JP2003221386A - Bicylic derivative, method for producing the same, and use of the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a heterocyclic compound having an inhibitory action on tyrosine kinase and a pharmaceutical composition containing the same. <P>SOLUTION: There is provided a compound represented by formula (V) [wherein R<SP>1b</SP>is a substituted 6-10C aryl, or the like; T<SP>a</SP>is single bond, a 1-6C alkyl, -CH<SB>2</SB>O-, or the like; X and Y, which may be the same or different from each other, are each (un)substituted nitrogen atom, or the like; the broken line is single bond or double bond; Z<SP>a</SP>is nitrogen atom or CH; W is single bond, oxygen atom, or the like; and Q is an (un)substituted 6-10C aryl, or an (un)substituted aromatic-heterocyclic group] or a salt thereof. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a bicyclic derivative which suppresses the receptor type tyrosine kinase HER2 protein and shows a selective growth inhibitory activity on HER2-expressing cancer cells, and a production method and use thereof.

[0002]

2. Description of the Related Art Receptor type tyrosine kinase HER2 protein (Human EGF Receptor-2: Akiyama et al., Science 23)
2 1646-1646, 1986) is also present in normal tissues in the early stages of development, but is absent in normal tissues after adulthood and is mainly found only in cancer cells. Therefore, for the treatment of cancer in which the HER2 protein is highly expressed,
An antibody that recognizes a homo- or hetero-dimer or a homo-multimer HER2 protein is used for the purpose of inhibiting the growth of the cells. That is, the anti-HER2 antibody Herceptin (trade name: trastuzumab) is used for the treatment of HER2-expressing breast cancer.

[0003]

An antibody that inhibits the receptor tyrosine kinase HER2 protein has many problems such as oral absorbability, administration form, induction of heart disease and allergic reaction. Therefore, there is a strong demand for a highly tolerable inhibitor that can be orally administered, can be repeatedly taken, and can selectively suppress the growth of HER2-expressing cancer cells.

[0004]

Means for Solving the Problems As a result of intensive investigations, the present inventors have found that HER2-expressing cancer cells are highly selective and inhibit their growth, but have little effect on the growth of HER2-expressing normal cells. A bicyclic derivative which does not give Moreover, it was found that these compounds can be orally administered, have extremely low toxicity, and are sufficiently satisfactory as a drug having a HER2 inhibitory action, and based on these findings, the present invention was completed. That is, the present invention provides (1) the general formula (V)

[Chemical 10] Wherein, R ^1b is _{C 6-10} aryl group substituted, indicates substituted _{C 3-8} cycloalkyl group or an optionally substituted heterocyclic group, ^{T a} is a single _{bond, C 1-6} alkyl _{group, -CH 2 O -, - OCH} 2 -, - CH 2 S-,
_{-SCH 2 -, - CH 2 -CH} 2 - or -CH = CH
-, X and Y are the same or different and each represents an optionally substituted nitrogen atom, oxygen atom or sulfur atom, a broken line represents a single bond or a double bond, and Z ^a represents a nitrogen atom or CH.
, W represents a single bond, an oxygen atom, a nitrogen atom or a sulfur atom, and Q represents an optionally substituted C _6-10 aryl group or an optionally substituted aromatic heterocyclic group. ] The compound or its salt represented by these;

(2) General formula (VI)

[Chemical 11] [In the formula, R^1cIs a substituted C_6-10Aryl group, placement
Converted C_3-8Cycloalkyl group or substituted
Represents a heterocyclic group which may be substituted with the above-mentioned substituted C_{6- 10}A
Reel group and substituted C_3-8Cycloalkyl
Substituents are halogen atoms, OH, CN, NO_Two, N
H_Two, NHCOR, NHCONHR, NHSO _TwoR, S
O_TwoR, COOH, COOR, CONHR, CON
H_Two, CF_Three, CF _ThreeO, optionally substituted C
_1-6Alkyl group, optionally substituted C_1-6Arco
Xyl group, optionally substituted C_1-6Alkoxy-ca
Rubonyl group and optionally substituted C_1-4Archi
1 to 5 groups arbitrarily selected from dioxy groups
R is C_1-6Alkyl group, C_3-8Cycloalkyl
Group or C _6-10An aryl group, T^aIs a single bond, C
_1-6Alkyl group, -CH_TwoO-, -OCH_Two-, -C
H_TwoS-, -SCH_Two-, -CH_Two-CH_Two-Or-
CH = CH-, X^aIs an optionally substituted nitrogen source
Child, oxygen atom or sulfur atom, Y^aIs a nitrogen atom, oxygen
An atom or a sulfur atom (provided that X^aAnd Y^aIs the same
Except for one or different oxygen or sulfur atoms
Ku. ), The broken line represents a single bond or a double bond, Z^aIs nitrogen source
Child or CH, W is a single bond, oxygen atom, nitrogen atom or
Is a sulfur atom, and Q is an optionally substituted C_6-10A
A reel group or an optionally substituted aromatic heterocyclic group
Shown respectively. ] The compound or its salt represented by these;

(3) The compound according to (1) to (4) above, wherein X or X ^a is ^a nitrogen atom which may be substituted; (4) The above (1) to where Y or Y ^a is a nitrogen atom. (5) The compound described in (5); (5) The compound described in (1) to (6) above, wherein Z or Z ^a is a nitrogen atom; (6) C in which R ¹ , R ^1a , R ^1b or R ^1c is substituted. The compound according to the above (1) to (7), which is a _6-10 aryl group;

(7) General formula (VII)

[Chemical 12] [In the formula, R ^1d represents an optionally substituted C _6-10 aryl group, an optionally substituted C _3-8 cycloalkyl group or an optionally substituted heterocyclic group, and ^Ta is a single group. Bond, C _1-6 alkyl group, —CH ₂ O—, —OCH
_{2 -, - CH 2 S -} , - SCH 2 -, - CH 2 -CH 2
- or -CH = CH-, ^{R 2} is a hydrogen atom, an optionally substituted _{C 1-6} alkyl group, which may be a good _{C 6-1 0} aryl group or substituted or optionally substituted C
_3-8 cycloalkyl group, W is a single bond, an oxygen atom, a nitrogen atom or a sulfur atom, and Q is an optionally substituted C
Shown _6-10 aryl group or a substituted optionally also an aromatic heterocyclic group, respectively. ] The compound or its salt represented by these;

(8) General formula (VIII)

[Chemical 13] [In the formula, R ^1d represents an optionally substituted C _6-10 aryl group, an optionally substituted C _3-8 cycloalkyl group or an optionally substituted heterocyclic group, and ^Ta is a single group. Bond, C _1-6 alkyl group, —CH ₂ O—, —OCH
_{2 -, - CH 2 S -} , - SCH 2 -, - CH 2 -CH 2
-Or -CH = CH-, W is a single bond, an oxygen atom, a nitrogen atom or a sulfur atom, and Q is an optionally substituted C.
_{6-10 represents an} aryl group or an optionally substituted aromatic heterocyclic group. ] The compound or its salt represented by these;

(9) General formula (IX)

[Chemical 14] [In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a halogen atom, OH, CN or N.
O ₂ , NH ₂ , NHCOR, NHCONHR, NHSO
₂ R, SO ₂ R, COOH, COOR, CONHR, C
ONH ₂ , CF ₃ , CF ₃ O, optionally substituted C
_1-6 alkyl group, optionally substituted C _1-6 alkoxy group or optionally substituted C _1-6 alkoxy-carbonyl group, or optionally substituted C ₁ together with an adjacent group _-4 alkylenedioxy group, R represents _{a C 1-6} alkyl _group, a _{C 3-8} cycloalkyl group or _{C 6-10} aryl group, ^{T a} is a single bond, C
_1-6 alkyl _{group, -CH 2 O -, - OCH} 2 -, - C
_{H 2 S -, - SCH 2} -, - CH 2 -CH 2 - or -
CH = CH-, R ² is a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C
_6-10 aryl group or optionally substituted C
_{A 3-8} cycloalkyl group, W ^a represents a single bond or an oxygen atom, and Q represents an optionally substituted C _6-10 aryl group or an optionally substituted aromatic heterocyclic group. ] The compound or its salt represented by these;

(10) General formula (X)

[Chemical 15] [In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a halogen atom, OH, CN or N.
O ₂ , NH ₂ , NHCOR, NHCONHR, NHSO
₂ R, SO ₂ R, COOH, COOR, CONHR, C
ONH ₂ , CF ₃ , CF ₃ O, optionally substituted C
_1-6 alkyl group, optionally substituted C _1-6 alkoxy group or optionally substituted C _1-6 alkoxy-carbonyl group, or optionally substituted C ₁ together with an adjacent group _-4 alkylenedioxy group, R represents _{a C 1-6} alkyl _group, a _{C 3-8} cycloalkyl group or _{C 6-10} aryl group, ^{T a} is a single bond, C
_1-6 alkyl _{group, -CH 2 O -, - OCH} 2 -, - C
_{H 2 S -, - SCH 2} -, - CH 2 -CH 2 - or -
CH = CH-, W ^a represents a single bond or an oxygen atom, Q represents a halogen atom, an optionally substituted C _6-10 aryl group or an optionally substituted aromatic heterocyclic group. However, when Q is a halogen atom, R ⁴
Or R ⁶ is not a hydrogen atom. ] The compound or its salt represented by these;

[0011] (11) ^{W a} is a compound or a salt thereof of (9) or (10) wherein is a single bond; the (9) or (10) wherein (12) ^{T a} and ^{W a} is a single bond (13) The compound or salt thereof according to the above (9) or (10), wherein R ⁴ or R ⁶ is a group other than a hydrogen atom;

(14) General formula (XI)

[Chemical 16] [In the formula, R ^3a represents a hydrogen atom, a halogen atom, OH, C
N, NO ₂ , NH ₂ , NHCOR, NHCONHR, N
HSO ₂ R, SO ₂ R, COOH, COOR, CONH
R, CONH ₂ , CF ₃ , CF ₃ O, optionally substituted C _1-6 alkyl group, optionally substituted C _1-6
An alkoxy group or an optionally substituted C _1-6 alkoxy-carbonyl group, R is a C _1-6 alkyl group, C
_3-8 cycloalkyl group or a _{C 6-10} aryl group, ^{T a} is a single _{bond, C 1-6} alkyl, _-CH 2 O
_{-, - OCH 2 -, -} CH 2 S -, - SCH 2 -, - C
H ₂ —CH ₂ — or —CH═CH—, m is 1 to 3
R ⁸ is an optionally substituted C _6-10 aryl group, an optionally substituted C _3-8 cycloalkyl group or an optionally substituted heterocyclic group, and Q is optionally substituted. C _6-10 aryl group which may be substituted or an aromatic heterocyclic group which may be substituted, respectively] or a salt thereof; (15) Q ¹ , Q ² , Q ³ , Q ⁴ or Q Is a substituted C _6-10 aryl group, and the substituted C
The compound according to (1 to 14) above, wherein the substituent of the _6-10 aryl group is 1 to 5 groups arbitrarily selected from a halogen atom, an optionally substituted C1-6 alkyl group and a cyano group. Or a salt thereof; (16) a prodrug of the compound described in (1) to (15); (17) a pharmaceutical composition containing the compound described in (1) to (16);

(18) General formula (I)

[Chemical 17] [In the formula, R ¹ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and T is a single bond or optionally substituted and has one or more heteroatoms. Optionally a divalent aliphatic hydrocarbon group, X and Y are the same or different, and an optionally substituted nitrogen atom, oxygen atom or sulfur atom, a broken line is a single bond or a double bond, and Z is Nitrogen atom or general formula (II)

[Chemical 18] In the group represented by, W ¹ , W ² , W ³ and W ⁴ are the same or different and each is a single bond, an optionally substituted nitrogen atom, an oxygen atom, a sulfur atom or an optionally substituted 2
A valent aliphatic hydrocarbon group with Q ¹ , Q ² , Q ³ and Q ⁴
Are the same or different and each is a hydrogen atom, an optionally substituted alicyclic hydrocarbon group, an optionally substituted aromatic hydrocarbon group or an optionally substituted heterocyclic group (however,
At least one of Q ¹ , Q ² , Q ³ and Q ⁴ is not a hydrogen atom). ] HER2 containing the compound represented by or its salt, or its prodrug
Protein inhibitors;

(19) The pharmaceutical composition according to (17), which is a HER2 protein inhibitor; (20) The pharmaceutical composition according to (17), which is a prophylactic / therapeutic agent for cancer; (21) cancer is breast cancer, The pharmaceutical composition according to the above (20), which is prostate cancer, lung cancer or pancreatic cancer; (22) The above (1) to (16) with respect to a mammal
HER characterized by administering an effective amount of the described compound
(23) The method (1) to (16) for a mammal
(24) Use of the compound according to (1) to (16) above for producing a HER2 protein inhibitor, and (25) Cancer. (1) for producing a prophylactic / therapeutic agent for
To the use of the compound described in (16).

The present invention further provides (26) a drug comprising a combination of the compound according to (1) to (16) and an anticancer agent; (27) the compound according to (1) to (16) and a kinase inhibitor. (28) A drug comprising a combination of the compound according to (1) to (16) above and a hormone therapy agent; (29) The above-mentioned (28), wherein the hormone therapy agent is an LH-RH modulator. (30) The medicament according to (29), wherein the LH-RH modulator is an LH-RH agonist; (31) The medicament according to (30), wherein the LH-RH agonist is leuprorelin or a salt thereof; (32) For mammals, the above (1) to (16)
(33) A method for inhibiting tyrosine kinase, which comprises administering an effective amount of the compound described above;
(34) A method for preventing or treating cancer, which comprises administering an effective amount of the compound described above and an effective amount of a hormone therapeutic agent in combination; (34) The hormone therapeutic agent is an LH-RH modulator, (33). (35) The method according to (34), wherein the LH-RH modulator is an LH-RH agonist; (36) The method according to (35), wherein the LH-RH agonist is leuprorelin or a salt thereof; (37) The above (1) to (16) after administration of another anticancer agent
(38) A method for preventing or treating cancer, which comprises administering an effective amount of the compound described above; (39) Surgery, radiation therapy, gene therapy, hyperthermia therapy, cryotherapy, a method for preventing or treating cancer, which comprises administering an effective amount of the compound according to (1) to (16) to an animal; And / or a method for preventing / treating cancer, which comprises administering an effective amount of the compound according to (1) to (16) to a mammal after applying laser ablation therapy; (40) Tyrosine Use of the compound according to the above (1) to (16) for producing an agent for inhibiting a kinase, and (41) the general formula (III)

[Chemical 19] [In the formula, R ^1a represents an optionally substituted alicyclic hydrocarbon group, an optionally substituted aromatic hydrocarbon group or an optionally substituted heterocyclic group, and T is a single bond or a substituted group. Optionally, a divalent aliphatic hydrocarbon group which may have one or more heteroatoms, X and Y are the same or different, and optionally substituted nitrogen atom, oxygen atom or sulfur Atoms, dashed lines are single or double bonds,
Z is a nitrogen atom or general formula (IV)

[Chemical 20] The group represented by^1a, W^2a, W^3aAnd W^4a
Are the same or different and may be single bond or substituted.
Nitrogen atom, oxygen atom or sulfur atom, Q¹, Q ^Two, Q
^ThreeAnd Q^FourAre the same or different, hydrogen atom,
Optionally substituted alicyclic hydrocarbon group, optionally substituted
Aromatic hydrocarbon group or optionally substituted heterocycle
Group (however, Q¹, Q^Two, Q^ThreeAnd Q^FourAt least
One is not a hydrogen atom). However,
1) One of X and Y is a nitrogen atom and the other is an oxygen atom
And Z is CH and T is a single bond,
2) T is a vinylene group, Z is CH, W^1a,
W^2a, W^3aAnd W^4aIs a single bond, and Q¹And
And Q^FourIs a hydrogen atom, and Q^TwoOr Q^ThreeIs a substitute
A nyl group, R^1aIs a biphenylyl group or N, N-diph
Compounds having a phenyl-4-amino-phenyl group and 3)
X and Y are nitrogen atoms, and T, W^1a, W^2a, W
^3aAnd W^4aIs a single bond, and Q¹, Q^TwoAnd Q
^FourIs a hydrogen atom, and Q^ThreeIs a 4-methylpiperazinyl group
Excludes certain compounds. ] The compound or its salt represented by
Or a HER2 protein inhibitor containing the prodrug thereof
Etc.

The present invention will be described in detail below. In the present specification, the definition of each symbol in each formula is as follows. As the hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R ¹ , for example, an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group, an aryl group and the like are used, and among them, an aryl group and the like. Is preferred. As the “aliphatic chain hydrocarbon group” as an example of the hydrocarbon group, for example, a linear or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group and an alkynyl group is used. Here, as the alkyl group, for example, methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl,
n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl , N-heptyl, 1-methylheptyl, 1-ethylhexyl, n-octyl, 1-methylheptyl, nonyl and the like C _1-10 alkyl group (preferably C _1-6 alkyl etc.) and the like are used. Examples of the alkenyl group include vinyl, allyl, isopropenyl, 2-methylallyl, 1
-Propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-
Butenyl, 2-methyl-2-butenyl, 3-methyl-2
C ₂ such as -butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like. _{A -6} alkenyl group or the like is used. Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2- A C _2-6 alkynyl group such as hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl is used.

As the "alicyclic hydrocarbon group" as an example of the hydrocarbon group, a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, a cycloalkanedienyl group or the like is used. To be Here, as the “cycloalkyl group”, for example, C _3-9 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like are used. Examples of the “cycloalkenyl group” include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1 -C such as cyclopenten-1-yl
_{A 3-6} cycloalkenyl group or the like is used. Examples of the “cycloalkanedienyl group” include C _4-6 such as 2,4-cyclopentanedien-1-yl, 2,4-cyclohexanedien-1-yl and 2,5-cyclohexanedien-1-yl. A cycloalkanedienyl group or the like is used. Examples of the “aryl group” as a hydrocarbon group include:
A monocyclic or condensed polycyclic aromatic hydrocarbon group is used and is not particularly limited, but is preferably a C _6-22 aromatic hydrocarbon group, more preferably a C _6-18 aromatic hydrocarbon group, and further preferably C _{6 -14} aromatic hydrocarbon group, still more preferably _{C 6-10} aromatic hydrocarbon group, most preferably such as _{C 6} aromatic hydrocarbon group. Specific examples of the "aromatic hydrocarbon group" include, for example, phenyl, naphthyl, anthryl, azulenyl, phenanthryl, phenalenyl, fluorenyl, indacenyl, biphenylenyl, heptanenyl, acenaphthylenyl and the like, among which phenyl, 1-naphthyl, 2-naphthyl. 1
-Anthryl, 2-anthryl and the like are preferable.

The aromatic hydrocarbon group of the "optionally substituted aromatic hydrocarbon group" represented by Q ¹ , Q ² , Q ³ , Q ⁴ , R ^1a is the same as the above "aryl group". , A monocyclic or condensed polycyclic aromatic hydrocarbon group is used and is not particularly limited, but is preferably a C _6-22 aromatic hydrocarbon group, more preferably a C _6-18 aromatic hydrocarbon group, and further preferably Is a C _6-14 aromatic hydrocarbon group, even more preferably a C _6-10 aromatic hydrocarbon group, and most preferably C ₆
Aromatic hydrocarbon groups and the like, and specific examples thereof include, for example, phenyl, naphthyl, anthryl, azulenyl, phenanthryl, phenalenyl, fluorenyl, indacenyl, biphenylenyl, heptanenyl, acenaphthylenyl, etc., among which phenyl, 1-naphthyl, 2 -Naphthyl, 1-anthryl, 2-anthryl and the like are preferable.

[0019] Q, R ^1d, R ^2, represented by R ⁸ "optionally substituted C _6-10 aryl group" and R ^1b, "C _6-10 aryl group substituted" represented by R ^1c C _6-10
The aryl group is a C _6-10 aromatic hydrocarbon group, more preferably a C ₆ aromatic hydrocarbon group, and specific examples thereof include phenyl, pentalenyl, indenyl, naphthyl, and the like. Among them, phenyl, 1
-Naphthyl, 2-naphthyl and the like are preferable.

Examples of the alicyclic hydrocarbon group of the "optionally substituted alicyclic hydrocarbon group" represented by Q ¹ , Q ² , Q ³ , Q ⁴ , R ^1a include the above-mentioned hydrocarbon groups. Has the same meaning as the “alicyclic hydrocarbon group”, for example, a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkanedienyl group is used. The same groups can be used as described.

[0021] R ^1d, R ^2, "optionally substituted C _3-8 cycloalkyl group" represented by R ^8, R ^1b, represented by R ^1c "substituted C _3-8 cycloalkyl group" and as the C _3-8 cycloalkyl group "C _3-8 cycloalkyl group" represented by R, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like are used.

R²Is shown as "optionally substituted C
_1-6"Alkyl group" and "C represented by R_1-6Archi
Lu's C_1-6The alkyl group may be linear or branched.
Chain C _1-6It is an alkyl group and is not particularly limited
Is, for example, methyl, ethyl, n-propyl, isopropyl
, N-butyl, isobutyl, sec-butyl, tert-butyl
Chill, n-pentyl, isopentyl, neopentyl, 1
-Methylpropyl, n-hexyl and the like are used and preferred.
Kumo is methyl, ethyl, n-propyl, isopropyl.
It

"C _1-4 alkyl group" represented by T ^a , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^3a and "substituted C _6-10 aryl group and substitution in R ^1c " The "C _1-4 alkyl group" as a substituent of the "provided C _3-8 cycloalkyl group" is a linear or branched C _1-4 alkyl group, and is not particularly limited, and examples thereof include Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like are used, preferably methyl, ethyl, n-propyl and isopropyl.

"C represented by R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^3a
_1-4 alkoxy group ”and“ C _1-4 alkoxy group ”as a substituent of“ substituted C _6-10 aryl group and substituted C _3-8 cycloalkyl group ”in R ^1c is a straight chain. Group or branched chain C _1-4 alkoxy group, which is not particularly limited, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. , Preferably methoxy, ethoxy, n-propoxy, isopropoxy.

"C shown by R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^3a
_1-4 alkoxy-carbonyl group "and" substituted C _6-10 aryl group and substituted C in R ^1c .
_{3-8 "C 1-4} as a substituent of the cycloalkyl group"
Examples of the “alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
Isobutoxycarbonyl, sec-butoxycarbonyl, t
ert-Butoxycarbonyl and the like can be used, and among them, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like are preferable.

"C _{1-4 represented by} R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷
“Alkylenedioxy group” and “C _1-4 alkylenedioxy group” as a substituent of “substituted C _6-10 aryl group and substituted C _3-8 cycloalkyl group” for R ^1c are adjacent to each other. And methylenedioxy, ethylenedioxy, propylenedioxy, butylenedioxy and the like can be used, among which methylenedioxy and ethylenedioxy are preferable. R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^3a
“Halogen atom” and R ^1c “substituted C _6-10 aryl group and substituted C _3-8
"Halogen atom" as a substituent of "cycloalkyl group"
As such, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like can be used, and a chlorine atom, a bromine atom or the like is preferable.

The divalent aliphatic hydrocarbon group of the “optionally substituted divalent aliphatic hydrocarbon group” represented by W ¹ , W ² , W ³ and W ⁴ is, for example, an aliphatic chain formula. A divalent group derived by removing one hydrogen atom from a hydrocarbon group, an alicyclic hydrocarbon group or the like is used. Specifically, for example, a linear or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group, or an alkynyl group and a saturated or unsaturated aliphatic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, or a cycloalkanedienyl group. A divalent group derived by removing one hydrogen atom from an alicyclic hydrocarbon group can be used, and examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylethylene and ethylethylene. ,
An alkylene group such as propylene, preferably C
_1-6 alkylene group; vinylene, propenylene,
An alkenylene group such as butenylene, pentenylene and methylvinylene, preferably a C _1-6 alkenylene group; an alkynylene group such as ethenylene, propynylene, butynylene, pentynylene and methylethenylene,
It is preferably a C _1-6 alkynylene group; a cycloalkylene group such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, etc., preferably C
_{It is a 3-8} cycloalkylene group; a cycloalkenylene group such as cyclopropenylene, cyclobutenylene, cyclopentenylene, etc., and preferably a C _3-8 cycloalkenylene group is used. Particularly preferably methylene,
A C _1-6 alkylene group such as ethylene or trimethylene,
Alkenylene groups such as vinylene, propenylene and butenylene.

"Optionally substituted 1"
Divalent aliphatic carbonization which may have the above hetero atoms
A hydrogen group ", which may have one or more heteroatoms
As the aliphatic hydrocarbon group of, an oxygen atom, a sulfur atom and
1 to 3 heteroatoms selected from nitrogen atom etc. (preferably
1 to 2 kinds), may have one or more
The "divalent aliphatic hydrocarbon group" can be used.
Specifically, for example, an alkyl group, an alkenyl group, an alkynyl group
Straight-chain or branched-chain aliphatic hydrocarbon groups such as
Cycloalkyl group, cycloalkenyl group, cycloalka
Saturated or unsaturated alicyclic hydrocarbon groups such as phenyldienyl groups
One or more hetero atoms derived by removing one hydrogen atom from
It is possible to use a divalent group which may have an atom.
, For example, -CH₂O-, -OCH₂-, -CH = CHO-, -CHOCH₂-, -C
H₂CH₂OCH₂-, -CH (CH₃) CH₂O-, -CH₂CH (CH₃) O-, -OCH₂O-,
 -OCH₂CH₂O-, -SCH₂CH₂O-, -OCH₂CH₂S-, -SCH₂CH₂S-,-
OCH₂CH₂CH₂O-, -CH₂OCH₂CH₂-, -CH₂S-, -SCH₂-, -CH = CH
S-, -CHSCH₂-, -CH₂CH₂SCH₂-, -CH (CH₃) CH₂S-, -CH₂CH
(CH₃) S-, -SCH₂O-,-CH₂SCH₂CH₂-, -CH₂NH-, -NHCH₂-,-C
HNHCH₂-, -CH₂CH₂NHCH₂-, -CH (CH₃) CH₂NH-, -CH₂CH (C
H₃) NH-, -NHCH₂O-,-CH₂NHCH₂CH₂-, -CH₂N (CH₃)-, -CHN
(CH₃) CH₂-, -CH₂CH₂N (CH₃) CH₂-, -CH (CH₃) CH₂N (CH ₃)-,
-CH₂CH (CH₃) N (CH₃)-, -N (CH₃) CH₂O-,-CH₂N (CH₃) CH₂CH
₂-, -CH₂N (C₂H_Five)-, -CHN (C₂H_Five) CH₂-, -CH₂CH₂N (C₂H_Five) CH
₂-, -CH (CH₃) CH₂N (C₂H_Five)-, -CH = CHN (C₂H_Five)-,-CH₂CH (C
H₃) N (C₂H_Five)-, -CH = C (CH₃) N (C₂H_Five)-, -N (C₂H_Five) CH₂O-,-CH
₂N (C₂H_Five) CH₂CH₂-, -N (CH₃) CH₂S-, -N (C₂H_Five) CH₂For S- etc.
Can be, but is not limited to. Preferably
Is -CH₂O-, -OCH₂-, -CH = CHO-, -CHOCH₂-, -CH₂CH₂OCH
₂-, -CH (CH ₃) CH₂O-, -CH₂CH (CH₃) O-, -OCH₂O-, -OCH₂CH
₂O-, -SCH₂CH₂O-, -OCH₂CH₂S-, -SCH₂CH₂S-, -OCH₂CH₂C
H₂O-, -CH₂OCH₂CH₂-And the like, and more preferably -CH₂O-,
-OCH ₂-, -CH = CHO-, -CHOCH₂-, -CH₂CH₂OCH₂-, -CH (CH₃)
CH₂O-, -CH₂CH (CH₃) O-, -OCH ₂O-, etc.

R ¹ , Q ¹ , Q ² , Q ³ , Q ⁴ , R ^1a , R ^1b , R ^1c ,
"An optionally substituted heterocyclic group" represented by R ^1d and R ⁸
Examples of the heterocyclic group include at least 1 to 3 heteroatoms (preferably 1 to 2 heteroatoms) selected from oxygen atom, sulfur atom, nitrogen atom and the like as atoms (ring atoms) constituting the ring system. One (preferably 1 to 4, more preferably 1 or 2) aromatic heterocyclic group, saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group), etc. are used, and particularly limited Not, but preferably 5
To 22-membered heterocyclic group, more preferably 5 to 18-membered heterocyclic group, further preferably 5 to 14-membered heterocyclic group, even more preferably 5 to 10-membered heterocyclic group, most preferably 5 to 6-membered heterocyclic group Groups, etc. Specific examples of the "aromatic heterocyclic group" include aromatic monocyclic heterocyclic groups (for example, furyl, thienyl, pyrrolyl, oxazolyl,
Isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl, 1,2,
4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,
2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.) 5- to 6-membered aromatic monocyclic heterocyclic group and aromatic condensed heterocyclic group ( For example, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzisothiazo. Ryl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-
Carborinyl, β-carbolinyl, γ-carbolinyl,
Acridinyl, phenoxazinyl, phenothiazinyl,
Phenazinyl, phenoxathinyl, thianthrenyl,
Phenatoridinyl, phenatrolinyl, indoridinyl, pyrrolo [1,2- b ] pyridazinyl, pyrazolo [1,
5- a ] pyridyl, imidazo [1,2- a ] pyridyl,
Imidazo [1,5- a ] pyridyl, imidazo [1,2-
b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,2,4-triazolo [4,3- a ] pyridyl, 1,
An 8- to 12-membered fused aromatic heterocyclic group such as 2,4-triazolo [4,3- b ] pyridazinyl) (preferably the 5- to 6-membered aromatic monocyclic heterocyclic group described above is a benzene ring). Or a heterocycle condensed with two or more of the same or different heterocycles of the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group). "Non-aromatic heterocyclic group"
When specifically exemplified as, for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,
3- to 8-membered (preferably 5 to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic) such as tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc. A heterocyclic group) or the like is used. Examples of the aromatic heterocyclic group of the “optionally substituted aromatic heterocyclic group” represented by Q include an atom (ring atom) constituting a ring system.
As the hetero atom selected from oxygen atom, sulfur atom, nitrogen atom, etc. 1 to 3 types (preferably 1 to 2 types)
An aromatic heterocyclic group containing at least 1 (preferably 1 to 4, more preferably 1 to 2) is used and is not particularly limited, but is preferably a 5- to 22-membered aromatic heterocyclic group, more preferably Is a 5- to 18-membered aromatic heterocyclic group, more preferably a 5- to 14-membered aromatic heterocyclic group, even more preferably a 5- to 10-membered aromatic heterocyclic group, most preferably a 5- to 6-membered aromatic heterocyclic group. And so on.
As a specific example, a group similar to the "aromatic heterocyclic group" in the definition of the "optionally substituted heterocyclic group" can be used.

[0030] Here, "optionally substituted hydrocarbon group" and R ¹ represented by ^{R 1, Q 1, Q 2} , Q 3, Q 4, R 1a,
The substituent of the “optionally substituted heterocyclic group” represented by R ^1b , R ^1c , R ^1d and R ⁸ is not particularly limited and may be optionally protected by a conventional method of organic chemical synthesis. But,
For example, (i) an optionally substituted alkyl group, (ii) an optionally substituted alkenyl group, (iii) an optionally substituted alkynyl group, (iv) an optionally substituted aryl group, ( v) optionally substituted aralkyl group, (vi) optionally substituted cycloalkyl group, (vii) optionally substituted cycloalkenyl group, (viii) optionally substituted heterocyclic group, (ix) optionally substituted amino group, (x) optionally substituted imidoyl group (for example,
A group represented by the formula: -C (U ') = N-U [in the formula, U and U'represent each the same or different and each represents a hydrogen atom or a substituent (U preferably represents a hydrogen atom)]. , (Xi)
An optionally substituted amidino group (eg, formula -C (N
E′E ″) = NE [in the formula, E, E ′ and E ″ are the same or different and each represents a hydrogen atom or a substituent (E is preferably a hydrogen atom)] Group, etc.), (xii) optionally substituted hydroxyl group, (xiii) optionally substituted thiol group, (xiv) optionally substituted alkylsulfinyl group, (xv) esterified or amidated Optionally carboxyl group, (xvi) optionally substituted thiocarbamoyl group, (xvii) optionally substituted sulfamoyl group, (xviii) halogen atom (eg, fluorine, chlorine, bromine, iodine, etc., preferably Chlorine, bromine, etc.), (xix) cyano group, (xx) isocyano group, (xx
i) cyanate group, (xxii) isocyanate group, (xxiii) thiocyanate group, (xxiv) isothiocyanate group, (xxv)
Nitro group, (xxvi) nitroso group, (xxvii) sulfonic acid-derived acyl group, (xxviii) carboxylic acid-derived acyl group, (xxi
x) an oxo group or the like is used, and these optional substituents are 1 to 5 (preferably 1 to 3) at substitutable positions.
It may be replaced.

Examples of the alkyl group in the “optionally substituted alkyl group” as the substituent include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n. - pentyl, isopentyl, neopentyl, 1-methylpropyl, n- hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, such as 3,3-dimethylpropyl _{C 1- 6} alkyl and the like can be used. Here, as the substituent of the alkyl group, a nitro group, a carboxyl group, a lower alkoxy group (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, etc.), a halogen atom (eg, fluorine, chlorine, bromine, iodine) etc.), lower alkyl group (e.g., methyl, ethyl, _{C 1-6} alkyl, etc.), lower alkenyl groups (examples of propyl, vinyl, _{C 2-6} alkenyl, etc.), lower alkynyl group (e.g. allyl, etc., ethynyl , C _2-6 alkynyl propargyl, etc.), an optionally substituted amino group, hydroxy group which may be substituted, a cyano group, an optionally substituted amidino group, carboxyl group, lower alkoxycarbonyl group (e.g. , C _1-6 alkoxycarbonyl such as methoxycarbonyl and ethoxycarbonyl),
An optionally substituted carbamoyl group (eg, 5 to 6)
Monocyclic aromatic Hajime Tamaki (e.g., pyridinyl, etc.) membered optionally substituted C _{1 -6} alkyl group or an acyl group (e.g., a formyl, C _2-6 alkanoyl, benzoyl,
Optionally halogenated C _1-6 alkoxycarbonyl, optionally halogenated C _1-6 alkylsulfonyl, benzenesulfonyl and the like) optionally substituted carbamoyl group, 1-azetidinylcarbonyl, 1
-Pyrrolidinyl carbonyl, piperidino carbonyl, morpholino carbonyl, 1-piperazinyl carbonyl, etc.), a fat which may have one or more hetero atoms (nitrogen atom, sulfur atom, oxygen atom, etc.) in the ring. A cyclic hydrocarbon group (eg, morpholinolino group, morpholinyl group, piperidino group, piperidyl group, pyrrolidinyl group, tetrahydrofuryl group, pyrazolidinyl group, piperazinyl group, quinuclidinyl group, etc.) can be used, and any of these substituents can be used. May have 1 to 3 substitutions at substitutable positions.

The "optionally substituted amino group", the "optionally substituted hydroxyl group", and the "optionally substituted amidino" as the substituents of the above-mentioned "optionally substituted alkyl group". As the "group", a "optionally substituted amino group", a "optionally substituted hydroxyl group", and a "group which may be substituted" in the "optionally substituted aromatic homocycle or heterocycle" described later are mentioned. The same thing as the "optionally substituted amidino group" can be used.

Examples of the alkenyl group in the "optionally substituted alkenyl group" as the substituent include vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1
-Butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,
C _2-6 such as 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like.
Alkenyl and the like can be used. Here, as the substituent of the alkenyl, the same number of the same substituents as those in the above-mentioned “optionally substituted alkyl group” as the substituent can be used.

Examples of the alkynyl group in the above-mentioned "optionally substituted alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl. C _2-6 alkynyl such as 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl can be used. Here, as the substituent of the alkynyl group, the same number of substituents as those in the above-mentioned "optionally substituted alkyl group" as the substituent can be used.

As the aryl group in the "optionally substituted aryl group" as the substituent, for example, C _6-14 aryl such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like can be used. Here, as the substituent of the aryl group, the “optionally substituted alkyl group” as the above-mentioned substituent
The same number of similar groups as the substituents in can be used.

The aralkyl group in the "optionally substituted aralkyl group" as the substituent is, for example, C such as benzyl, phenethyl, naphthylmethyl and the like.
_7-11 aralkyl and the like can be used. here,
As the substituent of the aralkyl group, the same number of the same substituents as those in the above-mentioned "optionally substituted alkyl group" as the substituent can be used.

As the cycloalkyl group in the "optionally substituted cycloalkyl group" as the substituent, for example, C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like can be used. You can Here, as the substituent of the cycloalkyl group, the same number of substituents as those in the above-mentioned "optionally substituted alkyl group" as the substituent can be used.

As the cycloalkenyl group in the "optionally substituted cycloalkenyl group" as the substituent, for example, C _3-7 cycloalkenyl such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like are used. You can Here, as the substituent of the optionally substituted cycloalkenyl group, the same number of the same substituents as those in the above-mentioned "optionally substituted alkyl group" can be used. .

