WO2004060892A1 - Fused n-containing heterocyclic compounds and medicinal use thereof - Google Patents

Abstract

It is intended to provide a compound which has an aggrecanase inhibitory effect or an MMP-13 inhibitory effect and is useful as a remedy for arthritis deformans, rheumatoid arthritis and so on, more specifically speaking, a fused N-containing heterocyclic compound represented by the following general formula (1), its prodrug or pharmaceutically acceptable salts thereof: (1) wherein R1 and R2 represent each hydrogen, etc.; R3 and R4 represent each hydrogen etc.; R5 represents, together with R6, R3 or R4, a group represented by any of the following general formulae: (A) (B) (C) (D) (wherein R8, R9, R10, R11, R12, R13 and R17 represent each hydrogen, etc.); R7 represents hydrogen, etc.; R21 represents hydrogen, etc.; A represents alkylene, etc.; the ring B represents aryl, etc.; m is 1, etc.; and n is 0, etc.

Description

 Specification

 Condensed N-containing heterocyclic compounds and their pharmaceutical uses

^: Technical field.

 The present invention relates to a novel condensed N-containing heterocyclic compound, and more particularly, to a condensed N-containing heterocyclic compound having Aggrecanase-damaging activity or MMP-13 inhibitory activity or a medicament thereof. The present invention relates to a pharmaceutically acceptable salt, a pharmaceutical composition containing the salt and a pharmaceutical use thereof. :

 : Background technology

 Aggrecan is the major proteoglycin in cartilage, and its degradation by its proteases is a chronic joint! It is one of the early signs of joint disease involving articular cartilage destruction such as osteoarthritis and osteoarthritis. This degradation process, which leads to cartilage destruction, begins with the loss of aggrecan on the cartilage surface, followed by the degradation of type I collagen fibers. The enzymes involved in the degradation of this aggrecan include MMPS (Matrix metalloproteinases), which cleaves A sn 341-P he 342, and aglycanase, which cleaves Glu 373-A la 374. Are both sold, and both are metalloproteases that have sub-^^ mainly in the catalytic activity. The latter was identified in 1969 as ADAMTS (A Disintegrin and Metaloproteinase with Tnrombosponain. Motifs). Although AD AMT S has been identified from 1 to 13, AD AMT S 4,5 correspond to aggrecanases 1 and 12. Previously, MMPs were thought to be the center of cartilage destruction, but studies have shown that aggrecanase fragments found in joints of patients with osteoarthritis (OA) are markedly cleaved by aggrecanase. Aggrecanase is reported to be an important malignant factor in pathological conditions.

Currently, there are conservative and surgical treatments for OA. Conservative therapies include weight loss to reduce risk factors, exercise therapy, physical therapy, pharmacotherapy (administration of anti-inflammatory drugs), and heat. In the course of these therapies, it is common practice to inject hyaluronic acid into the joints to smooth the joints. However, if conservative treatment, such as pharmacotherapy or physical therapy, does not help, surgical treatment will be required. There are several types of this, the joints are highly deformed, If the pain is severe, joint arthroplasty, such as implantation of a prosthetic joint, will eventually be performed. The prosthesis only lasts for about 15 to 20 years, after which the patient's quality of life (QOL) deteriorates.

 At present, there are no drugs that suppress the underlying cartilage destruction in the therapeutic area of OA. If conservative treatment does not improve ^ cartilage destruction will progress and surgical treatment will need to be considered. Therefore, it is important to prevent cartilage destruction prior to surgical treatment, and drugs that inhibit aggrecanase, which is involved in the destruction, are positioned as anti-OA drugs that have a sufficient cartilage destruction inhibitory effect. It is expected that the patient's QOL will be increased by not requiring the patient.

 The development of aglycanase inhibitors includes DuPont (WO 99-θ9

No. 00 pamphlet), P fizer (Japanese Patent Application Laid-Open No. 2001-114765), etc., but there is a concern about the problem of poor oral absorption in general, and MMP inhibitors being developed Some compounds cause systemic connective tissue toxicity due to non-selective collagenase inhibition, due to the suppression of normal connective tissue collagen turnover by collagenase-11 (MMP-1). It is suggested that this is the cause. As described above, the conventionally developed products were not sufficiently satisfactory in terms of the effects and side effects.

 The compound of the present invention has improved absorptivity and has strong agglase inhibitory activity. In addition, it has no inhibitory effect on MMP-1 but also has an inhibitory effect on aggrecanase as well as a selective inhibitory effect on other MMPs involved in joint destruction such as MMP-13, causing side effects. It is expected that the progression of arthropathy will be suppressed without performing.

 Furthermore, since gliomas express aggrecanase, it is suggested that aggrecanase is involved in tumor cell metastasis and tissue invasion, similar to MMPs. Considering the current situation in which inhibitors are being developed as anti-metastatics, the compounds of the present invention, which have both aggrecanase and MMP inhibitory effects, are expected to be more effective anticancer agents.

In bone metabolism, MMPs control the breakdown of bone matrix and play an important role in bone resorption. In respiratory diseases, lung structure rupture and remodeling Proteases play an important role in the process, and MMP, whose constituent is extracellular matrix (ECM), is thought to be an important factor. Therefore, it is considered that the compound of the present invention which also has an inhibitory action can be applied to bone resorption diseases and lung diseases involving MMP.

 Recently, various reports have been made on compounds aimed at treating diseases such as OA and rheumatoid arthritis by inhibiting aggrecanase.

 For example, Japanese Patent Application Laid-Open No. 2002-284686 discloses a sulfonamide derivative having an MMP-13 inhibitory action and an aggrecanase inhibitory action. However, the publication does not disclose any compound having a structure such as the compound of the present invention, nor does it mention any suggestion thereof.

 In addition, Japanese Patent Application Laid-Open No. 2001-111506 discloses a general formula

Wherein X is carbon or nitrogen; R ¹ and R ² are independently selected from the group consisting of hydrogen, hydroxy, and methyl, and at least one of R ¹ and R ² is methyl R ³ and R ⁴ are independently selected from the group consisting of hydrogen, hydroxy, and methyl; or R ³ and R ^{4 are} combined to form a functional reporter group. R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, halogen, cyano, methyl, and diethyl; provided that, when X is carbon, both R ⁷ and R ⁸ are hydrogen in, ^1, R \ R and R ⁴ at least one ^ ^ is hydroxy; X is case of R ⁵ is para one cog port carbon, at least one hydrogen of R ^6, R \ and R ⁴ None; when X is nitrogen, R ⁸ is absent and R ⁷ is hydrogen or a formula:

(Where Y is one CH ₂ —NH ₂ or one NH—CH ₃ ); when X is nitrogen and R ⁷ is hydrogen, R ³ and together form a radical group Are disclosed as having an aggrecanase inhibitory action. However, the compounds disclosed in the publication have a pyridine structure or a pyrazine ring having a substituent as a skeleton structure, and the disclosure of compounds having a condensed ring structure such as the compound of the present invention is also disclosed. There is no description that suggests.

 In the pamphlet of International Publication No. 0 1 7 2 7

 (A) (B) (C)

Represents any one of the following 潆 -shaped structures, wherein Ar ² represents a 6-membered aromatic ring which may include 1 to 2 nitrogen atoms, and D ¹ represents one (CH ₂ ) n-(n Is an integer of 1 to 3), an oxygen atom, a sulfur atom, one S (O) one, — S (O) ₂ — or one NR ⁴ — (R ⁴ is a hydrogen atom, a C i -C ₈ alkyl group or C , Represents a C ₈ acyl group), D ² represents one (CH) one or a nitrogen atom, R ² and R ³ represent a hydrogen atom, a hydroxyl group, an alkyl group or the like; R ¹ represents hydrogen It represents an atom or a methyl group; W is one S 0 ₂ - represents like; X is one substituted base may be benzene ring or an oxygen atom, a sulfur atom 1 Kowaka Sig contains 1-2 nitrogen atoms Which represents a 5- or 6-membered heteroaromatic ring]. However, the publication does not disclose a compound having a structure such as the present compound, and does not disclose any suggestion thereof. In addition, the compounds disclosed in the publication are used as inhibitors of solubilizing enzymes of heparin-binding epidermal growth factor-like growth factor. It is useful, and of course, there is no disclosure suggesting its usefulness as an aglicanase inhibitor, and no description suggesting this is found.

 Disclosure of the invention

 An object of the present invention is to prevent or treat rheumatoid arthritis, having an excellent inhibitory effect on aggrecanase or MMP-13, and preventing or treating osteoarthritis. ^ Or therapeutic drugs, joint damage, reactive arthritis, cancer, asthma, allergic reactions, chronic emphysema, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), pulmonary infections, polypneumonia, bone resorption disease, etc. An object of the present invention is to provide a compound useful as an agent for preventing or treating the above diseases.

 Another object of the present invention is to provide an aggrecanase inhibitor, an MMP-13 inhibitor, an agent for preventing or treating osteoarthritis, and an agent for preventing or treating rheumatoid arthritis.

 The present inventors have conducted intensive studies to achieve the above object, and consequently found that the condensed N-containing heterocyclic compound represented by the following general formula (1) has an excellent inhibitory effect on aggrecanase or MMP-13 inhibition. The present invention has been found to be effective as an aggrecanase inhibitor or an MMP-13 inhibitor, a prophylactic or therapeutic agent for osteoarthritis and a prophylactic or therapeutic agent for rheumatoid arthritis, and completed the present invention. . .

 The present invention relates to the following compounds [1] to [38] and pharmaceutical uses thereof. That is, the present invention is as follows.

 [1] General formula (1)

(1)

(Where 1 ^ and ¹² are each independently:

 (1) hydrogen atom, '

(2) a halogen atom, (3) hydroxyl group,

(4) C -! ₆ alkyl group,

 (5) an alkoxy group,

(6) a halo C _M alkyl group,

(7) halo C Preparative ₆ alkoxy group;

Or ':.,::'.

(8) One (CH ₂ ) _P -X- (CH _¾ ) _q — A ¹

(Wherein, p及Pi q are the same or different and each represent an integer of 0 or 1 to 4, X is a single bond, an alkylene group, C ₂ - ₆ alkenyl - alkylene group, C ₂ - ₆ alkynylene group, — O—, one N (R ²² ) one, one S (O) _r— , one CO—, -CON (R ²² ) —, one N (R ²² ) CO—, -SOgN (R ²² ) —, one N (R ²² ) S0 ₂ —, one N (R ²² ) CON (R ²³ ) —, one N (R ²² ) S0 ₂ N (R ²³ ) —, one OCON (R ²² ) one or — N (R ²² ) COO—

Wherein R ²² and R ²³ are the same or different, a hydrogen atom, C _ ₆ alkyl group, optionally substituted C ₃ - ₁₄ hydrocarbon ring group, optionally substituted fused be C ₆ _ ₁₄ hydrocarbons permanent ring A group, an optionally substituted heterocyclic group or an optionally substituted fused heterocyclic group,

 r represents 0 or an integer of 1 to 2,

A ¹ is an optionally substituted C ₃ _ ₁₄ hydrocarbon ring group, an optionally substituted fused C ₆ _ ₁₄ hydrocarbon group, an optionally substituted Which represents a fused ring group).

R ^s and R ⁴ are each independently a hydrogen atom, an alkyl group, an alkoxy group, an amino group, an amino-de-group, optionally substituted C _s - ₁₄ hydrocarbon ring group, a condensed C ₆ optionally substituted — ₁₄ hydrocarbon ring group, optionally substituted heterocyclic group or optionally substituted condensed heterocyclic group, or! ^ And together with the carbon atom to which R ⁴ is attached R ⁵ is a carbonyl group or a carbon atom to which R ³ and R ⁴ are bonded to form a C ₃ _ ₇ cycloalkyl group or a heterocyclic group. R ⁶ and turned on one cord,

(Wherein R ⁸ and R ⁹ are each independently:

 (1) hydrogen atom,

 (2) an alkyl group,

(3) a halo- ₆ alkyl group,

(4) C ₃ _ ₁₄ hydrocarbon ring optionally substituted,

(5) a condensed C ₆ hydrocarbon ring group which may be substituted:

 (6) an optionally substituted heterocyclic group,

 (7) an optionally substituted fused heterocyclic group,

(8) an optionally substituted C ₃ _ ₁₄ hydrocarbon ring-alkyl group,

(9) optionally substituted fused C ₆ - ₁₄ hydrocarbon ring one ₆ alkyl group,

(10) An optionally substituted heterocyclic ring-alkyl group.

Or

(11) a condensed heterocyclic ring which may be substituted-represents a C _M alkyl group, and R ^1Q and R ¹¹ are each independently

 (1) Hydrogen atom

Or

(2) represents a C- ₆ alkyl group, or

R ¹² may be taken together with the carbon atom to which it is attached to form a carbonyl group.

 (1) hydrogen atom,

(2) C _w . Alkyl group,

(3) halo 0 door ₆ alkyl group,

(4) optionally substituted C ₃ - ₁₄ hydrocarbon ring group,

(5) optionally substituted fused C ₆ - ₁₄ hydrocarbon潆基, (6) an optionally substituted heterocyclic group,

 (7) an optionally substituted fused heterocyclic group,

(8) C may be a C ^ hydrocarbon ring d_ ₆ alkyl

(9) An optionally substituted fused C ₆ _ ₁₄ hydrocarbon ring-alkyl group. (10) An optionally substituted heterocyclic ring-alkyl group.

Or

(11) substituted Te to good condensation be: Ro镡_ｰshows a C _M alkyl group, R ¹³ is,

 (1) hydrogen atom,

(2). To ₆ alkyl groups,

 (3) hydroxyl group,

(4) C- ₆ alkoxy group,

(5) One N (R ²⁶ ) (R ²⁷ ),

(6) — N (R ²⁸ ) — CO — R ²⁹ ,

(7) One N (R ²⁸ ) — S 0 ₂ — R ²⁹ ,

Or

(8) — CO— NH— R ²⁸ ,

Indicates that

Where R ²⁶ and R ²⁷ are each independently

(1) hydrogen atom,

(2) C, - ₆ alkyl group,

(3) halo — ₆ alkyl groups,

(4)笸換which may be C ₃ - ₁₄ hydrocarbon ring group,

(5) optionally substituted fused C ₆ - ₁₄ hydrocarbon ring group,

(6) optionally substituted heterocyclic group

Or

 (7) represents a fused heterocyclic group which may be substituted,

R ²⁸ and R ²⁹ are each independently

(1) hydrogen atom, (2) C preparative _w alkyl group,

 (3) a haloalkyl group,

(4) an optionally substituted C ₃ _ ₁₄ hydrocarbon ring group,

(5) optionally substituted condensed C ₆ — ₁₄ carbon hydrogen group,

(6) an optionally substituted heterocyclic group,

 (7) an optionally substituted fused heterocyclic group,

(8) an optionally substituted C ₃ _ ₁₄ hydrocarbon ring-C _H6 alkyl group,

(9) optionally substituted condensed C ₆ — ₁₄ coal water Ningxiang — C _M alkyl group,

 (10) optionally substituted hetero-CwT alkyl group

Or

 (11) represents an optionally substituted fused heterocyclic monoalkyl group,

R ¹⁷ is

 (1) hydrogen atom,

 (2) hydroxyl group,

(3) C -! ₆ alkyl group (the CM alkyl group may be substituted with a hydroxyl or amino group),

 (4) a haloalkyl group,

(5) an alkoxy C _M alkyl group,

Or

(6) — which represents a ₆ alkoxy group);

R ³ and R ⁴ together with R ⁵

Wherein R ⁸ , R ⁹ , R ¹⁰ , R ^U , R ¹² , R ¹³ and R ¹⁷ are as defined above, R ⁶ represents a hydrogen atom or a _CM alkyl group;

R ⁷ is (1) —OR ¹⁴ group (wherein R ¹⁴ represents a hydrogen atom or an alkyl group),

(2) — N (R ¹⁵ ) (R ¹⁶ ) group (wherein, R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom or a C ₆ alkyl group).

Or '

(3) a hydroxyamino group;

R ²¹ is

 (1) hydrogen atom,

(2) ( ₆ alkyl groups,

(3) halo C Preparative ₆ alkyl group,

(4) optionally substituted C ₃ -hydrocarbon Ping group,

(5) optionally substituted fused C ₆ - ₁₄ carbon Mizukotobuki ring group,

 (6) an optionally substituted heterocyclic group,

 (7) an optionally substituted fused heterocyclic group,

(8) an optionally substituted C ₃ _ ₁₄ hydrocarbon ring 1 _ ₆ alkyl group,

(9) optionally substituted fused C ₆ _ ₁₄ hydrocarbon ring — — ₆ alkyl group,

 (10) Hetero-optionally substituted CH alkyl group

Or

(11) a fused heterocyclic 1 c _M alkyl group which may be substituted;

A is ₆ alkylene group, C ₂ - ₆ Aruke - alkylene group or a C ₂ - shows a ₆ Arukyuren group; ring B,

(1) optionally substituted C ₃ - ₁₄ hydrocarbon ring group.

(2) an optionally substituted fused C ₆ _ ₁₄ hydrocarbon ring group,

 (3) An optionally substituted heterocyclic group

Or

(4) a fused heterocyclic group which may be substituted;

 Represents 1, 2 or 3;

n represents 0, 1, 2, or 3)

Or a prodrug thereof, or a pharmaceutically acceptable salt thereof [hereinafter, also referred to as “compound (1) j”]. [2] In the general formula (1), R ¹ and R ² are each independently

 (1) hydrogen atom,

 (2) a halogen atom,

 (3) hydroxyl group,

(4) ₆ alkyl groups,

(5) halo C Preparative ₆ alkyl group,

₍₆₎ C -! 6 alkoxy group,

(7) Halo. ₆ alkoxy group,

(8) An optionally substituted C ₆ _ ₁₄ aryl group,

(9) optionally substituted C ₆ - ₁₄ Ariruo sheet group,

(10) optionally substituted C ₆ - ₁₄ § Li Ichiru alkyl group,

(11) optionally substituted C ₆ — ₁₄ aryl C to ₆ alkoxy group,

(12) optionally substituted C ₆ - ₁₄ Ariruokishi ₆ alkyl group,

 (13) an optionally substituted heterocyclic group,

(14) an optionally substituted heterocyclic oxy group,

(15) optionally substituted fused heterocyclic ₆ alkoxy group

Or

. (16) optionally substituted C ₃ - ₇ a cycloalkyl alkoxy group;

R ³及Pi R ⁴ are each independently, if force represents a hydrogen atom or a C _{1 →} alkyl group>, C ₃ become carbon atoms and over鞯R ³ and R ⁴ are bonded - ₇ cycloalkyl Or when forming a heterocyclic group, R ⁵ is taken together with

(Wherein R ⁸ and R ⁹ are each independently:

 (1) hydrogen atom,

(2) C _wo alkynole group, (3) which may be substituted ₆ _ ₁₄ Ariru group,

(4) substituted optionally C ₆ - ₁₄ Ariru ₆ alkyl group,

(5)攆換expired which may be C ₃ _ ₇ cycloalkyl grave,

(6) optionally substituted C ₃ -? ₇ consequent 1 alkyl CH alkyl group,

(7) an optionally substituted heterocyclic group,

(8) optionally substituted fused C _E _ ₁₄ ^ (Arsenic: group

Or

( ⁹ ) a heterocyclic group which may be substituted;

R ^LC and R "are each independently

(1) Hydrogen atom

Or '(2) C -! ₆ represents an alkyl group, or Yuirei connexion such together with the carbon atoms to carbo - may form a group,

R ¹² is

(1) hydrogen atom,

(2) C _W. Alkyl group,

 (3) a haloalkyl group,

(4) optionally substituted C ₆ - ₁₄ Ariru group,

(5) C ₆ — ₁₄ aryl C! — ₆ alkyl group which may be replaced

(6) an optionally substituted heterocyclic group,

(7) optionally substituted 0 ₃ — ₇ cycloalkyl group

Or

(8) optionally substituted C ₃ - ₇ shows a cycloalkylalkyl group,

R ¹³ is

(1) hydrogen atom,

(2) C, - ₆ alkyl group,

 (3) hydroxyl group,

 (4) Arrecoxy group

Or (5) -M (R ²⁶ ) (R ²⁷ ) [where R ²⁶ and R ²⁷ are as defined above], and R ¹⁷ is

 (1) hydrogen atom,

 (2) hydroxyl group,

 (3) a C w alkyl group (the C M alkyl / reline may be substituted with a hydroxyl group or an amino group),

(4) halo C〗 - ₆ alkyl group,

(5) C Preparative ₆ alkoxy C DOO ₆ alkyl group

 'Or

(6) d_ shows a ₆ alkoxy group) to form;

R ³ and R ⁴ together with R ⁵

(Wherein R ⁸ , R ⁹ , R ^ie , R ″, R ¹² and R ¹³ are as defined above), R ⁶ represents a hydrogen atom or an alkyl group;

Ring B is

(1) C ₆ — ₁₄ reel group,

(2) C ₃ - ₇ cycloalkyl group

(3) C _M. Cycloalkenyl group

(4) fused C ₆ ^ hydrocarbon ring group,

Or

 (5) represents a heterocyclic group,

The fused N-containing heterocyclic compound according to the above [1], a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[3] — In the general formula (1), R ¹ and R ² are each independently

(1) hydrogen atom, (2) a halogen atom,

 (3) hydroxyl group,

 (4) Alkyl tomb,

(5) C ₆ alkoxy group,

(6) optionally substituted C ₆ - ₁₄ Ariru group,

(7) optionally substituted C ₆ - ₁₄ Ariruokishi group,

(8) optionally substituted C ₆ - ₁₄ Ariru _ ₆ alkyl group,

(9) may be substituted _6:14 Ariru Cw alkoxy group.

 (10) An optionally substituted heterocycle ¾:

Or-

 (11) an optionally substituted heterocyclic oxy group;

When R ³ and R ⁴ each independently represent a hydrogen atom or an alkyl group, R ⁵ is taken together with R ⁶

(Wherein R ⁸ and R ⁹ are each independently:

 (1) hydrogen atom,

 (2) an alkyl group,

 (3) C aryl group which may be substituted,

(4) optionally substituted C ₆ - ₁₄ Ariru alkyl group,

(5) an optionally substituted heterocyclic group,

(6) C ₃ _ ₇ cycloalkyl group which may be substituted

Or

(7) an optionally substituted C _a — ₇ cycloalkylalkyl group,

R ^1Q and R ¹¹ are each independently

(1) Hydrogen stable, Or

 (2) represents an alkyl group, or

 Together with the ginseng atoms that can be bound together, a reporter may also be formed.

R ¹² is

 (1) hydrogen atom,

(2) C Preparative ₆ alkyl group,

(3) an optionally substituted ₆ _ ₁₄ § Li group,

(4) optionally substituted C ₆ - ₁₄ § Li Le 0 DOO ₆ alkyl group,

 (5) an optionally substituted heterocyclic group,

(6) optionally substituted C ₃ _ ₇ cycloalkyl ^^ group

 Or

(7) optionally substituted C ₃ - ₇ consequent opening: shows the A ^ kills CM alkyl group,

 R is

 (1) hydrogen atom,

(2) Ci— _e alkyl group,

 (3) hydroxyl group

 Or

(4) represents a C- ₆ alkoxy group);

R ³ and R ⁴ together with R ⁵

(Wherein R ⁸ , R ⁹ , R ^1Q , R ^U , R ¹² and R ¹³ are as defined above), R ⁶ represents a hydrogen atom or an alkyl group;

R ²¹ represents a hydrogen atom;

 Ring B is

(1) C ₆ reel group, (2) C7 cycloalkyl group,

₍₃₎ C 3 - ₁₀ cycloalkenyl group

Or

 (4) represents a heterocyclic group,

[2] The fused N-containing heterocyclic compound of the above-mentioned [2], a prodrug thereof, or a pharmaceutically acceptable salt thereof.

 [4] — In general formula (1):

R ^s with R ⁶

(Wherein, R ⁸ and R ⁹ have the same meanings as in the above [1]). The fused N-containing heterocyclic compound or the prodrug thereof according to any of the above [1] to [3], or Pharmaceutically acceptable salts of

 [5] In the general formula (1),

R ⁵ is joined with R ⁶

Wherein R ⁸ has the same meaning as in the above [1]. The fused N-containing heterocyclic compound or the prodrug thereof described in the above [1] or [2], or a pharmaceutically acceptable salt thereof. Salt obtained.

 [6] In the general formula (1),

Connexion but such together with R ^6,

(Wherein R ¹² and R ¹⁷ have the same meanings as in the above [1]), or a fused N-containing heterocyclic compound or a prodrug thereof or a pharmaceutical thereof as described in the above [1] or C2] Acceptable salts.

 [7] — In general formula (1),.

R ³ and R ⁴ join with R ⁵

Where R ⁸ and R ⁹ are as defined above [1]. The condensed N-containing heterocyclic compound according to any one of [1] to [3], a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[8] — In the general formula (1), R ^{7 is} —OR ¹⁴ group (where R ″ is as defined in the above [1]) or hydroxyamino group, [1] to [7]. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

 [9] The fused N-containing heterocyclic compound or prodrug thereof according to any one of the above [1] to [8], wherein m is 1, or a pharmaceutically acceptable salt thereof.

 [10] The fused N-containing heterocyclic compound or prodrug thereof according to any one of the above [1] to [9], wherein n is 0, or a pharmaceutically acceptable salt thereof.

[1 1] R ¹ is — (CH ₂ ) _P -X- (CH ₂ ) _q — A ¹ (where each symbol is as defined in the above [1]), and R ² is a hydrogen atom A fused N-containing heterocyclic compound or a prodrug thereof according to any one of the above [1] to [10], or Their pharmaceutically acceptable salts.

 [1 2] wherein p and q are each independently 0 or 1, and X is a single bond or 1 O 1, wherein the fused N-containing heterocyclic compound described in [1 1] Is the prodrug, or a pharmaceutically acceptable salt thereof.

[13] The condensed N-containing heterocyclic compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of the above 1] 'to C12, wherein R ⁷ is a hydroxyl group.

[14] The fused N-containing heterocyclic compound or prodrug thereof according to any one of the above [1] to [12], wherein R ⁷ is a hydroxyamino group, or a pharmaceutically acceptable salt thereof.

 [15] The compound according to the above, which is selected from the following group; the compound according to [1], a prodrug thereof, or a pharmaceutically acceptable salt thereof:

 5- [4- (3,5-Dic-mouth-phenoxy) -benzenesulfol] -2- (4-fluoro-phenyl) -3-oxo-2,3,4,5,6,7 -Hexahydro-1H-pyrazo-mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-1),

 (R) -2-benzyl-5- (4-benzyloxy-benzenesulfol) -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3- c] pyridine-4-hydroxypropylhydroxyamide (Example 2),

 5- (4-Benzyloxy-benzenesulfol-)-2-meter- 3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine- 4-Hydroxyacid hydroxyamide (Example 3),

 2_benzyl-5- (4-benzyloxy-benzenesulfol) -1-methyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3- c] pyridine-4-hydroxycarboxylic acid hydroxyamide (Example 4),

5- (4-benzyloxy-benzenesulfonyl) -2-tert-butyl-3-oxo -2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4 -Rubonic acid t-droxyamide (Example 1-5),

5- (4-Benzyloxy-benzenesulfur) -3-oxo-2,3,4,5,6,7-hexahydrid-1H-pyrazolipid [4,3-c] pyridine-4-4-pyrupon Acid hydroxyamide (Example 1-6) 5- (4-benzyloxy-benzenesulfol) -2-butyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo-mouth [4,3-c] pyridine- 4-carboxylic acid hydroxyamide (Example 7),

 2-cyclohexyl-5- [4- (3,5-dichlorophenol) -benzenesulfol] -3-oxo-2,3,4,5,6,7-hexahydro-1H —Pizodi [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Example 1-8),

 5- (4-benzyloxy-benzenesulfol) -3-oxo-2--2-phenol-2,3,4,5,6,7-hexahydro-1H-pyrazo [4, ac] pyridine-4- Carboxylic acid hydroxyamide (Example 1-9),

5- (4-benzyloxy-benzenesulfol) -3-oxo-2-phenethyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4 -Carboxylic acid hydroxyamide (Example 10),

 5- (4-Benzyloxy-benzenesulfol) -1-butyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-virazo [4,3-c] pyridine- 4-Hydroxycarboxylic acid hydroxyamide (Examples 1-11),

 2-Benzyl-3-oxo-5- (4-phenoxy-benzenesulfol) -2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine- 4-hydroxysulfonic acid hydroxyamide (Example 12),

 2-Benzyl-5- (bibell-4-sulfol) -3-oxo-2,3,4,5,6,7-hexahydride-1H-Pyrazo [4,3-c] pyridine- 4-hydroxysulfonic acid hydroxyamide (Examples 1-13),

 2-Benzyl-5- (4-hydroxy-benzenesulfol) -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c ] Pyridine-4-carboxylic acid hydroxyamide (Example 1-14),

2-benzyl-5- [4- (3,5-diclo-phenoxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 1-15),

2-Benzyl-5- (4-benzyloxy-benzenesulfonyl) -7,7-dimethyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-virazo [4,3 -c] pyridine-4 -Hydronic acid Roxiamide (Examples 1-16),

 5- (4-benzyloxy-benzenesulfol) -2- (3-hydroxy-benzyl) -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4 , 3-c] pyridine-4-carboxylic acid hydroxyamide (Example 17),...

2-Benzyl-3-oxo-5- (4-methyl-pense sulfonyl) -2,3,4,5,6,7-hexahydrid-1H-pyrazo [4,3-c] pyridine-4 Gallbonic acid hydroxyamide (Example 18),

 5- [4- (2,4-Dic-mouth-benzyloxy) -benzenesulfol] -2- (3-pentyl) -3-oxo-2,3,4,5,6,7-hexahydro Pyrazo mouth [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide (Example 1-19),.

