JP2002338565A - Method for producing sulfone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a sulfone derivative. SOLUTION: This method for producing the sulfone derivative represented by the general formula: R-W-S(O)2 -X-Y-L<2> (IIIa) (wherein, R is a cyclic hydrocarbon which may be substituted or the like; W is a bond or a divalent chain hydrocarbon group which may be substituted; X is a divalent chain hydrocarbon group which may be substituted; Y is -N(R<5> )-,-CO-, -S(O)-, -S(O)2 -, -CH2 - or a bond; L<2> is a hydrogen atom, a hydroxy group or an alkoxy group which may be substituted; and R<5> is a hydrogen atom or the like) or a salt thereof is characterized in that a sulfinic acid derivative represented by the general formula: R-W-S(O)2 -M (I) (wherein, M is a hydrogen atom, an alkali metal or an alkaline earth metal; R and W have the same meanings as the above- mentioned) with a compound represented by the formula; L<1> -X-Y-L<2> (IIa) (wherein, L<1> is a leaving group; and X, Y and L<2> have the same meanings as the above-mentioned).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to activated blood coagulation X.
Thrombo-occlusive disease of arteries and veins, inflammation, which inhibit factor (FXa) and have anticoagulant and antithrombotic effects
The present invention relates to a method for producing a sulfone derivative or a salt thereof useful for prevention and treatment of cancer and the like.

[0002]

2. Description of the Related Art Japanese Patent Application No. 2000-221065 (WO02)
/ 06234) is an FXa inhibitor which is an anticoagulant effective for prevention and treatment of myocardial infarction, cerebral thrombosis, etc.
Various novel sulfone derivatives and methods for their preparation have been disclosed. In this production method, an arylsulfonyl chloride as a starting material is reduced with lithium aluminum hydride to produce an arylthiol, which is reacted with an alkenyl carboxylic acid ester derivative or a halogenoalkyl carboxylic acid ester derivative to give an aryl thioalkyl carboxylic acid. An ester derivative is produced, and an oxidation reaction using peracetic acid is further performed to produce an arylsulfonylalkylcarboxylic acid derivative. In this technique,
Since the reduction and oxidation reactions of sulfur atoms are performed once each, the number of steps is large. When the oxidation reaction step is performed on an industrial scale, it is necessary to take safety measures. As a method for synthesizing a sulfone derivative, for example, there are the following reports. Roczniki Chemii, Vol. 30, p. 243,
In 1956, a method of reacting a sulfinic acid derivative with an acrylic acid derivative was reported. However, F
No mention is made of the synthesis of compounds useful as Xa inhibitors or their intermediates. Special table 2000-5043
No. 37 describes a method for producing an FXa inhibitor in which a naphthylsulfonyl group is substituted with an aryl group using sodium 6-chloro-2-naphthalenesulfinate as a raw material. However, there is no description of an FXa inhibitor in which a naphthylsulfonyl group is substituted with an alkyl group. As a method for reductive amination of ketones with amines in the presence of sodium trisiloxyborohydride or sodium borohydride and an aliphatic carboxylic acid, for example, the following reports have been reported. Journal of
Organic Chemistry (J. Org. Chem.), 61
Volume, p. 3849, 1996 and USP 562505.
Describes a method for reductive amination of ketones with amines in the presence of sodium trisiloxyborohydride or sodium borohydride and an aliphatic carboxylic acid, but 1- (pyridine- No reductive amination of ketones having a substituent useful as an intermediate of an FXa inhibitor represented by a 4-yl) piperidin-4-one derivative is described. For example, there is the following report on a method for producing 4-amino-1- (4-pyridyl) piperidine, which is useful as an intermediate of an FXa inhibitor. EP107071
No. 4 and US Pat. No. 5,756,659 disclose 4-amino-1- (4-pyridyl) piperidine, but both require many steps for industrial production.

[0003]

In view of the above-mentioned problems, an industrial method for producing an FXa inhibitor and an arylsulfonylalkylcarboxylic acid derivative useful as an intermediate thereof, which has a small number of steps and which avoids an oxidation reaction, has been proposed. There is a demand for an advantageous production method. Further, as a method for producing amines useful as intermediates of FXa inhibitors, there is a demand for a safe, simple, industrially advantageous production method that does not use a highly toxic reducing agent.

[0004]

Under such circumstances, the present inventors have conducted intensive studies and unexpectedly found that arylsulfonyl chlorides were unexpectedly converted to arylsulfinic acids or salts thereof with a reducing agent such as sodium borohydride. Then, it was found that a sulfone derivative useful as an FXa inhibitor can be obtained by reacting with an alkenylcarboxylic acid ester or a halogenoalkylcarboxylic acid derivative. Further, in a reductive amination reaction of a ketone useful as an intermediate of an FXa inhibitor represented by a 1- (pyridin-4-yl) piperidin-4-one derivative with an amine, trisiloxy hydrogenation is used as a reducing agent. By using a combination of sodium boron or a palladium catalyst and formic acid or hydrogen, an amine derivative represented by the target N-methyl-1- (pyridin-4-yl) piperidin-4-amine derivative can be obtained safely and easily. And found that the present invention was completed. That is, the present invention provides (1) 1) a general formula RWS (O) ₂ -M (I) wherein R is an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group; A ring group; W represents a bond or a divalent chain hydrocarbon group which may be substituted; and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. And a salt thereof and a general formula L ¹ -XR ′ (IIa ′) wherein L ¹ represents a leaving group, and X represents a divalent chain which may be substituted. R ′ represents a carboxyl group or a cyano group which may be esterified or amidated. 2) The resulting compound of the formula RWS (O) ₂ -XR ′ (IIIa ′) wherein the symbols are as defined above. . A compound represented by] or subjected to hydrolysis optionally a salt thereof, 3) is obtained the formula R-W-S (O) 2 -X-CO 2 H (IVa ') [wherein the symbols The meaning is as defined above. A compound represented by the general formula:

Embedded image [Wherein, Z ″ is -N (R ^5b )-, -CO-, -S (O)-, -S
(O) _2- , -CH _2- , -N (R ^5b ) -CO-, -CO-CH ₂ -or a bond, and ring A 'represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5b and R ^6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group,
R ^6b may be bonded to a substituent of the ring A ′ to form a ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. A compound represented by the general formula:

Embedded image [Wherein the symbols are as defined above. (2) 1) a general formula RWS (O) ₂ -M (I) wherein R is a cyclic hydrocarbon group which may be substituted; Or an optionally substituted heterocyclic group; W represents a bond or an optionally substituted divalent chain hydrocarbon group; and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. And a salt thereof and a general formula (R ¹ ) (R ² ) C ＝ C (R ³ ) (R ′) (IIb ′) wherein R ¹ , R ² and R ³ are Each independently represents a hydrogen atom or a hydrocarbon group which may be substituted,
Alternatively, R ¹ and R ² , R ¹ and R ³ or R ² and R ³ may be bonded to each other to form an optionally substituted ring;
Represents a carboxyl group or a cyano group which may be esterified or amidated. ] With a compound or is reacted with a salt thereof, 2) obtained formula R-W-S (O) 2 -C (R 1) (R 2) -CH (R 3) -R '(IIIb ') Wherein the symbols are as defined above. A compound represented by] or subjected to hydrolysis optionally a salt thereof, 3) is obtained the formula R-W-S (O) 2 -C (R 1) (R 2) -CH (R 3) —CO ₂ H (IVb ′) wherein the symbols are as defined above. A compound represented by the general formula:

Embedded image [Wherein, Z ″ is -N (R ^5b )-, -CO-, -S (O)-, -S
(O) _2- , -CH _2- , -N (R ^5b ) -CO-, -CO-CH ₂ -or a bond, and ring A 'represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5b and R ^6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group,
R ^6b may be bonded to a substituent of the ring A ′ to form a ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. A compound represented by the general formula:

Embedded image [Wherein the symbols are as defined above. (3) 1) a general formula RWS (O) ₂ -M (I) wherein R is an optionally substituted cyclic hydrocarbon group; Or an optionally substituted heterocyclic group; W represents a bond or an optionally substituted divalent chain hydrocarbon group; and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. A sulfinic acid derivative or a salt thereof represented by the general formula R ⁴ C≡C—R ′ (IIc ′) wherein R ⁴
Represents a hydrogen atom or a hydrocarbon group which may be substituted, and R 'represents a carboxyl group or a cyano group which may be esterified or amidated. 2) The resulting compound of the formula: R—W—S (O) ₂ —C (R ⁴ ) = CH—R ′ (IIIc ′) wherein the symbols are The meaning is as defined above. A compound represented by] or subjected to hydrolysis optionally a salt thereof, 3) is obtained the formula R-W-S (O) 2 -C (R 4) = CH-CO 2 H (IVc ') [Wherein the symbols are as defined above. A compound represented by the general formula:

Embedded image [Wherein, Z ″ is -N (R ^5b )-, -CO-, -S (O)-, -S
(O) _2- , -CH _2- , -N (R ^5b ) -CO-, -CO-CH ₂ -or a bond, and ring A 'represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5b and R ^6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group,
R ^6b may be bonded to a substituent of the ring A ′ to form a ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. A compound represented by the general formula:

Embedded image [Wherein the symbols are as defined above. (4) General formula RWS (O) ₂ -M (I) wherein R is an optionally substituted cyclic hydrocarbon group or substituted A heterocyclic group which may be substituted, W represents a bond or a divalent chain hydrocarbon group which may be substituted, and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. A sulfinic acid derivative or a salt thereof represented by the general formula L ¹ -XYL ² (IIa) wherein L ¹ represents a leaving group, and X represents a divalent group which may be substituted Wherein Y is -N (R ⁵ )-, -CO
—, —S (O) —, —S (O) ₂ —, —CH ₂ — or a bond, L ² represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group, and R ⁵ represents hydrogen It represents an atom, a hydrocarbon group which may be substituted, an alkoxy group which may be substituted, a carboxyl group which may be esterified or amidated, or an acyl group. A compound represented by the formula: RWS (O) ₂ -XYL ² (IIIa) wherein the symbols are as defined above. Show. (5) The method according to the above (4), wherein R is a cyclic hydrocarbon group substituted with a halogen atom or an alkenyl group or a heterocyclic group which may be substituted. Production method; (6) Formula R ″ -WS (O) ₂ -M (I ′) wherein R ″ is a cyclic hydrocarbon group substituted with a halogen atom or an alkenyl group, or a substituted hydrocarbon group. And W represents a bond or optionally substituted 2
Represents a valent chain hydrocarbon group, and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. A sulfinic acid derivative or a salt thereof represented by the general formula (R ¹ ) (R ² ) C ＝ C (R ³ ) (Y′-L ² ) (IIb) wherein R ¹ , R ² and R ³ each independently represents a hydrogen atom or a hydrocarbon group which may be substituted,
Alternatively, R ¹ and R ² , R ¹ and R ³ or R ² and R ³ may be bonded to each other to form an optionally substituted ring;
Represents —CO—, —S (O) — or —S (O) ₂ —, and L ² represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group. ] Formula R '' is a compound or which comprises reacting a salt thereof represented by _{- W-S (O) 2} -C (R 1) (R 2) -CH (R 3) -Y'- L ² (IIIb) wherein the symbols are as defined above. (7) General formula RWS (O) ₂ -M (I) wherein R is an optionally substituted cyclic hydrocarbon group or It represents a heterocyclic group which may be substituted, W represents a bond or a divalent chain hydrocarbon group which may be substituted, and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. A sulfinic acid derivative or a salt thereof represented by the general formula R ⁴ C≡CY′-L ² (IIc) wherein R ⁴ represents a hydrogen atom or a hydrocarbon group which may be substituted , Y 'is -CO-, -S (O)-or -S
(O) _2- , and L ² represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group. A compound represented by the general formula R-
_{W-S (O) 2 -C} (R 4) = CH-Y'-L 2 (IIIc)
[The symbols in the formula are as defined above. (8) The method according to (7), wherein R is a cyclic hydrocarbon group substituted with a halogen atom or an alkenyl group or an optionally substituted heterocyclic group. (9) R is 6-halo-substituted (halogeno) naphthalene-2-
(10) The process according to (6), wherein R ″ is 6-halo-substituted naphthalen-2-yl. (11) the production method according to the above (1) to (10), wherein W is a bond; (12) a general formula R ″ -WS (O) ₂ -M (I ′) wherein R is '' Represents a cyclic hydrocarbon group substituted with a halogen atom or an alkenyl group or an optionally substituted heterocyclic group, and W represents a bond or an optionally substituted 2
Represents a valent chain hydrocarbon group, and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. A sulfinic acid derivative or a salt thereof], the general formula ^{(R 1) (R 2)} C = C (R 3) (Y '' - L 2a) (IIb '') wherein, R ^1, R ² and R ³ each independently represent a hydrogen atom or an optionally substituted hydrocarbon group,
Alternatively, R ¹ and R ² , R ¹ and R ³ or R ² and R ³ may be bonded to each other to form an optionally substituted ring, and Y ″
Represents -CO-, and L ^2a represents an optionally substituted alkoxy group. ] Wherein the compound or reacting a salt thereof represented by the general formula R '' - W-S ( O) 2 -C (R 1) (R 2) -CH (R 3) -Y ''-L ^2a (IIIb'') wherein the symbols are as defined above. (13) General formula RWS (O) ₂ -M (I) wherein R is an optionally substituted cyclic hydrocarbon group or It represents a heterocyclic group which may be substituted, W represents a bond or a divalent chain hydrocarbon group which may be substituted, and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. And a sulfinic acid derivative represented by the formula:

Embedded image Or the general formula

Embedded image [Wherein, R ^1a , R ^2a , R ^3a and R ^4a each independently represent a hydrogen atom or a hydrocarbon group which may be substituted, or R ^1a and R ^2a , R ^1a and R ^3a or R ^2a and R ^3a may be bonded to each other to form an optionally substituted ring, Y ′ represents —CO—, —S (O) — or —S (O) ₂ —, and Z represents -N (R ^5a )-, -CO-, -S (O)-,-S (O) ₂ -,-
CH ₂ — or a bond; ring A represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5a and R ^6a each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, Represents an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group, or R ^6a represents a substituent of ring A or R ^1a , R
^2a , R ^3a or R ^4a may combine with each other to form a ring, Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group, and n represents 0 or 1 is shown. Characterized by reacting a compound represented by the formula or a salt thereof,

Embedded image Or the general formula

Embedded image [The symbols in the formula are as defined above. (14) 1) a general formula RWS (O) ₂ -H (Ia) wherein R is a cyclic hydrocarbon which may be substituted; Represents a group or a heterocyclic group which may be substituted, and W represents a bond or a divalent chain hydrocarbon group which may be substituted. Represented by the sulfinic acid derivative or a salt thereof,
Formula ^{L 1 -X-R '(IIa} ') wherein, L ¹ represents a leaving group, X is a substituted by 2 may be divalent chain hydrocarbon group, R 'is esterified Or a carboxyl group or a cyano group which may be amidated. And a salt thereof, in the presence of a base, and 2) the resulting general formula RWS (O) ₂ -XR ′ (IIIa ′) wherein the symbols are as defined above. Is equivalent to A compound represented by] or subjected to hydrolysis optionally a salt thereof, 3) is obtained the formula R-W-S (O) 2 -X-CO 2 H (IVa ') [wherein the symbols The meaning is as defined above. A compound represented by the general formula:

Embedded image [Wherein, Z ″ is -N (R ^5b )-, -CO-, -S (O)-, -S
(O) _2- , -CH _2- , -N (R ^5b ) -CO-, -CO-CH ₂ -or a bond, and ring A 'represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5b and R ^6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group,
R ^6b may be bonded to a substituent of the ring A ′ to form a ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. Characterized by reacting with a compound represented by the formula or a salt thereof,
General formula

Embedded image [Wherein the symbols are as defined above. (15) A method for producing a compound represented by the formula (1) or a salt thereof;
(16) 1) General formula RWS (O) _2- H (Ia) wherein R is an optionally substituted cyclic hydrocarbon group or an optionally substituted cyclic hydrocarbon group. It represents a good heterocyclic group, and W represents a bond or an optionally substituted divalent chain hydrocarbon group. Represented by the sulfinic acid derivative or a salt thereof,
Formula (R ¹ ) (R ² ) C ＝ C (R ³ ) (R ′) (IIb ′) wherein R ¹ , R ² and R ³ are each independently a hydrogen atom or a substituted hydrogen atom. Shows a good hydrocarbon group,
Alternatively, R ¹ and R ² , R ¹ and R ³ or R ² and R ³ may be bonded to each other to form an optionally substituted ring;
Represents a carboxyl group or a cyano group which may be esterified or amidated. A compound or a salt thereof] in the presence of a base, 2) obtained formula R-W-S (O) 2 -C (R 1) (R 2) -CH (R 3) -R '(IIIb') wherein the symbols are as defined above. A compound represented by] or subjected to hydrolysis optionally a salt thereof, 3) is obtained the formula R-W-S (O) 2 -C (R 1) (R 2) -CH (R 3) —CO ₂ H (IVb ′) wherein the symbols are as defined above. With a compound represented by the formula

