JP6469272B2 - A pharmaceutical comprising a biaryl derivative or a salt thereof - Google Patents

Description

  The present invention relates to a pharmaceutical and an antifungal agent comprising a novel biaryl derivative or a salt thereof.

For mycosis, superficial mycosis represented by various ringworms, cutaneous candidiasis, folding screen, etc. There is deep mycosis to be.
Superficial mycosis is a mycosis in which the fungus infects the epidermis, hair, nails, etc., and ringworm with Trichophyton spp. It accounts for 10%. The number of cases of ringworm in Japan is estimated to be 21 million for foot ringworm and 12 million for onychomycosis.
Onychomycosis is an intractable disease, and oral antifungal agents such as terbinafine and itraconazole are generally used for treatment. However, the patient's adherence to medication is low because treatment is compulsory for at least 3 months. In addition, since the sterilization effect at the site of infection is insufficient, recurrence and relapse after treatment are also problems. Furthermore, drug-drug interactions and side effects such as liver and gastrointestinal disorders are also problematic, and treatment may be limited for elderly people and patients with complications or underlying diseases.
Therefore, an antifungal agent that is highly effective against onychomycosis by local administration without systemic side effects and drug-drug interactions is required. In order to exert an effect by local administration, it is necessary that the drug sufficiently penetrates the thick keratin of the nail plate and exhibits antifungal activity against ringworm fungus in the nail and nail bed.
As an external preparation for treating onychomycosis, nail lacquer preparation of amorolfine has already been clinically applied overseas. However, although amorolfine has an excellent anti-tinea fungus activity, it does not have sufficient clinical effects due to its low penetration into the nails.

By the way, the following compounds are known as biaryl derivatives. In Patent Document 1, as a compound having kinase inhibitory activity such as Tie-2, the formula:

(Wherein each symbol is as defined in Patent Document 1) is described.
In Patent Document 2, as a compound having protein kinase inhibitory activity such as Tie-2, the formula:

(Wherein each symbol is as defined in Patent Document 2) is described.
Patent Document 3 discloses a compound having Aurora kinase inhibitory activity as represented by the formula:

(Wherein each symbol is as defined in Patent Document 3) is described.
In Patent Document 4, as a compound having protein kinase inhibitory activity such as Tie-2, the formula:

(Wherein each symbol is as defined in Patent Document 4) is described.
It is disclosed that these compounds are useful for the treatment of angiogenesis and cancer by inhibiting various kinases.
On the other hand, in Patent Document 5, a compound having phosphodiesterase 10 inhibitory activity is represented by the formula:

(Wherein each symbol is as defined in Patent Document 5) is described.
Patent Document 6 discloses a compound having a phosphodiesterase 10 inhibitory activity represented by the formula:

(Wherein each symbol is as defined in Patent Document 6) is described.
It is disclosed that these compounds are useful for the treatment of obesity, non-insulin dependent diabetes mellitus, schizophrenia, bipolar disorder, obsessive compulsive disorder and the like by inhibiting phosphodiesterase 10.
However, these prior art documents do not specifically disclose the compound of the general formula (I) of the present invention, and have anti-tinea fungus activity, and are useful for the treatment of diseases caused by trichodermis. It is not described or suggested at all.

International Publication No. 2005/113494 International Publication No. 2007/100646 International Publication No. 2007/087276 International Publication No. 2008/057280 International Publication No. 2010/057126 International Publication No. 2010/077992

  An object of the present invention is to provide a novel compound or a salt thereof having high antifungal activity against ringworm, which is a main causative bacterium of superficial mycosis, and exhibiting high efficacy against diseases caused by ringworm. Is to provide a medicament. Another object of the present invention is to provide a pharmaceutical comprising a novel compound or a salt thereof useful as an external therapeutic agent for onychomycosis by having excellent nail permeability.

As a result of intensive studies to solve the above problems, the present inventors have found that a pharmaceutical comprising a biaryl derivative represented by the following general formula (I) or a salt thereof has excellent antifungal activity against ringworm The present invention was completed.

That is, the present invention provides the following.
(1-A) General formula (I)

[In the formula, ring A represents an optionally substituted phenyl, or an optionally substituted 5- or 6-membered heteroaryl (the ring A is further condensed and optionally substituted) A ring may be formed),
Q represents CH ₂ , CF ₂ , S═O, SO ₂ , C═O, NH, O or S;
X ¹ , X ² and X ³ each independently represent CH, CR ¹ or N;
Y represents CH or N;
Z represents CR ^2b or N;
R ¹ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group or a C ₁ -C ₆ haloalkoxy group,
R ^2a and R ^2b each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a formyl group, an optionally substituted C ₁ -C ₆ alkyl group, or an optionally substituted C ₁ -C ₆ haloalkyl group, optionally substituted C ₁ -C ₆ alkoxy group, optionally substituted C ₁ -C ₆ haloalkoxy group, optionally substituted C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, optionally substituted C ₁ -C ₄ alkoxy-C ₁ -C ₄ haloalkyl group, optionally substituted C ₁ -C ₆ alkylcarbonyl group, optionally substituted C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ alkylcarbonyloxy group which may be substituted, C ₃ -C ₇ cycloalkyl group which may be substituted, heterocycloalkyl group which may be substituted, substituted Optionally substituted heterocycloalkyloxy group, optionally substituted C ₂ -C ₆ alkenyl group, optionally substituted C ₂ -C ₆ alkenyloxy group, optionally substituted C ₂ -C ₆ alkenyl-C ₁ -C ₆ alkyl group, optionally substituted C ₂ -C ₆ alkenyl-C ₁ -C ₆ alkoxy group, optionally substituted C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ alkyl group, optionally substituted C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ alkoxy group,
Optionally substituted C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ haloalkyl group, optionally substituted C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ haloalkoxy group, optionally substituted good C ₂ -C ₆ alkynyl group, optionally substituted C ₂ -C ₆ alkynyloxy group, an optionally substituted C ₂ -C ₆ alkynyl -C ₁ -C ₆ alkyl group, optionally substituted Good C ₂ -C ₆ alkynyl-C ₁ -C ₆ alkoxy group, optionally substituted C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ alkyl group, optionally substituted C ₂ -C ₆ alkynyl Oxy-C ₁ -C ₄ alkoxy group, optionally substituted C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ haloalkyl group, optionally substituted C ₂ -C ₆ alkynyloxy-C ₁ -C _4- haloalkoxy group, -NR ^a R ^b (R ^a and R ^b each independently represent a hydrogen atom or an optionally substituted C ₁ -C ₆ alkyl group (only R ^a and R ^b are simultaneously hydrogen atoms)}, an optionally substituted C ₁ -C ₆ alkylthio group, an optionally substituted C ₁ -C ₆ haloalkylthio group, pentafluorosulfanyl Group or general formula (IA)

{Where
L is a single bond, one or more of (CH ₂ ) _p and (CH ₂ ) _q hydrogen atoms are each substituted with a halogen atom, a C ₁ -C ₄ alkyl group or a C ₃ -C ₇ cycloalkyl group. -(CH ₂ ) _p-
, -O (CH ₂ ) _p -,-(CH ₂ ) _p O-,-(CH ₂ ) _p O (CH ₂ ) _q- , -NR ^c (CH ₂ ) _p -,-(CH ₂ ) _p NR ^c- or-(CH ₂ ) _p NR ^c (CH ₂ ) _q-
p represents 1, 2 or 3,
q represents 1, 2 or 3,
R ^c represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
Ring B represents an optionally substituted carbocycle or an optionally substituted heterocycle. } Or a group represented by
When Z is CR ^2b , R ^2a and R ^2b may be taken together with the carbon atom to which they are attached to form an optionally substituted carbocycle or an optionally substituted heterocycle;
R ³ is a hydrogen atom, a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, an optionally substituted C ₁ -C ₆ alkoxy group, or a C ₁ -C ₆ haloalkoxy group, an optionally substituted C ₃ -C ₇ cycloalkyl group, optionally substituted C ₂ -C ₆ alkenyl group, optionally substituted C ₂ -C ₆ alkynyl group, or a substituted Represents an aralkyl group which may be substituted. ] The pharmaceutical which consists of a biaryl derivative represented by these, or its salt.

(1) General formula (I)

[Wherein ring A has the following formula:

(In the formula, n is 1 or 2,
R ⁴ is a hydrogen atom, halogen atom, cyano group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₃ -C ₇ cycloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, vinyl group, ethynyl group, C ₁ -C ₆ alkylthio group, —NR ^d R ^e (R ^d and R ^e each independently represents a hydrogen atom or a C ₁ -C ₆ alkyl group) C ₁ -C ₆ alkylcarbonyl group or C ₁ -C ₆ alkoxycarbonyl group,
X ⁴ is NR ^f (R ^f represents a hydrogen atom or a C ₁ -C ₆ alkyl group), O or S,
R ^5a , R ^5b and R ^5c are each independently a hydrogen atom, halogen atom, cyano group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkyl group, C ₁ A -C ₆ haloalkoxy group, a C ₃ -C ₇ cycloalkyl group, a C ₁ -C ₆ alkylcarbonyl group or a C ₁ -C ₆ alkoxycarbonyl group,
R ^6a and R ^6b are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₃ -C ₇ cycloalkyl group, or a C ₁ -C ₆ alkoxy group. , A C ₁ -C ₆ haloalkoxy group, or a C ₁ -C ₆ alkylthio group),
Q represents CH ₂ , CF ₂ , S═O, SO ₂ , C═O, NH, O or S;
X ¹ , X ² and X ³ each independently represent CH, CR ¹ or N;
Y represents CH or N;
Z represents CR ^2b or N;
R ¹ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group or a C ₁ -C ₆ haloalkoxy group,
R ^2a and R ^2b are each independently a hydrogen atom, a halogen atom, a cyano group, a C ₁ -C ₆ alkyl group, —OR ^g (R ^g is a C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl groups, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₂ -C ₆ alkenyl -C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkynyl -C ₁ -C ₆ alkyl group, a cyanomethyl group , -CONR ^j R ^k (R ^j and R ^k each independently represents a hydrogen atom or a C ₁ -C ₆ alkyl group), a C ₃ -C ₇ cycloalkyl group, or a C ₁ -C ₆ alkyl carbonyl Represents a group. C ₁ -C ₆ alkyl group substituted with a}, C ₁ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group substituted with a group, C ₁ -C ₆ alkyl substituted with cyano, C ₁ - A C ₆ haloalkyl group, a C ₁ -C ₆ haloalkyl group substituted with a heterocycloalkyl group, —NR ^h R ⁱ {R ^h represents a C ₁ -C ₆ alkyl group, R ⁱ represents a hydrogen atom, C ₁ A —C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a cyanomethyl group, a C ₁ -C ₆ alkylcarbonyl group or a C ₁ -C ₆ alkoxycarbonyl group; } C ₁ -C ₆ haloalkyl group substituted with C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkoxy group substituted with C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C C ₁ is substituted with _alkoxy -C ₄ alkoxy -C ₁ - C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ alkylcarbonyloxy group, C ₃ -C ₇ cycloalkyl group, C ₁ -C ₆ alkyl group A substituted C ₃ -C ₇ cycloalkyl group, a C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group substituted with a C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group, a heterocycloalkyloxy group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkenyl-C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl -C ₁ -C ₆ alkoxy group C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ alkyl group, C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ alkoxy group, C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ haloalkyl group, C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ haloalkoxy group, C ₂ -C ₆ alkynyl group, C ₂ -C ₆ alkynyloxy group, C ₂ -C ₆ alkynyl-C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkynyl-C ₁ -C ₆ alkoxy group, C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ alkyl group, C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ alkoxy group, C ₂ -C ₆ Alkynyloxy-C ₁ -C ₄ haloalkyl group, C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ haloalkoxy group, —NR ^a R ^b (R ^a and R ^b are each independently a hydrogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkyl group substituted with a cyano group, C ₁ -C ₆ alkyl group substituted with C ₁ -C ₄ alkoxy groups, substituted by C ₁ -C ₆ alkoxycarbonyl group C ₁ -C ₆ alkyl group, C ₃ -C ₇ Black alkyl C ₁ -C ₆ alkyl group substituted with a group, or a C ₂ -C represents the ₆ C ₁ -C ₆ alkyl group substituted with an alkenyl group (provided that when R ^a and R ^b simultaneously hydrogen atoms C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group, pentafluorosulfanyl group, or general formula (IA)

{Where
L is a single bond, one or more of (CH ₂ ) _p hydrogen atoms may be substituted with a halogen atom,-(CH ₂ ) _p- , -O (CH ₂ ) _p -,-( _{CH 2) p O -, -} NR c (CH 2) p - or ^{_{- (CH 2) p NR c}} - represents,
p represents 1 or 2,
R ^c represents a hydrogen atom or a methyl group,
Ring B represents phenyl, pyrrolyl, furyl, thienyl, imidazolyl, triazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. } Or a group represented by
When Z is CR ^2b , R ^2a and R ^2b may be combined to form — (CH ₂ ) _r — which may be substituted with a halogen atom, a hydroxyl group, or an oxo group (r is 3, 4, 5 or 6),
R ³ is a hydrogen atom, halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl Represents a group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, or an aralkyl group. ] The pharmaceutical which consists of a biaryl derivative represented by these, or its salt.

(2) A medicament comprising the biaryl derivative or salt thereof according to (1), wherein Q in the general formula (I) is NH, O or S.
(3) A medicament comprising the biaryl derivative or salt thereof according to (2), wherein Q in the general formula (I) is O.
(4) In the general formula (I), X ¹ and X ³ are CH, X ² is CR ¹ or N, R ¹ is a hydrogen atom or a halogen atom, (1) to (3) A medicament comprising the biaryl derivative or a salt thereof according to any one of the above.
(5) A medicament comprising the biaryl derivative or salt thereof according to (4), wherein, in the general formula (I), X ¹ and X ³ are CH and X ² is CH or N.
(6) A medicament comprising the biaryl derivative or a salt thereof according to any one of (1) to (5), wherein R ³ in the general formula (I) is a hydrogen atom, a fluorine atom or a methyl group.

(7) In the general formula (I),
Q is O;
X ¹ is CH;
X ² and X ³ are each independently CR ¹ or N;
R ¹ is a hydrogen atom or a halogen atom;
Z is CR ^2b ;
R ^2a and R ^2b are each independently a hydrogen atom, halogen atom, cyano group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ Haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl Group, C ₃ -C ₇ cycloalkyl group, C ₂ -C ₆ alkenyl-C ₁ -C ₆
Alkoxy groups, C ₂ -C ₆ alkynyl-C ₁ -C ₆ alkoxy groups, and general formula (IA)

{Where
L represents a single _{bond, - (CH 2) p -} , - O (CH 2) p - or - (CH ₂₎ represents _p O-,
p represents 1 or 2,
Ring B is a halogen atom, a C ₁ -C ₄ alkyl group, a phenyl optionally substituted with a C ₁ -C ₄ alkoxy group or a cyano group, or a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ represents a 5- or 6-membered heteroaryl optionally substituted by an alkoxy group or a cyano group. } (Except for the case where R ^2a and R ^2b are simultaneously hydrogen atoms);
R ³ is a hydrogen atom;
Ring A is represented by the following formula:

(In the formula, n is 1 or 2, and R ⁴ is a halogen atom, a cyano group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₃ -C ₇ cycloalkyl group, a C _1- Selected from the group consisting of C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, vinyl group, ethynyl group and C ₁ -C ₆ alkylthio group, and R ^5a , R ^5b and R ^5c are each independently hydrogen A biaryl derivative or a salt thereof according to (1), wherein the ring is selected from the group consisting of an atom, a halogen atom, a C ₁ -C ₄ alkyl group and a C ₁ -C ₄ haloalkyl group. A medicine consisting of
(8) In the general formula (I),
Ring A is the following formula

(Wherein, n, R ⁴ , R ^5a , R ^5b and R ^5c are rings selected from the group consisting of (7)), consisting of the biaryl derivative according to (7) or a salt thereof Medicine.

(9) In the general formula (I), R ⁴ is a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a cyclopropyl group, a C ₁ -C ₄ alkoxy group, and a C ₁ -C ₄ A pharmaceutical comprising the biaryl derivative or a salt thereof according to any one of (7) and (8), selected from the group consisting of a haloalkoxy group.
(10) In the general formula (I), R ^2a and R ^2b are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, Group consisting of C ₁ -C ₄ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ haloalkyl group and C ₃ -C ₇ cycloalkyl group A pharmaceutical comprising the biaryl derivative or a salt thereof according to any one of (7) to (9), wherein R ^2a and R ^2b are simultaneously selected from hydrogen atoms (except when R ^2a and R ^2b are simultaneously hydrogen atoms).
(11) The compound represented by the general formula (I) is

Or a pharmaceutical comprising the biaryl derivative or a salt thereof according to (1).
(12) The medicament according to any one of (1) to (11), which is an antifungal agent.
(13) The medicament according to any one of (1) to (11), which is a therapeutic agent for superficial mycosis.
(14) The medicament according to any one of (1) to (11), which is a therapeutic agent for onychomycosis.
(15) The medicament according to any one of (1) to (11), which is a therapeutic agent for external onychomycosis.
(16) Biaryl contained in the medicament according to any one of (1) to (11) for producing an antifungal agent, a superficial mycosis treatment agent, an onychomycosis treatment agent, or a topical onychomycosis treatment agent Use of derivatives or salts thereof.

  The biaryl derivative of the present invention or a salt thereof has excellent antifungal activity against ringworm fungus which is a main causative bacterium of superficial mycosis. Thus, the pharmaceutical comprising the biaryl derivative of the present invention or a salt thereof is useful as a preventive or therapeutic agent for infections caused by ringworm of mammals including humans. Furthermore, since the medicament comprising the biaryl derivative of the present invention or a salt thereof has excellent nail permeability, it is particularly useful as an external therapeutic agent for onychomycosis.

Next, each substituent in the general formula (I) will be described.
Specific examples of the “halogen atom” are a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The “C ₁ -C ₆ alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms,
Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-pentyl, 3-methylbutyl. Group (isopentyl group), neopentyl group, n-hexyl group and the like.
The “C ₁ -C ₄ alkyl group” means a linear or branched alkyl group having 1 to 4 carbon atoms,
Specific examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group and the like.
The “C ₁ -C ₆ haloalkyl group” means an alkyl group in which one or more of the hydrogen atoms of the “C ₁ -C ₆ alkyl group” are substituted with a halogen atom. Fluoromethyl group, difluoromethyl group, monofluoromethyl group, 1,1-difluoroethyl group, 2,2,2-trifluoroethyl group, 1,1,2-trifluoroethyl group, 1,1,2,2 , 2-pentafluoroethyl group, 2-bromo-1,1-difluoroethyl group and the like.
The “C ₁ -C ₄ haloalkyl group” means an alkyl group in which one or more of the hydrogen atoms of the “C ₁ -C ₄ alkyl group” is substituted with a halogen atom. Fluoromethyl group, difluoromethyl group, monofluoromethyl group, 1,1-difluoroethyl group, 2,2,2-trifluoroethyl group, 1,1,2-trifluoroethyl group, 1,1,2,2 , 2-pentafluoroethyl group, 2-bromo-1,1-difluoroethyl group and the like.

The “C ₁ -C ₆ alkoxy group” means an alkoxy group in which the alkyl moiety has the same meaning as the above-mentioned “C ₁ -C ₆ alkyl group”. Specific examples thereof include a methoxy group, an ethoxy group, and n-propoxy group. Group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group, n-pentyloxy group, tert-amyloxy group, 3-methylbutoxy group, neopentyloxy group, n-hexyloxy group Groups and the like.
The term “C ₁ -C ₄ alkoxy group” means an alkoxy group in which the alkyl moiety has the same meaning as the above “C ₁ -C ₄ alkyl group”. Specific examples include a methoxy group, an ethoxy group, and n-propoxy group. Group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group and the like.
The “C ₁ -C ₆ haloalkoxy group” means a haloalkoxy group in which the haloalkyl moiety has the same meaning as the “C ₁ -C ₆ haloalkyl group”. Specific examples include a trifluoromethoxy group, difluoromethoxy group, and the like. Group, 2,2,2-trifluoroethoxy group and the like.
The “C ₁ -C ₄ haloalkoxy group” means a haloalkoxy group in which the haloalkyl moiety has the same meaning as the “C ₁ -C ₄ haloalkyl group”. Specific examples include a trifluoromethoxy group, difluoromethoxy group, and the like. Group, 2,2,2-trifluoroethoxy group and the like.

“C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group” means the above “C ₁ -C ₄ alkyl group” and the above “C ₁ -C ₄ alkyl group”.
An “alkoxy group” is substituted, and these can be bonded at all substitutable positions. For example, a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group, an ethoxyethyl group, etc. are mentioned.
“C ₁ -C ₄ alkoxy-C ₁ -C ₄ haloalkyl group” means that the above “C ₁ -C ₄ alkoxy group” is substituted for the above “C ₁ -C ₄ haloalkyl group”, and these can be substituted. Can be combined at any position. Examples include a difluoro (methoxy) methyl group, a difluoro (ethoxy) methyl group, a 1,1-difluoro-2-methoxyethyl group, 1,1-difluoro-2-ethoxyethyl, and the like.
“C ₁ -C ₆ alkylcarbonyl group” means an alkylcarbonyl group in which the alkyl moiety is the aforementioned “C ₁ -C ₆ alkyl group”. Specific examples include a methylcarbonyl group, an ethylcarbonyl group, n -Propylcarbonyl group, isopropylcarbonyl group, n-butylcarbonyl group, isobutylcarbonyl group, tert-butylcarbonyl group, sec-butylcarbonyl group, n-pentylcarbonyl group, tert-amylcarbonyl group, 3-methylbutylcarbonyl group, A neopentylcarbonyl group, n-hexylcarbonyl group, etc. are mentioned.
“C ₁ -C ₆ alkoxycarbonyl group” means an alkoxycarbonyl group in which the alkoxy moiety is the aforementioned “C ₁ -C ₆ alkoxy group”. Specific examples include a methoxycarbonyl group, an ethoxycarbonyl group, n -Propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, sec-butoxycarbonyl group, n-pentyloxycarbonyl group, tert-pentyloxycarbonyl group, 3-methyl Examples include butoxycarbonyl group, neopentyloxycarbonyl group, n-hexyloxycarbonyl group and the like.
The “C ₁ -C ₆ alkylcarbonyloxy group” means an alkylcarbonyloxy group in which the alkylcarbonyl moiety is the aforementioned “C ₁ -C ₆ alkylcarbonyl group”. Specific examples include a methylcarbonyloxy group, Examples thereof include an ethylcarbonyloxy group, an n-propylcarbonyloxy group, and an isopropylcarbonyloxy group.
The “C ₃ -C ₇ cycloalkyl group” represents a monocyclic saturated carbocyclic group having 3 to 7 carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.

The “heterocycloalkyl group” represents a monocyclic saturated heterocyclic group. Specific examples include a pyrrolidinyl group (for example, 1-pyrrolidinyl group, 2-pyrrolidinyl group, 3-pyrrolidinyl group), piperidinyl group (for example, 1-piperidinyl group, 4-piperidinyl group), homopiperidinyl group (for example, 1-homopiperidinyl group). Group, 4-homopiperidinyl group), tetrahydrofuranyl group (for example, 2-tetrahydrofuranyl group, 3-tetrahydrofuranyl group), tetrahydropyranyl group (for example, 4-tetrahydropyranyl group), piperazinyl group (for example, 1-piperazinyl group) Group), homopiperazinyl group (for example, 1-homopiperazinyl group), morpholino group and the like. As preferable examples of the “heterocycloalkyl group”, a 5- to 7-membered monocyclic ring containing one or more (for example, 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom And a formula saturated heterocyclic group.
“Heterocycloalkyloxy group” means a heterocycloalkyloxy group in which the heterocycloalkyl moiety is the above “heterocycloalkyl group”. Specific examples include a pyrrolidinyloxy group and a tetrahydropyranyloxy group. Is mentioned.

The “C ₂ -C ₆ alkenyl group” means a linear or branched alkenyl group having 2 to 6 carbon atoms having one or more double bonds. Specific examples include a vinyl group, 1-propenyl group, isopropenyl group, allyl group, 2-methylallyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, isobutenyl group, 2-methyl-1-propenyl group, 1-methyl-1- Examples include propenyl group, 1-pentenyl group, 2-pentenyl group, 1-hexenyl group, 2-methylbut-3-en-1-yl group and the like.

“C ₂ -C ₆ alkenyloxy group” means an alkenyloxy group in which the alkenyl moiety is the aforementioned “C ₂ -C ₆ alkenyl group”. Specific examples include vinyloxy group, allyloxy group, 1-butenyloxy Group, 2-butenyloxy group, 3-butenyloxy group and the like.

“C ₂ -C ₆ alkenyl-C ₁ -C ₆ alkyl group” refers to the above “C ₁ -C ₆ alkyl group” and the above “C ₂ -C ₆ alkyl group”.
An “alkenyl group” is substituted, and these can be bonded at all substitutable positions. For example, an allyl group, 2-methylallyl group, but-3-en-1-yl group, 2-methylbut-3-en-1-yl group and the like can be mentioned.
“C ₂ -C ₆ alkenyl-C ₁ -C ₆ alkoxy group” is the above “C ₁ -C ₆ alkoxy group” substituted with the above “C ₂ -C ₆ alkenyl group”, which can be substituted. Can be combined at any position.
For example, allyloxy group, 2-methylallyloxy group, but-3-en-1-yloxy group, 2-methylbut-3-en-1-yloxy group and the like can be mentioned.

The “C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ alkyl group” is the above “C ₁ -C ₄ alkyl group” substituted with the above “C ₂ -C ₆ alkenyloxy”, which is substituted Can be combined at all possible positions. For example, an allyloxymethyl group etc. are mentioned.
The “C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ alkoxy group” is the above “C ₁ -C ₄ alkoxy group” substituted with the above “C ₂ -C ₆ alkenyloxy”, which is substituted Can be combined at all possible positions. For example, an allyloxymethoxy group etc. are mentioned.
“C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ haloalkyl group” is the above “C ₁ -C ₄ haloalkyl group” substituted with the above “C ₂ -C ₆ alkenyloxy”, which is substituted Can be combined at all possible positions.
The “C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ haloalkoxy group” refers to the above “C ₁ -C ₄ haloalkoxy group” substituted with the above “C ₂ -C ₆ alkenyloxy”. Can be attached at all substitutable positions.

The “C ₂ -C ₆ alkynyl group” means a linear or branched alkynyl group having 2 to 6 carbon atoms having one or more triple bonds. Specific examples thereof include an ethynyl group, 1 -Propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-1-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-pentynyl Group, 4-methyl-2-pentynyl group, 1-hexynyl group and the like.

The term “C ₂ -C ₆ alkynyloxy group” means an alkynyloxy group in which the alkynyl moiety is the above-mentioned “C ₂ -C ₆ alkynyl group”. Specific examples thereof include 2-propynyloxy group, 2-butynyloxy group Group, 2-pentynyloxy group, 4-methyl-2-pentynyloxy group and the like.

"C ₂ -C ₆ alkynyl -C ₁ -C ₆ alkyl group", wherein the "C ₁ -C ₆ alkyl group", "C ₂ -C ₆
An “alkynyl group” is substituted, and these can be bonded at all substitutable positions. For example, 2-propynyl group, 2-butenyl group, 2-pentynyl group, 4-methyl-2-pentynyl group and the like can be mentioned.
“C ₂ -C ₆ alkynyl-C ₁ -C ₆ alkoxy group” is the above “C ₁ -C ₆ alkoxy group” substituted with the above “C ₂ -C ₆ alkynyl group”, which can be substituted. Can be combined at any position.
For example, 2-propynyloxy group, 2-butenyloxy group, 2-pentynyloxy group, 4-methyl-2-pentynyloxy group and the like can be mentioned.

“C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ alkyl group” is the above “C ₁ -C ₄ alkyl group” substituted with the above “C ₂ -C ₆ alkynyloxy”, and these are substituted Can be combined at all possible positions.
“C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ alkoxy group” is the above “C ₁ -C ₄ alkoxy group” substituted with the above “C ₂ -C ₆ alkynyloxy”, and these are substituted Can be combined at all possible positions.
“C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ haloalkyl group” is the above “C ₁ -C ₄ haloalkyl group” substituted with “C ₂ -C ₆ alkynyloxy”, which is substituted Can be combined at all possible positions. Specific examples include 1,1-difluoro-2- (prop-2-yn-1-yloxy) ethyl group and the like.
“C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ haloalkoxy group” is the above “C ₁ -C ₄ haloalkoxy group” substituted with “C ₂ -C ₆ alkynyloxy”. Can be attached at all substitutable positions.

The “C ₁ -C ₆ alkylthio group” means an alkylthio group in which the alkyl portion has the same meaning as the above-mentioned “C ₁ -C ₆ alkyl group”. Specific examples include a methylthio group, an ethylthio group, and an n-propylthio group. Group, isopropylthio group, n-butylthio group, isobutylthio group, tert-butylthio group, sec-butylthio group, n-pentylthio group, tert-pentylthio group, 3-methylbutylthio group, neopentylthio group, n-hexylthio group Groups and the like.
The “C ₁ -C ₆ haloalkylthio group” is _one of the hydrogen atoms of the “C ₁ -C ₆ alkylthio group”.
The alkylthio group by which one or more was substituted by the halogen atom is meant, and a specific example includes a trifluoromethylthio group.

“Carbocycle” represents phenyl or a 5-7 membered monocyclic saturated or unsaturated carbocycle. “Heterocycle” represents “5- or 6-membered heteroaryl” or 5- to 7-membered monocyclic saturated or unsaturated heterocycle. The “5- or 6-membered heteroaryl” represents “5-membered heteroaryl” or “6-membered heteroaryl”.

The term “5-membered heteroaryl” refers to a 5-membered monocyclic aromatic heterocycle containing one or more (for example, 1 to 4) heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms. Represents. Examples thereof include pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, oxadiazole, triazole, tetrazole and the like.
Examples of the “5-membered heteroaryl” group include a pyrrolyl group (for example, a 2-pyrrolyl group),
Furyl group (for example, 3-furyl group), thienyl group (for example, 2-thienyl group), imidazolyl group (
For example, 4-imidazolyl group), pyrazolyl group (for example, 3-pyrazolyl group), oxazolyl group (for example, 2-oxazolyl group), isoxazolyl group (for example, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group) , Thiazolyl group (for example, 2-thiazolyl group, 5-thiazolyl group), isothiazolyl group (for example, 3-isothiazolyl group, 4-isothiazolyl group)
, Thiadiazolyl group, oxadiazolyl group, triazolyl group (for example, 1,2,3-triazol-2-yl group), tetrazolyl group and the like.

The “6-membered heteroaryl” represents a 6-membered monocyclic aromatic heterocycle containing one or more nitrogen atoms in addition to carbon atoms (for example, 1 to 3). For example, pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like can be mentioned.
Examples of the “6-membered heteroaryl” group include a pyridyl group (for example, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group), a pyridazinyl group (for example, 3-pyridazinyl group), and a pyrimidinyl group (for example, 5-pyrimidinyl group), pyrazinyl group (for example, 2-pyrazinyl group) and the like.

Ring A may be “further condensed to form an optionally substituted condensed ring”, wherein “further condensed” means at the position where ring A can be condensed, It means that the carbocyclic or heterocyclic ring is further condensed. For example, when ring A is “phenyl”, it becomes “a condensed ring in which phenyl and carbocycle are condensed” or “a condensed ring in which phenyl and heterocycle are condensed”, and when ring A is “5-membered heteroaryl” , "A condensed ring in which a 5-membered heteroaryl and a carbocycle are condensed" or "a condensed ring in which a 5-membered heteroaryl and a heterocyclic ring are condensed", and when the ring A is a "6-membered heteroaryl", It represents a “fused ring in which a membered heteroaryl and a carbocycle are fused” or a “fused ring in which a six-membered heteroaryl and a heterocycle are fused”.

Examples of the “condensed ring in which phenyl and carbocycle are condensed” include indane, indene, naphthalene, dihydronaphthalene, tetrahydronaphthalene and the like.
Examples of the “condensed ring in which phenyl and carbocycle are condensed” include, for example, indan-4-yl, indan-5-yl, 1H-inden-4-yl, 1H-inden-5-yl, naphthalen-1-yl , Naphthalen-2-yl, 5,6-dihydronaphthalen-1-yl, 7,8-dihydronaphthalen-1-yl, 5,6-dihydronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalene 1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl and the like.
Examples of the `` condensed ring in which phenyl and heterocycle are condensed '' include, for example, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, quinazoline, cinnoline, indole, indoline, isoindole, isoindoline, indazole, indazoline, benzofuran, dihydro Examples include benzofuran, isobenzofuran, 1,3-benzodioxole, 1,4-benzodioxan, benzothiophene, benzimidazole, benzothiazole, benzoxazole, benzoisoxazole, benzoisothiazole, chroman, chromene and the like.
Examples of the “fused ring in which phenyl and heterocycle are condensed” include, for example, quinolin-5-yl, quinolin-6-yl, quinolin-8-yl, isoquinolin-5-yl, isoquinolin-6-yl, quinoxaline-5 -Il, quinoxalin-6-yl, quinazolin-5-yl, quinazolin-6-yl, indol-4-yl, indol-5-yl, benzofuran-4-yl, benzofuran-5-yl, dihydrobenzofuran-7- Yl, benzo [d] [1,3] dioxol-4-yl, 1,4-benzodioxan-5-
Yl, benzothiophen-4-yl, benzothiophen-5-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzooxazol-4-yl Benzoxazol-5-yl, benzoxazol-7-yl, chroman-8-yl and the like.
Examples of the “condensed ring in which a 5-membered heteroaryl and a carbocyclic ring are condensed” include indole, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzoxazole, indazole, benzisoxazole, benzoisothiazole, and the like. .
Examples of the “fused ring in which a 5-membered heteroaryl and a carbocycle are fused” include, for example, indol-1-yl, indol-2-yl, indol-3-yl, benzofuran-2-yl, benzofuran-3-yl , Benzothiophen-2-yl, benzothiophen-3-yl, benzimidazol-2-
Yl, benzoxazol-2-yl, benzothiazol-2-yl, indazol-3-yl,
Examples thereof include benzoisoxazol-3-yl and benzoisothiazol-3-yl.

Examples of the “condensed ring in which a 5-membered heteroaryl and a heterocycle are condensed” include pyrrolopyridine, pyrazolopyridine, pyrazolopyrimidine, imidazopyridine, triazolopyridine, dihydropyrazolooxazole and the like.
Examples of the “condensed ring in which a 5-membered heteroaryl and a heterocycle are condensed” include 1H-pyrrolo [2,3-b] pyridin-3-yl, 1H-pyrazolo [3,4-b] pyridine-3 -Yl, pyrazolo [1,5-a] pyridin-3-yl, 2,3-dihydropyrazolo [5,1-b] oxazol-7-yl, [5,6,7,8] tetrahydropyrazolo [ 5,1-b] [1,3] oxazepin-3-yl and the like.
Examples of the “fused ring in which a 6-membered heteroaryl and a carbocycle are condensed” include quinoline, isoquinoline, quinazoline and the like.
Examples of the “fused ring in which a 6-membered heteroaryl and a carbocycle are condensed” include quinolin-4-yl, isoquinolin-1-yl, isoquinolin-4-yl, quinazolin-4-yl and the like.
Examples of the “condensed ring in which a 6-membered heteroaryl and a heterocyclic ring are condensed” include pyrazolopyridine, pyrazolopyrimidine, imidazopyridine, imidazopyrimidine, imidazopyrazine, triazolopyridine, naphthyridine, pyridopyrazine, azaindazole and the like. Can be mentioned.
Examples of the “fused ring in which a 6-membered heteroaryl and a heterocycle are condensed” include pyrazolo [1,5-a] pyridin-7-yl, pyrazolo [1,5-a] pyrimidin-7-yl, imidazo [1,5-a] pyridin-8-yl, imidazo [1,2-c] pyrimidin-8-yl, imidazo [1,2-a] pyrazin-5-yl, [1,2,4] triazolo [ 1,5-a] pyridin-5-yl, 1,5-naphthyridin-4-yl, pyrido [3,4-b] pyrazin-8-yl, azaindazolyl and the like.

The “aralkyl group” is a group in which the “C ₁ -C ₆ alkyl group” is substituted with a phenyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group or the like. They can be attached at all substitutable positions. For example, benzyl group, phenethyl group, 1-phenylethyl group, 1-phenylpropyl group, 3-phenylpropyl group and the like can be mentioned.

In the present specification, “substitution” means that one or more hydrogen atoms at any position are substituted with an atom or a functional group other than a hydrogen atom, unless otherwise specified.

In general formula (I), the substituent of “optionally substituted phenyl” and “optionally substituted 5- or 6-membered heteroaryl” in ring A is a halogen atom, cyano group, hydroxyl group, substituted An optionally substituted C ₁ -C ₆ alkyl group (synonymous with the “optionally substituted C ₁ -C ₆ alkyl group” in R ⁴ ), a C ₁ -C ₆ haloalkyl group, an optionally substituted C _{1 3-} C ₇ cycloalkyl group (same as “optionally substituted C ₃ -C ₇ cycloalkyl group” in R ⁴ ), heterocycloalkyl group, heterocycloalkyloxy group, 5-membered heteroaryl group, substituted Optionally substituted C ₁ -C ₆ alkoxy group (synonymous with “optionally substituted C ₁ -C ₆ alkoxy group” in R ⁴ ), C ₁ -C ₆ haloalkoxy group, C ₂ -C ₆ alkenyl Group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkynyl group, C ₂ -C ₆ alkynyloxy group, C ₁ -C ₆ alkylthio group, —NR ^d R ^e (R ^d and R ^e each independently represents a hydrogen atom or a C ₁ -C ₆ alkyl group), a nitro group, a formyl group, a C ₁ -C ₆ alkylcarbonyl group , A substituent selected from the group consisting of a C ₁ -C ₆ alkoxycarbonyl group and a C ₁ -C ₆ alkylcarbonyloxy group. These may be substituted one or more at all substitutable positions.
In general formula (I), the substituent of the “optionally substituted condensed ring” in ring A is an oxo group, a halogen atom, a cyano group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group and C ₁ -C ₆ Represents a substituent selected from the group consisting of alkylcarbonyloxy groups. These may be substituted one or more at all substitutable positions.

In general formula (IA), the substituent of “optionally substituted carbocycle” and “optionally substituted heterocycle” in ring B is a halogen atom, cyano group, C ₁ -C ₆ alkyl group , A substituent selected from the group consisting of a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group and a C ₁ -C ₆ haloalkoxy group. These may be substituted one or more at all substitutable positions.

In the general formula (I), in R ^2a and R ^2b , “optionally substituted C ₁ -C ₆ alkyl group”, “optionally substituted C ₁ -C ₆ haloalkyl group”, “substituted” The substituents of “optionally C ₁ -C ₆ alkoxy group” and “optionally substituted C ₁ -C ₆ haloalkoxy group” are halogen atom, cyano group, hydroxyl group, —OR ^g (R ^g is C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₂ -C ₆ alkenyl -C ₁ -C ₆ alkyl group, C ₂ -C ₆ Alkynyl-C ₁ -C ₆ alkyl group, cyanomethyl group, —CONR ^j R ^k (R ^j and R ^k each independently represents a hydrogen atom or a C ₁ -C ₆ alkyl group), C ₃ -C ₇ Represents a cycloalkyl group or a C ₁ -C ₆ alkylcarbonyl group}, C ₁ -C ₆
An alkylcarbonyl group, a C ₁ -C ₆ alkoxycarbonyl group, a C ₁ -C ₆ alkylcarbonyloxy group, a heterocycloalkyl group, and —NR ^h R ⁱ (R ^h represents a C ₁ -C ₆ alkyl group, R ⁱ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a cyanomethyl group, a C ₁ -C ₆ alkylcarbonyl group or a C ₁ -C ₆ alkoxycarbonyl group. } Represents a substituent selected from the group consisting of: These may be substituted one or more at all substitutable positions.

In the general formula (I), in R ^2a and R ^2b , “optionally substituted C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group”, “optionally substituted C ₁ -C ₄ alkoxy- C ₁ -C ₄ haloalkyl group "," optionally substituted C ₁ -C ₆ alkylcarbonyl group "," optionally substituted C ₁ -C ₆ alkoxycarbonyl group "," optionally substituted C ₁ -C ₆ alkylcarbonyloxy group ”,“ optionally substituted C ₃ -C ₇ cycloalkyl group ”,“ optionally substituted heterocycloalkyl group ”,“ optionally substituted heterocyclo alkyl group "," optionally substituted C ₂ -C ₆ alkenyl group "," optionally substituted C ₂ -C ₆ alkenyloxy group "," optionally substituted C ₂ -C ₆ Alkenyl-C ₁ -C ₆ alkyl group ”,“ optionally substituted C ₂ -C ₆ alkenyl-C ₁ -C ₆ alkoxy group ” , “Optionally substituted C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ alkyl group”, “optionally substituted C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ alkoxy group”, “ Optionally substituted C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ haloalkyl group ”,“ optionally substituted C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ haloalkoxy group ”,“ substituted May have been C
_“2- C ₆ alkynyl group”, “optionally substituted C ₂ -C ₆ alkynyloxy group”, “optionally substituted C ₂ -C ₆ alkynyl-C ₁ -C ₆ alkyl group”, “substituted” Optionally substituted C ₂ -C ₆ alkynyl-C ₁ -C ₆ alkoxy group ”,“ optionally substituted C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ alkyl group ”,“ substituted C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ alkoxy group ”,“ optionally substituted C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ haloalkyl group ”,“ optionally substituted ” C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ haloalkoxy group ”,“ optionally substituted C ₁ -C ₆ alkylthio group ”,“ optionally substituted C ₁ -C ₆ haloalkylthio group ” The substituent of
Halogen atom, cyano group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group and C ₁ -C ₄ alkoxy-C ₁ -C ₄ represents a substituent selected from the group consisting of alkyl groups. These may be substituted one or more at all substitutable positions.

In general formula (I), the substituent of “optionally substituted C ₁ -C ₆ alkyl group” in R ^a and R ^b is a halogen atom, a cyano group, a C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ alkylcarbonyloxy group, C ₃ -C ₇ cycloalkyl group, heterocycloalkyl group, hetero It represents a substituent selected from the group consisting of a cycloalkyloxy group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkenyloxy group, a C ₂ -C ₆ alkynyl group and a C ₂ -C ₆ alkynyloxy group. These may be substituted one or more at all substitutable positions.

In the general formula (I), when Z is CR ^2b , R ^2a and R ^2b are formed together with the carbon atom to which they are bonded to form an `` optionally substituted carbocycle '', `` substituted Examples of the substituent of “good heterocycle” include oxo group, halogen atom, cyano group, hydroxyl group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy groups, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ alkylcarbonyloxy group, and -NR ^j R ^k (R ^j and R ^k are each independently, Represents a hydrogen atom or a C ₁ -C ₆ alkyl group.) Represents a substituent selected from the group consisting of: These may be substituted one or more at all substitutable positions.

In the general formula (I), "optionally substituted C ₁ -C ₆ alkyl group" in R ^3, "optionally substituted C ₁ -C ₆ alkoxy group", "optionally substituted C _“3- C ₇ cycloalkyl group”, “optionally substituted C ₂ -C ₆ alkenyl group”, “optionally substituted C ₂ -C ₆ alkynyl group”, “optionally substituted aralkyl group” Are selected from the group consisting of halogen atoms, cyano groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ haloalkyl groups, C ₁ -C ₆ alkoxy groups, and C ₁ -C ₆ haloalkoxy groups. Represents a substituent. These may be substituted one or more at all substitutable positions.

In the general formula (I), the substituent of the “optionally substituted C ₁ -C ₆ alkyl group” and the “optionally substituted C ₁ -C ₆ alkoxy group” in R ⁴ is a halogen atom, Cyano group, hydroxyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₃ -C ₇ cycloalkyl group and heterocycloalkyl Represents a substituent selected from the group consisting of groups. These may be substituted one or more at all substitutable positions.
The substituent of the “optionally substituted C ₃ -C ₇ cycloalkyl group” in R ⁴ is a halogen atom, a cyano group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C _1- Represents a substituent selected from the group consisting of a C ₆ alkoxy group and a C ₁ -C ₆ haloalkoxy group. These may be substituted one or more at all substitutable positions.

In the general formula (I), in R ^6a and R ^6b "optionally substituted C ₁ -C ₆ alkyl group", "optionally substituted C ₁ -C ₆ alkoxy group", "substituted And the substituents of “optionally substituted C ₃ -C ₇ cycloalkyl group” and “optionally substituted C ₁ -C ₆ alkylthio group” include halogen atom, cyano group, C ₁ -C ₆ alkyl group, C _1- A substituent selected from the group consisting of a C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group and a C ₁ -C ₆ haloalkoxy group is represented. These may be substituted one or more at all substitutable positions.
In the above definition, the number of substituents is preferably 1 to 5, more preferably 1 to 3.

In the compound of the general formula (I) of the present invention or a pharmacologically acceptable salt thereof, preferred atoms or substituents will be described below.

Q preferably represents CH ₂ , CO, NH, O or S, more preferably NH, O or S, still more preferably NH or O, and particularly preferably O.
X ¹ , X ² and X ³ each independently represent CR ¹ or N, preferably X ¹ represents CR ¹ , X ² and X ³ represent CR ¹ or N, more preferably X ¹ and X ³ represent CR ¹ and X ² represents CR ¹ or N.
In another embodiment of the present invention, X ¹ , X ² and X ³ each independently represent CH, CR ¹ or N, preferably X ¹ represents CH, and X ² and X ³ are Each independently represents CR ¹ or N, more preferably X ¹ and X ³ represent CH, X ² represents CR ¹ or N, and more preferably X ¹ and X ³ represent CH. , X ² represents CH or N.
Z is preferably CR ^2b .
R ¹ preferably represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group, more preferably a hydrogen atom or a halogen atom, and still more preferably a hydrogen atom.

R ^2a and R ^2b are each independently preferably a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C ₁ -C ₆ alkyl group, or an optionally substituted C ₁ -C ₆ haloalkyl. group, optionally substituted C ₁ -C ₆ alkoxy group, optionally substituted C ₁ -C ₆ haloalkoxy group, an optionally substituted C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl Group, optionally substituted C ₁ -C ₄ alkoxy-C ₁ -C ₄ haloalkyl group, optionally substituted C ₁ -C ₆ alkylcarbonyl group, optionally substituted C ₁ -C ₆ alkoxy A carbonyl group, an optionally substituted C ₁ -C ₆ alkylcarbonyloxy group, an optionally substituted C ₃ -C ₇ cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted Good C ₂ -C ₆ alkenyl-C ₁ -C ₆ alkoxy group, optionally substituted C ₂ -C ₆ alkynyl-C ₁ -C ₆ alkoxy group, -NR ^a R ^b (R ^a and R ^b each independently represent a hydrogen atom or an optionally substituted C ₁ -C ₆ alkyl group (provided that R ^a and R ^b are simultaneously hydrogen atoms)}, an optionally substituted C ₁ -C ₆ alkylthio group,
Pentafluorosulfanyl group, or general formula (IA)

{Where
L is a single bond, one or more of (CH ₂ ) _p hydrogen atoms may be substituted with a halogen atom, — (CH ₂ ) _p —, —O (CH ₂ ) _p —, — ( _{CH 2) p O -, -} NR c (CH 2) p - or ^{_{- (CH 2) p NR c}} - represents,
p represents 1 or 2,
R ^c represents a hydrogen atom or a methyl group,
Ring B represents an optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl. } Or a group represented by
When Z is CR ^2b , R ^2a and R ^2b together with the carbon atom to which they are attached may form an optionally substituted carbocycle;
More preferably, R ^2a and R ^2b are each independently a hydrogen atom, a halogen atom, a cyano group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₆
Alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₃ -C ₇ cycloalkyl group, C ₂ -C ₆
Alkenyl-C ₁ -C ₆ alkoxy group, C ₂ -C ₆ alkynyl-C ₁ -C ₆ alkoxy group, or general formula (IA)

{Where
L represents a single _{bond, - (CH 2) p -} , - O (CH 2) p - or - (CH ₂₎ represents _p O-,
p represents 1 or 2,
Ring B is a halogen atom, a C ₁ -C ₄ alkyl group, a phenyl optionally substituted with a C ₁ -C ₄ alkoxy group or a cyano group, or a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ represents a 5- or 6-membered heteroaryl optionally substituted by an alkoxy group or a cyano group. } (Except for the case where R ^2a and R ^2b are simultaneously hydrogen atoms),
More preferably, R ^2a and R ^2b each independently represent a hydrogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, or a C ₁ -C ₄ haloalkoxy group. Group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ haloalkyl group or C ₃ -C ₇ cycloalkyl group (provided that R ^2a and R ^2b Except when is hydrogen atom at the same time),
Particularly preferably, R ^2a is a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkoxy group, a C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄
Examples thereof include a haloalkyl group or a cyclopropyl group, and R ^2b is a hydrogen atom or a C ₁ -C ₄ alkyl group.

