JP2006290791A - Azole-substituted sulfonylbenzene derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new therapeutic or prophylactic medicine for inflammatory diseases or autoimmune diseases, based on excellent PDE7 inhibitory action. <P>SOLUTION: The present inventors confirmed that a sulfonylbenzene derivative in which an azole ring such as pyrrole, imidazole or pyrazole is bonded through the nitrogen atom to a benzene ring has a strong PDE7 inhibitory action and excellent function-inhibiting action of T lymphocyte based on the PDE7 inhibitory action and found that the sulfonylbenzene derivative can become a good therapeutic or prophylactic medicine for inflammatory diseases or autoimmune diseases and completed the present invention. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to an azole-substituted sulfonylbenzene derivative useful as a therapeutic or preventive agent for a disease involving PDE7A such as a pharmaceutical, particularly an inflammatory disease or an autoimmune disease.

Cyclic adenosine monophosphate (cAMP) is a so-called “second messenger” signaling agent that mediates responses to cells and various hormones, neurotransmitters or inflammation-inducing substances. For example, in humans, many important physiological responses, such as psychological function, smooth muscle relaxation, cardiac contractility strength, release of histamine and other immunoreactive molecules, lymphocyte proliferation and platelet coagulation, are intracellular in cAMP. It is known to be controlled by concentration (Robison GA et al., Cyclic AMP, Academic Press, New York and London (1971)). The intracellular concentration of cAMP is controlled by the balance between their production by adenylyl cyclase (AC) and extinction by conversion to 5'-AMP. As a group of enzymes related to the latter, cyclic nucleotide phosphodiesterase (PDE) is known (Francis SH et al., Prog Nucleic Acid Res Mol Biol 65: 1-52 (2001)).
Among the PDE enzyme group, recently identified PDE7 is an enzyme that specifically converts cAMP and has two isotypes, PDE7A and 7B (Gardner C et al., Biochem Biophys Res Commun 272: 186-192 ( 2000), Hetman JM et al., Proc Natl Acad Sci USA 97: 472-476 (2000), Sasaki T et al., Biochem Biophys Res Commun 271: 575-583 (2000)). In particular, PDE7A is specifically expressed in immune tissues such as thymus, spleen and lymph nodes, or peripheral lymphocytes (Bloom TJ and Beavo JA, Proc Natl Acad Sci USA 93: 14188-14192 (1996), Han P et al. al., J Biol Chem 272: 16152-16457 (1997), Wang P et al., Biochem Biophys Res Commun 276: 1271-1277 (2000), Smith SJ et al., Am J Physiol Lung Cell Mol Physiol 284: L279 -L289 (2003)). It has also been reported that selective inhibition of PDE7A by treating human T lymphocytes with PDE7A antisense suppresses T lymphocyte functions such as cytokine production or cell proliferation from T lymphocytes (Li et al., Science 283: 848-851 (1999)), PDE7A has been shown to play an important role in the functional expression of T lymphocytes. Thus, since PDE7A is involved in many diseases in which T lymphocytes are involved in pathological conditions, it has been attracting attention as a new immunosuppressive drug and anti-inflammatory drug, and a search for PDE7A inhibitors is being conducted.

（式中、Ｒ¹はアリール又はヘテロアリールを、A、B、D及びEは、同一又は互いに異なって、窒素原子又はC（R²）基[ここで、R²は水素又はハロゲン原子等を示す]を、Xは酸素又は硫黄原子、或いはN(R³)基[ここで、R³は水素原子又はアルキル基を示す]を、Q、R、S及びTは、同一又は互いに異なって、窒素原子又はC（R⁴）基[ここで、R⁴は-L¹(Alk¹)_rL²(R⁵)_sで示される原子又は基を示す]を示す。詳細は当該公報参照。） It is described that a compound represented by the following formula has a PDE7 inhibitory action and is useful for the treatment of autoimmune diseases and the like (Patent Document 1).

(Wherein R ¹ is aryl or heteroaryl, A, B, D and E are the same or different from each other, a nitrogen atom or a C (R ² ) group [where R ² represents a hydrogen atom, a halogen atom, etc. X represents an oxygen or sulfur atom, or an N (R ³ ) group [wherein R ³ represents a hydrogen atom or an alkyl group], Q, R, S and T are the same or different from each other, A nitrogen atom or a C (R ⁴ ) group [wherein R ⁴ represents an atom or group represented by -L ¹ (Alk ¹ ) _r L ² (R ⁵ ) _s ].

（式中、R1は水素であり且つR2はフッ素、塩素、臭素等であるか、又は、R1は水素、フッ素、塩素、臭素等であり且つR2は水素であり、R’及びR”は共に水素又は結合を、R3は水素原子等を、R4は1-4C-アルキル、ナフタレニル、3,5-ジメチルイソオキサゾール-4-イル等、又は置換されていてもよいフェニル又はチオフェン基等を示す。詳細は当該公報参照。） Moreover, it is described that the compound represented by the following general formula is useful for the treatment of inflammatory diseases involving T cells (Patent Document 2).

(Wherein R1 is hydrogen and R2 is fluorine, chlorine, bromine or the like, or R1 is hydrogen, fluorine, chlorine, bromine or the like and R2 is hydrogen, and R ′ and R ″ are both Hydrogen or a bond, R3 represents a hydrogen atom, R4 represents 1-4C-alkyl, naphthalenyl, 3,5-dimethylisoxazol-4-yl, or an optionally substituted phenyl or thiophene group. (See the official gazette for details.)

International Publication No. 01/74786 Pamphlet International Publication No. 02/40450 Pamphlet

  An object of the present invention is to provide a novel therapeutic or prophylactic agent for inflammatory diseases or autoimmune diseases based on an excellent PDE7 inhibitory action.

As a result of intensive studies on compounds having a PDE7 inhibitory activity, the present inventors are characterized in that an azole ring such as pyrrole, imidazole or pyrazole represented by the following general formula is bonded to a benzene ring via the nitrogen atom. Sulphonylbenzene derivatives have strong PDE7, especially PDE7A inhibitory activity and excellent T lymphocyte function inhibitory activity, and can be a good therapeutic or preventive agent for inflammatory diseases or autoimmune diseases As a result, the present invention was completed. The azole-substituted sulfonylbenzene derivative of the present invention is different in structure from conventional compounds in that the azole ring is bonded to the benzene ring via the nitrogen atom.
That is, the present invention relates to a novel sulfonylbenzene derivative represented by the following general formula (I).

（式中の記号は以下の意味を有する。
R¹：H、置換されていてもよい低級アルキル、置換されていてもよいシクロアルキル、置換されていてもよいアリール又は置換されていてもよいヘテロ環、
X：N又はC(R⁶)、
Y：N又はC(R⁷)、
Z：N又はC(R⁸)、
R⁶、R⁷及びR⁸：同一又は互いに異なって、H、-CO-低級アルキル、ハロゲン、-OH、-O-低級アルキル、置換されていてもよい低級アルキル、或いは、隣接する２つの基が一体となって、低級アルキレン、-NR⁹-で中断された低級アルキレン又は1,3-ブタジエニレン基を形成し、各々、それらが結合する炭素原子とともに、シクロアルケニル、ヘテロシクロアルケニル又はフェニル基を形成してもよい、ここで、当該シクロアルケニル、ヘテロシクロアルケニル及びフェニル基は、１乃至３個の置換基を有していてもよい、
R⁹：H、低級アルキル、-CO-低級アルキル、-CO₂-低級アルキル、置換されていてもよいアリール、置換されていてもよいシクロアルキル又は置換されていてもよいヘテロ環、ここに、低級アルキルは、-OH、-O-低級アルキル、-CO₂H、-CO₂-低級アルキル、NH₂、NH(低級アルキル)及びN(低級アルキル)₂、及びフェニルからなる群より選択される1個の基で置換されていてもよい、
R²：同一又は互いに異なって、低級アルキル、ハロゲン、ハロゲノ低級アルキル、-OH又は-O-低級アルキル、
m：０、１又は２、
R³：-OH、-O-置換されていてもよいフェニル、又は下記式(i)〜(iii)からなる群より選択される基、

R⁴：H又は低級アルキル、
R⁵：H、置換されていてもよい低級アルキル、置換されていてもよいシクロアルキル又は置換されていてもよいアリール又は置換されていてもよいヘテロ環、及び、
Het：置換されていてもよい含窒素ヘテロ環。以下同様。）

(The symbols in the formula have the following meanings.
R ¹ : H, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocycle,
X: N or C (R ⁶ ),
Y: N or C (R ⁷ ),
Z: N or C (R ⁸ ),
R ⁶ , R ⁷ and R ⁸ are the same or different from each other, H, —CO-lower alkyl, halogen, —OH, —O-lower alkyl, optionally substituted lower alkyl, or two adjacent groups There together, lower alkylene, -NR ⁹ - lower alkylene or 1,3-butadienylene group interrupted with to form, respectively, together with the carbon atoms to which they are attached, a cycloalkenyl, a heterocycloalkenyl, or a phenyl group Where the cycloalkenyl, heterocycloalkenyl and phenyl groups may have 1 to 3 substituents,
R ⁹ : H, lower alkyl, —CO-lower alkyl, —CO ₂ -lower alkyl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted heterocycle, Lower alkyl is selected from the group consisting of —OH, —O-lower alkyl, —CO ₂ H, —CO ₂ -lower alkyl, NH ₂ , NH (lower alkyl) and N (lower alkyl) ₂ , and phenyl. Optionally substituted with one group,
R ² : the same or different from each other, lower alkyl, halogen, halogeno lower alkyl, —OH or —O-lower alkyl,
m: 0, 1 or 2,
R ³ : —OH, —O-optionally substituted phenyl, or a group selected from the group consisting of the following formulas (i) to (iii):

R ⁴ : H or lower alkyl,
R ⁵ : H, optionally substituted lower alkyl, optionally substituted cycloalkyl or optionally substituted aryl or optionally substituted heterocycle, and
Het: optionally substituted nitrogen-containing heterocycle. The same applies hereinafter. )

  Since the compound of the present invention has a strong PDE7 inhibitory action, diseases involving PDE7 such as inflammatory diseases or autoimmune diseases, particularly asthma, chronic obstructive pulmonary disease, psoriasis, atopic dermatitis, glomerulonephritis , Septic shock, autoimmune diabetes, organ transplant toxicity, cachexia, allergic rhinitis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, conjunctivitis, rheumatoid arthritis.