 5- [2- (4, -Biphenyl-4-yl) -ethanesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo Mouth [4,3-c] pyridine 4-carboxylic acid hydroxyamide (Example 20),

 5- (4-Benzyloxy-benzenesulfol) -2- (4-c-mouth-phenyl) -3-oxo-1- 2,3,4,5,6,7-hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Example 1-21),

 5- (4-Methoxy-benzenesulfol) -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine -4-Hydroxyamide hydrorubonic acid (Example

1-22),

2-Benzyl-5- (biphenyl-3-sulfol) -3-oxo -2,3,4,5,6,7-hexahydrid-1H-pyrazo [4,3-c] Viridin-4-hydroxysulfonic acid hydroxyamide (Example 23),

 2-Benzyl-5- (biphenyl-2-sulfol) -3-oxo-2,3,4,5,6,7 hexaldehyde mouth-1H-pyrazo mouth [4,3-c] pyridine -4-force ruponic acid hydroxyamide (Examples 1-24),

 2-Benzyl-3-oxo-5- (3-phenoxy-benzenesulfol) -2,3,4,5,6,7-hexahydr ti-1H-Pyrazo mouth [4,3-c] Pyridine-4-hydroxysulfonic acid hydroxyamide (Example 25),

3-oxo-5- (4-phenoxy-benzenesulfonyl) -2-phenyl-2,3,4,5,6,7-hex Sahydro-1H-pyrazo mouth [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide (Example 1-26),

 5- (Pifuer-4-sulfol-)> 3- 3-oxo-2-7-yl-2,3,4,5,6,7-hexahydrid-1H-pyrazo [4,3-c ] Pyridine- ^ "carboxylic acid hydroxyamide (Example 27), '

 2-Benzyl-5- (4-benzyloxy-benzenesulfol) -3-methoxy-4,5,6,7-tetrahydro-2H-pyrazo [4,3-c} pyridine-4 Acid hydroxyamide (Examples 1-28),

 2-benzyl-5- [2- (4-fluoro-benzoyl) -benzenesulfonyl] -3-oxo- 2,3,4,5,6,7-hexahydro-1H-pyrazo mouth, 3 -c] pyridine-4-carboxylic acid hydroxyamide (Examples 1-29),

 5-[2- (4-Fluoro-phenoxy) -benzenesulfur] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [ 4,3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 1-30),

5- [4- (2,4-Dic-mouth-benzyloxy) -benzenesulfol; 1-2- (2,5-dimethyl-phen-ole) -1-oxo-2,3,4,5 6,7-Hexahydro-1H-pyrazolo [4,3-c] pyridine-

4-hydroxysulfonic acid hydroxyamide (Examples 1-31),

5- [4- (2,4-Dikuguchi-benzyloxy) -benzenesulfol] -2- (2,5-dioctyl-phenyl) -3-oxo-2,3,4,5 , 6, 7 - to Kisahidoro - IH - pyrazole port [4, 3-c] pyridin - 4 - power carboxylic acid hydroxyamide (example 1 - ³ 2),

 3-oxo-5- (3-phenoxy-benzenesulfoel) -2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine- 4-hydroxycarboxylic acid amide (Examples 1-33),

 2- (4-c-mouth-phenyl) -3-oxo-5- (4-phenoxy-benzenesulfonyl) -2,3,4,5,6,7-hexahydro-1H-pyrazo [4 [3, c-pyridine] 4-carponic acid hydroxyamide (Examples 1-34),

5- (4-benzinoleoxy-benzenesnorrefo-nore) -2- (4-tert-butynole-phenyl) -3-oxo-2,3,4,5,6,7-hexahydro-1H-birazo [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide (Examples 1-35) ', 5- [4- (2,4-dichloro-benzyloxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamid F (Examples 1-36),

 2-benzyl-5- [4- (2,4-dichloro-benzyloxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo σ [ 4,3-c] pyridine-4-potassium hydronic acid hydride P xyamide (Examples 1-37);

 5- (4-butoxy-benzenesulfol) -34 oxo-2-phenyl -2,3,4,5,6,7-hexahydro-1Η-pyrazo [4,3-c] pyridine- 4-potassium hydroxyamide (Examples 1-38),

2- (3-c-mouth-fer) -3-oxo-5- (phenoxy-benzenesulfol) -2,3,4,5,6,7-hexahydro-1H-pyrazo Mouth [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide (Examples 1-39),

 2-Benzyl-5- [4- (2-methyl_benzyloxy) -benzenesulfonyl: H3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo mouth [4,3-c ] Pyridine-4-hydroxycarboxylic acid hydroxyamide (Examples 1-40),

 2-benzyl-5- [4- (3-methyl-benzyloxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7-hexahydrid-1H-pyrazo [4, 3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide (Examples 1-41),

 2-benzyl-5- [4- (4-methyl-benzyloxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo mouth [4, 3-c] pyridine-4-carboxylic acid hydramide hydroxyamide (Examples 1-42),

 5- [4- (4-fluoro-benzyloxy) -benzenesulfonyl] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 1-43),

2-Naphthalene-1-yl-3-oxo-5- (4-phenoxy-benzenesulfonyl) -2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] Pyridine-4-hydroxycarboxylic acid hydroxide (Examples 1-44),

5- [4- (2-Methyl-benzyloxy) -benzenesulfonyl] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4 , 3-c] pyridine-4-Hydroxyhydrocarbon Xyamide (Examples 1-45),

 5- [4- (3-Methyl-benzyloxy) -benzenesulfonyl] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyra [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 1-46),

5- [4- (4-methyl-benzyloxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [ : 4,3 c] pyridine-4-hydroxysulfonic acid hydroxyamide (Examples 1-47),

 5- [4- (2-cyano-benzyloxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [ 4,3-c] Pyridine-4-carboxylic acid hydramide oxiamide (Examples 1-48),

 2-Benzyl-5- (4_benzyloxy-benzenesulfoel) -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4 Ruponic acid hydroxyamide

(Examples 1-49),

 (R)-2-benzyl-5- [4- (4-fluoro-benzyloxy) -benzenesulfoel] -3-oxo-, 3,4,5,6,7-hexahydro-1H-pizazo Mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 1-50),

 3-oxo-2-phenyl-5- [4- (2-methyl-phenoxy) -benzenesulfoel] -2,3,4,5,6,7-hexahydro-1H-pyrazo [4 , 3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Examples 1-51),

2-Benzyl-3-oxo-5- [4- (2-methyl-phenoxy) -benzenesulfonyl] -2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3- c] pyridine-4-hydroxysulfonic acid hydroxyamide (Example 52),

 3-oxo-2-phenyl-5- [4- (4-methyl-phenoxy) -benzenes / lefonyl] -2,3,4,5,6,7-hexahydro-1H-pyrazo [4 , 3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Examples 1-53),

 2-benzyl-3-oxo-5- [4- (4-methyl-phenoxy) -benzenesulfonyl] -2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3- c] pyridine-4-hydroxycarboxylic acid hydroxyamide (Example 54),

3-oxo-2-phenyl-5- [4- (2-trifluoromethyl-benzyloxy) -benzene Sulfonyl] -2,3,4,5,6,7-hexahydro-1H-pyrazo-mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-55),

 2- (2-chloro-phenyl) -3-oxo-5- (4-phenoxy-benzenesulfol-)-2,3,4,5,6,7-hexahydro-1H-pyrazo [4 , 3-c] P-Vidin-4-potassium hydroxyamide (Example 56),

 5- [4- (3,4-dichro-phenoxy), benzenesulfonyl] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H- Pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 5.7),

5- [4- (4-Methoxy-phenoxy) -n-cis-isulfol] ³ -oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-virazo ^ [4, 3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Examples 1-58),

 5- [4- (4-Chloro-phenoxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4 (3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide (Example 59),

5- (4-benzyloxy-benzenesulfol) -2-naphthalene-1-yl-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3- c] Pyridine-4-carboxylic acid hydroxyamide (Examples 1-60),

 5- (4-Benzyloxy-benzenesulfol)-2- (2-c-mouth-phen-ole) -3-oxo-1- 2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 1-61),

 5- [4- (3,5-dimethoxy-phenoxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H- Pyrazolo [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Examples 1-62),

 5- [4- (2-Chloro-phenoxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo-mouth [4, 3-c] pyridine-4-hydroxycarboxylic acid amide (Example 63),

3-oxo-2-phenyl-5- [4- (pyridine-4-yloxy) -benzenesulfonyl] -2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3- c] pyridine-4-hydroxypropyl amide (Examples 1-64), 5- [4- (2-Methoxy-benzyloxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-birazolo [4, 3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 1-65),

 5-[4- (2-c-mouth-benzyloxy) -benzenesulfol]-3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H- Pyrazine [3-c3 pyridine-4-carbonic acid hydroxyamide (Example 1-66),

 2-Benzyl-5- [4- (2-methoxyl; noxy) -benzenesulfoel] -3-oxo-2,3,4,5,6,7-hexahydro-1H-benzo [Also 3_c] pyridine-4-hydroxysulfonic acid hydroxyamide (Examples 1-67),

2-Benzyl-5- [4- (2-chloro-phenoxy, n) -benzenesulfonyl] -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [3- c] pi Vdin-4-carponic acid hydroxyamide (Example 1-68),

 5- [4- (2-Fluoro mouth-benzyloxy) -benzenesulfonyl] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-virazo mouth [ 4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Examples 1-69),

 5- [4- (2,4-dichloro-benzyloxy) -benzenesulfol] -2- (5-fluoro-2-methyl-phenyl) -3-oxo-2,3,4,5,6,7 -Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-70),

 5- (4-benzyloxybenzene) sulfur-7,7-dimethyl-3-oxo-2-phenyl-2,3,4,5,6,7 hexahydro-1H-pyrazo [4,3- c] pyridine-4-carboxylic acid hydroxyamide (Examples 1-71),

 5- [4- (2,5-dimethyl-benzyloxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [ 4,3-c] pyridine-4-hydroxycarboxylic acid hydramide (Examples 1-72),

2-benzyl-3-oxo-5- [4- (2-trifluoromethyl-phenoxy) -benzenesulfol] -2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 1-73),

5- [4- (2,6-dichloro-benzyloxy) -benzenesulfonyl] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [ 4,3-c] pyridine-4-carboxylic acid hydride Roxyamide (Example 74),

 5- [4- (2,4-dicou-benzyloxy) -benzenesulfonyl]-2- (2,5-difluoro-phenyl) -3-3-oxo-2,3,4,5,6 7-Hexahi F mouth-1H-Pyrazo mouth [4,3-c] pyridin-4-hydroxysulfonic acid hydroxyamide (Example 1-75),

5- [4- (3,5-bis-trifluoromethyl); I-oxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7- Hexahydro 1H-birazolo [4,3-c] pyridine-4-carboxylic acid t-droxyamide (Examples 17 &),

 5- (4-benzyloxy-benzenesulfol) -methyl-2-phenyl-4,5,6,7-tetrahydro-2H-pyrazo [4,3-c] pyridinecarboxylic acid hydroxyamide ( Example 77),

 5- (4-benzyloxy-benzenesulfol) -3-oxo-2-phenyl-1,2,3,4,5,6,7,8-octahydro-1,2,5-triaza-azulene 4-hydroxycarboxylic acid amide (Example 78),

 2- (2,5-dichro-phenyl) -5- [4- (3-methoxy-5-methyl-phenoxy) -benzenesulfonyl] -3-oxo-2,3,4,5,6 7-hexahydro-1H-pyrazo [4,3-c] pyridin-4-carboxylic acid hydroxyamide (Examples 1-79),

 5- (4-benzyl-benzenesulfol) -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo mouth [4,3-c ] Pyridine-4-hydroxycarboxylic acid amide (Examples 1-80),

3-oxo-5- (4-phenethyl-benzenesulfol) -2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine- 4-hydroxycarboxylic acid hydroxyamide (Examples 1-81),

 5- (4-benzyloxy-benzenesulferyl) -2-cyclohexyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine- 4-carboxylic acid hydroxyamide (Examples 1-82),

 3 oxo-2-phenyl-5- [4- (3-methyl-phenoxy) -benzenesulfol-]-2,3,4,5,6,7-hexahydro-1H-pyrazo [4 (3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Examples 1-83),

5- [4- (3,5-dimethyl-phenoxy) -benzenesulfonyl] -3-oxo-2-furur- 2,3,4,5,6,7-hexahydro-1H-pyrazo-mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 1-84),

 5- [4- (2- ク 口 口 -6-Fluoro-benzyloxy) -benzenesulfol] -3--3-oxo-2,3-phenyl-2,3,4,5,6,7-hexahydrid- 1H-pyrazolo [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Examples 1-35),

 5-[4- (3,5-Dichloro-phenoxy) -3-fluoro-benzenesulfo-nore] -3-oxo-2 -phenyl-2,3,4,5,6,7-hexahydro-1H- Piso mouth [4,3-c] pyridine-4-carboxylate hydroxyamide (Example 1-),

 5- [4- (2,3-Dicyclohexyl-benzyloxy)-^ enesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H- Pyrazo mouth [4,32c] pyridine-4-hydroxysulfonic acid hydroxyamide (Examples 1-87),

 5- [4- (2,4-Dic-mouth-benzyloxy) -benzenesulfol] -7,7-dimethyl-3-oxo-2-phenyl-2,3,4,5,6,7- Hexahydro-1H-virazo mouth [4,3-c] pyridine-4-force rubonic acid hydroxyamide (Examples 1-88),

5- [4- (2-Chloro-4-fluoromethyl-benzyloxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Examples 1-89),

 5- [4- (3-Isopropyl-5-methyl-phenoxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo Mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 1-90),

 5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro- 1H-pyrazo mouth [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Examples 1-91),

 2-(3-Kuguchi-Fuel) -5- [4- (2,4-Diguguchi-benzyloxy) -benze, islufol] -3-Oxo-2,3,4,5,6, 7-hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-force rubonic acid hydroxyamide (Cold example 1-92),

 2-cyclohexyl-5- [4- (2,4-cyclohexyl-benzyloxy) -benzenesulfoninole]-

3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide (Examples 1-93), 2-cyclohexylmethyl-5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfoyl] -3--3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo Mouth [4, pyridine-4-force rubonic acid hydroxyamide (Examples 1-94),

 5- [4- (2,3-Dimethyl-N-hydroxy) -benzosulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro- 1H virazolo [4,3-C] pyridine-4-hydroxycarboxylic acid hydroxyamide (Example 95),

 5- [4- (2,5-dichlorophenol) -bensulfol] -3 -oxo-2-phenyl-2,3,4,5,6,7-hexahydro- 1H-Vilazo P [, 3-ρΙpyridine-4-carboxylic acid hydroxyamide (Example 96),

3-oxo-5- (4-phenoxymethyl-pentenesulfol) -2_phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] Pyridine-4-carboxylic acid hydroxyamide (Examples 1-97),

 2- (2,5-dibruole-phenyl) -5- [4- (3-Methoxy-5-methyl-phenoxy) -benzensulfonyl] -3-oxo-2,3,4,5,6 , 7-Hexahydro-1H-pyrazo mouth [4,3-c] pyridin-4-carboxylic acid hydroxyamide (Examples 1-98),

 5- [4- (3,5-Dic-mouth-phenoxy) -benzenesulfoel] -3-oxo-2-phenyl-2,3,4,5,6,7-Hexahydro-1H-Pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 1-99),

 3-oxo-2-phenyl-5- [4- (2,4,5-trifluoro-benzyloxy) -benzenesulfol] -2,3,4,5,6,7-hexahydrid-1H- Pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 1-100),

 5- [4- (3,5-difluoro-phenoxy) -benzenesulfonyl] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-virazo [4 , 3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Example 1-101),

5- [4- (2-Fluoro mouth-phenoxy) -benzenesulfoel] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo mouth [4, 3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Example 1-102),

5-[4-(2,4-Dic-mouth-benzyloxy) -benzenesulfur] -3-oxo-2- (4-heptyl) -2,3,4,5,6,7-hexahi Dro-1H-Pyrazo mouth [4,3-c] pyridine-4-forcenolevonic acid Hydroxyamide (Example 1-103),

 5-[4- (2-Ethyl-phenoxy) -benzenesulfonyl] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pizazo [4,3 -c] pyridine-4-carboxylic acid hydroxyamide (Example 1-104),

5- [4- (6-chloro-benzo [1,3] dioxol-5-ylmethoxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6 , 7 Hexahydrid -1H-Pyrazo [4,3-c] pyridin-4-carboxylic acid hydroxyad (Example:! 105),

 5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfonyl]-2- (2-ethyl-butyl) -3-oxo-2,3,4,5,6,7- To Sahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-106),

 5- [4- (2,4-Dic-mouth-benzyloxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H- Pyrazo mouth [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Example 1-107),

 (R) -5- [4- (2,4-Dichrolic-benzyloxy) -benzenesulfonyl] -3-oxo-2--2-phenyl-2,3,4,5,6,7-hexahydro-1H -Pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-108),

 5- [4- (4-Fluoro-2-methyl-phenoxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H- Pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-109),

5- [4- (2,3-Dimethyl-phenoxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo Mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 110),

 5- [4- (2,5-dicopen-benzyloxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H pyrazo Mouth [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide (Example 111),

 5- [4- (2,4-difluoro-benzyloxy) -benzenesulfol] -3-oxo-2 -phenyl-3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Example 1-112),

5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfol] -2- (2-fluoro-phenyl 3-Oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo-mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 113) ),

 5- [4- (2,5-Cimethyl-benzyloxy) -benzenesulfol] -2- (2-fluoro-phenol) -3-oxo-2,3,4,5,6,7 -Bexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide

2-cyclopentyl-5- [4- (3,5-dichloro-7-noxy) -benzenesulfonyl] -3-oxo-2,3,4,5,6,7-hexahydride -IH-It ⁰ ^, η [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Example 1-115),-

5- [4- (3, 5 - Axis every mouth - phenoxy) - base ^^ sulfo le] - ² _ (2-Furuoro - Hue - Le) - 3 - Okiso - 2, 3, 4, 5, 6, 7-hexahydro 1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example l il6 ',

 5- [4- (2,4-Dic-mouth-benzyloxy) -benzenesulfol] -3-oxo-2- (2-methyl-phenyl) -2,3,4,5,6 7-hexahydro-1H-birazolo [4,3-c] pyridine-4-force rubonic acid hydroxyamide (Examples 1-117),

5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfol] -3-oxo-2- (3-methyl-phenyl) -2,3,4,5,6, 7-hexahydro-1H-biazo mouth [4, $ -c] pyridine-4-force ruponic acid hydroxyamide (Example 1-118),

 5- [4- (3,5-Dic-mouth-phenoxy) -benzenesulfo-nore] -2- (2-Methoxy-phenyl) -3-oxo-2,3,4,5,6, 7-hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 1-119),

 5- [4- (2,5-difluoro-benzyloxy) -benzenesulfoel] 3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4 (3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Example 1-120),

 5-[4- (2,4-Dic-mouth-benzyloxy) -benzenesulfonyl] -2- (3-fluoro-phenyl) -3-oxo-2,3,4,5,6,7- Hexahydro-1H-pyrazo-mouth [4,3-c] pyridine-4-carbonic acid hydroxyamide (Example 121),

To 5- [4- (2,5-dimethyl-benzyloxy) -benzenesulfur] -2 (3-fluoro-phenyl) -3--3-oxo-2,3,4,5,6,7- Xahydro-1H-pyrazolo [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-122), 5- (4-cyclohexylmethoxy-benzenesulfonyl) -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4, 3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-123),

 5- [4- (3,5-dichloro-phenoxy) -benzenesulfel] -3-oxo-2- (3-methyl-phenyl) -2,3,4,5,6,7-hexahydro- -Pyrazo [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Examples 1-124),.

 5- [4- (3,5-Dichloro-phenoxy) -4benzenesulfonyl] -2- (3,5-dimethyl-phenyl) -3-oxo-2,3,4,5,6,7 -Hexahydro 1H-birazo mouth [4,3-c] pyridine-4-force rubonic acid hydroxyamide (Example 1-125),.

5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfur] -2- (2-ethyl-phenyl) -3-oxo-2,3,4,5,6,7 - to Kisahi mud - IH - pyrazole port [4, 3-c] pyridin - 4 - power carboxylic acid hydroxyamide (example 1-12 ^6),

 5-[4- (2,4-Dic-mouth-benzyloxy) -benzenesulfur] -3-oxo-2- (2-trifluoro-methyl-phenyl) -2,3,4,5,6 7-Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-127),

 To 2- (3-c-mouth-phenyl) -5- [4- (2,5-dimethyl-benzyloxy) -benzenesulfur] -3-oxo-2,3,4,5,6,7- Xahydro-1H-pyrazo mouth [4,3-c] pyridine-4-force rubonic acid hydroxyamide (Example 1-128),

 To 5- [4- (3,5-Dic-mouth-phenoxy) -benzenesulfonyl] -2- (3-fluoro-phenyl) -3-oxo-2,3,4,5,6,7- Xahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 129),

 2- (3- ク 口 口-ふ ;; ル ル) -5- [4- (2,4-Dicguchi-benzyloxy) -benzenesulfonyl] -3-oxo-2,3,4,5 6,7-hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-force rubonic acid hydroxyamide (Example 1-130),

2- (3-c-mouth-phenyl) -5- [4- (3,5-di-c-mouth-phenoxy) -benzenesulfo]-3-oxo-2,3,4,5,6,7 -Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-131),

To 5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfonyl] -2- (3-methoxy-phenyl) -3-oxo -2,3,4,5,6,7- Xahydro—1H-pyrazo mouth [4,3-c] pyridine-4-1 Carboxylic acid hydroxyamide (Examples 1-132),

 2-cyclopentyl-5- [4- (2,4-dichloro-benzyloxy) -benzenesulfonyl]-

3-oxo-2,3,4,5,6,7-hexahydro-1H-virazo [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide (Example 1-133),

5- [4-(3,5-dichloro-phenoxy, n) -sense / lefonyl]-2- (3-methoxy-phenyl) -3-oxo-2,3,4,5,6, 7-hexaΐϊί-birazolo [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 134),

 2-Silpentyl pentyl-5- [4- (2,4-dibruo penziloxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7-hexahi draw 1H-Pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-135),

5- [4- (3, 5-Axis every mouth - phenoxy) - benzenesulfonyl] - ² - (3, 5 - Axis every mouth - Hue Interview le) -3- Okiso -2 3, 4, 5, 6 , 7-hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-force rubonic acid hydroxyamide (Example 1-136),

 5- [4- (3,5-Dichloro-phenoxy) -benzenesulfonyl] -3-oxo-2- (3-Trifluoromethyl-phenyl) -2,3,4,5,6,7- Hexahydro-1H-pyrazo mouth [4,3-c] pyridin-4-hydroxycarboxylic acid hydroxyamide (Examples 1-137),

 5- [4- (2,4-Dic-mouth-benzyloxy) -benzenesulfoel]-2- (3,5-Dic-mouth-phenyl) -3--3-oxo-2,3,4,5, 6,7-Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-

4-hydroxysulfonic acid hydroxyamide (Examples 1-138),

5- [4- (2,4-dichloro-5-fluoro-benzyloxy) -benzesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7 -Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-139),

 (R) -5- [4- (2,5-Dic-mouth-benzyloxy) -benzenesulfol] -3-oxo-2--2-furnyl-2,3,4,5,6,7- Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Example 1 140),

 5- [4- (2,4-Dimethyl-benzyloxy) -benzenesulfonyl] -3-oxo-2- (3-trifluoromethyl-phenyl) -2,3,4,5,6,7- Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-141),

(R) -5- [4- (2,4-Difluoro-benzyloxy) -benzenesulfol] -3-oxo -2- Ferre-2,3,4,5,6,7-hexahydro-1H-pyrazo-mouth [4,3-c] pyridine-4-hydroxypyruroic acid hydroxyamide (Example 1-142),

 (R) -5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -3-oxo-

2-Phenyl-2,3,4,5,6,7-hexad pyrazo-opened [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide (Implementation 1-1 1 13) ',

 (R) -2-pentyl pentyl-5- [4- (3,5-ditalolo-phenoxy) -benzenesulfonyl]-

3-oxo-2,3,4,5,6,7-hexahi: do 1H—hi. Lazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-144),

 00-2-Cyclic pentyl-5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7-hexahydro-1H pyrazo Mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 1, -145),

 (R)-2-cyclopentyl -5- [4- (2,4-dicyclopentyl-benzyloxy) -benzenesulfonyl] -3-oxo--2,3,4,5,6,7- Xiahide mouth-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-146),

(R) -2-Cyclobutyl-5- [4- (2,4 dichloro-benzyloxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7-hexahydro-1H- Pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-147),

 (R) -2-Cyclopropyl-5- [4- (2,4-dichloro-benzyloxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7-hexahydro -1H-Vilazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (actual: ^ Example 1-148),

 (R) -2- (3-Couguchi-phenyl) -5- [4- (2,5-dicloro-benzyloxy) -benzenes / lefonyl] -3-oxo-2,3,4,5 6,7-Hexahydro-1H-pyrazo [4,3-c] pyridine-

4-carboxylic acid hydroxyamide (Example 1-149),

 (S) -2-cyclopentyl-5- [4- (3,5-dichloro-phenoxy) -benzenesulfonyl] -3-oxo-2,3,4,5,6,7-hexahydro -1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-150),

(R) -5- [4- (2,4-Dimethyl-benzyloxy) -benzenesulfonyl] -3-oxo-2--2-pyridin-2-yl-2,3,4,5,6 , 7-Hexahydro-1H-pyrazolo [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-151), 00- 5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfonyl] -3-oxo-2-pyridine-2-yl-2,3,4,5,6,7 -Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 1-152),

 (R) -5- [4- (2,4-Dichloro-benzyl-, n-)-benzenesulfol] -2-indane-1-yl-3-oxo-2,3,4,5 6,7-Hexahydro-1H birazolo [4,3-c] pyridine-4-force rubonic acid hydroxyamide (act; (11-153),

 (R)-2- (3-Chloro-pyridin-2-yl) -5- [4- (4-dimethoxy-benzyloxy) -benzenesulfol] -3-oxo-2,3,5 , 6,7-Xahydro-1H-pyrazo mouth [4,3-c] pyridin-4-carboxylic acid hydroxyamide (Examples 1-154),

(R) -5- [4- (2,4-Dimethyl-benzyloxy) -benzenesulfol] -3-oxo-2-quinolin-2-yl-2,3,5,6,5 7-hexahydrid 1H pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 11-15 &),

 (R) -2-tert-butyl-5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7- Hexahydro—1H-pyrazo mouth [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide (Example 1-156),

 (R) -5-[4- (2,4-Dic-mouth-benzyloxy) -benzenesulfonyl] -3-oxo-1,3,4,5,6,7-hexahydro-isoxazolo [4, 3-e] pyridine-4-carboxylic acid hydroxyamide (Example 1-157),

 (R) -5- [4- (2,4-Dimethoxy-benzyloxy) -benzenesulfol] -7,7-dimethyl-3-oxo-2-phenyl-2,3,4,5 , 6,7-Hexahydro-1H-pyrazo mouth [4,3-c] -pyridine-4-carboxylic acid hydroxyamide (Examples 1-158),

 (R) -5- [4- (2,4-Dimethyl-benzyloxy) -benzenesulfonyl] -spiro [cyclohexane-7,-(3-oxo-2-phenyl-2,3, 4,5,6,7-hexahydro-1H-pyrazo-mouth [4,3-c] pyridine)]-4-carboxylic acid hydroxyamide (Example 1-159.),

(R) -5- [4- (2,4-dichloro-benzyloxy) -benzenesulfonyl] -spiro [cyclopropane-7,-(3-oxo-2-phenyl-2,3,4,5 , 6,7-Hexahydrid-1H-pyrazolipid [4,3-c] pyridine)]-4-Hydroxyhydroxyhydramide (Example 160),

(R) -5- [4- (2,4-Dichloro-benzyloxy) -benzenesulfol] -spiro [, cyclobutane-7,1,-(3-oxo-2-phenyl-2,3 , 4,5,7-Hexahydro-1H-pyrazo mouth [4,3-c] pyridine)]-4-carboxylic acid hydroxyamide (Example 1-161),

(R) -5- [4- (2,4-Dic-mouth-benzyloxy) -benzenesulfonyl / le] -spiro [4, -tetrahydrodropyran—7,1, — (3-oxo-2--2-fue -Le-2,3,4,5,6,7-hexahydro-1H-pyrazo-mouth [4,3-c] pyridine)]-4-carboxylic acid hydroxyamide (Example 162), (R) -5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenes / lefonyl] -spiro [cyclopropane-7,1 (3-oxo-2-phenyl-, 3,4 , 5,6,7-Hexahydro-1H-benzo [4,3-c] pyridine)]-4-butane.hydriaxamide (Example 1-163), (R) -5- [ 4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -spi [hexahexane-7, Γ- (3-oxo- -phenyl -2, 3, 4, 5,6,7-hexahydro-1H-pyrazolo [4,3-c] pyridine)]-4-carboxylic acid hydroxyamide (Example 1-164),

To (R) -2-tert-butyl-5- [4- (2,4-dicopentyl-pentyloxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7- Xahydro-1H-pyrazo mouth [4,3-c J pyridine-4-carboxylic acid hydroxyamide (Example 1-165),

 (R) -5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -spiro [cyclobutane-7,1,-(3-oxo-2-phenyl-2) , 3,4,5,6,7-Hexahydro-1H-pyrazo mouth [4,3-c] pyridine)]-4-hydroxycarboxylic acid hydroxyamide (Example 1-166),

(R) -5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfonyl] -7,7-dimethinol-3-oxo-1-2-phenyl 2,3,4,5 6,7-hexahydro-1H-virazo [4,3-c] pyridin-4-hydroxypyruvonic acid hydroxyamide (Example 1-167),

(R) -5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -spiro [4, -tetrahydropyran-7,1,-(3-oxo-1-furyl- 2,3,4,5,6,7-Hexahydro-1H-pyrazo [4,3-c] pyridine)]-4-carboxylic acid hydroxyamide (Examples 1-168),

 (R) -5- (4-Benzyloxy-benzenesulfonyl) -2-tert-butyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3- c] pyridine-6-hydroxycarboxylic acid hydroxyamide (Example 2-1),

(R) -2-benzyl-5- (4-benzyloxy-benzenesulfonyl) -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3- c] pyridine-6-hydroxysulfonic acid hydroxyamide (Example 2-2), (R) -5- (4-Benzyloxy-benzenesulfol) -2-methyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3- c] pyridine-6-hydroxysulfonic acid hydroxyamide (Example 2-3),

 (R) -2-Benzyl-5- (4-benzyloxy-benzenesulfoel) -1-methyl-3-oxo-2,3,4,5,6,7-hexahydro-1uryl pyrazo [ 4,3-c] pyridine-6-carponic acid hydroxyamide (Example 2-4),

 ()-5- (4-benzyloxy-benze sulfoel) -2-butyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine 6-hydroxycarboxylic acid hydroxyamide (Example 2-5),

(R) -5- (4-Benzyloxy-benzen rufonyl) -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H pyrazo ^ [4 , 3-c] pyridine-6-hydroxycarboxylic acid amide (Examples 2-6),

 (R) -5- (4-benzyl / reoxy-benzenesulfol) -1-butyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4, 3-c] pyridine-6-carboxylic acid hydroxyamide (Example 2-7),

 (3aR, 4R) -5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfur] -3a-methyl-3-oxo-2-phenyl-3,3a, 4, 5,6,7-hexahydro-2H-pyrazo [4,3-c] pyridine-4-hydroxypyruvonic acid hydroxyamide (Example 3-1),

(3aR * _s 4R *) -5- [4- (2,4-dichloro-benzyloxy) -benzenesulfoel] -3a-methyl-3-oxo-2-phenyl-3,3a, 4,5 , 6,7-Hexahydro-2H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 3-2),

 (3aR *, 4R *)-5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfonyl]-3a-ethyl-3-oxo-2 -7-well-3,3a, 4 , 5,6,7-Hexahydro 2H-virazo [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide. (Example 3-3)

(3aR *, 4R *)-5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -3a-methyl-3-oxo-2-phenyl-3,3a, 4,4 5,6,7-hexahydro-2H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Examples 3-4),

(3aR, 4R)-5-[4- (3-methoxy-5-methyl-phenoxy) -benzenesulfoel]-3a-methyl-3-oxo-2-phenyl-3,3a, 4 5,6,7-Hexahydro-2H-pyrazo mouth [4,3-c] pi Lysine-4-carboxylic acid hydroxyamide (Example 3-5),

 (3aR *. 4R *)-5-[4-(3,5-Dic-mouth-phenoxy)-benzenesulfonyl]-3a-Methyl-3-oxo-2-phenyl-3, 3a, 4 , 5,6,7-Hexahydro-2H-pyrazo [4,3-c] pyridin-4-hydroxycarboxylic acid hydroxyamide (Example 3-6),

(3aR * ₅ 4R *) -5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfonyl] -3a-ethyl-3-oxo-2-phenyl-3,3a, 4,5 7 Hexahydro-2H-pyrazo-mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Example 3-7),

 (3aR *, 4R *) -3a-Ethyl-5- [4- (3-methoxy_5-methyl-phenoxy) -benzenesulfol] -3-oxo-2-fehell-3, 3a, 4, 5,6,7 "Hexahydro-2H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxy, amide (Example 3-8),

 (3aR *, 4R *)-5- [4- (2,4-dichloro-benzyl ^ oxy) -benzenesulfol] -3a-methyl-3-oxo-2--2-phenyl-3,3a, 4,5,6,7-hexahydro-2H-pyrazo opening [4,3-c] pyridine-4-carboxylic acid (Example 3_9),

 (3aR, 4R) -5- [4- (2,4-Dichloro-benzyloxy) -benzenesulfur] -3a-methyl-3-oxo-2-phenyl-3,3a, 4,5 6,7-hexahydro-2H-pyrazo mouth [4,3-c] pyridin-4-carboxylic acid (Examples 3-10),

(3aR * _s 4R *) -5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -3a-methyl-3-oxo-2-phenyl-3,3a, 4 5,6,7-Hexahydro-2H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid (Example 3-11),

(3aR *, 4R *)-5- [4- (2,4-Dimethyl-benzyloxy) -benzenesulfonyl] -3a-ethyl-3-oxo-2-phenyl-3,3a, 4,5 6,7-hexahydro-2H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid (Examples 3-12),

 (3aR *, 4R *) -5-(4, -black mouth -biphenyl-4-sulfol) -3a-ethyrlni-oxo-2 -phenyl-3,3a, 4,5 6,7-Hexahydro-2H-pyrazo-mouth [4,3-c] pyridine-4-carboxylic acid (Example 3-13),

 (3aR *, 4R *)-5- [4- (3,5-dic π-open_phenoxy> -benzenesulfur] -3a-methyl-3-oxo-2-phenyl-2,3a, 4 , 5,6,7-Hexahydro-2H-pyrazo mouth [4,3-c] pyridin-4-carboxylic acid (Examples 3-14),

(3aR *, 4R *)-3a-ethyl-3 -oxo-2-fuel-5-([1,1,; 4,, 1 ,,] terfel-4- Sulfo) -3,3a, 4,5,6,7-hexahydro-2H-pyrazo [4,3-c] pyridine-4-carboxylic acid (Examples 3-15),

(3aR * _} 4R *)-5-[5- (4-co-mouth-furyl) -thiophen-2-sulfol]-3a-methyl-3-oxo- 2-phenyl-3,3a, 4, 5, 6 ,; 7-hexahydro-2H-pyrazozo [4,3-c] pyridin-4-carboxylic acid (Example 3-16).