The heterocyclic group in the “optionally substituted heterocyclic group” as the substituent is, for example, an atom (ring atom) constituting the ring system selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like. Aromatic heterocyclic group containing at least one (preferably 1 to 4, more preferably 1 to 2) heteroatoms 1 to 3 (preferably 1 to 2), saturated or unsaturated non-aromatic Group heterocyclic groups (aliphatic heterocyclic groups) and the like can be used. Here, examples of the “aromatic heterocyclic group” include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,
2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,3-triazolyl,
5- to 6-membered monocyclic aromatic heterocyclic groups such as 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, and for example benzofuranyl, isobenzofuranyl, benzo [ b ].
Thienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl,
1,2-benzisoxazolyl, benzothiazolyl,
Benzopyranyl, 1,2-benzisothiazolyl, 1H
-Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxadinyl. Nyl, thianthrenyl, phenatridinyl, phenatorolinyl, indoridinyl, pyrrolo [1,2- b ] pyridazinyl, pyrazolo [1,5- a ] pyridyl, imidazo [1,2- a ].
Pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,2- b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,2,4-triazolo [4,3- a ] pyridyl, 1, 8 to 12-membered condensed polycyclic aromatic heterocyclic group such as 2,4-triazolo [4,3- b ] pyridazinyl (preferably, the aforementioned 5- to 6-membered monocyclic aromatic heterocyclic group is benzene). A heterocyclic group condensed with a ring or a heterocyclic group in which two identical or different heterocycles of the above-mentioned 5 to 6-membered monocyclic aromatic heterocyclic group are condensed), more preferably the above-mentioned 5 to 6-membered A heterocyclic group in which a monocyclic aromatic heterocyclic group is condensed with a benzene ring, particularly preferably benzofuranyl,
Benzopyranyl, benzo [ b ] thienyl, etc.) and the like can be used.

As the "non-aromatic heterocyclic group", for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc. Preferably 5 to 6 membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group), or 1,2,3,4-tetrahydroquinolyl, 1,2, Three and four
Using a non-aromatic heterocyclic group in which some or all of the double bonds are saturated in the above-mentioned monocyclic aromatic heterocyclic group or condensed polycyclic aromatic heterocyclic group such as tetrahydroisoquinolyl be able to. The substituent which the “optionally substituted heterocyclic group” as a substituent may have is a lower alkyl group (eg, C such as methyl, ethyl and propyl).
_1-6 alkyl etc.), a lower alkenyl group (eg vinyl,
C _2-6 alkenyl such as allyl), a lower alkynyl group (eg C _2-6 alkynyl such as ethynyl and propargyl), an acyl group (eg C _1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, etc.), Benzoyl etc.), optionally substituted amino group, optionally substituted hydroxyl group, halogen atom (eg fluorine, chlorine, bromine, iodine etc., preferably chlorine, bromine etc.), optionally substituted imidoyl group Alternatively, an amidino group which may be substituted may be used. These optional substituents are 1 to 5 (preferably 1 to 3) at substitutable positions.
Individual) may be substituted. The “optionally substituted heterocyclic group” as the substituent may have “optionally substituted amino group”, “optionally substituted hydroxyl group”, “optionally substituted” The “imidoyl group” and the “optionally substituted amidino group” are the “optionally substituted aromatic homolog or heterocyclic group” described later.
An “optionally substituted amino group” as a substituent of
The same groups as the "optionally substituted hydroxyl group", "optionally substituted imidoyl group", and "optionally substituted amidino group" can be used.

As the substituent, “may be substituted”
"Amino group", "optionally substituted imidoyl"
Group "," optionally substituted amidino group "," substituted "
Optionally substituted hydroxyl group ”,“ optionally substituted thiol ”
Examples of the substituent in the “aryl group” include halogen.
Atom (eg fluorine, chlorine, bromine, iodine etc.), halogen
C which may be converted to_1-6Alkoxy (eg Metho
Xy, ethoxy, trifluoromethoxy, 2,2,2-
Trifluoroethoxy, trichloromethoxy, 2,2
2-trichloroethoxy) and C_7-11Alkyl
Aryl groups (eg o-toluyl, m-toluyl, p-toluy)
Ru, xylyl, mesityl, etc., preferably C_{1 -5}Archi
Substituted with a substituent selected from
A lower alkyl group (eg, methyl, ethyl, propyl
, Isopropyl, butyl, isobutyl, tert-butyl
C such as le, pentyl and hexyl_1-6Alkyl, etc.)
Sil group (C _1-6Alkanoyl (eg formyl, acetyl
, Propionyl, pivaloyl, etc.), benzoyl, C
_1-6Alkylsulfonyl (eg, methanesulfonyl)
Etc.), benzenesulfonyl etc.), halogenated
Good C_1-6Alkoxycarbonyl group (eg, methoxy
Carbonyl, ethoxycarbonyl, trifluoromethoxy
Cycarbonyl, 2,2,2-trifluoroethoxycarb
Bonyl, trichloromethoxycarbonyl, 2,2,2-
Substituted with phenyl group)
May be C_1-6Alkoxycarbonyl group
(Eg, benzyloxycarbonyl, etc.), aryl (eg,
C such as phenyl, 1-naphthyl and 2-naphthyl_{6- 10}
Aryl etc.), aralkyl (eg benzyl, phenethyl)
Such as C_7-10Aralkyl, preferably Phenyl-C
_1-4Alkyl, etc., arylalkenyl (eg, cinna)
C such as mill_8-10Arylalkenyl, preferably
Phenyl-C_{2- Four}Alkenyl etc.), heterocyclic group (the above-mentioned substitution
In the "optionally substituted heterocyclic group" as a group
The same as the "heterocyclic group", preferably pyridyl, and further
And preferably 4-pyridyl etc.
It These optional substituents have 1 to 1 at the substitutable position.
You may substitute 3 pieces.

Further, as the above-mentioned substituent, "substituted
The “amino group” in the “optionally substituted amino group” is substituted
Optionally imidoyl groups (eg C_1-6Alkyl
Imidoyl (eg formylimidoyl, acetylimide
Ill etc.), C_1-6Alkoxyimidoyl, C_1-6A
Rutilethioimidoyl, amidino, etc.), 1 to 2 C
_1-6An amino group which may be substituted with an alkyl group, etc.
It may be substituted. Any of these substituents can be substituted
One or two may be substituted at any available position. Also, 2
Substituents together with the nitrogen atom form a cyclic amino group
In some cases, as a cyclic amino group
Is, for example, 1-azetidinyl, 1-pyrrolidinyl, pipet
Lysino, thiomorpholino, morpholino, 1-piperazini
And lower alkyl at the 4-position (eg, methyl, ethyl, propyl
Ropil, isopropyl, butyl, t-butyl, pliers
C such as le and hexyl_1-6Alkyl, etc.), aralkyl
(Eg C such as benzyl, phenethyl, etc._7-10Aralkyl
Etc.), aryl (eg, phenyl, 1-naphthyl, 2-na)
C such as futile_6-10Aryl etc.) and the like
1-piperazinyl, 1-pyrrolyl, 1-imidazolyl
A 3- to 8-membered (preferably 5- to 6-membered) cyclic amino, etc.
Can be used.

Examples of the alkylsulfinyl group in the “optionally substituted alkylsulfinyl group” as the substituent include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, se
C such as c-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl and hexylsulfinyl
_1-6 alkylsulfinyl can be used. Here, as the substituent of alkylsulfinyl, the same number of substituents as the above-mentioned substituent in the “optionally substituted alkyl” can be used.

The "esterified or amidated carboxyl group" as the substituent is as follows:
Carboxyl groups, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, carbamoyl, N-monosubstituted carbamoyl and N, N-disubstituted carbamoyl can be used. Here, as the “alkoxycarbonyl”, for example, methoxycarbonyl,
C _1-6 alkoxycarbonyl such as ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl (lower Alkoxycarbonyl) and the like can be used, and among them, C _1-3 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like are preferable. The "lower alkoxycarbonyl" may have a substituent,
As the substituent, a hydroxyl group or an optionally substituted amino group [the amino group is, for example, lower alkyl optionally substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) Groups (eg, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, tert-
C _1-6 alkyl such as butyl, pentyl and hexyl,
C _1-6 such as preferably methyl, ethyl, etc., acyl group (eg, formyl, acetyl, propionyl, pivaloyl, etc.)
Alkanoyl, benzoyl, etc.), carboxyl group, C
_It may have 1 or 2 such as _1-6 alkoxycarbonyl as a substituent. ], A halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, 1
To a lower alkoxy group (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy) optionally substituted with 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkoxy such as tert-butoxy, etc., preferably methoxy, ethoxy etc.) and the like can be used. Further, these substituents are preferably the same or different and substituted by 1 or 2 to 3 (preferably 1 or 2).

As the "aryloxycarbonyl", for example, C _6-14 aryloxycarbonyl such as phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl, 1-phenanthoxycarbonyl and the like are preferable. The “aryloxycarbonyl” may have a substituent, and as the substituent, the same number of the same substituents as the above-mentioned substituents in the “alkoxycarbonyl” can be used. As the “aralkyloxycarbonyl”, for example, C _7-14 aralkyloxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl and the like (preferably C _6-10 aryl-C _1-4 alkoxy-carbonyl and the like) is preferable. The "aralkyloxycarbonyl" may have a substituent, and as the substituent, the same number of the same substituents as the above-mentioned substituents in the "alkoxycarbonyl" can be used. Here, “N-monosubstituted carbamoyl” means a carbamoyl group having one substituent on the nitrogen atom, and examples of the substituent include lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl). ,
tert- butyl, pentyl, _{C 1-6} alkyl such as hexyl, etc.), lower alkenyl (e.g., vinyl, allyl, isopropenyl, propenyl, butenyl, pentenyl, _{C 2-6} alkenyl hexenyl, etc.), cycloalkyl (e.g. , C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
Aryl (eg, C _6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl etc.), aralkyl (eg, C _7-10 aralkyl such as benzyl, phenethyl, etc., preferably phenyl-C _1-4 alkyl etc.), Arylalkenyl (eg, C _8-10 arylalkenyl such as cinnamyl,
Preferably, phenyl-C _2-4 alkenyl, etc.), a heterocyclic group (for example, the same as the “heterocyclic group” in the “optionally substituted heterocyclic group” as the substituent), etc. can be used. it can. The lower alkyl, lower alkenyl, cycloalkyl, aryl, aralkyl, arylalkenyl, and heterocyclic group may have a substituent, and the substituent may be the substituent in the above "alkoxycarbonyl". A similar number of can be used.

Here, "N, N-disubstituted carbamoyl" means a carbamoyl group having two substituents on the nitrogen atom, and one example of the substituent is "N- as the above-mentioned substituent. The same substituents as those in the “mono-substituted carbamoyl” can be used, and as another example, for example, lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like C _{1 -6} alkyl, etc.), C _3-7 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _7-10 aralkyl (eg,
Benzyl, phenethyl and the like, preferably phenyl-C
_1-4 alkyl etc.) and the like can be used. Also, 2
In some cases, the substituents together with the nitrogen atom form a cyclic amino, and in such a case, cyclic aminocarbamoyl includes, for example, 1-azetidinylcarbonyl, 1-
Pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl and lower alkyl at the 4-position (eg methyl, ethyl, propyl,
Isopropyl, butyl, tert- butyl, pentyl, _{C 1-6} alkyl such as hexyl, etc.), aralkyl (e.g., benzyl, _{C 7- 10} aralkyl phenethyl, etc.), aryl (e.g., phenyl, 1-naphthyl, 2- C _6-10 aryl such as naphthyl and the like) 3 to 8 members such as 1-piperazinylcarbonyl which may have (preferably 5 to 6)
Member) cyclic aminocarbonyl and the like can be used.

The substituents of the “optionally substituted thiocarbamoyl group” and the “optionally substituted sulfamoyl group” as the substituents are the “esterified or amidated” as the substituents. The same substituents as "N-monosubstituted carbamoyl" and "N, N-disubstituted carbamoyl" in the "good carboxyl group" can be used.

As the "acyl derived from sulfonic acid" as the substituent, for example, the one in which the above-mentioned "N-monosubstituted carbamoyl" having one substituent on the nitrogen atom and sulfonyl are bonded can be used. However, preferably, C _1-6 such as methanesulfonyl, ethanesulfonyl, etc.
Acyl such as alkylsulfonyl can be used.

As the "carboxylic acid-derived acyl" as the substituent, one having a hydrogen atom or the above-mentioned "N-monosubstituted carbamoyl" having one substituent on the nitrogen atom and carbonyl is used, etc. However, preferably, C _1-6 alkanoyl such as formyl, acetyl, propionyl and pivaloyl, and acyl such as benzoyl can be used.

"Aromatic hydrocarbon group which may be substituted" represented by Q ¹ , Q ² , Q ³ , Q ⁴ and R ^1a , and "substituted by an aromatic hydrocarbon group represented by Q, R ^1d , R ² and R ⁸ " _Optionally substituted C _6-10 aryl group ”and“ substituted C _{6-10 represented} by R ^1b and R ^1c.
As the substituent that the “aryl group” may have or has, the same number of the same substituents as those in the above-mentioned “optionally substituted alkyl group” can be used.

The substituent which the “optionally substituted aromatic heterocyclic group” represented by Q may have is, as the above-mentioned substituent, “optionally substituted heterocyclic group”.
The same number of similar substituents as those which may have can be used.

"Optionally substituted alicyclic hydrocarbon group" represented by Q ¹ , Q ² , Q ³ , Q ⁴ , R ^1a and "substituted" represented by R ^1d , R ² , R ⁸ The "optionally substituted C _3-8 cycloalkyl group" and the "substituted C _3-8 cycloalkyl group" represented by R ^1b and R ^1c may have or have the above-mentioned substituents. The same number of the same groups as the substituents in the “optionally substituted alkyl group” can be used.

“Optionally substituted C” represented by R ²
_{As the} substituent that the “ _1-6 alkyl group” may have, the same number of the same substituents as those in the above-mentioned “optionally substituted alkyl group” as the substituent can be used. .

The substituent which the “optionally substituted nitrogen atom” represented by X, X ^a , Y, W ¹ , W ² , W ³ and W ⁴ may have is the above-mentioned substituent. The same substituents as those in the "optionally substituted amino group" can be used.

"May be substituted 1
And the above-mentioned "divalent aliphatic hydrocarbon group which may have a hetero atom" and "divalent aliphatic hydrocarbon group which may be substituted" represented by W ¹ , W ² , W ³ and W ^4. As the substituent that "may have," the same number of substituents as those in the above-mentioned "optionally substituted alkyl group" as the substituent can be used.

In R ¹ , R ^1a , R ^1b , R ^1c and R ^1d ,
An optionally substituted aromatic hydrocarbon group, an optionally substituted heterocyclic group and the like are preferable, and an optionally substituted phenyl group is particularly preferable. R ^{3 to} R ⁷ are the same or different and are preferably a C _1-6 alkoxy group which may be substituted with a hydrogen atom or a halogen atom. T, T ^a and T ^b is a single bond, a methylene group, an ethylene group or a vinylene group or the like, are preferable. X, X ^a and X ^b are preferably an optionally substituted nitrogen atom. Y, Y ^a and Y ^b is preferably a nitrogen atom. Z, Z ^a and Z ^b are preferably nitrogen atoms. W,
W ^a , W ^b , W ¹ , W ² , W ³ , W ⁴ , W ^1a , W ^2a , W ^3a and W ^4a are
A single bond, methylene, an oxygen atom and the like are preferable. Q, Q ¹ ,
Q ² , Q ³ and Q ⁴ are preferably a halogen atom, an optionally substituted aromatic hydrocarbon group or an optionally substituted heterocyclic group, etc., particularly preferably a halogen atom or a substituent group respectively. A phenyl group, a naphthyl group, a furyl group, a thienyl group, a benzofuryl group and the like which may be used are used. Further, the substituent in this case is preferably a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom. X is an optionally substituted nitrogen atom and Y = Z
A compound having a nitrogen atom is preferable. A compound in which X is an optionally substituted nitrogen atom and Y = Z ^a = nitrogen atom is preferable. A compound in which X ^a is an optionally substituted nitrogen atom and Y ^a = Z ^a = nitrogen atom is preferable.

In the general formula (IX), when W ^a represents ^a single bond,

[Chemical 21] [In the formula, each symbol has the same meaning as defined above. ] Or a salt thereof, represented by the general formula (X):
^{When a} represents ^a single bond,

[Chemical formula 22]

[In the formula, each symbol has the same meaning as defined above. ] It represents the compound represented by this, or its salt. Also,
In the general formula (IX), when T ^a and W ^a represent ^a single bond,

[Chemical formula 23] [In the formula, each symbol has the same meaning as defined above. ] The compound or its salt represented by these is represented by the general formula (X).
^{When a} and W ^a represent ^a single bond,

[Chemical formula 24] [In the formula, each symbol has the same meaning as defined above. ] It represents the compound represented by this, or its salt. In the present application, the compounds represented by these (IXa), (IXb), (Xa) and (Xb) are particularly preferable.

The compounds according to the present invention are preferably compounds represented by the above general formulas (I) to (XI), and particularly preferably the following general formulas (I '), (III') and (V ' ), (VI ') ~ (X
The compound represented by I ') is used.

[Chemical 25] [In the formula, each symbol has the same meaning as defined above. ] The compound or its salt represented by these;

[Chemical formula 26] [In the formula, each symbol has the same meaning as defined above. ] The compound or its salt represented by these;

[Chemical 27] [In the formula, each symbol has the same meaning as defined above. ] The compound or its salt represented by these;

[0060]

[Chemical 28] [In the formula, each symbol has the same meaning as defined above. ] The compound or its salt represented by these;

[Chemical 29] [In the formula, each symbol has the same meaning as defined above. ] The compound or its salt represented by these;

[Chemical 30] [In the formula, each symbol has the same meaning as defined above. ] The compound or its salt represented by these;

[0061]

[Chemical 31] [In the formula, each symbol has the same meaning as defined above. ] The compound or its salt represented by these;

[Chemical 32] [In the formula, each symbol has the same meaning as defined above. ] The compound or its salt represented by these;

[Chemical 33] [In the formula, each symbol has the same meaning as defined above. ] It is a compound or its salt represented by these.

In the present invention, the compounds represented by the general formulas (I) to (XI) and (I '), (III'), (V '), (VI') to (XI ') form salts. The salt is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a basic or acidic amino acid. Salt and the like are used. Preferable examples of the salt with an inorganic base include sodium salt,
Alkali metal salts such as potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; ammonium salts and the like. Suitable examples of salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine,
Salts with diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, etc. are used. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -A salt such as toluenesulfonic acid is used. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. To be

Further, when the compound of the present invention has an asymmetric carbon, optical isomers occur, and the present invention includes both these isomers alone and a mixture thereof. The compound of the present invention or a salt thereof may be a hydrate or a non-hydrate. Furthermore, the compound of the present invention may be labeled with an isotope (eg, ³ H, ¹⁴ C, etc.) and the like.

The compound (I) and the like according to the present invention can be produced by a method known per se, for example, the method shown below. The raw material compound and the synthetic intermediate may be used in the form of a free form as well as a salt similar to compound (I) and the like (the salt may be, for example, compound (I)).
And the like. ), Or may be used for the reaction as it is or after isolation by a known means. Compound (IVa-c) was prepared according to J. Me
d. Chem. (Journal of Medicinal Chemistry) Vol. 28, pp. 717-727 (1985) or a method analogous thereto.

Manufacturing Method 1 Manufacturing Method 1a

[0066]

[Chemical 34] [In the formula, each symbol has the same meaning as defined above, Y ^b represents an oxygen atom or a sulfur atom, Hal represents a halogen atom, and Pd represents a palladium catalyst. ]

Production Method 1b

[Chemical 35] [In the formula, each symbol has the same meaning as defined above, and X ^b represents an oxygen atom or a sulfur atom. ]

(Production Method 1a) A commercially available compound (IIa) is subjected to a commonly used reducing condition of a nitro group. Examples of the reducing condition include a combination of iron powder and a suitable acid such as hydrochloric acid, or a method such as catalytic reduction in which hydrogenation is performed in the presence of a palladium catalyst. The reaction is generally carried out in a suitable solvent, eg ethanol. The reaction temperature may be in the range of 0 ° C to 100 ° C. The reaction time is usually 30 minutes to 8 hours. Under the condition of using iron, it is desirable that the temperature is 80 ° C. for several hours in ethanol. The obtained compound (IIIa) is dehydrated and condensed with a carboxylic acid compound R ¹ COOH under an appropriate condensation condition to obtain the compound (IV
a) is obtained. Appropriate condensation conditions are, for example, heating in polyphosphoric acid ester (PPE) while stirring, or adding and heating an appropriate amount of diphosphorus pentoxide in methanesulfonic acid, or stirring in phosphorus oxychloride. The method of heating is mentioned. The reaction temperature may be room temperature to 180 ° C, preferably 100 ° C to 140 ° C. The reaction time is 1 to 12 hours. Compound (IVa) is dissolved in a solvent that does not influence the reaction, such as toluene, tetrahydrofuran, dimethoxyethane, etc., and in the presence of a suitable base, a suitable catalyst, for example, a palladium catalyst such as tetrakistriphenylphosphine palladium is added, and The compound (Ia) is obtained by heating and stirring with a suitable organic boric acid compound QB (OH) _{2 in} an active gas atmosphere. The reaction temperature can be from room temperature to about 100 ° C. The reaction time is 1 to 12 hours. The organic boric acid compound QB (OH) ₂ is preferably in an equivalent amount to a slight excess amount. Examples of the “base” include sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate,
Inorganic bases such as sodium hydroxide, potassium hydroxide and thallium hydroxide, or organic bases such as triethylamine and pyridine are used. The amount of the "base" to be used is about 2 mol-20 mol, preferably about 5 mol-12 mol, relative to 1 mol of compound (IVa). Compound (Ib) can also be produced from compound (IIb) in the same manner as in (Production method 1b).

Manufacturing Method 2 Manufacturing Method 2a

[0070]

[Chemical 36] [In the formula, each symbol has the same meaning as defined above, and W ^b represents NH, an oxygen atom, or a sulfur atom, respectively. ]

Production Method 2b

[Chemical 37] [In the formula, each symbol has the same meaning as defined above. ]

(Production Method 2a) Compound Obtained by Production Method 1
(IVa) is a solvent that does not influence the reaction, such as ethers (eg, ethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg. , Dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.) and the like, and under a basic condition, an appropriate catalyst, such as copper iodide or copper oxide. When an ionic catalyst is added and the nucleophilic reagent HW ^b Q is heated and stirred, (Ia ')
The compound is obtained. The reaction temperature is from room temperature to about 1
It can be carried out at 00 ° C. Reaction time is from 1 hour to 12
It's time. Reagent HW ^b Q with nucleophilic property, a slight excess is desirable eq. Examples of the "base" include inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and thallium hydroxide, or triethylamine,
An organic base such as pyridine is used. The amount of the "base" to be used is about 2 mol-20 mol, preferably about 5 mol-12 mol, relative to 1 mol of compound (IVa). (Production method 2b) Similarly, compound (Ib ') is obtained from compound (IVb) obtained in production method 1b.

Manufacturing Method 3

[Chemical 38] [In the formula, each symbol has the same meaning as defined above. ]

The commercially available compound (IIc) is subjected to a commonly used nitro group reducing condition. Examples of the reducing condition include a combination of iron powder and a suitable acid such as hydrochloric acid, or a method such as catalytic reduction in which hydrogenation is performed in the presence of a palladium catalyst. The reaction is carried out in a suitable solvent,
For example, it is generally performed in ethanol. The reaction temperature may be in the range of 0 ° C to about 100 ° C. The reaction time is usually 30 minutes to 8 hours. Under the condition of using iron, it is desirable that the temperature is 80 ° C. for several hours in ethanol. The obtained compound (IIIc) is dehydrated and condensed with a carboxylic acid compound R ¹ COOH under a suitable condensation condition to obtain a compound (IVc). Appropriate condensation conditions are, for example, heating in polyphosphoric acid ester (PPE) while stirring, or adding and heating an appropriate amount of diphosphorus pentoxide in methanesulfonic acid, or stirring in phosphorus oxychloride. The method of heating is mentioned. The reaction temperature ranges from room temperature to 180
C., preferably 100 to 140.degree. C. The reaction time is 1 to 12 hours. Compound (IV
c) is dissolved in a solvent that does not influence the reaction, for example, toluene, tetrahydrofuran, dimethoxyethane or the like,
In the presence of a suitable base, a suitable catalyst, for example, a palladium catalyst such as tetrakistriphenylphosphine palladium is added, and a suitable organoboric acid compound Q- is added under an inert gas atmosphere.
When heated and stirred with B (OH) ₂ , the (Vc) compound is obtained. The reaction temperature can be from room temperature to about 100 ° C. The reaction time is 1 to 12 hours. The organic boric acid compound QB (OH) ₂ is preferably in an equivalent amount to a slight excess amount.
As the "base", for example, an inorganic base such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide or thallium hydroxide, or an organic base such as triethylamine or pyridine is used. The amount of the “base” used is the compound (I
Vc) to 1 mol, about 2 to 20 mol, preferably,
It is about 5 to 12 mol. The obtained compound (Vc), a solvent that does not influence the reaction, for example, ethers (eg, ethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (e.g., dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.) is dissolved in such, under basic conditions, by reaction with a halide R ₂ -Hal, compound ( Ic) is obtained. Examples of the “base” include sodium carbonate, sodium hydrogen carbonate,
Potassium carbonate, potassium hydrogen carbonate, sodium hydroxide,
Inorganic bases such as potassium hydroxide, thallium hydroxide, sodium hydride, or triethylamine, pyridine,
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), an organic base such as BEMP resin is used. The amount of the “base” to be used is about 1 mol-10 mol, relative to 1 mol of compound (Vc),
It is preferably about 1 to 3 mol. Halide R ₂
The amount of -Hal used is about 1 mol-10 mol, preferably about 1 mol-2 mol, per 1 mol of compound (Vc). The reaction temperature can be 0 ° C to 100 ° C, preferably room temperature to 50 ° C. The reaction time is 1 hour to 24 hours.

Production Method 4

[Chemical Formula 39] [In the formula, each symbol has the same meaning as defined above. ]

The compound (IVc) obtained by the production method (3) is
Solvents that do not affect the reaction, such as ethers (eg,
Ethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, etc., aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane) Etc.) and the like, and under a basic condition, a suitable catalyst, for example, a copper ion catalyst such as copper iodide or copper oxide is added if necessary, and the mixture is heated with a nucleophilic reagent HW ^b Q and heated ( Vc ') compound is obtained. The reaction temperature can be from room temperature to about 100 ° C. The reaction time is 1 to 12 hours.
Reagent HW ^b Q with nucleophilic property, a slight excess is desirable eq. As the "base", for example, an inorganic base such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide or thallium hydroxide, or an organic base such as triethylamine or pyridine is used. The amount of the "base" to be used is about 2 mol-20 mol, preferably about 5 mol-12 mol, relative to 1 mol of compound (IVc). Obtained compound (Vc ')
Is a solvent that does not influence the reaction, such as ethers (eg, ethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, dimethylformamide) , Dimethylacetamide, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.) and the like, under basic conditions, halide R ₂ -H
The compound (Id) is obtained by reacting with al.
Examples of the "base" include inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, thallium hydroxide and sodium hydride, or triethylamine, pyridine, 2-tert. -Butylimino-2-diethylamino
-1,3-Dimethylperhydro-1,3,2-diazaphosphorine (BE
MP), an organic base such as BEMP resin, or the like is used. The amount of the “base” to be used is about 1 mol-10 mol, preferably about 1 mol-3 mol, relative to 1 mol of compound (Vc ′).
The amount of the halide R ₂ -Hal used is about 1 mol to 10 mol, preferably about 1 mol to 1 mol of the compound (Vc ′).
2 mol. The reaction temperature can be 0 ° C to 100 ° C, preferably room temperature to 50 ° C. The reaction time is 1 hour to 24 hours.

Production Method 5

[Chemical 40] [In the formula, each symbol has the same meaning as defined above. ]

A commercially available compound (IIc) is dissolved in a solvent that does not influence the reaction, such as toluene, tetrahydrofuran, dimethoxyethane, etc., and the compound is added in the presence of a suitable base, a suitable catalyst such as tetrakistriphenylphosphine palladium. When a palladium catalyst such as the above is added, and the mixture is heated and stirred with a suitable organic boric acid compound QB (OH) ₂ in an inert gas atmosphere, the compound (IIIe) is obtained. The reaction temperature can be from room temperature to about 100 ° C.
The reaction time is 1 to 12 hours. The organic boric acid compound QB (OH) ₂ is preferably in an equivalent amount to a slight excess amount. As the "base", for example, an inorganic base such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide or thallium hydroxide, or an organic base such as triethylamine or pyridine is used. The amount of the “base” used is the compound (II
c) about 2 to 20 moles, preferably 1 mole,
It is about 5 to 12 mol. The obtained compound (IIIe),
Subject to the commonly used nitro group reduction conditions. Examples of the reducing condition include a combination of iron powder and a suitable acid such as hydrochloric acid, or a method such as catalytic reduction in which hydrogenation is performed in the presence of a palladium catalyst. The reaction is generally carried out in a suitable solvent, eg ethanol. The reaction temperature may be in the range of 0 ° C to about 100 ° C. The reaction time is usually 30 minutes to 8 hours. Under the condition of using iron, it is desirable that the temperature is 80 ° C. for several hours in ethanol. The obtained compound (IVe) is dehydrated and condensed with a carboxylic acid compound R ¹ COOH under a suitable condensation condition to obtain a compound (Ie). Appropriate condensation conditions are, for example, heating in polyphosphoric acid ester (PPE) while stirring, or adding and heating an appropriate amount of diphosphorus pentoxide in methanesulfonic acid, or stirring in phosphorus oxychloride. The method of heating is mentioned. The reaction temperature ranges from room temperature to 180
C., preferably 100 to 140.degree. C. The reaction time is 1 to 12 hours.

Production Method 6

[Chemical 41] [In the formula, each symbol has the same meaning as defined above. ]

A commercially available compound (IIc) is used as a solvent which does not influence the reaction, such as ethers (eg, ethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene). , Toluene, etc.), amides (eg, dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.) and the like, and under a basic condition, an appropriate catalyst, for example, A (IIIe ′) compound is obtained by adding a copper ion catalyst such as copper iodide or copper oxide and heating and stirring with a nucleophilic reagent HW ^b Q. The reaction temperature can be from room temperature to about 100 ° C. The reaction time is 1 to 12 hours. Reagent HW ^b Q with nucleophilic property, a slight excess is desirable eq. Examples of the “base” include sodium carbonate,
An inorganic base such as sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide or thallium hydroxide, or an organic base such as triethylamine or pyridine is used. The amount of the “base” to be used is about 2 mol-20 mol, relative to 1 mol of compound (IIc),
It is preferably about 5 to 12 mol. The obtained compound (IIIe ′) is subjected to a commonly used nitro group reducing condition. Examples of the reducing condition include a combination of iron powder and a suitable acid such as hydrochloric acid, or a method such as catalytic reduction in which hydrogenation is performed in the presence of a palladium catalyst. The reaction is generally carried out in a suitable solvent, eg ethanol. The reaction temperature may be in the range of 0 ° C to about 100 ° C. The reaction time is usually 30 minutes to 8 hours. Under the condition of using iron, it is desirable that the temperature is 80 ° C. for several hours in ethanol. The obtained compound (IVe ′) is dehydrated and condensed with a carboxylic acid compound R ¹ COOH under a suitable condensation condition to obtain a compound (Ie ′). Suitable condensation conditions include, for example, heating in polyphosphate ester (PPE) with stirring,
Alternatively, a method of adding an appropriate amount of phosphorus pentoxide in methanesulfonic acid and stirring with heating, or heating with stirring in phosphorus oxychloride may be mentioned. The reaction temperature may be room temperature to 180 ° C, preferably 100 ° C to 140 ° C. The reaction time is 1 to 12 hours.

When the desired compound is obtained as a mixture of optically active compounds, it can be separated into the desired (R) form or (S) form by an optical resolution means known per se. Specifically, for example, an optically active column (eg, CHIR
Optical resolution can be efficiently carried out by using ALPAK AD, manufactured by Daicel Chemical Industries. Further, a diastereomer salt with an optically active acid is formed, and a desired optically active substance can be separated by utilizing the difference in solubility. When the compound of the present invention is obtained in a free state, it may be converted into a salt according to a conventional method, and when obtained as a salt, it may be converted into a free form or another salt according to a conventional method. it can. The compounds thus obtained and their optically active substances can be isolated and purified from the reaction solution by known means such as phase transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization and chromatography.

In each of the above-mentioned reactions, a protecting group may be used for the amino group, carboxyl group and hydroxyl group which are not involved in the reaction in the compound or salt thereof to be subjected to the reaction. Can be performed by known means. As a method for removing the protective group, a method known per se or a method analogous thereto can be used, and examples thereof include acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, and tetrabutylammonium fluoride. A method of treating with palladium acetate or the like is used.

A prodrug of compound (I) or the like or a salt thereof (hereinafter abbreviated as compound (I) or the like) is converted to compound (I) or the like by reaction with an enzyme, gastric acid or the like under physiological conditions in vivo. Compound, that is, a compound which is enzymatically oxidized, reduced, hydrolyzed or the like to be converted into a compound (I) or the like, or a compound (I) which is hydrolyzed by a gastric acid or the like
And so on. Examples of prodrugs of compound (I) and the like include compounds in which amino group (nitrogen) of compound (I) is acylated, alkylated or phosphorylated (eg, amino group (nitrogen) of compound (I) or the like is eicosanoyl. , Alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert -Butylated compound, etc.); Compound (I) or the like whose hydroxyl group is acylated, alkylated, phosphorylated, borated (eg, compound (I) or the like is acetylated, palmitoylated, propanoylated) , Pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); A compound in which a xyl group is esterified or amidated (eg, a carboxyl group of a compound (I) or the like is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, Ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound and the like); Etc. are used. These compounds can be produced from compound (I) and the like by a method known per se.

Further, prodrugs such as compound (I) are
Hirokawa Shoten The compound (I) may be changed under physiological conditions as described in 1990, "Development of Pharmaceuticals", Volume 7, Molecular Design, pages 163 to 198. In addition, the prodrug of compound (I) and the like may be either a hydrate or a non-hydrate. Further, the compound having one or more asymmetric carbons in the molecule, and any compound having R configuration or S configuration with respect to these asymmetric carbons is included in the present invention.

The compound (I) or the like of the present invention or a salt thereof or a prodrug thereof (hereinafter sometimes abbreviated as the compound of the present invention or the compound of the present invention) has an action of inhibiting tyrosine kinase, It can be used for the prevention or treatment of diseases that depend on tyrosine kinase in mammals. Diseases that depend on tyrosine kinases include diseases that promote cell proliferation due to abnormal tyrosine kinase enzyme activity. Further, the compounds of the present invention are
In order to specifically inhibit HER2 tyrosine kinase, H
It is also useful as a therapeutic agent that suppresses the growth of ER2-expressing cancers and as a preventive agent that prevents the transition of hormone-dependent cancers into hormone-independent cancers. In addition, in the present application, inhibiting tyrosine kinase means acting directly on an enzyme as an antagonist of tyrosine kinase to inhibit its activity, and indirectly, for example, reducing the protein amount of tyrosine kinase or reducing the enzyme activity. As a result, it also includes inhibiting tyrosine kinase.

That is, the compound of the present invention is used for various cancers (among them, breast cancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain tumor, nerve sheath). Tumor, non-small cell lung cancer, small cell lung cancer, liver cancer, kidney cancer, bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, skin cancer,
Hemangiomas, malignant lymphomas, malignant melanomas, thyroid cancers, bone tumors, angiofibromas, retinal sarcomas, penile cancers, pediatric solid tumors, Kaposi's sarcomas, Kaposi's sarcomas due to AIDS, maxillary sinus tumors,
Fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, leukemia, etc., atherosclerosis, angiogenesis (eg, angiogenesis with growth of solid tumors and sarcomas, angiogenesis with tumor metastasis, and It can be used as a safe preventive or therapeutic agent for diseases caused by abnormal cell proliferation such as angiogenesis associated with diabetic retinopathy) and viral diseases (HIV infection etc.).

Further for tyrosine kinase dependent diseases:
Included are cardiovascular diseases associated with aberrant tyrosine kinase enzyme activity. Therefore, the compound of the present invention can also be used as a prophylactic or therapeutic agent for cardiovascular diseases such as restenosis. The compound of the present invention is useful for preventing cancer, particularly breast cancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, colon cancer, etc.
It is useful as an anti-cancer agent for treatment. The compound of the present invention has low toxicity and can be used as a drug as it is, or as a mixture with a pharmaceutically acceptable carrier known per se, etc. (eg, human, horse, cow, dog, cat, rat, mouse, rabbit) , Pigs, monkeys, etc.) as a pharmaceutical composition. Other active ingredients together with the compound of the present invention in a pharmaceutical composition, such as hormone therapeutic agents, anticancer agents (for example, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factor and its receptor, etc.) ) Etc. may be contained.

