WO2006004191A1 - Pyrrolopyridazine derivatives which inhibit pde iv and tnf alfa - Google Patents

Abstract

The invention relates to compound of the formula (I) or its salt, in which R1, R2, R3 and R4 are as defined in the description, their use of as medicament, the process for their preparation and use for the treatment of PDE-IV or TNF-α mediated diseases.

Description

D E S C R I P T I O N

PYRROLOPYRIDAZINE DERIVATIVES WHICH INHIBIT PDE IV AND TNF ALFA

TECHNICAL FIELD

This invention relates to new pyrrolopyridazine derivatives and pharmaceutically acceptable salts thereof which inhibit enzymatic activity of phosphodiesterase IV (PDE rV) and production of tumor necrosis factor-α (TNF-α).

BACKGROUND ART

Cyclic adenosine monophosphate (adenosine 3', 5 '-cyclic monophosphate, "cAMP" or "cyclic AMP") is known as an intracellular second messenger, which is intermediated by a first messenger (hormone, neurotransmitter or autacoid) and the cellular responses. The first messenger stimulates the enzyme responsible for synthesis of cAMP, and then the cAMP intervenes in many functions such as metabolic, contractile or secretory. The effect of cAMP end when it is degraded by cyclic nucleotide phosphodiesterases, in particular phosphodiesterase-4 (PDE4 or PDE-IV), which is specific for cAMP. PDE-IV have been identified in many tissues including the central nervous systems, the heart, vascular smooth muscle, airway smooth muscle, myeloid lines, lymphoid, and the like. Evaluation of cAMP level by using the PDE-IV inhibitor would produce beneficial effect on inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells.

A major concern with the use of PDE-IV inhibitors is the side effect of emesis which has been observed for several candidate compounds as described in C.Burnouf et al., (Ann. Rep. In Med. Chem., 33:91-109(1998)). Burnouf describe the wide variation of the severity of the undesirable side effects exhibited by various compounds.

Some condensed heterocyclic derivatives having the inhibitory activity of PDE-IV have been known, for example in WO03/016279, WO03/018579, WO03/000679 and the like. However, there remains a need for novel compounds that inhibit PDE-IV with minimal side effects. Although some pyrrolopyridazine derivatives having the inhibitory activity of hydroxymethylglutaryl (HMG) CoA reductase have been known, for example, in WO91/18903, pyrrolopyridazine derivatives having the inhibitory activity of PDE-IV have not been known. DISCLOSURE OF INVENTION

This invention relates to new pyrrolopyridazine derivatives. The compounds of this invention inhibit cAMP phosphodiesterase enzymes, in particular phosphodiesterase-4 enzyme, and also inhibit the production of tumor necrosis factor-α (TNF-α), a serum glycoprotein.

Accordingly, one object of this invention is to provide the new and useful pyrrolopyridazine derivatives and pharmaceutically acceptable salts thereof which possess a strong phosphodiesterase-4 (PDE IV)-inhibitory activity and a strong inhibitory activity on the production of tumor necrosis factor (TNF).

Another object of this invention is to provide processes for preparation of the pyrrolopyridazine derivatives and salts thereof.

A further object of this invention is to provide a pharmaceutical composition comprising said pyrrolopyridazine derivatives or a pharmaceutically acceptable salt thereof.

Still further object of this invention is to provide a use of said pyrrolopyridazine derivatives or a pharmaceutically acceptable salt thereof as a medicament for prophylactic and therapeutic treatment of PDE-IV and TNF mediated diseases such as chronic inflammatory diseases, specific autoimmune diseases, sepsis-induced organ injury, and the like in human being and animals.

The object pyrrolopyridazine derivatives of the present invention are novel and can be represented by the following general formula (I):

in which

R¹ Is (1) hydrogen,

(2) carboxy or protected carboxy,

(3) -CONR⁶R⁷, (4) hydroxy or lower alkoxy,

(5) amino, cyclo(lower)alkylamino or mono- or di(lower)alkylamino optionally substituted by lower alkoxy,

(6) trihalo(lower)alkyl, (7) trihalo(lower)alkylsulfonyloxy or arylsulfonylamino,

(8) substituted or unsubstituted lower alkyl,

(9) substituted or unsubstituted aryl,

(10) substituted or unsubstituted heteroaryl, or

(11) substituted or unsubstituted heterocyclyl, R² is -(CH₂)_q- Y- R⁸

[wherein q is 0, 1, 2 or 3,

Y is bond, -O- or -CH(R⁹)- (wherein R⁹ is carboxy or protected carboxy), and R⁸ is (1) lower alkyl, (2) substituted or unsubstituted aryl, (3) substituted or unsubstituted heteroaryl, (4) substituted or unsubstituted heterocyclyl, or (5) substituted or unsubstituted cyclo(lower)alkyl, R³ is hydrogen or lower alkyl, or alternatively R² and R³, together with the nitrogen atom to which they are attached, represent azaheterocyclyl group], R⁴ is (1) substituted or unsubstituted aryl,

(2) substituted or unsubstituted heteroaryl, or

(3) lower alkyl substituted by (a) substituted or unsubstituted cyclb(lower)alkyl, or (b) substituted or unsubstituted heterocyclyl,

R⁵ is lower alkyl, and R⁶ and R⁷ each independently represents hydrogen, lower alkylsulfonyl, heteroaryl or lower alkyl optionally substituted by hydroxy, alkoxy, sulfo, carboxy or protected carboxy, or alternatively R⁶ and R⁷ together with the nitrogen atom to which they are attached, represent substituted or unsubstituted azaheterocyclyl, or a pharmaceutically acceptable salt thereof, or prodrug thereof.

Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.).

The "prodrug" means the derivatives of the object compound (I) having a chemically or metabolically degradable group, which became pharmaceutically active after chemo- or biotransformation.

The compounds of formula (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers. Furthermore certain compounds of formula (I) which contain alkenyl groups may exist as cis- or trans-isomers. In each instance, the invention includes both mixtures and separate individual isomers.

The compounds of the formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers. The compound of the formula (T) and its salt can be in a form of a solvate, which is included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate.

Also included in the scope of invention are radiolabeled derivatives of compounds of formula (T) which are suitable for biological studies.

Preferred embodiments of the object compound of the present invention are as follows.

(a) The pyrazolopyridine compound of the general formula (T) in which R¹ is (1) lower alkyl optionally substituted by (i) cyclo(lower)alkyloxy or (ii) lower alkoxy optionally substituted by cyclo(lower)alkyl or phenyl,

(2) phenyl,

(3) a radical of aromatic monocyclic ring system comprising 5 or 6 ring atoms and containing one to three heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by lower alkyl or lower alkoxy, or

(4) a radical of saturated monocyclic ring system comprising 5 or 6 ring atoms and containing one to three heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulfur, R² is -(CH₂)q-Y- R⁸ [wherein q is 0, 1 or 2, Y is bond, -O- or -CH(R⁹)- (wherein R⁹ is carboxy or esterified carboxy), and

R⁸ is (1) phenyl or indanyl optionally substituted by at least one substituent selected from the group consisting of halogen, lower alkyl, trihalo(lower)alkyl, lower alkoxy, carboxy, protected carboxy, cyano, CONR¹⁰R¹¹, and SO₂NR¹⁰R¹¹ [in which R¹⁰ and R¹¹ represent each independently hydrogen or lower alkyl], (2) a radical of aromatic monocyclic ring system comprising 5 or 6 ring atoms and containing one to three heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by at least one substituent selected from the group consisting of halogen, lower alkoxy, cyano, carboxy, protected carboxy and CONR¹⁰R¹¹ [in which R¹⁰ and R¹¹ represent each independently hydrogen or lower alkyl], (3) a radical of saturated monocyclic ring system comprising 5 or 6 ring atoms and containing one to three heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by lower alkyl, aryl, cyclo(lower)alkylcarbonyl, lower alkanoyl, aroyl, lower alkylsulfonyl or esterified carboxy, or (4) cyclo(lower)alkyl],

R³ is hydrogen or lower alkyl, or alternatively R² and R³, together with the nitrogen atom to which they are attached, represent a radical of saturated monocyclic ring system comprising 5 or 6 ring atoms and containing at least one nitrogen atom and one to two heteroatom(s) selected from the group consisting of oxygen and sulfur, which is optionally substituted by lower alkyl, phenyl or acyl, R⁴ is (1) phenyl optionally substituted by halogen, cyano or carbamoyl,

(2) a radical of aromatic monocyclic ring system comprising 5 or 6 ring atoms and containing one to three heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, lower alkyl, lower alkenyl, cyclo(lower)alkyl or lower alkanoyl, or

(3) lower alkyl substituted by (a) cyclo(lower)alkyl, or (b) a radical of saturated monocyclic ring system comprising 5 or 6 ring atoms and containing one to three heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by acyl or protected carboxy, R⁵ is lower alkyl.