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. Therefore, the “lower alkyl” is C _1-6 alkyl, preferably a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl group. “Lower alkenyl” is C _2-6 alkenyl, preferably vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl and 3-butenyl groups. “Lower alkynyl” is C _2-6 alkynyl, preferably ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and 1-methyl-2-propynyl. .
“Lower alkylene” is C _1-6 alkylene, preferably linear alkylene such as methylene, ethylene, trimethylene and tetramethylene, and branched alkylene such as methylmethylene and 1,2-dimethylethylene. is there.
“Lower alkylene interrupted by —NR ⁹ —” is a group in which one of the carbon atoms of the lower alkylene is substituted with —NR ⁹ —, preferably —NR ⁹ — (CH ₂ ) ₃ — ^{_{, -CH 2 -NR 9 - (CH}} 2) 2 -, - CH 2 -NR 9 -CH 2 -, - (CH 2) 2 -NR 9 - (CH 2) 2 - , more preferably an -CH ^{_{2 -NR 9 - (CH 2)}} 2 - it is.

“Halogen” refers to F, Cl, Br and I. “Halogeno lower alkyl” means C _1-6 alkyl substituted with one or more halogens, preferably C _1-6 alkyl substituted with one or more F, more preferably tri A fluoromethyl group;
“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. “Cycloalkenyl” is a group having one double bond at any position of the “cycloalkyl”, preferably cyclopentenyl, cyclohexenyl, or cycloheptenyl.
The term "aryl", C ₆ - ₁₄ a monocyclic - tricyclic aromatic hydrocarbon ring group, preferably phenyl and naphthyl groups. In addition, one in which one ring of bi- or tricyclic aryl is hydrogenated is included, and tetrahydronaphthyl and indanyl groups are preferable.

“Heterocycle” means a monocyclic 3- to 8-membered, preferably 5- to 7-membered ring structure containing 1 to 4 heteroatoms selected from O, S and N (hereinafter, monocyclic heterocycle). Is a general term for cyclic groups containing as a constituent component. “Heterocycle” includes, in addition to the above-mentioned monocyclic heterocycles, monocyclic heterocycles or bi to tricyclic heterocycles in which these monocyclic heterocycles are condensed with phenyl or cycloalkyl. To do. “Heterocycle” includes “heteroaryl” in which all of the constituent ring groups are unsaturated rings, “heterocycloalkyl” having a saturated ring in the constituent ring, and a partially unsaturated ring in the constituent ring. Also includes “heterocycloalkenyl” having
Heteroaryl is preferably pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, indolyl, indazolyl, quinazolyl, quinazolyl, quinazolyl, quinazolyl, quinazolyl, quinazolyl, quinazolyl Quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, imidazopyridyl, imidazopyrimidinyl, pyrrolopyridyl and chromanyl groups. The ring atom S or N may be oxidized to form an oxide or a dioxide.
Heterocycloalkyl or heterocycloalkenyl is preferably pyrrolidinyl, piperidyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, tetrahydropyridyl , Tetrahydropyrimidinyl, dihydropyrrolyl, indolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydrobenzimidazolyl, dihydrobenzodioxinyl and dihydrobenzimidazolidinyl groups. In heterocycloalkyl and heterocycloalkenyl, any carbon atom may be substituted with an oxo group. The heterocycle includes a spiro ring and a bridged heterocycle. The spiro ring and the bridged hetero ring are preferably quinuclidinyl, 8-azabicyclo [3.2.1] octane-3-yl, and 8-azabicyclo [3.2.1] octane-8-yl groups.

The “nitrogen-containing heterocycle” is a 5- to 6-membered monocyclic unsaturated or partly containing one N atom and further containing one or two heteroatoms composed of N, S and O It is an unsaturated nitrogen-containing heterocycle, and the ring group may be further condensed with a benzene ring to form a bicyclic nitrogen-containing heterocycle. Preferable monocyclic nitrogen-containing heterocycles are pyrrolidine, piperidine, piperazine, azepane, diazepane, morpholine, thiomorpholinyl, tetrahydropyridine, and tetrahydropyrimidine ring. The bicyclic nitrogen-containing heterocycle is preferably indolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, or tetrahydrobenzoimidazolyl. In particular, preferred nitrogen-containing heterocycles relating to the group R ³ in the general formula (I) are pyrrolidine, piperidine, piperazine, azepane, diazepan and morpholine rings for the group (ii) and dihydro Pyrimidine ring.

“Optionally substituted” means “unsubstituted” or “having 1 to 5 identical or different substituents”.
The substituent in the “optionally substituted aryl” and the “optionally substituted heterocycle” in R ¹ is preferably a lower alkyl group, a substituent shown in the following group G, and a group shown in the following group G. A lower alkyl group substituted with a substituent, more preferably lower alkyl, halogen, —OH, —O lower alkyl, —CN, —CO-lower alkyl, and —CHO.
Group G: _{halogen, -NH 2, -NO 2, -N} (R 10) R 11, -OH, -OR 12, -CN, -CHO, -CO 2 H, -CO 2 R 12, -CO- lower _{alkyl, -CO-NH 2, -CO-} n (R 10) R 11, -S (O) n - lower ^{_{alkyl, -NH-CO 2 R 12,}} -NH-CO- lower alkyl, -NH-S ( O) _n -Lower alkyl, phenyl, monocyclic heterocycloalkyl, -O-phenyl, -CO-phenyl, -O-monocyclic heterocycloalkyl and -CO-monocyclic heterocycloalkyl.
(Wherein R ¹⁰ and R ¹¹ are the same or different from each other, and are —OH, —O-lower alkyl, —CO ₂ H, —CO ₂ -lower alkyl, NH ₂ , NH (lower alkyl) and N (lower Alkyl) lower alkyl optionally substituted with one group selected from the group consisting of ₂ , R ¹² is halogen, —OH, —O-lower alkyl, —CO ₂ H, —CO ₂ -lower It represents lower alkyl optionally substituted with one group selected from the group consisting of alkyl, NH ₂ , NH (lower alkyl), N (lower alkyl) ₂ and phenyl, and to phenyl and monocyclic Terocycloalkyl may be substituted with one group selected from the group consisting of lower alkyl, halogen, —OH and —O-lower alkyl.)
The substituent of “lower alkyl which may be substituted” and “cycloalkyl which may be substituted” in R ¹ is preferably a substituent shown in the G group, more preferably halogen, OH and -O-lower alkyl.

As the substituent of “optionally substituted lower alkyl” in R ⁶ , R ⁷ and R ⁸ , preferably —OH, —O-lower alkyl, —CO ₂ H, —CO ₂ -lower alkyl, NH ₂ , NH (lower alkyl), N (lower alkyl) ₂ , monocyclic heterocycloalkyl optionally substituted with lower alkyl, monocyclic heterocycloalkyl optionally substituted with -CO-lower alkyl is there.
The substituent of “optionally substituted aryl” in R ⁶ , R ⁷ and R ⁸ is preferably lower alkyl, —OH, —O-lower alkyl, —CO ₂ H, —CO ₂ -lower alkyl, NH _2, NH (lower alkyl) and N (lower alkyl) ₂ .
Two adjacent groups of R ⁶ , R ⁷ and R ⁸ together form a lower alkylene, a lower alkylene interrupted by —NR ⁹ — or a 1,3-butadienylene group, and the carbon atom to which they are bonded In addition, when (1) cycloalkenyl, (2) heterocycloalkenyl, or (3) phenyl group is formed, the following substituents may be preferably substituted on the ring group.
(1) cycloalkenyl: oxo, ═NO-lower alkyl, —N (lower alkyl)-(monocyclic heterocycloalkyl optionally substituted with lower alkyl), and a group represented by Group G, and -O-lower alkylene-O- (wherein two oxygen atoms are bonded on the same carbon atom of the cycloalkenyl ring). More preferably, oxo, lower alkyl, -N (R ¹⁰ ) R ¹¹ , monocyclic heterocycloalkyl optionally substituted with lower alkyl and -N (lower alkyl)-(lower alkyl substituted May be monocyclic heterocycloalkyl). Preferred examples of the monocyclic heterocycloalkyl include piperazinyl, piperidinyl, homopiperazinyl, morpholinyl, pyrrolidinyl, oxazepanyl, azepanyl, thiomorpholinyl and tetrahydropyranyl.
(2) Heterocycloalkenyl: (1) A group similar to the substituent of cycloalkenyl, more preferably oxo and lower alkyl.
(3) Phenyl: a lower alkyl substituted with a group shown in the G group and a group shown in the G group, more preferably —O-lower alkyl.
R ⁹ is preferably monocyclic heterocycloalkyl optionally substituted with —CO— (lower alkyl substituted with N (lower alkyl) ₂ ) and lower alkyl. Here, a preferable group as the monocyclic heterocycloalkyl is the same as the preferable group of the monocyclic heterocycloalkyl described in the above (1).
Substituents on carbon atoms in heterocycloalkenyl