In another embodiment of the present invention, R ^2a and R ^2b are preferably each independently a hydrogen atom, a halogen atom, a cyano group, a C ₁ -C ₆ alkyl group, —OR ^g (R ^g is C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₂ -C ₆ alkenyl -C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkynyl-C ₁ -C ₆ alkyl group, cyanomethyl group, -CONR ^j R ^k (R ^j and R ^k each independently represents a hydrogen atom or a C ₁ -C ₆ alkyl group), C ₃ -C _{7 represents a} cycloalkyl group or a C ₁ -C ₆ alkylcarbonyl group. C ₁ -C ₆ alkyl group substituted with a}, C ₁ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group substituted with a group, C ₁ -C ₆ alkyl substituted with cyano, C ₁ - A C ₆ haloalkyl group, a C ₁ -C ₆ haloalkyl group substituted with a heterocycloalkyl group, —NR ^h R ⁱ {R ^h represents a C ₁ -C ₆ alkyl group, R ⁱ represents a hydrogen atom, C ₁ A —C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a cyanomethyl group, a C ₁ -C ₆ alkylcarbonyl group or a C ₁ -C ₆ alkoxycarbonyl group; }
C ₁ -C ₆ haloalkyl group substituted with, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkoxy group substituted with C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C ₄ alkoxy -C ₁ -C substituted with C ₁ -C ₄ alkoxy ₄ haloalkyl groups, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ alkylcarbonyloxy group, C ₃ -C ₇ cycloalkyl group, substituted with C ₁ -C ₆ alkyl group C ₃ -C ₇ cycloalkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group substituted C ₃ -C ₇ cycloalkyl group, heterocycloalkyl group, heterocycloalkyloxy group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkenyl -C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl -C ₁ -C ₆ alkoxy group C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ alkyl group, C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ alkoxy, C ₂ -C ₆ alkenyloxy -C ₁ -C ₄ haloalkyl groups, C ₂ -C ₆ alkenyloxy-C ₁ -C ₄ haloalkoxy group, C ₂ -C ₆ alkynyl group, C ₂ -C ₆ alkynyloxy group, C ₂ -C ₆ alkynyl-C ₁ -C ₆ alkyl group, C _2- C ₆ alkynyl-C ₁ -C ₆ alkoxy group, C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ alkyl group, C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ alkoxy group, C ₂ -C ₆ alkynyl Oxy-C ₁ -C ₄ haloalkyl group, C ₂ -C ₆ alkynyloxy-C ₁ -C ₄ haloalkoxy group, —NR ^a R ^b (R ^a and R ^b are each independently a hydrogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkyl group substituted with a cyano group, C ₁ -C ₆ alkyl group substituted with C ₁ -C ₄ alkoxy groups, substituted by C ₁ -C ₆ alkoxycarbonyl group C ₁ -C ₆ alkyl groups, C ₃ -C ₇ Shi Roarukiru C ₁ -C ₆ alkyl group substituted with a group, or an C ₂ -C ₆ C ₁ -C ₆ alkyl group substituted with an alkenyl group (provided that in the case of R ^a and R ^b are hydrogen atoms at the same time Excluded)}, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group,
Pentafluorosulfanyl group, or general formula (IA)

{Where
L is a single bond, one or more of (CH ₂ ) _p hydrogen atoms may be substituted with a halogen atom,-(CH ₂ ) _p- , -O (CH ₂ ) _p -,-( _{CH 2) p O -, -} NR c (CH 2) p - or ^{_{- (CH 2) p NR c}} - represents,
p represents 1 or 2,
R ^c represents a hydrogen atom or a methyl group,
Ring B represents phenyl, pyrrolyl, furyl, thienyl, imidazolyl, triazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. } Or a group represented by
When Z is CR ^2b , R ^2a and R ^2b may be combined to form — (CH ₂ ) _r — which may be substituted with a halogen atom, a hydroxyl group, or an oxo group (r is Represents 3, 4, 5 or 6).

More preferably, R ^2a is a hydrogen atom, a halogen atom, a cyano group, a C ₁ -C ₆ alkyl group, —OR ^g (R ^g is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₂ -C ₆ alkenyl -C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkynyl -C ₁ -C ₆ alkyl group, cyanomethyl group, -CONR ^j R ^k (R ^j and R ^k each independently represents a hydrogen atom or a C ₁ -C ₆ alkyl group), a C ₃ -C ₇ cycloalkyl group, or a C ₁ -C ₆ alkylcarbonyl group. C ₁ -C ₆ alkyl group substituted with a}, C ₁ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group substituted with a group, C ₁ -C ₆ alkyl substituted with cyano, C ₁ - C ₁ -C ₆ substituted with a C ₆ haloalkyl group or a heterocycloalkyl group
Haloalkyl group, —NR ^h R ⁱ {R ^h represents a C ₁ -C ₆ alkyl group, and R ⁱ represents a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkylcarbonyl group. } C ₁ -C ₆ haloalkyl group substituted with C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkoxy group substituted with C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy -C ₁ -C ₄ haloalkyl groups, C ₁ -C C ₁ is substituted with _alkoxy -C ₄ alkoxy -C ₁ - C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ alkylcarbonyloxy group, C ₃ -C ₇ cycloalkyl group, C ₁ -C ₆ alkyl group A substituted C ₃ -C ₇ cycloalkyl group, a C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group substituted with a C ₃ -C ₇ cycloalkyl group, a heterocycloalkyl group, a heterocycloalkyloxy group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkynyl group, C ₂ -C ₆ alkynyloxy group, C ₂ -C ₆ alkynyloxy group C ₁ -C ₄ alkyl group, -NR ^a R ^b {R ^a and R ^b are each independently hydrogen atom, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted with a cyano group , substituted by C ₁ -C ₄ C ₁ -C ₆ alkyl group substituted with an alkoxy group, C ₁ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group substituted with a group, C ₃ -C ₇ cycloalkyl group C ₁ -C ₆ alkyl group, or a C ₂ -C ₆ C ₁ -C ₆ alkyl group substituted with an alkenyl group (except in the case of R ^a and R ^b are simultaneously hydrogen atoms)}, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ haloalkylthio group, pentafluorosulfanyl group, or general formula (IA)

{Where
L is a single bond, one or more of (CH ₂ ) _p hydrogen atoms may be substituted with a halogen atom, — (CH ₂ ) _p —, —O (CH ₂ ) _p —, — ( _{CH 2) p O -, -} NR c (CH 2) p - or ^{_{- (CH 2) p NR c}} - represents,
p represents 1 or 2,
R ^c represents a hydrogen atom or a methyl group,
Ring B represents phenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, or oxadiazolyl. } Is a group represented by
R ^2b is a hydrogen atom, a halogen atom, a cyano group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or a C _3- A C ₇ cycloalkyl group,
When Z is CR ^2b , R ^2a and R ^2b may be combined to form — (CH ₂ ) _r — which may be substituted with a halogen atom, a hydroxyl group or an oxo group (r is 3 , 4, 5 or 6).

More preferably, R ^2a is a hydrogen atom, a halogen atom, a cyano group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₃ -C ₇ cycloalkyl group, -NR ^a R ^b {R ^a and R ^b are each independently hydrogen atom, C ₁ -C ₆ alkyl, C ₁ -C ₄ C ₁ substituted with an alkoxy group - C ₆ alkyl group,
Or a C ₁ -C ₆ alkyl group substituted with a C ₁ -C ₆ alkoxycarbonyl group (provided that R ^a and R ^b are simultaneously hydrogen atoms)}, or the general formula (IA)

{Where
L represents a single bond, may be substituted with one or more halogen atoms of (CH _{2) p} hydrogen _{atoms, - (CH 2) p -} , - O (CH 2) p -, or - (CH ₂ ) _p O-
p represents 1 or 2,
Ring B represents phenyl or pyrazolyl. } Is a group represented by
R ^2b is a hydrogen atom, a halogen atom, or a methyl group,
When Z is CR ^2b , R ^2a and R ^2b may be taken together to form — (CH ₂ ) _r — (r represents 3 or 4).

R ³ preferably represents a hydrogen atom, a fluorine atom or a methyl group, more preferably a hydrogen atom.

Ring A represents an optionally substituted phenyl, or an optionally substituted 5- or 6-membered heteroaryl (the ring A may be further condensed to form a condensed ring). ,
Preferably, ring A is each optionally substituted phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolyl, isoquinolyl, quinoxalinyl, naphthyridinyl, pyridopyrazinyl, indolyl, pyrazolopyridyl , Pyrazolopyrazinyl, triazolopyridyl, dihydrobenzofuranyl, chromanyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, azaindazolyl, pyrazolopyrimidinyl, benzoxazolyl, imidazopyridyl and Represents a ring selected from the group consisting of imidazopyrimidinyl.
More preferably, ring A has the following formula:

(Wherein the definitions of R ⁴ , R ^5a , R ^5b , R ^5c and n are the same as those defined in the embodiment (7)), and represent a ring selected from the group consisting of:
More preferably, ring A is represented by the following formula:

(Wherein the definitions of R ⁴ , R ^5a , R ^5b , R ^5c and n are the same as those defined in the embodiment (7)).

In another embodiment of the present invention, ring A represents phenyl (the ring A may be further condensed to form a condensed ring),
Preferably, ring A has the formula

(Wherein the definitions of R ⁴ , R ^5a , R ^5b , R ^5c and n are the same as those defined in the embodiment (7)), and represent a ring selected from the group consisting of:
More preferably, ring A has the following formula:

Wherein R ⁴ , R ^5a , R ^5b , R ^5c and n are the same as defined in the embodiment (7).
In another embodiment of the present invention, ring A represents a 6-membered heteroaryl (the ring A may be further condensed to form a condensed ring),
Preferably, ring A has the formula

(Wherein the definitions of R ⁴ , R ^5a , R ^5b and R ^5c are the same as those defined in the embodiment (7)), and represent a ring selected from the group consisting of:
More preferably, ring A has the following formula:

(Wherein the definitions of R ⁴ , R ^5a , R ^5b and R ^5c are the same as those defined in the embodiment (7)).

In another embodiment of the present invention, ring A represents a 5-membered heteroaryl (the ring A may be further condensed to form a condensed ring),
Preferably, ring A has the formula

(Wherein the definitions of R ^5a , R ^5b , R ^5c , R ^6a , R ^6b and X ⁴ are the same as those defined in the embodiment (1)), and represent a ring selected from the group consisting of:
More preferably, ring A has the following formula:

(Wherein the definitions of R ^5a , R ^5b and R ^5c are the same as those defined in the embodiment (1)).

R ⁴ represents a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an optionally substituted C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, or an optionally substituted C ₃ -C ₇ cycloalkyl. Group, heterocycloalkyl group, 5-membered heteroaryl group, C ₁ -C ₆ alkoxy group which may be substituted, C ₁ -C ₆ haloalkoxy group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ Alkynyl group, C ₁ -C ₆ alkylthio group, —NR ^d R ^e (R ^d and R ^e each independently represents a hydrogen atom or a C ₁ -C ₆ alkyl group), nitro group, formyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group or C ₁ -C ₆
Represents an alkylcarbonyloxy group,
R ⁴ is preferably a hydrogen atom, halogen atom, cyano group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₃ -C ₇ cycloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, vinyl group, ethynyl group, C ₁ -C ₆ alkylthio group, -NR ^d R ^e (R ^d and R ^e are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group Represents a C ₁ -C ₆ alkylcarbonyl group or a C ₁ -C ₆ alkoxycarbonyl group,
More preferably, a halogen atom, a cyano group, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl group, C ₃ -C ₇ cycloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy Represents a group, a vinyl group, an ethynyl group or a C ₁ -C ₆ alkylthio group,
More preferably, represents a halogen atom, C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, a cyclopropyl group, a C ₁ -C ₄ alkoxy or C ₁ -C ₄ haloalkoxy groups,
Particularly preferred is a halogen atom, a methyl group, an ethyl group or a methoxy group.

R ^5a , R ^5b and R ^5c are each independently a hydrogen atom, halogen atom, cyano group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ haloalkoxy group, C ₃ -C ₇ cycloalkyl group, C ₁ -C ₆ alkylcarbonyl group or C ₁ -C ₆ alkoxycarbonyl group,
R ^5a , R ^5b and R ^5c preferably represent a hydrogen atom, a halogen atom, a cyano group, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group or a C ₃ -C ₇ cycloalkyl group,
More preferably, a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ haloalkyl group is used.

R ^6a and R ^6b each independently represent a hydrogen atom, a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, or an optionally substituted C ₃ -C ₇ cycloalkyl group,
Represents an optionally substituted C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or an optionally substituted C ₁ -C ₆ alkylthio group,
R ^6a and R ^6b preferably represent a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group or a C ₁ -C ₆ haloalkoxy group. ,
More preferably, a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ haloalkyl group is used.

X ⁴ preferably represents NR ^f (R ^f represents a hydrogen atom or a C ₁ -C ₄ alkyl group) or O;
More preferably, NR ^f (R ^f represents a hydrogen atom or a methyl group.) Or O, and the like.

Further, in another aspect of the present invention, ring A is preferably a halogen atom, a cyano group, a hydroxyl group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkyl substituted with C ₁ -C ₆ alkoxy group group, C ₁ -C ₆ haloalkyl group, C ₃ -C ₇ cycloalkyl group, heterocycloalkyl group, heterocycloalkyl group, a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, oxazolyl group, isoxazolyl group , thiazolyl group, isothiazolyl group, thiadiazolyl group, oxadiazolyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₇ cycloalkyl C ₁ -C ₆ alkoxy groups substituted with one, C ₁ -C ₆ haloalkoxy group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkynyl group, C ₂ -C ₆ alkynyloxy group, C ₁ -C ₆ alkylthio group, -NR ^d R ^e (R ^d And ^Re are each independently a hydrogen atom Or a C ₁ -C ₆ alkyl group), a nitro group, a formyl group, a C ₁ -C ₆ alkylcarbonyl group, a C ₁ -C ₆ alkoxycarbonyl group and a C ₁ -C ₆ alkylcarbonyloxy group. Phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indanyl, each optionally substituted by one or more substituents , Indenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indolyl, benzofuranyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, benzothiophenyl , Benzimidazolyl, benzothiazolyl, benzoxazolyl, chromanyl, indazolyl, benzoisoxazolyl, benzisothiazolyl, pyrrolopyridyl, pyrazolopyridyl, dihydropyrazolooxazolyl, tetrahydropyrazolooxazepinyl, pyrazolopyrimidinyl, imidazo A ring selected from the group consisting of pyridyl, imidazopyrimidinyl, imidazopyrazinyl, triazolopyridyl, naphthyridinyl, pyridopyrazinyl, and azaindazolyl is shown.

More preferably, ring A is a halogen atom, a cyano group, a hydroxyl group, a C ₁ -C ₆ alkyl group, C ₁ -C ₆
C ₁ -C ₆ alkyl group substituted with alkoxy group, C ₁ -C ₆ haloalkyl group, C ₃ -C ₇ cycloalkyl group, heterocycloalkyl group, heterocycloalkyl group, an imidazolyl group, a pyrazolyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkoxy group substituted by C ₃ -C ₇ cycloalkyl group, C ₁ -C ₆ haloalkoxy group, C ₂ -C ₆ alkynyloxy group, C ₁ -C ₆ alkylthio Group, -NR ^d R ^e (R ^d and R ^e each independently represents a hydrogen atom or a C ₁ -C ₆ alkyl group), a nitro group, a formyl group, a C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, and a C ₁ -C ₆ one or more substituents selected from the group consisting of alkyl carbonyloxy group may be each substituted, phenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl , Pyridazinyl, Midinyl, pyrazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indolyl, dihydrobenzofuranyl, chromanyl, benzisoxazolyl, pyrrolopyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, imidazopyrazinyl, triazolopyridyl, naphthyridinyl, and pyridopyrazinyl A ring selected from the group consisting of:

More preferably, ring A is each substituted with one or more substituents selected from the group consisting of a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, and a C ₁ -C ₆ alkoxy group. And represents a ring selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, quinoxalinyl, dihydrobenzofuranyl, pyrazolopyridyl, triazolopyridyl, naphthyridinyl, and pyridopyrazinyl, which may be optionally substituted.

Preferred embodiments of the compound of the general formula (I) or a pharmaceutically acceptable salt thereof used in the medicament of the present invention include the above Q, ring A, X ¹ , X ² , X ³ , X ⁴ , Z, R ¹ , R ^2a , R ^2b , R ³ , R ⁴ , R ^5a , R ^5b , R ^5c , R ^6a and R ^6b are compounds composed of preferred atoms or combinations of groups. For example, the following compounds are preferred:
(i) in the general formula (I), Q is O;
X ¹ is CH;
X ² and X ³ are each independently CR ¹ or N;
R ¹ is a hydrogen atom or a halogen atom;
Z is CR ^2b ;
R ^2a and R ^2b are each independently a hydrogen atom, halogen atom, cyano group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ Haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl Group, C ₃ -C ₇ cycloalkyl group, C ₂ -C ₆ alkenyl-C ₁ -C ₆
Alkoxy groups, C ₂ -C ₆ alkynyl-C ₁ -C ₆ alkoxy groups, and general formula (IA)

{Where
L represents a single _{bond, - (CH 2) p -} , - O (CH 2) p - or - (CH ₂₎ represents _p O-,
p represents 1 or 2,
Ring B is a halogen atom, a C ₁ -C ₄ alkyl group, a phenyl optionally substituted with a C ₁ -C ₄ alkoxy group or a cyano group, or a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ represents a 5- or 6-membered heteroaryl optionally substituted by an alkoxy group or a cyano group. } (Except for the case where R ^2a and R ^2b are simultaneously hydrogen atoms);
R ³ is a hydrogen atom;
Ring A is represented by the following formula:

(In the formula, n is 1 or 2, and R ⁴ is a halogen atom, a cyano group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₃ -C ₇ cycloalkyl group, a C _1- Selected from the group consisting of a C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, a vinyl group, an ethynyl group and a C ₁ -C ₆ alkylthio group, wherein R ^5a , R ^5b and R ^5c are each independently hydrogen A compound which is a ring selected from the group consisting of: an atom, a halogen atom, a C ₁ -C ₄ alkyl group and a C ₁ -C ₄ haloalkyl group.
(ii) In the compound (i), ring A is represented by the following formula:

Wherein n, R ⁴ , R ^5a , R ^5b and R ^5c are rings selected from the group consisting of (i).
(iii) In the compound (i), R ⁴ is a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a cyclopropyl group, a C ₁ -C ₄ alkoxy group and a C ₁ -C ₄ halo group. A compound selected from the group consisting of alkoxy groups.
(iv) In the compound (i), R ^2a and R ^2b are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, a C 1 _1- C ₄ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ haloalkyl group and C ₃ -C ₇ cycloalkyl group A compound selected (unless R ^2a and R ^2b are simultaneously hydrogen atoms).
(v) Specifically, a compound selected from the following is more preferable.

In another embodiment of the present invention, preferred embodiments of the compound of general formula (I) or a pharmaceutically acceptable salt thereof used in the medicament of the present invention include the above Q, ring A, X ¹ , X ² , X ³ , X ⁴ , Z, R ¹ , R ^2a , R ^2b , R ³ , R ⁴ , R ^5a , R ^5b , R ^5c , R ^6a and R ^6b is there. For example, the following compounds are preferred:
(i) in the general formula (I), Q is O;
X ¹ is CH;
X ² and X ³ are each independently CR ¹ or N;
R ¹ is a hydrogen atom or a halogen atom;
Z is CR ^2b ;
R ^2a is a hydrogen atom, halogen atom, cyano group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₃ -C ₇ cyclo alkyl group, -NR ^a R ^b {R ^a and R ^b are each independently hydrogen atom, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted by C ₁ -C ₄ alkoxy group Or a C ₁ -C ₆ alkyl group substituted with a C ₁ -C ₆ alkoxycarbonyl group (provided that R ^a and R ^b are simultaneously hydrogen atoms)}, and the general formula (IA)

{Where
L represents a single bond, may be substituted with one or more halogen atoms of (CH _{2) p} hydrogen _{atoms, - (CH 2) p -} , - O (CH 2) p -, or - (CH ₂ ) _p O-
p represents 1 or 2,
Ring B represents phenyl or pyrazolyl. } Is selected from the group consisting of groups represented by:
R ^2b is selected from the group consisting of a hydrogen atom, a halogen atom, and a C ₁ -C ₆ alkyl group;
R ³ is a hydrogen atom or a halogen atom;
Ring A may be substituted with one or more substituents selected from the group consisting of a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, and a C ₁ -C ₆ alkoxy group. A compound that is a ring selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, quinoxalinyl, dihydrobenzofuranyl, pyrazolopyridyl, triazolopyridyl, naphthyridinyl, and pyridopyrazinyl.

(ii) in general formula (I), Q is O;
X ¹ and X ³ are CH;
X ² is CR ¹ or N;
R ¹ is a hydrogen atom or a halogen atom;
Z is CR ^2b ;
R ^2a is a hydrogen atom, halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₄ alkoxy- C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy-C ₁ -C ₄ haloalkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₃ -C ₇ cycloalkyl group, And -NR ^a R ^b {R ^a and R ^b are each independently a hydrogen atom, C ₁ -C ₆
An alkyl group, a C ₁ -C ₆ alkyl group substituted with a C ₁ -C ₄ alkoxy group, or a C ₁ -C ₆ alkyl group substituted with a C ₁ -C ₆ alkoxycarbonyl group (provided that R ^a and R ^b is selected from the group consisting of at the same time except in the case of hydrogen atom)};
R ^2b is selected from the group consisting of a hydrogen atom, a halogen atom, and a methyl group;
Ring A may be substituted with one or more substituents selected from the group consisting of a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, and a C ₁ -C ₆ alkoxy group. A compound that is a ring selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, quinoxalinyl, dihydrobenzofuranyl, pyrazolopyridyl, triazolopyridyl, naphthyridinyl, and pyridopyrazinyl.

(iii) in general formula (I), Q is O;
X ¹ and X ³ are CH;
X ² is CH or N;
Z is CR ^2b ;
R ^2a and R ^2b together form — (CH ₂ ) _r — optionally substituted with a halogen atom, a hydroxyl group or an oxo group (r represents 3, 4, 5 or 6) ),
Ring A may be substituted with one or more substituents selected from the group consisting of a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, and a C ₁ -C ₆ alkoxy group. A compound that is a ring selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, quinoxalinyl, dihydrobenzofuranyl, pyrazolopyridyl, triazolopyridyl, naphthyridinyl, and pyridopyrazinyl.

The salt of the compound represented by the general formula (I) is preferably a pharmacologically acceptable salt. The “pharmacologically acceptable salt” of the compound represented by the general formula (I) is not particularly limited as long as it is a pharmacologically acceptable salt, but hydrochloride, hydrobromide, nitrate , Inorganic salts such as sulfate, phosphate, acetate, oxalate, fumarate, maleate, malonate, citrate, succinate, lactate, tartrate, malate, etc. Organic carboxylates, salicylates, benzoates and other aromatic carboxylates, methanesulfonates, benzenesulfonates and other organic sulfonates, lithium salts, sodium salts, potassium salts and other alkali metal salts, Examples include alkaline earth metal salts such as calcium salts and magnesium salts.

In the compounds of the present invention represented by the general formula (I), when an asymmetric carbon is present, any of its racemates, diastereoisomers and individual optically active substances are included in the present invention. In the case where there is a geometric isomer, any of the (E) isomer, the (Z) isomer and a mixture thereof is included in the present invention.

In the compounds of the present invention represented by the general formula (I), when solvates such as hydrates are present, these are also included in the present invention.

Next, a method for producing the compound represented by the general formula (I) which is the biaryl derivative of the present invention will be described. The compound of the present invention can be produced by various methods. For example, it can be produced by the method shown in Scheme 1 or Scheme 2.

The compound represented by the general formula (I) can be produced by the method shown in the following scheme 1 (step 1-1 to step 1-4).
Scheme 1:

(In the formula, A, R ^2a , R ³ , Q, X ¹ , X ² , X ³ , Y and Z are as defined in the general formula (I); X ^a is a fluorine atom, a chlorine atom or bromine. Atom, X ^b is chlorine atom, bromine atom or iodine atom; X ^c is —B (OH) ₂ or —BPin (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) .)
The compound represented by the general formula (I) was a halogenated aryl compound (IV) by _SN aryl reaction between the compound represented by the general formula (II) and the compound represented by the general formula (III). Thereafter, it can be obtained by carrying out Suzuki-Miyaura cross coupling with various boronic acids or boronic esters (V) having ring A. In addition, compound (I) was prepared by introducing a halogenated aryl compound (IV) to a boronic acid compound (VIa) or a boronic ester compound (VIb), followed by various aryl halides (VII) having ring A and Suzuki It can also be obtained by performing a Miyaura cross-coupling reaction. Hereinafter, each process will be described in detail.

<Process 1-1>
In step 1-1, the compound represented by the general formula (II) and the compound represented by the general formula (III) are reacted in the presence of a base to produce the compound represented by the general formula (IV). . Bases used include potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, potassium Examples include hexamethyldisilazane or sodium hydride. In order to carry out the reaction smoothly, an additive may coexist, and as an additive, potassium iodide, sodium iodide, tetrabutylammonium iodide, potassium bromide, sodium bromide, tetrabutylammonium bromide, or the like is added. Can do. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran 1,4-dioxane, 2-methoxyethanol or a mixed solvent thereof is preferable. Moreover, water can also be added as a reaction solvent. The amount of water added is not particularly limited, and examples thereof include 10% (v / v) or less with respect to the entire solvent. The reaction temperature is not particularly limited, usually from room temperature to 150 ° C
The reaction time is preferably 1 to 24 hours. In addition, this reaction can also be performed using a microwave.
In Step 1-1, when the compound represented by the general formula (II) is an amine compound (Q = NH), the compound represented by the general formula (II) is represented by the general formula (III). A compound represented by the general formula (IV) can be produced by reacting the compound with an acid.

<Process 1-2>
In step 1-2, a palladium catalyst is allowed to act on a mixture of the compound represented by the general formula (IV) and the boronic acid or boronic ester represented by the general formula (V) in the presence of a base, A compound represented by the general formula (I) can be produced. This reaction is preferably carried out in an inert gas atmosphere such as argon. Bases used are potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, potassium hexamethyldisilazane, triethylamine, diisopropylethylamine Or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). In order to carry out the reaction smoothly, an additive may be allowed to coexist. Additives include trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triarylphosphines such as triphenylphosphine and tritolylphosphine; trimethylphosphite, Trialkyl phosphites such as triethyl phosphite and tributyl phosphite; tricycloalkyl phosphites such as tricyclohexyl phosphite; triaryl phosphites such as triphenyl phosphite; 1,3-bis (2,4, Imidazolium salts such as 6-trimethylphenyl) imidazolium chloride; diketones such as acetylacetone and octafluoroacetylacetone; trimethylamine, triethylamine, tripropylamine, triiso Amines such as propylamine and tributylamine; 1,1′-bis (diphenylphosphino) ferrocene; 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl; 2-dicyclohexylphosphino-2 ′, 6'-dimethoxybiphenyl; 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl; 2- (di-tert-butylphosphino) -2 ', 4', 6'-triisopropylbiphenyl; 2-dicyclohexylphosphino-2 '-(N, N-dimethylamino) biphenyl; 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene; and 2- (di-tert-butylphosphino) biphenyl These may be used in combination. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, methanol, ethanol, 2-propanol , N-butyl alcohol, t-amyl alcohol, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, toluene, cyclopentyl methyl ether (CPME), water, or a mixed solvent thereof. Palladium catalysts include palladium-carbon and palladium black metal palladium; tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium acetate, palladium chloride-1,1'-bis (diphenylphosphino) ferrocene Or organopalladium salts such as bis [di-tert-butyl (4-dimethylaminophenyl) phosphine] dichloropalladium; and polymer-supported bis (acetate) triphenylphosphine palladium (II) and polymer-supported di (acetate) dicyclohexylphenylphosphine Examples thereof include polymer-immobilized organic palladium complexes such as palladium (II), and these may be used in combination. The addition amount of the palladium catalyst is usually about 1 to 50 mol%, preferably about 5 to 20 mol% with respect to the compound represented by the general formula (IV). The reaction temperature is not particularly limited, and the reaction is usually performed at room temperature to 120 ° C., and the reaction time is preferably 1 to 24 hours. In addition, this reaction can also be performed under microwave irradiation at about 120 degreeC and reaction time 10 minutes-2 hours.

<Process 1-3A>
In step 1-3A, a compound represented by general formula (IV) is allowed to react with a Grignard reagent, an organolithium reagent or a zinc reagent to perform halometal exchange, a boronic acid ester is allowed to act, and hydrolysis is performed. A boronic acid compound represented by the formula (VIa) can be produced. This reaction is preferably carried out in an inert gas atmosphere such as argon. As Grignard reagents, magnesium, isopropylmagnesium bromide, isopropylmagnesium chloride, isopropylmagnesium chloride / lithium chloride, etc .; As organic lithium reagents, normal butyllithium, sec-butyllithium, tert-butyllithium, etc .; active as zinc reagents Zinc, zinc bromide or zinc chloride. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but tetrahydrofuran, diethyl ether, 1,4-dioxane, dimethoxyethane or the like is preferable. The reaction temperature is not particularly limited, and the reaction is usually performed at −78 ° C. to 100 ° C., and the reaction time is preferably 1 to 24 hours.

<Process 1-3B>
In Step 1-3B, a compound represented by the general formula (VIb) is obtained by allowing a palladium catalyst to act on a mixture of the compound represented by the general formula (IV) and the boronic ester compound in the presence of a base. Can be manufactured. This reaction is preferably carried out in an inert gas atmosphere such as argon. Bases used are potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, potassium hexamethyldisilazane, triethylamine, diisopropylethylamine Or DBU or the like. In order to carry out the reaction smoothly, an additive may coexist, and triphenylphosphine or the like can be added as an additive. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, methanol, ethanol, 2-propanol N-butyl alcohol, t-amyl alcohol, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, toluene, CPME, water, or a mixed solvent thereof. Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium acetate, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene,
Alternatively, bis [di-tert-butyl (4-dimethylaminophenyl) phosphine] dichloropalladium and the like can be mentioned. The amount of palladium catalyst added is usually 1 with respect to the compound represented by the general formula (IV).
˜50 mol%, preferably about 5 to 20 mol%. The reaction temperature is not particularly limited, and the reaction is usually performed at room temperature to 120 ° C., and the reaction time is preferably 1 to 24 hours. Similar to Step 1-2, this reaction can also be carried out under microwave irradiation at about 120 ° C. for a reaction time of 10 minutes to 2 hours.

<Process 1-4>
Step 1-4 can be performed in the same manner as Step 1-2. That is, in step 1-4, the boronic acid compound represented by the general formula (VIa) or the boronic acid ester compound represented by the general formula (VIb) and the halogenated aryl compound represented by the general formula (VII) A compound represented by the general formula (I) can be produced by allowing a palladium catalyst to act on the mixture in the presence of a base.

The compound (I) can also be produced by the method shown in the following scheme 2 (steps 2-1 to 2-2).
Scheme 2:

^{(Wherein, A, R 2a, R 3} , Q, X 1, X 2, X 3, Y and Z are as defined above; X ^a is a fluorine atom, a chlorine atom or a bromine atom, X ^b is chlorine atom, Bromine atom or iodine atom; X ^c is —B (OH) ₂ or —BPin)
The compound represented by the general formula (I) is produced by the Suzuki-Miyaura cross-coupling reaction between the compound represented by the general formula (III) and various boronic acids or boronic esters (V) having ring A. After obtaining the compound represented by (VIII), it can be obtained by conducting an _SN aryl reaction between the compound represented by the general formula (VIII) and the compound represented by the general formula (II). Step 2-1 can also be performed by exchanging ^Xb and ^Xc under the same conditions.

<Process 2-1>
In step 2-1, a palladium catalyst is allowed to act on a mixture of the compound represented by general formula (III) and the boronic acid or boronic ester represented by general formula (V) in the presence of a base. A compound represented by the formula (VIII) can be produced. This reaction is preferably carried out in an inert gas atmosphere such as argon. Bases used are potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, potassium hexamethyldisilazane, triethylamine, diisopropylethylamine Or DBU or the like. In order to carry out the reaction smoothly, an additive may coexist, and triphenylphosphine or the like can be added as an additive. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, methanol, ethanol, 2-propanol N-butyl alcohol, t-amyl alcohol, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, toluene, CPME, water, or a mixed solvent thereof. Palladium catalysts include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium acetate, palladium chloride-1,1'-bis (diphenylphosphino) ferrocene, or bis [di-tert-butyl (4 -Dimethylaminophenyl) phosphine] dichloropalladium and the like. The amount of palladium catalyst added is determined by the general formula (III)
Is usually about 1 to 50 mol%, preferably about 5 to 20 mol%, relative to the compound represented by The reaction temperature is not particularly limited, and the reaction is usually performed at room temperature to 120 ° C., and the reaction time is preferably 1 to 24 hours. This reaction can also be carried out under microwave irradiation at about 120 ° C. for a reaction time of 10 minutes to 2 hours.

<Process 2-2>
In Step 2-2, the compound represented by the general formula (VIII) and the compound represented by the general formula (II) are reacted in the presence of a base to produce the compound represented by the general formula (I). . Bases used include potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, potassium Examples include hexamethyldisilazane or sodium hydride. In order to carry out the reaction smoothly, an additive may coexist, and as an additive, potassium iodide, sodium iodide, tetrabutylammonium iodide, potassium bromide, sodium bromide, tetrabutylammonium bromide, or the like is added. Can do. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran 1,4-dioxane, 2-methoxyethanol or a mixed solvent thereof is preferable. Moreover, water can also be added as a reaction solvent. The amount of water added is not particularly limited, and is preferably 10% (v / v) or less with respect to the entire solvent, for example. The reaction temperature is not particularly limited, usually from room temperature to 180 ° C
The reaction time is preferably 1 to 24 hours. In addition, this reaction can also be performed using a microwave.
In Step 2-2, when the compound represented by the general formula (II) is an amine compound (Q = NH), the compound represented by the general formula (II) is represented by the general formula (VIII). A compound represented by the general formula (I) can be produced by reacting the compound with an acid.

The thus obtained compound of the general formula (I) or a salt thereof is, for example, a known reaction such as condensation reaction, addition reaction, oxidation reaction, reduction reaction, substitution reaction, halogenation reaction, dehydration reaction or hydrolysis. The compound can be derived into other compounds of the general formula (I) or salts thereof by attaching to or by appropriately combining them.
The compound of the present invention produced by the above-described method is isolated and purified as a free compound, a salt thereof, a solvate such as a hydrate or an ethanolate thereof, or a substance having a polymorphic form. The pharmacologically acceptable salt of the compound of the present invention can be produced by a conventional salt formation reaction. Isolation and purification are performed by applying chemical operations such as extraction fractionation, crystallization, and various types of fractional chromatography. The optical isomer can be obtained as a stereochemically pure isomer by selecting an appropriate raw material compound or by optical resolution of a racemate.

  The biaryl derivative (I) or a salt thereof of the present invention is excellent against trichophyton (for example, the genus Trichophyton, the genus Microsporum, etc.) which is a main causative bacterium of superficial mycosis. Exhibits antifungal activity. Therefore, the pharmaceutical which uses them as an active ingredient is useful as a preventive or therapeutic agent of the infectious disease caused by ringworm of mammals including humans. Examples of the infection caused by ringworm include tinea pedis, onychomycosis, body tinea, tinea rotata, and tinea cephalus. The compound of the present invention has an excellent effect on onychomycosis in that it has excellent nail permeability.

In the present specification, the compound of the general formula (I) and a salt thereof are used as a medicament by themselves. In addition, the pharmaceutical comprising the biaryl derivative (I) or a salt thereof of the present invention is a compound alone or a carrier on a liquid or solid preparation that is pharmacologically acceptable, such as an excipient, a binder, a diluent, an increased amount. An agent, a disintegrant, a stabilizer, a preservative, a buffer, an emulsifier, a fragrance, a colorant, a sweetener, a thickener, a corrigent, a solubilizer, and other additives may be mixed to form a pharmaceutical preparation. These can be prepared by conventional methods in the art.

Examples of the medicament of the present invention include tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules, oral solutions, injections, suppositories, sustained-release agents, lotions, liniments, ointments, patches. Preparations, suspensions, emulsions, transdermal absorption agents, topical solutions, creams, aerosols, etc., orally or parenterally, mammals (e.g., humans, monkeys, cows, horses, pigs, Dog,
Cat, rabbit, guinea pig, rat, mouse, etc.). Moreover, you may mix | blend another chemical | medical agent as needed.

When the compound of the present invention is locally administered, it is not particularly limited as long as it is a dosage form used as a pharmaceutical composition for topical administration. For example, when administered to the skin and nails, a liquid, a lotion, an ointment, Dosage forms such as creams, gels, patches (for example, tapes and poultices), and nail lacquers can be prepared. In preparing these, it is not particularly limited as long as it is pharmaceutically acceptable, such as a water-soluble base, an oily base, or an emulsion base, and can be prepared by a conventional method in this technical field. In the above preparation, the active ingredient may be in a suspended state.
When administered to the skin and nails as an external preparation, the content of the active ingredient is, for example, 0.01 to 20% by weight, preferably 0.5 to 15% by weight. In addition, the compound of the present invention which is an active ingredient is usually 1
The daily dose may be administered in the range of about 1 to about 100,000 μg / cm ² , preferably about 10 to about 10,000 μg / cm ² , and can be administered once or more daily.
When the compound of the present invention is orally administered, dosage forms such as tablets, orally disintegrating tablets, capsules, granules, powders, oral solutions, syrups, oral jelly agents, oral sprays and the like can be prepared. These can be prepared by conventional methods in the art. For example, when orally administered to an adult patient, the compound, which is an active ingredient, can usually be administered at a dose of about 0.1 to 100 mg / kg once or more daily.

Hereinafter, the features of the present invention will be described more specifically with reference to examples and test examples. The materials, amounts used, ratios, processing details, processing procedures, and the like shown in the following examples can be changed as appropriate without departing from the spirit of the present invention. Accordingly, the scope of the present invention should not be construed as being limited by the specific examples shown below. For the reaction by microwave irradiation, a microwave synthesizer Initiator + (manufactured by Biotage) was used.
The ¹ H-NMR spectrum shown below is based on a JNM-ECA400 type spectrum meter using deuterated chloroform (CDCl ₃ ) or deuterated dimethyl sulfoxide (DMSO-d ₆ ) as a solvent and tetramethylsilane (TMS) as an internal standard ( 400 MHz, manufactured by JEOL Ltd.) or AVANCEIII HD400 type (400 MHz, manufactured by Bruker BioSpin Corp.). The chemical shift measurement results were expressed as δ value in ppm and J value of binding constant in Hz. The abbreviations s are singlet, d is doublet, t is triplet, q is quartet, quin is quintet, sext is sextet, sep is septet, m is multiplet, br is broad. Mass spectrum (ESI-MS) was measured by Exactive (manufactured by Thermo Fisher Scientific Co., Ltd.) by electrospray ionization. The physical property values of Compound (I-1) to Compound (I-582) in each Example are shown in Tables 1 to 71.

In each embodiment, each abbreviation has the following meaning.
BINAP: 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl
Bn: benzyl
Boc: tert-butoxycarbonyl
t-Bu: tert-butyl
mCPBA: Metachloroperbenzoic acid
c-Pr: Cyclopropyl
DAST: N, N-diethylaminosulfur trifluoride
DCM: Dichloromethane
dba: Dibenzylideneacetone
dppf: 1,1'-bis (diphenylphosphino) ferrocene
DIAD: Diisopropyl azodicarboxylic acid
DIBAL: Diisobutylaluminum hydride
DIPEA: N, N-diisopropylethylamine
DMA: N, N-dimethylacetamide
DMAP: N, N-dimethyl-4-aminopyridine
DMF: N, N-dimethylformamide
DMP: Death Martin Periodinan
DMSO: Dimethyl sulfoxide
EDCI: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
HATU: 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate
HOBt: 1-hydroxybenzotriazole
i: Iso
IPA: Isopropyl alcohol
LDA: Lithium diisopropylamide
n: Normal
NBS: N-bromosuccinimide
NCS: N-chlorosuccinimide
NIS: N-iodosuccinimide
NMP: N-methyl-2-pyrrolidone
p: Para
Ph: Phenyl
Pin: Pinacol
Pr: Propyl
TBAB: Tetra-n-butylammonium bromide
TBAF: Tetra-n-butylammonium fluoride
TBAI: Tetra-n-butylammonium iodide
TBS: tert-butyldimethylsilyl
TEA: Triethylamine
Tf: trifluoromethanesulfonyl
TMS: Tetramethylsilane
THF: tetrahydrofuran
Ts: p-Toluenesulfonyl
(A- ^ta Phos) ₂ PdCl ₂ : Bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II)

Example 1
Preparation of 3- (2-methoxyphenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-1)

Process 1
Compound (III-1) (2.12 g, 11.0 mmol) and 6- (trifluoromethyl) pyridin-3-ol (II-1) (1.80 g, 11.0 mmol) were dissolved in DMSO (13 mL), and cesium carbonate was dissolved. (4.31 g, 13.2 mmol) was added, and the mixture was stirred at 120 ° C. for 18 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 90: 10) to obtain compound (IV-1) (yield 2.67 g, yield). 76%) was obtained as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.01 (1H, dd, J = 4.6, 7.8 Hz), 7.71 (1H, dd, J = 2.3, 8.7 Hz), 7.76 (1H, d, J = 8.2 Hz), 8.00 (1H, dd, J = 1.8, 7.8 Hz), 8.07 (1H, dd, J = 1.8, 5.0 Hz), 8.63 (1H, d, J = 2.3 Hz).
ESI-MS m / z: 319, 321 [M + H] ⁺ .
Process 2
Compound (IV-1) (40.0 mg, 0.125 mmol), 2-methoxyphenylboronic acid (V-1) (24.6 mg, 0.162 mmol), (A- ^ta Phos) ₂ PdCl ₂ (4.4 mg, 0.0062 mmol) and Cesium carbonate (81.0 mg, 0.249 mmol) was dissolved in 1,4-dioxane (1.0 mL) and water (0.2 mL), and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 80: 20) to obtain compound (I-1) (yield 32.9 mg, yield) 76%) was obtained as a white solid.

Example 2
Preparation of 3- (3-methoxyphenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-2) According to the same production method as for compound (I-1), compound Compound (I-2) (yield 40.5 mg, yield) from (IV-1) (40.0 mg, 0.125 mmol) and 3-methoxyphenylboronic acid (V-2) (24.8 mg, 0.163 mmol)
93%) was obtained as a pale yellow oil.

Example 3
Preparation of 3- (2-fluorophenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-3) Compound by a method similar to that for compound (I-1) Compound (I-3) (yield 39.2 mg, yield) from (IV-1) (40.0 mg, 0.125 mmol) and 2-fluorophenylboronic acid (V-3) (22.8 mg, 0.163 mmol)
94%) was obtained as a colorless oil.

Example 4
Preparation of 3- (2-chlorophenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-4) By a method similar to that for compound (I-1), compound (I IV-1) (40.0 mg, 0.125 mmol) and 2-chlorophenylboronic acid (V-4) (22.8 mg, 0.163 mmol) to give compound (I-4) (yield 41.4 mg, 94% yield) as a colorless oil Got as.

Example 5
Preparation of 3- (2-bromophenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-5)

Process 1
2-Chloro-3-iodopyridine (III-2) (1.00 g, 4.18 mmol) and compound (II-1) (819 mg, 5.20 mmol) were dissolved in DMSO (8.4 mL), and cesium carbonate (1.91 g, 5.85 mmol) was added and the mixture was stirred at 120 ° C. for 23 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (IV-2) (yield 964 mg, yield 63%) as a colorless oil. Obtained.
Process 2
According to the same production method as for compound (I-1), compound (IV-2) (305 mg, 0.834 mmol) and 2-bromophenylboronic acid (V-5) (168 mg, 0.834 mmol) were converted to compound (I- 5) (Yield 138 mg, Yield 42%) was obtained as a colorless oil.

Example 6
Preparation of 3- (2,6-difluorophenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-6) According to the same production method as compound (I-1) , Compound (IV-1) (30.0 mg, 0.0940 mmol) and 2,6-
Difluorophenylboronic acid (V-6) (22.3 mg, 0.141 mmol) to compound (I-6) (yield 4.5 mg,
(14% yield) was obtained as a colorless oil.

Example 7
Preparation of 3- (2,5-difluorophenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-7) According to the same production method as compound (I-1) , Compound (IV-1) (30.0 mg, 0.0940 mmol) and 2,5-
Compound (I-7) (26.9 mg, 81% yield) was obtained as a colorless oil from difluorophenylboronic acid (V-7) (22.3 mg, 0.141 mmol).

Example 8
Production of 3- (2,4-difluorophenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-8) According to the same production method as for compound (I-1) , Compound (IV-1) (30.0 mg, 0.0940 mmol) and 2,4-
Compound (I-8) (yield 30.6 mg, yield 92%) was obtained as a colorless oil from difluorophenylboronic acid (V-8) (22.3 mg, 0.141 mmol).

Example 9
Preparation of 3- (2,3-difluorophenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-9) According to the same production method as compound (I-1) , Compound (IV-1) (30.0 mg, 0.0940 mmol) and 2,3-
Compound (I-9) (yield 31.8 mg, yield 96%) was obtained as a colorless oil from difluorophenylboronic acid (V-9) (22.3 mg, 0.141 mmol).

Example 10
Preparation of 3- (2-fluoro-6-methoxyphenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-10) Preparation similar to compound (I-1) According to the method, compound (I-10) (yield 28.0 mg) was obtained from compound (IV-1) (30.0 mg, 0.0940 mmol) and 2-fluoro-6-methoxyphenylboronic acid (V-10) (23.4 mg, 0.141 mmol). Yield 82%) as a colorless oil.

Example 11
Preparation of 3- (5-fluoro-2-methoxyphenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-11) Preparation similar to compound (I-1) According to the method, compound (I-11) (yield 28.8 mg) was obtained from compound (IV-1) (30.0 mg, 0.0940 mmol) and 5-fluoro-2-methoxyphenylboronic acid (V-11) (20.1 mg, 0.122 mmol). , Yield 84%) as a colorless oil.

Example 12
Preparation of 3- (4-fluoro-2-methoxyphenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-12) Preparation similar to compound (I-1) According to the method, compound (I-12) (yield 33.4 mg) was obtained from compound (IV-1) (30.0 mg, 0.0940 mmol) and 4-fluoro-2-methoxyphenylboronic acid (V-12) (23.4 mg, 0.141 mmol). Yield 98%) as a colorless oil.

Example 13
Preparation of 3- (3-fluoro-2-methoxyphenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-13) Preparation similar to compound (I-1) According to the method, compound (I-13) (yield 34.0 mg) was obtained from compound (IV-1) (30.0 mg, 0.0940 mmol) and 3-fluoro-2-methoxyphenylboronic acid (V-13) (23.4 mg, 0.141 mmol). Yield 99%) as a colorless oil.

Example 14
Production of 3- [2- (methylthio) phenyl] -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-14) According to the same production method as for compound (I-1) Compound (IV-1) (30.0 mg, 0.0940 mmol) and 2-methylthiophenylboronic acid (V-14) (23.4 mg, 0.141 mmol) to Compound (I-14) (Yield 26.5 mg, Yield 73%) Was obtained as a white solid.

