JP2007277093A - Tricyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound useful as a drug for the remedy or prevention of an inflammatory disease or an autoimmune disease associated with an IKK2. <P>SOLUTION: The present invention has been accomplished by the finding that a tricyclic compound characterized by comprising a pyridine ring substituted with a nitrogen-containing saturated hetero ring or a substituted amino group and a thiophene ring substituted with a carboxamid group and an amino group has an excellent anti-inflammatory action based on its inhibitory action on IKK2 and is particularly useful as a drug for the remedy or prevention of an inflammatory disease or an autoimmune disease. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a tricyclic compound useful as a therapeutic or prophylactic agent for a disease involving IKK2, such as a pharmaceutical, particularly rheumatoid arthritis.

Nucleofactor κB (NF-κB) is an inflammation of cytokines (TNF-α, IL-1β, IL-6, etc.), chemokines (RANTES, IL-8, etc.), or arachidonic acid metabolizing enzymes (COX-2, etc.) It is a ubiquitous transcription factor that activates transcription and translation of proteins that contribute to the reaction, and plays an important role in acute and chronic inflammatory reactions in inflammatory diseases or autoimmune diseases (Mol. Cell Biol. 1999; 19: 4547-51). For example, in synovial cells of patients with rheumatoid arthritis (RA), NF-κB has been shown to be activated by translocation into the nucleus, and it can produce inflammatory mediators such as cytokines and eicosanoids at the inflammatory site. It has been pointed out that NF-κB plays a central role (Annu. Rev. Immunol. 1994; 12: 141-79).
It has been shown that inhibiting NF-κB activation can be an effective treatment for the aforementioned inflammatory diseases. For example, steroids, non-steroidal anti-inflammatory drugs (NSAIDs; salicylate, sulindac, etc.), immunomodulators (thalidomide, etc.) or antioxidants (flavonoids, etc.) that are widely used in clinical practice can activate NF-κB. It has an inhibitory effect (Nat. Rev. Drug Discov. 2004; 3: 17-26).
Normally, NF-κB is associated with its suppressor IκB and remains in the cytoplasm. When cells are stimulated with cytokines (TNF-α, IL-1β, etc.), bacterial or viral products (LPS, TAX, etc.), or chemicals (phorbol esters, etc.), IκB is stimulated by IκB kinases (IKK1 and IKK2) Phosphorylated. As a result, activated NF-κB released from IκB can be transferred into the nucleus, binds to a specific enhancer sequence in the nucleus, and initiates transcription and translation of cytokines and the like as described above.
IKK2 is important for NF-κB activation, and it has been suggested that inhibiting IKK2 is the most effective and selective method for suppressing NF-κB activation and inflammation based on it (Nat Rev. Drug Discov. 2004; 3: 17-26). In addition, it has been shown that fibroblasts lacking IKK2 do not activate NF-κB by cytokine stimulation (Science 1999; 284: 321-5). Furthermore, in various animal models, low molecular weight compounds that selectively inhibit IKK2 suppress the inflammatory response (Nat. Rev. Drug Discov. 2004; 3: 17-26), or IKK2 lacks enzyme activity. It has been reported that inflammatory responses are suppressed in animals in which mutants are expressed (Arthritis Rheum. 2001; 44: 1897-907).
In recent years, anti-cytokine antibody biologics such as TNF-α and IL-1 have attracted attention in the treatment of inflammatory diseases or autoimmune diseases, but it has been reported that the therapeutic effect alone is not sufficient. (Nat. Rev. Drug Discov. 2003; 2: 473-88). In fact, in clinical practice, biologics are usually used in combination with NSAIDs or steroids (Lancet 1999; 354: 1932-9). On the other hand, in a rat arthritis model, a synergistic therapeutic effect has been shown by using an anti-TNF-α preparation and an anti-IL-1 preparation together (Arthritis Rheum. 2001; 43: 2648-2659). Therefore, IKK2 inhibitors that simultaneously suppress various inflammatory factors in addition to TNF-α and IL-1 may have higher efficacy than drugs currently used to treat acute and chronic inflammation and autoimmune diseases There is.
In addition, IKK2 is involved in regulation of the expression of anti-apoptotic proteins (such as Bcl-2), and it has been reported that inhibitors of IKK2 exhibit antitumor activity (Drug Discovery Today 2002; 7: 653-63) .

（式中、R₁はフェニル、ヘテロアリール、ヘテロシクリル等、R₂はC_1-6アルキル、C_1-6アルコキシ、C_1-6アルキルアミノ、ヘテロシクリル(CH₂)_m-等、mは0又は1を示す。詳細は当該公報参照。）
また、4,5-ジヒドロナフト[1,2-b]チオフェン誘導体及び4H-インデノ[1,2-b]チオフェン誘導体（特許文献２及び特許文献３）等の三環系骨格を有するIKK2阻害化合物が報告されている。 The thienopyridine derivative represented by the following general formula (II) has an IKK2 inhibitory action and is suggested to be effective in the treatment of autoimmune diseases, inflammatory diseases, cancers and the like (Patent Document 1).

(Wherein R ₁ is phenyl, heteroaryl, heterocyclyl, etc., R ₂ is C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, heterocyclyl (CH ₂ ) _m — etc., m is 0 or (Refer to the publication for details.)
In addition, IKK2 inhibitor compounds having a tricyclic skeleton such as 4,5-dihydronaphtho [1,2-b] thiophene derivatives and 4H-indeno [1,2-b] thiophene derivatives (Patent Documents 2 and 3) Has been reported.

On the other hand, a compound represented by the following formula (III) is described as a raw material compound for producing a pharmaceutical compound (IV) (Patent Document 4 and Patent Document 5).

WO03 / 103661 pamphlet International Publication No. 04/009582 Pamphlet International Publication No. 03/086309 Pamphlet East German Patent No. 258018 East German Patent No. 258019

  An object of the present invention is to provide a pharmaceutical composition that has a potent anti-inflammatory action based on an IKK2 inhibitory action and is effective in the treatment or prevention of inflammatory diseases or autoimmune diseases such as rheumatoid arthritis.

As a result of intensive studies on compounds having an IKK2 inhibitory activity, the present inventors have shown that the pyridine ring is substituted with a nitrogen-containing saturated hetero ring or a substituted amino group, and the carboxamide group and amino group are substituted on the thiophene ring. That tricyclic compounds characterized by having an amino group have an excellent anti-inflammatory action based on IKK2 inhibitory action, and found that they can be a therapeutic or preventive drug for inflammatory diseases or autoimmune diseases Thus, the present invention has been completed.
That is, the present invention relates to a novel tricyclic compound represented by the following general formula (I) or a salt thereof.