(3aR *, 4R *) -5- (7-Bromo-9H-fluorene-2norefol) -3a-Methyl-3-oxo-2 phenyl-3,3a, 4,5,6,7 -He ^ Sahi P 2H-, Vilazo mouth [4,3-G] pyridine-4-carboxylic acid (Example 3-17) ₀

 [16] The condensed Ν-containing heterocyclic compound according to any one of the above [1] to [15] or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof. A pharmaceutical composition containing

 [17] An aggrecanase inhibitor comprising, as an active ingredient, the fused N-containing heterocyclic compound according to any one of the above [1] to [15], or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Agent.

 [18] MMP-13 containing, as an active ingredient, the fused N-containing heterocyclic compound according to any one of the above [1] to [15], a prodrug thereof, or a pharmaceutically acceptable salt thereof. Inhibitors.

 [19] A method for treating osteoarthritis comprising, as an active ingredient, the fused N-containing heterocyclized compound according to any one of the above [1] to [15], a prodrug thereof, or a pharmaceutically acceptable salt thereof. Prophylactic or therapeutic drugs.

 [20] A method for treating rheumatoid arthritis, comprising as an active ingredient the condensed N-containing heterocyclic compound according to any one of the above [1] to [15], a prodrug thereof, or a pharmaceutically acceptable salt thereof. Prophylactic or therapeutic agents.

 [21] A prophylactic or therapeutic agent for osteoarthritis, comprising as an active ingredient a compound having an aggrecanase inhibitory activity or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[22] A prophylactic or therapeutic agent for osteoarthritis, comprising as an active ingredient a compound having an MMP-13 inhibitory activity or a prodrug thereof, or a pharmaceutically acceptable salt thereof. [23] A prophylactic or therapeutic agent for chronic rheumatoid arthritis, comprising as an active ingredient a compound having an aggrecanase inhibitory activity or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

 [24] An agent for preventing or treating rheumatoid arthritis, comprising as an active ingredient a compound having an MMP-13 inhibitory activity or a prodrug thereof, or a pharmaceutically acceptable salt thereof. : '

 [25] administering the fused N-containing ^^ telocyclized compound according to any one of the above [1] to [15], a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal; A method for inhibiting aggrecanase.

 [26] The method according to any one of [1] to [15], wherein the fused N-containing heterocyclic compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof is administered to a category milk animal. The MMP-13 inhibition method.

 [27] administering the fused N-containing heterocyclic compound according to any one of the above [1] to [151, a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal; A method for preventing or treating osteoarthritis.

 [28] A method comprising administering the fused N-containing heterocyclic compound according to any one of the above [1] to [15], a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal. A method for preventing or treating rheumatoid arthritis.

 [29] A method for preventing or treating osteoarthritis, which comprises administering a compound having an aggrecanase inhibitory activity, a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal.

 [30] A method for preventing or treating osteoarthritis, which comprises administering a compound having an MP-13 inhibitory action, a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal.

 [31] A method for preventing or treating rheumatoid arthritis, which comprises administering a compound having an aglicanase inhibitory activity, a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal.

[32] administering a compound having an MMP-13 inhibitory activity, a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal, comprising administering the compound to a mammal. A method for preventing or treating rheumatoid arthritis.

 [33] The pharmaceutical composition according to the above [16], for use in combination with another therapeutic agent for osteoarthritis.

 [34] The pharmaceutical composition of the above-mentioned [16] for use in combination with other rheumatoid arthritis treatment lotus.

 [35] The condensed N-containing heterocyclic compound according to any of [1] to [1] or a prodrug thereof, or a pharmaceutically acceptable salt thereof, in combination with another therapeutic agent for osteoarthritis [27] The method for preventing or treating osteoarthritis according to the above [27].

 [36] The condensed N-containing heterocyclic compound according to any of the above [1] to [15], a prodrug thereof, or a pharmaceutically acceptable salt thereof, and another agent for treating rheumatoid arthritis. The method for preventing or treating rheumatoid arthritis according to the above [28], which is used in combination.

 [37] The pharmaceutical composition according to the above [16], and a pharmaceutical composition which describes that the pharmaceutical composition can or should be used for the purpose of preventing or treating osteoarthritis. A commercial package containing a description of the thing.

 [38] The pharmaceutical composition according to the above [16], and a description that the pharmaceutical composition can or should be used for the prevention or treatment of rheumatoid arthritis. A commercial package containing articles about objects.

 DETAILED DESCRIPTION OF THE INVENTION

 The definitions of each substituent and each site used in the present specification are as follows. In the present specification, rCwj indicates that the number of carbon atoms is 1 to 6.

As used herein, the term “single bond” means a direct connection. For example, in one (CH ₂ ) _p -X- (CH ₂ ) _q —A ¹ , when is a single bond J, _{(CH 2) p - (CH} 2) q - means that it is a ^1.

 The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and is preferably a fluorine atom or a chlorine atom.

Preferably the R \ R ² is a fluorine atom.

The “alkyl group” refers to a linear or branched alkyl group having 1 to 10 carbon atoms. Represents specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1 —Ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, ^ ^ "ethylbutyl, heptyl, octyl, Examples thereof include a nor group and a decyl group.

R ⁹ is preferably a methyl group, a butyl group, a tert-butyl group, a pentyl group, a hexyl group, or a heptyl group.

 “Alkyl group” means a linear or branched alkyl group having 1 to β carbon atoms, and specifically, a methyle group, a butyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group Group, tert-butynole group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-ethylpropyl group, hexyl group and the like. It is preferably a straight-chain or branched-chain alkyl group having 1 to 0.4 carbon atoms.

R], RR ³ , RR ⁶ , ¹⁰ R ", R ¹² , R ¹³ , R ¹⁴ , R ^1S , R ¹⁶ are preferably a methyl group, and R ⁸ is preferably a methyl group, a butyl group; ¹⁷ is preferably a methyl group or an ethyl group.

The “halo C _M alkyl group” is a group in which the above-defined “dialkyl group” is substituted with the above-defined “halogen atom”, specifically, a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group. Examples include a methyl group, a bromomethyl group, a chloromethyl group, a 1,2-dichloromethyl group, a 2,2-dichloromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, and the like. Preferably, the alkyl moiety is a halo C1 _→ alkyl group, which is a linear or branched alkyl group having 1 to 4 carbon atoms, more preferably a trifluoromethyl group or a pentafluoroethyl group. .

The “alkylene group” represents a linear or branched alkylene group having 1 to 6 carbon atoms, and examples thereof include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group. It is preferably a straight-chain or branched-chain alkylene group having 1 to 4 carbon atoms, particularly preferably a methylene group or a styrene group. 7

A is preferably an ethylene group.

The - "C _{2 6} alkenylene group", the ". ₆ alkylene group" of the "C ₂ _ ₆ alkylene group" any linear鎮又having a double bond in position of the partial skill chain number of 2 to 6 carbon atoms Alke is a diene group. The position and number of the double bond are not particularly limited. Specific examples include an ethylene group, a probene group, a pterene group, a pentylene group, and a hexylene group. It is preferably a climbing or branched-chain alkenylene group having 4 to 4 carbon atoms, and particularly preferably an ethenylene group.

 In A, it is preferably ethenylene block.

The "C ₂ - - ₆ alkylene group", the above! It is a straight-chain or branched-chain alkynylene group having 2 to 6 carbon atoms having a triple bond at any position of the “C ₂ -6 alkylene group” of the “^^ alkylene group”. The position and number of triple bonds are not particularly limited. It is preferably a straight-chain or branched-chain alkylene group having 2 to 4 carbon atoms, and particularly preferably an ethylene-group.

 A is preferably an ethynylene group.

“D„ ₆ alkoxy group ”refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, specifically, methoxy, ethoxy, propoxy, isopropoxy, butoxy, butoxy, tert. — Butoxy group, pliers / reoquine group, hexyloxy group and the like. Preferably, the straight chain X having 1 to 4 carbon atoms is a branched chain alkoxy group.

Preferably in RR ² is main butoxy group, a butoxy group, good Mashiku in R ¹³ is methoxy.

 The “halo CM alkoxy group” is a group in which the above-defined “0, -6 alkoxy group” is substituted with the above-defined “halogen atom”, specifically, a fluoromethoxy group, a difluoromethoxy group, a trifluoro group. Romethoxy group, bromomethoxy group, chloromethoxy group, 1,2-dichloroethoxy group, 2,2-dichloroethoxy group, 2,2,2-trifluoroethoxy group, pentafluoroethoxy group, etc. . Preferably, the alkoxy moiety is a haloalkoxy group having 1 to 4 carbon atoms, which is a linear or branched a / recoxy group.

"rc ^ ₆ alkoxy ₆ alkyl group" means "C w alkyl group" as defined above. It is substituted with the above defined "C ^ ₆ alkoxy group". Specifically, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, sec-butoxymethyl, tert-butoxymethyl, methoxytyl, ethoxytyl Tert-butoxyl, tert-butoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, butoxypropyl, sec-butoxypropyl, and tert-butoxypropyl. The direct linking moiety having 1 to 4 carbon atoms is a C w alkoxy C, _ ₄ alkyl group which is a branched alkyl group.

The "C ₃ _ ₁₄ hydrocarbon ring group" is a cyclic saturated or unsaturated hydrocarbon group of 3 to 1 4 carbon atoms, for example, Ji ₆ _ ₁₄ Ariru groups, C ₃ - ₇ cycloalkyl groups, C ₃ _ ₁₀ Kuroarukeniru group.

“C ₆ _14 aryl group” refers to an aromatic hydrocarbon group having 6 to ₁₄ carbon atoms, specifically, a phenyl group, a nabutyl group, a biphenyl group (eg, 2-biphenyl) -Ryl group, 3-biphenylyl group, 4-biphenyl group), anthryl group and the like. Preferred are a phenyl group, a naphthyl group and a biphenyl group, and more preferred are a phenyl group.

R ¹ , R ² , R ⁸ and R ¹² are preferably a phenyl group, R ⁹ is preferably a phenyl group or a naphthyl group, and ring B is preferably a phenyl group or a biphenyl group. is there.

The "C ₃ _ ₇ cycloalkyl group", a cycloalkyl group having 3 to 7 carbon atoms, specifically cyclopropyl group, Shikuropuchiru group, a cyclopentyl group, by key sill Moto及Pi consequent opening heptyl cycloheteroalkyl is there. Preferred are cycloalkyl groups having 5 to 7 carbon atoms, and particularly preferred are cyclohexyl groups.

R ⁸ , R ¹² and A ¹ are preferably a cyclohexyl group, and R ⁹ is preferably a cyclopropynole group, a cyclopentinole group, a cyclopentynole group or a cyclohexynole group.

“0 ^. Cycloalkenyl group” is a cycloalkenyl group having 3 to 10 carbon atoms, specifically, 2-cyclopentene-11-yl, 3-cyclopentene-11-yl, and 2-cyclopentene. Hexene 1-yl, 3-cyclohexene 1-yl and the like Can be Preferred are cycloalkenyl groups having 5 to 7 carbon atoms, particularly preferred are 2-cyclohexene-1-yl and 3-cyclohexene-11-yl.

"C ₃ - ₁₄ hydrocarbon ring - Okishi group" walking, the defined as "hydrocarbon ring" portion - a Kamizu Yasushi癔Okishi group having "C _{3 14} hydrocarbon ring group", for example, C ₆ — ₁₄ aryloxy group, C ₃ — _7- cycloalkyl: oxy group and. And a cycloalkenyl group.

The "C ₃ _ ₁₄ hydrocarbon漯_ｰalkyl group", the above-defined as the "hydrocarbon ring" portion - has a "C _{3 14} hydrocarbon ring group", the 12 defined before as "alkyl" moiety "d - ₆ hydrocarbon ring group having an alkyl group ", for example, 0 ₆ _ ₁₄ Ariru C w alkyl group, C ₃ - ₇ consequent opening alkyl CM alkyl group and. Cycloalkel C

W alkyl groups are mentioned.

The - "c _{6 14} Ariruokishi group" is a Ariruokishi group having "c ₆ _ ₁₄ Ariru group" defined as the "Ariru" moiety, specifically a phenoxy group, naphthyl Chiruokishi group, Bifue - Riruokishi group ( For example, 2-biphenyloxy group, 3-biphenyloxy group, 4-biphenyloxy group), anthroxy group and the like. Preferred are a phenoxy group and a biphenyloxy group, and more preferred is a phenoxy group.

In RR ² , it is preferably a phenoxy group.

The - "C _{6 14} Ariruokishi alkyl group", Ariruo having "has a" C ₆ _ ₁₄ Ariru group "defined as Ariru j moiety," Ji alkyl group defined as "alkyl" moiety " A xyalkyl group, specifically a phenoxymethyl group, a naphthyloxymethyl group, a biphenyloxymethyl group (eg, 2-biphenyloxymethyl group, 3-biphenyloxymethyl group, 4-biphenylyloxymethyl group) And an anthroxymethyl group. Preferred is a phenoxymethyl group.

The - "C _{6 14} Ariru ₆ alkyl group", the defined as "Ariru" portion - the "C _{6 14} Ariru group" is a Ararukiru group having an alkyl group as defined above as "alkyl" moiety ", specifically Specific examples include a benzyl group, a phenethyl group, a 3-phenylpropyl group, and the like. Preferably ₆ _ ₁₄ Ariru CH alkyl group And particularly preferably a benzyl group or a phenethyl group.

\ R ⁸ and R ⁹ are preferably a benzyl group and a phenethyl group, and R ¹² is preferably a benzyl group.

The "0 ₆ _ ₁₄ Ariru alkoxy棊J,." Te Ariru part of the definition of "C ₆ _ ₁₄ Ariru group" is a Ararukiruokishi group having "alkoxycarbonyl group defined above as alkoxy J moiety", specifically Targets include a benzyloxy group, a phenethyloxy group, and a 3-phenylpropyloxy group. Preferably Flip ₆ - ₁₄ are Ariru CH alkoxy group, 'particularly Ru preferably base Njiruokishi groups der.

In RR ² , a benzyloxy group is preferred. .

The "C _A _ ₇ consequent opening alkyl group", the defined as "consequent opening alkyl" moiety - has a "C _{3 7} cycloalkyl group" defined above as "alkyl" moiety "<^ _ ₆ Alkyl group '', specifically, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, 2-cyclopropynoleethyl tomb, (2) One-neck mouth butynolechi / re, two-neck mouth pentylethynole group, 2-cyclohexylenoethyl group, 2-cycloheptylethyl group, 3-cyclohexylpropyl group, 4-cyclohexylpropyl group, etc. Can be Preferably C ₃ - a _cycloalkyl C _M § alkyl group, more preferably C _S - a ₇ cycloalkyl CH group, preferably especially Ho, a cyclohexylmethyl group cyclohexylene.

R ⁹ is preferably a cyclohexylmethyl group.

“Fused C ₆ _ ₁₄ hydrocarbon ring group” means a saturated or unsaturated C ₆ _ ₁₄ hydrocarbon ring as defined above, wherein the C ₃ _ ₁₄ hydrocarbon rings are fused together (partially unsaturated and completely unsaturated). (Including saturation). Specifically, indul group, induel group, 1,4-dihydronaphthyl group, fluorenyl group, 9-oxo-fluorenyl group, 1,2,3,4-tetrahydronaphthyl group (1,2,3,4-tetrahydro A 2-naphthyl group, a 5,6,7,8-tetrahydro-2-naphthyl group), a perhydronaphthyl group and the like. Preferable is a condensed ring of a furyl group and another ring, for example, an indul group, a fluoro group, a 9-oxo-fluoro group and the like. You.

R ⁹ is preferably an indanyl group, and ring B is preferably fluorenyl.

A fused hydrocarbon ring Okishi group having ₁₄ hydrocarbon ring Sj -. "Fused C ₆ _ ₁₄ hydrocarbon ring one Okishi group" walk, "fused C ₆ before Symbol defined as f fused hydrocarbon ring" moiety.

“Fused C ₆ _ ₁₄ hydrocarbon ring-alkyl group” means “fused C _e _ ₁₄ carbon: main ring” as defined above as a “fused hydrocarbon ring” moiety, It is a condensed hydrocarbon ring alkyl group having a “C w alkyl group” as defined above as a part.

 The term "heterocyclic group" refers to a saturated or unsaturated (partially partially containing, in addition to carbon atoms, at least one, preferably one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom. (Including unsaturated and fully unsaturated) monocyclic 5- to 7-membered heterocyclic rings.

"Saturated monocyclic heterocyclic group J includes pyrrolidyl group (eg, pyrrolidine-12-yl group, etc.), 2-oxo-1-pyrrolidinyl group, tetrahydrofuryl group (eg, tetrahydrofuran-1-yl ¾ Etc.), tetrahydrochel group (eg, tetrahydrothiophene-2-yl group, etc.), imidazolidyl group (eg, imidazolidine-11-yl group, etc.), 2-oxo-imidazolidyl group, virazolizide -Nore group (eg, pyrazolidine-1-yl group, etc.), 1,3-dioxolar group, 1,3-oxathiolael group, oxazolidiel group (eg, oxazolidin-2-yl group, etc.), 2 —Oxooxazolidinyl group, thiazolidinyl group (eg, thiazolidine-1-yl group, etc.), 2-oxo-thiazolidinyl group, piperidyl group (eg, piperidin-2-yl group Etc.), 2-o Sopiperidiel group, pipergel group (eg, piperazine-121-yl group), 2,5-dioxopiperazyl group, hexahydropyridazinyl group, 3-oxotetrahydropyridazyl Group, 2-oxotetrahydropyrimidinyl group, tetrahydrovinyl group (eg, tetrahydropyran-13-yl group, etc.), tetrahydrothiopyral group, dioxanyl group (eg, dioxane-12-yl group, etc.), morpholiel Groups (eg, morpholine-2-yl group), 3-oxomorpholinyl group, thiomorpholinyl group, 3-oxothiomorpholinyl group, 2-oxopyrrolidiel group, 2-oxopiperidinyl Group, 4-oxopiberidyl group, 2,6-dioxo Piberidyl group, 2-oxo-1,3-oxazinael group, 2-oxo-1,3-thiazinanyl group,

 Is fisted.

 Preferably, a tetrahydropyrael group is used.

“The unsaturated monocyclic heterocyclic group J includes a pyrrolyl group (eg, pyrroyl-l-yl group, etc.), a 1,5-dihydro-12-oxopyrrolyl group, a furyl group (eg, furan- 2-yl group, etc., chel group (eg, thiophene-2-yl group, etc.), imidazolyl group (eg, imidazole-1-yl group, etc.), 1,2-dihydro-2- Oxomidazolyl group, 1,3-dihydro-12-oxoimidazolyl group, pyrazolyl group (eg, pyrazole-11-yl group, etc.), oxazolyl group (eg, oxazole-2-yl group, etc.), 2-oxo Oxazolyl group, isoxazolyl group (eg, isoxazolyl 3-yl group, etc.), thiazolyl group (eg, thiazol-2-yl group, etc.), 2-oxothiazolyl group, isothiazolyl group (eg, isothiazolyl group) 1, 2, 3, 4) Triazolyl group, 1,2,3-triazolyl group, terazolyl group, 1,3,4-oxodiazolyl group, 1,2,4-oxadiazolyl group, 3-oxo-1 1,4-oxazinyl group, 1,3, 4-thiadiazolyl group, 1,2,4-thiadiazolyl group, furazanyl group, pyridyl group (eg, pyridine-2-yl group, pyridyl-4-yl etc.), 2-oxopyridyl group, pyrimidinyl group (eg, pyrimidine 1-2) —Yl group, etc.), 2-oxopyrimidinyl group, 3,4-dihydro-14-oxopyrimidinyl group, pyridazinyl group (eg, pyridazine-13-yl group, etc.), 3-oxopyridazinyl group , Virazinyl group, 1,3,5-triadier group, imidazolinyl group, vilazolyl group, oxazolyl group (2-oxazolinyl group, 3- An oxazolinyl group, a 4-oxazolinyl group), an isooxazolinyl group, a thiazolyl group, an isothiazolyl group, a pyruryl group, a 2-oxobilal group, and the like. It is preferably an unsaturated 5- to 7-membered heterocyclic group, and particularly preferably a phenyl group or a pyridyl group.

In R \ R ² and R ⁹ , a pyr group is preferable; and in Ring B, a phenyl group is preferable.

The “heterocyclic oxy group” is a “heterocyclic oxy group having the“ heterocyclic group ”as defined above as a heterocyclic moiety, specifically, a furyloxy group (eg, a furan-2-yloxy group, etc.), Chenyloxy group (eg, thiophene 1-2-yloxy group, etc.), pyrrolyloxy group (eg, pyrrole-11-yloxy group, etc.), oxazolyloxy group (eg, oxazolyl-2-yloxy group, etc.), isoxazolylo Xy group (eg, isooxazole-13-yloxy group, etc.), thiazolyloxy group (eg, thiazole-2-yloxy group, etc.), isothiazolyloxy group (eg, isothiazol-13-yloxy group, etc.), imidazolyloxy Xy group (eg, imidazole-11-yloxy group, etc.), pyrazolyloxy group (eg, pyrazole-1-yloxy ), Pyridyloxy group (eg, pyridine-14-yloxy group, etc.), pyridazinyloxy group (eg, pyridazine-3-yloxy group, etc.), pyrimigeroxy group (eg, pyrimidine-12-yloxy group, etc.), Pidieloxy group, tetrahydrofuryloxy group (eg, tetrahydrofuran-2-yloxy group, etc.), detrahydroche-roxy group (eg, tetrahydrodithiophen-12-yloxy group, etc.), pyrrolidyloxy group (eg, pyrrolidine-12-yloxy group, etc.) ), A birazolidinyloxy group (eg, pyrazolidine ^1-2 -yloxy group, etc.), an imidazolidinyloxy group (eg, imidazolidin-11-yloxy group, etc.), an oxazolidinyloxy group (eg, Oxosazolidine-1-2-yloxy group, etc., thiazolidinyloxy group (eg, Thiazolidin-12-yloxy group, etc., tetrahydrovilla-roxy group (eg, tetrahydropyran-13-yloxy group, etc.), dioxanyloxy group (eg, dioxane-12-yloxy group, etc.), piberidi-roxy Groups (eg, piperidine-12-yloxy group, etc.), piperazuroxy groups (eg, piperazine-12-yloxy group, etc.), morpholinyloxy groups (eg, morpholine-12-yloxy group, etc.) and the like. Can be Like And a pyridyloxy group, more preferably a pyridine-14-yloxy group.

R ¹ and R ² are preferably a pyrinyl-4-yloxy group.

The "hetero ring one d_ ₆ alkyl group", as Γ heterocyclic "moieties:..雜曾has a" heterocyclic group "of his own definition," alkyl "portion and to" Ji alkyl of said荦鋒A heterocyclic alkyl group having a “group”.

The term “fused heterocyclic group” refers to a saturated or unsaturated group containing at least one, preferably 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Means a saturated (including partially unsaturated and fully unsaturated) 6- to 14-membered saturated or unsaturated fused heterocycle, wherein the saturated or unsaturated heterocycle as defined in B above and c _{3 as} defined above even _ ₁₄ condensed ring with a hydrocarbon ring or may be a condensed ring hetero rings to the saturated or unsaturated defined above. Specifically, indolyl, isoindolyl, 2,3-dihydroindolyl, 2,3-dihydroisoindolyl, 1,3-dihydro-2-oxoisoindolyl, 2,3-dihydro-indolyl 1-oxoisoindolyl, 1,3-dihydro-1,3-dioxoisoindolyl, benzimidazolyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, benzotria Zolyl group, benzothiazolyl group, benzisothiazolyl group, 4,5,6,7-tetrahydrobenzoisothiazolyl group, 2-oxobenzothiazolyl group, benzothiophenol group, dibenzothiophenyl group, 4, 5, 6, 7-tetrahydrobenzothiophenol, benzofuranyl, dibenzofuranyl, isobenzofuranyl, 4, 5, 6, 7-tetrahydrobenzofuran-

4,5,6,7-tetrahydroisobenzozofuranyl group, benzoxazolyl group, benzoisoxazolyl group, 2-oxobenzoxazolyl group, 4,5,6,7-tetrahydroiso Benzoxazolyl group, indolizinyl group, quinolyl group, isoquinolyl group, 1,2-dihydro-2-oxoquinolyl group, quinazolyl group, quinoxalinyl group, cinnoluryl group, phthalazyl grave, quinolizyl group, carpazo Ryl, prill, pteridyl, indole, isoindole, 4,

5,6,7-tetrahydroindolyl, 4,5,6,7-tetrahydroisoindolyl, 5,6,7,8-tetrahydroquinolyl, 1,2,3,4-tetra Lahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 2-oxo-1,2,3,4-tetrahydroisoquinolyl Tomb, 1,3-benzodioxolyl, 3,4-methylenedioxypyridyl, 4,5-ethylenedioxypyrimidyl, chromel, chromal, isochromal, 1, 2,4-benzotriazinyl group, 6: 7-dihydropyrindyl group, 6,7 hydrocyclopentavirazinyl group, 6: 7-dihydrocyclopentapyridazyl group, 6,: 7-dihydrocyclyl Pentapyrimidyl group, 2,3,4,5-tetradobenzoazepier group,

And the like.

A ¹ is preferably a 1,3-benzodioxolyl group.

 The term "condensed heterocyclic monoalkyl group" means "condensed heterocyclic ring j having a" condensed heterocyclic group "as defined above, and" alkyl "as a" CB alkyl group "as defined above. Is a fused heterocyclic alkyl group having

The “condensed hetero ring—C _M alkoxy group” has the “condensed hetero ring group” as defined above as the “condensed hetero ring” portion, and the “c alkoxy group” as defined above as the “alkoxy” portion. Having a fused heterocyclic alkoxy group. For example, a 1,3-benzodioxolylmethoxy group and the like can be mentioned.

The "C hydrocarbon ring group", "C ₆ _ ₁₄ Ariru group", "C ₃ - ₇ cycloalkyl group", "fused C ₆ _ ₁₄ hydrocarbon ring group", "heterocyclic group" and "terrorism to condensation The “ring group” (including a group containing them as a part) may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from the following groups. 2003/017067

(a) a halogen atom,

 (b) a cyano group,

 (c) a C H alkyl group,

(d) a halo- ₄ alkyl group,

(e) CH alkoxy group,

 (f) a hydroxyl group,

 (g) an amino group,

 (h) an alkylamino group,

(i) di (C] - ₆₎ Arekinoreamino group,

(j) carboxyl group

as well as

(k) C ₂ - ₇ alkoxy carboxyl group.

 Among the above substituents

(i) a halogen atom,

(ii) Siano Tomb,

 (iii) an alkyl group,

(iv) halo C! — ₄ alkyl groups,

Influence

 (V) CH alkoxy groups are preferred.

 The “halogen atom” as the substituent of the group which may be substituted includes the “halogen atom” as defined above, and is preferably a fluorine atom or a chlorine atom.

 The above alkyl group is a substituent of the group which may be substituted.

4, straight-chain or branched-chain alkyl groups, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group and tert-butyl group. Represents a methyl group, an isopropyl group and a tert-butyl group.

The `` halo CH alkyl group '' which is a substituent of the group which may be substituted is a haloalkyl group in which a linear or branched alkyl group having 1 to 4 carbon atoms is substituted with a `` halogen atom '' as defined above, Specifically, fluoromethyl, difluoromethy / re, Trifluoromethyl group, bromomethyl group, chloromethyl group, 1,2-dichloroethyl group, 2,2-dichloroethyl group, 2,2,2-trifluoromethyl group, pentafluoroethyl, etc. are preferably used. Roechiru a group _ό

 The `` C w alkoxy group '' which is a substituent of the group which may be substituted is a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms, specifically, methoxy group, ethoxy group, propoxy group. Group, isopropoxy group, butoxy group, isoptoxy group, tert-butoxy group, and preferably methoxy group. ,

 The "alkylamino group which is a substituent of the group which may be substituted" is an amino group mono-substituted by a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methylamino group , Ethylamino, propylamino, butylamino, isoptylamino, sec-butylamino /, tert-butylamino, pentylamino, isopentylamino, neopentylamino, tert-pentylamino, 1-ethyl Examples thereof include a propylamino group and a hexylamino group, and an alkylamino group is preferable.