Embedded image [Wherein, Z ″ is -N (R ^5b )-, -CO-, -S (O)-, -S
(O) _2- , -CH _2- , -N (R ^5b ) -CO-, -CO-CH ₂ -or a bond, and ring A 'represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5b and R ^6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group,
R ^6b may be bonded to a substituent of the ring A ′ to form a ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. A compound represented by the general formula:

Embedded image [Wherein the symbols are as defined above. (17) The method for producing a compound represented by the formula (1) or a salt thereof;
(18) 1) General formula RWS (O) _2- H (Ia) wherein R is an optionally substituted cyclic hydrocarbon group or an optionally substituted cyclic hydrocarbon group. It represents a good heterocyclic group, and W represents a bond or an optionally substituted divalent chain hydrocarbon group. Represented by the sulfinic acid derivative or a salt thereof,
Formula R ⁴ C≡C—R ′ (IIc ′) wherein R ⁴ represents a hydrogen atom or a hydrocarbon group which may be substituted, and R ′ may be esterified or amidated Shows a carboxyl group or a cyano group. A compound represented by or a salt thereof with] in the presence of a base, 2) obtained formula R-W-S (O) 2 -C (R 4) = CH-R '(IIIc') [ In the formula, the symbols are as defined above. A compound represented by] or subjected to hydrolysis optionally a salt thereof, 3) is obtained the formula R-W-S (O) 2 -C (R 4) = CH-CO 2 H (IVc ') [Wherein the symbols are as defined above. A compound represented by the general formula:

Embedded image [Wherein, Z ″ is -N (R ^5b )-, -CO-, -S (O)-, -S
(O) _2- , -CH _2- , -N (R ^5b ) -CO-, -CO-CH ₂ -or a bond, and ring A 'represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5b and R ^6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group,
R ^6b may be bonded to a substituent of the ring A ′ to form a ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. A compound represented by the general formula:

Embedded image [Wherein the symbols are as defined above. (19) The method for producing a compound represented by the formula (1) or a salt thereof;
(20) General formula RWS (O) ₂ -H (Ia) wherein R is an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group. A ring group, and W represents a bond or a divalent chain hydrocarbon group which may be substituted. Represented by the sulfinic acid derivative or a salt thereof,
General formula L ¹ -XYL ² (IIa) wherein L ¹ represents a leaving group, X represents a divalent chain hydrocarbon group which may be substituted, and Y represents -N (R ⁵ )-, -CO
—, —S (O) —, —S (O) ₂ —, —CH ₂ — or a bond, L ² represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group, and R ⁵ represents hydrogen It represents an atom, a hydrocarbon group which may be substituted, an alkoxy group which may be substituted, a carboxyl group which may be esterified or amidated, or an acyl group. Or a salt thereof, in the presence of a base, wherein RWS (O) ₂ -XYL ² (II
Ia) wherein the symbols are as defined above. (21) The method according to the above (20), wherein the base is an amine; (22) a method for producing a sulfone derivative represented by the general formula R ″ -WS (O) ₂ -H (Ia ′) wherein R ″ represents a cyclic hydrocarbon group or an optionally substituted heterocyclic group substituted with a halogen atom or an alkenyl group, and W represents a bond or an optionally substituted 2
A valent chain hydrocarbon group; And a salt thereof represented by the general formula (R ¹ ) (R ² ) C ＝ C
(R ³ ) (Y′-L ² ) (IIb) wherein R ¹ , R ² and R ³ each independently represent a hydrogen atom or a hydrocarbon group which may be substituted;
Alternatively, R ¹ and R ² , R ¹ and R ³ or R ² and R ³ may be bonded to each other to form an optionally substituted ring;
Is -CO -, - S (O) -, - S (O) 2 - a, L ² represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group. Or a salt thereof in the presence of a base, characterized by the general formula: R ″ -WS (O) ₂ -C (R ¹ ) (R ² ) —CH (R ^{3) -Y'-L 2 (IIIb} ) [ symbols in the formula are as defined above. (23) The process according to the above (22), wherein the base is an amine; (24) a general formula RWS (O) ₂ -H (Ia). [Wherein, R represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and W represents a bond or a divalent chain hydrocarbon group which may be substituted. Show. ]
And a sulfinic acid derivative or a salt thereof represented by the general formula: R ⁴ C≡CY′-L ² (IIc) wherein R ⁴ represents a hydrogen atom or a hydrocarbon group which may be substituted. , Y 'is -CO-, -S (O)-or -S
(O) _2- , and L ² represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group. Compound represented or a salt thereof in], characterized by reacting in the presence of a base, the general formula R-W-S (O) 2 -C (R 4) = CH-Y'-L 2 (IIIc Wherein the symbols are as defined above. (25) The method according to the above (24), wherein the base is an amine; (26) a method for producing a sulfone derivative represented by the general formula R ″ -WS (O) ₂ -H (Ia ′) wherein R ″ represents a cyclic hydrocarbon group substituted with a halogen atom or an alkenyl group or a heterocyclic group which may be substituted, and W represents a bond or an optionally substituted 2
A valent chain hydrocarbon group; And a salt thereof represented by the general formula (R ¹ ) (R ² ) C ＝ C
(R ³ ) (Y ″ -L ^2a ) (IIb ″) [wherein R ¹ , R ² and R ³ each independently represent a hydrogen atom or an optionally substituted hydrocarbon group. ,
Alternatively, R ¹ and R ² , R ¹ and R ³ or R ² and R ³ may be bonded to each other to form an optionally substituted ring, and Y ″
Represents -CO-, and L ^2a represents an optionally substituted alkoxy group. Or a salt thereof in the presence of a base, characterized by the general formula: R ″ -WS (O) ₂ -C (R ¹ ) (R ² ) —CH (R ^{3) -Y '' - L 2a} (IIIb '') [ symbols in the formula are as defined above. (27) The method according to the above (26), wherein the base is an amine; (28) a general formula RWS (O) ₂ -H (Ia [Wherein, R represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and W represents a bond or a divalent chain hydrocarbon group which may be substituted. Show. Represented by the sulfinic acid derivative or a salt thereof,
General formula

Embedded image Or the general formula

Embedded image [Wherein, R ^1a , R ^2a , R ^3a and R ^4a each independently represent a hydrogen atom or a hydrocarbon group which may be substituted, or R ^1a and R ^2a , R ^1a and R ^3a or R ^2a and R ^3a may be bonded to each other to form an optionally substituted ring, Y ′ represents —CO—, —S (O) — or —S (O) ₂ —, and Z represents -N (R ^5a )-, -CO-, -S (O)-,-S (O) ₂ -,-
CH ₂ — or a bond; ring A represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5a and R ^6a each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, Represents an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group, or R ^6a represents a substituent of ring A or R ^1a , R
^2a , R ^3a or R ^4a may combine with each other to form an optionally substituted ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. And n represents 0 or 1. Characterized by reacting a compound represented by the formula or a salt thereof in the presence of a base,

Embedded image Or the general formula

Embedded image [Wherein the symbols are as defined above. (29) The method according to the above (28), wherein the base is an amine; (30) a general formula:

Embedded image [In the formula, ring A ″ represents an optionally substituted nitrogen-containing aliphatic heterocyclic ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group.]
Or a salt thereof, and a compound represented by the general formula R ⁶ NH ₂
(X) [wherein, R ⁶ represents a hydrogen atom or a hydrocarbon group which may be substituted. Characterized by reacting a compound represented by the formula or a salt thereof in the presence of a trisiloxyborohydride complex compound,

Embedded image [The symbols in the formula are as defined above. (31) The method according to the above (30), wherein ring A ″ is an optionally substituted piperidine; (32) Trisiloxyborohydride (30) wherein the complex compound is sodium triacetoxyborohydride
(33) General formula

Embedded image [In the formula, ring A ″ represents an optionally substituted nitrogen-containing aliphatic heterocyclic ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group.]
Or a salt thereof and a compound represented by the general formula R ⁶ NH ₂
(X) [wherein, R ⁶ represents a hydrogen atom or a hydrocarbon group which may be substituted. Reacting a compound represented by the formula (I) or a salt thereof with formic acid or a salt thereof or hydrogen gas in the presence of a palladium catalyst;

Embedded image [The symbols in the formula are as defined above. (34) The production method according to the above (33), wherein ring A ″ is an optionally substituted piperidine; (35) the palladium catalyst is palladium carbon. (36) the production method according to (33), wherein the reaction with formic acid or a salt thereof in the presence of a palladium catalyst; (37) the reaction method with hydrogen gas in the presence of a palladium catalyst; (38) The production method described in (33); (38) The general formula produced in the above (30) to (37)

Embedded image [Wherein, R ⁶ represents a hydrogen atom or an optionally substituted hydrocarbon group, ring A ″ represents an optionally substituted nitrogen-containing aliphatic heterocyclic ring, and Z ′ may be substituted. Or an optionally substituted nitrogen-containing heterocyclic group.] Or a salt thereof, and a compound represented by the general formula (R ¹ ) (R ² ) C ＝ C (R ³ ) (Y′-L ³ ) (XIIa) or a general formula R ⁴ C≡C-Y′-L ³ (XIIb) wherein L ³ is a leaving group, R ¹ , R ² and R ³ are each independently a hydrogen atom Or a hydrocarbon group which may be substituted, or R ¹ and R ² , R ¹ and R ³ or R ²
And R ³ may combine with each other to form an optionally substituted ring, R ⁴ represents a hydrogen atom or an optionally substituted hydrocarbon group, and Y ′ represents —CO—, —S (O)-or-
S (O) _2- . A compound represented by the general formula:

Embedded image Or the general formula

Embedded image [The symbols in the formula are as defined above. (39) General formula RWS (O) ₂ -M (I) wherein R is an optionally substituted cyclic hydrocarbon group or substituted And W represents a bond or a divalent chain hydrocarbon group which may be substituted, and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. And a sulfinic acid derivative represented by the formula:

Embedded image Or the general formula

Embedded image [Wherein, R ¹ , R ² and R ³ each independently represent a hydrogen atom or an optionally substituted hydrocarbon group,
Or R ¹ and R ^2, R ¹ and R ³ or R ² and R ³ may form a even better ring is bonded to a substituted each other, R ⁴
Represents a hydrogen atom or an optionally substituted hydrocarbon group, R ⁶ represents a hydrogen atom or an optionally substituted hydrocarbon group, and Y ′ represents —CO—, —S (O) — or —. S (O) _2-
And ring A ″ represents an optionally substituted nitrogen-containing aliphatic heterocyclic ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group.]
Characterized by reacting with a compound represented by the formula or a salt thereof,

Embedded image Or general formula

Embedded image[The symbols in the formula are as defined above. Compound represented by]
(40) General formula RWS (O)_Two-X-Y-L^Two (IIIa) or general formula RWS (O)_Two-C (R^Four) = CH-Y'-L^Two (IIIc) wherein R is an optionally substituted cyclic hydrocarbon group or
Represents an optionally substituted heterocyclic group, and W represents a bond
Or a divalent chain hydrocarbon group which may be substituted
X represents an optionally substituted divalent chain hydrocarbon group.
And Y is -N (R^Five)-, -CO-, -S (O)-, -S (O)_Two-,
-CH_Two-Or a bond, Y 'is -CO-, -S (O)-or
Or -S (O)_Two-Indicates L^TwoIs a hydrogen atom, a hydroxyl group or
Represents an optionally substituted alkoxy group;^FourIs hydrogen
An atom or a hydrocarbon group which may be substituted;
^FiveIs a hydrogen atom, an optionally substituted hydrocarbon group,
An optionally substituted alkoxy group, esterified or
Carboxyl group or acyl group which may be imidized
Is shown. The sulfone derivative represented by the formula
General formula RWS (O) for making_Two-M (I) wherein M is a hydrogen atom, an alkali metal or an alkaline earth
And R and W are as defined above. 〕so
Use of a sulfinic acid derivative represented by the following or a salt thereof; (41) Formula R ″ -WS (O)_Two-C (R¹) (R^Two) -CH (R^Three) -Y'-L^Two (IIIb) wherein R ″ is substituted with a halogen atom or an alkenyl group
Cyclic hydrocarbon group or optionally substituted heterocyclic group
A ring group, and W is a bond or an optionally substituted 2
A divalent chain hydrocarbon group;¹, R^TwoAnd R^ThreeIs
Each independently a hydrogen atom or an optionally substituted charcoal
Represents a hydride group, or R¹And R^Two, R ¹And R^ThreeOr
R^TwoAnd R^ThreeAre bonded to each other to form an optionally substituted ring
Y 'may be -CO-, -S (O)-or -S (O)_Two-
And L^TwoIs a hydrogen atom, a hydroxyl group or may be substituted
Represents an alkoxy group. The sulfone derivative represented by
Or a general formula R ″ -WS (O) for producing a salt thereof._Two-M (I ') wherein M is a hydrogen atom, an alkali metal or an alkaline earth
And R ″ and W are as defined above. ]
(42) use of a sulfinic acid derivative represented by the following formula or a salt thereof;

Embedded image Or the general formula

Embedded image [Wherein, R represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and W represents a bond or a divalent chain hydrocarbon group which may be substituted. , R ^1a , R ^2a , R ^3a and R ^4a each independently represent a hydrogen atom or a hydrocarbon group which may be substituted, or R ^1a and R ^2a , R ^1a and R ^3a or R ^2a R ^3a
May combine with each other to form an optionally substituted ring, and Y ′ represents —CO—, —S (O) — or —S (O) ₂ —,
Z is -N (R ^5a )-, -CO-, -S (O)-, -S (O) _2- , -CH ₂
-Or a bond, ring A represents a nitrogen-containing heterocyclic ring which may be substituted, and R ^5a and R ^6a each independently represent a hydrogen atom, a hydrocarbon group which may be substituted, Represents an alkoxy group, a carboxyl group or an acyl group which may be esterified or amidated, or R ^6a represents a substituent of ring A or R ^1a , R ^2a ,
R ^3a or R ^4a may be bonded to form an optionally substituted ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group, n represents 0 or 1. Represented for the production of sulfone derivative, or a salt thereof in], in the general formula R-W-S (O) 2 -M (I) [wherein, M represents a hydrogen atom, an alkali metal or alkaline earth metal , R and W are as defined above. Use of a sulfinic acid derivative or a salt thereof represented by the formula:

[0005] The terms used in the present specification are described below. R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group. Examples of the cyclic hydrocarbon group of the “optionally substituted cyclic hydrocarbon group” represented by R include an alicyclic hydrocarbon group, an aryl group, and the like, and among them, an aryl group and the like are preferable. "Alicyclic hydrocarbon group" as an example of a cyclic hydrocarbon group
Examples thereof include a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group and a cycloalkadienyl group.

Here, the “cycloalkyl group” includes
Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, C _3-9 cycloalkyl such as cyclononyl and the like. As the “cycloalkenyl group”, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, - cyclopenten-1-cyclohexen-1-yl, and the like C _3-9 cycloalkenyl groups such as 1-cycloheptene-1-yl. As the “cycloalkadienyl group”, for example, 2,4-cyclopentadiene-1
-Yl, 2,4-cyclohexadien-1-yl, 2,5
And C _4-6 cycloalkadienyl groups such as -cyclohexadien-1-yl.

The "aryl group" as an example of the cyclic hydrocarbon group includes a monocyclic or condensed polycyclic aromatic hydrocarbon group, for example, phenyl, naphthyl, anthryl,
C _6-14 aryl groups such as phenanthryl and acenaphthylenyl are preferable, and among them, phenyl, 1-naphthyl, 2-
Naphthyl and the like are particularly preferred. Examples of the cyclic hydrocarbon group include the above-mentioned alicyclic hydrocarbon groups such as 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, dihydrobenzocycloheptenyl, and fluorenyl. And a bi- or tricyclic hydrocarbon group derived from the condensation of two or three (preferably two or more) same or different groups selected from aromatic hydrocarbon groups.

The heterocyclic group of the "optionally substituted heterocyclic group" for R is selected, for example, from the oxygen atom, sulfur atom, nitrogen atom and the like as the atoms (ring atoms) constituting the ring system. 1 to 3 heteroatoms (preferably 1
Or 2) at least one (preferably 1 to 4)
, More preferably 1 or 2), a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) and the like.

The "aromatic heterocyclic group" includes, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 5- or 6-membered aromatic monocyclic heterocyclic groups such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and, for example, benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, indolyl, isoindolyl, 1H
-Indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl , Quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenazinyl, phenatronilyl, phenatronilyl, phenatronilyl, phenatronilyl , 2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b Pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3- a] pyridyl, 1,2,4-triazolo [4,3
- b] 8-16 membered like pyridazinyl (preferably, 8 to
A 12-membered) aromatic condensed heterocyclic group (preferably, the above-mentioned 5- to 6-membered aromatic monocyclic heterocyclic group having 8 to 16 members (preferably 8 to 12 members) has 1 to 2 benzene rings ( Preferably a heterocyclic ring condensed with 1) or 5 to 6
A heterocyclic ring obtained by condensing two to three (preferably two) heterocyclic rings of the same or different heterocyclic monocyclic heterocyclic groups, more preferably the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group; Heterocycles in which a ring group is condensed with a benzene ring, particularly preferably benzofuranyl, benzopyranyl, benzo [ b ] thienyl and the like are mentioned.