Example 15
Preparation of 3- (2-nitrophenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-15) Compound by a method similar to that for compound (I-1) Compound (I-15) (yield 470 mg, 83% yield) from (IV-1) (500 mg, 1.57 mmol) and 2-nitrophenylboronic acid (V-15) (394 mg, 2.34 mmol) Obtained as a solid.

Example 16
Preparation of 3- (2-ethylphenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-16) Compound by the same production method as compound (I-1) Compound (I-16) (29.8 mg, 92% yield) was colorless from (IV-1) (30.0 mg, 0.0940 mmol) and 2-ethylphenylboronic acid (V-16) (21.1 mg, 0.141 mmol). Obtained as an oil.

Example 17
3- (2-Ethoxyphenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine
Production of (I-17) By the same production method as for compound (I-1), compound (IV-1) (30.0 mg, 0.0940 mmol) and 2-ethoxyphenylboronic acid (V-17) (23.4 mg, 0.141 mmol) gave compound (I-17) (yield 37.4 mg, quantitative yield) as a colorless oil.

Example 18
Preparation of 2- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) phenol (I-18) Compound by the same production method as compound (I-1) Compound (I-18) (Yield 190 mg, Yield 91%) from (IV-1) (200 mg, 0.627 mmol) and 2-hydroxyphenylboronic acid (V-18) (130 mg, 0.941 mmol) in orange Obtained as a solid.

Example 19
Preparation of 1- [2- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) phenyl] ethanone (I-19) Similar to compound (I-1) Depending on the production method, compound (I-19) (yield 472 mg, yield) was obtained from compound (IV-1) (500 mg, 1.57 mmol) and 2-acetylphenylboronic acid (V-19) (284 mg, 1.73 mmol). 84%) was obtained as a yellow oil.

Example 20
Preparation of methyl 2- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) benzoate (I-20) According to the same production method as compound (I-1), From compound (IV-1) (500 mg, 1.57 mmol) and 2-methoxycarbonylphenylboronic acid (V-20) (367 mg, 2.04 mmol) to compound (I-20) (yield 414 mg, 71% yield) Was obtained as a colorless oil.

Example 21
Production of 3- (2-trifluoromethoxyphenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-21) According to the same production method as for compound (I-1) Compound (IV-1) (30.0 mg, 0.0940 mmol) and 2-trifluoromethoxyphenylboronic acid (V-21) (29.0 mg, 0.141 mmol) to Compound (I-21) (Yield 34.1 mg, Yield 91 %) As a colorless oil.

Example 22
Preparation of [2- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) phenyl] methanol (I-22) Compound (IV-1) (162 mg, 0.509 mmol), 2-hydroxymethylphenylboronic acid (V-22) (113
mg, 0.764 mmol), (A- ^ta Phos) ₂ PdCl ₂ (18.1 mg, 0.0255 mmol) and cesium carbonate (332 mg,
1.02 mmol) was dissolved in 1,4-dioxane (2.5 mL) and water (0.50 mL) and stirred at room temperature for 20 hours. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-22) (yield 146 mg, yield 83%) as a white solid. It was.

Example 23
Preparation of 3- (5-chloro-2-methoxyphenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-23) Preparation similar to compound (I-1) According to the method, compound (I-23) (yield 191) was obtained from compound (IV-1) (200 mg, 0.627 mmol) and 5-chloro-2-methoxyphenylboronic acid (V-23) (175 mg, 0.940 mmol).
mg, yield 80%) was obtained as a pale yellow solid.

Example 24
Preparation of 2-methyl-2 '-{[6- (trifluoromethyl) pyridin-3-yl] oxy} -3,3'-bipyridine (I-24) According to the same production method as compound (I-1) , Compound (IV-1) (30.0 mg, 0.0944 mmol) and 2-methylpyridine-3-boronic acid (V-24) (18.3 mg, 0.141 mmol) to compound (I-24) (yield 23.5 mg,
Yield 75%) was obtained as a white solid.

Example 25
Production of 4′-methyl-2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} -3,3′-bipyridine (I-25) According to the production method similar to that for compound (I-1) , Compound (IV-1) (30.0 mg, 0.0943 mmol) and 4-methylpyridine-3-boronic acid (V-25) (17.3 mg, 0.113 mmol) to compound (I-25) (yield 16.1 mg,
Yield 52%) was obtained as a colorless oil.

Example 26
Production of 2-methoxy-2 '-{[6- (trifluoromethyl) pyridin-3-yl] oxy} -3,3'-bipyridine (I-26) According to the same production method as for compound (I-1) Compound (IV-1) (40.0 mg, 0.125 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (24.9 mg, 0.163 mmol) to compound (I-26) (yield 43.0 mg,
Yield 99%) was obtained as a white solid.

Example 27
Production of 3'-methoxy-2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} -3,4'-bipyridine (I-27) According to the same production method as for compound (I-1) Compound (IV-1) (40.0 mg, 0.125 mmol) and 3-methoxypyridine-4-boronic acid (V-27) (24.9 mg, 0.163 mmol) to compound (I-27) (yield 7.1 mg, yield) 16%) was obtained as a colorless oil.

Example 28
Production of 4′-methoxy-2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} -3,3′-bipyridine (I-28) Compound (IV-1) (40.0 mg, 0.125 mmol) and 4-methoxypyridine-3-boronic acid (V-28a) (24.9 mg, 0.163 mmol) to compound (I-28) (yield 15.4 mg, yield) 35%) was obtained as a white solid.

Example 29
2-Methoxy-6-methyl-2 '-{[6- (trifluoromethyl) pyridin-3-yl] oxy} -3,3'-bipyridine (I-29) Preparation Same as Compound (I-1) The compound (I-29) was prepared from compound (IV-1) (30.0 mg, 0.0940 mmol) and 2-methoxy-6-methylpyridine-3-boronic acid (V-29) (20.4 mg, 0.122 mmol). ) (Yield 25.4 mg, Yield 75%) was obtained as a colorless oil.

Example 30
2-Methoxy-5-methyl-2 '-{[6- (trifluoromethyl) pyridin-3-yl] oxy} -3,3'-bipyridine (I-30) Preparation Same as Compound (I-1) According to the production method of the compound (IV-1) (30.0 mg, 0.0940 mmol) and 2-methoxy-5-methylpyridine-3-boronic acid (V-30) (20.4 mg, 0.122 mmol) to the compound (I-30 (Yield 22.4 mg, 66% yield) was obtained as a pale yellow oil.

Example 31
Preparation of 5-chloro-2-methoxy-2 '-{[6- (trifluoromethyl) pyridin-3-yl] oxy} -3,3'-bipyridine (I-31) Same as compound (I-1) According to the production method of the compound (IV-1) (30.0 mg, 0.0940 mmol) and 5-chloro-2-methoxypyridine-3-boronic acid (V-31) (19.4 mg, 0.103 mmol) to the compound (I-31 ) (Yield 24.2 mg, Yield 67%) was obtained as a colorless oil.

Example 32
Preparation of 5-fluoro-2-methoxy-2 '-{[6- (trifluoromethyl) pyridin-3-yl] oxy} -3,3'-bipyridine (I-32) Compound (IV-1) (32.0 mg, 0.100 mmol), 5-fluoro-2-methoxypyridine-3-boronic acid (V-32) (22.3 mg, 0.130 mmol), (A- ^ta Phos) ₂ PdCl ₂ (3.6 mg, 0.0050 mmol) and carbonic acid Cesium (65.4 mg, 0.201 mmol) was dissolved in a 1,4-dioxane (0.8 mL) / water (0.16 mL) mixture and stirred at 100 ° C. for 4 hours. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 95: 5 → 85: 15) to obtain compound (I-32) (yield 22.7 mg Yield 62%) as a colorless oil.

Example 33
Preparation of 5- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) isoquinoline (I-33) Compound (IV-1) (307 mg, 0.961 mmol), 5-isoquinolineboronic acid (V-33) (258 mg, 1.44 mmol), (A- ^ta Phos) ₂ PdCl ₂ (34.1 mg, 0.0481 mmol) and cesium carbonate (626 mg, 1.92 mmol) were combined with 1,4-dioxane. (4.0 mL) and water (0.80 mL) were dissolved, and the mixture was stirred at 110 ° C. for 14 hours. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-33) (yield 222 mg, yield 63%) as a white solid. It was.

Example 34
Preparation of 8- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) quinoline (I-34) Compound by a method similar to that for compound (I-33) Compound (I-34) (yield 182 mg, 79% yield) from (IV-1) (200 mg, 0.627 mmol) and 8-quinolineboronic acid (V-34) (163 mg, 0.941 mmol) as a white solid Got as.

Example 35
Preparation of 3- (2,3-dihydrobenzofuran-7-yl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-35) Same as compound (I-1) The compound (IV-1) (40.0 mg, 0.125 mmol) and 2,3-dihydrobenzofuran-7-boronic acid pinacol ester (V-35a) (40.0 mg, 0.163 mmol) ) (Yield 37.2 mg, Yield 83%) as a white solid.

Example 36
Preparation of 5- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) quinoline (I-36)

Process 1
To a THF (25 mL) solution of magnesium (1.52 g, 62.5 mmol) and lithium chloride (1.33 g, 31.3 mmol), a 0.99 mol / L DIBAL toluene solution (253 μL, 0.250 mmol) was slowly added dropwise and stirred for 5 minutes. . A solution of compound (IV-1) (7.98 g, 25.0 mmol) in THF (10 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Triisopropyl borate (11.5 mL, 50.0 mmol) was added under ice cooling, and the mixture was stirred for 1 hour under ice cooling. 0.1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 0: 100, then ethyl acetate: methanol = 90: 10), and compound ( VIa-1) (yield 3.94 g, 56% yield) was obtained as a light brown solid.
Process 2
5-Bromoquinoline (VII-1) (200 mg, 0.961 mmol), Compound (VIa-1) (380 mg, 1.44 mmol)
(A- ^ta Phos) ₂ PdCl ₂ (34.1 mg, 0.0481 mmol) and cesium carbonate (626 mg, 1.92 mmol) were dissolved in 1,4-dioxane (4.0 mL) and water (0.8 mL) at 110 ° C. Stir for 14 hours. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 → 70: 30) to give compound (I-36) (yield 312 mg, yield) 90%) was obtained as a white solid.

Example 37
Preparation of 5- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) quinoxaline (I-37) According to the same production method as for compound (I-36), -Bromoquinoxaline (VII-2) (29.7 mg, 0.137
mmol) and Compound (VIa-1) (30.0 mg, 0.108 mmol) to give Compound (I-37) (Yield 18.4 mg, Yield 47%) as a colorless oil.

Example 38
Production of 3- (chroman-8-yl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-38) According to the production method similar to that of compound (I-36), 8-Bromochroman (VII-3) (27.0 mg, 0.127 mmol) and Compound (VIa-1) (30.0 mg, 0.106 mmol) to Compound (I-38) (Yield 6.2 mg, Yield 16%)
Was obtained as a colorless oil.
8-Bromochroman can be synthesized according to a known method. For example, Tetrahedron Lett. 1998; 39: 2219-2222.

Example 39
Preparation of 3- (2,2-difluorobenzo [1,3] dioxol-4-yl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-39) Compound ( 4-bromo-2,2-difluorobenzo [1,3] dioxole (VII-4) (30.0 mg, 0.127 mmol) and compound (VIa-1) (30.0 mg, 0.106 mmol) gave compound (I-39) (yield 12.2 mg, 29% yield) as a colorless oil.

Example 40
7- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) -2,3-dihydro-1H-inden-1-one (I-40) Compound In the same manner as in (I-36), 7-bromo-1-indanone (VII-5) (324 mg, 1.14 mmol) and compound (VIa-1) (200 mg, 0.948 mmol) were converted to compound (I- 40) (yield 185 mg, 53% yield) was obtained as a yellow solid.

Example 41
Preparation of 3- (5-Fluoro-2,3-dihydrobenzofuran-7-yl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-41) Compound (I- 36) from the compound (VIa-1) (39.3 mg, 0.138 mmol) and 7-bromo-5-fluoro-2,3-dihydrobenzofuran (VII-6) (30.0 mg, 0.138 mmol) Compound (I-41) (Yield 24.6 mg, Yield 47%) was obtained as a white solid.
7-Bromo-5-fluoro-2,3-dihydrobenzofuran can be synthesized according to a known method. For example, it is described in US Pat. No. 5,817,690.

Example 42
7- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) -1H-indole (I-42) Production Method Similar to Compound (I-36) 7-bromoindole (VII-7) (30.0 mg, 0.153 mmol) and compound (VIa-1) (65.0 mg, 0.230 mmol) to compound (I-42) (yield 20.8 mg, 38% yield) Obtained as a colorless oil.

Example 43
Preparation of 8- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) isoquinoline (I-43) Compound by a method similar to that for compound (I-33) Compound (I-43) (yield 118 mg, quantitative yield) from (IV-1) (100 mg, 0.313 mmol) and 8-isoquinolineboronic acid (V-36) (81.3 mg, 0.470 mmol) as a white solid Got as.

Example 44
7- (2-{[6- (Trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) pyrazolo [1,5-a] pyridine (I-44) Preparation Compound (I-36) The compound (I-44) was prepared from 7-bromopyrazolo [1,5-a] pyridine (VII-8) (30.5 mg, 0.155 mmol) and compound (VIa-1) (40.0 mg, 0.141 mmol) by the same production method. (Yield 39.6
mg, yield 79%) was obtained as a white solid.

Example 45
5- (2-{[6- (Trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl)-[1,2,4] triazolo [1,5-a] pyridine (I-45) According to the same production method as for compound (I-36), 5-bromo- [1,2,4] triazolo [1,5-a] pyridine (VII-9) (27.2 mg, 0.137 mmol) and compound ( Compound (I-45) (yield 7.1 mg, 19% yield) was obtained as a white solid from VIa-1) (30.0 mg, 0.108 mmol).

Example 46
Preparation of 3- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) -1H-pyrazolo [3,4-b] pyridine (I-46)

Process 1
Compound (M-1) (100 mg, 0.839 mmol) was dissolved in acetonitrile (2.8 mL), NIS (208 mg, 0.923 mmol) was added, and the mixture was stirred at 75 ° C. for 17 hours. The reaction mixture was allowed to cool, ethyl acetate was added, and the mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain compound (M-2).
Process 2
Compound (M-2) was dissolved in THF (8.4 mL), and TEA (234 μL, 1.68 mmol), (Boc) ₂ O (289 μL, 1.26 mmol) and DMAP (10.3 mg, 0.0839 mmol) were sequentially added. Thereafter, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (VII-10) (yield 151 mg, 52%) as a white solid. It was.
Process 3
By the same production method as for compound (I-36), compound (I-46) (yield 63.7) from compound (VII-10) (100 mg, 0.290 mmol) and compound (VIa-1) (99.6 mg, 0.377 mmol) mg, yield 62%) was obtained as a colorless oil.

Example 47
1-methyl-3- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) -1H-pyrazolo [3,4-b] pyridine (I-47) Production Compound (I-46) (29.6 mg, 0.0828 mmol) was dissolved in DMF (1.0 mL), sodium hydride (4.8 mg, 0.099 mmol) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 15 min. Then, methyl iodide (6.2
μL, 0.099 mmol) was added, and the mixture was warmed to room temperature and stirred for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (I-47) (yield 17.2 mg, yield 56%) as a colorless oil. Obtained.

Example 48
Preparation of 5-methyl-7- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) pyrazolo [1,5-a] pyrimidine (I-48)

Process 1
3-aminopyrazole (M-3) (1.00 g, 12.0 mmol) was dissolved in acetic acid (6.0 mL), methyl acetoacetate (1.30 mL, 12.0 mmol) was added, and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration and washed successively with water and ethanol to give compound (M-4) (yield 910 mg, 51% yield) as a white solid.
Process 2
Compound (M-4) (800 mg, 5.36 mmol) is dissolved in acetonitrile (50 mL), potassium carbonate (2.23 g, 16.1 mmol) and phosphorus oxybromide (4.62 g, 16.1 mmol) are added, and the mixture is heated under reflux. Stir for 4 hours. The mixture was allowed to cool to room temperature, and the solvent was distilled off under reduced pressure. Chloroform was added, and the organic layer was washed with saturated sodium bicarbonate and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (VII-11) (yield 833 mg, yield 73%) as a pale yellow solid.
Process 3
According to the same production method as for compound (I-36), compound (I-48) (yield 63.3) was obtained from compound (VII-11) (100 mg, 0.472 mmol) and compound (VIa-1) (201 mg, 0.707 mmol). mg, yield 36%) was obtained as a white solid.

Example 49
Preparation of 3- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) pyrazolo [1,5-a] pyridine (I-49)

Process 1
Pyrazolo [1,5-a] pyridine (M-5) (300 mg, 2.54 mmol) was dissolved in acetonitrile (5.0 mL), NIS (628 mg, 2.79 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (VII-12) (yield 556 mg, yield 90%) as a pale yellow solid.
Process 2
According to the same production method as for compound (I-36), compound (I-49) (yield: 2.9) from compound (VII-12) (33.7 mg, 0.138 mmol) and compound (VIa-1) (30.0 mg, 0.106 mmol) mg, 8% yield) was obtained as a colorless oil.

Example 50
1- (2-{[6- (Trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) -1H-pyrrolo [2,3-b] pyridine (I-50) Preparation Compound (IV -1) (100 mg, 0.313 mmol), 7-azaindole (48.1 mg, 0.407 mmol), cesium carbonate (204 mg, 0.627 mmol) and 1,10-phenanthroline (11.3 mg, 0.0627 mmol) in 1,4- It melt | dissolved in dioxane (1.0 mL), copper iodide (I) (6.0 mg, 0.031 mmol) was added, and it stirred at 120 degreeC under argon atmosphere for 48 hours. The mixture was allowed to cool, diluted with ethyl acetate, and filtered through Celite (registered trademark). The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30 → 40: 60) to give compound (I-50) (yield
16.6 mg, 15% yield) was obtained as a colorless oil.

Example 51
Preparation of 3-chloro-7- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) pyrazolo [1,5-a] pyridine (I-51) Compound ( I-44) (40.0 mg, 0.112 mmol) was dissolved in DMF (0.55 mL), NCS (16.5 mg, 0.123 mmol) was added, and the mixture was stirred at room temperature for 22 hours, and then NCS (6.0 mg, 0.045 mmol) was added. The mixture was further stirred for 16 hours. Then, water was added and extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 70: 30) to obtain compound (I-51) (yield 27.6 mg, yield 63%) as a white solid.

Example 52
Preparation of 3-bromo-7- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) pyrazolo [1,5-a] pyridine (I-52) Compound ( I-44) (100 mg, 0.281 mmol) was dissolved in DMF (1.4 mL), NBS (54.9 mg, 0.309 mmol) was added, and the mixture was stirred at room temperature for 17 hours. Water was added and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 70: 30) to obtain compound (I-52) (yield 116 mg, yield 95%) as a pale green solid. .

Example 53
Preparation of 3-methyl-7- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) pyrazolo [1,5-a] pyridine (I-53) Compound ( I-52) (50.0 mg, 0.115 mmol), methylboronic acid (21.0 mg, 0.351 mmol), potassium carbonate (47.6 mg, 0.345 mmol) and Pd (PPh ₃ ) ₄ (6.6 mg, 5.7 μmol) in 1,4- Dioxane (0.50
mL) and water (0.10 mL), and stirred at 120 ° C. for 30 minutes under microwave irradiation. Methylboronic acid (34.0 mg, 0.568 mmol) was added, and the mixture was further stirred at 120 ° C. for 30 minutes under microwave irradiation. The mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 80: 20) to obtain compound (I-53) (yield 9.2 mg, yield 21%) as a colorless oil. .

Example 54
7- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (I-54) Compound (I-52) (100 mg, 0.230 mmol) was dissolved in NMP (1.0 mL), copper cyanide (45.3 mg, 0.506 mmol) was added, and the mixture was stirred at 180 ° C. for 2 hours under microwave irradiation. The mixture was allowed to cool, diluted with ethyl acetate, and filtered through celite. The filtrate was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30 → 50: 50) to obtain compound (I-54) (yield 52.8 mg, yield 60%) as a pale yellow solid. .

Example 55
3- [2- (Cyclobutylmethoxy) phenyl] -2-{[6- (trifluoromethyl) pyridin-3-yl]
Preparation of Oxy} pyridine (I-55) Compound (I-18) (30.0 mg, 0.0903 mmol) was dissolved in DMF (0.5 mL), 50-72% sodium hydride (6.5 mg, 0.14 mmol) and bromomethyl Cyclobutane (15.2 μL, 0.135 mmol) was sequentially added, and the mixture was stirred at room temperature for 4.5 hours. Water was added and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-55) (yield 16.7 mg, yield 46%) as a colorless oil. It was.

Example 56
3- [2- (2-Propin-1-yloxy) phenyl] -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-56) Compound (I-55) The compound (I-56) (27.4 mg, 82% yield) was obtained from the compound (I-18) (30.0 mg, 0.0903 mmol) and propargyl bromide (10.2 μL, 0.135 mmol) as a colorless oil by the same production method as above. Obtained as a thing.

Example 57
Preparation of 3- [2- (cyclopropylmethoxy) phenyl] -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-57) Preparation similar to compound (I-55) The compound (I-18) (30.0 mg, 0.0903 mmol) and bromomethylcyclopropane (13.1 μL, 0.135 mmol) were converted into the compound (I-57) (yield 22.0 mg, yield 63%) as a colorless oil. Obtained.

Example 58
3- {2-[(Tetrahydro-2H-pyran-4-yl) oxy] phenyl} -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-58) Compound (I-18) (30.0 mg, 0.0903 mmol), triphenylphosphine (28.3 mg, 0.108 mmol), DIAD (27.0 μL, 0.135 mmol) and 4-hydroxytetrahydropyran (113 mg, 0.764 mmol) in THF (0.5 mL) ) And stirred at room temperature for 23 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (I-58) (
Yield 11.7 mg, 31% yield) was obtained as a white solid.

Example 59
Preparation of 3- (2-cyclopropylphenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-59) By the same production method as compound (I-53), Compound (I-59) (yield 7.6 mg, 21% yield) was obtained as a colorless oil from compound (I-5) (40.0 mg, 0.101 mmol) and cyclopropylboronic acid (15.8 mg, 0.152 mmol).

Example 60
Preparation of 3- [2- (methoxymethyl) phenyl] -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-60) Compound (I-22) (40.0 mg, 0.116 mmol) was dissolved in DCM (0.40 mL), and then TEA (50.0 μL, 0.358 mmol) and methanesulfonyl chloride (10.0 μL, 0.129 mmol) were sequentially added under ice cooling, followed by stirring at room temperature for 30 minutes. Methanol (1.0 mL) and sodium methoxide (25.0 mg, 0.463 mmol) were added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (I-60) (13.4 mg, 32% yield) as a colorless oil Got as.

Example 61
Preparation of 2- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) aniline (I-61) Compound (I-15) (250 mg, 0.692 mmol) The residue was dissolved in methanol (4.0 mL) and ethyl acetate (2.0 mL), palladium carbon (25.0 mg, 10 w / w%) was added, and the mixture was stirred at room temperature for 5 hours in a hydrogen atmosphere. After the reaction solution was filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-61) (yield 173 mg, 76% yield). ) Was obtained as a white solid.

Example 62
Preparation of N, N-dimethyl-2- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) aniline (I-62) Compound (I-61) (30.0 mg, 0.0906 mmol) was dissolved in DMF (0.30 mL), 50% sodium hydride (17.4 mg, 0.362 mmol) and methyl iodide (26 μL, 0.0362 mmol) were added, and the mixture was stirred at room temperature for 14.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (I-62) (yield 20.1 mg, 62% yield) as a colorless oil. Obtained.

Example 63
Preparation of 2- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) benzaldehyde (I-63) Compound by the same production method as compound (I-1) Compound (I-63) (yield 260 mg, yield 80%) was converted to white from (IV-1) (300 mg, 0.940 mmol) and 2-formylphenylboronic acid (V-37) (367 mg, 2.04 mmol). Obtained as a solid.

Example 64
Preparation of 3- (2-ethynylphenyl) -2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-64) Compound (I-63) (30.0 mg, 0.0870 mmol) and Potassium carbonate (24.1 mg, 0.174 mmol) was dissolved in methanol (0.87 mL), and dimethyl (1-diazo-2-oxopropyl) phosphonate (Ohira-
Bestman's reagent) (15.7 μL, 0.105 mmol) was added, and then the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-64) (yield 18.4
mg, yield 63%) was obtained as a colorless oil.

Example 65
Preparation of 3- (2-methoxyphenyl) -4-methyl-2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-65)

Process 1
Compound (III-3) (200 mg, 0.969 mmol) and compound (II-1) (158 mg, 0.969 mmol) are dissolved in DMSO (3.0 mL), cesium carbonate (411 mg, 1.26 mmol) is added, and 120 Stir at 16 ° C. for 16 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (IV-3) (
Yield 79.4 mg, 25% yield) was obtained as a white solid.
Process 2
Compound (IV-3) (35.6 mg, 0.107 mmol), 2-methoxyphenylboronic acid (V-1) (24.5 mg, 0.161 mmol), (A- ^ta Phos) ₂ PdCl ₂ (11.4 mg, 0.0161 mmol) and Cesium carbonate (105 mg, 0.322 mmol) was dissolved in 1,4-dioxane (1.0 mL) and water (0.2 mL), and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-65) (yield 33.2 mg, yield 86%) as a white solid. It was.

Example 66
Preparation of 3- (2-methoxyphenyl) -5-methyl-2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-66)

Process 1
According to the same production method as for compound (IV-3), compound (IV-4) (yield 33.3) was obtained from compound (II-1) (158 mg, 0.969 mmol) and compound (III-4) (200 mg, 0.969 mmol). mg, yield 10%) was obtained as a colorless oil.
Process 2
According to the same production method as for compound (I-65), compound (I-66) (yield 32.9) was obtained from compound (IV-4) (33.3 mg, 0.100 mmol) and compound (V-1) (22.8 mg, 0.150 mmol). mg, yield 91%) was obtained as a colorless oil.

Example 67
Preparation of 3- (2-methoxyphenyl) -6-methyl-2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridine (I-67)

Process 1
According to the same production method as for compound (IV-3), compound (IV-5) (yield 137) was obtained from compound (II-1) (158 mg, 0.969 mmol) and compound (III-5) (200 mg, 0.969 mmol). mg, yield 43%) was obtained as a white solid.
Process 2
According to the same production method as for compound (I-65), compound (I-67) (yield 30.2 mg) from compound (IV-5) (37.2 mg, 0.112 mmol) and compound (V-1) (25.5 mg, 0.168 mmol) mg, yield 75%) was obtained as a colorless oil.

Example 68
Preparation of 3- (2-methoxyphenyl) -2-[(6-methylpyridin-3-yl) oxy] pyridine (I-68)

Process 1
Compound (III-1) (5.46 g, 28.4 mmol) and compound (II-2) (3.25 g, 29.8 mmol) were dissolved in DMSO (20 mL), cesium carbonate (13.9 g, 42.5 mmol) was added, and 130 Stir at 17 ° C. for 17 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 40: 60)
Compound (IV-6) (yield 7.30 g, yield 97%) was obtained as a yellow oil.
Process 2
Compound (IV-6) (7.29 g, 27.5 mmol), 2-methoxyphenylboronic acid (V-1) (4.39 g, 28.9 mmol), (A- ^ta Phos) ₂ PdCl ₂ (195 mg, 0.275 mmol) and Cesium carbonate (26.9 g, 82.5 mmol) was dissolved in 1,4-dioxane (50 mL) and water (5 mL), and the mixture was stirred at 120 ° C. for 20 hours. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40) to obtain compound (I-68) (yield 7.86 g, yield). 98%) was obtained as an orange oil.

Example 69
Preparation of (5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) methyl acetate (I-69) Compound (I-68) (7.86 g, 26.9 mmol) MCPBA (8.07 g, 32.3 mmol) was added to DCM (30 mL) solution at 0 ° C., and the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure.
The residue was dissolved in acetic anhydride (25 mL) and stirred at 60 ° C. for 14 hours. Evaporate the solvent under reduced pressure,
The mixture was diluted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 98: 2 → 0: 100) to give compound (I-69) (yield 6.59 g , Yield 70%) as a white solid.

Example 70
Preparation of (5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) methanol (I-70) Compound (I-69) (6.59 g, 18.8 mmol) in methanol (50 mL) To the solution was added potassium carbonate (0.520 g, 3.76 mmol) at 0 ° C., and the mixture was stirred at room temperature for 67 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 98: 2 → 0: 100) to give compound (I-70) (yield 5.80 g). ,
Yield quantitative) was obtained as a colorless oil.

Example 71
Preparation of 5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} picolinaldehyde (I-71) Compound (I-70) (500 mg, 1.62 mmol) in DCM (8.0 mL) solution DMP (825 mg, 1.95 mmol) was added and stirred at room temperature for 7 hours. The reaction solution was diluted with chloroform, and an aqueous sodium sulfite solution and a saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 40: 60 → 0: 100) to give compound (I-71) (yield 492 mg, yield) 99%) was obtained as a white solid.

Example 72
Preparation of 2-{[6- (difluoromethyl) pyridin-3-yl] oxy} -3- (2-methoxyphenyl) pyridine (I-72) Compound (I-71) (50.0 mg, 0.163 mmol) in DCM DAST (72.0 μL, 0.490 mmol) was added to the (1.0 mL) solution, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 70: 30) to give compound (I-72) (yield 48.3 mg, yield) 90%) was obtained as a colorless oil.

Example 73
Preparation of 2-{[6- (difluoromethyl) pyridin-3-yl] oxy} -3- (4-fluoro-2-methoxyphenyl) pyridine (I-73)

Process 1
To a solution of compound (III-1) (400 mg, 2.30 mmol) and compound (II-3) (487 mg, 2.53 mmol) in DMSO (4.6 mL) was added cesium carbonate (1.50 g, 4.60 mmol), and 120 ° C. For 19 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (IV-7) (yield 372 mg, yield 49%) as a white solid.
Process 2
To a solution of compound (IV-7) (372 mg, 1.13 mmol) and ethyl 2-bromo-2,2-difluoroacetate (145 μL, 1.13 mmol) in DMSO (3.8 mL) was added copper (165 mg, 2.59 mmol). The mixture was further stirred at 80 ° C. for 16 hours. The reaction solution was cooled and diluted with isopropyl acetate, and then a saturated potassium dihydrogen phosphate solution was added and stirred for 10 minutes. The reaction solution was extracted with ethyl acetate, the organic layer was washed successively with water and saturated brine, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-8) (yield 172 mg, 40% yield) as a colorless oil.
Process 3
Magnesium chloride hexahydrate (1.09 g, 5.36 mmol) was added to a solution of compound (IV-8) (2.00 g, 5.36 mmol) in NMP (10.0 mL), and the mixture was stirred at 180 ° C. for 15 minutes under microwave irradiation. . The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 → 80: 20) to obtain compound (IV-9) (yield 946 mg, yield) 59%) was obtained as a white solid.
Process 4
According to the same production method as for compound (I-1), from compound (IV-9) (30.0 mg, 0.100 mmol) and 4-fluoro-2-methoxyphenylboronic acid (V-12) (22.0 mg, 0.130 mmol) Compound (I-73) (yield 27.9 mg, yield 81%) was obtained as a white solid.

Example 74
2-{[6- (Difluoromethyl) pyridin-3-yl] oxy} -3- (2-fluoro-5-methoxyphenyl) pyridine (I-74) Production Method Similar to Compound (I-1) From compound (IV-9) (30.0 mg, 0.100 mmol) and 2-fluoro-5-methoxyphenylboronic acid (V-38) (22.0 mg, 0.130 mmol) to compound (I-74) (yield 33.7 mg, Yield 98%) was obtained as a white solid.

Example 75
2-{[6- (Difluoromethyl) pyridin-3-yl] oxy} -3- (4-fluoro-3-methoxyphenyl) pyridine (I-75) Production Method Similar to Compound (I-1) From compound (IV-9) (30.0 mg, 0.100 mmol) and 4-fluoro-3-methoxyphenylboronic acid (V-39) (22.0 mg, 0.130 mmol) to compound (I-75) (yield 30.5 mg, Yield 88%) was obtained as a white solid.

Example 76
Preparation of 3- (4,5-difluoro-2-methoxyphenyl) -2-{[6- (difluoromethyl) pyridin-3-yl] oxy} pyridine (I-76) Similar to compound (I-1) Depending on the production method, compound (I-76) (40.0 mg, 0.133 mmol) and 4,5-difluoro-2-methoxyphenylboronic acid (V-40) (32.5 mg, 0.173 mmol)
Yield 43.5 mg, 90% yield) was obtained as a colorless oil.

Example 77
Preparation of 3- (2,4-difluoro-5-methoxyphenyl) -2-{[6- (difluoromethyl) pyridin-3-yl] oxy} pyridine (I-77) Similar to compound (I-1) Depending on the production method, compound (I-77) (30.0 mg, 0.100 mmol) and 2,4-difluoro-5-methoxyphenylboronic acid (V-41) (24.3 mg, 0.130 mmol)
Yield 24.0 mg, 66% yield) was obtained as a white solid.

Example 78
Production of 2 ′-{[6- (difluoromethyl) pyridin-3-yl] oxy} -2,6-dimethoxy-3,3′-bipyridine (I-78) Production method similar to compound (I-1) From compound (IV-9) (30.0 mg, 0.100 mmol) and 2,6-dimethoxypyridine-3-boronic acid (V-42) (23.7 mg, 0.130 mmol) to compound (I-78) (yield 29.7
mg, yield 83%) was obtained as a colorless oil.

Example 79
Preparation of 2,2-difluoro-2- (5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) ethanol (I-79)

Process 1
Compound (IV-8) (372 mg, 1.00 mmol) is dissolved in a mixture of methanol (2.5 mL) and THF (2.5 mL), and sodium borohydride (56.6 mg, 1.50 mmol) is added under ice-cooling at room temperature. Stir for 15 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane:
Purification with ethyl acetate) gave Compound (IV-10) (Yield 273 mg, Yield 83%) as a colorless oil. Process 2
According to the same production method as for compound (I-1), compound (IV-10) (142 mg, 0.448 mmol) and 2-methoxyphenylboronic acid (V-1) (102 mg, 0.672 mmol) were converted to compound (I- 79) (yield 24.4 mg, yield 74%) was obtained as a colorless oil.

Reference Example 80
2,2-Difluoro-2- (5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) ethyl Preparation of trifluoromethanesulfonate (I-80) Compound (I- 79) (244 mg, 0.681 mmol) in DCM (3.4 mL) under ice-cooling, pyridine (83.0 μL, 1.02 mmol) and trifluoromethanesulfonic anhydride (127 μL, 0.749 mmol) were sequentially added at room temperature. Stir for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (I-80) (yield 220 mg, 66% yield) as a pale yellow oil. Obtained.

Example 81
2-{[6- (1,1-Difluoroethyl) pyridin-3-yl] oxy} -3- (2-methoxyphenyl) pyridine (I-81) Preparation Compound (I-80) (50.0 mg, 0.102 mmol) in THF (0.50 mL) was added with sodium borohydride (38.6 mg, 1.02 mmol) under ice-cooling, and the mixture was stirred at 70 ° C. for 16 hours. After adding water to the reaction solution and extracting with chloroform, the organic layer was subjected to silica gel column chromatography (n-hexane:
Purification with ethyl acetate) gave Compound (I-81) (yield 6.2 mg, 18% yield) as a colorless oil.

Example 82
Preparation of 2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -3- (4-fluoro-2-methoxyphenyl) pyridine (I-82)

Process 1
According to the same production method as for compound (I-80), compound (IV-11) (yield 3.18) was obtained from compound (IV-10) (2.50 g, 7.55 mmol) and trifluoromethanesulfonic anhydride (1.91 mL, 11.3 mmol). mg, yield 91%) was obtained as a pale yellow oil.
Process 2A
To a solution of compound (IV-11) (500 mg, 1.08 mmol) in THF (3.6 mL) was added 1 mol / L THF solution (5.40 mL, 5.40 mmol) of lithium aluminum hydride under ice-cooling, and the mixture was heated to 60 ° C. For 4.5 hours. A saturated aqueous Rochelle salt solution was added to the reaction solution and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (IV-13) (yield 61.0 mg, yield 18%) as a colorless oil. It was.
Process 2B
Compound (IV-11) (28.0 g, 60.4 mmol) was dissolved in acetone (121 mL), sodium iodide (45.3 g, 302 mmol) was added, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain compound (IV-12) (yield 26.6 g, yield quantitative) as a white solid.
Process 3
Compound (IV-12) was dissolved in THF (121 mL), tributyltin hydride (48.4 mL, 181 mmol) was added, and the mixture was stirred at 60 ° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Organic layer with water,
The extract was washed successively with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-13) [Yield 14.1 g, Yield 74% (2 steps)]. It was.
Process 4
According to the same production method as for compound (I-1), from compound (IV-13) (30.0 mg, 0.0952 mmol) and 4-fluoro-2-methoxyphenylboronic acid (V-12) (24.3 mg, 0.143 mmol) , Compound (I-82) (
(28.8 mg, 88% yield) was obtained as a colorless oil.

Example 83
Preparation of 2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -3- (5-fluoro-2-methoxyphenyl) pyridine (I-83) Compound (I-1) and According to a similar production method, from compound (IV-13) (30.0 mg, 0.0952 mmol) and 5-fluoro-2-methoxyphenylboronic acid (V-11) (19.4 mg, 0.114 mmol), compound (I-83) (
Yield 32.5 mg, 95% yield) was obtained as a white solid.

Example 84
Preparation of 2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -3- (2,5-dimethoxyphenyl) pyridine (I-84) Similar to compound (I-1) Depending on the production method, compound (IV-13) (40.0 mg, 0.127 mmol) and 2,5-
Compound (I-84) (yield 39.5 mg, 84% yield) was obtained as a colorless oil from dimethoxyphenylboronic acid (V-43) (30.0 mg, 0.165 mmol).

Example 85
Preparation of 3- (2,4-difluoro-5-methoxyphenyl) -2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} pyridine (I-85) Compound (I-1 )) From compound (IV-13) (30.0 mg, 0.0952 mmol) and 2,4-difluoro-5-methoxyphenylboronic acid (V-41) (21.5 mg, 0.114 mmol). -85) (yield 22.3 mg, 62% yield) was obtained as a colorless oil.

Example 86
Preparation of 2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -3- [2- (difluoromethyl) phenyl] pyridine (I-86)

Process 1
To a THF (9.5 mL) solution of the compound (IV-13) (1.50 g, 4.76 mmol), a 1.3 mol / L THF solution (7.3 mL, 9.5 mmol) of iPrMgBr · LiCl was added and stirred for 30 minutes. Thereafter, triisopropyl borate (3.3 mL, 14 mmol) was added under ice-cooling and stirred for 1 hour, and then 1 mol / L hydrochloric acid (20 mL) was added and stirred for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain compound (VIa-2) (yield 1.20 g, yield 90%) as a pale yellow solid.
Process 2
According to the same production method as for compound (I-36), compound (Ia-36) from compound (VIa-2) (33.8 mg, 0.121 mmol) and 2-difluoromethylbromobenzene (VII-13) (30.0 mg, 0.145 mmol) 86) (Yield 24.1 mg, Yield 55%) was obtained as a colorless oil.

Example 87
2- (2-{[6- (1,1-Difluoroethyl) pyridin-3-yl] oxy} pyridin-3-yl) -6-fluorobenzonitrile (I-87) Compound (VIa-2) (40.0 mg, 0.143 mmol), 2-bromo-6-fluorobenzonitrile (VII-14) (19.1 mg, 0.0955 mmol), (A- ^ta Phos) ₂ PdCl ₂ (3.4 mg, 0.0048 mmol) and cesium carbonate ( 62.1 mg, 0.191 mmol) is dissolved in n-butanol (0.50 mL), and 120 ° C under microwave irradiation
For 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 → 50: 50) to obtain compound (I-87) (yield 19.4 mg, yield) 57%) was obtained as a colorless oil.

Example 88
Preparation of 2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -2'-methoxy-3,3'-bipyridine (I-88) Similar to compound (I-1) According to the production method, compound (I-88) (yield 16.4 mg) from compound (IV-13) (30.0 mg, 0.0952 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (21.8 mg, 0.143 mmol) , Yield 50%) as a colorless oil.

Example 89
Preparation of 2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -3'-methoxy-3,4'-bipyridine (I-89) Similar to compound (I-1) Depending on the production method, compound (I-89) (yield from compound (IV-13) (50.5 mg, 0.159 mmol) and 3-methoxypyridine-4-boronic acid pinacol ester (V-27a) (29.1 mg, 0.124 mmol) 9.3 mg, yield 17%) was obtained as a white solid.

Example 90
Preparation of 2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -4'-methoxy-3,3'-bipyridine (I-90) Similar to compound (I-1) According to the production method, compound (I-90) from compound (IV-13) (30.0 mg, 0.0952 mmol) and 4-methoxypyridine-3-boronic acid monohydrate (V-28) (17.5 mg, 0.102 mmol) (Yield 22.3 mg, 68% yield) was obtained as a white solid.

Example 91
Preparation of 2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -4'-methyl-3,3'-bipyridine (I-91) Similar to compound (I-1) Depending on the production method, compound (I-91) (yield 15.4 mg) from compound (IV-13) (30.0 mg, 0.0952 mmol) and 4-methylpyridine-3-boronic acid (V-25) (17.5 mg, 0.129 mmol) ,
Yield 44%) was obtained as a white solid.

Example 92
Preparation of 2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -3'-fluoro-3,4'-bipyridine (I-92) Similar to compound (I-1) Depending on the production method, compound (I-92) (yield 15.2 mg) from compound (IV-13) (30.0 mg, 0.0952 mmol) and 3-fluoropyridine-4-boronic acid (V-44) (20.1 mg, 0.143 mmol) Yield 48%) as a colorless oil.

Example 93
Preparation of 2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -5'-methyl-3,3'-bipyridine (I-93) Similar to compound (I-1) Depending on the production method, compound (I-93) (yield 46.7 mg) from compound (IV-13) (60.0 mg, 0.190 mmol) and 5-methylpyridine-3-boronic acid (V-45) (20.1 mg, 0.143 mmol) ,
(75% yield) was obtained as a colorless oil.

Example 94
Preparation of 2 '-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -2,6-dimethoxy-3,3'-bipyridine (I-94) Compound (I-1) According to the same production method, compound (I-94) from compound (IV-13) (30.0 mg, 0.0952 mmol) and 2,6-dimethoxypyridine-3-boronic acid (V-42) (20.8 mg, 0.114 mmol) (Yield 29
.6 mg, 83% yield) was obtained as a colorless oil.

Example 95
Preparation of 2 '-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -6-methoxy-2,3'-bipyridine (I-95) Similar to compound (I-1) Depending on the production method, compound (I-95) (yield) from compound (IV-13) (40.0 mg, 0.127 mmol) and 6-methoxypyridine-2-boronic acid pinacol ester (V-46a) (38.8 mg, 0.165 mmol) 21.3 mg, yield 49%) was obtained as a colorless oil.

Example 96
Preparation of 2 ′-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -3,6-dimethoxy-2,3′-bipyridine (I-96) Compound (I-36) According to the same production method, compound (I-96) (40.0 mg, 0.143 mmol) and 2-bromo-3,6-dimethoxypyridine (VII-15) (40.5 mg, 0.186 mmol) Yield 36.8 mg, 69% yield) was obtained as a colorless oil.

Example 97
4'-chloro-2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -5'-fluoro-3,3
Production of '-bipyridine (I-97)

Process 1
To a THF (45 mL) solution of LDA (2.0 mol / L THF solution, 8.9 mL, 18 mmol) cooled to -78 ° C, a solution of compound (VII-16) (2.60 g, 14.8 mmol) in THF (12 mL) Was added dropwise and stirred at -78 ° C for 45 minutes. To the reaction solution was added dropwise a solution of hexachloroethane (3.85 g, 16.3 mmol) in THF (12 mL), and the mixture was stirred at -78 ° C for 30 minutes, then warmed to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 85: 15) to obtain compound (VII-17) (yield 2.18 g, yield 70). %) Was obtained as a pale yellow solid.
Process 2
Compound (VII-17) (100 mg, 0.475 mmol), Compound (VIa-2) (146 mg, 0.523 mmol), (A- ^ta Phos) ₂ PdCl ₂ (16.8 mg, 0.0240 mmol) and cesium carbonate (310 mg , 0.950 mmol) was dissolved in a mixture of 1,4-dioxane (1.5 mL) and water (0.30 mL) and stirred at 70 ° C. for 10 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 97: 3 → 75: 25) to obtain compound (I-97) (yield 138 mg, Yield 79%) was obtained as a colorless oil.

Example 98
2-{[6- (1,1-Difluoroethyl) pyridin-3-yl] oxy} -5'-fluoro-4'-methoxy-3,3'-bipyridine (I-98) Preparation Compound (I- 97) (40.0 mg, 0.109 mmol) was dissolved in methanol (0.50 mL), sodium methoxide (8.9 mg, 0.16 mmol) was added, and the mixture was stirred at 70 ° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 50: 50) to obtain compound (I-98) (yield 1.8 mg, yield) 5%) was obtained as a colorless oil.

Example 99
2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -5'-fluoro-4'-methyl-3,3
Production of '-bipyridine (I-99) By the same production method as for compound (I-53), compound (I-97) (76.5 mg, 0.209 mmol) and methylboronic acid (62.6 mg, 1.05 mmol) were converted to compound (I -99) (yield 9.3 mg, 13% yield) as a colorless oil.

Example 100
5'-chloro-2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -4'-methoxy-3,3
Production of '-bipyridine (I-100)

Process 1
LDA (2.0 mol / L THF solution, 7.2 mL, 14 mmol) and compound (VII-18) (6.0 mol / L THF solution, 2.0 mL, 12 mmol) were added dropwise to THF (9.0 mL) at -78 ° C. And stirred for 45 minutes. Hexachloroethane (6.6 mol / L THF solution, 2.0 mL, 13.2 mmol) was added dropwise at −78 ° C. and stirred for 30 minutes, then warmed to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-
Purification with hexane: ethyl acetate afforded Compound (VII-19) (2.30 g, 85% yield) as a yellow solid.
Process 2
Compound (VII-19) (1.00 g, 4.41 mmol) was dissolved in THF (10 mL), sodium methoxide (28% methanol solution, 1.30 mL, 31.6 mmol) was added, and the mixture was stirred at 70 ° C. for 1 hr. Water was added, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound (VII-20) (Yield 950 mg, Yield 97%) as a light brown solid.
Process 3
According to the same production method as for compound (I-36), compound (I-100) (yield 2.45) from compound (VII-20) (2.70 g, 12.1 mmol) and compound (VIa-2) (4.08 g, 14.6 mmol) g, yield 53%) was obtained as a white solid.

Example 101
Preparation of 4- (2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} pyridin-3-yl) -3,5-dimethylisothiazole (I-101)

Process 1
Dissolve the compound (M-6) in concentrated sulfuric acid (5.0 mL) and water (50 mL), add sodium nitrite (4.08 g, 59.1 mmol) dissolved in water (20 mL), and stir at 0 ° C. for 30 min. did. Furthermore, potassium iodide (26.2 g, 158 mmol) dissolved in water (30 mL) was added, and the mixture was stirred at room temperature for 3 hours. Sodium carbonate was added to the reaction solution, followed by extraction with ethyl acetate, and then the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (M-7) (yield 3.50 g, yield 40%).
Process 2
Compound (M-7) (400 mg, 1.78 mmol), methylboronic acid (1.06 g, 17.8 mmol), (A- ^ta Phos) ₂ PdCl ₂ (62.9 mg, 0.0888 mmol) and cesium carbonate (2.90 g, 8.89 mmol) Was dissolved in 1,4-dioxane (1.0 mL) and water (0.1 mL), and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (M-8).
Process 3
Compound (M-8) (201 mg, 1.78 mmol) was dissolved in concentrated nitric acid (2.0 mL), iodine (673 mg, 2.65 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hr. The reaction mixture was neutralized with 4 mol / L aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried with sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane) to obtain Compound (VII-21) [Yield 85.0 mg, Yield 20% (2 steps)].
Process 4
According to the same production method as for compound (I-36), compound (I-101) (yield 32.0) was obtained from compound (VII-21) (51.2 mg, 0.214 mmol) and compound (VIa-2) (50.0 mg, 0.179 mmol). mg, yield 52%) was obtained as a white solid.

