WO2011093365A1

WO2011093365A1 - Nitrogenated heterocyclic compound

Info

Publication number: WO2011093365A1
Application number: PCT/JP2011/051572
Authority: WO
Inventors: 潤一郎山本; 慶輔金原; 裕一福田; 宜資中里; 賢司内田; 知之西川
Original assignee: 協和発酵キリン株式会社
Priority date: 2010-01-27
Filing date: 2011-01-27
Publication date: 2011-08-04

Abstract

A nitrogenated heterocyclic ring compound represented by formula (I) [wherein Z represents a monocyclic nitrogenated aliphatic heterocyclic group which may have a substituent, or the like; G¹ represents a nitrogen atom, N⁺-O^-, or CR⁵ (wherein R⁵ represents a hydrogen atom, or the like); G² represents a nitrogen atom, or N⁺-O^-; Ar represents an aromatic carbocyclic ring, or the like; m represents an integer of 0 to 8, wherein R¹'s may be the same as or different from each other when m represents an integer of 2 to 8; R¹ represents -OR^15a1 (wherein R^15a1 represents a hydrogen atom, a lower alkyl group which may have a substituent, or the like), or the like; R² and R³ may be the same as or different from each other and independently represent a hydrogen atom, a lower alkyl group which may have a substituent, or the like; n represents an integer of 0 to 4, wherein R⁴'s may be the same as or different from each other when n is 2, 3 or 4; and R⁴ represents a halogen atom, a lower alkyl group which may have a substituent, or the like] or a pharmaceutically acceptable salt or the like thereof, which has an anti-tumor activity.

Description

Nitrogen-containing heterocyclic compounds

The present invention relates to a nitrogen-containing heterocyclic compound having antitumor activity or a pharmaceutically acceptable salt thereof.

In cancer chemotherapy, various types of antitumor agents such as microtubule agonists such as taxanes and vinca alkaloids, topoisomerase inhibitors, alkylating agents and the like are used. However, these have problems such as side effects such as bone marrow toxicity and neuropathy and emergence of resistance, and new antitumor agents that have improved these are always in demand.
On the other hand, kinase modulators having a quinoline structure (Patent Document 1), kinase inhibitors (Patent Document 2), UV-decomposing compounds (Patent Document 3), heat shock protein 90 inhibitors (Patent Document 6), ion channel modulators (Patent Document 1) Reference 7) is known. Further, a PKB inhibitor having a quinoxaline structure (Patent Document 4) and a photostable optical filter containing a quinoxaline derivative (Patent Document 5) are known. A derivative having a phenyl group at the 2-position of quinoxaline (Patent Document 8, Non-Patent Document 1) is known.

International Publication No. 2005/087742 Pamphlet International Publication No. 2004/080463 Pamphlet JP 2006-213615 International Publication No. 2005/007099 Pamphlet International Publication No. 2001/068047 Pamphlet International Publication No. 2010/042489 Pamphlet International Publication No. 2010/056865 Pamphlet International Publication No. 2010/093808 Pamphlet

An object of the present invention is to provide a nitrogen-containing heterocyclic compound having antitumor activity or a pharmaceutically acceptable salt thereof.

The present invention relates to the following (1) to (63).
(1) Formula (I)

[In the formula, Z represents a monocyclic nitrogen-containing aliphatic heterocyclic group which may have a substituent, a bridged nitrogen-containing aliphatic heterocyclic group which may have a substituent, or a substituent. A monocyclic nitrogen-containing aliphatic heterocyclic group, a bridged nitrogen-containing aliphatic heterocyclic group, or a condensed nitrogen-containing aliphatic heterocyclic group. The group is attached to the adjacent carbon atom at its nitrogen atom;
G ¹ is nitrogen atom, N ⁺ -O ^- or in CR ⁵ {wherein, R ⁵ is a hydrogen atom, a halogen, cyano, carbamoyl, optionally substituted lower alkyl, which may have a substituent Good lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted lower alkanoyl, optionally substituted lower Alkylthio, optionally substituted lower alkylsulfonyl, optionally substituted aryl, —NR ^6a R ^6b (wherein R ^6a and R ^6b are the same or different and are a hydrogen atom, substituted A lower alkylsulfonyl which may have a group, a lower alkyl which may have a substituent, a lower alkoxycarbonyl which may have a substituent, or a lower alkanoyl which may have a substituent. Represent or R ^6a and R ^{6 b} forms a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom) or -OR ⁷ (wherein R ⁷ has a hydrogen atom or a substituent, Lower alkyl, which may have a substituent, cycloalkyl which may have a substituent, lower alkanoyl which may have a substituent, lower alkylsulfonyl which may have a substituent, which may have a substituent A good aliphatic heterocyclic group, an optionally substituted aromatic heterocyclic group, or -CONR ^8a R ^8b (wherein R ^8a and R ^8b are the same or different and represent a hydrogen atom, a substituent, The lower alkylsulfonyl which may have, the lower alkyl which may have a substituent, or the lower alkanoyl which may have a substituent, or R ^8a and R ^{8b and the} adjacent nitrogen atom Together form a nitrogen-containing heterocyclic group which may have a substituent) Represents]},

G ² is a nitrogen atom or N ⁺ -O ^- represents,
Ar represents an aromatic carbocycle or an aromatic heterocycle,
m represents an integer of 0 to 8, and when m represents an integer of 2 to 8, each R ¹ may be the same or different,
R ¹ is cyano, carboxy, halogen, nitro, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted. Optionally substituted cycloalkyl, optionally substituted lower alkanoyl, optionally substituted lower alkylthio, optionally substituted lower alkoxycarbonyl, optionally substituted. Aryl which may have a substituent, aroyl which may have a substituent, arylsulfonyl which may have a substituent, lower alkylsulfonyl which may have a substituent, those aliphatic heterocyclic group, the substituent aromatic heterocyclic group which may have a, -NR ^14a1 R ^14b1 (wherein, R ^14a1 and R ^14b1 are respectively the same as the aforementioned R ^6a and R ^6b) , -OR ^15a1 (in the formula, R ^15a1 before Represents R ⁷ as synonymous) or -CONR ^16a1 R ^16b1 (wherein, R ^16a1 and R ^16b1 are respectively the same as the aforementioned R ^8a and R ^8b),
R ² and R ³ are the same or different and each has a hydrogen atom, cyano, carboxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, or optionally substituted. Lower alkynyl, optionally substituted cycloalkyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxycarbonyl or —CONR ^9a R ^9b (wherein , R ^9a and R ^9b are the same or different and each represents a hydrogen atom or a lower alkyl optionally having substituent (s).

n represents an integer of 0 to 4, and when n is 2, 3 or 4, each R ⁴ may be the same or different,
R ⁴ has halogen, cyano, nitro, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted. Cycloalkyl which may have a substituent, lower alkanoyl which may have a substituent, lower alkylsulfonyl which may have a substituent, lower alkoxycarbonyl which may have a substituent, a substituent An aromatic heterocyclic group which may have, —NR ^10a R ^10b (wherein R ^10a and R ^10b are the same or different and each is a hydrogen atom, optionally substituted lower alkylsulfonyl, substituted Represents a lower alkyl which may have a group, or a lower alkanoyl which may have a substituent, or R ^10a and R ^10b together represent a diphenylmethylene which may have a substituent. next carded or R ^10a and R ^10b, is Nitrogen atom and together form a nitrogen-containing heterocyclic group which may have a substituent) which, - OR ¹¹ (wherein, R ¹¹ which may have a hydrogen atom, an optionally substituted lower Alkyl, cycloalkyl which may have a substituent, lower alkanoyl which may have a substituent, lower alkylsulfonyl which may have a substituent, aryl which may have a substituent, An aliphatic heterocyclic group which may have a substituent, or an aromatic heterocyclic group which may have a substituent, or -CONR ^12a R ^12b (wherein R ^12a and R ^12b are The same or different, a hydrogen atom, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkylsulfonyl, having a substituent Aryl which may be substituted, aromatic heterocyclic group which may have substituent or Or represents optionally substituted lower alkanoyl which may have a substituent, or R ^12a and R ^12b form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom) the Or a pharmaceutically acceptable salt thereof.

(2) The nitrogen-containing heterocyclic compound according to (1) or a pharmaceutically acceptable salt thereof, wherein G ¹ is CR ⁵ , R ⁵ is a hydrogen atom, halogen or cyano, and G ² is a nitrogen atom salt.
(3) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (1), wherein G ¹ and G ² are nitrogen atoms.
(4) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (1), wherein G ¹ is N ⁺ —O ² ^— and G ² is a nitrogen atom.
(5) R ² and R ³ are the same or different and each has a hydrogen atom, cyano, optionally substituted lower alkyl, optionally substituted lower alkenyl, or optionally substituted. The nitrogen-containing heterocycle according to any one of the above (1) to (4), which is an optionally substituted lower alkynyl, an optionally substituted cycloalkyl, or an optionally substituted lower alkanoyl A compound or a pharmaceutically acceptable salt thereof.

(6) The device according to any one of (1) to (5), wherein n is 1, and R ⁴ is —NR ^10a R ^10b (wherein R ^10a and R ^10b are as defined above). A nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof.
(7) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (6), wherein R ^10a and R ^10b are hydrogen atoms.
(8) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (7), wherein Ar is a benzene ring.
(9) Ar- (R ¹ ) _m is

(Wherein R ^1a and R ^1b are the same or different and each represents an optionally substituted lower alkoxy, and R ^1c represents cyano, an optionally substituted lower alkoxy or a substituent. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (7), which represents an aromatic heterocyclic group which may be present.
(10) Z is

(Wherein p represents 1 or 2,
R ¹⁷ represents a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted lower alkenyl, an optionally substituted lower alkynyl or cycloalkyl. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (9).
(11) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (10), wherein p is 2.
(12) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to (10) or (11), wherein R ¹⁷ is lower alkyl.
(13) Formula (IA)

Wherein, R ^4A and Z ^A are respectively the same as the aforementioned R ⁴ and Z,
mA represents an integer of 0 to 5, and when mA is 2, 3, 4 or 5, each R ^13A may be the same or different,
nA represents an integer of 0 to 4, and when nA is 2, 3 or 4, each R ^4A may be the same or different,
R ^2A and R ^3A may be the same or different and each may have a hydrogen atom, cyano, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted. Represents lower alkynyl, or optionally substituted cycloalkyl,
R ^13A represents cyano, carboxy, halogen, nitro, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, and optionally substituted. Cycloalkyl optionally having, lower alkanoyl optionally having substituent, lower alkoxycarbonyl optionally having substituent, aryl optionally having substituent, having substituent Aroyl, which may have a substituent, arylsulfonyl which may have a substituent, lower alkylsulfonyl which may have a substituent, an aliphatic heterocyclic group which may have a substituent, and a substituent. An aromatic heterocyclic group that may be substituted, —NR ^14a R ^14b (wherein R ^14a and R ^14b have the same ^{meanings as} R ^6a and R ^6b , respectively), —OR ^15a (wherein R ^15a is the same as defined above) R ⁷ synonymous) or -CONR ^16a R ^16b (wherein, R ^{16 a} and R ^16b represent the same as R ^8a and R ^8b , respectively,] or a pharmaceutically acceptable salt thereof.

(14) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to (13), wherein R ^2A is a hydrogen atom.
(15) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (13) or (14), wherein R ^3A is a hydrogen atom.
(16) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (13) to (15), wherein nA is 1.
(17) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of the above (13) to (15), wherein nA is 1 and R ^4A is bonded to the 6-position of quinoxaline.
(18) The nitrogen-containing heterocyclic compound according to any one of (13) to (17) above, wherein R ^4A is —NR ^10a R ^10b (wherein R ^10a and R ^10b are as defined above) Its pharmaceutically acceptable salt.
(19) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (18), wherein R ^10a and R ^10b are hydrogen atoms.
(20) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (13) to (15), wherein nA is 0.
(21) Z ^A

(Wherein p and R ¹⁷ are the same as defined above), or the nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (13) to (20).
(22) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (21), wherein p is 2.
(23) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to (21) or (22), wherein R ¹⁷ is lower alkyl.
(24) Z ^A is

(Wherein R ^17A represents lower alkyl, and R ^19A represents a hydrogen atom or hydroxy) or the nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (13) to (20) above Salt.
(25) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (24), wherein R ^17A is methyl and R ^19A is a hydrogen atom.
(26) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (24), wherein R ^17A is methyl and R ^19A is hydroxy.
(27)

(Wherein R ^13A and mA are the same as defined above)

(In the formula, R ^13A1 represents an optionally substituted lower alkoxy, R ^13A2 represents a hydrogen atom or an optionally substituted lower alkoxy, R ^13A3 represents a hydrogen atom, cyano, substituted A nitrogen-containing heterocyclic compound according to any one of (13) to (26) above, which represents a lower alkoxy which may have a group or an aromatic heterocyclic group which may have a substituent) Its pharmaceutically acceptable salt.
(28) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (27), wherein R ^13A1 and R ^13A2 are the same or different and are lower alkoxy, and R ^13A3 is cyano.
(29) The nitrogen-containing heterocyclic compound according to (27) above, wherein R ^13A1 and R ^13A2 are the same or different and are lower alkoxy, and R ^13A3 is an aromatic heterocyclic group which may have a substituent, or A pharmaceutically acceptable salt.
(30) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (27), wherein R ^13A3 is a monocyclic 5-membered aromatic heterocyclic group which may have a substituent.
(31) Formula (IB)

(Wherein R ^2B , R ^3B , R ^4B , R ^13B and Z ^B are the same as R ^2A , R ^3A , R ⁴ , R ^13A and Z, respectively,
mB represents an integer of 0 to 5, and when mB is 2, 3, 4 or 5, each R ^13B may be the same or different,
nB represents an integer of 0 to 4, and when nB is 2, 3 or 4, each R ^4B may be the same or different) or a pharmaceutically acceptable compound thereof Salt.
(32) nB is 1, R ^4B is halogen, cyano or —NR ^10a R ^10b (wherein R ^10a and R ^10b are as defined above), and R ^4B is at the 8-position of quinoxaline The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (31), which is bound.
(33) nB is 1, R ^4B is halogen, cyano or —NR ^10a R ^10b (wherein R ^10a and R ^10b are as defined above), and R ^4B is at the 6-position of quinoxaline The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (31), which is bound.
(34) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to (32) or (33), wherein R ^4B is amino.
(35) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (31) to (34), wherein R ^2B and R ^3B are hydrogen atoms.
(36) Z ^B is

(Wherein p and R ¹⁷ have the same meanings as described above), or the nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (31) to (35).
(37) Z ^B is

(Wherein R ^17B represents lower alkyl, and R ^19B represents a hydrogen atom or hydroxy) or the nitrogen-containing heterocyclic compound according to any one of the above (31) to (35) or a pharmaceutically acceptable salt thereof Salt.
(38) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (37), wherein R ^17B is methyl and R ^19B is a hydrogen atom.
(39) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (37), wherein R ^17B is methyl and R ^19B is hydroxy.
(40)

Wherein R ^13B and mB are as defined above.

(Wherein, R ^13B1 represents an lower alkoxy which may have a substituent, R ^13B2 represents a hydrogen atom or a lower alkoxy which may have a substituent, R ^13B3 is a hydrogen atom, cyano, substituted Or a nitrogen-containing heterocyclic compound according to any one of (31) to (39) above, which represents a lower alkoxy which may have a group or an aromatic heterocyclic group which may have a substituent) Its pharmaceutically acceptable salt.
(41) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (40), wherein R ^13B1 and R ^13B2 are the same or different and are lower alkoxy, and R ^13B3 is cyano.
(42) The nitrogen-containing heterocyclic compound according to (40) above, wherein R ^13B1 and R ^13B2 are the same or different and are lower alkoxy, and R ^13B3 is an aromatic heterocyclic group which may have a substituent, or A pharmaceutically acceptable salt.
(43) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to (40), wherein R ^13B3 is a monocyclic 5-membered aromatic heterocyclic group which may have a substituent.
(44) Formula (IC)

[Wherein R ^2C , R ^3C , R ^4C , R ^13C and Z ^C are the same as R ^2A , R ^3A , R ⁴ , R ^13A and Z, respectively,
mC represents an integer of 0 to 5, and when mC is 2, 3, 4 or 5, each R ^13C may be the same or different,
nC represents an integer of 0 to 4, and when nC is 2, 3 or 4, each R ^4C may be the same or different,
R ^5C is a hydrogen atom, halogen, cyano, carbamoyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, substituent Cycloalkyl optionally having substituent (s), lower alkylthio optionally having substituent (s), lower alkylsulfonyl optionally having substituent (s), or -OR ¹⁸ (wherein R ¹⁸ represents R ⁷ and The nitrogen-containing heterocyclic compound represented by the above or a pharmaceutically acceptable salt thereof.