The "non-aromatic heterocyclic group" includes, for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl,
3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) such as piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and piperazinyl
A non-aromatic heterocyclic group (aliphatic heterocyclic group) or the above-mentioned aromatic unit such as 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, etc. A non-aromatic heterocyclic group in which the double bond is partially or entirely saturated in the cyclic heterocyclic group or the aromatic condensed heterocyclic group is exemplified.

"Optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" for R
Examples of the substituent of (i) optionally substituted alkyl, (ii) optionally substituted alkenyl, (iii)
Optionally substituted alkynyl, (iv) optionally substituted aryl, (v) optionally substituted aralkyl, (vi) optionally substituted cycloalkyl, (vii)
Optionally substituted cycloalkenyl, (viii) optionally substituted heterocyclic group, (ix) optionally substituted amino, (x) optionally substituted imidoyl (for example,
(Xi) a group represented by the formula -C (U ') = NU [wherein U and U' each represent a hydrogen atom or a substituent (U preferably represents a hydrogen atom)]; An optionally substituted amidino (eg, formula -C (NT'T ") = NT
[Wherein T, T ′ and T ″ each represent a hydrogen atom or a substituent (T preferably represents a hydrogen atom)] and (xii) an optionally substituted hydroxyl group , (Xii
i) an optionally substituted thiol group, (xiv) an optionally substituted alkylsulfinyl, (xv) a carboxyl group which may be esterified or amidated, (xvi)
Optionally substituted thiocarbamoyl, (xvii) optionally substituted sulfamoyl, (xviii) halogen atom (eg, fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine etc.), (xix) cyano group , (Xx) nitro group, (xxi) acyl derived from sulfonic acid, (xxii) acyl derived from carboxylic acid, etc., and these optional substituents are 1 to 5 (preferably 1 to 5) at substitutable positions. 3) may be substituted. Further, the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R may have an oxo group, for example, when R is benzopyranyl. , R is benzo-α-pyronyl,
Benzo-γ-pyronyl and the like may be formed.

[0012] An optionally substituted cyclic group represented by R
"Hydrocarbon group" and "optionally substituted heterocyclic group"
"Optionally substituted alkyl" as a substituent of
Examples of the alkyl in the formula include methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, se
c-butyl, tert-butyl, n-pentyl, isopench
, Neopentyl, 1-methylpropyl, n-hexyl
, Isohexyl, 1,1-dimethylbutyl, 2,2-di
Methylbutyl, 3,3-dimethylbutyl, 3,3-dimethyl
C such as rupropyl_1-6Alkyl and the like. here
Wherein the alkyl substituent is a lower alkoxy group
(Eg, C such as methoxy, ethoxy, propoxy, etc.) _1-6Al
Coxy, etc.), halogen atoms (eg, fluorine, chlorine, bromine,
Iodine, etc.), lower alkyl (eg, methyl, ethyl, pro
C such as pill_1-6Alkyl, etc.), lower alkenyl (eg,
C such as nil and allyl_2-6Alkenyl, etc.), lower alkini
(Eg, C such as ethynyl, propargyl, etc.)_2-6Alkynyl
Etc.), optionally substituted amino, optionally substituted amino
Good hydroxyl group, cyano group, amido which may be substituted
No, carboxy, lower alkoxycarbonyl (eg, meth
C such as xycarbonyl and ethoxycarbonyl_1-6Arco
Carbamoy which may be substituted)
(Eg, a 5- or 6-membered aromatic monocyclic heterocyclic group (eg,
Optionally substituted with lysinyl)_1-6Alkyl
Or acyl (eg, formyl, C_2-6Alkanoyl, ba
Nzoyl, optionally halogenated C_1-6Alkoki
Cicarbonyl, optionally halogenated C_1-6Al
Alkylsulfonyl, benzenesulfonyl, etc.)
Carbamoyl group, 1-azetidinyl carbonyl
, 1-pyrrolidinylcarbonyl, piperidinocarboni
, Morpholinocarbonyl, thiomorpholinocarbonyl
(Sulfur atom may be oxidized), 1-piperazini
And any of these substituents
May have 1 to 3 substitutions at substitutable positions.
“Optionally substituted alkyl” as a substituent
"Optionally substituted amino", "optionally substituted
Good hydroxyl group "and" optionally substituted amidi
“No” includes “substituted
Cyclic hydrocarbon group "and" optionally substituted
"Substituted as a substituent which the" heterocyclic group "may have
Optionally substituted amino "," optionally substituted hydroxyl
Group "and" optionally substituted amidino "
Are included.

"Optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" for R
"Optionally substituted alkenyl" as a substituent of
As alkenyl in, for example, vinyl, allyl,
Isopropenyl, 2-methylallyl, 1-propenyl,
2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-
Methyl-2-butenyl, 3-methyl-2-butenyl, 1
-Pentenyl, 2-pentenyl, 3-pentenyl, 4-
C _2-6 alkenyl such as pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like. Here, examples of the substituent of alkenyl include the same number and similar substituents as those in the aforementioned “optionally substituted alkyl”.

"Optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" for R
"Optionally substituted alkynyl" as a substituent of
Examples of alkynyl in ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,
3-pentynyl, 4-pentynyl, 1-hexynyl, 2
-Hexynyl, 3-hexynyl, 4-hexynyl, 5-
C _2-6 alkynyl such as hexynyl; Here, examples of the substituent of alkynyl include the same number of the same substituents as those in the above-mentioned “optionally substituted alkyl”.

"Optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" for R
Examples of the aryl in the "optionally substituted aryl" as a substituent include phenyl, naphthyl,
C such as anthryl, phenanthryl and acenaphthylenyl
_6-14 aryl and the like. Here, examples of the substituent of the aryl include the same number of the same substituents as in the above-mentioned “optionally substituted alkyl”.

"Optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" for R
"Optionally substituted aralkyl" as a substituent of
Examples of the aralkyl include C _7-11 aralkyl such as benzyl, phenethyl and naphthylmethyl. Here, as the substituent of the aralkyl, the same number of the same substituents as those in the aforementioned “optionally substituted alkyl” can be mentioned.

"Optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" represented by R
Examples of the cycloalkyl in the “optionally substituted cycloalkyl” as the substituent include C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Here, examples of the substituent of the cycloalkyl include the same number of the same substituents as in the above-mentioned “optionally substituted alkyl”.

"Optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" for R
Examples of the cycloalkenyl in the “optionally substituted cycloalkenyl” as the substituent for include a C _3-6 cycloalkenyl such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. Here, examples of the substituent of the optionally substituted cycloalkenyl include the same number of the same substituents as those in the above-mentioned “optionally substituted alkyl”.

"Optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" for R
Examples of the heterocyclic group in the “optionally substituted heterocyclic group” as the substituent include the same as the above-mentioned “optionally substituted heterocyclic group” for R.
Examples of the substituent which the “optionally substituted heterocyclic group” may have include lower alkyl (eg, C _1-6 alkyl such as methyl, ethyl and propyl), lower alkenyl ( For example, C _2-6 alkenyl such as vinyl and allyl, etc., lower alkynyl (eg, C _2-6 alkynyl such as ethynyl and propargyl), acyl (eg, C _1-6 such as formyl, acetyl, propionyl, pivaloyl) Alkanoyl, benzoyl, etc.), optionally substituted amino, optionally substituted hydroxyl group, halogen atom (eg, fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.), optionally substituted imidoyl And optionally substituted amidino. "Optionally substituted amino", "optionally substituted hydroxyl", "optionally substituted imidoyl" which the "optionally substituted heterocyclic group" may have as a substituent "And" optionally substituted amidino "include" optionally substituted cyclic hydrocarbon group "represented by R described below.
And `` optionally substituted amino '' as a substituent which the `` optionally substituted heterocyclic group '' may have, `` optionally substituted hydroxyl group '', `` optionally substituted Imidoyl "and the same as" optionally substituted amidino ".

"Optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" for R
As an optionally substituted `` optionally substituted amino '', `` optionally substituted imidoyl '',
Examples of the substituent in “optionally substituted amidino”, “optionally substituted hydroxyl group”, and “optionally substituted thiol group” include, for example, a halogen atom (for example, fluorine, chlorine, bromine, iodine) Etc.) and optionally halogenated C _1-6 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trichloromethoxy, 2,2,2
Lower alkyl (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.) ), Acyl (C _1-6 alkanoyl (eg, formyl, acetyl,
Propionyl, pivaloyl, etc.), benzoyl, C _1-6 alkylsulfonyl (eg, methanesulfonyl, etc.), benzenesulfonyl, etc.), optionally halogenated C _1-6
Alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, trifluoromethoxycarbonyl,
2,2,2-trifluoroethoxycarbonyl, trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), C _1-6 alkoxycarbonyl optionally substituted with phenyl (eg, benzyloxycarbonyl, etc.), Heterocyclic group (the same as the “heterocyclic group” in the “optionally substituted heterocyclic group” for R,
Preferably, pyridyl, more preferably, 4-pyridyl and the like are mentioned. “Amino” in “optionally substituted amino” as a substituent is optionally substituted imidoyl (for example, C _1-6 alkylimidoyl (eg, formylimidoyl, acetylimidoyl, etc.)) , C _1-6 alkoxyimidoyl, C _1-6 alkylthioimidoyl, amidino, etc.), amino which may be substituted with 1 to 2 C _1-6 alkyl, and the like. In addition, two substituents may form a cyclic amino together with a nitrogen atom. In such a case, examples of the cyclic amino include 1-azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1
- piperazinyl and 4-position a lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, t- butyl, pentyl, C _1-6 alkyl hexyl, etc.), aralkyl (e.g., benzyl, C ₇ of phenethyl _{- 10} aralkyl, etc.), aryl (eg, phenyl, 1-naphthyl, 2
And 3- to 8-membered (preferably 5 to 6-membered) cyclic aminos such as 1-piperazinyl, 1-pyrrolyl, 1-imidazolyl and the like which may have a C _6-10 aryl such as naphthyl and the like. Can be

"Optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" for R
Examples of the alkylsulfinyl in the `` optionally substituted alkylsulfinyl '' as a substituent which may have a methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sebutyl
C _1-6 such as c-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, hexylsulfinyl and the like
Alkylsulfinyl. Here, examples of the substituent of the alkylsulfinyl include the same number of the same substituents as in the above-mentioned “optionally substituted alkyl”.

"Optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" for R
Examples of the `` carboxyl group which may be esterified or amidated '' as the substituent which may have a carboxyl group, an alkoxycarbonyl, an aryloxycarbonyl, an aralkyloxycarbonyl, a carbamoyl, an N-monosubstituted carbamoyl and N, N-disubstituted carbamoyl. "Alkoxycarbonyl" includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxy C _1-6 such as carbonyl
Alkoxycarbonyl and the like can be mentioned, and among them, C _1-3 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl is preferable. The “lower alkoxycarbonyl” may have a substituent, and the substituent may be a hydroxyl group, an amino which may be substituted, for example, 1 to 5 halogen atoms (eg, fluorine, chlorine , Bromine, iodine, etc.) which may be substituted with lower alkyl (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc., preferably methyl, Ethyl or the like), acyl (eg, formyl, acetyl, propionyl, pivaloyl or the like C _1-6 alkanoyl, benzoyl or the like), carboxyl group, C _1-6 -alkoxycarbonyl or the like, as a substituent. You may. ], A halogen atom (for example, fluorine, chlorine,
Lower alkoxy (eg, methoxy, ethoxy, n-propoxy, iso-) which may be substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), nitro group, cyano group, and the like. Propoxy,
n-butoxy, isobutoxy, sec-butoxy, tert-
C _1-6 alkoxy such as butoxy, preferably methoxy, ethoxy and the like). Further, these substituents are preferably the same or different and are substituted with 1 or 2 to 3 (preferably 1 or 2).

"Aryloxycarbonyl" includes:
For example, C _6-12 aryloxycarbonyl such as phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl and the like are preferable. The “aryloxycarbonyl” may have a substituent, and examples of the substituent include the same number of the same substituents as in the above “alkoxycarbonyl”. The “aralkyloxycarbonyl” includes, for example, C _7-10 aralkyloxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl and the like (preferably C _6-10 aryl-
C _1-4 alkoxy-carbonyl and the like) are preferred. The “aralkyloxycarbonyl” may have a substituent, and examples of the substituent include the same number of the same substituents as in the above “alkoxycarbonyl”.

Examples of the substituent in "N-monosubstituted carbamoyl" include lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, te
C _1-6 alkyl such as rt-butyl, pentyl, hexyl, etc., lower alkenyl (eg, C _2-6 alkenyl such as vinyl, allyl, isopropenyl, propenyl, butenyl, pentenyl, hexenyl, etc.), cycloalkyl (eg, , cyclopropyl, cyclobutyl, cyclopentyl, C _3-6 cycloalkyl such as cyclohexyl, etc.), aryl (e.g., phenyl, 1-naphthyl, C 2-naphthyl
_6-10 aryl, etc.), aralkyl (e.g., benzyl, C _7-10 aralkyl phenethyl, preferably phenyl -C
_1-4 alkyl, etc.), arylalkenyl (eg, C _8-10 arylalkenyl such as cinnamyl, preferably phenyl-C _2-4 alkenyl, etc.), heterocyclic group (for example, R
And the like for the “heterocyclic group” in the “optionally substituted heterocyclic group”), amino which may be substituted with 1 to 2 C _1-6 alkyl, and the like. The lower alkyl, lower alkenyl, cycloalkyl, aryl, aralkyl, arylalkenyl, and heterocyclic group may have a substituent, and the substituent may have the same number as the substituent in the aforementioned “alkoxycarbonyl”. And the like.

"N, N-disubstituted carbamoyl" means a carbamoyl group having two substituents on a nitrogen atom. One example of such a substituent is the above-mentioned "N-monosubstituted carbamoyl". The same substituents may be mentioned, and the other examples include lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-
C _1-6 alkyl such as butyl, pentyl, hexyl, etc.),
C _3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _{7- 10} aralkyl (e.g., benzyl, phenethyl, preferably phenyl -C _1-4 alkyl and the like) and the like. Also, 2
May form a cyclic amino together with the nitrogen atom. In such a case, examples of the cyclic aminocarbamoyl include 1-azetidinylcarbonyl and 1-azetidinylcarbonyl.
Pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl (the sulfur atom may be oxidized), 1-piperazinylcarbonyl and lower alkyl at the 4-position (eg, methyl, ethyl,
C _1-6 alkyl such as propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.), aralkyl (eg, C _7-10 aralkyl such as benzyl, phenethyl), aryl (eg, phenyl, 1-naphthyl, etc.) 1 which may have a C _6-10 aryl such as 2-naphthyl)
3 to 8 members such as piperazinylcarbonyl (preferably 5
To 6-membered) cyclic aminocarbonyl.

"Optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" for R
As the substituents of `` optionally substituted thiocarbamoyl '' and `` optionally substituted sulfamoyl '' as the substituents which may be possessed, `` optionally substituted "N-monosubstituted carbamoyl" in the "carboxy group which may be esterified or amidated" as a substituent which the "cyclic hydrocarbon group" and the "optionally substituted heterocyclic group" may have And "N, N-disubstituted carbamoyl".

"Optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" for R
Examples of the “acyl derived from sulfonic acid” as the substituent which may be possessed include, for example, those in which the above-mentioned “N-monosubstituted carbamoyl” has one substituent on a nitrogen atom bonded to a sulfonyl and the like. But preferably,
Examples include acyl such as C _1-6 alkylsulfonyl such as methanesulfonyl and ethanesulfonyl.

Examples of the “acyl derived from carboxylic acid” as a substituent include those in which a carbonyl is bonded to a hydrogen atom or the above-mentioned “N-monosubstituted carbamoyl” having one substituent on a nitrogen atom. But preferably
C such as formyl, acetyl, propionyl, pivaloyl, etc.
Acyl such as _1-6 alkanoyl, benzoyl and the like can be mentioned.

R represents a halogen atom, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, optionally substituted amino, nitro, cyano, optionally substituted amidino and esterification or amidated aryl group which may be substituted with the substituent which is selected from a carboxyl group which optionally; or halogen atom, C _1-6
Selected from alkyl, C _2-6 alkenyl, C _2-6 alkynyl, optionally substituted amino, nitro, cyano, optionally substituted amidino and optionally esterified or amidated carboxyl group A heterocyclic group which may be substituted with a substituent is preferable. Of these, an aryl optionally substituted with a halogen atom or C _2-4 alkenyl, a heterocyclic group optionally substituted with a halogen atom is preferable, and particularly, naphthyl or benzopyranyl optionally substituted with a halogen atom, For example, 6-halo substituted naphthalen-2-yl is preferred.