When the compound of the present invention is administered as a medicine to mammals such as humans, the administration method is usually, for example, tablets, capsules (including soft capsules and microcapsules), powders, granules, etc. orally or by injection. It can be parenterally administered as a drug, suppository, pellet or the like.
"Parenteral" means intravenous, intramuscular, subcutaneous, organ, intranasal, intradermal, eye drop, intracerebral, rectal, vaginal and intraperitoneal, intratumoral, proximal to tumor, or the like. Includes direct lesion administration. The dose of the compound of the present invention depends on the administration route,
When orally administered as an anticancer agent to a patient (body weight 40 to 80 kg) having breast cancer or prostate cancer, for example, 0.5 to 100 mg / kg body weight per day, preferably 1 to 50 mg / kg body weight per day, depending on symptoms and the like. , And more preferably 1 to 25 mg / kg body weight per day. This amount can be administered once a day or divided into two to three times a day.

The compound of the present invention is mixed with a pharmaceutically acceptable carrier, and is orally or parenterally as a solid preparation such as tablets, capsules, granules and powders; or as a liquid preparation such as syrups and injections. Can be administered to. As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances that are commonly used as a formulation material are used. Excipients, lubricants, binders, disintegrants in solid formulations; solvents and dissolutions in liquid formulations It is blended as an auxiliary agent, a suspending agent, an isotonicity agent, a buffering agent, a soothing agent and the like. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used. Suitable examples of excipients include
For example, lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like are used. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch,
Carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like are used.

Suitable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Suitable examples of the suspending agent include stearyl triethanolamine,
Surfactants such as sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glycerin monostearate;
For example, polyvinyl alcohol, polyvinylpyrrolidone,
Hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose are used. Preferable examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffer agent include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Preferable examples of soothing agents include benzyl alcohol and the like. Preferable examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite,
Ascorbic acid or the like is used.

The pharmaceutical composition varies depending on the dosage form, administration method, carrier, etc., but the compound of the present invention is usually added in an amount of 0.1 to 95% (w / w) based on the total amount of the preparation, and the compound is prepared according to a conventional method. It can be manufactured. Also, a group consisting of (1) administering an effective amount of a compound of the present invention, (2) administering an effective amount of another anticancer agent, administering an effective amount of a hormone therapeutic agent, and non-drug therapy. By combining 1 to 3 selected from the above, it is possible to more effectively prevent and treat cancer. As the non-drug therapy, for example, surgery, radiation therapy, gene therapy, hyperthermia, cryotherapy, laser ablation therapy, etc. are used, and these may be used in combination of two or more.

For example, the compound of the present invention includes other hormone therapeutic agents, anticancer agents (eg, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factor and its receptor) (hereinafter referred to as concomitant drug (Abbreviated) and can be used in combination. The compound of the present invention shows an excellent anticancer activity even when used as a single agent, but by further combining with one or several of the above-mentioned concomitant drugs (multi-drug combination), the effect can be further enhanced. it can. Examples of the “hormone therapeutic agent” include phosfestrol, diethylstilbestrol, chlorotrianiserine, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, Mepartricin, raloxifene, olmeroxifene, levormeroxifene, anti-estrogens (eg, tamoxifen citrate, toremifene citrate, etc.), pill preparations, mepithiostane, testrolactone, aminoglutethiimide, LH-RH agonists (eg, goserelin acetate, Buserelin, leuprorelin, etc.), droloxifene,
Epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitors (eg, fadrozole hydrochloride,
Anastrozole, letrozole, exemestane, borozole, formestane, etc.), androgens (eg, flutamide, bicalutamide, nilutamide, etc.),
Delay the metabolism of 5α-reductase inhibitors (eg, finasteride, epristeride), corticosteroids (eg, dexamethasone, prednisolone, betamethasone, triamcinolone), androgen synthesis inhibitors (eg, abiraterone), retinoids and retinoids Drugs (eg, Liarozole, etc.) are used,
Among them, LH-RH agonists (eg, goserelin acetate,
Buserelin, leuprorelin, etc.) are preferred.

Examples of the "chemotherapeutic agent" include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents and the like. Examples of the “alkylating agent” include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carbocon, and the like.
Improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etogluside,
Carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, predonimustine, pumitepa, ribomustine, temozolomide, threosulfan, trofosfamide, zinostatin stimalamer, carbocon system, adzelecin. Sutin, bizeresin, etc. are used. Examples of the “antimetabolite” include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine ocfosphate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, Doxyfluridine, carmofur, gallocitabine, emitefur, etc.), aminopterin, leucovorin calcium, tabloid, butosine, folineate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritrexime, guadoxituridine, mitofuridone, mitofurin, mitofurin , Ambamustine, etc. are used. Examples of the "anti-cancer antibiotics" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride. , Neocarzinostatin, mithramycin, zarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and the like are used. As the "plant-derived anticancer agent", for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine and the like are used.

Examples of the "immunotherapy agent (BRM)" include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin,
BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, procodazole and the like are used. The "cell growth factor" in the "drugs that inhibit the action of cell growth factor and its receptor" may be any substance that promotes cell growth, and usually has a molecular weight of 20,000. In the following peptides, a factor that exerts an action at a low concentration by binding to a receptor is used. Specifically, (1) EGF (epidermal gr
owth factor) or a substance having substantially the same activity as that (eg, EGF, heregulin (HER2 ligand))
Etc.), (2) Insulin or a substance having substantially the same activity as that [eg, insulin, IGF (insul
in-like growth factor) -1, IGF-2, etc.], (3)
FGF (fibroblast growth factor) or a substance having substantially the same activity as that [eg, acidic FGF, basic FGF, KGF (keratinocyte growth factor), F
GF-10 etc.], (4) Other cell growth factors [eg C
SF (colony stimulating factor), EPO (erythro
poietin), IL-2 (interleukin-2), NGF (nerve
growth factor), PDGF (platelet-derived growth)
factor), TGFβ (transforming growth factor)
β), HGF (hepatocyte growth factor), VEGF
(Vascular endothelial growth factor)] and the like. The "cell growth factor receptor" may be any receptor as long as it has the ability to bind to the above-mentioned cell growth factor, and specifically, EGF receptor,
Hallegulin receptor (HER2), insulin receptor,
IGF receptor, FGF receptor-1 or FGF receptor-
2, etc. Examples of the "drug that inhibits the action of cell growth factor" include inhibitors of various kinases, trastuzumab (Herceptin (Herceptin (trademark): HER2 antibody), imatinib mesylate (Gleevec Gleevec (trademark)), Iressa (trademark). : ZD1839), Cetuximab, etc. In addition to the above agents, L-asparaginase, asegraton, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercury hematoporphyrin sodium, topoisomerase 1
I inhibitors (eg, irinotecan, topotecan, etc.), topoisomerase II inhibitors (eg, sobuzoxane, etc.), differentiation inducers (eg, retinoids, vitamin Ds, etc.), angiogenesis inhibitors, α-blockers (eg, tamsulosin hydrochloride) Etc.) can also be used. Among the above, as a concomitant drug, an LH-RH agonist (eg, goserelin acetate, buserelin acetate, leuprorelin, etc.),
Herceptin (trademark: anti-HER2 antibody) and the like are preferable.

When the compound of the present invention and the concomitant drug are used in combination, the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug are administered to the administration subject.
It may be administered at the same time or at different times. The dose of the concomitant drug may be in accordance with the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like. The administration form of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such a dosage form include (1)
Administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, (2) by the same administration route of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug Simultaneous administration of (3) the compound of the present invention and the concomitant drug, which are obtained by separately formulating two types of preparations, with different time lags in the same administration route, (4) the compound of the present invention and the concomitant drug Simultaneous administration of two kinds of preparations obtained by separately formulating and, (5) Different administration routes of two kinds of preparations obtained by separately formulating the compound of the present invention and a concomitant drug (For example, administration of the compound of the present invention → concomitant drug in this order, or administration in the reverse order) is used. Hereinafter, these administration forms will be collectively referred to as the concomitant drug of the present invention. The concomitant drug of the present invention has low toxicity, and for example, a compound of the present invention or (and) the concomitant drug is mixed with a pharmaceutically acceptable carrier according to a method known per se, to obtain a pharmaceutical composition such as a tablet ( (Including sugar-coated tablets, film-coated tablets), powders, granules, capsules (including soft capsules), liquids,
It can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration, etc.) as injections, suppositories, sustained-release agents and the like. Injections can be intravenous, intramuscular, subcutaneous, intra-organ,
It can be administered intranasally, intradermally, instillation, intracerebrally, rectally, intravaginally and intraperitoneally, inside a tumor, proximal to a tumor, or directly into a lesion. As the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention, the same carriers as those used in the above-mentioned pharmaceutical composition of the present invention can be used.

The compounding ratio of the compound of the present invention to the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like. For example, the content of the compound of the present invention in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight based on the whole preparation. And more preferably about 0.5 to 20% by weight. The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably It is about 0.5 to 20% by weight. The content of additives such as a carrier in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. . Also, when the compound of the present invention and the concomitant drug are separately formulated, the same content may be used.

These formulations can be produced by a method known per se which is generally used in the formulation process. For example, the compound of the present invention or a concomitant drug is a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethyl cellulose, sodium alginate, hydroxypropyl methyl cellulose). ,
Dextrin, etc.), stabilizers (eg, ascorbic acid,
Sodium pyrosulfite etc.), surfactants (eg polysorbate 80, macrogol etc.), solubilizers (eg glycerin, ethanol etc.), buffers (eg phosphoric acid and its alkali metal salts, citric acid and its alkali metals) Salt, etc.), isotonicity agent (eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.), pH adjuster (eg,
Hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, ethyl paraoxybenzoate, benzoic acid, methylparaben, propylparaben, benzyl alcohol, etc.), solubilizers (eg, concentrated glycerin, meglumine, etc.), solubilizing agents (eg, propylene) Glycols, sucrose, etc.), soothing agents (eg, glucose, benzyl alcohol, etc.) in aqueous injections, or vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, etc., and solubilizing agents such as propylene glycol. Alternatively, it can be emulsified and molded into an oil-based injection to prepare an injection.

In order to prepare a preparation for oral administration, according to a method known per se, the compound of the present invention or the concomitant drug is used, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrant (eg,
Add starch (calcium carbonate, etc.), binder (eg starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose etc.) or lubricant (eg talc, magnesium stearate, polyethylene glycol 6000 etc.) etc. Then, the composition can be compression-molded, and then, if necessary, coated by a method known per se for the purpose of taste masking, enteric coating or sustainability, to give an oral administration preparation. As the coating agent, for example, hydroxypropylmethyl cellulose, ethyl cellulose,
Hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 8
0, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, methacrylic acid / acrylic acid copolymerization) and dye (eg, red iron oxide,
Titanium dioxide etc.) is used. The preparation for oral administration may be either an immediate release preparation or a sustained release preparation.

For example, in the case of a suppository, the compound of the present invention or the concomitant drug can be made into an oily or aqueous solid, semisolid or liquid suppository according to a method known per se. Examples of the oily base used in the composition include glycerides of higher fatty acids [eg, cacao butter, witepsols (Dynamite Nobel, Germany), etc.], intermediate fatty acids [eg, miglyols (Dynamite Nobel, Germany) ) Etc.], or vegetable oil (eg, sesame oil, soybean oil, cottonseed oil, etc.) and the like are used. Further, as the aqueous base, for example, polyethylene glycols and propylene glycol are used, and as the aqueous gel base, for example, natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers and the like are used. As the sustained-release preparation, sustained-release microcapsules and the like are used. A method known per se can be used to form the sustained-release microcapsules.
The compound of the present invention may be molded into a preparation for oral administration such as solid preparation (eg, powder, granule, tablet, capsule), or
It is preferably molded into a preparation for rectal administration such as a suppository. Particularly preferred is a preparation for oral administration. The concomitant drug can be in the above-mentioned dosage form depending on the type of drug.

The injection of the compound of the present invention or the concomitant drug and its preparation are specifically described below. Injection and preparation thereof An injection prepared by dissolving the compound of the present invention or the concomitant drug in water is preferable. The injection may contain benzoate and / or salicylate. The injection can be obtained by dissolving both the compound of the present invention or the concomitant drug and optionally a benzoate and / or a salicylate in water. Examples of the salts of benzoic acid and salicylic acid include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, meglumine salts, and organic acid salts such as trometamol. The concentration of the compound of the present invention or the concomitant drug in the injection is 0.5 to 50 w / v%, preferably about 3 to 20 w / v%. Benzoate or /
The salicylate concentration is preferably 0.5 to 50 w / v%, more preferably 3 to 20 w / v%.

In addition, the present agent contains additives generally used for injection, such as stabilizers (eg, ascorbic acid, sodium pyrosulfite, etc.), surfactants (eg, polysorbate 80, macrogol, etc.), Solvents (eg, glycerin, ethanol, etc.), buffers (eg, phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), tonicity agents (eg, sodium chloride, potassium chloride, etc.), dispersants (Eg, hydroxypropylmethylcellulose, dextrin), pH adjuster (eg, hydrochloric acid, sodium hydroxide, etc.), preservative (eg, ethyl paraoxybenzoate, benzoic acid, etc.), solubilizer (eg, concentrated glycerin, meglumine, etc.) ,
A solubilizing agent (eg, propylene glycol, sucrose, etc.), a soothing agent (eg, glucose, benzyl alcohol, etc.) and the like can be appropriately added. These additives are generally added in the proportions usually used for injections. PH for injection
It may be adjusted to 2 to 12, preferably 2.5 to 8.0 by adding a regulator. The injectable preparation is obtained by dissolving both the compound of the present invention or the concomitant drug, and optionally benzoate and / or salicylate, and, if necessary, the additive in water. These may be dissolved in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injectable solution. The aqueous solution for injection is preferably heated, and can be provided as an injectable solution by performing, for example, filter sterilization, high-pressure heat sterilization, etc. in the same manner as a normal injectable solution. The aqueous solution for injection is preferably subjected to high-pressure heat sterilization at 100 ° C. to 121 ° C. for 5 minutes to 30 minutes. Furthermore, it may be a preparation in which the solution has antibacterial properties so that it can be used as a multiple-dose preparation.

The composition may contain secondary components such as a preservative, an antioxidant, a surfactant, a thickener, a coloring agent, a pH adjusting agent, a flavoring agent, a sweetener or a taste masking agent. Suitable colorants include red, black and yellow iron oxides and FD & Eberd & Eberard FD &
FD such as C Blue No. 2 and FD & C Red No. 40
& C dye is used. Suitable flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, terry and grape flavors and combinations thereof. Suitable pH
Modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, acesulfame K and thaumatin. Suitable taste-masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbent materials and microencapsulated apomorphine. The formulation usually contains about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight of the compound of the present invention or the concomitant drug, and the period of about 1 minute to about 60 minutes, preferably about 1 minute. Minutes to about 15 minutes, more preferably about 2 minutes to
A formulation capable of dissolving 90% or more of the compound of the present invention or the concomitant drug (in water) in about 5 minutes (sublingual tablet, buccal, etc.) or within 1 to 60 seconds after being placed in the oral cavity In particular, an intraoral quick disintegrating agent which disintegrates within 1 to 30 seconds, more preferably within 1 to 10 seconds is preferable.

The content of the above-mentioned excipient in the whole preparation is
It is about 10 to about 99% by weight, preferably about 30 to about 90% by weight. The content of β-cyclodextrin or β-cyclodextrin derivative in the whole preparation is 0 to about 30.
% By weight. The content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight.
Is. The content of the isotonicity agent in the whole preparation is about 0.
1 to about 90% by weight, preferably about 10 to about 70% by weight
Is. The content of the hydrophilic carrier in the whole preparation is about 0.
1 to about 50% by weight, preferably about 10 to about 30% by weight. The content of the water-dispersible polymer in the whole preparation is
It is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight. The content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight. The formulation may further contain additives such as colorants, sweeteners and preservatives, if necessary.

The dose of the concomitant drug of the present invention varies depending on the type, age, body weight, symptom, dosage form, administration method, administration period, etc. of the compound of the present invention. ) Per person, as a compound of the present invention and a concomitant drug, usually about 0.01 to about 100 each day.
0 mg / kg, preferably about 0.01 to about 100 mg / kg, more preferably about 0.1 to about 100 mg / kg, especially about 0.1 to about 50 mg / kg, especially about 1.5 to about 30 mg / Kg is intravenously administered once to several times a day. Of course, since the dose varies depending on various conditions as described above, a dose smaller than the above dose may be sufficient in some cases, or a dose exceeding the range may be required in some cases.
It is possible to set any amount of the concomitant drug as long as side effects do not pose a problem. The daily dose as a concomitant drug depends on the degree of symptoms, age of the subject, sex, body weight,
Sensitivity difference, timing of administration, interval, properties of pharmaceutical preparation, preparation,
It depends on the type, the type of active ingredient, etc., and is not particularly limited, but the amount of the drug is usually about 0.001 to 2000 mg per kg body weight of the mammal by oral administration,
The amount is preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg, and this is usually administered in 1 to 4 divided doses per day.

When the concomitant drug of the present invention is administered, it may be administered at the same time, but after the concomitant drug is administered first,
The compound of the invention may be administered, or the compound of the invention may be administered first, followed by the concomitant drug. When administered with a time lag, the time lag is the active ingredient to be administered,
Depending on the dosage form and administration method, for example, when the concomitant drug is administered first, 1 minute to 3 days, preferably 10 minutes to 1 day, more preferably 15 minutes after the concomitant drug is administered.
A method of administering the compound of the present invention within minutes to 1 hour is used. When the compound of the present invention is administered first, it is preferably within 1 minute to 1 day, preferably 10 after the administration of the compound of the present invention.
A method of administering the concomitant drug within minutes to 6 hours, more preferably within 15 minutes to 1 hour is used. As a preferable administration method, for example, about 0.001 to 200 mg / kg of a concomitant drug formed into an oral administration preparation is orally administered, and about 15 minutes later, the compound of the present invention formed into the oral administration preparation.
The daily dose of about 0.005 to 100 mg / kg is orally administered.

The pharmaceutical composition of the present invention or the concomitant drug of the present invention may be administered, for example, in (1) surgery or (2) angiotensin.
Booster chemotherapy using II etc., (3) gene therapy,
It can also be combined with non-drug therapy such as (4) hyperthermia, (5) cryotherapy, (6) laser ablation, and (7) radiation therapy. For example, by using the pharmaceutical composition of the present invention or the concomitant drug of the present invention before or after surgery, etc., or before or after treatment with a combination of two or three of these, prevention of resistance development, disease-free stage (Disease- Free Sur
vival) extension, suppression of cancer metastasis or recurrence, and prolongation of life. Further, treatment with the pharmaceutical composition of the present invention or the concomitant drug of the present invention, supportive therapy [(i) antibiotics for coexistence of various infectious diseases (for example, β-lactams such as pansporin, macrolides such as clarithromycin) System, etc.), (ii) high calorie infusion for improving nutritional disorders, amino acid preparation, multivitamin preparation, (iii)
Administration of morphine for pain relief, (iv) drug improving side effects such as nausea, vomiting, loss of appetite, diarrhea, leukopenia, thrombocytopenia, hemoglobin concentration reduction, hair loss, liver damage, renal damage, DIC, fever, etc. And (v) administration of a drug for suppressing multidrug resistance of cancer, etc.] can also be combined.

Before or after the above treatment, the pharmaceutical composition of the present invention or the combination drug of the present invention is orally administered (including sustained release), intravenously administered (including bolus, infusion and clathrate). ), Subcutaneous and intramuscular (including bolus, infusion, sustained release), transdermal, intratumoral and proximal administration. When the pharmaceutical composition of the present invention or the concomitant drug of the present invention is administered before surgery or the like, it may be administered once, for example, about 30 minutes to 24 hours before surgery or the like. 1 to 3 to 6 months before
It can also be divided into 3 cycles for administration. Thus, by administering the pharmaceutical composition of the present invention or the concomitant drug of the present invention before surgery or the like, for example, cancer tissue can be reduced, and thus surgery or the like is facilitated. When the pharmaceutical composition of the present invention or the combination drug of the present invention is administered after surgery or the like, it can be repeatedly administered about 30 minutes to 24 hours after surgery or the like, for example, for several weeks to 3 months. . Thus, by administering the pharmaceutical composition of the present invention or the combination agent of the present invention after surgery or the like, the effect of surgery or the like can be enhanced.

[0108]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in detail below with reference to Reference Examples, Examples, Formulation Examples and Test Examples, but the present invention is not limited to these and is within the scope of the present invention. You may change with. Elution by column chromatography of Reference Example and Example was carried out by TLC (Th
in Layer Chromatography)
Under the observation by. In the observation of TLC, T
Kieselgel 60F made by Merck as an LC plate
_{A 254} plate was used, the developing solvent was the solvent used as the elution solvent in column chromatography, and the UV detector was used as the detection method. The silica gel for the column is Kieselgel 60F ₂₅₄ (70
˜230 mesh) was used. Nuclear magnetic resonance spectrum ( ¹
(H-NMR) was measured by using a JMTCO400 / 54 (400 MHz) type device (or Varian Gemini-200 (200 MHz) type device) manufactured by JEOL Ltd. using tetramethylsilane as an internal standard, and the δ value is shown in ppm. It was The symbols in the examples and reference examples have the following meanings. The abbreviations used in the examples have the following meanings.

The abbreviations used in Reference Examples and Examples have the following meanings. s: singlet br: broad (wide) d: doublet t: triplet q: quartet dd: double doublet dt: double triplet m: multiplet J: coupling constant Hz: Hertz DMF: N, N-dimethylformamide THF: tetrahydrofuran The structural formulas of the compounds produced in Reference Examples and Examples are shown separately in Tables 1 to 5. “Reference” in the table is a reference example,
“Actual” indicates each example.

[0110]

Examples Reference Example 1 A suspension of 2-amino-5-bromo-3-nitropyridine (21.0 g), iron powder (26.9 g) and ethanol (150 ml) was ice-cooled,
Concentrated hydrochloric acid (20 ml) was added dropwise. After the completion of dropping, the mixture was stirred at room temperature for 10 minutes and at 80 ° C. for 50 minutes. The reaction mixture was poured into ice, neutralized with 8 N sodium hydroxide solution, and extracted with ethyl acetate-tetrahydrofuran (3: 1, v / v) (insoluble matter was filtered off using Celite). . After drying the organic layer (MgSO ₄ ), the solvent was distilled off under reduced pressure, the crystals were collected by filtration,
2,3-Diamino-5-bromopyridine (15.8 g, 87%) was obtained. ¹ H NMR (CDCl ₃ ) δ 3.38 (2H, broad s), 4.21 (2H, br
oad s), 7.01 (1H, d, J = 2.2 Hz), 7.69 (1H, d, J =
2.2 Hz) ppm IR (KBr) ν 3179, 1632, 1476 cm ^-1

Reference Example 2 Phosphorus pentoxide (23.8 g) was added to methanesulfonic acid (85 ml).
In addition, the mixture was stirred at 100 ° C. for 1 hour to dissolve it. 2,3-Diamino-5-bromopyridine (Compound of Reference Example 1) (15.8 g) and 3-methoxybenzoic acid (12.7 g) were added to this solution, and the mixture was stirred at 100 ° C for 1 hr, and the reaction mixture was added. It was poured into ice, neutralized with 8 N sodium hydroxide solution, and extracted with ethyl acetate-tetrahydrofuran (3: 1, v / v). The organic layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, and the crystals were collected by filtration to give 6-bromo-2- (3-methoxyphenyl) -1H-imidazo [4,5-b] pyridine. (21.3 g, 84%) was obtained. ¹ H NMR (DMSO-d ₆ ) δ 3.87 (3H, s), 7.13 (1H, d, J =
8.6 Hz), 7.49 (1H, t, J = 7.8 Hz), 7.80 (1H, s),
7.82 (1H, d, J = 7.4 Hz), 8.28 (1H, s), 8.42 (1H,
s) ppm IR (KBr) ν 3103, 1489, 1264, 1233 cm ^-1 HPLC (220 nm) Purity 89% (retention time 2.92 minutes) MS (APCI +, m / e) 304 (M + 1) The measurement was performed under the following conditions. Column: CAPCELLPAKCC18UG120, S-3 μm, 2.0 x 50 mm Solvent: Solution A (water containing 0.1% trifluoroacetic acid), solution B (0.
Acetonitrile containing 1% trifluoroacetic acid) Gradient cycle: 0.00 minutes (solution A / solution B = 90/10),
4.00 minutes (Solution A / B = 5/95), 5.50 minutes (Solution A / B = 5/95),
5.51 minutes (Solution A / B = 90/10), 8.00 minutes (Solution A / B = 90/1
0) Flow rate: 0.5 ml / min

The compound of Reference Example 1 and various carboxylic acids were appropriately selected as starting materials, and the following compounds of Reference Examples 3 to 8 were synthesized according to the method of Reference Example 2. Reference Example 3 6-Bromo-2-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.68 minutes) MS (ESI +, m / e) 274 (M + 1) Reference Example 4 6-Bromo-2- (2-methoxyphenyl) -1H-imidazo [4,5-b]
Pyridine HPLC (220 nm) Purity 99% (retention time 2.67 minutes) MS (ESI +, m / e) 304 (M + 1) Reference Example 5 6-Bromo-2- (4-methoxyphenyl) -1H-imidazo [4 , 5-b]
Pyridine HPLC (220 nm) Purity 98% (retention time 2.66 min) MS (ESI +, m / e) 304 (M + 1)

Reference Example 6 2- (1,3-benzodioxol-5-yl) -6-bromo-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 95% (retention time 2.74) Min) MS (ESI +, m / e) 318 (M + 1) Reference Example 7 6-Bromo-2- [4- (trifluoromethoxy) phenyl] -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.64 min) MS (ESI +, m / e) 358 (M + 1) Reference Example 8 6-Bromo-2- (5-methyl) -2-thienyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 95% (retention time 2.95 minutes) MS (ESI +, m / e) 294 (M + 1)

Reference Example 9 2,3-Diamino-5-bromopyridine (Compound of Reference Example 1)
(1.32 g), 3-chlorobenzoic acid (1.10 g), and polyphosphoric acid (30 g) were stirred at 170 ° C for 2 hours, poured into ice, neutralized with 8 N sodium hydroxide solution, and added with acetic acid. It was extracted with ethyl-tetrahydrofuran (3: 1, v / v). The organic layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, the crystals were collected by filtration, and 6-bromo-2- (3-chlorophenyl) -1H-imidazo [4,5-b] pyridine ( 1.50 g, 69%) was obtained. ¹ H NMR (DMSO-d ₆ ) δ 7.59-7.62 (2H, m), 8.19-8.28
(2H, m), 8.35 (1H, s), 8.43 (1H, s) ppm IR (KBr) ν 3096, 1466, 1427, 957 cm ^-1 HPLC (220 nm) Purity 99% (retention time 3.42 min) MS (APCI +, m / e) 308 (M + 1)

The compound of Reference Example 1 and various carboxylic acids were appropriately selected as starting materials, and the compounds of Reference Examples 10 to 13 below were synthesized according to the method of Reference Example 9. Reference Example 10 6-Bromo-2-[(E) -2-phenylethenyl] -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 99% (retention time 3.64 minutes) MS (APCI +, m / e) 300 (M + 1) Reference Example 11 6-Bromo-2- (2-naphthyl) -1H- Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 4.10 minutes) MS (APCI +, m / e) 324 (M + 1) Reference Example 12 6-Bromo-2- (3-phenoxy) Phenyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 85% (retention time 4.50 min) MS (APCI +, m / e) 366 (M + 1)

Reference Example 13 2- (4-benzoylphenyl) -6-bromo-1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 99% (retention time 4.31 minutes) MS (APCI +, m / e) 378 (M + 1) Reference Example 14 2,3-diamino-5-bromopyridine (Compound of Reference Example 1 )
(1.32 g) and 4-methoxyphenylacetyl chloride (1.
The mixture (29 g) was stirred without solvent at 170 ° C for 1.5 hours, and then partitioned between ethyl acetate-tetrahydrofuran (3: 1, v / v) and water (the aqueous layer was diluted with 1 N sodium hydroxide solution). Neutralized). The organic layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, and the crystals were collected by filtration to give 6-bromo-2- (4-methoxybenzyl) -1H-imidazo [4,5-b] pyridine. (1.22 g,
55%). ¹ H NMR (CDCl ₃ ) δ 3.82 (3H, s), 4.30 (2H, s), 6.90
(2H, d, J = 8.8 Hz), 7.24 (2H, d, J = 9.2 Hz), 7.8
2 (1H, s), 8.10 (1H, s), 12.14 (1H, broad s) ppm IR (KBr) ν 3007, 1512, 1433, 1254 cm ^-1 HPLC (220 nm) Purity 100% (retention time 2.57 minutes ) MS (APCI +, m / e) 318 (M + 1)

The compounds of Reference Example 1 and various carboxylic acid chlorides were appropriately selected as starting materials, and the following compounds of Reference Examples 15 to 25 were synthesized according to the method of Reference Example 14. Reference Example 15 6-Bromo-2- (phenoxymethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.02 minutes) MS (ESI +, m / e) 304 (M +1) Reference Example 16 6-Bromo-2-cyclohexyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 2.29 minutes) MS (ESI +, m / e) 280 (M +1) Reference Example 17 6-Bromo-2- (2-cyclopentylethyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.78 min) MS (ESI +, m / e) 294 (M + 1)

Reference Example 18 6-Bromo-2-[(phenylthio) methyl] -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 99% (retention time 2.95 minutes) MS (APCI +, m / e) 320 (M + 1) Reference Example 19 6-Bromo-2- (2-phenylethyl) -1H-imidazo [4,5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.62 minutes) MS (APCI +, m / e) 302 (M + 1)

Reference Example 20 2-Benzyl-6-bromo-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.51 minutes) MS (APCI +, m / e) 288 (M +1) Reference Example 21 6-Bromo-2- (3-methoxybenzyl) -1H-imidazo [4,5-b]
Pyridine HPLC (220 nm) Purity 97% (retention time 2.63 minutes) MS (APCI +, m / e) 318 (M + 1) Reference Example 22 6-Bromo-2- (2,5-dimethoxybenzyl) -1H-imidazo [Four,
5-b] Pyridine HPLC (220 nm) Purity 97% (retention time 2.62 minutes) MS (APCI +, m / e) 348 (M + 1)

Reference Example 23 6-Bromo-2- (3,4-dimethoxybenzyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 95% (retention time 2.41 minutes) MS (APCI +, m / e) 348 (M + 1) Reference Example 24 6-Bromo-2- (4-chlorobenzyl) -1H -Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 95% (retention time 2.96 min) MS (APCI +, m / e) 322 (M + 1) Reference Example 25 6-Bromo-2-[(4 -Chlorophenoxy) methyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.47 minutes) MS (APCI +, m / e) 338 (M + 1)

Reference Example 26 4-Fluorophenylacetic acid (678 mg) was dissolved in tetrahydrofuran (15 ml) to give oxalyl chloride (0.67 g).
And N, N-dimethylformamide (10 μl) were sequentially added.
After stirring at room temperature for 1.5 hours, the solvent and excess oxalyl chloride were distilled off under reduced pressure. Toluene (2 ml) was added to the residue, and the mixture was evaporated again under reduced pressure to completely remove oxalyl chloride. 2,3-Diamino-5-bromopyridine (compound of Reference Example 1) (752 mg) was added to the residue, and the mixture was stirred without solvent at 170 ° C. for 1.5 hours, and then ethyl acetate-tetrahydrofuran (3: 1, v / v) and water (wherein the aqueous layer was neutralized with 1 N sodium hydroxide solution). The organic layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, the crystals were collected by filtration, and 6-bromo-2- (4-fluorobenzyl) -1H-
Imidazo [4,5-b] pyridine (722 mg, 59%) was obtained. ¹ H NMR (DMSO-d ₆ ) δ 4.20 (2H, s), 7.14 (2H, t, J =
9.0 Hz), 7.38 (2H, dd, J = 8.8, 6.0 Hz), 8.15 (1
H, d, J = 2.2 Hz), 8.34 (1H, d, J = 2.2 Hz) ppm IR (KBr) ν 3083, 1508, 1429, 1235 cm ^-1 HPLC (220 nm) Purity 100% (retention time 2.67 min. ) MS (APCI +, m / e) 306 (M + 1)

The compounds of Reference Example 1 and various carboxylic acids were appropriately selected as starting materials, and the compounds of Reference Examples 27 to 42 below were synthesized according to the method of Reference Example 26. Reference Example 27 6-Bromo-2- (3-chlorobenzyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 2.97 minutes) MS (APCI +, m / e) 322 (M + 1) Reference Example 28 6-Bromo-2- (2-chlorobenzyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 2.77 minutes) MS (APCI +, m / e) 322 (M + 1) Reference Example 29 6-Bromo-2- (2,4-difluorobenzyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 99% (retention time 2.76 min) MS (APCI +, m / e) 324 (M + 1)

Reference Example 30 6-Bromo-2- (3,4-dichlorobenzyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 99% (retention time 3.32 minutes) MS (APCI +, m / e) 358 (M + 1) Reference Example 31 6-Bromo-2- [4- (trifluoromethyl) benzyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.23 minutes) MS (APCI +, m / e) 356 (M + 1)

Reference Example 32 6-Bromo-2- [4- (trifluoromethoxy) benzyl] -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.27 min) MS (APCI +, m / e) 372 (M + 1) Reference Example 33 6-Bromo-2- (4-nitro) (Benzyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.86 minutes) MS (APCI +, m / e) 333 (M + 1)

Reference Example 34 6-Bromo-2- (4-methylbenzyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 2.84 minutes) MS (APCI +, m / e) 302 (M + 1) Reference Example 35 2-[(1,1'-biphenyl) -4-ylmethyl] -6-bromo-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97 % (Retention time 3.38 minutes) MS (APCI +, m / e) 364 (M + 1) Reference Example 36 6-Bromo-2- (2-naphthylmethyl) -1H-imidazo [4,5-b] pyridine HPLC ( 220 nm) Purity 99% (retention time 3.17 minutes) MS (APCI +, m / e) 338 (M + 1) Reference Example 37 2- (1,3-benzodioxol-5-ylmethyl) -6-bromo- 1
H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.66 min) MS (APCI +, m / e) 332 (M + 1) Reference Example 38 6-Bromo-2- (3 , 4,5-Trimethoxybenzyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 84% (retention time 2.67 minutes) MS (APCI +, m / e) 378 (M + 1)

Reference Example 39 6-Bromo-2- (2-thienylmethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 2.58 minutes) MS (APCI +, m / e) 294 (M + 1) Reference Example 40 6-Bromo-2-[(1-methyl-1H-indol-3-yl) methyl]
-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.93 minutes) MS (APCI +, m / e) 341 (M + 1) Reference Example 41 6-Bromo-2- [ 2- (3,4-Dimethoxyphenyl) ethyl] -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) 100% purity (retention time 2.58 minutes) MS (APCI +, m / e) 362 (M + 1) Reference Example 42 6-Bromo-2- [4- ( Methylthio) benzyl] -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.00 min) MS (APCI +, m / e) 334 (M + 1)

Reference Example 43 Phosphorus pentoxide (2.84 g) was added to methanesulfonic acid (10 ml).
In addition, the mixture was stirred at 100 ° C. for 1 hour to dissolve it. Add 2-amino-4-bromophenol (1.88 g) and trans to this solution.
-Cinnamic acid (1.48 g) was added, and the mixture was stirred at 100 ° C for 1.5 hr, the reaction mixture was poured into ice, and the mixture was neutralized with 8 N sodium hydroxide solution, and ethyl acetate-tetrahydrofuran (3:
1, v / v). The organic layer was washed with water, dried (MgSO ₄₎
After that, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:
The crystals obtained by concentrating the fractions eluted at 3, v / v) under reduced pressure were collected by filtration to give 5-bromo-2-[(E) -2-phenylethenyl] benzoxazole (966 mg, 32% ) Got. ¹ H NMR (CDCl ₃ ) δ 7.05 (1H, d, J = 16.4 Hz), 7.37-
7.48 (5H, m), 7.58-7.62 (2H, m), 7.81 (1H, d, J =
16.4 Hz), 7.84-7.85 (1H, m) ppm IR (KBr) ν 1535, 1260, 974, 756 cm ^-1 HPLC (220 nm) Purity 100% (retention time 4.92 min) MS (APCI +, m / e) 300 (M + 1)

Various carboxylic acids were appropriately selected as starting materials, and the compounds of Reference Examples 44 to 45 below were synthesized according to the method of Reference Example 43. Reference Example 44 5-Bromo-2-[(E) -2- [4- (trifluoromethyl) phenyl]
Ethenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 5.17 min) MS (APCI +, m / e) 368 (M + 1) Reference Example 45 5-Bromo-2-[(E) -2- (2 , 4-Difluorophenyl) ethenyl] benzoxazole HPLC (220 nm) Purity 97% (retention time 5.04 minutes) MS (APCI +, m / e) 336 (M + 1)