(45) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (44), wherein R ^2C and R ^3C are hydrogen atoms.
(46) nC is 1, R ^4C is halogen, cyano or —NR ^10a R ^10b (wherein R ^10a and R ^10b are as defined above), and R ^4C is at the 7-position of the quinoline The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (44) or (45), which binds thereto.
(47) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (44) to (46), wherein R ^4C is amino.
(48) R ^5C is a hydrogen atom, cyano, or —OR ^18a (wherein R ^18a represents a hydrogen atom, optionally substituted lower alkyl, or optionally substituted cycloalkyl. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (44) to (47).
(49) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (44) to (47), wherein R ^5C is —OR ^18a (wherein R ^18a has the same meaning as described above). Salt.
(50) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (44) to (47), wherein R ^5C is halogen.
(51) Z ^C

(Wherein p and R ¹⁷ are as defined above) or the nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (44) to (50).
(52) Z ^C

(Wherein R ^17C represents lower alkyl, and R ^19C represents a hydrogen atom or hydroxy) or the nitrogen-containing heterocyclic compound according to any one of the above (44) to (50) or a pharmaceutically acceptable salt thereof Salt.
(53) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (52), wherein R ^17C is methyl and R ^19C is a hydrogen atom.
(54) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (52), wherein R ^17C is methyl and R ^19C is hydroxy.
(55)

Wherein R ^13C and mC are as defined above.

(In the formula, R ^13C1 represents an optionally substituted lower alkoxy, R ^13C2 represents a hydrogen atom or an optionally substituted lower alkoxy, R ^13C3 represents a hydrogen atom, cyano, substituted Or a nitrogen-containing heterocyclic compound according to any one of the above (44) to (54), which represents a lower alkoxy which may have a group or an aromatic heterocyclic group which may have a substituent) Its pharmaceutically acceptable salt.
(56) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to (55), wherein R ^13C1 and R ^13C2 are the same or different and are lower alkoxy, and R ^13C3 is cyano.
(57) The nitrogen-containing heterocyclic compound according to the above (55), wherein R ^13C1 and R ^13C2 are the same or different and are lower alkoxy, and R ^13C3 is an optionally substituted aromatic heterocyclic group, or a compound thereof A pharmaceutically acceptable salt.

(58) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (55), wherein R ^13C3 is a monocyclic 5-membered aromatic heterocyclic group which may have a substituent.
(59) A medicament comprising the nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (58) as an active ingredient.
(60) An antitumor agent comprising the nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (58) as an active ingredient.
(61) A method for treating a tumor, comprising a step of administering an effective amount of the nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (58).
(62) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (58) for use in the treatment of tumors.
(63) Use of the nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (58) for the manufacture of an antitumor agent.

The present invention provides a nitrogen-containing heterocyclic compound having antitumor activity or a pharmaceutically acceptable salt thereof.

Hereinafter, the compounds represented by the formulas (I), (IA), (IB) and (IC) are referred to as compounds (I), (IA), (IB) and (IC), respectively. The same applies to the compounds of other formula numbers.
In the definition of each group of formula (I), (IA), (IB) and (IC)
(I) Examples of the lower alkyl in lower alkyl and lower alkylthio, lower alkylsulfonyl, lower alkanoyl and lower alkoxycarbonyl include linear or branched alkyl having 1 to 10 carbon atoms. Specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
(Ii) Examples of lower alkenyl include linear or branched alkenyl having 2 to 10 carbon atoms. Specific examples include vinyl, allyl, 1-propenyl, isopropenyl, methacryl, butenyl, crotyl, pentenyl, hexenyl, heptenyl, decenyl and the like.
(Iii) Examples of lower alkynyl include linear or branched alkynyl having 2 to 10 carbon atoms. Specific examples include ethynyl, propargyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like.

(Iv) Examples of cycloalkyl include cyclic alkyl having 3 to 10 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
Examples of (v) aryl and the aryl moiety of arylsulfonyl and aroyl include aryl having 6 to 14 carbon atoms. Specific examples include phenyl, naphthyl, indenyl, anthryl and the like. In addition, examples of the aromatic carbocycle include aromatic carbocycles corresponding to these aryls.

(Vi) Examples of the aliphatic heterocyclic group include a 3- to 8-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and a 3- to 8-membered ring. And a condensed cyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically, aziridinyl, azetidinyl, Pyrrolidinyl, piperidino, piperidyl, azepanyl, 1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 5,6-dihydro-2H- Pyranyl, tetrahydrothiopyranyl, oxazolidinyl, morpholino, morpholinyl, thioxazolidinyl, thiomorphol Lino, thiomorpholinyl, 2H-oxazolyl, 2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, benzimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, benzodioxolinyl, Tetrahydroquinolyl, tetrahydroisoquinolyl, dihydro-2H-chromanyl, dihydro-1H-chromanyl, dihydro-2H-thiochromanyl, dihydro-1H-thiochromanyl, tetrahydroquinoxalinyl, tetrahydroquinazolinyl, dihydrobenzodioxanyl, Dihydroquinolyl, dihydroisoquinolyl, dihydrodibenzazepinyl and the like can be mentioned.

(Vii) The monocyclic nitrogen-containing aliphatic heterocyclic group includes a 3- to 8-membered monocyclic nitrogen-containing aliphatic heterocyclic group containing at least one nitrogen atom, and the monocyclic nitrogen-containing aliphatic group The group heterocyclic group may further have another hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom in the ring. Specific examples include aziridinyl, azetidinyl, pyrrolidinyl, piperidino, azepanyl, 1,2,5,6-tetrahydropyridyl, piperazinyl, homopiperazinyl, morpholino, thiomorpholino and the like.
(Viii) The condensed nitrogen-containing aliphatic heterocyclic group includes a 3- to 8-membered monocyclic nitrogen-containing aliphatic heterocyclic group containing at least one nitrogen atom (the monocyclic nitrogen-containing aliphatic heterocyclic group). Group may further have another nitrogen atom, oxygen atom, sulfur atom or other hetero atom in its ring), but 1 or 2 aliphatic carbocycle, aliphatic heterocycle, aromatic carbocycle or And a group condensed with an aromatic heterocycle. Specifically, dihydroindolyl, dihydroisoindolyl, dihydrobenzothioxazolyl, benzodioxolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroquinoxalinyl, tetrahydroquinazolinyl, dihydroquinolyl , Dihydroisoquinolyl, dihydrodibenzazepinyl and the like.
(Ix) The bridged nitrogen-containing aliphatic heterocyclic group includes a bridged nitrogen-containing aliphatic cyclic group containing at least one nitrogen atom, specifically, diazabicyclononanyl and the like.

(X) As the aromatic heterocyclic group, for example, a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, Examples thereof include a condensed bicyclic or tricyclic ring-condensed aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. Specifically pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxopyridazinyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, pyrrolyl, pyrazolyl, imidazolyl, triazinyl, triazolyl, tetrazolyl, thienyl, furyl, thialyl, Isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, indolyl, isoindolyl, indazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzoimidazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, pyrazolopyridyl, pyrazolopyrimidinyl, purinyl, dibenzo Furanyl, dibenzoazepinyl and the like can be mentioned. Examples of the aromatic heterocycle include aromatic heterocycles corresponding to these aromatic heterocycle groups.

Examples of the (xi) monocyclic 5-membered aromatic heterocyclic group include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl and the like.
(Xii) Examples of the nitrogen-containing heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group). The ring group may contain other nitrogen, oxygen or sulfur atoms), a bicyclic or tricyclic condensed 3- to 8-membered ring and containing at least one nitrogen atom. Ring group (the condensed heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and more specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, azepanyl, pyrrolyl , Imidazolidinyl, imidazolyl, pyrazolidinyl, pyrazolyl, piperazinyl, homopiperazinyl, oxazolidinyl, 2H-oxazolyl, thioxazolidinyl, 2H-thioxazolyl, morpholino, thiomorpholino, Hydroindolyl, dihydroisoindolyl, indolyl, isoindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, benzimidazolidinyl, benzoimidazolyl, dihydroindazolyl, indazolyl, benzo Examples include triazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl and the like.
(Xiii) Halogen means each atom of fluorine, chlorine, bromine and iodine.

(Xiv) Lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkynyl optionally having substituent, lower alkoxy optionally having substituent A lower alkoxycarbonyl optionally having a substituent, a lower alkanoyl optionally having a substituent, a lower alkylthio optionally having a substituent, and a lower alkyl optionally having a substituent Examples of the substituent in sulfonyl are the same or different, and examples thereof include halogen having 1 to 3 substituents, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, N-lower alkylcarbamoyl, N, N-dilower alkylcarbamoyl, cycloalkyl , Aryl which may have a substituent, aliphatic heterocyclic group which may have a substituent, aromatic which may have a substituent Heterocyclic group, optionally substituted lower alkoxy which may have a substituent, cycloalkoxy, in aryloxy, lower alkanoyloxy, aroyloxy, lower alkylthio, lower alkylsulfonyloxy, arylsulfonyloxy, -NR ^X1 R ^Y1 (wherein, R ^X1 and R ^Y1 are the same or different and have a hydrogen atom, optionally substituted lower alkyl, lower alkylsulfonyl, cycloalkyl, aryl, aromatic heterocyclic group, lower alkanoyl, aroyl or substituent. And lower alkanoyl, aroyl, lower alkoxycarbonyl, aryloxycarbonyl and the like.

The substituents in the aryl which may have a substituent shown here, the aliphatic heterocyclic group which may have a substituent and the aromatic heterocyclic group which may have a substituent (xiv- 1) is the same or different, for example, halogen having 1 to 3 substituents; lower alkyl; lower alkoxy; lower alkoxycarbonyl; N-lower alkylcarbamoyl; N, N-dilower alkylcarbamoyl; lower alkanoyl; Cyano; oxo; hydroxy; aryl and the like.

The substituent (xiv-2) in the lower alkyl optionally having substituent, the lower alkoxycarbonyl optionally having substituent, and the lower alkoxy optionally having substituent may be as follows: , The same or different, for example, a halogen having 1 to 3 substituents; lower alkoxy; lower alkoxycarbonyl; N-lower alkylcarbamoyl; N, N-dilower alkylcarbamoyl; lower alkanoyl; carboxy; cyano; hydroxy; Can be mentioned.
(Xv) aryl which may have a substituent, aroyl which may have a substituent, arylsulfonyl which may have a substituent, aromatic heterocycle which may have a substituent The substituents in the group, diphenylmethylene which may have a substituent, and monocyclic 5-membered aromatic heterocyclic group which may have a substituent are the same or different, for example, the number of substitutions is 1. ~ 3 halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, optionally substituted lower alkyl, cycloalkyl, optionally substituted aliphatic heterocyclic group, aryl, substituted Aromatic heterocyclic group optionally having a group, aromatic heterocyclic oxy, optionally substituted lower alkoxy, cycloalkoxy, aryloxy, lower alkanoyloxy, aroyloxy Shi, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyloxy, -NR ^X2 R ^Y2 (wherein, R ^X2 and R ^Y2 are each synonymous with the R ^X1 and R ^Y1), lower alkanoyl, aroyl, lower alkoxycarbonyl Aryloxycarbonyl, N-lower alkylcarbamoyl, N, N-dilower alkylcarbamoyl and the like. The aromatic heterocyclic group which may have a substituent and the monocyclic 5-membered aromatic heterocyclic group which may have a substituent are oxadiazolyl which may have a substituent. In that case, the substituent may be oxo.

The substituent (xv-1) in the lower alkoxy which may have a substituent shown here is the same or different, for example, halogen, cyano, lower alkoxy, lower alkoxycarbonyl having 1 to 3 substituents, Examples thereof include aryl optionally having a substituent. Examples of the substituent (xv-1-1) in the substituted aryl include halogen; lower alkyl; lower alkoxy; lower alkoxycarbonyl; N-lower alkylcarbamoyl; N, N-dilower alkylcarbamoyl; lower alkanoyl; carboxy; Oxo; hydroxy; aryl and the like.

The substituent (xv-2) in the lower alkyl which may have a substituent shown here is the same or different, and examples thereof include hydroxy having 1 to 3 substituents, halogen, cyano, lower alkoxy and the like. .
The substituent (xv-3) in the aliphatic heterocyclic group which may have a substituent shown here is the same or different, and examples thereof include oxo having 1 to 3 substituents and lower alkyl.

The substituents (xv-4) in the aromatic heterocyclic group which may have a substituent shown here are the same or different, for example, oxo, lower alkyl, cyano lower alkyl having 1 to 3 substituents, Examples include lower alkoxy lower alkyl, cycloalkyl, carbamoyl, N-lower alkylcarbamoyl, N, N-dilower alkylcarbamoyl and the like.
(Xvi) a cycloalkyl optionally having a substituent, an aliphatic heterocyclic group optionally having a substituent, a monocyclic nitrogen-containing aliphatic heterocyclic group optionally having a substituent, Formed together with a condensed nitrogen-containing aliphatic heterocyclic group which may have a substituent, a bridged nitrogen-containing aliphatic heterocyclic group which may have a substituent, and an adjacent nitrogen atom The substituents in the nitrogen-containing heterocyclic group optionally having substituents are the same or different, for example, oxo, halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl having 1 to 3 substituents, Lower alkyl optionally having a substituent [substituents in the substituted lower alkyl include the substituents mentioned in (xiv) above], lower alkenyl optionally having a substituent [the Substitution in substituted lower alkenyl As the substituents mentioned in the above (xiv)], lower alkynyl optionally having a substituent [the substituents in the substituted lower alkynyl include the substituents mentioned in the above (xiv), etc. Cycloalkyl, aryl, aliphatic heterocyclic group, aromatic heterocyclic group, optionally substituted lower alkoxy, cycloalkoxy, aryloxy, lower alkanoyloxy, aroyloxy, lower alkylthio, lower Alkylsulfonyl, —NR ^X3 R ^Y3 (wherein R ^X3 and R ^Y3 have the same ^{meanings as} R ^X1 and R ^Y1 ), lower alkanoyl, aroyl, lower alkoxycarbonyl, aryloxycarbonyl, N-lower alkylcarbamoyl, N, N-dilower alkylcarbamoyl and the like can be mentioned.

The substituent (xvi-1) in the lower alkoxy which may have a substituent shown here is the same or different, for example, an aryl having a substituent having 1 to 3 substituents. Etc. Examples of the substituent (xvi-1-1) in the substituted aryl include the substituents mentioned in the above (xv-1-1).
Lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkoxy lower alkyl, lower alkanoyl, lower alkanoyloxy, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyloxy, N-lower alkylcarbamoyl represented by the above (xiv) to (xvi) Examples of the lower alkyl moiety of N, N-di-lower alkylcarbamoyl include the groups exemplified in the above-mentioned (i) lower alkyl. The two lower alkyls in N, N-dilower alkylcarbamoyl may be the same or different.

The alkylene part in cyano lower alkyl and lower alkoxy lower alkyl has the same meaning as that obtained by removing one hydrogen atom from the group exemplified in the above-mentioned (i) lower alkyl.
Examples of the cycloalkyl part of cycloalkyl and cycloalkoxy include the groups exemplified in the above-mentioned (iv) cycloalkyl.
Examples of the aryl moiety of aryl, aryloxy, aroyl, arylsulfonyloxy, aroyloxy and aryloxycarbonyl include the groups exemplified in the above-mentioned (v) aryl.

Examples of the aliphatic heterocyclic group, the aromatic heterocyclic group, the aromatic heterocyclic group portion of the aromatic heterocyclic oxy, and the halogen include (vi) the aliphatic heterocyclic group and (x) the aromatic heterocyclic ring, respectively. And the groups mentioned in the examples of (xiii) halogen.
In compound (I), G ² is preferably a nitrogen atom, and Z is preferably a monocyclic nitrogen-containing aliphatic heterocyclic group,

(Wherein p and R ¹⁷ are each as defined above), Ar is preferably an aromatic carbocycle, more preferably a benzene ring, m is preferably ¹ , 2 or 3, and R ¹ is Is —OR ^15a1 (wherein R ^15a1 has the same ^{meaning as} described above), cyano or an optionally substituted aromatic heterocyclic group, preferably lower alkoxy, cyano or substituted A preferable monocyclic 5-membered aromatic heterocyclic group is more preferable, and R ² and R ³ are preferably the same or different lower alkyl optionally having a hydrogen atom or a substituent, and n is 0 or 1 is preferable, and R ⁴ is preferably lower alkyl which may have a substituent or —NR ^10a R ^10b (wherein R ^10a and R ^10b are as defined above), and G ¹ is CR ⁵ R ⁵ is a hydrogen atom, halogen, cyano, lower alkyl. , Lower alkylthio or carbamoyl is preferred, and a hydrogen atom is more preferred.