W is a bond or an optionally substituted 2
A valent chain hydrocarbon group; The “optionally substituted divalent chain hydrocarbon group” represented by W includes, for example, C _1-6 alkylene such as methylene, ethylene, trimethylene and tetramethylene, for example, vinylene, propylene, 1-
Or 2-alkenylene C _2-6, such as butenylene include alkadienylene etc. C _2-6 such butadienylene. Examples of the substituent which the divalent chain hydrocarbon group of the “optionally substituted bivalent chain hydrocarbon group” represented by W may include, for example, “ The same substituents as the “cyclic hydrocarbon group” of the “cyclic hydrocarbon group which may be substituted” may be mentioned. As W, a bond or C _1-6 alkylene is preferable, and among them, a bond is preferably used.

X represents a divalent chain hydrocarbon group which may be substituted. X represents “optionally substituted 2”
Examples of the “valent chain hydrocarbon group” include C _1-8 alkylene such as methylene, ethylene, trimethylene, and tetramethylene; for example, C _2-8 alkenylene such as vinylene, propylene, and 1- or 2-butenylene; C _2-8 alkadienylene, ethynylene, 1- or 2
And C _2-8 alkynylene such as -propynylene, 1- or 2-butynylene and the like, among which C _1-6 lower alkylene which may be substituted is preferable. Examples of the substituent which the “optionally substituted divalent hydrocarbon group” represented by X may have include the above-mentioned “optionally substituted cyclic hydrocarbon group” represented by R And oxo groups, and the like, among which, among others, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amino, substituted An amidino which may be substituted, a hydroxyl group which may be substituted, a carboxyl group which may be esterified or amidated, a cyano group, or an oxo group, and the like. May have 1 to 3 substituents.

R 'represents a carboxyl group or a cyano group which may be esterified or amidated. The “carboxyl group which may be esterified or amidated” represented by R ′ is the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by the aforementioned R. And the "carboxy group which may be esterified or amidated" as a substituent which "may have.

General formula

Embedded image [Wherein, Z ″ is -N (R ^5b )-, -CO-, -S (O)-, -S
(O) _2- , -CH _2- , -N (R ^5b ) -CO-, -CO-CH ₂ -or a bond (preferably, -N (R ^5b )-, -CO-, -S (O )-, -S
(O) _2- , -CH ₂ -or a bond), ring A ′ represents an optionally substituted nitrogen-containing heterocyclic ring, and R ^5b and R ^6b each independently represent a hydrogen atom, R ^6b represents a hydrocarbon group which may be substituted, an alkoxy group which may be substituted, a carboxyl group which may be esterified or amidated, or an acyl group, and R ^6b is bonded to a substituent of ring A ′ to form a ring Z ′ represents an imidoyl group which may be substituted or a nitrogen-containing heterocyclic group which may be substituted. In the above, the "optionally substituted hydrocarbon group" for R ^5b and R ^6b includes an optionally substituted alkyl, an optionally substituted alkenyl,
Optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl and the like. "Optionally substituted alkyl", "optionally substituted alkenyl" as a substituent of the indicated "optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" , "Optionally substituted alkynyl",
"Optionally substituted aryl", "optionally substituted aralkyl", "optionally substituted cycloalkyl", "optionally substituted cycloalkenyl"
And the same. ^{Examples of the} alkoxy group of the “optionally substituted alkoxy group” represented by R ^5b and R ^6b include C _1-6 alkoxy such as methoxy, ethoxy, propoxy and tert-butoxy, and C ₆ such as benzyloxy and phenethyloxy. _-10 aryl -C _1-4 alkoxy, and the like. Examples of the substituent of the “optionally substituted alkoxy group” include the “optionally substituted cyclic hydrocarbon group” represented by R and the “optionally substituted heterocyclic group” as a substituent. The same number and the same as the substituents of "optionally substituted alkyl" can be mentioned.

The “carboxyl group which may be esterified or amidated” represented by R ^5b and R ^6b and the “acyl” include the “cyclic hydrocarbon group which may be substituted” represented by R and "A carboxyl group which may be esterified or amidated" as a substituent which the "heterocyclic group which may be substituted" may have, and "acyl derived from sulfonic acid", "derived from carboxylic acid" And acyl.

The “nitrogen-containing heterocyclic ring” in the “optionally substituted nitrogen-containing heterocyclic ring” for ring A ′ includes the “optionally substituted heterocyclic group” for the aforementioned R.
Among those exemplified as "heterocycle" constituting, for example, those containing at least one nitrogen atom, for example, containing at least one nitrogen atom as an atom (ring atom) constituting a ring system, Further, a nitrogen-containing aromatic compound which may contain 1 to 3 (preferably 1 to 2) 1 to 3 (preferably 1 to 2) heteroatoms selected from oxygen, sulfur, nitrogen and the like. A heterocyclic group, a saturated or unsaturated nitrogen-containing non-aromatic heterocyclic group (nitrogen-containing aliphatic heterocyclic group) and the like, and a nitrogen-containing aliphatic heterocyclic group (nitrogen-containing non-aromatic heterocyclic group). And the like are preferably used.

The “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” for ring A ′ includes:
"Monocyclic or bicyclic 5 to 12-membered nitrogen-containing heterocyclic ring" is preferable, and among them, "monocyclic or bicyclic 5 to 12-membered nitrogen-containing aliphatic heterocyclic ring" is preferable. `` Nitrogen-containing aliphatic heterocycle ''
Examples thereof include 3 to 3 such as azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine and piperazine.
An 8-membered (preferably 5 to 6-membered) saturated or unsaturated (preferably saturated) monocyclic nitrogen-containing aliphatic heterocyclic group, or 1,2,3,4-tetrahydroquinoline, 1,2,3 ,
4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine, 4,5
6,7-tetrahydropyrazolo [4,3-c] pyridine, 4,5,6,7-tetrahydroimidazolo [4,5
-C] 8 to 12 members such as pyridine (preferably 10 to 1 member)
The “aromatic” constituting the aromatic monocyclic heterocyclic group or the aromatic condensed heterocyclic group as R as described above, such as a 2-membered) saturated or unsaturated bicyclic nitrogen-containing aliphatic heterocyclic group. Among those exemplified as the "heterocyclic group", a nitrogen-containing aliphatic heterocyclic group in which a part or all of the double bonds of the "nitrogen-containing aromatic heterocycle" containing at least one nitrogen atom are saturated, Among them, piperazine, piperidine and the like are preferably used.

As the substituent which the "nitrogen-containing heterocycle" in the "optionally substituted nitrogen-containing heterocycle" for ring A 'may have, And the same substituents as the “heterocyclic group” of the “optionally heterocyclic group” may have, as well as oxo and thiooxo groups.

The structure of the “optionally substituted nitrogen-containing heterocyclic ring” represented by ring A ′ and the bonding with Z ″ and Z ′ are represented by the formula

Embedded image [Wherein, rings A ′, Z ″, and Z ′ have the same meanings as described above;
⁷ and R ⁸ are each independently a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl,
Optionally substituted alkynyl, optionally substituted hydroxyl group, optionally substituted thiol group, optionally substituted alkylsulfinyl, optionally substituted amino, esterified or amidified which may carboxyl group, a halogen atom, an acyl derived from a cyano group or a sulfonic acid, R ⁷ and R ⁸ or R ⁷ and R
^6b may be taken together to form a ring]. “Optionally substituted alkyl”, “optionally substituted alkenyl”, “optionally substituted alkynyl”, “optionally substituted hydroxyl group”, “substituted” represented by R ⁷ and R ⁸ Optionally substituted thiol group, `` optionally substituted alkylsulfinyl '', `` optionally substituted amino '', `` optionally esterified or amidified carboxyl group '' and `` derived from sulfonic acid As the "acyl", "optionally substituted alkyl", "optionally substituted alkenyl" as a substituent which the "optionally substituted heterocyclic group" for R may have , "Optionally substituted alkynyl", "optionally substituted hydroxyl group", "optionally substituted thiol group", "optionally substituted alkylsulfinyl Le "," amino which may be substituted ", but ones similar to the" optionally esterified or amidated carboxyl group which may be "and" acyl derived from sulfonic acid ". Among these, R ⁷ and R Preferred as ⁸ is a hydrogen atom, an optionally substituted amino or a carboxyl group which may be esterified or amidated.

When R ^6b is bonded to a substituent of ring A ′ (preferably, R ⁷ as a substituent of ring A ′ in the above formula) to form a ring, ring A ′ is —N Together with —Z ″ — (a carbon atom or a nitrogen atom in which Z ″ is bonded to ring A ′) — together with “optionally substituted spiro ring” or “optionally substituted fused nitrogen-containing heterocycle” It may be formed. That is, when the substituent position of the substituent of the ring A ′ to which R ^6b is bonded is on the carbon atom bonded to Z ″ and the ring A ′, the “optionally substituted spiro ring” is formed. , R ^6b
Is bonded to the substituent of the ring A ′, and Z ″ is the ring A ′
When it is not on the atom (carbon atom or nitrogen atom) bonded to, it forms a "nitrogen-containing fused heterocyclic ring which may be substituted". The “spiro ring” in the “optionally substituted spiro ring” includes, as an atom (ring atom) constituting a ring other than one nitrogen atom contained in the ring, an oxygen atom, a sulfur atom, a nitrogen atom, and the like. 1 to 3 (preferably 1 to 2) heteroatoms selected from 1 to 4
And a spiro ring formed by bonding two rings such as a saturated or unsaturated nitrogen-containing aliphatic heterocycle which may be contained (preferably 1 or 2). For example, azetidine, pyrrolidine, pyrazolidine, oxazolidine, isoxazolidine, imidazolidine, thiazolidine, isothiazolidine, pyrazoline, 1,2,4-oxadiazoline, oxazoline, isoxazoline, imidazoline, thiazoline, isothiazoline, piperidine,
Two identical or different rings selected from a 3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) nitrogen-containing aliphatic heterocycle such as morpholine, thiomorpholine, piperazine, etc. And a spiro ring formed. The “nitrogen-containing fused heterocycle” in the “optionally substituted nitrogen-containing fused heterocycle” is a heterocycle (preferably a monocyclic heterocycle) of the “optionally substituted heterocyclic group” represented by R. And a ring formed by condensing the same ring with ring A ′.

The “optionally substituted imidoyl group” for Z ′ includes, for example, a group represented by the formula —C (R ⁹ ) = NR
¹⁰ wherein R ⁹ is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group or a carboxylic acid-derived Wherein R ¹⁰ is a hydrogen atom,
It represents an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an esterified carboxyl group or an acyl derived from a carboxylic acid. And the like.

In the “imidoyl group which may be substituted”, R ⁹ represents a thiol group or a hydroxyl group;
^{When 10} represents a hydrogen atom, the “optionally substituted imidoyl group” has the formula —C (＝ O) —NH ₂ or —
C (= S) may be a group represented by -NH _2.

The “optionally substituted hydrocarbon group” represented by R ⁹ and R ¹⁰ includes R ^5b and R ⁵ described above.
^{The same} as the “optionally substituted hydrocarbon group” shown in ^6b . The “optionally substituted hydroxyl group” and “carboxylic acid-derived acyl” represented by R ⁹ and R ¹⁰ include the “optionally substituted cyclic hydrocarbon group” and the “substituted A heterocyclic group which may be optionally substituted as an optionally substituted hydroxyl group or a carboxylic acid-derived acyl group
And the same. As the “optionally substituted amino group” for R ⁹ , the “optionally substituted cyclic hydrocarbon group” for the aforementioned R may be a “substituted amino group” And an amino group which may have one or two " ^optionally substituted hydrocarbon groups" represented by R ^6b described above. Examples of the “optionally substituted thiol group” for R ⁹ include the aforementioned R
And the "optionally substituted thiol group" as a substituent which the "optionally substituted cyclic hydrocarbon group" may have. The “esterified carboxyl group” represented by R ¹⁰ is “esterified or amidated” as a substituent which the “optionally substituted cyclic hydrocarbon group” represented by R may have. And the same as the "lower alkoxycarbonyl", "aryloxycarbonyl", and "aralkyloxycarbonyl" of the "optionally carboxyl group".

The compounds R ¹⁰ is an acyl group derived from a carboxylic acid, are useful as prodrugs of compounds R ¹⁰ is a hydrogen atom. Here, when R ⁹ represents an optionally substituted amino group (preferably, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, hydrazino, piperidino, piperazino, morpholino, thiomorpholino, etc.) The “optionally substituted imidoyl group” for Z ′ forms an optionally substituted amidino group. Specific examples of the amidino group which may be substituted include one or two lower (C _1-6 ) alkyl groups, lower (C _1-6 ) alkanoyl groups, benzoyl groups and the like. Good amidino groups (e.g., amidino, N-methylamidino, N-ethylamidino, N-propylamidino, N, N'-dimethylamidino, N, N'-diethylamidino, N-methyl-
N'-diethylamidino, N-formylamidino, N-
Acetylamidino, etc.).

Preferred examples of R ⁹ include a hydrogen atom, a lower alkyl group (eg, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl), and an optionally substituted amino group (eg, , 1-2
Or the same or different lower alkyl groups (for example, C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl) or acyl groups (for example, C _1-6 such as formyl, acetyl, propionyl, pivaloyl, etc.)
_1-6 alkanoyl, benzoyl, etc.) optionally substituted amino group, hydrazino group, 5- to 6-membered cyclic amino group (for example, piperidino, thiomorpholino, morpholino,
An optionally substituted hydroxyl group (e.g., a hydroxyl group, a C _1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, etc.), an optionally substituted thiol group, for example, A thiol group, a C _1-6 alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, etc.). More preferably, hydrogen, a lower alkyl group or an amino group which may be substituted, particularly, a lower alkyl group or an amino group which may be substituted, especially an amino group which may be substituted (C _{1- For example,} amino optionally substituted with ₄ alkyl) is preferable.

Preferred examples of R ¹⁰ include hydrogen, a lower alkyl group (for example, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl), a hydroxyl group, and an esterified carboxyl group (for example, methoxy group). C _1-8 alkoxycarbonyl such as carbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl; C _7-10 aralkyloxycarbonyl such as benzyloxycarbonyl and phenethyloxycarbonyl; (For example, C _1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl and the like; benzoyl), and among them, hydrogen is preferable.

The “nitrogen-containing heterocyclic group” in the “optionally substituted nitrogen-containing heterocyclic group” for Z ′ includes:
As an atom (ring atom) constituting the ring system, at least one nitrogen atom (preferably 1 to 4 other than carbon atom,
More preferably, 1 to 3)) and 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom.
And a saturated or unsaturated non-aromatic nitrogen-containing heterocyclic group (aliphatic nitrogen-containing heterocyclic group). Examples of the “aromatic nitrogen-containing heterocyclic group” include, for example, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl (1H
-Imidazol-1-yl, 1H-imidazole-4-
Yl), pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,
4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,
2,3-triazolyl, 1,2,4-triazolyl (1,
2,4-triazolyl-1-yl, 1,2,4-triazolyl-4-yl, etc.), tetrazolyl, pyridyl (2-,
3- or 4-pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and other aromatic monocyclic nitrogen-containing heterocyclic groups and N-oxides thereof, and for example, indolyl, isoindolyl, 1H-indazolyl, benzin Dazolyl, benzoxazolyl, 1,
2-benzoisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
Naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiadinyl, phenazinyl, phenathridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5 -A] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4 -Triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3
-B] 8 to 16 members such as pyridazinyl (preferably 8 to 16 members)
12-membered) aromatic condensed nitrogen-containing heterocyclic group and its N-oxide (preferably, 1 to 2 (preferably 1) 5- or 6-membered aromatic monocyclic nitrogen-containing heterocyclic group described above) Is a heterocyclic ring condensed with 1 to 2 (preferably 1) benzene rings or 2 to 3 (preferably the same or different heterocyclic rings of the aforementioned 5- or 6-membered aromatic monocyclic nitrogen-containing heterocyclic group) Is a heterocyclic ring condensed with 2), more preferably a heterocyclic ring in which the 5- or 6-membered aromatic monocyclic nitrogen-containing heterocyclic group is condensed with a benzene ring, and the like. Above all,
A 5- to 6-membered aromatic monocyclic nitrogen-containing heterocyclic group is preferable, and imidazolyl and pyridyl are particularly preferable. The pyridyl may have a substituent at the 2-position (eg, an optionally substituted lower alkyl group, etc.).
-Pyridyl is preferred.