The compound of Reference Example 1 and 3-methylbenzoic acid were selected as starting materials, and the compound of Reference Example 46 below was synthesized according to the method of Reference Example 2. Reference Example 46 6-Bromo-2- (3-methylphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.20 minutes) MS (ESI +, m / e) 288 (M + 1) Reference Example 47 2,3-diamino-5-bromopyridine (Compound of Reference Example 1)
A mixture of (1.13 g), 3-ethoxybenzoic acid (997 mg) and phosphorus oxychloride (24 ml) was stirred at 120 ° C for 2 hours, poured into ice and neutralized with 8 N sodium hydroxide solution, 2
Stir for 0 minutes, and mix with ethyl acetate-tetrahydrofuran (3:
1, v / v). The organic layer was washed with water, dried (MgSO ₄₎
After that, the solvent was distilled off under reduced pressure, the crystals were collected by filtration, and 6-bromo-2-
(3-Ethoxyphenyl) -1H-imidazo [4,5-b] pyridine (9
(78 mg, 51%) was obtained. ¹ H NMR (DMSO-d ₆ ) δ 1.39 (3H, t, J = 7.0 Hz), 4.14
(2H, q, J = 7.0 Hz), 7.08-7.12 (1H, m), 7.47 (1H,
t, J = 8.2 Hz), 7.78-7.82 (2H, m), 8.26 (1H, s),
8.41 (1H, d, J = 1.8 Hz) ppm IR (KBr) ν 2973, 1491, 1262 cm ^-1 HPLC (220 nm) 100% purity (retention time 3.42 min) MS (ESI +, m / e) 318 (M +1)

The compounds of Reference Example 1 and various carboxylic acids were appropriately selected as starting materials, and the following compounds of Reference Examples 48 to 50 were synthesized according to the method of Reference Example 47. Reference Example 48 6-Bromo-2- (3-propoxyphenyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.71 minutes) MS (ESI +, m / e) 332 (M + 1) Reference Example 49 6-Bromo-2- (3-isopropoxyphenyl) -1H- Imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.59 min) MS (ESI +, m / e) 332 (M + 1) Reference Example 50 6-Bromo-2- (3-butoxyphenyl) ) -1H-imidazo [4,5-b]
Pyridine HPLC (220 nm) Purity 100% (retention time 3.98 minutes) MS (ESI +, m / e) 346 (M + 1) As a starting material, the compound of Reference Example 1 and various carboxylic acids were appropriately selected, and Reference Example 26 The compound of the following Reference Example 51 was synthesized according to the method of 1. Reference Example 51 6-Bromo-2- (4-methoxy-3-methylbenzyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.03 minutes) MS (APCI +, m / e) 332 (M + 1)

The compounds of Reference Example 1 and various carboxylic acids were appropriately selected as starting materials, and the following compounds of Reference Examples 52 to 58 were synthesized according to the method of Reference Example 47. Reference Example 52 6-Bromo-2- [3- (hexyloxy) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 4.46 min) MS (APCI +, m / e) 374 (M + 1) Reference Example 53 6-Bromo-2- [3- (3-butenyloxy) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.78 min) MS (APCI +, m / e) 344 (M + 1) Reference Example 54 6-Bromo-2- [3- (3-methylbutoxy) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 4.48 min) MS (APCI +, m / e) 360 (M + 1) Reference Example 55 6-Bromo-2- [3- (neopentyloxy) phenyl] -1H-imidazo [4,5-b] Pyridine HPLC (220 nm) Purity 99% (retention time 4.24 min) MS (APCI +, m / e) 360 (M + 1)

Reference Example 56 6-Bromo-2- [3- (cyclohexylmethoxy) phenyl] -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 4.50 min) MS (APCI +, m / e) 386 (M + 1) Reference Example 57 6-Bromo-2- [3- (Cyclopentyloxy) phenyl] -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.96 min) MS (APCI +, m / e) 358 (M + 1) Reference Example 58 6-Bromo-2- [3- ( 2-Phenylethoxy) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 4.11 min) MS (APCI +, m / e) 394 (M + 1) as starting material The compound of Reference Example 1 and various carboxylic acids were appropriately selected, and the compound of Reference Example 59 below was synthesized according to the method of Reference Example 2. Reference Example 59 6-Bromo-2- (3-ethylphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 95% (retention time 3.47 minutes) MS (APCI +, m / e) 302 (M + 1)

Various carboxylic acids were appropriately selected as starting materials, and the following compounds of Reference Examples 60 to 66 were synthesized according to the method of Reference Example 43. Reference Example 60 5-Bromo-2- (3-methoxyphenyl) benzoxazole HPLC (220 nm) Purity 98% (retention time 4.82 minutes) MS (ESI +, m / e) 304 (M + 1) Reference Example 61 5- Bromo-2-[(E) -2- (4-chlorophenyl) ethenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 5.21 minutes) MS (ESI +, m / e) 334 (M + 1) Reference example 62 5-Bromo-2-[(E) -2- (3-fluorophenyl) ethenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 4.95 minutes) MS (ESI +, m / e) 318 (M + 1) Reference example 63 5-bromo-2-[(E) -2- (2-fluorophenyl) ethenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 5.04 minutes) MS (ESI +, m / e) 318 (M + 1)

Reference Example 64 5-Bromo-2-[(E) -2- (3,4-dichlorophenyl) ethenyl]
Benzoxazole HPLC (220 nm) Purity 98% (retention time 5.45 min) MS (ESI +, m / e) 370 (M + 1) Reference Example 65 5-Bromo-2-[(E) -2- (4-methyl) (Phenyl) ethenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 5.19 min) MS (ESI +, m / e) 314 (M + 1) Reference Example 66 5-Bromo-2-[(E) -2- [3- (Trifluoromethoxy) phenyl] ethenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 5.24 min) MS (ESI +, m / e) 384 (M + 1)

Reference Example 67 Diphosphorus pentoxide (2.27 g) was added to methanesulfonic acid (8 ml), and the mixture was stirred at 120 ° C. for 1 hr to dissolve it. 2-Amino-5-bromophenol (1.50 g) and 4-chlorophenylacetic acid (1.36 g) were added to this solution, and the mixture was stirred at 100 ° C for 1 hr. Then, the reaction mixture was poured into ice and then 8N sodium hydroxide solution was added. It was neutralized and extracted with ethyl acetate-tetrahydrofuran (3: 1, v / v). Wash the organic layer with water and dry (MgS
O ₄₎ After the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, the fraction eluted with ethyl acetate-hexane (1: 4, v / v) was concentrated under reduced pressure, and the crystals obtained were collected by filtration to give 6-bromo-2- ( 4-Chlorobenzyl) benzoxazole (1.83 g, 71%) was obtained. ¹ H NMR (CDCl ₃ ) δ 4.22 (2H, s), 7.32 (4H, s), 7.43
(1H, dd, J = 8.4, 1.4Hz), 7.55 (1H, d, J = 8.4 H
z), 7.64 (1H, d, J = 1.8 Hz) ppm IR (KBr) ν 1564, 1493, 1424 cm ^-1 HPLC (220 nm) Purity 99% (retention time 4.76 min) MS (APCI +, m / e) 322 (M + 1)

Various carboxylic acids were appropriately selected as starting materials, and the compounds of Reference Examples 68 to 72 below were synthesized according to the method of Reference Example 67. Reference Example 68 6-Bromo-2-[(E) -2-phenylethenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 4.97 minutes) MS (APCI +, m / e) 300 (M + 1) Reference Example 69 6-Bromo-2-[(E) -2- (2,4-difluorophenyl) ethenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 5.10 minutes) MS (APCI +, m / e) 336 (M + 1) Reference Example 70 6-Bromo-2-[(E) -2- (2-fluorophenyl) ethenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 5.07 minutes) MS (APCI +, m / e) 318 (M + 1) Reference Example 71 6-Bromo-2-[(E) -2- [4- (trifluoromethyl) phenyl]
Ethenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 5.22 minutes) MS (APCI +, m / e) 368 (M + 1) Reference Example 72 6-Bromo-2- (2-phenylethyl) benzoxazole HPLC (220 nm) Purity 97% (retention time 4.70 minutes) MS (APCI +, m / e) 302 (M + 1)

The compounds of Reference Example 1 and various carboxylic acids were appropriately selected as starting materials, and the following compounds of Reference Examples 73 to 82 were synthesized according to the method of Reference Example 2. Reference Example 73 6-Bromo-2- (2,3-dihydro-1,4-benzodioxin-6-yl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 2.92 min) MS (APCI +, m / e) 332 (M + 1) Reference Example 74 6-Bromo-2- (2-pyridinyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 83 % (Retention time 3.05 minutes) MS (APCI +, m / e) 275 (M + 1) Reference Example 75 6-Bromo-2- (3-fluorophenyl) -1H-imidazo [4,5-b]
Pyridine HPLC (220 nm) Purity 99% (retention time 3.34 minutes) MS (APCI +, m / e) 292 (M + 1) Reference Example 76 6-Bromo-2- (2-fluorophenyl) -1H-imidazo [4 , 5-b]
Pyridine HPLC (220 nm) Purity 94% (retention time 3.12 minutes) MS (APCI +, m / e) 292 (M + 1) Reference Example 77 6-Bromo-2- (4-fluorophenyl) -1H-imidazo [4 , 5-b]
Pyridine HPLC (220 nm) Purity 89% (retention time 3.15 minutes) MS (APCI +, m / e) 292 (M + 1)

Reference Example 78 3- (6-Bromo-1H-imidazo [4,5-b] pyridin-2-yl) benzonitrile HPLC (220 nm) Purity 83% (retention time 3.29 minutes) MS (APCI +, m / e) 299 (M + 1) Reference Example 79 6-Bromo-2- (3-fluoro-4-methoxyphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 82% (retention Time 3.23 minutes) MS (APCI +, m / e) 322 (M + 1) Reference Example 80 N- (3- (6-bromo-1H-imidazo [4,5-b] pyridin-2-yl)
Phenyl) -N, N-dimethylamine HPLC (220 nm) Purity 99% (retention time 2.59 minutes) MS (APCI +, m / e) 317 (M + 1) Reference Example 81 6-Bromo-2- (3- ( 1-Pyrrolidinyl) phenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 3.35 min) MS (APCI +, m / e) 343 (M + 1) Reference Example 82 6 -Bromo-2- (3-morpholinophenyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 97% (retention time 2.96 min) MS (APCI +, m / e) 359 (M + 1)

The compounds of Reference Example 1 and various carboxylic acid chlorides were appropriately selected as starting materials, and the following compounds of Reference Examples 83 to 85 were synthesized according to the method of Reference Example 14. Reference Example 83 6-Bromo-2- (2- (3-methoxyphenyl) ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 2.90 minutes) MS (ACPI +, m / e) 332 (M + 1) Reference Example 84 6-Bromo-2- (2- (2-methoxyphenyl) ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (Retention time 2.89 minutes) MS (ACPI +, m / e) 332 (M + 1) Reference Example 85 6-Bromo-2- (2- (4-methoxyphenyl) ethyl) -1H-imidazo [4,5-b ] Pyridine HPLC (220 nm) Purity 98% (retention time 2.87 minutes) MS (ACPI +, m / e) 332 (M + 1)

The compounds of Reference Example 1 and various carboxylic acids were appropriately selected as starting materials, and the following compounds of Reference Examples 86 to 111 were synthesized according to the method of Reference Example 47. Reference Example 86 6-Bromo-2- (3- (2-methoxyethoxy) phenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 83% (retention time 3.10 minutes) MS (ACPI +, m / e) 348 (M + 1) Reference Example 87 6-Bromo-2- (4- (2-methoxyethoxy) phenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 93% (Retention time 2.87 minutes) MS (ACPI +, m / e) 348 (M + 1) Reference Example 88 6-Bromo-2- (3- (trifluoromethyl) phenyl) -1H-imidazo [4,5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.86 min) MS (ACPI +, m / e) 342 (M + 1) Reference Example 89 6-Bromo-2- (3- (methylsulfonyl) phenyl) -1H- Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.01 min) MS (ACPI +, m / e) 352 (M + 1) Reference Example 90 6-Bromo-2- (5-methyl) -3-Phenyl-4-isoxazolyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.52 minutes) MS (ACPI +, m / e) 355 (M + 1)

Reference Example 91 6-Bromo-2- (2- (4-chlorophenyl) ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 3.19 minutes) MS ( ACPI +, m / e) 336 (M + 1) Reference Example 92 6-Bromo-2- (2- (2-chlorophenyl) ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100 % (Retention time 3.19 minutes) MS (ACPI +, m / e) 336 (M + 1) Reference Example 93 6-Bromo-2- (2- (4-methylphenyl) ethyl) -1H-imidazo [4,5- b] Pyridine HPLC (220 nm) Purity 99% (retention time 3.07 minutes) MS (ACPI +, m / e) 316 (M + 1) Reference Example 94 6-Bromo-2- (2- (3,4-dichlorophenyl) Ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 88% (retention time 3.43 minutes) MS (ACPI +, m / e) 371 (M + 1) Reference Example 95 4- (2- (6-Bromo-1H-imidazo [4,5-b] pyridin-2-yl)
Ethyl) benzonitrile HPLC (220 nm) Purity 97% (retention time 2.83 min) MS (ACPI +, m / e) 327 (M + 1) Reference Example 96 6-Bromo-2- (2- (4- (trifluoro Methyl) phenyl) ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.38 min) MS (ACPI +, m / e) 370 (M + 1)

Reference Example 97 6-Bromo-2- (2-phenylcyclopropyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 98% (retention time 3.05 min) MS (ACPI +, m / e) 314 (M + 1) Reference Example 98 6-Bromo-2- (2- (4 -Fluorophenyl) ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 2.95 minutes) MS (ACPI +, m / e) 320 (M + 1) Reference Example 99 6 -Bromo-2- (2- (4-isopropylphenyl) ethyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.46 min) MS (ACPI +, m / e) 344 (M + 1) Reference Example 100 6-Bromo-2- (2- ( 2-thienyl) ethyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.77 minutes) MS (ACPI +, m / e) 308 (M + 1) Reference Example 101 6-Bromo-2- (2- (4-nitrophenyl) ethyl ) -1H-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.00 min) MS (ACPI +, m / e) 347 (M + 1)

Reference Example 102 6-Bromo-2- (2- (4-ethoxyphenyl) ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.07 minutes) MS (ACPI +, m / e) 346 (M + 1) Reference Example 103 6-Bromo-2- (2-phenylpropyl) -1H-imidazo [4,5-b]
Pyridine HPLC (220 nm) Purity 100% (retention time 2.96 min) MS (ACPI +, m / e) 316 (M + 1) Reference Example 104 6-Bromo-2- (5-phenylpentyl) -1H-imidazo [4 , 5-b]
Pyridine HPLC (220 nm) Purity 100% (retention time 3.37 min) MS (ACPI +, m / e) 344 (M + 1) Reference Example 105 2-((1S) -1- (6-bromo-1H-imidazo [ 4,5-b] Pyridine-2-
Yl) -2-Phenylethyl) -1H-isoindole-1,3 (2H)-
Dione HPLC (220 nm) Purity 96% (retention time 3.87 minutes) MS (ACPI +, m / e) 447 (M + 1) Reference Example 106 6-Bromo-2- (2- (4-butoxyphenyl) ethyl)- 1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.53 minutes) MS (ACPI +, m / e) 374 (M + 1) Reference Example 107 6-Bromo-2- (2 -(3,4,5-Trimethoxyphenyl) ethyl)-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 2.74 min) MS (ACPI +, m / e) 392 (M + 1)

Reference Example 108 6-Bromo-2- (2- (3-chlorophenyl) ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.19 minutes) MS ( ACPI +, m / e) 336 (M + 1) Reference Example 109 6-Bromo-2- (3- (2,2,2-trifluoroethoxy) phenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 92% (retention time 3.77 minutes) MS (ACPI +, m / e) 372 (M + 1) Reference Example 110 6-Bromo-2- (3-isopropoxy-2-methylphenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.53 minutes) MS (ACPI +, m / e) 346 (M + 1) Reference Example 111 6-Bromo-2- (2- ( 4-isopropoxyphenyl) ethyl) -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.22 minutes) MS (ACPI +, m / e) 360 (M + 1) Reference Example 112 6-Chloro-3-nitro-2 -Pyridineamine (2.0 g), phenylboronic acid (2.1 g), tetrakis (triphenylphosphine) palladium (0) (1.3 g), 2 M sodium carbonate solution (35 ml), toluene (40 ml), tetrahydrofuran (20 g) The mixture was stirred at 90 ° C for 12 hours in an argon stream, and then ethyl acetate-tetrahydrofuran (3: 1,
v / v) and water. The organic layer was washed with water, dried (MgSO ₄₎
After that, the solvent was distilled off under reduced pressure, the crystals were collected by filtration, and 3-nitro-6-
Phenyl-2-pyridinamine (1.3 g, 53%) was obtained. ¹ H NMR (CDCl ₃ ) δ 7.20 (1H, d, J = 8.4 Hz), 7.49-
7.54 (3H, m), 8.00-8.05 (2H, m), 8.49 (1H, d, J =
8.4 Hz) ppm IR (KBr) ν 3501, 3382, 1617, 1586, 1578, 1271, 12
44 cm ^-1 HPLC (220 nm) Purity 97% (retention time 3.86 min) MS (ESI, m / e) 216 (M + 1)

Reference Example 113 3-Nitro-6-phenyl-2-pyridinamine (Compound of Reference Example 112) (0.8 g), iron powder (1.3 g), methanol (7 m
The suspension of l) was ice-cooled, and concentrated hydrochloric acid (3 ml) was added dropwise. After the completion of dropping, the mixture was stirred at room temperature for 10 minutes and at 80 ° C. for 50 minutes.
The reaction mixture was poured into ice and neutralized with 8N sodium hydroxide solution, and then ethyl acetate-tetrahydrofuran (3: 1, v /
v)) (insoluble matter was filtered off using Celite). The organic layer was dried (MgSO _4), the solvent was distilled off under reduced pressure, the crystals were collected by filtration to give 6-phenyl-2,3-pyridine-diamine (0.7 g, 99%). ¹ H NMR (CDCl ₃ ) δ 3.00-3.60 (2H, broad s), 4.00-4.
60 (2H, broad s), 6.95 (1H, d, J = 8.0 Hz), 7.09 (1
H, d, J = 8.0 Hz), 7.22-7.41 (3H, m), 7.87 (2H, d,
J = 7.2 Hz) ppm IR (KBr) ν 3337, 1622, 1470, 754, 696 cm ^-1 HPLC (220 nm) Purity 99% (retention time 2.31 min) MS (ESI, m / e) 186 (M + 1 )

Reference Example 114 6-chloro-3-nitro-2-pyridinamine (1.2 g), phenol (3.1 g) and sodium methoxide (0.4 g) were dissolved in acetonitrile (20 ml) and heated under reflux for 12 hours. did. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was washed with water and dried (MgSO ₄ ),
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:10, v
/ v) and the crystals obtained by concentrating the fractions eluted under reduced pressure are collected by filtration to give 3-nitro-6-phenoxy-2-pyridinamine (1.1
g, 66%) was obtained. ¹ H NMR (CDCl ₃ ) δ 6.27 (1H, d, J = 9.0 Hz), 7.10-
7.46 (7H, m), 8.41 (2H, d, J = 9.0 Hz) ppm IR (KBr) ν 3372, 1620, 1447, 1250 cm ^-1 HPLC (220 nm) Purity 98% (retention time 3.84 min) MS ( ESI, m / e) 232 (M + 1)

Reference Example 115 3-Nitro-6-phenoxy-2-pyridinamine (Reference Example 114
(Compound of Example 2) (0.1 g), palladium-carbon (10 mg), and methanol (2 ml) were stirred under a hydrogen stream at room temperature for 10 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.
The residue was subjected to silica gel chromatography, and the fraction eluted with ethyl acetate-hexane (1: 1, v / v) was concentrated under reduced pressure to give 6-phenoxy-2,3-pyridinediamine (0.06
g, 59%) was obtained. ¹ H NMR (CDCl ₃ ) δ 2.50-3.00 (2H, broad s), 4.00-4.
50 (2H, broad s), 6.12 (1H, d, J = 8.1 Hz), 6.93 (1
H, d, J = 8.1 Hz), 7.02-7.20 (3H, m), 7.29-7.36 (2
H, m) ppm IR (KBr) ν 3328, 1622, 1591, 1464, 1238, 693 cm ^-1 HPLC (220 nm) Purity 90% (retention time 2.31 minutes) MS (ESI, m / e) 202 (M + 1)

Example 1 6-Bromo-2- (3-methoxyphenyl) -1H-imidazo [4,5-b]
Pyridine (compound of Reference Example 2) (21.3 g), phenylboronic acid (22.2 g), tetrakis (triphenylphosphine) palladium (0) (7.60 g), 2 M sodium carbonate solution (175 ml), toluene (525 ml) ) And tetrahydrofuran (175 ml) in an argon stream at 90 ° C. for 24 hours, and then ethyl acetate-tetrahydrofuran (3:
1, v / v) and water. Wash the organic layer with water and dry (MgS
After O ₄ ), the solvent was distilled off under reduced pressure and the crystals were collected by filtration to give 2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridine (14.0 g, 66%). Got Recrystallized from chloroform-methanol. ¹ H NMR (DMSO-d ₆ ) δ 3.89 (3H, s), 7.09-7.14 (1H,
m), 7.36-7.56 (4H, m), 7.75-7.88 (4H, m), 8.30 (1H,
s), 8.66 (1H, s) ppm IR (KBr) ν 3098, 1489, 1267, 1055 cm ^-1 HPLC (220 nm) Purity 100% (retention time 3.05 minutes) MS (APCI +, m / e) 302 (M +1) The compounds of Reference Examples 2 to 42 and various boronic acids are appropriately selected as starting materials, and the following Examples 2 to 4 are prepared according to the method of Example 1.
96 compounds were synthesized. At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 2 2- (1,3-benzodioxol-5-yl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.82 minutes) MS (ESI +, m / e) 316 (M + 1) Example 3 2- (3-chlorophenyl) -6-phenyl-1H-imidazo [4,5-b]
Pyridine HPLC (220 nm) Purity 94% (retention time 3.20 minutes) MS (ESI +, m / e) 306 (M + 1) Example 4 6-phenyl-2- [4- (trifluoromethoxy) phenyl] -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 93% (retention time 3.39 min) MS (ESI +, m / e) 356 (M + 1)

Example 5 2- (5-Methyl-2-thienyl) -6-phenyl-1H-imidazo [4,5
-b] Pyridine HPLC (220 nm) Purity 93% (retention time 3.33 minutes) MS (ESI +, m / e) 292 (M + 1) Example 6 2- (4-methoxybenzyl) -6-phenyl-1H- Imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 86% (retention time 2.82 minutes) MS (ESI +, m / e) 316 (M + 1)

Example 7 2- (2-Cyclopentylethyl) -6-phenyl-1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 94% (retention time 3.03 min) MS (ESI +, m / e) 292 (M + 1) Example 8 6- (2-Fluorophenyl) -2- (2-Methoxyphenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 2.95 minutes) MS (APCI +, m / e) 320 (M + 1) Example 9 6- (2-Fluorophenyl) -2 -(4-Methoxyphenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 2.89 min) MS (APCI +, m / e) 320 (M + 1)

Example 10 2- (1,3-benzodioxol-5-yl) -6- (2-fluorophenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99 % (Retention time 2.89 minutes) MS (APCI +, m / e) 334 (M + 1) Example 11 2- (3-chlorophenyl) -6- (2-fluorophenyl) -1H-imidazo [4,5-b ] Pyridine HPLC (220 nm) Purity 99% (retention time 3.35 min) MS (APCI +, m / e) 324 (M + 1)

Example 12 6- (2-Fluorophenyl) -2- [4- (trifluoromethoxy)
Phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.52 minutes) MS (APCI +, m / e) 374 (M + 1) Example 13 6- (2- Fluorophenyl) -2- (5-methyl-2-thienyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.95 minutes) MS (APCI +, m / e) 310 (M + 1)

Example 14 6- (2-Fluorophenyl) -2- (4-methoxybenzyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.87 minutes) MS (APCI +, m / e) 334 (M + 1) Example 15 2- (2-Cyclopentylethyl) -6 -(2-Fluorophenyl)-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.08 minutes) MS (APCI +, m / e) 310 (M + 1) Example 16 6- (2-Fluorophenyl) -2- (phenoxymethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.11 minutes) MS (APCI +, m / e) 320 (M + 1)

Example 17 2- (2-Methoxyphenyl) -6- (1-naphthyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 98% (retention time 3.23 min) MS (APCI +, m / e) 352 (M + 1) Example 18 2- (3-methoxyphenyl) -6- (1-naphthyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.30 min) MS (APCI +, m / e) 352 (M + 1) Example 19 2- (4-methoxyphenyl) -6- (1-naphthyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 99% (retention time 3.17 min) MS (APCI +, m / e) 352 (M + 1) Example 20 2- (1,3-benzodioxole -5-yl) -6- (1-naphthyl) -1
H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.18 min) MS (APCI +, m / e) 366 (M + 1) Example 21 2- (3-chlorophenyl)- 6- (1-naphthyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 91% (retention time 3.60 minutes) MS (APCI +, m / e) 356 (M + 1)

Example 22 6- (1-naphthyl) -2- [4- (trifluoromethoxy) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.73 Min) MS (APCI +, m / e) 406 (M + 1) Example 23 2- (5-methyl-2-thienyl) -6- (1-naphthyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 97% (retention time 3.24 min) MS (APCI +, m / e) 342 (M + 1) Example 24 2- (4-methoxybenzyl) -6- (1-naphthyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 98% (retention time 3.16 minutes) MS (APCI +, m / e) 366 (M + 1)

Example 25 2- (2-Cyclopentylethyl) -6- (1-naphthyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.33 minutes) MS ( APCI +, m / e) 342 (M + 1) Example 26 2- (2-methoxyphenyl) -6- (3-methoxyphenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 2.96 minutes) MS (APCI +, m / e) 332 (M + 1)

Example 27 6- (3-Methoxyphenyl) -2- (4-methoxyphenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) 90% purity (retention time 2.91 min) MS (APCI +, m / e) 332 (M + 1) Example 28 2- (3-chlorophenyl) -6- (3-Methoxyphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 91% (retention time 3.28 min) MS (APCI +, m / e) 336 (M + 1) Example 292 -(4-Methoxybenzyl) -6- (3-methoxyphenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 94% (retention time 2.90 minutes) MS (APCI +, m / e) 346 (M + 1)

Example 30 2,6-Bis (3-methoxyphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.01 minutes) MS (APCI +, m / e ) 332 (M + 1) Example 31 2- (1,3-benzodioxol-5-yl) -6- (3-methoxyphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 80% (retention time 2.91 minutes) MS (APCI +, m / e) 346 (M + 1)

Example 32 6- (3-methoxyphenyl) -2- [4- (trifluoromethoxy)
Phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 81% (retention time 3.45 min) MS (APCI +, m / e) 386 (M + 1) Example 33 2- (2- Methoxyphenyl) -6- [3- (trifluoromethyl) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.29 min) MS (APCI +, m / e) 370 (M + 1)

Example 34 2- (3-Methoxyphenyl) -6- [3- (trifluoromethyl) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.39 min) MS (APCI +, m / e) 370 (M + 1) Example 35 2- (4-methoxyphenyl) -6- [3- (trifluoromethyl) phenyl] -1H-imidazo [4,5- b] Pyridine HPLC (220 nm) Purity 96% (retention time 3.25 min) MS (APCI +, m / e) 370 (M + 1) Example 36 2- (1,3-benzodioxol-5-yl) -6- [3- (Trifluoromethyl) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 85% (retention time 3.27 min) MS (APCI +, m / e) 384 (M +1)

Example 37 2- (3-Chlorophenyl) -6- [3- (trifluoromethyl) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 92% (retention time 3.73 Min) MS (APCI +, m / e) 374 (M + 1) Example 38 2- [4- (trifluoromethoxy) phenyl] -6- [3- (trifluoromethyl) phenyl] -1H-imidazo [4 , 5-b] Pyridine HPLC (220 nm) Purity 92% (retention time 3.85 min) MS (APCI +, m / e) 424 (M + 1) Example 39 2- (5-methyl-2-thienyl) -6 -[3- (trifluoromethyl)
Phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 93% (retention time 3.35 min) MS (APCI +, m / e) 360 (M + 1) Example 40 2- (4- Methoxybenzyl) -6- [3- (trifluoromethyl) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 3.22 minutes) MS (APCI +, m / e) 384 (M + 1) Example 41 2- (2-Cyclopentylethyl) -6- [3- (trifluoromethyl) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (Retention time 3.37 minutes) MS (APCI +, m / e) 360 (M + 1)

Example 42 4- [2- (2-Methoxyphenyl) -1H-imidazo [4,5-b] pyridin-6-yl] benzonitrile HPLC (220 nm) Purity 100% (retention time 2.90 minutes) MS (APCI +, m / e) 327 (M + 1) Example 43 4- [2- (3-Methoxyphenyl) -1H-imidazo [4,5-b] pyridin-6-yl] benzonitrile HPLC (220 nm) Purity 98% (retention time 3.02 minutes) MS (APCI +, m / e) 327 (M + 1) Example 44 4- [2- (4-methoxyphenyl) -1H-imidazo [4,5-b] Pyridine-6-yl] benzonitrile HPLC (220 nm) Purity 100% (retention time 2.86 min) MS (APCI +, m / e) 327 (M + 1) Example 45 4- [2- (1,3-benzo Dioxole-5-yl) -1H-imidazo
[4,5-b] Pyridin-6-yl] benzonitrile HPLC (220 nm) Purity 98% (retention time 2.88 minutes) MS (APCI +, m / e) 341 (M + 1) Example 46 4- [2 -(3-Chlorophenyl) -1H-imidazo [4,5-b] pyridine
-6-yl] benzonitrile HPLC (220 nm) Purity 82% (retention time 3.33 minutes) MS (APCI +, m / e) 331 (M + 1) Example 47 4- [2- [4- (trifluoromethoxy ) Phenyl] -1H-imidazo [4,5-b] pyridin-6-yl] benzonitrile HPLC (220 nm) Purity 98% (retention time 3.52 minutes) MS (APCI +, m / e) 381 (M + 1)

Example 48 4- [2- (4-Methoxybenzyl) -1H-imidazo [4,5-b] pyridin-6-yl] benzonitrile HPLC (220 nm) Purity 98% (retention time 2.82 minutes) MS (APCI +, m / e) 341 (M + 1) Example 49 4- [2- (2-Cyclopentylethyl) -1H-imidazo [4,5-b] pyridin-6-yl] benzonitrile HPLC (220 nm) Purity 99% (retention time 3.01 minutes) MS (APCI +, m / e) 317 (M + 1) Example 50 2- (2-methoxyphenyl) -6- [4- (methylsulfonyl) phenyl] -1H -Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 2.65 min) MS (APCI +, m / e) 380 (M + 1) Example 51 2- (3-methoxyphenyl)- 6- [4- (Methylsulfonyl) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 88% (retention time 2.74 minutes) MS (APCI +, m / e) 380 (M + 1 ) Example 52 2- (4-methoxyphenyl) -6- [4- (methylsulfonyl) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 2.63 minutes) MS (APCI +, m / e) 380 (M + 1)

Example 53 2- (1,3-benzodioxol-5-yl) -6- [4- (methylsulfonyl) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm ) Purity 93% (retention time 2.62 minutes) MS (APCI +, m / e) 394 (M + 1) Example 54 2- (3-chlorophenyl) -6- [4- (methylsulfonyl) phenyl] -1H-imidazo [4,5-b] Pyridine HPLC (220 nm) Purity 90% (retention time 3.03 minutes) MS (APCI +, m / e) 384 (M + 1) Example 55 6- [4- (methylsulfonyl) phenyl] -2- [4- (Trifluoromethoxy) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.25 min) MS (APCI +, m / e) 434 (M +1) Example 56 2- (4-methoxybenzyl) -6- [4- (methylsulfonyl) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.57 Min) MS (APCI +, m / e) 394 (M + 1) Example 57 2- (2-Cyclopentylethyl) -6- [4- (methylsulfonyl)
Phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 94% (retention time 2.80 minutes) MS (APCI +, m / e) 370 (M + 1)

Example 58 6- (2-Fluorophenyl) -2-[(phenylthio) methyl] -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.04 min) MS (APCI +, m / e) 336 (M + 1) Example 59 6- (2-Fluorophenyl)- 2- (2-Phenylethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.91 min) MS (APCI +, m / e) 318 (M + 1) Example 60 2-Benzyl-6- (2-fluorophenyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 99% (retention time 2.81 min) MS (APCI +, m / e) 304 (M + 1) Example 61 6- (2-Fluorophenyl) -2- (3-methoxybenzyl) ) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.90 minutes) MS (APCI +, m / e) 334 (M + 1) Example 62 2- (2,5-dimethoxybenzyl) -6- (2-Fluorophenyl)-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 2.93 minutes) MS (APCI +, m / e) 364 (M + 1)

Example 63 2- (3,4-dimethoxybenzyl) -6- (2-fluorophenyl)-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 89% (retention time 2.76 min) MS (APCI +, m / e) 364 (M + 1) Example 64 2- (4-chlorobenzyl) -6- (2-Fluorophenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.11 minutes) MS (APCI +, m / e) 338 (M + 1) Example 65 6- (2-fluorophenyl) -2-[(E) -2-phenylethenyl]-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.06 minutes) MS (APCI +, m / e) 316 (M + 1) Example 66 6- (2-fluorophenyl) -2- (3-phenoxyphenyl) -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 87% (retention time 3.62 minutes) MS (APCI +, m / e) 382 (M + 1) Example 67 2- (4-benzoylphenyl)- 6- (2-fluorophenyl) -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.54 min) MS (APCI +, m / e) 394 (M + 1)

Example 68 2- (phenoxymethyl) -6-phenyl-1H-imidazo [4,5-b]
Pyridine HPLC (220 nm) Purity 97% (retention time 2.98 minutes) MS (APCI +, m / e) 302 (M + 1) Example 69 6-Phenyl-2-[(phenylthio) methyl] -1H-imidazo [4 ,
5-b] Pyridine HPLC (220 nm) Purity 99% (retention time 2.95 minutes) MS (APCI +, m / e) 318 (M + 1) Example 70 6-Phenyl-2- (2-phenylethyl) -1H -Imidazo [4,5-b]
Pyridine HPLC (220 nm) Purity 97% (retention time 2.88 minutes) MS (APCI +, m / e) 300 (M + 1) Example 71 2-Benzyl-6-phenyl-1H-imidazo [4,5-b] Pyridine HPLC (220 nm) Purity 99% (retention time 2.76 min) MS (APCI +, m / e) 286 (M + 1) Example 72 2- (3-methoxybenzyl) -6-phenyl-1H-imidazo [4 ,Five-
b] Pyridine HPLC (220 nm) Purity 99% (retention time 2.84 minutes) MS (APCI +, m / e) 316 (M + 1)

Example 73 2- (2,5-Dimethoxybenzyl) -6-phenyl-1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 99% (retention time 2.88 min) MS (APCI +, m / e) 346 (M + 1) Example 74 2- (3,4-dimethoxybenzyl)- 6-phenyl-1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 92% (retention time 2.68 min) MS (APCI +, m / e) 346 (M + 1) Example 75 2- (4-chlorobenzyl) -6- Phenyl-1H-imidazo [4,5-b]
Pyridine HPLC (220 nm) Purity 99% (retention time 3.02 minutes) MS (APCI +, m / e) 320 (M + 1) Example 76 6-phenyl-2-[(E) -2-phenylethenyl]- 1H-Imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 99% (retention time 2.97 minutes) MS (APCI +, m / e) 298 (M + 1) Example 77 2- (3-phenoxyphenyl) -6- Phenyl-1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 94% (retention time 3.48 min) MS (APCI +, m / e) 364 (M + 1)

Example 78 2- (4-benzoylphenyl) -6-phenyl-1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.38 min) MS (APCI +, m / e) 376 (M + 1) Example 79 6- (1-benzofuran-2-yl) -2- (4-fluorobenzyl) -1
H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.25 min) MS (APCI +, m / e) 344 (M + 1) Example 80 6- (1-benzofuran-2 -Yl) -2- (3-chlorobenzyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.44 min) MS (APCI +, m / e) 360 (M + 1) Example 81 6- (1-benzofuran-2-yl) ) -2- (2-Chlorobenzyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.31 minutes) MS (APCI +, m / e) 360 (M + 1) Example 82 6- (1-benzofuran-2-yl) ) -2- (2,4-Difluorobenzyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.30 min) MS (APCI +, m / e) 362 (M + 1)

Example 83 6- (1-benzofuran-2-yl) -2- (3,4-dichlorobenzyl)
-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.66 min) MS (APCI +, m / e) 394 (M + 1) Example 84 6- (1-benzofuran- 2-yl) -2- [4- (trifluoromethyl) benzyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.58 min) MS (APCI +, m / e ) 394 (M + 1) Example 85 6- (1-benzofuran-2-yl) -2- [4- (trifluoromethoxy) benzyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm ) Purity 100% (retention time 3.74 minutes) MS (APCI +, m / e) 410 (M + 1) Example 86 6- (1-benzofuran-2-yl) -2- (4-nitrobenzyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.47 min) MS (APCI +, m / e) 371 (M + 1) Example 87 6- (1-benzofuran-2-yl) ) -2- (4-Methylbenzyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.42 min) MS (APCI +, m / e) 340 (M + 1)

Example 88 6- (1-benzofuran-2-yl) -2-[(1,1'-biphenyl) -4-
Ilmethyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.79 min) MS (APCI +, m / e) 402 (M + 1) Example 89 6- (1- Benzofuran-2-yl) -2- (2-naphthylmethyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.62 minutes) MS (APCI +, m / e) 376 (M + 1) Example 90 2- (1,3-Benzodioxy Sole-5-ylmethyl) -6- (1-benzofuran-2-yl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.29 min) MS (APCI +, m / e) 370 (M + 1) Example 91 6- (1-benzofuran-2-yl) -2- (3,4,5-trimethoxybenzyl) -1H-imidazo [4,5-b] pyridine HPLC ( 220 nm) Purity 99% (retention time 3.25 min) MS (APCI +, m / e) 416 (M + 1) Example 92 6- (1-benzofuran-2-yl) -2- (2-thienylmethyl)- 1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.27 min) MS (APCI +, m / e) 332 (M + 1)

