM ethylene glycol bis-) containing CENP-E 0.375 ng and Microtubule 132 ng in 384 well Optiplate (Perkin Elmer, USA) 2-aminoethyl ether tetraacetic acid (EGTA), 1 mM dithiothreitol, 0.01% w / v Brij-35, 0.2% w / v bovine serum albumin (BSA)) dissolved in 2 μL of dimethyl sulfoxide (DMSO) After adding 2 μL of the test compound, the mixture was incubated at room temperature for 10 minutes. 2 μL of 75 μM ATP solution was added to the resulting mixture, the plate was centrifuged at 900 rpm, and reacted at room temperature for 60 minutes. 6 μL of ADP-Glo reagent was added and incubated at room temperature for 30 minutes. After adding 12 μL of Kinase Detection Reagent (Promega) and incubating for 40 minutes at room temperature, the amount of luminescence was measured by Envision (PerkinElmer, USA). The inhibition rate (%) of the test compound with respect to CENP-E was calculated by the following formula.
Inhibition rate (%) = (1-(test compound count-blank) ÷ (control-blank)) x 100
The count of the CENP-E reaction solution under the condition where no compound was added was shown as a control, and the count under the condition where no compound was added and CENP-E was not added was shown as blank.

Table 2 shows the results obtained.

Thereby, it was shown that the compound of the present invention has excellent CENP-E inhibitory activity.
Test Example 2 Inhibition of proliferation of human uterine cancer cell Hela cells in vitro A cell suspension of human uterine cancer cell Hela cells (purchased from ATCC) was seeded in a 96-well plate (100 μL / well, 2,000 cells / well), The 96-well plate was allowed to stand at 37 ° C. for half a day in a 5% carbon dioxide incubator. 100 μL of a 6 μM test compound solution was added, and allowed to stand for 3 days in a 5% carbon dioxide incubator. 50 μL of CellTiter-Glo ™ Luminescent Cell Viability Assay reagent (Promega) was added to the 96-well plate after standing for 3 days, and the amount of luminescence was measured with a luminometer.

The amount of luminescence was used as an index of the number of viable cells. The cell growth inhibitory activity of the test compound was calculated as the growth inhibition rate (%) using the following formula.
Growth inhibition rate (%) = (1- (test compound luminescence) ÷ (control luminescence)) x 100
(In the above formula, the amount of luminescence in the control group means the amount of luminescence under the condition where no test compound is added.)
Table 3 shows the cell growth inhibition rate (%) of the test compound at a test compound concentration of 3 μM.

Test Example 3 Colorectal Cancer Cell Colo205 Tumor-bearing Mouse Tumor Phosphorylated Histone H3 Protein Elevating Action Human colorectal cancer cell Colo205 was suspended in 50% Matrigel solution and 6-7 weeks old BALB / c female nude mice (CLEA Japan) ) Was implanted subcutaneously at 5.0 × 10 ⁶ pieces. The tumor diameter of the tumor engrafted 7 to 14 days after the transplantation was measured, and the tumor volume was calculated by the following formula.

Tumor volume = major axis x minor axis x minor axis x (1/2)

Test compounds dissolved in vehicle solvent (10% DMSO, 9% Cremophor EL, 18% PEG400, 0.09 mol / L citric acid solution) once or twice intraperitoneally for individuals with tumor volumes of 150-600 mm ³ Administered once. The second administration was performed 8 hours after the first administration. Tumors were collected under ether anesthesia 24 hours after the first administration, and the tumors were homogenized in Cell Lysis Buffer (Cell Signaling) to obtain a tumor lysate.

The protein concentration of the obtained tumor lysate was measured using a BCA Protein assay kit (Thermo Scientific) to adjust the protein concentration of each tumor lysate. Laemmli® Sample® Buffer® (BioRad) was added to each obtained tumor lysate and heated at 95 ° C. for 5 minutes to obtain a sample solution.