In compound (IA), Z ^A is preferably a monocyclic nitrogen-containing aliphatic heterocyclic group,

(Wherein, p and R ¹⁷ are as defined above),

(Wherein R ^17A and R ^19A are as defined above), mA is preferably 1, 2 or 3, nA is preferably 0 or 1, and R ^2A and R ^3A are the same. Alternatively, a lower alkyl optionally having a hydrogen atom or a substituent is preferable, and R ^4A may be a lower alkyl optionally having a substituent or —NR ^10a R ^10b (wherein R ^10a and R ^10b ^Are preferably the same as defined above, more preferably amino, and R ^13A is —OR ^15a (wherein R ^15a is as defined above) or an aromatic heterocyclic ring optionally having substituent (s) Group is preferable, and lower alkoxy or a monocyclic 5-membered aromatic heterocyclic group which may have a substituent is more preferable.

In the compound (IB), Z ^B is preferably a monocyclic nitrogen-containing aliphatic heterocyclic group,

(Wherein, p and R ¹⁷ are as defined above),

(Wherein R ^17B and R ^19B are as defined above), mB is preferably 1, nB is preferably 0 or 1, and R ^2B and R ^3B are the same or different and hydrogen. A lower alkyl optionally having an atom or a substituent is preferred, R ^4B is preferably a lower alkyl optionally having a substituent, and R ^13B is —OR ^15a (wherein R ^15a is as defined above. Or an aromatic heterocyclic group which may have a substituent, and a monocyclic 5-membered aromatic heterocyclic group which may have a lower alkoxy or a substituent is more preferable.

In the compound (IC), Z ^C is preferably a monocyclic nitrogen-containing aliphatic heterocyclic group,

(Wherein, p and R ¹⁷ are as defined above),

(Wherein R ^17C and R ^19C are the same as defined above), mC is preferably 1, nC is preferably 0 or 1, and R ^2C and R ^3C are the same or different and hydrogen. A lower alkyl optionally having an atom or a substituent is preferred, R ^4C is preferably a lower alkyl optionally having a substituent, R ^5C is preferably a hydrogen atom, and R ^13C is —OR ^15a (Wherein R ^15a has the same ^{meaning as} described above) or an aromatic heterocyclic group which may have a substituent, preferably a lower alkoxy or a monocyclic 5-membered aromatic which may have a substituent A group heterocyclic group is more preferred.

Pharmaceutically acceptable salts of compounds (I), (IA), (IB) and (IC) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acids Examples include addition salts.
Pharmaceutically acceptable acid addition salts of compounds (I), (IA), (IB) and (IC) include, for example, inorganic acid salts such as hydrochloride, sulfate, phosphate, acetate, maleic acid Organic salts such as salts, fumarate, citrate, methanesulfonate and the like, and pharmaceutically acceptable metal salts include, for example, alkali metal salts such as sodium salt and potassium salt, magnesium salt, calcium Examples thereof include alkaline earth metal salts such as salts, aluminum salts, and zinc salts. Examples of pharmaceutically acceptable ammonium salts include salts such as ammonium and tetramethylammonium, and pharmaceutically acceptable organic salts. Examples of amine addition salts include addition salts such as morpholine and piperidine. Examples of pharmaceutically acceptable amino acid addition salts include addition salts such as lysine, glycine, and phenylalanine. Salting can be mentioned.

The present invention also includes prodrugs of the compounds (I), (I-A), (I-B) and (I-C). Prodrugs are compounds that are converted into compounds (I), (I-A), (I-B), and (I-C) by reactions with enzymes, gastric acid, and the like in vivo. Many types of prodrugs applicable to the present invention are known, and an appropriate prodrug is selected from known literature (for example, see Drug Development, Yodogawa Shoten, 1990, Vol. 7, page 163). It is possible to synthesize using this method. For example, prodrugs of compounds (I), (IA), (IB), and (IC) include compounds (I), (IA), (IB), and (IC) that have amino, , Alkylated, phosphorylated compounds; when compounds (I), (IA), (IB) and (IC) have a hydroxy, the hydroxy is acylated, alkylated, phosphorylated, borated When the compounds (I), (IA), (IB) and (IC) have carboxy, examples thereof include compounds in which the carboxy is esterified or amidated. The prodrugs of the compounds (I), (IA), (IB) and (IC) may be any of hydrates, non-hydrates and solvates, and the compounds (I), (IA ), (IB) and (IC) as well as pharmaceutically acceptable salts.

Next, production methods of compounds (I), (IA), (IB) and (IC) will be described.
In the production method shown below, when the defined group changes under the conditions of the production method or is inappropriate for carrying out the production method, introduction of a protective group commonly used in organic synthetic chemistry and Removal methods [e.g., Protective Groups in Organic Synthesis, 4th edition, written by TWGreene, John Wiley & Sons Inc. (2006), etc. ] Can be used to produce the target compound. Further, the order of reaction steps such as introduction of substituents can be changed as necessary.
Production method 1
Among the compounds (I), the compound (I-Aa) can be produced by the following production method 1.

[Wherein, R ^4A , R ^13A , mA, nA and Z ^A are the same as defined above, R ²⁰ represents methyl or lower alkoxy, R ^3A1 represents a hydrogen atom or methyl, and X and Y represent chlorine, respectively. An atom, a bromine atom or an iodine atom, W is a chlorine atom, a bromine atom, an iodine atom or —OR ²¹ (wherein R ²¹ represents a lower alkylsulfonyl or an arylsulfonyl which may have a substituent; And the substituents in arylsulfonyl which may have a group are the same or different and include lower alkyl having 1 to 3 substituents, and M represents a tin atom, a boron atom, or a silicon atom. , R ^A represents halogen, hydroxy, lower alkyl, lower alkoxy, aryl or aryloxy, and q represents an integer of 0 to 3. Here, the lower alkyl in lower alkyl and lower alkylsulfonyl and lower alkoxy are as defined above, the aryl moiety in aryl, arylsulfonyl and aryloxy is as defined above, and halogen is as defined above.
Process 1
Compound (IV) is obtained by mixing 1 to 30 equivalents of compound (II) with compound (II) in the presence of 0.001 to 1 equivalent of a transition metal catalyst at a temperature between -50 ° C. and 200 ° C. for 5 minutes. For 100 hours. At this time, 0.01 to 30 equivalents of an appropriate additive can be added to promote the reaction.

Examples of the solvent include methanol, ethanol, dichloromethane, acetonitrile, toluene, ethyl acetate, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), water and the like. These may be used alone or in combination.
Examples of the transition metal catalyst include palladium acetate, tetrakis (triphenylphosphine) palladium, palladium chloride, palladium bromide, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, dichlorobis (acetonitrile) palladium, [1 , 1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride / dichloromethane complex (1: 1) and other palladium catalysts, nickel chloride, nickel acetylacetonate, bis (1,5-cyclooctadiene) nickel, Examples include nickel catalysts such as nickel bromide.

Examples of the additive include triphenylphosphine, tri (o-tolyl) phosphine, tricyclohexylphosphine, silver oxide, copper iodide, lithium chloride, cesium carbonate, triethylamine, diethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, Examples thereof include tripotassium phosphate, and these can be used alone or in combination.
Compound (II) can be obtained according to the method described in Reference Examples or a known method [for example, tetrahedron, 60, p. 2937 (2004)].

Compound (III) can be obtained as a commercial product or according to a known method [for example, 4th edition Experimental Chemistry Course 24, 4th edition, p.252, Maruzen (2000)].
Process 2
Compound (V) contains 1 to 30 equivalents of tributyl (1-ethoxyvinyl) tin in a solvent, or 1 equivalent to a large excess of alcohol in a carbon monoxide atmosphere with compound (IV). In the presence of 0.001 to 1 equivalent of a transition metal catalyst, the reaction can be carried out at a temperature between −50 ° C. and 200 ° C. for 5 minutes to 100 hours. At this time, 0.01 to 30 equivalents of an appropriate additive can be added to promote the reaction. Thereafter, an acid can be added to react.

Examples of the solvent include methanol, ethanol, dichloromethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, N, N-dimethylacetamide (DMA), NMP, water, and the like. Or it can mix and use.
Examples of the alcohol include methanol, ethanol, n-propanol, and n-butanol.

Examples of the transition metal catalyst include palladium acetate, tetrakis (triphenylphosphine) palladium, palladium chloride, palladium bromide, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, dichlorobis (acetonitrile) palladium, [1 1, 1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride / dichloromethane complex (1: 1) and other palladium catalysts.

Examples of the additive include triphenylphosphine, tri (o-tolyl) phosphine, 1,1′-bis (diphenylphosphino) ferrocene, 1,2-bis (diphenylphosphino) propane, 2,2′-bis ( Diphenylphosphino) -1,1'-binaphthyl, 1,2-bis (diphenylphosphino) ethane, silver oxide, copper iodide, lithium chloride, cesium fluoride, cesium carbonate, triethylamine, diethylamine, N, N-diisopropyl Examples include ethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, tripotassium phosphate, and the like. These can be used alone or in combination.

Examples of the acid include concentrated hydrochloric acid, concentrated sulfuric acid, trifluoroacetic acid, DL-10-camphorsulfonic acid, p-toluenesulfonic acid, boron trifluoride and the like.
Process 3
Compound (VI) can be produced by treating compound (V) in a solvent at a temperature between 0 ° C. and 100 ° C. with an oxidizing agent for 5 minutes to 100 hours.

Examples of the oxidizing agent include aqueous hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, tert-butyl hydroperoxide, and the like, and these can be used alone or in combination.
Examples of the solvent include dichloromethane, chloroform, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, DMA, NMP, water and the like, and these can be used alone or in combination.
Process 4
Compound (VII) can be produced by treating compound (VI) in a solvent at a temperature between −80 ° C. and 200 ° C. with 0.1 to 10 equivalents of a reducing agent for 5 minutes to 100 hours.

Examples of the solvent include methanol, ethanol, dichloromethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, water and the like, and these can be used alone or in combination.
Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium trimethoxyborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
Process 5
Compound (VIII) can be produced by treating compound (VII) with a halogenating agent or sulfonylating agent in a solvent at a temperature between room temperature and 120 ° C. for 5 minutes to 100 hours. At this time, 0.01 to 30 equivalents of base can be added to promote the reaction.

Examples of the solvent include dichloromethane, chloroform, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, DMA, NMP and the like.
Examples of the halogenating agent include chlorine, hydrogen chloride gas, concentrated hydrochloric acid, hydrobromic acid, tetra-n-butylammonium tribromide, bromine, iodine, N-chlorosuccinimide (NCS), and N-brominated succinic acid. Examples include imide (NBS), N-iodosuccinimide (NIS), iodine monochloride, pyridinium bromide perbromide, 4-dimethylaminopyridinium bromide perbromide, and the sulfonylating agents include, for example, methanesulfonyl chloride, ethane Examples include sulfonyl chloride, benzenesulfonyl chloride, 4-toluenesulfonyl chloride and the like.

Examples of the base include triethylamine, N, N-diisopropylethylamine, pyridine, sodium hydride, sodium hydroxide, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like.
Process 6
Compound (I-Aa) can be produced by reacting compound (VIII) and compound (IX) in a solvent at a temperature between room temperature and 120 ° C. for 5 minutes to 100 hours. At this time, 0.01 to 30 equivalents of an additive can be added to promote the reaction.

Examples of the solvent include dichloromethane, chloroform, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, DMA, NMP, dimethyl sulfoxide (DMSO), and the like. Examples of the additive include sodium iodide, Examples include potassium iodide and n-tetrabutylammonium iodide (TBAI).
Compound (IX) can be obtained as a commercially available product or according to a known method (for example, 5th edition Experimental Chemistry Course 14 Synthesis of Organic Compounds II Alcohol / Amine, 5th edition, p.352, Maruzen, etc.) it can.
Production method 2
Among the compounds (I), the compound (I-Ba) can be produced by the following production method 2.

(Wherein R ^4B , R ^13B , R ²⁰ , W, Z ^B , mB and nB are as defined above, and R ^3B1 is as defined above for R ^3A1 )
Process 1
Compound (X) can be produced according to Step 4 of Production Method 1 using Compound (VB).

Compound (VB) can be obtained according to Production Method 1.
Process 2
Compound (XI) can be produced according to Step 5 of Production Method 1 using Compound (X).
Process 3
Compound (I-Ba) can be produced according to production method 1, step 6 using compound (XI).
Production method 3
Among the compounds (I), the compound (I-Ca) can be produced by the following production method 3.

(Wherein R ^3C , R ^4C , R ^5C , R ^13C , mC, nC, Z ^C , M, W, R ^A and q are as defined above, and R ²² may have a substituent. Represents lower alkyl, wherein lower alkyl is as defined above, and the substituents in substituted lower alkyl are as defined above.
Process 1
Compound (XIV) can be produced according to Step 1 of Production Method 1 using Compound (XIII) and Compound (IIIa). Compound (XIII) can be obtained according to the method described in Reference Examples or a known method [eg, Tetrahedron, Vol. 60, p. 2937 (2004), etc.].
Process 2
Compound (XV) can be produced according to Step 4 of Production Method 1 using Compound (XIV).
Process 3
Compound (XVI) can be produced according to production method 1, step 5 using compound (XV).
Process 4
Compound (I-Ca) can be produced according to Step 6 of Production Method 1 using Compound (XVI) and Compound (XVII).
Production method 4
Among the compounds (I), the compound (Ia) can also be produced by the following production method 4.

(Wherein R ¹ , R ⁴ , m, n, G ¹ and G ² are as defined above, and R ²³ represents an optionally substituted lower alkyl)
Process 1
Compound (XIX) can be produced by treating Compound (XVIII) at a temperature between −80 ° C. and 25 ° C. with 0.1 to 10 equivalents of a reducing agent for 5 minutes to 10 hours.

Examples of the solvent include methanol, ethanol, dichloromethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, water and the like, and these can be used alone or in combination.
Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride and the like.
Process 2
Compound (Ia) can be produced by reacting compound (XIX) and compound (XX) in the presence of a reducing agent in a solvent. At this time, 0.01 to 30 equivalents of an appropriate additive can be added to promote the reaction.

Examples of the solvent include methanol, ethanol, dichloromethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, N, N-dimethylacetamide (DMA), NMP, water, and the like. Or it can mix and use.
Examples of the reducing agent include sodium borohydride, sodium cyanotrihydroborate, sodium triacetoxyborohydride, pyridine-borane complex, and the like.

Examples of the additive include acetic acid, molecular sieves, magnesium sulfate and the like.
It is preferable to use 1 to 20 equivalents of the reducing agent and compound (XX) with respect to compound (XIX). The reaction is usually carried out at a temperature between -20 ° C and 80 ° C and is completed in 10 minutes to 100 hours.
Among the compounds (I), G ² is N ⁺ -O ^- compounds in which can be produced according to step 3 of Preparation 1 from compound G ² is a nitrogen atom.

Conversion of each group contained in the compounds (I), (IA), (IB) and (IC) and intermediates thereof can be carried out by a known method [for example, Comprehensive Organic Transformations 2nd Edition (Comprehensive Organic Transformations (2nd edition), R. C, Larock, Vch Verlagsgesellscaft, Mbh (1999), etc.], or in accordance with them.

The intermediates and target compounds in each of the above production methods are isolated and purified by subjecting them to separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to. The intermediate can be subjected to the next reaction without any particular purification.
Among compounds (I), (IA), (IB), and (IC), there may exist stereoisomers such as geometric isomers and optical isomers, tautomers, and the like. Includes all possible isomers, including these, and mixtures thereof.

When it is desired to obtain salts of compounds (I), (IA), (IB) and (IC), and when compounds (I), (IA), (IB) and (IC) are obtained in the form of salts, they are purified as they are. In addition, when it is obtained in a free form, the compound (I), (IA), (IB) and (IC) are dissolved or suspended in an appropriate solvent, and then isolated by adding an acid or base. What is necessary is just to refine.
In addition, compounds (I), (IA), (IB) and (IC) and pharmaceutically acceptable salts thereof may exist in the form of adducts with water or various solvents. Adducts are also encompassed by the present invention.

Specific examples of compounds (I), (IA), (IB) and (IC) obtained by the present invention are shown in Tables 1, 2, 3-1, 3-2, 4, 5, 6, 7-1 to 7- Shown in 7, 8-1, 8-2, 9, 10 and 11. In the table, Me, Et, ⁿ Pr, ⁱ Pr, ^t Bu, Ph and Bn represent methyl, ethyl, n-propyl, isopropyl, tert-butyl, phenyl and benzyl, respectively.

Next, the pharmacological action of typical compounds (I), (IA), (IB) and (IC) will be specifically described with reference to test examples.
Test Example 1: Cell proliferation inhibition test for human fibrosarcoma cells As a fibrosarcoma cell line, human fibrosarcoma cells HT-1080 (JCRB number: 9113) were used. For cell culture, 10% fetal calf serum (SAFC Biosciences, catalog number 12203C), 10% / L non-Essential Amino Acids Solution, 1% containing liquid (Invitrogen, catalog number 11140-050) Medium Earle's, liquid (Invitrogen, catalog number 11095-080) was used. The cells were cultured at 37 ° C. and 5% carbon dioxide.