Example 102
4- (2-{[6- (1,1-Difluoroethyl) pyridin-3-yl] oxy} pyridin-3-yl) -3,5-dimethylisoxazole (I-102) Compound (I- According to the same production method as in 1), compound (IV-13) (30.0 mg, 0.0952 mmol) and 3,5-dimethylisoxazole-4-boronic acid (V-47) (16.1 mg, 0.114 mmol) I-102) (yield 12.7 mg, yield 40%) was obtained as a white solid.

Example 103
Preparation of 5- (2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} pyridin-3-yl) -3-methylisoxazole (I-103)

Process 1
To a solution of compound (IV-13) (230 mg, 0.730 mmol) in TEA (4.0 mL) was added TBS acetylene (307 mg, 2.19
mmol), copper iodide (13.9 mg, 0.0730 mmol) and PdCl ₂ (dppf) (26.7 mg, 0.0360 mmol) were sequentially added, and the mixture was stirred at 60 ° C. for 2 hours under an argon atmosphere. The reaction solution was filtered and washed with ethyl acetate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 75: 25) to obtain compound (M-9) (yield 225 mg, yield). 82%) was obtained as a brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.80 (9H, s), 1.85 (3H, t, J = 18.5 Hz), 6.84 (1H, dd,
J = 5.0, 8.2 Hz), 7.45 (1H, dd, J = 2.7, 8.7 Hz), 7.51 (1H, d, J = 0.6, 8.7 Hz), 7.65
(1H, dd, J = 2.0, 7.5 Hz), 7.86 (1H, dd, J = 2.0, 5.0 Hz), 8.33-8.36 (1H, m).
ESI-MS m / z: 333 [M + H] ⁺ .
Process 2
Compound (M-9) (209 mg, 0.558 mmol) was dissolved in THF (3.0 mL), TBAF (0.67 mL, 0.670 mmol) was added, and the mixture was stirred at room temperature for 15 hours. After evaporating the solvent under reduced pressure, the residue was filtered through silica gel and washed with ethyl acetate. Evaporation of the solvent under reduced pressure gave compound (M-10) (yield 139 mg, yield).
96%) was obtained as a brown solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.05 (3H, t, J = 18.4 Hz), 3.42 (1H, s), 7.06 (1H, dd,
J = 5.0, 7.8 Hz), 7.64 (1H, dd, J = 2.7, 8.8 Hz), 7.72 (1H, d, J = 0.6, 8.8 Hz), 7.89
(1H, dd, J = 1.9, 7.4 Hz), 8.10 (1H, dd, J = 1.9, 5.0 Hz), 8.52-8.56 (1H, m).
ESI-MS m / z: 261 [M + H] ⁺ .
Process 3
Aldoxime (59 μL, 0.96 mmol) was dissolved in DMF (1.0 mL), NCS (154 mg, 1.15 mmol) was added, and the mixture was stirred at room temperature for 21 hours. Water was added and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to prepare aldoxime chloride, and ethanol (1.0 mL) was added to make an ethanol solution.
Compound (M-10) (50.0 mg, 0.192 mmol) is dissolved in ethanol (0.5 mL), and TEA (0.13 mL, 0.961 mmol) and an ethanol solution of aldoxime chloride (1.0 mL, 0.96 mmol) are sequentially added to the solution at room temperature. For 2 days. Water was added and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 75: 25) to give compound (I-103) (yield 46.9 mg, yield 77). %) Was obtained as a white solid.

Example 104
Preparation of 4-chloro-5- (2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} pyridin-3-yl) -3-methylisoxazole (I-104) Compound ( I-103) (20.0 mg, 0.0630 mmol) was dissolved in DMF (0.50 mL) and NCS (10.1 mg, 0.0756
mmol) was added and stirred at 70 ° C. for 24 hours. Water was added and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 80: 20) to give compound (I-104) (yield 10.8 mg, yield 49 %) As a colorless oil.

Example 105
2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -2 '-(pyrrolidin-1-yl) -3,3
Production of '-bipyridine (I-105)

Process 1
Pyrrolidine (2.0 mL, 24.4 mmol) and sodium hydride (120 mg, 5.20 mmol) are added to a DMF (15 mL) solution of compound (III-1) (500 mg, 2.60 mmol), and the mixture is stirred at 120 ° C. for 4 hours. did. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 75: 25) to obtain compound (VII-22) (yield 430 mg, yield) 73%) was obtained as a colorless oil.
Process 2
According to the same production method as for compound (I-36), compound (I-105) (yield 22.4) from compound (VII-22) (100 mg, 0.440 mmol) and compound (VIa-2) (185 mg, 0.661 mmol) mg, yield 13%) was obtained as a colorless oil.

Example 106
Production process of 2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -2 '-(1H-imidazol-1-yl) -3,3'-bipyridine (I-106) 1
According to the same production method as for compound (VII-22), 3-bromo-2- (1H-imidazol-1-yl) was obtained from compound (III-1) (500 mg, 2.60 mmol) and imidazole (2.00 g, 29.4 mmol). ) Pyridine (VII-23) (yield 466 mg, 80% yield) was obtained as a colorless oil.
Process 2
Compound (VIa-2) (60.0 mg, 0.214 mmol), Compound (VII-23) (32.0 mg, 0.143 mmol), Pd (PPh ₃ ) ₄ (16.5 mg, 0.0143 mmol) and tripotassium phosphate (60.6 mg, 0.286 mmol) was dissolved in n-butanol (0.50 mL) and stirred at 120 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 25: 75 → 0: 100) to give compound (I-106) (
Yield 4.8 mg, 9% yield) was obtained as a colorless oil.

Example 107
Production process of 2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -2 '-(1H-pyrazol-1-yl) -3,3'-bipyridine (I-107) 1
According to the same production method as for compound (VII-22), compound (III-1) (500 mg, 2.60 mmol) and pyrazole (2.00 g, 29.4 mmol) were converted to 3-bromo-2- (1H-pyrazol-1-yl Pyridine (VII-24) (
Yield 507 mg, 87% yield) was obtained as a colorless oil.
Process 2
According to the same production method as for compound (I-106), compound (Ia-107) (yield 4.3) from compound (VIa-2) (60.0 mg, 0.214 mmol) and compound (VII-24) (19.1 mg, 0.0955 mmol) mg, yield 8%) was obtained as a colorless oil.

Example 108
4- (2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} pyridin-3-yl) quinoline (I-108) Production Method Similar to Compound (I-36) 4-bromoquinoline (VII-25) (22.3 mg, 0.107 mmol) and compound (VIa-2) (20.0 mg, 0.0714 mmol) to compound (I-108) (yield 12.8 mg, yield 49%) Obtained as a colorless oil.

Example 109
4- (2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} pyridin-3-yl) isoquinoline (I-109) Production Method Similar to Compound (I-36) 4-bromoisoquinoline (VII-26) (24.7 mg, 0.143 mmol) and compound (VIa-2) (30.0 mg, 0.0952 mmol) to compound (I-109) (yield 19.5 mg, yield 56%) Obtained as a yellow oil.

Example 110
5- (2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} pyridin-3-yl) quinoxaline (I-110) Production Method Similar to Compound (I-36) 5-bromoquinoxaline (VII-2) (90.0 mg, 0.429
mmol) and compound (VIa-2) (40.0 mg, 0.143 mmol) gave compound (I-110) (yield 21.4 mg, yield 41%) as a white solid.

Example 111
Preparation of 8- (2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} pyridin-3-yl) pyrido [3,4-b] pyrazine (I-111)

Process 1
3-Bromopyridine-4,5-diamine (M-11) (1.0 g, 5.32 mmol) is dissolved in ethanol (21 mL), acetic acid (300 μL, 5.3 mmol) and glyoxal (4.9 mL, 43 mmol) are added. In addition, 14 at 100 ° C
Stir for hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (VII-27) (yield 721 mg, yield 65%) as a white solid.
Process 2
8-Bromopyrido [3,4-b] pyrazine (VII-27) (27.1) by the same production method as for compound (I-36)
mg, 0.129 mmol) and compound (VIa-2) (30.0 mg, 0.107 mmol) to compound (I-111) (yield 17.8
mg, yield 46%) was obtained as a pale yellow solid.

Example 112
1- (2-{[6- (1,1-Difluoroethyl) pyridin-3-yl] oxy} pyridin-3-yl) isoquinoline (I-112) Production Method Similar to Compound (I-36) From 1-bromoisoquinoline (VII-28) (22.3 mg, 0.107 mmol) and compound (VIa-2) (20.0 mg, 0.0714 mmol), compound (I-112) (yield 16.7 mg, yield 64%) Obtained as a white solid.

Example 113
4- (2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} pyridin-3-yl) benzo [d]
Preparation of oxazole (I-113) 4-Bromobenzo [d] oxazole (VII-29) (26.5) was prepared by a method similar to that for compound (I-36).
mg (0.134 mmol) and compound (VIa-2) (25.0 mg, 0.0890 mmol) gave compound (I-113) (yield 5.6 mg, 18% yield) as a white solid.

Example 114
7- (2-{[6- (1,1-Difluoroethyl) pyridin-3-yl] oxy} pyridin-3-yl) benzo [d]
Production of Oxazole (I-114) By a production method similar to that of Compound (I-36), 7-bromobenzo [d] oxazole (VII-30) (26.5
mg (0.134 mmol) and Compound (VIa-2) (25.0 mg, 0.0890 mmol) gave Compound (I-114) (Yield 3.2 mg, Yield 10%) as a yellow oil.

Example 115
Preparation of 7- (2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} pyridin-3-yl) pyrazolo [1,5-a] pyridine (I-115) Compound (I -36) from 7-bromopyrazolo [1,5-a] pyridine (VII-8) (1.26 g, 6.41 mmol) and compound (VIa-2) (2.00 g, 7.12 mmol) I-115) (yield 800 mg, yield 32%) was obtained as a white solid.

Example 116
3-chloro-7- (2-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} pyridin-3-yl)
Preparation of pyrazolo [1,5-a] pyridine (I-116) Compound (I-115) (30.0 mg, 0.0851 mmol) was dissolved in DMF (280 μL) and NCS (12.5 mg, 0.0937
mmol) was added and stirred at room temperature for 3 hours. Water was added and extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (I-116) (yield 23.7 mg, yield).
72%) was obtained as a white solid.

Example 117
Preparation of 5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} -3-methyl-2- (trifluoromethyl) pyridine (I-117)

Process 1
2,5-Dibromo-3-methylpyridine (M-12) (5.02 g, 20.0 mmol) in acetonitrile (50 mL)
Sodium iodide (12.0 g, 80.0 mmol) and acetyl chloride (2.85 mL, 40.0 mmol) were added to the solution, and the mixture was stirred for 24 hours while heating under reflux. The reaction mixture was cooled, water was added, and the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution (pH 8). The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 98: 2 → 70: 30) to give compound (M-13) (yield 5.76 g, yield 97). %) Was obtained as a red oil.
Process 2
A mixture of copper iodide (5.71 g, 30.0 mmol) and potassium fluoride (3.49 g, 60.0 mmol) was stirred under reduced pressure at 180 ° C. until green. The mixture was allowed to cool to room temperature, a solution of compound (M-13) (5.96 g, 20.0 mmol) and trimethylsilyltrifluoromethane (3.85 mL, 26.0 mmol) in NMP (30 mL) was added, and the mixture was stirred at 40 ° C. for 18 hr. The reaction solution was added to an aqueous ammonia solution and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and then filtered. After evaporating the solvent under reduced pressure, the residue was purified by distillation to obtain compound (M-14) (yield 3.95 g, yield 82%) as an oil.
Process 3
Compound (M-14) (3.95 g, 16.5 mmol) in benzyl alcohol (10.2 mL, 99.0 mmol) in cesium carbonate (8.04 g, 24.7 mmol), 1,10-phenanthroline (297 mg, 1.65 mmol) and iodide Copper (157 mg, 0.823 mmol) was added, and the mixture was stirred at 120 ° C. for 19 hours. The reaction mixture was cooled, diluted with ethyl acetate, and filtered through celite. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 99: 1 → 70: 30) to obtain compound (M-15) (yield 3.84 g, yield 87). %) As a pale yellow oil.
Process 4
To a solution of compound (M-15) (3.84 g, 14.4 mmol) in ethyl acetate (20 mL) was added palladium hydroxide / carbon (115 mg), and the mixture was stirred at 50 ° C. for 5 hours in a hydrogen atmosphere. The reaction was cooled and filtered through celite. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (n-
Purification was performed with hexane: ethyl acetate = 95: 5 → 25: 75) to obtain compound (II-4) (yield 2.32 g, yield 91%) as a white solid.
Process 5
Cesium carbonate (6.04 g, 18.6 mmol) was added to a solution of compound (II-4) (2.30 g, 13.0 mmol) and compound (III-1) (2.38 g, 12.4 mmol) in DMSO (8.0 mL) at 130 ° C. Stir for 17 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 99: 1 → 80: 20) to obtain compound (IV-14) (yield 3.58 g, yield). 87%) as a colorless oil.
Process 6
In the same manner as in compound (I-1), compound (IV-14) (30.0 mg, 0.0901 mmol) and 2-methoxyphenylboronic acid (V-1) (17.8 mg, 0.117 mmol) were converted into compound (I- 117) (Yield 28.2 mg,
Yield 87%) was obtained as a colorless oil.

Example 118
5-{[3- (4-Fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -3-methyl-2- (trifluoromethyl) pyridine (I-118) Compound (I-1) In the same manner as described above, compound (IV-14) (30.0 mg, 0.0901 mmol) and 4-fluoro-2-methoxyphenylboronic acid (V-12) (19.9 mg, 0.117 mmol) were converted into compound (I-118). (Yield 28.6 mg, 84% yield) was obtained as a colorless oil.

Example 119
5-Fluoro-2-methoxy-2 '-{[5-methyl-6- (trifluoromethyl) pyridin-3-yl] oxy} -3,3'-bipyridine (I-119) Preparation Compound (I- In the same manner as in 1), compound (IV-14) (30.0 mg, 0.0901 mmol) and 5-fluoro-2-methoxypyridine-3-boronic acid (V-32) (20.0 mg, 0.117 mmol) (I-119) (Yield 11.4 mg, Yield 33%) was obtained as a colorless oil.

Example 120
Preparation of 2- (difluoromethyl) -5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} -3-methylpyridine (I-120)

Process 1
Compound (III-1) (4.80 g, 24.9 mmol) and Compound (II-5) (4.92 g, 26.2 mmol) in DMSO (24.9
To the solution was added cesium carbonate (12.2 g, 37.4 mmol), and the mixture was stirred at 120 ° C. for 16 hours. The reaction solution was allowed to cool to room temperature, added to water (100 mL), and stirred for 1 hour under ice cooling. The precipitated solid was collected by filtration, washed with water (25 mL × 2), and dried under reduced pressure to obtain compound (IV-15) (yield 8.40 g, yield 98%) as a light brown solid.
Process 2
Compound (IV-15) (3.85 g, 11.2 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.58 mL,
Copper (powder, <75 μm, 99.9%, 1.64 g, 25.7 mmol) was added to a solution of 12.3 mmol) in DMSO (12 mL), and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was ice-cooled, diluted with ethyl acetate (60 mL), saturated aqueous potassium dihydrogen phosphate solution was added, and the mixture was stirred for 30 min. The reaction solution was filtered through celite, and the organic layer was separated. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (n
-Hexane: ethyl acetate = 95: 5 → 70: 30) to obtain compound (IV-16) (yield 2.53 g, yield 58%) as a colorless oil.
Process 3
Magnesium chloride hexahydrate (1.05 g, 5.17 mmol) was added to a solution of compound (IV-16) (2.00 g, 5.17 mmol) in NMP (10.0 mL), and the mixture was stirred at 180 ° C. for 15 minutes under microwave irradiation. . The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 → 80: 20) to obtain compound (IV-17) (yield 1.03 g, yield). 63%) was obtained as a white solid.
Process 4
In the same manner as in compound (I-1), compound (IV-17) (30.0 mg, 0.0952 mmol) and 2-methoxyphenylboronic acid (V-1) (18.8 mg, 0.124 mmol) were converted to compound (I- 120) (Yield 29.8 mg, Yield 91%) as a white solid.

Example 121
Preparation of 2- (difluoromethyl) -5-{[3- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -3-methylpyridine (I-121) Compound (I-1) and By a similar production method, Compound (IV-17) (683 mg, 2.17 mmol) and 4-fluoro-2-methoxyphenylboronic acid (V-12) (479 mg, 2.82 mmol) were converted to Compound (I-121) ( Yield 673 mg, 86% yield) was obtained as a white solid.

Example 122
Preparation of 2- (difluoromethyl) -5-{[3- (5-fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -3-methylpyridine (I-122) Compound (I-1) and By a similar production method, compound (I-122) from compound (IV-17) (30.0 mg, 0.0952 mmol) and 5-fluoro-2-methoxyphenylboronic acid (V-11) (21.0 mg, 0.124 mmol) ( Yield 30.0 mg, 87% yield) was obtained as a colorless oil.

Example 123
Preparation of 2 ′-{[6- (difluoromethyl) -5-methylpyridin-3-yl] oxy} -2,6-dimethoxy-3,3′-bipyridine (I-123) Compound (I-1) According to a similar production method, compound (I-123) from compound (IV-17) (30.0 mg, 0.0952 mmol) and 2,6-dimethoxypyridine-3-boronic acid (V-42) (22.7 mg, 0.124 mmol) (Yield 32.3 mg, 91% yield) was obtained as a colorless oil.

Example 124
Preparation of 2-[(6-ethylpyridin-3-yl) oxy] -3- (2-methoxyphenyl) pyridine (I-124)

Process 1
Compound (II-3) (5.00 g, 28.7 mmol) was dissolved in DMF (30 mL) and potassium carbonate (7.94 g, 57.5
mmol), benzyl bromide (4.1 mL, 35 mmol) and TBAI (531 mg, 1.44 mmol) were added under ice-cooling, and the mixture was warmed to room temperature and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 80: 20) to obtain compound (M-16) (yield 6.97 g, yield 92%) as a white solid.
Process 2
Compound (M-16) (1.00 g , 3.79 mmol) was dissolved in _{THF (8.0 mL), PdCl 2} (dppf) · DCM (77.0 mg, 0.0950 mmol) and diethylzinc (1.0 mol / L THF solution, 5.7 mL , 5.7 mmol) were sequentially added, and the mixture was stirred at 70 ° C for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 97: 3 → 70: 30) to obtain compound (M-17) (yield 338 mg Yield 42%) as a colorless oil.
Process 3
Compound (M-17) (338 mg, 1.59 mmol) is dissolved in a mixture of THF (3.0 mL) / methanol (3.0 mL), 20% palladium hydroxide / carbon (33.8 mg) is added, and hydrogen atmosphere is used at room temperature. Stir for 1 hour. After filtration through celite, the solvent was distilled off under reduced pressure to obtain compound (II-6) (yield 176 mg, yield 90%) as a white solid.
Process 4
According to the same production method as for compound (IV-1), compound (IV-18) (yield 344) was obtained from compound (II-6) (176 mg, 3.24 mmol) and compound (III-1) (330 mg, 1.72 mmol). mg, 86% yield) was obtained as a colorless oil.
Process 5
According to the same production method as for compound (I-1), compound (I-18) (40.0 mg, 0.164 mmol) and 2-methoxyphenylboronic acid (V-1) (32.7 mg, 0.215 mmol) were converted to compound (I -124) (yield 40.4 mg, 92% yield) was obtained as a colorless oil.

Example 125
Production of 3- (2,3-dihydrobenzofuran-7-yl) -2-[(6-ethylpyridin-3-yl) oxy] pyridine (I-125) According to the same production method as for compound (I-1) , Compound (IV-18) (40.0 mg, 0.164 mmol) and 2,3-
Dihydrobenzofuran-7-boronic acid (V-35) (35.2 mg, 0.215 mmol) to compound (I-125) (yield
34.0 mg, 75% yield) was obtained as a colorless oil.

Example 126
Preparation of 2-[(6-ethylpyridin-3-yl) oxy] -2'-methoxy-3,3'-bipyridine (I-126) Compound (IV) was prepared by a method similar to that for compound (I-1). -18) (40.0 mg, 0.164 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (32.9 mg, 0.215 mmol), compound (I-126) (yield 39.9
mg, yield 91%) was obtained as a colorless oil.

Example 127
Preparation of 2-[(6-ethylpyridin-3-yl) oxy] -4'-methoxy-3,3'-bipyridine (I-127) Compound (IV-18) (40.0 mg, 0.164 mmol), 4- Methoxypyridine-3-boronic acid monohydrate (V-28) (36.7 mg, 0.215 mmol), (A- ^ta Phos) ₂ PdCl ₂ (5.9 mg, 7.2 μmol) and TEA (73 μL, 0.717
mmol) was dissolved in n-butanol (0.60 mL) and then stirred at 120 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 97: 3 → 70: 30) to give compound (I-127) (yield 24.5 mg, yield 56%) was obtained as a colorless oil.

Example 128
Preparation of 2-[(6-cyclopropylpyridin-3-yl) oxy] -3- (2-methoxyphenyl) pyridine (I-128)

Process 1
Compound (M-16) (2.50 g, 9.47 mmol) was dissolved in THF (12 mL), c-PrZnBr (0.5 mol / L THF solution, 28 mL, 14 mmol), Pd (PPh) ₄ (219 mg, 0.189 mmol) was sequentially added, and the mixture was stirred at 70 ° C. for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (n-
Purification was performed with hexane: ethyl acetate = 97: 3 → 85: 15) to obtain compound (M-18) (yield 1.70 g, yield 80%) as a colorless oil.
Process 2
Compound (II-7) (yield 686 mg, yield 67%) was obtained as a white solid from compound (M-18) (1.70 g, 7.55 mmol) by the same production method as compound (II-6).
Process 3
According to the same production method as for compound (IV-1), compound (IV-19) (yield 580) from compound (II-7) (300 mg, 2.22 mmol) and compound (III-1) (513 mg, 2.66 mmol) mg, yield 90%) was obtained as a white solid.
Process 4
In the same manner as in compound (I-1), compound (IV-19) (40.0 mg, 0.137 mmol) and 2-methoxyphenylboronic acid (V-1) (25.1 mg, 0.165 mmol) were converted into compound (I- 128) (yield 41.5 mg, yield 95%) was obtained as a white solid.

Example 129
Production of 2-[(6-cyclopropylpyridin-3-yl) oxy] -3- (4-fluoro-2-methoxyphenyl) pyridine (I-129) According to a production method similar to that of compound (I-1), Compound (I-129) (yield 16.3 mg, yield) from compound (IV-19) (40.0 mg, 0.137 mmol) and 4-fluoro-2-methoxyphenylboronic acid (V-12) (28.0 mg, 0.165 mmol) 35%) was obtained as a colorless oil.

Example 130
2-[(6-Cyclopropylpyridin-3-yl) oxy] -2'-methoxy-3,3'-bipyridine (I-130)
According to the same production method as for compound (I-1), compound (IV-19) (40.0 mg, 0.137 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (25.2 mg, 0.165 mmol) To give compound (I-130) (yield 27.2 mg, 62% yield) as a colorless oil.

Example 131
Preparation of 2-[(5-chloro-6-cyclopropylpyridin-3-yl) oxy] -2'-methoxy-3,3'-bipyridine (I-131)

Process 1
According to the same production method as for compound (IV-1), compound (IV-20) (yield 314) was obtained from compound (II-8) (200 mg, 1.18 mmol) and compound (III-1) (272 mg, 1.42 mmol). mg, yield 82%) was obtained as a colorless oil.
Process 2
By the same production method as for compound (I-1), from compound (IV-20) (40.0 mg, 0.123 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (22.6 mg, 0.148 mmol), Compound (I-131) (25.3 mg, 58% yield) was obtained as a colorless oil.

Example 132
Preparation of 2-[(5-chloro-6-cyclopropylpyridin-3-yl) oxy] -4'-methoxy-3,3'-bipyridine (I-132)

According to the same production method as for compound (I-127), compound (IV-20) (50.0 mg, 0.154 mmol) and 4-
From methoxypyridine-3-boronic acid monohydrate (V-28) (28.2 mg, 0.184 mmol), compound (I-132) (yield 11.1 mg, 20% yield) was obtained as a pale yellow oil.

Example 133
Preparation of 2-[(6-cyclopropylpyridin-3-yl) oxy] -4′-methoxy-3,3′-bipyridine (I-133) Compound (I) as a by-product of the compound (I-132) -133) (yield 13.2 mg, 27% yield) was obtained as a pale yellow oil.

Example 134
Preparation of 3-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} -5,6,7,8-tetrahydroquinoline (I-134)

Process 1
Compound (M-19) (160 mg, 0.754 mmol), 1,10-phenanthroline (27.2 mg, 0.151 mmol)
And cesium carbonate (492 mg, 1.51 mmol) in benzyl alcohol (1.0 mL, 9.6 mmol), add copper (I) iodide (14.37 mg, 0.075 mmol), and stir at 120 ° C. for 24 hours under an argon atmosphere. did. The reaction was allowed to cool, diluted with ethyl acetate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 0)
: 100 → 85: 15) to obtain compound (M-20) (yield 155 mg, yield 86%).
Compound (M-19) can be synthesized according to a known method. Such a method is described, for example, in J. Am. Chem. Soc. 2011; 133: 12285-12292.
Process 2
Compound (M-20) (140 mg, 0.585 mmol) was dissolved in ethanol (1.4 mL) and 10% Pd / C (28.0 mg,
20 w / w%) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was diluted with ethanol and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure to obtain compound (II-9) (yield 82.0 mg, yield 94%).
Process 3
Compound (III-1) (700 mg, 3.64 mmol), 2-methoxyphenylboronic acid (V-1) (553 mg, 3.64
mmol), (A- ^ta Phos) ₂ PdCl ₂ (129 mg, 0.182 mmol) and cesium carbonate (2.37 g, 7.28 mmol)
Was dissolved in 1,4-dioxane and water (5: 1, 12 mL) and stirred at 70 ° C. for 4 hours. The reaction was cooled and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (VIII-1) (yield 629 mg, 79%) as a colorless oil. Obtained.
Process 4A
Compound (VIII-1) (45.0 mg, 0.205 mmol) and compound (II-9) (30.1 mg, 0.202 mmol) are dissolved in NMP (1 mL), cesium carbonate (79.0 mg, 0.242 mmol) is added, and The mixture was stirred at 180 ° C. for 20 minutes under wave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 60: 40 → 85: 15) to obtain compound (I-134) (yield 34.5 mg, yield 51%) as a brown oil. .
Process 4B
According to the same production method as for compound (IV-1), compound (IV-21) (yield 4.18) was obtained from compound (II-9) (2.24 g, 15.0 mmol) and compound (III-1) (2.89 g, 15.0 mmol). g, yield 91%).

Example 135
3-{[2'-Methoxy- (3,3'-bipyridin) -2-yl] oxy} -5,6,7,8-tetrahydroquinoline (I-135)

Process 1
Compound (III-1) (1.00 g, 5.20 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (795 mg, 5.20 mmol) were prepared by the same production method as for compound (VIII-1). (VIII-2) (865 mg, 75% yield) was obtained as a white solid.
Process 2
According to the same production method as for compound (I-134), compound (I-135) (yield 30.4) from compound (VIII-2) (45.0 mg, 0.204 mmol) and compound (II-9) (30.1 mg, 0.202 mmol) mg, yield 45%) was obtained as a white solid.

Example 136
Preparation of 3-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} -6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine (I-136)

Process 1
Compound (M-21) (2.00 g, 12.5 mmol) was dissolved in chloroform (25.0 mL), 4Å molecular sieve (400 mg, powder) was added, and compound (M-22) (3.10 g, 18.8 g) was added at 0 ° C. mmol) and add 0
Stir at 5 ° C. for 5 minutes. After stirring at 45 ° C. for 40 minutes, the mixture was allowed to cool to room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (M-23) (yield 1.90 g, yield 67%).
Process 2
Compound (M-23) (1.70 g, 7.52 mmol), cesium carbonate (4.90 g, 15.0 mmol) and 1,10-phenanthroline (0.271 g, 1.50 mmol) were dissolved in benzyl alcohol (7.82 mL, 75 mmol), Copper (I) iodide (0.143 g, 0.752 mmol) was added, and the mixture was stirred at 120 ° C. for 24 hours. After allowing the reaction solution to cool,
The mixture was diluted with ethyl acetate, filtered through celite, and washed with ethyl acetate. The solvent of the filtrate and washings was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (M-24) (yield 1.11 g, yield 58%). Obtained.
Process 3
Compound (M-24) (1.06 g, 4.18 mmol) is dissolved in ethanol (10 mL), 10% Pd / C (0.212 g, 20 w / w%) is added, and the mixture is stirred at room temperature for 2 hours under a hydrogen atmosphere. did. Dilute the reaction with ethanol,
After filtration through celite, the mixture was washed with ethyl acetate. The solvent of the filtrate and washings was distilled off under reduced pressure, and the residue was dried under reduced pressure to obtain compound (II-10) (yield 0.665 g, yield 97%) as a white solid.
Process 4
Compound (IV-22) (yield 1.15 g, yield 90%) was obtained from compound (II-10) (650 mg, 3.98 mmol) by the same production method as compound (IV-1).
Process 5
According to the same production method as for compound (I-1), compound (IV-22) (40.0 mg, 0.125 mmol) and 2-methoxyphenylboronic acid (V-1) (25.4 mg, 0.163 mmol) were converted to compound (I- 136) (Yield 38.7 mg, Yield 89%) was obtained as a colorless oil.

Example 137
3-{[3- (2,3-Dihydrobenzofuran-7-yl) pyridin-2-yl] oxy} -5,6,7,8-tetrahydroquinoline (I-137) Preparation Compound (I-1) The compound (IV-21) (30.0 mg, 0.098 mmol) and the compound (V-35) (21.0 mg, 0.128 mmol) to the compound (I-137) (yield 33.6 mg, 99% yield) ) Was obtained as a colorless oil.

Example 138
3-{[3- (2,3-Dihydrobenzofuran-7-yl) pyridin-2-yl] oxy} -6,7-dihydro-5H-
Production of cyclopenta [b] pyridine (I-138)

Process 1
Compound (M-26) (yield 1.97 g, yield 87%) was obtained as a white solid from compound (M-25) (2.00 g, 10.1 mmol) by the same production method as compound (M-24).
Process 2
Compound (II-11) (yield 1.04 g, 98% yield) was obtained as a white solid from compound (M-26) (1.77 g, 7.86 mmol) by the same production method as compound (II-10).
Process 3
According to the same production method as for compound (IV-1), compound (II-11) (800 mg, 5.92 mmol) and compound
Compound (IV-23) (yield 1.64 g, yield 95%) was obtained from (III-1) (1.14 g, 5.92 mmol).
Process 4
According to the same production method as for compound (I-1), compound (I-138) (yield 223) from compound (IV-23) (200 mg, 0.687 mmol) and compound (V-35) (146 mg, 0.893 mmol) mg, yield 98%) was obtained as a white solid.

Preparation of 8,8-difluoro-3-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} -5,6,7,8-tetrahydroquinoline (I-142)

Example 139
3-{[3- (2-Methoxyphenyl) pyridin-2-yl] oxy} -5,6,7,8-tetrahydroquinolin-8-yl acetate (I-139) Preparation Compound (I-134) ( 300 mg, 0.903 mmol) was dissolved in DCM (3.0 mL), mCPBA (271 mg, 1.08 mmol) was added under ice cooling, and the mixture was stirred at room temperature overnight. The reaction solution was allowed to cool, an aqueous sodium sulfite solution and a saturated aqueous sodium hydrogen carbonate solution were added, extracted with chloroform, and then washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude N-oxide. The crude N-oxide was dissolved in acetic anhydride (1.0 mL, 10.6 mmol) and stirred at 60 ° C. for 11 hours. The reaction mixture was allowed to cool, diluted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30 → 30: 70) to obtain compound (I-139) (yield 317 mg, yield 90%) as a white solid.

Example 140
3-{[3- (2-Methoxyphenyl) pyridin-2-yl] oxy} -5,6,7,8-tetrahydroquinolin-8-ol (I-140) Compound (I-139) (295 mg, 0.756 mmol) was dissolved in methanol (3 mL), potassium carbonate (313 mg, 2.23 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30 → 20: 80) to give compound (I-140) (yield 184 mg, yield 70 %) Was obtained as a white solid.

Example 141
3-{[3- (2-Methoxyphenyl) pyridin-2-yl] oxy} -6,7-dihydroquinolin-8 (5H) -one (I-141) Preparation Compound (I-140) (111 mg , 0.319 mmol) was dissolved in DCM (2.0 mL), DMP (176 mg, 0.414 mmol) was added, and the mixture was stirred at room temperature for 7 hours. The reaction solution was diluted with chloroform, and an aqueous sodium sulfite solution and a saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50 → 10: 90) to obtain compound (I-141) (yield 103 mg, yield). 93%) was obtained as a pale yellow solid.

Example 142
Production of 8,8-difluoro-3-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} -5,6,7,8-tetrahydroquinoline (I-142) Compound (I-141) (30.0 mg, 0.0866 mmol) was dissolved in DCM (1.0 mL), Deoxo-Fluor (registered trademark) (76.0 μL, 0.371 mmol) was added, and the mixture was stirred at room temperature for 4 days. Water was slowly added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (n-
Purification was performed with hexane: ethyl acetate = 90: 10 → 20: 80) to obtain compound (I-142) (yield 3.9 mg, yield 12%) as a white solid.

Examples 143 and 144
Preparation of 3-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} -N, N-dimethyl-5,6,7,8-tetrahydroquinolin-8-amine (I-143)
Preparation of 3-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} -5,6-dihydroquinoline (I-144) Compound (I-140) (30.0 mg, 0.086 mmol) and TEA ( 24.0 μL, 0.172 mmol) was dissolved in THF (1.0 mL), methanesulfonyl chloride (8.7 μL, 0.112 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. A 50% dimethylamine aqueous solution (36.0 μL) was added, and the mixture was further stirred at room temperature for 7 hours. Furthermore, 50% dimethylamine aqueous solution (36.0 μL) was added, and the mixture was stirred at room temperature for 17 hours. Ethyl acetate was added for extraction, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 100: 0 → 20: 80, NH silica, n-hexane: ethyl acetate =
70:30 → 30:70), compound (I-143) (yield 6.0 mg, yield 19%) and compound (I-144) (yield 0.9 mg, yield 3%) were each colorless. Obtained as an oil.

Example 145
2-{[6- (1,1-Difluoro-2-methoxyethyl) pyridin-3-yl] oxy} -3- (2-methoxyphenyl) pyridine (I-145) Compound (I-79) ( 30.0 mg, 0.0837 mmol) in DMF (0.55 mL) under ice-cooling, 60% sodium hydride (4.4 mg, 0.092 mmol) and methyl iodide (5.8 μL, 0.092 mmol) were sequentially added, and then at room temperature for 14 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-145) (20.8 mg, 67% yield) as a white solid. .

Example 146
Preparation of 2,2-difluoro-2- (5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) -N-methylethanamine (I-146) Compound ( I-80) (500 mg, 1.02 mmol) dissolved in DMF (3.3 mL) and DIPEA (3.6 mL, 20 mmol)
, Cesium carbonate (1.65 g, 5.10 mmol) and methylamine hydrochloride (344 mg, 5.10 mmol) were sequentially added at room temperature, heated to 60 ° C. and stirred for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-146) (yield 260 mg, yield 69%) as a colorless oil. It was.

Example 147
Preparation of 2,2-difluoro-2- (5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) -N, N-dimethylethanamine (I-147) According to the same production method as for compound (I-146), compound (I-147) (yield 31.1 mg, yield from compound (I-80) (50.0 mg, 0.102 mmol) and dimethylamine hydrochloride (63.0 mg, 1.02 mmol) Yield 79%) was obtained as a colorless oil.

Example 148
Preparation of 4- [2,2-difluoro-2- (5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) ethyl] morpholine (I-148) Compound ( Compound (I-148) (yield 31.1 mg, yield 79%) from compound (I-80) (50.0 mg, 0.102 mmol) and morpholine (44 μL, 0.51 mmol) by the same production method as I-146) Was obtained as a colorless oil.

Example 149
N-ethyl-2,2-difluoro-2- (5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) -N-methylethanamine (I-149) Compound (I-80) (68.6 mg, 0.102 mmol) was dissolved in DMF (420 μL) and pyridine (17 μL, 0.21
mmol) and methylethylamine (13 μL, 0.15 mmol) were sequentially added at room temperature, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-149) (yield 1.2 mg, yield 2%) as a colorless oil. It was.

Example 150
N- [2,2-difluoro-2- (5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) ethyl] -N, O-dimethylhydroxylamine (I -150) Compound (I-80) (50.0 mg, 0.102 mmol) and N, O-dimethylhydroxylamine hydrochloride (49.7 mg, 0.510 mmol) according to the same production method as compound (I-146) (I-150) (yield 41.0 mg, quantitative yield) was obtained as a colorless oil.

Example 151
N- [2,2-difluoro-2- (5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) ethyl] -N-methylacetamide (I-151) Compound (I-146) (30.0 mg, 0.0808 mmol) was dissolved in DCM (400 μL), DIPEA (42 μL, 0.24 mmol) and acetyl chloride (7.5 μL, 0.11 mmol) were added, and the mixture was stirred at room temperature for 15 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with chloroform. Silica gel column chromatography (n-
Purification with hexane: ethyl acetate gave Compound (I-151) (Yield 32.7 mg, Yield 98%) as a colorless oil.

Example 152
Preparation of methyl [2,2-difluoro-2- (5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) ethyl] (methyl) carbamate (I-152) Using the same production method as for compound (I-151), compound (I-152) (yield 26.7 mg, yield) was obtained from compound (I-146) (30.0 mg, 0.0808 mmol) and methyl chloroformate (8.1 μL, 0.11 mmol). Yield 74%) as a colorless oil.

Example 153
2-({6- [1,1-difluoro-2- (4-methyl-1H-pyrazol-1-yl) ethyl] pyridin-3-yl} oxy) -3- (2-methoxyphenyl) pyridine (I -153) According to the same production method as for compound (I-146), compound (I-80) (30.0 mg, 0.0612 mmol) and 4-
Compound (I-153) (yield 18.2 mg, 70% yield) was obtained as a colorless oil from methyl-1H-pyrazole (50.2 mg, 0.612 mmol).

Example 154
Preparation of 2,2-difluoro-2- (5-{[3- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) ethanol (I-154) Compound (I -1), the compound (IV-10) (260 mg, 0.785 mmol) and 4-fluoro-2-methoxyphenylboronic acid (V-12) (160 mg, 0.942 mmol) to compound (I -154) (yield 272 mg, 92% yield) was obtained as a colorless oil.

Example 155
2-{[6- (2-Ethoxy-1,1-difluoroethyl) pyridin-3-yl] oxy} -3- (4-fluoro-2-
Preparation of (methoxyphenyl) pyridine (I-155) Compound (I-154) (30.0 mg, 0.080 mmol) and ethyl bromide (7.1 μL, 0.096 mmol) were prepared in the same manner as for compound (I-145). (I-155) (Yield 26.2 mg, Yield 81%) was obtained as a colorless oil.

Reference Example 156
2,2-Difluoro-2- (5-{[3- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) ethyl Preparation of trifluoromethanesulfonate (I-156) Compound (I-156) (yield 410) from compound (I-154) (682 mg, 1.81 mmol) and trifluoromethanesulfonic anhydride (610 μL, 3.6 mmol) by the same production method as compound (I-80). mg, yield 65%) was obtained as a pale yellow oil.

Example 157
2-({6- [1,1-difluoro-2- (1H-pyrazol-1-yl) ethyl] pyridin-3-yl} oxy) -3- (4-fluoro-2-methoxyphenyl) pyridine (I -157) According to the same production method as for compound (I-146), compound (I-157) (31.1 mg, 0.0612 mmol) and 1H-pyrazole (41.6 mg, 0.612 mmol) Yield 9.3 mg, 36% yield) was obtained as a colorless oil.

Example 158
2-({6- [1,1-difluoro-2- (1H-imidazol-1-yl) ethyl] pyridin-3-yl} oxy) -3- (4-fluoro-2-methoxyphenyl) pyridine (I -158) According to the same production method as for compound (I-146), from compound (I-156) (31.1 mg, 0.0612 mmol) and 1H-imidazole (41.6 mg, 0.612 mmol), compound (I-158) ( Yield 16.7 mg, 64% yield) was obtained as a colorless oil.

Example 159
2-({6- [1,1-difluoro-2- (2-methoxyethoxy) ethyl] pyridin-3-yl} oxy) -3- (4-fluoro-2-methoxyphenyl) pyridine (I-159) According to the same production method as for compound (I-145), compound (I-154) (30.0 mg, 0.080 mmol) and 1-
Bromo-2-methoxyethane (9.0 μL, 0.096 mmol) to compound (I-159) (yield 15.0 mg, yield)
45%) was obtained as a colorless oil.

Example 160
2-({6- [1,1-difluoro-2- (2-propyn-1-yloxy) ethyl] pyridin-3-yl} oxy)-
Preparation of 3- (2-methoxyphenyl) pyridine (I-160) In the same manner as in compound (I-145), compound (I-79) (30.0 mg, 0.0761 mmol) and propargyl bromide (6.3 μL, 0.092 mmol) gave compound (I-160) (yield 15.9 mg, 48% yield) as a colorless oil.

Example 161
2-{[6- (1,1-Difluoro-2-methoxyethyl) pyridin-3-yl] oxy} -3- (4-fluoro-2-
Production of (methoxyphenyl) pyridine (I-161)

Process 1
According to the same production method as for compound (I-145), compound (IV-24) was obtained from compound (IV-10) (100 mg, 0.302 mmol) and methyl iodide (21 μL, 0.332 mmol) (yield 84.5 mg, Yield 81%) was obtained as a white solid.
Process 2
According to the same production method as for compound (I-1), from compound (IV-24) (27.0 mg, 0.0782 mmol) and 4-fluoro-2-methoxyphenylboronic acid (V-12) (16.0 mg, 0.0939 mmol) Compound (I-161) (
Yield 25.1 mg, 82% yield) was obtained as a white solid.

Example 162
2-{[6- (1,1-Difluoro-2-methoxyethyl) pyridin-3-yl] oxy} -3- (5-fluoro-2-
Preparation of (methoxyphenyl) pyridine (I-162) In the same manner as in compound (I-1), compound (IV-24) (27.0 mg, 0.0782 mmol) and 5-fluoro-2-methoxyphenylboronic acid (V -11) (16.0 mg, 0.0939 mmol) to compound (I-162) (
(19.5 mg, 64% yield) was obtained as a colorless oil.

Example 163
Preparation of 3- (5-chloro-2-methoxyphenyl) -2-{[6- (1,1-difluoro-2-methoxyethyl) pyridin-3-yl] oxy} pyridine (I-163) Compound (I -1) from the compound (IV-24) (30.0 mg, 0.0869 mmol) and 5-chloro-2-methoxyphenylboronic acid (V-23) (21.1 mg, 0.113 mmol) -163) (Yield
31.4 mg, yield 89%) was obtained as a colorless oil.

Example 164
2- (5-{[3- (2,4-Difluoro-5-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) -2,2-difluoroethanol (I-164) Compound According to the same production method as (I-1), compound (IV-10) (400 mg, 1.21 mmol) and 2,4-difluoro-5-methoxyphenylboronic acid (V-41) (204 mg, 1.07 mmol) To give compound (I-164) (yield 246 mg, yield 86%) as a colorless oil.

Example 165
2-{[6- (1,1-Difluoro-2-methoxyethyl) pyridin-3-yl] oxy} -3- (2,4-difluoro
Preparation of (5-methoxyphenyl) pyridine (I-165) Compound (I-164) (38.0 mg, 0.0964 mmol) and methyl iodide (7.8 μL, 0.13 mmol) were prepared in the same manner as for compound (I-145). ) To give compound (I-165) (yield 36.4 mg, yield 92%) as a colorless oil.

Example 166
2-{[6- (1,1-Difluoro-2-methoxyethyl) pyridin-3-yl] oxy} 3- (2,3-dihydrobenzofuran-7-yl) pyridine (I-166) Compound ( In the same manner as in (I-1), compound (IV-24) (27.0 mg, 0.0782 mmol) and 2,3-dihydrobenzofuran-7-boronic acid (V-35) (15.4 mg, 0.0939 mmol) (I-166) (Yield 19.4 mg, Yield 65%) was obtained as a colorless oil.

Example 167
7- (2-{[6- (1,1-difluoro-2-methoxyethyl) pyridin-3-yl] oxy} pyridin-3-yl) pyrazolo [1,5-a] pyridine (I-167) Manufacturing

Process 1
Compound (IV-24) (150 mg, 0.435 mmol) was dissolved in THF (2.2 mL), and iPrMgBr · LiCl (1.3 mol / L THF solution, 400 μL, 0.522 mmol) was added and stirred for 30 minutes. Thereafter, triisopropyl borate (300 μL, 1.30 mmol) was added under ice-cooling and stirred for 1 hour, and then 1 mol / L hydrochloric acid (5 mL) was added and stirred for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain compound (VIa-3) (yield 48.3 mg, yield 36%) as a white solid.
Process 2
By the same production method as compound (I-36), 7-bromopyrazolo [1,5-a] pyridine (VII-8) (30.3 mg, 0.145 mmol) and compound (VIa-3) (30.0 mg, 0.0968 mmol) To give compound (I-167) (yield 31.1 mg, yield 84%) as a colorless oil.

Example 168
Preparation of 5- (2-{[6- (1,1-difluoro-2-methoxyethyl) pyridin-3-yl] oxy} pyridin-3-yl) quinoxaline (I-168) Compound (I-36) By a similar production method, 5-bromoquinoxaline (VII-2) (24.3 mg, 0.115
mmol) and compound (VIa-3) (24.0 mg, 0.0774 mmol) to compound (I-168) (yield 20.3 mg, yield)
67%) was obtained as a colorless oil.

Example 169
Preparation of 8- (2-{[6- (1,1-difluoro-2-methoxyethyl) pyridin-3-yl] oxy} pyridin-3-yl) quinoline (I-169) Compound (I-1) and By a similar production method, compound (I-169) (yield 20.3 mg, yield) was obtained from compound (IV-24) (30.0 mg, 0.0869 mmol) and 8-quinolineboronic acid (V-34) (19.6 mg, 0.113 mmol). Yield 59%) as a colorless oil.

Example 170
Preparation of 5- (2-{[6- (1,1-difluoro-2-methoxyethyl) pyridin-3-yl] oxy} pyridin-3-yl) -7-fluoroquinoxaline (I-170)

Process 1
Compound from 3-bromo-5-fluorobenzene-1,2-diamine (M-27) (300 mg, 1.46 mmol) and glyoxal (1.3 mL, 11 mmol) by the same production method as compound (VII-27) (VII-31) (
Yield 128 mg, 39% yield) was obtained as a colorless oil.
Process 2
According to the same production method as for compound (I-36), compound (I-170) (yield 11.4) from compound (VII-31) (32.9 mg, 0.145 mmol) and compound (VIa-3) (30.0 mg, 0.0968 mmol) mg, yield 29%) was obtained as a colorless oil.

Example 171
Preparation of 2-{[6- (benzyloxy) pyridin-3-yl] oxy} -3- (2-methoxyphenyl) pyridine (I-171)

Process 1
According to the same production method as for compound (IV-1), compound (III-1) (956 mg, 4.97 mmol) and 6- (benzyloxy) pyridin-3-ol (II-12) (1.00 g, 4.97 mmol) From this, compound (IV-25) (yield 1.23 g, yield 69%) was obtained.
Process 2
According to the same production method as for compound (I-1), compound (IV-25) (751 mg, 2.10 mmol) and 2-methoxyphenylboronic acid (V-1) (639 mg, 4.20 mmol) were converted to compound (I- 171) (yield 750 mg, 93% yield) as a white solid.