(b) The pyrazolopyridine compound of (a) in which

R¹ is (1) lower alkyl optionally substituted by (i) cyclo(lower)alkyloxy or (ii) lower alkoxy optionally substituted by cyclo(lower)alkyl or phenyl, (2) phenyl, (3) furanyl, oxazolyl, isooxazolyl, thiophenyl or thiazolyl, each of which is optionally substituted by lower alkyl or lower alkoxy, or

(4) pyrrolidinyl or morpholyl, R² is -(CH₂VY- ^R8

[wherein q is 0, 1 or 2,

Y is bond, -O- or -CH(R⁹)- (wherein R⁹ is carboxy or esterified carboxy), and R⁸ is (1) phenyl or indanyl optionally substituted by at least one substituent selected from the group consisting of halogen, lower alkyl, trihalo(lower)alkyl, lower alkoxy, carboxy, protected carboxy, cyano, CONR¹⁰R¹¹, and SO₂NR¹⁰R¹¹ [in which R¹⁰ and R¹¹ represent each independently hydrogen or lower alkyl], (2) pyridinyl optionally substituted by at least one substituent selected from the group consisting of halogen, lower alkoxy, cyano, carboxy, protected carboxy and CONR¹⁰R¹¹ [in which R¹⁰ and R¹¹ represent each independently hydrogen or lower alkyl], (3) piperidinyl optionally substituted by lower alkyl, aryl, cyclo(lower)alkylcarbonyl, lower alkanoyl, aroyl, lower alkylsulfonyl or esterified carboxy, or (4) cyclo(lower)alkyl], R³ is hydrogen or lower alkyl, or alternatively R² and R³, together with the nitrogen atom to which they are attached, represent piperidinyl optionally substituted by lower alkyl, phenyl or acyl, R⁴ is (1) phenyl optionally substituted by halogen, cyano or carbamoyl,

(2) pyridinyl optionally substituted by halogen, lower alkyl, lower alkenyl, cyclo(lower)alkyl or lower alkanoyl, or (3) lower alkyl substituted by (a) cyclohexyl or norbornanyl, or (b) piperidinyl or tetrahydropyranyl, each of which is optionally substituted by acyl or protected carboxy, R⁵ is ethyl.

The object compound (I) of the present invention can be prepared by the following processes.

at the amino group, or its salt ( π ) or its reactive derivative ( I ) or its salt at carboxy group, or its salt wherein R¹ R², R³, R⁴ and R⁵ are each as defined above.

The starting compound (II) of the present invention can be prepared according to a conventional manner or in a similar manner as described in the following Preparations and/or Examples.

Both of the above tautomeric isomers are included within the scope of the present invention, and in the present specification and claims, however, the object compound (I) is represented for convenience¹ sake by one expression of the possible tautomeric forms of pyrrolopyridazine ring.

In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows. It is to be noted that these definitions apply regardless of whether a term is used by itself or in combination with other terms. Hence the definition of "alkyl" applies to "alkyl" as well as to the "alkyl" portions of "alkoxy", "alkylamino" etc.

The term "lower" is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.

The term "lower alkyl" means straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like, and in which more preferable example may be C₁- C₄ alkyl.

The term "lower alkenyl" means vinyl(ethenyl), l-(or 2-)propenyl, l-(or 2- or 3- )butenyl, l-(or 2- or 3- or 4-)pentenyl, l-(or 2- or 3- or 4- or 5-)hexenyl, 1-methylvinyl, 1- ethylvinyl, l-(or 2-)methyl-l-(or 2-)propenyl, l-(or 2-)ethyl-l-(or 2-)propenyl, l-(or 2- or 3-)methyl-l-(or 2- or 3-)butenyl, and the like, in which more preferable example may be C₂-C₄ alkenyl.

The term "lower alkylene" may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene, propylene, and the like, in which more preferable example may be "Ci-C₂ alkylene" such as methylene or ehthylene, and the most preferable one may be methylene.

Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.

Suitable "trihalo(lower)alkyl" may include trichloromethyl, trifluoromethyl, trichloroethyl, tribromoethyl, and the like. Suitable "mono- or di(lower)alkylamino" may include amino group substituted by one or two lower alkyl such as methylamino, ethylamino, dimethylamino, and the like.

Example of "mono- or di(lower)alkylamino substituted by lower alkoxy" may be methoxymetylamino, methoxyethylamino, methoxyethyl(methyl)amino, methoxyethyl(ethyl)amino, di(methoxyethyl)amino, ethoxymethylamino, ethoxyethylamino, and the like.

Suitable "lower alkylthio" may include conventional ones such as methylthio, ethylthio, propylthio, butylthio, and the like.

Suitable "lower alkylsulfinyl" may include conventional ones such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, and the like.

Suitable "lower alkylsulfonyl" may include conventional ones such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, bytylsulfonyl, and the like.

The term "halogen" may include fluorine, bromine, chlorine and iodine. The term "protected carboxy" means a carboxy group bonded to the carboxy- protecting group, which may include esterified carboxy and the like.

Suitable examples of the ester moieties of the esterified carboxy may include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl) which may have suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl [e.g., acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, hexanoyloxymethyl or acetoxyethyl], halo(lower)alkyl (e.g., 2-iodoethyl or 2,2,2-trichloroethyl), and lower alkoxycarbonyloxy(lower)alkyl (e.g., methoxycarbonyloxymethyl or 2- methoxycarbonyloxyethyl); lower alkenyl (e.g., vinyl or allyl); lower alkynyl (e.g., ethynyl or propynyl); ar(lower)alkyl which may have suitable substituent(s) such as phenyl(lower)alkyl (e.g., benzyl, 4-methoxybenzyl, 4- nitrobenzyl, phenethyl, trityl, bis(methoxyphenyl)methyl, 3,4- dimethoxybenzyl or 4-hydroxy-3,5-di-tert-butylbenzyl); aryl which may have suitable substituent(s) (e.g., phenyl, 4-chlorophenyl, tolyl, tert- butylphenyl, xylyl, mesityl or cumenyl); and the like. Suitable "acyl" and "acyl moiety" may include aliphatic acyl group, and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.

Suitable example of said acyl may be illustrated as follows: Aliphatic acyl such as lower alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, etc.); in which preferable "lower alkanoyl" may include straight or branched one such as formyl, acetyl, propionyl, butyryl, and the like, lower alkenoyl (e.g., acryloyl, 2-(or 3-)-butenoyl, 2-(or 3- or 4-)pentenoyl, 2-(or 3- or 4- or 5-)-hexenoyl, etc.); lower alkadienoyl (e.g., heptadienoyl, hexadienoyl, etc.); cyclo(lower)alkylcarbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.); lower alkylglyoxyloyl (e.g., methylglyoxyloyl, ethylglyoxyloyl, propylglyoxyloyl, etc.); lower alkoxyglyoxyloyl (e.g., methoxyglyoxyloyl, ethoxyglyoxyloyl, propoxyglyoxyloyl, etc.); or the like;

Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); ar(lower)alkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl(lower)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; ar(lower)alkenoyl [e.g., phenyl(lower)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl(lower)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.]; aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.); arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.); heterocyclic acyl such as heterocycliccarbonyl; heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.); heterocyclic(lower)alkenoyl(e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl; heterocyclicoxycarbonyl; or the like.

Example of suitable acyl is lower alkanoyl (such as, formyl, acetyl and the like) and aroyl (such as, benzoyl, and the like).

The term "cyclo(lower)alkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 7 carbon atoms. Non-limiting examples of suitable monocyclic cyclo(lower)alkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cyclo(lower)alkyls include bicycloheptyl (e.g. bicycle[2,2,l]heptyl etc.), adamantyl and the like. The term "aryl" means a radical of mono- or bicyclic carbocyclic ring system having 6 to 10 cabon atoms and one or two aromatic rings. Non-limiting examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.

The term "heteroaryl" means a radical of aromatic monocyclic or multicyclic ring system comprising about 3 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of heteroaryls include a radical of aromatic monocyclic ring system comprising 5 or 6 ring atoms and containing one to three heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulfur, such as pyridinyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, and the like. The term "heterocyclyl" means a radical of saturated or partially saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S- dioxide. Non-limiting examples of heterocyclyl include a radical of monocyclic heterocyclyl rings include saturated or partially saturated monocyclic ring system comprising 5 or 6 ring atoms and containing one to three heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulfur, such as piperidinyl, pyrrolidinyl, piperazinyl, pyranyl, tetrahydropyranyl, tetrahydrothiophenyl, morpholinyl and the like. Suitable substituent of "substituted aryl", "substituted heteroaryl" or "substituted heterocyclyl" is halogen, lower alkyl, cyclo(lower)alkyl, trihalo(lower)alkyl, hydroxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, mono- or di(lower)alkylamino, acylamino, alkylsulfonylamino, carboxy, protected carboxy, cyano, -CONR¹⁰R¹¹ or -SO₂ R¹⁰R¹¹ [in which R¹⁰ and R¹¹ represent each independently hydrogen, lower alkyl or cyclo(lower)alkyl, or alternatively R¹⁰ and R¹¹, together with the nitrogen atom to which they are attached, represent azaheterocyclyl group]

The above Processes can be carried out according to a conventional manner such as the one described in Preparations and/or Examples, or in a similar manner thereto. According to the Process 1, pyrrolopyridazine derivatives (I) can be prepared by reacting the pyrrolopyridazine-3-carboxylic acid derivative (D) or its reactive derivative at the carboxy group, or its salt, and amino derivative (IH) or its reactive derivative at the amino group, or its salt. Suitable reactive derivative of the compound (II) may include an acid chloride, acid azide, an acid anhydride, an activated amide, an activated ester, or the like.