The substituent of “optionally substituted phenyl” in R ³ is preferably lower alkyl.
Preferred as a substituent in “optionally substituted lower alkyl”, “optionally substituted cycloalkyl”, “optionally substituted aryl” and “optionally substituted heterocycle” in R ⁵ Is the same as the substituent for R ¹ , and more preferably lower alkyl, —O-lower alkyl, phenyl and halogeno-lower alkyl.
The substituent in the “optionally substituted aryl”, “optionally substituted cycloalkyl” or “optionally substituted heterocycle” in R ⁹ is preferably lower alkyl, —OH, —O—. Lower alkyl, —CO ₂ H, —CO ₂ -lower alkyl, NH ₂ , NH (lower alkyl) and N (lower alkyl) ₂ .

Preferred embodiments of the compound of the present invention represented by the general formula (I) are shown below.
[1] A compound in which R ¹ is an optionally substituted phenyl group.
[2] A compound in which R ³ is represented by the above formula (i), more preferably, R ⁴ in the group (i) is H and R ⁵ is optionally substituted heteroaryl, More preferably, the compound wherein the heteroaryl is pyrimidinyl.
[3] A compound in which Y is C (R ⁷ ), Z is C (R ⁸ ), and X is CH. More preferably, R ⁷ and R ⁸ are combined to form a tetramethylene group, and together with the carbon atom to which they are bonded, a compound that forms a cyclohexenyl group.
[4] A compound in which only one of X, Y or Z is N.
Particularly preferred embodiments of the compound of the present invention are compounds corresponding to any of the above [1] to [3].

The compound of the present invention represented by formula (I) (hereinafter abbreviated as compound (I) of the present invention) may have tautomers and optical isomers depending on the type of the substituent. The present invention includes a mixture or an isolated form of these isomers.
Furthermore, the present invention includes “pharmaceutically acceptable prodrugs” relating to the compound (I) of the present invention. “Pharmaceutically acceptable prodrug” means that the compound (I) of the present invention is produced by solvolysis or conversion to a group such as CO ₂ H, NH ₂ , OH and the like under physiological conditions. It is a compound to be damped. 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. .
Moreover, this invention compound (I) may form N-oxide depending on the kind of substituent, and this invention also includes these N-oxide body.

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 of the present invention can be produced by applying various known synthesis 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 are cases. 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 protecting group, the desired compound can be obtained by removing the protecting group as necessary or converting it to a desired group.
Similarly to the protecting group, a prodrug of the compound of the present invention can be produced by introducing a specific group at the stage of a raw material or an intermediate, or performing a reaction using the obtained compound of the present invention. The reaction can be carried out by applying a method known by those skilled in the art, such as ordinary esterification and amidation.
Hereinafter, typical production methods of the compound of the present invention will be described.

本製法は、化合物（II）と化合物（III）とを反応させ、本発明化合物（Ia）を製造する方法である。
本製法は、化合物（II）と化合物（III）とを等量若しくは一方を過剰量用い、酸触媒存在下、反応に不活性な溶媒中又は無溶媒下、室温から加熱還流下、好ましくは５０℃から１５０℃で、通常0.5時間〜5日間反応させることによって行なわれる。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、テトラヒドロフラン（THF）、ジオキサン等のエーテル類、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、メタノール、エタノール等のアルコール類、N,N-ジメチルホルムアミド（DMF）、ジメチルアセトアミド（DMA）、N-メチルピロリドン（NMP）等が挙げられる。酸触媒としては、通常酸触媒反応に用いられるものであれば特に限定されないが、好ましくは、p-トルエンスルホン酸及び酢酸である。 Manufacturing method A pyrrole ring construction

This production method is a method for producing the present compound (Ia) by reacting the compound (II) with the compound (III).
In this production method, the compound (II) and the compound (III) are used in an equal amount or in an excess amount, and in the presence of an acid catalyst, in a solvent inert to the reaction or in the absence of a solvent, from room temperature to reflux with heating, preferably 50 C. to 150.degree. C., usually by reacting for 0.5 hour to 5 days. Here, the solvent is not particularly limited. For example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran (THF) and dioxane, and halogenated hydrocarbons such as 1,2-dichloroethane and chloroform. Alcohols such as methanol and ethanol, N, N-dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) and the like. The acid catalyst is not particularly limited as long as it is usually used for acid-catalyzed reactions, but is preferably p-toluenesulfonic acid and acetic acid.

（式中、R¹³は-N(低級アルキル)-(低級アルキルで置換されていてもよい単環式へテロシクロアルキル)又は前記Ｇ群に示される基を示す。以下同様。）
本製法は、製法Ａに従って得られる化合物（Ia）中、特にR⁷及びR⁸が一緒になってシクロヘキセン環を形成した化合物（Ib）を酸化反応に付し、インドール誘導体（Ic）を得る方法である。
本製法は、酸化剤の存在下、反応に不活性な溶媒中、冷却下から加熱還流下、好ましくは０℃から１５０℃で、通常1時間〜5日間反応させることによって行なわれる。溶媒としては製法Ａに用いたもののほか、アセトニトリルも好適に使用できる。酸化剤としては、パラジウム炭素、2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン（DDQ）又は空気中の酸素等が好適に用いられる。 Manufacturing method B Indole ring construction

(Wherein R ¹³ represents —N (lower alkyl)-(monocyclic heterocycloalkyl which may be substituted with lower alkyl) or a group represented by Group G. The same shall apply hereinafter.)
This production method is a method of obtaining indole derivative (Ic) by subjecting compound (Ib) obtained according to production method A to an oxidation reaction, particularly compound (Ib) in which R ⁷ and R ⁸ are combined to form a cyclohexene ring. It is.
This production method is carried out in the presence of an oxidizing agent in a solvent inert to the reaction by cooling to heating under reflux, preferably at 0 ° C. to 150 ° C., usually for 1 hour to 5 days. As the solvent, in addition to those used in production method A, acetonitrile can also be suitably used. As the oxidizing agent, palladium carbon, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), oxygen in the air, or the like is preferably used.

本製法は、化合物（IV）を分子内環化反応に付し、本発明化合物（Id）を得る方法である。
本製法は、反応に不活性な溶媒中、化合物（IV）を製法Ａと同様、酸触媒で処理することによって行われる。本反応においても製法Ａと同様の反応条件が適用できる。
また、本発明化合物（Id）中、R⁷がHである化合物は、化合物（IV）の代わりに化合物（V）を用いて、上記と同様の反応を行うことによっても製造することができる。

Production Method C Imidazole Ring Construction (1)

This production method is a method for obtaining the compound (Id) of the present invention by subjecting the compound (IV) to an intramolecular cyclization reaction.
This production method is carried out by treating compound (IV) with an acid catalyst in the same manner as in Production Method A in a solvent inert to the reaction. In this reaction, the same reaction conditions as in production method A can be applied.
In the compound (Id) of the present invention, the compound in which R ⁷ is H can also be produced by performing the same reaction as above using the compound (V) instead of the compound (IV).

本製法は、アルデヒド化合物（VI）及びアミン化合物（VII）を反応させ、本発明化合物（If）を得る方法である。
本製法は、まず、化合物（VI）及び化合物（VII）を等量若しくは一方を過剰量用い、脱水縮合によりイミン体を生成させ、次いで、これを単離した後、または単離することなく、塩基の存在下、等量乃至過剰量のp-トルエンスルホニルメチルイソシアニドと反応させることにより行われる。脱水縮合反応は、当業者に自明の脱水によるイミン合成の常法により実施することができる。p-トルエンスルホニルメチルイソシアニドとの反応は、反応に不活性な溶媒中、室温から加熱還流下、好ましくは５０℃から１２０℃で、通常0.1時間〜5日間行われる。塩基としては、トリエチルアミン、N,N-ジイソプロピルエチルアミン若しくはN-メチルモルホリン等の有機塩基、又は炭酸カリウム若しく炭酸ナトリウム等の無機塩基が好適に用いられる。また、溶媒としては、芳香族炭化水素類、エーテル類、ハロゲン化炭化水素類、DMF、DMA、NMPが好ましい。 Production Method D Imidazole Ring Construction (2)

This production method is a method for obtaining the compound (If) of the present invention by reacting the aldehyde compound (VI) and the amine compound (VII).
In this production method, first, compound (VI) and compound (VII) are used in an equal amount or in excess, and an imine is formed by dehydration condensation, and then, after or without isolation, The reaction is carried out in the presence of a base by reacting with an equal amount to an excess amount of p-toluenesulfonylmethyl isocyanide. The dehydration condensation reaction can be carried out by a conventional method of imine synthesis by dehydration, which is obvious to those skilled in the art. The reaction with p-toluenesulfonylmethyl isocyanide is carried out in a solvent inert to the reaction from room temperature to heating under reflux, preferably from 50 ° C. to 120 ° C., usually for 0.1 hour to 5 days. As the base, an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, or an inorganic base such as potassium carbonate or sodium carbonate is preferably used. As the solvent, aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMA, and NMP are preferable.