Example 93 6- (1-benzofuran-2-yl) -2-[(1-methyl-1H-indol-3-yl) methyl] -1H-imidazo [4,5-b] pyridine HPLC ( 220 nm) Purity 98% (retention time 3.44 minutes) MS (APCI +, m / e) 379 (M + 1) Example 94 6- (1-benzofuran-2-yl) -2-[(4-chlorophenoxy)
Methyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.90 min) MS (APCI +, m / e) 376 (M + 1) Example 95 6- (1- Benzofuran-2-yl) -2- [4- (methylthio) benzyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.49 min) MS (APCI +, m / e ) 372 (M + 1) Example 96 6- (1-benzofuran-2-yl) -2- [2- (3,4-dimethoxyphenyl) ethyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.19 min) MS (APCI +, m / e) 400 (M + 1)

Example 97 6-Bromo-2- (3,4-dimethoxybenzyl) -1H-imidazo [4,
5-b] pyridine (compound of Reference Example 23) (140 mg), 2- (tributylstannyl) furan (185 mg), dichlorobis (triphenylphosphine) palladium (II) (14 mg), N, N-
The mixture of dimethylformamide (4 ml) was stirred at 80 ° C. for 24 hours in an argon stream, poured into water, and extracted with ethyl acetate-tetrahydrofuran (3: 1, v / v). The organic layer was washed with water, dried (MgSO _4), evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, ethyl acetate - chloroform (1: 1, v / v ) and the fraction eluted with concentrated under reduced pressure The resulting crystals are collected by filtration to give 2- (3,4-dimethoxybenzyl) -6- (2-furyl) -1H-imidazo [4,5-b] pyridine (55 mg, 41%). It was ¹ H NMR (CDCl ₃ ) δ 3.80 (3H, s), 3.82 (3H, s), 4.33
(2H, s), 6.53 (1H, dd, J = 3.4, 1.8 Hz), 6.69 (1
H, d, J = 3.4 Hz), 7.54 (1H, d, J = 1.8 Hz), 8.24
(1H, s), 8.36 (1H, s) ppm IR (KBr) ν 2928, 1516, 1263, 1236 cm ^-1 HPLC (220 nm) Purity 100% (retention time 2.66 min) MS (APCI +, m / e) 336 (M + 1)

The compounds of Reference Examples 2 to 42 and various tributyltin compounds were appropriately selected as starting materials, and the compounds of Examples 98 to 145 below were synthesized according to the method of Example 97.
At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 98 6- (2-furyl) -2- (2-methoxyphenyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 99% (retention time 2.74 minutes) MS (APCI +, m / e) 292 (M + 1) Example 99 6- (2-furyl) -2- (3-methoxy) Phenyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.83 min) MS (APCI +, m / e) 292 (M + 1) Example 100 6- (2-furyl) -2- (4-methoxy) Phenyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.70 min) MS (APCI +, m / e) 292 (M + 1) Example 101 2- (1,3-benzodioxole-5- (Il) -6- (2-furyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.70 minutes) MS (APCI +, m / e) 306 (M + 1) Example 102 2- (3-chlorophenyl) -6- (2-furyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.16 min) MS (APCI +, m / e) 296 (M + 1)

Example 103 6- (2-furyl) -2- [4- (trifluoromethoxy) phenyl]-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.37 min) MS (APCI +, m / e) 346 (M + 1) Example 104 6- (2-furyl)- 2- (5-methyl-2-thienyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.76 min) MS (APCI +, m / e) 282 (M + 1) Example 105 6- (2-furyl) -2- ( 4-methoxybenzyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 98% (retention time 2.68 min) MS (APCI +, m / e) 306 (M + 1) Example 106 6- (2-furyl) -2- (phenoxymethyl) -1H-Imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.91 min) MS (APCI +, m / e) 292 (M + 1) Example 107 2- (2-Cyclopentylethyl) -6- (2-furyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 2.91 minutes) MS (APCI +, m / e) 282 (M + 1)

Example 108 6- (2-furyl) -2-[(phenylthio) methyl] -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 95% (retention time 3.61 min) MS (APCI +, m / e) 308 (M + 1) Example 109 6- (2-furyl) -2- ( 2-phenylethyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 92% (retention time 2.74 minutes) MS (APCI +, m / e) 290 (M + 1) Example 110 2-benzyl-6- (2-furyl) -1H-imidazo [ 4,5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.61 minutes) MS (APCI +, m / e) 276 (M + 1) Example 111 6- (2-furyl) -2- (3 -Methoxybenzyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 98% (retention time 2.70 min) MS (APCI +, m / e) 306 (M + 1) Example 112 2- (2,5-dimethoxybenzyl) -6- ( 2-Furyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 83% (retention time 2.74 minutes) MS (APCI +, m / e) 336 (M + 1)

Example 113 2- (4-chlorobenzyl) -6- (2-furyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.93 minutes) MS (APCI +, m / e) 310 (M + 1) Example 114 6- (2-furyl) -2-[(E) -2 -Phenylethenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 2.89 min) MS (APCI +, m / e) 288 (M + 1) Example 115 6- (2-furyl) -2- (3-phenoxyphenyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 85% (retention time 3.49 min) MS (APCI +, m / e) 354 (M + 1) Example 116 2- (4-benzoylphenyl) -6- (2-furyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 90% (retention time 3.39 min) MS (APCI +, m / e) 366 (M + 1) Example 117 2- (phenoxymethyl) -6- (2 -Thienyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 99% (retention time 3.05 min) MS (APCI +, m / e) 308 (M + 1)

Example 118 2-[(phenylthio) methyl] -6- (2-thienyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 95% (retention time 2.99 minutes) MS ( APCI +, m / e) 324 (M + 1) Example 119 2- (2-phenylethyl) -6- (2-thienyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 94% (retention time 2.84 min) MS (APCI +, m / e) 306 (M + 1) Example 120 2-benzyl-6- (2-thienyl) -1H- Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.73 minutes) MS (APCI +, m / e) 292 (M + 1) Example 121 2- (2,5-dimethoxybenzyl) -6- (2-thienyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 2.84 minutes) MS (APCI +, m / e) 352 (M + 1) Example 122 2- (3,4-Dimethoxybenzyl) -6- (2-thienyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 88% (retention time 2.66 min) MS (APCI +, m / e) 352 (M + 1)

Example 123 2- (4-chlorobenzyl) -6- (2-thienyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 98% (retention time 3.04 min) MS (APCI +, m / e) 326 (M + 1) Example 124 2- (3-phenoxyphenyl) -6- (2- Thienyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 95% (retention time 3.62 minutes) MS (APCI +, m / e) 370 (M + 1) Example 125 2- (3- Methoxybenzyl) -6- (2-thienyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 98% (retention time 2.82 minutes) MS (APCI +, m / e) 322 (M + 1) Example 126 2-[(E) -2-phenylene Tenyl] -6- (2-thienyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.00 min) MS (APCI +, m / e) 304 (M + 1) Example 127 2- (4-benzoylphenyl) -6- (2-thienyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 92% (retention time 3.52 minutes) MS (APCI +, m / e) 382 (M + 1)

Example 128 2- (4-Fluorobenzyl) -6- (2-furyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 83% (retention time 2.82 min) MS (APCI +, m / e) 294 (M + 1) Example 129 2- (3-chlorobenzyl) -6- (2- Ruffle) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.99 min) MS (APCI +, m / e) 310 (M + 1) Example 130 2- (2,4-difluorobenzyl) -6- (2- Furyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 84% (retention time 2.85 minutes) MS (APCI +, m / e) 312 (M + 1) Example 131 2- (3, 4-dichlorobenzyl) -6- (2-furyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.25 min) MS (APCI +, m / e) 344 (M + 1) Example 132 6- (2-furyl) -2- [ 4- (Trifluoromethyl) benzyl] -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) 100% purity (retention time 3.20 min) MS (APCI +, m / e) 344 (M + 1)

Example 133 6- (2-furyl) -2- [4- (trifluoromethoxy) benzyl]-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.24 min) MS (APCI +, m / e) 360 (M + 1) Example 134 6- (2-furyl)- 2- (4-nitrobenzyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 97% (retention time 2.89 min) MS (APCI +, m / e) 321 (M + 1) Example 135 6- (2-furyl) -2- (4-methylbenzyl) -1H-Imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 84% (retention time 2.91 minutes) MS (APCI +, m / e) 290 (M + 1) Example 136 6- (2-furyl) -2- (2-naphthylmethyl) -1H-Imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.15 minutes) MS (APCI +, m / e) 326 (M + 1) Example 137 2- (1,3-benzodioxol-5-ylmethyl) -6- (2-Furyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 86% (retention time 2.75 minutes) MS (APCI +, m / e) 320 (M + 1)

Example 138 6- (2-furyl) -2- (3,4,5-trimethoxybenzyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 2.66 min) MS (APCI +, m / e) 366 (M + 1) Example 139 6- (2-furyl) -2- (2-thienylmethyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.54 minutes) MS (APCI +, m / e) 282 (M + 1) Example 140 6- (2-furyl) -2-[(1-methyl- 1H-Indol-3-yl) methyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 2.93 minutes) MS (APCI +, m / e) 329 (M + 1) Example 141 2-[(4-chlorophenoxy) methyl] -6- (2-furyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.19 minutes) MS ( APCI +, m / e) 326 (M + 1) Example 142 2- [2- (3,4-dimethoxyphenyl) ethyl] -6- (2-furyl)-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 2.65 min) MS (APCI +, m / e) 350 (M + 1)

Example 143 6- (2-furyl) -2- [4- (methylthio) benzyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 2.93 minutes) MS (APCI +, m / e) 322 (M + 1) Example 144 2- (2-chlorobenzyl) -6- (2-furyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.85 minutes) MS (APCI +, m / e) 310 (M + 1) Example 145 2-[(1,1'-biphenyl) -4-ylmethyl] -6- (2-furyl) -1
H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 94% (retention time 3.34 minutes) MS (APCI +, m / e) 352 (M + 1) Example 146 2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-
b] Pyridine (compound of Example 1) (50 mg), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine resin (PS-BEMP, 2.2 mmol /
g) (113 mg) and N, N-dimethylformamide (2 ml) were shaken at room temperature for 30 minutes, and then iodomethane (28 m
g) was added and shaken at room temperature for another hour. After the resin was filtered off, the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, and ethyl acetate-chloroform-hexane (1: 1: 4 to 1: 1: 0, v /
The crystals obtained by concentrating the fraction eluted under v) under reduced pressure are collected by filtration to give 2- (3-methoxyphenyl) -1-methyl-6-phenyl-1.
H-imidazo [4,5-b] pyridine (22 mg, 41%) was isolated (after reaction, a mixture of two component isomers is obtained, but the more polar component is the target compound). ¹ H NMR (CDCl ₃ ) δ 3.95 (3H, s), 4.43 (3H, s), 7.00
-7.05 (1H, m), 7.37-7.61 (6H, m), 7.81 (1H, d, J =
1.6 Hz), 8.06-8.15 (2H, m), 8.40 (1H, d, J = 1.4 H
z) ppm IR (KBr) ν 1472, 1397, 1292, 1252 cm ^-1 HPLC (220 nm) Purity 100% (retention time 2.87 minutes) MS (APCI +, m / e) 316 (M + 1)

The compounds of Example 1 and various alkyl halides were appropriately selected as starting materials, and the following compounds of Examples 147 to 153 were synthesized according to the method of Example 146 (however, the reaction time was 15 hours). . Example 147 1- (2-methoxyethyl) -2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 86% (retention time 3.06 minutes) MS (APCI +, m / e) 360 (M + 1) Example 148 1- (Cyclohexylmethyl) -2- (3-methoxyphenyl) -6-
Phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 3.70 minutes) MS (APCI +, m / e) 398 (M + 1) Example 149 2- (3-methoxy Phenyl) -6-phenyl-1- (2-phenylethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.50 min) MS (APCI +, m / e) 406 (M + 1) Example 150 2- (3-methoxyphenyl) -1- (3-phenoxypropyl) -6-
Phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.50 min) MS (APCI +, m / e) 436 (M + 1) Example 151 N- [3- [ 2- (3-Methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridin-1-yl] propyl] phthalimide HPLC (220 nm) Purity 99% (retention time 3.31 minutes) MS (APCI +, m / e) 489 (M + 1)

Example 152 1-decyl-2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 4.32 minutes) MS ( APCI +, m / e) 442 (M + 1) Example 153 2-[[2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridin-1-yl] methyl acetate ] Phenyl HPLC (220 nm) Purity 97% (retention time 3.36 min) MS (APCI +, m / e) 450 (M + 1)

Example 154 2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-
b] Pyridine (Compound of Example 1) (250 mg), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine resin (PS-BEMP, 2.2 mmol /
g) (566 mg) and a mixture of N, N-dimethylformamide (10 ml) were shaken at room temperature for 30 minutes, tert-butyl bromoacetate (194 mg) was added, and the mixture was further shaken at room temperature for 1 hour. After the resin was filtered off, the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 2-1: 1: 1.5, v / v). Were concentrated under reduced pressure to give [2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridin-1-yl].
Tert-Butyl acetate was isolated. [2- (3-methoxyphenyl)
-6-Phenyl-1H-imidazo [4,5-b] pyridin-1-yl] acetic acid
4 N hydrogen chloride (ethyl acetate solution) (8.0 ml) was added to tert-butyl (209 mg), and the mixture was stirred at room temperature for 5 hr for hydrolysis. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, and the crystals were collected by filtration to give [2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b]. Pyridin-1-yl] acetic acid (129 m
g, 43%) was obtained. ¹ H NMR (DMSO-d ₆ ) δ 3.86 (3H, s), 5.56 (2H, s), 7.
02-7.07 (1H, m), 7.45-7.55 (4H, m), 7.79-7.92 (4H,
m), 8.63 (1H, s), 8.72 (1H, s) ppm IR (KBr) ν 3368, 1634, 1478, 1362 cm ^-1 HPLC (220 nm) Purity 100% (retention time 2.73 minutes) MS (APCI +, m / e) 360 (M + 1)

Example 155 [2- (3-Methoxyphenyl) -6-phenyl-1H-imidazo [4,5
-b] pyridin-1-yl] acetic acid (compound of Example 154) (100
mg), glycine tert-butyl hydrochloride (56 mg), 1-ethyl
-3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl) (80 mg), 1-hydroxybenzotriazole (HOBt) (56 mg), N, N-diisopropylethylamine (108 mg), N, N -A mixture of dimethylformamide (5 ml) was stirred at room temperature for 3 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer is washed with water and dried (MgSO
₄ ) After that, the solvent was distilled off under reduced pressure, the crystals were collected by filtration, and [[[2- (3-
Methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridin-1-yl] acetyl] amino] tert-butyl acetate (78
mg, 60%) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.41 (9H, s), 3.95 (3H, s), 3.95
(2H, d, J = 5.0 Hz), 5.38 (2H, s), 7.00-7.05 (1H,
m), 7.36-7.58 (6H, m), 7.95 (1H, d, J = 1.6Hz), 8.
05-8.12 (3H, m), 8.40 (1H, d, J = 1.4 Hz) ppm IR (KBr) ν 2980, 1748, 1667, 1292 cm ^-1 HPLC (220 nm) Purity 100% (retention time 3.24 minutes) MS (APCI +, m / e) 473 (M + 1)

Example 156 [[[2- (3-Methoxyphenyl) -6-phenyl-1H-imidazo
[4,5-b] Pyridin-1-yl] acetyl] amino] acetic acid tert-
Butyl (compound of Example 155) (50 mg) in 4 N hydrogen chloride
(Ethyl acetate solution) (10.0 ml) was added for 5 hours at room temperature
Mix and hydrolyze. Pour the reaction mixture into water and add acetic acid.
Extracted with chill. The organic layer is washed with water and dried (MgSO _Four), Then melt
The medium was evaporated under reduced pressure, the crystals were collected by filtration, and [[[2- (3-methoxy
Phenyl) -6-phenyl-1H-imidazo [4,5-b] pyridin-1-y
Lu] acetyl] amino] acetic acid (19 mg, 42%) was obtained.¹ H NMR (DMSO-d₆) δ 3.87 (3H, s), 3.91 (2H, d, J =
 5.6 Hz), 5.58 (2H, s), 7.04-7.09 (1H, m), 7.39-7.
59 (4H, m), 7.79-7.97 (4H, m), 8.65 (1H, s), 8.66 (1
H, s), 8.97 (1H, t, J = 5.6 Hz) ppm IR (KBr) ν 3015, 1688, 1591, 1478 cm^-1 HPLC (220 nm) Purity 93% (Retention time 2.59 minutes) MS (APCI +, m / e) 417 (M + 1)

Example 157 2-[[2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridin-1-yl] methyl] phenyl acetate (Example
Compound (153) (177 mg) was dissolved in tetrahydrofuran-methanol (1: 1, v / v, 20 ml), and 2 N lithium hydroxide solution (6.8 ml) was added. After stirring at room temperature for 1.5 hours, the reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (3: 1, v / v). The organic layer was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure, and the crystals were collected by filtration to give 2
-[[2- (3-Methoxyphenyl) -6-phenyl-1H-imidazo
[4,5-b] Pyridin-1-yl] methyl] phenol (133 mg,
83%). Recrystallized from tetrahydrofuran-ethyl acetate. ¹ H NMR (DMSO-d ₆ ) δ 3.88 (3H, s), 5.89 (2H, s), 6.
79-6.92 (2H, m), 7.03-7.08 (1H, m), 7.15-7.23 (1H,
m), 7.41-7.58 (5H, m), 7.76-7.80 (2H, m), 7.93-8.
00 (2H, m), 8.59 (1H, d, J = 1.4 Hz), 8.75 (1H, d,
J = 1.4 Hz), 10.96 (1H, s) ppm IR (KBr) ν 3063, 1468, 1404, 1238 cm ^-1 HPLC (220 nm) Purity 100% (retention time 3.30 min) MS (ESI +, m / e) 408 (M + 1)

Example 158 2-[[2- (3-methoxyphenyl) -6-phenyl-1H-imidazo
[4,5-b] Pyridin-1-yl] methyl] phenol (Example 15
Compound of 7) (41 mg), ethyl bromoacetate (18 mg), N,
Potassium carbonate (19 mg) was added to a solution of N-dimethylformamide (1 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, the crystals were collected by filtration,
[2-[[2- (3-Methoxyphenyl) -6-phenyl-1H-imidazo
Ethyl [4,5-b] pyridin-1-yl] methyl] phenoxy] acetate (37 mg, 74%) was obtained. HPLC (220 nm) Purity 100% (retention time 3.59 minutes) MS (APCI +, m / e) 494 (M + 1)

Example 159 [2-[[2- (3-methoxyphenyl) -6-phenyl-1H-imidazo
[4,5-b] Pyridin-1-yl] methyl] phenoxy] ethyl acetate (the compound of Example 158) (28 mg) was dissolved in tetrahydrofuran-ethanol (1: 1, v / v, 3.6 ml), A 2N lithium hydroxide solution (1.2 ml) was added. After stirring at room temperature for 2 hours, the reaction mixture was poured into water, 2N hydrochloric acid was added, and
Adjusted to H3, ethyl acetate-tetrahydrofuran (3:
1, v / v). The organic layer was washed with water, dried (MgSO ₄₎
After that, the solvent was distilled off under reduced pressure, and the crystals were collected by filtration to give [2-[[2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridin-1-yl]. Methyl] phenoxy] acetic acid (15 mg, 55%)
Got ¹ H NMR (DMSO-d ₆ ) δ 3.87 (3H, s), 4.85 (2H, s), 5.
98 (2H, s), 6.94-7.05 (3H, m), 7.28-7.55 (6H, m),
7.74-7.78 (2H, m), 7.96-8.03 (2H, m), 8.54 (1H,
s), 8.66 (1H, s) ppm IR (KBr) ν 3403, 1605, 1474, 1235 cm ^-1 HPLC (220 nm) Purity 98% (retention time 3.27 minutes) MS (APCI +, m / e) 466 (M +1)

Example 160 The compound of Example 157 and ethyl 4-bromobutyrate were selected as starting materials, and 4- [2-[[2-
(3-Methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b]
Pyridin-1-yl] methyl] phenoxy] butyric acid was synthesized. ¹ H NMR (DMSO-d ₆ ) δ 1.95 (2H, quintet, J = 6.7 H
z), 2.39 (2H, t, J = 6.8Hz), 3.86 (3H, s), 4.07 (2
H, t, J = 6.1 Hz), 5.96 (2H, s), 6.89-7.07 (3H,
m), 7.27-7.56 (6H, m), 7.75-7.79 (2H, m), 7.93-8.0
1 (2H, m), 8.52 (1H, s), 8.56 (1H, s) ppm IR (KBr) ν 2940, 1713, 1470, 1244 cm ^-1 HPLC (220 nm) Purity 95% (retention time 3.34 minutes) MS (APCI +, m / e) 494 (M + 1)

Example 161 2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-
b] Pyridine (Compound of Example 1) (80 mg), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine resin (PS-BEMP, 2.2 mmol /
g) (181 mg) and a mixture of N, N-dimethylformamide (3.2 ml) were shaken at room temperature for 1 hour, 4-fluorobenzyl chloride (46 mg) was added, and the mixture was further shaken at room temperature for 15 hours. After removing the resin by filtration, the filtrate was concentrated under reduced pressure and the residue was collected.
After subjecting to HPLC, the target fraction was concentrated and then partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The organic layer was separated with a PTFE filter tube and concentrated under reduced pressure to give 1- (4-fluorobenzyl) -2-
(3-Methoxyphenyl) -6-phenyl-1H-imidazo [4,5-
b] Pyridine (84 mg, 78%) was obtained. ¹ H NMR (CDCl ₃ ) δ 3.96 (3H, s), 5.91 (2H, s), 7.01
-7.12 (3H, m), 7.39-7.57 (8H, m), 7.76 (1H, d, J =
1.8 Hz), 8.09-8.18 (2H, m), 8.37 (1H, d, J = 1.8 H
z) ppm HPLC (220 nm) Purity 100% (retention time 3.72 minutes) MS (APCI +, m / e) 410 (M + 1)

The compounds of Example 1 and various alkyl halides were appropriately selected as starting materials, and the compounds of Examples 162 to 206 below were synthesized according to the method of Example 161. Example 162 1- (2-Fluorobenzyl) -2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.52 minutes) MS (APCI +, m / e) 410 (M + 1) Example 163 1- (3-Fluorobenzyl) -2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.56 minutes) MS (APCI +, m / e) 410 (M + 1) Example 164 1- (2,4-difluorobenzyl) -2- (3-methoxyphenyl) -
6-Phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.59 min) MS (APCI +, m / e) 428 (M + 1) Example 165 1- (3 , 5-Difluorobenzyl) -2- (3-methoxyphenyl)-
6-Phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.62 min) MS (APCI +, m / e) 428 (M + 1) Example 166 1- (2 , 6-Difluorobenzyl) -2- (3-methoxyphenyl)-
6-Phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.65 minutes) MS (APCI +, m / e) 428 (M + 1)

Example 167 1- (2-chlorobenzyl) -2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 3.66 min) MS (APCI +, m / e) 426 (M + 1) Example 168 1- (3,4-dichlorobenzyl) -2- (3-methoxyphenyl) -6-
Phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 4.01 min) MS (APCI +, m / e) 460 (M + 1) Example 169 1- (3-bromo (Benzyl) -2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 3.74 minutes) MS (APCI +, m / e) 470 (M + 1) Example 170 2- (3-Methoxyphenyl) -6-phenyl-1- [2- (trifluoromethyl) benzyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 3.71 minutes) MS (APCI +, m / e) 460 (M + 1) Example 171 2- (3-methoxyphenyl) -6-phenyl-1- [3- (trifluoromethyl) benzyl ] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 3.75 minutes) MS (APCI +, m / e) 460 (M + 1)

Example 172 2- (3-Methoxyphenyl) -6-phenyl-1- [4- (trifluoromethyl) benzyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98 % (Retention time 3.78 minutes) MS (APCI +, m / e) 460 (M + 1) Example 173 2- (3-methoxyphenyl) -6-phenyl-1- [4- (trifluoromethoxy) benzyl]- 1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.84 min) MS (APCI +, m / e) 476 (M + 1) Example 174 2- (3-methoxyphenyl) -1- (2-Methylbenzyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.65 minutes) MS (APCI +, m / e) 406 (M +1) Example 175 2- (3-methoxyphenyl) -1- (4-methylbenzyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 3.72 min) MS (APCI +, m / e) 406 (M + 1) Example 176 1- (3,4-dimethylbenzyl) -2- (3-methoxyphenyl) -6-
Phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.95 minutes) MS (APCI +, m / e) 420 (M + 1)

Example 177 1- (4-tert-butylbenzyl) -2- (3-methoxyphenyl) -6
-Phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 4.20 min) MS (APCI +, m / e) 448 (M + 1) Example 178 1- (3- Methoxybenzyl) -2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.71 minutes) MS (APCI +, m / e) 422 (M + 1) Example 179 1- (4-Methoxybenzyl) -2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (Retention time 3.71 minutes) MS (APCI +, m / e) 422 (M + 1) Example 180 1- (3,5-dimethoxybenzyl) -2- (3-methoxyphenyl)-
6-Phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.62 minutes) MS (APCI +, m / e) 452 (M + 1) Example 181 2- (3 -Methoxyphenyl) -1- (2-nitrobenzyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.62 minutes) MS (APCI +, m / e ) 437 (M + 1)

Example 182 2- (3-Methoxyphenyl) -1- (3-nitrobenzyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 95% (retention time 3.52 min) MS (APCI +, m / e) 437 (M + 1) Example 183 2- (3-methoxyphenyl) -1- (4-nitrobenzyl) -6-phenyl-1H-imidazo [4,5- b] Pyridine HPLC (220 nm) Purity 99% (retention time 3.64 min) MS (APCI +, m / e) 437 (M + 1) Example 184 4-[[2- (3-methoxyphenyl) -6-phenyl -1H-Imidazo
[4,5-b] Pyridin-1-yl] methyl] benzonitrile HPLC (220 nm) Purity 93% (retention time 3.53 minutes) MS (APCI +, m / e) 417 (M + 1) Example 185 1- [(1,1'-Biphenyl) -2-ylmethyl] -2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 4.00 min) MS (APCI +, m / e) 468 (M + 1) Example 186 1-[(1,1′-biphenyl) -4-ylmethyl] -2- (3-methoxyphenyl) -6-phenyl- 1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 4.10 minutes) MS (APCI +, m / e) 468 (M + 1)

Example 187 2- (3-Methoxyphenyl) -1- (1-naphthylmethyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.94 min) MS (APCI +, m / e) 442 (M + 1) Example 188 2- (3-methoxyphenyl) -1- (2-naphthylmethyl) -6-phenyl-1H-imidazo [4,5- b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.95 minutes) MS (APCI +, m / e) 442 (M + 1) Example 189 1-Benzhydryl-2- (3-methoxyphenyl) -6-phenyl
-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 4.04 minutes) MS (APCI +, m / e) 468 (M + 1) Example 190 1- (9H-fluorene- 9-yl) -2- (3-methoxyphenyl) -6-
Phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 91% (retention time 4.06 min) MS (APCI +, m / e) 466 (M + 1) Example 191 2- (3-methoxy Phenyl) -1- (3-phenoxybenzyl) -6-
Phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 4.07 minutes) MS (APCI +, m / e) 484 (M + 1)

Example 192 1- (4-benzoylbenzyl) -2- (3-methoxyphenyl) -6-
Phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 3.88 min) MS (APCI +, m / e) 496 (M + 1) Example 193 4-[[2- (3-Methoxyphenyl) -6-phenyl-1H-imidazo
Methyl [4,5-b] pyridin-1-yl] methyl] benzoate HPLC (220 nm) Purity 90% (retention time 3.62 minutes) MS (APCI +, m / e) 450 (M + 1) Example 194 [ 2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5
-b] Pyridin-1-yl] (phenyl) methyl acetate HPLC (220 nm) Purity 97% (retention time 3.71 min) MS (APCI +, m / e) 450 (M + 1) Example 195 2- (3- Methoxyphenyl) -1-phenacyl-6-phenyl-1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) 90% purity (retention time 3.62 min) MS (APCI +, m / e) 420 (M + 1) Example 196 1- (4-chlorophenacyl)- 2- (3-Methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.82 minutes) MS (APCI +, m / e) 454 (M + 1)

Example 197 1- (4-methoxyphenacyl) -2- (3-methoxyphenyl) -6-
Phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.65 min) MS (APCI +, m / e) 450 (M + 1) Example 198 4-[[2- (3-Methoxyphenyl) -6-phenyl-1H-imidazo
[4,5-b] Pyridin-1-yl] acetyl] benzonitrile HPLC (220 nm) Purity 100% (retention time 3.55 minutes) MS (APCI +, m / e) 445 (M + 1) Example 199 2- (3-Methoxyphenyl) -6-phenyl-1-[(E) -3-phenyl-2-propenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.87) Min) MS (APCI +, m / e) 418 (M + 1) Example 200 1-[(3,5-Dimethyl-4-isoxazolyl) methyl] -2- (3-methoxyphenyl) -6-phenyl-1H -Imidazo [4,5-b] pyridine HPLC (220 nm) 100% purity (retention time 3.38 min) MS (APCI +, m / e) 411 (M + 1) Example 201 1-Ethyl-2- (3- Methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.27 min) MS (APCI +, m / e) 330 (M + 1)

Example 202 1- (Cyclopropylmethyl) -2- (3-methoxyphenyl) -6-
Phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 3.54 minutes) MS (APCI +, m / e) 356 (M + 1) Example 203 1- (2-cyclohexyl) Ethyl) -2- (3-methoxyphenyl)-
6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 4.15 min) MS (APCI +, m / e) 412 (M + 1) Example 204 1-isobutyl- 2- (3-methoxyphenyl) -6-phenyl-1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 94% (retention time 3.61 minutes) MS (APCI +, m / e) 358 (M + 1) Example 205 2- (3-methoxyphenyl) -1 -(4-Pentenyl) -6-phenyl
-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.68 min) MS (APCI +, m / e) 370 (M + 1) Example 206 4- [2- (3 -Methoxyphenyl) -6-phenyl-1H-imidazo
[4,5-b] Pyridin-1-yl] butanenitrile HPLC (220 nm) Purity 100% (retention time 3.19 min) MS (APCI +, m / e) 369 (M + 1)

Example 207 2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-
b] Pyridine (Compound of Example 1) (80 mg), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine resin (PS-BEMP, 2.2 mmol /
g) (326 mg) and a mixture of N, N-dimethylformamide (4.5 ml) were shaken at room temperature for 1 hour, 3-pyridylmethyl chloride hydrochloride (52 mg) was added, and the mixture was further shaken at room temperature for 15 hours. Hereinafter, purified according to the method of Example 222, 2- (3-
Methoxyphenyl) -6-phenyl-1- (3-pyridylmethyl)
-1H-imidazo [4,5-b] pyridine (67 mg, 65%) was obtained. HPLC (220 nm) Purity 98% (retention time 2.68 minutes) MS (APCI +, m / e) 393 (M + 1)

The compounds of Example 208 to 213 below were prepared according to the method of Example 207 by appropriately selecting the compound of Example 1 and various alkyl halide hydrochlorides (or alkyl halide hydrobromide) as starting materials. Was synthesized. Example 208 2- (3-Methoxyphenyl) -6-phenyl-1- (4-pyridylmethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 2.60 minutes) MS (APCI +, m / e) 393 (M + 1) Example 209 2-[[2- (3-methoxyphenyl) -6-phenyl-1H-imidazo
[4,5-b] Pyridin-1-yl] methyl] quinoline HPLC (220 nm) Purity 97% (retention time 3.67 minutes) MS (APCI +, m / e) 443 (M + 1) Example 210 2- ( 3-Methoxyphenyl) -6-phenyl-1- (thiazole-4-
Ilmethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 81% (retention time 3.28 min) MS (APCI +, m / e) 399 (M + 1)

Example 211 N, N-diethyl-N- [2- [2- (3-methoxyphenyl) -6-phenyl-1H-imidazo [4,5-b] pyridin-1-yl] ethyl] amine HPLC (220 nm) Purity 96% (retention time 2.64 minutes) MS (APCI +, m / e) 401 (M + 1) Example 212 2- (3-methoxyphenyl) -6-phenyl-1- (2-piperidinoethyl) ) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 2.67 minutes) MS (APCI +, m / e) 413 (M + 1) Example 213 2- (3-methoxy Phenyl) -1- (2-morpholinoethyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 2.59 minutes) MS (APCI +, m / e) 415 (M + 1)

Example 214 5-Bromo-2-[(E) -2- [4- (trifluoromethyl) phenyl]
Ethenyl] benzoxazole (Compound of Reference Example 44) (1
29 mg), phenylboronic acid (171 mg), tetrakis (triphenylphosphine) palladium (0) (61 mg), 2 M sodium carbonate solution (1.05 ml), toluene (3.15 ml),
The mixture of tetrahydrofuran (1.05 ml) was stirred in an argon stream at 90 ° C for 24 hours, and then partitioned between ethyl acetate-tetrahydrofuran (3: 1, v / v) and water. The organic layer was washed with water, dried (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, the fraction eluted with ethyl acetate-hexane (1: 6, v / v) was concentrated under reduced pressure, and the obtained crystals were collected by filtration to give 5-phenyl-2-[[ (E) -2-
[4- (Trifluoromethyl) phenyl] ethenyl] benzoxazole (70 mg, 55%) was obtained. Recrystallized from ethyl acetate-hexane. ¹ H NMR (CDCl ₃ ) δ 7.18 (1H, d, J = 16.6 Hz), 7.34-
7.52 (3H, m), 7.60-7.75 (8H, m), 7.83 (1H, d, J =
16.4 Hz), 7.93 (1H, t, J = 1.3 Hz) ppm IR (KBr) ν 1337, 1121, 1073, 829 cm ^-1 HPLC (220 nm) Purity 97% (retention time 5.37 min) MS (APCI +, m / e) 366 (M + 1)

The compounds of Reference Examples 43 to 45 and various boronic acids were appropriately selected as starting materials, and the following compounds of Examples 215 to 219 were synthesized according to the method of Example 214. Example 215 5-phenyl-2-[(E) -2-phenylethenyl] benzoxazole HPLC (220 nm) Purity 93% (retention time 5.14 minutes) MS (APCI +, m / e) 298 (M + 1) Example 216 2-[(E) -2- (2,4-difluorophenyl) ethenyl] -5-phenylbenzoxazole HPLC (220 nm) Purity 100% (retention time 5.26 minutes) MS (APCI +, m / e) 334 (M + 1) Example 217 5- (2-furyl) -2-[(E) -2-phenylethenyl] benzoxazole HPLC (220 nm) Purity 97% (retention time 4.94 minutes) MS (APCI +, m / e) 288 (M + 1)

Example 218 5- (2-furyl) -2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] benzoxazole HPLC (220 nm) Purity 92% (retention time 5.19 min. ) MS (APCI +, m / e) 356 (M + 1) Example 219 2-[(E) -2- (2,4-difluorophenyl) ethenyl] -5- (2-furyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.06 minutes) MS (APCI +, m / e) 324 (M + 1) Example 220 5-Bromo-2-[(E) -2-phenylethenyl] benzoxazole (reference example) 43 compound) (105 mg), p-cresol (45 mg), potassium carbonate (97 mg), copper (II) oxide (70 m
g) and pyridine (1.5 ml) in an argon stream.
The mixture was stirred at C for 24 hours, poured into water, and extracted with ethyl acetate. The organic layer was washed with a 5% potassium hydrogen sulfate solution, washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, and extracted with ethyl acetate-
The fractions eluted with hexane (1: 6, v / v) were concentrated under reduced pressure and the crystals obtained were collected by filtration to give 5- (4-methylphenoxy) -2-
[(E) -2-Phenylethenyl] benzoxazole (69 mg,
60%). Recrystallized from ethyl acetate-hexane. ¹ H NMR (CDCl ₃ ) δ 2.34 (3H, s), 6.92 (2H, d, J =
8.8 Hz), 7.03 (1H, dd, J = 8.6, 2.2 Hz), 7.06 (1H,
d, J = 16.4 Hz), 7.14 (2H, d, J = 8.4 Hz), 7.32 (1
H, d, J = 2.6 Hz), 7.38-7.48 (4H, m), 7.58-7.63 (2
H, m), 7.79 (1H, d, J = 16.6 Hz) ppm IR (KBr) ν 1532, 1507, 1472, 1223 cm ^-1 HPLC (220 nm) Purity 95% (retention time 5.30 min) MS (APCI +, m / e) 328 (M + 1) The compounds of Reference Examples 43 to 44 and various substituted phenols were appropriately selected as starting materials, and the compounds of the following Examples 221-222 were synthesized according to the method of Example 220. . Example 221 2-[(E) -2-Phenylethenyl] -5- [4- [4- (1H-1,2,3-triazol-1-yl) butyl] phenoxy] benzoxazole HPLC (220 nm ) Purity 97% (retention time 4.76 min) MS (APCI +, m / e) 437 (M + 1) Example 222 5- [4- [4- (1H-1,2,3-triazol-1-yl) Butyl] phenoxy] -2-[(E) -2- [4- (trifluoromethyl) phenyl]
Ethenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 5.00 minutes) MS (APCI +, m / e) 505 (M + 1)