Example 172
Preparation of 5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-ol (I-172) Compound (I-171) (300 mg, 0.780 mmol) in ethanol (5.0 mL) ) / Ethyl acetate (5.0 mL) / THF (5.0 mL), 20% palladium hydroxide / carbon (50.0 mg) was added, and the mixture was stirred at room temperature for 3 hours under hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (I-172) (yield 175 mg, yield 76%).

Example 173
3- (2-Methoxyphenyl) -2-[(6-phenethylpyridin-3-yl) oxy] pyridine (I-173)
Compound (I-172) (40.0 mg, 0.136 mmol) was dissolved in DMF (2 mL), potassium carbonate (75.0 mg, 0.780 mmol) was added, and the mixture was stirred for 20 minutes. Further, (2-bromoethyl) benzene was added and stirred at room temperature for 20 hours. Water was added to stop the reaction, and ethyl acetate was added for extraction. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (I-173) (Yield 23.9 mg, Yield 44%) as a colorless oil.

Example 174
Preparation of 3- (2-methoxyphenyl) -2-{[6- (pyridin-3-ylmethoxy) pyridin-3-yl] oxy} pyridine (I-174) According to the same production method as for compound (I-173) Compound (I-172) (74.0 mg, 0.251 mmol) and 3- (bromomethyl) pyridine hydrobromide (127 mg, 0.503 mmol) to compound (I-174) (yield 5.0 mg,
(5% yield) was obtained as a colorless oil.

Example 175
Preparation of 3- (2-methoxyphenyl) -2-{[6- (phenoxymethyl) pyridin-3-yl] oxy} pyridine (I-175) Compound (I-70) (30.0 mg, 0.097 mmol) was converted to THF. After dissolving in (0.5 mL), TEA (50 μL, 0.36 mmol) and methanesulfonyl chloride (10 μL, 0.10 mmol) were added under ice-cooling, and the mixture was stirred for 30 minutes (Reaction Solution 1). Phenol (30.0 mg, 0.319 mmol) was dissolved in THF (0.5 mL), sodium hydride (16.0 mg, 0.333 mmol) was added, and the mixture was stirred at room temperature for 30 min (reaction solution 2). Reaction solution 1 was added to reaction solution 2, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (I-175) (yield 6.0 mg,
Yield 16%) was obtained as a yellow oil.

Example 176
Preparation of 2-{[6- (benzyloxy) pyridin-3-yl] oxy} -2'-methoxy-3,3'-bipyridine (I-176) By the same production method as compound (I-1), Compound (I-176) (yield 685 mg, yield 80%) was obtained as a white solid from compound (IV-25) (795 mg, 2.23 mmol) and compound (V-26) (443 mg, 2.89 mmol). .

Example 177
Preparation of 2-{[6- (benzyloxy) pyridin-3-yl] oxy} -4'-methoxy-3,3'-bipyridine (I-177) By the same production method as compound (I-1), Compound (IV-25) (455 mg, 1.27 mmol) and compound (V-28) (253 mg, 1.66 mmol) were used to obtain compound (I-177) (yield 230 mg, 47%) as a colorless oil. It was.

Example 178
5-{[3- (2-Methoxyphenyl) pyridin-2-yl] oxy} -2- (trifluoromethyl) pyrimidine (I-178)

Process 1
5-Bromo-2-trifluoromethylpyrimidine (M-28) (1.00 g, 4.41 mmol) in benzyl alcohol (4.58 mL, 44.1 mmol) was added to cesium carbonate (2.87 g, 8.81 mmol), 1,10-phenanthroline ( 159 mg, 0.881 mmol) and copper (I) iodide (84.0 mg, 0.441 mmol)
Stir for hours. The reaction mixture was cooled, diluted with ethyl acetate, and filtered through celite. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 95: 5 → 80: 20) to obtain compound (M-29) (yield 863 mg, Yield 77%) was obtained as a pale yellow solid.
Process 2
10% Palladium / carbon (172 mg) was added to a solution of the compound (M-29) (859 mg, 3.38 mmol) in ethanol (10.0 mL), and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. Diluted with ethanol and filtered through celite. The solvent was distilled off under reduced pressure to obtain compound (II-13) (yield 510 mg, yield 92%) as a light gray solid.
Process 3
Compound (II-13) (400 mg, 2.44 mmol) and Compound (III-1) (469 mg, 2.44 mmol) in DMSO (5.0
To the solution was added cesium carbonate (1.19 g, 3.66 mmol), and the mixture was stirred at 120 ° C. for 20 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 85: 15) to obtain compound (IV-26) (yield 163 mg, yield) 21%) was obtained as a yellow oil.
Process 4
According to the same production method as for compound (I-1), compound (I-26) (30.0 mg, 0.0937 mmol) and 2-methoxyphenylboronic acid (V-1) (18.5 mg, 0.122 mmol) were converted to compound (I- 178) (yield 23.0 mg, 71% yield) as a colorless oil.

Example 179
Preparation of 5-{[3- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -2- (trifluoromethyl) pyrimidine (I-179) Preparation similar to compound (I-1) According to the method, compound (I-179) (yield 28.5 mg) from compound (IV-26) (30.0 mg, 0.0937 mmol) and 4-fluoro-2-methoxyphenylboronic acid (V-12) (20.7 mg, 0.122 mmol) , Yield 83%) was obtained as a colorless oil.

Example 180
Preparation of 5-chloro-2-methoxy-2 '-{[2- (trifluoromethyl) pyrimidin-5-yl] oxy} -3,3'-bipyridine (I-180) Same as compound (I-1) The compound (IV-26) (30.0 mg, 0.0937 mmol) and 5-chloro-2-methoxypyridine-3-boronic acid (V-31) (19.3 mg, 0.103 mmol) were converted into the compound (I-180 ) (
Yield 21.6 mg, 60% yield) was obtained as a colorless oil.

Example 181
5-{[3- (2-Methoxyphenyl) pyridin-2-yl] oxy} -2- (pentafluoroethyl) pyrimidine (I-181)

Process 1
To a solution of ethyl 2,2,3,3,3-pentafluoropropanoate (S-1) (7.69 g, 40.0 mmol) in p-xylene (30 mL), 1,3-diaminopropan-2-ol (S- 2) (3.61 g, 40.0 mmol) was added, and the mixture was stirred at 160 ° C. for 4 hours. The solvent was distilled off under reduced pressure to obtain compound (S-3) (yield 10.1 g) as a yellow oil.
Process 2
A solution of compound (S-3) (8.72 g, 29.8 mmol) in nitrobenzene (40 mL) is heated to 90 ° C., 28% sodium methoxide in methanol (31.8 mL, 160 mmol) is gradually added, and methanol is added. The mixture was stirred for 3 hours while distilling off. Thereafter, the mixture was further stirred at 120 ° C. for 1 hour. Let the reaction cool,
Water was added and extracted with ethyl acetate. The aqueous layer was washed with ethyl acetate and adjusted to pH 4 with 6 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 30: 70) to obtain compound (II-14) [yield 1.19 g, yield. 14% (2 steps)] was obtained as a yellow oil.
Process 3
Add cesium carbonate (2.28 g, 7.01 mmol) to a solution of compound (II-14) (1.00 g, 4.67 mmol) and compound (III-1) (899 mg, 4.67 mmol) in DMSO (10 mL) at 120 ° C. The mixture was stirred for 21 hours, and then stirred at 140 ° C. for 9 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. Organic layer with water,
The extract was washed successively with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 85: 15) to obtain compound (IV-27) (yield 163 mg, yield) 21%) was obtained as a yellow oil.
Process 4
By the same production method as for compound (I-1), compound (IV-27) (30.0 mg, 0.0811 mmol) and 2-methoxyphenylboronic acid (V-1) (16.0 mg, 0.105 mmol) were converted to compound (I- 181) (Yield 29.4 mg, Yield 91%) was obtained as a colorless oil.

Example 182
5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} -N-methyl-N-propylpyrimidine-
Production of 2-amine (I-182)

Process 1
According to the same production method as for compound (IV-1), compound (III-1) (2.32 g, 12.1 mmol) and 2-aminopyrimidin-5-ol (II-15) (1.12 g, 10.1 mmol) IV-28) (yield 1.23 g, yield 46%).
Process 2
Compound (IV-28) (1.50 g, 5.62 mmol) is dissolved in DCM (5.0 mL), concentrated hydrochloric acid (5.0 mL, 58 mmol) and zinc (II) chloride (1.30 g, 9.55 mmol) are added, and ice-cooled. Stirred under for 30 minutes. Further, sodium nitrite (659 mg, 9.55 mmol) was added and stirred for 3 hours. Ice water was added to stop the reaction, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-29) (yield 622 mg, yield 39%).
Process 3
Compound (IV-29) (100 mg, 0.349 mmol) is dissolved in NMP (1 mL), and N-methylpropan-1-amine (128 mg, 1.75 mmol) and potassium carbonate (241 mg, 1.75 mmol) are added. And stirred at 80 ° C. for 18 hours. Water was added to stop the reaction, and ethyl acetate was added for extraction. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-30) (yield 105 mg, yield 93%).
Process 4
According to the same production method as for compound (I-1), compound (I-182) (yield 28.5) from compound (IV-30) (26.0 mg, 0.0800 mmol) and compound (V-1) (18.3 mg, 0.121 mmol) mg, yield quantitative) was obtained as a colorless oil.

Example 183
5-{[2'-Methoxy- (3,3'-bipyridin) -2-yl] oxy} -N-methyl-N-propylpyrimidin-2-amine (I-183) Preparation Compound (I-1) In the same manner as described above, compound (IV-30) (26.0 mg, 0.0800 mmol) and compound (V-26) (18.5 mg, 0.121 mmol) to compound (I-183) (yield 25.8 mg, yield 91% ) Was obtained as a colorless oil.

Example 184
Preparation of N-ethyl-5-{[3- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -N-methylpyrimidin-2-amine (I-184)

Process 1
According to the same production method as for compound (IV-30), compound (IV-29) (80.0 mg, 0.279 mmol) and N-
Compound (IV-31) (yield 69.0 mg, yield 80%) was obtained from ethylmethylamine (83.0 mg, 1.40 mmol).
Process 2
According to the same production method as for compound (I-1), compound (I-184) (yield 20.7%) from compound (IV-31) (19.0 mg, 0.0615 mmol) and compound (V-12) (15.7 mg, 0.0922 mmol) mg, yield 95%) was obtained as a colorless oil.

Example 185
Preparation of 5-{[3- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -N, N-dimethylpyrimidin-2-amine (I-185) Same as compound (IV-30) From the compound (I-191) (25.0 mg, 0.0591 mmol) and dimethylamine (53.3 mg, 0.591 mmol), the compound (I-185) (yield 17.6 mg, yield 88%) was obtained as a white solid. It was.

Example 186
Preparation of 2- (propylthio) -5-{[3- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} pyrimidine (I-186)

Process 1
Propane-1-thiol (137 mg, 1.80 mmol) was dissolved in THF (1 mL), sodium hydride (72.0 mg, 1.80 mmol) was added, and the mixture was stirred at room temperature for 20 min. Further, compound (IV-29) (172 mg, 0.600
mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours. Water was added to stop the reaction, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-33) (yield 58.0 mg, yield 30%).
Process 2
According to the same production method as for compound (I-1), compound (I-186) (yield 17.8 mg) from compound (IV-33) (25.0 mg, 0.0766 mmol) and compound (V-12) (19.5 mg, 0.115 mmol) mg, yield 63%).

Example 187
Preparation of 2-ethoxy-5-{[3- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} pyrimidine (I-187)

Process 1
Compound (IV-29) (100 mg, 0.349 mmol) was dissolved in THF (1.0 mL), 50% sodium hydride (16.8 mg, 0.419 mmol) was added, and the mixture was stirred for 10 minutes. Furthermore, ethanol (24.4 μL, 0.419 mmol) was added, and the mixture was stirred at 80 ° C. for 4 hours. Water was added to stop the reaction, and ethyl acetate was added for extraction. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-34) (yield 48.0 mg, yield 46%).
Process 2
According to the same production method as for compound (I-1), compound (I-187) (yield 18.7) from compound (IV-34) (17.0 mg, 0.0570 mmol) and compound (V-12) (14.6 mg, 0.0861 mmol) mg, yield 95%) was obtained as a colorless oil.

Example 188
Preparation of 5-{[3- (4-Fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -N- (2-methoxyethyl) -N-methylpyrimidin-2-amine (I-188)

Process 1
By the same production method as for compound (IV-30), compound (IV-29) (100 mg, 0.349 mmol) and 2-methoxy-N-methylethanamine (200 μL, 1.85 mmol) were converted to compound (IV-35 ) (Yield 122 mg, yield quantitative).
Process 2
According to the same production method as for compound (I-1), compound (I-188) (yield: 25.2) from compound (IV-35) (20.0 mg, 0.0590 mmol) and compound (V-12) (15.0 mg, 0.0884 mmol) mg, yield quantitative) was obtained as a colorless oil.

Example 189
Preparation of 2-[(5-{[3- (4-Fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} pyrimidin-2-yl) (methyl) amino] acetonitrile (I-189)

Process 1
Compound (IV-29) (100 mg, 0.349 mmol) is dissolved in DMA (1.0 mL), N, N-diisopropylethylamine (0.2 mL, 1.15 mmol) is added, and 2- (methylamino) acetonitrile (200 mg , 2.96 mmol) and stirred at 100 ° C. overnight. Water was added to stop the reaction, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-36) (Yield 73.0 mg, Yield 65%).
Process 2
According to the same production method as for compound (I-1), compound (I-189) (yield 18.1) was obtained from compound (IV-36) (20.0 mg, 0.0625 mmol) and compound (V-12) (16.5 mg, 0.0938 mmol). mg, yield 79%) was obtained as a colorless oil.

Reference Example 190
5-{[3- (4-Fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} pyrimidin-2-amine (I-190) was produced by the same production method as for compound (I-1). Compound (I-190) (yield 2.40 g, yield 82%) was obtained from (IV-28) (2.50 g, 9.36 mmol) and compound (V-12) (2.39 g, 14.0 mmol).

Example 191
Preparation of 5-{[3- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -2-iodopyrimidine (I-191) Compound (I-190) (3.50 g, 11.2 mmol) Dissolve in THF (9.6 mL), add isoamyl nitrite (0.39 mL, 2.90 mmol), diiodomethane (0.78 mL, 9.65 mmol) and copper iodide (92.0 mg, 0.483 mmol) sequentially, and stir at 60 ° C for 1 hour. did. The reaction solution was allowed to cool and filtered through celite, and then the solvent was distilled off under reduced pressure. The residue was purified by amino silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40) to give compound (I-191) (yield 3.00 g, yield 63%) as a pale yellow oil. Obtained.

Example 192
Preparation of methyl 2-[(5-{[3- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} pyrimidin-2-yl) (methyl) amino] acetate (I-192) Compound ( In the same manner as in (IV-30), compound (I-192) (yield 22.0 mg, yield 47) was obtained from compound (I-191) (50 mg, 0.118 mmol) and sarcosine methyl ester (82.0 mg, 0.590 mmol). %) As a colorless oil.

Example 193
5-{[3- (4-Fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -N-methyl-N- (oxazol-4-ylmethyl) pyrimidin-2-amine (I-193) According to the same production method as for compound (IV-30), compound (I-191) (30.0 mg, 0.071 mmol) and N-methyl-1- (oxazol-4-yl) methanamine (30.0 mg, 0.268 mmol) (I-193) (Yield 24.6 mg, Yield 85%) was obtained as a colorless oil.

Example 194
5-{[3- (4-Fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -N-methyl-N- (thiazol-2-ylmethyl) pyrimidin-2-amine (I-194) Compound (I-191) (30.0 mg, 0.071 mmol) was dissolved in 1,4-dioxane (0.6 mL) / DMA (0.6 mL) mixed solution, and then N-methyl-1- (thiazol-2-yl) methanamine ( 20.0 mg, 0.156 mmol) and DIPEA (50 μL, 0.29 mmol) were added, and the mixture was stirred at 120 ° C. for 2 hours. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (I-194) (yield 3.3 mg, yield 11%) as a colorless oil.

Example 195
Preparation of ethyl 3- (5-{[3- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} pyrimidin-2-yl) propionate (I-195) Compound (I-191) (300 mg, 0.709 mmol) was dissolved in THF solution (0.5 mol / L, 12 mL, 6.0 mmol) of 3-ethoxy-3-oxopropylzinc bromide, followed by tetrakis (triphenylphosphine) palladium (82.0 mg, 0.071 mmol) And stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was neutralized with hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-195) (yield 200 mg, 71%) as a yellow oil.

Example 196
Preparation of ethyl 2-[(5-{[3- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} pyrimidin-2-yl) oxy] acetate (I-196)

Process 1
Sodium hydride (400 mg, 8.33 mmol) was suspended in toluene (10 mL), 2-hydroxyethyl acetate (0.70 mL, 7.40 mmol) was added, and the mixture was stirred at room temperature for 30 min. (M-30) (1.00 g, 4.53 mmol) was added to the reaction solution, and the mixture was stirred at 60 ° C. for 18 hours. The reaction mixture was allowed to cool, saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (M-31) (yield 650 mg, yield 50%) as a colorless oil.
Process 2
The compound (M-31) (650 mg, 2.26 mmol) was dissolved in ethanol (10 mL), 10% Pd / C (300 mg) was added, and the mixture was stirred under a hydrogen atmosphere (3 atm) for 16 hours. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give compound (II-16) (440 mg, yield 98%) as a colorless oil.
Process 3
By the same production method as for compound (IV-1), compound (IV-37) (yield 180%) was obtained from compound (III-1) (450 mg, 2.34 mmol) and compound (II-16) (440 mg, 2.22 mmol). mg, yield 23%) was obtained as a colorless oil.
Process 4
According to the same production method as for compound (I-1), compound (I-196) (yield 23.6) from compound (IV-37) (30.0 mg, 0.0847 mmol) and compound (V-12) (20.0 mg, 0.118 mmol) mg, yield 70%) was obtained as a colorless oil.

Reference Example 197
5-{[3- (4-Fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -2-[(1-methyl-1H-pyrazol-4-yl) ethynyl] pyrimidine (I-197) Preparation Compound (I-191) (100 mg, 0.236 mmol) was dissolved in THF (5.0 mL), and then 1-methyl-4-ethynylpyrazole (75.2 mg, 0.709 mmol), PdCl ₂ (PPh ₃ ) ₂ (16.6 mg, 0.0236 mmol), copper iodide (9.0 mg, 0.047 mmol) and TEA (66 μL, 0.47 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-197) (yield 26.1 mg, yield 28%) as a yellow solid. It was.

Example 198
5-{[3- (4-Fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -2- [2- (1-methyl-1H-
Preparation of pyrazol-4-yl) ethyl] pyrimidine (I-198) Compound (I-197) (15.0 mg, 0.0374 mmol) was dissolved in ethanol (2.0 mL), and then 10% Pd / C (5.0 mg) was dissolved. In addition, the mixture was stirred for 16 hours under a hydrogen atmosphere (3 atm). The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (I-198) (yield 6.5 mg, yield). 43%) was obtained as a colorless oil.

Example 199
Preparation of 2- (4-chlorophenoxy) -3- (2-methoxyphenyl) pyridine (I-199)

Process 1
Compound (III-1) (647 mg, 3.36 mmol) and 4-chlorophenol (II-17) (431 mg, 3.36 mmol) were dissolved in DMF (10 mL), and potassium carbonate (557 mg, 4.03 mmol) was dissolved. In addition, the mixture was stirred at 90 ° C. for 29 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 100
: 0 → 85: 15) to obtain compound (IV-38) (yield 107 mg, yield 11%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.91 (1H, dd, J = 5.0, 7.8 Hz), 7.08-7.14 (2H, m), 7.34-7.41 (2H, m), 7.94 (1H, dd , J = 1.8, 7.8 Hz), 8.06 (1H, dd, J = 1.8, 5.0 Hz).
ESI-MS m / z: 284, 286, 288 [M + H] ⁺ .
Process 2
According to the same production method as for compound (I-1), compound (I-38) (50.0 mg, 0.176 mmol) and 2-methoxyphenylboronic acid (V-1) (34.7 mg, 0.228 mmol) were converted to compound (I- 199) (yield 47.3 mg, yield 86%) was obtained as a white solid.

Example 200
Preparation of 2- (4-chlorophenoxy) -3- (3-methoxyphenyl) pyridine (I-200) Compound (IV-38) (50.0 mg, 0.176 mmol) was prepared in the same manner as for compound (I-1). ) And 3-methoxyphenylboronic acid (V-2) (34.7 mg, 0.228 mmol) to give compound (I-200) (yield 49.5 mg, yield 90%) as a colorless oil.

Example 201
Preparation of 3- (2-methoxyphenyl) -2- [4- (trifluoromethyl) phenoxy] pyridine (I-201)

Process 1
By the same production method as for compound (IV-1), 4-trifluoromethylphenol (II-18) (10.0
g, 61.7 mmol) and compound (III-1) (14.3 g, 74.0 mmol) gave compound (IV-39) (yield 6.8 g, yield 35%) as a white solid.
Process 2
According to the same production method as for compound (I-1), compound (I-39) (30.0 mg, 0.0943 mmol) and 2-methoxyphenylboronic acid (V-1) (17.2 mg, 0.113 mmol) were converted to compound (I- 201) (yield 19.9 mg, 61% yield) as a colorless oil.

Example 202
Preparation of 2-methoxy-2 '-[4- (trifluoromethyl) phenoxy] -3,3'-bipyridine (I-202) Compound (IV-39) was prepared by a method similar to that for compound (I-1). Compound (I-202) (21.1 mg, 65% yield) was obtained as a colorless oil from (30.0 mg, 0.0943 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (17.3 mg, 0.113 mmol). Got as.

Example 203
Preparation of 2,4-dimethoxy-2 '-[4- (trifluoromethyl) phenoxy] -3,3'-bipyridine (I-203)

Process 1
To a THF (9.4 mL) solution of the compound (IV-39) (1.50 g, 4.72 mmol), 1.3 mol / L iPrMgBr · LiCl THF solution (7.3 mL, 9.4 mmol) was added and stirred for 30 minutes. Thereafter, triisopropyl borate (3.3 mL, 14 mmol) was added under ice-cooling and stirred for 1 hour, and then 1 mol / L hydrochloric acid (20 mL) was added and stirred for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain compound (VIa-4) (yield 1.20 g, yield 90%) as a pale yellow solid.
Process 2
According to the same production method as for compound (I-36), from compound (VIa-4) (30.0 mg, 0.105 mmol) and 3-bromo-2,4-dimethoxypyridine (VII-32) (27.7 mg, 0.127 mmol) Compound (I-203) (yield 34.3 mg, yield 86%) was obtained as a colorless oil.

Example 204
Production of 3′-methoxy-2- [4- (trifluoromethyl) phenoxy] -3,4′-bipyridine (I-204) Compound (IV-39) was prepared by the same production method as for compound (I-1). Compound (I-204) (31.3 mg, 48% yield) was obtained as a colorless oil from (50.5 mg, 0.159 mmol) and 3-methoxypyridine-4-boronic acid (V-27) (29.1 mg, 0.190 mmol). Got as.

Example 205
Production of 3'-methyl-2- [4- (trifluoromethyl) phenoxy] -3,4'-bipyridine (I-205)
A 1.0 mol / L aqueous sodium hydroxide solution was added to 4-bromo-3-methylpyridine / hydrobromide (24.6 mg, 0.118 mmol), and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered. The solvent was distilled off under reduced pressure to give 4-bromo-3-methylpyridine (VII-33) as a colorless oil.
After the residue was dissolved in n-butanol (0.6 mL), (A- ^ta Phos) ₂ PdCl ₂ (4.2 mg, 0.0059 mmol), cesium carbonate (76.8 mg, 0.236 mmol) and compound (VIa-4) (50.0 mg, 0.079 mmol) was added, and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (I-205) (yield 30.2 mg, yield 78%) as a colorless oil. Obtained.

Example 206
Production of 4′-methyl-2- [4- (trifluoromethyl) phenoxy] -3,3′-bipyridine (I-206) Compound (IV-39) was prepared by the same production method as for compound (I-1). Compound (I-206) (24.0 mg, 77% yield) as a white solid from (30.0 mg, 0.0943 mmol) and 4-methylpyridine-3-boronic acid (V-25) (19.5 mg, 0.139 mmol) Obtained.

Example 207
Production of 4′-chloro-5′-fluoro-2- [4- (trifluoromethyl) phenoxy] -3,3′-bipyridine (I-207) Compound by a production method similar to that of compound (I-36) Compound (I-207) (Yield 259 mg, Yield 74%) was obtained as a colorless oil from (VIa-4) (296 mg, 1.05 mmol) and Compound (VII-17) (200 mg, 0.950 mmol). .

Example 208
Production of 5′-fluoro-4′-methyl-2- [4- (trifluoromethyl) phenoxy] -3,3′-bipyridine (I-208) Compound by a production method similar to that for compound (I-53) Compound (I-208) (Yield 31.5 mg, Yield 67%) was obtained as a colorless oil from (I-207) (50.0 mg, 0.136 mmol) and methylboronic acid (48.7 mg, 0.814 mmol).

Example 209
Production of 5-fluoro-2-methoxy-2 ′-[4- (trifluoromethyl) phenoxy] -3,3′-bipyridine (I-209) By a production method similar to that of compound (I-1), compound ( IV-39) (30.0 mg, 0.0943 mmol) and 5-fluoro-2-methoxypyridine-3-boronic acid (V-32) (19.4 mg, 0.113 mmol) to compound (I-209) (yield 13.4 mg, yield 39%) was obtained as a colorless oil.

Example 210
Preparation of 4′-methoxy-2- [4- (trifluoromethyl) phenoxy] -3,3′-bipyridine (I-210) Compound (IV-39) (2.50 g, 7.86 mmol), Compound (V-28 ) (1.44 g, 9.43 mmol), (A- ^ta Phos) ₂ PdCl ₂ (278 mg, 0.393 mmol) and TEA (1.3 mL, 9.43 mmol) were dissolved in n-butanol (15 mL) and subjected to microwave irradiation. The mixture was stirred at 120 ° C. for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-210) (yield 1.42 g, yield 52%) as a white solid. It was.

Example 211
Production of 5′-chloro-4′-methoxy-2- [4- (trifluoromethyl) phenoxy] -3,3′-bipyridine (I-211) Compound by a production method similar to that of compound (I-36) Compound (I-211) (Yield 31.3 mg, Yield 48%) was obtained as a colorless oil from (VIa-4) (52.9 mg, 0.187 mmol) and Compound (VII-20) (37.8 mg, 0.170 mmol). .

Example 212
Preparation of 5'-fluoro-4'-methoxy-2- [4- (trifluoromethyl) phenoxy] -3,3'-bipyridine (I-212)

Process 1
According to the same production method as for compound (VII-20), compound (VII-17) (300 mg, 1.43 mmol) and sodium methoxide (28% methanol solution, 0.520 mL, 2.14 mmol) were converted to compound (VII-34) ( Yield 93.0 mg, 32% yield) was obtained as a colorless oil.
Process 2
According to the same production method as for compound (I-36), compound (Ia-212) (yield 18.7) from compound (VIa-4) (74.2 mg, 0.262 mmol) and compound (VII-34) (45.0 mg, 0.218 mmol) mg, 24% yield) was obtained as a pale yellow oil.

Example 213
Preparation of 6-methoxy-2 '-[4- (trifluoromethyl) phenoxy] -2,3'-bipyridine (I-213) Compound (IV-39) was prepared by a method similar to that for compound (I-1). (30.0 mg, 0.0943 mmol) and 6-methoxypyridine-2-boronic acid (V-46) (21.3 mg, 0.139 mmol) to compound (I-213) (yield 17.5 mg, 54% yield) as a colorless oil Got as.

Reference Example 214
Preparation of 4'-methoxy-5-nitro-2- [4- (trifluoromethyl) phenoxy] -3,3'-bipyridine (I-214)

Process 1
According to the same production method as for compound (IV-1), compound (IV-40) (yield 770) was obtained from compound (III-6) (1.00 g, 4.21 mmol) and compound (II-18) (819 mg, 5.05 mmol). mg, yield 50%) was obtained as a pale yellow solid.
Process 2
According to the same production method as for compound (I-127), compound (IV-40) (400 mg, 1.10 mmol) and 4-methoxypyridine-3-boronic acid monohydrate (V-28) (219 mg, 1.43 mmol) to Compound (I-214) (Yield
208 mg, 48% yield) was obtained as a pale yellow solid.

Reference Example 215
Preparation of 4'-methoxy-2- [4- (trifluoromethyl) phenoxy] -3,3'-bipyridin-5-amine (I-215) Compound (I-214) (189 mg, 0.483 mmol) in methanol (1.6 mL) and ethyl acetate (0.8 mL) were dissolved, tin chloride dihydrate (436 mg, 1.93 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated, diluted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 60: 40 → 10: 90) to obtain compound (I-215) (yield 163 mg, Yield 93%) was obtained as a pale yellow solid.

Example 216
Preparation of 5-fluoro-4'-methoxy-2- [4- (trifluoromethyl) phenoxy] -3,3'-bipyridine (I-216) Compound (I-215) (140 mg, 0.387 mmol) HBF ₄ aqueous solution (1.6 mL, 0.387 mmol) was added, sodium nitrite (29.4 mg, 0.426 mmol) dissolved in water (1.0 mL) was added at 0 ° C., and the mixture was stirred for 1 hr. The precipitate was filtered, washed with water and n-hexane, and then dried under reduced pressure at room temperature to obtain a brown solid. Toluene (3.3 mL) was added to this solid and stirred at 120 ° C. for 2 hours. The reaction mixture was concentrated, diluted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel: developing solvent n-hexane: ethyl acetate = 70: 30 → 40: 60) to give compound (I-216) (yield 35.0 mg Yield 25%) as a yellow oil.

Example 217
Preparation of 5-chloro-4'-methoxy-2- [4- (trifluoromethyl) phenoxy] -3,3'-bipyridine (I-217)

Process 1
According to the same production method as for compound (IV-1), compound (IV-7) (500 mg, 2.20 mmol) and compound (II-18) (429 mg, 2.64 mmol) to compound (IV-41) (yield 543 mg, yield 47%) was obtained as a colorless oil.
Process 2
According to the same production method as for compound (I-127), compound (IV-41) (100 mg, 0.284 mmol) and 4-methoxypyridine-3-boronic acid monohydrate (V-28) (65.1 mg, 0.425 mmol) gave compound (I-217) (yield 26.0 mg, yield 23%) as a white solid.

Example 218
Preparation of 2-methoxy-3- {2- [4- (trifluoromethyl) phenoxy] pyridin-3-yl} pyrazine (I-218)

  According to the same production method as for compound (I-36), compound (VIa-4) (30.0 mg, 0.105 mmol) and 2-bromo-3-methoxypyrazine (VII-35) (24.0 mg, 0.127 mmol) I-218) (yield 11.2 mg, yield 30%) was obtained as a white solid.

Example 219
Preparation of 4-methoxy-5- {2- [4- (trifluoromethyl) phenoxy] pyridin-3-yl} pyrimidine (I-219)

Process 1
Compound (VII-36) (9.90 g, 41.2 mmol) was dissolved in methanol (140 mL), 28% sodium methoxide methanol solution (24 mL, 120 mmol) was added, and the mixture was stirred at 60 ° C. for 15 hr. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain compound (VII-37) (yield 7.72 g, yield 79%) as a pale yellow solid.
Process 2
According to the same production method as for compound (I-36), compound (Ia-219) (yield 16.0) from compound (VIa-4) (30.0 mg, 0.105 mmol) and compound (VII-37) (29.9 mg, 0.127 mmol) mg, yield 44%) was obtained as a white solid.

Example 220
Preparation of 3- (5-chloro-1,3-dimethyl-1H-pyrazol-4-yl) -2- [4- (trifluoromethyl) phenoxy] pyridine (I-220) Compound (IV-39) (100 mg, 0.314 mmol), 5-chloro-1,3-dimethyl-1H-pyrazole (41.0 mg, 0.314 mmol), Pd (OAc) ₂ (1.4 mg, 0.0063 mmol) and potassium acetate (61.7 mg, 0.629 mmol). The product was dissolved in DMA (1.0 mL) and stirred at 160 ° C. for 45 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (I-220) (yield 3.0 mg, yield 3%) as a colorless oil. Obtained.

Example 221
Preparation of 3- (1-methyl-1H-pyrazol-5-yl) -2- [4- (trifluoromethyl) phenoxy] pyridine (I-221) Compound by a method similar to that for compound (I-1) Compound (I-221) (yield 440 mg, yield) from (IV-39) (1.00 g, 3.14 mmol) and 1-methyl-1H-pyrazole-5-boronic acid (V-48) (475 mg, 3.77 mmol) 44%) was obtained as a colorless oil.

Example 222
3- (4-Chloro-1-methyl-1H-pyrazol-5-yl) -2- [4- (trifluoromethyl) phenoxy]
Preparation of pyridine (I-222) Compound (I-221) (40.0 mg, 0.125 mmol) was dissolved in DMF (1.0 mL), NCS (20.1 mg, 0.150 mmol) was added, and the mixture was stirred at 80 ° C for 3 hours. Then, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (I-222) (Yield 32.0 mg, Yield 72%) as a colorless oil.

Example 223
Production process 1 of 3- (5-methoxy-1-methyl-1H-pyrazol-4-yl) -2- [4- (trifluoromethyl) phenoxy] pyridine (I-223)
5-Methoxy-1-methyl-1H-pyrazole (343 mg, 3.06 mmol) was dissolved in acetonitrile (5.0 mL), NIS (757 mg, 3.36 mmol) was added, and the mixture was stirred at 70 ° C. for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate), and 4-iodo-5-methoxy-1-methyl-1H-pyrazole (VII-38) ( The yield was 225 mg, and the yield was 31%.
Process 2
Compound (VIa-4) (212 mg, 0.890 mmol), Compound (VII-38) (210 mg, 0.742 mmol), (A- ^ta Phos) ₂ PdCl ₂ (26.3 mg, 0.037 mmol) and cesium carbonate (484 mg) , 1.48 mmol) was dissolved in n-butanol (1.0 mL) and water (0.10 mL) and stirred at 120 ° C. for 30 minutes under microwave irradiation.
Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-223) (yield 35.0 mg, yield 14%) as a white solid. It was.

Example 224
Preparation of 5- {2- [4- (trifluoromethyl) phenoxy] pyridin-3-yl} quinoxaline (I-224) By a method similar to that for compound (I-36), compound (VIa-4) (100 mg, 0.353 mmol) and 5-bromoquinoxaline (VII-2) (73.9 mg, 0.353 mmol) to compound (I-224) (yield 35.0 mg, yield)
27%) was obtained as a white solid.

Example 225
8- {2- [4- (Trifluoromethyl) phenoxy] pyridin-3-yl} -1,6-naphthyridine (I-225)
According to the same production method as for compound (I-36), compound (VIa-4) (30.0 mg, 0.106 mmol) and 8-bromo-1,6-naphthyridine (VII-39) (26.9 mg, 0.129 mmol) To give compound (I-225) (yield 15.4 mg, yield 44%) as a white solid.

Example 226
4- {2- [4- (trifluoromethyl) phenoxy] pyridin-3-yl} -1,5-naphthyridine (I-226)
According to the same production method as for compound (I-36), compound (VIa-4) (30.3 mg, 0.107 mmol) and 4-bromo-1,5-naphthyridine (VII-40) (26.9 mg, 0.129 mmol) To Compound (I-226) (Yield 7.7 mg,
(20% yield) was obtained as a colorless oil.

Example 227
Production of 8- {2- [4- (trifluoromethyl) phenoxy] pyridin-3-yl} pyrido [3,4-b] pyrazine (I-227) According to the same production method as for compound (I-36), Compound (I-227) (yield 5.6) from compound (VIa-4) (30.0 mg, 0.106 mmol) and 8-bromopyrido [3,4-b] pyrazine (VII-27) (27.1 mg, 0.129 mmol)
mg, yield 22%) was obtained as a yellow solid.

Example 228
Production of 7- {2- [4- (trifluoromethyl) phenoxy] pyridin-3-yl} pyrazolo [1,5-a] pyridine (I-228) By the production method similar to that of Compound (I-1), Compound (I-228) (yield 6.5) from compound (IV-39) (28.6 mg, 0.0899 mmol) and pyrazolo [1,5-a] pyridine-7-boronic acid (V-49) (29.2 mg, 0.180 mmol) mg, yield 20%) was obtained as a colorless oil.

Example 229
Production process 1 of 8- {2- [4- (trifluoromethyl) phenoxy] pyridin-3-yl} imidazo [1,2-a] pyridine (I-229)
2-Amino-3-bromopyridine (VII-41) (5.00 g, 28.9 mmol) was dissolved in ethanol (100 mL), sodium bicarbonate (3.64 g, 43.3 mmol) and 2-chloroacetaldehyde (7.1 mL, 43 mL).
mmol) was added and stirred for 4 hours under reflux. After allowing to cool, the solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30 → 40: 60) to give 8-bromoimidazo [1,2-a] pyridine (VII-42) (yield 5.71 g, Yield quantitative) was obtained.
Process 2
According to the same production method as for compound (I-36), compound (I-229) (yield 12.2) from compound (VIa-4) (58.2 mg, 0.206 mmol) and compound (VII-42) (48.6 mg, 0.247 mmol) mg, yield 17%) was obtained as a colorless oil.

Example 230
5- {2- [4- (Trifluoromethyl) phenoxy] pyridin-3-yl} [1,2,4] triazolo [1,5-a]
Preparation of pyridine (I-230) According to the same production method as for compound (I-36), compound (VIa-4) (60.0 mg, 0.212 mmol) and 5-bromo [1,2,4] triazolo [1,5 Compound (I-230) (yield 2.0 mg, yield 3%) was obtained as a white solid from -a] pyridine (VII-9) (54.6 mg, 0.276 mmol).

Example 231
Preparation of 5- {2- [4- (trifluoromethyl) phenoxy] pyridin-3-yl} imidazo [1,2-a] pyrazine (I-231)

According to the same production method as for compound (I-1), compound (VIa-4) (40.0 mg, 0.141 mmol) and 5-bromoimidazo [1,2-a] pyrazine (VII-43) (28.0 mg, 0.141 mmol) ) To give compound (I-231) (yield 11.8 mg, yield 30%) as a white solid.

Example 232
Preparation of 6-methyl-7- {2- [4- (trifluoromethyl) phenoxy] pyridin-3-yl} -2,3-dihydropyrazolo [5,1-b] oxazole (I-232)

Process 1
Compound (M-32) (1.00 g, 10.2 mmol) and potassium carbonate (2.82 g, 20.4 mmol) were dissolved in acetonitrile (20 mL), TBAB (657 mg, 2.04 mmol) and 1,2-dibromoethane (2.87 g, 15.3 mmol) was added, and the mixture was stirred at 50 ° C. for 14 hours. Then, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered. The solvent was distilled off under reduced pressure to obtain a crude compound (M-33).
Process 2
Compound (M-33) was dissolved in acetonitrile (20 mL), and NIS (2.29 g, 10.2 mmol) was added.
Stir at 1 ° C. for 1 hour. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (VII-44) [Yield 332 mg, Yield 13% (2 steps)].
Process 3
According to the same production method as for compound (I-1), compound (I-232) (yield 12.8) from compound (VIa-4) (50.0 mg, 0.177 mmol) and compound (VII-44) (53.0 mg, 0.212 mmol) mg, yield 20%) was obtained as a white solid.

Example 233
2-Methyl-3- {2- [4- (trifluoromethyl) phenoxy] pyridin-3-yl} -5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] oxazepine Production of (I-233)

Process 1
Compound (M-32) (1.00 g, 10.2 mmol) and potassium carbonate (4.23 g, 30.6 mmol) are dissolved in acetonitrile (30 mL), 1,4-dibromobutane (2.64 g, 12.2 mmol) is added, and 50 Stir at 12 ° C. for 12 hours. Then, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (M-34).
Process 2
Compound (M-34) was dissolved in acetonitrile (30 mL), NIS (3.22 g, 14.3 mmol) was added, and 70
Stir at 30 ° C. for 30 minutes. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (VII-45) [Yield 825 mg, Yield 29% (2 steps)].
Process 3
According to the same production method as for compound (I-36), compound (I-233) (yield 10.1) from compound (VIa-4) (61.1 mg, 0.216 mmol) and compound (VII-45) (50.0 mg, 0.180 mmol) mg, yield 14%) was obtained as a colorless oil.

Example 234
Preparation of 2- (4-bromophenoxy) -4'-methoxy-3,3'-bipyridine (I-234)

Process 1
Bipyridyl compound (VIII-3) (yield) from compound (III-8) (2.55 g, 14.5 mmol) and compound (V-28) (3.32 g, 21.7 mmol) by the same production method as compound (VIII-1) 1.48 g, yield 50%).
Process 2
Compound (VIII-3) (25.0 mg, 0.122 mmol) and 4-bromophenol (II-19) (63.5 mg, 0.367 mmol) were dissolved in NMP (0.50 mL), and cesium carbonate (120 mg, 0.367 mmol) was dissolved. In addition, the mixture was stirred at 180 ° C. for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool, 1 mol / L aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (I-234) (yield 13.2 mg, yield 30%) as a colorless oil. Obtained.

Example 235
Preparation of 2- (4-chlorophenoxy) -4'-methoxy-3,3'-bipyridine (I-235) By a method similar to that for compound (I-1), compound (IV-38) (50.0 mg, 0.176 mmol) and compound (V-28) (32.3 mg, 0.211 mmol) gave compound (I-235) (23.3 mg, 43% yield) as a colorless oil.

Example 236
Preparation of 2- (4-fluorophenoxy) -4'-methoxy-3,3'-bipyridine (I-236) By a method similar to that for compound (I-234), compound (VIII-3) (30.0 mg, 0.147 mmol) and 4-fluorophenol (II-20) (63.5 mg, 0.367 mmol) gave compound (I-236) (yield 24.0 mg, yield 55%) as a white solid.

Example 237
Production of 4'-methoxy-2- [4- (trifluoromethoxy) phenoxy] -3,3'-bipyridine (I-237)

Process 1
According to the same production method as for compound (IV-1), compound (III-1) (455 mg, 2.36 mmol) and 4- (trifluoromethoxy) phenol (II-21) (350 mg, 1.97 mmol) IV-42) (yield 328 mg, yield 50%) was obtained as a white solid.
Process 2
According to the same production method as for compound (I-1), compound (I-237) (yield 21.0) was obtained from compound (IV-42) (50.0 mg, 0.150 mmol) and compound (V-28) (34.4 mg, 0.224 mmol). mg, yield 39%) was obtained as a colorless oil.

Example 238
Preparation of 2- [4- (difluoromethoxy) phenoxy] -4'-methoxy-3,3'-bipyridine (I-238)

Process 1
According to the same production method as for compound (IV-1), compound (IV-1) (3.12 g, 12.5 mmol) and 4- (difluoromethoxy) phenol (II-22) (2.00 g, 12.5 mmol) were converted to compound (IV -43) (Yield 3.12
g, yield 79%).
Process 2
According to the same production method as for compound (I-1), compound (IV-43) (112 mg, 0.354 mmol) and compound (V-28) (81.0 mg, 0.531 mmol) were converted to compound (I-238) (yield 7.3 mg, yield 6%) was obtained as a colorless oil.

Example 239
4'-methoxy-2- {4-[(trifluoromethyl) thio] phenoxy} -3,3'-bipyridine (I-239)
Manufacturing of

Process 1
According to the same production method as for compound (IV-1), compound (III-1) (1.00 g, 5.20 mmol) and 4- (trifluoromethylthio) phenol (II-23) (1.51 g, 7.79 mmol) IV-44) (yield 1.10 g, 61% yield) was obtained as a colorless oil.
Process 2
According to the same production method as for compound (I-1), compound (I-239) (yield 28.0) from compound (IV-44) (50.0 mg, 0.143 mmol) and compound (V-28) (36.6 mg, 0.214 mmol) mg, yield 52%) was obtained as a colorless oil.

Example 240
Preparation of 4'-methoxy-2- [4- (pentafluorosulfanyl) phenoxy] -3,3'-bipyridine (I-240)

Process 1
According to the same production method as for compound (IV-1), compound (III-1) (315 mg, 1.64 mmol) and 4- (pentafluorosulfanyl) phenol (II-24) (300 mg, 1.36 mmol) IV-45) (
Yield 309 mg, 60% yield) was obtained as a white solid.
Process 2
According to the same production method as for compound (I-1), compound (I-240) (yield 15.1) from compound (IV-45) (50.0 mg, 0.133 mmol) and compound (V-28) (34.1 mg, 0.199 mmol) mg, yield 28%) was obtained as a colorless oil.

Example 241
Production of 4'-methoxy-2- [4- (methylthio) phenoxy] -3,3'-bipyridine (I-241)

  According to the same production method as for compound (I-234), compound (I-234) was prepared from compound (VIII-3) (30.0 mg, 0.147 mmol) and 4- (methylthio) phenol (II-25) (63.5 mg, 0.367 mmol). 241) (Yield 24.0 mg, Yield 55%) was obtained as a white solid.

Example 242
Production of 4'-methoxy-2- (4-methoxyphenoxy) -3,3'-bipyridine (I-242)

Process 1
According to the same production method as for compound (IV-1), compound (IV-46) (yield 827) was obtained from compound (III-1) (1.00 g, 5.20 mmol) and hydroquinone (II-26) (1.14 g, 10.4 mmol). mg, yield 60%) was obtained as a white solid.
Process 2
Compound (IV-46) (100 mg, 0.376 mmol) is dissolved in DMF (1.9 mL), and sodium hydride (36.1 mg, 0.752 mmol) and methyl iodide (35.2 μL, 0.564 mmol) are added sequentially, and at room temperature. Stir for 1 hour. Water was added and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (IV-47) (yield 102 mg,
Yield 97%) was obtained as a white solid.
Process 3
According to the same production method as for compound (I-1), compound (I-242) (yield 20.2) from compound (IV-47) (50.0 mg, 0.179 mmol) and compound (V-28) (54.8 mg, 0.358 mmol) mg, yield 37%) was obtained as a white solid.

Example 243
Preparation of 4-{[4'-methoxy- (3,3'-bipyridin) -2-yl] oxy} benzonitrile (I-243)

Process 1
According to the same production method as for compound (IV-1), compound (IV-48) was prepared from compound (III-1) (200 mg, 1.14 mmol) and 4-hydroxybenzonitrile (II-27) (149 mg, 1.25 mmol). ) (Yield 213 mg, 68% yield).
Process 2
According to the same production method as for compound (I-1), compound (IV-48) (30.0 mg, 0.109 mmol) and compound (V-28) (25.0 mg, 0.164 mmol) were converted to compound (I-243) (yield 9.9 mg, yield 30%) was obtained as a white solid.

Example 244
Preparation of 1- (4-{[4'-methoxy- (3,3'-bipyridin) -2-yl] oxy} phenyl) ethanone (I-244)

Process 1
According to the same production method as for compound (IV-1), compound (IV-49) from compound (III-1) (3.00 g, 17.0 mmol) and 4-hydroxyacetophenone (II-28) (2.79 g, 20.5 mmol) (Yield 4.23 g, 85% yield) was obtained as a white solid.
Process 2
According to the same production method as for compound (I-1), compound (I-244) (yield 10.1) was obtained from compound (IV-49) (50.0 mg, 0.171 mmol) and compound (V-28) (39.3 mg, 0.257 mmol). mg, yield 18%) was obtained as a white solid.

Example 245
4-{[4'-Methoxy- (3,3'-bipyridin) -2-yl] oxy} production of ethyl benzoate (I-245)

Process 1
According to the same production method as for compound (IV-1), compound (IV-1) (10.0 g, 52.0 mmol) and ethyl 4-hydroxybenzoate (II-29) (10.4 g, 62.6 mmol) to compound (IV- 50) (Yield 11.8 g, Yield 71%) was obtained as a white solid.
Process 2
Compound (IV-50) (300 mg, 0.931 mmol), Compound (V-28) (214 mg, 0.140 mmol) and (A- ^ta Phos) ₂ PdCl ₂ (33.0 mg, 0.0470 mmol) were converted to 1,4-dioxane. (2.5 mL), 3.7 mol / L cesium fluoride aqueous solution (0.50 mL, 1.86 mmol) was added, and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 95: 5 → 50: 50) to obtain compound (I-245) (yield 101 mg Yield 31%) as a white solid.