（式中の記号は以下の意味を有する。

Het：含窒素飽和ヘテロ環基、
R¹：-R⁰、ハロゲン、ハロゲノ置換低級アルキル、-Y¹-NR⁴(R⁵)、-Y¹-NR⁴-CO(R⁶)、-Y¹-OR⁶、-Y¹-O-CO-R⁰、-Y¹-CO₂-R⁶、-Y¹-CO-R⁶、-Y¹-CO-NR⁴(R⁵)、-Y¹-SO₂-R⁰、-Y¹-SO-R⁰、-Y¹-S-R⁰、-Y¹-CN、-Y¹-CO-R⁰⁰-NR⁴(R⁵)、-Y¹-CO-R⁰⁰-OR⁶、-Y¹-CO-NR⁴-R⁰⁰-OR⁶、-Y¹-NR⁴-R⁰⁰-OR⁶、-Y¹-NR⁴-R⁰⁰-NR⁵R⁶、-Y¹-NR⁴-CO-NR⁵R⁶、-Y²-置換されていてもよいフェニル、-Y²-置換されていてもよい単環若しくは２環式ヘテロ環基、-Y²-置換されていてもよいシクロアルキル、-Y³-置換されていてもよいフェニル、
R⁰：低級アルキル、
R⁰⁰：低級アルキレン、
Y¹：結合又は-R⁰⁰-、
Y²：結合、-R⁰⁰-、-O-、-R⁰⁰-O-、-R⁰⁰-CO-、-R⁰⁰-SO₂-又は-CO₂-R⁰⁰-、
Y³：フェニル及び-CO₂-R⁶から選択される基で置換された低級アルキレン、
R⁴及びR⁶：同一又は互いに異なって、H又は-R⁰、
R⁵：H、-R⁰、ハロゲンで置換されていてもよいフェニル又はハロゲンで置換されていてもよいベンジル、
k：0、１、２又は3、
但し、基Hetがモルホリノ基のときkは1、2又は3を示す、
R²及び R³：同一又は互いに異なって、H、-R⁰、-R⁰⁰-OR⁶、-R⁰⁰-NR⁰R⁴、-R⁰⁰-CN、-R⁰⁰-CO₂-R⁶、-R⁰⁰-CO-NR⁴(R⁵)、-R⁰⁰-SO₂-R⁰、-R⁰⁰-置換されていてもよいフェニル、-R⁰⁰-置換されていてもよい単環若しくは２環式ヘテロ環基、-R⁰⁰-置換されていてもよいシクロアルキル、-Y³-CO₂-R⁰、-Y³-OR⁶、-Y³-置換されていてもよい単環若しくは２環式ヘテロ環基、置換されていてもよいフェニル、置換されていてもよい単環若しくは２環式ヘテロ環基、置換されていてもよいシクロアルキル、
X：-CR⁷R⁸-、-O-、-CO-、-S(O)_p-又は-NR⁴-、
R⁷及びR⁸：同一又は互いに異なって、H、-R⁰、ハロゲン又は-OR⁶、
p：0、1又は2、
m：0、１、２又は3、
n：0、１、２又は3、
ここで、m+nは2以上5以下の整数を表す。以下同様。）

(The symbols in the formula have the following meanings.

Het: nitrogen-containing saturated heterocyclic group,
R ^1: -R ^0, halogen, halogeno-substituted lower ^{alkyl, -Y 1 -NR 4 (R 5} ), - Y 1 -NR 4 -CO (R 6), - Y 1 -OR 6, -Y 1 -O -CO-R ⁰ , -Y ¹ -CO ₂ -R ⁶ , -Y ¹ -CO-R ⁶ , -Y ¹ -CO-NR ⁴ (R ⁵ ), -Y ¹ -SO ₂ -R ⁰ , -Y ¹ -SO-R ⁰ , -Y ¹ -SR ⁰ , -Y ¹ -CN, -Y ¹ -CO-R ⁰⁰ -NR ⁴ (R ⁵ ), -Y ¹ -CO-R ⁰⁰ -OR ⁶ , -Y ¹ -CO-NR ⁴ -R ⁰⁰ -OR ⁶ , -Y ¹ -NR ⁴ -R ⁰⁰ -OR ⁶ , -Y ¹ -NR ⁴ -R ⁰⁰ -NR ⁵ R ⁶ , -Y ¹ -NR ⁴ -CO- NR ⁵ R ⁶ , —Y ² —optionally substituted phenyl, —Y ² —optionally substituted monocyclic or bicyclic heterocyclic group, —Y ² —optionally substituted cycloalkyl, -Y ³ -optionally substituted phenyl,
R ⁰ : lower alkyl,
R ⁰⁰ : lower alkylene,
Y ¹ : bond or -R ^00- ,
Y ^{2: bond, -R 00 -, - O -} , - R 00 -O -, - R 00 -CO -, - R 00 -SO 2 - or -CO ₂ -R ⁰⁰ -,
Y ³ : lower alkylene substituted with a group selected from phenyl and —CO ₂ —R ⁶ ,
R ⁴ and R ⁶ : the same or different from each other, H or -R ⁰ ,
R ⁵ : H, —R ⁰ , phenyl optionally substituted with halogen or benzyl optionally substituted with halogen,
k: 0, 1, 2, or 3,
Provided that when the group Het is a morpholino group, k represents 1, 2 or 3,
R ² and R ³ : the same or different from each other, H, -R ⁰ , -R ⁰⁰ -OR ⁶ , -R ⁰⁰ -NR ⁰ R ⁴ , -R ⁰⁰ -CN, -R ⁰⁰ -CO ₂ -R ⁶ , -R ⁰⁰ -CO-NR ⁴ (R ⁵ ), -R ⁰⁰ -SO ₂ -R ⁰ , -R ⁰⁰ -optionally substituted phenyl, -R ⁰⁰ -optionally substituted monocyclic or bicyclic Heterocyclic group, -R ⁰⁰ -optionally substituted cycloalkyl, -Y ³ -CO ₂ -R ⁰ , -Y ³ -OR ⁶ , -Y ³ -optionally substituted monocyclic or bicyclic ring A heterocyclic group, an optionally substituted phenyl, an optionally substituted monocyclic or bicyclic heterocyclic group, an optionally substituted cycloalkyl,
^{X: -CR 7 R 8 -,} - O -, - CO -, - S (O) p - or -NR ⁴ -,
R ⁷ and R ⁸ : the same or different from each other, H, -R ⁰ , halogen or -OR ⁶ ,
p: 0, 1 or 2,
m: 0, 1, 2, or 3,
n: 0, 1, 2, or 3,
Here, m + n represents an integer of 2 or more and 5 or less. The same applies below. )

  Since the compound of the present invention has an excellent anti-inflammatory action based on IKK2 inhibition, inflammatory diseases or autoimmune diseases, particularly rheumatic diseases (such as rheumatoid arthritis), digestive system diseases (ulcerative colitis, Crohn's disease, etc.) , Useful as a therapeutic or prophylactic agent for skin inflammatory diseases (e.g. atopic dermatitis, psoriasis), endocrine diseases (e.g. diabetes), central diseases (e.g. multiple sclerosis), respiratory diseases (e.g. asthma) and cancer diseases It is.

Hereinafter, the present invention will be described in detail.
In the definition of the general formula in the present specification, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms (hereinafter abbreviated as C _1-6 ) unless otherwise specified. To do. Accordingly, “lower alkyl” is C _1-6 alkyl, preferably linear alkyl such as methyl, ethyl, propyl and butyl groups, and branched alkyl such as isopropyl, isobutyl and tert-butyl groups. . Particularly preferred are the methyl, ethyl, propyl and isopropyl groups.
“Lower alkylene” is C _1-6 alkylene, preferably linear alkylene such as methylene, ethylene, propylene and butylene groups, and branched alkylene such as methylmethylene groups. Methylene, trimethylene and tetramethylene groups are particularly preferred.
“Halogen” refers to F, Cl, Br and I. “Halogeno lower alkyl” preferably means C _1-6 alkyl substituted with one or more halogens, more preferably C _1-6 alkyl substituted with one or more F, even more preferred. Are fluoromethyl, difluoromethyl, trifluoromethyl and trifluoroethyl groups.
“Cycloalkyl” is a C _3-10 saturated hydrocarbon ring group, which may have a bridge. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl groups are preferred.