HT-1080 cells (180 cells / well) were seeded in each well of a 96-well plate (Nunk, catalog number 167008) and cultured overnight. Serially diluted test compounds were added and incubated for a further 72 hours (final volume 100 μL / well). 10 μL of Cell Proliferation Reagent WST-1 (Roche Diagnostics, catalog number 11644087001) was added to each well and incubated at 37 ° C. After 60 minutes, the absorbance at 450 nm (control wavelength: 655 nm) was measured with a plate reader (Molecular Device, SpectraMax 340PC ³⁸⁴ ). The growth rate of cells in control wells treated with a solvent (dimethyl sulfoxide (DMSO)) at 72 hours was calculated as 100%, and the growth rate of cells in wells treated with a test compound was calculated.

Compounds 3, 7, 11, 14, 53, 109, 149, 155, 158 and 161 inhibit cell proliferation by 90% or more at a concentration of 100 nmol / L against human fibrosarcoma cell line HT-1080 cells, Compound 55 inhibited cell proliferation by 60% or more at a concentration of 100 nmol / L against human fibrosarcoma cell line HT-1080 cells.
From the above, it was found that compounds (I), (IA), (IB) and (IC) have cell growth inhibitory activity against human cancer cells. That is, the compounds (I), (IA), (IB) and (IC) are considered useful as antitumor agents.

Compounds (I), (IA), (IB) and (IC) or pharmaceutically acceptable salts thereof can be administered alone as they are, but are usually provided as various pharmaceutical preparations. desirable. These pharmaceutical preparations are used for animals and humans.
The pharmaceutical preparation according to the present invention comprises compounds (I), (IA), (IB) and (IC) or pharmaceutically acceptable salts thereof as active ingredients alone or for any other treatment. It can contain as a mixture with an active ingredient. In addition, these pharmaceutical preparations are produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient together with one or more pharmaceutically acceptable carriers.

As an administration route, it is desirable to use one that is most effective in the treatment, and examples thereof include oral or parenteral such as intravenous administration.
Examples of the dosage form include tablets and injections.
For example, tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.

For example, an injection suitable for parenteral administration can be produced using a salt solution, a glucose solution, a mixed solution of a salt solution and a glucose solution, or the like.
The dosage and frequency of administration of compounds (I), (IA), (IB) and (IC) or pharmaceutically acceptable salts thereof depends on the dosage form, patient age, body weight, nature of the condition to be treated or Oral administration is usually 0.01 mg to 1 g, preferably 0.05 to 100 mg per adult once or several times daily, depending on the severity. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg, preferably 0.01 to 10 mg per adult is administered once to several times a day. However, the dose and the number of doses vary depending on the various conditions described above.

Below, the aspect of this invention is demonstrated with an Example and a reference example. Unless otherwise specified, the raw materials and reagents used were obtained as commercially available products or according to known methods. The present invention is not limited to these examples and reference examples.
Reference example 1
Step 1: 2-chloro-3- (2-ethoxyphenyl) quinoxaline (compound R1)
2,3-dichloroquinoxaline (100 mg, 0.50 mmol) was dissolved in dioxane (1.50 mL), 2-ethoxyphenylboronic acid (92.0 mg, 0.550 mmol), tris (dibenzylideneacetone) dipalladium (6.90 mg, 0.0075 mmol), tricyclohexylphosphine (5.00 mg, 0.018 mmol), and cesium carbonate (326 mg, 1.00 mmol) were added, and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 0-10 / 1) to obtain Compound R1 (121 mg, 85.2%).
ESI-MS m / z: 285 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.29 (t, J = 7.0 Hz, 3H), 4.10 (q, J = 7.0 Hz, 2H), 6.99-7.15 (m, 2H), 7.39-7.52 (m, 2H), 7.72-7.84 (m, 2H), 8.04-8.20 (m, 2H).
Step 2: 3-acetyl-2- (2-ethoxyphenyl) quinoxaline (compound R2)
Compound R1 (320 mg, 1.12 mmol) was dissolved in toluene (3.00 mL), bis (triphenylphosphine) palladium dichloride (79.0 mg, 0.112 mmol), and tributyl (1-ethoxyvinyl) tin (0.456 mL, 1.35 mmol). And stirred at 120 ° C. for 1 hour under microwave irradiation. The same operation was performed twice, the crude products were combined, filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 0-7 / 1) to obtain Compound R2 (238 mg, 42.2%).
ESI-MS m / z: 293 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.25 (t, J = 7.1 Hz, 3H), 2.81 (s, 3H), 4.01 ( q, J = 7.1 Hz, 2H), 6.91 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.43 (td, J = 1.6, 7.5 Hz, 1H), 7.71 ( dd, J = 1.6, 7.5 Hz, 1H), 7.77-7.88 (m, 2H), 8.14-8.20 (m, 2H).

Step 3: 3-acetyl-2- (2-ethoxyphenyl) quinoxaline 1-oxide (compound R3)
Compound R2 (191 mg, 0.653 mmol) was dissolved in dichloromethane (4.0 mL), m-chloroperbenzoic acid (titer 65%, 434 mg, 1.63 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 17.5 hours. The solvent was distilled off under reduced pressure, saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (hexane / ethyl acetate = 7/3) to obtain Compound R3 (142 mg, yield 71%).
ESI-MS m / z: 309 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.22 (t, J = 6.6 Hz, 3H), 2.68 (s, 3H), 3.96- 4.08 (m, 2H), 6.99 (d, J = 7.9 Hz, 1H), 7.14 (dt, J = 1.0, 7.6 Hz, 1H), 7.42-7.53 (m, 2H), 7.78-7.90 (m, 2H) , 8.17-8.21 (m, 1H), 8.63-8.66 (m, 1H).
Step 4: 2- (2-Ethoxyphenyl) -3- (1-hydroxyethyl) quinoxaline 1-oxide (Compound R4)
Compound R3 (118 mg, 0.383 mmol) is dissolved in a mixed solvent of THF (2.0 mL) and methanol (0.5 mL), sodium borohydride (15.9 mg, 0.421 mmol) is added at 0 ° C, and 10 minutes at 0 ° C. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (hexane / ethyl acetate = 7/3) to obtain Compound R4 (105 mg, yield 88%).
ESI-MS m / z: 311 [M + H] ⁺ ; ¹ H-NMR (300 MHz, CDCl ₃ , δ): 1.17-1.28 (m, 6H), 4.01-4.12 (m, 3H), 4.72-4.91 (m, 1H), 7.05-7.36 (m, 3H), 7.48-7.54 (m, 1H), 7.71-7.76 (m, 1H), 7.81-7.86 (m, 1H), 8.12-8.85 (m, 1H) , 8.58-8.62 (m, 1H).

Reference Example 2: 3- (2-Ethoxyphenyl) -2- (1-hydroxyethyl) quinoxaline (Compound R5)
Compound R2 (215 mg, 0.730 mmol) was dissolved in methanol (4.00 mL), sodium borohydride (83.0 mg, 2.20 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The solvent of the reaction mixture was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/0 to 1/1) to obtain Compound R5 (114 mg, 53.0%).
ESI-MS m / z: 295 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.22 (t, J = 6.8 Hz, 3H), 1.57 (s, 3H), 3.94- 4.17 (m, 2H), 4.53-4.80 (m, 1H), 5.12 (br s, 1H), 7.02 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 7.1 Hz, 1H), 7.37- 7.53 (m, 2H), 7.73-7.84 (m, 2H), 8.11-8.20 (m, 2H).

Reference example 3
Step 1: 3- (2-Ethoxyphenyl) -2- (n-propoxycarbonyl) quinoxaline (Compound R6)
Compound R1 (1.60 g, 5.62 mmol) was dissolved in a mixed solvent of DMF (8.0 mL) and n-propanol (16 mL), and palladium acetate (252 mg, 1.12 mmol), 1,2-bis (diphenylphosphino) Propane (462 mg, 1.12 mmol) and N, N-diisopropylethylamine (2.38 mL, 26.0 mmol) were added, and the mixture was stirred at 90 ° C. for 17 hours in a carbon monoxide atmosphere. The reaction mixture was filtered through celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 19 / 1-4 / 1) to obtain Compound R6 (747 mg, 40.0%).
ESI-MS m / z: 337 [M + H] ⁺ .
Step 2: 3- (2-Ethoxyphenyl) -2- (hydroxymethyl) quinoxaline (Compound R7)
Compound R6 (0.497 mg, 1.48 mmol) was dissolved in THF (10 mL), diisobutylaluminum hydride-hexane solution (1.00 mol / L, 4.43 mL, 4.44 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Methanol (2.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After filtration through celite, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-7 / 3) to obtain Compound R7 (128 mg, 31.0%).
ESI-MS m / z: 281 [M + H] ⁺ .

Reference example 4
Process 1: 2-aminobenzaldehyde (compound R8)
2-Nitrobenzaldehyde (200 mg, 1.32 mmol) is dissolved in a mixed solvent of ethanol (2.00 mL) and water (2.00 mL), and reduced iron (370 mg, 6.62 mmol) and ammonium chloride (14.1 mg, 0.264 mmol) are added. The mixture was further stirred at 80 ° C. for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 0-3 / 1) to obtain Compound R8 (110 mg, 68.8%).
ESI-MS m / z: 122 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 6.11 (br s, 2H), 6.65 (d, J = 8.4 Hz, 1H), 6.72 -6.79 (m, 1H), 7.28-7.39 (m, 1H), 7.49 (dd, J = 1.6, 7.9 Hz, 1H), 9.88 (s, 1H).
Step 2: Ethyl 3-aminoquinoline-2-carboxylate (Compound R9)
Ethyl 3-bromopyruvate (1.18 g, 6.04 mmol) was dissolved in ethanol (9.76 mL), and a mixture of pyridine (0.489 mL, 6.04 mmol) and ethanol (14.6 mL) was slowly added dropwise. After dropping, the mixture was stirred at 70 ° C. for 1 hour. The mixture was allowed to cool to room temperature, a mixed solution of compound R8 (610 mg, 5.04 mmol) and pyridine (1.00 mL) was added, and the mixture was stirred at 80 ° C. for 4 and a half hours. Pyrrolidine (1.00 mL) was added thereto, and the mixture was further stirred at 80 ° C. for 3 hours. The solvent of the reaction mixture was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/0 to 1/2) to obtain Compound R9 (500 mg, 45.9%).
ESI-MS m / z: 217 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.51 (t, J = 7.1 Hz, 3H), 4.56 (q, J = 7.1 Hz, 2H), 5.62 (br s, 2H), 7.37 (s, 1H), 7.39-7.62 (m, 3H), 8.01-8.11 (m, 1H).

Step 3: Ethyl 3-iodoquinoline-2-carboxylate (Compound R10)
Compound R9 (500 mg, 2.31 mmol) was dissolved in chloroform (10.0 mL), iodine (646 mg, 2.54 mmol) and isoamyl nitrite (0.618 mL, 4.62 mmol) were added, and the mixture was stirred at 70 ° C. for 19 hours. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 0-5 / 1) to obtain Compound R10 (373 mg, 49.4%).
ESI-MS m / z: 328 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.49 (t, J = 7.1 Hz, 3H), 4.55 (q, J = 7.1 Hz, 2H), 7.57-7.67 (m, 1H), 7.72-7.83 (m, 2H), 8.01-8.18 (m, 1H), 8.75 (s, 1H).
Step 4: Ethyl 3- (2-ethoxyphenyl) quinoline-2-carboxylate (Compound R11)
Compound R10 (260 mg, 0.795 mmol) was dissolved in a mixed solvent of dioxane (1.00 mL) and water (0.20 mL), and 2-ethoxyphenylboronic acid (172 mg, 1.03 mmol), tetrakis (triphenylphosphine) palladium ( 46.0 mg, 0.040 mmol) and sodium carbonate (126 mg, 1.19 mmol) were added, and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 0-3 / 1) to give compound 11 (205 mg, 67.4%).
ESI-MS m / z: 322 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.12 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 3.97 (q, J = 7.1 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H), 6.92 (d, J = 8.3 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H) , 7.33-7.43 (m, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.72-7.81 (m, 1H), 7.87 (d, J = 7.9 Hz, 1H), 8.16 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H).

Step 5: 3- (2-Ethoxyphenyl) -2- (hydroxymethyl) quinoline (Compound R12)
Compound R11 (183 mg, 0.569 mmol) was dissolved in THF (3.66 mL) and cooled to 0 ° C. using an ice bath. Lithium aluminum hydride (23.8 mg, 0.626 mmol) was added there, and it stirred at 0 degreeC for 1 hour, lithium aluminum hydride (47.6 mg, 1.25 mmol) was added again, and it stirred at room temperature for 5 hours. An excess amount of sodium sulfate decahydrate was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through celite, and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 0-6 / 1) to obtain Compound R12 (80.3 mg, 50.5%).
ESI-MS m / z: 280 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.23 (t, J = 7.0 Hz, 3H), 4.02 (q, J = 7.0 Hz, 2H), 4.67 (s, 2H), 4.96 (br s, 1H), 6.99 (d, J = 8.4 Hz, 1H), 7.05 (t, J = 7.3 Hz, 1H), 7.19 (dd, J = 1.8, 7.3 Hz, 1H), 7.37-7.46 (m, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.70-7.79 (m, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.98 ( s, 1H), 8.14 (d, J = 8.1 Hz, 1H).

Reference Example 5
Step 1: Ethyl 3-hydroxyquinoxaline-2-carboxylate (Compound R13)
Dissolve 1,2-phenylenediamine (3.38 g, 31.3 mmol) in ethanol (68 mL), then add diethylketomalonate (7.24 mL, 46.9 mmol) and hydrogen chloride-ethanol solution (2 mol / L, 15.63 ml, 31.3 mmol). mmol) and stirred at 80 ° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration and dried to give compound R13 (5.31 g, 78%).
ESI-MS m / z: 219 [M + H] ⁺
Step 2: Ethyl 3-bromoquinoxaline-2-carboxylate (Compound R14)
Compound R13 (700 mg, 3.21 mmol) was dissolved in chloroform (28 mL), phosphorus oxybromide (2.76 g, 9.62 mmol) was added, DMF (0.70 mL) was added at 40 ° C., and the mixture was stirred for 30 min. The reaction mixture was filtered through celite, water was added, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 97/3 to 85/15) to obtain Compound R14 (921 mg, quantitative yield).
ESI-MS m / z: 282 [M + H] ⁺

Step 3: 3-Ethoxycarbonyl-2- (4-tert-butoxycarbonyl-2,6-diethoxyphenyl) quinoxaline (Compound R15)
4- (tert-butoxycarbonyl)-obtained by dissolving Compound R14 (600 mg, 2.13 mmol) in a mixed solvent of DMF (15.0 mL) and water (3.00 mL) in the same manner as in Step 5 of Reference Example 7. 2,6-diethoxyphenylboronic acid (662 mg, 2.13 mmol), triethylamine (2.97 mL, 21.3 mmol) and 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (220 mg , 0.301 mmol), and stirred at 60 ° C. for 2 hours. The mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1: 0-4: 1) to obtain Compound R15 (760 mg, 76%).
ESI-MS m / z: 467 [M + H] ⁺
Step 4: 3-Ethoxycarbonyl-2- (4-tert-butoxycarbonyl-2,6-diethoxyphenyl) quinoxaline 1-oxide (Compound R16)
Compound R15 (760 mg, 1.63 mmol) was dissolved in dichloromethane (16.3 mL), m-chloroperbenzoic acid (titer 70%, 602 mg, 2.44 mmol) was added, and the mixture was stirred at room temperature for 10 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (hexane / ethyl acetate = 1: 0 to 3: 2) to obtain Compound R16 (440 mg, yield 56%).
ESI-MS m / z: 483 [M + H] ⁺

Step 5: 3-Ethoxycarbonyl-2- (4-carboxy-2,6-diethoxyphenyl) quinoxaline 1-oxide (Compound R17)
Compound R16 (440 mg, 0.912 mmol) was dissolved in a mixed solvent of dichloromethane (6.00 mL) and trifluoroacetic acid (3.00 mL), and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction mixture was distilled off under reduced pressure, and toluene azeotropy was performed. The residue was purified by silica gel chromatography (chloroform / methanol = 1: 0-9: 1) to give compound R17 (370 mg, yield 95%).
ESI-MS m / z: 427 [M + H] ⁺
Step 6: 3-Ethoxycarbonyl-2- (4-carbamoyl-2,6-diethoxyphenyl) quinoxaline 1-oxide (Compound R19)
Compound R18 (100 mg, 0.235 mmol) was dissolved in DMF (1.20 mL), triethylamine (0.098 mL, 0.704 mmol), ammonia-methanol solution (2.00 mol / L, 0.586 mL, 1.17 mmol) and hexafluorophosphoric acid ( Benzotriazol-1-yloxy) tripyrrolidinophosphonium (183 mg, 0.352 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by amino silica gel chromatography (chloroform / methanol = 1: 0 to 9: 1) to obtain Compound R19 (76 mg, yield 76%).
ESI-MS m / z: 426 [M + H] ⁺