本製法は、ジカルボニル化合物（VIII）とヒドラジン化合物（IX）とを反応させ、本発明化合物（Ig）を得る方法である。
本製法は、化合物（VIII）と化合物（IX）とを等量若しくは一方を過剰量用い、
反応に不活性な溶媒中、室温から加熱還流下、好ましくは５０℃から１５０℃で、反応させることにより行われる。ここで、溶媒としては製法Ａと同様のものを使用できる。塩酸や酢酸等の酸やトリエチルアミン、水酸化ナトリウムや酢酸ナトリウム等の塩基の存在下に反応させるのが、反応を円滑に進行させる上で有利な場合がある。 Manufacturing method E Pyrazole ring construction

This production method is a method for obtaining the compound (Ig) of the present invention by reacting the dicarbonyl compound (VIII) with the hydrazine compound (IX).
In this production method, compound (VIII) and compound (IX) are used in an equal amount or in an excess amount,
The reaction is carried out in a solvent inert to the reaction by heating at room temperature to reflux, preferably at 50 ° C. to 150 ° C. Here, the same solvent as in production method A can be used. The reaction in the presence of an acid such as hydrochloric acid or acetic acid, or a base such as triethylamine, sodium hydroxide or sodium acetate may be advantageous for smoothly proceeding the reaction.

Production Method F Other Production Methods The compounds of the present invention having various functional groups can also be produced by applying methods that are obvious to those skilled in the art or known production methods, or modifications thereof. For example, a part of the compound (I) of the present invention can be produced by applying the following reaction using the compound (I) of the present invention as a raw material.
F-1: Alkylation (1)
In the compound (I) of the present invention, a compound having a hydroxyl group is reacted with various alkylating agents (for example, alkyl halides and alkylsulfonic acid esters) in the presence of a base (for example, potassium carbonate and sodium hydride). A compound having an alkoxy group can be produced. For the reaction, for example, the method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th edition, Volume 20, 1992, 187) can be applied.
F-2: Alkylation (2)
In the compound (I) of the present invention, an amino group-containing compound is converted into various alkylating agents (for example, alkyl halides, alkylsulfonic acid esters and alkyl carbonates) and triethylamine, N, N-diisopropylethylamine or N-methylmorpholine. By reacting in the presence of an organic base such as cesium carbonate, potassium carbonate, sodium carbonate or potassium hydroxide, a compound having an alkylamino group can be produced. For the reaction, for example, the method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th Edition, Volume 20, 1992, 284) can be applied.

F-3: Alkylation (3)
In the compound (I) of the present invention, the compound having an amino group is reacted with various carbonyl compounds with an equal or excess amount of a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, etc. Thus, a compound having an alkylamino group can be produced. For the reaction, for example, the method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th edition, Volume 20, 1992, 300) can be applied.
F-4: Alkylation (4)
In the compound (I) of the present invention, a compound in which any one of X, Y, or Z is CH is reacted with various secondary amines under the conditions of Mannich reaction to obtain a compound having an aminomethyl group on the ring. Can be manufactured. For the reaction, for example, the method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th edition, volume 20, 1992, 296) can be applied.
F-5: Alkylation (5)
In the compound (I) of the present invention, a compound having a carbonyl group can be treated with an alkyl magnesium reagent or an alkyl lithium reagent to produce an alkyl carbinol derivative. For the reaction, for example, a method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th edition, 25, 1991, 13, 61) can be applied.

F-6: Amidation In the compound (I) of the present invention, a compound having an amide group can be produced by reacting a compound having an amino group with various carboxylic acid compounds or reactive derivatives thereof. Similarly, in the compound (I) of the present invention, a compound having an amide group can be produced by condensing a compound having a carboxyl group with various amine compounds. 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 (Maruzen)” edited by The Chemical Society of Japan (4th edition, volume 22, 1992, 137) can be applied.
F-7: Oxidation In the compound (I) of the present invention, a compound having a sulfone or a sulfoxide can be produced by oxidizing a compound having a sulfide. For the reaction, for example, the method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th edition, volume 23, 1991, 276) can be applied.
F-8: Reduction (1)
In the compound (I) of the present invention, a compound having an carbonyl can be produced using a reducing agent such as sodium borohydride or lithium aluminum hydride. For the reaction, for example, the method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th edition, Volume 26, 1992, 209) can be applied. Moreover, an alkyl compound can also be manufactured by performing the said reduction | restoration in presence of boron trifluoride etc. For the reaction, for example, the method described in J. Org. Chem., 2196 (1968) can be applied.
F-9: Reduction (2)
In the compound (I) of the present invention, a compound having a carboxyl group can be produced by a reduction reaction using a palladium catalyst to produce a compound having an aldehyde. For the reaction, for example, the method described in Chem. Commun., 836-837 (2002) can be applied.
F-10: Reduction (3)
In the compound (I) of the present invention, a compound having an amino group can be produced by catalytic hydrogenation of a compound having a nitro group or a reduction reaction using iron or zinc. For the reaction, for example, the method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th edition, Volume 20, 1992, 279) can be applied.

F-11: Amination (1)
In the compound (I) of the present invention, a compound having a carbonyl group is reacted with various amine compounds with an equal or excess amount of a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride or sodium borohydride. Can produce a compound having an alkylamino group.
F-12: Amination (2)
In the compound (I) of the present invention, a compound having an amino group can be produced by reacting a compound having a halogen atom with a primary or secondary amine compound. In the case of a compound having a hydroxyl group in compound (I), the hydroxyl group is converted into various leaving groups (for example, halogen atom, trifluoromethanesulfonyloxy, etc.), and then the same reaction is performed. Substituted amino compounds can be prepared. In addition, when reacting the compound which has a leaving group in an aromatic ring, it carries out in presence of transition metals, such as palladium, or its phosphine complex. For the reaction, for example, the method described in J. Org. Chem., 1144-1157 (2000) can be applied.
F-13: Oximation In this invention compound (I), the compound which has oxime can be manufactured by making the compound which has a carbonyl group react with a hydroxylamine compound. For the reaction, for example, the method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th edition, volume 20, 1992, 353) can be applied.

（上記式中、Lはクロロ又はブロモ等のハロゲン、あるいはアルキルスルホニル基等の脱離基を示す。）
上記式中、アルキル化は日本化学会編「実験化学講座（丸善）」（第４版、２１巻、１９９１年、２９８）等に記載の方法を、また、クロロ化並びにアミジン化は日本化学会編「実験化学講座（丸善）」（第４版、１９９２年、３３４）記載の方法を参照して実施できる。 Manufacturing method G Manufacturing method of raw material compound The raw material compound used by the said manufacturing method can be manufactured according to the following synthetic pathway, for example.

(In the above formula, L represents a halogen such as chloro or bromo, or a leaving group such as an alkylsulfonyl group.)
In the above formula, alkylation is the method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th edition, Volume 21, 1991, 298) and the like, and chlorination and amidineization are the Chemical Society of Japan. It can be carried out with reference to the method described in ed.

The pharmacological activity of the compound of the present invention was confirmed by the following test.
1. PDE7A inhibitory activity
(1) Acquisition of PDE7A PDE7A used in this experiment was expressed and purified according to the method of Bloom et al. (Bloom TJ and Beavo JA, Porc Natl Acad Sci USA 93: 14188-14192 (1996)). Similarly, PDE7B was expressed and purified according to the method of Gardner et al. (Gardner C et al., Biochem Biophys Res Commun 272: 186-192 (2000)).
(2) Evaluation of PDE7A inhibitory activity
PDE7A and 7B inhibitory activity was measured by the following method. That is, a buffer solution containing Tris-HCl (40 mM, pH 8.0), MgCl ₂ (5 mM) and 2-mercaptoethanol (4 mM) plus cAMP (1 μM) and ³ H-cAMP (22 nM) Was used as a substrate buffer. To this, add 1/100 volume of test compound solution adjusted to 100 times the final concentration and enzyme solution of final concentration 10 μg / ml (1/20 volume adjusted to 20 times concentration) at 30 ° C. For 15 minutes. The enzymatic reaction was stopped by adding Phosphodiesterase Scintillation Proximity Assay (SPA) beads (Amersham, Sweden) containing 1.67 mM IBMX. The amount of 5′-AMP, which is a reaction degradation product bound to SPA beads, was measured with a TopCount microplate reader (Hewlett Packard, USA). Inhibition of the compound group when the radioactivity of the subject group to which only the lysate was added instead of the compound was set to 0% inhibition rate, and the radioactivity of the non-reactive group to which the buffer solution was added instead of the enzyme was assumed to be 100% inhibition rate The rate was determined. Further, from the obtained results, the compound concentration that inhibits 50% from the linear regression by the maximum likelihood method was calculated as an IC ₅₀ value.
The compounds of Examples 1-3, 8, 26, 29, 34-39, 41, 42, 56, 72-74, 113, 125, 128, 130, 132, 134-136, 138, 140 and 154 described below are IC ₅₀ values below 20 nM were shown. This test confirmed that the compounds of the present invention have good PDF7 inhibitory activity.

2. IL-2 production inhibitory effect
The IL-2 production inhibitory action was evaluated based on the inhibition rate of the test compound-treated group with respect to the amount of IL-2 produced from mouse spleen cells by stimulation with anti-CD3 antibody. That is, the spleen was removed from a Balb / c male mouse that had been killed by cervical dislocation, and splenocytes were released into the medium by chopping in RPMI1640 medium containing 5% fetal bovine serum (FBS). Then, the medium was permeated through a nylon mesh having a diameter of 100 μm to remove the contaminants. The medium permeated through the mesh is centrifuged (250 g, room temperature, 10 minutes) to collect the precipitate, suspended in 0.87% NH ₄ Cl solution, and left at room temperature for 5 minutes to hemolyze the mixed red blood cells. It was. The separated splenocytes were washed 3 times with phosphate buffered saline (PBS, pH = 7.4), then suspended in RPMI1640 medium containing 5% FBS to give 4 × 10 ⁶ cells / ml, and used for the experiment. .
For anti-mouse CD3 antibody (clone 145-2C11, Cedar Lane, Canada), dispense 5 μg / ml into a flat-bottom 96-well plate, 50 μl of each well, and incubate at 4 ° C for at least one day and night. Coated. After washing the plate 3 times with PBS, 100 μl of the mouse spleen cells prepared above were dispensed into each well, 100 μl of the test compound solution prepared to a double concentration was added, and 37 ° C, 5% CO _The culture was performed under ₂ conditions for 40 hours. After the culture, the amount of IL-2 produced in the supernatant was measured with an ELISA kit (BD Bioscience, USA). Compound group when the amount of IL-2 in the target group to which only the lysate was added instead of the compound was 0%, and the amount of IL-2 in the non-reactive group to which no anti-CD3 antibody stimulation was added was 100% The inhibition rate was determined. Further, from the obtained results, the compound concentration that inhibits 50% from the linear regression by the maximum likelihood method was calculated as an IC ₅₀ value.
The compounds of Examples 36, 39, 41, 72, 73, 113, 130, 132, 134, 135 and 154 described below exhibited IC ₅₀ values of 1 μM or less. This test confirmed that the compound of the present invention has an IL-2 production inhibitory action, that is, suppresses the function of T lymphocytes.

3. Delayed type hypersensitivity reaction (DTH) inhibitory effect Delayed type hypersensitivity reaction (DTH) was induced by sensitizing mice with sheep red blood cells (SRBC, Japan Biomaterials Center, Japan) twice. That is, SRBC was washed 3 times with PBS, suspended in PBS to 2 × 10 ⁷ cells / 200 μl, and inoculated subcutaneously in the back of the back of Balb / c male mice (8-10 weeks old). Six days after the first sensitization, SRBC suspended in PBS at 1 × 10 ⁸ cells / 25 μl was inoculated subcutaneously to the left footpad to induce footpad swelling. The test compound was suspended in 0.5% methylcellulose (MC) solution and orally administered 90 minutes before and 3 hours after the final SRBC sensitization. After 18 hours of the final sensitization, the mice were killed by anesthesia with ether, and the toes were cut from the tibial-tarsal joint. For the DTH reaction, the degree of swelling was evaluated based on the weight difference between the right footpad inoculated with the solvent alone and the sensitized left footpad as a control. The suppression rate of the compound group was determined when the suppression rate was 0% for the subject group administered only the MC solution instead of the compound, and the suppression rate was 100% for the non-sensitized group without SRBC sensitization. .
The compounds of Examples 132 and 134, which will be described later, exhibited an inhibition rate of 50% or more after oral administration at 30 mg / kg. This test confirmed that the compounds of the present invention have excellent T lymphocyte function-suppressing activity.

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.

External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.
In addition, the pharmaceutical composition containing the compound (I) of the present invention or a salt thereof as an active ingredient includes other therapeutically effective active ingredients such as β2 agonists, steroids, leukotriene antagonists, antihistamines, immunosuppressants, diseases They may be used in combination with appropriate modifying anti-rheumatic agents (DMARDs), cyclooxygenase inhibitors, cytokine production inhibitors, cytokine antagonists and the like. When used in combination with these, it is provided as a combination for simultaneous administration or as a combination of separate preparations 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.
In addition, the following abbreviations are used in Reference Examples, Examples and Tables below.
The number before the substituent indicates the substitution position, and a plurality of numbers indicates a plurality of substitutions. For example, 3,4- (MeO) ₂ -represents a 3,4-dimethoxy group. However, 3,4-O (CH ₂ ) ₂ O— represents an ethylenedioxy group crosslinked at the 3-position and 4-position.
Me: methyl, Et: ethyl, Ac: acetyl, Boc: tert-butoxycarbonyl, REx: reference example number, Ex: example number, No: compound number, Sal: salt (no description: free form; HCl: hydrochloride salt Ox: oxalate; Fu: fumarate; TsOH: p-toluenesulfonate; the numbers indicate the molar ratio of the acid component, eg 2HCl means dihydrochloride), Dat: physicochemical Properties (F: FAB-MS (M + H) ⁺ , FN: FAB-MS (MH) ⁻ , ESI: ESI-MS (M + H) ⁺ , ESIN: ESI-MS (MH) ⁻ ), NMR: nucleus Δ value of magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard).

Reference example 1
Cesium carbonate was added to a chloroform solution of dimedone, and 2-bromo-1- (3-methoxyphenyl) ethanone was added. After stirring at room temperature for 5 hours, the solid was collected by filtration and washed with chloroform. Water was added thereto, and the mixture was acidified with 6 M hydrochloric acid. The resulting solid was collected by filtration and dried to give 5,5-dimethyl-2- [2- (3-methoxyphenyl) -2-oxoethyl]. Cyclohexane-1,3-dione was obtained. F: 289.
Reference Examples 2-21
In the same manner as in Example 1, the compounds of Reference Examples 2 to 21 shown in the table below were produced.
Reference Example 22
Pyrrolidine and p-toluenesulfonic acid monohydrate were added to a benzene solution of cyclohexanone, and the mixture was heated to reflux overnight while removing the generated water. The reaction solution was concentrated under reduced pressure, dissolved in toluene, and a toluene solution of 2-bromo-1- (4-cyanophenyl) ethanone was added dropwise with heating, followed by further heating to reflux to give 2- [2- (4 -Cyanophenyl) -2-oxoethyl] cyclohexanone was obtained. F: 242.
Reference Examples 23 to 28
In the same manner as in Example 2, the compounds of Reference Examples 23 to 28 shown in the table below were produced.

Reference Example 29
4-Amino-N- (4,6-dimethylpyrimidin-2-yl) benzenesulfonamide and potassium carbonate were added to a dimethylsulfoxide solution of 2-fluoronitrobenzene, and the mixture was stirred at 90 ° C. for 4 hours and 110 ° C. for 2 hours. The solvent was distilled off, water was added, neutralized with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Ethanol was added to the resulting residue, the insoluble material was removed by filtration, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain N- (4,6-dimethylpyrimidin-2-yl) -4-[(2-nitrophenyl) amino] benzenesulfonamide (F: 400). It was. Ammonium chloride and reduced iron were added to a water-ethanol solution of this compound, and the mixture was heated to reflux for 30 minutes. Insoluble matter was removed by filtration, the filtrate was concentrated, and the resulting residue was recrystallized from ethanol to give 4-[(2-aminophenyl) amino] -N- (4,6-dimethylpyrimidin-2-yl. ) Benzenesulfonamide was obtained. F: 370.

Example 1
5,5-dimethyl-2- [2- (4-methoxyphenyl) -2-oxoethyl] cyclohexane-1,3-dione (0.58 g), 4-amino-N- (4,6-dimethylpyrimidine-2- Yl) Toluene (10 ml) and DMF (2 ml) were added to benzenesulfonamide (0.56 g) and p-toluenesulfonic acid monohydrate (0.08 g), and the mixture was heated to reflux for 3 days. And the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 → 50: 1), and the obtained solid was recrystallized from ethanol to give 4- {6,6-dimethyl-2 -(4-Methoxyphenyl) -4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl} -N- (4,6-dimethylpyrimidin-2-yl) benzenesulfonamide (90 mg) was obtained as a white solid.
Examples 2-61
In the same manner as in Example 1, the compounds of Examples 2 to 61 shown in the table below were produced.
Example 62
N- (4,6-Dimethylpyrimidin-2-yl) -4- [2 '-(4-methoxyphenyl) -6', 7'-dihydrospiro [1,3-dioxolane-2,5'-indole] -1 '(4'H) -yl] benzenesulfonamide was dissolved in acetic acid (130 ml) and water (30 ml) was added. The reaction was heated to reflux for 15 minutes and allowed to cool to room temperature. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and diethyl ether to give N- (4,6-dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -5-Oxo-4,5,6,7-tetrahydro-1H-indol-1-yl] benzenesulfonamide (21.4 g) was obtained as a white solid.
Example 63
N- (4,6-Dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -5-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl] benzene Sodium borohydride (0.05 g) was added to an ethanol solution of sulfonamide (0.25 g), and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1), and the resulting solid was washed with diethyl ether to give N- (4,6-dimethylpyrimidin-2-yl) -4. -[5-Hydroxy-2- (4-methoxyphenyl) -4,5,6,7-tetrahydro-1H-indol-1-yl] benzenesulfonamide (102 mg) was obtained.

Example 64
N- (4,6-Dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole -1-yl] benzenesulfonamide (500 mg) in tetrahydrofuran (5 ml) was added sodium borohydride (80 mg) in an ice bath, and boron trifluoride ethyl ether complex (0.37 ml) was added dropwise at room temperature. For 1 hour. To the reaction solution, 2.1 ml of cold 5% hydrochloric acid was added dropwise in an ice bath, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) and recrystallized from ethanol to give N- (4,6-dimethylpyrimidin-2-yl) -4- [2- (4- Methoxyphenyl) -6,6-dimethyl-4,5,6,7-tetrahydro-1H-indol-1-yl] benzenesulfonamide (117 mg) was obtained as colorless crystals.

Example 65
N- (4,6-Dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -4,5,6,7-tetrahydro-1H-indol-1-yl] benzenesulfonamide (0.40 To a solution of g) in xylene (20 ml) was added 10% palladium carbon (0.50 g), and the mixture was stirred under reflux for 2 days. The insoluble material was removed by filtration, the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform), and the resulting solid was recrystallized from ethanol to give N- (4, 6-Dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -1H-indol-1-yl] benzenesulfonamide (205 mg) was obtained as colorless crystals.
Examples 66-67
The compounds of Examples 66 to 67 shown in the table below were produced in the same manner as in Example 1.

Example 68
4-Anisoyl chloride (235 mg) in a solution of 4-[(2-aminophenyl) amino] -N- (4,6-dimethylpyrimidin-2-yl) benzenesulfonamide (425 mg) in pyridine (2 ml) And stirred at 120 ° C. overnight. The solvent was distilled off, 0.5 M hydrochloric acid was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform / methanol), and N- {2- [4-{[(4,6-dimethylpyrimidin-2-yl) amino] sulfonyl} phenyl) amino] phenyl } -4-Methoxybenzamide and N- (4,6-dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -1H-benzimidazol-1-yl] benzenesulfonamide (699) mg). A solution of this mixture (691 mg) in acetic acid (7 ml) was stirred at 110 ° C. for 3 days. The solvent was distilled off, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. To a solution of the obtained residue (586 mg) in ethanol (6 ml) was added 4 M hydrogen chloride-ethyl acetate solution (0.31 ml), and the mixture was stirred at room temperature. The solvent was distilled off and recrystallized from ethanol-diethyl ether to give N- (4,6-dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -1H-benzimidazole-1 -Il] benzenesulfonamide hydrochloride (149 mg) was obtained as pale yellow crystals.
Example 69
tert-butyl 1- (4-{[(4,6-dimethylpyrimidin-2-yl) amino] sulfonyl} phenyl) -2- (4-methoxyphenyl) -1,4,6,7-tetrahydro-5H- To a solution of pyrrolo [3,2-c] pyridine-5-carboxylate (6.03 g) in ethyl acetate was added 4 M hydrogen chloride-ethyl acetate solution (50 ml), and the mixture was stirred at room temperature for 10 minutes. Distilled off under reduced pressure. The obtained residue was crystallized from ethanol, and N- (4,6-dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -4,5,6,7-tetrahydro-1H- Pyrrolo [3,2-c] pyridin-1-yl] benzenesulfonamide hydrochloride (3.90 g) was obtained as a light gray solid.
Example 70
N- (4,6-Dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine-1 Benzaldehyde (0.20 g), acetic acid (0.10 g) and sodium triacetoxyborohydride (0.42 g) were added to a solution of -yl] benzenesulfonamide hydrochloride (0.50 g) in DMF (10 ml) overnight at room temperature. Stir. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 → 50: 1), and then the resulting acetate was neutralized and dissolved in ethanol. 4M hydrogen chloride-ethyl acetate solution was added and concentrated under reduced pressure, and the resulting solid was recrystallized from ethanol to give 4- [5-benzyl-2- (4-methoxyphenyl) -4,5,6 , 7-Tetrahydro-1H-pyrrolo [3,2-c] pyridin-1-yl] -N- (4,6-dimethylpyrimidin-2-yl) benzenesulfonamide hydrochloride (450 mg) was obtained as colorless crystals. It was.

Example 71
N- (4,6-Dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine-1 4- (N, N-dimethylamino) pyridine (24 mg) and succinic anhydride (30 mg) were added to a solution of -yl] benzenesulfonamide hydrochloride (0.10 g) in DMF (2 ml) and added at room temperature. After stirring for 4 hours, 4- (N, N-dimethylamino) pyridine (5 mg) and succinic anhydride (10 mg) were further added, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with water, the organic phase was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from a mixed solvent of ethyl acetate and diethyl ether to give 4- [1- (4-{[(4,6-dimethylpyrimidin-2-yl) amino] sulfonyl} phenyl) -2. -(4-Methoxyphenyl) -1,4,6,7-tetrahydro-5H-pyrrolo [3,2-c] pyridin-5-yl] -4-oxobutanoic acid (82 mg) was obtained as colorless crystals.
Examples 72-73
The compound of Example 72 shown in a postscript table | surface by the method similar to postscript Example 87 and the compound of Example 73 shown in a postscript table | surface by the method similar to postscript Example 124 were each manufactured.
Example 74
N- (4,6-Dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole Hydroxylamine hydrochloride (990 mg) was added to a solution of 1-yl] benzenesulfonamide (1.51 g) in ethanol (110 ml), and the mixture was stirred at 85 ° C. overnight. Further, hydroxylamine hydrochloride (1 g) was added, and the mixture was stirred at 85 ° C. for 5 hours. The solvent was distilled off, neutralized by adding 4 M hydrochloric acid in an ice bath, and the precipitated crystals were collected by filtration and washed with water and diethyl ether. The obtained crude crystals were purified by silica gel column chromatography (chloroform / methanol) and recrystallized from ethanol to give N- (4,6-dimethylpyrimidin-2-yl) -4-[(4Z) -4 -(Hydroxyimino) -2- (4-methoxyphenyl) -6,6-dimethyl-4,5,6,7-tetrahydro-1H-indol-1-yl] benzenesulfonamide (74- (2)) ( 55 mg) was obtained as colorless crystals. The filtrate was distilled off and recrystallized from ethanol to give N- (4,6-dimethylpyrimidin-2-yl) -4-[(4E) -4- (hydroxyimino) -2- (4- Methoxyphenyl) -6,6-dimethyl-4,5,6,7-tetrahydro-1H-indol-1-yl] benzenesulfonamide (74- (1)) (65 mg) was obtained as colorless crystals.
Examples 75-76
In the same manner as in Example 1, the compounds of Examples 75 to 76 shown in the table below were produced.

Example 77
N- (4,6-Dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole To a solution of 1-yl] benzenesulfonamide (300 mg) in DMF (3 ml) was added 55% sodium hydride (27 mg) in an ice bath, and the mixture was stirred at 5 ° C. for 10 minutes. Iodomethane (39 μl) was added, and the mixture was stirred at 5 ° C. for 30 min, and further stirred at room temperature for 2 hr. The solvent was distilled off, water was added, and the mixture was extracted with chloroform-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform / methanol), and 4- [2- (4-methoxyphenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro -1H-Indol-1-yl] -N- (1,4,6-trimethylpyrimidine-2 (1H) -ylidene) benzenesulfonamide (77- (1)) 250 mg and N- (4,6-dimethyl Pyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl] -N- 10 mg of methylbenzenesulfonamide (77- (2)) was obtained.
Compound 77- (1) was recrystallized from ethanol (7 ml) to give 4- [2- (4-methoxyphenyl) -6,6-dimethyl-4-oxo-4,5,6,7- Tetrahydro-1H-indol-1-yl] -N- (1,4,6-trimethylpyrimidine-2 (1H) -ylidene) benzenesulfonamide (217 mg) was obtained as colorless crystals. Compound 77- (2) was crystallized from ethanol to give N- (4,6-dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -6,6-dimethyl-4 -Oxo-4,5,6,7-tetrahydro-1H-indol-1-yl] -N-methylbenzenesulfonamide (3 mg) was obtained as pale yellow crystals.
Examples 78-81
The compounds of Examples 78 to 81 shown in the table below were produced in the same manner as in Example 77.
Example 82
4- [1- (4-{[(4,6-Dimethylpyrimidin-2-yl) amino] sulfonyl} phenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H To a mixed solution of -indol-2-yl] ethyl benzoate (10.4 g) in ethanol (90 ml) and THF (90 ml) was added 1 M aqueous sodium hydroxide solution (27 ml), and the mixture was stirred at room temperature for 3 hours. 1 M Aqueous sodium hydroxide solution (85 ml) was added in several portions and stirred at room temperature for 5 hours. The mixture was neutralized with 1 M hydrochloric acid in an ice bath, and the precipitated crystals were collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 4- [1- (4-{[(4,6-dimethyl Pyrimidin-2-yl) amino] sulfonyl} phenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl] benzoic acid (7.93 g) as crude crystals Got as. This compound (0.48 g) was washed with hot ethanol (60 ml) to give 4- [1- (4-{[(4,6-dimethylpyrimidin-2-yl) amino] sulfonyl} phenyl) -6, 6-Dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl] benzoic acid (459 mg) was obtained as pale yellow crystals.
Examples 83-86
In the same manner as in Example 82, the compounds of Examples 83 to 86 shown in the table below were produced.

Example 87
4- [1- (4-{[(4,6-Dimethylpyrimidin-2-yl) amino] sulfonyl} phenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H -Indol-2-yl] benzoic acid (300 mg) in DMF (3 ml) solution with 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (116 mg) and 1-hydroxybenzotriazole (82 mg) and ammonium carbonate (47 mg) were added, and the mixture was stirred at room temperature for 3 days. The solvent was distilled off, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) and recrystallized from ethanol-acetonitrile to give 4- [1- (4-{[(4,6-dimethylpyrimidine-2- (Il) amino] sulfonyl} phenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl] benzamide (159 mg) was obtained as colorless crystals.
Examples 88-95
The compounds of Examples 88 to 95 shown in the table below were produced in the same manner as in Example 87.
Example 96
4- {6,6-Dimethyl-2- [4- (methylsulfanyl) phenyl] -4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl} -N- (4,6 A solution of -dimethylpyrimidin-2-yl) benzenesulfonamide (892 mg) in methylene chloride (8 ml) was stirred at room temperature, and oxone (1.00 g) and basic alumina (500 mg) were added. After stirring at room temperature for 1.5 hours, the reaction solution was filtered and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 93: 7) and recrystallized from ethyl acetate to give 4- {6,6-dimethyl-2- [4- (methylsulfinyl) Phenyl] -4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl} -N- (4,6-dimethylpyrimidin-2-yl) benzenesulfonamide (619 mg) as a white solid Got as.
Example 97
4- {6,6-Dimethyl-2- [4- (methylsulfanyl) phenyl] -4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl} -N- (4,6 A solution of -dimethylpyrimidin-2-yl) benzenesulfonamide (425 mg) in chloroform (2 ml) was stirred at room temperature, and oxone (1.43 g) and basic alumina (770 mg) were added. After heating under reflux for 18 hours, oxone (500 mg) and basic alumina (600 mg) were added. After further stirring for 7 hours, the reaction solution was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized twice from ethanol to give 4- {6,6-dimethyl-2- [4- (methylsulfonyl) phenyl] -4-oxo-4,5,6,7- Tetrahydro-1H-indol-1-yl} -N- (4,6-dimethylpyrimidin-2-yl) benzenesulfonamide (159 mg) was obtained as a white solid.

Example 98
4- [6,6-Dimethyl-2- (4-nitrophenyl) -4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl] -N- (4,6-dimethylpyrimidine Ethanol (30 ml) and DMF (15 ml) were added to -2-yl) benzenesulfonamide (1.28 g), 10% palladium carbon (0.20 g) was added, and the mixture was stirred at room temperature. A 4 M hydrogen chloride-ethyl acetate solution was added to the reaction solution, and the resulting amine was dissolved, and then the catalyst was filtered off. The filtrate was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with a mixed solvent of chloroform-2-propanol. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled under reduced pressure. Left. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give 4- [2- (4-aminophenyl) -6,6-dimethyl-4-oxo-4,5,6 , 7-Tetrahydro-1H-indol-1-yl] -N- (4,6-dimethylpyrimidin-2-yl) benzenesulfonamide (1.28 g) was obtained. By recrystallizing this compound (0.28 g) from ethanol, 4- [2- (4-aminophenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole -1-yl] -N- (4,6-dimethylpyrimidin-2-yl) benzenesulfonamide (116 mg) was obtained as a yellow powder.
Example 99
The compound of Example 99 shown in the table below was prepared in the same manner as in Example 98.
Example 100
4- [2- (4-Benzyloxyphenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl] -N- (4,6-dimethyl Trifluoroacetic acid (10 ml) was added to a mixture of pyrimidin-2-yl) benzenesulfonamide (549 mg) and pentamethylbenzene (814 mg). After stirring overnight at room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5). The obtained solid was recrystallized from 2-propanol to give N- (4,6-dimethylpyrimidin-2-yl) -4- [2- (4-hydroxyphenyl) -6,6-dimethyl-4- Oxo-4,5,6,7-tetrahydro-1H-indol-1-yl] benzenesulfonamide (151 mg) was obtained as a white solid.
Examples 101-102
In the same manner as in Example 100, the compounds of Examples 101 to 102 shown in the table below were produced.

Example 103
4- [2- (4-Bromophenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl] -N- (4,6-dimethylpyrimidine -2-yl) benzenesulfonamide (330 mg), 2- (di-tert-butylphosphino) biphenyl (74 mg), sodium tert-butoxide (135 mg) and tris (dibenzylideneacetone) dipalladium (II) To a solution of (13 mg) in dimethoxyethane (1.6 ml), morpholine (75 μl) and DMF (0.5 ml) were added. After stirring at 80 ° C. for 4.5 hours, the mixture was diluted with chloroform and washed with an aqueous ammonium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1), and the obtained solid was recrystallized from ethanol-ethyl acetate to give 4- [6,6-dimethyl-2 -(4-Morpholin-4-ylphenyl) -4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl] -N- (4,6-dimethylpyrimidin-2-yl) benzene Sulfonamide (59 mg) was obtained.
Examples 104-105
The compound of Example 104 shown in the table below and the compound of Example 105 shown in the table below were prepared in the same manner as Example 69, respectively.
Example 106
4- (6,6-Dimethyl-4-oxo-2-piperidin-4-yl-4,5,6,7-tetrahydro-1H-indol-2-yl) -N- (4,6-dimethylpyrimidine- To a solution of 2-yl) benzenesulfonamide (118 mg) in pyridine (2 ml), add ethyl chloroformate (25 μl) and stir at room temperature for 1.5 hours, and then add ethyl chloroformate (25 μl). At rt overnight. The reaction mixture was concentrated under reduced pressure, purified by silica gel column chromatography (chloroform: methanol = 50: 1), and crystallized from ethyl acetate-diethyl ether to give 4- [1- (4-{[( 4,6-dimethylpyrimidin-2-yl) amino] sulfonyl} phenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl] piperidin-1- Ethyl carboxylate (49 mg) was obtained.
Examples 107-110
The compounds of Examples 107 to 108 shown in the table below were prepared in the same manner as Example 106, and the compounds of Examples 109 to 110 shown in the table below were prepared in the same manner as Example 71.

Example 111
4- [1- (4-{[(4,6-Dimethylpyrimidin-2-yl) amino] sulfonyl} phenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H -Indol-2-yl] benzoic acid (500 mg), potassium phosphate (195 mg), sodium hypophosphite hydrate (147 mg) in anhydrous tetrahydrofuran (10 ml) with palladium acetate (6 mg) A solution of tricyclohexylphosphine (18 mg) in dehydrated tetrahydrofuran (2 ml) was added, pivalic anhydride (0.47 ml) and water (0.1 ml) were added, and the mixture was stirred at 60 ° C. overnight. The precipitate was removed by filtration and washed with tetrahydrofuran and methanol. The filtrate was distilled off, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) and crystallized from diethyl ether-hexane to give N- (4,6-dimethylpyrimidin-2-yl)- 4- [2- (4-Formylphenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl] benzenesulfonamide (36 mg) was pale yellow Obtained as crystals.
Example 112
The compound of Example 112 shown in the table below was produced in the same manner as in Example 63.
Example 113
4- [1- (4-{[(4,6-Dimethylpyrimidin-2-yl) amino] sulfonyl} phenyl) -6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H -Indol-2-yl] -N-methoxy-N-methylbenzamide (416 mg) in tetrahydrofuran (4 ml) was added dropwise with 1 M methylmagnesium bromide-tetrahydrofuran solution (1.42 ml) under ice-cooling. The mixture was stirred at ° C for 2 hours and at room temperature for 1.5 hours. Further, 1 M methylmagnesium bromide-tetrahydrofuran solution (0.8 ml) was added dropwise under ice cooling, and the mixture was stirred for 4 hours while raising the temperature from 5 ° C to room temperature. A saturated aqueous ammonium chloride solution and water were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) and recrystallized from ethanol to give 4- [2- (4-acetylphenyl) -6,6-dimethyl-4-oxo-4. , 5,6,7-Tetrahydro-1H-indol-1-yl] -N- (4,6-dimethylpyrimidin-2-yl) benzenesulfonamide (83 mg) was obtained as pale yellow crystals.
Examples 114-122
The compound of Example 114 shown in a postscript table | surface by the method similar to Example 113, and the compound of Examples 115-122 shown in a postscript table | surface by the method similar to Example 62 were each manufactured.

Example 123
N- (4,6-Dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -5-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl] benzene Sulfonamide (511 mg) was suspended in 1,2-dichloroethane, and acetic acid (120 μl) was added and dissolved. Subsequently, 1,1-dimethylaminoethylenediamine and sodium triacetoxyborohydride (432 mg) were added. After stirring at room temperature for 13 hours, water and saturated aqueous sodium hydrogen carbonate were added to stop the reaction. The reaction solution was extracted with chloroform, and the organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. The solid obtained by evaporating the solvent under reduced pressure was recrystallized from a mixed solvent of acetonitrile and ethanol, and then fumaric acid was added and recrystallized from ethanol to give 4- [5-{[2- ( Dimethylamino) ethyl] amino} -2- (4-methoxyphenyl) -4,5,6,7-tetrahydro-1H-indol-1-yl] -N- (4,6-dimethylpyrimidin-2-yl) Benzenesulfonamide fumarate (156 mg) was obtained as a white solid.
Example 124
N- (4,6-Dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -5-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl] benzene To a suspension of sulfonamide (553 mg) and 4-hydroxypiperidine (222 mg) in methanol (3 ml) were added sodium borohydride (70 mg) and acetic acid (300 μl). After stirring at room temperature for 7 hours, 1N aqueous sodium hydroxide solution was added dropwise to neutralize the reaction solution, and the mixture was extracted with a mixed solvent of chloroform and isopropanol (3: 1). The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 100: 15: 1), fumaric acid was added, and recrystallized from a mixed solvent of methanol and ethyl acetate. N- (4,6-dimethylpyrimidin-2-yl) -4- [5- (4-hydroxypiperidin-1-yl) -2- (4-methoxyphenyl) -4,5,6,7-tetrahydro -1H-Indol-1-yl] benzenesulfonamide fumarate (128 mg) was obtained as a white solid.
Examples 125-148
The compounds of Examples 125 to 148 shown in the table below were prepared in the same manner as Example 124, and the compounds of Examples 149 to 150 shown in the table below were prepared in the same manner as Example 1.

Example 151
N- (4,6-dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -5-methyl-1H-pyrrol-1-yl] benzenesulfonamide (495 mg) in acetonitrile (4 ml) A mixed solution of 40% aqueous formaldehyde solution (83 mg), 1-methylpiperazine (110 mg) and acetic acid (1 ml) was added dropwise to the solution, and the mixture was stirred at room temperature overnight. A sodium hydroxide aqueous solution was added, followed by extraction with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) and crystallized from ethanol to give N- (4,6-dimethylpyrimidin-2-yl) -4- {2- (4-methoxyphenyl) -5-methyl-3-[(4-methylpiperazin-1-yl) methyl] -1H-pyrrol-1-yl} benzenesulfonamide (151- (1)) (158 mg) and N- (4,6 -Dimethylpyrimidin-2-yl) -4- {5- (4-methoxyphenyl) -2-methyl-3-[(4-methylpiperazin-1-yl) methyl] -1H-pyrrol-1-yl} benzene The sulfonamide (151- (2)) (117 mg) was obtained. To a mixed solution of compound 151- (1) (158 mg) in methanol (15 ml) and THF (30 ml) was added fumaric acid (65 mg), and the mixture was stirred at room temperature for 15 minutes. Evaporate the solvent and recrystallize with ethanol (3 ml) to give N- (4,6-dimethylpyrimidin-2-yl) -4- {2- (4-methoxyphenyl) -5-methyl-3- [(4-Methylpiperazin-1-yl) methyl] -1H-pyrrol-1-yl} benzenesulfonamide difumarate (140 mg) was obtained as colorless crystals. Fumaric acid (48 mg) was added to a mixed solution of compound 151- (2) (117 mg) in methanol (10 ml) and THF (18 ml), and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off, crystallized with ethanol (13 ml) and washed with hot methanol to give N- (4,6-dimethylpyrimidin-2-yl) -4- {5- (4-methoxyphenyl)- 2-Methyl-3-[(4-methylpiperazin-1-yl) methyl] -1H-pyrrol-1-yl} benzenesulfonamide fumarate (77 mg) was obtained as pale yellow crystals.
Examples 152-153
The compound of Example 152 shown in a postscript table | surface by the method similar to Example 1 and the compound of Example 153 shown in a postscript table | surface by the method similar to Example 87 were each manufactured.

Example 154
A solution of 4-anisaldehyde (1.36 g) and 4-amino-N- (4,6-dimethylpyrimidin-2-yl) benzenesulfonamide (2.78 g) in toluene (25 ml) and DMF (10 ml) overnight The mixture was heated to reflux and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (30 ml) and dimethoxyethane (30 ml), p-toluenesulfonylmethyl isocyanide (2.92 g) and potassium carbonate (2.76 g) were added, and the mixture was stirred overnight under reflux. After allowing to cool, water was added to the reaction solution, and the mixture was extracted with chloroform. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 100: 10: 1), dissolved in ethanol, added with 4 M hydrogen chloride-ethyl acetate solution, and recrystallized from ethanol-diethyl ether. N- (4,6-dimethylpyrimidin-2-yl) -4- [5- (4-methoxyphenyl) -1H-imidazol-1-yl] benzenesulfonamide hydrochloride (265 mg) Obtained as crystals.
Example 155
Phosphorus pentachloride (600 mg) in a suspension of N- (4-{[(4,6-dimethylpyrimidin-2-yl) amino] sulfonyl} phenyl) -4-methoxybenzamide (1.00 g) in toluene (120 ml) ) Was added and heated to reflux for 1.5 hours, then toluene (50 ml) and phosphorus pentachloride (180 mg) were added, and the mixture was further heated to reflux for 5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. THF (50 ml) was added to the residue, a solution of 2,2-diethoxyethylamine (1.05 g) in THF (15 ml) was added at 0 ° C., and the mixture was stirred at room temperature for 5 days. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 97: 3), and N- (2,2-diethoxyethyl) -N ′-(4-{[( 4,6-Dimethylpyrimidin-2-yl) amino] sulfonyl} phenyl) -4-methoxybenzenecarboxymidamide (593 mg) was obtained. Toluene (35 ml), DMF (5 ml) and p-toluenesulfonic acid monohydrate (427 mg) were added thereto, and the mixture was heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 100: 15: 1) and recrystallized from ethanol to give N- (4,6 -Dimethylpyrimidin-2-yl) -4- [2- (4-methoxyphenyl) -1H-imidazol-1-yl] benzenesulfonamide p-toluenesulfonate (190 mg) was obtained as a light brown powder. It was.
Example 156
Ethanol (5 ml) -water (2.5 ml) and sodium acetate (70 mg) were added to hydrazine (0.42 g) and diketone (0.28 g), and the mixture was stirred under reflux. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 → 50: 1) and crystallized from diethyl ether to give N- (4,6-dimethylpyrimidin-2-yl. ) -4- [5- (4-Methoxyphenyl) -3-methyl-1H-pyrazol-1-yl] benzenesulfonamide (207 mg) was obtained as colorless crystals.

  The structures and physicochemical data of the compounds of Reference Examples 2 to 28 and Examples 1 to 156 are shown in Tables 1 to 20. Table 21 shows the structure of another compound of the present invention. These can be easily synthesized by using the above-described production methods, the methods described in the Examples, methods obvious to those skilled in the art, or variations thereof.

Claims (1)

An azole-substituted sulfonylbenzene derivative represented by the following general formula (I) or a salt thereof.

(The symbols in the formula have the following meanings.
R ¹ : H, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclic group,
X: N or C (R ⁶ ),
Y: N or C (R ⁷ ),
Z: N or C (R ⁸ ),
R ⁶ , R ⁷ and R ⁸ are the same or different from each other, H, —CO-lower alkyl, halogen, —OH, —O-lower alkyl, optionally substituted lower alkyl, or two adjacent groups There together, lower alkylene, -NR ⁹ - lower alkylene or 1,3-butadienylene group interrupted with to form, respectively, together with the carbon atoms to which they are attached, a cycloalkenyl, a heterocycloalkenyl, or a phenyl group Where the cycloalkenyl, heterocycloalkenyl and phenyl groups may have 1 to 3 substituents,
R ⁹ : H, lower alkyl, —CO-lower alkyl, —CO ₂ -lower alkyl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted heterocycle, Lower alkyl is selected from the group consisting of —OH, —O-lower alkyl, —CO ₂ H, —CO ₂ -lower alkyl, NH ₂ , NH (lower alkyl) and N (lower alkyl) ₂ , and phenyl. Optionally substituted with one group,
R ² : the same or different from each other, lower alkyl, halogen, halogeno lower alkyl, —OH or —O-lower alkyl,
m: 0, 1 or 2,
R ³ : —OH, —O-optionally substituted phenyl, or a group selected from the group consisting of the following formulas (i) to (iii):

R ⁴ : H or lower alkyl,
R ⁵ : H, optionally substituted lower alkyl, optionally substituted cycloalkyl or optionally substituted aryl or optionally substituted heterocycle, and
Het: optionally substituted nitrogen-containing heterocycle. )