The “monocyclic heterocyclic group” is a monocyclic 3 to 8-membered, preferably 5 to 7-membered cyclic group containing 1 to 4 heteroatoms selected from O, S and N. And a monocyclic heterocycloalkyl that is a saturated ring, and a ring group in which the monocyclic heteroaryl is partially hydrogenated. The monocyclic heteroaryl is preferably a pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl group. The ring group in which the monocyclic heterocycloalkyl or heteroaryl group is partially hydrogenated is preferably piperidinyl, pyrrolidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl group.
The “bicyclic heterocyclic group” is a ring group in which the above-mentioned monocyclic heterocycles or a benzene ring and a monocyclic heterocycle are condensed, preferably indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl Benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, dihydrobenzofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl and indolinyl groups.
In the “monocyclic heterocyclic group” and “bicyclic heterocyclic group”, S or N which is a ring atom may be oxidized to form an oxide or a dioxide. In the cyclic group in which heterocycloalkyl and heteroaryl are partially hydrogenated, any carbon atom may be substituted with an oxo group.
The “nitrogen-containing saturated heterocyclic group” includes one N atom, may further contain one heteroatom composed of N, S and O, and may be bridged 5-8 membered saturated or A general term for a cyclic group containing a partially unsaturated monocyclic heterocycle (hereinafter, a nitrogen-containing saturated monocyclic heterocycle) as a constituent component. The “nitrogen-containing saturated heterocyclic group” includes, in addition to the above-mentioned nitrogen-containing saturated monocyclic heterocyclic group, these monocyclic heterocycles, or these monocyclic heterocycle and phenyl group or cycloalkyl. A condensed bicyclic group (hereinafter, a nitrogen-containing saturated bicyclic heterocyclic group) is included. In addition, nitrogen-containing saturated monocyclic heterocyclic groups, or a nitrogen group saturated monocyclic heterocyclic group and a cycloalkyl or nitrogen-containing saturated bicyclic heterocyclic group bonded by a spiro bond (hereinafter referred to as “containing”). A nitrogen-saturated spiro ring group). The nitrogen-containing saturated monocyclic heterocyclic group is preferably piperidinyl, piperazinyl, pyrrolidinyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, tetrahydropyridyl and tetrahydro-1,4-oxazepin-4 (5H) -yl. The nitrogen-containing saturated bicyclic heterocyclic group is preferably tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, 2,5-diazabicyclo [2.2.1] hept-2-yl, hexahydropyrrolo [1,2 -a] pyrazin-2 (1H) -yl and 3,4-dihydro-pyrrolo [1,2-a] pyrazin-2 (1H) -yl. The nitrogen-containing saturated spiro ring group is preferably 4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl, 3-oxo-1′H, 3H-spiro [2- Benzofuran-1,4'-piperidin] -1'-yl, 1-oxo-2,8-diazaspiro [4.5] dec-8-yl and 1'H, 3H-spiro [2-benzofuran-1,4'- Piperidin] -1′-yl.

“Optionally substituted” means “unsubstituted” or “having 1 to 5 identical or different substituents”.
For example, the substituent in “optionally substituted phenyl” and “optionally substituted monocyclic or bicyclic heterocyclic group” is preferably lower alkyl, halogen, halogeno-substituted lower alkyl, — OR ⁶ , -NR ⁴ (R ⁵ ), -R ⁰⁰ -OR ⁶ , -R ⁰⁰ -NR ⁴ (R ⁵ ), -NR ⁴ -CO (R ⁶ ), -CO-NR ⁴ (R ⁵ ),- CN, —NO ₂ , phenyl, benzyl, monocyclic heteroaryl. As the “optionally substituted phenyl” and “optionally substituted monocyclic or bicyclic heterocyclic group” in R ¹ , in particular, lower alkyl, halogen, —OR ⁶ , —NR ⁴ (R ⁵ ), -R ⁰⁰ -OR ⁶ are preferred, and the substituents in R ² and R ³ are particularly lower alkyl, halogen, -OR ⁶ , -NR ⁴ (R ⁵ ), -R ⁰⁰ -OR ⁶ , CN, phenyl, benzyl and monocyclic heteroaryl are preferred. Further, the substituent in the “optionally substituted cycloalkyl” is preferably R ⁰ , —OR ³ , —NR ⁴ (R ⁵ ), oxo, or —CO ₂ —R ³ .
In addition, when k is plural, the groups R ¹ may be the same or different.

で表される化合物、より好ましくは、Hetが含窒素飽和単環へテロ環基、より好ましくは、ピペラジニル、ピペリジニル、アゼパニル、ジアゼパニル、ピロリジニル、更に好ましくはピペラジニル、ピペリジニルである化合物。特に好ましくは、更にkが0又は1であり、kが1のとき、R¹が、-R⁰、-NR⁴(R⁵)、-OR⁶、-CO-NR⁴(R⁵)、-CO-R⁰⁰-NR⁴(R⁵)、-CO-R⁰⁰-OR⁶、-CO-NR⁴-R⁰⁰-OR⁰、-R⁰⁰-OH、-R⁰⁰-OR⁰である化合物。 Preferred embodiments of the compound of the present invention represented by the general formula (I) are shown below.
i) A compound wherein X is —CH ₂ —, —O— or —NMe—, more preferably a compound of —CH ₂ —.
ii) A compound in which m and n are the same or different from each other and are 1 or 2, more preferably a compound in which one is 1 and the other is 2.
iii) A is the following formula:

And more preferably a compound in which Het is a nitrogen-containing saturated monocyclic heterocyclic group, more preferably piperazinyl, piperidinyl, azepanyl, diazepanyl, pyrrolidinyl, still more preferably piperazinyl, piperidinyl. Particularly preferably, when k is 0 or 1, and k is 1, R ¹ is -R ⁰ , -NR ⁴ (R ⁵ ), -OR ⁶ , -CO-NR ⁴ (R ⁵ ),- ^{CO-R 00 -NR 4 (R} 5), - CO-R 00 -OR 6, -CO-NR 4 -R 00 -OR 0, -R 00 -OH, the compound is -R ⁰⁰ -OR ^0.

The compound (I) of the present invention may have geometric isomers and tautomers. The present invention includes separated or mixed isomers.
Moreover, this invention compound (I) may have an asymmetric carbon atom, and the optical isomer based on this may exist. The present invention includes all of these optical isomers and isolated ones.
Further, the compound (I) of the present invention includes pharmaceutically acceptable prodrugs. Pharmaceutically acceptable prodrugs are compounds having groups that can be converted to NH ₂ , OH, CO ₂ H, etc. of the present invention by solvolysis or under physiological conditions. Examples of groups that form prodrugs include groups described in Prog. Med., 5, 2157-2161 (1985) and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. .

The salt of the compound (I) of the present invention is a pharmaceutically acceptable salt, specifically, an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, etc. Acids with organic acids such as acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid Examples include addition salts. Further, depending on the type of the substituent, a salt with a base may be formed, for example, an inorganic base containing a metal such as sodium, potassium, magnesium, calcium, aluminum, or methylamine, ethylamine, ethanolamine, lysine, Examples thereof include salts with organic bases such as ornithine and ammonium salts.
Furthermore, this invention compound (I) and its salt include various hydrates, solvates and polymorphic substances.