Example 246
Preparation of 4-{[4'-methoxy- (3,3'-bipyridin) -2-yl] oxy} benzaldehyde (I-246)

Process 1
According to the same production method as for compound (IV-1), compound (IV-51) was prepared from compound (III-1) (5.00 g, 26.0 mmol) and 4-hydroxybenzaldehyde (II-30) (2.11 g, 17.3 mmol). (Yield 1.13 g,
Yield 23%) was obtained as a white solid.
Process 2
According to the same production method as for compound (I-1), compound (I-246) (yield 493) from compound (IV-51) (1.00 g, 3.60 mmol) and compound (V-28) (715 mg, 4.18 mmol) mg, yield 45%) was obtained as a yellow oil.

4'-Methoxy-2- [4- (2,2,2-trifluoroethyl) phenoxy] -3,3'-bipyridine (I-249)
Manufacturing of

Example 247
Preparation of 2,2,2-trifluoro-1- (4-{[4'-methoxy- (3,3'-bipyridin) -2-yl] oxy} phenyl) ethanol (I-247) Compound (I- 246) (200 mg, 0.653 mmol) in THF (2.0 mL), trimethylsilyltrifluoromethane (115 μL, 0.778 mmol) and TBAF (65 μL, 0.065 mmol) were sequentially added under ice cooling, and the temperature was raised to room temperature. Stir for hours. The reaction mixture was ice-cooled and trimethylsilyltrifluoromethane (30
μL, 0.203 mmol) and a 1.0 mol / L THF solution (0.65 mL, 0.59 mmol) of TBAF were sequentially added, and the mixture was warmed to room temperature and stirred for 17 hours. 1 mol / L hydrochloric acid (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 50: 50
→ 0: 100) to give compound (I-247) (yield 167 mg, 68% yield) as a white solid.

Reference Example 248
2,2,2-trifluoro-1- (4-{[4'-methoxy- (3,3'-bipyridin) -2-yl] oxy} phenyl) ethyl 4-methylbenzenesulfonate (I-248) PreparationIn a DCM (3.0 mL) solution of compound (I-247) (100 mg, 0.266 mmol), DMAP (1.6 mg, 0.013 mmol) and TEA (74 μL, 0.53 mmol) under ice cooling, TsCl (55.7 mg, 0.292 mmol) was added and stirred at room temperature for 5 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 40: 60 → 0: 100) to obtain compound (I-248) (yield 78.1 mg Yield 55%) as a white solid.

Example 249
4'-Methoxy-2- [4- (2,2,2-trifluoroethyl) phenoxy] -3,3'-bipyridine (I-249)
Compound (I-248) (70.0 mg, 0.132 mmol) was dissolved in ethanol (3.0 mL), palladium hydroxide / carbon (Pd 20%) (14.0 mg) was added, and the reaction was carried out at room temperature under a hydrogen atmosphere of 0.3 MPa. For 2 hours. The reaction mixture was filtered through celite, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 95: 5 → 20: 80), and the compound ( I-249) (yield 30.9 mg, yield 65%) was obtained as a colorless oil.

Example 250
Production process 1 of (4-{[4'-methoxy- (3,3'-bipyridin) -2-yl] oxy} phenyl) methanol (I-250)
According to the same production method as for compound (IV-1), compound (IV-52) was prepared from compound (III-1) (412 mg, 2.14 mmol) and 4-hydroxymethylphenol (II-31) (500 mg, 1.79 mmol). ) (Yield 682 mg,
Yield 60%) was obtained as a yellow oil.
Process 2
Compound (I-250) (yield 98.0) from compound (IV-52) (200 mg, 0.714 mmol) and compound (V-28) (164 mg, 1.07 mmol) by the same production method as compound (I-1) mg, yield 45%) was obtained as a colorless oil.

Example 251
Production of 4'-methoxy-2- [4- (methoxymethyl) phenoxy] -3,3'-bipyridine (I-251)

Compound (I-250) (30.0 mg, 0.097 mmol) was dissolved in DMF (1.0 mL), 50% sodium hydride (9.3 mg, 0.19 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Methyl iodide (12 μL, 0.19 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 0: 100 → 33: 67) to obtain compound (I-251) (yield 3.2 mg, yield 10%) as a colorless oil. .

Example 252
Production of 4'-methoxy-2- (p-triloxy) -3,3'-bipyridine (I-252)

Process 1
According to the same production method as for compound (IV-1), compound (IV-1) (1.00 g, 5.25 mmol) and p-cresol (II-32) (0.62 mL, 5.8 mmol) were converted to compound (IV-53) ( Yield 1.09 g, 78% yield) was obtained as a yellow oil.
Process 2
According to the same production method as for compound (I-1), compound (I-252) (yield 34.8) from compound (IV-53) (50.0 mg, 0.189 mmol) and compound (V-28) (43.4 mg, 0.284 mmol) mg, yield 63%) was obtained as a colorless oil.

Example 253
Preparation of 2- (4-ethylphenoxy) -4'-methoxy-3,3'-bipyridine (I-253)

Process 1
Compound (IV-54) was prepared from Compound (III-1) (1.00 g, 5.25 mmol) and 4-ethylphenol (II-33) (698 mg, 5.78 mmol) by the same production method as Compound (IV-1). (Yield 1.14 g, 82% yield) was obtained as a white solid.
Process 2
According to the same production method as for compound (I-1), compound (I-253) (yield 10.5) from compound (IV-54) (50.0 mg, 0.180 mmol) and compound (V-28) (41.2 mg, 0.270 mmol) mg, yield 19%) was obtained as a white solid.

Example 254
Production of 4'-methoxy-2- (4-propylphenoxy) -3,3'-bipyridine (I-254)

Process 1
According to the same production method as for compound (IV-1), compound (IV-55) was prepared from compound (III-1) (500 mg, 2.60 mmol) and 4-propylphenol (II-34) (425 mg, 3.12 mmol). (Yield 601 mg, 79% yield) was obtained as a colorless oil.
Process 2
According to the same production method as for compound (I-1), compound (I-254) (yield 34.4) from compound (IV-55) (50.0 mg, 0.171 mmol) and compound (V-28) (43.9 mg, 0.257 mmol) mg, yield 63%) was obtained as a colorless oil.

Example 255
Preparation of 2- (4-isopropylphenoxy) -4'-methoxy-3,3'-bipyridine (I-255)

Process 1
According to the same production method as for compound (IV-1), compound (IV-56) was prepared from 4-isopropylphenol (II-35) (1.00 g, 7.34 mmol) and compound (III-1) (1.41 g, 7.34 mmol). (Yield 1.93 g, 90% yield) was obtained as a white solid.
Process 2
According to the same production method as for compound (I-1), compound (I-255) (yield 23.8) was obtained from compound (IV-56) (50.0 mg, 0.171 mmol) and compound (V-28) (43.9 mg, 0.257 mmol). mg, yield 43%) was obtained as a colorless oil.

Example 256
Preparation of 2- [4- (sec-butyl) phenoxy] -4'-methoxy-3,3'-bipyridine (I-256)

Process 1
According to the same production method as for compound (IV-1), compound (IV-57) was prepared from compound (III-1) (500 mg, 2.60 mmol) and 4-sec-butylphenol (II-36) (468 mg, 3.12 mmol). ) (Yield 720 mg, 91% yield) as a colorless oil.
Process 2
According to the same production method as for compound (I-1), compound (I-256) (yield 21.2) was obtained from compound (IV-57) (50.0 mg, 0.163 mmol) and compound (V-28) (41.9 mg, 0.245 mmol). mg, yield 39%) was obtained as a colorless oil.

Example 257
2- (4-{[4'-Methoxy- (3,3'-bipyridin) -2-yl] oxy} phenyl) ethanol (I-257)
Manufacturing of

Process 1
According to the same production method as for compound (IV-1), compound (III-1) (2.01 g, 11.4 mmol) and 4- (2-
Compound (IV-58) (yield 3.29 g, yield 98%) was obtained as a white solid from hydroxyethyl) phenol (II-37) (1.74 g, 12.6 mmol).
Process 2
According to the same production method as for compound (I-1), compound (I-257) (yield 330) was obtained from compound (IV-58) (400 mg, 1.36 mmol) and compound (V-28) (312 mg, 2.04 mmol). mg, yield 75%) was obtained as a colorless oil.

Example 258
Production of 4'-methoxy-2- (4-vinylphenoxy) -3,3'-bipyridine (I-258)

Compound (I-257) (22.0 mg, 0.0680 mmol) is dissolved in DCM (1.0 mL), TEA (29 μL, 0.205 mmol) and methanesulfonyl chloride (8.0 μL, 0.10 mmol) are added sequentially, and then at room temperature for 30 minutes. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain a mesyl body.
The obtained mesyl form was dissolved in ethanol (0.50 mL), cesium carbonate (44.5 mg, 0.136 mmol) was added, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction solution, followed by extraction with chloroform, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (I-258) [Yield 5.8 mg, Yield 28% (2 steps)] as a white solid.

Reference Example 259
Preparation of 4'-methoxy-2- {4-[(trimethylsilyl) ethynyl] phenoxy} -3,3'-bipyridine (I-259)

Compound (I-234) (300 mg , 0.840 mmol), copper iodide (16.0 mg, 0.0840 mmol) and _{PdCl 2 (dppf) (34.3 mg} , 0.0420 mmol) was suspended in TEA (3.0 mL), trimethylsilyl acetylene ( 0.24 mL, 1.7 mmol) was added, and the mixture was stirred at 100 ° C. for 30 minutes under microwave irradiation. Then, it stirred for 30 minutes at 120 degreeC under microwave irradiation. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (NH silica gel, n-
Purification by hexane: ethyl acetate = 95: 5 → 60:40), compound (I-259) (yield 297 mg, yield)
94%) was obtained as an orange solid.

Example 260
Preparation of 2- (4-ethynylphenoxy) -4'-methoxy-3,3'-bipyridine (I-260)

Compound (I-259) (285 mg, 0.761 mmol) was dissolved in THF (2.0 mL), TBAF (1.0 mol / L THF solution, 1.9 mL, 1.9 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, it stirred for 30 minutes at 120 degreeC under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Organic layer with water,
The extract was washed successively with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 97 → 50: 50) to obtain compound (I-260) (yield 67.8 mg, yield) 30%) was obtained as a white solid.

Example 261
Preparation of 2- (4-cyclopropylphenoxy) -4'-methoxy-3,3'-bipyridine (I-261)

Process 1
Compound (IV-59) was prepared from Compound (III-1) (9.62 g, 50.0 mmol) and 4-iodophenol (II-38) (10.0 g, 45.5 mmol) by the same production method as Compound (IV-1). (Yield 14.8 g, Yield 87%) was obtained.
Process 2
Compound (IV-59) (500 mg, 1.33 mmol) dissolved in THF (2.0 mL), cyclopropylzinc bromide (0.5 mol / L THF solution, 2.9 mL, 1.5 mmol) and tetrakis (triphenylphosphine) palladium (77.0 mg, 0.0660 mmol) was sequentially added, and the mixture was stirred at room temperature for 3.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 80: 20) to obtain compound (IV-60) (yield 172 mg, yield) 45%) was obtained as a colorless oil.
Process 3
According to the same production method as for compound (I-1), compound (I-261) (yield 14.4) was obtained from compound (IV-60) (40.0 mg, 0.138 mmol) and compound (V-28) (31.6 mg, 0.207 mmol). mg, yield 33%) was obtained as a colorless oil.

Example 262
Preparation of 2- (3,4-dimethylphenoxy) -4'-methoxy-3,3'-bipyridine (I-262)

Process 1
According to the same production method as for compound (IV-1), compound (IV-) was obtained from compound (III-1) (1.57 g, 8.18 mmol) and 3,4-dimethylphenol (II-39) (1.00 g, 8.18 mmol). 61) (Yield 960 mg, 42% yield) was obtained as a colorless oil.
Process 2
According to the same production method as for compound (I-1), compound (I-262) (yield 12.3) from compound (IV-61) (100 mg, 0.360 mmol) and compound (V-28) (82.6 mg, 0.540 mmol) mg, yield 11%) was obtained as a colorless oil.

Example 263
Preparation of 2- (4-ethyl-3-methylphenoxy) -4'-methoxy-3,3'-bipyridine (I-263)

Process 1
According to the same production method as for compound (IV-1), compound (III-1) (1.97 g, 10.3 mmol) and 4-iodo-3-methylphenol (II-40) (2.00 g, 8.55 mmol) IV-62) (yield 3.12 g, 94% yield) was obtained as a white solid.
Process 2
Compound (IV-62) (515 mg, 1.32 mmol) was dissolved in THF (3.0 mL), PdCl ₂ (dppf) -DCM (53.9 mg, 0.0660 mmol) and diethylzinc (1.0 mol / L THF solution, 1.4 mL) , 1.39 mmol) were added sequentially and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 85: 15) to obtain compound (IV-63) (yield 309 mg, yield) 80%) was obtained as a colorless oil.
Process 3
According to the same production method as for compound (I-1), compound (I-263) (yield 13.8) from compound (IV-63) (50.0 mg, 0.171 mmol) and compound (V-28) (39.3 mg, 0.257 mmol) mg, yield 25%) was obtained as a colorless oil.

Example 264
Preparation of 2- (3-ethyl-4-methylphenoxy) -4'-methoxy-3,3'-bipyridine (I-264)

Process 1
3-Bromo-4-methylphenol (II-41) (500 mg, 2.67 mmol) dissolved in DMF (3.0 mL), potassium carbonate (739 mg, 5.35 mmol), benzyl bromide (0.38 mL, 3.2 mmol) and TBAI (49.4 mg, 0.134 mmol) was sequentially added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 85: 15) to obtain the benzyloxy compound (M-35) (yield 635 mg, yield). 88%) was obtained as a pale yellow oil.

Process 2
4- (Benzyloxy) from benzyloxy compound (M-35) (400 mg, 1.44 mmol) and diethyl zinc (1.0 mol / L THF solution, 2.2 mL, 2.2 mmol) by the same production method as compound (IV-63) -2-Ethyl-1-methylbenzene (M-36) (Yield 290 mg, Yield 89%) was obtained as a colorless oil.
Process 3
4- (Benzyloxy) -2-ethyl-1-methylbenzene (M-36) (290 mg, 1.28 mmol) was dissolved in THF (2.0 mL) and methanol (2.0 mL), and 20% palladium hydroxide / carbon ( 29.0 mg) was added, and the mixture was stirred at room temperature for 17 hours under a hydrogen atmosphere (1 atm). After removing the solid reagent through celite, the solvent was distilled off under reduced pressure to obtain Compound (II-42) (yield 175 mg, quantitative yield) as a pale orange oil.
Process 4
According to the same production method as for compound (IV-1), compound (IV-64) (yield 320) from compound (III-1) (297 mg, 1.54 mmol) and compound (II-42) (175 mg, 1.29 mmol) mg, yield 85%) was obtained as a colorless oil.
Process 5
According to the same production method as for compound (I-1), compound (I-264) (yield 36.7) from compound (IV-64) (50.0 mg, 0.171 mmol) and compound (V-28) (43.9 mg, 0.257 mmol) mg, yield 67%) was obtained as a colorless oil.

Example 265
Preparation of 2- (3-ethylphenoxy) -4'-methoxy-3,3'-bipyridine (I-265)

Process 1
According to the same production method as for compound (IV-1), compound (IV-65) was prepared from compound (III-1) (1.00 g, 5.20 mmol) and 3-ethylphenol (II-43) (0.75 mL, 6.2 mmol). (Yield 1.22 g, 84% yield) was obtained as a colorless oil.
Process 2
According to the same production method as for compound (I-1), compound (I-265) (yield 271) was obtained from compound (IV-65) (100 mg, 0.360 mmol) and compound (V-28) (82.0 mg, 0.539 mmol). mg, yield 57%) was obtained as a white solid.

Example 266
Preparation of 2-[(2,3-dihydro-1H-inden-5-yl) oxy] -4'-methoxy-3,3'-bipyridine (I-266)

Process 1
According to the same production method as for compound (IV-1), compound (IV-66) (yield 198) was obtained from compound (II-44) (209 mg, 1.56 mmol) and compound (III-1) (200 mg, 1.04 mmol). mg, yield 66%).
Process 2
By the same production method as for compound (I-1), compound (I-266) (yield 59) was obtained from compound (IV-66) (50.0 mg, 0.172 mmol) and compound (V-28) (39.0 mg, 0.258 mmol). mg, yield quantitative) was obtained as a colorless oil.

Example 267
Production of 4'-methoxy-2-[(5,6,7,8-tetrahydronaphthalen-2-yl) oxy] -3,3'-bipyridine (I-267)

Process 1
According to the same production method as for compound (IV-1), compound (III-1) (4.00 g, 20.8 mmol) and 5,6,7,8-tetrahydronaphthalen-2-ol (II-45) (3.23 g, 21.8 mmol) gave compound (IV-67) (yield 6.15 g, yield 97%) as a pale yellow oil.
Process 2
According to the same production method as for compound (I-1), compound (I-267) (yield 27.5) from compound (IV-67) (50.0 mg, 0.164 mmol) and compound (V-28) (30.2 mg, 0.197 mmol) mg, yield 50%) was obtained as a colorless oil.

Example 268
Preparation of 3- (2-methoxyphenyl) -2-[(5,6,7,8-tetrahydronaphthalen-2-yl) oxy] pyridine (I-268)

  Compound (VIII-1) (50.0 mg, 0.228 mmol) and 5,6,7,8-tetrahydronaphthalen-2-ol (II-45) (38.0 mg, 0.254 mmol) were dissolved in NMP (1 mL), Cesium carbonate (90.0 mg, 0.276 mmol) was added, and the mixture was stirred at 180 ° C. for 4 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to give compound (I-268) (yield 17.0 mg, yield 23%) as an oil Obtained as a thing.

Example 269
Preparation of 2-methoxy-2 '-[(5,6,7,8-tetrahydronaphthalen-2-yl) oxy] -3,3'-bipyridine (I-269)

According to the same production method as for compound (I-268), compound (I-269) (yield 40.0) from compound (VIII-2) (50.0 mg, 0.227 mmol) and compound (II-45) (38.0 mg, 0.254 mmol) mg, yield 53%) was obtained as an oil.

Example 270
Preparation of 2-[(2,3-dihydro-1H-inden-5-yl) oxy] -2'-methoxy-3,3'-bipyridine (I-270)

According to the same production method as for compound (I-1), compound (I-270) (yield 99) was obtained from compound (IV-66) (100 mg, 0.345 mmol) and compound (V-26) (79.1 mg, 0.518 mmol). mg, yield 90%) was obtained as a white solid.

Example 271
4-Methoxy-5- {2-[(5,6,7,8-tetrahydronaphthalen-2-yl) oxy] pyridin-3-yl}
Production of pyrimidine (I-271)

Process 1
Compound (V-50) (yield 180 mg, yield 14%) was obtained as a pale yellow solid from compound (VII-37) (2.00 g, 8.47 mmol) by the same production method as compound (VIa-4) .
Process 2
According to the same production method as for compound (I-1), compound (I-271) (yield 5.4) from compound (IV-67) (30.0 mg, 0.0960 mol) and compound (V-50) (17.8 mg, 0.115 mmol) mg, yield 16%) was obtained as a colorless oil.

Example 272
Preparation of 6-{[2'-methoxy- (3,3'-bipyridin) -2-yl] oxy} -3,4-dihydronaphthalen-1 (2H) -one (I-272)

Process 1
Compound (III-1) (300 mg, 1.56 mmol), Compound (II-46) (279 mg, 1.72 mmol), Tris (dibenzylideneacetone) dipalladium (143 mg, 0.156 mmol), xanthophos (271 mg, 0.468) mmol) and cesium carbonate (1.52 g, 4.68 mmol) were dissolved in 1,4-dioxane (5.0 mL) and stirred at 90 ° C. for 16 hours. After the reaction solution was filtered, the filtrate was diluted with ethyl acetate and washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-68) (yield 222 mg, 52%) as a pale yellowish white solid.
Process 2
According to the same production method as for compound (I-1), compound (I-272) (yield 20) was obtained from compound (IV-68) (50.0 mg, 0.183 mmol) and compound (V-26) (41.8 mg, 0.275 mmol). mg, yield 32%) was obtained as a white solid.

Example 273
7-{[3- (2-Methoxyphenyl) pyridin-2-yl] oxy} -3,4-dihydronaphthalene-1 (2H)-
On (I-273) manufacturing

Process 1
According to the same production method as for compound (IV-1), compound (IV-69) (yield 150) was obtained from compound (III-1) (200 mg, 1.04 mmol) and compound (II-47) (253 mg, 1.56 mmol). mg, yield 45%).
Process 2
According to the same production method as for compound (I-1), compound (I-273) (yield 40) was obtained from compound (IV-69) (50.0 mg, 0.157 mmol) and compound (V-1) (36.0 mg, 0.236 mmol). mg, yield 74%) was obtained as a colorless oil.

Example 274
Preparation of 2- [4- (2-ethoxyethyl) phenoxy] -4'-methoxy-3,3'-bipyridine (I-274)

Process 1
Compound (IV-70) (yield 52.9 mg, yield 97) was prepared from compound (IV-58) (50.0 mg, 0.170 mmol) and iodoethane (41 μL, 0.51 mmol) by the same production method as compound (IV-24). %).
Process 2
According to the same production method as for compound (I-1), compound (I-274) (yield 23.8) from compound (IV-70) (52.9 mg, 0.164 mmol) and compound (V-28) (37.7 mg, 0.246 mmol) mg, yield 43%) was obtained as a colorless oil.

Example 275
Production of 4'-methoxy-2- [4- (1-methoxy-2-methylpropan-2-yl) phenoxy] -3,3'-bipyridine (I-275)

Process 1
According to the same production method as for compound (IV-1), compound (IV-71) (yield 330) was obtained from compound (III-1) (1.00 g, 5.20 mmol) and compound (II-48) (1.04 g, 6.24 mmol). mg, yield 20%) was obtained as a colorless oil.
Process 2
Compound (IV-71) (330 mg, 1.02 mmol) is dissolved in DMF (5.0 mL), 50% sodium hydride (148 mg, 3.08 mmol) is added under ice cooling, and the mixture is stirred for 15 minutes under ice cooling. did. Methyl iodide (0.19 mL, 3.1 mmol) was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. After adding water to the reaction solution,
Extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 0: 100 → 100: 0) to give compound (IV-72) (yield 86.2
mg, yield 24%).
Process 3
Sodium borohydride (60.9 mg, 1.61 mmol) was added to a solution of compound (IV-72) (86.0 mg, 0.246 mmol) in THF (4.0 mL) and methanol (4.0 mL), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 0: 100 → 50:50) to obtain the alcohol (IV-73) (yield 61.5 mg, 78% yield) as a colorless oil. It was.
Process 4
According to the same production method as for compound (IV-24), alcohol (IV-73) (61.0 mg, 0.189 mmol)
Compound (IV-74) (yield 46.4 mg, yield 73%) was obtained from methyl iodide (18 μL, 0.28 mmol).
Process 5
According to the same production method as for compound (I-1), compound (I-275) (yield 10.0% from compound (IV-74) (23.0 mg, 0.0684 mmol) and compound (V-28) (15.8 mg, 0.103 mmol)) mg, yield 40%) was obtained as a white solid.

Example 276
Production of 4'-methoxy-2- {4- [1- (methoxymethyl) cyclopropyl] phenoxy} -3,3'-bipyridine (I-276)

Process 1
Compound (II-48) (3.00 g, 18.1 mmol) was dissolved in DMF (18 mL), potassium carbonate (5.00 g, 36.2 mmol), benzyl bromide (3.2 mL, 27.2 mmol) and TBAI (669 mg, 1.81 mmol) ) Were sequentially added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 97: 3 → 85: 15) to obtain compound (M-37) (yield 3.01 g Yield 65%) as a colorless oil.
Process 2
Compound (M-37) (930 mg, 3.63 mmol) was dissolved in toluene (12 mL), and potassium carbonate (778 mg,
5.63 mmol), paraformaldehyde hydrate (172 mg, 5.45 mmol) and TBAI (67.2 mg, 0.182 mmol) were sequentially added, and the mixture was stirred at 80 ° C. for 18.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (n-hexane:
The product was purified by ethyl acetate = 97: 3 → 80: 20) to obtain compound (M-38) (yield 294 mg, yield 30%) as a colorless oil.
Process 3
Trimethylsulfonium iodide (315 mg, 1.43 mmol) was dissolved in DMSO (1.0 mL), KOt-Bu (185 mg, 1.65 mmol) was added, and the mixture was stirred at room temperature for 1 hour. A solution of compound (M-38) (294 mg, 1.10 mmol) in DMSO (3.0 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 80: 20) to give a cyclopropyl form (M-39) (yield 184 mg, Yield 59%) was obtained as a colorless oil.
Process 4
The cyclopropyl compound (M-39) (184 mg, 0.652 mmol) was dissolved in ethanol (6.5 mL), palladium / carbon (36.8 mg) was added, and the mixture was stirred at room temperature for 17 hours in a hydrogen atmosphere (1 atm). After removing the solid reagent by filtration, the solvent was distilled off under reduced pressure to give compound (II-49) (yield 130 mg, quantitative yield)
Was obtained as a white solid.
Process 5
According to the same production method as for compound (IV-1), compound (IV-1) (188 mg, 0.978 mmol) and compound (II-49) (125 mg, 0.652 mmol) to compound (IV-75) (yield 227 mg, yield quantitative) was obtained as a colorless oil.
Process 6
Compound (IV-75) (227 mg, 1.61 mmol) was dissolved in THF (4.0 mL) and ethanol (3.0 mL), and then lithium borohydride (3.0 mol / L THF solution, 0.33 mL, 0.98 mmol) was added to ice. Add under cold,
Stir at room temperature for 18 hours. Thereafter, lithium borohydride (3.0 mol / L THF solution, 0.33 mL, 0.98 mmol) was further added under ice cooling, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 50: 50) to obtain compound (IV-76) (yield 139 mg, yield) 67%) was obtained as a colorless oil.
Process 7
According to the same production method as for compound (IV-24), compound (IV-77) (yield 90.9 mg, yield) was obtained from compound (IV-76) (128 mg, 0.400 mmol) and methyl iodide (32 μL, 0.52 mmol). 68%) was obtained as a white solid.
Process 8
According to the same production method as for compound (I-1), compound (I-276) (yield 21.4) from compound (IV-77) (30.0 mg, 0.0898 mmol) and compound (V-28) (20.6 mg, 0.135 mmol) mg, 66% yield) was obtained as a white solid.

Example 277
Preparation of 2- [4- (benzyloxy) phenoxy] -2′-methoxy-3,3′-bipyridine (I-277) Compound (VIII-2) (60.0) was prepared by a method similar to that for compound (I-268). mg (0.272 mmol) and 4- (benzyloxy) phenol (II-50) (59.0 mg, 0.298 mmol) gave compound (I-277) (yield 24.0 mg, yield 23%) as a solid.

Example 278
4-{[4'-Methoxy- (3,3'-bipyridin) -2-yl] oxy} phenethyl propionate (I-278) Preparation of Compound (I-257) (40.1 mg, 0.124 mmol) in DMF (0.62 in TE) (21 μL, 0.15
mmol) and propionic acid chloride (13.8 mg, 0.149 mmol) were added and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (I-278) (Yield 29.1 mg, Yield 62%) as a colorless oil.

Example 279
Preparation of methyl 3- (4-{[4'-methoxy- (3,3'-bipyridin) -2-yl] oxy} phenyl) propionate (I-279)

Process 1
According to the same production method as for compound (IV-1), compound (III-1) (2.00 g, 10.4 mmol) and methyl
Compound (IV-78) (yield 2.14 g, 61% yield) was obtained as a colorless oil from 3- (4-hydroxyphenyl) propionate (II-51) (2.81 g, 15.6 mmol).
Process 2
According to the same production method as for compound (I-1), compound (I-279) (yield 14.9) was obtained from compound (IV-78) (50.0 mg, 0.149 mmol) and compound (V-28) (34.3 mg, 0.224 mmol). mg, yield 27%) was obtained as a white solid.

Example 280
Preparation of 2- (4-ethylphenoxy) -2'-methoxy-3,3'-bipyridine (I-280) By a method similar to that for compound (I-1), compound (IV-54) (20.0 mg, 0.0856 mmol) and 2-methoxy-3-pyridineboronic acid (V-26) (19.6 mg, 0.128 mmol) gave compound (I-280) (yield 15.3 mg, 58% yield) as a white solid.

Example 281
Preparation of 2- (4-ethylphenoxy) -3'-methoxy-3,4'-bipyridine (I-281) By a method similar to that for compound (I-1), compound (IV-54) (40.0 mg, 0.144 mmol) and 3-methoxy-4-pyridineboronic acid pinacol ester (V-27a) (44.0 mg, 0.187 mmol) gave compound (I-281) (13.5 mg, 31% yield) as a pale yellow solid. It was.

Example 282
Preparation of 5- [2- (4-ethylphenoxy) pyridin-3-yl] -4-methoxypyrimidine (I-282)

Process 1
Compound (IV-54) (1.00 g, 3.60 mmol) is dissolved in THF (3.0 mL) and iPrMgCl ・ LiCl (1.3 mol / L
(THF solution, 5.5 mL, 7.19 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, B (OiPr) ₃ (2.5 mL, 11 mmol) was added and stirred at room temperature for 1 hour. 1 mol / L hydrochloric acid (7.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain compound (VIa-5) (yield 851 mg, yield 97%) as a white solid.
Process 2
5-Iodo-4-methoxypyrimidine (VII-37) (50.5) by the same production method as for compound (I-36)
mg, 0.214 mmol) and compound (VIa-5) (40.0 mg, 0.165 mmol) to compound (I-282) (yield 27.1
mg, yield 54%) was obtained as a colorless oil.

Example 283
Preparation of 2- (4-ethylphenoxy) -5'-fluoro-4'-methoxy-3,3'-bipyridine (I-283) Compound (VII-34) (45.0 mg, 0.218 mmol), Compound (VIa- 5) (63.7 mg, 0.262 mmol), (A- ^ta Phos) ₂ PdCl ₂ (7.7 mg, 11 μmol) and cesium carbonate (142 mg, 0.437 mmol) in 1,4-dioxane (0.60 mL) / water (0.12 The mL) suspension was stirred at 70 ° C. for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with chloroform. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 70: 30) to give compound (I-283) (yield 9.4
mg, yield 13%) was obtained as a colorless oil.

Example 284
Production of 5′-chloro-2- (4-ethylphenoxy) -4′-methoxy-3,3′-bipyridine (I-284) Compound (VII-20) was prepared by the same production method as for compound (I-283). ) (50.0 mg, 0.225 mmol) and Compound (VIa-5) (65.6 mg, 0.270 mmol) to give Compound (I-284) (Yield 27.2 mg, Yield 36%) as a colorless oil.

Example 285
Preparation of 5'-bromo-2- (4-ethylphenoxy) -4'-methoxy-3,3'-bipyridine (I-285)

Process 1
4-pyridinol (M-40) (20.0 g, 210 mmol) was suspended in carbon tetrachloride (400 mL), NBS (77.0 g, 431 mmol) was added, and the mixture was stirred at room temperature for 24 hours in the dark. After evaporating the solvent under reduced pressure, the residue was suspended in acetone (400 mL) / methanol (120 mL) and stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration, suspended in acetonitrile (1.0 L), and stirred at room temperature for 1 hour. The solid was collected by filtration and dried under reduced pressure to give compound (M-41) (yield 46.0 g, yield 86%) as a white solid.
Process 2
Compound (M-41) (10.0 g, 39.5 mmol) was suspended in acetonitrile (50 mL), DIPEA (15 mL, 87 mmol) was added at room temperature, and phosphoryl chloride (7.4 mL, 79 mmol) was then ice-cooled. The mixture was added under stirring and stirred for 17 hours while heating under reflux. After allowing to cool, the reaction mixture was added dropwise to ice water, and sodium carbonate (11.6 g, 138
mmol). Thereafter, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a chloro product (yield 10.6 g, yield 99%) as a brown solid. The chloro compound (10.6 g, 39.1 mmol) was dissolved in THF (70 mL), sodium methoxide (28% methanol solution, 14 mL, 59 mmol) was added, and the mixture was stirred at 60 ° C. for 30 min. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give compound (VII-46) (yield 9.21 g,
Yield 88%) was obtained as a yellow solid.
Process 3
According to the same production method as for compound (I-283), compound (I-285) (yield 60.4) from compound (VII-46) (132 mg, 0.494 mmol) and compound (VIa-5) (100 mg, 0.411 mmol) mg, yield 38%) was obtained as a colorless oil.

Example 286
Preparation of 2- (4-ethylphenoxy) -4′-methoxy-5′-methyl-3,3′-bipyridine (I-286) By a method similar to that for compound (I-53), compound (I-285 ) (40.0 mg, 0.104 mmol) and methylboronic acid (31.1 mg, 0.519 mmol) to give compound (I-286) (17.3 mg, 52% yield) as a colorless oil.

Example 287
Preparation of 2 '-(4-ethylphenoxy) -4-methoxy- (3,3'-bipyridine) -5-carbaldehyde (I-287)

Process 1
Compound (VII-46) (100 mg, 0.369 mmol) was dissolved in THF (0.75 mL), iPrMgCl·LiCl (1.3 mol / L THF solution, 0.30 mL, 0.39 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, DMF (86 μL, 1.1 mmol) was added and stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 50: 50) to obtain compound (VII-47) (yield 59.8 mg, yield) 74%) was obtained as a white solid.
Process 2
According to the same production method as for compound (I-283), compound (I-287) (yield 22.3) from compound (VII-47) (59.6 mg, 0.276 mmol) and compound (VIa-5) (101 mg, 0.414 mmol) mg, 24% yield) was obtained as a pale yellow oil.

Example 288
Preparation of 5 '-(difluoromethyl) -2- (4-ethylphenoxy) -4'-methoxy-3,3'-bipyridine (I-288) Compound (I-287) (20.0 mg, 0.0600 mmol) in DCM (1.0 mL), Deoxo-Fluor (registered trademark) (22 μL, 0.12 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 50: 50) to obtain compound (I-288) (yield 18.4 mg, yield) 86%) was obtained as a colorless oil.

Example 289
Preparation of 2- (4-ethylphenoxy) -4'-methyl-3,3'-bipyridine (I-289) By a method similar to that for compound (I-1), compound (IV-54) (50.0 mg, 0.180 mmol) and 4-methylpyridine-3-boronic acid (V-25) (36.9 mg, 0.270 mmol) gave compound (I-289) (yield 1.9 mg, 7%) as a colorless oil.

Example 290
Production of 4′-chloro-2- (4-ethylphenoxy) -3,3′-bipyridine (I-290) 3-Bromo-4-chloropyridine (VII -48) (109 mg,
Compound (I-290) (yield 95.9 mg, yield 55%) was obtained as a colorless oil from 0.566 mmol) and compound (VIa-5) (165 mg, 0.680 mmol).

Example 291
Production of 4′-ethyl-2- (4-ethylphenoxy) -3,3′-bipyridine (I-291) According to the same production method as for compound (IV-63), compound (I-290) (40.0 mg, 0.129 mmol) and diethyl zinc (1.0 mol / L THF solution, 0.19 mL, 0.19 mmol) gave compound (I-291) (yield 32.6 mg, yield 83%) as a colorless oil.

Example 292
Preparation of 7- [2- (4-ethylphenoxy) pyridin-3-yl] pyrazolo [1,5-a] pyridine (I-292) By a method similar to that for compound (I-1), compound (IV- 54) (50.0 mg, 0.180 mmol) and pyrazolo [1,5-a] pyridine-7-boronic acid (V-49) (58.3 mg, 0.360 mmol) to compound (I-292) (yield 12.9 mg, yield) 23%) was obtained as a white solid.

Example 293
Preparation of 7- [2- (4-Ethylphenoxy) pyridin-3-yl] -6-methylimidazo [1,2-a] pyridine (I-293)

Process 1
Dissolve compound (VII-49) (200 mg, 1.07 mmol) in ethanol (5.0 mL), add sodium bicarbonate (135 mg, 1.60 mmol) and 2-chloroacetaldehyde (0.27 mL, 1.6 mmol), and heat to reflux. The mixture was stirred for 4 hours. After allowing to cool, the solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50 → 0: 100) to obtain compound (VII-50) (yield 213 mg, yield 94%) as a light brown solid. .
Process 2
According to the same production method as for compound (I-36), compound (I-293) (yield 30.6) from compound (VII-50) (41.7 mg, 0.197 mmol) and compound (VIa-5) (40.0 mg, 0.165 mmol) mg, yield 57%) was obtained as a colorless oil.

Example 294
Preparation of 2- [4- (difluoromethyl) phenoxy] -4'-methoxy-3,3'-bipyridine (I-294)

Process 1
DAST (0.71 mL, 5.4 mmol) was added to a DCM (15 mL) solution of the compound (IV-51) (500 mg, 1.80 mmol), and the mixture was stirred at room temperature for 18 hours. After adding water to the reaction solution, chloroform was added for extraction. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-79) (yield 408 mg, yield 76%).
Process 2
According to the same production method as for compound (I-1), compound (I-294) (yield 27.2) from compound (IV-79) (50.0 mg, 0.167 mmol) and compound (V-28) (38.2 mg, 0.250 mmol) mg, yield 50%) was obtained as a white solid.

Example 295
Preparation of 2- [4- (difluoromethyl) -3-methylphenoxy] -4'-methoxy-3,3'-bipyridine (I-295)

Process 1
According to the same production method as for compound (IV-1), compound (III-1) (6.35 g, 33.0 mmol) and 4-hydroxy-2-methylbenzaldehyde (II-52) (3.00 g, 22.0 mmol) IV-80) (yield 965 mg, 15% yield) was obtained as a white solid.
Process 2
According to the same production method as for compound (IV-79), compound (IV-81) (yield 655 mg, yield 69) was obtained from compound (IV-80) (771 mg, 2.64 mmol) and DAST (1.1 mL, 7.9 mmol). %) Was obtained as a white solid.
Process 3
According to the same production method as for compound (I-210), compound (I-295) (yield 25.0) from compound (IV-81) (30.0 mg, 0.167 mmol) and compound (V-28) (21.9 mg, 0.143 mmol) mg, yield 77%) was obtained as a white solid.

Example 296
Preparation of 2- [4- (difluoromethyl) -3-ethylphenoxy] -4'-methoxy-3,3'-bipyridine (I-296)

Process 1
Cesium carbonate (651 mg, 2.00 mmol) was added to a solution of compound (III-1) (281 mg, 1.60 mmol) and 2-ethyl-4-hydroxybenzaldehyde (II-53) (200 mg, 1.33 mmol) in NMP (3.0 mL). )
The mixture was stirred at 140 ° C. for 30 minutes under microwave irradiation. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 70: 30) to obtain compound (IV-82) (yield 299 mg,
Yield 73%) was obtained as a colorless oil.
Process 2
Compound (IV-83) (yield) from compound (IV-82) (108 mg, 0.353 mmol) and Deoxo-Fluor (0.20 mL, 1.1 mmol) by the same production method as compound (IV-79) 66.6 mg, yield 58%) was obtained as a colorless oil.
Process 3
According to the same production method as for compound (I-210), compound (I-296) (yield 10.1) was obtained from compound (IV-83) (55.1 mg, 0.168 mmol) and compound (V-28) (43.1 mg, 0.252 mmol). mg, yield 17%) was obtained as a white solid.

Example 297
Preparation of 2- [4- (1,1-difluoroethyl) phenoxy] -4'-methoxy-3,3'-bipyridine (I-297)

Process 1
Compound (IV-59) (5.46 g, 14.5 mmol), ethyl 2-bromo-2,2-difluoroacetate (2.95 g, 14.5 mmol), copper (powder, <75 μm, 99.9%, 2.12 g, 33.4 mmol) Of DMSO (70 mL) was stirred at 80 ° C. for 2 hours. The reaction mixture was allowed to cool, saturated aqueous potassium monohydrogen phosphate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-84).
Process 2
Compound (IV-84) was dissolved in methanol (40 mL), sodium borohydride (549 mg, 14.5 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (IV-85) [yield 1.17 g, yield 24% (2 steps)]. Obtained.
Process 3
Compound (IV-85) (1.15 g, 3.48 mmol) and pyridine (1.7 mL, 21 mmol) are dissolved in DCM (5.0 mL), and trifluoromethanesulfonic anhydride (1.8 mL, 10 mmol) is added under ice cooling. The mixture was further stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-86) (yield 1.25 g, yield 78%).
Process 4
Compound (IV-86) (1.18 g, 2.55 mmol) was dissolved in acetone (12 mL), sodium iodide (1.91 g, 12.8 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (IV-87) (yield 1.05 g, yield 93%).
Process 5
Compound (IV-87) (1.00 g, 2.27 mmol) was dissolved in THF (2.5 mL), tributyltin hydride (3.0 mL, 11 mmol) was added, and the mixture was stirred at 60 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (IV-88) (yield 75 mg, 11%) as a colorless oil. Obtained.
Process 6
Compound (IV-88) (22.0 mg, 0.0700 mmol), Compound (V-28) (16.1 mg, 0.105 mmol), (A- ^ta Phos) ₂ PdCl ₂ (2.5 mg, 0.004 mmol) and cesium carbonate (45.6 mg , 0.140 mmol) was suspended in a mixed solution of n-butanol (1.0 mL) / water (0.1 mL) and stirred at 120 ° C. for 20 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (n-
Purification with hexane: ethyl acetate gave Compound (I-297) (17.0 mg, 71% yield) as a white solid.

Example 298
Preparation of 2- [4- (1,1-difluoroethyl) phenoxy] -2′-methoxy-3,3′-bipyridine (I-298) Compound (IV) was prepared by a method similar to that for compound (I-1). -88) (40.0 mg, 0.127 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (29.2 mg, 0.191 mmol) to give compound (I-298) (yield 37.0 mg, yield 85%) Obtained as a colorless oil.

Example 299
Preparation of 2- [4- (1,1-difluoroethyl) phenoxy] -4′-methyl-3,3′-bipyridine (I-299) Compound (IV) was prepared by a method similar to that for compound (I-1). -88) (40.0 mg, 0.127 mmol) and 4-methylpyridine-3-boronic acid (V-25) (26.2 mg, 0.191 mmol) to give compound (I-299) (yield 13.7 mg, yield 33%) Obtained as a colorless oil.

Example 300
Preparation of 5'-chloro-2- [4- (1,1-difluoroethyl) phenoxy] -4'-methoxy-3,3'-bipyridine (I-300)

Process 1
IPrMgBr · LiCl (1.3 mol / L THF solution, 2.00 mL, 2.60 mmol) was added to a THF (4.0 mL) solution of the compound (IV-88) (600 mg, 1.90 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, triisopropyl borate (1.32 mL, 5.69 mmol) was added under ice-cooling and stirred for 10 minutes. Add 1 mol / L hydrochloric acid,
Extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain Compound (VIa-6) (Yield 352 mg, Yield 66%).
Process 2
According to the same production method as for compound (I-36), compound (Ia-300) (yield 24.5) from compound (VIa-6) (40.0 mg, 0.180 mmol) and compound (VII-20) (60.2 mg, 0.216 mmol) mg, yield 36%) was obtained as a colorless oil.

Example 301
Production of 2- [4- (1,1-difluoroethyl) phenoxy] -5'-fluoro-4'-methoxy-3,3'-bipyridine (I-301) Production method similar to compound (I-36) From compound (VIa-6) (50.0 mg, 0.243 mmol) and compound (VII-34) (74.5 mg, 0.267 mmol) to compound (I-301) (yield 45.8 mg, yield 52%) as a colorless oil Got as.

Example 302
Preparation of 2- [4- (1,1-difluoroethyl) -2-fluorophenoxy] -4'-methoxy-3,3'-bipyridine (I-302)

Process 1
Compound (III-8) (200 mg, 1.14 mmol) and compound (II-54) (193 mg, 1.25 mmol) are dissolved in NMP (2.0 mL), cesium carbonate (555 mg, 1.71 mmol) is added, and Under wave irradiation, 120
Stir at 30 ° C. for 30 minutes. The reaction mixture was cooled, water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (IV-89) (yield 192 mg, yield 55%).
Process 2
Compound (IV-89) (168 mg, 0.542 mmol) was dissolved in THF (1.0 mL), Deoxo-Fluor (registered trademark) (1.50 mL, 8.13 mmol) was added, and the mixture was stirred at 70 ° C. for 36 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (IV-90) (yield 99 mg, yield 55%).
Process 3
According to the same production method as for compound (I-1), compound (IV-90) (45.0 mg, 0.135 mmol) and 4-methoxypyridine-3-boronic acid monohydrate (V-28) (31.1 mg, 0.203 mmol) gave compound (I-302) (yield 36.1 mg, yield 74%) as a white solid.

Example 303
Production of 2- [4- (1,1-difluoroethyl) -2-fluorophenoxy] -4'-methyl-3,3'-bipyridine (I-303) According to the same production method as compound (I-1) , Compound (IV-90) (45.0 mg, 0.135 mmol) and 4-methylpyridine-3-boronic acid (V-25) (27.8 mg, 0.203 mmol) to compound (I-303) (yield 25.2 mg, yield) 54%) was obtained as a colorless oil.

Example 304
Preparation of 2- [4- (1,1-difluoroethyl) -3-fluorophenoxy] -4'-methoxy-3,3'-bipyridine (I-304)

Process 1
According to the same production method as for compound (IV-89), compound (IV-91) (yield 330) was obtained from compound (III-8) (394 mg, 2.24 mmol) and compound (II-55) (230 mg, 1.49 mmol). mg, yield 71%).
Process 2
Compound (IV-92) (yield) from Compound (IV-91) (160 mg, 0.516 mmol) and Deoxo-Fluor (0.951 mL, 5.16 mmol) by the same production method as Compound (IV-90) 98 mg, 57% yield).
Process 3
According to the same production method as for compound (I-1), compound (IV-92) (45.0 mg, 0.135 mmol) and 4-methoxypyridine-3-boronic acid monohydrate (V-28) (31.1 mg, 0.203 mmol) gave compound (I-304) (yield 36.1 mg, yield 74%) as a white solid.

Example 305
Production of 2- [4- (1,1-difluoroethyl) -3-fluorophenoxy] -4'-methyl-3,3'-bipyridine (I-305) According to the same production method as compound (I-1) Compound (IV-92) (45.0 mg, 0.135 mmol) and 4-methylpyridine-3-boronic acid (V-25) (27.8 mg, 0.203 mmol) to compound (I-305) (yield 27.1 mg, yield) 58%) was obtained as a colorless oil.

Example 306
Production of 4'-methyl-2- [4- (1,1,2-trifluoroethyl) phenoxy] -3,3'-bipyridine (I-306)

Process 1
Compound (IV-85) (300 mg, 0.909 mmol) was dissolved in DCM (3.0 mL), DAST (180 μL, 1.36 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (IV-93) (yield 112 mg, yield 37%).
Process 2
Compound (IV-93) (50.0 mg, 0.151 mmol) and 4-methylpyridine-3-boronic acid (V-25) (30.9 mg, 0.226 mmol) were prepared by the same production method as for compound (I-1). (I-306) (Yield 19.3 mg, Yield 37%) was obtained as a colorless oil.

Example 307
Preparation of 7- {2- [4- (1,1-difluoroethyl) phenoxy] pyridin-3-yl} pyrazolo [1,5-a] pyridine (I-307) Preparation similar to compound (I-36) According to the method, compound (I-307) (yield 11.2) was obtained from compound (VIa-6) (60.0 mg, 0.215 mmol) and 7-iodopyrazolo [1,5-a] pyridine (VII-51) (63.0 mg, 0.258 mmol). mg, yield 15%) was obtained as a colorless oil.