The “di (C w) alkynoleamino group” which is a substituent of the group which may be substituted is an amino group disubstituted with a linear or branched alkyl group having 1 to 6 carbon atoms, Specific examples include a dimethylamino group, a dimethylamino group, a dipropylamino group, a dibutylamino group, a dipentylamino group, a dihexylamino group, and the like, and preferably a di (C- ₄ ) alkylamino group.

Is a substituent group which may be the above-mentioned substituent. The term "C ₂ - - ₇ alkoxy force Lupo Le group" Ri Karuponiru groups der substituted with straight or branched chain alkoxy group having 1 to 6 carbon atoms Specifically, methoxycarbyl group, ethoxycarbol group, propoxycarbol group, isopropoxycarbol group, butoxycarbyl group, isoptoxycarbonyl group, tert-butoxycarboyl group, . Le oxy Kano levo sulfonyl group hexyl O propoxycarbonyl - Le group and the like, preferably a C ₂ _ ₅ alkoxy force Lupo two Le group.

 In the general formula (1), preferred substituents are as follows.

R ¹ and is preferably one is a hydroxyl group, a halogen atom (e.g., bromine atom), one ₆ alkyl group (e.g., methyl group), _e alkoxy group (e.g., main butoxy. Butoxy Group) or — (CH ₂ ) _P —X— (CH ₂ ) _Q —A ¹ (wherein each symbol is as defined above), and the other is a hydrogen atom or a halogen atom (preferably a fluorine atom). And more preferably one is one (CH _A ) _{P to} X— (CH ₂ ) _Q —A ¹ and the other is a hydrogen atom.

In the above — (CH ₂ ) _P —X— (CH ₂ :) _Q— , I> and <1 are each independently preferably 0 or 1.

 X is preferably a single bond or 1 O—.

The A ^1,

(1) O ₆ _ ₁₄ aryl group (eg, phenyl group) which may be substituted,

(2) an optionally substituted heterocyclic group,

 (3) an optionally substituted fused heterocyclic group (eg, 1,3-benzodioxolyl group) or

(4) optionally substituted C ₃ _ ₇ cycloalkyl group (e.g., cyclohexyl group).

Is preferred.

Examples of the substituent of A ^1,

 (i) halogen atom (eg, chlorine atom, fluorine atom),

 (ii) a cyano group,

 (iii) alkyl groups (eg, methyl, ethyl, isopropyl),

 (iv) halo CH alkyl groups (eg, trifluoromethyl),

Or

(V) C _W Anorekokishi group (e.g., methoxy)

And the number of substituents is preferably 1 to 3.

The above (CH ₂ ) _P -X- (CH ₂ ) _Q — A ¹ is preferably

(1) optionally substituted C ₆ - ₁₄ Ariru group (eg, Fueyuru group),

(2) may be substituted 0 ₆ - ₁₄ Ariruokishi group (e.g., phenoxy group),

(3) an optionally substituted C ₆ _ ₁₄ arylalkyl group (eg, benzyl group),

(4) C ₆ _ ₁₄ 7 reel alkoxy group (eg, benzyloxy group) which may be substituted,

(5) _{6 to 14} aryloxy _6- alkyl groups which may be substituted (eg, phenoxime Tyl group),

 (6) an optionally substituted heterocyclic group,

 (7) Heterocyclic oxy group that may be substituted (eg, tomb of zeridyloxy)

 (8) Condensed heterocyclic C alkoxy group which may be substituted (eg, 1,3-benzodioxolylmethoxy group)

Influence

(9) C ₃ _ ₇ cycloalkyl C _M alkoxy group which may be substituted (eg, cyclohexylmethoxy group)

The preferred substituent is

(i) halogen atoms (eg, chlorine atoms, fluorine atoms),

 (ii) a cyano group,

(iii) d_ ₄ alkyl groups (eg, methyl, ethyl, isopropyl),

 (iv) haloalkyl groups (eg, trifluoromethyl), and

(v) C _w alkoxy group. (eg, methoxy)

Is mentioned. Further, the number of substituents is preferably 1 to 3.

Preferred one (CH ₂ ) _p — X— (CH ₂ ) _q — A ¹

(1) may be substituted with at least one halogen atom 0 ₆ - ₁₄ Ariru group (Hue - / Les, 4 one black port Hue - Z les etc.);

(2) It may be substituted with one or two substituents selected from the group consisting of a halogen atom, a _4- alkyl group, a haloalkyl group and an alkoxy group. 6_ ₁₄ aryloxy group (for example, phenoxy, 2-chlorophenoxy, 4-chlorophenoxy, 2-phenylenophenoxy, 4-fluorophenoxy, 2,3-dichlorophenoxy 2,5— Dichlorophenoxy, 3,5-dichlorophenoxy, 3,4-dichloromouth phenoxy, 3,5-difluorophenoxy, 4-fluoro-2-methylphenoxy, 2-methinolephenoxy, 3-methyl ^ "Phenoxy, 4-methylphenoxy, 2-ethyl ^ / lephenoxy, 2,3-dimethylphenoxy, 3,5-dimethylphenoxy, 3-isopropyl- 15-methylphenoxy, 2-methoxyphenoxy, 4-methan Toxiphenoxy, 3-Methoxy 5-Methylphenoxy, 2-Trifluor Oral methylphenoxy, 3,5-bis-trifluoromethylphenoxy, etc.);

(3) It may be substituted. ₆ - ₁₄ Ariru alkyl group (e.g., benzyl, Fuenechi Le etc.>;

(4) a halogen atom, Shiano group, - A key group, halo C _ ₄ alkyl Moto及Pi CH § alkoxy may be substituted with 1 to 3 m substituents ho selected from the group consisting of group C ₆ _

₁₄ aryl CH alkoxy group (eg, benzyloxy, 2-chlorobenzyloxy, 2-fluorobenzyloxy, 4-7luo τ? Benzisoxy, 2,3-dichlorobenzyl / reoxy, 2,4 —Dichlorobenzene / reoxy, 2,5-dichlorobenzene 7-reoxy, 2,6-dichloromouth benzyloxy, 2,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 2 " Loro 4-fluoropentinoleoxy, 2-chloro-6-Fleo benzoyl, 2,4-dichloro-5-funoleo benzyloxy, 2-methylbenzyloxy, 3-methylbenzyloxy , 4-Methylbenzimeleoxy, 2,5-dimethylbenzyloxy, 2-trifluoromethylbenzoxy, 2-cyanobenzyloxy, 2-methoxybenzyloxy, 2,4,5-trifluoro Benji O key, etc.);

(5) optionally substituted C ₆ - ₁₄ Ariruokishi alkyl group (e.g., Fuenokishime ethyl group, etc.);

 (6) an optionally substituted heterocyclic oxy group (eg, pyridine-1-yloxy and the like);

(8) a condensed heterocyclic alkoxy group which may be substituted with at least one halogen atom (eg, 6-chlorobenzo [1,3] dioxol-15-ylmethoxy, etc.);

as well as

(9) C ₃ _ ₇ cycloalkyl alkoxy group which may be substituted (eg, cyclohexylmethoxy group)

Is mentioned.

R ³ and R ⁴ are each preferably a hydrogen atom or an _alkyl group (e.g., methylation) are either, connexion C ₃ _ ₇ cycloalkyl group (e.g. a together with the carbon atoms to which they are attached cyclo propyl group, Forms a cyclobutyl group, a cyclohexyl group) or a heterocyclic group (eg, a tetrahydrovinyl group). More preferably, each is a hydrogen atom. The group formed by R ⁵ together with R ⁶ is preferably

More preferably

(Wherein, R ⁸ , R, R ¹² and R ″ are as defined above).

Group 3及Pi 1 ⁴ forms together with R ⁵ is preferably

(Wherein, R ⁸ and R ⁹ are as defined above).

R ⁶ is preferably a hydrogen atom.

R ⁷ is preferably a hydroxyl group or a hydroxyamino group.

R ⁸ is preferably a hydrogen atom or an alkyl group (eg, a methyl group, a butyl group), and more preferably a hydrogen atom.

R ⁹ is preferably

 (1) hydrogen atom,

 (2). Alkyl groups (eg, methyl, butyl, tert-butyl, pentyl, hexyl, heptyl),

(3) substituted optionally C ₆ - ₁₄ Ariru group (eg, Fueyuru group), (4) optionally substituted ₆ _ ₁₄ aryl C 6 alkyl group (eg benzyl group),

(5) optionally substituted C ₃ - ₇ cycloalkyl (e.g., cyclopropyl, Shikuropu ethyl group, cyclopentyl grave, cyclohexyl group),

(6) an optionally substituted C ₃ _ cycloalkylalkyl group (eg, cyclohexylmethyl group),

 (7) optionally substituted heterocyclic group, (eg, .lysyl group),

(8) optionally substituted fused C ₆ _ ₁₄ hydrocarbon ring group (eg, indole group),

as well as

 (9) An optionally substituted fused heterocyclic group (eg, a quinolyl group) is exemplified.

 As the substituent in the above-mentioned optionally substituted group, preferably

 (i) halogen atoms (eg, chlorine atoms, fluorine atoms),

(ii) C- ₄ alkyl group (eg, methyl group, ethyl group, tert-butyl group),

 (iii) halo CH alkyl group (eg, U-fluoromethyl group),

Influence

(iv) C phenolic alkoxy group (eg, methoxy group),

Is mentioned. Further, the number of substituents is preferably 1 to 3.

More preferred R ⁹ is

(1) C- ₁₀ alkyl group (eg, methyl, butyl, tert-butyl, 3-pentyl, 2

—Ethyl butyl, 4-heptyl, etc.);

(2) a halogen atom, C _i-4 alkyl group, halo CH alkyl optionally substituted with a group and 1 or 2 substituents selected from the group consisting of alkoxy _<6 _ ₁₄ Ariru group (eg, Fueyu / Les , 2-Funore Lofenore, 3-Funole Lofenore, 4-Fenole Lofenore, 3-Black Fennole, 4-Black Feninole, 2,5-Dicloth Fenore, 3, 5-Dichlorophenol, 2-chlorophenol, 3-chlorophenol, 25-difluorophenyl, 2-methylphenyl, 3-methylphenol, 2-ethylphenyl, 4-tert-butylphenol 2,5-Dimethynolephenyl, 3,5-Dimethylphenol, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 5-fluoro-2-methinolephenyl, Naphthalene !: one inole etc.); (3) at least one may be substituted with a halogen atom Ji ₆ - ₁₄ Ariru C ^ - ₆ alkyl Le group (e.g., benzyl, phenethyl, 3-black port base Njiru etc.);

. (4) may be expired substituted C ₃ - ₇ cycloalkyl tomb (e.g., cyclopropyl, Shikuropuchi Le, cyclohexyl and the like cyclopentyl, cyclohexylene);

(5) optionally substituted C ₃ _ ₇ cycloalkyl group (e.g., cyclopropyl base cyclohexyl methyl and the like);

 (6) A heterocyclic group which may be substituted with at least one halogen atom (eg, pyridin-1-yl, 3-cyclopyridine-12: -yl, etc.);

(7) a condensation optionally substituted C ₆ - ₁₄ hydrocarbon Hajime Tamaki (e.g., indane - 1 Iru etc.);及Pi

 (8) Condensed heterocyclic groups which may be substituted (eg, quinolin-12-yl, etc.).

R ^{1 ()} and R ¹¹ preferably forms a connexion Karuboeru groups together with the carbon atom bonded.

R ¹² is preferably optionally substituted 0 ₆ - is a ₆ alkyl group (e.g., benzyl group) - ₁₄ Ariru group (e.g., Hue - Le group), which may be substitution C ₆ - ₁₄ Ariru.

R ¹³ is preferably an alkyl group (eg, a methyl group) or an alkoxy group (eg, a methoxy group).

R ¹⁴ is preferably a hydrogen atom.

R ¹⁵ and R ¹⁶ are each preferably a hydrogen atom.

R ¹⁷ is preferably an alkyl group (eg, methyl, ethyl, etc.).

R ²¹ is preferably a hydrogen atom.

A is preferably C - a ₆ alkylene group (e.g., ethylene group)!.

Ring B is preferably a C ₆ - ₁₄ Ariru group (e.g., Hue - Le group), condensed C ₆ - ₁₄ hydrocarbons瀵基(eg, Furuoreniru group) or a Hajime Tamaki (e.g., thienyl group ). When ring B is a filer group, the substitution position is preferably the 3-position and the 4-position, particularly preferably the 4-position. When ring B is a fluorenyl group, the substitution position is preferably the 7-position. When ring B is a phenyl group, the substitution position is preferably the 5-position.

m is preferably 1 or 2, and more preferably 1. n is preferably 0 or 2, and more preferably 0.

 The “pharmaceutically acceptable salt” may be any salt as long as it forms a nontoxic salt with the compound represented by the above general formula (1), for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid Or inorganic acids such as oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, lingoic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, benzylsulfonic acid, etc. Or inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, etc .; or methylamine, getylamine, triethylamine, triethanolamine, ethylenediamine, tris (Hydroxymethyl) methylamine, guanidine, choline, cinchonine, N-methyl-D-glucamine, etc. Machine base; or lysine, histidine, arginine, can be obtained by Rukoto reacted with amino acids such Aranin. In the present invention, a hydrate or a hydrate and a solvate of each compound are also included.

 In addition, various isomers exist in the compound represented by the above general formula (1). For example, when an E-form and a Z-form exist as geometric isomers, and when an asymmetric carbon atom exists, enantiomers and diastereomers exist as stereoisomers based on these. In some cases, 14 tautomers may exist. Accordingly, the scope of the present invention includes all these isomers and mixtures thereof.

 In the present invention, prodrugs and metabolites of the compound represented by the general formula (1) are also included.

The term “prodrug” refers to a derivative of a drug molecule that is chemically modified and has no physiological activity per se, but has a reconstituted effect on the original drug molecule in the body after administration. The “prodrug” in the present invention has a group that can be chemically or metabolically degraded, and is a pharmaceutically active condensation by hydrolysis or solvolysis, or by decomposition under physiological conditions. It is a derivative of the N-containing heterocyclic compound (1). For example, relative to the hydroxyl group of the compound, -CO- alkyl, - C 0 ₂ - alkyl, - CO NH- alkyl Le, -CO- Arukeniru, -C 0 ₂ - Arukeyuru, - CO NH- Aruke - le, - CO —Aryl, —C 0 ₂ —Aryl, —CONH—Aryl, —CO—Heterocycle—C 0 ₂ —Heterocycle, —CO NH—Heterocycle (the alkyl, alkaryl, aryl, Heterocycle halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a carboxy group, § amino group, amino acid residue, mono P0 ₃ H _2, one SO _s H, One OP0 ₃ H _2, substituted Broken one OS0 ₃ H, etc. May be. .) And one CO- polyethylene glycol Zanhaka one C0 ₂ - poly ethylene glycol residue, mono CO ~~ polyethylene glycol mono Ano gravel / Reete Le residue, mono CO ₂ - polyethylene grayed Le ^-alkyl ether residue, — PO,

H ₂ , saccharides (eg, glucose), or other substituted prodrugs, etc .;

For the amino group of the compound, —CO—alkyl, one co ₂ —alkyl, one CO—alkenyl, —co ₂ —alkenyl, —CO ^ —aryl, —CO—aryl, one CO—heterocycle, — co ₂ - heterocycle (wherein alkyl, alkenyl, Ariru, heterocycle, halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a carboxy group, amino group, amino acid residue, mono P0 ₃ H _2, one S0 ₃ H, one . the OP0 ₃ H _2, may be substituted by one OS0 ₃ H, etc.) and one CO- polyethylene glycol residue, mono co ₂ - Poryechi glycol residue, mono CO- polyethylene glycol monoalkyl ether residue, -C0 ₂ - polyethylene glycol monoalkyl ether residue, mono P0 ₃ H _2, sugars (such as glucose), or other known polymers such as a prodrug those they replaced; or

Against Karupokishi group of compounds, an alkoxy group, Ariruokishi group (said an alkoxy group, Ariruokishi group is a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a carboxy group, an amino group, an amino acid residue, mono P0 ₃ H _2, one S0 ₃ H, one OP0 ₃ H _2, -. OS0 may be substituted with ₃ H and the like) or polyethylene glycol residue, polyethylene Chi glycol monoalkyl ether groups, sugars (such as glucose), or for the other prodrugs Examples include those substituted by known polymers and the like. These prodrugs can be produced by a means known per se used in the art, for example, esterification, acylation, alkoxycarbonylation and the like. When the compound of the present invention is used as a pharmaceutical preparation, it is usually known as a pharmaceutically acceptable carrier, excipient, diluent, bulking agent, disintegrant, stabilizer, preservative, buffer, emulsifier, fragrance, Coloring agents, sweeteners, thickeners, flavoring agents, solubilizers, and other additives, specifically, water, vegetable oils, alcohols such as ethanol or benzyl alcohol, and polyethylene Combine with carbohydrates such as lenglycol, glycerol triacetate, gelatin, lactose, starch, etc., magnesium stearate, talc, lanolin, petrolatum, etc. , Eye drops, liquids, capsules, lozenges, aerosols, elixirs, suspensions, emulsions, syrups, etc., to be administered systemically or locally, orally or parenterally be able to.

 The dose of the compound of the present invention varies depending on the age, body weight, and symptoms: the disease to be treated, the administration method, and the like. However, it is generally within the range of 1 mg to 10 mg of Omg per day per adult. One to several doses are administered.

 The compound (1) of the present invention is an ataricanase inhibitor, ¾!?-13 (5 harmful agent, a preventive or therapeutic agent for osteoarthritis (OA), a preventive or therapeutic agent for rheumatoid arthritis (RA), Aglicanase or MMP for joint damage, reactive arthritis, cancer, asthma, allergic reaction, chronic emphysema, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), lung infection, interstitial pneumonia, bone resorption disease, etc. — Can be administered to mammals (humans, mice, rats, rabbits, dogs, cats, rabbits, pigs, monkeys, etc.) as prophylactic or therapeutic agents for 13-mediated diseases.

 As used herein, the term “prevention” includes, for example, both preventing recurrence of the disease and prevention of the occurrence of the disease.

 The compound (1) of the present invention can be co-administered to a mammal together with another therapeutic agent for osteoarthritis for the purpose of preventing or treating osteoarthritis. The compound (1) of the present invention can be co-administered to a mammal together with another therapeutic agent for rheumatoid arthritis for the purpose of preventing or treating rheumatoid arthritis.

 In the case of co-administration, the compound of the present invention may be administered simultaneously with other drugs for treating osteoarthritis or other drugs for treating rheumatoid arthritis (hereinafter referred to as concomitant drugs), or may be administered at intervals of time. Good. In the case of co-administration, it can be administered as a pharmaceutical composition containing the compound of the present invention and a concomitant drug. Alternatively, the pharmaceutical composition containing the compound of the present invention and the pharmaceutical composition containing the concomitant drug may be separately administered. The route of administration of each pharmaceutical composition may be the same or different.

When administered in combination, the compounds of the invention may range from lmg to 100 mg at a time. The dosage may be administered once to several times a day, or may be administered in a smaller dosage. Concomitant medications may be administered at normal dosages where they can be used for the prevention or treatment of osteoarthritis, or for the prevention or treatment of chronic rheumatoid arthritis, or at lower doses. r is also good.

 In addition, a compound having an inhibitory activity on adalicanase or an inhibitory activity on MMP-13 such as the compound (1) of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof, may be used for osteoarthritis, rheumatoid arthritis, etc. Can be used as a prophylactic or therapeutic agent for diseases mediated by aggrecanase or MMP-13.

 Further, the present invention provides a pharmaceutical composition comprising the compound (1) and a pharmaceutically acceptable carrier, and the g drug composition, which can be used for the prevention or treatment of osteoarthritis or rheumatoid arthritis. Alternatively, there is provided a commercial package containing a description of the pharmaceutical composition stating that it should be used.

 Next, an example of a method for producing the compound (1) of the present invention will be described, but the method of the present invention is not limited thereto.

 In performing the reaction described below, the functional group other than the site may be protected beforehand as necessary, and may be deprotected at an appropriate stage.

 Further, in each step, the reaction may be carried out by a usual method, and the isolation and purification may be carried out by appropriately selecting or combining conventional methods such as crystallization, recrystallization, column chromatography, and preparative HPLC. Just do it.

 In addition, compounds (2) [(22), (22,)], (3), (6) [(29)], (18), (34) and (35) ) Is commercially available or can be easily synthesized by a conventionally known method.

(Production method 1)

(16) (1-aa) (1-a) (Wherein, RR ² , RRR ⁸ , R ⁹ , A, B, m, and n are as defined above, and X is a halogen atom.)

This production process is a process for preparing a compound of the following cases become R ^s and R ⁶ Gar cord (1).

Process 1— 1

 By reacting the compound represented by the general formula (2) with the compound represented by the general formula (3) in a solvent in the presence or absence of a base, the compound represented by the general formula (4) You can get things.

 Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as potassium tert-butoxide; alkali metal amides such as lithium diisopropylamide; sodium carbonate potassium carbonate Alkali metal carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, etc .; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, hydroxylating lime; Alkali metal carboxylate such as sodium acetate, acetic acid rim; phosphoric acid Alkali metal phosphates such as sodium potassium phosphate; organic bases such as triethylamine, pyridine and N-methylmorpholine; and sodium methoxide is preferred.

Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; and dichloromethane. Halogen-based solvents such as chloromethane, carbon form, carbon tetrachloride, and 1,2-dichloroethane; alcohol-based solvents such as methanol, ethanol, ethanol, tert-butanol, etc .; ethyl acetate, acetic acid Estenole solvents such as methyl and butyl acetate; polar solvents such as acetone N, N-dimethylformamide and water; these can be used alone or in combination. A preferred solvent in this reaction is methanol. The reaction temperature is usually in at O ^e C to 6 0, preferably room temperature. The reaction time is generally 1 hour to 48 hours, preferably 2 hours to 24 hours.

Step 1—2

 This is a general reduction reaction. By reacting the compound represented by the general formula (4) in a solvent in the presence of a reducing agent, the compound represented by the formula (5) can be obtained.

As the solvent, for example, Jechirue - Te, tetrahydrofuran (THF), Jiokisan, 1, ² - dimethoxy ethane:, ^ E ether solvents such as glyme; benzene, toluene, hexane, hydrocarbons present containing solvents such as xylene Halogen-based solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; alcohol-based solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; N, N-dimethylformamide; Examples thereof include polar solvents such as dimethyl sulfoxide and water, and these can be used alone or in combination. The preferred solvent in this reaction is water.

 Examples of the reducing agent used in the reaction include sodium borohydride, lithium borohydride, lithium aluminum hydride, and the like. A preferable reducing agent in this reaction is sodium borohydride.

 The reaction temperature is usually from 30 ° C. to 50, preferably from 0 ° C. to room temperature. The reaction time is usually 30 minutes to 24 hours, preferably 3 hours to 12 hours.

Process 1 _ 3

 This is a general sulfonamidation reaction. By reacting the compound represented by the general formula (6) with ammonia water in a solvent, the compound represented by the general formula (7) can be obtained.

Examples of the solvent include ether solvents such as diethyl ether, tetrahydrofura (THF), dioxane, 1,2-dimethyloxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, and chloroform. Halogen solvents such as mouth form, carbon tetrachloride and 1,2-dichloroethane; alcohols such as methanol, ethanol, isopropyl alcohol and tert-butanol Polar solvents such as acetone, N, N-dimethylformamide, dimethylsulfoxide, water and the like, and these can be used alone or in combination. Preferred solvents in this reaction are tetrahi, drofuran.

 The reaction temperature is usually from 130 ° C to 100 ^, preferably from 0 to room temperature. The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 14 hours. Process 1—4

 By reacting the compound represented by the general formula (7) ^ / with methyl 2-hydroxy-12-methoxyacetate, a compound represented by the general formula (8) can be obtained.

 Solvents include, for example, ether solvents such as jeti-earth, tetrahydrofuran (THF), dioxane, 1,2-dimethoxy "^ ene, and diglyzine; benzene, toluene, hexane, xylene and the like. Hydrocarbon-based solvents; halogen-based solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; ester-based solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone, N, Examples thereof include polar solvents such as N-dimethylformamide and the like, which can be used alone or in combination The preferred solvent in this reaction is dichloromethane.

 The reaction temperature is usually 0 to 100 ° C, preferably room temperature.

 The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours. In this reaction, the same target compound (8) can be obtained also by using methyldaryoxalate in place of 2-hydroxy-12-methoxyacetic acid.

Process 1-5

 This is a general halo-forming reaction. In a solvent, a compound represented by the general formula (.8)

By reacting with the halogenated thiol compound represented by the formula (9),

The compound represented by (10) can be obtained.

Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride, and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone, N, N-dimethyl Examples thereof include polar solvents such as formamide and dimethyl sulfoxide, and these can be used alone or in combination. The preferred solvent in this reaction is dichloromethane or no solvent.

 The reaction temperature is usually from 0 ° C to 100 ° C, preferably from room temperature to 40 ° C.

 The reaction time is generally 1 hour to 2.0 hours, preferably 2 hours to 10 hours. Process 1-6

By reacting a compound represented by ^ (10), which is a general coupling reaction, with a compound represented by 1 ^; ( ⁵ ) in a solvent in the presence of a base or a Lewis acid, the compound represented by the general formula (1) The compound represented by 1) can be obtained.

 The base used in the reaction includes, for example, sodium metal hydroxide, metal hydride such as hydrogen hydride; alkali metal alkoxide such as potassium tert-butoxide; alkali metal amide such as lithium diisopropylamide; Alkali metal carbonates such as sodium, carbon dioxide, sodium bicarbonate and hydrogen carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carboxylate such as sodium acetate and acetate lime Alkali metal phosphates such as sodium phosphate and potassium phosphate; and organic bases such as triethylamine, pyridine and N-methylmorpholine. N-methylmorpholine is preferred.

 Examples of the Lewis acid include boron trifluoride, aluminum chloride, titanium tetrachloride and the like.

 Solvents include, for example, edel solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxetane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, chloroform Halogen solvents such as oral form, carbon tetrachloride, and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as acetone and N, N-dimethylformamide; These can be used alone or in combination. A preferred solvent in this reaction is tetrahydrofuran.

 The reaction temperature is usually 0 ° C. to 60 ° C., preferably room temperature.

The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 10 hours. Process 1-7

 This is a general mesylation reaction. The compound represented by the general formula (1.2) can be obtained by reacting the compound represented by the general formula (11) with a mesylation reagent in a solvent in the presence of a base.

 Examples of the base used in the reaction include hydrogen hydride metal such as sodium hydride and hydrogen hydride; potassium te :; r: metal alkoxide such as r-t-poxide; lithium diisopropyl TMI; Alkali metal amides; sodium carbonate Alkali metal carbonates such as potassium carbonate, sodium bicarbonate, sodium bicarbonate; alkali metal carboxylate such as sodium acetate and potassium acetate; sodium phosphate, phosphoric acid such as potassium phosphate Metal salts; organic bases such as triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine and the like, preferably diisopropylethylamine.

 Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; and dichloromethane. Halogen-based solvents such as chloroform, carbon tetrachloride, and 1,2-dichloroethane; ester-based solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as acetone and N, N-dimethylformamide. These can be used alone or in combination. A preferred solvent in this reaction is tetrahydrofuran.

 Examples of the mesylation reagent used in the reaction include methanesulfonyl chloride, methanesulfonic anhydride and the like, and preferred is methanesulfonyl chloride. .

The reaction temperature is usually in at 0 ° C to 6 0, preferably room temperature _ώ

The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 10 hours ₍ Steps 1-8

 This is a general cyclization reaction. The compound represented by the general formula (13) can be obtained by reacting the compound represented by the general formula (12) in a solvent in the presence of a base.

Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and hydrogenation hydride; alkali metal alkoxides such as potassium tert-butoxide. Alkali metal amides such as lithium disopropyl amide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; carboxyl acids such as sodium acetate and acetic acid rim; Alkali metal phosphates such as sodium phosphate and potassium phosphate; tritylamine and diisoprophyl; Organic bases such as leutylamine, lysine, N-methylmorpholine and the like are mentioned, and cesium carbonate is preferred.

 Examples of the solvent include ether solvents such as gelate, tetrahydrofuran (THF), dioxane, 1,2-dimethoxytan and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, Halogen solvents such as chromatoform, carbon tetrachloride, and 1,2-dichloro: loethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide These can be used alone or in combination. A preferred solvent in this reaction is dioxane.

 The reaction temperature is usually 0 ° C. to 60 ° C., preferably room temperature.

 The reaction time is usually 2 hours to 48 hours, preferably 10 hours to 24 hours.

Process 1-9

 This is a general hydrolysis reaction. The compound represented by the general formula (14) can be obtained by reacting the compound represented by the general formula (13) in a solvent in the presence of a base.

 Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and hydrogenation hydride; alkali metal alkoxides such as potassium tert-butoxide; alkali metal amides such as lithium diisopropylamide; sodium carbonate; potassium carbonate; Alkali metal carbonates such as cesium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; and sodium hydroxide is preferable.

Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, Black Halogen solvents such as mouth form, carbon tetrachloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; polar solvents such as water are used. Can be used together. Preferred solvents in this reaction are tedrahi, drofuran (THF), and methanol.

 The reaction temperature is generally 0 to 60, preferably room temperature.

 The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours. Process 1—10

 This is a general alkylation reaction. By reacting the compound represented by the general formula (14) with an alkylating reagent represented by the general formula (15) in a solvent in the presence of a base, a compound represented by the general formula (16) is obtained. be able to.

 Examples of the solvent include ether solvents such as getyl-ter, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone and N, N-dimethylformamide These can be used alone or in combination. A preferred solvent in this reaction is N, N-dimethylformamide. Bases include, for example, sodium hydride, alkali metal alkoxides such as potassium tert-butoxide, alkali metal amides such as lithium diisopropylamide; sodium carbonate, carbonated lithium, etc. And alkali metal carbonates such as cesium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, with potassium carbonate being preferred.

 The reaction temperature is usually 0 ° C. to 60, preferably room temperature.

 The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 10 hours. Process 1-11

This is a general hydrolysis reaction. By reacting the compound represented by Formula (16) in a solvent in the presence of a base, a compound represented by Formula (1-aa) is obtained. Can be

 Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as potassium tert-butoxide; alkali metal amides such as lithium diisopropylamide; sodium carbonate, carbon dioxide lime; Alkali metal carbonates such as cesium carbonate, sodium hydrogen carbonate, hydrogen carbonate and the like; and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and the like, with sodium hydroxide being preferred.