Example 223 6-Bromo-2-phenyl-1H-imidazo [4,5-b] pyridine (compound of Reference Example 3) (90 mg), phenylboronic acid (104 m
g), tetrakis (triphenylphosphine) palladium
A mixture of (0) (38 mg), 2 M sodium carbonate solution (0.82 ml) and tetrahydrofuran (3.3 ml) in an argon stream.
After stirring at 85 ° C for 24 hours, the mixture was partitioned between ethyl acetate-tetrahydrofuran (3: 1, v / v) and water. The organic layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, ethyl acetate-
The fractions eluted with chloroform-hexane (1: 1: 4, v / v) were concentrated under reduced pressure, and the crystals obtained were collected by filtration to give 2,6-diphenyl-1H-imidazo [4,5-b] pyridine. (20 mg, 22%) was obtained. Recrystallized from chloroform-methanol. HPLC (220 nm) Purity 97% (retention time 2.78 minutes) MS (ESI +, m / e) 272 (M + 1) The compounds of Reference Examples 3, 11 and 16 and various boronic acids were appropriately selected as starting materials, The compounds of Examples 224 to 237 below were synthesized according to the method of Example 223. At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 224 2-Cyclohexyl-6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 85% (retention time 2.74 minutes) MS (ESI +, m / e) 278 (M + 1) Example 225 6- (2-fluorophenyl) -2-phenyl-1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 99% (retention time 2.88 min) MS (APCI +, m / e) 290 (M + 1) Example 226 2-Cyclohexyl-6- (2-fluorophenyl) -1H-imidazo [4,5-b] Pyridine HPLC (220 nm) Purity 99% (retention time 2.79 min) MS (APCI +, m / e) 296 (M + 1) Example 227 6- (1-naphthyl) -2-phenyl -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.18 minutes) MS (APCI +, m / e) 322 (M + 1) Example 228 2-Cyclohexyl-6- ( 1-naphthyl) -1H-imidazo [4,5-b]
Pyridine HPLC (220 nm) Purity 96% (retention time 3.11 min) MS (APCI +, m / e) 328 (M + 1) Example 229 2-Cyclohexyl-6- (3-methoxyphenyl) -1H-imidazo [4 , 5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.83 min) MS (APCI +, m / e) 308 (M + 1) Example 230 6- (3-methoxyphenyl) -2-phenyl- 1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.87 minutes) MS (APCI +, m / e) 302 (M + 1) Example 231 2-Cyclohexyl-6- [3- (trifluoromethyl) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 3.13 min) MS (APCI +, m / e) 346 (M + 1) Example 232 4- (2-phenyl-) 1H-imidazo [4,5-b] pyridin-6-yl) benzonitrile HPLC (220 nm) Purity 100% (retention time 2.87 min) MS (APCI +, m / e) 297 (M + 1) Example 2334 -(2-Cyclohexyl-1H-imidazo [4,5-b] pyridine-6-
Il) benzonitrile HPLC (220 nm) Purity 99% (retention time 2.71 minutes) MS (APCI +, m / e) 303 (M + 1) Example 234 6- [4- (methylsulfonyl) phenyl] -2-phenyl -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 80% (retention time 2.58 minutes) MS (APCI +, m / e) 350 (M + 1)

Example 235 2-Cyclohexyl-6- [4- (methylsulfonyl) phenyl]-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 2.48 min) MS (APCI +, m / e) 356 (M + 1) Example 236 6- (2-fluorophenyl) -2- (2-naphthyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 98% (retention time 3.34 minutes) MS (APCI +, m / e) 340 (M + 1) Example 237 2- (2-naphthyl) -6-phenyl -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.21 minutes) MS (APCI +, m / e) 322 (M + 1)

Example 238 6-Bromo-2-phenyl-1H-imidazo [4,5-b] pyridine (Compound of Reference Example 3) (90 mg), 2- (tributylstannyl) furan (305 mg), dichlorobis A mixture of (triphenylphosphine) palladium (II) (23 mg) and N, N-dimethylformamide (4 ml) was stirred at 80 ° C. for 24 hours in an argon stream and then poured into water, and ethyl acetate-tetrahydrofuran (3: 1, v / v). Wash the organic layer with water and dry (MgS
O ₄₎ after distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, ethyl acetate - chloroform -
The fractions eluted with hexane (1: 1: 4, v / v) were concentrated under reduced pressure, and the crystals obtained were collected by filtration, and 6- (2-furyl) -2-phenyl-
1H-imidazo [4,5-b] pyridine (49 mg, 57%) was obtained. HPLC (220 nm) Purity 100% (retention time 2.66 minutes) MS (APCI +, m / e) 262 (M + 1) As a starting material, the compounds of Reference Examples 3, 11, and 16 and various tributyltin compounds are appropriately selected, The compounds of the following Examples 239 to 241 were synthesized according to the method of Example 238. At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 239 2-Cyclohexyl-6- (2-furyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.57 minutes) MS (APCI +, m / e) 268 ( M + 1) Example 240 6- (2-furyl) -2- (2-naphthyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.18 minutes) MS ( APCI +, m / e) 312 (M + 1) Example 241 2- (2-naphthyl) -6- (2-thienyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (Retention time 3.31 minutes) MS (APCI +, m / e) 328 (M + 1)

Various carboxylic acids were appropriately selected as starting materials, and the compounds of Examples 242 to 254 below were synthesized according to the method of Reference Example 67. Example 242 6-Bromo-2- (3-methoxyphenyl) benzoxazole HPLC (220 nm) Purity 97% (retention time 4.85 minutes) MS (APCI +, m / e) 304 (M + 1) Example 243 6- Bromo-2- (2-naphthyl) benzoxazole HPLC (220 nm) Purity 95% (retention time 5.41 min) MS (APCI +, m / e) 324 (M + 1) Example 244 6-Bromo-2-phenylbenzo Oxazole HPLC (220 nm) Purity 99% (retention time 4.83 min) MS (APCI +, m / e) 274 (M + 1) Example 245 6-Bromo-2- (3-methylphenyl) benzoxazole HPLC (220 nm ) Purity 97% (retention time 5.12 minutes) MS (APCI +, m / e) 288 (M + 1) Example 246 6-Bromo-2- (4-methoxyphenyl) benzoxazole HPLC (220 nm) Purity 98% ( Retention time 4.81 minutes) MS (APCI +, m / e) 304 (M + 1)

Example 247 6-Bromo-2- (3,4-dimethoxyphenyl) benzoxazole HPLC (220 nm) Purity 95% (retention time 4.50 min) MS (APCI +, m / e) 334 (M + 1) Example 248 6-Bromo-2- (2-methoxyphenyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 4.41 minutes) MS (APCI +, m / e) 304 (M + 1) Example 249 6- Bromo-2- (3,4,5-trimethoxyphenyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 4.57 minutes) MS (APCI +, m / e) 364 (M + 1) Example 250 6- Bromo-2- (3-fluorophenyl) benzoxazole HPLC (220 nm) Purity 96% (retention time 4.95 minutes) MS (APCI +, m / e) 292 (M + 1) Example 251 6-Bromo-2- [ 3- (Trifluoromethyl) phenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 5.23 min) MS (APCI +, m / e) 342 (M + 1) Example 252 6-Bromo-2- [3 -(Trifluoromethoxy) phenyl] benzoxazole HPLC (220 nm) 100% purity (retention time 5.30 min) MS (APC I +, m / e) 358 (M + 1)

Example 253 3- (6-Bromobenzoxazol-2-yl) benzamide HPLC (220 nm) Purity 98% (retention time 3.65 min) MS (APCI +, m / e) 317 (M + 1) Example 254 6-Bromo-2- (3-butoxyphenyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 5.71 minutes) MS (APCI +, m / e) 346 (M + 1) Example 255 3- (6 -Bromobenzoxazol-2-yl) benzamide (compound of Example 253) (1.09 g), pyridine (0.41
Oxalyl chloride (0.52 g) was added dropwise to a mixture of g) and N, N-dimethylformamide (20 ml) at 0 ° C. At 0 ° C
After stirring for 50 minutes, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with 1 N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure.
The crystals were collected by filtration to give 3- (6-bromobenzoxazol-2-yl) benzonitrile (949 mg, 92%). ¹ H NMR (CDCl ₃ ) δ 7.53 (1H, dd, J = 8.7, 1.7 Hz),
7.64-7.72 (2H, m), 7.80 (1H, d, J = 1.8 Hz), 7.84
(1H, dt, J = 7.7, 1.5 Hz), 8.45-8.53 (2H, m) ppm IR (KBr) ν 2232, 1333, 804 cm ^-1 HPLC (220 nm) Purity 98% (retention time 4.57 minutes) MS (ESI +, m / e) 299 (M + 1)

Various carboxylic acids were appropriately selected as starting materials, and the compounds of Examples 256 to 266 below were synthesized according to the method of Reference Example 67. Example 256 6-Bromo-2- [3-[(trifluoromethyl) thio] phenyl]
Benzoxazole HPLC (220 nm) Purity 98% (retention time 5.42 min) MS (APCI +, m / e) 374 (M + 1) Example 257 6-Bromo-2- [3-fluoro-5- (trifluoromethyl) ) Phenyl] benzoxazole HPLC (220 nm) 100% purity (retention time 5.28 min) MS (APCI +, m / e) 360 (M + 1) Example 258 6-Bromo-2- (3-ethoxyphenyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.13 minutes) MS (APCI +, m / e) 318 (M + 1) Example 259 2- [3,5-bis (trifluoromethyl) phenyl] -6-bromo Benzoxazole HPLC (220 nm) Purity 100% (retention time 5.48 min) MS (APCI +, m / e) 410 (M + 1) Example 260 6-Bromo-2- (3,5-difluorophenyl) benzoxazole HPLC (220 nm) 100% purity (retention time 5.07 minutes) MS (APCI +, m / e) 310 (M + 1)

Example 261 6-Bromo-2- (3-phenoxyphenyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.46 min) MS (APCI +, m / e) 366 (M + 1) Example 262 6-Bromo-2- (5-methyl-2-thienyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 4.91 min) MS (APCI +, m / e) 294 (M + 1) Example 2632 -(1-Benzofuran-2-yl) -6-bromobenzoxazole HPLC (220 nm) Purity 99% (retention time 4.92 minutes) MS (APCI +, m / e) 314 (M + 1) Example 264 2- ( 1-benzothiophen-2-yl) -6-bromobenzoxazole HPLC (220 nm) Purity 97% (retention time 5.31 min) MS (APCI +, m / e) 330 (M + 1) Example 265 6- (6 -Bromobenzoxazol-2-yl) quinoline HPLC (220 nm) Purity 97% (retention time 3.40 min) MS (APCI +, m / e) 325 (M + 1) Example 266 6-Bromo-2- (3- Nitrophenyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 4.70 min) MS (APCI +, m / e) 319 (M + 1)

Example 267 6-Bromo-2- (3-nitrophenyl) benzoxazole (Compound of Example 266) (5.96 g), nickel bromide (I
Sodium borohydride (2.12 g) was added little by little to a mixture of I) (204 mg), methanol (100 ml) and tetrahydrofuran (100 ml) at 0 ° C. After stirring at 0 ° C. for 10 minutes and at room temperature for 1 hour, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer is washed with water and dried (MgSO
₄ ), after treatment with activated carbon, the solvent was distilled off under reduced pressure, and the crystals were collected by filtration to obtain 3- (6-bromobenzoxazol-2-yl) aniline (4.46 g, 83%). ¹ H NMR (CDCl ₃ ) δ 3.86 (2H, s), 6.86 (1H, ddd, J =
7.8, 2.3, 0.8 Hz), 7.26-7.37 (2H, m), 7.47 (1H, d
d, J = 8.5, 1.9 Hz), 7.54-7.64 (2H, m), 7.74 (1H,
d, J = 1.8 Hz) ppm IR (KBr) ν 3206, 1456, 1335 cm ^-1 HPLC (220 nm) Purity 85% (retention time 3.28 min) MS (APCI +, m / e) 289 (M + 1)

Example 268 3- (6-Bromobenzoxazol-2-yl) aniline (Compound of Example 267) (925 mg), triethylamine (390
Acetyl chloride (276 mg) was added to a solution of (mg) and tetrahydrofuran (35 ml) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (3: 1, v / v). 1 N organic layer
Wash sequentially with hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, and water, and dry (MgS
After O ₄ ), the solvent was distilled off under reduced pressure, the crystals were collected by filtration, and N- [3- (6-
Bromobenzoxazol-2-yl) phenyl] acetamide (923 mg, 87%) was obtained. ¹ H NMR (CDCl ₃ ) δ 2.24 (3H, s), 7.34-7.39 (1H, m),
7.45-7.53 (2H, m), 7.62 (1H, d, J = 8.0 Hz), 7.74
(1H, d, J = 1.8 Hz), 7.79-7.84 (1H, m), 7.96-8.00
(1H, m), 8.28 (1H, s) ppm IR (KBr) ν 3274, 1663, 1564 cm ^-1 HPLC (220 nm) Purity 86% (retention time 4.00 min) MS (ESI +, m / e) 331 ( (M + 1)

The compound of Example 267 and benzene were used as starting materials.
Zoyl chloride was selected and prepared according to the method of Example 268.
The compound of Example 269 below was synthesized. Example 269 N- [3- (6-bromobenzoxazol-2-yl) phenyl]
Benzamide HPLC (220 nm) Purity 89% (retention time 4.72 minutes) MS (ESI +, m / e) 393 (M + 1) Example 270 3- (6-Bromobenzoxazol-2-yl) aniline (actual
Compound of Example 267) (925 mg), triethylamine (490
 mg), 4-dimethylaminopyridine (39 mg), tetrahi
Add methanesulfonyl chloride to a solution of drofuran (35 ml).
(440 mg) was added at room temperature. Stir at room temperature for 2 hours
After that, the reaction mixture was poured into water and extracted with ethyl acetate. Existence
The machine layer was washed with 1 N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water in that order and dried.
Dried (MgSO 4 _FourAfter that, the solvent was distilled off under reduced pressure, and the crystals were collected by filtration, and N
-[3- (6-Bromobenzoxazol-2-yl) phenyl] me
Tansulphonamide (686 mg, 58%) was obtained. Ethyl acetate
Recrystallized from ru-hexane.¹ H NMR (DMSO-d₆) δ 3.07 (3H, s), 7.44-7.48 (1H,
m), 7.55-7.63 (2H, m), 7.79 (1H, d, J = 8.8 Hz), 7.
90-7.94 (1H, m), 8.08-8.15 (2H, m), 10.13 (1H, s)
ppm IR (KBr) ν 3270, 1321, 1159 cm^-1 HPLC (220 nm) Purity 93% (retention time 4.10 minutes) MS (ESI +, m / e) 367 (M + 1)

Example 271 To a solution of 3- (6-bromobenzoxazol-2-yl) aniline (the compound of Example 267) (925 mg) in pyridine (15 ml) was added ethyl isocyanate (680 mg) at room temperature. It was After stirring at room temperature for 3 hours, the reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (3: 1, v / v).
The organic layer was washed successively with 1 N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water,
After drying (MgSO _4), the solvent was distilled off under reduced pressure, and the crystals were collected by filtration, N- [3- (6- bromo-benzoxazol-2-yl) phenyl] -N ^'- ethyl urea (986 mg, 86 %). ¹ H NMR (DMSO-d ₆ ) δ 1.09 (3H, t, J = 7.2 Hz), 3.15
(2H, quintet, J = 6.7Hz), 6.20 (1H, t, J = 5.5 H
z), 7.40-7.60 (3H, m), 7.70-7.78 (2H, m), 8.12 (1
H, d, J = 1.4 Hz), 8.46 (1H, s), 8.78 (1H, s) ppm IR (KBr) ν 3281, 1645, 1570 cm ^-1 HPLC (220 nm) Purity 92% (retention time 4.10 min) ) MS (ESI +, m / e) 360 (M + 1)

Example 272 6-Bromo-2- (3-methoxyphenyl) benzoxazole (Compound of Example 242) (19.45 g) in chloroform (8
To the solution (00 ml), boron tribromide (100.05 g) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 4 hrs and at 65 ° C for 9 hrs. The reaction mixture was poured into ice, stirred at room temperature for 30 minutes, and then extracted with chloroform-tetrahydrofuran (4: 1, v / v). The organic layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, and the crystals were collected by filtration to give 3- (6-bromobenzoxazol-2-yl) phenol (16.46 g, 89%). . ¹ H NMR (DMSO-d ₆ ) δ 7.03 (1H, ddd, J = 8.2, 2.4,
0.9 Hz), 7.41 (1H, t, J = 7.9 Hz), 7.54-7.65 (3H,
m), 7.75 (1H, d, J = 8.4 Hz), 8.09 (1H, d, J = 1.8
Hz), 9.95 (1H, s) ppm IR (KBr) ν 3094, 1460, 1300 cm ^-1 HPLC (220 nm) Purity 97% (retention time 4.14 minutes) MS (APCI +, m / e) 290 (M + 1 )

Example 273 A solution of 3- (6-bromobenzoxazol-2-yl) phenol (the compound of Example 272) (1.02 g) in N, N-dimethylformamide (6 ml) was treated with 2-iodopropane (0.68). g) and potassium carbonate (0.63 g) were added at 50 ° C, and the mixture was stirred at 50 ° C for 1.5 hr. 2-Iodopropane (0.34 g) and potassium carbonate (0.31 g) were added, and the mixture was further stirred at 50 ° C. for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (3: 1, v / v). The organic layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 20-1: 6, v / v). Concentrate under reduced pressure,
6-Bromo-2- (3-isopropoxyphenyl) benzoxazole (896 mg, 77%) was isolated. ¹ H NMR (CDCl ₃ ) δ 1.39 (6H, d, J = 6.2 Hz), 4.69
(1H, sevenplet, J = 6.0Hz), 7.08 (1H, ddd, J = 8.
4, 2.6, 1.0 Hz), 7.38-7.50 (2H, m), 7.63 (1H, d, J
= 8.8 Hz), 7.73-7.82 (3H, m) ppm IR (KBr) ν 2975, 1557, 1265 cm ^-1 HPLC (220 nm) Purity 100% (retention time 5.30 min) MS (APCI +, m / e) 332 (M + 1)

The compounds of Example 272 and various alkyl halides were appropriately selected as starting materials, and the following compounds of Examples 274 to 279 were synthesized according to the method of Example 273. Example 274 6-Bromo-2- [3- (hexyloxy) phenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 6.33 minutes) MS (APCI +, m / e) 374 (M + 1) Example 275 6-Bromo-2- [3- (3-methylbutoxy) phenyl] benzoxazole HPLC (220 nm) Purity 98% (retention time 5.90 minutes) MS (APCI +, m / e) 360 (M + 1) Example 276 6-Bromo-2- [3- (cyclopentyloxy) phenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 5.75 min) MS (APCI +, m / e) 358 (M + 1) Example 277 6 -Bromo-2- [3- (cyclopropylmethoxy) phenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 5.29 min) MS (APCI +, m / e) 344 (M + 1) Example 278 2- [3- (Benzyloxy) phenyl] -6-bromobenzoxazole HPLC (220 nm) Purity 100% (retention time 5.41 min) MS (APCI +, m / e) 380 (M + 1) Example 279 [3- ( 6-Bromobenzoxazol-2-yl) phenoxy]
Tert-Butyl acetate HPLC (220 nm) Purity 100% (retention time 5.12 minutes) MS (APCI +, m / e) 404 (M + 1)

Example 280 [3- (6-Bromobenzoxazol-2-yl) phenoxy]
4N Hydrochloric acid-ethyl acetate (50 ml) was added to a solution of tert-butyl acetate (the compound of Example 279) (2.22 g) in tetrahydrofuran (10 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (3: 1, v / v). Wash the organic layer with water and dry (MgS
After O ₄ ), the solvent was distilled off under reduced pressure, and the crystals were collected by filtration to give [3- (6-bromobenzoxazol-2-yl) phenoxy] acetic acid (1.2
7 g, 66%) was obtained. Recrystallized from tetrahydrofuran-ethyl acetate. ¹ H NMR (DMSO-d ₆ ) δ 4.83 (2H, s), 7.19-7.25 (1H,
m), 7.50-7.64 (3H, m), 7.76-7.80 (2H, m), 8.12 (1H,
d, J = 1.8 Hz) ppm IR (KBr) ν 2913, 1717, 1327 cm ^-1 HPLC (220 nm) Purity 99% (retention time 4.06 min) MS (APCI +, m / e) 348 (M + 1)

Example 281 [3- (6-Bromobenzoxazol-2-yl) phenoxy]
Acetic acid (the compound of Example 280) (1.17 g) was dissolved in tetrahydrofuran (35 ml), and oxalyl chloride (0.51) was added.
g) and N, N-dimethylformamide (15 μl) were sequentially added. After stirring at room temperature for 2 hours, the solvent and excess oxalyl chloride were distilled off under reduced pressure. Dissolve the residue in tetrahydrofuran (11 ml) and add 40% methylamine aqueous solution (9 m
l) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and ethyl acetate-tetrahydrofuran (3: 1,
v / v). The organic layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, the crystals were collected by filtration, and 2- [3- (6-bromobenzoxazol-2-yl) phenoxy] -N-methylacetamide ( 1.16 g, 96%) was obtained. ¹ H NMR (CDCl ₃ ) δ 2.95 (3H, d, J = 5.0 Hz), 4.61
(2H, s), 6.64 (1H, broad s), 7.11 (1H, ddd, J = 8.
4, 2.8, 1.2 Hz), 7.45-7.53 (2H, m), 7.64 (1H, d, J
= 8.0 Hz), 7.76-7.80 (2H, m), 7.91 (1H, ddd, J =
8.0, 1.4, 0.7 Hz) ppm IR (KBr) ν 3330, 1678, 1055 cm ^-1 HPLC (220 nm) Purity 100% (retention time 3.98 minutes) MS (APCI +, m / e) 361 (M + 1)

The compounds of Example 272 and various alkyl halides were appropriately selected as starting materials, and the following compounds of Examples 282 to 284 were synthesized according to the method of Example 273. Example 282 6-Bromo-2- (3- (2-methoxyethoxy) phenyl) benzoxazole HPLC (220 nm) Purity 98% (retention time 4.65 min) MS (ACPI +, m / e) 348 (M + 1) Example 283 4- (3- (6-bromobenzoxazol-2-yl) phenoxy) butanenitrile HPLC (220 nm) Purity 98% (retention time 4.65 min) MS (ACPI +, m / e) 357 (M + 1 ) Example 284 6-Bromo-2- (3- (2-morpholinoethoxy) phenyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 3.30 minutes) MS (ACPI +, m / e) 403 (M + 1 )

The compounds of Reference Examples 46 to 51 and various boronic acids were appropriately selected as starting materials, and the compounds of Examples 285 to 302 below were synthesized according to the method of Example 1. At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 285 2- (3-Methylphenyl) -6-phenyl-1H-imidazo [4,5-b]
Pyridine HPLC (220 nm) Purity 100% (retention time 3.14 minutes) MS (APCI +, m / e) 286 (M + 1) Example 286 2- (3-ethoxyphenyl) -6-phenyl-1H-imidazo [4 ,Five-
b] Pyridine HPLC (220 nm) Purity 96% (retention time 3.27 min) MS (APCI +, m / e) 316 (M + 1) Example 287 6-phenyl-2- (3-propoxyphenyl) -1H-imidazo [Four,
5-b] Pyridine HPLC (220 nm) Purity 97% (retention time 3.49 min) MS (APCI +, m / e) 330 (M + 1) Example 288 2- (3-isopropoxyphenyl) -6-phenyl- 1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.40 min) MS (APCI +, m / e) 330 (M + 1) Example 289 2- (3-butoxyphenyl) -6-phenyl-1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 98% (retention time 3.68 min) MS (APCI +, m / e) 344 (M + 1)

Example 290 2- (4-methoxy-3-methylbenzyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.19 minutes) MS ( APCI +, m / e) 330 (M + 1) Example 291 6- (2-Fluorophenyl) -2- (3-methylphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.24 minutes) MS (APCI +, m / e) 304 (M + 1) Example 292 2- (3-ethoxyphenyl) -6- (2-fluorophenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.38 min) MS (APCI +, m / e) 334 (M + 1) Example 293 6- (2-Fluorophenyl) -2 -(3-propoxyphenyl) -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.60 minutes) MS (APCI +, m / e) 348 (M + 1) Example 294 6- (2-Fluorophenyl)- 2- (3-Isopropoxyphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.50 min) MS (APCI +, m / e) 348 (M + 1) Example 295 2- (3-butoxyphenyl) -6- (2-fluorophenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.79 min) MS (APCI +, m / e) 362 (M + 1)

Example 296 6- (2-Fluorophenyl) -2- (4-methoxy-3-methylbenzyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.25 min) MS (APCI +, m / e) 348 (M + 1) Example 297 6- (2-furyl) -2- (3-methylphenyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 99% (retention time 3.03 minutes) MS (APCI +, m / e) 276 (M + 1) Example 298 2- (3-ethoxyphenyl) -6- (2-furyl) -1H-Imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 94% (retention time 3.20 min) MS (APCI +, m / e) 306 (M + 1) Example 299 6- (2-furyl) -2- (3-propoxy) Phenyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 95% (retention time 3.43 min) MS (APCI +, m / e) 320 (M + 1) Example 300 6- (2-furyl) -2- ( 3-Isopropoxyphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 95% (retention time 3.34 minutes) MS (APCI +, m / e) 320 (M + 1) Example 301 2 -(3-butoxyphenyl) -6- (2-furyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 96% (retention time 3.66 min) MS (APCI +, m / e) 334 (M + 1) Example 302 6- (2-furyl) -2- (4-methoxy) -3-Methylbenzyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 3.06 minutes) MS (APCI +, m / e) 320 (M + 1)

The compounds of Reference Examples 2, 10, 15, and 23 and various boronic acids were appropriately selected as starting materials, and the compounds of Examples 303 to 311 below were synthesized according to the method of Example 1. At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 303 2- (3,4-Dimethoxybenzyl) -6-[(E) -2-phenylethenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.17 min) MS (APCI +, m / e) 372 (M + 1) Example 304 2- (phenoxymethyl) -6-[(E) -2-phenylethenyl] -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.46 min) MS (APCI +, m / e) 328 (M + 1) Example 305 2,6-bis [(E) -2-Phenylethenyl] -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 98% (retention time 3.45 min) MS (APCI +, m / e) 324 (M + 1) Example 306 6- (2-acetylphenyl) -2- (3-methoxyphenyl) ) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 93% (retention time 2.97 minutes) MS (APCI +, m / e) 344 (M + 1)

Example 307 6- (2-Acetylphenyl) -2- (3,4-dimethoxybenzyl)-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 91% (retention time 2.76 min) MS (APCI +, m / e) 388 (M + 1) Example 308 6- (2-acetylphenyl) -2- (phenoxymethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.05 minutes) MS (APCI +, m / e) 344 (M + 1) Example 309 6- (2-Acetylphenyl) -2-[(E) -2-phenylethenyl]-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 90% (retention time 3.04 minutes) MS (APCI +, m / e) 340 (M + 1) Example 310 2- (3-methoxyphenyl) -6- (3-pyridyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 92% (retention time 2.20 minutes) MS (APCI +, m / e) 303 (M + 1) Example 311 2- (3,4-dimethoxybenzyl)- 6- (3-Pyridyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 95% (retention time 2.01 min) MS (APCI +, m / e) 347 (M + 1)

The compounds of Reference Examples 52 to 59 and various boronic acids were appropriately selected as starting materials, and the following compounds of Examples 312 to 335 were synthesized according to the method of Example 1. At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 312 2- [3- (hexyloxy) phenyl] -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 4.07 minutes) MS (APCI +, m / e) 372 (M + 1) Example 313 2- [3- (3-butenyloxy) phenyl] -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.56 min) MS (APCI +, m / e) 342 (M + 1) Example 314 2- [3- (3-Methylbutoxy) phenyl] -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 3.86 minutes) MS (APCI +, m / e) 358 (M + 1) Example 315 2- [3- (neopentyloxy) phenyl] -6-phenyl-1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.89 min) MS (APCI +, m / e) 358 (M + 1) Example 316 2- [3- (cyclohexylmethoxy) phenyl ] -6-phenyl-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 4.11 min) MS (APCI +, m / e) 384 (M + 1) Example 317 2- [3- (Cyclopentyloxy) ) Phenyl] -6-phenyl-1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.69 min) MS (APCI +, m / e) 356 (M + 1)

Example 318 6-Phenyl-2- [3- (2-phenylethoxy) phenyl] -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.81 min) MS (APCI +, m / e) 392 (M + 1) Example 319 2- (3-ethoxyphenyl) -6 -Phenyl-1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 96% (retention time 3.33 minutes) MS (APCI +, m / e) 300 (M + 1) Example 320 6- (2-Fluorophenyl) -2- [3- (hexyl) (Oxy) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 4.18 minutes) MS (APCI +, m / e) 390 (M + 1) Example 321 2- [ 3- (3-butenyloxy) phenyl] -6- (2-fluorophenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.66 min) MS (APCI +, m / e) 360 (M + 1) Example 322 6- (2-Fluorophenyl) -2- [3- (3-methylbutoxy) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.97 minutes) MS (APCI +, m / e) 376 (M + 1) Example 323 6- (2-fluorophenyl) -2- [3- (neopentyloxy) phenyl] -1H- Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 4.02 min) MS (APCI +, m / e) 376 (M + 1)

Example 324 2- [3- (Cyclohexylmethoxy) phenyl] -6- (2-fluorophenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 4.20) Min) MS (APCI +, m / e) 402 (M + 1) Example 325 2- [3- (Cyclopentyloxy) phenyl] -6- (2-fluorophenyl) -1H-imidazo [4,5-b] Pyridine HPLC (220 nm) Purity 98% (retention time 3.79 min) MS (APCI +, m / e) 374 (M + 1) Example 326 6- (2-Fluorophenyl) -2- [3- (2-phenyl (Ethoxy) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.91 min) MS (APCI +, m / e) 410 (M + 1) Example 327 2- ( 3-Ethoxyphenyl) -6- (2-fluorophenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.41 min) MS (APCI +, m / e) 318 (M + 1) Example 328 6- (2-furyl) -2- [3- (Hexyloxy) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 4.07 min) MS (APCI +, m / e) 362 (M + 1) Example 329 2- [3- (3-butenyloxy) phenyl] -6- (2-furyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 3.52 minutes) MS (APCI +, m / e) 332 (M + 1)

Example 330 6- (2-furyl) -2- [3- (3-methylbutoxy) phenyl] -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 3.84 min) MS (APCI +, m / e) 348 (M + 1) Example 331 6- (2-furyl) -2- [3- (neopentyloxy) phenyl] -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.89 min) MS (APCI +, m / e) 348 (M + 1) Example 332 2- [3- (cyclohexylmethoxy) Phenyl] -6- (2-furyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 4.10 minutes) MS (APCI +, m / e) 374 (M + 1) Example 333 2- [3- (Cyclopentyloxy) phenyl] -6- (2-furyl)-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 3.65 min) MS (APCI +, m / e) 346 (M + 1) Example 334 6- (2-furyl)- 2- [3- (2-phenylethoxy) phenyl] -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 3.81 min) MS (APCI +, m / e) 382 (M + 1) Example 335 2- (3-ethylphenyl)- 6- (2-furyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 94% (retention time 3.26 min) MS (APCI +, m / e) 290 (M + 1)

The compounds of Reference Example 49 and various boronic acids were appropriately selected as starting materials, and the compounds of Examples 336 to 351 below were synthesized according to the method of Example 1. At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 336 6- (3-Fluorophenyl) -2- (3-isopropoxyphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.58 minutes) MS (APCI + , m / e) 348 (M + 1) Example 337 6- (4-Fluorophenyl) -2- (3-isopropoxyphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.51 minutes) MS (APCI +, m / e) 348 (M + 1) Example 338 6- (2,4-difluorophenyl) -2- (3-isopropoxyphenyl) -1H-imidazo [ 4,5-b] Pyridine HPLC (220 nm) Purity 99% (retention time 3.63 minutes) MS (APCI +, m / e) 366 (M + 1) Example 339 6- (3,4-difluorophenyl) -2 -(3-Isopropoxyphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.68 min) MS (APCI +, m / e) 366 (M + 1) Example 340 6- (2-chlorophenyl) -2- (3-isopropoxyphenyl)-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.66 min) MS (APCI +, m / e) 364 (M + 1)

Example 341 2- (3-isopropoxyphenyl) -6- [2- (trifluoromethyl) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention Time (3.76 min) MS (APCI +, m / e) 398 (M + 1) Example 342 2- (3-isopropoxyphenyl) -6- [3- (trifluoromethyl) phenyl] -1H-imidazo [4, 5-b] Pyridine HPLC (220 nm) Purity 99% (retention time 3.87 min) MS (APCI +, m / e) 398 (M + 1) Example 343 2- (3-isopropoxyphenyl) -6- [4 -(Trifluoromethoxy) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.91 minutes) MS (APCI +, m / e) 414 (M + 1) Example 344 2- (3-isopropoxyphenyl) -6- (2-methoxyphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.41 min) MS (APCI +, m / e) 360 (M + 1) Example 345 2- (3-isopropoxyphenyl) -6- (3-methoxyphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (Maintenance Time 3.50 min) MS (APCI +, m / e) 360 (M + 1) Example 346 6- (1,3-benzodioxol-5-yl) -2- (3-isopropoxyphenyl) -1H- Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.43 min) MS (APCI +, m / e) 374 (M + 1)

Example 347 2- (3-isopropoxyphenyl) -6- (4-phenoxyphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.96 minutes) MS (APCI +, m / e) 422 (M + 1) Example 348 2- (3-isopropoxyphenyl) -6- [4- (methylthio) phenyl] -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.65 min) MS (APCI +, m / e) 376 (M + 1) Example 349 3- [2- (3-isopropoxyphenyl) -1H-imidazo [4,5 -b]
Pyridine-6-yl] benzonitrile HPLC (220 nm) Purity 98% (retention time 3.51 min) MS (APCI +, m / e) 355 (M + 1) Example 350 N- [3- [2- (3- Isopropoxyphenyl) -1H-imidazo [4,5
-b] Pyridin-6-yl] phenyl] acetamide HPLC (220 nm) Purity 97% (retention time 3.12 min) MS (APCI +, m / e) 387 (M + 1) Example 351 6- (1-benzofuran- 2-yl) -2- (3-isopropoxyphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.98 min) MS (APCI +, m / e) 370 ( (M + 1)

The compounds of Example 97 and various alkyl halides were appropriately selected as starting materials, and the compounds of Examples 352 to 359 below were synthesized according to the method of Example 161. Example 352 2- (3,4-dimethoxybenzyl) -6- (2-furyl) -1-methyl-1
H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 2.93 min) MS (ESI +, m / e) 350 (M + 1) Example 353 2- (3,4-dimethoxy) (Benzyl) -6- (2-furyl) -1- (2-methoxyethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.10 minutes) MS (ESI +, m / e) 394 (M + 1) Example 354 1- (Cyclopropylmethyl) -2- (3,4-dimethoxybenzyl) -6- (2-furyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.35 min) MS (ESI +, m / e) 390 (M + 1) Example 355 2- (3,4-dimethoxybenzyl) -6- (2-furyl)- 1-Isobutyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.44 min) MS (ESI +, m / e) 392 (M + 1) Example 356 2- (3 , 4-Dimethoxybenzyl) -6- (2-furyl) -1- (4-pentenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.50 min) MS ( ESI +, m / e) 404 (M + 1) Example 357 4- [2- (3,4-dimethoxybenzyl) -6- (2-furyl) -1H-imidazo [4,5-b ] Pyridin-1-yl] butanenitrile HPLC (220 nm) Purity 100% (retention time 3.11 min) MS (ESI +, m / e) 403 (M + 1)

Example 358 2- (3,4-dimethoxybenzyl) -6- (2-furyl) -1- (2-phenylethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.62 minutes) MS (ESI +, m / e) 440 (M + 1) Example 359 Acetate 2-[[2- (3,4-dimethoxybenzyl) -6- (2-furyl)- 1H
-Imidazo [4,5-b] pyridin-1-yl] methyl] phenyl HPLC (220 nm) 100% purity (retention time 3.43 minutes) MS (ESI +, m / e) 484 (M + 1) Performed as starting material The compound of Example 359 was selected to give Example 157.
The compound of the following Example 360 was synthesized according to the method of 1. Example 360 2-[[2- (3,4-Dimethoxybenzyl) -6- (2-furyl) -1H-imidazo [4,5-b] pyridin-1-yl] methyl] phenol HPLC (220 nm) Purity 100% (retention time 3.21 minutes) MS (ESI +, m / e) 442 (M + 1)

The compounds of Example 301 and various alkyl halides were appropriately selected as starting materials, and the compounds of Examples 361 to 366 below were synthesized according to the method of Example 161. Example 361 2- (3-butoxyphenyl) -6- (2-furyl) -1-methyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.48 minutes) MS (APCI +, m / e) 348 (M + 1) Example 362 2- (3-butoxyphenyl) -6- (2-furyl) -1- (2-methoxyethyl) -1H-imidazo [4,5- b] Pyridine HPLC (220 nm) Purity 97% (retention time 3.63 minutes) MS (APCI +, m / e) 392 (M + 1) Example 363 2- (3-butoxyphenyl) -1- (cyclopropylmethyl) -6-
(2-Furyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.90 minutes) MS (APCI +, m / e) 388 (M + 1) Example 364 2- (3-Butoxyphenyl) -6- (2-furyl) -1- (4-pentenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 4.02 minutes) MS ( APCI +, m / e) 402 (M + 1) Example 365 4- [2- (3-butoxyphenyl) -6- (2-furyl) -1H-imidazo
[4,5-b] Pyridin-1-yl] butanenitrile HPLC (220 nm) Purity 99% (retention time 3.59 min) MS (APCI +, m / e) 401 (M + 1) Example 366 Acetate 2- [ [2- (3-Butoxyphenyl) -6- (2-furyl) -1H-imidazo [4,5-b] pyridin-1-yl] methyl] phenyl HPLC (220 nm) Purity 91% (retention time 3.93 minutes ) MS (APCI +, m / e) 482 (M + 1)

The compound of Example 366 was selected as a starting material, and the compound of Example 367 below was synthesized according to the method of Example 157. Example 367 2-[[2- (3-Butoxyphenyl) -6- (2-furyl) -1H-imidazo [4,5-b] pyridin-1-yl] methyl] phenol HPLC (220 nm) Purity 97 % (Holding time 3.85 minutes) MS (ESI +, m / e) 440 (M + 1) The compounds of Reference Examples 60 to 66 and various boronic acids were appropriately selected as the starting materials, and the following were carried out according to the method of Example 214. Example 3
68-380 compounds were synthesized. At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 368 2- (3-Methoxyphenyl) -5-phenylbenzoxazole HPLC (220 nm) Purity 98% (retention time 5.04 minutes) MS (ESI +, m / e) 302 (M + 1) Example 369 2- [(E) -2- (3-Fluorophenyl) ethenyl] -5-phenylbenzoxazole HPLC (220 nm) Purity 98% (retention time 5.15 minutes) MS (ESI +, m / e) 316 (M + 1) Example 370 2-[(E) -2- (2-fluorophenyl) ethenyl] -5-phenylbenzoxazole HPLC (220 nm) Purity 97% (retention time 5.24 minutes) MS (ESI +, m / e) 316 (M +1) Example 371 2-[(E) -2- (3,4-dichlorophenyl) ethenyl] -5-phenylbenzoxazole HPLC (220 nm) Purity 91% (retention time 5.44 min) MS (ESI +, m / e) 366 (M + 1) Example 372 2-[(E) -2- (4-methylphenyl) ethenyl] -5-phenylbenzoxazole HPLC (220 nm) Purity 100% (retention time 5.37 min) MS ( ESI +, m / e) 321 (M + 1)

Example 373 5-phenyl-2-[(E) -2- [3- (trifluoromethoxy) phenyl] ethenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 5.42 minutes) MS (ESI + , m / e) 382 (M + 1) Example 374 5- (2-furyl) -2- (3-methoxyphenyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 4.82 minutes) MS (ESI +, m / e) 292 (M + 1) Example 375 2-[(E) -2- (4-chlorophenyl) ethenyl] -5- (2-furyl)
Benzoxazole HPLC (220 nm) Purity 99% (retention time 5.21 minutes) MS (ESI +, m / e) 322 (M + 1) Example 376 2-[(E) -2- (3-fluorophenyl) ethenyl] -5- (2-Furyl) benzoxazole HPLC (220 nm) Purity 90% (retention time 4.96 min) MS (ESI +, m / e) 306 (M + 1)

Example 377 2-[(E) -2- (2-fluorophenyl) ethenyl] -5- (2-furyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.03 minutes) MS (ESI + , m / e) 306 (M + 1) Example 378 2-[(E) -2- (3,4-dichlorophenyl) ethenyl] -5- (2-furyl) benzoxazole HPLC (220 nm) Purity 95% (Retention time 5.46 minutes) MS (ESI +, m / e) 356 (M + 1) Example 379 5- (2-furyl) -2-[(E) -2- (4-methylphenyl) ethenyl]
Benzoxazole HPLC (220 nm) Purity 99% (retention time 5.17 min) MS (ESI +, m / e) 302 (M + 1) Example 380 5- (2-furyl) -2-[(E) -2- [3- (Trifluoromethoxy) phenyl] ethenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 5.24 min) MS (ESI +, m / e) 372 (M + 1)

The compounds of Reference Examples 43, 45 and 60 and various boronic acids were appropriately selected as starting materials, and the compounds of Examples 381 to 389 below were synthesized according to the method of Example 214. At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 381 2- (3-methoxyphenyl) -5-[(E) -2-phenylethenyl]
Benzoxazole HPLC (220 nm) Purity 99% (retention time 5.30 min) MS (APCI +, m / e) 328 (M + 1) Example 382 2,5-bis [(E) -2-phenylethenyl] benzo Oxazole HPLC (220 nm) Purity 93% (retention time 5.38 min) MS (APCI +, m / e) 324 (M + 1) Example 383 2-[(E) -2- (2,4-difluorophenyl) ethenyl ] -5-[(E)-
2-Phenylethenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 5.21 min) MS (APCI +, m / e) 360 (M + 1) Example 384 5- (2-acetylphenyl) -2- (3-Methoxyphenyl) benzoxazole HPLC (220 nm) Purity 93% (retention time 4.61 min) MS (APCI +, m / e) 344 (M + 1) Example 385 5- (2-acetylphenyl) -2- [(E) -2-Phenylethenyl]
Benzoxazole HPLC (220 nm) Purity 92% (retention time 4.73 minutes) MS (APCI +, m / e) 340 (M + 1)

Example 386 5- (2-Acetylphenyl) -2-[(E) -2- (2,4-difluorophenyl) ethenyl] benzoxazole HPLC (220 nm) Purity 86% (retention time 4.86 minutes) MS (APCI +, m / e) 376 (M + 1) Example 387 2- (3-methoxyphenyl) -5- (3-pyridyl) benzoxazole HPLC (220 nm) Purity 97% (retention time 3.04 minutes) MS (APCI +, m / e) 303 (M + 1) Example 388 2-[(E) -2-phenylethenyl] -5- (3-pyridyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 3.21 min) MS (APCI +, m / e) 299 (M + 1) Example 389 2-[(E) -2- (2,4-difluorophenyl) ethenyl] -5- (3-pyridyl) benzoxazole HPLC (220 nm) Purity 98% (retention time 3.32 minutes) MS (APCI +, m / e) 335 (M + 1)

Reference Examples 67 to 72 and Example 242 as starting materials
˜243 compounds and phenylboronic acid were selected, Example 214
The compounds of Examples 390 to 397 below were synthesized according to the method described in 1. At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 390 2- (3-methoxyphenyl) -6-phenylbenzoxazole HPLC (220 nm) Purity 99% (retention time 5.06 minutes) MS (APCI +, m / e) 302 (M + 1) Example 391 2- (4-chlorobenzyl) -6-phenylbenzoxazole HPLC (220 nm) Purity 98% (retention time 4.98 minutes) MS (APCI +, m / e) 320 (M + 1) Example 392 6-phenyl-2- [ (E) -2-Phenylethenyl] -benzoxazole HPLC (220 nm) Purity 98% (retention time 5.16 minutes) MS (APCI +, m / e) 298 (M + 1) Example 393 2-[(E) -2- (2,4-Difluorophenyl) ethenyl] -6-phenylbenzoxazole HPLC (220 nm) Purity 99% (retention time 5.28 min) MS (APCI +, m / e) 334 (M + 1)

Example 39 2-[(E) -2- (2-fluorophenyl) ethenyl] -6-phenylbenzoxazole HPLC (220 nm) Purity 97% (retention time 5.26 min) MS (APCI +, m / e ) 316 (M + 1) Example 395 6-phenyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] benzoxazole HPLC (220 nm) Purity 90% (retention time 5.42 min. ) MS (APCI +, m / e) 366 (M + 1) Example 396 6-phenyl-2- (2-phenylethyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 4.92 minutes) MS (APCI +, m / e) 300 (M + 1) Example 397 2- (2-naphthyl) -6-phenylbenzoxazole HPLC (220 nm) Purity 97% (retention time 5.58 minutes) MS (APCI +, m / e) 322 ( (M + 1)

Example 398 6-Bromo-2- (3-methoxyphenyl) benzoxazole (compound of Example 242) (137 mg), 2- (tributylstannyl) furan (321 mg), dichlorobis (triphenylphosphine) ) A mixture of palladium (II) (24 mg) and N, N-dimethylformamide (4.5 ml) was added at 80 ° C in an argon stream at 24 ° C.
After stirring for an hour, the mixture was poured into water and extracted with ethyl acetate.
The organic layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1: 9, v / v) was concentrated under reduced pressure. The crystals thus obtained are collected by filtration, and 6- (2-furyl) -2-
(3-Methoxyphenyl) benzoxazole (76 mg, 58
%). ¹ H NMR (CDCl ₃ ) δ 3.93 (3H, s), 6.52 (1H, dd, J =
3.2, 1.8 Hz), 6.72 (1H, dd, J = 3.4, 0.8 Hz), 7.10
(1H, ddd, J = 8.3, 2.5, 0.6 Hz), 7.45 (1H, t, J =
7.8 Hz), 7.52 (1H, dd, J = 1.8, 0.8 Hz), 7.66-7.89
(5H, m) ppm HPLC (220 nm) Purity 99% (retention time 4.86 minutes) MS (APCI +, m / e) 292 (M + 1)

Reference Examples 67 to 72 and Example 243 as starting materials
The compounds of Examples 255 to 255 and 2- (tributylstannyl) furan were selected, and the compounds of Examples 399 to 416 below were synthesized according to the method of Example 398. At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 399 2- (4-chlorobenzyl) -6- (2-furyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 4.78 minutes) MS (APCI +, m / e) 310 (M + 1) Example 400 6- (2-furyl) -2-[(E) -2-phenylethenyl] -benzoxazole HPLC (220 nm) Purity 99% (retention time 4.97 minutes) MS (APCI +, m / e) 288 ( M + 1) Example 401 2-[(E) -2- (2,4-difluorophenyl) ethenyl] -6- (2-furyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 5.09 minutes) MS (APCI +, m / e) 324 (M + 1) Example 402 2-[(E) -2- (2-fluorophenyl) ethenyl] -6- (2-furyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 5.06 minutes) MS (APCI +, m / e) 306 (M + 1) Example 403 6- (2-furyl) -2-[(E) -2- [4- (trifluoromethyl) Phenyl] ethenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 5.23 min) MS (APCI +, m / e) 356 (M + 1)

Example 404 6- (2-furyl) -2- (2-phenylethyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 4.72 minutes) MS (APCI +, m / e) 290 (M + 1) Example 405 6- (2-furyl) -2- (2-naphthyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.37 minutes) MS (APCI +, m / e) 312 (M + 1) Example 406 6- (2-furyl) -2-phenylbenzoxazole HPLC (220 nm) Purity 100% (retention time 4.81 minutes) MS (APCI +, m / e) 262 (M + 1) Example 407 6- ( 2-furyl) -2- (3-methylphenyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 5.07 min) MS (APCI +, m / e) 276 (M + 1) Example 408 6- (2 -Furyl) -2- (4-methoxyphenyl) benzoxazole HPLC (220 nm) Purity 98% (retention time 4.78 min) MS (APCI +, m / e) 292 (M + 1) Example 409 2- (3, 4-Dimethoxyphenyl) -6- (2-furyl) benzoxazole HPLC (220 nm) Purity 98% (retention time 4.50 minutes) MS (APCI +, m / e) 322 (M + 1)

Example 410 6- (2-furyl) -2- (2-methoxyphenyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 4.42 minutes) MS (APCI +, m / e) 292 (M + 1) Example 411 6- (2-furyl) -2- (3,4,5-trimethoxyphenyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 4.58 minutes) MS (APCI +, m / e) 352 (M + 1) Example 412 2- (3-Fluorophenyl) -6- (2-furyl) benzoxazole HPLC (220 nm) Purity 98% (retention time 4.96 minutes) MS (APCI +, m / e) 280 (M + 1) Example 413 6- (2-furyl) -2- [3- (trifluoromethyl) phenyl] benzoxazole HPLC (220 nm) Purity 98% (retention time 5.21 minutes) MS (APCI +, m / e) 330 (M + 1) Example 414 6- (2-furyl) -2- [3- (trifluoromethoxy) phenyl]
Benzoxazole HPLC (220 nm) Purity 99% (retention time 5.28 min) MS (APCI +, m / e) 346 (M + 1) Example 415 3- [6- (2-furyl) benzoxazol-2-yl] Benzonitrile HPLC (220 nm) Purity 98% (retention time 4.63 minutes) MS (APCI +, m / e) 287 (M + 1) Example 416 2- (3-butoxyphenyl) -6- (2-furyl) benzo Oxazole HPLC (220 nm) Purity 99% (retention time 5.60 minutes) MS (APCI +, m / e) 334 (M + 1)

The compounds of Examples 242, 244-255 and various boronic acids were appropriately selected as starting materials, and the following compounds of Examples 417-448 were synthesized according to the method of Example 214. At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 417 6- (2-Fluorophenyl) -2- (3-methoxyphenyl) benzoxazole HPLC (220 nm) Purity 95% (retention time 5.01 minutes) MS (APCI +, m / e) 320 (M + 1) Example 418 6- (2-Fluorophenyl) -2-phenylbenzoxazole HPLC (220 nm) Purity 100% (retention time 5.02 minutes) MS (APCI +, m / e) 290 (M + 1) Example 419 6- (2-Fluorophenyl) -2- (3-methylphenyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 5.26 min) MS (APCI +, m / e) 304 (M + 1) Example 420 6- (2-Fluorophenyl) -2- (4-methoxyphenyl) benzoxazole HPLC (220 nm) Purity 97% (retention time 4.97 minutes) MS (APCI +, m / e) 320 (M + 1) Example 421 2- (3,4-dimethoxyphenyl) -6- (2-fluorophenyl)
Benzoxazole HPLC (220 nm) Purity 97% (retention time 4.71 minutes) MS (APCI +, m / e) 350 (M + 1)

Example 422 6- (2-Fluorophenyl) -2- (2-methoxyphenyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 4.63 minutes) MS (APCI +, m / e) 320 (M +1) Example 423 6- (2-Fluorophenyl) -2- (3,4,5-trimethoxyphenyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 4.79 min) MS (APCI +, m / e) 380 (M + 1) Example 424 6- (2-Fluorophenyl) -2- (3-fluorophenyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 5.13 minutes) MS (APCI +, m / e) 308 (M + 1) Example 425 6- (2-Fluorophenyl) -2- [3- (trifluoromethyl) phenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 5.37 minutes) MS ( APCI +, m / e) 358 (M + 1) Example 426 6- (2-fluorophenyl) -2- [3- (trifluoromethoxy)
Phenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 5.43 min) MS (APCI +, m / e) 374 (M + 1) Example 427 3- [6- (2-fluorophenyl) benzoxazole-2 -Yl] benzonitrile HPLC (220 nm) Purity 99% (retention time 4.81 min) MS (APCI +, m / e) 315 (M + 1)

Example 428 2- (3-methoxyphenyl) -6- [2- (trifluoromethyl) phenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 5.09 minutes) MS (APCI +, m / e ) 370 (M + 1) Example 429 2-phenyl-6- [2- (trifluoromethyl) phenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 5.08 minutes) MS (APCI +, m / e) 340 (M + 1) Example 430 2- (3-Methylphenyl) -6- [2- (trifluoromethyl) phenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 5.32 minutes) MS (APCI +, m / e) 354 (M + 1) Example 431 2- (4-methoxyphenyl) -6- [2- (trifluoromethyl) phenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 5.08 minutes) MS (APCI +, m / e) 370 (M + 1) Example 432 2- (3,4-Dimethoxyphenyl) -6- [2- (trifluoromethyl) phenyl] benzoxazole HPLC (220 nm) Purity 100% (Retention time 4.83 minutes) MS (APCI +, m / e) 400 (M + 1) Example 433 2- (2-me Kishifeniru) -6- [2- (trifluoromethyl) phenyl] benzoxazole HPLC (220 nm) 100% pure (retention time 4.78 min) MS (APCI +, m / e) 370 (M + 1)

Example 434 6- [2- (trifluoromethyl) phenyl] -2- (3,4,5-trimethoxyphenyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 4.91 minutes) MS ( APCI +, m / e) 430 (M + 1) Example 435 2- (3-Fluorophenyl) -6- [2- (trifluoromethyl) phenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 5.22 Min) MS (APCI +, m / e) 358 (M + 1) Example 436 6- [2- (trifluoromethyl) phenyl] -2- [3- (trifluoromethyl) phenyl] benzoxazole HPLC (220 nm ) Purity 99% (retention time 5.43 minutes) MS (APCI +, m / e) 408 (M + 1) Example 437 2- [3- (trifluoromethoxy) phenyl] -6- [2- (trifluoromethyl) Phenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 5.49 min) MS (APCI +, m / e) 424 (M + 1) Example 438 3- [6- [2- (trifluoromethyl) phenyl] Benzoxazol-2-yl] benzonitrile HPLC (220 nm) Purity 99% (at retention 4.92 mins) MS (APCI +, m / e) 365 (M + 1)

Example 439 2,6-Bis (3-methoxyphenyl) benzoxazole HPLC (220 nm) Purity 93% (Retention time 4.97 min) MS (APCI +, m / e) 332 (M + 1) Example 440 6- (3-Methoxyphenyl) -2-phenylbenzoxazole HPLC (220 nm) Purity 98% (retention time 4.95 min) MS (APCI +, m / e) 302 (M + 1) Example 441 6- (3- Methoxyphenyl) -2- (3-methylphenyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 5.20 min) MS (APCI +, m / e) 316 (M + 1) Example 442 6- (3- Methoxyphenyl) -2- (4-methoxyphenyl) benzoxazole HPLC (220 nm) Purity 98% (retention time 4.94 minutes) MS (APCI +, m / e) 332 (M + 1) Example 443 2- (3, 4-dimethoxyphenyl) -6- (3-methoxyphenyl)
Benzoxazole HPLC (220 nm) Purity 91% (retention time 4.67 minutes) MS (APCI +, m / e) 362 (M + 1) Example 444 2- (2-methoxyphenyl) -6- (3-methoxyphenyl) Benzoxazole HPLC (220 nm) Purity 93% (retention time 4.59 minutes) MS (APCI +, m / e) 332 (M + 1)

Example 445 2- (3-Fluorophenyl) -6- (3-methoxyphenyl) benzoxazole HPLC (220 nm) Purity 97% (retention time 5.08 minutes) MS (APCI +, m / e) 320 (M +1) Example 446 6- (3-methoxyphenyl) -2- [3- (trifluoromethyl) phenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 5.34 minutes) MS (APCI +, m / e ) 370 (M + 1) Example 447 6- (3-methoxyphenyl) -2- [3- (trifluoromethoxy)
Phenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 5.40 min) MS (APCI +, m / e) 386 (M + 1) Example 448 3- [6- (3-methoxyphenyl) benzoxazole-2 -Yl] benzonitrile HPLC (220 nm) Purity 100% (retention time 4.80 min) MS (APCI +, m / e) 327 (M + 1)

With the compounds of Examples 256-271 as starting materials
2- (Tributylstannyl) furan was selected and the compounds of the following Examples 449 to 464 were synthesized according to the method of Example 398. At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 449 6- (2-furyl) -2- [3-[(trifluoromethyl) thio] phenyl] benzoxazole HPLC (220 nm) Purity 96% (retention time 5.41 min) MS (APCI +, m / e) 362 (M + 1) Example 450 2- [3-Fluoro-5- (trifluoromethyl) phenyl] -6- (2
-Furyl) benzoxazole HPLC (220 nm) Purity 93% (retention time 5.32 minutes) MS (APCI +, m / e) 348 (M + 1) Example 451 2- (3-ethoxyphenyl) -6- (2- Furyl) benzoxazole HPLC (220 nm) Purity 98% (retention time 5.06 minutes) MS (APCI +, m / e) 306 (M + 1) Example 452 2- [3,5-bis (trifluoromethyl) phenyl] -6- (2-Furyl) benzoxazole HPLC (220 nm) Purity 93% (retention time 5.55 minutes) MS (APCI +, m / e) 398 (M + 1) Example 453 2- (3,5-difluorophenyl) ) -6- (2-Furyl) benzoxazole HPLC (220 nm) Purity 95% (retention time 5.14 minutes) MS (APCI +, m / e) 298 (M + 1)

Example 45 6- (2-furyl) -2- (3-phenoxyphenyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.43 min) MS (APCI +, m / e) 354 (M + 1) Example 455 6- (2-furyl) -2- (5-methyl-2-thienyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 4.91 min) MS (APCI +, m / e) 282 ( M + 1) Example 456 2- (1-benzofuran-2-yl) -6- (2-furyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 4.95 minutes) MS (APCI +, m / e) 302 (M + 1) Example 457 2- (1-benzothiophen-2-yl) -6- (2-furyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.30 min) MS (APCI +, m / e) 318 (M + 1) Example 458 6- [6- (2-furyl) benzoxazol-2-yl] quinoline HPLC (220 nm) Purity 100% (retention time 3.51 min) MS (APCI +, m / e) 313 (M + 1) Example 459 6- (2-furyl) -2- (3-nitrophenyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 4.82 minutes) MS (APCI +, m / e ) 307 (M + 1)

Example 460 3- [6- (2-furyl) benzoxazol-2-yl] aniline HPLC (220 nm) Purity 92% (retention time 3.37 minutes) MS (APCI +, m / e) 277 (M + 1) Example 461 N- [3- [6- (2-furyl) benzoxazol-2-yl] phenyl] acetamide HPLC (220 nm) Purity 83% (retention time 4.08 minutes) MS (APCI +, m / e) 319 (M + 1) Example 462 N- [3- [6- (2-furyl) benzoxazol-2-yl] phenyl] benzamide HPLC (220 nm) Purity 86% (retention time 4.72 min) MS (APCI +, m / e) 381 (M + 1) Example 463 N- [3- [6- (2-furyl) benzoxazol-2-yl] phenyl] methanesulfonamide HPLC (220 nm) Purity 92% (retention time 4.16) Min) MS (APCI +, m / e) 355 (M + 1) Example 464 N-ethyl-N ^' -[3- [6- (2-furyl) benzoxazole-2-
Il] phenyl] urea HPLC (220 nm) Purity 95% (retention time 4.16 min) MS (APCI +, m / e) 348 (M + 1)

With the compounds of Examples 256-271 as starting materials
2-Fluorophenylboronic acid was selected and the compounds of the following Examples 465 to 480 were synthesized according to the method of Example 214.
At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 465 6- (2-fluorophenyl) -2- [3-[(trifluoromethyl)
Thio] phenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 5.56 minutes) MS (APCI +, m / e) 390 (M + 1) Example 466 6- (2-fluorophenyl) -2- [3 -Fluoro-5- (trifluoromethyl) phenyl] benzoxazole HPLC (220 nm) Purity 97% (retention time 5.46 min) MS (APCI +, m / e) 376 (M + 1) Example 467 2- (3- Ethoxyphenyl) -6- (2-fluorophenyl) benzoxazole HPLC (220 nm) Purity 96% (retention time 5.23 minutes) MS (APCI +, m / e) 334 (M + 1) Example 468 2- [3, 5-bis (trifluoromethyl) phenyl] -6- (2-fluorophenyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 5.68 min) MS (APCI +, m / e) 426 (M + 1) Example 469 2- (3,5-difluorophenyl) -6- (2-fluorophenyl)
Benzoxazole HPLC (220 nm) Purity 100% (retention time 5.29 min) MS (APCI +, m / e) 326 (M + 1) Example 470 6- (2-Fluorophenyl) -2- (3-phenoxyphenyl) Benzoxazole HPLC (220 nm) Purity 100% (retention time 5.57 minutes) MS (APCI +, m / e) 382 (M + 1)

Example 471 6- (2-Fluorophenyl) -2- (5-methyl-2-thienyl) benzoxazole HPLC (220 nm) Purity 99% (retention time 5.08 minutes) MS (APCI +, m / e) 310 (M + 1) Example 472 2- (1-Benzofuran-2-yl) -6- (2-fluorophenyl) benzoxazole HPLC (220 nm) Purity 97% (retention time 5.12 minutes) MS (APCI +, m / e) 330 (M + 1) Example 473 2- (1-benzothiophen-2-yl) -6- (2-fluorophenyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.44 min) MS (APCI +, m / e) 346 (M + 1) Example 474 6- [6- (2-Fluorophenyl) benzoxazol-2-yl] quinoline HPLC (220 nm) Purity 99% (retention time 3.74 minutes) MS (APCI +, m / e) 341 (M + 1) Example 475 6- (2-Fluorophenyl) -2- (3-nitrophenyl) benzoxazole HPLC (220 nm) 100% purity (retention time 4.99 min) MS (APCI +, m / e) 335 (M + 1) Example 476 3- [6- (2-Fluorophenyl) benzoxazol-2-yl] anili HPLC (220 nm) Purity 97% (retention time 3.62 minutes) MS (APCI +, m / e) 305 (M + 1)

Example 477 N- [3- [6- (2-fluorophenyl) benzoxazole-2-
Il] phenyl] acetamide HPLC (220 nm) Purity 90% (retention time 4.28 min) MS (APCI +, m / e) 347 (M + 1) Example 478 N- [3- [6- (2-fluorophenyl) Benzoxazole-2-
Il] phenyl] benzamide HPLC (220 nm) Purity 87% (retention time 4.88 min) MS (APCI +, m / e) 409 (M + 1) Example 479 N- [3- [6- (2-fluorophenyl) Benzoxazole-2-
Il] phenyl] methanesulfonamide HPLC (220 nm) Purity 95% (retention time 4.35 min) MS (APCI +, m / e) 383 (M + 1) Example 480 N-ethyl-N ^' -[3- [6 -(2-Fluorophenyl) benzoxazol-2-yl] phenyl] urea HPLC (220 nm) Purity 96% (retention time 4.36 min) MS (APCI +, m / e) 376 (M + 1)

With the compounds of Examples 273 to 281 as starting materials
2- (Tributylstannyl) furan was selected, and the compounds of the following Examples 481 to 488 were synthesized according to the method of Example 398. At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 481 6- (2-furyl) -2- (3-isopropoxyphenyl) benzoxazole HPLC (220 nm) Purity 95% (retention time 5.25 minutes) MS (APCI +, m / e) 320 (M + 1) Example 482 6- (2-furyl) -2- [3- (hexyloxy) phenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 6.20 min) MS (APCI +, m / e) 362 (M + 1) Example 483 6- (2-furyl) -2- [3- (3-methylbutoxy) phenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 5.83 minutes) MS (APCI +, m / e) 348 (M + 1) Example 484 2- [3- (Cyclopentyloxy) phenyl] -6- (2-furyl)
Benzoxazole HPLC (220 nm) Purity 99% (retention time 5.66 min) MS (APCI +, m / e) 346 (M + 1) Example 485 2- [3- (cyclopropylmethoxy) phenyl] -6- (2 -Furyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.25 minutes) MS (APCI +, m / e) 332 (M + 1) Example 486 2- [3- (benzyloxy) phenyl] -6- (2-Furyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.36 min) MS (APCI +, m / e) 368 (M + 1) Example 487 [3- [6- (2-furyl) benzo Oxazol-2-yl] phenoxy] tert-butylacetate HPLC (220 nm) Purity 99% (retention time 5.10 min) MS (APCI +, m / e) 392 (M + 1) Example 488 2- [3- [6 -(2-Furyl) benzoxazol-2-yl] phenoxy] -N-methylacetamide HPLC (220 nm) Purity 97% (retention time 4.06 minutes) MS (APCI +, m / e) 349 (M + 1)

The compounds of Examples 273 to 281 and various boronic acids were appropriately selected as starting materials, and the compounds of Examples 489 to 504 below were synthesized according to the method of Example 214. that time,
If necessary, recrystallization or purification by silica gel column chromatography was carried out. Example 489 6- (2-fluorophenyl) -2- (3-isopropoxyphenyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.47 min) MS (APCI +, m / e) 348 (M + 1 ) Example 490 6- (2-Fluorophenyl) -2- [3- (hexyloxy) phenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 6.52 minutes) MS (APCI +, m / e) 390 ( M + 1) Example 491 6- (2-Fluorophenyl) -2- [3- (3-methylbutoxy) phenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 6.10 min) MS (APCI +, m / e) 376 (M + 1) Example 492 2- [3- (Cyclopentyloxy) phenyl] -6- (2-fluorophenyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.93 minutes) MS ( APCI +, m / e) 374 (M + 1) Example 493 2- [3- (Cyclopropylmethoxy) phenyl] -6- (2-fluorophenyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.46) Min) MS (APCI +, m / e) 360 (M + 1)

Example 494 2- [3- (benzyloxy) phenyl] -6- (2-fluorophenyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.57 minutes) MS (APCI +, m / e) 396 (M + 1) Example 495 [3- [6- (2-Fluorophenyl) benzoxazol-2-yl] phenoxy] acetate tert-butyl HPLC (220 nm) Purity 100% (retention time 5.30 min) MS ( APCI +, m / e) 420 (M + 1) Example 496 2- [3- [6- (2-fluorophenyl) benzoxazole-2-
Il] phenoxy] -N-methylacetamide HPLC (220 nm) Purity 97% (retention time 4.23 min) MS (APCI +, m / e) 377 (M + 1) Example 497 6- (2,4-difluorophenyl) -2- (3-isopropoxyphenyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.48 min) MS (APCI +, m / e) 366 (M + 1) Example 498 6- (2,4- Difluorophenyl) -2- [3- (hexyloxy) phenyl] benzoxazole HPLC (220 nm) Purity 100% (retention time 6.49 min) MS (APCI +, m / e) 408 (M + 1) Example 499 6- (2,4-difluorophenyl) -2- [3- (3-methylbutoxy)
Phenyl] benzoxazole HPLC (220 nm) Purity 99% (retention time 6.10 min) MS (APCI +, m / e) 394 (M + 1)

Example 500 2- [3- (Cyclopentyloxy) phenyl] -6- (2,4-difluorophenyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.92 minutes) MS (APCI +, m / e) 392 (M + 1) Example 501 2- [3- (Cyclopropylmethoxy) phenyl] -6- (2,4-difluorophenyl) benzoxazole HPLC (220 nm) Purity 100% (retention time 5.47 minutes) MS (APCI +, m / e) 378 (M + 1) Example 502 2- [3- (benzyloxy) phenyl] -6- (2,4-difluorophenyl) benzoxazole HPLC (220 nm) Purity 100% ( Retention time 5.58 minutes) MS (APCI +, m / e) 414 (M + 1) Example 503 [3- [6- (2,4-difluorophenyl) benzoxazole-2
-Yl] phenoxy] tert-butyl acetate HPLC (220 nm) Purity 100% (retention time 5.32 min) MS (APCI +, m / e) 438 (M + 1) Example 504 2- [3- [6- (2 , 4-Difluorophenyl) benzoxazole
-2-yl] phenoxy] -N-methylacetamide HPLC (220 nm) Purity 100% (retention time 4.30 min) MS (APCI +, m / e) 395 (M + 1)

The compounds of Reference Examples 73 to 111 and various boronic acids were appropriately selected as starting materials, and the following compounds of Examples 505 to 588 were synthesized according to the method of Example 1. At that time, if necessary, recrystallization or purification by silica gel column chromatography was performed. Example 505 2- (2-Methoxyphenyl) -6-phenyl-1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 94% (retention time 3.07 minutes) MS (APCI +, m / e) 302 (M + 1) Example 506 2- (2- (2-methoxyethoxy) phenyl) -6- Phenyl-1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.24 min) MS (APCI +, m / e) 346 (M + 1) Example 507 2- (2,3-dihydro-1) , 4-Benzodioxin-6-yl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 83% (retention time 3.05 minutes) MS (APCI +, m / e) 330 ( M + 1) Example 508 2- (3-fluorophenyl) -6-phenyl-1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 96% (retention time 3.23 minutes) MS (APCI +, m / e) 290 (M + 1) Example 509 2- (3-fluorophenyl) -6- (2-furyl) -1H-Imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 95% (retention time 3.13 minutes) MS (APCI +, m / e) 280 (M + 1)

Example 510 2- (2-Fluorophenyl) -6-phenyl-1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.09 minutes) MS (APCI +, m / e) 290 (M + 1) Example 511 2- (2-fluorophenyl) -6- (2-furyl) -1H-Imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.98 minutes) MS (APCI +, m / e) 280 (M + 1) Example 512 2- (4-Fluorophenyl) -6-phenyl-1H -Imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 99% (retention time 3.13 minutes) MS (APCI +, m / e) 290 (M + 1) Example 513 2- (4-fluorophenyl) -6- (2-furyl) -1H-Imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 92% (retention time 3.01 min) MS (APCI +, m / e) 280 (M + 1) Example 514 N- (3- (6- (2-methoxyphenyl)) -1H-imidazo [4,5-b] pyridin-2-yl) phenyl) -N, N-dimethylamine HPLC (220 nm) Purity 99% (retention time 2.81 minutes) MS (APCI +, m / e) 345 ( M + 1) Example 515 2- (2-fluorophenyl) -6- (2-methoxyphenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.20 min) MS (APCI +, m / e) 320 (M + 1)

Example 5 16 2- (3-Fluorophenyl) -6- (2-methoxyphenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.20 min) MS (APCI +, m / e) 320 (M + 1) Example 517 2- (4-fluorophenyl) -6 -(2-Methoxyphenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 95% (retention time 3.08 minutes) MS (APCI +, m / e) 320 (M + 1) Example 518 N, N-dimethyl-N- (3 -(6-Phenyl-1H-imidazo [4,5-b] pyridin-2-yl) phenyl) amine HPLC (220 nm) Purity 100% (retention time 2.80 minutes) MS (APCI +, m / e) 315 (M +1) Example 519 N- (3- (6- (2-furyl) -1H-imidazo [4,5-b] pyridin-2-yl) phenyl) -N, N-dimethylamine HPLC (220 nm) Purity 98% (retention time 2.58 minutes) MS (APCI +, m / e) 305 (M + 1) Example 520 3- (6-Phenyl-1H-imidazo [4,5-b] pyridin-2-yl) benzo Nitrile HPLC (220 nm) Purity 98% (retention time 3.21 minutes) MS (APCI +, m / e) 297 (M + 1) Example 521 3- (6- (2-methoxyphenyl) -1H-imidazo [4, 5-b] Pyridin-2-yl) benzonitrile HPLC (220 nm) Purity 99% (retention time 3.20 min) MS (APCI +, m / e) 327 (M + 1)

Example 522 2- (2-Fluorophenyl) -6- (3-methoxyphenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.15 minutes) MS (APCI +, m / e) 320 (M + 1) Example 523 2- (3-fluorophenyl) -6 -(3-Methoxyphenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.28 minutes) MS (APCI +, m / e) 320 (M + 1) Example 524 2- (4-fluorophenyl) -6 -(3-Methoxyphenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.17 min) MS (APCI +, m / e) 320 (M + 1) Example 525 6-phenyl-2- (3- ( Trifluoromethyl) phenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 93% (retention time 3.61 min) MS (APCI +, m / e) 340 (M + 1) Example 526 6- (2-furyl) -2- (3- (trifluoromethyl) phenyl) -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 85% (retention time 3.58 minutes) MS (APCI +, m / e) 330 (M + 1) Example 527 6- (2-methoxyphenyl)- 2- (3- (Trifluoromethyl) phenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.54 minutes) MS (APCI +, m / e) 370 (M + 1)

Example 528 2- (3- (methylsulfonyl) phenyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 94% (retention time 2.98 minutes) MS (APCI +) , m / e) 350 (M + 1) Example 529 6- (2-methoxyphenyl) -2- (3- (methylsulfonyl) phenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm ) Purity 99% (retention time 2.96 minutes) MS (APCI +, m / e) 380 (M + 1) Example 530 6- (2-furyl) -2- (3- (methylsulfonyl) phenyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.89 min) MS (APCI +, m / e) 340 (M + 1) Example 531 6- (2-furyl) -2- (3- (2-methoxyethoxy) phenyl) -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 89% (retention time 3.00 min) MS (APCI +, m / e) 336 (M + 1) Example 532 6- (2-furyl) -2 -(4- (2-Methoxyethoxy) phenyl) -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) 90% purity (retention time 3.53 min) MS (APCI +, m / e) 336 (M + 1) Example 533 2- (3-morpholinophenyl)- 6-phenyl-1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.03 minutes) MS (APCI +, m / e) 357 (M + 1)