Example 308
Preparation of 5- {2- [4- (1,1-difluoroethyl) phenoxy] pyridin-3-yl} quinoxaline (I-308) Compound (VIa-6) was prepared by a method similar to that for compound (I-36). ) (60.0 mg, 0.215 mmol) and 5-bromoquinoxaline (VII-2) (53.9 mg, 0.258 mmol) gave compound (I-308) (yield 9.6 mg, 12%) as a yellow oil.

Example 309
Preparation of 2- (2-methoxyphenyl) -3-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyrazine (I-309)

Process 1
According to the same production method as for compound (IV-1), compound (III-9) (500 mg, 3.36 mmol) and 6- (trifluoromethyl) pyridin-3-ol (II-1) (547 mg, 3.36 mmol) ) To give compound (IV-94) (yield 846 mg, 78% yield) as a white solid.
Process 2
According to the same production method as for compound (I-1), compound (IV-94) (50.0 mg, 0.181 mmol) and 2-methoxyphenylboronic acid (V-1) (35.8 mg, 0.236 mmol) were converted to compound (I- 309) (yield 62.0 mg, 98% yield) was obtained as a white solid.

Example 310
Preparation of 5- (2-methoxyphenyl) -4-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyrimidine (I-310)

Process 1
According to the same production method as for compound (IV-1), compound (III-10) (6.18 g, 25.7 mmol) and 6- (trifluoromethyl) pyridin-3-ol (II-1) (5.00 g, 30.8 mmol) ) To give compound (IV-95) (yield 7.40 g, yield 79%) as a white solid.
Process 2
According to the same production method as for compound (I-1), compound (I-95) (100 mg, 0.0272 mmol) and 2-methoxyphenylboronic acid (V-1) (49.7 mg, 0.327 mmol) were converted to compound (I- 310) (yield 78.7 mg, 83% yield) was obtained as a colorless oil.

Example 311
Preparation of 4- (2-methoxyphenyl) -3-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridazine (I-311)

Process 1
To a solution of 4,5-dichloropyridazinone (M-43) (100 mg, 0.606 mmol) in THF (3.5 mL) under an argon atmosphere, 1.0 mol / L 2-methoxyphenylmagnesium bromide (1.50 mL, 1.50 mmol) was added. In addition, the mixture was heated to reflux for 3 hours. An ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (M-44) (yield 130 mg, 91%) as a white solid.
Process 2
Compound (M-44) (130 mg, 0.549 mmol) was dissolved in DMF (1.0 mL), then 1.0 mol / L sodium hydroxide (1.4 mL, 1.40 mmol) and 10% Pd / C (10.0 mg, 7.7 wt) %) Were sequentially added, and the mixture was stirred under a hydrogen atmosphere (3 atm) for 18 hours. The reaction mixture was filtered through celite, hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (M-45) (yield 60.0 mg, yield 54%) as a white solid.
Process 3
The compound (M-45) (60.0 mg, 0.297 mmol) was dissolved in phosphorus oxychloride (1.0 mL, 1.5 mmol) and then heated to reflux for 1 hour. Ice and sodium bicarbonate were sequentially added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound (VIII-4) (yield 65.0 mg, yield 99%) as a yellow oil.
Process 4
Compound (VIII-4) (30.0 mg, 0.136 mmol) and 6-trifluoromethylpyridin-3-ol (II-1) (25.0 mg, 0.153 mmol) were dissolved in N, N-dimethylacetamide (0.5 mL) Thereafter, cesium carbonate (70.0 mg, 0.215 mmol) was added, and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-311) (yield 14.0 mg, yield 30%) as a yellow oil.

Example 312
Preparation of 4-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -5- (2-methoxyphenyl) pyrimidine (I-312)

Process 1
Compound (II-56) (5.00 g, 28.7 mmol), copper (powder, <75 μm, 99.9%, 7.58 g, 37.4 mmol)
And 2-bromo-2,2-difluoroethyl acetate (4.16 g, 66.1 mmol) was dissolved in DMSO (70 mL), and the mixture was stirred at 70 ° C. for 2 hours. The reaction mixture was allowed to cool, saturated aqueous potassium monohydrogen phosphate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (II-57) (yield 1.30 g, yield 21%).
Process 2
According to the same production method as for compound (IV-1), compound (IV-96) (yield 6.90) was obtained from compound (II-57) (5.05 g, 26.1 mmol) and compound (III-11) (5.15 g, 23.7 mmol). g, yield 78%).
Process 3
Compound (IV-96) (16.4 g, 43.8 mmol) was dissolved in methanol (80 mL), sodium borohydride (6.63 g, 175 mmol) was added, and the mixture was stirred at room temperature for 10 min. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (n-
Purification with hexane: ethyl acetate gave compound (IV-97) (yield 6.30 g, yield 43%).
Process 4
According to the same production method as for compound (I-80), compound (IV-98) (yield 7.40) was obtained from compound (IV-97) (6.30 g, 19.0 mmol) and trifluoromethanesulfonic anhydride (9.61 mL, 56.9 mmol). g,
Yield 84%) was obtained.
Process 5
According to the same production method as for compound (IV-12), compound (IV-99) (yield 6.70 g, yield) was obtained from compound (IV-98) (7.30 g, 15.7 mmol) and sodium iodide (11.8 g, 79.0 mmol). Rate 96%).
Process 6
Compound (IV-100) (yield 3.00) was prepared from compound (IV-99) (6.70 g, 15.2 mmol) and tributyltin hydride (13.2 g, 45.5 mmol) by the same production method as in step 3 of compound (I-82). g, yield 63%).
Process 7
According to the same production method as for compound (I-1), compound (IV-100) (45.0 mg, 0.142 mmol) and 2-methoxyphenylboronic acid (V-1) (32.4 mg, 0.214 mmol) were converted to compound (I- 312) (yield 45.0 mg, 92% yield) was obtained as a white solid.

Example 313
Preparation of 3- (2-methoxyphenyl) -N- [6- (trifluoromethyl) pyridin-3-yl] pyridin-2-amine (I-313)

Process 1
Compound (III-1) (500 mg, 2.60 mmol) and 6- (trifluoromethyl) pyridin-3-amine (IIb-1) (463 mg, 2.86 mmol) were dissolved in IPA (5.0 mL), and p- Toluenesulfonic acid monohydrate (494 mg, 2.60 mmol) was added, and the mixture was stirred at 160 ° C. for 2 hours under microwave irradiation. The reaction mixture was allowed to cool, diluted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 → 80: 20) to give compound (IV-101) (yield 188 mg, yield 23 %) Was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.80 (1H, dd, J = 5.0, 7.8 Hz), 7.25 (1H, br s), 7.65 (1H, d, J = 8.2 Hz), 7.83 (1H , dd, J = 1.8, 7.8 Hz), 8.22 (1H, dd, J = 1.8, 5.0 Hz), 8.53 (1H, dd, J = 2.7, 8.7 Hz), 8.78 (1H, d, J = 1.8 Hz) .
ESI-MS m / z: 318, 320 [M + H] ⁺ .
Process 2
According to the same production method as for compound (I-1), compound (I-313) (yield 32.4) from compound (IV-101) (40.0 mg, 0.126 mmol) and compound (V-1) (24.8 mg, 0.163 mmol) mg, yield 75%) was obtained as a pale yellow solid.

Example 314
Preparation of 2- (4-chlorophenoxy) -3- (naphthalen-1-yl) pyrazine (I-314)

Process 1
2,3-dichloropyrazine (III-9) (500 mg, 3.36 mmol) and 4-chlorophenol (II-17) (431 mg, 3.36 mmol) were dissolved in DMF (10 mL), and potassium carbonate (557 mg , 4.03 mmol), 90
Stir at 15 ° C. for 15 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 → 85: 15) to obtain compound (IV-102) (yield 809 mg, yield quantitative) as a white solid.
Process 2
According to the same production method as for compound (I-1), compound (IV-102) (50.0 mg, 0.207 mmol) and 1-naphthylboronic acid (V-51) (47.0 mg, 0.273 mmol) were converted to compound (I-314 ) (Yield 33.0 mg, Yield 48%) as a solid.

Example 315
Preparation of 2- (2-methoxyphenyl) -3-[(5,6,7,8-tetrahydronaphthalen-2-yl) oxy] pyrazine (I-315)

Process 1
According to the same production method as for compound (IV-102), compound (III-9) (500 mg, 3.36 mmol) and 5,6,7,8-tetrahydronaphthalen-2-ol (II-45) (497 mg, 3.36 mmol) to compound (IV-103) (
Yield 846 mg, 97% yield) was obtained as a colorless oil.
Process 2
By the same production method as for compound (I-1), compound (IV-103) (50.0 mg, 0.192 mmol) and 2-methoxyphenylboronic acid (V-1) (37.9 mg, 0.249 mmol) were converted to compound (I- 315) (yield 27.4 mg, 43% yield) as a colorless oil.

Example 316
2- (2-Methoxypyridin-3-yl) -3-[(5,6,7,8-tetrahydronaphthalen-2-yl) oxy]
Production of pyrazine (I-316) By a production method similar to that of compound (I-1), compound (IV-103) (50.0 mg, 0.192 mmol) and 2-methoxypyridine-3-boronic acid (V-26) ( 38.1 mg, 0.249 mmol) gave compound (I-316) (yield 53.8 mg, 84% yield) as a colorless oil.

Example 317
2- (4-Methoxypyridin-3-yl) -3-[(5,6,7,8-tetrahydronaphthalen-2-yl) oxy]
Production of pyrazine (I-317) By a production method similar to that of compound (I-1), compound (IV-103) (50.0 mg, 0.192 mmol) and 4-methoxypyridine-3-boronic acid (V-28a) ( 38.1 mg, 0.249 mmol) to Compound (I-317) (Yield 12.9
mg, yield 20%) was obtained as a colorless oil.

Example 318
Preparation of 2- [4- (benzyloxy) phenoxy] -3- (2-methoxypyridin-3-yl) pyrazine (I-318)

Process 1
2,3-dichloropyrazine (III-9) (925 mg, 6.21 mmol), 2-methoxypyridine-3-boronic acid (V-26) (1.23 g, 8.07 mmol), (A- ^ta Phos) ₂ PdCl ₂ (221 mg, 0.312 mmol) and cesium carbonate (4.05 g, 12.4 mmol) were dissolved in 1,4-dioxane (30 mL) and water (6 mL), and the mixture was stirred at 90 ° C. for 1.5 hours. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and filtered, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain Compound (VIII-5) (844 mg, yield 61%) as an oil.
Process 2
Compound (VIII-5) (65.0 mg, 0.293 mmol) and 4-benzyloxyphenol (II-50) (64.0 mg, 0.323 mmol) were dissolved in NMP (1.0 mL), and cesium carbonate (115 mg, 0.383 mmol) And stirred at 180 ° C. for 5 hours. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to obtain compound (I-318) (yield 18.0 mg, yield 16%). Obtained as a solid.

Example 319
Preparation of 4- (4-chlorophenoxy) -5- (2-methoxyphenyl) pyrimidine (I-319)

Process 1
According to the same production method as for compound (IV-1), compound (IV-104) from compound (III-10) (400 mg, 1.66 mmol) and 4-chlorophenol (II-17) (257 mg, 2.00 mmol) (Yield 360 mg, Yield 65%)
Was obtained as a white solid.
Process 2
By the same production method as for compound (I-1), compound (IV-104) (48.9 mg, 0.147 mmol) and 2-methoxyphenylboronic acid (V-1) (26.8 mg, 0.175 mmol) were converted to compound (I- 319) (Yield 50.3 mg,
(Quantitative) was obtained as a colorless oil.

Example 320
Preparation of 4- (4-isopropylphenoxy) -5- (2-methoxyphenyl) pyrimidine (I-320)

Process 1
According to the same production method as for compound (IV-1), compound (IV-105) was prepared from compound (III-10) (400 mg, 1.66 mmol) and 4-isopropylphenol (II-35) (272 mg, 2.00 mmol). (Yield 312 mg, Yield
55%) was obtained as a colorless oil.
Process 2
In the same manner as in compound (I-1), compound (IV-105) (50.0 mg, 0.147 mmol) and 2-methoxyphenylboronic acid (V-1) (26.8 mg, 0.175 mmol) were converted to compound (I- 320) (Yield 51.3 mg,
Yield quantitative) was obtained as a colorless oil.

Example 321
Preparation of 5- (2-methoxyphenyl) -4- [4- (trifluoromethyl) phenoxy] pyrimidine (I-321)

Process 1
According to the same production method as for compound (IV-1), compound (III-10) (1.00 g, 4.16 mmol) and 4- (trifluoromethyl) phenol (II-18) (909 mg, 4.99 mmol) IV-106) (yield 1.20 g, yield 79%) was obtained as a white solid.
Process 2
According to the same production method as for compound (I-1), compound (IV-106) (30.0 mg, 0.0838 mmol) and 2-
Compound (I-321) (yield 36.0 mg, quantitative yield) was obtained as a colorless oil from methoxyphenylboronic acid (V-1) (18.7 mg, 0.123 mmol).

Example 322
Production of 4- [4- (difluoromethyl) phenoxy] -5- (2-methoxyphenyl) pyrimidine (I-322)

Process 1
Compound (III-10) (1.80 g, 7.49 mmol) and compound (II-30) (0.914 g, 7.49 mmol) were dissolved in DMSO (3.0 mL), cesium carbonate (407 mg, 1.25 mmol) was added, and The mixture was stirred at 80 ° C. for 30 minutes under wave irradiation. After extraction with ethyl acetate and water, the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (IV-107) (
Yield 1.35 g, 55% yield) was obtained as a yellow solid.
Process 2
Compound (IV-107) (1.30 g, 3.99 mmol) was dissolved in DCM (10 mL), DAST (1.58 mL, 12.0 mmol) was added, and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-108) (yield 1.21 g, yield 87%).
Process 3
According to the same production method as for compound (I-1), compound (I-108) (40.0 mg, 0.115 mmol) and 2-methoxyphenylboronic acid (V-1) (26.2 mg, 0.172 mmol) were converted to compound (I- 322) (yield 21.0 mg, yield 56%) was obtained as a colorless oil.

Example 323
Preparation of 4- [4- (difluoromethyl) -3-methylphenoxy] -5- (2-methoxyphenyl) pyrimidine (I-323)

Process 1
According to the same production method as for compound (IV-107), compound (IV-109) (yield 1.29) was obtained from compound (III-10) (1.32 g, 5.49 mmol) and compound (II-52) (0.897 g, 6.59 mmol). g, yield 69%). Process 2
Compound (IV-110) (yield 580 mg, yield 44) was prepared from compound (IV-109) (1.25 g, 3.68 mmol) and DAST (2.43 mL, 18.4 mmol) by the same production method as compound (IV-108). %).
Process 3
According to the same production method as for compound (I-1), compound (IV-110) (30.0 mg, 0.0830 mmol) and 2-
Compound (I-323) (yield 16.5 mg, yield 58%) was obtained as a white solid from methoxyphenylboronic acid (V-1) (18.9 mg, 0.124 mmol).

Example 324
Preparation of 4-{[6- (difluoromethyl) -5-methylpyridin-3-yl] oxy} -5- (2,3-dihydrobenzofuran-7-yl) pyrimidine (I-324)

Process 1
In the same manner as in compound (II-57), compound (II-5) (2.00 g, 10.6 mmol) and 2-bromo-2,2-difluoroethyl acetate (2.59 g, 12.7 mmol) were converted to compound (II- 58) (yield 1.18 g, 48% yield) was obtained as a colorless oil.
Process 2
According to the same production method as for compound (IV-1), compound (IV-111) (yield 670) was obtained from compound (II-58) (1.18 g, 5.10 mmol) and compound (III-11) (987 mg, 5.10 mmol). mg, yield 34%) was obtained as a colorless oil.
Process 3
According to the same production method as for compound (IV-17), compound (IV-111) (200 mg, 0.515 mmol) and magnesium chloride hexahydrate (241 mg, 1.19 mmol) were converted to compound (IV-112) (yield 120 mg, yield 74%) was obtained as a white solid.
Process 4
According to the same production method as for compound (I-1), compound (IV-112) (30.0 mg, 0.0949 mmol) and 2,3-dihydrobenzofuran-7-boronic acid (V-35) (32.4 mg, 0.214 mmol) To give compound (I-324) (yield 20.1 mg, yield 59%) as a colorless oil.

Example 325
Preparation of 5- (2,4-difluoro-5-methoxyphenyl) -4-{[6- (difluoromethyl) -5-methylpyridin-3-yl] oxy} pyrimidine (I-325) Compound (I-1 )) From compound (IV-112) (30.0 mg, 0.0949 mmol) and 2,4-difluoro-5-methoxyphenylboronic acid (V-41) (26.8 mg, 1.42 mmol). -325) (yield 20.1 mg, yield 56%) was obtained as a colorless oil.

Example 326
7- {4-[(2,3-Dihydro-1H-inden-5-yl) oxy] pyrimidin-5-yl} pyrazolo [1,5-a]
Production of pyridine (I-326)

Process 1
According to the same production method as for compound (IV-1), compound (III-10) (200 mg, 0.832 mmol) and 2,3-dihydro-1H-indene-5-ol (II-44) (134 mg, 0.998 mmol) gave compound (IV-113) (yield 157 mg, yield 56%) as a white solid.
Process 2
According to the same production method as for compound (VIa-2), compound (IV-113) (119 mg, 0.352 mmol), iPrMgBr-LiCl in 1.3 mol / L THF (0.325 mL, 4.22 mmol) and triisopropyl borate ( 245 μL, 1.06 mmol) gave compound (VIa-7) (yield 80.8 mg, yield 90%) as a yellow solid.
Process 3
According to the same production method as for compound (I-36), compound (VIa-7) (50.0 mg, 0.195 mmol) and 7-iodopyrazolo [1,5-a] pyridine (VII-51) (39.7 mg, 0.163 mmol) To give compound (I-326) (yield 36.0 mg, quantitative) as a colorless oil.

Example 327
Preparation of 5- (2,3-dihydrobenzofuran-7-yl) -4-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyrimidine (I-327) Same as compound (I-1) The compound (IV-95) (30.0 mg, 0.0817 mmol) and 2,3-dihydrobenzofuran-7-boronic acid (V-35) (16.1 mg, 0.0981 mmol) to compound (I-327) ( Yield 10.2 mg, 35% yield) was obtained as a colorless oil.

Example 328
Preparation of 5- (4,5-difluoro-2-methoxyphenyl) -4-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyrimidine (I-328) Same as compound (I-1) According to the production method of the compound (IV-95) (30.0 mg, 0.0817 mmol) and 4,5-difluoro-2-methoxyphenylboronic acid (V-40) (18.4 mg, 0.0981 mmol) to compound (I-328) (Yield 8.5 mg, 27% yield) was obtained as a colorless oil.

Example 329
Preparation of 5- (2,4-difluoro-5-methoxyphenyl) -4-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyrimidine (I-329) Same as compound (I-1) According to the production method of the compound (IV-95) (40.0 mg, 0.109 mmol) and 2,4-
Compound (I-329) (yield 35.1 mg, 84% yield) was obtained as a colorless oil from difluoro-5-methoxyphenylboronic acid (V-41) (26.6 mg, 0.142 mmol).

Example 330
Preparation of 5- (2-methoxypyridin-3-yl) -4- [4- (trifluoromethyl) phenoxy] pyrimidine (I-330) By a method similar to that for compound (I-1), compound (IV- 106) (30.0 mg, 0.0838 mmol) and 2-
The compound (I-330) (yield 26.5 mg, yield 90%) was obtained as a colorless oil from methoxypyridine-3-boronic acid (V-26) (18.8 mg, 0.123 mmol).

Example 331
Preparation of 5- (5-chloro-4-methoxypyridin-3-yl) -4- [4- (trifluoromethyl) phenoxy] pyrimidine (I-331)

Process 1
According to the same production method as for compound (VIa-2), compound (IV-106) (200 mg, 0.515 mmol), iPrMgBr-LiCl in 1.3 mol / L THF (504 μL, 0.655 mmol) and triisopropyl borate ( 380 μL, 1.64 mmol) gave compound (VIa-8) (yield 107 mg, 69% yield) as a pale yellow solid.
Process 2
According to the same production method as for compound (I-36), compound (VIa-8) (50.0 mg, 0.225 mmol) and 3-bromo-5-chloro-4-methoxypyridine (VII-20) (77.0 mg, 0.270 mmol) ) To compound (I-331) (
Yield 6.3 mg, 7% yield) was obtained as a colorless oil.

Example 332
Production of 7- {4- [4- (trifluoromethyl) phenoxy] pyrimidin-5-yl} pyrazolo [1,5-a] pyridine (I-332) By the production method similar to that of Compound (I-36), Compound (I-332) (yield 1.30 g, yield) from compound (VIa-8) (4.45 g, 15.7 mmol) and 7-iodopyrazolo [1,5-a] pyridine (VII-51) (3.82 g, 15.7 mmol) Yield 23%) as a white solid.

Example 333
Preparation of 7- {4- [4- (1,1-Difluoroethyl) phenoxy] pyrimidin-5-yl} pyrazolo [1,5-a] pyridine (I-333)

Process 1
Compound (IV-114) was prepared from Compound (III-11) (10.0 g, 51.7 mmol) and 4-iodophenol (II-38) (13.7 g, 62.0 mmol) by the same production method as for Compound (IV-1). (Yield 15.5 g, Yield 80%)
Got.
Process 2
Compound (IV-114) (15.0 g, 39.7 mmol), ethyl 2-bromo-2,2-difluoroacetate (8.61 g, 39.7 mmol) and copper (powder, <75 μm, 99.9%, 5.75 g, 91.0 mmol) Was dissolved in DMSO (50 mL) and stirred at 70 ° C. for 12 hours. The reaction mixture was allowed to cool, saturated aqueous potassium monohydrogen phosphate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-115).
Process 3
Compound (IV-115) was dissolved in THF (10 mL), sodium borohydride (1.21 g, 31.9 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (IV-116) [yield 905 mg, yield 23% (2 steps)]. Obtained.
Process 4
Compound (IV-116) (900 mg, 2.72 mmol) and pyridine (1.76 mL, 21.7 mmol) are dissolved in DCM (5.0 mL), and trifluoromethanesulfonic anhydride (1.84 mL, 10.9 mmol) is added under ice cooling. The mixture was further stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-117) (yield 682 mg, yield 54%).
Process 5
Compound (IV-117) (682 mg, 1.47 mmol) was dissolved in acetone (3.0 mL), sodium iodide (1.10 g, 7.36 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-118) (yield 440 mg, yield 68%).
Process 6
Compound (IV-118) (435 mg, 0.986 mmol) was dissolved in THF (0.40 mL), tributyltin hydride (1.32 mL, 4.93 mmol) was added, and the mixture was stirred at 70 ° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (IV-119) (yield 265 mg, 85%) as a colorless oil. Obtained.
Process 7
According to the same production method as for compound (I-1), compound (IV-119) (50.0 mg, 0.159 mmol) and pyrazolo [1,5-a] pyridine-7-boronic acid (V-49) (51.4 mg, 0.317 mmol) gave compound (I-333) (yield 13.0 mg, yield 23%) as a colorless oil.

Example 334
Preparation of 4-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -5- (2,4-difluoro-5-methoxyphenyl) pyrimidine (I-334) Compound (I-1 ), The compound (IV-100) (40.0 mg, 0.127 mmol) and 2,4-difluoro-5-methoxyphenylboronic acid (V-41) (30.9 mg, 0.165 mmol) to compound (I -334) (yield 41.2 mg, yield 86%) was obtained as a white solid.

Example 335
Preparation of 4-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -5- (2,3-dihydrobenzofuran-7-yl) pyrimidine (I-335) Compound (I-1 ) From compound (IV-100) (45.0 mg, 0.142 mmol) and 2,3-dihydrobenzofuran-7-boronic acid (V-35) (35.0 mg, 0.214 mmol). 335) (Yield
39.1 mg, yield 77%) was obtained as a white solid.

Example 336
Preparation of 4-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -5- (4,5-difluoro-2-methoxyphenyl) pyrimidine (I-336) Compound (I-1 ), The compound (IV-100) (40.0 mg, 0.127 mmol) and 4,5-difluoro-2-methoxyphenylboronic acid (V-40) (30.9 mg, 0.165 mmol) to compound (I -336) (Yield 37.1 mg, Yield 77%) was obtained as a white solid.

Reference Example 337
Preparation of 5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} -pyrimidin-2-amine (I-337) According to the same production method as for compound (I-1), compound (IV- 28) Compound (I-337) (452 mg, 82% yield) was obtained as a white solid from (500 mg, 1.87 mmol) and 2-methoxyphenylboronic acid (V-1) (341 mg, 2.25 mmol). It was.

Example 338
Production of 2-chloro-5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyrimidine (I-338) According to the same production method as for compound (IV-29), compound (I-337 ) (136 mg, 0.462 mmol), zinc chloride (II) (107 mg, 0.786 mmol) and sodium nitrite (54.2 mg, 0.786 mmol) to give compound (I-338) (yield 55.0 mg, 38% yield). Obtained as a white solid.

Example 339
Preparation of N-benzyl-5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} -N-methylpyrimidin-2-amine (I-339) Compound (I-338) (23.0 mg, 0.0733 mmol) was dissolved in DMF (1 mL), and N-methyl-1-phenylmethanamine (26.7 mg, 0.220 mmol) and potassium carbonate (50.7 mg, 0.367 mmol) were added.
Stir at 18 ° C. for 18 hours. Water was added to stop the reaction, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (I-339) (yield 15.6 mg, yield 53%) as a colorless oil.

Example 340
5-{[3- (2,3-Dihydrobenzofuran-7-yl) pyridin-2-yl] oxy} -N-ethyl-N-methylpyrimidin-2-amine (I-340) Preparation Compound (I- In the same manner as in 1), compound (I-31) (19.0 mg, 0.0615 mmol) and 2,3-dihydrobenzofuran-7-boronic acid (V-35) (15.1 mg, 0.0922 mmol) were converted to compound (I -340) (yield 21.3 mg, yield 99%) was obtained as a colorless oil.

Example 341
Preparation of 2- [4- (trifluoromethyl) phenoxy] -3- (1,3,5-trimethyl-1H-pyrazol-4-yl) pyridine (I-341) Preparation similar to compound (I-1) According to the method, compound (IV-39) (30.0 mg, 0.0943 mmol) and 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (V-52) (26.7 mg, 0.113 mmol) I-341) (yield 10.1 mg, 31% yield) was obtained as a white solid.

Example 342
Production of 2,4-dimethyl-5- {2- [4- (trifluoromethyl) phenoxy] pyridin-3-yl} thiazole (I-342) By a production method similar to that of compound (I-1), compound ( IV-39) (30.0 mg, 0.0943 mmol) and 2,4-dimethylthiazole-5-boronic acid pinacol ester (V-53) (27.1 mg, 0.113 mmol) to compound (I-342) (yield 25.5 mg, yield) Yield 77%) as a colorless oil.

Example 343
5- (2-{[6- (1,1-difluoro-2-methoxyethyl) pyridin-3-yl] oxy} pyridin-3-yl)-[1,2,4] triazolo [1,5-a Preparation of pyridine (I-343) By the same production method as compound (I-36), 5-bromo [1,2,4] triazolo [1,5-a] pyridine (VII-9) (28.7 mg, 0.145 mmol) and compound (VIa-3) (30.0 mg, 0.0968 mmol) gave compound (I-343) (yield 21.5 mg, yield 58%) as a colorless oil.

Example 344
Preparation of ethyl 2-[(5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) (methyl) amino] acetate (I-344)

Process 1
According to the same production method as for compound (I-47), compound (M-47) was prepared from 5-bromopyridin-2-amine (M-46) (5.00 g, 28.9 mmol) and methyl iodide (1.8 mL, 29 mmol). (Yield 1.19 g, 22% yield).
Process 2
Compound (M-47) (1.19 g, 6.36 mmol) was dissolved in DMF (21 mL), sodium hydride (229 mg, 9.54 mmol) was added, and the mixture was stirred for 20 minutes under ice cooling. Ethyl bromoacetate (1.4 mL, 13 mmol) was added under ice cooling, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. Thereafter, the temperature was raised to 70 ° C. and stirred for 16 hours. Water was added and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (M-48) (yield 644 mg, yield 37%).
Process 3
Compound (M-48) (640 mg, 2.34 mmol) was dissolved in DMF (8.0 mL), and bis (pinacolato) diboron (714 mg, 2.81 mmol), potassium acetate (689 mg, 7.02 mmol) and palladium acetate (26.3 mg, 0.117 mmol) was sequentially added, followed by stirring at 80 ° C. for 16 hours. The resulting solid was removed by filtration, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was dissolved in THF (12 mL) and water (12 mL), sodium perborate (1.30 g, 8.42 mmol) was added, and the mixture was stirred at room temperature for 13 hr. Saturated aqueous ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 50: 50) to obtain compound (II-59) (yield 357 mg, yield 73 %).
Process 4
According to the same production method as for compound (IV-1), compound (IV-120) (yield 82.0) was obtained from compound (III-1) (489 mg, 2.54 mmol) and compound (II-59) (356 mg, 1.69 mmol). mg, yield 13%).
Process 5
According to the same production method as for compound (I-1), compound (IV-120) (26.7 mg, 0.0729 mmol) and 2-
Compound (I-344) (yield 18.5 mg, yield 65%) was obtained as a pale yellow solid from methoxyphenylboronic acid (V-1) (14.5 mg, 0.0948 mmol).

Example 345
Production of 2-[(2,3-dihydro-1H-inden-5-yl) oxy] -3- (2-methoxyphenyl) pyridine (I-345) According to the production method similar to that of compound (I-1), Compound (I-345) (yield 115 mg, quantitative yield) was obtained from compound (IV-66) (100 mg, 0.345 mmol) and 2-methoxyphenylboronic acid (V-1) (79.0 mg, 0.518 mmol). Obtained as a colorless oil.

Example 346
2-{[6- (Trifluoromethyl) pyridin-3-yl] oxy} -3- (1,3,5-trimethyl-1H-pyrazol-4-yl) pyridine (I-346) Preparation Compound (I -1), the compound (IV-1) (50.0 mg, 0.157 mmol) and 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (V-52) (48.1 mg) , 0.204 mmol) gave compound (I-346) (21.2 mg, 39% yield) as a colorless oil.

Example 347
2,2-difluoro-2- (5-{[2'-methoxy- (3,3'-bipyridin) -2-yl] oxy} pyridine-2-
Yl) Preparation of ethanol (I-347) According to the same production method as for compound (I-1), compound (IV-10) (176 mg, 0.555 mmol) and 2-methoxypyridine-3-boronic acid (V-26 ) (127 mg, 0.833 mmol) to compound (I-347) (yield 182 mg,
Yield 95%) was obtained as a colorless oil.

Example 348
2-{[6- (1,1-Difluoro-2-methoxyethyl) pyridin-3-yl] oxy} -2'-methoxy-3,3
Production of '-bipyridine (I-348) By the same production method as for compound (I-145), compound (I-347) (30.0 mg, 0.834 mmol) and methyl iodide (5.7 μL, 0.092 mmol) I-348) (Yield 15.5 mg, Yield 50%) was obtained as a colorless oil.

Example 349
2-{[6- (1,1-Difluoro-2-methoxyethyl) pyridin-3-yl] oxy} -4'-methoxy-3,3
Production of '-bipyridine (I-349) According to the same production method as for compound (I-1), compound (IV-24) (50.0 mg, 0.145 mmol) and 4-methoxypyridine-3-boronic acid (V-28a ) (26.6 mg, 0.174 mmol) to compound (I-349) (yield 32.5
mg, yield 60%) was obtained as a colorless oil.

Example 350
2-({6- [1,1-difluoro-2- (1H-pyrazol-1-yl) ethyl] pyridin-3-yl} oxy) -3- (2-methoxyphenyl) pyridine (I-350) Production By the same production method as for compound (I-146), compound (I-80) (50.0 mg, 0.102 mmol) and 1H-
The compound (I-350) (yield 35.6 mg, yield 85%) was obtained as a colorless oil from pyrazole (69.4 mg, 1.02 mmol).

Example 351
2-({6- [1,1-difluoro-2- (1H-imidazol-1-yl) ethyl] pyridin-3-yl} oxy) -3- (2-methoxyphenyl) pyridine (I-351) Production By the same production method as for compound (I-146), compound (I-80) (50.0 mg, 0.102 mmol) and 1H-
Compound (I-351) (yield 33.1 mg, yield 79%) was obtained as a colorless oil from imidazole (69.4 mg, 1.02 mmol).

Reference Example 352
Preparation of 5-{[2'-methoxy- (3,3'-bipyridin) -2-yl] oxy} pyrimidin-2-amine (I-352) Compound by a method similar to that for compound (I-1) Compound (I-352) (yield 560 mg, from (IV-28) (500 mg, 1.87 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (372 mg, 2.43 mmol)
Yield quantitative) was obtained as a white solid.

Example 353
Production of 2-[(2-iodopyrimidin-5-yl) oxy] -2′-methoxy-3,3′-bipyridine (I-353) Compound (I) was prepared by the same production method as compound (I-191). -352) (285 mg, 0.965 mmol), isoamyl nitrite (0.39 mL, 2.90 mmol) and diiodomethane (0.78 mL, 9.65 mmol) to compound (I-353) (yield 263 mg, 67% yield) Obtained as an oil.

Example 354
Preparation of methyl 2-[(5-{[2'-methoxy- (3,3'-bipyridin) -2-yl] oxy} pyrimidin-2-yl) (methyl) amino] acetate (I-354) Compound ( I-353) (50.0 mg, 0.123 mmol) was dissolved in DMA (1.0 mL), DIPEA (100 μL, 0.581 mmol) and sarcosine methyl ester (30.0 mg, 0.215 mmol) were sequentially added, and the mixture was stirred at 100 ° C. overnight. . Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (I-354) (Yield 35.0 mg, Yield 75%) as a colorless oil.

Example 355
Preparation of 5'-chloro-2- [4- (difluoromethyl) phenoxy] -4'-methoxy-3,3'-bipyridine (I-355)

Process 1
By the same production method as compound (VIa-6), compound (IV-79) (500 mg, 1.67 mmol), iPrMgBr-LiCl (1.3 mol / L THF solution, 2.56 mL, 1.16 mmol) and triisopropyl borate ( 1.16 mL,
5.00 mmol) gave compound (VIa-9) (yield 442 mg, quantitative yield) as a pale yellow solid.
Process 2
According to the same production method as for compound (I-36), compound (Ia-355) (yield 41.6) was obtained from compound (VIa-9) (71.5 mg, 0.270 mmol) and compound (VII-20) (50.0 mg, 0.225 mmol). mg, yield 51%) was obtained as a colorless oil.

Example 356
Preparation of 2- [4- (difluoromethyl) phenoxy] -5′-fluoro-4′-methoxy-3,3′-bipyridine (I-356) By a method similar to that for compound (I-36), compound (I Compound (I-356) (yield 54.1 mg, yield 80%) was obtained as a colorless oil from VIa-9) (61.7 mg, 0.233 mmol) and compound (VII-34) (40.0 mg, 0.194 mmol).

Example 357
Production of 4- (4-chlorophenoxy) -5- (4-methoxypyridin-3-yl) pyrimidine (I-357) According to the same production method as for compound (I-1), compound (IV-104) (48.9 mg (0.147 mmol) and 4-methoxypyridine-3-boronic acid (V-28a) (44.9 mg, 0.294 mmol) to compound (I-357) (yield 36.1
mg, yield 78%) was obtained as a colorless oil.

Example 358
7- {4- [4- (Difluoromethyl) phenoxy] pyrimidin-5-yl} pyrazolo [1,5-a] pyridine (I-358) Preparation According to the same manufacturing method as for compound (I-1), Compound (I-358) (yield 46.0 mg) from (IV-108) (50.0 mg, 0.144 mmol) and pyrazolo [1,5-a] pyridine-7-boronic acid (V-49) (58.2 mg, 0.359 mmol) Yield 95%) as a white solid.

Example 359
Production of 4-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -5- (4-fluoro-2-methoxyphenyl) pyrimidine (I-359) Compound (I-1) and According to a similar production method, compound (I-359) from compound (IV-100) (45.0 mg, 0.142 mmol) and 4-fluoro-2-methoxyphenylboronic acid (V-12) (36.3 mg, 0.214 mmol) ( Yield 21.5 mg, 42% yield) was obtained as a colorless oil.

Example 360
Preparation of 4-{[6- (1,1-difluoroethyl) pyridin-3-yl] oxy} -5- (5-fluoro-2-methoxyphenyl) pyrimidine (I-360) Compound (I-1) By a similar production method, compound (I-360) (4-100 mg (45.0 mg, 0.142 mmol)) and 5-fluoro-2-methoxyphenylboronic acid (V-11) (36.3 mg, 0.214 mmol) ( Yield 48.8 mg, 95% yield) was obtained as a white solid.

Example 361
Preparation of 4-{[6- (1,1-difluoro-2-methoxyethyl) pyridin-3-yl] oxy} -5- (2-methoxypyridin-3-yl) pyrimidine (I-361)

Process 1
Compound (M-16) (14.1 g, 53.4 mmol) and ethyl bromodifluoroacetate (10 mL, 80 mmol)
Was dissolved in DMSO (76 mL), copper (powder, <75 μm, 99.9%, 7.80 g, 123 mmol) was added, and the mixture was stirred at 90 ° C. for 13 hr. The reaction solution was cooled and diluted with isopropyl acetate, and then a saturated potassium dihydrogen phosphate solution was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate, the organic layer was washed successively with water and saturated brine, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (M-49) (yield 12.3 g, yield 75%) as a colorless oil.
Process 2
Compound (M-49) (12.3 g, 40.0 mmol) was dissolved in methanol (80 mL), sodium borohydride (4.64 g, 120 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred for 1 hour, extracted with ethyl acetate, the organic layer was washed successively with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (M-50) (yield 10.8 g, yield 99%) as a colorless oil.
Process 3
Compound (M-50) (10.8 g, 40.0 mmol) was dissolved in DMF (133 mL), and 50% sodium hydride (2.11 g, 44.0 mmol) and methyl iodide (2.8 mL, 44 mmol) were added under ice cooling. Sequentially added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:
Purification with ethyl acetate) gave Compound (M-51) (yield 11.2 g, quantitative) as a colorless oil.
Process 4
Compound (M-51) (11.2 g, 40.1 mmol) was dissolved in methanol (134 mL), 20% palladium hydroxide / carbon (1.12 g, 10 w / w%) was added, and the mixture was added at room temperature under a hydrogen atmosphere at room temperature. Stir for hours. After filtration through celite, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (II-60) (yield 11.2 g, quantitative) as colorless. Obtained as an oil.
Process 5
According to the same production method as for compound (IV-1), compound (IV-121) (yield 134) was obtained from compound (III-10) (500 mg, 2.08 mmol) and compound (II-60) (375 mg, 1.98 mmol). mg, yield 17%) was obtained as a white solid.
Process 6
According to the same production method as for compound (I-1), compound (IV-121) (30.0 mg, 0.0763 mmol) and 2-
The compound (I-361) (yield 10.6 mg, 37% yield) was obtained as a colorless oil from methoxypyridine-3-boronic acid (V-26) (14.0 mg, 0.0915 mmol).

Example 362
Preparation of 5- (pyrazolo [1,5-a] pyridin-7-yl) -N- [4- (trifluoromethyl) phenyl] pyrimidin-4-amine (I-362)

Process 1
Compound (III-11) (120 mg, 0.620 mmol) and compound (IIb-2) (150 mg, 0.931 mmol) were dissolved in NMP (2.0 mL), and p-toluenesulfonic acid monohydrate (118 mg, 0.620 mmol) and add 2 at 60 ° C.
Stir for hours. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-122) (yield 100 mg, 51%).
Process 2
According to the same production method as for compound (I-1), compound (IV-122) (60.0 mg, 0.189 mmol) and pyrazolo [1,5-a] pyridine-7-boronic acid (V-49) (61.1 mg, 0.377 mmol) gave compound (I-362) (yield 49.0 mg, yield 73%) as a white solid.

Example 363
Preparation of 5- (2,4-difluoro-5-methoxyphenyl) -4-{[6- (difluoromethyl) pyridin-3-yl] oxy} pyrimidine (I-363)

Process 1
According to the same production method as for compound (IV-1), compound (IV-123) (yield 6.10) was obtained from compound (II-57) (5.00 g, 23.0 mmol) and compound (III-10) (5.03 g, 20.9 mmol). g, yield 69%) was obtained as a pale yellow solid.
Process 2
According to the same production method as for compound (IV-17), compound (IV-124) (yield 301) was obtained from compound (IV-123) (1.00 g, 2.37 mmol) and magnesium chloride hexahydrate (241 mg, 1.19 mmol). mg, Yield 36%)
Was obtained as a white solid.
Process 3
According to the same production method as for compound (I-1), compound (IV-124) (40.0 mg, 0.115 mmol) and 2,4-difluoro-5-methoxyphenylboronic acid (V-41) (25.8 mg, 0.138 mmol) ) To give Compound (I-363) (Yield 33.9 mg, Yield 81%) as a colorless oil.

Example 365
Preparation of 5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} -N, N-dimethylpyrimidin-2-amine (I-365)

Process 1
According to the same production method as for compound (IV-1), compound (III-1) (200 mg, 1.04 mmol) and 2-aminopyridin-5-ol (II-61) (137 mg, 1.25 mmol) IV-125) (yield 262 mg, 95% yield) was obtained as a light brown oil.
Process 2
According to the same production method as for compound (I-1), from compound (IV-125) (260 mg, 0.977 mmol) and 2-methoxyphenylboronic acid (V-1) (223 mg, 1.47 mmol), compound (I -364) (yield 210 mg,
Yield 73%) was obtained as a white solid.
Process 3
Compound (I-364) (20.0 mg, 0.0628 mmol) is dissolved in acetonitrile (1.0 mL), then formalin (56 μL, 0.68 mmol) and sodium triacetoxyborohydride (43.4 mg, 0.205 mmol) under ice-cooling And stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (I-365) (Yield 7.0 mg, Yield 32%) as a yellow solid.

Example 366
Preparation of 2-[(6-chloropyridin-3-yl) oxy]-[3- (4-fluoro-2-methoxyphenyl) pyridine (I-366)

Process 1
Compound (IV-125) (500 mg, 1.88 mmol) was dissolved in DCM (4.0 mL), 6 mol / L hydrochloric acid (407 μL, 24.4 mmol) was added, and then zinc (II) chloride ( 512 mg, 3.76 mmol) was added, and the mixture was stirred for 30 minutes under ice cooling. Further, sodium nitrite (259 mg, 3.76 mmol) was added, and the mixture was stirred at room temperature for 41 hours. The reaction solution was added to ice-cold water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound (IV-126) (yield 250 mg, 47%).
Process 2
According to the same production method as for compound (I-1), from compound (IV-126) (115 mg, 0.403 mmol) and 4-fluoro-2-methoxyphenylboronic acid (V-12) (75.0 mg, 0.444 mmol) Compound (I-366) (yield 115 mg, yield 86%) was obtained as an oil.

Example 367
Preparation of N-ethyl-5-{[3- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -N-methylpyridin-2-amine (I-367)

Compound (I-366) (50.0 mg, 0.151 mmol) was dissolved in toluene, N-methylethanamine (17.9 mg, 0.302 mmol), sodium t-butoxide (29.1 mg, 0.302 mmol), BINAP (9.4 mg, 0.0015 mmol) and Pd ₂ (dba) ₃ (6.9 mg, 0.0076 mmol) were added, and the mixture was stirred at 100 ° C. for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound (I-367) (yield 33.9 mg, yield 64%) as an oil.

Example 368
5-{[3- (4-Fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -N-methyl-N-propylpyridin-2-amine (I-368) Preparation Compound (I-367) According to the same production method as described above, compound (I-366) (39.7 mg, 0.120 mmol) and N-
Methyl-N-propylamine (24.1 μL, 17.6 mmol) to compound (I-368) (yield 22.6 mg, yield)
51%) was obtained as an oil.

Example 369
5-{[3- (4-Fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -N, N, 3-trimethylpyrimidin-2-amine (I-369)

Process 1
Compound (M-52) (1.00 g, 3.99 mmol) was dissolved in an aqueous dimethylamine solution (6.0 mL), and the mixture was stirred at 150 ° C. for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 → 80: 20) to obtain compound (M-53) (yield 843 mg, yield) 98%) was obtained as a colorless oil.
Process 2
Compound (M-53) (842 mg, 3.91 mmol) dissolved in benzyl alcohol (4.1 mL), copper iodide (74.5 mg, 0.391 mmol), 1,10-phenanthroline (141 mg, 0.782 mmol) and cesium carbonate (2.55 g, 7.82 mmol) was sequentially added, and the mixture was stirred at 120 ° C. for 23 hours. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 80: 20) to give compound (M-54 )
Process 3
The compound (M-54) was dissolved in ethanol (30 mL), 10% Pd / C (350 mg) was added, and the mixture was stirred at room temperature for 12 hours in a hydrogen atmosphere. The reaction mixture was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 80: 20 → 10: 90) to give compound (II- 62) [Yield 344 mg, 58% yield (2 steps)] was obtained as a white solid.
Process 4
Compound (II-62) (344 mg, 2.26 mmol) and compound (III-1) (652 mg, 3.39 mmol) were converted to DMSO (4.5
The mixture was dissolved in mL), cesium carbonate (1.47 g, 4.52 mmol) was added, and the mixture was stirred at 120 ° C. for 4 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 75: 25) to obtain compound (IV-127) (yield 708 mg, yield) (Quantitative) was obtained as a colorless oil.
Process 5
According to the same production method as for compound (I-1), from compound (IV-127) (50.0 mg, 0.162 mmol) and 4-fluoro-2-methoxyphenylboronic acid (V-12) (35.9 mg, 0.211 mmol) Compound (I-369) (yield 43.8 mg, yield 77%) was obtained as a colorless oil.

Example 370
Preparation of 2-{[6- (difluoromethoxy) pyridin-3-yl] oxy} -3- (2-methoxyphenyl) pyridine (I-370)

Process 1
The compound (M-55) (1.00 g, 5.75 mmol) was dissolved in acetonitrile (100 mL), sodium hydride (303 mg, 6.33 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Further, 2,2-difluoro-2- (fluorosulfonyl) acetic acid (1.13 g, 6.33 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction solution, and acetonitrile was distilled off under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 100: 0
→ 90:10) to give compound (M-56) (yield 810 mg, 63% yield) as a colorless oil.
Process 2
Compound (M-56) (800 mg, 3.57 mmol) is dissolved in THF (5.0 mL), then i-PrMgCl ・ LiCl (1.3 mol / L THF solution, 4.0 mL, 5.2 mmol) is added, and the mixture is stirred at room temperature for 1 hour. Stir. Triisopropyl borate (1.5 mL, 6.5 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. A 1 mol / L aqueous sodium hydroxide solution (5.0 mL) and hydrogen peroxide (5.0 mL) were added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. 2 in the reaction solution
mol / L Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 → 70: 30) to give compound (II-63) (yield 216 mg, yield) 38%) was obtained as a colorless oil.
Process 3
According to the same production method as for compound (IV-1), compound (IV-128) (yield 70.2) from compound (II-63) (200 mg, 1.24 mmol) and compound (III-1) (239 mg, 1.24 mmol) mg, yield 18%) was obtained as a colorless oil.
Process 4
According to the same production method as for compound (I-1), compound (IV-128) (20.0 mg, 0.0631 mmol) and 2-
Compound (I-370) (yield 5.1 mg, 23% yield) was obtained as a colorless oil from methoxyphenylboronic acid (V-1) (14.4 mg, 0.0946 mmol).

Example 371
Production of N-[(5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyridin-2-yl) methyl] aniline (I-371)

Compound (I-70) (30 mg, 0.097 mmol) was dissolved in DCM (0.60 mL), TEA (50 μL, 0.39 mmol)
And methanesulfonyl chloride (10 μL, 0.13 mmol) was added under ice cooling and stirred for 30 minutes. Aniline (20 μL, 0.22 mmol) was added and stirred at room temperature for 3 days. The reaction mixture was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 100: 0 → 50: 50) to give compound (I-371) (yield 11.1 mg, 30% yield) as a colorless oil Got as.