 Solvents include, for example, ether solvents such as getyl ether, tedrahydrofuran (THF), dioxane, 1,2-dimethoxane, and dig] dimethyl; benzene, toluene, hexane, xylene, and the like. Hydrocarbon solvents; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloro; halogen solvents such as mouth ethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol; water, etc. And these can be used alone or in combination. Preferred solvents in this reaction are tetrahydrofuran (THF) and methanol.

 The reaction temperature is usually 0. C to 60 ° C, preferably room temperature.

 The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours.

The compound obtained in this reaction can be used in the next reaction without isolation.

Process 1— 1 2

This is a general amidation reaction. The compound represented by the general formula (1-1a), which is one of the target compounds, is reacted with a hydroxyamine derivative using a condensing agent in a solvent in the presence of a base in a solvent in a solvent. The compounds represented can be obtained. Examples of the base used in the reaction include alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, and sodium hydrogen carbonate; alkali metal carboxylate such as sodium acetate and potassium acetate; sodium phosphate; Metal phosphate metal such as potassium phosphate; organic bases such as triethylamine, diisopropylethylamine, pyridine, and N-methylmorpholine; and N-methylmorpholine is preferable. Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen-based solvents such as chloroform, carbon tetrachloride, 1,2-dichloro, and mouth; esters such as ethyl acetate, methyl acetate, and butyl acetate; certain solvents; acetone, N, N-dimethylformamide; and acetonitrile, etc. Polar solvents and the like can be mentioned, and these can be used alone or in combination. A preferred solvent in this reaction is tetrahydrofuran.

 The condensing agent may be a condensing agent used in an ordinary peptide condensation method (for example, an acid chloride method, a mixed acid anhydride method, etc.), and among them, a combination of ethyl ethyl carbonate and N-methylmorpholine is preferable.

 Examples of the hydroxyamine derivative used for the reaction include O- (trimethylsilyl) hydroxylamine.

 The reaction temperature is usually 0 T to 100 ° C, preferably room temperature to 60.

The reaction time is usually from 1 hour to 24 hours, preferably from 2 hours to 2 hours. (Production method 2)

(Wherein, RR ² , R ⁸ , RA, B, and n are as defined above, and X is a halogen atom.)

In this method, R ³ and R ^S are joined together to obtain the following formula; ! ! This is a production method of the compound (1) when is 0.

R8 R9

Process 2— 1

 The compound represented by the general formula (19) can be obtained by reacting the compound represented by the general formula (18) with an acrylic acid derivative in a solvent in the presence of a base. Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and hydrogenation hydride; alkali metal alkoxides such as potassium tert-butoxide; alkali metal amides such as lithium diisopropylamide; sodium carbonate potassium carbonate; Alkali metal carbonates such as sodium hydrogen and potassium hydrogen carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carboxylate such as sodium acetate and potassium acetate; sodium phosphate and potassium phosphate Organic bases such as alkali metal phosphate; triethylamine, pyridine, N-methylmorpholine and the like are preferred, and preferably triethylamine. Examples of the solvent include ether solvents such as getyl ether, tetrahydro 7 lan (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate Solvent: acetone. Ν, ジ メ チ ル -dimethylformamide; polar solvents such as water, etc., which can be used alone or in combination. Preferred solvents in this reaction are methanol and Ν, Ν-dimethylformamide.

 Examples of the acrylic acid derivative used for the reaction include methyl acrylate.

The reaction temperature is usually from 130 ° C. to 100 ° C., preferably from 0 ° to room temperature. The reaction time is usually 1 hour to 48 hours, preferably 2 hours to 24 hours. . Compound (19) can be used in the next reaction without isolation.

Process 2—2

This is a general tert-butoxycarbonylation (hereinafter referred to as B 0 c) reaction. Formula (1-9) compound standing under solvent _Λ Shiomo represented by one boat by each reacting with di one tert- Puchiruka one Poneito ^: it is possible to obtain a compound represented by (2 0) .

 Examples of the solvent include ether solvents such as getyl-tere, tetrahydrofuran (THF), dioxane, 1,2-dimethyloxetane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride, and 1,2-dichlorotan; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ethyl acetate, methyl acetate, and butyl acetate And other polar solvents such as acetone, N, N-dimethylformamide, dimethylsulfoxide and water. These solvents can be used alone or in combination. A preferred solvent in this reaction is a mixed solvent of dioxane and water.

 Examples of the base used in the reaction include alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and hydroxylated lime. Metal salts of carboxylic acids such as sodium acetate and potassium acetate; alkali metal phosphates such as sodium phosphate and potassium phosphate; and organic bases such as triethylamine, pyridine and N-methylmorpholine. Min.

 The reaction temperature is usually from 130 ° C to 60 ° C, preferably from 0 ° C to room temperature.

 The reaction time is generally 5 minutes to 60 hours, preferably 10 hours to 50 hours.

Process 2—3

This is a general cyclization reaction. The compound represented by the general formula (21) can be obtained by reacting the compound represented by the general formula (20) in a solvent in the presence of a base. In this reaction, the following positional isomers are obtained.

 Examples of the solvent used in the reaction include: diethyl ether, tetrahydrofuran

Ether solvents such as (THF), dioxane, 1,2-metho-shetan and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, chloroform, tetrachloride; ,: Halogen solvents such as 2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; polar solvents such as N, N-dimethylformamide, dimethylsulfoxide and the like. Or they can be used in combination. Preferred solvents in this reaction are tetrahydrofuran and methanol.

 Examples of the base include alkali metal hydrides such as sodium hydride and lithium hydride; alkali metal alkoxides such as potassium tert-butoxide; alkali metal amides such as lithium diisopropylamide; sodium carbonate; Alkali metal carbonates such as sodium bicarbonate and hydrogen bicarbonate; Alkali metal carboxylate such as sodium acetate and acetate lithium; Alkali metal phosphates such as sodium phosphate and potassium phosphate; Triethylamine; Organic bases such as pyridine and m-methylmorpholine are exemplified, and sodium methoxide is preferred.

 The reaction temperature is usually from 130 ° C. to 100 ° C., preferably from 0 ° C. to 60 ° C. The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours, step 2-4

 This is a general cyclization reaction. By reacting the compound represented by the general formula (21) with a hydrazine compound represented by the general formula (22) in a solvent, a compound represented by the general formula (23) can be obtained.

Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride, and 1,2-dichloroethane; methanol Examples of such solvents include phenolic solvents such as phenol, ethanol, isopropyl alcohol, tert-butanol, and the like; polar solvents such as N, N-dimethylformamide, and the like, and these can be used alone or in combination. A preferred solvent in this reaction is methanol.

 The reaction temperature is usually from 80 ° C. to 150, preferably from 100 ^ to 120.

 The reaction time is generally from 10 hours to 48 hours, preferably from 12 hours to 24 hours.

 The compound .. (22) obtained in this reaction can be used in the next reaction without isolation.

Process 2-5

 This is a general esterification reaction. The compound represented by the general formula (24) can be obtained by reacting the compound represented by the general formula (23) with a carboxylic acid activator or an acid erosion medium in a solvent.

 Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; esters such as ethyl acetate, methyl acetate, and butyl acetate And the like. These can be used alone or in combination. A preferred solvent in this reaction is methanol.

 Examples of the carboxylic acid activator include thiol chloride.

 Examples of the acid catalyst include sulfuric acid and p-toluenesulfonic acid.

 The reaction temperature is usually from 80 ° C to 150 ° C, preferably from 100 ° C to 120 ° C.

 The reaction time is generally from 10 hours to 48 hours, preferably from 12 hours to 24 hours.

The compound (24) obtained in this reaction can be used in the next reaction without isolation. Can be.

Process 2-6

 This is a general Boc conversion reaction. The compound represented by the general formula (25) is reacted with a compound represented by the general formula (24) in the presence of a base in a solvent using di-tert-butyl / regiophilic nucleophilic compound. You can be Chiang.

 Examples of bases used in the reaction include: ^, alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as potassium hydride and the like; sodium carbonate, sodium carbonate, sodium hydrogen carbonate, hydrogen carbonate and the like. Alkali metal carbonates such as sodium chloride; sodium carboxylate metals such as sodium acetate and potassium acetate; aluminum phosphate metals such as sodium phosphate and potassium phosphate; triethylamine, pyridine, N-methylmorpholine And the like. Preferred is triethylamine.

 Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen-based solvents such as chloroform, carbon tetrachloride, and 1,2-dichloroethane; alcohol-based solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester-based solvents such as ethyl acetate, methyl acetate, and butyl acetate Bright solvents; acetone N, N-dimethylformamide; dimethylsulfoxide; polar solvents such as water, etc., which can be used alone or in combination. A preferred solvent in this reaction is a mixed solvent of dioxane and water.

 The reaction temperature is usually from 130 ° C to 60 ° C, preferably from 0 ° C to room temperature.

 The reaction time is generally 1 hour to 36 hours, preferably 2 hours to 24 hours <Step 2-7

 The compound represented by the general formula (27) is obtained by reacting the compound represented by the general formula (25) with a compound represented by the general formula (26) in a solvent in the presence of a base. Can be

Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; Hydrocarbon solvents such as toluene, toluene, hexane, and xylene; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; polyester solvents such as ethyl acetate, dimethyl, and butyl acetate. Polar solvents such as acetone, N.N-dimethylformamide, water and the like, and these can be used alone or in combination. The preferred solvent in this reaction is N, N-dimethylformamide. As the base, for example, hydrogen: alkali metal hydrides such as tri, kum, potassium hydroxide and the like; alkali metal alkoxides such as potassium tert-butoxyne; alkali metals such as lithium methylene isopropylamide; Amides; alkali metal carbonates such as sodium carbonate, carbonic acid carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. Preferably, it is potassium carbonate.

 The reaction temperature is usually 0 ° C. to 60 ° C., preferably room temperature.

 The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 10 hours. Process 2-8

 This is a general de-Boc reaction. The compound represented by the general formula (28) can be obtained by reacting the compound represented by the general formula (27) in a solvent in the presence of an acid.

 Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxetane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, chloroform Halogen-based solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; ester-based solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as acetone and N, N-dimethylformamide These can be used alone or in combination. A preferred solvent in this reaction is dioxane.

 Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; and organic acids such as trifluoroacetic acid, trichloroacetic acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid, and hydrochloric acid is preferable.

 The reaction temperature is usually from 130 ° C. to 60 ° C., preferably from O 2 to room humidity.

The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours. In addition, the obtained compound (28) can be used in the next reaction without isolation. Process 2—9

 It is a general null-holing reaction. The compound represented by the general formula (30) is obtained by reacting the compound represented by the general formula (2S) with the chemical corrosion represented by the general formula (29) in a solvent in the presence of a base to obtain the compound represented by the general formula (30) Can be.

 Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; sodium metal hydride, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium borohydride and the like; Sodium, acetic acid, carboxylic acid such as lime; metal phosphate, such as sodium phosphate and potassium phosphate; organic bases, such as triethylamine, diisopropylethylamine, pyridine and N-methylmorpholine O, preferably with triethylamine

 Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethyloxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone and N, N-dimethylformamide These can be used alone or in combination. A preferred solvent in this reaction is N, N-dimethylformamide. Reaction temperature is usually -30. C to 60 ^, preferably O to room temperature.

 The reaction time is usually 2 hours to 24 hours, preferably 4 hours to 12 hours. Process 2-10

 This is a general hydrolysis reaction. By reacting the compound represented by the general formula (30) in a solvent in the presence of a base, the compound represented by the general formula (31) can be obtained.

 Examples of the base used for the reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, and preferably lithium hydroxide.

Examples of the solvent include getyl ether, tetrahydrofuran (THF), Ether solvents such as dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, chloroform, 4: Hazardous charcoal, 1,2 zita P Halogen solvents such as octane, etc .; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol, etc .; polar solvents such as acetone, etc .: These may be used alone or in combination. Can be. Preferred solvents in this reaction are methanol and tetrahydrofuran.

 The reaction temperature is usually 0 ° C. to 60 ° C., preferably room temperature.

 The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours. The compound obtained in this reaction (3.3.1) can be used in the next reaction without separation.

Process 2— 1 1

 —This is a general amidation reaction. By reacting the compound represented by the general formula (31) with a compound represented by the general formula (32) in a solvent in the presence of a base using a condensing agent, the compound represented by the general formula (33) ) Can be obtained.

 Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; Alkali metal hydroxides such as lithium, sodium hydroxide, and hydroxylated aluminum; alkali metal carboxylate such as sodium acetate and potassium acetate; aluminum phosphate metal such as sodium phosphate and potassium phosphate Organic bases such as triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine and the like, and preferably N-methylmorpholine.

Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethyloxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, and chloroform. Halogen solvents such as form, carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide These can be used alone or in combination You. A preferred solvent in this reaction is N, N-dimethylformamide. The condensing agent may be any condensing agent used in a usual peptide condensation method (for example, an acid chloride method, a mixed acid anhydride method, etc.), and among them, 1-hydroxybenzotriazole-hydrate and 1- ( Combination with 3- (dimethylamino) propyl) -1-ethylcarbodiimide hydrochloride is preferred.

 The reaction temperature is usually from 130 ° C. to 60 ° C., preferably 0. (: To room temperature.

 The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours, step 2-1 2

 This is a general deprotection reaction. By reacting the compound represented by the general formula (3.3) in a solvent in the presence of an acid, a compound represented by the general formula (1-b), which is one of the target compounds, can be obtained. it can.

 Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; and dichloromethane. Halogen-based solvents such as methane, chloroform, carbon tetrachloride and 1,2-dichloroethane; alcohol-based solvents such as methanol, ethanol, isopropylaryl, tert-butanol; ethyl acetate, methyl acetate, butyl acetate, etc. And polar solvents such as acetone N, N-dimethylformamide and water, which can be used alone or in combination. A preferred solvent in this reaction is methanol.

 Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; and organic acids such as trifluoroacetic acid, trichloroacetic acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid. Hydrochloric acid.

 The reaction temperature is usually from 130 ° C to 6.0 ° C, preferably 0 ° C. C to room temperature.

The reaction time is usually 1 hour to 2 ^4. H, Konomashigu is 2 hours to 12 hours, Manufacturing Method 3]

(Wherein, RR ² , R ³ , RR ¹² , R ¹⁷ , A, B, m, n and X are as defined above.)

This production method is the production method of compound (1) in the case where R and R ⁶ are taken together to form the following formula.

Process 3-1

 A compound represented by the general formula (36) is subjected to a reductive amination reaction with a compound represented by the general formula (35) in a solvent; Can be obtained.

 Examples of the solvent used in the reaction include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogen-based solvents such as dichloromethane, methane, chloroform, carbon tetrachloride, and 1,2-dichloroethane.

 Examples of the reducing agent used in the reaction include sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, aluminum hydride, and the like.A preferred reducing agent in this reaction is hydrogenation It is sodium triacetoxyborohydride.

 The reaction temperature is usually from 30 ° C to 50, preferably from 0 ° to room temperature. The reaction time is generally 30 minutes to 24 hours, preferably 3 hours to 12 hours.

When a compound in which R ³ and R ⁴ are hydrogen atoms in the compound represented by the general formula (1) is desired, an acrylic acid derivative may be used in the same manner as in Step 2_1. Process 3-2

 The compound represented by the general formula (37) can be obtained from the compound represented by the general formula (36) in the same manner as in Step 2-2 of Production Method 2.

Process 3—3

This is a general cyclization reaction. The compound represented by the general formula (38) can be obtained by reacting the compound represented by the general formula (37) in a solvent in the presence of a base. When one of R ^{3 and} R ⁴ is a hydrogen atom, The isomer is obtained.

 Solvents used in the reaction include, for example, dityl ether, tetrahydrofuran

(THF), dioxane, 1,2-dimethoxy; ether solvents such as π-tan and diglyme; hydrogen peroxide solvents such as benzene, toluene, hexane, and xylene; dichloromethane, methane, chloroform, carbon tetrachloride, 1, a halogen-based solvent such as 2-dichloroethane; an alcohol-based solvent such as methanol, ethanol, isopropyl alcohol, and tert-butanol; and a polar solvent such as N, N-dimethylformamide, dimethylsulfoxide, and water. These can be used alone or in combination. A preferred solvent in this reaction is tetrahydrofuran.

 Examples of the base include alkali metal hydrides such as sodium hydride and hydrogenation hydride; alkali metal alkoxides such as potassium tert-butoxide and lithium hexamethyldisilazide; alkali metal amides such as lithium diisopropylamide And the like, and preferred is lithium hexamethyldisilazide.

 The reaction temperature is usually from 100 ° C. to 60 ° C., preferably from 180 ° C. to room temperature. The reaction time is generally 2 hours to 24 hours, preferably 2 hours to 12 hours. Process 3—4

 The compound represented by the general formula (40) is obtained by reacting the compound represented by the general formula (38) with the compound represented by the general formula (39) in a solvent in the presence of a base. Can be

Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as chloroform, carbon tetrachloride, and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone, N, N-dimethyl Examples thereof include polar solvents such as formamide and water, which can be used alone or in combination. A preferred solvent in this reaction is tetrahydrofuran.

The Shiohaka, for example, hydrogenation Nadoriu arm, hydrogenated force _Liu;. Alkali excess genus such as lithium diisopropylamide; al force Li metal Al Kishido such as potassium tert- butoxide; hydrogenated Al force Li metal arm parable ^ Mid; alkali metal carbonates such as sodium carbonate, sodium carbonate, sodium bicarbonate and potassium bicarbonate; carboxylic acids such as sodium acetate and sodium acetate: lithium metal; sodium phosphate, potassium phosphate And organic bases such as triethylamine, pyridine and N-methylmorpholine, and preferably sodium hydride.

 The reaction temperature is usually from −30 to 60 ° C., preferably from 110 ° C. to room temperature. The reaction time is usually from 1 hour to 2 hours, preferably from 2 hours to 15 hours. Process 3-5

 By reacting the compound represented by the general formula (40) with the compound represented by the general formula (22 ′) in a solvent, the compound represented by the general formula (41) can be obtained. You.

 Examples of the solvent include ether solvents such as getyl ether, tetrahydrophenyl (THF), dioxane, 1,2-dimethoxyethane, and diglyme; and hydrocarbon solvents such as benzene, toluene, hexane, and xylene. Halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc .; Alcohol solvents such as methanol, ethanol, isopropyl alcohol, tei: t-butanol; N, N-dimethylformamide, etc. And these can be used alone or in combination. A preferred solvent in this reaction is ethanol.

 The reaction temperature is usually from 130 to 60 ° C, preferably from 0 ° C to room temperature.

 The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours. Process 3-6

This is a general cyclization reaction. By reacting the compound represented by the general formula (41) in a solvent in the presence of a base, the compound represented by the general formula (42) can be obtained. Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane, Halogen-based solvents such as chloroform, carbon tetrachloride, and 1,2-dichloro-13ethane; alcohol-based solvents such as methanol, ethanol, isopropyl alcohol tert-butanol, and 2-methoxyethanol:] S (A polar solvent such as dimethylformamide and the like can be used, and these can be used alone or in combination. A preferred solvent in this reaction is 2-methoxyethanol).

 Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as potassium tert-butoxide; alkali metal amides such as lithium dimethylisopropylamide; sodium carbonate; Alkali metal carbonates such as lime, sodium bicarbonate, hydrogen carbonate, etc .; Alkali metal carboxylate, such as sodium acetate, acetate lime; Alkaline metal phosphate, such as sodium phosphate, potassium phosphate Organic bases such as triethylamine, pyridine, N-methylmorpholine and the like, preferably sodium hydride.

 The reaction temperature is usually from 130 ° C to 200 ° C. C, preferably between −10 ° C. and 150 ° C.

 The reaction time is generally 2 hr to 48 hr, preferably 6 hr to 24 hr <Step 3-7

 This is a general esterification reaction. The compound represented by the general formula (43) can also be obtained by reacting the compound represented by the general formula (42) in a solvent in the presence of an acid.

Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetraoxide, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol, and 2-methoxyethanol; N, N-dimethylformamide And the like, and these can be used alone or in combination. Preferred in this reaction A new solvent is methanol.

 Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; and organic acids such as tributanol, acetic acid, trichloroacetic acid, acetic acid, medansulfonic acid, ϊ> -toluenesulfonic acid, and thiol chloride. Preferred: The sign is thiol chloride.

 At the time of the reaction, Boc.

 The reaction temperature is usually from −20 ° C. to 60, preferably from 0 ° C. to room temperature. The reaction time is usually from 6 hours to 48 hours, preferably from 12 hours to 24 hours.

Process 3-8

 By reacting the compound represented by the general formula (43) with the compound represented by the general formula (29) in the same manner as in step 2-9 of Production method 2, the compound represented by the general formula (44) The compound represented can be obtained.

 Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; sodium acetate, acetic acid Alkali metal carboxylate such as lime; alkali metal phosphate such as sodium phosphate and potassium phosphate; organic base such as triethylamine, diisopropylethylamine, pyridine N-methylmorpholine, and preferably pyridine. is there. Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride, and 1,2-dichloroethane; polar solvents such as N, N-dimethylformamide; and pyridine, which can be used alone or in combination. A preferred solvent in this reaction is pyridine. The reaction temperature is usually from 130 ° C to 60 ° C. C, preferably from 0 ° C to room temperature. The reaction time is generally from 6 hours to 72 hours, preferably from 12 hours to 48 hours.

Process 3-9

This is a general hydrolysis reaction. A compound represented by the general formula (44) in a solvent, By reacting in the presence of a group, a compound represented by the general formula (1-1c) can be obtained.

 The base used for the reaction includes, for example, alkali hydroxides such as lithium hydroxide, sodium hydroxide, and hydroxide hydroxide, and is preferably sodium hydroxide.

 Examples of the solvent include ether solvents such as dimethyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxy ^: ^ tan, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, Halogen solvents such as chloroform, carbon tetrachloride and 1,2-dichloromethane; phenolic solvents such as methanol, ethanol, isopropyl and tert-butanol; and polar solvents such as acetone. These can be used alone or in combination. Preferred solvents in this reaction are methanol and tetrahydrofuran.

 The reaction temperature is usually from 0 ^ to 60, preferably room temperature.

 The reaction time is usually 1 hour to 24 hours, preferably 2 hours to 12 hours. The compound (1-c) obtained by this reaction can be subjected to a general optical resolution method to give an optically active compound as one of the target compounds.

 Examples of the optically active amine used in the reaction include phenethylamine, kyun, cudine, cinchonine, cinchon-gin or an optically active amino acid derived from an amino acid. Preferred optically active amines are Kyun, Keyzin, Cinchonine and Cinchonidine.

Step 3-1 0

 By reacting the compound represented by the general formula (1-1c) with a hydroxyamine derivative in a solvent in the presence of a base using a condensing agent in the same manner as in step 1-12 of Production method 1. A compound represented by the general formula (1-d), which is one of the target compounds, can be obtained.

Examples of the base used in the reaction include alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, and hydrogen carbonate; alkali metal carboxylate such as sodium acetate and potassium acetate; sodium phosphate; Rin Alkali metal phosphates such as potassium acid; organic bases such as triethylamine, diisopropylethylamine, pyridine and N-methylmorpholine; and N-methylmorpholine is preferable.

 Examples of the solvent include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and diglyme; benzene, toluene, hexane, and xenium; Halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; ester solvents; acetone, N, N-dimethylformamide Acetonitrile, etc., which can be used alone or in combination. A preferred solvent in this reaction is N, N-dimethylformamide or tetrahydrofuran.

 The condensing agent may be a condensing agent used in a usual peptide condensation method (for example, an acid chloride method, a mixed acid anhydride method, etc.), and among them, ethyl ethyl carbonate and N-methylmorpholine or oxalyl chloride and N- Combinations with methylmorpholine are preferred. Examples of the hydroxyamine derivative used for the reaction include O- (trimethylsilyl) hydroxylamine.

 The reaction temperature is usually 0. C to 100, preferably room temperature to 60.

 The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours. The production method described in the present specification is an example of the production method of the compound of the present invention, and a compound other than the above-described compound is produced by combining conventional methods known in the field of synthetic organic chemistry. be able to.

 Example

 Next, the compound represented by the general formula (1) according to the present invention and the method for producing the same will be described specifically with reference to Examples, but the present invention is not limited to these Examples. .

Example 1

 (Example 11)

5- [4- (3,5-Dic-mouth-phenoxy) -benzenesulfoninole] -2- (4-fluoro-phenyl) -3-oxo-2,3,4,5,6, 7-Hexahydro-1H-birazolo [4,3-c] pyridine-4-cal Ponic acid hydroxyamide

a) Methyl [1- (4-fluorofur: i-l) -5-oxo-2,5-dihydro-1H-pyrazo, ru-3-yl] acetate (Step 11)

 Under a nitrogen atmosphere, 4-fluorobenzenehydrazine monohydrochloride (3.0 g) was added to an ice-cooled solution of sodium methoxide (3.6 g of 28% methanol solution, 18 mmo 1) in methanol (3 OmL, 10 v / w). , 18 mmo 1) and dimethyl 1,3-acetonedicarbonate were added sequentially. After stirring at room temperature for 20 hours, the solvent was removed. Water (30 mL, 10 v / w) and methanol (3 mL, 1 v / w) were added, and the mixture was stirred at room temperature for 30 minutes. The resulting crystals were filtered, washed with water (30 mL, 10 v / w), and depressurized. Drying afforded the title compound as a white solid (3.9 g, 85% yield).

b) 2- (4-Fluoro mouth) -5- (2-hydroxyethyl) -1,2-dihydro-3H-pyranol-3-one (Step 1-2)

A suspension of ice-cooled sodium borohydride U. 5 g, 4 Ommo 1) in water (3 OmL, 10 v / w) was treated with the methyl [1- (4-) obtained in a) of Example 1-1. Fluorophenol> -5-oxo-2,5-dihydro-1H-birazol-3-yl] acetate (3.9 g, 16 mmo 1) and carry the mixture under ice-cooling for 30 minutes. Sodium borohydride (1.5 g, 4 Ommo 1) was added and stroked at 3:00. After cooling the reaction solution on ice, 6N hydrochloric acid (55 mL, 33 Ommo J) 'was added. (PH = l).

 After extracting twice with black-mouthed form (40 mL, 10 vZw), it was dried over magnesium sulfate (2 g). After filtration and removal of the solvent, diisopropyl ether (40 mL, 10 v / w) was added, and the mixture was stirred at room temperature for 10 minutes. F The crystals were filtered, washed with diisopropyl ether (40 mL, 10 v / w), and reduced. The residue was dried under reduced pressure to give the title compound as a white solid (2.7 g, yield 78%).

c) 4- (3,5-dichlorophenoxy) benzenesulfonamide (Step 1-3)

 To a solution of ice-cooled 4- (3,5-dichroic phen / xy) benzenesulfonic acid chloride (5.0 g, 15 mmo 1) in tetrahydrofuran (1 OmL, 2 v “w) was added aqueous ammonia (28% The solution was added with OmL, 74 mmo 1), stirred under ice-cooling for 0 minutes, and stirred at room temperature for 1 hour.After removing the solvent from the reaction solution, the resulting crystals were filtered and n-hexane (25 mL) was added. , 5 v / w) and water (25 mL, 5 v / w), and then dried under reduced pressure to give the title compound (4.5 g, yield 95%) as a white solid.

d) Methyl ({[4- (3,5-dichlorophenoxy) phenyl] sulfol} amino) (hydroxy) acetate (Step 1-4)

Dichloromethane of 4- (3,5-dichlorophenoxy) benzenesulfonamide (0.95 g, 3. Ommo 1) obtained in c) of Example 1-1 under an argon atmosphere (7 mL, 7 vZw) was added to a solution of methyl 2-hydroxy-2-methoxyacetate (0.40 g, 3.3 mmol) in dichloromethane (3 mL, 3 vZw), and the mixture was stirred under reflux for 12 hours and methanol was added. Was distilled off. The crude product of the title compound (1.3 g of a white solid) obtained by removing the solvent was used as it was in the next step.

e) Methyl chloride ({[4 (3,5 ditalonuenoxy) phenyl] sulfol} amino) acetate (Step 1-5)

 Example 11 Methyl ({[4-(. 5-Dicguchi-T3phenoxy) phenyl] sulfonyl} amino) (hydroxy) acetate (0.97 g, 2. To 3mmo 1), add thionyl chloride (3mL, 3v / V) solution and add 40-45. The mixture was stirred at C for 2 hours. After removing the solvent, toluene (10 mL, 10 v / w) was added, the solvent was removed, and the residue was dried under reduced pressure. The crude product of the title compound (0.98 g of a white solid) obtained was directly used in the next reaction.

 f) Methyl ({[4- (3,5-dichlorophenoxy) phenyl] sulfonyl} amino) [2- (4-fluorophenyl) -5- (2-hydroxyethyl) -3 -Oxo-2,3-dihydro-1H-pyrazol-4-yl] acetate (Steps 1-6)

In an argon atmosphere, methyl chloride ({[4- (3,5-dichlorophenoxy) phenol]] sulfonyl} amino) acetate obtained in Example 11 _e )) (0.41 g, 0.9 mmo 1) in tetrahydrofuran (2 mL, 5 v Zw) solution was added to 2- (4-fluorophenyl) -5- (2-hydroxyxethyl) -1,2- obtained in Example 1-1 b). 2-jihi A solution of dro-3H-pyrazol-3-one (0.21 g, 0.96 mmo 1) in tetrahydrofuran (4 mL, 10 v / w) and N-methylmorpholine (0.20 g, 1.9 mmo 1) were also added. After 12:00 at nitriding temperature, IN-hydrochloric acid (2 mL) was added (pH = 1). After stirring at room temperature for 10 minutes, add water (5 mL), extract twice with ethyl acetate (10 mL), and wash the organic layer with water (5 mL) and brine (5 mL) sequentially.