Example 534 6- (2-furyl) -2- (3-morpholinophenyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 2.92 min) MS (APCI +, m / e) 347 (M + 1) Example 535 6- (2-fluorophenyl) -2- (3-morpholinophenyl) -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.11 min) MS (APCI +, m / e) 375 (M + 1) Example 536 6- (2-furyl) -2 -(3- (1-Pyrrolidinyl) phenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.31 minutes) MS (APCI +, m / e) 331 (M + 1 ) Example 537 6- (3-furyl) -2- (3-methoxyphenyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 93% (retention time 2.91 min) MS (APCI +, m / e) 292 (M + 1) Example 538 2- (5-methyl-3-phenyl-4-isoxazolyl) ) -6-Phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.38 min) MS (APCI +, m / e) 353 (M + 1) Example 539 6- (2-Furyl) -2- (5-methyl-3-phenyl-4-isoxazolyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.32 minutes) MS (APCI + , m / e) 343 (M + 1)

Example 54 6-Phenyl-2- (3- (2,2,2-trifluoroethoxy) phenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 86% (retention Time 3.53 minutes) MS (APCI +, m / e) 370 (M + 1) Example 541 6- (2-furyl) -2- (3- (2,2,2-trifluoroethoxy) phenyl) -1H- Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 92% (retention time 3.53 minutes) MS (APCI +, m / e) 360 (M + 1) Example 542 6- (2-Fluorophenyl) -2 -(3- (2,2,2-Trifluoroethoxy) phenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 87% (retention time 3.65 minutes) MS (APCI +, m / e ) 388 (M + 1) Example 543 2- (3-isopropoxy-2-methylphenyl) -6-phenyl-1
H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.45 min) MS (APCI +, m / e) 344 (M + 1) Example 544 6- (2-furyl)- 2- (3-isopropoxy-2-methylphenyl)
-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 95% (retention time 3.37 minutes) MS (APCI +, m / e) 334 (M + 1) Example 545 6- (2-fluorophenyl ) -2- (3-Isopropoxy-2-methylphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.54 minutes) MS (APCI +, m / e) 362 (M + 1)

Example 54 6- (2,4-difluorophenyl) -2- (3-isopropoxy-2-
Methylphenyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 3.62 minutes) MS (APCI +, m / e) 380 (M + 1) Example 547 2- (2 -(2-Methoxyphenyl) ethyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 98% (retention time 3.17 minutes) MS (APCI +, m / e) 330 (M +1) Example 548 6- (2-furyl) -2- (2- (2-methoxyphenyl) ethyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 97% (retention time 3.01 min) MS (APCI +, m / e) 320 (M + 1) Example 549 2- (2- (4-methoxyphenyl) ) Ethyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 94% (retention time 3.13 min) MS (APCI +, m / e) 330 (M + 1) Example 550 6- (2-furyl) -2- (2- (4-methoxyphenyl) ethyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.97 minutes) MS (APCI +, m / e) 320 (M + 1) Example 551 2- (2- (3-methoxyphenyl) ) Ethyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 89% (retention time 3.14 minutes) MS (APCI +, m / e) 330 (M + 1)

Example 55 6- (2-Furyl) -2- (2- (3-methoxyphenyl) ethyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 2.98 minutes) MS (APCI +, m / e) 320 (M + 1) Example 553 2- (2- (4-chlorophenyl) Ethyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 3.33 min) MS (APCI +, m / e) 334 (M + 1) Example 5542 -(2- (4-chlorophenyl) ethyl) -6- (2-furyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.20 min) MS (APCI +, m / e) 324 (M + 1) Example 555 2- (2- (2-chlorophenyl) ethyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention Time 3.24 min) MS (APCI +, m / e) 334 (M + 1) Example 556 2- (2- (2-chlorophenyl) ethyl) -6- (2-furyl) -1H-imidazo [4,5- b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.10 min) MS (APCI +, m / e) 324 (M + 1) Example 557 2- (2- (3-chlorophenyl) ethyl) -6-phenyl -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 3.31 minutes) MS (APCI +, m / e) 334 (M + 1)

Example 558 2- (2- (3-chlorophenyl) ethyl) -6- (2-furyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 3.19) Min) MS (APCI +, m / e) 324 (M + 1) Example 559 2- (2- (4-methylphenyl) ethyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC ( 220 nm) Purity 99% (retention time 3.26 minutes) MS (APCI +, m / e) 314 (M + 1) Example 560 6- (2-furyl) -2- (2- (4-methylphenyl) ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.13 minutes) MS (APCI +, m / e) 304 (M + 1) Example 561 2- (2- (3 , 4-Dichlorophenyl) ethyl) -6-phenyl-1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 87% (retention time 3.47 min) MS (APCI +, m / e) 368 (M + 1) Example 562 2- (2- (3,4- Dichlorophenyl) ethyl) -6- (2-furyl) -1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 94% (retention time 3.38 min) MS (APCI +, m / e) 358 (M + 1) Example 563 4- (2- (6-phenyl) -1H-imidazo [4,5-b] pyridin-2-yl) ethyl) benzonitrile HPLC (220 nm) Purity 98% (retention time 3.03 minutes) MS (APCI +, m / e) 325 (M + 1)

Example 5 64- (2- (6- (2-furyl) -1H-imidazo [4,5-b] pyridin-2-yl) ethyl) benzonitrile HPLC (220 nm) Purity 100% (retention Time (2.88 minutes) MS (APCI +, m / e) 315 (M + 1) Example 565 2- (2- (4-fluorophenyl) ethyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 94% (retention time 3.17 minutes) MS (APCI +, m / e) 318 (M + 1) Example 566 2- (2- (4-fluorophenyl) ethyl) -6- (2- Frill) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.03 min) MS (APCI +, m / e) 308 (M + 1) Example 567 6-phenyl-2- (2- ( 4- (Trifluoromethyl) phenyl) ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.45 min) MS (APCI +, m / e) 368 (M + 1 ) Example 568 6- (2-furyl) -2- (2- (4- (trifluoromethyl) phenyl)
Ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 90% (retention time 3.34 minutes) MS (APCI +, m / e) 358 (M + 1) Example 569 6-Phenyl-2 -(2-Phenylcyclopropyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.20 min) MS (APCI +, m / e) 312 (M + 1)

Example 570 6- (2-furyl) -2- (2-phenylcyclopropyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.07 minutes) MS (APCI +, m / e) 302 (M + 1) Example 571 2- (2- (4-isopropylphenyl) ethyl) -6-phenyl-1H
-Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 96% (retention time 3.57 min) MS (APCI +, m / e) 342 (M + 1) Example 572 6- (2-furyl) -2 -(2- (4-isopropylphenyl) ethyl)-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 80% (retention time 3.47 min) MS (APCI +, m / e) 332 (M + 1) Example 573 6-phenyl-2- (2 -(2-thienyl) ethyl) -1H-imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.03 min) MS (APCI +, m / e) 306 (M + 1) Example 574 6- (2-furyl) -2- (2- ( 2-thienyl) ethyl) -1H-imidazo
[4,5-b] Pyridine HPLC (220 nm) Purity 99% (retention time 2.88 minutes) MS (APCI +, m / e) 296 (M + 1) Example 575 2- (2- (4-ethoxyphenyl)) Ethyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.27 min) MS (APCI +, m / e) 344 (M + 1)

Example 576 2- (2- (4-ethoxyphenyl) ethyl) -6- (2-furyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.15 min) MS (APCI +, m / e) 334 (M + 1) Example 577 2- (2- (4-nitrophenyl) ) Ethyl) -5-phenyl-1H-benzimidazole HPLC (220 nm) Purity 100% (retention time 3.16 min) MS (APCI +, m / e) 344 (M + 1) Example 578 6-phenyl-2- ( 2-phenylpropyl) -1H-imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.20 min) MS (APCI +, m / e) 314 (M + 1) Example 579 6- (2-furyl) -2- (2-phenylpropyl) -1H-Imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.05 min) MS (APCI +, m / e) 304 (M + 1) Example 580 6-Phenyl-2- (5-phenylpentyl) -1H -Imidazo [4,5-
b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.53 minutes) MS (APCI +, m / e) 342 (M + 1) Example 581 6- (2-furyl) -2- (5-phenylpentyl) -1H-Imidazo [4,
5-b] Pyridine HPLC (220 nm) Purity 100% (retention time 3.41 min) MS (APCI +, m / e) 332 (M + 1)

Example 582 2- (2- (4-butoxyphenyl) ethyl) -6-phenyl-1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 99% (retention time 3.62 minutes) MS (APCI +, m / e) 372 (M + 1) Example 583 2- (2- (4-butoxyphenyl) ethyl) -6- (2-furyl) -1H-
Imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.52 min) MS (APCI +, m / e) 362 (M + 1) Example 584 6-phenyl-2- (2- ( 3,4,5-Trimethoxyphenyl) ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100% (retention time 3.01 minutes) MS (APCI +, m / e) 390 (M + 1) Example 585 6- (2-furyl) -2- (2- (3,4,5-trimethoxyphenyl) ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 100 % (Retention time 2.86 minutes) MS (APCI +, m / e) 380 (M + 1) Example 586 2- (2- (4-isopropoxyphenyl) ethyl) -6-phenyl-
1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 92% (retention time 3.38 min) MS (APCI +, m / e) 358 (M + 1) Example 587 6- (2-furyl)- 2- (2- (4-isopropoxyphenyl) ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 88% (retention time 3.26 min) MS (APCI +, m / e) 348 ( M + 1) Example 588 6- (2-Fluorophenyl) -2- (2- (4-isopropoxyphenyl) ethyl) -1H-imidazo [4,5-b] pyridine HPLC (220 nm) Purity 88% (Retention time 3.40 minutes) MS (APCI +, m / e) 376 (M + 1)

Example 589 2- (2- (4-Nitrophenyl) ethyl) -5-phenyl-1H-benzimidazole (the compound of Example 577) (0.5 g) was dissolved in acetic acid (50 ml) and palladium was added. -After adding carbon (0.1 g), the mixture was stirred under a hydrogen stream at room temperature for 16 hours. After removing the catalyst, the solvent was distilled off under reduced pressure and the crystals were collected by filtration to give 4- (2
-(6-Phenyl-1H-imidazo [4,5-b] pyridin-2-yl) ethyl) aniline (0.44 g, 95%) was obtained. ¹ H NMR (DMSO-d ₆ ) δ 2.96-3.12 (4H, m), 4.74 (2H,
s), 6.49 (2H, d, J = 8.4 Hz), 6.90 (1H, d, J = 8.4
Hz), 7.34-7.70 (5H, m), 7.95-8.10 (1H, broads),
8.24 (1H, s), 8.42-8.60 (1H, broad s) ppm IR (KBr) ν 3032, 1622, 1518, 1424, 1393, 764, 700
cm ^-1 HPLC (220 nm) Purity 94% (retention time 2.39 min) MS (APCI +, m / e) 315 (M + 1)

Example 590 4- (2- (6-phenyl-1H-imidazo [4,5-b] pyridin-2-yl) ethyl) aniline (Compound of Example 589) (25 mg)
After stirring the mixture with acetic anhydride (0.01 ml) at room temperature for 6 hours in pyridine, the reaction mixture was poured into ice, neutralized with 5% aqueous ammonium acetate solution, and extracted with ethyl acetate. The organic layer was washed with water and dried (Na ₂ SO ₄ ), the solvent was distilled off, and the crystals were collected by filtration to give N- (4- (2- (6-phenyl-1H-imidazo [4,5-b] Pyridin-2-yl) ethyl) phenyl) acetamide (22 mg, 78
%). ¹ H NMR (DMSO-d ₆ ) δ 2.02 (3H, s), 3.12 (4H, s), 7.1
6 (2H, d, J = 8.7 Hz), 7.34-7.49 (5H, m), 7.70 (2H,
d, J = 8.7 Hz), 7.79-8.57 (2H, m), 9.80 (1H, s),
12.9 (1H, s) ppm IR (KBr) ν 3293, 3032, 1659, 1539, 1387, 764 cm ^-1 HPLC (220 nm) Purity 99% (retention time 2.75 minutes) MS (APCI +, m / e) 357 ( (M + 1)

Example 591 Diphosphorus pentoxide (0.5 g) was added to methanesulfonic acid (2 ml), and the mixture was stirred at 120 ° C. for 1 hr to dissolve. 2,3-Diamino-6-phenylpyridine (Compound of Reference Example 113) (0.2 g) and 3-methoxybenzoic acid (0.17 g) were added to this solution, and the mixture was stirred at 120 ° C for 1 hr, and the reaction mixture was added. It was poured into ice, neutralized with 8 N sodium hydroxide solution, and extracted with ethyl acetate-tetrahydrofuran (3: 1, v / v). The organic layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, and the crystals were collected by filtration to give 5-phenyl-2- (3-methoxyphenyl) -1H-.
Imidazo [4,5-b] pyridine (0.18 g, 55%) was obtained. ¹ H NMR (CDCl ₃ ) δ 3.88 (3H, s), 6.97-7.02 (1H, m),
7.30-7.78 (8H, m), 7.95-8.20 (3H, m) ppm IR (KBr) ν 3005, 2938, 1590, 1466, 1227, 762 cm ^-1 HPLC (220 nm) Purity 89% (retention time 2.92 min. ) MS (APCI +, m / e) 304 (M + 1)

Example 592 6-Phenoxy-2,3-pyridinediamine (Compound of Reference Example 115) (0.2 g) and 3-methoxybenzoic acid (0.08 g) were dissolved in phosphorus oxychloride (5 ml). After stirring at 140 ° C. for 4 hours, the reaction mixture was poured into ice, neutralized with 8 N sodium hydroxide solution, and extracted with ethyl acetate-tetrahydrofuran (3: 1, v / v). Wash the organic layer with water and dry (MgS
After O ₄ ), the solvent was distilled off under reduced pressure and the crystals were collected by filtration to give 5-phenoxy-2- (3-methoxyphenyl) -1H-imidazo [4,5-b] pyridine (0.04 g, 23%). Got ¹ H NMR (CDCl ₃ ) δ 3.87 (3H, s), 6.84 (1H, d, J =
8.8 Hz), 7.00 (1H, dd, J = 8.4, 2.4 Hz), 7.10-7.26
(3H, m), 7.30-7.44 (3H, m), 7.53-7.73 (3H, m), 8.0
8 (1H, d, J = 8.8 Hz) ppm IR (KBr) ν 3009, 1590, 1490, 1227, 762 cm ^-1 HPLC (220 nm) Purity 80% (retention time 3.29 min) MS (APCI +, m / e ) 318 (M + 1)

The compounds of Examples 282 to 284 and various boronic acids were appropriately selected as starting materials, and the compounds of Examples 593 to 601 below were synthesized according to the method of Example 214. that time,
If necessary, recrystallization or purification by silica gel column chromatography was carried out. Example 593 2- (3- (2-methoxyethoxy) phenyl) -6-phenylbenzoxazole HPLC (220 nm) Purity 99% (retention time 4.93 minutes) MS (APCI +, m / e) 346 (M + 1) Example 594 6- (2-furyl) -2- (3- (2-methoxyethoxy) phenyl) benzoxazole HPLC (220 nm) Purity 87% (retention time 4.71 minutes) MS (APCI +, m / e) 336 ( M + 1) Example 595 6- (2-Fluorophenyl) -2- (3- (2-methoxyethoxy) phenyl) benzoxazole HPLC (220 nm) Purity 97% (retention time 4.91 min) MS (APCI +, m / e) 364 (M + 1) Example 596 4- (3- (6-phenylbenzoxazol-2-yl) phenoxy) butanenitrile HPLC (220 nm) Purity 99% (retention time 4.90 minutes) MS (APCI +, m / e) 355 (M + 1) Example 597 4- (3- (6- (2-furyl) benzoxazol-2-yl) phenoxy) butanenitrile HPLC (220 nm) Purity 95% (retention time 4.69 min. ) MS (APCI +, m / e) 345 (M + 1)

Example 598 4- (3- (6- (2-fluorophenyl) benzoxazole-2-
Il) phenoxy) butanenitrile HPLC (220 nm) Purity 98% (retention time 4.87 min) MS (APCI +, m / e) 373 (M + 1) Example 599 2- (3- (3- (2-morpholinoethoxy) ) Phenyl) -6-phenylbenzoxazole HPLC (220 nm) Purity 95% (retention time 3.69 min) MS (APCI +, m / e) 401 (M + 1) Example 600 6- (2-furyl) -2- (3- (2-morpholinoethoxy) phenyl)
Benzoxazole HPLC (220 nm) Purity 99% (retention time 3.40 min) MS (APCI +, m / e) 391 (M + 1) Example 601 6- (2-fluorophenyl) -2- (3- (2- (Morpholino ethoxy)
Phenyl) benzoxazole HPLC (220 nm) Purity 92% (retention time 3.69 min) MS (APCI +, m / e) 419 (M + 1)

[0289]

[Table 1]

[0290]

[Table 2]

[0291]

[Table 3]

[0292]

[Table 4]

[0293]

[Table 5]

[0294]

[Table 6]

[0295]

[Table 7]

[0296]

[Table 8]

[0297]

[Table 9]

[0298]

[Table 10]

[0299]

[Table 11]

[0300]

[Table 12]

[0301]

[Table 13]

[0302]

[Table 14]

[0303]

[Table 15]

[0304]

[Table 16]

[0305]

[Table 17]

[0306]

[Table 18]

[0307]

[Table 19]

[0308]

[Table 20]

[0309]

[Table 21]

[0310]

[Table 22]

[0311]

[Table 23]

[0312]

[Table 24]

[0313]

[Table 25]

[0314]

[Table 26]

[0315]

[Table 27]

[0316]

[Table 28]

[0317]

[Table 29]

[0318]

[Table 30]

[0319]

[Table 31]

[0320]

[Table 32]

[0321]

[Table 33]

[0322]

[Table 34]

[0323]

[Table 35]

[0324]

[Table 36]

[0325]

[Table 37]

[0326]

[Table 38]

[0327]

[Table 39]

[0328]

[Table 40]

[0329]

[Table 41]

[0330]

[Table 42]

[0331]

[Table 43]

[0332]

[Table 44]

[0333]

[Table 45]

[0334]

[Table 46]

[0335]

[Table 47]

[0336]

[Table 48]

[0337]

[Table 49]

[0338]

[Table 50]

[0339]

[Table 51]

[0340]

[Table 52]

[0341]

[Table 53]

[0342]

[Table 54]

[0343]

[Table 55]

[0344]

[Table 56]

[0345]

[Table 57]

[0346]

[Table 58]

[0347]

[Table 59]

[0348]

[Table 60]

[0349]

[Table 61]

[0350]

[Table 62]

[0351]

[Table 63]

[0352]

[Table 64]

[0353]

[Table 65]

[0354]

[Table 66]

[0355]

[Table 67]

[0356]

[Table 68]

[0357]

[Table 69]

[0358]

[Table 70]

[0359]

[Table 71]

[0360]

[Table 72]

Formulation Example 1 (Dose per Capsule) (1) Compound Obtained in Example 1 10.0 mg (2) Lactose 90.0 mg (3) Microcrystalline Cellulose 70.0 mg (4) Magnesium Stearate 10 0.0 mg The whole amount of the above (1), (2) and (3) was mixed with 5.0 mg of (4), and the mixture was granulated, and the remaining 5.0 mg of (4) was added to the mixture to form a whole gelatin capsule. Enclose in. Formulation Example 2 (Dose per tablet) (1) Compound obtained in Example 1 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5) Stearic acid Magnesium 2.0 mg 10.0 mg of the compound obtained in Example 4 and lactose 60.0
mg and corn starch 35.0 mg to a mixture of 10
Using 0.03 ml of a weight% gelatin aqueous solution (3.0 mg as gelatin), the mixture is granulated through a 1 mm mesh sieve, dried at 40 ° C. and filtered again. The obtained granules are mixed with 2.0 mg of magnesium stearate and compressed. The obtained central tablets are coated with a sugar coating of a suspension of sucrose, titanium dioxide, talc and gum arabic, and frosted with beeswax to give sugar-coated tablets. Formulation Example 3 (Dose per tablet) (1) Compound obtained in Example 1 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Solubilized starch 7.0 mg (5) Magnesium stearate 3.0 mg 10.0 mg of the compound obtained in Example 4 and 3.0 mg of magnesium stearate were added to an aqueous solution of solubilized starch.
Granulated with 07 ml (7.0 mg as solubilized starch), dried, lactose 70.0 mg and corn starch 5
Mix 0.0 mg. The mixture is compressed to give tablets.

Reference Formulation Example 1 (Dose per tablet) (1) Leuprorelin acetate 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Solubilized starch 7.0 mg (5) Magnesium stearate 3.0 mg Leuprorelin acetate 10.0 mg and magnesium stearate 3.0 mg Solubilized starch aqueous solution 0.07
After granulating with ml (7.0 mg as solubilized starch),
Dried, lactose 70.0 mg and corn starch 50.
Mix 0 mg. The mixture is compressed to give tablets. Formulation Example 4 The formulations obtained in Production Examples 1 to 3 and the formulation obtained in Reference Formulation Example 1 are combined.

Test Example 1 Selective Cancer Cell Growth Inhibitory Action HER2-expressing human breast cancer cells SK-BR-3 or BT-474 cell suspension 100 μl (2,000 cells) or human normal fibroblast MRC
-5 cell suspension (100 μl, 4,000 cells) was dispensed into a 96-well microplate and cultured at 37 ° C. in a 5% carbon dioxide gas incubator. Next day, 100 μl of 2-fold serially diluted test compound solution
Was added and the culture was carried out for 3 or 5 days. The cells were fixed with 5% glutaraldehyde solution, washed, and further fixed with 10% trichloroacetic acid solution, and then dye SRB 0.4% (W / V) solution (1%
(Dissolved in acetic acid) was added to stain cellular proteins. After removing the dye solution and washing with 1% acetic acid solution, 100 μl of extract (10 mM Tris buffer) was added to extract the dye, and the absorbance at an absorption wavelength of 550 nm was measured to calculate the cell amount as the protein amount. . The cell number of each treatment group was calculated as a percentage with respect to the cell number of the control group to which the compound solution was not added, and the compound concentration (IC ₅₀ value) giving 50% of the cell number of the control group was calculated. The results are shown in [Table 73]. The compound of the present invention showed a growth inhibitory effect on human breast cancer cell lines SK-BR-3 and BT-474 expressing HER2. On the other hand, no inhibitory effect was observed on normal cells. It was found that the compound of the present invention is a substance that selectively and strongly inhibits the growth of tumor cells, particularly cancer cells expressing HER2.

[Table 73]

Test Example 2 Antitumor Test 1 × 10 ⁷ human cancer cells BT-474 were suspended in Matrigel solution and subcutaneously transplanted into BALB / c female nude mice (5 weeks old). At the time of transplantation and 7 days after the transplantation, an estrogen preparation was intramuscularly administered to the hind legs for the purpose of increasing the tumor engraftment rate.
On the 14th day after transplantation, mice in which tumor engraftment was confirmed were selected and grouped into 5 mice per group. Gelucire solution (0.3 or 1 mg / mL) of the compound of the present invention was orally administered at a dose of 10 mL / kg twice a day for 14 days. The tumor diameter was measured on the administration start day and the administration end day, and the tumor volume was calculated by the formula: tumor volume = major axis x minor axis x minor axis x (1/2). Gel
The value obtained by subtracting the tumor volume at the start of administration from the tumor volume at the end of administration in the control group administered with ucire alone, and the value obtained by subtracting the tumor volume from the start of administration at the end of administration in the drug administration group Was calculated as T / C (%). The results are shown in [Table 74].
Shown in. The compound of the present invention is a HER2-expressing human cancer cell line BT-474.
The tumor growth was significantly and dose-dependently suppressed in the nude mouse transplant model. During the test period, no weight loss of mice was observed due to the administration of the compound of the present invention.

[Table 74]

Test Example 3: Receptor tyrosine of human breast cancer cells
Of phosphorylation of human breast cancer cells BT-474 cell suspension 500 μl (3
(10,000 cells) are seeded on a 24-well plate and cultured at 37 ° C. in a 5% carbon dioxide gas incubator. The next day, 500 μl of a 4-fold serially diluted test compound solution is added, and after 2 hours, an extract is added to stop the reaction and extract the protein. After fractionating this protein by the protein electrophoresis method, the protein in the electrophoresis gel is transferred to a nylon filter. This filter is reacted with a phosphorylated tyrosine-specific antibody, and the reaction product is fluorescently labeled and quantified by an image analyzer. HER2 tyrosine phosphorylation amount of cells in the untreated group was set to 100%, and HER of cells in the group to which each concentration of the test compound solution was added
The ratio of the phosphorylation amount of 2 tyrosine was calculated and
The compound concentration (IC ₅₀ value) required to suppress the phosphorylation amount of ER2 tyrosine to 50% of the control is calculated.

[0366]

EFFECT OF THE INVENTION The compound (V) of the present invention or a salt thereof or a prodrug thereof has an action of inhibiting tyrosine kinase and has low toxicity, and therefore, prevents or treats tyrosine kinase-dependent diseases in mammals. Can be used for. Tyrosine kinase-dependent diseases include diseases in which cell growth is promoted due to abnormal tyrosine kinase enzyme activity. Furthermore, the compound (V) of the present invention or a salt thereof or a prodrug thereof has an action of specifically inhibiting tyrosine kinase, and therefore, as a therapeutic agent for suppressing the growth of HER2-expressing cancer, or It is also very useful as a preventive agent for preventing the transition of hormone-dependent cancer to hormone-independent cancer. Similarly, the HER2 protein inhibitor containing the compound represented by the general formula (I) or the salt thereof or the prodrug thereof, which is the preparation of the present invention, is a therapeutic agent for suppressing the growth of HER2-expressing cancer. Alternatively, it is also very useful as a preventive agent for preventing the transition of hormone-dependent cancer to hormone-independent cancer.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/4545 A61K 31/4545 31/4709 31/4709 31/5377 31/5377 A61P 35/00 A61P 35 / 00 43/00 111 43/00 111 123 123 C07D 413/04 C07D 413/04 413/14 413/14 471/04 107 471/04 107K 107Z (72) Inventor Toshiya Tamura 239 No. 1 Takamatsu, Sakai City, Osaka Prefecture 403 (72) Inventor Shuichi Furuya 1-7-9 Kasuga, Tsukuba, Ibaraki Takeda Kasuga Heights No.603 F-term (reference) 4C056 AA01 AB01 AC02 AD03 AE03 AF05 CA02 CA03 CA05 CA06 CA08 CA09 CA11 CA12 CC01 CD02 CD03 CD05 CD06 4C063 AA01 AA03 BB01 CC62 CC75 CC76 CC92 CC94 DD14 DD52 EE01 4C065 AA04 BB06 CC01 DD03 EE02 HH02 HH03 HH04 HH07 JJ01 KK02 KK03 KK04 KK05 KK06 KK07 KK09 LL01 PP03 PP04 PP06 PP07 PP 09 PP10 PP12 PP13 PP16 PP17 PP18 PP19 QQ04 4C086 AA01 AA02 AA03 BC70 CB05 GA02 GA04 GA07 GA08 GA09 GA12 MA01 MA04 MA17 MA22 MA23 MA31 MA35 MA36 MA37 MA41 MA43 MA52 MA56 MA58 MA59 MA60 MA65 MA66 NA14 NA15 ZB26 ZC41

Claims (25)

[Claims] 1. A general formula (V): [In the formula, R ^1b represents a substituted C _6-10 aryl group, a substituted C _3-8 cycloalkyl group or an optionally substituted heterocyclic group, and Ta represents ^a single bond, C _1-6 alkyl _{group, -CH 2 O -, - OCH} 2 -, - CH 2 S-,
_{-SCH 2 -, - CH 2 -CH} 2 - or -CH = CH
-, X and Y are the same or different and each represents an optionally substituted nitrogen atom, oxygen atom or sulfur atom, a broken line represents a single bond or a double bond, and Z ^a represents a nitrogen atom or CH.
, W represents a single bond, an oxygen atom, a nitrogen atom or a sulfur atom, and Q represents an optionally substituted C _6-10 aryl group or an optionally substituted aromatic heterocyclic group. ] The compound or its salt represented by these. 2. A compound represented by the general formula (VI): [Wherein, R ^1c represents a substituted C _6-10 aryl group, a substituted C _3-8 cycloalkyl group or an optionally substituted heterocyclic group, and the substituted C _6-10 aryl group And the substituent of the substituted C _3-8 cycloalkyl group is a halogen atom, OH, CN, NO ₂ , N
H ₂ , NHCOR, NHCONHR, NHSO ₂ R, S
O ₂ R, COOH, COOR, CONHR, CON
H ₂ , CF ₃ , CF ₃ O, optionally substituted C
Optional from a _1-6 alkyl group, an optionally substituted C _1-6 alkoxy group, an optionally substituted C _1-6 alkoxy-carbonyl group and an optionally substituted C _1-4 alkylenedioxy group is 1 to 5 substituents selected in, R represents _{C 1-6} alkyl _group, a _{C 3-8} cycloalkyl group or _{C 6-10} aryl group, ^{T a} is a single bond, C
_1-6 alkyl _{group, -CH 2 O -, - OCH} 2 -, - C
_{H 2 S -, - SCH 2} -, - CH 2 -CH 2 - or -
CH = CH-, X ^a is an optionally substituted nitrogen atom, oxygen atom or sulfur atom, Y ^a is a nitrogen atom, oxygen atom or sulfur atom (provided that X ^a and Y ^a are the same or different. , Except for an oxygen atom or a sulfur atom), a broken line is a single bond or a double bond, Z ^a is a nitrogen atom or CH, W is a single bond, an oxygen atom, a nitrogen atom or a sulfur atom, and Q is a substituent. And C _6-10 aryl group which may be substituted or aromatic heterocyclic group which may be substituted, respectively. ] The compound or its salt represented by these. 3. The compound according to claim 1, wherein X or X ^a is an optionally substituted nitrogen atom. 4. The compound according to claim 1, wherein Y or Y ^a is a nitrogen atom. 5. The compound according to claim 1, wherein Z or Z ^a is a nitrogen atom. 6. The compound according to claim ¹ , wherein R ¹ , R ^1a , R ^1b or R ^1c is a substituted C _6-10 aryl group. 7. A compound represented by the general formula (VII): [In the formula, R ^1d represents an optionally substituted C _6-10 aryl group, an optionally substituted C _3-8 cycloalkyl group or an optionally substituted heterocyclic group, and ^Ta is a single group. Bond, C _1-6 alkyl group, —CH ₂ O—, —OCH
_{2 -, - CH 2 S -} , - SCH 2 -, - CH 2 -CH 2
-Or -CH = CH-, R ² is a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _6-10 aryl group or an optionally substituted C
_3-8 cycloalkyl group, W is a single bond, an oxygen atom, a nitrogen atom or a sulfur atom, and Q is an optionally substituted C
_{6-10 represents an} aryl group or an optionally substituted aromatic heterocyclic group. ] The compound or its salt represented by these. 8. A compound represented by the general formula (VIII): [In the formula, R ^1d represents an optionally substituted C _6-10 aryl group, an optionally substituted C _3-8 cycloalkyl group or an optionally substituted heterocyclic group, and ^Ta is a single group. Bond, C _1-6 alkyl group, —CH ₂ O—, —OCH
_{2 -, - CH 2 S -} , - SCH 2 -, - CH 2 -CH 2
-Or -CH = CH-, W is a single bond, an oxygen atom, a nitrogen atom or a sulfur atom, and Q is an optionally substituted C.
_{6-10 represents an} aryl group or an optionally substituted aromatic heterocyclic group. ] The compound or its salt represented by these. 9. General formula (IX): [In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a halogen atom, OH, CN or N.
O ₂ , NH ₂ , NHCOR, NHCONHR, NHSO
₂ R, SO ₂ R, COOH, COOR, CONHR, C
ONH ₂ , CF ₃ , CF ₃ O, optionally substituted C
_1-6 alkyl group, optionally substituted C _1-6 alkoxy group or optionally substituted C _1-6 alkoxy-carbonyl group, or optionally substituted C ₁ together with an adjacent group _-4 alkylenedioxy group, R represents _{a C 1-6} alkyl _group, a _{C 3-8} cycloalkyl group or _{C 6-10} aryl group, ^{T a} is a single bond, C
_1-6 alkyl _{group, -CH 2 O -, - OCH} 2 -, - C
_{H 2 S -, - SCH 2} -, - CH 2 -CH 2 - or -
CH = CH-, R ² is a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C
_6-10 aryl group or optionally substituted C
_{A 3-8} cycloalkyl group, W ^a represents a single bond or an oxygen atom, and Q represents an optionally substituted C _6-10 aryl group or an optionally substituted aromatic heterocyclic group. ] The compound or its salt represented by these. 10. A compound represented by the general formula (X): [In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a halogen atom, OH, CN or N.
O ₂ , NH ₂ , NHCOR, NHCONHR, NHSO
₂ R, SO ₂ R, COOH, COOR, CONHR, C
ONH ₂ , CF ₃ , CF ₃ O, optionally substituted C
_1-6 alkyl group, optionally substituted C _1-6 alkoxy group or optionally substituted C _1-6 alkoxy-carbonyl group, or optionally substituted C ₁ together with an adjacent group _-4 alkylenedioxy group, R represents _{a C 1-6} alkyl _group, a _{C 3-8} cycloalkyl group or _{C 6-10} aryl group, ^{T a} is a single bond, C
_1-6 alkyl _{group, -CH 2 O -, - OCH} 2 -, - C
_{H 2 S -, - SCH 2} -, - CH 2 -CH 2 - or -
CH = CH-, W ^a represents a single bond or an oxygen atom, Q represents a halogen atom, an optionally substituted C _6-10 aryl group or an optionally substituted aromatic heterocyclic group. However, when Q is a halogen atom, R ⁴
Or R ⁶ is not a hydrogen atom. ] The compound or its salt represented by these. 11. The method according to claim 9, wherein W ^a is a single bond.
The described compound or a salt thereof. 12. The method according to claim 9, wherein T ^a and W ^a are single bonds.
Alternatively, the compound according to 10 or a salt thereof. 13. The compound or a salt thereof according to claim 9 or 10, wherein R ⁴ or R ⁶ is a group other than a hydrogen atom. 14. A compound represented by the general formula (XI): [In the formula, R ^3a represents a hydrogen atom, a halogen atom, OH, C
N, NO ₂ , NH ₂ , NHCOR, NHCONHR, N
HSO ₂ R, SO ₂ R, COOH, COOR, CONH
R, CONH ₂ , CF ₃ , CF ₃ O, optionally substituted C _1-6 alkyl group, optionally substituted C _1-6
An alkoxy group or an optionally substituted C _1-6 alkoxy-carbonyl group, R is a C _1-6 alkyl group, C
_3-8 cycloalkyl group or a _{C 6-10} aryl group, ^{T a} is a single _{bond, C 1-6} alkyl, _-CH 2 O
_{-, - OCH 2 -, -} CH 2 S -, - SCH 2 -, - C
H ₂ —CH ₂ — or —CH═CH—, m is 1 to 3
An integer, R ⁸ is optionally substituted C _6-10 also be an aryl group, an optionally substituted C ₃ even though _-8 cycloalkyl group, or an optionally substituted heterocyclic group, Q is substituted Or an optionally substituted C _6-10 aryl group or an optionally substituted aromatic heterocyclic group] or a salt thereof. 15. Q ¹ , Q ² , Q ³ , Q ⁴ or Q is a substituted C _6-10 aryl group, and the substituted C
_15. The compound according to claim 1, wherein the substituent of the _6-10 aryl group is 1 to 5 groups arbitrarily selected from a halogen atom, an optionally substituted C1-6 alkyl group and a cyano group. Its salt. 16. A prodrug of the compound according to any one of claims 1 to 15. 17. A pharmaceutical composition containing the compound according to claim 1. 18. A compound represented by the general formula (I): [In the formula, R ¹ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and T is a single bond or optionally substituted, and has 1 or more hetero atoms. Optionally a divalent aliphatic hydrocarbon group, X and Y are the same or different, and an optionally substituted nitrogen atom, oxygen atom or sulfur atom, a broken line is a single bond or a double bond, and Z is Nitrogen atom or general formula (II) In the group represented by, W ¹ , W ² , W ³ and W ⁴ are the same or different and each is a single bond, an optionally substituted nitrogen atom, an oxygen atom, a sulfur atom or an optionally substituted 2
A valent aliphatic hydrocarbon group with Q ¹ , Q ² , Q ³ and Q ⁴
Are the same or different and each is a hydrogen atom, an optionally substituted alicyclic hydrocarbon group, an optionally substituted aromatic hydrocarbon group or an optionally substituted heterocyclic group (however,
At least one of Q ¹ , Q ² , Q ³ and Q ⁴ is not a hydrogen atom). ] HER2 containing the compound represented by or its salt, or its prodrug
Protein inhibitors. 19. The pharmaceutical composition according to claim 17, which is a HER2 protein inhibitor. 20. The pharmaceutical composition according to claim 17, which is a prophylactic / therapeutic agent for cancer. 21. The pharmaceutical composition according to claim 20, wherein the cancer is breast cancer, prostate cancer, lung cancer or pancreatic cancer. 22. A mammal according to any one of claims 1 to 16.
HER characterized by administering an effective amount of the described compound
2 Method of suppressing protein. 23. A mammal according to any one of claims 1 to 16.
A method for preventing or treating cancer, which comprises administering an effective amount of the described compound. 24. Use of the compound according to any one of claims 1 to 16 for producing a HER2 protein inhibitor. 25. Use of the compound according to any one of claims 1 to 16 for producing a prophylactic / therapeutic agent for cancer.