Step 7: 3-Formyl-2- (4-carbamoyl-2,6-diethoxyphenyl) quinoxaline 1-oxide (Compound R20)
Compound R19 (50.0 mg, 0.118 mmol) was dissolved in THF (2.40 mL), cooled to −78 ° C., diisobutylaluminum-toluene solution (1.00 mol / L, 0.588 mL, 0.588 mmol) was added, and then -40 Stir at 1 ° C. for 1 hour. A saturated aqueous Rochelle salt solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / methanol = 1: 0-9: 1) to obtain Compound R20 (36.0 mg, yield 80%).
ESI-MS m / z: 382 [M + H] ⁺
Step 8: 3-Formyl-2- (4-cyano-2,6-diethoxyphenyl) quinoxaline 1-oxide (Compound R21)
Compound R20 (22.0 mg, 0.0580 mmol) is dissolved in dichloromethane (2.90 mL), and triethylamine (0.0240 mL, 0.173 mmol) and trifluoroacetic anhydride (0.0120 mL, 0.0870 mmol) are added under ice cooling at room temperature. Stir for 1 hour. Thereafter, triethylamine (0.0240 mL, 0.173 mmol) and trifluoroacetic anhydride (0.0120 mL, 0.0870 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 0.5 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (hexane / ethyl acetate = 1: 0-7: 3) to obtain Compound R21 (19.0 mg, yield 91%).
ESI-MS m / z: 364 [M + H] ⁺

Reference Example 6
Step 1: 3-hydroxy-7-nitroquinoxaline-2-carboxylic acid (compound R22)
3-Hydroxyquinoxaline-2-carboxylic acid (2.00 g, 10.5 mmol) was dissolved in sulfuric acid (20.0 mL), cooled to 0 ° C., potassium nitrate (3.19 g, 31.6 mmol) was slowly added, and the mixture was stirred at room temperature for 2 hours. . The reaction mixture was cooled to 0 ° C., and the precipitated solid was collected by filtration to obtain Compound R22 (1.74 g, 71%).
ESI-MS m / z: 236 [M + H] ⁺
Step 2: Ethyl 3-hydroxy-7-nitroquinoxaline-2-carboxylate (Compound R23)
Compound R22 (1.74 g, 7.42 mmol) was dissolved in ethanol (35.0 mL), thionyl chloride (0.812 mL, 11.1 mmol) was added, and the mixture was stirred at 70 ° C. for 2 hr. The mixture was allowed to cool to room temperature, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the slurry was purified to obtain compound R23 (1.13 g, 58%).
ESI-MS m / z: 264 [M + H] ⁺

Step 3: Ethyl 3-bromo-7-nitroquinoxaline-2-carboxylate (Compound R24)
Compound R23 (1.13 g, 4.29 mmol) was dissolved in chloroform (20.0 mL), phosphorus oxybromide (2.46 g, 8.59 mmol) and DMF (1.00 mL) were added, and the mixture was stirred at 45 ° C. for 0.5 hr. The mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain Compound R24 (1.38 g, 99%).
ESI-MS m / z: 326, 328 [M + H] ⁺
Step 4: Ethyl 3- [4- (tert-butoxycarbonyl) -2-ethoxy-6-methoxyphenyl] -7-nitroquinoxaline-2-carboxylate (Compound R25)
Compound R24 (200 mg, 0.613 mmol) is dissolved in a mixed solvent of DMF (3.50 mL) and water (0.700 mL). Compound R36 (200 mg, 0.675 mmol), triethylamine (0.855 mL, 6.13 mmol) and 1,1 '-Bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (100 mg, 0.123 mmol) was added, and the mixture was stirred at 60 ° C for 1 hour and at 70 ° C for 1 hour. The mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 0-2 / 3) to obtain Compound R25 (101 mg, 33%).
ESI-MS m / z: 498 [M + H] ⁺
Step 5: Ethyl 3- (4-carbamoyl-2-ethoxy-6-methoxyphenyl) -7-nitroquinoxaline-2-carboxylate (Compound R26)
Compound R25 (218 mg, 0.438 mmol) was dissolved in dichloromethane (3.00 mL), trifluoroacetic acid (1.50 mL, 19.5 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was dissolved in DMF (3.00 mL), triethylamine (0.183 mL, 1.31 mmol), ammonia-methanol solution (2.00 mol / L, 1.09 mL, 2.19 mmol) and hexafluorophosphoric acid (benzotriazol-1-yloxy) tri Pyrrolidinophosphonium (341 mg, 0.656 mmol) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the precipitated solid was collected by filtration to obtain Compound R26 (173 mg, 90%).
ESI-MS m / z: 441 [M + H] ⁺

Step 6: 3-Ethoxy-4- [3- (hydroxymethyl) -6-nitroquinoxalin-2-yl] -5-methoxybenzonitrile (Compound R27)
Compound R26 (173 mg, 0.393 mmol) was dissolved in THF (7.00 mL), cooled to 0 ° C, diisobutylaluminum hydride-toluene solution (1.00 mol / L, 1.96 mL, 1.96 mmol) was added, and the mixture was brought to 0 ° C. And stirred for 0.5 hour. A saturated aqueous Rochelle salt solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in a mixed solvent of methanol (3.00 mL) and THF (3.00 mL), cooled to 0 ° C., sodium borohydride (22.0 mg, 0.590 mmol) was added, and the mixture was stirred at 0 ° C. for 0.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in dichloromethane (8.00 mL), cooled to 0 ° C., triethylamine (0.549 mL, 3.94 mmol) and trifluoroacetic anhydride (0.278 mL, 1.97 mmol) were added, and the mixture was stirred at 0 ° C. for 15 min. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 1/0 to 33/1) to obtain Compound R27 (58.0 mg, 39%).
ESI-MS m / z: 381 [M + H] ⁺
Step 7: 3-Ethoxy-5-methoxy-4- {3-[(4-methyl-1,4-diazepan-1-yl) methyl] -6-nitroquinoxalin-2-yl} benzonitrile (Compound R28)
Compound R27 (58.0 mg, 0.152 mmol) was dissolved in dichloromethane (2.00 mL), cooled to 0 ° C., triethylamine (0.064 mL, 0.457 mmol) and methanesulfonyl chloride (0.024 mL, 0.305 mmol) were added, and the mixture was brought to 0 ° C. And stirred for 0.5 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in THF (3.00 mL), 1-methyl-1,4-diazepane (0.076 mL, 0.611 mmol) was added, and the mixture was stirred at 80 ° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by amino silica gel column chromatography (Yamazen, n-hexane / ethyl acetate = 1/0 to 1/1) to obtain Compound R28 (47.0 mg, 65%).
ESI-MS m / z: 477 [M + H] ⁺

Reference Example 7
Step 1: Ethyl 4-bromo-3,5-dihydroxybenzoate (Compound R29)
4-Bromo-3,5-dihydroxybenzoic acid (7.66 g, 32.9 mmol) was dissolved in ethanol (100 mL), concentrated sulfuric acid (2.0 mL) was added at room temperature, and the mixture was heated to reflux for 10 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain Compound R29 (8.14 g, 95%).
ESI-MS: m / z 258 [M-H] ⁺
Step 2: Ethyl 4-bromo-3-ethoxy-5-hydroxybenzoate (Compound R30)
Under an argon atmosphere, Compound R29 (10.1 g, 38.7 mmol) was dissolved in DMF (100 mL), 60% sodium hydride (3.09 g, 77.4 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 15 min. The reaction mixture was cooled to 0 ° C., bromoethane (3.18 mL, 42.6 mmol) was added, and the mixture was stirred at room temperature for 1 hr. 1 mol / L hydrochloric acid and water were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 19: 1 to 11: 9) to obtain Compound R30 (7.80 g, 70%).
ESI-MS: m / z289 [M + H] ⁺

Step 3: 4-Bromo-3-ethoxy-5-methoxybenzoic acid (Compound R31)
Using compound R30 (9.50 g, 32.9 mmol) and methyl p-toluenesulfonate (5.95 mL, 39.4 mmol), quantitatively determine ethyl 4-bromo-3-ethoxy-5-methoxybenzoate in the same manner as in Step 2. I got it. This was dissolved in ethanol (80 mL), 4 mol / L aqueous sodium hydroxide solution (40 mL) was added at room temperature, and the mixture was stirred at 50 ° C. for 40 min. The reaction mixture was cooled to room temperature, 6 mol / L hydrochloric acid was added, and the precipitated solid was collected by filtration and dried to obtain Compound R31 (9.05 g, quantitative yield).
ESI-MS: m / z 272 [M-H] ⁺
Step 4: 4-Bromo-3-ethoxy-5-methoxybenzonitrile (Compound R32)
Compound R31 (941 mg, 3.42 mmol) dissolved in THF (25 mL), 28% aqueous ammonia (694 μL, 10.3 mmol), 1-hydroxybenzotriazole monohydrate (1.57 g, 10.3 mmol) at room temperature And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.95 mL, 10.3 mmol) was added and stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, the residue was dissolved in dichloromethane (15 mL), triethylamine (1.43 mL, 10.3 mmol) and trifluoroacetic anhydride (966 μL, 6.84 mmol) were added at room temperature, and the mixture was stirred for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 19: 1-3: 1) to give compound R32 (820 mg, 94%).

Step 5: 4-Cyano-2-ethoxy-6-methoxyphenylboronic acid (Compound R33)
Compound R32 (4.65 g, 18.2 mmol) was dissolved in THF (93 mL), and n-butyllithium-n-hexane solution (2.66 mol / L, 10.2 mL, 27.2 mmol) was added at -93 ° C, followed by stirring for 10 minutes. did. Trimethyl borate (6.09 mL, 54.5 mmol) was added and stirred for 20 minutes. Hydrochloric acid was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4: 1 to 0: 1) to obtain Compound R33 (3.57 g, 89%).
ESI-MS: m / z222 [M + H] ⁺
Step 6: 3-iodoquinoline-2-carbaldehyde (Compound R34)
In an argon atmosphere, compound R10 (1.09 g, 3.33 mmol) was dissolved in toluene (20 mL), and a diisobutylaluminum hydride-toluene solution (1.0 mol / L, 6.66 mL, 6.66 mmol) was added at -78 ° C. Stir for 90 minutes. Methanol (5.0 mL) was added little by little to the reaction mixture, and the mixture was warmed to room temperature. Then, saturated potassium sodium tartrate aqueous solution was added, stirred for 30 minutes, and extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9: 1 to 3: 2) to obtain Compound R34 (901 mg, 96%).
ESI-MS: m / z283 [M + H] ⁺
Step 7: 3- (4-Cyano-2-ethoxy-6-methoxyphenyl) quinoline-2-carbaldehyde (Compound R35)
Compound R35 (521 mg, 64%) was obtained according to Step 4 of Reference Example 4 using Compound R34 (666 mg, 2.35 mmol) and Compound R33 (608 mg, 2.59 mmol).
ESI-MS: m / z347 [M + H] ⁺

2- (2-Ethoxyphenyl) -3- [1- (4-methyl-1,4-diazepan-1-yl) ethyl] quinoxaline 1-oxide (Compound 1)
Compound R4 (122 mg, 0.393 mmol) was dissolved in dichloromethane (3.0 mL), triethylamine (0.275 mL, 1.97 mmol) and methanesulfonyl chloride (0.152 mL, 0.197 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (hexane / ethyl acetate = 7/3) to obtain a crude product (154 mg). This was dissolved in THF (5.0 mL), N-methylhomopiperazine (0.0985 mL, 0.792 mmol) and tetrabutylammonium iodide (14.8 mg, 0.040 mmol) were added, and the mixture was stirred at 50 ° C. for 8 hours. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol = 17/3) to obtain Compound 1 (109 mg, yield 68%).
ESI-MS m / z: 407 [M + H] ⁺ ; ¹ H-NMR (300 MHz, CDCl ₃ , δ): 1.19 (t, J = 6.6 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 1.57-1.66 (m, 2H), 2.27 (s, 3H), 2.29-2.82 (m, 8H), 4.00-4.12 (m, 3H), 7.02-7.09 (m, 2H), 7.18 (dd, J = 1.8, 7.3 Hz, 1H), 7.42-7.48 (m, 1H), 7.66-7.71 (m, 1H), 7.75-7.81 (m, 1H), 8.14 (dd, J = 1.5, 8.4 Hz, 1H) , 8.59 (dd, J = 1.5, 8.4 Hz, 1H).

The following compounds were synthesized according to the synthesis method of Compound 1.

2- (2-Ethoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline 1-oxide (Compound 5); ESI-MS m / z: 393 [M + H ] ⁺
2- [2-Ethoxy-4- (trifluoromethoxy) phenyl] -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline 1-oxide (Compound 6); ESI-MS m / z: 477 [M + H] ⁺
6-amino-2- (2-ethoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline 1-oxide (Compound 10); ESI-MS m / z: 408 [M + H] ⁺
2- [2-Ethoxy-6-methoxy-4- (4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) phenyl] -3-[(4 -Methyl-1,4-diazepan-1-yl) methyl] quinoxaline 1-oxide (Compound 11); ESI-MS m / z: 521 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.20 (t, J = 7.0 Hz, 3H), 1.58-1.65 (m, 2H), 2.28 (s, 3H), 2.34-2.43 (m, 2H), 2.45-2.53 (m, 2H), 2.54 -2.66 (m, 4H), 3.55 (s, 3H), 3.70 (s, 2H), 3.81 (s, 3H), 4.02-4.16 (m, 2H), 7.14 (s, 2H), 7.71 (ddd, J = 8.5, 7.0, 1.1 Hz, 1H), 7.81 (ddd, J = 8.4, 7.0, 1.1 Hz, 1H), 8.16 (dd, J = 8.4, 1.1 Hz, 1H), 8.60 (dd, J = 8.5, 1.1 Hz, 1H).
2- [2-Ethoxy-6-methoxy-4- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl] -3-[(4-methyl-1,4-diazepan-1 -Yl) methyl] quinoxaline 1-oxide (compound 12); ESI-MS m / z: 505 [M + H] ⁺
6-amino-2- (2,6-diethoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline 1-oxide (compound 13); ESI-MS m / z: 452 [M + H] ⁺
6-amino-2- (2-ethoxy-6-methoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline 1-oxide (compound 14); ESI-MS m / z: 438 [M + H] ⁺
3- (2-Ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline 1-oxide (Compound 15); ESI-MS: m / z 393 [M + H ] ⁺

2- (2-Ethoxyphenyl) -3- [1- (4-methyl-1,4-diazepan-1-yl) ethyl] quinoxaline (Compound 2)
Compound R5 (100 mg, 0.340 mmol) was dissolved in dichloromethane (2.00 mL), triethylamine (0.142 mL, 1.02 mmol) was added, and the mixture was cooled to 0 ° C. using an ice bath. The mesyl chloride (0.053 mL, 0.680 mmol) was added there, and it stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue were added THF (2.00 mL) and N-methylhomopiperazine (0.211 mL, 1.70 mmol), and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 1 / 0-5 / 1) to obtain Compound 2 (98.0 mg, 74.0%).
ESI-MS m / z: 391 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.18 (t, J = 7.0 Hz, 3H), 1.24-1.61 (m, 5H), 2.03-2.72 (m, 11H), 3.91-4.11 (m, 2H), 4.21 (q, J = 6.6 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 7.5 Hz , 1H), 7.35-7.50 (m, 2H), 7.66-7.78 (m, 2H), 8.08-8.17 (m, 2H).

2- (2-Ethoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline (compound 3)
Compound R7 (70.0 mg, 0.250 mmol) was dissolved in dichloromethane (1.50 mL), triethylamine (0.101 mL, 0.749 mmol) was added, and the mixture was cooled to 0 ° C. using an ice bath. The mesyl chloride (0.0380 mL, 0.500 mmol) was added there, and it stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue were added THF (1.50 mL) and N-methylhomopiperazine (0.062 mL, 0.500 mmol), and the mixture was stirred at 50 ° C. for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 85/15 to 1/1) to obtain Compound 3 (48.0 mg, 51.0%).
ESI-MS m / z: 377 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.20 (t, J = 6.9 Hz, 3H), 1.59-1.67 (m, 2H), 2.26 (s, 3H), 2.35-2.38 (m, 2H), 2.46-2.50 (m, 2H), 2.55-2.67 (m, 4H), 3.94 (s, 2H), 4.02 (q, J = 6.9 Hz, 2H), 6.96-6.99 (m, 1H), 7.07-7.12 (m, 1H), 7.38-7.44 (m, 2H), 7.69-7.78 (m, 2H), 8.10-8.18 (m, 2H).