 Methyl ({[4- (3,5-dichlorophenoxy) phenyl] sulfol} amino) obtained in f) of Example 1-1 under an argon atmosphere [2- (4-fluorophenyl) -5 -(2-Hydroxitytyl) -3-oxo-2,3-dihydro-1H-pyrazole-4-yl] acetate (0.31 g, 0.51 mmo 1) in tetrahydrofuran (3 mL, 10 v / w) ) To the solution were added diisopropylethylethylamine (0.17 g, 1.3 mmo 1) and methanesulfonyl chloride (0.14 g, 1.2 mmo 1) sequentially under ice-cooling, For 2 hours. 1N-hydrochloric acid (0.22 mL) and water (5 mL) were added, and the mixture was extracted twice with ethyl acetate (10 mL). The organic layer was washed successively with water (5 mL) and saturated saline (5 mL), and then sodium sulfate. (2 g). After filtration and removal of the solvent, a crude product of the title compound (0.42 g of a yellow oil) obtained by drying under reduced pressure was used in the next reaction as it was.

h) 5- [4- (3,5-Dicyclophenoxy) phenyl] sulfonyl-2- (4-fluorophen -3)-[(Methylsulfuryl) oxy] -4,5,6,7-tetrahydro-2H-pyrazomethyl [4,3-c] pyridine-4-methyl carboxylate (Steps 1-8)

Methyl ({[4- (3,5-dichlorobuenoxy) phenyl] sulfol} amino> obtained in Example 11 under g atmosphere in an argon atmosphere [2- (4-fluorophenol)] -5- {2-[(Methylsulfol-oxy) oxy] ethyl} -3-oxo-2,3-dihydro-1H-pyrazole-4-yl] acetate (0.42 g, 0.51 mmo 1) Then, cesium carbonate (0.37 g, 1. lmmo 1) and dioxane (3.5 mL, 8 v /) were sequentially added, and the mixture was stirred at room temperature for 12 hours. 1N-hydrochloric acid (1.7 mL), water ( 5 mL), extracted twice with ethyl acetate (10 mL), and the organic layer was washed with water (5 mL) and saturated saline (5 mL) sequentially, and dried over sodium sulfate (2 _g ). After removing the solvent, the residue was dried under reduced pressure to give the title compound (0.31 g, yield 89%) as a yellow solid.

 i) 5- [4- (3,5-Dicyclobutenoxy) phenyl] sulfol-2- (4-fluorophenyl) -3-oxo-2,3,4,5,6,7- Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-force rubonic acid (Steps 1-9)

Under an argon atmosphere, the 5- [4- (3,5-dichlorophenoxy) phenyl] sulfol-2- (4-fluorophenyl) -3-([methylsulfo) obtained in Example 1-1, h)) was obtained. L> oxy] -4,5,6,7-tetrahydro-2H-pyrazo mouth [4,3-c] pyridine-4-methyl methyl sulfonate (0.31 g, 0.46 mmol) in tetrahydrofuran (1.5 mL, 5 v / w) solution, methanol (1.5 mL, 5 v / w), 4N-aqueous sodium hydroxide solution (0. 57 mL, 2.3 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the removal of the solvent, 2N-hydrochloric acid (1.2 mL) was added, and the mixture was extracted twice with porcine (10 mL), and the organic layer was washed with water (5 mL). After removing the solvent, toluene (3 mL, 10 v / w) was added to further remove the solvent, and dried under reduced pressure to obtain a yellow solid title compound (0.24 g, yield 92%).

 j) 5- [4- (3,5-Dichloromouth-phenoxy) -benzenesulfonyl] -2- (4-fluoro-phenyl) -3-oxo- 2,3,4,5,6, 7-Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide (Steps 11-10)

5- [4- (3,5-Dichlorophenoxy) pheninole] sulfinole-2- (4-fluorophenole) obtained in Example 11-i) in an argon atmosphere —Oxo—2,3,4,5,6,7—Hexahydro-1H-pyrazo-mouth [4,3-c] pyridine-4-carboxylic acid tetrahydrofuran (0.2 g, 0.39 mmo 1) (2.5 mL, 11 v "w) solution, under ice-cooling, N-Methylemonorephorin (0.16 g, 1.6 mmol), and ethyl formate 7 (0.13 g, 1.2 mmo) 1) was added successively, and the mixture was stirred for 30 minutes. Then, 0- (trimethylsilyl) hydroxylamine (0.25 g, 2.3 mmo 1) was added, and the mixture was stirred for 10 minutes. (0.2 mL, 1 v / w) and stirred at room temperature for 30 minutes.After removing the solvent, water (ImL) was added, extracted twice with ethyl acetate (1 OmL), and the organic layer was extracted with water (5 mL). After removing the solvent, the resulting crude product was subjected to thin-layer silica gel chromatography. Purification by chromatography (chloropho / rem: methanol: 10: 1), and after removing the solvent, ethyl acetate (0.2 mL), diisopropyl ether (ImL), and n-hexane (2 mL) were gradually added to the brown oil obtained. Add and stir at room temperature for 20 minutes The precipitated crystals were filtered, washed successively with n-hexane and diisopropylamine, and dried under reduced pressure to obtain the title compound as a pale brown solid (72 mg, yield 31%).

Melting point 138-140. C (decomposition)

 (Examples 1-2 to 1-168).

 In the same manner as in Example 1-1, the compounds of Example J 1: —2 to Cold Example 1-168 were obtained.

The structural formulas and NMR data of the compounds of Examples 11 to 1 to 168 are shown in Tables 1 to 34. ■■ ':,: ...

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Example 2

 (Example 2-1)

(R) -5- (4-Benzyloxy-benzenesulfol) -2-tert-butyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazine [4, 3-c] pyridine-6-carboxylic acid hydroxyamide

a) (R) -2- [tert-Butoxycarbonyl- (2-methoxycarbyl-ethyl) -ano] -succinic acid 4-methyl ester (Step 2-1)

HO

eO

Under an argon atmosphere, methyl-D-aspartate methyl stellate (71 g, 0.39mo 1) in methanol: Ν, Ν-dimethylformamide = 1: 1 (70 OmL, 10 v / w) was mixed with triethylamine. (16 OmL, 1.2 mό1) and methyl acrylate (100 mL, 1.2 moI) were sequentially dropped at 0. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. Dityl ether (40 OmL) was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The resulting crystals were filtered, washed with getyl ether (10 OmL), and dried under reduced pressure to give (R) -2. -(2-Methoxycarbol-ethylamino:)-succinic acid 4-methyl ester was obtained as a crude product (91 g) containing triethylamine.hydrochloride.

 The crude product (91 g) was suspended in a solution of 1,4-dioxane: water = 1: 1 (90 OmL, 10 v Zw), and triethylamine (61 mL, 0.26 mol), di- Tert-butyl di-iron ponate (58 g, 0.26 mo 1) was added sequentially at 0. After stirring at room temperature for 4'8 hours, the solvent was distilled off under reduced pressure, and a 5% aqueous potassium hydrogen sulfate solution was carefully added dropwise until the pH reached about 3. After extraction with ethyl acetate (90 OmL x 2), the extract was dried over sodium sulfate (50 g). Filtration, solvent removal, and colorless oil)-2- [tert-butoxycarbol- (2-methoxycarbol-ethyl) -amino] -succinic acid 4-methyl ester (61 g, 47% yield) Got.

b) (R) -4-oxo-piperidine-1,2,3-tricarboxylic acid 1-tert-butyl ester 3-methinoleestenole;

(R)-4-oxo-piperidine-1,2,5-tricarboxylic acid 1-tert-butyl ester 5-methyl ester (Step 2-2)

 (R) -2- [tert-Butoxycarboyl- (2-methoxycarbol-dimethyl) -amino; 1-succinic acid 4-methyl ester obtained in Example 2-10 a) under an argon atmosphere

To a solution of (37 g, 0.1 lmo 1) in tetrahydrane (37 OmL, 10 vZw) was added 28 ° / o sodium methoxide methanol solution (64 mL, 0.33 mo 1) dropwise at 0 ° C. The temperature was raised for 2 hours. The reaction solution was cooled to 0, and a 5% aqueous solution of sodium hydrogen sulfate was injected until the pH reached about 3, then the organic layer was extracted with ethyl acetate (50 QmL x 2), and saturated aqueous sodium chloride (50 OmL) was added. ). After drying with magnesium sulfate (50 g), remove the solvent after filtration and remove the solvent. (R) -4-oxo-piperidine-1,2,3-tricarboxylic acid tert-butyl ester 3-methylester and 3-methylester 26 g (76% yield) of a yellow oil of (R) -4-oxo-piperidine-1,2,5-tricarboxylic acid 1-tert-butylester-5-methyl ester as a 1: 1 mixture were obtained. .

c) 2-tert-Butyl-3-oxo-1,2,3,4,6,7-hexahydro-pyrazo mouth [4,3-c] pyridin-4,5-dicarboxylic acid 5-tert-butyles Le 4-ethyl ester;

(R) -2-tert-butyl-3-oxo-1,2,3,4,6,7-hexahydro-virazo [4,3-c] pyridine-5,6-dicarboxylic acid 5- tert-butyl ester 6-ethyl ether (Step 2—

3)

Tert-butylhydrazine hydrochloride (0.98 ig, 7.9 mmol) was added, and the mixture was stirred at 100 ° C for 12 hours. After concentration under reduced pressure, the obtained residue was made into a solution of ethanol (2 OmL, 10 v / w), and thiol chloride (1.2 mL, 16 mmo 1) was added dropwise. Stirring was performed for a while. The solvent was distilled off under reduced pressure, and 1,4-dioxane: water = 1 :: 1 (2 OmL, 10 v / w) was added dropwise to the residue. Triethylamine (4. OmL, 29 mmol) -tert-butyl dicarbonate (1.7 g, 7.9 mmol 1) was added sequentially at 0. After stirring at room temperature for 12 hours, the solvent was distilled off under reduced pressure, and a 5% aqueous potassium hydrogen sulfate solution was carefully added dropwise until the pH reached about 4. After extracting twice with ethyl acetate (20 OmL), it was dried over magnesium sulfate (5.0 g). The crude product obtained after filtration and removal of the solvent was separated and purified by silica gel chromatography (form: methanol = 30: 1) to give 2-tert-butyl-3-oxo-1,2,3,4. , 6,7-Hexahydro-pyrazo-mouth [4,3-c] pyridine-4,5-dicarponic acid 5-tert-butyl ester 4-ethyl ester (0.24 g, yield 9.4%) and ( R〉-2 -tert-butyl-3 -oxo-1,2,3,4,6,7-hexahydro-pyrazo-mouth [4,3-c] pyridine-5,6-dicarbone versicolor 5-tert-butylester 6-Ethyl ester (0.36 g, yield 14%) was obtained as a colorless oil. d) (R) -5- (4-Benzyloxy-benzenesulfonyl) -3- (4-benzyloxy-benzenesulfonyloxy) -2-tert-butyl-4,5,6,7-tetrahydro- 2H-Pyrazo mouth

(R) 2 -tert-butyl-3-oxo-1,2,3,4,6,7-hexahydro-pyrazo mouth obtained in c) of Example 2-1 [4,3-c] To a solution of pyridine-5,6 dicarponic acid 5-tert-butylester 6-ethynoleester (18 Omg, 0.5 mmo1) was added 4N hydrochloric acid 1,4-dioxane solution (2.OmL, 10 v / w) to 0. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The residue was dissolved in N, N-dimethylformamide (1.5 mL, 8 v / w), and triethynoleamine (0.27 mL, 2. Ommo 1), 4-benzoyloxybenzenesulfoyl chloride (0, 31 g, 1. lmmol) were added sequentially at 0. After stirring at room temperature for 2 hours, water (10 mL) was added, and ethyl acetate was added.

(5 OmL × 2), and then dried over sodium sulfate (1.0 g). The crude product obtained after filtration and removal of the solvent is separated and purified by silica gel chromatography (hexane: ethyl acetate = 4: 1) to give (R) -5- (4-benzyloxy-benzenesulfonyl) -3 -(4-Benzyloxy-benzenesulfo-roxy) -2-tert-butyl 4,5,6,7-tetrahydro-2H-pyrazo-mouth [4,3-c] pyridine-6-hexyl ethyl ester (0. 19 g, 52% yield) as a yellow oil.

e) (R) -5- (4-Benzyloxy-benzenesulfol) -2-tert-butyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-birazolo [ 4,3-c] pyridine-6-hydroxysulfonic acid (tetrahydrofuran-pyran-2-yloxy) -amide (Step 2-5)

 (R) -5- (4-benzyloxy-benzenesulfonyl) -3- (4-benzoxy, benzenesulfonyl / reoxy) obtained in Example 2-1) in an argon atmosphere -Methanol of tert-butyl-4,5,6,7-tetrahydro-2H-pizolo [4,3-c] pyridine-6-carboxylic acid ethyl ester (0.19 g, 0.25 mmo 1): To a mixed solution of tetrahydrofuran = 1: 1 (2. OmL, 10 v /) was added a 6 N aqueous potassium hydroxide solution (0.5 OmL, 3. Ommo 1), and the mixture was stirred at room temperature for 2 hours. After adding water (2.OmL) to the residue, 6N aqueous hydrochloric acid was carefully added dropwise until the pH reached about 1. The resulting crystals were filtered and the crystals were washed with water (2.OmL). After washing, it is dried under reduced pressure to give (R) -5- (4-benzyloxy-benzenesulfol) -2 -tert-butyl-3-oxo-2,3,4,5,6,7-hexahydro- 1H-Pyrazo mouth [4, 3-c] - Obtained 6-carboxylic acid crude product containing 4-benzyl O carboxy benzenesulfonic acid and (0. 14 g).

The crude product (0.14 g) was added to Ν, Ν-dimethylformamide solution (1.5 mL, 10 v / w). In C, N-methylmorpholine (0.035 mL, 0.32 mmo 1), 0- (tetrahydro-2H-pyran-2-yl) -hydroxylamine (37 mg, 0.32 mmoΓ), 1-hydroxybenzotria Toluyl hydrate (49 mg, 0.32 mmo 1) and 1-ethyl-3- (3-dimethylaminopropyl) carbodimid hydrochloride (6 mg, 0.32 mmo 1) were sequentially added. After stirring at room temperature for 6 hours, water (2. OmL) was added, and the organic layer was extracted with ethyl acetate (5 OmL X 2), and a saturated aqueous solution of sodium hydrogen carbonate (2. OmL), water (2. OmL), The extract was washed sequentially with saturated saline (2.0 mL) and dried over sodium sulfate (1. Og). The crude product obtained after filtration and removal of the solvent is separated and purified by silica gel chromatography (chlorohonolem: methanol = 50: 1) to give (R) -5- (4-benzyloxy-benzenesulfol) -2-tert. -Butyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-Vilazo mouth [4,3-c] pyridine-6-force Rubonic acid (tetrahydro-pyran-2-yloxy) -amide was obtained as a diastereomer mixture (0.12 g, yield 69%) as a yellow oil.

 f) (R) -5- (4-Benzyloxy-benzenesulfol) -2-tert-butyl-3-oxo

 -6-carboxylic acid hydride

 (R) -5- (4-Benzyloxy-benzenesnorehonoure) -2-tert-butyl-3-oxo obtained in e) of Example 2-1 under an argon atmosphere Diastereomeric mixture of 1,6,6,7-hexahydro-1H-pyrazo-mouth [4,3-c] pyridine-6-pyruroic acid (tetrahydro-bilan-2-yloxy) -amide (0.12 mg, 0. To a solution of 2 Ommo 1) in methanol (2. OmL, 20 v / w) was added dropwise a 2N aqueous hydrochloric acid solution (0.5 mL, 0.99 mmol) at room temperature, and the mixture was stirred for 1.5 hours. After concentration under reduced pressure, the obtained residue was azeotroped with toluene (0.5 mL), and the obtained crude product was separated and purified by silica gel chromatography (form: methanol = 30: 1). Thereafter, ethyl acetate (0.2 mL) and diisopropyl ether (lmL) were gradually added to the obtained yellow oil, and the precipitated crystals were filtered and filtered with diisopropyl ether (1. OmL). After washing, the residue is dried under reduced pressure to give a white-yellow solid (R) -5- (4-benzyloxy-benzenesulfonyl) -2-tert-butyl-3-oxo-2,3,4,5,6,7- Xahydro-1H-pyrazo mouth [4,3-c] pyridine-6-carboxylic acid hydroxyamide (47 mg, yield 48%) was obtained.

Melting point 1 55.0 ° C (decomposition)

 (Examples 2-2 to 2-7)

The compounds of Examples 2-2 to 2-7 were obtained in the same manner as in Example 2-1. Tables 35 and 36 show the structural formulas and NMR data of the compounds of Examples 2-1 to 2-7. Table 35

Table 36

Example 3

 (Example 3-1)

 (3aR, 4R) -5- [4- (2,4-Dic-mouth-benzyloxy) -benzenesulfonyl] -3a-methyl-3-oxo-2-phenyl-3,3a, 4,5,6 , 7-Hexahydro-2H-pyrazo mouth [4,3-c] pyridin-4-carboxylic acid hydroxyamide

a) 4-tert-butyl ester of 2- (2-methoxycarbo-luethylamino) -succinic acid (Step 3-1)

Under an argon atmosphere, D-aspartic acid-] 3-tert-butyl ester (50 g, 0.26 mo 1) in methanol: N, N-dimethylformamide = 3: 4 (4 O Om L, 8 vZw) Triethylamine (11 OmL, 0.79 mol) and methyl acrylate (71 mL, 0.79 mol) were added dropwise at 0 at the same time. After stirring at room temperature for 4 hours, the mixture was concentrated under reduced pressure. Getyl ether (50 OmL) in the residue After stirring at room temperature for 30 minutes, the resulting crystals were filtered, washed with getyl ether (10 OmL), and dried under reduced pressure to give the title compound as a white solid (61 g, yield 84%) Got.

 Le> Amino]

Under an argon atmosphere, 4-tert-butyl succinate (41 g, 0.15 mo 1) obtained in Example 3-1 a) in Example 3-1 a) was added to 1,4-dioxane : Water = 1: 1 (41 OmL, 10 vZw) Suspended in a solution, and triethylamine (62 mL, 0.44 mo1) and di-tert-butyl dicarbonate (39 g, 0.18 mol) were added. C sequentially added. After stirring at room temperature for 24 hours, the solvent was distilled off under reduced pressure, and a 6 N hydrochloric acid aqueous solution was carefully added dropwise at 0 at 0 until the pH reached about 3. After extraction with ethyl acetate (70 OmL × 2), the extract was dried over sodium sulfate (40 g). Filtration and solvent removal gave the title compound as a white solid (55 g, yield 99 ° / ₀ ).

c) 4-Hydroxy-5,6-dihydro-2H-pyridine-1,2,3-tricarboxylic acid 1,3-di-tert-butyl ester (Step 3-3)

Under an argon atmosphere, 2- [tert-butoxycarbyl- (2-methoxycarbopropyl) amino] -succinic acid 4-tert-butyl ester obtained in b) of Example 3-1 (55 g, 0 1.5mo1) in tetrahydrofuran (500mL, 9v / w) A 1.OM lithium hexamethyldisilazidetetrahydrofuran solution (320 mL, 0.32 mol) was added dropwise to the solution at 170 for 2.5 hours. After stirring at 170 ° C for 1 hour, a 2N aqueous hydrochloric acid solution was carefully added dropwise at 0 ° C until the pH reached about 3. The solvent was distilled off under reduced pressure, extracted with ethyl acetate (.50 OmL x 2), and dried with magnesium sulfate (40 g). After filtration and filtration, n-hexane (50 OmL) was added to the mixture to give the title compound (14 g, yield 28%) as a white solid.

d) 3-Methyl-4-oxo-piperidine-1,2,3-tricarboxylic acid 1,3-di-tert-butyl ester (Step 3-4)

 In an argon atmosphere, the 4-hydroxy-5,6-dihydroxyl-2H-pyridine-1,2,3-tricarboxylic acid 1,3-di-tert-butyl obtained in c) of Example 3-1 was obtained. To a solution of the ester (1.7 g, 5. Ommo 1) in tetrahydrofuran (8 OmL, 40 vZw) was added sodium hydride (0.40 g, 1 Ommo 1) at 0 and stirred for> 30 minutes. Further, lodomethane (0.69 mL, 1 lmmo 1) was added dropwise to the reaction solution at 0, and the mixture was stirred at room temperature for 12 hours. After injecting a 2N aqueous hydrochloric acid solution until the pH reached about 3, the organic layer was extracted with ethyl acetate (20 OmL × 2>), washed with saturated saline solution (20 rtiL), and dried over magnesium sulfate (20 g). The crude product obtained after filtration and removal of the solvent was separated and purified by silica gel chromatography (form: methanol: 40: 1) to give the title compound (1.8 g, yield 100%) as a white amorphous substance. .

e) 1,3-Di-tert-butylestenole 3- (4-methyl-hydrazono) -piperidine-1,2,3-tricarponic acid (Step 3-5)

Under an argon atmosphere, 3-methyl-4-oxo-pyridine-1,2,3-trinolevonic acid 1, -di-tert-butyl ester obtained in d) of Example 3-11 (1. To a solution of 8 g, 5.0 mm o 1) in ethanol (18 mL, 1 O v ow) was added phenylhydrazine (0.49 mL, 5.0 mm o U), and the mixture was subjected to nitrogen treatment for 3 hours. After the reaction solution was concentrated under reduced pressure, isopropyl ether (10 mL) and n-hexane (10 mL) were added to the obtained residue, and the mixture was stirred for 10 minutes. The resulting crystals were filtered, and n-hexane (1 OmL) was added. After drying under reduced pressure, the title compound (1.7 g, yield 76%) was obtained as a white solid.

f) 3a-Methyl-3-oxo-2-fluoro-2,3,3a, 4,6,7-hexahydro-virazo mouth [4,3-c] pyridine-4,5-dicarponic acid 5-tert-butylester (Step 3-6)

Under an argon atmosphere, a solution of sodium hydride (0.28 g, 7. lmmol) in 2-methoxyethanol (16 mL, 10 v / w) was added to a solution of 3-tyl-4- obtained in e) of Example 3. (Feel-hydrazono) -piperidine-1,2,3-tripyrronic acid 1,3-di-teft-butyl ester (1.6 g, 3.4 mmo 1) at 0 ° C. The temperature was raised to 20 and the mixture was stirred for 12 hours. After the reaction solution was concentrated under reduced pressure, a 1N aqueous hydrochloric acid solution was added to the obtained residue until the pH reached about 3, and the organic layer was added to ethyl acetate (50 mL × The mixture was extracted with 2) and washed with saturated saline (10 mL). After drying over magnesium sulfate (10 g), filtration and removal of the solvent, a crude product of the title compound (1.5 g) was obtained. g) 3a-Methyl-3-oxo-2-phenyl-3,3a, 4,5,6,7-hexahydro-2H-pyrazo

 (S; 3 7)

 The crude product 3a-methyl-3-oxo-2-phenyl-2,3,3a, 4,6,7-hexahydrobirazolo obtained in f) of Example 3-1 under ice-cooling [4, 3-c] Pyridine-4,5-dicarboxylic acid 5-tert-ptynoleate (1.54 g) in methanol (15 mL, 10 / w) in thionyl chloride (1.5 mL, 1 v / w) Was added dropwise, and the mixture was stirred at room temperature for 12 hours. Then, thiol chloride (3. OmL, 2 v / w) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 12 hours. Then, the reaction solution is concentrated under reduced pressure while azeotropically evaporating with toluene, and crude product of the title compound 3a-methyl-3-oxo-2-fur-3,3a, 4,5,6,7-hexahydro -2H-Pyrazo mouth [4,3-c] pyridine-4-methyl sulfonate methylester hydrochloride was obtained.

 h) (3aR *, 4R *)-5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfonyl] -3a-methyl-3-oxo-2-phenyl-3,3a, 4 , 5,6,7-Hexahydro-2H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid methyl ester (Step 3-8)

The crude product obtained in Example 3-1 g) under ice-cooling, 3a-methyl-3-oxo- ² -phenyl 4- (3,3a, 4,5,6,7-hexahydro-2H virazo [4,3-c] pyridine-4- (4-methylpyruponic acid) hydrochloride in pyridine (10 mL) 2,4-Dicyclohexylbenzene-sulfonic acid chloride (1.2 g, 3.4 mmol) was added, and the mixture was stirred at room temperature for 2 days. Then water卞methanol (7 mL), potassium carbonate _{(2. 3 g, 17mm 0 1} ) anti裤:. Medium ί¾ successively added, and the mixture was stirred for 6 hours Te Shitsu瘟, and concentrated under reduced pressure. Ethyl acetate (5 OmL) and an aqueous solution of IN hydrochloric acid (50 mL) were added to the residue, and the aqueous layer was extracted with ethyl acetate (5 OmL ic 2) and dried over magnesium sulfate. The crude product obtained by filtration and solvent removal is separated and purified by silica gel chromatography (n-hexane: ethyl acetate 10: 1 to 2: 1) to give the title compound (3aR *, 4R *)-5- [ 4- (2,4-dichloro-benzyloxy) -benzenesulfonyl] -3a-methyl-3-oxo-2-phenyl-3,3a, 4,5,6,7-hexahydro-2H-pyrazo Mouth [4,3-c] pyridine-4-carboxylic acid methyl ester (1.19 g, yield over two steps 59%) was obtained as a yellow solid.

'H-MRiCDCls, 300MHz) 1.62 (s, 3H), 2.68-2.89 (m, 2H), 3.00 (dt, J = 6.0, 10.5Hz, 1H), 3.35 (s, 3H), 4.14 (dd, J = 6.0, 12.0Hz, 1H), 5.06 (s, 1H), 5.18 (s, 2H), 7.06 (d, J = 9.0Hz, 2H), 7.18 (t, J = 9.0Hz, 1H), 7.29-7.32 ( m, 1H), 7.39 (t, J = 9.0Hz, 2H), 7.45 (dd, J = 3.0, 3.0Hz, 2H) ₉ 7.76-7.89 (m, 4H) i) (3aR *, 4R *) -5 -[4- (2,4-Dichlo-benzyloxy) -benzenesulfonyl] -3a-methyl-3-oxo-2-phenyl-3,3a, 4,5,6,7-hexahydro- 2H-Vilazo mouth [4,3-c] pyridine-4-carboxylic acid (Step 3-9)

(3aR *, 4R *)-5- [4- (2,4-dimethoxyl-benzyloxy) -benzenesulfol] -3a-methyl-3- obtained in Example 3-1 g) Oxo-2-Fe-3,3a, 4,5,6,7-hex Sahydro-2H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid methyl ester (1.0 g 1.7 mmo 1) tetrahydrofuran: methanol = 1: 1 (24 mL, 24 v / w) mixed solution To the mixture was added a 4N sodium peroxide solution (1.28 mL, 5.13 mmol), and the mixture was stirred at room temperature for 2 hours. The organic solvent was concentrated under reduced pressure. The ice layer added IN aqueous hydrochloric acid solution to a residue in _P H reaches about 3 and extracted with acetic acid Echiru (30mLx 3). Wash the combined organic layers with water (20 mL x l), dry over sodium sulfate, filter and remove the solvent to remove the title compound (3aR *, 4) -5- [4 (2,4 dicuff-benzyloxy) -benzensulfur] -3a - methyl - 3 off Le - 3, 3a, 4, 5 , 6, to 7-Kisahido Russia - ² H - Birazoro ^[4, 3-c] pyridin - ⁴ -耝product of a carboxylic驗(1. (0 g, yield 100%) as brown amorphous.

^ -NMRiDMSO-dG, 300MHz) 1.43 (s _s 3H) _J: 2.62-2.8 ^ (m, 2H), 2.88-3.03 (m, 1H), 4.05 (dd, J = 6.0, 12.0Hz, 1H), 4.78 (s, 1H), 5.24 ( s, 2H), 7.15-7.28 (m, 3H), 7.42 (t, J = 7.5Hz, 2H), 7.50 (dd, J = 3 4 0, 9.0Hz, 1H), 7.65 (d, J = 9 GHz, 1H), 7.72 (d, J = 3.0 Hz, 1H), 7.77 (d, J = 6.0 Hz, 2H), 7.86 (d, J = 9, 0 Hz, 2H) j ) (3aR, 4R)-5- [4- (2,4-diclo-benzyloxy) -benzenesulfonyl] -3a-methyl-3-oxo-2-phenyl-3,3a, 4,5,6 , 7 Xahydro-2H-pyrazo mouth [4,3-c] pyridine-4-hexanoic acid (Step 3-10)

(3aR *, 4R *)-5- [4- (2,4-dichloro-benzyloxy) -benzenesulfol] -3a-methyl-3-oxo- obtained in i) of Example 3-1 2-Fuel-3,3a, 4,5,6,7-hexahydro-2H-birazolo [4,3-c] pyridine-4-pyruonic acid (74 mg, 1.26 mMol) -In a solution of propanol (3 OmL, 40 v / w), add Kyun (409 mg, 1.26 mmol 1) at room temperature, and add 50-55. After stirring for 1 hour at C The mixture was further stirred at room temperature for 1 hour. The resulting crystals were filtered, and the crystals were washed with 2-propanol (15 mL) to obtain a Kyun salt as a white solid. A 1N hydrochloric acid solution (20 mL) and ethyl acetate (20 mL) were added to this quin salt, the aqueous layer was extracted with ethyl acetate (2 OmL × 2), and the combined organic layers were combined with a 1N aqueous hydrochloric acid solution ( 1 OmLx 1) and water (l OmLxl): Wash with sodium sulfate, filter, remove solvent, and dry under reduced pressure to obtain (3aR, 4R) -5- {4- (2,4-dichloro-benzyloxyl) ) -Benzensulfol] -3a-methyl-3-oxo-2, fuenole-3,3a, 4,5,6,7-hexahydro-2H-pyrazo [4,3-c] Pyridine-4-calpond (313 mg, yield 36%, optical purity 83% ee) was obtained. By repeating the above procedure, the title compound (3aR, 4R) -5- [4- [2,4-dichloro-benzyloxy) was obtained from the above compound (3 13 mg, optical purity 83% ee). [Benzenebenzenesulfon] n3a-methyl-3-oxo-2-enyl-3,3a, 4,5,6,7-hexahydro-2H-pyrazo-mouth [4,3-c] pyridine-4-potulponic acid (242 mg, yield 73%, optical purity> 99% 66) was obtained as a white amorphous. Melting point 190-193. C (de c.)

- Keio _{R (CDC1 3, 300MHz) 1.57} (s, 3H), 2.48-2.88 (m, 2H), 3.00 (dt, J = 6.0, 10.5Hz, 1H), 4.06 (dd, J = 6.0, 12.0Hz, 1H), 5.13 (s, 1H), 5.16 (s, 2H), 7.03 (d, J = 9.0Hz, 2H), 7.17 (t, J = 7.5Hz, 1H), 7.23-7.32 (m, 1H), 7.36 (t, J = 7.5Hz, 2H), 7.41- 7.48 (m, 2H), 7.80 (d, J = 9.0Hz, 2H), 7.85 (d, J = 9.0Hz, 2H)

k) (3aR, 4R)-5- [4- (2,4-Dic-mouth-benzyloxy) -benzenesulfoel] -3a-methyl-3-oxo-2 -phenyl-3,3a, 4,5 6,7-Hexahydro-2H-pyrazo mouth [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide (Steps 3-11)

(3 ^, 4¾-5- [4- (2,4-dic-mouth-benzyloxy) -benzenesulfonyl] -3a-methyl-3-) obtained in Example 3-1; i) under an argon atmosphere. Oxo- 2-Fe-

3,4,5,6,7-Hexahydro-2H-pyrazo-mouth [4,3-c] pyridine-4-carboxylic acid (1 16 mg, 0.197 mmo 1) tetrahydrofuran (2, _; 3mL, 20 v / w) solution in chloride Okizariru (2 ... 0 M di port main emissions solution, 0. 138mL, 0. 276mmo 1) , N, N- dimethylformamidine de (O. O l OmL, 0.12 9mmo 1) to 20. C sequentially added.温 The temperature was raised from 0 ° C to 0 ° C over 1 hour, and further stirred at 0 for 30 minutes. Then, N-methylmorpholine (0.065 mL, 0.59 lmmo 1) and 0-methylsilylhydroxylamine (0.121 mL, 0.985 mMol) were sequentially added dropwise. The temperature was then raised from 0 to 0 ° C over 30 minutes, and further stirred at 0 for 1 hour, and the reaction solution was concentrated under reduced pressure.The residue was diluted with ethyl acetate (20 mL) and purified with water (5 mL x 3). The crude product obtained by filtration and removal of the solvent was separated and purified by silica gel chromatography (chloroform: methanol = 50: 1 to 15: 1), and dimethyl ether / n. —The title compound (3aR, 4R) -5- [4- (2,4-Diculo-benzyloxy) -benzenesulfol] -3a-methyl 3-oxo-2 by crystallization from hexane -Feru 3,3a, 4,5,6,7-Hexahydro-2H-pyrazo [4,3-c] pyridine-4-hydroxycarboxylic acid (76 mg, yield 64%, Optical purity> 99% ee) was obtained as a white solid.