The "non-aromatic nitrogen-containing heterocyclic group" includes the above-mentioned partially reduced form of "aromatic nitrogen-containing heterocyclic group" (eg, imidazolinyl, tetrahydropyrimidinyl, etc.)
For example, azetidinyl, pyrrolidinyl, piperidyl (2
-, 3- or 4-piperidyl), morpholinyl, thiomorpholinyl, piperazinyl (such as 1-piperazinyl), homopiperazinyl and the like, among which a 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group is preferable. As the substituent of the “nitrogen-containing heterocyclic group” represented by Z ′, the same substituents as those of the aforementioned “heterocyclic group” represented by R are used. Further, the nitrogen atom constituting the nitrogen-containing heterocyclic group is
It may be oxidized. Further, the substituents of the “nitrogen-containing heterocyclic group” represented by Z ′ may be bonded to each other to form a ring (eg, a benzene ring or the like). As Z ′, an optionally substituted nitrogen-containing heterocyclic group or the like is preferable, and in particular, it is substituted with a substituent selected from an optionally substituted C _1-4 alkyl and an optionally substituted amino. A nitrogen-containing heterocyclic group which may be substituted is preferred. Further, as Z ′, an optionally substituted aromatic nitrogen-containing heterocyclic group or the like is preferable, and among them, an optionally substituted pyridyl group is preferable, and in particular, an optionally substituted 4-pyridyl group is preferable. preferable.

Preferred examples of the optionally substituted nitrogen-containing heterocyclic group as Z ′ include, for example,

Embedded image[R¹²And R¹³Are each independently a hydrogen atom,
Optionally substituted alkyl, optionally substituted alk
Nil, optionally substituted alkynyl, substituted
Amino, carboxyl which may be esterified
Sil group, carbamoyl which may be substituted, halogen
An atom, a cyano group or a nitro group; ¹²And R¹³
May combine to form a ring.)
Is mentioned. R¹²And R¹³Is replaced with
Optionally substituted alkyl '', `` optionally substituted
Nil '', `` optionally substituted alkynyl '', `` substituted
Amino which may be
Good carboxyl group "and" optionally substituted
“Rubamoyl” includes “substituted and substituted”
Cyclic hydrocarbons "" Heterocyclic rings which may be substituted
"Substituted" as a substituent which the "group" may have
Alkyl, which may be substituted or alkenyl which may be substituted
'', `` Optionally substituted alkynyl '', `` substituted
May be esterified "," esterified
Carboxyl group "and" optionally substituted
Similar to "Vamoyl". Among them, replaced
C that may be_1-4Alkyl or substituted
Good aminos are preferred and R¹²And R^{1 Three}One of them is a hydrogen source
More preferably, it is a child.

The “optionally substituted hydrocarbon group” represented by R ¹ , R ² and R ³ includes the aforementioned R ^5b and R ^6b
And the same as the “optionally substituted hydrocarbon group”. R ¹ and R ² , R ¹ and R ³ , R ² and R ³ are bonded to each other, for example, by the formula

Embedded image[Ring B and C represent a 3- to 8-membered aliphatic homo- or heterocyclic ring
And D represents a 5- to 9-membered homo- or heterocyclic ring. ]so
The rings B, C and D represented may be formed. Ring B is like
For example, cyclopropane, cyclobutane, cyclopentane,
Homocyclic rings such as cyclohexane and cycloheptane are preferred.
Cyclopentane, cyclohexane, cyclo
Heptane and the like are more preferred. Examples of the heterocyclic ring B
For example, tetrahydropyran, tetrahydrothiopyran,
Peridine rings are preferred. Ring C is cyclobutene, cyclo
Homogenous rings such as pentene, cyclohexene and cycloheptene
Are preferred, and cyclopentene and cyclohexene are particularly preferred.
And cycloheptene are preferred. Ring D is, for example,
Loheptene, cyclooctene, etc. are preferred.
Crooctene is preferred. These rings B, C and D are
May have a substituent, and such a substituent is represented by R
The ring of the "optionally substituted cyclic hydrocarbon group" shown
Are the same as the substituents that the linear hydrocarbon group may have
And so on. R^FourThe "may be substituted
A hydrocarbon group ”described above as R^5bAnd R ^6bIndicated by
Similar to the "optionally substituted hydrocarbon group"
Is mentioned.

The "optionally substituted hydrocarbon group", the "optionally substituted alkoxy group" for R ⁵ ,
“Carboxyl group which may be esterified or amidated”, “acyl group” includes “optionally substituted hydrocarbon group”, “optionally substituted alkoxy group” represented by R ^5b , The same as "carboxyl group which may be esterified or amidated" and "acyl group" can be mentioned. Examples of the alkoxy group of the “optionally substituted alkoxy group” for L ² include R
^Examples include the same as the “optionally substituted alkoxy group” represented by ^5b and R ^6b .

In the formula, the "cyclic hydrocarbon group" represented by "a cyclic hydrocarbon group substituted by a halogen atom or an alkenyl group" represented by R "includes a" cyclic hydrocarbon group which may be substituted "represented by R And the same as the cyclic hydrocarbon group represented by "hydrocarbon group". The “halogen atom” represented by “the cyclic hydrocarbon group substituted by a halogen atom or an alkenyl group” represented by R ″ includes chlorine, bromine, fluorine, iodine and the like. "Alkenyl" represented by "a cyclic hydrocarbon group substituted with a halogen atom or an alkenyl group" includes, for example, vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1- Butenyl, 2-butenyl, 3
-Butenyl, 2-ethyl-1-butenyl, 2-methyl-
2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl,
-Hexenyl, 3-hexenyl, 4-hexenyl, 5-
And C _2-6 alkenyl such as hexenyl. In the formula, the “heterocyclic group” represented by “optionally substituted heterocyclic group” represented by R ″ is a heterocyclic group represented by “optionally substituted heterocyclic group” represented by R Examples are the same as the groups.

As the alkoxy group of the “optionally substituted alkoxy group” for L ^2a , those similar to the “optionally substituted alkoxy group” for L ² can be mentioned.

The “optionally substituted hydrocarbon group” represented by R ^1a , R ^2a and R ^3a includes the above-mentioned R ¹ , R ² and R 3
Examples include the same as the “optionally substituted hydrocarbon group” shown in ³ . R ^1a and R ^2a , R ^1a and R ^3a , R ^2a
And R ^3a may be bonded to each other to form a ring, these rings, R ¹ and R ^2, R ¹ and R ^3, R ² and R ³ are the same as the ring formed bonded to each other Is mentioned. As the “optionally substituted hydrocarbon group” for R ^4a , those similar to the “optionally substituted hydrocarbon group” for R ⁴ described above can be mentioned.

Here, "optionally substituted hydrocarbon group", "optionally substituted alkoxy group", and "optionally esterified or amidated carboxyl group" represented by R ^5a and R ^6a , "Acyl group"
“Optionally substituted hydrocarbon group”, “optionally substituted alkoxy group”, “optionally esterified or amidated carboxyl group”, and “acyl” represented by R ^5b and R ^6b above. And the like. As the “optionally substituted nitrogen-containing heterocyclic ring” represented by ring A, those similar to the “optionally substituted nitrogen-containing heterocyclic ring” represented by the aforementioned ring A ′ can be mentioned.
When R ^6a is bonded to a substituent of ring A to form a ring, ring A together with —N—Z ″ — (carbon atom or nitrogen atom to which Z ″ is bonded to ring A) — It may form an "optionally substituted spiro ring" or an "optionally substituted fused nitrogen-containing heterocycle". The “optionally substituted spiro ring” or the “optionally substituted nitrogen-containing fused heterocyclic ring” represented by the “substituted ring formed by bonding R ^6b with the substituent of ring A ′” And an optionally substituted spiro ring or an optionally substituted nitrogen-containing fused heterocyclic ring. R ^6a is bonded to R ^1a , R ^2a , R ^3a , and R ^4a to form, for example,

Embedded image [Ring E represents a 5- to 10-membered nitrogen-containing heterocyclic ring;
Represents a 10 to 10-membered nitrogen-containing heterocyclic ring, G represents a 4- to 8-membered nitrogen-containing heterocyclic ring, and H represents a 5- to 10-membered nitrogen-containing heterocyclic ring. And the rings E, F, G and H represented by the following formulas may be formed. These rings E, F, G, and H may have a substituent, and examples of the substituent include a cyclic hydrocarbon group of “optionally substituted cyclic hydrocarbon group” represented by R. And the same as the substituents which may be substituted.

Y 'is -CO-, -S (O)-, -S (O) _2- , and Z is -N
(R ^5a )-, -CO-, -S (O)-, -S (O) _2- , -CH ₂ -or a bond is shown. Specific examples of the combination of Y and Z include a case where Y is —CO— and Z is —N (R ^5a ) —;
O- and Z is -CO-; Y is -CO- and Z is
Y is —CO— and Z is —S (O) ₂ —; Y is —CO— and Z is —CH ₂ —; But-
CO— and Z is a bond; Y is —S (O) — and Z is —N (R ^5a ) —; Y is —S (O) — and Z is
When -CO-; Y is -S (O)-and Z is -S (O)-; Y is -S (O)-and Z is -S (O) _2-. If; Y
Is -S (O)-and Z is -CH _2- ; Y is -S (O)-and Z is a bond; Y is -S (O) _2- , Z
Is -N (R ^5a )-; Y is -S (O) _2- and Z is -CO-
When Y is -S (O) _2- and Z is -S (O)-; Y is -S (O) _2- and Z is -S (O) _2- If there is; Y is
-S (O) _2- and Z is -CH _2- ; Y is -S (O) _2- and Z is a bond; In the above, n may be combined with either 0 or 1. However, when Y and Z are —N (R ^5a ) —, b preferably represents 0. Above all, Y is -C
O- or -S (O) _2- , and it is preferable that Z is -CO- or a bond, in particular, Y is -CO- or -S (O) _2- , and Z is In some cases; Also, if Z is
-CO- is also a preferred example

As the compound (VIIIa), 3-[(6-chloro-2-naphthyl) sulfonyl] -N-methyl-N- [1- (4-pyridyl) -4-piperidyl] propanamide, 2- [ N- [3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl] -N- [1- (4-
Pyridyl) -4-piperidyl] amino] ethyl acetate, 3- [N- [3-
[(6-Chloro-2-naphthyl) sulfonyl] propanoyl] -N-
Ethyl [1- (4-pyridyl) -4-piperidyl] amino] propionate, 3-[(6-chloro-2-naphthyl) sulfonyl] -N-methyl
-N- [1- (2-methyl-4-pyridyl) -4-piperidyl] propanamide, N- [2- (acetylamino) ethyl] -3-[(6-chloro-
2-naphthyl) sulfonyl] -N- [1- (2-methyl-4-pyridyl)-
4-Piperidyl] propanamide, N- (2-aminoethyl) -3-
[(6-Chloro-2-naphthyl) sulfonyl] -N- [1- (4-pyridyl) -4-piperidyl] propanamide (preferably its ditrifluoroacetate), N- [2- (acetylamino) ethyl ]
-3-[(6-chloro-2-naphthyl) sulfonyl] -N- [1- (4-pyridyl) -4-piperidyl] propanamide, 3-[(6-chloro-2-
Naphthyl) sulfonyl] -N- [2-[(methanesulfonyl) amino] ethyl] -N- [1- (4-pyridyl) -4-piperidyl] propanamide or a salt thereof is particularly preferably used.

The "leaving group" represented by L ¹ or L ³ in the formula may be substituted with a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) or 1 to 3 halogen atoms.
C _1-6 alkylsulfonyloxy group (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), and optionally substituted arylsulfonyloxy group (eg, benzenesulfonyloxy, p-toluenesulfonyl) Oxy, p-bromobenzenesulfonyloxy, etc.) or hydroxyl group, free carboxylic acid, its salt (inorganic salt, organic salt, etc.) or its reactive derivative (eg, acid halide, ester, acid azide, acid anhydride, mixed acid) Anhydride, active amide, active ester, active thioester, etc.).

The "alkali metal or alkaline earth metal" represented by M in the formula includes, for example, alkali metals such as sodium and potassium, and alkaline earth metals such as calcium and magnesium, with sodium being preferred.

As the “optionally substituted nitrogen-containing aliphatic heterocycle” represented by ring A ″, the “optionally substituted nitrogen-containing heterocycle” represented by the aforementioned ring A ′ can be used. Examples thereof include those in which a nitrogen-containing aromatic heterocyclic ring is partially excluded, and among them, piperidine, piperazine, and the like are preferable, and piperidine is particularly preferable.

The hydrocarbons of “optionally substituted hydrocarbons” represented by R ⁶ include R ^5b and R ^{5
The same} as the “optionally substituted hydrocarbon group” shown in ^6b .

Each production method and raw materials and reagents used in each production method will be described below.
And a salt thereof may be referred to as a “compound I”, and a compound represented by the formula (II) or a salt thereof and a compound represented by the formula (IV) or a salt thereof are referred to as “compound II”. , IV ". The cyclic ketone derivative (compound IX) is reacted with a compound VII using a trisiloxyborohydride complex compound or a combination of a palladium catalyst and a hydrogen source (hydrogen gas or formic acid or a salt thereof) as a reducing agent. In the method for producing the derivative (compound XI), the trisiloxyborohydride complex compound used is a product obtained by reacting a borohydride complex compound with 3 equivalents of a carboxylic acid. For example, triformyloxyborohydride hydride Sodium, sodium triacetoxyborohydride, sodium tribenzoyloxyborohydride and the like can be mentioned, and preferably, sodium triacetoxyborohydride and the like can be mentioned. Examples of the above borohydride complex compound include metal borohydride, alkali metal borohydride, alkaline earth metal borohydride, and quaternary ammonium borohydride, such as sodium borohydride and hydrogen hydride. In addition to lithium borohydride, potassium borohydride, calcium borohydride, barium borohydride, and the like, a combination of sodium borohydride and an alkali (earth) metal salt (eg, lithium chloride, calcium chloride) and the like can be mentioned. Examples of the carboxylic acid include C _1-6 aliphatic carboxylic acids (eg, formic acid, acetic acid, etc.) and aromatic carboxylic acids (eg, benzoic acid).
_1-6 aliphatic carboxylic acids are preferably used. As the palladium catalyst, a heterogeneous catalyst such as palladium black, palladium carbon, palladium-silica gel, palladium-barium sulfate, palladium acetate (II), palladium trifluoroacetate (II), palladium chloride (II), palladium bromide ( II), Yoka palladium (II), divalent palladium salts such as bis (triphenylphosphine) palladium (II) and complexes thereof, palladium black, palladium carbon, tetrakistriphenylphosphine palladium (0), bis ( A zero-valent palladium metal such as dibenzalacetone) dipalladium (0) and a complex thereof are used. Among them, palladium carbon, palladium (II) acetate,
Palladium (II) chloride is preferred, and palladium on carbon is particularly preferred. In the present reaction, in addition to the palladium catalyst, a ligand for forming a palladium complex in the reaction system may be used.Examples of such a ligand include triphenylphosphine and tri (o-tolyl) phosphine. , Tri (3-methoxyphenyl) phosphine, tri (4-chlorophenyl) phosphine, tri (2-furyl) phosphine, tri (2-phenyl)
Phosphine, 1,2-bis (diphenylphosphino) ethane and the like are used.

Each of the above manufacturing methods will be described below. [Production Method 1] Sulfine derivative (I) or (I ′) and compound (IIa ′)-(IIc ′), (IIa)-(II
c), (VIIa) or (VIIb) is reacted to give the sulfone derivative (IIIa ′)-(IIIc ′), (II
Ia)-(IIIc), (VIIIa) or (VII)
In the method for producing Ib), the solvent used is not particularly limited as long as it does not affect the reaction. For example, benzene, toluene, aromatic hydrocarbons such as xylene, hexane, pentane, aliphatic hydrocarbons such as heptane, ethyl acetate, esters such as butyl acetate, diethyl ether, diisopropyl ether, t-butyl methyl ether, Ethers such as tetrahydrofuran,
Aliphatic halogen hydrocarbons such as methylene chloride, chloroform, dichloroethane, methanol, ethanol, 1-
Alcohols such as propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpiperidone, dimethyl sulfoxide , Hexamethylphosphoric amide, dimethylimidazolidinone, water and the like, among which the above alcohols, esters, ethers, and aromatic hydrocarbons are preferable, and particularly methanol, ethanol, 2-propanol, ethyl acetate, Tetrahydrofuran and toluene are preferred. The amount of the solvent used in this reaction is 5 to 50 times by weight, preferably 5 to 30 times by weight, particularly preferably 5 to 2 times by weight, relative to the sulfinic acid derivative (I) or (I ').
It is 0 times by weight. In this case, compound (IIa ′)-
(IIc ′), (IIa)-(IIc), (VIIa)
Alternatively, the amount of (VIIb) to be used is 1 to 10 moles, preferably 1 to 5 moles, particularly preferably 1 to 3 moles relative to the sulfinic acid derivative (I) or (I ′). This reaction may be performed in the presence of a base. Examples of such a base include alkali metal hydrides such as potassium hydride and sodium hydride, for example, lithium ethoxide, lithium tert-butoxide, sodium methoxide, and sodium ethoxy. Metal alkoxides having 1 to 6 carbon atoms, such as chloride and carboxyl-tert-butoxide; inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate; (N-propyl) amine, tri (n-butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
Tertiary amines such as N-methylmorpholine are used. Among them, it is preferable to use a tertiary amine. The amount of these bases used is 1 to 30 times, preferably 1 to 10 times the mol of the sulfinic acid derivative (I) or (I ′).
The molar amount is twice as much, particularly preferably 1 to 5 times. The reaction temperature is usually 0 to 200 ° C, preferably 10 to 100 ° C, and the reaction time is generally 1 to 100 hours, preferably 1 to 50 hours, particularly preferably 1 to 20 hours.