The amount of phosphorylated histone H3 protein contained in the obtained sample solution was measured by Western blotting. That is, the obtained sample solution was subjected to SDS-PAGE and then transferred to a PVDF membrane. After blocking the PVDF membrane with StartingBlock (T20) (PBS) (Blocking Buffer) (Thermo (Scientific)) (Catalog number 06570, Upstate Biotechnology) solution was reacted. The obtained PVDF membrane was washed with Tris buffered saline (BioRad) containing 0.05% Tween20 (BioRad), HRP-labeled rabbit IgG diluted 10,000 times with Can, Get Signal, Immunoreaction, Enhanced Solution, Solution (2) (Toyobo). Polyclonal antibody (Amersham Biosciences NA9340) and the obtained PVDF membrane were reacted for 1 hour at room temperature. After washing the PVDF membrane with Tris buffered saline, the amount of labeled protein was detected using SuperSignal® West® FemtoMaximum® Sensitivity® Substrate® (Pierce® Biotechnology) ®. In detection, a lumino image analyzer LAS-1000 (Fuji Film) was used to detect the amount of labeled protein as the amount of luminescence.

The increase rate (fold) of phosphorylated histone H3 protein in each sample was calculated by the following formula.
Phosphorylated histone H3 protein increase rate (times) = phosphorylated histone H3 protein luminescence amount of test compound ÷ phosphorylated histone H3 protein luminescence amount of control group Phosphorylated histone H3 protein increase rate (times) of each test compound is shown in Table 4 Show.

These results indicate that the compound of the present invention causes an increase in phosphorylated histone H3 protein observed when cell growth is suppressed, and that the present compound has an activity of suppressing cell growth in vivo.

Thus, it was shown that the compound of the present invention has cancer cell growth inhibitory activity.

Since the compound of the present invention exhibits an excellent inhibitory action on CENP-E, it can provide a clinically useful preventive or therapeutic agent for cancer and the like. The compound of the present invention is also useful as a pharmaceutical because it is excellent in terms of drug efficacy, pharmacokinetics, solubility, interaction with other pharmaceuticals, safety and stability.

Claims

formula:

[Where
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 with adjacent carbon atoms,
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. ]
Or a salt thereof.
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 claim 1, wherein n is 1.
The compound or a salt thereof according to claim 1, wherein R 1 is C 1-6 alkoxy.
The compound or a salt thereof according to claim 1, wherein R 2 is a hydrogen atom.
The compound or a salt thereof according to claim 1, wherein R 3 is a hydrogen atom.
R 4 is
(1) amino having 1 or 2 C 1-6 alkyl, and
(2) 1 selected from (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 The compound or a salt thereof according to claim 1, which is C 1-6 alkyl optionally having 3 substituents.
Ar ring is
(1) a halogen atom, and
(2) The compound or salt thereof according to claim 1, 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 A C 1-6 alkyl optionally having 1 to 3 substituents selected from the group consisting of heterocyclic groups;
R 5 is
(1) hydrogen atom,
(2) C 1-6 alkyl-carbonyl,
(3) C 1-6 alkoxy-carbonyl, or
(4) carbamoyl optionally having 1 or 2 C 1-6 alkyl;
R 7 and R 8 are the same or different,
(1) a hydrogen atom, or
(2) C 1-6 alkyl;
R 9 and R 10 are the same or different,
(1) hydrogen atom,
(2) a halogen atom,
(3) cyano, or
(4) C 1-6 alkyl optionally having 1 to 3 halogen atoms;
X a and X b are the same or different and are each CH or N;
X c is CH;
Y a is CH 2 , O, NR 5 (R 5 is as defined above), S, or SO 2 ;
Y b is a bond;
The compound or a salt thereof according to claim 1, wherein n is an integer of 1 to 3.
(+)-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 or a salt thereof.
(+)-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 or a salt thereof.
(+)-N- [7-cyano-1,1-dioxide-6- (trifluoromethyl) -2,3-dihydro-1-benzothiophen-3-yl] -N- [2- (dimethylamino) Ethyl] -3- (4-fluoro-3-methylphenyl) -5-methoxyimidazo [1,2-a] pyridine-2-carboxamide or a salt thereof.
A medicament comprising the compound according to claim 1 or a salt thereof.
The medicament according to claim 12, which is a CENP-E inhibitor.
The medicament according to claim 12, which is a preventive or therapeutic agent for cancer.
A method for inhibiting CENP-E in a mammal, comprising administering an effective amount of the compound or salt thereof according to claim 1 to the mammal.
A method for preventing or treating cancer in a mammal, comprising administering an effective amount of the compound or salt thereof according to claim 1 to the mammal.
Use of the compound according to claim 1 or a salt thereof for producing a preventive / therapeutic agent for cancer.
The compound according to claim 1 or a salt thereof for use in the prevention / treatment of cancer.