 (Examples 3-2 to 3-17)

In the same manner as in Example 3-1, the compounds of Examples 3-2 to 3-17 were obtained. Tables 37 to 40 show the structural formulas and NMR data of the compounds of Examples 3-1 to 3-17. Table 37

¾ 38

Table 39

Next, the results of tests performed on the aglycanase-11 inhibitory activity and the matrix metallobutyltinase-1 (MMP-1) inhibitory activity of the compound of the present invention are shown. (Pharmacological test)

Test Example 1: Aggregana-1 inhibitory effect

 Particle Assay was used for aggrecanase activity measurement.

 That is, a test compound diluted with the enzyme aglycanase-11 and dimethylsulfoxide (DMSO) was added to a 96-well plate, and polyacrylamide gel particles containing aggrecan as a substrate were added, followed by incubation at 37 ° C for 15 hours. Was done. Tris monohydrochloride buffer was used for the enzymatic reaction.

After the incubation, transfer the supernatant to another plate, add 1,9-dimethylmethylpurine, and measure the absorbance at 595 nm to determine the amount of glycosaminodalican (GAG) released into the reaction supernatant. Was quantified. Inhibition% (IC ₅₀ ) was calculated based on the value of the enzyme-added and non-added cells. Whale chondroitin sulfate was used as a standard.

Test example 2: MMP-1 inhibitory effect For MMP-1 Atsushi, Type I collagen activity measurement kit (YA GA I YU-72013) was used after changing to 96 ゥ L plate format.

 The principle of the kit is that the denatured collagen, which is cleaved by non-denatured collagen, and Μ ^ ίΡ1, has different solubility in ethanol.

 The test mixture diluted with enzyme II-1 and DMS II was added to a 96-well plate, Fluorescein isothiocyanate (FITC) -labeled type I collagen was added as a substrate, and incubation was carried out at 37 for 3 hours.

 After the incubation, the reaction was stopped by adding Tris monohydrochloride containing ethanol, centrifugation was performed, and the ethanol-soluble denatured collagen was separated by collecting the supernatant on another plate.

Since the type I collagen that has been fluorescently labeled is denatured when cleaved by MMP-1 and becomes soluble in ethanol, the collagenase activity of MMP-1 increases the FITC fluorescence intensity of the dissolved type I collagen ( The excitation wavelength was 485 nm, and the absorption wavelength was 530 nm. Inhibition% (IC ₆₀ ) was calculated based on the values of gels with and without enzyme added. .

 The results of Test Examples 1 and 2 are shown in Tables 41 and 42. In the table, + is 1 ^

Less than M, + + less than 0. 1 _mu Micromax one is 1 M or more, eleven are: shows a more lO tlva. .

Table 4 1

Table 42

Next, the results of a test performed on the inhibitory effect of the compound of the present invention on matrix meta-oral proteinase 13 (MMP-13) are shown.

Test Example 3: MMP-13 enzyme Atsusei (Fluorescent synthetic substrate method)

The MMP-13 inhibitory activity of the compounds was determined by enzyme assay using a quenching fluorescent substrate. This assay is based on the fact that when a synthetic peptide substrate having a fluorescent substance and a quencher at both ends is cleaved with MMP-13, fluorescence increases in proportion to the amount of enzyme reaction. I understand.

96 μl plate was added with 4 μl of a test compound solution (containing 10% DMSO) and 16 μl of an enzyme MMP-13 solution (100 ng / ml). After pre-incubation for 15 minutes at 25 ^, the reaction was carried out for 25 minutes with addition of 20 µl of 1 ml of grave tobacco (10 µl). The reaction was stopped by adding 260 μl of 3% acetic acid, and the mixture was allowed to stand for 10 minutes, and then the fluorescence intensity (excitation wavelength: 325 nm, emission wavelength: 405 nm) of each well was measured. M MP- 1 3 inhibitory activity (IC _s 0 or wind damage. / ₀₎ were calculated.

The results of Test Example 3 above are shown in Table 4: 3: 彔::, medium, + indicates less than 1.M, and ++ indicates less than 0.

Table 43

From the above test results and the like, the compound according to the present invention. (1) has an excellent inhibitory effect on aggrecanase or MMP-13, and has a higher selectivity for aggrecanase as compared with the activity of MMP-1. It was shown to have Industrial applicability

 According to the present invention, osteoarthritis (OA), rheumatoid arthritis (RA), joint injury, reactive arthritis, cancer, asthma, allergic reaction, chronic emphysema, pulmonary fibrosis, acute respiratory distress syndrome (ARDS) ), Pulmonary infections, interstitium: compounds useful as a therapeutic agent for the treatment of aggrecanase or MMP-13 for 3p, such as pneumonia, bone resorption disease, etc .; : '

 This application is based on application No. 2 $ 82573 filed in Japan, the contents of which are incorporated herein by reference; .

Claims

The scope of the claims

[Wherein, R ¹ and R ² are each independently

 (1) hydrogen atom,

 (2) a halogen atom,

 (3) hydroxyl group,

 (4) CH alkyl group,

(5) Ci- ₆ alkoxy group,

(6) Halo Ci- ₆ alkyl group,

(7) Halo C] — ₆ alkoxy group

(Wherein, p及Pi q are the same or different and each represents 0 or an integer of 1 to 4, X is a single bond, an alkylene甚, 0 ₂ - ₆ Aruke - alkylene group, C ₂ - _e Arukyuren group, , 0—, one N (R ²² ) —, — S (hi) _r one, one CO—, one CON (R ²² ) —, -N (R ²² ) CO—, -S0 ₂ N (R ²² ) — ^{, - N (R 22) S0} 2 -, - N (R 22) CON (R 23) -, one _{^{N (R 22) S 0 2}} N (R 23) -, - OCON (R 22) - or - N (R ²² ) COO—

Here, R ²² and R ²³ are the same or different and each is a hydrogen atom, a ₆ alkyl group, an optionally substituted C ₃ _ ₁₄ hydrocarbon ring group, an optionally substituted fused C ₆ _ ₁₄ hydrocarbon ring group, A heterocyclic group which may be substituted or a condensed heterocyclic group which may be substituted;

Represents 0 or an integer of 1 to 2, A ¹ is optionally substituted C ₃ - ₁₄ hydrocarbon ring group, optionally substituted fused C ₆ _ ₁₄ be hydrocarbon ring ¾, unsubstituted or Yo Le, terrorist ring group or be substituted to Insufficient tetracyclic groups for good condensation;

(Wherein R ⁸ and R ⁹ are each independently:

 (1) hydrogen atom,

(2) C _w . Alkyl group,

(3) halo C ₆ aryl group,

(4) optionally substituted C ₃ - ₁₄ hydrocarbon缚基,

(5) an optionally substituted fused C _e _ ₁₄ hydrocarbon ring group,

 (6) an optionally substituted heterocyclic group,

 (7) an optionally substituted fused heterocyclic group,

(8) an optionally substituted C ₃ _ ₁₄ hydrocarbon ring- ₆ alkyl group,

(9) an optionally substituted fused C ₆ _ ₁₄ hydrocarbon ring-C ₆ alkyl group,

 (10) An optionally substituted heterocyclic alkyl group

Or

(11) substituted also to be fused heterocyclic - indicates c, _ ₆ alkyl group,

R ^{1 (>} and R ¹¹ are each independently (1) Hydrogen atom

Or

(2) (Do you also show ₆ alkyl tombs?

. Together with the carbon atom forces bind may form a ball le group, R ¹² is: ';':

 (1) hydrogen atom,

(2) Ci— _10- anolekyl group,

(3) a halo- ₆ alkyl group,

(4) C ₃ _ ₁₄ hydrocarbon Ningine which may be substituted,

(5) optionally substituted condensed C ₆ _ ₁₄ charcoal

 (6) an optionally substituted heterocyclic group,.

 (7) an optionally substituted fused heterocyclic group,

(8) optionally substituted C ₃ - ₁₄ hydrocarbon Hata琛- alkyl group,

(9) an _optionally substituted fused C _{e _14} hydrocarbon ring-C _M alkyl group, (10) an _optionally substituted hetero ring-alkyl group

Or

(11) an optionally substituted fused heterocyclic Cw alkyl group, wherein R ¹³ is

 (1) hydrogen atom,

(2) C- ₆ alkyl group,

 (3) hydroxyl group,

(4) C ₆ alkoxy group,

(5)-N (R ²⁶ ) (R ²⁷ ),

(6) — N (R ²⁸ ) — CO — R ²⁹ ,

(7) — N (R ²⁸ ) — SO ₂ — R ²⁹

Or

(8) — CO— NH— R ²⁸ ,

Indicates that

Where R ²⁶ and R ²⁷ are each independently (1) hydrogen atom,

 (2) arequinole group,

(3) halo C -! ₆ alkyl甚,

(4) an optionally substituted C ₃ _ ₁₄ hydrocarbon ring group,

(5) optionally obtaining a substituted C _M4 carbonized,

 (6) optionally substituted heterocyclic group

Or

 (7) represents a fused heterocyclic group which may be substituted,

R ²⁸ and R ²⁹ are each independently:

 (1) hydrogen atom,

(2) ₁₀ alkyl groups,

 (3) a haloalkyl group,

(4) optionally substituted C ₃ - ₁₄ hydrocarbon ring group,

 (5) an optionally substituted fused C ^ hydrocarbon ring group,

 (6) an optionally substituted heterocyclic group,

 (7) an optionally substituted fused heterocyclic group,

(8) optionally substituted C ₃ - ₁₄ hydrocarbon ring primary alkyl group,

(9) unsubstituted or Yo Le, fused C _{6 14} hydrocarbon ring -. C w alkyl group,

 (10) An optionally substituted heterocyclic C! -E alkyl group

Or

 (11) represents an optionally substituted fused heterocyclic monoalkyl group,

R ¹⁷ is

 (1) hydrogen atom,

 (2) hydroxyl group,

 (3) an alkyl group (the alkyl group may be substituted with a hydroxyl group or an amino group),

 (4) a haloalkyl group,

(5) C! — ₆ alkoxy alkyl group

Or (6) indicating an alkoxy group);

R ³ and R ⁴ are joined with R ^s ,

(Wherein R ⁸ , R ⁹ , R ¹⁰ , R ", R ¹² , R ¹³ and R ¹⁷ are as defined above), R ⁸ represents a hydrogen atom or an alkyl group;

R ⁷ is

(1) One OR ¹⁴ group (where R ¹⁴ represents a hydrogen atom! ^ Or an alkyl group),

(2) — N (R ¹⁵ ) (R ¹⁶ ) group (wherein ^RIS and R ¹⁶ each independently represent a hydrogen atom or an alkyl group)

Or

 (3) a hydroxyamino group;

R ²¹ is

 (1) hydrogen atom,

 (2) C alkyl group,

(3) halo _6- anolealkyl group,

(4) optionally substituted c ₃ - ₁₄ hydrocarbon ring group,

(5) optionally substituted fused c ₆ _ ₁₄ hydrocarbon ring group,

 (6) an optionally substituted heterocyclic group,

 (7) substituted or condensed heterocyclic group,

(8) optionally substituted c ₃ _ ₁₄ hydrocarbon ring one C _M alkyl group,

(9) an optionally substituted fused c ₆ _ ₁₄ hydrocarbon ring — c _M alkyl group,

 (10) An optionally substituted heterocyclic mono-C w alkyl group

Or

 (11) an optionally substituted condensed heterocyclic-alkyl group;

A is an alkylene group, C ₂ - shows a ₆ alkenylene or C ₂ _ ₆ alkynylene group And;

Ring B is

(1) C ₃ — ₁₄ hydrocarbon Ning tomb, which may be replaced

(2) condensation optionally substituted C ₆ - _i4 carbide present rate隳華,

(3) Heterocycle leather that may be substituted

Or

 (4) indicates the height of a condensed hetero ring which may be substituted;

m represents 1, 2 or 3;

n represents 0, 1, 2, or 3)

Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

2. In the general formula (1), R ¹ and R ² are each independently

 (I) a hydrogen atom,

(2) a halogen atom,

 (3) hydroxyl group,

(4) ₆ alkyl groups,

(5) Halo. To ₆ alkyl groups,

 (6) an alkoxy group,

(7) halo C Preparative ₆ alkoxy group,

(8) C ₆ _ ₁₄ aryl group which may be substituted,

(9) may be substituted 0 ₆ _ ₁₄ Ariruokishi group,

(10) which may be substituted 0 ₆ _ ₁₄ Ariru - ₆ alkyl group.

(II) optionally substituted _ ₁₄ aryl ₆ alkoxy group,

(12) optionally substituted C _e - ₁₄ Ariruokishi - ₆ alkyl group,

 (13) an optionally substituted heterocyclic group,

 (14) an optionally substituted heterocyclic oxy group,

 (15) Condensed heterocyclic ring which may be substituted Alkoxy group

Or (16) a C ₃ _ ₇ cycloalkyl d_ ₆ alkoxy group which may be substituted;

R ³ and R ⁴ are each independently a hydrogen atom or force represents an alkyl group, and becomes carbon atoms and over Color G binding e ₃ - ₇ consequent opening alkyl group or to terrorist

(Wherein R ⁸ and R ⁹ are each independently:

 (1) hydrogen atom,

 (2) i. Alkyl group,

(3) substituted optionally C _e - ₁₄ Ariru group,

(4) substituted optionally C ₆ - ₁₄ Ariru C _w alkyl group,

(5) optionally substituted C ₃ - ₇ cycloalkyl group,

(6) optionally substituted C ₃ - ₇ cycloalkyl C ^ alkyl group,

 (7) an optionally substituted heterocyclic group,

(8) optionally substituted fused C ₆ - ₁₄ hydrocarbon ring group

Or

 (9) represents a fused heterocyclic group which may be substituted,

R ¹⁰ and R ¹¹ are each independently

 (1) Hydrogen atom

Or

(2) C _M alkyl group or shown, or coupled to may be formed into a connexion force Lupo alkenyl group together with the carbon atom,

R ¹²ゝ

 (1) hydrogen atom,

(2) C to _1Q alkyl group,

(3) halo C Preparative ₆ alkyl group, (4) optionally substituted C ₆ - ₁₄ Ariru group,

(5) substituted C ₆ _ ₁₄ may be Ariru C Bok ₆ Arukiru group,

 (6) Heterocycle tombs that may be replaced.

(7) optionally substituted C ₃ - ₇ consequent Anore: Kill group:.

Or

(8) optionally substituted C ₃ - ₇ show the cycloalkyl G alkyl group,

R ¹³ is

 (1) hydrogen atom,

 (2) CB alkyl group,

(3) hydroxyl group,

 (4) alkoxy group

Or

^{(5) - N (R 26} ) (R 27) [ wherein R ²⁶及Pi R ²⁷ are as defined above:] shows the, R ¹⁷ is

(1) hydrogen atom,

 (2) hydroxyl group,

(3) ₆ alkyl groups (the alkyl group may be substituted with a hydroxyl group or an amino group),

 (4) a haloalkyl group,

(5) Alkoxy alkyl group

Or

(6) _ ₆ shows an alkoxy group) to form;

R ³ and R ⁴ are joined together with R ⁵

(Where R ⁸ , R \ RR ", R ¹² and R ¹³ are as defined above) If, R ⁶ represents a hydrogen atom or a C _e alkyl group;

Ring B is

(1) ₆ —] ₄

(2) C ₃ _ ₇ cycloalkyl

(3) C ₃ — ₁₀ cycloalkyl group

(4) Condensation C ₆ -.. ₁₄ hydrocarbon ring group or

 (5) represents a heterocyclic group,

2. The fused N-containing heterocyclic compound according to claim 1, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

3. In the general formula (1), R ¹ and R ² are each independently

 (1) hydrogen atom,

 (2) a halogen atom,

(3) hydroxyl group,

(4) C Preparative ₆ alkyl group,

(Five) . ₆ alkoxy group,

(6) optionally substituted C ₆ - ₁₄ 7 aryl group,

(7) optionally substituted C ₆ - ₁₄ Ariruokishi group,

(8) an optionally substituted C ₆ _ ₁₄ 7 reel alkyl group,

(9) optionally substituted C ₆ _ ₁₄ Ariru CH alkoxy group,

 (10) An optionally substituted heterocyclic group

Or

 (11) an optionally substituted heterocyclic oxy group;

When R ³ and R ⁴ each independently represent a hydrogen atom or an alkyl group, R ⁵ is taken together with R ⁶ ,

(Where R ⁸ and R ⁹ are each independently

 (1) hydrogen atom,

(2) C, — ₆ alkyl group,

(3) optionally substituted C ₆ - ₁₄ 7 aryl group,

(4) optionally substituted C ₆ - ₁₄ Ariru 0 DOO ₆ alkyl group,

 (5) an optionally substituted heterocyclic group,

(6)箧換which may be C ₃ - ₇ cycloalkyl group

Or

(7) represents an optionally substituted C ₃ _ ₇ cycloalkylalkyl group, R ¹⁰ and R ¹¹ are each independently

 (1) Hydrogen atom

Or

(2) C -! ₆ represents an alkyl group, or

R ¹² may form a carboxy group together with the carbon atom to which it is attached,

 (1) hydrogen atom,

(2) C, _ ₆ alkynole group,

(3) C ₆ _ ₁₄ 7 reel group which may be substituted,

(4) It may be substituted. ₆ — ₁₄ aryl ₆ alkyl group,

(5) ft Heterocyclic group which may be replaced,

(6) C ₃ _ ₇ cycloalkyl group which may be substituted

Or

(7) optionally substituted C ₃ - ₇ shows a cycloalkylalkyl group, R ¹³ is, (1) hydrogen atom,

 (2) an alkyl group,

 (3) hydroxyl group

Or

(4) indicating an alkoxy group);

R ³ and R ⁴ are joined together with R ⁵

(Wherein R ⁸ , R ⁹ , R ¹⁰ , R ", R ¹² and R ¹³ are as defined above), R ⁶ represents a hydrogen atom or an alkyl group;

R ²¹ represents a hydrogen atom;

Ring B is

(1) C ₆ — ₁₄ reel group,

(2) C ₃ - ₇ cycloalkyl group,

 (3). Cycloalkenyl group

Or

 (4) represents a heterocyclic group,

3. The fused N-containing heterocyclic compound according to claim 2, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. 4. In the general formula (1),

R ⁵ joins R ⁶

(Wherein R ⁸ and: ⁹ have the same meanings as in claim 1), wherein the fused N-containing heterocyclized compound according to any one of claims 1 to 3, a prodrug, or a prodrug thereof. Pharmaceutically acceptable salts.

5. — In general formula (1),

R ⁵ joins R ⁶

(Wherein R ⁸ has the same meaning as in claim 1). 3. The fused N-containing heterocyclic compound or prodrug thereof according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

6. In the general formula (1),

R ⁵ joins R ⁶

(Wherein R ¹² and R ¹⁷ have the same meanings as in claim 1), wherein the fused N-containing heterocyclic compound or a prodrug thereof according to claim 1 or 2, or a medicament thereof. Acceptable salts.

7. In general formula (1),

R ³ and are together with R ⁵ :

Wherein R ⁸ and R ⁹ have the same meanings as in claim 1>, wherein the fused N-containing headero ring compound or prodrug thereof according to any one of claims 1 to 3, or a prodrug thereof. 8. A pharmaceutically acceptable salt of: 8. —In the general formula (1), R ⁷ is —OR ¹⁴ group (where R ¹⁴ is as defined in claim 1) or hydroxyamino group. The fused N-containing heterocyclic compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7. 9. The method according to any one of claims 1 to 8, wherein m is 1. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

10. The fused N-containing heterocyclic compound according to any one of claims 1 to 9, wherein n is 0, a prodrug thereof, or a pharmaceutically acceptable salt thereof. -

11. A claim wherein R ¹ is one (CH ₂ ) _p -X- (CH ₂ ) _q — A ¹ (wherein each symbol is as defined in claim 1), and R ² is a hydrogen atom. The condensed N-containing heterocyclic compound described in any one of 1 to 10, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

12. The fused N-containing heterocyclic compound or a prodrug thereof according to claim 11, wherein p and q are each independently 0 or 1, and X is a single bond or 1 O—. Pharmaceutically acceptable salts of . 1 3 R ⁷ is a hydroxyl group, condensation N-containing heterocyclic compound or a flop Dora according to any one of claims 1 to 1 2 Tsu grayed,:. _Further: is acceptable salts their pharmaceutically.

1 4. R ⁷ is a hydroxy § amino group, fused N heterocyclic compound containing or ^ Because flop p drag, or salts capable of their pharmaceutically allowable according to any one of claims 1 to 1 2. '"' ■ '·

15. A compound according to claim 1 selected from the following group or a prodrug thereof or a pharmaceutically acceptable salt thereof:

 5-[4- (3,5-Dicyclophenoxy) -benzenesulfonyl] -2- (4-fluoro-phenyl) -3-oxo-2,3,4,5,6,7- Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

 (R)-2-Benzyl-5- (4-benzyloxy-benzenesulfol) -3-oxo-2,3,4,5,6,7-hexahydro-1H-virazo [4,3-c ] Pyridine-4-potency reponic acid hydroxyamide,

5- (4-benzyloxy-benzenesulfol) -2-methyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4 -Hydronic acid hydroxyamide, 2-benzyl-5- (4-benzyloxy-benzenesulfol) -1-methyl-3-oxo -2,3,5,6,7-hexahydro-1H-pyrazo Mouth [4,3-c] pyridine-4 mono-hydroxy acid amide,

5- (4-benzyloxy-benzenesulfonyl) -2-tert-butyl, 3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine -4-hydroxysulfonic acid,

5- (4-Benzyloxy-benzenesulfonyl) -3-oxo-2,3,4,5,6,7-hexahydrid-1H-pyrazolipid [4,3-c] pyridine-4-hexanoic acid Hydroxyamide, 5- (4-benzyloxy-benzenesulfonyl) -2 -butyl-3-oxo -2,3,4,5,6,7-hexahydro-1H-pyrazo-mouth [4,3-c] pyridine -4 -force Rubonic acid hydroxyamide,

2-cyclohexyl-5- [4- (3,5-dimethoxy-phenoxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7-hexahydro 1KK pyrazine [4 ,, 3-c] pyridine-4-hydroxysulfonic acid hydroxyamide,

 5- (4-benzyloxy-benzenesulfol)--oxo-2-phenyl -2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyri.di ^ 4-. Canoleponic acid hydroxyamide, 5- (4-benzyloxy-benzene-rubo-JV-3-oxo-2-phenethyl-2,3,4,5,6,7-hexahydro-1H-H. Mouth [4, 3-] lysine-4-carboxylic acid hydroxyamide,

 5- (4-benzyloxy-benzenesulfol) -1-butyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo-mouth [4,3-c] pyridine-4 -Carboxylic acid hydroxyamide, 2-benzyl-3-oxo-5- (4-phenoxy-benzenesulfonyl) -2,3,4,5,6,7-hexahydro-1H-pyrazo mouth [4,3 -c] pyridine-4-hydroxysulfonic acid,

2-Benzyl-5- (biphenyl-4-sulfol) -3-oxo-2,3,4,5,6,7-hexahydrid-1H-pyrazo [4,3-c] pyridine- 4-Hydronic acid hydroxyamide,

2-Benzyl-5- (4-hydroxy-benzenesulfonyl) -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine- 4-Hydroxycarboxylic acid hydroxyamide,

2-benzyl-5- [4- (3,5-dicopen-phenoxy) -benzenesulfoel] -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4-carboxylic acid hydramide oxiamide,

 2-Benzyl-5- (4-benzinoleoxy-benzenesulfol) -7, todimethyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3 -c] Pyridine-4-hydroxysulfonic acid hydroxyamide,

5-(4-benzyloxy-benzenesulfoel)-2- (3-co-mouth-benzyl)-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo-mouth [4 , 3-c] pyridine-4-hydroxysulfonic acid,

2-Benzyl-3-oxo-5- (4-methyl-benzenesulfonyl) -2,3,4,5,6,7-hexahydrid-1H-pyrazo [4,3-c] pyridine- 4-potassium hydroxyamide, 5- [4- (2,4-dicopen-benzyloxy) -benzenesulfoel] -2- (3-pentyl) -3-oxo-2,3,4,5,6,7-hexahydro-1H -Pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

 5- [2- (4, -biphenyl-4-yl)-: ethasles.hol] -3-oxo-2-buenyl-2,3,4,5,6,7- Xahydro-1H-la-lysine-4-carboxylic acid hydroxyamide,

5- ( _4- benzyloxy-benzenesulfonyl) 2-(-co-mouth-phenyl) _-3- oxo-

2, 3, 4, 5, 6, Kisahidoro to 7 - La ^ lysine - ⁴ - The Power carboxylic acid arsenate mud Kishiami de, ':' .. ";^'-':: .- ':'. '. '

5- (4-Methoxy-benzenesulfol) -3-oxo 2-phenyl -2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] Pyridine- ^ "carboxylic acid hydroxyamide,

 2-Benzyl-5- (biphenyl-3-sulfol) -3-oxo-2,3,4,5,6, hexahydrid -1Η-pyrazo [4,3-c] pyridine- 4-ca ^ bonic acid hydroxyamide,

 2-Benzyl-5- (biphenyl-2-sulfur) -3-oxo-2,3,4,5,6,7-hexahydrid-1H-pyrazo [4,3-c] pyridine- 4-carboxylic acid hydroxyamide,

 2-Benzyl-3-oxo-5- (3-phenoxy-benzenesulfol) -2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine- 4-carboxylic acid hydroxyamide,

 3-oxo-5- (4-phenoxy-benzenesulfol) -2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4 -Hydroxycarboxylic acid hydroxyamide,

5-(Bifur-4-sulfol)-3-oxo-2-phenol-2,3,4,5,6,7-hexahydrid-1H -pyrazo [4,3-c] Pyridine-4-hydroxyluronic acid hydroxyamide,

2-Benzyl-5- (4-benzyloxy-benzenesulfoel) -3-methoxy-4,5,6,7-tetrahydro-2H-pyrazo [4,3-c] pyridine-4--4-sulfonic acid Hydroxamide, 2-benzyl-5- [2- (4-fluoro-phenoxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo Mouth [4,3-c] pyridine-4 monohydroxy ruponic acid,

5- [2- (4-Fluoro mouth-phenoxy) -benzenesulfonyl] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo mouth [ 4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide, 5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfonyl] -2- (2,5-dimethyl-phenyl) -3-oxo-2,3,4,5,6,7 -Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-

4-Hydroxycarboxylic acid

 5- [4- (2,4-Dic-mouth-benzyloxy) benzenesulfol]-2- (2,5-dichloro-phenyl) -3-oxo-2,3,4,5,6 7-Hexazide-1H -Vilazo mouth [4,3-c] pyridine-

4-Hydroxycarboxylic acid hydroxyamide,

3-Oxo-5- (3-phenoxy-benzenesnolle) -2-Fe-nore-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c ] Pyridine:-4-hydroxycarboxylic acid hydramide, 2- (4-octanol-phenyl) -3-oxo-5-:( 4, phenyloxybenzene) -2,3,4,5,6 , 7-Hexahydro-18-pyrazo [4, c] hydrolysin-4-hydroxypropyl amide,.: ''' ^: · ^:

 5- (4-benzyloxy-benzenesulfol) -2 (4-tert-butyl-phenyl) -3-oxo-2,3,4,5,6,7-hexahydro-1H-virazo [4 , 3-c] pyridine-4-carponic acid hydroxyamide,

5- [4- (2,4-Dic-mouth-benzyloxy) -benzenesulfoel] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-birazolo [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide,

 2-benzyl-5- [4- (2,4-dichloro-benzyloxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide,

 5- (4-Butoxy-benzenesulfonyl) _3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo-mouth [4,3-c] pyridine-4-force Ruponic acid hydroxyamide,

 2- (3-cuffed loafure) —3-oxo-5- (4-phenoxy-benzenes / levoninole) -2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3 -c] pyridine-4--4-hydroxysulfonic acid,

 2-Benzyl-5- [4- (2-methyl-benzyloxy) -benzenesulfol;]-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo mouth [ 4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide,

2-Benzyl-5- [4- (3-methyl-pentinoleoxy) -benzenesulfoel] -3-oxo- 2,3,4,5,6,7-Hexahydro-1H-pyrazo-mouth [4,3-c] pyridine-4-pyruvonic acid hydroxyamide,

 2-Benzyl-5- [4- (4-methyl-benzyloxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4 , .3 "^] pyridine-4-carboxylic acid hydroxyamide,

 5-[4- (4-Fluoro-mouth-benzyloxy) -benzenesulfol;]-3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-benzo [ 4, 3-G] pyridine-4-hydroxycarboxylic acid amide,

 2-Naphthalene-1-yl-3-oxo-5- (4-phenoxy-benzenesulfol) -2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3 -c] pyridine- ^ carboxylic acid hydroxyamide,

 5- [4- (2-methyl-benzyloxy) -ben'zensulfur] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4, : 3-e] pyridine-4-casolepon 蹿 hydroxyamide,

5- [4- (3-Methyl-benzyloxy) -benzenesulfur] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [ 4, 3-c) pyridine-4-carboxylic acid hydroxyamide,

 5-[4- (4-Methyl-benzyloxy) -benzenesulfoel] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo mouth [4 , 3-c] pyridine-4-hydroxycarboxylic acid hydroxide,

 5- [4- (2-cyano-benzyloxy) -benzenesulfol] -3-oxo-2-phenynole-2,3,4,5,6,7-hexahydro-1H-pyrazo mouth [4,3 -c] pyridine-4-carboxylic acid hydroxyamide,

 2-Benzyl-5- (4-pentyloxy-benzenesulfonyl) -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyri. Gin-4-carboxylic acid hydroxyamide,

(R) -2-benzyl-5- [4- (4-fluoro-benzyloxy) -benzenesulfoel] -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo Mouth [4,3-c] pyridine-4-hydroxysulfonic acid, hydroxyamide,

3-oxo-2-phenyl-5- [4- (2-methyl-phenoxy) -benzenesulfur]- 2,3,4,5,6,7-Hexahydro-1H-pyrazo-mouth [4,3-c] pyridine-4-hydroxypyruvonic acid hydroxyamide,