[Production Method 2] Cyclic Ketone Derivative (Compound I)
X) is reacted with an alkylamine (compound X) using a combination of sodium trisiloxyborohydride or palladium catalyst and hydrogen gas or formic acid or a salt thereof to produce an amine derivative (compound XI). In the method, the solvent to be used is not particularly limited as long as it does not affect the reaction, and the same carboxylic acids as those of Production Method 1 and carboxylic acids such as acetic acid are used. The amount of the solvent used in this reaction is 5 to 50 times by weight, preferably 5 to 50 times the weight of the cyclic ketone derivative (Compound IX).
It is 30 to 30 times by weight, particularly preferably 5 to 20 times by weight.
In this case, the amount of the alkylamine (compound X)) used is 1 to 10 with respect to the cyclic ketone derivative (compound VI).
The molar amount is 0 times, preferably 1 to 50 times, particularly preferably 1 to 30 times. When a trisiloxyborohydride complex compound is used as the reducing agent, the amount of the trisiloxyborohydride complex compound to be used is 1 to 30 times mol, preferably 1 to 10 times mol, relative to the cyclic ketone derivative (compound IX). Particularly preferably, it is 1 to 5 moles. When a combination of a palladium catalyst and a hydrogen source (hydrogen gas or formic acid or a salt thereof) is used as the reducing agent, the amount of the palladium catalyst used is about 0.0 with respect to the cyclic ketone derivative (compound VI).
001 to about 2 moles, preferably about 0.001 to about 1 mole. The hydrogen pressure is 1 to 100 atm, preferably 1 to 3 atm. The amount of formic acid used is 1 to 30 moles, preferably 1 to 10 moles, particularly preferably 1 to 5 moles relative to the cyclic ketone derivative (compound VI). The reaction temperature is usually 0 to 150 ° C, preferably 10 to 100 ° C,
Particularly preferred is 10 to 50 ° C., and the reaction time is usually 1 to 20
Time, preferably 1 to 10 hours, particularly preferably 1 to 5 hours.

The starting compounds (I), (I '), (IIa')-(II) used in the above production methods 1 and 2
c ′), (IIa)-(IIc), (VIIa), (V
IIb), (IX) or (X) can be produced by a method known per se or a method analogous thereto. For example, the compound (I) is represented by the general formula RWS (O) ₂ -H
al (XV) [wherein, R represents a cyclic hydrocarbon group or a heterocyclic group which may be substituted, W represents a bond or a divalent chain hydrocarbon group which may be substituted, and Hal Represents a halogen atom] and is reduced by a suitable reducing agent. Examples of such a reducing agent include, in addition to the above-mentioned borohydride complex compound, aluminum hydride compounds (eg, sodium dihydrobis (2-methoxyethoxy) aluminate, diisobutylaluminum hydride, trimethoxylithiumaluminum hydride, Lithium tert-butoxy, sodium aluminum hydride, sodium triethoxyaluminum hydride) and sulfites (eg, sodium sulfite) are used. Among them, borohydride complex compounds (particularly sodium borohydride), ) Sodium aluminate Sodium sulfite is preferred. As the compound (X), commercially available ammonia and primary amines are used.
It can be synthesized according to a general method for synthesizing an amine described on pages 9-372, 1992, and the like.

When the compound is obtained in a free state by each reaction of the present invention, it may be converted into a salt according to a conventional method, and when the compound is obtained as a salt, a free form or other compound may be obtained according to a conventional method. It can also be converted to salt. Compound (IIIa ′)-(III) thus obtained
c ′), (IIIa)-(IIIc), (VIIIa)
And (VIIIb) can be isolated and purified from the reaction mixture by a means known per se, such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin-layer chromatography, and the like. Can be.
If desired, the reaction mixture may be used for the next reaction without isolation and purification. Compound (IIIa ')-
(IIIc ′), (IIIa)-(IIIc), (VI
The salts of IIa) and (VIIIb) can be prepared according to the methods known per se, for example, from compounds (IIIa ′)-(III
c ′), (IIIa)-(IIIc), (VIIIa)
And (VIIIb) by adding an inorganic acid or an organic acid. Compound (III
a ′)-(IIIc ′), (IIIa)-(III
When stereoisomers may exist in c), (VIIIa) and (VIIIb), each of these individual isomers and mixtures thereof is, of course, included in the scope of the present invention, and if desired, these isomers Can also be manufactured individually. Compound (IIIa ′)-(III
c ′), (IIIa)-(IIIc), (VIIIa)
And (VIIIb) or a salt thereof may be a hydrate, and both a hydrate and a non-hydrate are included in the scope of the present invention. Compound (IIIa ′)-(I
IIc ′) is subjected to hydrolysis under acidic or basic conditions and condensed with an amine derivative represented by the general formula (V) to give a compound of the general formula (VI) having an FXa inhibitory action.
a ′)-(VIc ′) or a salt thereof can also be produced. The starting compound used in each of the above-mentioned production methods and the target compound obtained in each of the above-mentioned production methods may form a salt.Examples of such a salt include trifluoroacetic acid, acetic acid, lactic acid, succinic acid, maleic acid, Tartaric acid, citric acid, gluconic acid, ascorbic acid,
Acid addition salts with acids such as benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid, phosphonic acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, sulfuric acid, Examples thereof include metal salts such as sodium, potassium, magnesium, and calcium, and organic salts such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine, and N-methylmorpholine, which do not inhibit the reaction. Any one may be used. Examples of the formic acid salt used in each of the above production methods include, for example, metal salts such as sodium, potassium, magnesium, and calcium, such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine,
Organic salts such as N-methylmorpholine and the like, ammonium formate and the like can be mentioned, and any one may be used as long as it does not inhibit the reaction.

Compound (VI) obtained by the production method of the present invention
a ′)-(VIc ′), (VIIIa) and (VII)
Ib) is low toxic and safe, inhibits FXa and has an anticoagulant effect, so that it can be used in animals, particularly mammals (eg, human, monkey, cat, pig, horse, cow, mouse, rat,
For guinea pigs, dogs, rabbits, etc.), for example, it is useful for the prevention or treatment of the following diseases. Brain: Cerebral embolism, cerebral infarction due to atrial fibrillation, acute ischemic stroke, acute cerebral thrombosis, cerebral vasospasm after subarachnoid hemorrhage, Alzheimer's disease, transient ischemic attack (TIA), mixed dementia, cerebrovascular Sexual / multiple infarct dementia, heart:
Acute coronary artery disease, acute myocardial infarction, sequelae of myocardial infarction, improvement of prognosis and prevention of secondary onset of myocardial infarction, unstable angina, angina, stent placement or PTCA (percutaneous intracoronary angioplasty) and atherectomy Vascular reocclusion and stenosis after isocoronary intervention, peripheral: deep vein thrombosis,
Prevention of onset / secondary onset of deep vein thrombosis, chronic arterial occlusion, peripheral vascular disease, pulmonary thromboembolism, economy class syndrome, adult respiratory distress syndrome, chronic kidney disease (eg, diabetic nephropathy, chronic glomerulus) Nephritis, IgA nephropathy, etc.), diabetic circulatory disorder, pain, neuropathy, etc .: thrombocytopenia due to dialysis, thrombocytopenia during major surgery, arteriosclerosis, cancer metastasis,
Systemic Inflammatory Response Syndrome (SIRS) or Pancreatic Intravascular Coagulation Syndrome (DIC) in pancreatitis and cancer patients Organ failure (eg, lung failure, liver failure, renal failure, heart failure, etc.)

Compound (IIIa ')-(III
c ′) is optionally a carboxylic acid form (IVa ′)-(I
Vc ′), is condensed with compound (V), and is induced into compound (VIa ′)-(VIc ′), and thus is useful as an intermediate of an FXa inhibitor. Similarly, compound (III)
a)-(IIIc) are also useful as intermediates for FXa inhibitors.

The present condensation reaction is generally carried out in a solvent, and if necessary, a base or a condensing agent (for example, carbodiimides (DC
C (dicyclohexylcarbodiimide), WSC (hydrochloric acid 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide), DIC (2-dimethylaminoisopropyl chloride hydrochloride), etc., phosphoric acid derivatives (eg, diethyl cyanophosphate, DPPA (diphenylphosphoryl azide), BOP-Cl
(Bis (2-oxo-3-oxazolidinyl) phosphinic chloride), etc.). As such a solvent and a base, the solvents and bases described in the above-mentioned Production Method 1 are used as they are. The reaction is carried out with the compound (IV
a ′)-(IVc ′) with respect to compound (V)
It is 5 equivalents, preferably 0.8 to 2 equivalents. The reaction temperature is -50 to 150C, preferably -20 to 100C. The reaction time varies depending on the type of compound (IVa ')-(IVc') or (V), the type of solvent and base, the reaction temperature and the like, but is usually about 1 minute to about 100 hours, preferably about 15 minutes to about 48 hours. Time.

[0069]

Now, the present invention will be described in further detail with reference to Examples, Reference Examples and Experimental Examples, but the present invention is not limited thereto.

Reference Example 1 Production of 1- (2-methylpyridin-4-yl) piperidin-4-one

Embedded image Add 4-chloro-2-picoline (150 g, 1.18 mo
l), 4-Piperidone hydrochloride monohydrate (181 g, 1.18 mol),
Sodium acetate (96.8 g, 1.16 mol) and acetic acid (591 ml)
And reacted at 118 to 120 ° C. for 6.5 hours under a nitrogen stream. The reaction solution was concentrated under reduced pressure to about 400 ml, diluted with city water (500 ml) and ethyl acetate (150 ml), and neutralized by adding potassium carbonate (200 g) and sodium hydroxide (50 g). After dilution with city water (500 ml), the mixture was extracted with ethyl acetate (350 ml + 150 ml), and sodium hydroxide (50 g) was further added to the aqueous layer to add ethyl acetate (5 ml).
00 ml). All the organic layers were combined, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and dried to give 1- (2-methylpyridin-4-yl) piperidin-4-one (198 g). (Confirmation) ¹ H-NMR (CDCl ₃ , TMS, 3OOMHz) δ (ppm): 2.46 (3
H, s), 2.53 (4H, t, J = 6.1 Hz), 3.70 (2H, t, J =
6.2 Hz), 6.54 (1H, dd, J = 5.9 and 2.4 Hz), 6.57 (1
H, d, J = 2.4 Hz), 8.20 (1H, d, J = 5.9 Hz)

[0071]

EXAMPLES Example 1 Preparation of methyl 3-[(6-chloro-2-naphthyl) sulfonyl] propionate

Embedded image Charge tetrahydrofuran (1 L) to a 3 L 4-necked corbene and stir in a nitrogen stream at room temperature while stirring sodium borohydride (3 L).
(7.8 g, 1.0 mol) was added. Followed by 6-chloronaphthalene
A suspension of 2-sulfonyl chloride (131 g, 0.5 mmol) in tetrahydrofuran (1 L) was added. After stirring at about 40 ° C for 2.5 hours, cool to room temperature, slowly pour the reaction solution in a nitrogen stream into ice water (2.3 L) and ethyl acetate (200 ml) in a separately prepared 5 L beaker, and then add concentrated hydrochloric acid (350 ml) was added dropwise. The mixture was extracted with ethyl acetate (2 L + 1 LX2), the organic layers were combined, washed with a saturated saline solution and city water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a slurry of about 1 L. Charge the concentrated slurry into a 2L4 neck colben and add methyl acrylate
(43.0 g, 0.5 mol), triethylamine (76.7 g, 0.5 mol)
And reacted at 75-85 ° C. for 7 hours. After completion of the reaction, the resultant was cooled to room temperature and concentrated under reduced pressure. Ethanol was added to the residue, and the mixture was concentrated under reduced pressure. After heating and dissolving with ethanol (1.2 l), foreign substances were removed by filtration while hot and washed with ethanol. The filtrate was concentrated under reduced pressure to about 1 L under reduced pressure, stirred at room temperature, and the crystals were collected by filtration, dried at 40 ° C. under reduced pressure, and methyl 3-[(6-chloro-2-naphthyl) sulfonyl] propionate (138 g) I got (Yield 88%) (confirmation) ¹ H-NMR (CDCl ₃ , TMS, 3OOMHz) δ (ppm): 2.83 (2
(H, t, J = 7.4Hz), 3.54 (2H, t, J = 7.4Hz), 3.62 (3H, s), 7.6
2 (1H, dd, J = 8.7and 2.0Hz), 7.9-8.0 (4H, m), 8.50 (1H, d,
(J = 0.9Hz)

Embodiment 2

Embedded image 200 ml 4-necked corvene was charged with sodium dihydrobis (2-methoxyethoxy) aluminate (26.3 g.90.5 mmol) and tetrahydrofuran (100 ml), and stirred at room temperature in a nitrogen stream at room temperature to give 6-chloronaphthalene-2-sulfonyl chloride (19.7 g). g, 75.4 mmol) in tetrahydrofuran (100 ml)
The suspension was added. After stirring at room temperature for 2 hours, separately prepared 5
The reaction solution was slowly poured in a stream of nitrogen into ice water (300 ml) ethyl in an L beaker, and then 6N-hydrochloric acid (200 ml) was added dropwise. The mixture was extracted with ethyl acetate (600 ml + 300 ml), and the organic layers were combined, washed with saturated saline and city water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate (200 m
l), methyl acrylate (6.86 g, 79.2 mmol) and triethylamine (9.16 g, 90.5 mmol) were added, and the mixture was heated under reflux for 9 hours. After completion of the reaction, the resultant was cooled to room temperature and concentrated under reduced pressure. After crystallizing the residue by adding ethanol (100 ml), the crystals were collected by filtration,
Drying under reduced pressure at 40 ° C. gave methyl 3-[(6-chloro-2-naphthyl) sulfonyl] propionate (20.0 g). (85% yield)

Example 3 Preparation of 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid

Embedded image 3-L (6-chloro-2-naphthyl) sulfonyl]
Methyl propionate (133 g, 405 mmol), acetic acid (810 ml),
City water (81 ml) and concentrated sulfuric acid (81 ml) were charged and reacted under reflux for 2 hours. After completion of the reaction, the reaction solution is cooled to room temperature,
City water (1970 ml) was added, and the mixture was stirred under ice-cooling, and the crystals were collected by filtration. The crude crystals were washed with municipal water (2 L) at room temperature and repulp washed. [Naphthyl) sulfonyl] propionic acid (123 g) was obtained. (Yield 94%) (confirmation) ¹ H-NMR (CDCl ₃ , TMS, 3OOMHz) δ (ppm): 2.83
(2H, t, J = 7.4 Hz), 3.48 (2H, t, J = 7.6Hz), 7.60
(1H, dd, J = 8.7 and 1.9 Hz), 7.8-8.0 (4H, m), 8.
47 (1H, s)

Example 4 3-[(6-chloro-2-naphthyl) sulfonyl] -N-methyl-N-[[1
Preparation of [-(2-methyl-4-pyridyl) -4-piperidinyl] propanamide

Embedded image A 200 ml eggplant-type corben was charged with 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (6.43 g, 21.5 mmol), hydroxybenzotriazole (4.59 g, 30.0 mmol) and tetrahydrofuran (50 ml), and the mixture was stirred at room temperature. After dissolving with stirring, triethylamine (6.13 g, 60.0 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.75 g, 3
0.0 mmol) and tetrahydrofuran (26 ml) were added and suspended. Subsequently, at the same temperature, 20 ml of a solution of N-methyl-1- (2-methylpyridin-4-yl) piperidin-4-amine (4.10 g, 20.0 mmol) in tetrahydrofuran (24 ml) was added, and after 30 minutes, The remaining solution was added, and the mixture was stirred as it was for 6 hours. After completion of the reaction, the reaction solution was diluted with city water (200 ml), and ethyl acetate (200 ml) was added.
ml + 100 ml × 2). Combine organic layers and saturated saline
(50 ml × 2) and city water (50 ml), and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was treated with ethyl acetate (60
After cooling under ice-cooling, the crystals were collected by filtration and dried under reduced pressure to give crude crystals of the desired product (8.67 g). The above crude crystals (8.00 g) and methanol-denatured ethanol (200 ml) were charged into a 300 ml eggplant-type corben, and dissolved by stirring under reflux. . Combine the washings,
It concentrated under reduced pressure to about 80 ml. The concentrated solution was again heated under reflux, cooled slowly (suspended at about 50 ° C.), and stirred for 1 hour under ice cooling.
The crystals were collected by filtration, sprinkled and washed with methanol-denatured ethanol (40 ml), dried at 40 ° C. under reduced pressure, and dried with 3-[(6-chloro-2-naphthyl) sulfonyl] -N-methyl-N-[[1- ( 2-Methyl-4-pyridyl) -4-piperidinyl] propanamide (7.34 g) was obtained. (Confirmation) ¹ H-NMR (CDCl ₃ , TMS, 3OOMHz) δ (ppm): 1.5-1.9
(4H, m), 2.4-2.5 (3H, m), 2.8-3.1 (7H, m), 3.5-3.
6 (2H, m), 3.8-4.0 (2H, m), 4.5-4.7 (1H, m), 6.4-
6.6 (2H, m), 7.59 (1H, dd, J = 8.8 and 1.9 Hz), 7.
8-8.0 (2H, m), 8.1-8.3 (1H, m), 8.50 (1H, s) Elemental analysis (C ₂₅ H ₂₈ N ₃ O ₃ SCl) Theoretical C: 61.78, H: 5.81, N: 8.65 Found C: 61.70, H: 5.66, N: 8.48