The suitable acid anhydride may include a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfuric acid, thiosulfuric acid, alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkanoic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, etc.), aromatic carboxylic acid (e.g., benzoic acid, chlorobenzoic acid, fluorobenzoic acid, nitrobenzoic acid, etc.),or the like.

Suitable activated amide may be imidazoylamide, 4-substituted imidazoylamide, dimethylpyrazolylamide, triazolylamide tetrazolylamide, or the like.

Suitable activated ester may be dimethyliminomethyl ester, vinyl ester, propargyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, methanesulfonylphenyl ester, phenyl thioester, p-nitrophenyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, 8- quinolyl thioester, an ester with a N-hydroxy compound (e.g., N₅N- dimethylhydroxylamine, l-hydroxy-2H-pyridone, N-hydroxysuccinimido, N- hydroxybenzotriazole, N-hydroxyphthalimide, etc.), or the like.

Suitable reactive derivative at the amino group of the compound (HI) may include Schiff s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (JJS) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (III) with a silylating reagent such as trimethylsilyl chloride, N,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide, or the like.

These reactive derivatives can optionally be selected from them according to the kind of compound (II) to be used.

When the compound (II) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of condensing agent. Suitable condensing agent may include a carbodiimide (e.g., N,N- dicyclohexylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N- ethyl-N'-(3-dimethylaminopropyl)carbodiimide or its hydrochloride, etc.), O-(7- azabenzotriazole-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, diphenylphosphinic azido, diphenylphosphinic chloride, diethylphosphoryl cyanide, bis(2-oxo-3-oxazolidinyl)-phosphinic chloride, N,N'-carbonyldiimidazole, 2-ethoxy-l- ethoxycarbonyl-l,2-dihydroquinoline, cyanuric chloride, or the like.

The reaction may be also carried out in the presence of organic or inorganic base such as alkali metal carbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, or the like. The reaction is usually carried out in a conventional solvent such as water, acetone, alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

The compounds of the present invention can be purified by any conventional purification methods employed for purifying organic compounds, such as re- crystallization, column chromatography, thin-layer chromatography, high-performance liquid chromatography and the like. The compounds can be identified by conventional methods such as NMR spectrography, mass spectrography, IR spectrography, elemental analysis, and measurement of melting point.

The new pyrrolopyridazine derivatives (I) and pharmaceutically acceptable salts thereof hardly possess a strong inhibitory activity against phosphodiesterase HI (PDE JS), but possess a strong inhibitory activity against phosphodiesterase IV (PDE IV) and a strong inhibitory activity on the tumor necrosis factor (TNF).

That is, the pyrrolopyridazine derivatives (I) and pharmaceutically acceptable salts thereof are selective inhibitors of phosphodiesterase IV (PDE IV) and inhibitors on the production of tumor necrosis factor (TNF).

Accordingly, the new pyrrolopyridazine derivatives (I) and a pharmaceutically acceptable salt thereof can be used for prophylactic and therapeutic treatment of PDE-IV and TNF mediated diseases such as chronic inflammatory diseases (e.g., rheumatoid arthritis, osteoarthritis, emphysema, chronic bronchiolitis, allergic rhinitis, etc.), osteoporosis, rejection by transplantation, asthma, chronic obstructive pulmonary disease (COPD), eosinophilia, fibrotic disease (e.g., cystic fibrosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, etc.), (viral alcoholic, drug-induced) acute and fulminant hepatitis, hepatic steatosis (alcoholic and non-alcoholic steato-hepatitis), chronic (viral and non- viral) hepatitis, hepatic cirrhosis, autoimmune hepatitis, pancreatitis, nephritis, endotoxin shock, specific autoimmune diseases [e.g., ankylosing spondylitis, autoimmune encephalomyelitis, autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, etc.), systemic lupus erythematosus (SLE), polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis (Wilson's disease, etc.), myasthenia gravis, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease, etc.), endocrine ophthalmopathy, Grave's disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), Reiter's syndrome, non infection uveitis, autoimmune keratitis (e.g., keratoconjunctivitis sicca, vernal keratoconjunctivitis, etc.), interstitial lung fibrosis, psoriatic arthritis, etc.], dermatological disorders associated with PDE-IV enzyme (such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria), neurodegenerative disorders such as Parkinson disease, Alzheimer's disease, depression, acute and chronic multiple sclerosis, cancer cachexia, viral infection, AIDS cachexia, thrombosis, and the like.

For therapeutic administration, the compound (I), or its prodrug, or a salt thereof can be administered alone or in the form of a mixture, preferably, with a pharmaceutical vehicle or carrier.

The active ingredient of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains a compound (I), as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external (topical), enteral, intravenous, intramuscular, parenteral or intra-mucous applications. The active ingredient can be formulated, for example, with the conventional non-toxic, pharmaceutically acceptable carriers for ointment, cream, plaster, tablets, pellets, capsules, suppositories, solution (saline, for example), emulsion, suspension (olive oil, for example), aerosols, pills, powders, syrups, injections, troches, cataplasms, aromatic waters, lotions, buccal tablets, sublingual tablets, nasal drops and any other form suitable for use. The carriers which can be used are water, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paster, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active compound is included in a pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the diseases.

The active ingredient can be formulated into, for example, preparations for oral application, preparations for injection, preparations for external application, preparations for inhalation, and preparations for application to mucous membranes.

Further, the compound of this invention can be used in combination with other therapeutic compounds. In particular, the combinations of the PDE4 inhibiting compound of this invention can be advantageously used in combination with i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii) COX-2 selective inhibitors, iv) statins, v) NSAIDs, vi) M2/M3 antagonists, vii) corticosteroids, viii) Hi (histamine) receptor antagonists, ix) beta 2 adrenoceptor agonist, x) interferon, xi) antiviral drugs for hepatitis C virus (HCV) such as protease inhibitor, helicase inhibitor, polymerase inhibitor, or the like, xii) antiviral drug for hepatitis B virus such as lamivudine, xiii) ursodesoxycholic acid, xiv) glycyrrhizin, xv) human grouth factor (HGF), xvi) aminosalicylic acid such as salazosulfapyridine, mesalazin, or the like, xvii) steroids such as prednisolone farnesylate, xviii) immunosuppressant such as azathioprine, 6-mercaptopurine, tacrolimus, and the like.

Mammals which may be treated by the present invention include livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and humans, preferably humans.

While the dosage of therapeutically effective amount of the compound (I) will vary depending upon the age and condition of each individual patient, an average single dose to a human patient of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, and 1000 mg of the compound (I) may be effective for treating the above- mentioned diseases. In general, amounts between 0.01 mg/body and about 1,000 mg/body may be administered per day.

In order to show the utilities of the pyrrolopyridazine derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention, pharmacological test data of the representative compound of the pyrrolopyridazine derivatives (I) are illustrated in the following.

(a) Inhibition of U937 phosphodiesterase IV (PDE IV) 1. Test method:

Cultured U937 cells were washed twice and harvested with phosphate-buffered saline (PBS) by cell-scraper. After centrifugation, the cell pellet was suspended in homogenizing buffer (0.5 % deoxycholate [DOC], 5 mM 2-mercaptoethanol, 1 μM leupeptin, 100 μM PMSF, 20 μM p-tosyl-L-lysine-chloromethyl ketone [TLCK] in PBS). The cell suspension was then sonicated for a couple of minutes and homogenized by a glass-Teflon homogenizer with twenty strokes. The homogenate was centrifuged at 20Og for 30 minutes, and the supernatant was further ultra-centrifuged at 100,000 x g for 90 minutes (4°C). The final supernatant was dialyzed against dialysis buffer, which was the same component as homogenizing buffer without DOC. The dialysate of enzyme preparation was stored at -20⁰C until assay.

PDE4, activity was estimated with a Phosphodiesterase [³H] cAMP SPA Enzyme Assay System (Amersham Pharmacia Biotech), using a 96 well Opti-plate. Reactions were initiated by addition of 0.025 μCi/well of [³H]cAMP to the enzyme mixture containing 50 mM Tris-HCl (pH 7.5), 8.3 mM MgCl₂ , 1.7 mM EGTA, and various concentrations of the test compound or vehicle. CI-930 (10 μM in final), a specific PDE3, inhibitor, was also added in the reaction mixture. After incubation at 30⁰C for 15 minutes, 50 μL of SPA beads suspension was added to each well. The well-plate was then shaken for 20 minutes by a plate mixer. Radio-activity in each well was counted by a Top Counter.