The following compounds were synthesized according to the synthesis method of Compound 3.

4-{[(3- (2-Ethoxyphenyl) quinoxalin-2-yl] methyl} -1,4-diazabicyclo [3.2.2] nonane (Compound 16); ESI-MS m / z: 389 [M + H ] ⁺
{1-{[3- (2-Ethoxyphenyl) quinoxalin-2-yl] methyl} -4-methyl-1,4-diazepan-6,6-diyl} dimethanol (Compound 17); ESI-MS m / z: 437 [M + H] ⁺
1-{[3- (2-Ethoxyphenyl) quinoxalin-2-yl] methyl} -4-methyl-1,4-diazepan-6-carboxylate (Compound 18); ESI-MS m / z: 435 [ M + H] ⁺
1-{[3- (2-Ethoxyphenyl) quinoxalin-2-yl] methyl} -1,4-diazepan-6-carboxylate methyl compound (Compound 19); ESI-MS m / z: 421 [M + H] ⁺
1-{[3- (2-Ethoxyphenyl) quinoxalin-2-yl] methyl} -4-methyl-1,4-diazepan-6-ol (Compound 20); ESI-MS m / z: 393 [M + H] ⁺
1-{[3- (2-Ethoxyphenyl) quinoxalin-2-yl] methyl} -1,4-diazepan-6-ol (Compound 21); ESI-MS m / z: 379 [M + H] ⁺
2- (2-Ethoxyphenyl) -3-[(4-methylpiperazin-1-yl) methyl] quinoxaline (Compound 26); ESI-MS m / z: 363 [M + H] ⁺
2- (2-Ethoxyphenyl) -3- (piperazin-1-ylmethyl) quinoxaline (Compound 27); ESI-MS m / z: 349 [M + H] ⁺

4-{[3- (2-Ethoxyphenyl) quinoxalin-2-yl] methyl} piperazine-1-carboxylate tert-butyl (compound 28); ESI-MS m / z: 449 [M + H] ⁺
2- {4-{[3- (2-Ethoxyphenyl) quinoxalin-2-yl] methyl} -1,4-diazepan-1-yl} ethanamine (Compound 29); ESI-MS m / z: 406 [M + H] ⁺
2- {4-{[3- (2-Ethoxyphenyl) quinoxalin-2-yl] methyl} -1,4-diazepan-1-yl} acetonitrile (Compound 30); ESI-MS m / z: 402 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.20 (t, J = 6.9 Hz, 3H), 1.59-1.71 (m, 2H), 2.46-2.71 (m, 8H), 3.46 (s, 2H), 3.84-4.16 (m, 4H), 6.99 (d, J = 8.6 Hz, 1H), 7.09-7.17 (m, 1H), 7.38-7.47 (m, 2H), 7.69-7.80 (m , 2H), 8.09-8.18 (m, 2H).
2- (2-Ethoxyphenyl) -3-[(4-isopropyl-1,4-diazepan-1-yl) methyl] quinoxaline (Compound 31); ESI-MS m / z: 405 [M + H] ⁺
2- {4-{[3- (2-Ethoxyphenyl) quinoxalin-2-yl] methyl} -1,4-diazepan-1-yl} methyl acetate (Compound 32); ESI-MS m / z: 435 [ M + H] ⁺
2- (2-Ethoxyphenyl) -3-{[4- (2-methoxyethyl) -1,4-diazepan-1-yl] methyl} quinoxaline (Compound 33); ESI-MS m / z: 421 [M + H] ⁺
2- (2-Ethoxyphenyl) -3-{[4- (methylsulfonyl) -1,4-diazepan-1-yl] methyl} quinoxaline (Compound 34); ESI-MS m / z: 441 [M + H ] ⁺
1- {4-{[3- (2-Ethoxyphenyl) quinoxalin-2-yl] methyl} -1,4-diazepan-1-yl} ethanone (Compound 35); ESI-MS m / z: 405 [M + H] ⁺
2- (2-Ethoxyphenyl) -3-[(4-ethyl-1,4-diazepan-1-yl) methyl] quinoxaline (Compound 36); ESI-MS m / z: 391 [M + H] ⁺
2-[(1,4-diazepan-1-yl) methyl] -3- (2-ethoxyphenyl) quinoxaline (Compound 37); ESI-MS m / z: 363 [M + H] ⁺
4-{[3- (2-Ethoxyphenyl) quinoxalin-2-yl] methyl} -1,4-diazepane-1-carboxylate tert-butyl (compound 38); ESI-MS m / z: 463 [M + H] ⁺
2- [2-Ethoxy-4- (trifluoromethoxy) phenyl] -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline (Compound 53); ESI-MS m / z: 461 [M + H] ⁺

3- (2-Ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (compound 4)
Compound R12 (78.0 mg, 0.279 mmol) was dissolved in dichloromethane (2.00 mL), triethylamine (0.117 mL, 0.838 mmol) was added, and the mixture was cooled to 0 ° C. using an ice bath. The mesyl chloride (0.432 mL, 0.558 mmol) was added there, and it stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. THF (2.00 mL) and N-methylhomopiperazine (0.174 mL, 1.40 mmol) were added to the residue, and the mixture was stirred at 70 ° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 1 / 0-7 / 1) to give compound 4 (50.6 mg, 48.7%).
ESI-MS m / z: 376 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.21 (t, J = 7.0 Hz, 3H), 1.54-1.68 (m, 2H), 2.26 (s, 3H), 2.29-2.70 (m, 8H), 3.88 (s, 2H), 4.01 (q, J = 7.0 Hz, 2H), 6.98 (d, J = 8.1 Hz, 1H), 7.00-7.08 (m, 1H), 7.23-7.40 (m, 2H), 7.48-7.56 (m, 1H), 7.65-7.73 (m, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.94 (s, 1H ), 8.15 (d, J = 8.8 Hz, 1H).

The following compounds were synthesized according to the synthesis method of Compound 4.

2- (2-Ethoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] -6-nitroquinoxaline (Compound 41); ESI-MS: m / z 422 [M + H] ⁺
3- (2-Ethoxy-4-fluorophenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 60); ESI-MS: m / z 394 [M + H] ⁺
3- (2-Isopropyloxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 61); ESI-MS: m / z 390 [M + H] ⁺
3- (4,5-Difluoro-2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 62); ESI-MS: m / z 412 [ M + H] ⁺
3- (2,4-Diethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 63); ESI-MS: m / z 420 [M + H ] ⁺
3- (6-Fluoro-2-n-propyloxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 64); ESI-MS: m / z 408 [M + H] ⁺
3- (2,6-diethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 65); ESI-MS: m / z 420 [M + H ] ⁺

3- (2-Ethoxy-4-trifluoromethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 66); ESI-MS: m / z 460 [ M + H] ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ , δ): 1.23 (t, J = 7.0 Hz, 3H), 1.54-1.62 (m, 2H), 2.24 (s, 3H), 2.30 (t , J = 4.8 Hz, 2H), 2.44 (t, J = 5.7 Hz, 2H), 2.51-2.58 (m, 4H), 3.85 (s, 2H), 4.01 (q, J = 7.0 Hz, 2H), 6.80 -6.81 (m, 1H), 6.92 (dq, J = 8.4, 1.1 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.50-7.56 (m, 1H), 7.68-7.73 (m, 1H ), 7.79 (dd, J = 8.1, 1.1 Hz, 1H), 7.92 (s, 1H), 8.14 (d, J = 7.7 Hz, 1H).
3- (2-Benzyloxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 67); ESI-MS: m / z 438 [M + H] ⁺
3- (2,4,6-trimethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 68); ESI-MS: m / z 422 [M + H] ⁺
3- (2-Hydroxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 69); ESI-MS: m / z 348 [M + H] ⁺
3- (4-tert-butyl-2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 76); ESI-MS: m / z 432 [ M + H] ⁺
3- [2,6-Diethoxy-4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl ) Methyl] quinoline (Compound 118); ESI-MS: m / z 502 [M + H] ⁺

3- [2,6-Diethoxy-4- (1,2,4-oxadiazol-3-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 119); ESI-MS: m / z 488 [M + H] ⁺
3- [2,6-Diethoxy-4- (4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) phenyl] -2-[(4-methyl -1,4-diazepan-1-yl) methyl] quinoline (compound 120); ESI-MS: m / z 518 [M + H] ⁺ ; ¹ H NMR (270 MHz, CDCl ₃ , δ): 1.18 (t , J = 6.9 Hz, 6H), 1.53-1.63 (m, 2H), 2.24 (s, 3H), 2.30-2.35 (m, 2H), 2.42-2.48 (m, 2H), 2.50-2.59 (m, 4H ), 3.54 (s, 3H), 3.80 (m, 2H), 4.03 (q, J = 6.9 Hz, 4H), 7.10 (s, 2H), 7.49 (ddd, J = 1.1, 6.9, 8.1 Hz, 1H) , 7.69 (ddd, J = 1.5, 6.9, 8.1 Hz, 1H), 7.79 (dd, J = 1.5, 8.1 Hz, 1H), 7.91 (s, 1H), 8.14 (dd, J = 1.1, 8.1 Hz, 1H ).
3- [2,6-Diethoxy-4- (4-cyanomethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) phenyl] -2-[(4-methyl -1,4-diazepan-1-yl) methyl] quinoline (Compound 127); ESI-MS: m / z 543 [M + H] ⁺
3- [2-Ethoxy-6-methoxy-4- (4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) phenyl] -2-[(4 -Methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 128); ESI-MS: m / z 504 [M + H] ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ , δ): 1.19 (t, J = 7.0 Hz, 3H), 1.53-1.62 (m, 2H), 2.25 (s, 3H), 2.30-2.35 (m, 2H), 2.43-2.48 (m, 2H), 2.50-2.58 (m , 4H), 3.55 (s, 3H), 3.75-3.79 (m, 5H), 4.00-4.08 (m, 2H), 7.10-7.12 (m, 2H), 7.51 (ddd, J = 1.1, 6.9, 8.1 Hz , 1H), 7.70 (ddd, J = 1.5, 6.9, 8.4 Hz, 1H), 7.79 (dd, J = 1.5, 8.1 Hz, 1H), 7.90 (s, 1H), 8.14 (dd, J = 1.1, 8.4 Hz, 1H).

4-chloro-3- (2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 134); ESI-MS m / z: 410 [M + H] ⁺
3- (2-Ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] -4- (methylthio) quinoline (Compound 135); ESI-MS m / z: 422 [ M + H] ⁺
6-chloro-3- (2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 136); ESI-MS: m / z 410 [M + H] ⁺
5-chloro-3- (2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (compound 137); ESI-MS: m / z 410 [M + H] ⁺
8-chloro-3- (2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 138); ESI-MS: m / z 410 [M + H] ⁺
7-chloro-3- (2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 139); ESI-MS: m / z 410 [M + H] ⁺
3- (2-Ethoxyphenyl) -4-methoxy-2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 140); ESI-MS m / z: 406 [M + H] ⁺
3- (2-Ethoxyphenyl) -4-methyl-2-((4-methyl-1,4-diazepan-1-yl) methyl) quinoline (Compound 141); ESI-MS m / z: 390 [M + H] ⁺

N- (diphenylmethylene) -3- (2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinolin-7-amine (Compound 142); ESI-MS m / z: 555 [M + H] ⁺
3- (2-Ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinolin-7-amine (Compound 143); ESI-MS m / z: 393 [M + H] ⁺
3- (2-Ethoxyphenyl) -7- (4-methoxybenzyloxy) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 144); ESI-MS m / z: 512 [M + H] ⁺
3- (2-Ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline-4-carbonitrile (Compound 145); ESI-MS m / z: 401 [M + H] ⁺
7-ethoxy-3- (2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 146); ESI-MS: m / z 420 [M + H] ⁺
3- (2-Ethoxyphenyl) -7-methanesulfonyloxy-2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 147); ESI-MS: m / z 470 [ M + H] ⁺
4-Chloro-3- (2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinolin-7-amine (Compound 148); ESI-MS m / z: 425 [M + H] ⁺
7-Amino-3- (2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline-4-carbonitrile (Compound 149); ESI-MS m / z : 416 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.21 (t, J = 7.0 Hz, 3H), 1.57-1.67 (m, 2H), 2.27 (s, 3H) , 2.30-2.68 (m, 8H), 3.64-3.83 (m, 2H), 4.04 (q, J = 7.0 Hz, 2H), 4.19 (br s, 2H), 6.97-7.14 (m, 3H), 7.25- 7.32 (m, 2H), 7.37-7.44 (m, 1H), 7.97 (d, J = 8.8 Hz, 1H).

2- [3- (2-Ethoxyphenyl) quinolin-2-yl] -2- (4-methyl-1,4-diazepan-1-yl) acetonitrile (Compound 150); ESI-MS m / z: 401 [ M + H] ⁺
3- (3-Chloropyridin-4-yl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 151); ESI-MS: m / z 367 [M + H] ⁺
3- [2-Ethoxy-4- (trifluoromethoxy) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinolin-7-amine (Compound 152); ESI-MS : m / z 475 [M + H] ⁺
4- {4-Chloro-2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinolin-3-yl} -3,5-diethoxybenzonitrile (Compound 153); ESI-MS m / z: 480 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.18 (t, J = 7.1 Hz, 6H), 1.53-1.69 (m, 2H), 2.28 (s , 3H), 2.31-2.64 (m, 8H), 3.67 (s, 2H), 4.02 (q, J = 7.1 Hz, 4H), 6.91 (s, 2H), 7.63 (ddd, J = 8.3, 6.9, 1.1 Hz, 1H), 7.77 (ddd, J = 8.6, 6.9, 1.3 Hz, 1H), 8.15 (dd, J = 8.6, 1.1 Hz, 1H), 8.26 (dd, J = 8.3, 1.3 Hz, 1H).
4- {4-Chloro-2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinolin-3-yl} -3-ethoxyphenyl methanesulfonate (Compound 154); ESI-MS m / z: 505 [M + H] ⁺
4- {4-cyano-2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinolin-3-yl} -3-ethoxyphenyl methanesulfonate (Compound 155); ESI-MS m / z: 495 [M + H] ⁺
3- (2-Ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline-4-carboxamide (Compound 156); ESI-MS m / z: 419 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.22 (t, J = 6.9 Hz, 3H), 1.56-1.76 (m, 2H), 2.29 (s, 3H), 2.35-2.74 ( m, 8H), 3.65 (s, 2H), 3.94-4.18 (m, 2H), 5.49 (s, 1H), 6.00 (s, 1H), 6.97 (d, J = 8.2 Hz, 1H), 7.00-7.08 (m, 1H), 7.23-7.42 (m, 2H), 7.58 (ddd, J = 8.3, 6.9, 1.1 Hz, 1H), 7.74 (ddd, J = 8.6, 6.9, 1.3 Hz, 1H), 8.03 (dd , J = 8.6, 1.1 Hz, 1H), 8.17 (dd, J = 8.3, 1.3 Hz, 1H).