Example 374
Preparation of 6-methoxy-2 '-{[6- (trifluoromethyl) pyridin-3-yl] oxy} -2,3'-bipyridine (I-374)

Process 1
According to the same production method as for compound (I-36), compound (I-372) (yield 198) was obtained from compound (VII-52) (200 mg, 0.757 mmol) and compound (VIa-1) (279 mg, 0.984 mmol). mg, yield 62%) was obtained as a white solid.
Process 2
Compound (I-372) (182 mg, 0.429 mmol) was dissolved in methanol (2.0 mL) and THF (8.0 mL), 20% Pd (OH) _{2 /} C (18.2 mg) was added, and hydrogen was added using a balloon. Stir for 16 hours at room temperature under atmosphere. Filter through Celite and wash with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, chloroform: methanol = 100: 0 → 95: 5) to give compound (I-373) (yield 143 mg, yield quantitative) Was obtained as a white solid.
Process 3
Compound (I-373) (27.7 mg, 0.0831 mmol) was dissolved in DMF (1.0 mL) and potassium carbonate (10.3 mg
, 0.166 mmol) and methyl iodide (7.8 μL, 0.13 mmol) were sequentially added, and the mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 95: 5 → 40: 40) to obtain compound (I-374) (yield 9.1 mg Yield 32%) as a colorless oil.

Example 375
Preparation of 2-chloro-7- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) pyrazolo [1,5-a] pyridine (I-375)

Process 1
To a solution of compound (M-56) (200 mg, 1.31 mmol) in THF (2.6 mL), n-butyllithium (1.6 mol / L
n-hexane solution, 0.98 mL, 1.6 mmol) was added at -78 ° C, and the mixture was stirred at -78 ° C for 30 minutes. 1,2-Diiodoethane (443 mg, 1.57 mmol) was added to the reaction solution at -78 ° C, and the mixture was stirred at -78 ° C for 30 minutes. Then, after warming up slowly to room temperature, saturated ammonium chloride aqueous solution was added to the reaction liquid, and ethyl acetate extracted. The organic layer was washed successively with a saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 80: 20) to obtain compound (VII-53) (yield 258 mg, yield) 71%) was obtained as a beige solid.
Process 2
According to the same production method as for compound (I-36), compound (I-375) (yield 12.6) from compound (VII-53) (50.0 mg, 0.180 mmol) and compound (VIa-1) (56.1 mg, 0.198 mmol) mg, yield 18%) was obtained as a white solid.

Example 377
Preparation of 4-bromo-3-methyl-5- (2-{[6- (trifluoromethyl) pyridin-3-yl] oxy} pyridin-3-yl) isothiazole (I-377)

Process 1
In the same manner as in compound (I-36), 5-bromo-3-methylisothiazole (VII-54) (47
Compound (I-376) (yield 7.7 mg, yield 13%) was obtained as a white solid from .0 mg, 0.264 mmol) and compound (VIa-1) (50.0 mg, 0.176 mmol).
Process 2
Compound (I-376) (30.0 mg, 0.0890 mmol) was dissolved in acetic acid (1.0 mL), bromine (5.5 μL, 0.11 mmol) was added, and the mixture was stirred at 100 ° C. for 3 hr. The reaction mixture was cooled at room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-377) (yield 13.0 mg, yield 35%) as a white solid. It was.

Example 378
5-{[3- (4-Fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -2- (prop-1-en-2-yl) pyrimidine (I-378)

Compound (I-191) (100 mg, 0.236 mmol), isopropenyl boronic acid pinacol ester (67
μL, 0.35 mmol), (A- ^ta Phos) ₂ PdCl ₂ (8.4 mg, 0.012 mmol) and cesium carbonate (154 mg, 0.472 mmol) dissolved in 1,4-dioxane (1.0 mL) and water (0.20 mL) The mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. Furthermore, isopropenyl boronic acid pinacol ester (44 μL, 0.24 mmol) and cesium carbonate (76.9 mg, 0.236 mmol) were sequentially added to the reaction solution, and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (NH silica gel, n-
Purification was performed with hexane: ethyl acetate = 95: 5 → 70: 30) to obtain compound (I-378) (yield 61.4 mg, yield 77%) as a pale yellow oil.

Example 379
Preparation of 5-{[3- (4-Fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} -2- (1-methylcyclopropyl) pyrimidine (I-379)

Trimethyloxosulfonium iodide (76.4 mg, 0.347 mmol) was dissolved in THF (0.40 mL) and DMSO (0.60 mL), potassium tert-butoxide (38.9 mg, 0.347 mmol) was added, and the mixture was stirred at room temperature for 30 min. Thereafter, a THF (0.60 mL) solution of compound (I-378) (77.9 mg, 0.231 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Then, it heated up at 60 degreeC and stirred for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 → 85: 15)
Compound (I-379) (yield 28.7 mg, yield 35%) was obtained as a white solid.

Example 380
Preparation of 2- (benzyloxy) -5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyrimidine (I-380) benzyl alcohol (63.0 μL, 0.606 mmol) in DMF (1.0 mL) 60% sodium hydride (24.2 mg, 0.606 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Compound (I-338) (19.0 mg, 0.061 mmol) was added, and the mixture was stirred at 100 ° C. for 18 hours. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain compound (I-380) (yield 13.2 mg, yield 57%) as an oil.

Example 381
Preparation of N-benzyl-5-{[2'-methoxy- (3,3'-bipyridin) -2-yl] oxy} -N-methylpyrimidin-2-amine (I-381)

Process 1
5-Bromo-2-chloropyrimidine (M-57) (5.00 g, 25.8 mmol) was dissolved in IPA (10 mL), DIPEA (10 mL) and benzylmethylamine (4.50 mL, 34.9 mmol) were added, and 100 The mixture was stirred at ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 → 90: 10), and N-benzyl-5-bromo-N-methylpyrimidine-2-
The amine (M-58) (yield 7.15 g, 99% yield) was obtained as a white solid.
Process 2
Compound (M-59) (yield 980 mg, 89% yield) was obtained as a yellow oil from compound (M-58) (1.00 g, 3.60 mmol) by the same production method as compound (M-53) .
Process 3
Compound (II-64) (yield 340 mg, yield 49%) was obtained as a white solid from compound (M-59) (980 mg, 3.21 mmol) by the same production method as compound (M-54).
Process 4
According to the same production method as for compound (IV-1), compound (IV-129) (yield 580) was obtained from compound (III-1) (310 mg, 1.61 mmol) and compound (II-64) (340 mg, 1.58 mmol). mg, 99% yield) was obtained as a yellow oil.
Process 5
By the same production method as for compound (I-1), from compound (IV-129) (580 mg, 1.56 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (300 mg, 1.96 mmol), Compound (I-381) (Yield 600 mg,
(96% yield) was obtained as a colorless oil.

Example 384
Preparation of N-butyl-5-{[4'-methoxy- (3,3'-bipyridin) -2-yl] oxy} -N-methylpyrimidin-2-amine (I-384)

Process 1
According to the same production method as for compound (I-1), compound (IV-28) (1.00 g, 3.74 mmol) and 4-methoxypyridine-3-boronic acid monohydrate (V-28) (858 mg, 5.61 mmol) gave compound (I-382) (yield 626 mg, 57% yield) as a white solid.
Process 2
Compound (I-383) (yield 396 mg, 46% yield) was obtained from compound (I-382) (626 mg, 2.12 mmol) by the same production method as compound (I-191).
Process 3
Compound (I-384) (yield 41.2 mg) from compound (I-383) (100 mg, 0.246 mmol) and N-methyl-butylamine (0.29 mL, 2.5 mmol) by the same production method as compound (IV-30) Yield 46%) as a colorless oil.

Example 386
Preparation of ethyl 2-[(5-{[3- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] oxy} pyrimidin-2-yl) (methyl) amino] acetate (I-386)

Process 1
Compound (I-192) (100 mg, 0.251 mmol) was dissolved in THF (1.5 mL) and methanol (1.5 mL), 4 mol / L aqueous sodium hydroxide solution (0.75 mL) was added, and the mixture was stirred at room temperature overnight. 1 mol / L hydrochloric acid was added and washed with ethyl acetate. The aqueous layer was neutralized with 4 mol / L sodium hydroxide aqueous solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain compound (I-385) (yield 93.0 mg, yield 96%) as a white solid.
Process 2
Compound (I-385) (30.0 mg, 0.0780 mmol) was dissolved in ethanol (1.0 mL), thionyl chloride (0.20 mL) was added, and the mixture was heated to reflux overnight. The reaction solution was allowed to cool, and then the solvent was distilled off under reduced pressure.
The residue was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound (I-386) (Yield 18.0 mg, Yield 57%) as a colorless oil.

Example 387
Methyl 2-[(5-{[3- (2-methoxyphenyl) pyridin-2-yl] oxy} pyrimidin-2-yl) (
Methyl) amino] acetate (I-387)

Process 1
Compound (M-57) (30.0 g, 155 mmol) and sarcosine methyl ester (27.6 g, 310 mmol) were dissolved in DMF (155 mL), TEA (43 mL, 310 mmol) was added, and the mixture was heated at 100 ° C. overnight. Refluxed. The reaction mixture was allowed to cool, water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (M-60) (yield 36.6 g, yield 91%) as a colorless oil.
Process 2
Compound (M-60) (36.6 g, 141 mmol), dissolved in DMF (140 mL), bis (pinacolato) diboron (39.4 g, 155 mmol), cesium carbonate (91.9 g, 282 mmol) and palladium acetate ( 1.58 g, 7.05 mmol) was added, and the mixture was stirred at 80 ° C. overnight. The solid was removed by filtration, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was dissolved in THF (12 mL) and water (12 mL), sodium perborate (23.0 g, 282 mmol) was added, and the mixture was stirred at room temperature for 13 hr. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (II-65) (yield 27.7 g, yield quantitative) as a white solid. .
Process 3
According to the same production method as for compound (IV-1), compound (IV-130) (yield: 22.3 g) from compound (III-1) (26.9 g, 140 mmol) and compound (II-65) (27.7 g.140 mmol) g, yield 45%) was obtained as a white solid.
Process 4
According to the same production method as for compound (I-1), compound (IV-130) (40.0 mg, 0.113 mmol) and 2-methoxyphenylboronic acid (V-1) (25.8 mg, 0.170 mmol) were converted to compound (I- 387) (yield 43.9 mg, yield quantitative) was obtained as a colorless oil.

Example 388
Preparation of 2- [4- (1-ethoxy-2-methylpropan-2-yl) phenoxy] -2'-methoxy-3,3'-bipyridine (I-388)

Process 1
According to the same production method as for compound (I-145), compound (IV-131) (yield 83.5 mg, yield) was obtained from compound (IV-73) (200 mg, 0.621 mmol) and ethyl bromide (70 μL, 0.93 mmol). 38%) as a colorless oil.
Process 2
According to the same production method as for compound (I-1), compound (IV-131) (27.7 mg, 0.0771 mmol) and 2-
Compound (I-388) (27.3 mg, 94% yield) was obtained as a white solid from methoxypyridine-3-boronic acid (V-26) (17.7 mg, 0.116 mmol).

Example 390
Preparation of 2- (4-ethynylphenoxy) -2'-methoxy-3,3'-bipyridine (I-390)

Process 1
Compound (IV-51) (1.50 g, 5.39 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (1.07 g, 7.01 mmol) were prepared by the same production method as for compound (I-1). (I-389) (Yield 1.45 g,
Yield 88%) was obtained as a pale yellow solid.
Process 2
Compound (I-389) (1.00 g, 3.26 mmol) is dissolved in methanol (10 mL), and potassium carbonate (901 mg, 6.52 mmol) and Ohira-Bestman reagent (0.73 mL, 4.9 mmol) are sequentially added to the solution at room temperature. For 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 75: 25) to obtain compound (I-390) (yield 727 mg, yield) 74%) was obtained as a pale yellow oil.

Example 392
Preparation of 2- (4-ethyl-3-fluorophenoxy) -4'-methoxy-3,3'-bipyridine (I-392)

Process 1
Compound (III-8) (571 mg, 3.24 mmol) and 2-fluoro-4-hydroxyacetophenone (II-66) (500 mg, 3.24 mmol) were dissolved in NMP (5.0 mL), and then cesium carbonate (1.27 g , 3.89 mmol)
And stirred at 120 ° C. for 6 hours. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 0: 100 → 80: 20) to obtain compound (IV-132) (yield 715 mg, 71%) as a colorless oil. .
Process 2
Sodium borohydride (60.9 mg, 1.61 mmol) was added to a solution of compound (IV-132) (500 mg, 1.61 mmol) in THF (4.0 mL) and methanol (4.0 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction is complete
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 0: 100 → 50: 50) to obtain compound (IV-133) (yield 488 mg, yield 97%) as a white solid.
Process 3
According to the same production method as for compound (I-127), compound (IV-133) (400 mg, 1.28 mmol) and 4-methoxypyridine-3-boronic acid monohydrate (V-28) (294 mg, 1.92 mmol) gave compound (I-391) (yield 249 mg, 57% yield) as a colorless oil.
Process 4
Compound (I-391) (30.0 mg, 0.0881 mmol) was dissolved in TFA (1.0 mL), and then triethylsilane (1.0
mL, 6.3 mmol) was added, and the mixture was stirred at 50 ° C. overnight. The reaction solution was allowed to cool, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 0: 100
→ 30:70) to obtain Compound (I-392) (Yield 14.6 mg, Yield 51%) as a colorless oil.

Example 394
Preparation of 2- (4-ethyl-2-fluorophenoxy) -4'-methoxy-3,3'-bipyridine (I-394)

Process 1
Compound (III-8) (500 mg, 2.84 mmol), 3-fluoro-4-hydroxyacetophenone (II-67) (876 mg, 5.68 mmol), cesium carbonate (1.85 g, 5.68 mmol) in NMP (5 mL) And stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was cooled, 1 mol / L aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate / n-hexane. The organic layer was dried over anhydrous sodium sulfate and then filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain Compound (IV-134) (yield 465 mg, yield 53%).
Process 2
Compound (IV-135) (yield 438 mg, 95% yield) was obtained from compound (IV-134) (460 mg, 1.48 mmol) by the same production method as compound (IV-133).
Process 3
According to the same production method as for compound (I-127), compound (IV-135) (438 mg, 1.40 mmol) and 4-methoxypyridine-3-boronic acid monohydrate (V-28) (322 mg, 2.11 mmol) to Compound (I-393) (Yield
271 mg, 57% yield) was obtained as a white solid.
Process 4
Compound (I-393) (50.0 mg, 0.147 mmol) was dissolved in TFA (10 mL), triethylsilane (51.2 mg, 0.441 mmol) was added, and the mixture was stirred at 60 ° C. for 1 hr. Thereafter, the reaction solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to separate the layers. The organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (I-394) (yield 14.6 mg, yield).
31%) was obtained as a colorless oil.

Example 396
Preparation of 2- [4- (2-ethoxyethyl) phenoxy] -2'-methoxy-3,3'-bipyridine (I-396)

Process 1
Compound (IV-58) (1.00 g, 3.40 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (676 mg, 4.42 mmol) were prepared according to the same production method as for compound (I-1). (I-395) (Yield 944 mg,
Yield 86%) was obtained as an orange oil.
Process 2
According to the same production method as for compound (I-145), compound (I-396) (yield 9.8 mg, yield) was obtained from compound (I-395) (30.0 mg, 0.0931 mmol) and ethyl bromide (10 μL, 0.14 mmol). Yield 37%) as a colorless oil.

Example 397
4-{[2'-Methoxy- (3,3'-bipyridin) -2-yl] oxy} phenethyl acetate (I-397) Preparation of Compound (I-395) (30.0 mg, 0.0931 mmol) in DMF (1.0 mL) and then acetyl chloride (8.0
μL, 0.112 mmol) and DIPEA (24 μL, 0.140 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Thereafter, sodium hydride (5.4 mg, 0.112 mmol) was added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-397) (yield 4.9
mg, 15% yield) was obtained as a white solid.

Example 398
4-{[2'-Methoxy- (3,3'-bipyridin) -2-yl] oxy} phenethyl Preparation of dimethylcarbamate (I-398) Compound (I-397) was prepared by a method similar to that for compound (I-397). -395) (30.0 mg, 0.0931 mmol) and dimethylcarbamoyl chloride (10 μL, 0.11 mmol) gave compound (I-398) (20.5 mg, 56% yield) as a colorless oil.

Example 400
Preparation of 2- {4- [2- (1H-pyrazol-1-yl) ethyl] phenoxy} -2'-methoxy-3,3'-bipyridine (I-400)

Process 1
Compound (I-395) (100 mg, 0.310 mmol) is dissolved in DCM (1.5 mL), then TEA (0.13 mL, 0.93 mmol) and methanesulfonyl chloride (36 μL, 0.47 mmol) are added, and the mixture is stirred at room temperature for 10 minutes. Stir. Thereafter, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain Compound (I-399) (Yield 120 mg, Yield 97%).
Process 2
Compound (I-399) (40.0 mg, 0.0999 mmol) was dissolved in DMF (0.50 mL), and then pyrazole (10.2
mg, 0.150 mmol) and cesium carbonate (65.1 mg, 0.200 mmol) were added, and the mixture was stirred at room temperature for 19 hours. Thereafter, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 97: 3 → 60: 40) to obtain compound (I-400) (yield 21.4 mg, Yield 58%) was obtained as a colorless oil.

Example 401
2-Methoxy-2 '-{4- [2- (4-methyl-1H-pyrazol-1-yl) ethyl] phenoxy} -3,3'-bipyridine (I-401) Compound (I-400) Compound (I-401) (Yield 13.1 mg, Yield 34%) from Compound (I-399) (40.0 mg, 0.0999 mmol) and 4-methylpyrazole (12.3 mg, 0.150 mmol) Obtained as a colorless oil.

Example 404
2- {4- [2- (1-Ethyl-1H-pyrazol-4-yl) ethyl] phenoxy} -2'-methoxy-3,3'-bipyridine (I-404)

Process 1
Compound (I-390) (118 mg, 0.390 mmol) dissolved in DMF (1.0 mL), compound (M-61) (138 mg, 0.468 mmol), Pd (PPh ₃ ) ₄ (13.7 mg, 0.0195 mmol) , Copper iodide (7.4 mg, 0.039 mmol) and TEA (1.0 mL) were sequentially added, and the mixture was stirred at room temperature for 13 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-
Purification was performed with hexane: ethyl acetate = 97: 3 → 60: 40) to obtain compound (I-402) (yield 54.8 mg, yield 38%) as a white solid.
Process 2
Compound (I-402) (50.2 mg, 0.135 mmol) was dissolved in methanol (2.0 mL) and ethyl acetate (1.0 mL), 20% Pd (OH) _{2 /} C (10.0 mg) was added, and a balloon was used. The mixture was stirred at room temperature for 13 hours under a hydrogen atmosphere. The reaction mixture was filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 80: 20 → 0: 100) to give compound (I-403 ) (Yield 33.8 mg, Yield 67%) was obtained as a colorless oil.
Process 3
Compound (I-404) (yield 12.9 mg, yield) was obtained from compound (I-403) (19.9 mg, 0.0534 mmol) and ethyl bromide (6.0 μL, 0.080 mmol) by the same production method as for compound (I-145). 60%) was obtained as a colorless oil.

Example 407
Preparation of 2- [4- (but-3-in-1-yl) phenoxy] -2'-methoxy-3,3'-bipyridine (I-407)

Process 1
Lithium borohydride (3 mol / L) was added to a solution of compound (IV-78) (1.50 g, 4.46 mmol) in THF (15 mL).
(THF solution, 1.5 mL, 4.5 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 10 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 40: 60) to obtain compound (IV-136) (yield 1.40 g, yield). (Quantitative) was obtained as a colorless oil.
Process 2
Compound (IV-136) (500 mg, 1.62 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (323 mg, 2.11 mmol) were prepared using the same production method as for compound (I-1). (I-405) (Yield 495 mg,
Yield 91%) was obtained as a yellow solid.
Process 3
Compound (I-405) (420 mg, 1.25 mmol) was dissolved in DCM (3.0 mL), DMP (797 mg, 1.88 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, a saturated aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 60: 40) to obtain compound (I-406) (yield 193 mg, yield 46 %) As a colorless oil.
Process 4
Compound (I-406) (152 mg, 0.453 mmol) is dissolved in methanol (2.0 mL), potassium carbonate (125 mg, 0.906 mmol) and Ohira-Bestman reagent (0.10 mL, 0.680 mmol) are sequentially added at room temperature. For 4.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-407) (yield 142
mg, yield 95%) was obtained as a white solid.

Example 408
Preparation of 5- (4-{[2'-methoxy- (3,3'-bipyridin) -2-yl] oxy} phenethyl) -3-methylisoxazole (I-408)

Process 1
Compound (M-62) (50 μL, 0.81 mmol) was dissolved in DMF (2.0 mL) and NCS (130 mg, 0.976 mmol)
And stirred at room temperature for 17 hours. Water was added and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure to prepare the compound (M-63), ethanol (1.0 mL) was added to obtain an ethanol solution.
Process 2
Compound (I-407) (50.0 mg, 0.151 mmol) is dissolved in ethanol (1.0 mL), and TEA (63 μL, 0.45 mmol) and compound (M-63) in ethanol (1.0 mL, 0.81 mmol) are sequentially added. Plus 20 at room temperature
Stir for hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 97: 3 → 70: 30). (I-408) (Yield 21.8 mg, Yield 37%) was obtained as a colorless oil.

Example 409
Production of methyl 3- (4-{[2'-methoxy- (3,3'-bipyridin) -2-yl] oxy} phenyl) propionate (I-409) Production method similar to compound (I-1) From compound (IV-78) (50.0 mg, 0.149 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (34.3 mg, 0.224 mmol) to compound (I-409) (yield 47.4 mg, yield Yield 87%) as a white solid.

Example 411
Preparation of 5- (4-{[2'-methoxy- (3,3'-bipyridin) -2-yl] oxy} phenethyl) -3-methyl-1,2,4-oxadiazole (I-411)

Process 1
Compound (I-409) (2.60 g, 7.14 mmol) was dissolved in methanol (12 mL) and THF (12 mL), 2 mol / L aqueous sodium hydroxide solution (7.2 mL, 14 mmol) was added, and the mixture was stirred at room temperature for 30. Stir for minutes. 2 mol / L hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain compound (I-410) (yield 2.50 g, yield quantitative) as a white solid.
Process 2
Compound (I-410) (50.0 mg, 0.143 mmol) was dissolved in DMF (1.0 mL), DIPEA (0.10 mL, 0.57 mmol) and HATU (81.4 mg, 0.22 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. . Thereafter, N′-hydroxyacetimidamide (21.2 mg, 0.286 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was dissolved in DMF (1.0 mL), followed by stirring at 140 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40) to give compound (I-411) (yield 17.8 mg, yield) 32%) was obtained as a colorless oil.

Example 412
Preparation of 7- {2- [4- (2-ethoxyethyl) phenoxy] pyridin-3-yl} pyrazolo [1,5-a] pyridine (I-412)

Process 1
Compound (IV-137) (yield 286 mg, yield) was obtained from compound (IV-58) (300 mg, 1.02 mmol) and ethyl bromide (0.11 mL, 1.5 mmol) by the same production method as compound (I-145). 87%) as a colorless oil.
Process 2
According to the same production method as for compound (I-1), compound (IV-137) (30.0 mg, 0.0931 mmol) and pyrazolo [1,5-a] pyridine-7-boronic acid (V-49) (30.1 mg, 0.186 mmol) gave Compound (I-412) (Yield 3.0 mg, Yield 9%) as a white solid.

Example 413
Preparation of 7- {2- [4- (1,1-difluoro-2-methoxyethyl) phenoxy] pyridin-3-yl} pyrazolo [1,5-a] pyridine (I-413)

Process 1
According to the same production method as for compound (I-145), compound (IV-138) (yield 410 mg, yield) was obtained from compound (IV-85) (500 mg, 1.52 mmol) and methyl iodide (190 μL, 3.0 mmol). Rate 79%).
Process 2
According to the same production method as for compound (VIa-2), compound (IV-138) (209 mg, 0.607 mmol), iPrMgBr-LiCl in 1.3 mol / L THF (700 μL, 0.910 mmol) and triisopropyl borate ( 423 μL, 1.82 mmol) gave compound (VIa-10) (yield 188 mg, quantitative yield) as a yellow solid.
Process 3
According to the same production method as for compound (I-36), compound (VIa-10) (60.0 mg, 0.194 mmol) and 7-
Compound (I-413) (yield) from iodopyrazolo [1,5-a] pyridine (VII-51) (61.6 mg, 0.252 mmol)
28.0 mg, yield 38%) was obtained as a colorless oil.

Example 414
4-{[4'-Chloro- (3,3'-bipyridin) -2-yl] oxy} production of ethyl benzoate (I-414)

Process 1
Compound (IV-50) (1.50 g, 4.66 mmol), bis (pinacolato) diboron (2.36 g, 9.26 mmol), PdCl ₂ (dppf) -DCM (190 mg, 0.233 mmol) and potassium acetate (1.37 g, 14.0 mmol) ) In 1,4-dioxane (15 mL) was stirred at 100 ° C. for 18 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 70: 30) to give compound (VIb-1) (yield 749 mg, yield) 44%) was obtained as a pale yellow oil.
Process 2
According to the same production method as for compound (I-36), compound (I-414) (yield 127) was obtained from compound (VII-48) (141 mg, 0.733 mmol) and compound (VIb-1) (300 mg, 0.488 mmol). mg, yield 73%) was obtained as a colorless oil.

Example 415
4-{[4'-Ethoxy- (3,3'-bipyridin) -2-yl] oxy} production of ethyl benzoate (I-415)

Process 1
Sodium ethoxide (20% ethanol solution, 1.8 mL, 4.6 mmol) was added to a solution of compound (VII-48) (300 mg, 1.56 mmol) in THF (5.0 mL), and the mixture was stirred at 55 ° C. for 6 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 95: 5 → 50: 50) to obtain compound (VII-55) (yield 264 mg Yield 84%) as a yellow oil.
Process 2
Compound (VIb-1) (300 mg, 0.488 mmol), Compound (VII-55) (148 mg, 0.732 mmol), (A- ^ta Phos) ₂ PdCl ₂ (17.3 mg, 0.0244 mmol), and cesium fluoride ( 148 mg, 0.974 mmol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.30 mL), and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give Compound (I-415) (yield 162 mg, 91%) as a colorless oil. Obtained.

Example 416
Preparation of 4-{[4'-ethyl- (3,3'-bipyridin) -2-yl] oxy} ethyl benzoate (I-416) Compound (I-414) (39.1 mg, 0.110 mmol) in THF ( 0.50 mL) solution was added PdCl ₂ (dppf) -DCM (9.0 mg, 0.011 mmol) and diethylzinc (1.0 mol / L THF solution, 0.17 mL, 0.17 mmol).
Stir at 1 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (I-416) (yield 24.2 mg, yield).
63%) was obtained as a colorless oil.

Example 418
4-{[4'-Methoxy- (3,3'-bipyridin) -2-yl] oxy} preparation of isopropyl benzoate (I-418)

Process 1
Compound (I-245) (343 mg, 0.979 mmol) is dissolved in ethanol (2.0 mL) and THF (2.0 mL), 4 mol / L aqueous sodium hydroxide solution (0.49 mL, 1.96 mmol) is added, and the mixture is stirred at room temperature. Stir for hours.
5 mol / L hydrochloric acid (0.50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-417) (yield 250 mg, yield 79%) as a white solid. It was.
Process 2
Compound (I-417) (23.0 mg, 0.0710 mmol) in DMF (0.90 mL) solution, isopropyl alcohol (55 μL, 0.71 mmol), TEA (50 μL, 0.36 mmol), EDCI ・ HCl (20.5 mg, 0.107 mmol) ) And HOBt · H ₂ O (10.9 mg, 0.0710 mmol) were sequentially added, and the mixture was stirred at 30 ° C. for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (NH
Purification by silica gel, n-hexane: ethyl acetate = 95: 5 → 50: 50) gave Compound (I-418) (yield 1.7 mg, 7%) as a colorless oil.

Example 419
4-{[4'-Methyl- (3,3'-bipyridin) -2-yl] oxy} production of ethyl benzoate (I-419) Compound (IV) was prepared by the same production method as for compound (I-1). -50) (50.0 mg, 0.155 mmol) and 4-methylpyridine-3-boronic acid (V-25) (31.9 mg, 0.233 mmol) to give compound (I-419) (yield 11.3 mg, yield 22%) Obtained as a colorless oil.

Example 421
Preparation of 5- (4-{[4'-methyl- (3,3'-bipyridin) -2-yl] oxy} phenyl) -3-methyl-1,2,4-oxadiazole (I-421)

Process 1
Compound (I-420) (yield 200 mg, yield 74%) was obtained as a white solid from compound (I-419) (297 mg, 0.888 mmol) by the same production method as compound (I-417).
Process 2
According to the same production method as for compound (I-411), compound (I-420) (30.0 mg, 0.0979 mmol) and N
'-Hydroxyacetimidamide (14.5 mg, 0.196 mmol) to compound (I-421) (yield 2.5 mg,
Yield 7%) was obtained as a white solid.

Example 422
Production of 1- (4-{[4'-methyl- (3,3'-bipyridin) -2-yl] oxy} phenyl) ethanone (I-422) By a production method similar to that of compound (I-127), Compound (I-422) (yield 747 mg) from compound (IV-49) (1.00 g, 3.42 mmol) and 4-methylpyridine-3-boronic acid (V-25) (703 mg, 5.13 mmol)
72% yield) was obtained as a yellow solid.

Example 423
Preparation of 2-methyl-5- (4-{[4'-methyl- (3,3'-bipyridin) -2-yl] oxy} phenyl) oxazole (I-423)

To a solution of thallium acetate (56.4 mg, 0.148 mmol) in acetonitrile (0.50 mL) was added trifluoromethanesulfonic acid (39 μL, 0.44 mmol), and the mixture was stirred at room temperature for 15 minutes. A solution of compound (I-422) (30.0 mg, 0.0986 mmol) in acetonitrile (1.0 mL) was added to the reaction solution at 80 ° C., and the mixture was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-423) (yield
9.7 mg, 29% yield) was obtained as a white solid.

Example 424
Preparation of 1- (4-{[4'-Methyl- (3,3'-bipyridin) -2-yl] oxy} phenyl) butane-1,3-dione (I-424)

Sodium hydride (65.7 mg, 1.64 mmol) was added to a solution of compound (I-422) (100 mg, 0.329 mmol) in THF (1.5 mL) under ice cooling, and the mixture was stirred at room temperature for 15 minutes. Ethyl acetate (0.13 mL, 1.3 mmol) was added to the reaction solution at 45 ° C, and the mixture was stirred at 45 ° C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80: 20 → 20: 80) to obtain compound (I-424) (yield 50.7 mg, yield). 45%) was obtained as a white solid.

Example 425
Preparation of 3-methyl-5- (4-{[4'-methyl- (3,3'-bipyridin) -2-yl] oxy} phenyl) isoxazole (I-425)

To a suspension of hydroxylamine hydrochloride (44.0 mg, 0.630 mmol) in IPA (0.50 mL), TEA (9.0
μL, 0.065 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. TFA (10 μL, 0.13 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes. Compound (I-424) (20.0 mg, 0.0577 mmol) was added to the reaction mixture, and 60
The mixture was stirred at ° C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 95: 5 → 50: 50) to give compound (I-425) (yield 13.1 mg). Yield 66%) as a white solid.

Example 426
Preparation of 2- (4-iodophenoxy) -4'-methyl-3,3'-bipyridine (I-426)

Process 1
By the same production method as compound (I-127), from compound (III-8) (3.00 g, 17.0 mmol) and 4-methylpyridine-3-boronic acid (V-25) (3.96 g, 25.6 mmol), Compound (VIII-6) (yield 1.90 g, yield 59%) was obtained as a yellow oil.
Process 2
According to the same production method as for compound (IV-1), compound (I-426) was prepared from compound (VIII-6) (1.90 g, 10.1 mmol) and 4-iodophenol (II-38) (2.67 g, 12.1 mmol). (Yield 2.86 g, 73% yield) was obtained as a white solid.

Example 428
Preparation of 5-methyl-2- (4-{[4'-methyl- (3,3'-bipyridin) -2-yl] oxy} phenyl) thiazole (I-428)

Process 1
Compound (I-426) (1.70 g , 4.38 mmol), bis (pinacolato) diboron (358 mg, 0.438 mmol), PdCl 2 (dppf) · DCM (358 mg, 0.438 mmol) and potassium acetate (1.29 g, 13.1 mmol ) Was dissolved in 1,4-dioxane (10 mL) and stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain compound (I-427) (yield 1
.64 g, 96% yield) was obtained as a brown solid.
Process 2
Compound (I-427) (50.0 mg, 0.129 mmol), 2-bromo-5-methylthiazole (34.4 mg, 0.193
mmol), (A- ^ta Phos) ₂ PdCl ₂ (4.6 mg, 6.5 μmol) and 1,4-dioxane (1.0 mL) suspension of cesium carbonate (83.9 mg, 0.258 mmol) under microwave irradiation. Stir at 30 ° C. for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50 → 0: 100) to give compound (I-428) (yield 7.8 mg, yield) 17%) was obtained as a colorless oil.

Example 429
Production of 4′-methyl-2- [4- (pyrimidin-2-yl) phenoxy] -3,3′-bipyridine (I-429) Compound (I-428) was prepared by the same production method as for compound (I-428). 427) (50.0 mg, 0.129 mmol) and 2-
Compound (I-429) (yield 3.8 mg, 9% yield) was obtained as a colorless oil from bromopyrimidine (30.7 mg, 0.193 mmol).

Example 430
Preparation of 4'-methyl-2- [4- (pyridin-4-yl) phenoxy] -3,3'-bipyridine (I-430) Compound (I-427) (50.0 mg, 0.129 mmol), 4-iodo Pyridine (39.6 mg, 0.193 mmol), (A- ^ta Phos) ₂ PdCl ₂ (4.6 mg, 0.0064 mmol) and cesium fluoride (58.7 mg, 0.386 mmol) were added to 1,4-
The product was dissolved in dioxane (0.50 mL) and water (0.050 mL), and stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give compound (I-430) (yield
13.8 mg, yield 32%) was obtained as a colorless oil.

Example 431
Production of 4′-methyl-2- [4- (pyridin-2-yl) phenoxy] -3,3′-bipyridine (I-431) According to the same production method as for compound (I-430), compound (I- 427) (50.0 mg, 0.129 mmol) and 2-
Compound (I-431) (yield 5.1 mg, 12% yield) was obtained as a colorless oil from bromopyridine (30.5 mg, 0.193 mmol).

Example 432
Preparation of 4'-methyl-2- [4- (4-methyl-1H-pyrazol-1-yl) phenoxy] -3,3'-bipyridine (I-432)

To a solution of compound (I-426) (30.0 mg, 0.0773 mmol) in toluene (1.0 mL), 4-methylpyrazole (12.9 mg, 0.157 mmol), copper iodide (1.5 mg, 0.0079 mmol), (1S, 2S) -N, N'-dimethylcyclohexane-1,2-diamine (2.2 mg, 0.015 mmol) and potassium carbonate (32.0 mg, 0.232 mmol) were sequentially added, and the mixture was stirred at 150 ° C. for 30 minutes under microwave irradiation. Then add 4-
Methylpyrazole (12.9 mg, 0.157 mmol) and copper iodide (1.5 mg, 0.0079 mmol) were sequentially added, and the mixture was stirred at 160 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 95: 5 → 60: 40), and the compound ( I-432) (yield 3.4 mg, yield 13%) was obtained as a white solid.

Example 433
Preparation of 2- [4- (1H-pyrazol-1-yl) phenoxy] -4'-methyl-3,3'-bipyridine (I-433)

Compound (I-433) (yield 2.0 mg, yield 5) was prepared from compound (I-426) (50.0 mg, 0.129 mmol) and pyrazole (17.5 mg, 0.257 mmol) by the same production method as compound (I-432). %) As a colorless oil.

Example 434
Preparation of 2,2-difluoro-2- (4-{[2'-methoxy- (3,3'-bipyridin) -2-yl] oxy} phenyl) ethanol (I-434)

  By the same production method as compound (I-1), from compound (IV-85) (150 mg, 0.454 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (83.0 mg, 0.545 mmol), Compound (I-434) (yield 136 mg, yield 84%) was obtained as a colorless oil.

Example 435
Preparation of 2-methoxy-2 '-{[4- (trifluoromethyl) phenyl] thio} -3,3'-bipyridine (I-435)

Process 1
According to the same production method as for compound (IV-1), 4-trifluoromethylthiophenol (IIc-1) (184 μL, 1.36 mmol) and compound (III-8) (200 mg, 1.14 mmol) were converted to compound (IV- 139) (yield 325 mg, 86% yield) as a white solid.
Process 2
Compound (IV-139) (40.0 mg, 0.120 mmol) and 2-methoxypyridine-3-boronic acid (V-26) (27.5 mg, 0.180 mmol) were synthesized from compound (IV-139) by the same production method as compound (I-1). (I-435) (Yield 33.1 mg, Yield 76%) was obtained as a colorless oil.

Example 436
Preparation of 3- (2-methoxyphenyl) -2-{[4- (trifluoromethyl) phenyl] thio} pyridine (I-436) Compound (IV-138) was prepared by a method similar to that for compound (I-1). ) (40.0 mg, 0.120 mmol) and 2-methoxyphenylboronic acid (V-1) (94.1 mg, 0.619 mmol) to compound (I-436) (yield 116 mg,
Yield 77%) was obtained as a white solid.

Example 439
Preparation of 3- (2-methoxyphenyl) -2- [4- (trifluoromethyl) benzyl] pyridine (I-439)

Process 1
After dissolving 3-bromopicolinic acid (M-64) (2.02 g, 10.0 mmol) in DCM (20.0 mL), DIPEA (5.19 mL, 30.0 mmol), HATU (4.56 g, 12.0 mmol) and N, O- Dimethylhydroxylamine hydrochloride (1.17 g, 12.0 mmol) was added and stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (NH
The product was purified by silica gel, n-hexane: ethyl acetate = 80: 20 → 20: 80) to obtain compound (M-65) (yield 1.91 g, yield 78%) as a white solid.
Process 2
Compound (M-65) (1.00 g, 4.08 mmol), 2-methoxyphenylboronic acid (V-1) (806 mg, 5.30 mmol), (A- ^ta Phos) ₂ PdCl ₂ (144 mg, 0.204 mmol) and Cesium carbonate (2.66 g, 8.16 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL), and stirred at 120 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 80: 20
→ 30:70) to obtain compound (M-66) (yield 947 mg, yield 85%) as a white solid.
Process 3
Magnesium powder (60.0 mg, 2.47 mmol) and iodine (1 grain) were added to a THF solution (2.5 mL) of 4-trifluoromethylbromobenzene (563 mg, 2.50 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was ice-cooled, a solution of compound (M-66) (610 mg, 2.24 mmol) in THF (6.5 mL) was added, and the mixture was stirred at room temperature for 3 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (n-hexane:
Purification with ethyl acetate = 100: 0 → 70:30) gave Compound (I-437) (yield 447 mg, 56% yield) as a white solid.
Process 4
Sodium borohydride (46.0 mg, 1.22 mmol) was added to a solution of compound (I-437) (215 mg, 0.602 mmol) in methanol (4.0 mL) under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 50: 50) to obtain compound (I-438) (yield 217
mg, yield quantitative) was obtained as a colorless oil.
Process 5
Compound (I-438) (50.0 mg, 0.139 mmol) is dissolved in DCM (0.70 mL), TEA (29.1 μL, 0.209 mmol) and methanesulfonyl chloride (14.0 μL, 0.181 mmol) are added under ice cooling for 30 minutes. Stir. The reaction mixture was ice-cooled, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (1.0 mL), 10% Pd / C (15 mg) was added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere using a balloon. The reaction mixture was filtered through celite and washed with methanol. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (first time: silica gel, n-hexane: ethyl acetate = 95: 5
→ 60:40, 2nd: NH silica gel, n-hexane: ethyl acetate = 100: 0 → 80:20) and purified compound (I-439) (yield 8.8 mg, 18% yield) as a colorless oil Got as.

Compound (I-440) to Compound (I-502), Compound (I-576) and Compound (I-577) were prepared by the same production method (Suzuki / Miyaura cross-coupling reaction) as Compound (I-1). Synthesized. The structures and physical property values of the respective compounds are shown in Table 54 to Table 61 and Table 71.
Compound (I-503) to Compound (I-507) were synthesized by the same production method (Suzuki / Miyaura cross-coupling reaction) as compound (I-127). Table 61 and Table 62 show the structures and physical property values of the respective compounds.
Compound (I-508) to Compound (I-515) were synthesized by the same production method (Suzuki / Miyaura cross-coupling reaction) as compound (I-36). Tables 62 and 63 show the structures and physical property values of the respective compounds.

After obtaining aryl halide compound (IV) by _SN aryl reaction in the same manner as compound (I-1) (step 1), by Suzuki-Miyaura cross-coupling reaction (step 2), compound (I-516) to Compound (I-527) was synthesized. Table 63 and Table 64 show the structures and physical property values of the respective compounds.

After obtaining the compound represented by the general formula (VIII) by the Suzuki-Miyaura cross-coupling reaction in the same manner as the compound (I-318) (Step 1), S _N with the compound represented by the general formula (II) By aryl reaction,
Compound (I-528) to compound (I-532) were synthesized. Table 65 shows the structure and physical property values of each compound.

Similar to compound (I-331), after the aryl halide compound (IV) was led to the boronic acid compound (VIa) or boronic ester compound (VIb) (step 1), the aryl halide (VII) and Suzuki
Compound (I-533) to Compound (I-537) were synthesized by Miyaura cross-coupling reaction (Step 2). Tables 65 and 66 show the structures and physical property values of the respective compounds.

Compound (I-538) was synthesized by the same production method as for compound (I-175). Table 66 shows the structures and physical property values of the compounds.
Compound (I-539) was synthesized by the same production method as for compound (I-173). Table 66 shows the structures and physical property values of the compounds.
Compound (I-540) to Compound (I-547) were synthesized by the same production method as for compound (I-145).
Table 66 and Table 67 show the structures and physical property values of the respective compounds.
Compound (I-548) and Compound (I-549) were synthesized by the same production method as Compound (I-146). Table 67 shows the structure and physical property values of each compound.
Using the same production method as for compound (IV-30), compound (I-550) to compound (I-554) and compound (I-578) are synthesized from compound (I) wherein R ^2a is halogen by _SN aryl reaction. Synthesized. Tables 67, 68 and 71 show the structures and physical property values of the respective compounds.

  After amination from various halogen compounds (IV) by the same production method as compound (I-182) (step 1), by Suzuki-Miyaura cross-coupling reaction (step 2), compound (I-555) to compound (I-565) was synthesized. Table 68 and Table 69 show the structures and physical property values of the respective compounds.

Compound (I-566) was synthesized by the same production method as for compound (I-186). Table 69 shows the structures and physical properties of the compounds.
Compound (I-567) was synthesized by the same production method as for compound (I-386). Table 69 shows the structures and physical properties of the compounds.
NCS (reaction reagent) was replaced with NBS by the same production method as for compound (I-222) to synthesize compound (I-568). Table 70 shows the structures and physical property values of the compounds.

By the same production method as for compound (I-198), Sonogashira cross-coupling reaction (step 1), followed by catalytic hydrogenation reaction (step 2), compound (I-569) to compound (I-573), compound ( I-579) and compound (I-580) were synthesized. Tables 70 and 71 show the structures and physical property values of the respective compounds.
By the same production method as compound (I-326), from compound (III-10) to _SN aryl reaction (step 1), borylation (step 2), followed by Suzuki-Miyaura cross-coupling reaction (step 3), Compound (I-574) was synthesized. Table 70 shows the structures and physical property values of the compounds.
Compound (I-575) was synthesized from 5-bromo-2-t-butylpyrimidine in four steps by the same production method as for compound (I-178). Table 70 shows the structures and physical property values of the compounds.
Compound (I-581) was synthesized by the same production method as for compound (I-400). Table 71 shows the structures and physical property values of the compounds.
Compound (I-582) was synthesized by the same production method as for compound (I-52), replacing NBS (reaction reagent) with SelectFluor (registered trademark). Table 71 shows the structures and physical property values of the compounds.

Test Example 1: Antifungal activity evaluation test The minimum inhibitory concentration (MIC) for Trichophyton Mentagrophytes and Trichophyton rubrum was determined by referring to the Guidelines M38-A2 of Clinical and Laboratory Standards Institute (CLSI) as follows: Measured according to the procedure.
Reference method: National Committee for Clinical Laboratory Standards.Reference method for broth dilution antifungal susceptibility testing of filamentous fungi.Approved standard Second edition M38-A2. Wayne, PA: National Committee for
Clinical Laboratory Standards, 2008.

Test compound solution: A test compound was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 2.5 mg / mL, and this was diluted as appropriate with DMSO as a stock solution to prepare a 2-fold dilution series. Terbinafine and amorolfine were used as control compounds.
Test strains: Trichophyton mentagrophytes SM-110 and Trichophyton rubrum KD-1130 were used.
Preparation of inoculum solution: The above-mentioned test strain was suspended in physiological saline containing 0.05% Twin 80, and Trichophyton fungus was prepared to a bacterial concentration of 1 × 10 ⁶ cells / mL using a hemocytometer. Next, the MOPS buffer RPMI1640 medium (pH 7.0) as a test medium was used to dilute the Trichophyton fungus solution 250 times (4 × 10 ³ cells / mL) to obtain an inoculum solution.
MIC measurement for Trichophyton fungi: MOPS in a given well of a 96-well U-bottom microplate
Buffered RPMI1640 medium (pH 7.0) was dispensed at 100 μL each. Next, 2 μL of the test compound solution was added and stirred thoroughly with a plate mixer. 100 μL of the bacterial solution was inoculated and cultured at 35 ° C. for 4 days (final bacterial concentration: 2 × 10 ³ cells / mL). After the culture, the minimum drug concentration in the well in which a growth inhibitory effect of 80% or more was observed macroscopically compared with the growth control was defined as the minimum growth inhibitory concentration (MIC: μg / mL).
The results are shown in Tables 72-79.
Abbreviations in the table mean the following fungi and compounds.
T. menta .: Trichophyton mentagrophytes
T. rubrum: Trichophyton rubrum
TBF: terbinafine
AMF: amorolfine

Test Example 2: Nail permeability test The permeability to human nails was measured by the following method using Franz cell.
Test preparation: The test compound was dissolved in a propylene glycol: ethanol (1: 4) mixture at a concentration of 5% to prepare a test preparation. Terbinafine and amorolfine were used as control compounds.
(1) A human nail (thickness 300-500 μm) was set on a nail adapter for Franz cell, and then mounted on the Franz cell.
(2) After filling the receptor side of Franz cell with phosphate buffer, it was placed in a constant temperature bath at 32 ° C.
(3) After dropping the test preparation onto the human nail at 61 μL / cm ² , the receptor solution was collected over time, and the concentration of the test compound in the receptor was measured by liquid chromatography mass spectrometry (LC / MS / MS). The cumulative permeation drug amount (μg / cm ² ) was calculated from the obtained drug concentration in the receptor.
The slope at the last 4 time points when the cumulative permeation drug amount was plotted against the time after the start of the test was defined as Flux (μg / cm ² / day).
The results are shown in Table 80.
Abbreviations in the table mean the following compounds.
TBF: terbinafine
AMF: amorolfine

The biaryl derivative (I) or a salt thereof of the present invention exhibits excellent antifungal activity against the causative fungus of superficial mycosis. Therefore, pharmaceuticals or antifungal agents containing these as active ingredients are useful for the treatment and prevention of infections caused by fungi in mammals including humans.

Claims (6)

Following formula




A pharmaceutical comprising a biaryl derivative selected from the group consisting of the compounds represented by: The medicament according to claim 1, which is an antifungal agent. The medicament according to claim 1, which is a therapeutic agent for superficial mycosis. The medicament according to claim 1, which is a therapeutic agent for onychomycosis. The medicament according to claim 1, which is a therapeutic agent for external onychomycosis. The following formula for producing an antifungal agent, a superficial mycosis treatment agent, an onychomycosis treatment agent, or a topical onychomycosis treatment agent




Use of the biaryl derivative or its salt selected from the group which consists of a compound shown by these .