Example 5 3-[(6-chloro-2-naphthyl) sulfonyl] -N-methyl-N-[[1
Preparation of [-(2-methyl-4-pyridyl) -4-piperidinyl] propanamide

Embedded image N-methyl-1- (2-methylpyridine)
-4-yl) piperidin-4-amine (1.43 g, 6.96 mmol), triethylamine (1.54 g, 15.3 mmol), acroyl chloride (756 mg, 8.35 mmol) and tetrahydrofuran (28.6
ml) and reacted at room temperature for 4 hours. A 2N aqueous solution of sodium hydroxide (30 ml) was added to the reaction solution, and the mixture was extracted with tetrahydrofuran (30 ml × 3). The organic layers were combined, washed with a saturated saline solution (100 ml), dried over anhydrous MgSO ₄ , and concentrated under reduced pressure to obtain an acrylamide compound. 6-chloronaphthalene-2-sulfonyl chloride (1.82 g, 6.96 m)
mol) and tetrahydrofuran (72.8 ml), and stirred at room temperature in a nitrogen stream while mixing sodium borohydride.
(1.84 g, 48.7 mmol) was added. After stirring at the same temperature for 11 hours, the mixture was left overnight (13.5 hours), and further stirred for 2.5 hours.
After the reaction is completed, ice water (180 ml) in a 1L beaker prepared separately
The reaction mixture was slowly poured into a stream of nitrogen, and 6N-hydrochloric acid (9 ml) was slowly added. Extract with ethyl acetate (70 ml X3), combine the organic layers, wash with city water (200 ml) solution,
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to obtain a sulfinic acid compound. Ethyl acetate (18.
2 ml), the above sulfinic acid compound, triethylamine (845 m
g, 8.35 mmol) and methanol (9.1 ml).
The reaction was performed for 56.5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure.
-Add aqueous sodium hydroxide solution (50 ml) and add ethyl acetate (5
0 ml + 25 ml × 2). The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate (100 ml) and city water (100 ml × 2), and dried over anhydrous magnesium sulfate. Ethyl acetate (4 ml) and hexane (2 ml) were added to the concentrated residue, and the mixture was crystallized under heating.After slowly cooling and cooling with ice, the crystals were collected by filtration, dried at 40 ° C. under reduced pressure, and crude (1.04 g) I got The above crude product (800 mg) was washed with ethanol (8 ml) under re-pulp under reflux, allowed to cool, and cooled with ice.
Dry under reduced pressure to give 3-[(6-chloro-2-naphthyl) sulfonyl] -N-
Methyl-N-[[1- (2-methyl-4-pyridyl) -4-piperidinyl]
Propanamide (670 mg) was obtained (26% yield) (confirmed) ¹ H-NMR (CDCl ₃ , TMS, 3OOMHz) δ (ppm): 1.5-1.9
(4H, m), 2.4-2.5 (3H, m), 2.8-3.1 (7H, m), 3.5-3.6
(2H, m), 3.8-4.0 (2H, m), 4.5-4.7 (1H, m), 6.4-6.6
(2H, m), 7.59 (1H, dd, J = 8.8 and 1.9 Hz), 7.8-
8.0 (2H, m), 8.1-8.3 (1H, m), 8.50 (1H, s) Elemental analysis (C ₂₅ H ₂₈ N ₃ O ₃ SCl) Theoretical C: 61.78, H: 5.81, N: 8.65 Value C: 61.79, H: 5.69, N: 8.56

Example 6 N-methyl-1- (2-methylpyridin-4-yl) piperidin-4-
Amine production

Embedded image 1- (2-methylpyridin-4-yl) piperidin-4-one (198 g, 1.04 mol) and acetic acid (1980 ml) were charged to a 5L4 neck colvene, and under nitrogen flow, the temperature was kept at around 30 ° C. or less while 40%. A methanol solution of methylamine (1070 ml, 10.4 mmol) was slowly added dropwise. Sodium triacetoxyborohydride (265 g,
(1.25 mol) was added and reacted for 1.5 hours. Reaction water in city water
(600 ml), concentrate under reduced pressure to about 2 L, add city water (1 L), ethyl acetate (250 ml), potassium carbonate (500 g), sodium hydroxide (500 g) and add tetrahydrofuran (500 ml × 3 +
250 ml). The organic layers were combined, dried over anhydrous magnesium sulfate without washing with water, concentrated under reduced pressure, and dried to give N-methyl-1- (2-methylpyridin-4-yl) piperidin-4-amine (179 g). (Yield 84%) (confirmed) ¹ H-NMR (CDCl ₃ , TMS, 3OOMHz) δ (ppm): 1.3-1.4
(2H, m), 1.9-2.0 (2H, m), 2.41 (3H, s), 2.43 (3H,
s), 2.5-2.6 (1H, m), 2.8-3.0 (2H, m), 3.7-3.8 (2H,
m), 6.47 (1H, dd, J = 6.0 and 2.6 Hz), 6.51 (1H,
d, J = 2.4 Hz), 8.10 (1H, d, J = 5.9 Hz)

Example 7 N-methyl-1- (2-methylpyridin-4-yl) piperidin-4-
Amine production

Embedded image 1- (2-methylpyridin-4-yl) piperidin-4-one (2.00 g, 10.5 mmol), methanol (20 ml), 5% palladium on carbon (wet. , And a 40% methanol solution of methylamine (8.15 g, 105 mmol) and formic acid (1.45 g, 31.5 mmol) were added with stirring at room temperature, and the mixture was reacted at an internal temperature of 55 to 60 ° C for 2 hours. After completion of the reaction, the catalyst was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure to obtain N-methyl-1- (2-methylpyridin-4-yl) piperidin-4-amine formate (2.70 g).

[0078]

The production method of the present invention is characterized in that activated blood coagulation X
Thrombo-occlusive disease of arteries and veins, inflammation, which inhibit factor (FXa) and have anticoagulant and antithrombotic effects
It is advantageously used for producing a sulfone derivative or a salt thereof useful for prevention and treatment of cancer and the like.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C063 AA01 BB02 CC12 DD10 EE01 4H006 AA02 AC62 BB15 BB17 BB31 BE03 TA02 TB56 TC11

Claims (42)