Test compounds were dissolved in 100% dimethylsulfoxide (DMSO) and diluted into respective concentrations with the final solution containing 1% v/v of DMSO.

IC₅₀ values of test compounds for the enzyme activity of PDE4 was determined from regression analysis for log-logit conversion values of percent inhibition in the compound-treated tubes compared to that of the control. Percent inhibition was calculated with the following equation: Inhibition (%) = {1-(C-B)/(A-B)} x 100; in which A, B and C means mean values of radio-activity counts (dpm) of control, blank and the compound-treated tubes, respectively.

2. Test results

The following table illustrates the inhibitory activity on PDE-IV of the representative compound of formula (I):

(b) Inhibition on TNF-alpha production in rat mononuclear cells 1. Test method

(1) Rat peripheral blood mononuclear cells (PBMC) preparation

Male Wistar rat at the age of 15 weeks was anesthetized with ether and the blood (about 15 ml) was collected with a disposable syringe from the abdominal artery under celiotomy. Collected blood was transferred to a heparin containing polyethylene tube and an equal volume of RPMIl 640 was added to each tube. Diluted blood was then piled up to 20 ml of Lympholyte-Rat (Cedarlane Laboratories, Canada) in polystyrene centrifuge tube. After centrifugation at 3,000 rpm for 30 minutes, cells gathering in the center area of the gradient were collected by capillary and washed with 40 mL of RPMIl 640 by twice of centrifugation at 1,200 rpm for 10 minutes. Precipitate was then suspended in 10 ml of Tris-ammonium-chloride buffer and stood for 10 minutes in order to lyse remaining erythrocytes. After centrifugation at 1,200 rpm for 10 minutes, the precipitate was washed twice with 50 ml of RPMI1640 by centrifugation. PBMC finally precipitated were suspended in RPMI1640 containing 1% fetal bovine serum and antibiotics. After cell counting, final suspension at 3 x 10⁶cells/mL in culture medium was prepared.

(2) TNF-alpha production from stimulated PBMCs

Rat PBMC prepared by the density gradient method using Lympholyte-Rat, were suspended in the culture medium mentioned above with the concentration of 3 x 10⁶ cells/mL and 0.5 ml of the suspension was sowed into each well of a 24-well culture plate. Cells were incubated in the CO₂ incubator for 24 hours with 0.25 ml of LPS in addition of 0.25 ml of concentrations of drugs or vehicle at the start of the incubation. Final concentration of LPS in the incubation medium was 1 μg/mL. After 24 hours, the supernatant of each well by centrifugation at 1,700 rpm for 10 minutes was stored at - 80°C until assay. TNF-alpha levels in the medium were measured by ELISA.

The IC5₀ values of drugs on cytokine productions in LPS stimulated PBMC were estimated by the regression analysis for the relative values of cytokine level in the drug- treated wells compared to those of the vehicle-treated ones. ,

2. Test results

The following table illustrates the inhibitory activity on TNF-alpha production in rat of the representative compound of formula (I):

Best Mode for carrying out the Invention

The following examples are provided to further illustrate details for the preparation of the compounds of the present invention. The examples are not intended to be limitations on the scope of the instant invention in any way, and they should nqt be so construed. Furthermore, the compounds described in the following examples are not to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The starting materials and intermediates are prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.

The abbreviations, symbols and terms used in the Preparations, Examples and Formulae have the following meanings.

DMF N,N-dimethylformamide

EtOAc or AcOEt Ethyl acetate

THF Tetrahydrofuran Et3N Triethylamine

MeOH Methanol

EtOH Ethanol

BuOH Butanol

DCM Dichloromethane Pd/C Palladium on carbon powder

Preparation 1

To a solution of 2-ethyl-lH-pyrrole (7.00 g) in tetrahydrofuran (14 mL) was added 0,93 M solution of methylmagnesium bromide in THF (198 mL) on an ice bath under a nitrogen atmosphere. The mixture was stirred for 1 h at room temperature. Then the solution was added to a suspension of 5-bromonicotinoyl chloride in THF (110 mL) in the ice bath. After stirring for 15 min in the bath, the reaction was quenched by adding satd. NH₄Cl. The mixture was partitioned between EtOAc and water. The organic layer was washed with satd. NaHCO₃ and brine, dried over MgSO₄, and evaporated to give a dark colored gum. The gum was dispersed in EtOAc-hexanes (1-3, 150 mL) in the presence of silica gel (150 mL). The mixture was filtered, and the filtrate was concentrated. Flash silica gel column chromatography eluting with ethyl acetate-hexanes = 1-20 to 4-5 afforded (5-bromo-3-pyridinyl)(5-ethyl-lH-pyrrol-2-yl)methanone as a pale yellow solid (7.11 g). ¹H-NMR (CDCl₃) δ 1.33 (3H, t, J = 7 Hz), 2.75 (2H, q, J= 7 Hz), 6.14 (IH, m), 6.83

(IH, m), 8.27 (IH, m). 8.82 (IH, m), 8.98 (IH, m) MS (ESI⁺): m/z 279 (M+H)

Preparation 2 To a solution of (5-bromo-3-pyridinyl)(5-ethyl-lH-pyrrol-2-yl)methanone (7.11 g) in N,N-dimethylformamide (71 mL) was added 60% sodium hydride (1.22 g) in an ice bath under a nitrogen atmosphere. After stirring for 1 h, O-(2,4- dinitrophenyl)hydroxylamine (6.09 g) was added portionwise. The resulting mixture was stirred for 0.5 h in the bath and 1 h at room temperature. The reaction was quenched by adding water in the ice bath to give (l-amino-5-ethyl-lH-pyrrol-2-yl)(5-bromo-3- pyridinyl)methanone as pale brown crystals, which were collected by filtration, washed with water and diisopropyl ether, and dried in the air (6.49 g). ¹H-NMR (CDCl₃) δ 1.29 (3H, t, J = 7 Hz), 2.76 (2H, q, J= 7 Hz), 5.72 (2H, s). 5.96 (IH, m), 6.65 (IH, m), 8.19 (IH, m). 8.70 (IH, m), 8.89 (IH, m)

Preparation 3

To a solution of S-methyl-S-isoxazolecarboxylic acid (3.00 g), 2,2-dimethyl-l,3- dioxane-4,6-dione (4.08 g), and 4-(dimethylamino)pyridine (5.80 g) in dichloromethane (30 mL) was added a solution of dicyclohexylcarbodiimide (5.37 g) in dichloromethane (10 mL). The mixture was stirred for 2 h at room temperature. The mixture was filtered off, and the filtrate was evaporated. The residue was dissolved in EtOH (33 mL), and to the solution was added p-toluenesulfonic acid monohydrate (10.8 g). The mixture was refluxed for 1.5 h. The solvent was evaporated off, and the residue was partitioned between EtOAc and satd. NaHCO₃. The organic layer was washed with 1 N HCl and brine, dried over MgSO₄, and evaporated. Flash silica gel column chromatography (acetone-hexanes = 1-10) afforded ethyl 3-(5-methyl-3-isoxazolyl)-3-oxopropanoate as a colorless oil (2.80 g). ¹H-NMR (CDCl₃) δ (mixture of keto- and enol- form) (keto form) 1.27 (3H, t, J = 7.1 Hz), 2.50 (3H, s), 4.04 (2H ,s), 4.21 (2H ,q, J = 7.1 Hz), 6.41 (IH, s); (enol form) 1.29 (3H ,t, J = 7.1 Hz), 2.50 (3H, s), 4.27 (2H ,q, J = 7.1 Hz), 5.86 (IH, s), 6.29 , (IH, s), 12.18 (IH, s)

Preparation 4

To a solution of [l-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid (500 mg) in THF (5 mL) was added N,N-dimethylformamide (0.008 mL) followed by oxalyl chloride (0.188 mL) in an ice bath under a nitrogen atmosphere. The mixture was stirred for 1 h at room temperature. The volatile was evaporated off to give tert-butyl 4-(2-chloro-2- oxoethyl)-l-piperidinecarboxylate, which was used for the next reaction immediately.