(Production method)
The compound (I) of the present invention and a salt thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent. In this case, depending on the type of functional group, it is effective in terms of production technology to protect the functional group with an appropriate protective group at the raw material or intermediate stage, or to replace it with a group that can be easily converted to the functional group. There is a case. Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like, and examples of protective groups thereof include those described in “Protective Groups in Organic Synthesis (3rd edition, by TW Greene) and Utz (PGM Wuts)”. 1999) ”, which may be appropriately selected depending on the reaction conditions. In such a method, after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group or converting it to a desired group as necessary.
Moreover, the prodrug of a compound can be manufactured by introduce | transducing a specific group in the step of the obtained compound (I) or a raw material thru | or an intermediate body. The reaction can be carried out by applying a method known by those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.

本製法は化合物(1)と2-ブロモアセトアミド(2)とを用いて、連続するS-アルキル化反応と環化反応を同時に行うことにより、本発明化合物(I)を製造する方法である。
本反応は化合物(1)と2-ブロモアセトアミド(2)とを適当な塩基存在下、等量もしくは2-ブロモアセトアミド(2)を過剰量用い、反応に不活性な溶媒中、室温〜加熱還流下に通常1時間〜3日間撹拌することにより行われる。適当な塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等のアルカリ金属水酸化物類、炭酸リチウム、炭酸ナトリウム、炭酸カリウム等のアルカリ金属炭酸塩類、炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属炭酸水素塩類、水酸化マグネシウム、水酸化カルシウム等のアルカリ土類金属水酸化物、ナトリウムメトキシド、ナトリウムエトキシド、カリウム-ｔ-ブトキシドのような金属アルコキシド類、トリエチルアミン、ジイソプロピルエチルアミン(DIPEA)、N-メチルモルホリン、ピリジン、ピロリジン、1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(DBU)等の有機アミン類を用いることができるが、化合物の他の部位に影響を与えないものであれば特に限定されることはない。また溶媒としては、メタノール、エタノール、2-プロパノール、ブタノール等のアルコール類、ジエチルエーテル、テトラヒドロフラン(THF)、1,4-ジオキサン、1,2-ジメトキシエタン、1,2-ジエトキシエタン等のエーテル類、ジクロロメタン、1,2-ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、N,N-ジメチルホルムアミド(DMF)、N-メチルピロリドン(NMP)、ジメチルスルホキシド(DMSO)、ピリジン、ルチジン、水等を用いることができるが、反応に不活性な溶媒であればこれらに限定されることはない。 (First manufacturing method)

This production method is a method for producing the compound (I) of the present invention by simultaneously performing continuous S-alkylation reaction and cyclization reaction using the compound (1) and 2-bromoacetamide (2).
In this reaction, an equal amount of compound (1) and 2-bromoacetamide (2) in the presence of a suitable base or an excess of 2-bromoacetamide (2) are used, and the mixture is heated to reflux in a solvent inert to the reaction. It is usually carried out by stirring for 1 hour to 3 days below. Suitable bases include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. Alkali metal bicarbonates, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine (DIPEA) , Organic amines such as N-methylmorpholine, pyridine, pyrrolidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) can be used, but other parts of the compound are not affected If it is a thing, it will not specifically limit. Examples of the solvent include alcohols such as methanol, ethanol, 2-propanol and butanol, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane. , Halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), pyridine, lutidine, water, etc. Although it can be used, it is not limited to these as long as it is an inert solvent for the reaction.

（Ａ²は、式（Ｉ）中のＡで示される基のうち、窒素原子でピリジン環と結合する基を、TfOはトリフルオロメタンスルホニルオキシ基を示す。）
本製法は、トリフルオロメタンスルホナート化合物(3)とアミン化合物(4)とを用いて、置換反応と環化反応を組み合わせて本発明化合物(Ia)を製造する方法である。
まず、本発明化合物(Ia)は、置換反応により化合物(5)を生成させ、同一反応容器中で引き続く環化反応を行うことにより製造できる。置換反応は、両方の原料化合物を等量もしくはアミン誘導体(4)を過剰量用い、第一製法で記した反応に不活性な溶媒中、室温〜加熱還流下に通常1時間〜3日間撹拌することにより行われる。引き続く環化反応は、同一容器内に第一製法で記した適当な塩基を加え、室温〜加熱還流下に通常1時間〜3日間撹拌することにより行われる。
また、本発明化合物(Ia)は、化合物(3)を環化反応により(6)とした後に、化合物(4)と置換させることによっても製造できる。環化反応においては、THF溶媒中、DBUを用いて室温で反応させることが好ましい。 (Second manufacturing method)

(A ² represents a group bonded to the pyridine ring by a nitrogen atom among the groups represented by A in formula (I), and TfO represents a trifluoromethanesulfonyloxy group.)
This production method is a method for producing the present compound (Ia) by using a trifluoromethanesulfonate compound (3) and an amine compound (4) in combination with a substitution reaction and a cyclization reaction.
First, the compound (Ia) of the present invention can be produced by producing a compound (5) by a substitution reaction and performing a subsequent cyclization reaction in the same reaction vessel. In the substitution reaction, the same amount of both starting compounds or an excess of amine derivative (4) is used, and the mixture is stirred in a solvent inert to the reaction described in the first production method at room temperature to heating under reflux for usually 1 hour to 3 days. Is done. The subsequent cyclization reaction is carried out by adding an appropriate base described in the first production method in the same vessel and stirring usually at room temperature to heating under reflux for 1 hour to 3 days.
The compound (Ia) of the present invention can also be produced by converting the compound (3) to (6) by a cyclization reaction and then substituting the compound (4). In the cyclization reaction, the reaction is preferably carried out at room temperature using DBU in a THF solvent.

(Third Production Method) Other Production Methods The compound of the present invention having various functional groups can also be produced by applying a method obvious to those skilled in the art, a known production method, or a modified method thereof. For example, a part of the compound (I) of the present invention can be produced by applying the following reaction to the conversion of the substituent A using the compound (I) of the present invention as a raw material.
(1) Amidation, sulfonamidation and esterification A compound having an amide group can be produced by condensing a compound having a carboxyl group in group A with various amine compounds. Similarly, a compound having an amide group can be produced by reacting a compound having an amino group in the group A with various carboxylic acid compounds or reactive derivatives thereof. Moreover, various sulfonamide derivatives can be produced by using various sulfonic acid derivatives (preferably reactive derivatives such as sulfonic acid halides and sulfonic acid anhydrides) instead of carboxylic acids. For the reaction, for example, the method described in “Chemical Experiment Course (4th edition)” volume 22 (1992) (Maruzen) edited by the Chemical Society of Japan can be applied.
(2) N-alkylation The compound of the present invention having an N-alkylamino group can be produced by subjecting a compound having an amino group in the group A to an alkylation reaction. The reaction can be carried out with reference to the method described in “Chemical Experiment Course (Maruzen)” volume 20 (1992) (Maruzen) edited by the Chemical Society of Japan.
(3) Hydrolysis The present compound having a carboxyl group can be produced by subjecting a compound having an ester in the group A to a hydrolysis reaction. The reaction can be carried out with reference to the method described in the above-mentioned “Protective Groups in Organic Synthesis (3rd edition)” of the carboxyl group deprotection reaction and the like.

化合物(1)は、カルボン酸誘導体(7)とカルボニル誘導体(8)を縮合反応に付して得られるジケトン誘導体(9)と、2-シアノチオアセトアミド(10)との環化反応により製造することができる。縮合反応は,Journal of Medicinal Chemistry, 1997, 40, 2374-2385に記載の方法を参考に行うことができる。環化反応は、第一製法で記した適当な塩基存在下、化合物(9)及び化合物(10)を等量もしくは(10)を過剰量用い、第一製法で記した反応に不活性な溶媒中、室温〜加熱還流下に通常1時間〜3日間撹拌することにより行われる。好ましくはエタノール溶媒中、ナトリウムエトキシドを用いて、室温〜還流温度において反応させる。

（Ｅは低級アルキル基を示す。）
化合物(3)はβ-ケトエステル(11)と2-シアノチオアセトアミド(10)を環化反応に付した後、2-ブロモアセトアミド(2)によるアルキル化反応、引き続くトリフルオロメタンスルホニル化反応により製造することができる。環化反応は第二製法、アルキル化は第一製法と同様の条件で行うことができる。トリフルオロメタンスルホニル化は、化合物(13)とトリフルオロメタンスルホニルクロライド、トリフルオロメタンスルホン酸無水物、N-フェニルビス(トリフルオロメタンスルホンイミド)等のトリフルオロメタンスルホニル化剤を第一製法で記した適当な塩基存在下、第一製法で記した反応に不活性な溶媒中、0℃〜室温下に通常1時間〜3日間撹拌することにより行われる。好ましくは1,4-ジオキサン溶媒中、DIPEA存在下、室温で反応させることにより行うことができる。 (Manufacture of raw material compounds)
The raw material compound used in the production method can be produced, for example, according to the following synthesis route.

Compound (1) is produced by cyclization reaction of diketone derivative (9) obtained by subjecting carboxylic acid derivative (7) and carbonyl derivative (8) to a condensation reaction and 2-cyanothioacetamide (10). be able to. The condensation reaction can be performed with reference to the method described in Journal of Medicinal Chemistry, 1997, 40, 2374-2385. The cyclization reaction is carried out using an equivalent amount of compound (9) and compound (10) or an excess amount of (10) in the presence of an appropriate base described in the first production method, and a solvent inert to the reaction described in the first production method. The reaction is usually carried out by stirring for 1 hour to 3 days under room temperature to heating under reflux. Preferably, the reaction is performed at room temperature to reflux temperature using sodium ethoxide in an ethanol solvent.

(E represents a lower alkyl group.)
Compound (3) is produced by subjecting β-ketoester (11) and 2-cyanothioacetamide (10) to cyclization, followed by alkylation with 2-bromoacetamide (2) and subsequent trifluoromethanesulfonylation. be able to. The cyclization reaction can be carried out under the same conditions as in the second production process, and the alkylation can be carried out under the same conditions as in the first production process. The trifluoromethanesulfonylation is carried out by using a suitable base in which the compound (13) and a trifluoromethanesulfonylating agent such as trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide) are described in the first production method. In the presence, the reaction is carried out in a solvent inert to the reaction described in the first production method by stirring at 0 ° C. to room temperature for usually 1 hour to 3 days. Preferably, the reaction can be carried out in a 1,4-dioxane solvent at room temperature in the presence of DIPEA.

Compound (I) produced in this manner is isolated or purified as it is in the free state or is subjected to salt formation treatment by a conventional method. Isolation / purification is performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.
Various isomers can be isolated by a conventional method utilizing the difference in physicochemical properties between the isomers. For example, optical isomers can be obtained by a method such as fractional crystallization after introducing a racemate into a diastereomeric salt with an optically active organic acid (such as tartaric acid), or a column chromatography using a chiral filler. It can be separated and purified. The optically active compound can also be produced by using an appropriate optically active compound as a raw material. A mixture of diastereomers can also be separated by fractional crystallization or chromatography.

(Test method)
The effect of the compound of the present invention was confirmed by the following pharmacological test.
(1) Rat IKK2 enzyme inhibition evaluation
(i) Enzyme preparation The rat IKK2 (Genbank AF115282) ORF was cloned from a rat pancreatic cDNA library and expressed in an Sf9 cell line with a FLAG-tag, and cell lysate (50 mM Tris-HCl pH 7.5). , 0.15M NaCl, 1% NP-40, 10% Glycerol, 1mM EDTA, 1mM EGTA pH7.5, 1mM Na ₃ VO ₄ , 5mM p-nitrophenylphosphate, 10mM β-glycerophosphate, 1mM DTT, 1mM PMSF, 10μg / ml Leupeptin , 10 μg / ml Aprotinin (Sigma)), and a large amount of cell extract was prepared and purified with anti-FLAG M2 antibody (Sigma). The above experimental procedures were in accordance with known methods, ie, genetic manipulation experiment manuals (Sambrook, J. et al, Molecular Cloning-A Laboratory Manual, Cold Spring Harbor laboratory, NY, 1989) and instructions attached to the reagents. Purified rat IKK2 is stored in enzyme preservation solution (20 mM Tris-HCl pH 7.5, 10% Glycerol, 12.5 mM β-glycerophosphate, 0.5 mM EDTA, 0.5 mM EGTA, 0.05% Brij35, 1 mM DTT, 1 mM PMSF (Sigma) ) And stored at -80 ° C.
(ii) Enzyme assayPurified rat IKK2, 1X enzyme reaction buffer (20 mM Tris-HCl pH 7.5, 12.5 mM β-glycerophosphate, 20 mM MgCl ₂ , 0.1 mM DTT), 0.01% BSA (Sigma), 0.5 μM ATP, 0.2 μM biotinylated substrate peptide (amino acid residues 18 to 49 of rat I-kappa B alpha (Genbank Q63746)) and DMSO solution in which the compound was dissolved were added to a total of 10 μl in a 384-well plate (catalog number 3679: Corning). And left at room temperature for 90 minutes. Then, 10 μl of stop solution (100 mM Hepse pH 8, 0.01% BSA, 0.8 M KF, 50 mM EDTA pH 8, 1% Triton X-100, Europium cryptate labeling of anti-phosphorylated I-kappa B alpha antibody (Santa Cru)) Body, Streptavidin-labeled XL665 (Nippon Schering) was added, and the mixture was incubated for 30 minutes and then measured with DISCOVERY (Perkin-Elmer) The rat IKK2 enzyme activity inhibitory action of the test compound was determined by the following formula. Each dose was tested independently three times.
Inhibition rate by test compound (%) = ((average value without compound, with rat IKK2)-(average value with test compound, with rat IKK2)) / ((no compound, with rat IKK2) (Mean value of the state)) − (mean value of the state without rat IKK2)) × 100.
From the inhibition rate (%) of each dose, 50% inhibition (IC ₅₀ ) was calculated by the probit method. The compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 14, 15, 17, 18, and 20 exhibited IC ₅₀ values of 0.5 μM or less. From this result, the IKK2 inhibitory action of the compound of the present invention was confirmed.

(2) Rat carrageenan paw edema model After measuring the body weight of the animals, the groups were divided so that the average value of the body weight of 5 animals per group was equal to each group. Thereafter, the test compound (10 ml / kg solution adjusted according to the dose, the solvent alone in the control group was 10 ml / kg) was orally administered, and Sprague-Dawley male rats (6-10 weeks old, male) 30 minutes after drug administration. Inflammation was induced by injecting 100 μL of 1% carrageenin (Sigma Aldrich Japan) solution into the right footpad subcutaneously. Three hours after the induction of inflammation, the mice were killed by ether deep anesthesia, and the left and right footpad tissues were cut and collected and weighed.
The result is a weight difference (g) obtained by subtracting the weight of the left foot not administered with carrageenin from the weight of the right foot administered with carrageenin for 3 hours after administration of carrageenin for each individual, and the inhibition rate relative to the average of the control group was calculated. Expressed as mean ± standard error. A multi-group comparison between the control group and the test substance-administered group was performed by Dunnett's multiple comparison test, and was considered statistically significant when the P value was less than 0.05. All the above statistical analyzes were performed using SAS.
The compound of Example 7 showed good inhibitory activity after oral administration at 30 mg / kg. From this result, it was confirmed that the compound of the present invention has an inhibitory action against acute inflammation.

(3) Action on collagen-induced arthritis The action on rat collagen-induced arthritis can be evaluated using the method described in The Japanese Journal of Pharmacology, 1997 Aug; 74 (4): 313-22. The effect on mouse collagen-induced arthritis can be evaluated using the method described in The Japanese Journal of Pharmacology, 2002 Apr; 88 (3): 332-340.

A pharmaceutical composition containing the compound (I) of the present invention or a salt thereof as an active ingredient is usually prepared using carriers, excipients, and other additives used for formulation.
Administration is oral by tablet, pill, capsule, granule, powder, liquid, etc., or parenteral administration by injection such as intravenous injection, intramuscular injection, suppository, transdermal agent, nasal agent or inhalant. Either form may be sufficient. The dosage is appropriately determined according to the individual case, taking into account the symptoms, age of the subject, sex, etc. In general, in the case of oral administration, it is about 0.001 mg / kg to 100 mg / kg per day for an adult. This is administered once, or divided into 2 to 4 times. In addition, when intravenously administered depending on symptoms, it is usually administered once or multiple times in a range of 0.0001 mg / kg to 10 mg / kg per adult. In the case of inhalation, it is usually administered once or several times a day in the range of 0.0001 mg / kg to 1 mg / kg per adult.
As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances are present in at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. Mixed with magnesium aluminate acid. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a gastric or enteric coating agent.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and include commonly used inert solvents such as purified water, ethanol, etc. . In addition to the inert solvent, the composition may contain adjuvants such as solubilizers, wetting agents, and suspending agents, sweeteners, corrigents, fragrances, and preservatives.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solvent include distilled water for injection and physiological saline. Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (Pharmacopeia name), and the like. Such a composition may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving and suspending it in sterile water or a sterile solvent for injection before use.

Transmucosal agents such as inhalants and nasal agents are used in the form of solids, liquids, and semisolids, and can be produced according to conventionally known methods. For example, excipients such as lactose and starch, and pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be added as appropriate. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. The dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable gas such as a suitable propellant such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
The pharmaceutical composition containing the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is another therapeutically active ingredient such as a nonsteroidal anti-inflammatory agent (NSAIDs). , Disease-modifying anti-rheumatic agents (DMARDs), steroid agents, cytokine production inhibitors, cytokine antagonists, immunosuppressants, etc. may be used in appropriate combination. When used in combination with these, they may be used as a combination preparation for simultaneous administration or as separate preparations combined for independent administration.

  Hereinafter, based on an Example, the manufacturing method of this invention compound (I) is demonstrated in detail. The present invention is not limited to the invention of the compounds described in the following examples. Moreover, the manufacturing method of a raw material compound is shown in a reference example.

Reference example 1
Triethylamine and thionyl chloride were added to a toluene solution of 1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid. After stirring at 90 ° C. for 1.5 hours, the precipitate was filtered. The filtrate was added to a toluene solution of 1-pyrrolidino-1-cyclohexene and triethylamine and heated under reflux for 15 hours to obtain tert-butyl 3-[(2-oxocyclohexyl) carbonyl] piperidine-1-carboxylate. FAB-MS (M + H) ⁺ : 310
Reference example 2
Sodium ethoxide was added to an ethanol solution of cyanothioacetamide, and the mixture was stirred at 60 ° C. for 30 minutes. Then, tert-butyl 3-[(2-oxocyclohexyl) carbonyl] piperidine-1-carboxylate was added, and the mixture was stirred at 60 ° C. for 15 hours. By reacting, tert-butyl 3- (4-cyano-3-thioxo-2,3,5,6,7,8-hexahydroisoquinolin-1-yl) piperidine-1-carboxylate was obtained. FAB-MS (MH) ^- : 372
Reference example 3
Sodium ethoxide was added to an ethanol solution of cyanothioacetamide and stirred at 60 ° C. for 1 hour, and then an ethanol solution of ethyl 2-oxocyclohexanecarboxylate was added and reacted at 60 ° C. for 14 hours to give 1-oxo-3. -Sulfanyl-1,2,5,6,7,8-hexahydroisoquinoline-4-carbonitrile sodium salt was obtained. FAB-MS (MH) ^- : 205
Reference example 4
By reacting 1-oxo-3-sulfanyl-1,2,5,6,7,8-hexahydroisoquinoline-4-carbonitrile sodium salt with 2-bromoacetamide in DMF at 70 ° C. for 3 hours, 2 -[(4-Cyano-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-3-yl) sulfanyl] acetamide was obtained. FAB-MS (MH) ^- : 262
Reference Example 5
Of 2-[(4-cyano-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-3-yl) sulfanyl] acetamide, N-phenylbis (trifluoromethanesulfonimide) and diisopropylethylamine By reacting the 1,4-dioxane solution for 14 hours, 3-[(2-amino-2-oxoethyl) sulfanyl] -4-cyano-5,6,7,8-tetrahydroisoquinolin-1-yl trifluoromethanesulfone I got a nat. FAB-MS (M + H) ⁺ : 396

Reference Example 6
Add DBU to THF solution of 3-[(2-amino-2-oxoethyl) sulfanyl] -4-cyano-5,6,7,8-tetrahydroisoquinolin-1-yl trifluoromethanesulfonate and react for 3 hours Gave 1-amino-2- (aminocarbonyl) -6,7,8,9-tetrahydrothieno [2,3-c] isoquinolin-5-yl trifluoromethanesulfonate. FAB-MS (M + H) ⁺ : 396
Reference Example 7
Add 1.5M lithium diisopropylamide cyclohexane solution and tetrahydro-4H-pyran-4-one to THF at -78 ° C and stir for 1 hour. Separately prepared 1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid and carbonyl A solution of imidazole in THF was added at -78 ° C. The cooling bath was removed, and the mixture was reacted for 1.5 hours with stirring until the temperature returned to room temperature, whereby tert-butyl 3-[(4-oxotetrahydro-2H-pyran-3-yl) carbonyl] piperidine-1-carboxylate was obtained. . FAB-MS (MH) ^- : 310
Reference Example 8
Sodium methoxide was added to a methanol solution of cyanothioacetamide and stirred at 60 ° C for 1 hour, and then a methanol solution of 1-tert-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate was added to the solution. For 17 hours. Subsequent treatment with 1M hydrochloric acid gave tert-butyl 5-cyano-8-oxo-6-sulfanyl-3,4,7,8-tetrahydro-2,7-naphthyridine-2 (1H) -carboxylate. . FAB-MS (MH) ^- : 306
Reference Example 9
tert-butyl 5-cyano-8-oxo-6-sulfanyl-3,4,7,8-tetrahydro-2,7-naphthyridine-2 (1H) -carboxylate, 2-bromoacetamide and triethylamine in DMF solution at room temperature Tert-butyl 6-[(2-amino-2-oxoethyl) sulfanyl] -5-cyano-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine- 2 (1H) -carboxylate was obtained. FAB-MS (M + H) ⁺ : 365
The compound of Reference Example 10 was prepared in the same manner as in Reference Example 2, the compound of Reference Example 11 in the same manner as in Reference Example 3, the compound of Reference Example 12 in the same manner as in Reference Example 4, and the reference example. 3 and Reference Example 4 were carried out in the same manner for 2 steps, whereby the compound of Reference Example 13 was converted to the compound of Reference Examples 14 to 17 in the same manner as Reference Example 5 and the method of Reference Example 8 was performed. Thus, the compound of Reference Example 18 and the compound of Reference Example 19 were produced in the same manner as in Reference Example 9 using the corresponding starting materials.
The structures and physicochemical data of the compounds of Reference Examples 10 to 19 are shown in Table 1.

Example 1
(1) tert-butyl 3- (4-cyano-3-thioxo-2,3,5,6,7,8-hexahydroisoquinolin-1-yl) piperidine-1-carboxylate 253 mg and 2-bromoacetamide 113 mg 1.5 ml of 1M aqueous potassium hydroxide solution was added to 10 ml of DMF and stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the resulting precipitate was collected by filtration, dried under reduced pressure, and tert-butyl 3- [1-amino-2- (aminocarbonyl) -6,7,8,9-tetrahydrothieno [2 , 3-c] isoquinolin-5-yl] piperidine-1-carboxylate 387 mg was obtained as a pale yellow solid.
(2) Next, 3 ml of 4M hydrogen chloride-1,4-dioxane solution was added to 3 ml of 1,4-dioxane in 100 mg of this compound, and the mixture was stirred at room temperature for 13 hours. After concentrating the reaction solution, the obtained solid was recrystallized with ethanol to give 1-amino-5-piperidin-3-yl-6,7,8,9-tetrahydrothieno [2,3-c] isoquinoline- 2-Carboxamide hydrochloride 23 mg was obtained as a pale yellow solid.
Example 2
(1) 3-[(2-Amino-2-oxoethyl) sulfanyl] -4-cyano-5,6,7,8-tetrahydroisoquinolin-1-yl trifluoromethanesulfonate 395 mg and tert-butyl piperidin-4-yl A solution of carbamate (601 mg) in 1,4-dioxane (10 ml) was stirred at 100 ° C. for 3 hours, 4 ml of 2M aqueous sodium carbonate solution was added, and the mixture was stirred at 100 ° C. for 15 hours. The reaction mixture was concentrated, 50 ml of water was added to the resulting residue, and the mixture was extracted with 100 ml of chloroform. The organic layer was washed with 50 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 99: 1 to 90:10) to give tert-butyl {1- [1-amino-2- (aminocarbonyl) -6,7, 490 mg of 8,9-tetrahydrothieno [2,3-c] isoquinolin-5-yl] piperidin-4-yl} carbamate was obtained as a pale yellow amorphous.
(2) Next, by using 490 mg of this compound and carrying out the same reaction as in Example 1 (2), 1-amino-5- (4-aminopiperidin-1-yl) -6,7,8, 9-Tetrahydrothieno [2,3-c] isoquinoline-2-carboxamide dihydrochloride (367 mg) was obtained as a pale yellow solid.

Example 3
3-[(2-Amino-2-oxoethyl) sulfanyl] -4-cyano-5,6,7,8-tetrahydroisoquinolin-1-yl trifluoromethanesulfonate 236 mg and 4-hydroxypiperidine 182 mg 1,4-dioxane The 10 ml solution was stirred at 100 ° C. for 24 hours, then 3 ml of 2M aqueous sodium carbonate solution was added and stirred at 100 ° C. for 15 hours. The reaction mixture was concentrated, 50 ml of water was added to the resulting residue, and the mixture was extracted with 100 ml of chloroform. The organic layer was washed with 50 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was washed with diethyl ether to give 1-amino-5- (4-hydroxypiperidin-1-yl) -6,7,8,9-tetrahydrothieno [2,3-c] isoquinoline-2 -177 mg of carboxamide was obtained as a colorless solid.
Subsequently, 1-amino-5- (4-hydroxypiperidin-1-yl) -6,7,8,9-tetrahydro was obtained by carrying out the same reaction as in Example 1 (2) using 177 mg of this compound. Thieno [2,3-c] isoquinoline-2-carboxamide hydrochloride 179 mg was obtained as a pale yellow solid.
Example 4
1-amino-2- (aminocarbonyl) -6,7,8,9-tetrahydrothieno [2,3-c] isoquinolin-5-yl trifluoromethanesulfonate 200 mg and N-methylpiperazine 222 mg 1,4-dioxane The solution was stirred at 100 ° C. for 18 hours. The reaction mixture was concentrated, 50 ml of water was added to the resulting residue, and the mixture was extracted with 100 ml of chloroform. The organic layer was washed with 50 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was washed with diethyl ether to give 1-amino-5- (4-methylpiperazin-1-yl) -6,7,8,9-tetrahydrothieno [2,3-c] isoquinoline-2 -120 mg of carboxamide was obtained as a pale yellow solid.
Subsequently, 1-amino-5- (4-methylpiperazin-1-yl) -6,7,8,9-tetrahydro was obtained by carrying out the same reaction as in Example 1 (2) using 100 mg of this compound. Thieno [2,3-c] isoquinoline-2-carboxamide dihydrochloride 104 mg was obtained as a yellow solid.

Example 5
1-amino-5-piperazin-1-yl-6,7,8,9-tetrahydrothieno [2,3-c] isoquinoline-2-carboxamide dihydrochloride 404 mg, N- (tert-butoxycarbonyl) glycine 210 mg, To a solution of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 230 mg and 1-hydroxybenzotriazole 162 mg in DMF 10 ml, 223 mg of triethylamine was added and stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the resulting precipitate was filtered and washed with ethanol to give tert-butyl (2- {4- [1-amino-2- (aminocarbonyl) -6,7,8,9 There was obtained 467 mg of -tetrahydrothieno [2,3-c] isoquinolin-5-yl] piperazin-1-yl} -2-oxoethyl) carbamate as a colorless solid.
Subsequently, 1-amino-5- [4- (aminoacetyl) piperazin-1-yl] -6,7,8,9 was obtained by performing the same reaction as in Example 1 (2) using 450 mg of this compound. -387 mg of tetrahydrothieno [2,3-c] isoquinoline-2-carboxamide dihydrochloride was obtained as a yellow solid.
Examples 6-20
In the same manner as in Examples 1 to 5, the compounds of Examples 6 to 20 were produced. Their structural formulas and physical properties are shown in Tables 2 and 3 below.

Example 21
1-Amino-2- (aminocarbonyl) -6,7,8,9-tetrahydrothieno [2,3-c] isoquinolin-5-yl trifluoromethanesulfonate 12 mg to 23 mg of 1- (2-benzenesulfonylethyl) piperazine Of 1,4-dioxane in 0.2 ml was added and stirred at 100 ° C. for 10 hours. The reaction solution was distilled off under reduced pressure, and the resulting residue was subjected to HPLC (column: Symmetry (registered trademark) C18 5 μm 19 mm × 100 mm, solvent: MeOH / 0.1% HCOOH—H ₂ O = 10/90 (0 min) − 10 / 90 (1 min) -100/0 (9 min)-100/0 (12 min), flow rate: 25 mL / min), preparative purification is performed, and 1-amino-5- {4- [2- 0.3 mg of (methylsulfonyl) ethyl] piperazin-1-yl} -6,7,8,9-tetrahydrothieno [2,3-c] isoquinoline-2-carboxamide was obtained.
Example 22
tert-Butyl (1S, 4S) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate to 24 mg 1-amino-2- (aminocarbonyl) -6,7,8,9-tetrahydrothieno [2 , 3-c] isoquinolin-5-yl trifluoromethanesulfonate (12 mg) in 1,4-dioxane (0.2 ml) was added, and tert-butyl (1S, 1S, obtained using the same procedure as in Example (CL-265726) was added. 4S) -5- [1-amino-2- (aminocarbonyl) -6,7,8,9-tetrahydrothieno [2,3-c] isoquinolin-5-yl] -2,5-diazabicyclo [2.2.1 ] To heptane-2-carboxylate, 0.5 ml of 4M hydrogen chloride-1,4-dioxane solution was added and stirred at room temperature for 10 hours. The reaction solution was distilled off under reduced pressure, and the residue was subjected to HPLC (column: Symmetry (registered trademark) C18 5 μm 19 mm × 100 mm, solvent: MeOH / 0.1% HCOOH-H ₂ O = 10/90 (0 min)-10/90 ( 1 min) -100/0 (9 min)-100/0 (12 min), flow rate: 25 mL / min), preparative purification is carried out to give 1-amino-5-[(1S, 4S) -2, 5.0 mg of 5-diazabicyclo [2.2.1] hept-2-yl] -6,7,8,9-tetrahydrothieno [2,3-c] isoquinoline-2-carboxamide was obtained.

Examples 23-208
The compounds of Examples 23 to 204 were produced in the same manner as in Example 21, and the compounds of Examples 205 to 208 were produced in the same manner as in Example 22. Their structural formulas and physical properties are shown in Tables 4 to 10 below.
In addition, the compounds shown in Table 11 below can be easily produced by substantially the same methods as those described in the above Examples and production methods, or by applying some variations obvious to those skilled in the art from those methods. it can.
The following abbreviations are used in the following tables.
Ex: Example No., REx: Reference Example No., No: Compound No., Str: Structural Formula, Syn: Production Method (Numbers are Example Nos. Produced in the same manner), pos: Substituent substitution position (multiple numbers) Some indicate multiple substitutions, diMe- (3,5) indicates that the methyl group is in the 3rd and 5th positions), Dat: physicochemical data (F1: FAB-MS (M + H ) ⁺ , F2: FAB-MS (MH) ⁻ , E1: ESI-MS (M + H) ⁺ , NMR: δ (ppm) of the characteristic peak in ¹ H NMR in DMSO-d ₆ , H _{: HPLC Retention time in minutes (HPLC conditions:} Wakosil-II 5C18AR 5μm 2.0x30 mm, 5 mM TFA-H ₂ O / MeOH = 9/1 (0 min) -0/10 (4 min) -0/10 (4.5 min ) 1.2 ml / min, 254 nm, 35.0 ° C. _] ), Sal: salt (HCl: hydrochloride, 2HCl: dihydrochloride, not shown: free), Pos: substitution position, Me: methyl, Et: ethyl, iPr : Isopropyl, nPr: n-propyl, tBu: tert-butyl, cHex: cyclohexyl, Ph: phenyl, Bn: benzyl and Boc: tert-butoxycarbonyl, TfO Trifluoromethanesulfonyloxy.
The number before the substituent indicates the substitution position. For example, 4Cl-Ph- represents 4-chlorophenyl.

Claims (1)

A tricyclic compound represented by the following general formula (I) or a salt thereof.

(The symbols in the formula have the following meanings.

Het: nitrogen-containing saturated heterocyclic group,
R ^1: -R ^0, halogen, halogeno-substituted lower ^{alkyl, -Y 1 -NR 4 (R 5} ), - Y 1 -NR 4 -CO (R 6), - Y 1 -OR 6, -Y 1 -O -CO-R ⁰ , -Y ¹ -CO ₂ -R ⁶ , -Y ¹ -CO-R ⁶ , -Y ¹ -CO-NR ⁴ (R ⁵ ), -Y ¹ -SO ₂ -R ⁰ , -Y ¹ -SO-R ⁰ , -Y ¹ -SR ⁰ , -Y ¹ -CN, -Y ¹ -CO-R ⁰⁰ -NR ⁴ (R ⁵ ), -Y ¹ -CO-R ⁰⁰ -OR ⁶ , -Y ¹ -CO-NR ⁴ -R ⁰⁰ -OR ⁶ , -Y ¹ -NR ⁴ -R ⁰⁰ -OR ⁶ , -Y ¹ -NR ⁴ -R ⁰⁰ -NR ⁵ R ⁶ , -Y ¹ -NR ⁴ -CO- NR ⁵ R ⁶ , —Y ² —optionally substituted phenyl, —Y ² —optionally substituted monocyclic or bicyclic heterocyclic group, —Y ² —optionally substituted cycloalkyl, -Y ³ -optionally substituted phenyl,
R ⁰ : lower alkyl,
R ⁰⁰ : lower alkylene,
Y ¹ : bond or -R ^00- ,
Y ^{2: bond, -R 00 -, - O -} , - R 00 -O -, - R 00 -CO -, - R 00 -SO 2 - or -CO ₂ -R ⁰⁰ -,
Y ³ : lower alkylene substituted with a group selected from phenyl and —CO ₂ —R ⁶ ,
R ⁴ and R ⁶ : the same or different from each other, H or -R ⁰ ,
R ⁵ : H, —R ⁰ , phenyl optionally substituted with halogen or benzyl optionally substituted with halogen,
k: 0, 1, 2, or 3,
Provided that when the group Het is a morpholino group, k represents 1, 2 or 3,
R ² and R ³ : the same or different from each other, H, -R ⁰ , -R ⁰⁰ -OR ⁶ , -R ⁰⁰ -NR ⁰ R ⁴ , -R ⁰⁰ -CN, -R ⁰⁰ -CO ₂ -R ⁶ , -R ⁰⁰ -CO-NR ⁴ (R ⁵ ), -R ⁰⁰ -SO ₂ -R ⁰ , -R ⁰⁰ -optionally substituted phenyl, -R ⁰⁰ -optionally substituted monocyclic or bicyclic Heterocyclic group, -R ⁰⁰ -optionally substituted cycloalkyl, -Y ³ -CO ₂ -R ⁰ , -Y ³ -OR ⁶ , -Y ³ -optionally substituted monocyclic or bicyclic ring A heterocyclic group, an optionally substituted phenyl, an optionally substituted monocyclic or bicyclic heterocyclic group, an optionally substituted cycloalkyl,
^{X: -CR 7 R 8 -,} - O -, - CO -, - S (O) p - or -NR ⁴ -,
R ⁷ and R ⁸ : the same or different from each other, H, -R ⁰ , halogen or -OR ⁶ ,
p: 0, 1 or 2,
m: 0, 1, 2, or 3,
n: 0, 1, 2, or 3,
Here, m + n represents an integer of 2 or more and 5 or less. )