 2-Benzyl-3-oxo-5- [4- (2-methyl-phenoxy) -benzenesulfur] -2,3,4,5,6,7-hexahydro-1H-If ≠> " c] .Pyridine 4-ruponic acid hydroxyamide,, '

3-oxo-2-phenyl-5- [4- (4-methylphenoxy) -benzenesulfonyl] -2,3,4,5,6,7-hexahydro-1H-lazolo [4,3 _c]: pyridine - ⁴ _ carboxylic acid hydrochloride Kishiami de, ''

 2-Benzyl-3-oxo-5- [4- (4-Methyl-phenyl) -benzenesulfonyl] -2,3,4,5,6,7-Hexahydro-1H-villa: / ^ Sc] pyridine-4-carboxylic acid hydroxyamide,

 3-oxo-2-phenyl-5- [4- (2-rifluoromethyl-benzyloxy) -benzenesulfonyl] -2,3,4,5,6,7-hexahydro-1H-birazolo [4, 3-c] pyridine-4-hydroxysulfonic acid, hydroxyamide,

2- (2-c-mouth-fuel)-3-oxo-5- (4-phenoxy-benzenesulfoel)-2,3,4,5,6,7-hexahydro-1H-pyrazo [4 [, 3-c] pyridine-4-carboxylic acid hydroxyamide,

 5- [4- (3,4-dimethoxy-phenoxy) -benzenesulfoel] -3-oxo-2--2-phenyl-2,3,4,5,6,7-hexahydro-1H- Pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

 5-[4- (4-Methoxy-phenoxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4-hydroxypropyl amide,

 5- [4- (4-c-mouth-phenoxy) -benzenesulfonyl] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo mouth [ 4,3-c] pyridine-4-hydroxysulfonic acid, hydroxyamide,

5- (4-Pendinoleoxy-benzenesulfo-nore) -2-naphthalene-1-yl-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo mouth [4,3 -c] pyridine-4-carboxylic acid hydride P xyamide, 5- (4-benzyloxy-benzenesnorrehole) -2- (2-chloro-phenyl) -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4 , 3-c] pyridine-4-hydroxysulfonic acid hydroxyamide,

 5- [4- (3,5-dichloro-phenoxy, n) "be ^^^ sul ^ l] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro- 1H-razo >> c] pyridine-4-hydroxycarboxylic acid hydroxyamide,

 5- [4- (2-chloro-phenoxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4 , 3 c] Pyridine-4-hydroxypropyl amide,

3-oxo-2-phenyl-5- [4- (pyridine-4-yloxy) -benzenesulfonyl] -2,3,4,5,6,7-hexahydro-1H-pyrazo. [3,3, c] pyridine-4-carponic acid hydroxyamide,

 5- [4- (2-Methoxy-benzyloxy) -benzenesulfonole] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-virazo [ 4, 3-c] pyridine-4-hydroxycarboxylic acid hydroxide,

 5- [4- (2-c-mouth-benzyloxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo Mouth [4,3-c] pyridine-4-carboxylic acid

 2-Benzyl-5- [4- (2-Methoxy-phenoxy) -benzenesulfoel] -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4 , 3-c] pyridine-4-hexanoic acid hydramide oxiamide,

 2-Benzyl-5- [4- (2- (co-mouth-phenoxy) -benzenesulfur]-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazolo [4 , 3-c] Pyridine-4-potassium heptadroxyamide,

5- [4- (2-Fluoro-benzyloxy) -benzenesulfonyl] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [ 4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide,

5- [4- (2,4-dicopen-benzyloxy) -benzenesulfonyl] -2- (5-fluoro-2-methyl-phenyl) -3-oxo-2,3,4,5,6,7 -Hexahydrid-1H -Pyrazo [4,3-c] 4-lysine lysine rubonic acid hydroxyamide,

 5- (4-benzyloxy-benzenesulfonyl) -7,7-dimethyl-3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-111-pyrazolo [4,3- (5) pyridine 4-carboxylic acid hydroxyamide,

5- [4- (2,5-dimethyl-benzyloxy) n-sulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1 pyrazo [4, -cl pyridine- 4-hydroxycarboxylic acid,

2 - base Njiru - 3 - Okiso 5- [4- (2-Torifuruo ^ methyl phenoxy) - benzene sul Honiru] - ^2, 3, 4, 5, 6, 7 - to Kisahi mud pyrazole port [4, 3- c] pyridine-4-carbonic acid hydroxyamide,

 5- [4- (2,6-Dic-mouth-benzyloxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-birazo Mouth [4,3-c] pyridine-; 4-hydroxyluronic acid hydroxyamide,

 5-[4- (2,4-Dicopen-benzyloxy) -benzenesulfol] -2- (2,5-difluoroopent-phenyl) -3 -oxo-2,3,4,5,6,7 -Hexahydro-1H-pyrazo-mouth [4,3-c] pyridin-4-hydroxycarboxylic acid hydroxyamide,.

 5- [4- (3,5-Bis-trifluoromethyl-phenoxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7- Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

5- (4-benzyloxy-benzenesulfur) -3-methyl-2-phenyl-4,5,6,7-tetrahydro-2H-birazolo [4,3-c] pyridine-4-carboxylic acid Hydroxyamide,

5- (4-Benzyloxy-benzenesnorrehol) -3-oxo-2-furyl-1,2,3,4,5,6,7,8-otatahydro-1,2,5-triaza-azulene -4-Hydrorubic acid hydroxyamide,

2- (2,5-dimethoxy-phenyl) -5- [4- (3-Methoxy-5-methyl-phenoxy) benzenesulfol] -3-oxo-2,3,4,5 , 6,7-hexahydrid-1H-pyrazolic [4,3-c] pyridin-4 -pyruronic acid hydroxyamide,

5- (4-benzyl-benzenesulfol) -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo-mouth [4,3-c] pyridine -4-potassium hydroxyamide, 3-oxo-5- (4-phenethyl-benzenesulfur) -2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine 4-hydroxycarboxylic acid amide,

 5- (4-Pendyloxy-benzenesulfol) -2-cyclohexyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo E4,3-C3.pyridine -4-Ruponic acid hydroxyamide,

 3-oxo-2-phenyl-5- [4- (3-thi ^^-phen / xy) -benzenes / lefonyl] -2,3,4,5,6,7-hexahydro-1H- Villa: [4, 3-0]: t-lysine-4 ^ -hydroxysulfonic acid,

 5- [4- (3,5-Dimethinole-phenoxy) -benzenesulfol] -3-oxo-2-phenyl -2,3,4,5,6,7-hexahydro-1H-pyrazo mouth [ 4,3-c] pyridine-4-hydroxysulfonic acid 4-hydroxyamide,

 5- [4- (2-chloro-6-fluoro-benzyloxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydrid-1H- Pyrazolo [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide,

5- [4- (3,5-dic-mouth-phenoxy) -3-fluoro-benzene-sulfur] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydride Mouth-Vilazo Mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

 5- [4- (2,3-dichloro-benzyloxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

 5- [4- (2,4-dichloro-benzyloxy) -benzenesulfol] -7,7-dimethyl-3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro -1H-Vilazo mouth [4,3-c] pyridine-4-force rubonic acid hydroxyamide,

 5- [4_ (2-Chloro-4-fluoromouth-benzyloxy) -benzenesnolephonyl] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H -Pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

5- [4- (3-Isopropyl-5-methyl-phenoxy) -benzenesnolejoel] -3-oxo-2--2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [ [4,3-c] pyridine-4-carboxylic acid hydroxyamide, 5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfur] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H- Pyrazo mouth [4,3-c] pyridine-4-carboxylic acid

2-cyclohexylmethyl-5- [4- (2,4-dicopen-benzyloxy) -benzenesulfoyl] -3-oxo-2,3,4,5,6,7-hexahydro-1H -Villazo mouth [4, 3 c]! Gin-4 rubonic acid hydroxyamide,

 5- [4- (2,3-Dic-mouth-phenoxy) -benzenesulfonyl] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo Mouth [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide,

 5- [4- (2,5-Dic-mouth-phenoxy) -benzenesulfonyl] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H -Pyrazo mouth [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide,

 3-oxo-5- (4-phenoxymethyl-benzenesnorrenol) -2-pheninolae 2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4 -Hydrorubic acid hydroxyamide,

 2- (2,5-difluoro mouth-phenol) -5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -3- 3-oxo-2,3,4, 5,6,7-Hexahydro-1H-pyrazolo [4,3-c] pyridin-4-hydroxypyruroic acid hydroxyamide,

5- [4- (3,5-dicyclophenoxy) -benzenesulfur] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H -Pyrazo mouth [4,3-c] pyridine-4-hydroxysulfonic acid,

3-oxo-2-phenyl-5- [4- (2,4,5-trifluoro-benzyloxy) -benzenesulfol] -2,3,4,5,6,7-hexahydro-1H -Vilazo π [4,3-c] pyridine-4-carboxyl Acid hydroxyamide,

 5-[4- (3,5-Difluoro-phenoxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo Mouth [4,3-ό] pyridine-4-butyronic acid hydroxyamide, '

5- [4- (2-Fluoro mouth-phenoxy) -benhole] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1 --H. La _{.9:. [4, t °} V Gin - 4- force carboxylic acid arsenate mud Kishiami de,, Two: ',..

 5- [4- (2,4-Dichrolic-benzyloxy) benzene sulfol] -3-oxo-2- (4-heptyl) -2,3,4,5,6,7-hexahydro- 1H-pyrazo mouth 4; 3-c] pyridine-4-hydroxysulfonic acid hydroxyamide,

 5- [4- (2-Ethyl-phenoxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4 , 3-c] pyridine-4-rubonic acid hydroxyamide,

 5-[4- (6-Cupro-benzo [1,3] dioxyl-5-ylmethoxy) -benzenesulfonyl] -3-oxo-2--2-phenyl-2,3, 4,5,6,7-Hexahydro-1H-pyrazo mouth [4,3-c] pyridin-4-carboxylic acid hydroxyamide,

 5-[4- (2,4-Dic-mouth-benzyloxy) -benzenesulfol] -2- (2-tyl-butyl) -3-oxo -2,3,4,5,6,7- Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

5- [4- (2,4-Dic-mouth-benzyloxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H- Pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

 To (R) -5- [4- (2,4-dichloro-benzyloxy) -benzenesulfoere] -3-oxo-2-fu: nil-2,3,4,5,6,7- Xahydrid-1H-pyrazo [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide,

 5- [4- (4-Fluoro-2-methyl-phenoxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro- 1H-Pyrazo mouth [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide,

5- [4- (2,3-dimethyl-phenoxy) -benzenesulfel] -3-oxo-2-phenyl- 2,3,4,5,6,7-Hexahydro-1H-pyrazo [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide,

 5- [4- (2,5-dichloro-benzyloxy) -benzenesulfol] -3-oxo-2-fueni

Ehl) -3-oxo-2,3,4,5,6,7-hexahydrol 1H-pyrazo-mouth [4,3-c] pyridine-14-carboxylic acid hydroxyamide,

2-cyclopentyl-5- [4- (3,5-dichloro-phenoxy) -benzenesulfur] -3-year-old oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo Mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

 5-[4- (3,5-Dic-mouth-phenoxy) -benzenesulfol] -2- (2-Fluoro-mouth) -3 -oxo-2,3,4,5,6, 7-hexahydro-1H-pyrazo [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

 To 5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfol] -3oxo- 2- (2-methyl-furyl) -2,3,4,5,6,7- Xahydrid-1H-pyrazolic [4,3-c] pyridine-4-potency rubonic acid hydroxyamide,

 5-[4- (2,4-Dic-mouth-benzyloxy) -benzenesulfonyl] -3-oxo y-2- (3-methyl-phenyl) -2,3,4,5,6, 7-Hexahydro-1H-pyrazo-mouth [4,3-c] pyridine-4-force rubonic acid hydroxyamide,

5- [4- (3,5-dimethoxy-phenoxy) -benzenesulfoel] -2-(2-methoxy-phenol) -3-oxo -2,3,4,5,6,7 -Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide, 5- [4- (2,5-difluoro-benzyloxy) -benzenesulfonyl] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydrid-1H-pyrazo [4,3-c] pyridine-4-carboxylic acid

5- (4-cyclohexylmethoxy, benzenesulfol) -3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro 1H-pyrazo [4,3- c) Pyridine-4-hydroxycarboxylic acid,

 To 5- [4- (3,5-dichloro-phenoxy) -benzene: sulfoel] -3-oxo-2- (3-methyl-furyl) -2,3,4,5,6,7- Xahydro-1H-birazo mouth [4,3-c] pyridine-4-hydroxysulfonic acid hydroxyamide,

 5- [4- (3,5-Dic-mouth-phenoxy) -benzenesulfonyl] -2- (3,5-dimethyl-phenyl) -1-oxo-2,3,4,5,6 7-hexahydrid-1H-pyrazolipid [4,3-c] pyridine-4-potency rubonic acid hydroxyamide,

 5- [4- (2,4-Dichloro-benzyloxy) -benzenesulfol] -2- (2-ethyl-phenyl) -3- 3-oxo-2,3,4,5,6,7- Xahydro- 1H-pyrazo-mouth [3-c] pyridin-4-force rubonic acid hydroxyamide,

 5- [4- (2,4-dichloro-benzyloxy) -benzenesulfonyl] -3-oxo-2-(2-trifluoromethyl-phenyl) -2,3,4,5,6 , 7-Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

2- (3-chloro-phenyl) -5- [4- (2,5-dimethyl-benzyloxy) -benzenesulfonyl] -3-oxo-2,3,4,5,6,7-hexahydro- 1H-pyrazo mouth [4,3-c] pyridine-4-force hydronic acid hydroxyamide,

5- [4- (3,5-Dic-mouth-Phenoxy) -benzenesulfur] -2- (3-Fluoro-mouth) -3-oxo-2,3,4,5 6,7-Hexahydro-1H-virazo mouth [4,3-c] pi Vzin-4-cal Ponic acid hydroxyamide,

 2- (3-chloro-phenyl) -5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfonyl] -3-oxo-2,3,4,5,6,7- Hexahiro-1H-pyrazo mouth [4,3-c] pyridine-4-force rubonic acid hydroxyamide, :::: ,,

2- (3-chloro mouth-phenyl) -5- [4- (3,5-di-c-σ-phenoxy) -benzenesnolehonyl] -3-oxo-2,3,4,5,6 7 · Kisapi: Lazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide,: '

 5-[4- (2,4-Dic-mouth-benzyloxy) -benzenesulfonyl] -2- (3-methoxy-phenyl) -3-oxo -2,3,4,5,6,7 -Hexahydride II ^ birazolo [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

 2-cyclopentyl-5- [4- (2,4-dicopen-pentyloxy) -benzenesulfol]-

3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo-mouth [4,3-c] pyridine 4-carboxylic acid hydroxy, amide,

 5- [4- (3,5-Dichro-phenoxy) -benzenesulfol] -2- (3 methoxy-phenyl) -3-oxo-2,3,4,5,6,7- Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

 2-cyclopentyl-5- [4- (2,4-difluoromouth-benzyloxy) -benzenesulfonyl] -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo Mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

5-[4- (3,5-Dichloro-phenoxy) -benzenesulfol]-2- (3,5 dichloromouth-phenol) -3-3-oxo-2,3,4,5,6,7 -Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4 rubonic acid hydroxyamide,

 5- [4- (3,5-dic-mouth-phenoxy) -benzenesulfonyl] -3- 3-oxo-2-(3-trifluoro-methyl-phenyl) -2,3,4,5 6,7-Hexahydro-1H-pyrazo [4,3-c] pyridin-4-hydroxysulfonic acid hydroxyamide,

 5- [4- (2,4-Dic-mouth-benzyloxy) -benzenesulfol] -2- (3,5-dic-mouth-phenyl) -3-oxo-2,3,4,5 , 6, 7-Hexahydro-1H-pyrazo [4,3-c] pyridine-

4-Hydronic acid hydroxyamide,

5- [4- (2,4-dimethoxy-5-fluoro-benzyloxy) -benzenesulfol] -3-oxo So-2-phenyl-2,3,4,5,6,7-hexahydro-1H-birazolo [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

 (R) -5- [4- (2,5-Dichloro-benzyloxy) -benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7- Xahiide p “rH.lazo £ 4,3-c] pyridine 4-carboxylic acid hydroxyamide,:,::

 5-[4- (2,4-Dic-mouth-benzyloxybennul-fur)] -3-oxo-2- (3-trifluoro-methyl-phenyl) -2,3,4, H, Hydro- 1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide;

 (R) -5- [4- (2, ^ difluoro-open-benzene, rooki;) benzenesulfol] -3-oxo-2-phenyl-2,3,4,5,6,7-hexahi 1H-Pyzo [4,3-c] pyridine-4-carbonic acid hydroxyamide,

 (R) -5- [4- (3-Methoxy-5-methyl-fue, xy) -benzenesulfonyl] 3-oxo-

2-Fuel-2,3,4,5,6,7-Hexahydro-1H-pyrazo-mouth [4,3-c] pyridine-4-Hydroxycarboxylic acid hydroxyamide,

(R)-2-cyclopentyl -5- [4- (3,5-dicyclopent-phenoxy) -benzenesulfol]-

3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

 To (R) -2-pentyl-pentyl-5- [4- (3-methoxy-5-methyl-phenoxy) -benzenesulfur] -3-3-oxo-2,3,4,5,6,7- Xahydro-1H-pyrazo mouth [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide,

 (R)-2-pentyl pentyl -5-[4- (2,4-dichlorobenzene / reoxy) -benzenes / lefonyl]-3-oxo -2, 3, 4, 5, 6, 7-hexahydro-1H-pyrazo [4,3-c] viridine 4-carboxylic acid hydroxyamide,

 ) -2-Cyclobutyl-5- [4- (2,4-dichloro-benzyloxy) -benzenesulfonyl] -3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3_c] pyridine-4-carboxylic acid hydroxyamide,

(R) -2-cyclopropyl-5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7-hexahydro -1H-Pyrazo mouth [4,3-c] pyridine— 4-carboxylic acid hydroxyamide, (R) -2-(3-Cu-ro-phenyl) -5- [4- (2,5-Di-c-ro-benzene / reoxy) -benzenesulfonyl] -3-oxo-2,3 4,5,6,7-Hexahydro-1H-pyrazo [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide,

 (S) -2-cyclopentyl pentyl-5 -5 hexose, PX noxyl) -benzene-sulfonyl] -3-oxo--2,3,4,5,6,7-hexahi .. 4, 3-c] pyridine-4-carboxylic acid hydroxyamide,

(R) - 5- [4 - (2, 4 - Axis every mouth - benzylidene O ^ sheet) Penzensuruho -] -3- Okiso -2 - peak lysine - ² - I le - ^2, 3, 4, 5, 6, to 7-hexa 13 arsenide Razoro [4, 3-c] pyridin ^-? 4 Chikararu Bonn acid hydroxyamidine de,

(R) -5- [4- (3-Methoxy-5-methylhook: ki) -benzenesulfol] -3-oxo-

2-pyridine-2-yl-2,3,4,5,6,7-hexahydro 1H-pyrazo-mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

 (4R) -5- [4- (2,4-Dic-mouth-benzyloxybenzenesulfonyl} -2-indan-tolyl-3-oxo-2,3,4,5,6,7-hexahydro -1H-Bilazolo [4,3-c] pyridine-4-force ruponic acid hydroxyamide,

 (R)-2- (3-kuguchi-pyridin-2-yl) -5- [4- (≥, 4dichloro-benzyloxy) -benzenesulfoel] -3-oxo -2,3,, 5, 6,7-Hexahydrid-1H-Pizazo [4,3-c] pyridine-4-hydroxyluronic acid hydroxyamide,

 (R) -5- [4- (2,4-Dic-mouth-benzyloxy) -benzenesulfol] -3-oxo-2--2-quinolin-2-yl-2,3,4,5,6 , 7-Hexahydro-1H-pyrazo [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide,

 (R) -2-tert-butyl-5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -3-oxo-2,3,4,5,6,7- Hexahydro-1H-pyrazo mouth [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide,

(R) -5-[4- (2,4-Dic-mouth-benzyloxy) -benzenesulfonyl] -oxo-1, 3,4,5,6,7-hexahydro-isoxazolo [4,3-c] Pyridine-4-hydroxycarboxylic acid,

 () -5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfol] -7,7-dimethyl-

3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine- 4-Hydronic acid hydroxyamide,

 (R) -5- [4- (2,4-Dic-mouth-benzyloxy) -benzenesulfonyl] -spiro [Sic-mouth hexane-7,1,-(3-oxo-2--2-phenyl- Si 4,5,6,7-Hexahydro-1H-pyrazo [4,3-c] pyridine)]-4-carboxylic acid.

(R) -5- [4- (2 , 4 - Axis every mouth - Benjiruo> - emission ^ Nsuruho - le - spiro [consequent opening propane - 7, - (3 - Okiso -2 - off Bruno, 5; 7 -Hexahydro-1H-pyrazo mouth [4,3-c] pyridine)]-4-carboxylic acid:

 (R) -5- [4- (2,4-Dichloro-benzoyloxy) -nzenesulfol] -spiro [cyclo-butane— 7, 1 '-(3-oxo-2-phenyl-2,3 , 4,5,6,7-Hexahydro-1H-pyrazo [4,3-c] pyridine)]-4-Hydroxycarboxylic acid amide,

(R) - 5-[4-(2, ⁴ - dichloro port - Benjiruoki) - benzenesulfonyl] - spiro [4, - Te Torahi Doropiran - 7, - (3-Okiso-2-phenyl - 2, 3 , 4,5,6,7-Hexahydro-1H-birazolo [4,3-c] pyridine)]-4-carboxylic acid hydroxyamide,

(R) -5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -spiro [cyclopropane-7,1,-(3-oxo-2fur-2, 3,4,5,6, M-hexahydride U-IH-Razo mouth [4,3-c] pyridine)]-4-Hydroxycarboxylic acid hydroxide,

 (R) -5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfe / le] -spiro [cyclohexane-7,1 '-(3-oxo-2- Feninole-2,3,4,5,6,7-hexahydro-1H-benzo [4,3-c] pyridine)]-4--4-hydroxysulfonic acid,

(R)-2-tert-butyl-5- [4- (2,4-dichloro-benzyloxy) -benzenes / lefonyl] -3-oxo-2,3,4,5,6,7- Xahydro-1H-pyrazo mouth [4,3-c] pyridine-4-carboxylic acid hydroxyamide,

 (R) -5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -spiro [cyclobutane-7, Γ- (3-oxo-2-furr-2,3, 4,5,6,7-Hexahydro-1H-pyrazo mouth [4,3-c] pyridine)]-4-Hydronic acid hydroxyamide,

 (R) -5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -7,7-dimethyl-3-oxo-2-phenyl-2,3,4,5 6,7-Hexahydro-1H-pyrazo-mouth [4,3-c] pyridinin-4-hydroxypropyl amide,

(R) -5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -spi [4'- Tetrahydropyran-7,--(3-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c] pyridine) -4 -Hydroxycarboxylic acid hydroxyamide,

(R) -5- (4-Penzyloxy-benzenesulfol) -2-tert-butyl-3- 3-quine-2,3,4,5,6,7-hexahydro-lH “£ 33: zine -6-carboxylic acid hydroxyamide, "'': '^; ..

(R)-2-Benzyl-5- (4-benzio.gishi X-zensulfoel) -3-oxo- 2,3,4,5,6,7-hexahydro-lg- ^ rak P¾: -c Pyridine- ⁶ -carboxylic acid hydroxyamide,

 (R) -5- (4-Benzyloxy-... K-fluoro) -2-methyl-3-oxo-2,3,4,5,6,7-hexahydrolH ^ fci. Lysine-6-carboxylic acid hydroxyamide,: ::> '■;:' ..: ·

 (R) -2_benzyl-5- (4-benzyloxy-benzesulfol) -1-methinole-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4, 3-c] pyridine-6-hydroxycarboxylic acid hydroxide,

(R) -5- (4-Benzyloxy-benzenesulfol) -2-butyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c ] Pyridine-6-hydroxysulfonic acid,

 (R) -5- (4-Benzyloxy-benzenesulfol) -3-oxo-2-phenenole-2,3,4,5,6,7-Hexahydro-1H-pyrazo [4,3 -c] pyridine-6-hydroxysulfonic acid,

 (R) -5- (4-Benzyloxy-benzenesnorehol) -1- 1-ptynole-3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazo [4,3-c ] Pyridine-6-hydroxycarboxylic acid,

 (3aR, 4R) -5- [4-(2,4-dimethoxy-benzyloxy) -benzenesulfol] -3a-methyl-3-oxo-2 -phenyl-3,3a, 4 , 5,6,7-Hexahydro-2H-pyrazo-mouth [4,3-c] pyridine-4-hydroxylhydroxyamide,

(3aR *, 4R *) -5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfo / le] -3a-methyl-3-oxo-2-phenyl-3,3a, 4,5 , 6,7-Hexahydro-2H-pyrazo mouth [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide, (3aR *, 4R *) -5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfonyl] -3a-ethyl-3-oxo-2-phenyl-2,3a, 4,5,6,7-Hexahydro-2H-pyrazo-mouth [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyami,: '

 (3aR *, 4R *) -5- [4- (2,4-dimethoxy-benzyloxy) -benzenesulfonyl] -3a-ethyl-3-oxo-2-phenyl-3,3a, 4,5 6,7-Hexahydro-2H-pyrazo [4,3-c] pyridine-4-hydroxycarboxylic acid hydroxyamide,

 (3a *, 4R *)-3a-Ethyl-5-[4- (3-Methoxy-5-methyl-phenoxy) -benzenesulfol] -3 -oxo-2-phenyl-3,3a , 4,5,6,7-Hexahydro-2H nihi. Lazolo [4,3-c] pyridine-4-hydroxysulfonic acid,

 (3aR *, 4R *) -5- [4- (2,4-dichloro-benzyloxy) -benzenesulfol] -3a-methyl-3-oxo-2-phenyl-3,3a, 4,5 , 6,7-Hexahydro-2H-pyrazo [4,3-c] pyridine-4-carboxylic acid,.

 (3aR, 4R) -5- [4- (2,4-dichloro-benzyloxy) -benzenesulfol] -3a-methyl-3-oxo-2-phenyl-3,3a, 4,5 6,7-hexahydro-2H-pyrazo [4,3-c] pyridin-4-carboxylic acid,

(3 &, 411 *) -5- [4- (3-Methoxy-5-methyl-phenoxy) -benzenesulnyl] -3a-methyl-3-oxo-2-phenyl-3,3a, 4,5 6,7-hexahydro-2H-pyrazo-mouth [4,3-c] pyridine-4-carboxylic acid,

(3aR *, 4R *) -5- [4- (2,4-dichloro-benzyloxy) benzenesulfonyl] -3a-ethyl-3--3-oxo-2-phenyl-3,3a, 4,5 , 6, 7-hexahydrid -2H-pyrazo ά [4,3-c] Lysine-4-carboxylic acid,

(3aR *, 4R *) -5- (4'-clo-biphenyl-4-sulfol) -3a-ethyl-3-oxo-2-phenyl-3,3a, 4,5,6 , 7 - to Kisahidoro - 2H - Ratho [4, 3-c] pyridine -. 4- carboxylic acid _{(3aR * 5 4R *) -5-} [4- (3, 5- Axis every mouth - j ^ ^ ^ our presence ^ e le] - a-methyl - ³ - Okiso - ² - Fe - Le - ^3, 3a, ^5, ¾ Ban de Contact ² H pyrazole port ^[4, 3-c] pyridine down -? 4-carboxylic acid, :: ':::

 (3aR *, 4R *)-3a-Ethyl-3-oxo-2-fu, 5 [1,; 4 ',,] terfener-4 -sulfoel) -3,3a, 4,5,6,7 -Hexa mouth ".: Zoro [4,3-c] pyridine-4-carboxylic acid, ■, '': ■"

(3aR *, 4R *)-5-[5- (4-Kuguchi-Fu2thiophene-2-Sulfonyl 3a-methyl-3-Oxo-2-phenyl-3,3a, 4,5, ^ '^ ^ De 2Η-pyrazo mouth [4,3-c] pyridin-4-carboxylic acid and

 (3aR *, 4R *) -5- (7-Pu-mo-9H-fluorene-2-sulfol) -3a-methyl-3-oxo-2-phenyl-3,3a, 4,5,6 7-Hexahydro-2H-pyrazo-mouth [4,3-c] pyridine-4-Hydronic acid.

16. A medicament comprising the fused N-containing heterocyclic compound according to any one of claims 1 to 15 or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Composition.

17. An aggrecanase inhibitor comprising the fused N-containing heterocyclic compound according to any one of claims 1 to 15 or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. 18. An MMP containing, as an active ingredient, a fused N-containing heterocyclic compound or a prodrug thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15. — 13 inhibitors.

9. The fused N-containing heterocyclic compound according to any one of claims 1 to 15, A prophylactic or therapeutic agent for osteoarthritis, comprising a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

22. A prophylactic or therapeutic agent for osteoarthritis comprising a compound having an MM P-13 inhibitory activity or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

23. A prophylactic or therapeutic agent for rheumatoid arthritis, comprising as an active ingredient a compound having an aglicanase inhibitory activity or a prodrug thereof, or a pharmaceutically acceptable salt thereof. 24. An agent for preventing or treating rheumatoid arthritis, which comprises a compound having an MMP-13 inhibitory activity or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

25. The method according to any one of claims 1 to 15, wherein the fused N-containing heterocyclic compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof is administered to a mammal. A method for inhibiting aglycanase.

26. Administering a fused N-containing heterocyclic compound or a prodrug thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 1.5 to a mammal. A method for inhibiting MMP-13.

A method for preventing or treating arthritis. 30. A method for preventing or treating osteoarthritis, which comprises administering a compound having a 13-13 inhibitory action, a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal.

31. A method for preventing or treating rheumatoid arthritis, which comprises administering a compound having an aggrecanase inhibitory activity, a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal.

32. A method for preventing or treating rheumatoid arthritis, which comprises administering a compound having a 13-13 inhibitory action, a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal.

33. The pharmaceutical composition according to claim 16, which is used in combination with another therapeutic agent for osteoarthritis.

34. The pharmaceutical composition according to claim 16, which is used in combination with another therapeutic agent for rheumatoid arthritis. Adult c

35. Any of Claims 1 to 15 in combination with a JB-condensed Φ condensate! ^-Containing heterocyclic compound or a prodrug thereof, or a salt from which Jf can be obtained, and a therapeutic agent for osteoarthritis ^ .7 IB Ning's method for preventing or treating osteoarthritis.

36. A condensed N-containing heterocyclic compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 15, and other rheumatoid arthritis. ( ² ) A method for preventing or treating chronic rheumatism listed on $ ia. .

37. The pharmaceutical composition according to claim 16, and the pharmaceutical composition, which states that the pharmaceutical composition can or should be used for prevention or treatment of osteoarthritis. A commercial package containing a statement about the.

38. The pharmaceutical composition according to claim 16, and the pharmaceutical composition, which states that the pharmaceutical composition can or should be used for the prevention or treatment of rheumatoid arthritis. A commercial package containing a description of the thing. .