4- {4-Chloro-2-[(6-hydroxy-4-methyl-1,4-diazepan-1-yl) methyl] quinolin-3-yl} -3-ethoxy-5-methoxybenzonitrile (Compound 157 ); ESI-MS m / z: 495 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.13-1.24 (m, 3H), 2.38 (s, 3H), 2.42-2.90 (m, 8H), 3.55-3.80 (m, 6H), 3.96-4.13 (m, 2H), 6.93-7.00 (m, 2H), 7.63 (ddd, J = 8.3, 6.8, 0.9 Hz, 1H), 7.77 (ddd, J = 8.5, 6.8, 1.2 Hz, 1H), 8.17 (dd, J = 8.5, 0.9 Hz, 1H), 8.24 (dd, J = 8.3, 1.2 Hz, 1H).
4- {4-Chloro-2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinolin-3-yl} -3-ethoxy-5-methoxybenzonitrile (Compound 158); ESI- MS m / z: 465 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.18 (t, J = 7.0 Hz, 3H), 1.53-1.65 (m, 2H), 2.27 ( s, 3H), 2.32-2.38 (m, 2H), 2.45-2.58 (m, 6H), 3.65 (s, 2H), 3.75 (s, 3H), 4.02 (q, J = 7.0 Hz, 2H), 6.91 -6.96 (m, 2H), 7.63 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 7.77 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H), 8.17 (dd, J = 8.4, 1.3 Hz , 1H), 8.24 (dd, J = 8.2, 1.5 Hz, 1H).
3,5-diethoxy-4- {2- [1- (4-methyl-1,4-diazepan-1-yl) ethyl] quinolin-3-yl} benzonitrile (Compound 159); ESI-MS m / z : 459 [M + H] ⁺

4- {7-Amino-2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinolin-3-yl} -3,5-diethoxybenzonitrile (Compound 160); ESI-MS m / z: 460 [M + H] ⁺
5- {4- {4-Chloro-2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinolin-3-yl} -3-ethoxy-5-methoxyphenyl} -3-methyl -1,3,4-oxadiazol-2 (3H) -one (Compound 162); ESI-MS m / z: 538 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ) : 1.11 (t, J = 7.0 Hz, 3H), 1.49-1.61 (m, 2H), 2.22 (s, 3H), 2.27-2.37 (m, 2H), 2.40-2.58 (m, 6H), 3.48 (s , 3H), 3.62 (s, 2H), 3.71 (s, 3H), 3.99 (q, J = 7.0 Hz, 2H), 7.06 (s, 2H), 7.55 (ddd, J = 8.5, 7.0, 1.2 Hz, 1H), 7.69 (ddd, J = 8.5, 7.0, 1.2 Hz, 1H), 8.08 (dd, J = 8.5, 1.2 Hz, 1H), 8.19 (dd, J = 8.5, 1.2 Hz, 1H).
4-Chloro-3- [2-ethoxy-6-methoxy-4- (2-methyl-2H-tetrazol-5-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl ) Methyl] quinoline (Compound 163); ESI-MS: m / z 522 [M + H] ⁺
3- [2-Ethoxy-6- (2-methoxyethoxy) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 164); ESI-MS: m / z 450 [M + H] ⁺

2- (4-Cyano-2,6-diethoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline 1-oxide (Compound 7)
Compound R21 (18.0 mg, 0.0500 mmol) is dissolved in THF (1.7 mL), 1-methylhomopiperazine (12.0 μL, 0.0990 mmol), sodium triacetoxyborohydride (21.0 mg, 0.0990 mmol) and acetic acid at room temperature (1.40 μL) was added and stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by amino silica gel chromatography (manufactured by Yamazen, amino 40 μm syringe type, ethyl acetate / methanol = 1: 0-19: 1) to give compound 7 (18.0 mg, yield) 78%).
ESI-MS m / z: 462 [M + H] ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ , δ): 1.20 (t, J = 7.0 Hz, 6H), 1.54-1.68 (m, 2H), 2.28 (s, 3H), 2.34-2.41 (m, 2H), 2.45-2.63 (m, 6H), 3.70 (s, 2H), 3.99-4.11 (m, 4H), 6.92 (s, 2H), 7.67-7.76 (m, 1H), 7.78-7.86 (m, 1H), 8.12-8.19 (m, 1H), 8.55-8.62 (m, 1H).

The following compounds were synthesized according to the synthesis method of Compound 7.

2- (4-Cyano-2-ethoxy-6-methoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline 1-oxide (Compound 8); ESI-MS m / z: 448 [M + H] ⁺ ; ¹ H-NMR (270 MHz, CDCl ₃ , δ): 1.20 (t, J = 7.0 Hz, 3H), 1.56-1.67 (m, 2H), 2.29 (s, 3H), 2.31-2.42 (m, 2H), 2.44-2.64 (m, 6H), 3.68 (s, 2H), 3.78 (s, 3H), 3.99-4.11 (m, 2H), 6.92-6.96 (m, 2H), 7.72 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.82 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H), 8.15 (dd, J = 8.4, 1.4 Hz, 1H), 8.59 (dd, J = 8.4, 1.5 Hz, 1H).
2- (4-Cyano-2,6-dimethoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline 1-oxide (Compound 9); ESI-MS m / z : 434 [M + H] ⁺

4- {6-Amino-3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxalin-2-yl} -3-ethoxy-5-methoxybenzonitrile (Compound 57)
Compound R28 (45.0 mg, 0.094 mmol) is dissolved in a mixed solvent of ethanol (1.60 mL) and water (0.800 mL), ammonium chloride (5.05 mg, 0.094 mmol) and reduced iron (16.0 mg, 0.283 mmol) are added, Stir at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in THF (3.00 mL), 1-methyl-1,4-diazepane (0.076 mL, 0.611 mmol) was added, and the mixture was stirred at 80 ° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification using reverse phase liquid chromatography (Waters, SunFire Prep C18 OBD Column, 5 μm, 19 × 100 mm, 0.01 mol / L aqueous ammonium acetate / methanol = 9/1 to 1/9) gave compound 57 (20.0 mg, 47%).
ESI-MS m / z: 447 [M + H] ⁺ ; ¹ H-NMR (270 MHz, DMSO, δ): 1.06 (t, J = 6.9 Hz, 3H), 1.37-1.50 (m, 2H), 2.13 (s, 3H), 2.14-2.22 (m, 2H), 2.23-2.43 (m, 6H), 3.47-3.61 (m, 2H), 3.71 (s, 3H), 3.95-4.11 (m, 2H), 5.99 (br s, 2H), 6.91 (d, J = 2.3 Hz, 1H), 7.17 (dd, J = 9.2, 2.3 Hz, 1H), 7.25 (s, 2H), 7.66 (d, J = 9.2 Hz, 1H ).

The following compounds were synthesized according to the synthesis method of Compound 57.

6-amino-2- (2-ethoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline (Compound 39); ESI-MS: m / z 392 [M + H] ⁺
6-amino-3- (2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline (Compound 40); ESI-MS: m / z392 [M + H ] ⁺
6-Bromo-3- (2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline (Compound 42); ESI-MS m / z: 455 [M + H] ⁺
6-Bromo-2- (2-ethoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline (Compound 43); ESI-MS m / z: 455 [M + H] ⁺
n-propyl 2- (2-ethoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline-6-carboxylate (compound 44); ESI-MS m / z: 463 [M + H] ⁺
2- (2-Ethoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline-6-carbonitrile (Compound 45); ESI-MS m / z: 402 [M + H] ⁺
3- (2-Ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline-6-carbonitrile (Compound 46); ESI-MS m / z: 402 [M + H] ⁺

n-propyl 3- (2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline-6-carboxylate (compound 47); ESI-MS m / z: 463 [M + H] ⁺
{3- (2-Ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxalin-6-yl} methanol (Compound 48); ESI-MS m / z: 407 [M + H] ⁺
2- (2-Ethoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] -6- (1-methyl-1H-pyrazol-4-yl) quinoxaline (Compound 49) ; ESIMS m / z: 457 [M + H] ⁺
3- (2-Ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline-6-carboxamide (Compound 50); ESIMS m / z: 420 [M + H ] ⁺
3- {2- (2-ethoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxalin-6-ylamino} propane-1,2-diol (Compound 51); ESI-MS m / z: 466 [M + H] ⁺
N- {2- (2-ethoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxalin-6-yl} propane-1,3-diamine (Compound 52); ESI-MS m / z: 449 [M + H] ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ , δ): 1.20 (t, J = 7.0 Hz, 3H), 1.48-1.75 (m, 4H), 2.00 -2.10 (m, 2H), 2.27 (s, 3H), 2.30-2.70 (m, 8H), 3.33-3.45 (m, 2H), 3.75-3.93 (m, 2H), 3.94-4.06 (m, 2H) , 6.94 (d, J = 8.1 Hz, 1H), 7.00-7.10 (m, 3H), 7.32-7.41 (m, 2H), 7.80-7.87 (m, 1H).
ESI-MS m / z: 449 [M + H] ⁺

2- (2-Chlorophenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxaline-6-amine (Compound 54); ESI-MS m / z: 382 [M + H ] ⁺
2- (2-Ethoxyphenyl) -3- [1- (4-methyl-1,4-diazepan-1-yl) ethyl] quinoxaline-6-amine (Compound 55); ESI-MS m / z: 406 [ M + H] ⁺
3,5-diethoxy-4- {3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxalin-2-yl} benzonitrile (Compound 56); ESI-MS m / z: 446 [M + H] ⁺
N-benzyl-2- (2-ethoxyphenyl) -3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxalin-6-amine (Compound 58); ESI-MS m / z: 482 [M + H] ⁺
3-Ethoxy-5-methoxy-4- {3-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoxalin-2-yl} benzonitrile (Compound 59); ESI-MS m / z : 432 [M + H] ⁺

3- (4-Cyano-2-ethoxy-6-methoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 108)
Compound R35 (200 mg, 0.602 mmol) is dissolved in THF (5.0 mL) and 1-methylhomopiperazine (112 μL, 0.903 mmol), sodium triacetoxyborohydride (383 mg, 1.81 mmol) and acetic acid are dissolved at room temperature. (50.0 μL) was added and stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by amino silica gel column chromatography (manufactured by Yamazen, amino 40 μm syringe type, ethyl acetate / methanol = 1: 0 to 17: 1) to give compound 108 (210 mg, 81%).
ESI-MS: m / z431 [M + H] ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ , δ): 1.19 (t, J = 7.0 Hz, 3H), 1.50-1.60 (m, 2H), 2.25 ( s, 3H), 2.27-2.32 (m, 2H), 2.41-2.54 (m, 6H), 3.74 (s, 3H), 3.75 (s, 2H), 4.00 (q, J = 7.0 Hz, 2H), 6.90 -6.93 (m, 2H), 7.52 (ddd, J = 1.1, 6.9, 8.1 Hz, 1H), 7.71 (ddd, J = 1.4, 6.9, 8.4 Hz, 1H), 7.79 (dd, J = 1.4, 8.1 Hz , 1H), 7.87 (s, 1H), 8.14 (dd, J = 1.1, 8.4 Hz, 1H).

The following compounds were synthesized according to the synthesis method of Compound 108.

3- (2,6-Dichlorophenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 70); ESI-MS: m / z 400 [M + H] ⁺
3- (2-Chlorophenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 71); ESI-MS: m / z 366 [M + H] ⁺
3- (2-Ethoxy-4-hydroxymethylphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 72); ESI-MS: m / z 406 [M + H] ⁺
3- (2-Ethoxy-4-nitrophenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 73); ESI-MS: m / z 421 [M + H] ⁺
3- (4-Amino-2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (compound 74); ESI-MS: m / z 391 [M + H] ⁺
3- (4-Cyano-2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 75); ESI-MS: m / z 401 [M + H] ⁺
3- (2-Ethoxy-4-methoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 77); ESI-MS: m / z 406 [M + H] ⁺
3- (2-Ethoxy-4-hydroxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 78); ESI-MS: m / z 392 [M + H] ⁺
3- (2-Chloro-4-cyanophenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 79); ESI-MS: m / z 391 [M + H] ⁺

3- (4-Isopropyloxy-2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 80); ESI-MS: m / z 434 [M + H] ⁺
3- [2-Ethoxy-4- (thiazol-2-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 81); ESI-MS: m / z 459 [M + H] ⁺
3- [2- (2-Fluoroethoxy) -4-trifluoromethoxyphenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 82); ESI-MS: m / z 458 [(M－HF) + H] ⁺
3- [2- (2-methoxyethoxy) -4-trifluoromethoxyphenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 83); ESI-MS: m / z 490 [M + H] ⁺
3- [2-Ethoxy-4- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl ] Quinoline (compound 84); ESI-MS: m / z 458 [M + H] ⁺
3- (2-Ethoxy-4-methanesulfonyloxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 85); ESI-MS: m / z 470 [ M + H] ⁺
3- (4-Chloro-2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 86); ESI-MS: m / z 410 [M + H] ⁺
3- [2-Ethoxy-4- (oxazol-2-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 87); ESI-MS: m / z 443 [M + H] ⁺
3- (4-Cyano-2,6-diethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 88); ESI-MS: m / z 445 [M + H] ⁺

3- (4-Cyanomethoxy-2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 89); ESI-MS: m / z 431 [M + H] ⁺
3- (4-tert-Butoxycarbonylamino-2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 90); ESI-MS: m / z 491 [M + H] ⁺
3- (2-Ethoxy-4-methoxycarbonylmethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 91); ESI-MS: m / z 464 [ M + H] ⁺
3- [2-Ethoxy-4- (thiazol-2-yloxy) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 92); ESI-MS: m / z 475 [M + H] ⁺
3- (2-Ethoxy-4-methylaminophenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 93); ESI-MS: m / z 405 [M + H] ⁺
3- (4-Carbamoyl-2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 94); ESI-MS: m / z 419 [M + H] ⁺
3- (4-Dimethylcarbamoyl-2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 95); ESI-MS: m / z 447 [M + H] ⁺
3- (4-Ethanesulfonyloxy-2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 96) ESI-MS: m / z 484 [M + H] ⁺
3- [2,6-Diethoxy-4- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl ) Methyl] quinoline (Compound 97); ESI-MS: m / z 502 [M + H] ⁺

3- (2-Ethoxy-6-methoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 98); ESI-MS: m / z 406 [M + H] ⁺
3- (2-Ethoxy-6-fluorophenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 99); ESI-MS: m / z 394 [M + H] ⁺
3- (2-Ethoxy-6-hydroxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 100); ESI-MS: m / z 392 [M + H] ⁺
3- (2-Cyanomethoxy-6-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 101); ESI-MS: m / z 431 [M + H] ⁺
3- (2-Ethoxy-6-methoxycarbonylmethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 102); ESI-MS: m / z 464 [ M + H] ⁺
3- [2-Ethoxy-4- (pyrimidin-5-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 103); ESI-MS: m / z 454 [M + H] ⁺
3- (2,6-Dimethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 104); ESI-MS: m / z 392 [M + H] ⁺

3- [2-Ethoxy-4- (pyridin-4-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 105); ESI-MS: m / z 453 [M + H] ⁺
3- [2-Ethoxy-4- (pyridin-3-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 106); ESI-MS: m / z 453 [M + H] ⁺
3- [2-Ethoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 107) ; ESI-MS: m / z 456 [M + H] ⁺
3- [2-Ethoxy-4- (5-methyl-1,3,4-oxadiazol-2-yl) -6-methoxyphenyl] -2-[(4-methyl-1,4-diazepan-1 -Yl) methyl] quinoline (Compound 109); ESI-MS: m / z 488 [M + H] ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ , δ): 1.20 (t, J = 7.0 Hz, 3H) , 1.52-1.61 (m, 2H), 2.23 (s, 3H), 2.30-2.35 (m, 2H), 2.42-2.47 (m, 2H), 2.50-2.58 (m, 4H), 2.67 (s, 3H) , 3.78-3.80 (m, 5H), 4.04-4.12 (m, 2H), 7.30-7.32 (m, 2H), 7.52 (ddd, J = 1.1, 6.9, 8.1 Hz, 1H), 7.70 (ddd, J = 1.5, 6.9, 8.1 Hz, 1H), 7.80 (dd, J = 1.5, 8.1 Hz, 1H), 7.92 (s, 1H), 8.15 (dd, J = 1.1, 8.1 Hz, 1H).
3- [2-Cyanomethoxy-6-ethoxy-4- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl] -2-[(4-methyl-1,4-diazepane- 1-yl) methyl] quinoline (compound 110); ESI-MS: m / z 513 [M + H] ⁺

3- (2-methoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 111); ESI-MS: m / z 362 [M + H] ⁺
3- (6-Cyano-2-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 112); ESI-MS: m / z 401 [M + H] ⁺
3- (4-Cyano-2,6-dimethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 113); ESI-MS: m / z 417 [ M + H] ⁺
3- [2,6-Diethoxy-4- (1,3,4-oxadiazol-2-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 114); ESI-MS: m / z 488 [M + H] ⁺
3- [2,6-Dimethoxy-4- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl ) Methyl] quinoline (compound 115); ESI-MS: m / z 474 [M + H] ⁺
3- (2-Ethoxy-6-methanesulfonyloxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 116); ESI-MS: m / z 470 [ M + H] ⁺
3- [2-Ethoxy-4- (2-oxopyrrolidin-1-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 117); ESI- MS: m / z 459 [M + H] ⁺
3- [4- (5-Cyclopropyl-1,3,4-oxadiazol-2-yl) -2,6-diethoxyphenyl] -2-[(4-methyl-1,4-diazepan-1 -Yl) methyl] quinoline (compound 121); ESI-MS: m / z 528 [M + H] ⁺

3-Cyanomethoxy-5-ethoxy-4- {2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinolin-3-yl} benzonitrile (Compound 122); ESI-MS: m / z 456 [M + H] ⁺
3- (2-Dimethylcarbamoylmethoxy-6-ethoxyphenyl) -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 123); ESI-MS: m / z 477 [ M + H] ⁺
3- [2,6-Diethoxy-4- (2-methyl-2H-tetrazol-5-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (compound 124); ESI-MS: m / z 502 [M + H] ⁺
3- [2,6-Diethoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (compound 125); ESI-MS: m / z 502 [M + H] ⁺
3- [2,6-Diethoxy-4- (5-methoxymethyl-1,3,4-oxadiazol-2-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1- Yl) methyl] quinoline (Compound 126); ESI-MS: m / z 532 [M + H] ⁺

2- {5-cyano-3-ethoxy-2- {2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinolin-3-yl} phenoxy} acetamide (Compound 129); ESI- MS: m / z 474 [M + H] ⁺
3- [2-Carbamoylmethoxy-6-ethoxy-4- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl] -2-[(4-methyl-1,4-diazepane- 1-yl) methyl] quinoline (compound 130); ESI-MS: m / z 531 [M + H] ⁺
3- [4- (5-Dimethylcarbamoyl-1,3,4-oxadiazol-2-yl) -2-ethoxy-6-methoxyphenyl] -2-[(4-methyl-1,4-diazepan- 1-yl) methyl] quinoline (compound 131); ESI-MS: m / z 545 [M + H] ⁺
3- [4- (5-carbamoyl-1,3,4-oxadiazol-2-yl) -2-ethoxy-6-methoxyphenyl] -2-[(4-methyl-1,4-diazepan-1 -Yl) methyl] quinoline (compound 132); ESI-MS: m / z 517 [M + H] ⁺
3- [2-Ethoxy-6- (2-methoxyethoxy) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 133); ESI-MS: m / z 450 [M + H] ⁺
3- [2-Ethoxy-6-methoxy-4- (2-methyl-2H-tetrazol-5-yl) phenyl] -2-[(4-methyl-1,4-diazepan-1-yl) methyl] quinoline (Compound 161); ESI-MS: m / z 488 [M + H] ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ , δ): 1.20 (t, J = 6.9 Hz, 3H), 1.53-1.61 (m , 2H), 2.23 (s, 3H), 2.32-2.37 (m, 2H), 2.43-2.48 (m, 2H), 2.53-2.61 (m, 4H), 3.80-3.82 (m, 5H), 4.05-4.15 (m, 2H), 4.44 (s, 3H), 7.45-7.54 (m, 3H), 7.64-7.73 (m, 1H), 7.78-7.82 (m, 1H), 7.94 (s, 1H), 8.15 (d , J = 8.5 Hz, 1H).

Claims

Formula (I)

[In the formula, Z represents a monocyclic nitrogen-containing aliphatic heterocyclic group which may have a substituent, a bridged nitrogen-containing aliphatic heterocyclic group which may have a substituent, or a substituent. A monocyclic nitrogen-containing aliphatic heterocyclic group, a bridged nitrogen-containing aliphatic heterocyclic group, or a condensed nitrogen-containing aliphatic heterocyclic group. The group is attached to the adjacent carbon atom at its nitrogen atom;
G 1 is nitrogen atom, N + -O - or in CR 5 {wherein, R 5 is a hydrogen atom, a halogen, cyano, carbamoyl, optionally substituted lower alkyl, which may have a substituent Good lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted lower alkanoyl, optionally substituted lower Alkylthio, optionally substituted lower alkylsulfonyl, optionally substituted aryl, —NR 6a R 6b (wherein R 6a and R 6b are the same or different and are a hydrogen atom, substituted A lower alkylsulfonyl which may have a group, a lower alkyl which may have a substituent, a lower alkoxycarbonyl which may have a substituent, or a lower alkanoyl which may have a substituent. Represent or R 6a and R 6 b forms a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom) or -OR 7 (wherein R 7 has a hydrogen atom or a substituent, Lower alkyl, which may have a substituent, cycloalkyl which may have a substituent, lower alkanoyl which may have a substituent, lower alkylsulfonyl which may have a substituent, which may have a substituent A good aliphatic heterocyclic group, an optionally substituted aromatic heterocyclic group, or -CONR 8a R 8b (wherein R 8a and R 8b are the same or different and represent a hydrogen atom, a substituent, The lower alkylsulfonyl which may have, the lower alkyl which may have a substituent, or the lower alkanoyl which may have a substituent, or R 8a and R 8b and the adjacent nitrogen atom Together form a nitrogen-containing heterocyclic group which may have a substituent) Represents]},
G 2 is a nitrogen atom or N + -O - represents,
Ar represents an aromatic carbocycle or an aromatic heterocycle,
m represents an integer of 0 to 8, and when m represents an integer of 2 to 8, each R 1 may be the same or different,
R 1 is cyano, carboxy, halogen, nitro, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted. Optionally substituted cycloalkyl, optionally substituted lower alkanoyl, optionally substituted lower alkylthio, optionally substituted lower alkoxycarbonyl, optionally substituted. Aryl which may have a substituent, aroyl which may have a substituent, arylsulfonyl which may have a substituent, lower alkylsulfonyl which may have a substituent, those aliphatic heterocyclic group, the substituent aromatic heterocyclic group which may have a, -NR 14a1 R 14b1 (wherein, R 14a1 and R 14b1 are respectively the same as the aforementioned R 6a and R 6b) , -OR 15a1 (in the formula, R 15a1 before Represents R 7 as synonymous) or -CONR 16a1 R 16b1 (wherein, R 16a1 and R 16b1 are respectively the same as the aforementioned R 8a and R 8b),
R 2 and R 3 are the same or different and each has a hydrogen atom, cyano, carboxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, or optionally substituted. Lower alkynyl, optionally substituted cycloalkyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxycarbonyl or —CONR 9a R 9b (wherein , R 9a and R 9b are the same or different and each represents a hydrogen atom or a lower alkyl optionally having substituent (s).
n represents an integer of 0 to 4, and when n is 2, 3 or 4, each R 4 may be the same or different,
R 4 has halogen, cyano, nitro, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted. Cycloalkyl which may have a substituent, lower alkanoyl which may have a substituent, lower alkylsulfonyl which may have a substituent, lower alkoxycarbonyl which may have a substituent, a substituent An aromatic heterocyclic group which may have, —NR 10a R 10b (wherein R 10a and R 10b are the same or different and each is a hydrogen atom, optionally substituted lower alkylsulfonyl, substituted Represents a lower alkyl which may have a group, or a lower alkanoyl which may have a substituent, or R 10a and R 10b together represent a diphenylmethylene which may have a substituent. next carded or R 10a and R 10b, is Nitrogen atom and together form a nitrogen-containing heterocyclic group which may have a substituent) which, - OR 11 (wherein, R 11 which may have a hydrogen atom, an optionally substituted lower Alkyl, cycloalkyl which may have a substituent, lower alkanoyl which may have a substituent, lower alkylsulfonyl which may have a substituent, aryl which may have a substituent, An aliphatic heterocyclic group which may have a substituent, or an aromatic heterocyclic group which may have a substituent, or -CONR 12a R 12b (wherein R 12a and R 12b are The same or different, a hydrogen atom, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkylsulfonyl, having a substituent Aryl which may be substituted, aromatic heterocyclic group which may have substituent or Or represents optionally substituted lower alkanoyl which may have a substituent, or R 12a and R 12b form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom) the Or a pharmaceutically acceptable salt thereof.
2. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein G 1 is CR 5 , R 5 is a hydrogen atom, halogen or cyano, and G 2 is a nitrogen atom.
2. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein G 1 and G 2 are nitrogen atoms.
G 1 is N + -O - and is, salts G 2 is allowed claims 1 nitrogen-containing heterocyclic compound according or a pharmaceutically nitrogen atom.
R 2 and R 3 may be the same or different and each may have a hydrogen atom, cyano, optionally substituted lower alkyl, optionally substituted lower alkenyl, or optionally substituted. 5. The nitrogen-containing heterocyclic compound according to claim 1, which is lower alkynyl, cycloalkyl optionally having substituent (s), or lower alkanoyl optionally having substituent (s). Acceptable salt.
6. The nitrogen-containing heterocyclic compound according to claim 1, wherein n is 1, and R 4 is —NR 10a R 10b (wherein R 10a and R 10b are as defined above), Its pharmaceutically acceptable salt.
7. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 6, wherein R 10a and R 10b are hydrogen atoms.
The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein Ar is a benzene ring.
Ar- (R 1 ) m is

(Wherein R 1a and R 1b are the same or different and each represents an optionally substituted lower alkoxy, and R 1c represents cyano, an optionally substituted lower alkoxy or a substituent. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, which represents an aromatic heterocyclic group which may be present.
Z is

(Wherein p represents 1 or 2,
R 17 represents a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted lower alkenyl, an optionally substituted lower alkynyl or cycloalkyl). Item 10. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 9.
11. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein p is 2.
12. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 10 or 11, wherein R 17 is lower alkyl.
Formula (IA)

Wherein, R 4A and Z A are respectively the same as the aforementioned R 4 and Z,
mA represents an integer of 0 to 5, and when mA is 2, 3, 4 or 5, each R 13A may be the same or different,
nA represents an integer of 0 to 4, and when nA is 2, 3 or 4, each R 4A may be the same or different,
R 2A and R 3A may be the same or different and each may have a hydrogen atom, cyano, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted. Represents lower alkynyl, or optionally substituted cycloalkyl,
R 13A represents cyano, carboxy, halogen, nitro, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, and optionally substituted. Cycloalkyl optionally having, lower alkanoyl optionally having substituent, lower alkoxycarbonyl optionally having substituent, aryl optionally having substituent, having substituent Aroyl, which may have a substituent, arylsulfonyl which may have a substituent, lower alkylsulfonyl which may have a substituent, an aliphatic heterocyclic group which may have a substituent, and a substituent. An aromatic heterocyclic group that may be substituted, —NR 14a R 14b (wherein R 14a and R 14b have the same meanings as R 6a and R 6b , respectively), —OR 15a (wherein R 15a is the same as defined above) R 7 synonymous) or -CONR 16a R 16b (wherein, R 16 a and R 16b represent the same as R 8a and R 8b , respectively,] or a pharmaceutically acceptable salt thereof.
14. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 13, wherein R 2A is a hydrogen atom.
15. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 13, wherein R 3A is a hydrogen atom.
The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 13 to 15, wherein nA is 1.
The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 13 to 15, wherein nA is 1 and R 4A is bonded to the 6-position of quinoxaline.
The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 13 to 17, wherein R 4A is -NR 10a R 10b (wherein R 10a and R 10b are as defined above). Salt.
19. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 18, wherein R 10a and R 10b are hydrogen atoms.
The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 13 to 15, wherein nA is 0.
Z A

21. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 13, wherein p and R 17 are as defined above.
22. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 21, wherein p is 2.
23. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 21 or 22, wherein R 17 is lower alkyl.
Z A

21. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 13, wherein R 17A represents lower alkyl, and R 19A represents a hydrogen atom or hydroxy.
25. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 24, wherein R 17A is methyl and R 19A is a hydrogen atom.
25. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 24, wherein R 17A is methyl and R 19A is hydroxy.
(Wherein R 13A and mA are the same as defined above)

(In the formula, R 13A1 represents an optionally substituted lower alkoxy, R 13A2 represents a hydrogen atom or an optionally substituted lower alkoxy, R 13A3 represents a hydrogen atom, cyano, substituted 27. A nitrogen-containing heterocyclic compound or a pharmaceutical product thereof according to any one of claims 13 to 26, which represents a lower alkoxy which may have a group or an aromatic heterocyclic group which may have a substituent. Acceptable salt.
28. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 27, wherein R 13A1 and R 13A2 are the same or different and are lower alkoxy and R 13A3 is cyano.
The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 27, wherein R 13A1 and R 13A2 are the same or different and are lower alkoxy, and R 13A3 is an aromatic heterocyclic group which may have a substituent. Salt.
28. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 27, wherein R 13A3 is a monocyclic 5-membered aromatic heterocyclic group which may have a substituent.
Formula (IB)

(Wherein R 2B , R 3B , R 4B , R 13B and Z B are the same as R 2A , R 3A , R 4 , R 13A and Z, respectively,
mB represents an integer of 0 to 5, and when mB is 2, 3, 4 or 5, each R 13B may be the same or different,
nB represents an integer of 0 to 4, and when nB is 2, 3 or 4, each R 4B may be the same or different) or a pharmaceutically acceptable compound thereof Salt.
Claim that nB is 1, R 4B is halogen, cyano or —NR 10a R 10b (wherein R 10a and R 10b are as defined above), and R 4B is bonded to position 8 of quinoxaline Item 31 is a nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof.
Claim that nB is 1, R 4B is halogen, cyano or —NR 10a R 10b (wherein R 10a and R 10b are as defined above), and R 4B is bonded to position 6 of quinoxaline Item 31 is a nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof.
34. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 32 or 33, wherein R 4B is amino.
The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 31 to 34, wherein R 2B and R 3B are hydrogen atoms.
Z B

The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 31 to 35, wherein p and R 17 are as defined above.
Z B

The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 31 to 35, wherein R 17B represents lower alkyl, and R 19B represents a hydrogen atom or hydroxy.
38. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 37, wherein R 17B is methyl and R 19B is a hydrogen atom.
38. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 37, wherein R 17B is methyl and R 19B is hydroxy.
Wherein R 13B and mB are as defined above.

(Wherein, R 13B1 represents an lower alkoxy which may have a substituent, R 13B2 represents a hydrogen atom or a lower alkoxy which may have a substituent, R 13B3 is a hydrogen atom, cyano, substituted A nitrogen-containing heterocyclic compound or a pharmaceutical product thereof according to any one of claims 31 to 39, which represents a lower alkoxy which may have a group or an aromatic heterocyclic group which may have a substituent) Acceptable salt.
41. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 40, wherein R 13B1 and R 13B2 are the same or different and are lower alkoxy, and R 13B3 is cyano.
The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable one thereof according to claim 40, wherein R 13B1 and R 13B2 are the same or different and are lower alkoxy, and R 13B3 is an aromatic heterocyclic group which may have a substituent. Salt.
41. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 40, wherein R 13B3 is a monocyclic 5-membered aromatic heterocyclic group which may have a substituent.
Formula (IC)

[Wherein R 2C , R 3C , R 4C , R 13C and Z C are the same as R 2A , R 3A , R 4 , R 13A and Z, respectively,
mC represents an integer of 0 to 5, and when mC is 2, 3, 4 or 5, each R 13C may be the same or different,
nC represents an integer of 0 to 4, and when nC is 2, 3 or 4, each R 4C may be the same or different,
R 5C is a hydrogen atom, halogen, cyano, carbamoyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, substituent Cycloalkyl optionally having substituent (s), lower alkylthio optionally having substituent (s), lower alkylsulfonyl optionally having substituent (s), or -OR 18 (wherein R 18 represents R 7 and The nitrogen-containing heterocyclic compound represented by the above or a pharmaceutically acceptable salt thereof.
45. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 44, wherein R 2C and R 3C are hydrogen atoms.
Claim that nC is 1, R 4C is halogen, cyano or —NR 10a R 10b (wherein R 10a and R 10b are as defined above), and R 4C is bonded to position 7 of quinoline Item 44. The nitrogen-containing heterocyclic compound according to item 44 or 45 or a pharmaceutically acceptable salt thereof.
The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 44 to 46, wherein R 4C is amino.
R 5C is a hydrogen atom, cyano, or —OR 18a (wherein R 18a represents a hydrogen atom, lower alkyl which may have a substituent, or cycloalkyl which may have a substituent). 48. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 44 to 47.
48. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 44, wherein R 5C is —OR 18a (wherein R 18a has the same meaning as described above).
The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 44 to 47, wherein R 5C is halogen.
Z C

The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 44 to 50, wherein p and R 17 are as defined above.
Z C

51. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 44, wherein R 17C represents lower alkyl, and R 19C represents a hydrogen atom or hydroxy.
53. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 52, wherein R 17C is methyl and R 19C is a hydrogen atom.
53. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 52, wherein R 17C is methyl and R 19C is hydroxy.
Wherein R 13C and mC are as defined above.

(Wherein R 13C1 represents an optionally substituted lower alkoxy, R 13C2 represents a hydrogen atom or an optionally substituted lower alkoxy, R 13C3 represents a hydrogen atom, cyano, substituted A nitrogen-containing heterocyclic compound or a pharmaceutical product thereof according to any one of claims 44 to 54, which represents a lower alkoxy which may have a group or an aromatic heterocyclic group which may have a substituent) Acceptable salt.
56. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 55, wherein R 13C1 and R 13C2 are the same or different and are lower alkoxy, and R 13C3 is cyano.
The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 55, wherein R 13C1 and R 13C2 are the same or different and are lower alkoxy, and R 13C3 is an aromatic heterocyclic group which may have a substituent. Salt.
56. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 55, wherein R 13C3 is a monocyclic 5-membered aromatic heterocyclic group which may have a substituent.
A medicament comprising the nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 58 as an active ingredient.
An antitumor agent comprising the nitrogen-containing heterocyclic compound according to any one of claims 1 to 58 or a pharmaceutically acceptable salt thereof as an active ingredient.
A method for treating a tumor, comprising a step of administering an effective amount of the nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 58.
The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 58 for use in treating a tumor.
Use of the nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 58 for the manufacture of an antitumor agent.