Preparation 5

To a suspension of MgC12 (2.27 g) in THF (30 mL) was added solution of methyl 4-methoxy-3-oxobutanoate (2.9 g) followed by pyridine (5.62 mL) in an ice bath under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. To the mixture was added a solution of bicyclo[2.2.1]hept-2-ylacetyl chloride in THF (40 mL) in an ice bath. The mixture was stirred at room temperature over night. The mixture was partitioned between EtOAc and 1 N hydrochloric acid. The organic layer was washed with water and brine, dried over anhydrous MgSO₄, and evaporated in vacuo. The residue was purified by Flash silica gel column chromatography (eluent; hexne-EtOAc = 5-1) to give methyl 4-bicyclo[2.2.1]hept-2-yl-2-(methoxyacetyl)-3-oxobutanoate as a colorless oil (3.7O g). ¹H-NMR (CDCl₃) δ 1.04-2.72 (15H, m), 3.43 (3H, s), 3.79 (3H, s), 4.41 (2H, s) MS (m/z) 281 (M-I)

The following compound(s) was(were) obtained in a similar manner to that of Preparation 5. Preparation 6

Ethyl 2-acetyl-4-cyclohexyl-3-oxobutanoate

¹H-NMR (CDCl₃) δ 0.98 (2H, m), 1.11-1.27 (4H, m), 1.35 (3H, t, J = 7.1 Hz), 1.60-

1.88 (5H, m), 2.33 (3H, s), 2.53 (2H, d, J = 6.9 Hz), 4.27 (2H, q, J = 7.1 Hz), . ESI (m/z): 255 (M+H)

Preparation 7 tert-Butyl 4-[3-(ethoxycarbonyl)-2,4-dioxopentyl]-l-piperidinecarboxylate

¹H-NMR (CDCl₃) δ 1.10-1.28 (2H, m), 1.35 (3H, t, J = 7.1 Hz), 1.45 (9H, s), 1.63- 1.72 (2H, m), 1.98 (IH, m), 2.35 (3H, s), 2.60 (2H, d, J = 6.8 Hz), 2.71 (2H, m), 4.08 (2H, m), 4.27 (2H, q, J = 7.1 Hz)

ESI (m/z): 255 (M+H)

Preparation 8

Ethyl 2-acetyl-3-oxo-4-(tetrahydro-2H-pyran-4-yl)butanoate ¹H-NMR (CDCl₃) δ 1.38 (2H, m), 1.35 (3H, t, J = 7.1 Hz), 1.62 (2H, m), 2.08 (IH, m),

2.35 (3H, s), 2.61 (2H, d, J = 7.0 Hz), 3.39 (2H, m), 3.94 (2H, m), 4.28 (2H, q, J =

7.1 Hz) Preparation 9 tert-Butyl 2-(4-cyanobenzoyl)-3 -oxobutanoate

¹H-NMR (CDCl₃) δ (mixture of tautomers) 1.16 and 1.24 (9H, s), 2.20 and 2.44 (3H, s), 7.62 and 7.74 (2H, d, J = 8.6 Hz), 7.73 and 7.81 (2H, d, J = 8.6 Hz), 13.80 (IH, s)

Preparation 10

Ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-4-methoxy-3-oxobutanoate

¹H-NMR (CDCl₃) δ 0.96-1.10 (3H, m), 3.23 (1.5H, s), 3.49 (1.5H, s), 4.00-4.34 (4H, m), 4.57 (IH, s), 8.00 (0.5H, br s), 8.23 (0.5H, br s), 8.60-8.91 (2H, m)

Preparation 11

To a solution of ethyl 4-(cyclohexyloxy)acetoacetate (93.1 mg), (l-amino-5- ethyl-lH-pyrrol-2-yl)(5-bromo-3-pyridinyl)methanone (100 mg) and p-toluenesulfonic acid monohydrate (64.7 mg) was refluxed for 10 min with Dean-Stark condenser.

The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with saturated NaHCO₃ aq. and brine, dried over anhydrous MgSO₄, and evaporated in vacuo. The residue was purified by preparative thin layer silica gel chromatography (eluent; hexne-EtOAc = 5-1) to give ethyl 4-(5-bromo-3-pyridinyl)-7- ethyl-2-[(cyclohexyloxy)methyl]pyrrolo[l,2-b]pyridazine-3-carboxylate as an yellow oil (35 mg).

¹H-NMR (CDCl₃) δ 1.06-2.00 (16H, m), 3.06 (2H, q, J = 7 Hz), 3.25-3.41 (IH, m), 4.06 (2H, q, J = 7 Hz), 4.10 (2H, s), 6.31 (IH, d, J = 4 Hz), 6.62 (IH, d, J = 4 Hz), 8.16 (IH, dd, J = 2, 2 Hz), 8.77 (IH, d, J = 2 Hz), 8.84 (IH, d, J = 2 Hz) MS (m/z) 486 (M+l)

The following compound(s) was(were) obtained in a similar manner to that of Preparation 11. Preparation 12 Ethyl 4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[l,2-b]pyridazine-3-carboxylate

¹H-NMR (CDCl₃) δ 0.83 (3H ,t, J = 7.1 Hz), 1.40 (3H, t, J = 7.5 Hz), 3.09 (2H, q, J = 7.5 Hz), .89 (2H, q, J = 7.1 Hz), 6.39 (IH ,d, J = 4.4 Hz), 6.76 (IH ,d, J = 4.4 Hz),

7.40-7.58 (6H, m), 7.61-7.65 (2H, m), 7.96 (IH, m) ESI (m/z): 405.17 (M+H)

Preparation 13

Ethyl 4-(3-chlorophenyl)-7-ethyl-2-(3-furyl)pyrrolo[l,2-b]pyridazine-3-carboxylate ¹H-NMR (CDCl₃) δ 0.99 (3H, t, J = 7.1 Hz), 1.40 (3H, t, J = 7.5 Hz), 3.08 (2H, q, J = 7.5 Hz), 4.04 (2H, q, J = 4.04 Hz), 6.37 (IH, d, J = 4.4 Hz), 6.73 (IH, d, J = 4.4 Hz), 6.83 (IH, m), 7.40-7.46 (3H, m), 7.49 (IH, m), 7.53 (IH, m), 7.18 (IH, m) ESI (m/z): 395.06 (M+H)

Preparation 14

A mixture of 4-bicyclo[2.2.1]hept-2-yl-2-(methoxyacetyl)-3-oxobutanoate (3.70 g), 2-ethyl-lH-pyrrol-l-amine (1.73 g) and p-toluenesulfonic acid monohydrate (499 mg) in toluene (40 mL) was stirred at 60 °C for 3 hours. The solvent was evaporated in vacuo. The residue was purified by Flash silica gel column chromatography (eluent; hexne- EtOAc = 20-1) to give methyl 4-(bicyclo[2.2.1]heρt-2-ylmethyl)-7-ethyl-2-

(methoxymethyl)pyrrolo[l,2-b]pyridazine-3-carboxylate as an yellow oil (2.44 g)

¹H-NMR (CDCl₃) δ 1.00-2.39 (13H, m), 3.02 (2H, q, J = 7 Hz), 3.33 (3H, s), 3.89 (3H, s), 4.62 (IH, d, J = 12 Hz), 4.70 (IH, d, J = 12 Hz), 6.65 (IH, d, J = 4 Hz), 6.67 (IH, d, J = 4 Hz)

The following compound(s) was(were) obtained in a similar manner to that of Preparation 14. Preparation 15

Ethyl 4-(cyclohexylmethyl)-7-ethyl-2-methylpyrrolo[l,2-b]pyridazine-3-carboxylate ¹H-NMR (CDCl₃) δ 1.00 (2H, m), 1.10-1.23 (4H, m), 1.36 (3H, t, J = 7.1 Hz), 1.40 (3H, t, J = 7.5 Hz), 1.60-1.75 (5H, m), 2.50 (3H, s), 2.80 (2H, d, J = 7.0 Hz), 2.98 (2H, q, J = 7.5 Hz), 4.38 (2H, q, J = 7.1 Hz), 6.58 (IH, d, J = 4.4 Hz), 6.60 (IH, d, J = 4.4 Hz)

ESI (m/z): 329 (M+H) .

Preparation 16

Ethyl 4-{[l-(tert-butoxycarbonyl)-4-piperidinyl]methyl}-7-ethyl-2-methylpyrrolo[l,2- b]pyridazine-3-carboxylate ¹H-NMR (CDCl₃) δ 1.25 (2H, m), 1.36 (3H, t, J = 7.1 Hz), 1.40 (3H, t, J = 7.5 Hz), 1.45 (9H, s), 1.57-1.66 (2H, m), 1.89 (IH, m), 2.51 (3H, s), 2.59 (2H, m), 2.85 (2H, d, J = 6.8 Hz), 2.99 (2H, q, J = 7.5 Hz), 4.06 (2H, m), 4.38 (2H, q, J = 7.1 Hz), 6.58 (IH, d, J = 4.4 Hz), 6.63 (IH, d, J = 4.4 Hz)

Preparation 17

Ethyl 7-ethyl-2-methyl-4-(tetrahydro-2H-pyran-4-ylmethyl)pyrrolo[l,2-b]pyridazine-3- carboxylate

¹H-NMR (CDCl₃) δ 1.36 (3H, t, J = 7.5 Hz), 1.40 (2H, m), 1.41 (3H, t, J = 7.2 Hz), 1.53 (2H, m), 2.00 (IH, m), 2.51 (3H, s), 2.87 (2H, d ,J = 7.1 Hz), 2.99 (2H ,q, J =