[Claims] (1) A compound represented by the general formula: RWS (O) ₂ -M (I) wherein R is an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group. W represents a bond or a divalent chain hydrocarbon group which may be substituted, and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. A sulfinic acid derivative represented by the following formula: or a salt thereof, and a general formula L ¹ -XR ′ (IIa ′) wherein L ¹ represents a leaving group, and X represents a divalent group which may be substituted. R ′ represents a carboxyl group or a cyano group which may be esterified or amidated. 2) The resulting compound of the formula RWS (O) ₂ -XR ′ (IIIa ′) wherein the symbols are as defined above. . A compound represented by] or subjected to hydrolysis optionally a salt thereof, 3) is obtained the formula R-W-S (O) 2 -X-CO 2 H (IVa ') [wherein the symbols The meaning is as defined above. A salt thereof or a reactive derivative thereof, and a compound represented by the general formula: [Wherein, Z ″ is -N (R ^5b )-, -CO-, -S (O)-, -S
(O) _2- , -CH _2- , -N (R ^5b ) -CO-, -CO-CH ₂ -or a bond, and ring A 'represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5b and R ^6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group,
R ^6b may be bonded to a substituent of the ring A ′ to form a ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. A compound represented by the general formula: [Wherein the symbols are as defined above. ] Or a salt thereof. 2. A compound represented by the general formula: R—W—S (O) ₂ —M (I) wherein R is an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group. W represents a bond or a divalent chain hydrocarbon group which may be substituted, and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. A sulfinic acid derivative or a salt thereof represented by the general formula (R ¹ ) (R ² ) C ＝ C (R ³ ) (R ′) (IIb ′) wherein R ¹ , R ² and R ³ Each independently represents a hydrogen atom or a hydrocarbon group which may be substituted,
Alternatively, R ¹ and R ² , R ¹ and R ³ or R ² and R ³ may be bonded to each other to form an optionally substituted ring;
Represents a carboxyl group or a cyano group which may be esterified or amidated. ] With a compound or is reacted with a salt thereof, 2) obtained formula R-W-S (O) 2 -C (R 1) (R 2) -CH (R 3) -R '(IIIb ') Wherein the symbols are as defined above. A compound represented by] or subjected to hydrolysis optionally a salt thereof, 3) is obtained the formula R-W-S (O) 2 -C (R 1) (R 2) -CH (R 3) —CO ₂ H (IVb ′) wherein the symbols are as defined above. And a salt thereof or a reactive derivative thereof, and a compound represented by the general formula: [Wherein, Z ″ is -N (R ^5b )-, -CO-, -S (O)-, -S
(O) _2- , -CH _2- , -N (R ^5b ) -CO-, -CO-CH ₂ -or a bond, and ring A 'represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5b and R ^6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group,
R ^6b may be bonded to a substituent of the ring A ′ to form a ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. A compound represented by the following general formula: [Wherein the symbols are as defined above. ] Or a salt thereof. 3) A compound represented by the general formula: RWS (O) ₂ -M (I) wherein R is an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group; W represents a bond or a divalent chain hydrocarbon group which may be substituted, and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. And a sulfinic acid derivative or a salt thereof represented by the general formula R ⁴ C≡C—R ′ (IIc ′) wherein R ⁴ represents a hydrogen atom or a hydrocarbon group which may be substituted, R 'represents a carboxyl group or a cyano group which may be esterified or amidated. 2) The resulting compound of the formula: R—W—S (O) ₂ —C (R ⁴ ) = CH—R ′ (IIIc ′) wherein the symbols are The meaning is as defined above. A compound represented by] or subjected to hydrolysis optionally a salt thereof, 3) is obtained the formula R-W-S (O) 2 -C (R 4) = CH-CO 2 H (IVc ') [Wherein the symbols are as defined above. And a salt thereof or a reactive derivative thereof, and a compound represented by the general formula: [Wherein, Z ″ is -N (R ^5b )-, -CO-, -S (O)-, -S
(O) _2- , -CH _2- , -N (R ^5b ) -CO-, -CO-CH ₂ -or a bond, and ring A 'represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5b and R ^6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group,
R ^6b may be bonded to a substituent of the ring A ′ to form a ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. Wherein the compound is represented by the following general formula: [Wherein the symbols are as defined above. ] Or a salt thereof. 4. A compound represented by the general formula: R—W—S (O) ₂ —M (I) wherein R represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; W represents a bond or a divalent chain hydrocarbon group which may be substituted, and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. A sulfinic acid derivative or a salt thereof represented by the general formula L ¹ -XYL ² (IIa) wherein L ¹ represents a leaving group, and X represents a divalent group which may be substituted Wherein Y is -N (R ⁵ )-, -CO
—, —S (O) —, —S (O) ₂ —, —CH ₂ — or a bond, L ² represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group, and R ⁵ represents hydrogen It represents an atom, a hydrocarbon group which may be substituted, an alkoxy group which may be substituted, a carboxyl group which may be esterified or amidated, or an acyl group. Wherein the compound or the reaction of a salt thereof], in the general formula R-W-S (O) 2 -X-Y-L 2 (IIIa) [wherein the symbols are as defined above Show. ] The method for producing a sulfone derivative or a salt thereof represented by the formula: 5. The method according to claim 4, wherein R is a cyclic hydrocarbon group substituted with a halogen atom or an alkenyl group or a heterocyclic group which may be substituted. 6. A compound of the general formula R ″ —WS (O) ₂ -M (I ′) wherein R ″ is a cyclic hydrocarbon group substituted with a halogen atom or an alkenyl group or a substituted hydrocarbon group. And W is a bond or an optionally substituted 2
Represents a valent chain hydrocarbon group, and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. A sulfinic acid derivative or a salt thereof represented by the general formula (R ¹ ) (R ² ) C ＝ C (R ³ ) (Y′-L ² ) (IIb) wherein R ¹ , R ² and R ³ each independently represents a hydrogen atom or a hydrocarbon group which may be substituted,
Alternatively, R ¹ and R ² , R ¹ and R ³ or R ² and R ³ may be bonded to each other to form an optionally substituted ring;
Represents —CO—, —S (O) — or —S (O) ₂ —, and L ² represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group. ] Wherein the compound or reacting a salt thereof represented by the general formula R '' - W-S ( O) 2 -C (R 1) (R 2) -CH (R 3) -Y ' -L ² (IIIb) wherein the symbols are as defined above. ] The method for producing a sulfone derivative or a salt thereof represented by the formula: 7. A compound represented by the general formula: R—W—S (O) ₂ -M (I) wherein R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, W represents a bond or a divalent chain hydrocarbon group which may be substituted, and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. A sulfinic acid derivative or a salt thereof represented by the general formula R ⁴ C≡CY′-L ² (IIc)
⁴ represents a hydrogen atom or a hydrocarbon group which may be substituted, Y ′ represents —CO—, —S (O) — or —S (O) ₂ —
² represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group. Wherein the compound or the reaction of a salt thereof], the general formula R-W-S (O) 2 -C (R 4) = CH-Y'-L 2 (IIIc) [ in the formula The symbols are as defined above. ] The method for producing a sulfone derivative or a salt thereof represented by the formula: 8. The process according to claim 7, wherein R is a cyclic hydrocarbon group substituted with a halogen atom or an alkenyl group or a heterocyclic group which may be substituted. 9. The method according to claim 1, wherein R is 6-halo-substituted naphthalen-2-yl. 10. The method according to claim 6, wherein R ″ is 6-halo-substituted naphthalen-2-yl. 11. The method according to claim 1, wherein W is a bond. 12. A compound of the general formula R ″ -WS (O) ₂ -M (I ′) wherein R ″ is a cyclic hydrocarbon group substituted by a halogen atom or an alkenyl group or a substituted hydrocarbon group. And W is a bond or optionally substituted 2
Represents a valent chain hydrocarbon group, and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. A sulfinic acid derivative or a salt thereof], the general formula ^{(R 1) (R 2)} C = C (R 3) (Y '' - L 2a) (IIb '') wherein, R ^1, R ² and R ³ each independently represent a hydrogen atom or an optionally substituted hydrocarbon group,
Alternatively, R ¹ and R ² , R ¹ and R ³ or R ² and R ³ may be bonded to each other to form an optionally substituted ring, and Y ″
Represents -CO-, and L ^2a represents an optionally substituted alkoxy group. ] Wherein the compound or reacting a salt thereof represented by the general formula R '' - W-S ( O) 2 -C (R 1) (R 2) -CH (R 3) -Y ''-L ^2a (IIIb'') wherein the symbols are as defined above. ] The method for producing a sulfone derivative or a salt thereof represented by the formula: 13. A compound represented by the general formula: R—W—S (O) ₂ —M (I) wherein R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, W represents a bond or a divalent chain hydrocarbon group which may be substituted, and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. A sulfinic acid derivative or a salt thereof represented by the general formula: Or the general formula: [Wherein, R ^1a , R ^2a , R ^3a and R ^4a each independently represent a hydrogen atom or a hydrocarbon group which may be substituted, or R ^1a and R ^2a , R ^1a and R ^3a or R ^2a and R ^3a may be bonded to each other to form an optionally substituted ring, Y ′ represents —CO—, —S (O) — or —S (O) ₂ —, and Z represents -N (R ^5a )-, -CO-, -S (O)-,-S (O) ₂ -,-
CH ₂ — or a bond; ring A represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5a and R ^6a each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, Represents an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group, or R ^6a represents a substituent of ring A or R ^1a , R
^2a , R ^3a or R ^4a may combine with each other to form an optionally substituted ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. And n represents 0 or 1. Wherein a compound represented by the formula: or a salt thereof is reacted. Or the general formula: [The symbols in the formula are as defined above. ] The method for producing a sulfone derivative or a salt thereof represented by the formula: 14. A compound represented by the general formula: R—W—S (O) ₂ —H (Ia) wherein R is an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group. And W represents a bond or a divalent chain hydrocarbon group which may be substituted. Represented by the sulfinic acid derivative or a salt thereof,
Formula ^{L 1 -X-R '(IIa} ') wherein, L ¹ represents a leaving group, X is a substituted by 2 may be divalent chain hydrocarbon group, R 'is esterified Or a carboxyl group or a cyano group which may be amidated. And a salt thereof, in the presence of a base, and 2) obtained general formula RWS (O) ₂ -XR ′ (IIIa ′) wherein the symbols are as defined above. Is equivalent to A compound represented by] or subjected to hydrolysis optionally a salt thereof, 3) is obtained the formula R-W-S (O) 2 -X-CO 2 H (IVa ') [wherein the symbols The meaning is as defined above. And a salt thereof or a reactive derivative thereof, and a compound represented by the general formula: [Wherein, Z ″ is -N (R ^5b )-, -CO-, -S (O)-, -S
(O) _2- , -CH _2- , -N (R ^5b ) -CO-, -CO-CH ₂ -or a bond, and ring A 'represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5b and R ^6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group,
R ^6b may be bonded to a substituent of the ring A ′ to form a ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. Characterized by reacting with a compound represented by the formula or a salt thereof,
General formula [Wherein the symbols are as defined above. ] Or a salt thereof. 15. The method according to claim 14, wherein the base used in 1) is an amine. 16. A compound represented by the general formula: R—W—S (O) ₂ —H (Ia) wherein R is an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group. And W represents a bond or a divalent chain hydrocarbon group which may be substituted. Represented by the sulfinic acid derivative or a salt thereof,
Formula (R ¹ ) (R ² ) C ＝ C (R ³ ) (R ′) (IIb ′) wherein R ¹ , R ² and R ³ are each independently a hydrogen atom or a substituted hydrogen atom. Shows a good hydrocarbon group,
Alternatively, R ¹ and R ² , R ¹ and R ³ or R ² and R ³ may be bonded to each other to form an optionally substituted ring;
Represents a carboxyl group or a cyano group which may be esterified or amidated. A compound or a salt thereof] in the presence of a base, 2) obtained formula R-W-S (O) 2 -C (R 1) (R 2) -CH (R 3) -R '(IIIb') wherein the symbols are as defined above. A compound represented by] or subjected to hydrolysis optionally a salt thereof, 3) is obtained the formula R-W-S (O) 2 -C (R 1) (R 2) -CH (R 3) —CO ₂ H (IVb ′) wherein the symbols are as defined above. And a salt thereof, and [Wherein, Z ″ is -N (R ^5b )-, -CO-, -S (O)-, -S
(O) _2- , -CH _2- , -N (R ^5b ) -CO-, -CO-CH ₂ -or a bond, and ring A 'represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5b and R ^6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group,
R ^6b may be bonded to a substituent of the ring A ′ to form a ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. A compound represented by the following general formula: [Wherein the symbols are as defined above. ] Or a salt thereof. 17. The process according to claim 16, wherein the base used in 1) is an amine. 18. A compound represented by the general formula R—W—S (O) ₂ —H (Ia) wherein R is an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group. And W represents a bond or a divalent chain hydrocarbon group which may be substituted. Represented by the sulfinic acid derivative or a salt thereof,
Formula R ⁴ C≡C—R ′ (IIc ′) wherein R ⁴ represents a hydrogen atom or a hydrocarbon group which may be substituted, and R ′ may be esterified or amidated Shows a carboxyl group or a cyano group. A compound represented by or a salt thereof with] in the presence of a base, 2) obtained formula R-W-S (O) 2 -C (R 4) = CH-R '(IIIc') [ In the formula, the symbols are as defined above. A compound represented by] or subjected to hydrolysis optionally a salt thereof, 3) is obtained the formula R-W-S (O) 2 -C (R 4) = CH-CO 2 H (IVc ') [Wherein the symbols are as defined above. And a salt thereof or a reactive derivative thereof, and a compound represented by the general formula: [Wherein, Z ″ is -N (R ^5b )-, -CO-, -S (O)-, -S
(O) _2- , -CH _2- , -N (R ^5b ) -CO-, -CO-CH ₂ -or a bond, and ring A 'represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5b and R ^6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group,
R ^6b may be bonded to a substituent of the ring A ′ to form a ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. Wherein the compound is represented by the following general formula: [Wherein the symbols are as defined above. ] Or a salt thereof. 19. The process according to claim 18, wherein the base used in 1) is an amine. 20. A compound represented by the general formula: R—W—S (O) ₂ —H (Ia) wherein R represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; W represents a bond or a divalent chain hydrocarbon group which may be substituted. Represented by the sulfinic acid derivative or a salt thereof,
General formula L ¹ -XYL ² (IIa) wherein L ¹ represents a leaving group, X represents a divalent chain hydrocarbon group which may be substituted, and Y represents -N (R ⁵ )-, -CO
—, —S (O) —, —S (O) ₂ —, —CH ₂ — or a bond, L ² represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group, and R ⁵ represents hydrogen It represents an atom, a hydrocarbon group which may be substituted, an alkoxy group which may be substituted, a carboxyl group which may be esterified or amidated, or an acyl group. A compound represented by the general formula RWS (O) ₂ -XYL ² (IIIa), wherein the compound represented by the formula The meaning is as defined above. ] The method for producing a sulfone derivative or a salt thereof represented by the formula: 21. The method according to claim 20, wherein the base is an amine. 22. A compound of the general formula R ″ -WS (O) ₂ —H (Ia ′) wherein R ″ is a cyclic hydrocarbon group substituted with a halogen atom or an alkenyl group or a substituted hydrocarbon group. And W is a bond or optionally substituted 2
A valent chain hydrocarbon group; And a salt thereof represented by the general formula (R ¹ ) (R ² ) C ＝ C
(R ³ ) (Y′-L ² ) (IIb) wherein R ¹ , R ² and R ³ each independently represent a hydrogen atom or a hydrocarbon group which may be substituted;
Alternatively, R ¹ and R ² , R ¹ and R ³ or R ² and R ³ may be bonded to each other to form an optionally substituted ring;
Is -CO -, - S (O) -, - S (O) 2 - a, L ² represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group. Or a salt thereof in the presence of a base, characterized by the general formula: R ″ -WS (O) ₂ -C (R ¹ ) (R ² ) —CH (R ^{3) -Y'-L 2 (IIIb} ) [ symbols in the formula are as defined above. ] The method for producing a sulfone derivative or a salt thereof represented by the formula: 23. The method according to claim 22, wherein the base is an amine. 24. A compound of the general formula R—W—S (O) ₂ —H (Ia) wherein R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, W represents a bond or a divalent chain hydrocarbon group which may be substituted. Represented by the sulfinic acid derivative or a salt thereof,
Formula ^{R 4 C≡C-Y'-L 2} (IIc) wherein, R ⁴ represents a hydrogen atom or an optionally substituted hydrocarbon group, Y 'is -CO -, - S (O )-Or -S
(O) _2- , and L ² represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group. Compound represented or a salt thereof in], characterized by reacting in the presence of a base, the general formula R-W-S (O) 2 -C (R 4) = CH-Y'-L 2 (IIIc Wherein the symbols are as defined above. ] The method for producing a sulfone derivative or a salt thereof represented by the formula: 25. The method according to claim 24, wherein the base is an amine. 26. A compound of the general formula R ″ —WS (O) ₂ —H (Ia ′) wherein R ″ is a cyclic hydrocarbon group substituted by a halogen atom or an alkenyl group or a substituted hydrocarbon group. And W is a bond or an optionally substituted 2
A valent chain hydrocarbon group; And a salt thereof represented by the general formula (R ¹ ) (R ² ) C ＝ C
(R ³ ) (Y ″ -L ^2a ) (IIb ″) [wherein R ¹ , R ² and R ³ each independently represent a hydrogen atom or an optionally substituted hydrocarbon group. ,
Alternatively, R ¹ and R ² , R ¹ and R ³ or R ² and R ³ may be bonded to each other to form an optionally substituted ring, and Y ″
Represents -CO-, and L ^2a represents an optionally substituted alkoxy group. Or a salt thereof in the presence of a base, characterized by the general formula: R ″ -WS (O) ₂ -C (R ¹ ) (R ² ) —CH (R ^{3) -Y '' - L 2a} (IIIb '') [ symbols in the formula are as defined above. ] The method for producing a sulfone derivative or a salt thereof represented by the formula: 27. The method according to claim 26, wherein the base is an amine. 28. A compound of the general formula RWS (O) ₂ -H (Ia) wherein R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, W represents a bond or a divalent chain hydrocarbon group which may be substituted. Represented by the sulfinic acid derivative or a salt thereof,
General formula Or the general formula: [Wherein, R ^1a , R ^2a , R ^3a and R ^4a each independently represent a hydrogen atom or a hydrocarbon group which may be substituted, or R ^1a and R ^2a , R ^1a and R ^3a or R ^2a and R ^3a may be bonded to each other to form an optionally substituted ring, Y ′ represents —CO—, —S (O) — or —S (O) ₂ —, and Z represents -N (R ^5a )-, -CO-, -S (O)-,-S (O) ₂ -,-
CH ₂ — or a bond; ring A represents an optionally substituted nitrogen-containing heterocyclic ring; R ^5a and R ^6a each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, Represents an optionally substituted alkoxy group, an optionally esterified or amidated carboxyl group or an acyl group, or R ^6a represents a substituent of ring A or R ^1a , R
^2a , R ^3a or R ^4a may combine with each other to form an optionally substituted ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. And n represents 0 or 1. Wherein the compound or a salt thereof is reacted in the presence of a base. Or the general formula: [Wherein the symbols are as defined above. ] The method for producing a sulfone derivative or a salt thereof represented by the formula: 29. The method according to claim 28, wherein the base is an amine. 30. A compound of the general formula [In the formula, ring A ″ represents an optionally substituted nitrogen-containing aliphatic heterocyclic ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group.]
Or a salt thereof, and a compound represented by the general formula R ⁶ NH ₂
(X) [wherein, R ⁶ represents a hydrogen atom or a hydrocarbon group which may be substituted. Or a salt thereof in the presence of a trisiloxyborohydride complex compound, characterized by the following general formula: [The symbols in the formula are as defined above. ] The method for producing a secondary amine derivative or a salt thereof represented by the formula: 31. The method according to claim 30, wherein ring A ″ is an optionally substituted piperidine. 32. The method according to claim 30, wherein the trisiloxyborohydride complex is sodium triacetoxyborohydride. 33. A compound of the general formula [In the formula, ring A ″ represents an optionally substituted nitrogen-containing aliphatic heterocyclic ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group.]
Or a salt thereof and a compound represented by the general formula R ⁶ NH ₂
(X) [wherein, R ⁶ represents a hydrogen atom or a hydrocarbon group which may be substituted. Wherein the compound or a salt thereof is reacted with formic acid or a salt thereof or hydrogen gas in the presence of a palladium catalyst. [The symbols in the formula are as defined above. ] The method for producing a secondary amine derivative or a salt thereof represented by the formula: 34. The method according to claim 33, wherein ring A "is an optionally substituted piperidine. 35. The method according to claim 33, wherein the palladium catalyst is palladium carbon. 36. The method according to claim 33, wherein formic acid or a salt thereof is used. 37. The method according to claim 33, wherein hydrogen gas is used. 38. A compound of the general formula, prepared according to claims 30 to 37. [Wherein, R ⁶ represents a hydrogen atom or an optionally substituted hydrocarbon group, ring A ″ represents an optionally substituted nitrogen-containing aliphatic heterocyclic ring, and Z ′ may be substituted. Or an optionally substituted nitrogen-containing heterocyclic group.] Or a salt thereof, and a compound represented by the general formula (R ¹ ) (R ² ) C ＝ C (R ³ ) (Y′-L ³ ) (XIIa) or a general formula R ⁴ C≡C-Y′-L ³ (XIIb) wherein L ³ is a leaving group, R ¹ , R ² and R ³ are each independently a hydrogen atom Or a hydrocarbon group which may be substituted, or R ¹ and R ² , R ¹ and R ³ or R ²
And R ³ may combine with each other to form an optionally substituted ring, R ⁴ represents a hydrogen atom or an optionally substituted hydrocarbon group, and Y ′ represents —CO—, —S (O)-or-
S (O) _2- . A compound represented by the following general formula: or a salt thereof. Or the general formula: [The symbols in the formula are as defined above. ] Or a salt thereof. 39. A compound represented by the general formula: R—W—S (O) ₂ —M (I) wherein R represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; W represents a bond or a divalent chain hydrocarbon group which may be substituted, and M represents a hydrogen atom, an alkali metal or an alkaline earth metal. And a sulfinic acid derivative represented by the general formula: Or the general formula: [Wherein, R ¹ , R ² and R ³ each independently represent a hydrogen atom or an optionally substituted hydrocarbon group,
Or R ¹ and R ^2, R ¹ and R ³ or R ² and R ³ may form a even better ring is bonded to a substituted each other, R ⁴
Represents a hydrogen atom or an optionally substituted hydrocarbon group, R ⁶ represents a hydrogen atom or an optionally substituted hydrocarbon group, and Y ′ represents —CO—, —S (O) — or —. S (O) _2-
And ring A ″ represents an optionally substituted nitrogen-containing aliphatic heterocyclic ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group.]
Wherein the compound is reacted with a compound represented by the formula: or a salt thereof. Or the general formula: [The symbols in the formula are as defined above. ] Or a salt thereof. 40. A general formula R-W-S (O) 2 -X-Y-L 2 (IIIa) or formula R-W-S (O) 2 -C (R 4) = CH-Y'- L ² (IIIc) [wherein, R represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and W represents a bond or a divalent chain which may be substituted. X represents a hydrocarbon group, X represents a divalent chain hydrocarbon group which may be substituted, and Y represents -N (R ⁵ )-, -CO-, -S (O)-, -S (O ) _2- ,
—CH ₂ — or a bond, Y ′ represents —CO—, —S (O) — or —S (O) ₂ —, and L ² represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group R ⁴ represents a hydrogen atom or a hydrocarbon group which may be substituted;
⁵ represents a hydrogen atom, a hydrocarbon group which may be substituted, an alkoxy group which may be substituted, a carboxyl group which may be esterified or amidated, or an acyl group. Represented for the production of sulfone derivative, or a salt thereof in], in the general formula R-W-S (O) 2 -M (I) [wherein, M represents a hydrogen atom, an alkali metal or alkaline earth metal , R and W are as defined above. Use of a sulfinic acid derivative or a salt thereof represented by the formula: 41. The general formula R ″ -WS (O)_Two-C (R¹) (R^Two) -CH (R^Three) -Y'-L^Two (IIIb) wherein R ″ is substituted with a halogen atom or an alkenyl group
Cyclic hydrocarbon group or optionally substituted heterocyclic group
A ring group, and W is a bond or an optionally substituted 2
A divalent chain hydrocarbon group;¹, R^TwoAnd R^ThreeIs
Each independently a hydrogen atom or an optionally substituted charcoal
Represents a hydride group, or R¹And R^Two, R ¹And R^ThreeOr
R^TwoAnd R^ThreeAre bonded to each other to form an optionally substituted ring
Y 'may be -CO-, -S (O)-or -S (O)_Two-
And L^TwoIs a hydrogen atom, a hydroxyl group or may be substituted
Represents an alkoxy group. The sulfone derivative represented by
Or a general formula R ″ -WS (O) for producing a salt thereof._Two-M (I ') wherein M is a hydrogen atom, an alkali metal or an alkaline earth
And R ″ and W are as defined above. ]
Use of a sulfinic acid derivative represented by or a salt thereof. 42. The general formula: Or the general formula: [Wherein, R represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and W represents a bond or a divalent chain hydrocarbon group which may be substituted. , R ^1a , R ^2a , R ^3a and R ^4a each independently represent a hydrogen atom or a hydrocarbon group which may be substituted, or R ^1a and R ^2a , R ^1a and R ^3a or R ^2a R ^3a
May combine with each other to form an optionally substituted ring, and Y ′ represents —CO—, —S (O) — or —S (O) ₂ —,
Z is -N (R ^5a )-, -CO-, -S (O)-, -S (O) _2- , -CH ₂
-Or a bond, ring A represents a nitrogen-containing heterocyclic ring which may be substituted, and R ^5a and R ^6a each independently represent a hydrogen atom, a hydrocarbon group which may be substituted, Represents an alkoxy group, a carboxyl group or an acyl group which may be esterified or amidated, or R ^6a represents a substituent of ring A or R ^1a , R ^2a ,
R ^3a or R ^4a may be bonded to form an optionally substituted ring, and Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group, n represents 0 or 1. Represented for the production of sulfone derivative, or a salt thereof in], in the general formula R-W-S (O) 2 -M (I) [wherein, M represents a hydrogen atom, an alkali metal or alkaline earth metal , R and W are as defined above. Use of a sulfinic acid derivative or a salt thereof represented by the formula: