JP2002516325A - New substituted imidazole compounds - Google Patents

Abstract

  (57) [Summary] Disclosed are novel 1,4,5-substituted imidazole compounds and compositions for use as ERK / MAP inhibitors in the treatment of ERK / MAP mediated diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to a novel series of imidazole compounds, a process for producing the same, and an ERK / MAP thereof.
It relates to the use in the treatment of intervening diseases and to pharmaceutical compositions for use in such therapies. There is a need in the art for treatment with compounds that have the ability to inhibit the action of ERK / MAP kinase.

The present invention relates to novel compounds of formula (I) and pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier or diluent. The present invention relates to a method of treating an ERK / MAP kinase-mediated disease in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of formula (I). The present invention also relates to a method of inhibiting ERK / MAP kinase in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of formula (I).

Accordingly, the present invention provides a compound of formula (I):

Embedded image

Wherein R ₁ is hydrogen, C _1-5 alkyl, halogen, C _1-5 alkoxy or aryl C _1-5 alkyl; R ₂ is hydrogen, C _1-5 alkyl, aryl, aryl C R ₃ is hydrogen or C _1-3 alkyl; R ₄ is hydrogen, C _1-5 alkyl, heteroaryl, heteroaryl C _1-5 alkyl, heterocyclic or heterocyclic C _1-5 alkyl; _1-5 alkyl, aryl, aryl C _1-5 alkyl, heteroaryl, heteroaryl C _1-5 alkyl, heterocyclic or heterocyclic C _1-5 alkyl] or a pharmaceutically acceptable compound thereof. Provide salt.

DETAILED DESCRIPTION OF THE INVENTION In formula (I), suitable R ₁ groups include hydrogen, C _1-5 alkyl, halogen, C _1-5 alkoxy or aryl C _1-5 alkyl. I do. Preferably, the group is C _1-5 alkyl, which may be branched or unbranched. Suitably, R ₂ is hydrogen, C _1-5 alkyl, aryl, aryl C _1-5 alkyl,
Heteroaryl, heteroaryl C _1-5 alkyl, heterocyclic, heterocyclic C _1-5 alkyl, and all of these groups may be substituted as described below. When R ₂ is a heterocyclic or heterocyclic alkyl group,
The heterocyclic ring is a saturated or partially saturated 4- to 10-membered ring system in which one or more rings contains one or more heteroatoms selected from the group consisting of N, O or S. Yes, for example, but not limited to, pyrrolidinyl, piperidine, morpholine, tetrahydropyran, tetrahydrothiopyranyl, tetrahydrothiopyransulfinyl, tetrahydrothiopyransulfonyl, pyrrolidinyl or indole ring.

When R ₂ is a heteroaryl or heteroarylalkyl group, the heteroaryl moiety contains one or more heteroatoms wherein one or more rings are selected from the group consisting of N, O or S A 5- to 10-membered aromatic ring system
For example, but not limited to, pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, tetrazole, triazole, imidazole or benzimidazole. Suitably, R ₃ is hydrogen or C _1-3 alkyl (branched or unbranched). Suitably, R ₄ is hydrogen, C _1-5 alkyl, aryl, aryl C _1-5 alkyl,
Heteroaryl, heteroaryl C _1-5 alkyl, heterocyclic, heterocyclic C _1-5 alkyl, and all of these groups may be substituted as described below. Suitable heteroaryl and groups containing heterocyclic for use in the present invention is the same as group described above for R _2.

[0007] As used herein, the term "optionally substituted", unless otherwise defined, is halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy-substituted C _1-10 alkyl; _1-10 alkoxy, for example, methoxy or ethoxy; halo-substituted C _1-10 alkoxy; S (O) _m alkyl, wherein m is 0, 1, or 2, for example, methylthio, methylsulfinyl or methyl sulfonyl; amino or mono- and di-substituted C _{1-5-alkyl-substituted} amino, for example, a group R ₇ R ₁₇ (wherein, R ₇ and R ₁₇ are hydrogen or C _1-5 alkyl, or R ₇ and R _{The 17} substituents are cyclized together with the nitrogen to which they are attached to form
/ N / S, which may form a 5- to 7-membered ring which may contain additional heteroatoms); C _1-10 alkyl, C _3-7 cycloalkyl, or C _{3- 7} cycloalkyl C _1-10 alkyl groups, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc., or cyclopropylmethyl; halo-substituted C _1-10 alkyl, such as CF ₂ CF ₂ H or CF ₃ ; Optionally substituted aryl, such as phenyl or optionally substituted arylalkyl, such as benzyl or phenethyl, wherein these aryl moieties are halogen; hydroxy;
Hydroxy substituted alkyl; C _1-10 alkoxy; S (O) _m alkyl; amino, mono- and di-substituted amino, for example, NR ₇ R _17; means a group such as an alkyl or CF _3.

[0008] Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, acetic, malic, tartaric, citric, and the like. Acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid,
Includes basic salts of inorganic or organic acids such as salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of the compounds of formula (I) may also be formed with pharmaceutically acceptable cations, for example when the substituent comprises a carboxy group. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali, alkaline earth, ammonium and quaternary ammonium cations.

The terms used herein are as follows: “Halo” or “halogen” is halogen, ie, chloro, fluoro,
Includes bromo and iodo. “C _1-5 alkyl” or “alkyl” includes both straight-chain and branched-chain groups having 1 to 5 carbon atoms, unless otherwise specified, and includes methyl, ethyl,
n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-
Butyl, n-pentyl and the like, but are not limited thereto. The term “cycloalkyl” is used herein to refer to a cyclic group, preferably 3
Used to mean a cyclic group having from 8 to 8 carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like. -"Aryl" refers to phenyl and naphthyl.

“Heteroaryl” (alone or “heteroaryloxy” or “heteroaryloxy”
Heteroarylalkyl) and the like) is a 5- to 10-membered aromatic ring system wherein one or more rings comprises one or more heteroatoms selected from the group consisting of N, O or S; For example, but not limited to, pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, tetrazole, triazole, imidazole or benzimidazole.・ "Heterocyclic" (alone or "heterocyclylalkyl")
And the like) is a saturated or partially unsaturated 4 or 4 ring wherein one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S.
And 10-membered ring systems, such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran or imidazolidine. “Aralkyl” or “heteroarylalkyl” or “heterocyclicalkyl” as used herein, unless stated otherwise, the above C _1-4 attached to an aryl, heteroaryl or heterocyclic moiety as defined above Used to mean alkyl.

The compounds of the present invention may exist as stereoisomers, regioisomers or diastereomers. These compounds may have one or more asymmetric carbon atoms and may exist in racemic or optically active forms. All of these compounds are included within the scope of the present invention.

As the compound of the formula (I), for example, 1- (4-piperidinyl) -4-methyl-5- (3-
Aminopyrimidin-4-yl) imidazole; or a pharmaceutically acceptable salt thereof. Compounds of formula (I) can be prepared by synthetic methods, some of which are shown in the scheme below. The syntheses shown in these schemes employ a variety of different R ₁ , R ₂ , R ₃ and R ₄ groups using optionally substituted substituents and reacting to be compatible with the reactions described herein. Suitable for preparing compounds of formula (I) having the formula: In these cases, deprotection is later performed to obtain compounds of the type widely disclosed. Suitable protecting groups for use with imidazole nitrogen are well known in the art and are well-known in many literature, for example, "Protecting Groups in Organic Synthesis, Greene TW, Wille.
y-Interscience, New York, 1981. Preferably, one example of an imidazole nitrogen protecting group is tetrahydropyranyl.

[0013]

Embedded image Scheme 1

The synthesis of 4-formyl-2-thioalkylpyrimidine (R = Pr, R ₂ ＝ H), 1 is described in US Pat. No. 5,658,903, the disclosure of which is hereby incorporated by reference. Part of One imine is reacted with t-Boc-4-aminopiperidine under dehydrating conditions, for example using MgSO ₄ in CH ₂ Cl ₂ , followed by addition of cyanide to give α-aminonitrile. The nitrile is hydrolyzed under acidic conditions to give the deprotected free amino acid, 2. Formylation with a mixed acid of formic acid and acetic anhydride or other suitable formylating agent provides the required precursor of the 1,3-dipolar cycloadduct, 3. As in the dehydration conditions described in the formylation of 2, 3
Need not be isolated, and a cyclodehydration occurs to form the intermediate munchnone. The munchone thus formed is reacted with a sulfonylimine (formed by condensing a sulfonamide with R ₂ COH) to give the imidazole cycloaddition products 4. General procedures for this compound and specific methods for forming imidazole are described in Consonni, R. et al., J. Chem. Research (S).
p188 (1991) and Croce, PD et al., J. Heterocyclic Chem. 24, 179.
3 (1987). 2-thioalkyl pyrimidines further oxidized to activated sulfoxide and / or sulfone leaving group, including sulfur and ammonia and simple alkyl amines (R _3), to facilitate the replacement of the various nucleophiles, The desired 2-aminopyrimidine, 5 is obtained. The pharmaceutically acceptable acid addition salts of the compounds of formula (I) can be obtained in a known manner, for example by treating them with an appropriate amount of an acid in the presence of a suitable solvent.

Therapeutic Methods The compound of formula (I) or a pharmaceutically acceptable salt thereof, may include, but is not limited to, excessive or unregulated ERK2 // by mammalian cells such as monocytes and / or macrophages. It can be used for the manufacture of a medicament for the prophylaxis or treatment of ERK kinase-mediated conditions in humans or other mammals, exacerbated or caused by MAP kinase activation. Intracellular signal transduction is the means by which cells respond to extracellular stimuli. Regardless of the properties of cell surface receptors (e.g., protein tyrosine kinases or seven transmembrane G-binding proteins), protein kinases and phosphatases, along with phospholipases, are essential mechanistic factors, whereby signals travel further within the cell. [Marshall, JC Ce
ll, 80, 179-278 (1995)]. Protein kinases can be divided into five classes, the two main classes being tyrosine, depending on whether the enzyme phosphorylates its substrate on specific tyrosine residues or on serine / threonine residues. Kinase and Serine / Threonine Kinase [Hunter, T. Methods in Enzymol
ogy (Protein Kinase Classification) p.3, Hunter, T .; Sefton, BM, second
00, Academic Press; San Diego, 1991].

The MAP kinase or ERK (extracellular signal-regulated kinase) family
Closely related to each other, they are a new class of kinases that are often required for the intracellular transmission of mitogens or growth signals. ERK1 and ERK2 are the first two members of that family to be identified. A characteristic requirement for activating these kinases is dual phosphorylation on the TEY sequence of the kinase activation loop, the reaction of which has been described by a selected family of MAP kinase kinases (MAPKKs). Done by the kinase upstream of ERK1 / E
Additional signal transduction elements both upstream and downstream of RK2 have been identified, elucidating the pathway from extracellular receptor activation to transcriptional regulation [Marshall, CJ Cell
, 80, 179 (1995); Herskowitz, I. Cell, 80, 187 (1995).
Hunte, T. Cell, 80, 225 (1995); Seger, R. and Krebs, EG FASE;
B J., 726-735 (1995)]. This ERK kinase and related MA
A schematic of the P-kinase pathway is shown in FIG. ERK2 kinase also provides p44MAP
Also called a kinase.

JNK and p38 kinase are mainly activated by “stress” signals,
It constitutes two more arms of the MAP kinase pathway. All three pathways are independent and are composed of additional family members. Although independent, there is considerable crosstalk between the pathways, and in most cases, one extracellular signal activates several parts of the pathway; Wax, signal patterns and intensities are revealed from these kinase cascades. Different MAP family members are distinguished by the identity of the dual activation sequence. JNK kinase is TPY and p38 kinase is TGY
In contrast, as described above, ERK kinase contains TEY.

[0018]

[Table 1]

[0019] Growth or mitogen signals are the most important activators of ERK kinase and considerable evidence supports the requirement of ERK signaling to respond to these stimuli (FIG. 2 ERK1 / ERK2 The cascade is explained in more detail)
. Thus, inhibition of ERK kinase may be therapeutically useful in many conditions, and most importantly, it may block the uncontrolled growth of cancer cells. Another potential use of ERK kinase inhibitors is inflammation, allergy,
It is an autoimmune disease and a neurodegenerative disease (FIG. 2).

[0020]

[Table 2]

The compounds of formula (I) may be used for local conditions mediated by or exacerbated by excessive ERK / MAP kinase production, such as joint inflammation, eczema, psoriasis and other inflammatory skin conditions such as sunburn Inflammatory symptoms of the eye, including conjunctivitis, fever (pyresi
s), can also be used topically for the treatment or prevention of pain and other symptoms associated with inflammation. Compounds of formula (I) modulate ERK / MAP activity to normal levels or, in some cases, below normal levels, such that ERK / MAP is ameliorated or prevented. Administered in an amount sufficient to inhibit activity. The finding that the compound of formula (I) is an inhibitor of ERK / MAP is based on the effect of the compound of formula (I) in the in vitro assays described herein.

As used herein, the term “inhibiting the activity of ERK / MAP kinase” refers to: a) everything including but not limited to monocytes or macrophages Reducing the excessive in vivo levels of the kinase in humans to normal or subnormal levels by inhibiting the in vivo release of the kinase by the cells of b. Down-regulating to sub-normal levels; c) down-regulating by inhibiting direct synthesis of the kinase as a post-translational event; or d) normal or excessive levels of kinase in vivo in humans at the translational level. Down-regulating to below normal levels. For use in therapy, the compounds of formula (I) or a pharmaceutically acceptable salt thereof will generally be formulated into pharmaceutical compositions according to standard pharmaceutical practice. Accordingly, the present invention also relates to pharmaceutical compositions comprising an effective non-toxic amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.

The compounds of formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating them, are conveniently prepared by any of the routes conventionally used for administration, eg, oral, It can be administered topically, parenterally or by inhalation. The compounds of formula (I) can be administered in conventional dosage forms prepared by combining the compounds of formula (I) with standard pharmaceutical carriers, according to conventional procedures. The compounds of formula (I) may also be administered in conventional doses in combination with other known therapeutically active compounds. These methods include mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. The form and properties of a pharmaceutically acceptable carrier or diluent are determined by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. The carrier (s) must be "acceptable" in the sense that they are compatible with the other ingredients of the formulation and are not harmful to the recipient.

The pharmaceutical carrier used may be, for example, either a solid or liquid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay substances well known in the art, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. A wide variety of pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge.
The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 g.
When a liquid carrier is used, the preparation will be in the form of a sterile injectable solution or non-aqueous liquid suspension such as a syrup, emulsion, soft gelatin capsule, ampoule or the like.

The compound of formula (I) can be administered locally, ie, by non-systemic administration.
This includes topical application of the compound of formula (I) to the epidermis or buccal cavity so that it does not significantly enter the bloodstream, and inhalation of the compound into the ears, eyes and nose. Conversely, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration. Formulations suitable for topical administration are liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as liniment, lotion, cream, ointment or paste, and eye, ear or nose. Includes drops suitable for administration. The active ingredient may comprise, for topical administration, from 0.001% to 10% w / w of the formulation, for example from 1% to 2% by weight. However, it may be in an amount such as 10% w / w of the formulation, but is preferably less than 5% w / w, more preferably 0.1% to 1% w / w.

The lotions of the present invention include those suitable for application to the skin or eyes. Ophthalmic lotions contain a sterile aqueous solution which may contain a bactericide and are prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may additionally contain agents that promote drying of the skin, such as alcohol or acetone, and / or moisturizing agents such as glycerol, or oils such as castor oil or peanut oil. The cream, ointment or paste of the present invention is a semi-solid formulation of the active ingredient for external application. These can be used alone or in a finely divided or powdered form by mixing the active ingredients, or by using a suitable machine with a solution or suspension in an aqueous or non-aqueous fluid with a grease-like or non-greasy base. Prepared in form. Bases are hydrocarbons, for example, solid, soft or liquid paraffin, glycerol, beeswax, metal soaps; slurries; oils of natural origin, such as tonsil oil, corn oil, peanut oil, castor oil or olive oil; wool fat or Derivatives or alcohols, such as propylene glycol or macrogels, may also contain fatty acids such as stearic acid or oleic acid. The formulation may include a suitable surfactant, such as an anionic, cationic or nonionic surfactant, such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents may include, for example, natural gums, cellulose derivatives or inorganic materials, such as siliceous silica, and other ingredients, such as lanolin.

The drops of the present invention may include sterile aqueous or oily solutions or suspensions, wherein the active ingredient is a fungicide and / or fungicide and / or other suitable preservative, preferably at the surface. It is prepared by dissolving in a suitable aqueous solution containing an active agent. The resulting solution is then clarified by filtration, transferred to a suitable container, which is sealed and autoclaved or sterilized by maintaining at 98-100 ° C for 30 minutes. Alternatively, the solution may be sterilized by filtration and transferred to the container by aseptic technique. Examples of fungicides or fungicides suitable for inclusion in drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). It is. Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol. The compounds of formula (I) can be administered parenterally, ie, intravenously, intramuscularly, subcutaneously, intranasally,
It is administered by rectal, vaginal or intraperitoneal administration. Subcutaneous and intramuscular parenteral administration forms are generally preferred. Dosage forms suitable for such administration are prepared by conventional techniques. The compounds of formula (I) may also be administered by inhalation, ie, by intranasal or oral inhalation. Dosage forms suitable for such administration, such as an aerosol formulation or a metered dose inhaler, are prepared by conventional techniques.

For any of the methods of use described herein for the compounds of formula (I), the oral daily dose will preferably be from about 0.1 to about 80 m / kg of total body weight.
g, preferably about 0.2 to 30 mg / kg, more preferably about 0.5 mg / kg.
To 15 mg. The parenteral daily dosage is from about 0.1 to about 80 mg / kg of total body weight, preferably from about 0.2 to about 30 mg / kg, more preferably
It is about 0.5 mg to 15 mg / kg. The local daily dose is preferably about 0.1
mg to 150 mg, administered 1 to 4 times, preferably 2 or 3 times a day. The daily inhalation dose is preferably between about 0.01 mg / kg and about 1 mg / kg per day. The optimal amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the interval between each administration will be determined by the nature and extent of the condition to be treated, the mode of administration, the route and site, and the individual patient to be treated. The optimal value is
Those skilled in the art will also recognize that they can be determined by conventional techniques. Also, the optimal dosage unit, ie, the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof administered daily for a predetermined number of days, may be determined using routine treatment unit determination tests. It will also be appreciated by those skilled in the art that it can be ascertained by those skilled in the art. The novel compounds of formula (I) can also be used in combination with veterinary treatment of non-human mammals, which require the inhibition of ERK / MAP kinase production. The present invention is described by way of the following biological examples, which are merely illustrative and should not be construed as limiting the scope of the invention.

Biological Examples The ERK / MAP inhibitory effect of the compounds of the present invention is determined by the following in vitro assay. ERK kinase assay was performed using a commercially available kit (P44MPK, Upstate Biotechnolog
y Inc.). The following sequence of ³² P from γ- [ ³² P] ATP: KREL
EGFR-derived peptide with VEPLTPSGEAPNQALLR (T66
Kinase activity was determined by measuring incorporation into 9). Reactant (30 μl)
Are 25 mM Hepes buffer (pH 7.4), 8 mM MgCl ₂ , 10 μM
Na-vanadate, 1 mM EDTA, 0.8 μCi / 170 μM ³² P / A
It contained TP, 0.4 ng of ERK kinase and 0.4 mM peptide. Compounds were incubated with enzymes and peptides at 4 ° C. for 20 minutes before adding ATP. The reaction was incubated at 30 ° C. for 10 minutes and the reaction was stopped by adding 10 μL of 0.3 M phosphoric acid. Phosphorylated peptide was added to phosphocellulose filter paper (
It was isolated from the reaction mixture using p81). The filter paper was washed with 75 mM phosphoric acid and counted using a liquid scintillation counter.

Synthetic Examples The present invention is described by way of the following examples, which are merely illustrative and should not be construed as limiting the scope of the invention. All temperatures were in degrees Celsius, all solvents were the highest purity solvents available, and all reactions were performed under anhydrous conditions under an argon atmosphere unless otherwise noted. In the examples, all temperatures are degrees Celsius (° C.). Mass spectra were obtained on a VGAab mass spectrometer using fast atom bombardment, unless otherwise specified, or on a micromass platform electrospray ionization in cationic form using CH ₃ CN / CH ₃ OH (95: 5) + 1% formic acid as the carrier solvent. Performed on a mass spectrometer. ¹ H-NMR (
The spectrum is hereinafter referred to as “NMR” by Bruker AM 250 or Am
Recording was performed at 250 MHz using a 400 spectrometer. The indicated multiplicities are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and br mean broad signal. Saturated means a saturated solution and equivalents means the ratio of a given molar amount of reagent to the main reactant. Flash chromatography is performed on Merck silica gel 60 (230-400 mesh).

Example 1 1- (4-Piperidinyl) -4-methyl-5- (3-amino-pyrimidin-4-yl) imidazole Consonni, R. et al., J. Chem. Research (S) p188 (1991) And Croce, P.
The title compound was prepared according to the synthetic route shown in Scheme 2 using the reaction conditions described in D. et al., J. Heterocyclic Chem. 24, 1793 (1987) or modified conditions apparent to those skilled in the art of organic synthesis. The synthesis of the starting materials pyrimidine aldehyde and t-Boc-4-aminopiperidine is described in US Pat.
No. 7, the contents of which are incorporated by reference.

[0032]

Embedded image

All publications, including patents and patent applications, cited herein are
Identify the source, even if fully disclosed, of each publication, even though each is specifically and individually stated to be a part of this specification by explicitly stating the source. Is a part of the present specification. The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore, it should be understood that the examples in this specification are merely examples and do not limit the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are limited to those described above.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 7/02 A61P 7/02 9/00 9/00 11/00 11/00 11/06 11/06 13 / 12 13/12 17/00 17/00 17/06 17/06 19/02 19/02 19/06 19/06 19/08 19/08 19/10 19/10 25/00 25/00 25/28 25/28 27/02 27/02 29/00 101 29/00 101 31/04 31/04 33/06 33/06 37/06 37/06 43/00 43/00 111 111 F term (reference) 4C063 AA03 BB01 BB02 CC31 DD25 EE01 4C086 AA01 AA02 AA03 BC42 GA07 GA12 MA01 MA04 NA14 ZA01 ZA02 ZA16 ZA33 ZA36 ZA51 ZA54 ZA59 ZA66 ZA81 ZA89 ZA96 ZA97 ZB07 ZB08 ZB15 ZB32 ZC20 ZC31 ZC35

Claims (8)

[Claims] 1. The formula: embedded image Wherein R ₁ is hydrogen, halogen, C _1-5 alkyl, C _1-5 alkoxy or aryl C _1-5 alkyl; R ₂ is hydrogen, C _1-5 alkyl, aryl, aryl C _1-5 Alkyl, heteroaryl, heteroaryl C _1-5 alkyl, heterocyclic or heterocyclic C _1-5 alkyl, all of which may be substituted; R ₃ is hydrogen or C _1-3 alkyl R ₄ is hydrogen, C _1-5 alkyl, aryl, aryl C _1-5 alkyl, heteroaryl, heteroaryl C _1-5 alkyl, heterocyclic or heterocyclic C _1-5 alkyl; All the groups may be substituted.] Or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R ₁ is C _1-5 alkyl. 3. The compound according to claim ₂ , wherein R ₂ is hydrogen or a heterocyclic or heterocyclic alkyl ring. 4. The compound according to claim 2, wherein R ₃ is hydrogen. 5. The compound according to claim 2, wherein R ₄ is hydrogen. 6. A pharmaceutical composition comprising an effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier or diluent. 7. A method of treating an ERK / MAP kinase-mediated disease in a mammal in need thereof, comprising administering an effective amount of a compound of formula (I) according to any one of claims 1 to 6. A method comprising administering to said mammal. 8. The method of claim 1, wherein the mammal is a psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid arthritis,
Rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome, Alzheimer's disease, seizures, neurotrauma, asthma, adult respiratory distress syndrome, Cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, osteoporosis, restenosis, heart and renal reperfusion injury, thrombosis, glomerulonephritis, diabetes, graft-versus-host reaction, allogeneic Graft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, muscle degeneration, eczema, contact dermatitis, psoriasis, sunburn,
8. The method of claim 7, wherein the patient has an ERK / MAP kinase-mediated disease selected from conjunctivitis.