7.5 Hz), 3.29 (2H, m), 3.92 (2H, m), 4.39 (2H ,q, J = 7.2 Hz), 6.59 (IH, d, J = 4.4 Hz), 6.63 (IH, d, J = 4.4 Hz)

Preparation 18 tert-Butyl 4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[l,2-b]pyridazine-3-carboxylate ' ¹H-NMR (CDCl₃) δ 1.25 (9H, s), 1.37 (3H, t ,J = 7.5 Hz), 2.60 (3H, s), 3.03 (2H, q, J = 7.5 Hz), 6.19 (IH, d, J = 4.4 Hz), 6.65 (IH, d, J = 4.4 Hz), 7.58 (2H, d, J = 8.4 Hz), 7.77 (2H ,d, J = 8.4 Hz)

Preparation 19

Ethyl 4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[l,2-b]pyridazine-3- carboxylate

¹H-NMR (CDCl₃) δ 1.04 (3H, t, J = 8 Hz), 1.38 (3H, t, J = 8 Hz), 3.06 (2H, q, J = 8

Hz), 3.39 (3H, s), 4.10 (2H, q, J = 8 Hz), 4.76 (2H, s), 6.33 (IH, d, J = 5 Hz), 6.74 (IH, d, J = 5 Hz), 7.96 (IH, br s), 8.61 (IH, br s), 8.78 (IH, d, J = 2 Hz)

MS (ESI⁺): m/z 418, 420 (M+H)

Preparation 20

To a solution of (l-amino-5-ethyl-lH-pyrrol-2-yl)(5-bromo-3- pyridinyl)methanone (70.0 mg) and ethyl 3-(5-methyl-3-isoxazolyl)-3-oxopropanoate (70.4 mg) in toluene (2 mL) was added trifluoromethanesulfonic acid (0.004 mL). The mixture was refluxed for 1.5 h with Dean-Stark equipment. The mixture was partitioned between EtOAc and satd. NaHCO₃. The organic layer was washed with brine, dried over MgSO₄, and evaporated. The residue was dissolved in N-methylpyrrolidone (1 mL). The solution was stirred for 40 min at 180°C. The mixture was partitioned between EtOAc and water. The organic layer was washed with water (two times) and brine, dried over MgSO₄, and evaporated. Preparative thin layer silica gel chromatography (EtOAc- hexanes - 1-3) afforded ethyl 4-(5-bromo-3-pyridinyl)-7-ethyl-2-(5-methyl-3- isoxazolyl)pyrrolo[l,2-b]pyridazine-3-carboxylate as an yellow gum, which was crystallized upon standing (48.1 mg).

¹H-NMR (CDCl₃) δ 1.08 (3H, t, J = 7.1 Hz), 1.40 (3H, t, J = 7.5 Hz), 2.52 (3H, s),

3.09 (2H ,q, J = 7.5 Hz), 4.15 (2H ,q, J = 7.1 Hz), 6.39 (IH, d, J = 4.4 Hz), 6.56 (IH, s), 6.83 (IH, d, J = 4.4 Hz), 8.03 (IH, m), 8.69 (IH, m), 8.80 (IH, m)

ESI (m/z): 455 and 457 (M+H)

Preparation 21

To a solution of tert-butyl 4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[l,2- b]pyridazine-3-carboxylate (137 mg) in ethanol (2.5 mL) were added 1 N NaOH (0.703 mL) and 3% hydrogen peroxide (1.12 mL). The mixture was stirred for 2 h at room temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over MgSO₄, and evaporated to give an orange gum. The gum was triturated in hexanes to give tert-butyl 4-[4-(aminocarbonyl)phenyl]- 7-ethyl-2-methylpyrrolo[l,2-b]pyridazine-3-carboxylate as an yellow powder (124 mg). ¹H-NMR (CDCl₃) δ 1.38 (3H ,t, J = 7.5 Hz), 3.04 (2H, q, J = 7.5 Hz), 5.71 (IH, s, br), 6.15 (IH, s, br), 6.24 (IH, d, J = 4.3 Hz), 6.64 (IH, d, J = 4.3 Hz), 7.58 (2H, d, J = 8.3 Hz), 7.93 (2H, d, J = 8.3 Hz)

Preparation 22

A mixture of methyl 4-(bicyclo[2.2.1]hept-2-ylmethyl)-7-ethyl-2- (methoxymethyl)pyrrolo[l,2-b]pyridazine-3-carboxylate (500 mg) and 85% KOH (2.78 g, 42.1 mmol) in EtOH (5 mL) and water (2.5 mL) was refluxed for 1 h. The reaction was quenched by adding cone, hydrochlonic acid in an ice bath. The mixture was partitioned between CHC13 and brine. The organic layer was dried over anhydrous MgSO₄ and evaporated in vacuo to give 4-(bicyclo[2.2.1]hept-2-ylmethyl)-7-ethyl-2- (methoxymethyl)pyrrolo[l,2-b]pyridazine-3-carboxylic acid as an yellow oil (792 mg).

¹H-NMR (CDCl₃) δ 1.00-2.39 (13H, m), 3.02 (2H, q, J = 7 Hz), 3.41 (3H, s), 4.71 (IH, d, J = 12 Hz), 4.76 (IH, d, J = 12 Hz), 6.70 (IH, d, J = 4 Hz), 6.73 (IH, d, J = 4 Hz) MS (m/z) 341 (M-I).

The following compound(s) was(were) obtained in a similar manner to that of

Preparation 22. Preparation 23 4-(Cyclohexylmethyl)-7-ethyl-2-methylpyrrolo[l,2-b]pyridazine-3-carboxylic acid

¹H-NMR (CDCl₃) δ 1.00-1.25 (6H, m), 1.37 (3H, t, J = 7.5 Hz), 1.60-1.80 (5H, m), 2.63 (3H, s), 2.98 (2H, d, J = 6.9 Hz), 2.99 (2H, q, J = 7.5 Hz), 6.65 (IH, d, J = 4.4

Hz), 6.69 (IH, d, J = 4.4 Hz) ESI (m/z): 301 (M+H) and 299 (M-H)

Preparation 24 4-{[l-(tert-Butoxycarbonyl)-4-piperidinyl]methyl}-7-ethyl-2-methylpyrrolo[l,2- b]pyridazine-3-carboxylic acid

¹H-NMR (CDCl₃) δ 1.20-1.31 (2H, m), 1.37 (3H, t, J = 7.5 Hz), 1.45 (9H, s), 1.63 (2H, m), 1.95 (IH, m), 2.62 (3H, s), 2.99 (2H, q, H = 7.5 Hz), 3.01 (2H, m), 4.09 (2H, m), 6.66 (2H, m)

Preparation 25

7-Ethyl-2-methyl-4-(tetrahydro-2H-pyran-4-ylmethyl)pyrrolo[l,2-b]pyridazine-3- carboxylic acid

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J = 7.5 Hz), 1.46-1.64 (4H, m), 2.06 (IH, m), 2.62 (3H, s), 2.97-3.04 (4H, m), 3.34 (2H, m), 3.99 (2H, m), 6.67 (2H, m)

ESI (m/z): 301 (M-H)

Preparation 26

4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(5-methyl-3-isoxazolyl)pyrrolo[l,2-b]pyridazine-3- carboxylic acid

¹H-NMR (CDCl₃) δ 1.41 (3H, t, J = 7.5 Hz), 2.52 (3H, s), 3.10 (2H₅ q, J = 7.5 Hz), 6.41 (IH, d, J = 4.4 Hz), 6.57 (IH, s), 6.85 (IH, d, J = 4.3 Hz), 8.15 (IH, m), 8.75 (IH, m), 8.77 (IH, m) Preparation 27

4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[l,2-b]pyridazine-3- carboxylic acid ¹H-NMR (CDCl₃) δ 1.39 (3H, t, J = 8 Hz), 3.06 (2H, q, J = 8 Hz), 3.44 (3H, s), 4.82

(2H, s), 6.36 (IH, d, J = 5 Hz), 6.77 (IH, d, J = 5 Hz), 8.09 (IH, br s), 8.65 (IH, br s), 8.72 (IH, br s) MS (ESI⁺): m/z 390, 392 (M+H)

Preparation 28

4-(5-Bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-ethylpyrrolp[l,2-b]pyridazine-3- carboxylic acid

¹H-NMR (CDCl₃) δ 0.90-1.80 (13H, m), 3.00 (2H, q, J = 7 Hz), 3.32-3.45 (IH, m),

3.98 (2H, s), 6.28 (IH, d, J = 4 Hz), 6.65 (IH, d, J = 4 Hz), 8.20 (IH, dd, J = 2, 2 Hz), 8.76 (IH, d, J = 2 Hz), 8.86 (IH, d, J = 2 Hz)

MS (m/z) 458 (M+l) .

Preparation 29

4-(3-Chlorophenyl)-7-ethyl-2-(3-furyl)pyrrolo[l,2-b]pyridazine-3-carboxylic acid ¹H-NMR (CDCl₃) δ 1.40 (3H, t, J = 7.5 Hz), 3.08 (2H, q, J = 7.5 Hz), 6.39 (IH, d, J = 4.4 Hz), 6.75 (IH, d, J = 4.4 Hz), 6.82 (IH, m), 7.41-7.48 (3H, m), 7.50 (IH, m), 7.54 (IH, m), 7.85 (IH, m) ESI (m/z): 367 (M + H), 365 (M-H)

Preparation 30

A solution of tert-butyl 4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[l,2- b]pyridazine-3-carboxylate (27.5 mg) in trifluoroacetic acid (0.5 mL) was stirred for 1 h at room temperature. The volatile was evaporated off to give an yellow solid. The solid was triturated in hexanes to give 4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[l,2- b]pyridazine-3-carboxylic acid an yellow powder (17.8 mg).

¹H-NMR (CDCl₃) δ 1.88 (3H, t, J = 7.5 Hz), 3.07 (3H, s), 3.06 (2H ,q, J = 7.5 Hz), 6.26 (IH, m), 7.21 (IH, m), 8.07 (2H, d, J = 8.1 Hz), 8.28 (2H, d, J = 8.1 Hz).

ESI (m/z): 304 (M-H) The following compound(s) was(were) obtained in a similar manner to that of Preparation 30. Preparation 31 4-[4-(Aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[l,2-b]pyridazine-3-carboxylic acid

¹H-NMR (CDCl₃) δ 1.31 (3H, t, J = 7.5 Hz), 2.53 (3H, s), 2.98 (2H ,q, J = 7.5 Hz), 6.26 (IH, d, J = 4.3 Hz), 6.74 (IH, d, J = 4.2 Hz), 7.50 (IH, s, br), 7.55 (2H, d, J = 8.1 Hz), 7.99 (2H, d, J = 8.1 Hz), 8.10 (IH, s, br) ,

The following compound(s) was(were) obtained in a similar manner to that of Preparation 11. Preparation 32

Methyl 4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[l,2-b]pyridazine-3-carboxylate ¹H-NMR (CDCl₃) δ 1.41 (3H, t, J = 7.5 Hz), 3.09 (2H, q, J = 7.5 Hz), 3.73 (3H ,s),

6.39 (IH, d, J = 4.5 Hz), 6.82 (IH, d, J = 4.5 Hz), 7.89 (IH, m), 8.54 (IH, m), 8.72 (IH, m), 8.79 (IH, m)

The following compound(s) was(were) obtained in a similar manner to that of Preparation 22. Preparation 33 4-(5-Bbromo-3-pyridinyl)-7-ethylpyrrolo[l,2-b]pyridazine-3-carboxyric acid

¹H-NMR (CDCl₃ + CD₃OD) d 1.40 (3H, t, J = 7.5 Hz), 3.09 (2H ,q, J = 7.5 Hz), 6.36

(IH, d, J = 4.6 Hz), 6.81 (IH, d, J = 4.6 Hz), 7.92 (IH, m), 8.53 (IH, d, J = 1.8 Hz), 8.73 (IH, d, J = 2.1 Hz), 8.75 (IH, s)

Example 1

To a solution of 4-(bicyclo[2.2.1]hept-2~ylmethyl)-7-ethyl-2- (methoxymethyl)pyrrolo[l,2-b]pyridazine-3-carboxylic acid (30 mg) in DMF (2 mL), was added O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphete (36.6 mg), 4-(dimethylamino)pyridine (27.8 mg) and 4- (aminomethyl)benzenesulfonamide (25.4 mg) at room temperature. This mixture was stirred at room temperature for 3 hours and then stirred at 50¹C for 2 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with 1 N hydrochloric acid, saturated NaHCO₃ aq. and brine, dried over anhydrous MgSO₄, and evaporated in vacuo. The residue was purified by preparative thin layer silica gel chromatography (eluent; hexne-EtOAc = 1-2) to give N-[4-(aminosulfonyl)benzyl]-4- (bicyclo[2.2.1]hept-2-ylmethyl)-7-ethyl-2-(methoxymethyl)pyrrolo[l,2-b]pyridazine-3- carboxamideas an yellow powder (14 mg).

¹H-NMR (CDCl₃) δ 0.80-1.41 (HH, m), 1.82-1.96 (2H, m), 2.17-2.23 (IH, m), 2.84- 2.92 (2H, m), 3.00 (2H, q, J = 7 Hz), 3.34 (3H, s), 4.50 (2H, s), 4.66 (IH, d, J = 7 Hz), 4.72 (IH, d, J = 7 Hz), 4.76 (2H, br s), 6.65 (IH, d, J = 4 Hz), 6.70 (IH, d, J = 4 Hz), 7.12 (IH, br s), 7.58 (2H, d, J = 8 Hz), 7.92 (2H, d, J = 8 Hz)

The following compound(s) was(were) obtained in a similar manner to that of Example 1. Example 2 4-(Cyclohexylmethyl)-7-ethyl-N-(4-methoxybenzyl)-2-methylpyrrolo[l,2-b]pyridazine-3- carboxamide

¹H-NMR (CDCl₃) δ 0.87 (2H, m), 1.03-1.15 (4H, m), 1.34 (3H ,t, J = 7.5 Hz), 1.56- 1.66 (4H, m), 1.77 (IH, m), 2.46 (3H, s), 2.61 (2H, d, J = 7.4 Hz), 2.96 (2H ,q, J = 7.5 Hz), 3.81 (3H, s), 4.55 (2H, d, J = 5.7 Hz), 5.88 (IH, m), 6.47 (IH, d, J = 4.3 Hz), 6.57 (IH, d, J = 4.3 Hz), 6.89 (2H, d, J = 8.7 Hz), 7.32 (2H, d, J = 8.7 Hz)

ESI (m/z): 420 (M + H) and 839 (2M+H)

Example 3

N-[4-(Aminosulfonyl)benzyl]-4-(cyclohexylmethyl)-7-ethyl-2-methylpyrrolo[l,2- b]pyridazine-3 -carboxamide

¹H-NMR (CDCl₃) δ 0.89 (2H, m), 1.06-1.20 (4H, m), 1.35 (3H, t, J = 7.5 Hz), 1.55- 1.68 (4H, m), 1.76 (IH, m), 2.43 (3H, s), 2.62 (2H, d, J = 7.4 Hz), 2.81 (2H, s, br), 2.96 (2H, q, J = 7.5 Hz), 4.64 (2H ,m), 6.52 (IH, d, J = 4.3 Hz), 6.60 (IH, d, J = 4.4 Hz), 7.23 (IH, br), 7.54 (2H ,d, J = 8.4 Hz), 7.91 (2H, d, J = 8.4 Hz)

Example 4 tert-Butyl 4-[({[4-(cyclohexylmethyl)-7-ethyl-2-methylpyrrolo[l,2-b]pyridazin-3- yl] carbonyl} amino)methyl] - 1 -piperidinecarboxylate ¹H-NMR (CDCl₃) δ 1.00 (2H, m), 1.12-1.27 (4H, m), 1.35 (3H ,t ,J = 7.5 Hz), 1.46 (9H, s), 1.64-1.85 (8H, m), 2.46 (3H, s), 2.67 (2H, d, J = 7.2 Hz), 2.72 (2H, m), 2.97 (2H, q, J = 7.5 Hz), 3.35 (2H, m), 4.16 (2H, m), 6.77 (IH, br), 6.51 (IH, d, J = 4.4 Hz), 6.60 (IH, d, J = 4.4 Hz)

Example 5

4-(Cyclohexylmethyl)-7-ethyl-2-methyl-3-[(4-phenyl-l-piperazinyl)carbonyl]pyrrolo[l,2- b]pyridazine

¹H-NMR (CDCl₃) δ 0.95-1.26 (6H, m), 1.37 (3H ,t, J = 7.5Hz), 1.57-1.77 (4H, m), 1.86 (IH, m), 2.43 (3H, s), 2.45 (IH, m), 2.75 (IH, m), 2.97 (2H, q, J = 7.5 Hz),

3.08 (2H, m), 3.26 (2H, m), 3.43 (2H, m), 3.98 (2H, m), 6.53 (IH, d, J = 4.3 Hz), 6.62 (IH ,d, J = 4.4 Hz), 6.89-6.95 (3H, m), 7.27 (2H, m) ESI (m/z): 445 (M+H) and 889 (2M+H)

Example 6

3-[(4-Acetyl-l-piperazinyl)carbonyl]-4-(cyclohexylmethyl)-7-ethyl-2-methylpyrrolo[l,2- b]pyridazine

¹H-NMR (CDCl₃) δ 0.95-1.26 (6H, m), 1.36 (3H, t, J = 7.5 Hz), 1.60-1.77 (4H, m),

1.85 (IH, m), 2.16 (3H, s), 2.36 (IH, m), 2.38 (3H, s), 2.75 (IH, m), 3.00 (2H, m), 3.25-3.43 (3H ,m), 3.28 (2H, m) ,3.70-3.95 (3H, m), 6.55 (IH ,d, J = 4.4 Hz), 6.64

(IH ,d, J = 4.4 Hz) ESI (m/z): 411 (M+H)

Example 7 tert-Butyl 4-[(7-ethyl-3-{[(4-methoxybenzyl)amino]carbonyl}-2-methylpyrrolo[l,2- b]pyridazin-4-yl)methyl] - 1 -piperidinecarboxylate

¹H-NMR (CDCl₃) δ 1.12 (2H, m), 1.34 (3H, t, J = 7.5 Hz), 1.45 (9H, s) ,1.53 (2H, m), 1.90 (IH, m), 2.46 (3H, s), 2.55 (2H, m), 2.65 (2H, m), 2.96 (2H, q, J = 7.5 Hz), 3.81 (3H, s), 4.03 (2H, m), 6.55 (2H, d, J = 5.7 Hz), 6.89 (IH, br), 6.48 (IH, d, J = 4.4 Hz), 6.59 (IH ,d, J = 4.4 Hz), 6.90 (2H, d, J = 8.7 Hz), 7.30 (2H, d, J = 8.8 Hz)

Example 8

N-[4-(Aminosulfonyl)benzyl]-7-ethyl-2-methyl-4-(tetrahydro-2H-pyran-4- ylmethyl)pyrrolo [ 1 ,2-b]pyridazine-3-carboxamide

¹H-NMR (CDCl₃ + CD₃OD) δ 0.96(2H, m), 1.35 (3H, t, J = 7.5 Hz), 1.39 (2H, m), 1.94 (IH, m), 2.46 (3H, s), 2.61 (2H ,d, J = 7.3 Hz), 2.96 (2H, q, J = 7.5 Hz), 3.19 (2H, m), 3.78 (2H, m), 4.61 (2H, s), 6.48 (IH, d ,J = 4.3 Hz), 6.60 (IH, d, J = 4.4 Hz), 7.58 (2H, d ,J = 8.4 Hz), 7.94 (2H, d, J= = 8.5 Hz)

Example 9

N-[4-(Aminosulfonyl)benzyl]-4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[l,2- b]pyridazine-3-carboxamide ¹H-NMR (DMSO-d₆) δ 1.30 (3H, t, J = 7.5 Hz), 2.97 (2H ,q, J = 7.5 Hz), 3.33 (3H ,s), 4.28 (2H, d, J = 5.9 Hz), 6.21 (IH, d, J = 4.3 Hz), 6.73 (IH, d, J = 4.2 Hz), 7.03 (2H ,d, J = 8.5 Hz), 7.32 (IH, s), 7.66 (2H ,d, J = 8.2 Hz), 7.68 (2H, d, J = 8.2 Hz9, 8.00 (2H, d, J = 8.3 Hz), 8.86 (IH, br)

Example 10

4- [4-(Aminocarbonyl)phenyl] -7-ethyl-N-(4-methoxybenzyl)-2-methylpyrrolo [1,2- b]pyridazine-3-carboxamide

¹H-NMR (DMSOd₆) δ 1.31 (3H, t, J = 7.5 Hz9, 2.97 (2H, q, J = 7.5 Hz), 3.69 (3H, s), 4.16 (2H, d, J = 6.2 Hz), 6.20 (IH, d, J = 4.2 Hz), 6.60-6.70 (5H, m), 7.56 (3H, m), 7.97 (2H, d, J = 8.3 Hz), 8.12 (IH, br), 8.63 (IH, br)

Example 11

N-[4-(Aminosulfonyl)benzyl]-4-(5-bromo-3-pyridinyl)-7-ethyl-2-(5-methyl-3- isoxazolyl)pyrrolo[l,2-b]pyridazine-3-carboxamide ¹H-NMR (CDCl₃ + CD₃OD) δ 1.40 (3H, t, J = 7.5 Hz), 3.08 (2H, q, J = 7.5 Hz), 3.15 (3H, s)l, 3.15-3.26 (2H, m), 4.35 (2H, s), 6.33 (IH ,d, J = 4.5 Hz), 6.55 (IH ,s), 6.83 (IH, d, J = 4.5 Hz), 7.11 (2H, d, J = 8.4 Hz), 7.76 (2H, d, J = 8.4 Hz), 8.06 (IH, m), 8.56 (IH, m), 8.70 (IH, m)

Example 12

4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)-3-[(4-methyl-l- piperazinyl)carbonyl]pyrrolo[l,2-b]pyridazine

¹H-NMR (CDCl₃) δ 1.38 (3H ,t, J = 7.5 Hz), 1.60 (2H, m), 2.01 (IH, m), 2.18-2.26 (3H, m), 2.41 (IH, m), 2.86 (IH, m), 3.04 (2H ,q, J = 7.5 Hz), 3.17 (IH, m), 3.41 (3H, s), 3.56 (2H, m), 4.41 (IH, d, J = 10.8 Hz), 4.83 (IH ,d, J = 10.8 Hz), 6.42 (IH, d, J = 4.3 Hz), 6.74 (IH, d, J = 4.4 Hz), 8.09 (IH, m), 8.79 (2H, m) ESI (m/z): 943 and 945 (2M+H)

Example 13

3-[(4-Acetyl-l-piperazinyl)carbonyl]-4-(5-bromo-3-pyridinyl)-7-ethyl-2-

(methoxymethyl)pyrrolo[l,2-b]pyridazine

¹H-NMR (CDCl₃) δ (mixture of two conformers) 1.39 (3H, t, J = 7.5 Hz), 2.01 and 2.08 (3H, s), 2.71-3.00 (3H, m), 3.05 (2H, q, J = 7.5 Hz), 3.18 (2H, m), 3.39 and

3.41 (3H ,s), 3.50 (IH, m), 3.72 (IH, m), 4.41 (IH, m), 4.85 (IH, m), 6.44 (IH, m), 6.76 (IH, d, J = 4.4 Hz), 8.12 (IH, m), 8.81 (IH, m) ESI (m/z): 500 and 502 (M+H)

Example 14

4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)~3-[(4-phenyl-l- piperazinyl)carbonyl]pyrrolo [ 1 ,2-b]pyridazine

¹H-NMR (CDCl₃) δ 1.39 (3H ,t, J = 7.5 Hz), 2.34 (2H, m), 21.83 (IH, m), 2.92 (2H, m), 3.02-3.16 (3H, m), 3.30 (IH, m), 3.40 (3H, s), 3.56 (IH, m), 3.81 (IH, m), 4.42 (IH, d, J = 10.8 Hz), 4.86 (IH, d, J = 10.7 Hz),6.44 (IH, d, J = 4.2 Hz9, 6.75

(IH,- d, J = 4.3 Hz9, 6.81 (2H, d, J = 7.7 Hz), 6.89 (IH, m), 7.22-7.23 (2H, m), 8.12 (IH, t, J = 2.0 Hz), 8.75 (IH, d, J = 2.1 Hz), 8.82 (IH, d, J = 2.2 Hz)

Example 15 tert-Butyl 4-({ [4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[l,2- b]pyridazin-3-yl]carbonyl}ammo)-l-piperidinecarboxylate

¹H-NMR (CDCl₃) δ 1.16-1.26 (2H, m), 1.38 (3H, t, J = 7.5 Hz), 1.45 (9H, s), 1.77 (2H, m), 2.85 (2H, m), 3.07 (2H, q, J = 7.5 Hz), 3.47 (3H, s), 3.90-4.02 (3H, m), 4.64 (2H, s), 6.24 (IH, br), 8.37 (IH, d, J = 4.4 Hz), 8.76 (IH ,d, J = 4.2 Hz), 8.01 (IH, m), 8.68 (IH, m), 8.78 (IH, m)

Example 16 tert-Butyl 4-[({[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[l,2- b]pyridazin-3-yl]carbonyl}amino)methyl]-l-piperidinecarboxylate

¹H-NMR (CDCl₃) δ 1.00 (2H, m), 1.38 (3H ,t, J = 7.5 Hz), 1.45 (9H, s), 1.40-1.56 (3H, rri), 2.63 (2H, m), 3.05 (2H, q, J = 7.5 Hz), 3.13 (2H, m), 3.46 (3H, s), 4.07 (2H, m), 4.64 (2H, s), 6.28 (IH, br), 6.35 (IH, d, J = 4.4 Hz), 6.75 (IH ,d, J = 4.4 Hz9, 8.02 (IH, m), 8.70 (IH, m), 8.77 (IH, m)

ESI (m/z): 586 and 588 (M+H)

Example 17

Methyl 4-[({[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[l,2- b]pyridazin-3-yl]carbonyl}amino)methyl]benzoate

¹H-NMR (CDCl₃) δ 1.38 (3H ,t, J = 7.5 Hz), 3.06 (2H ,q ,J = 7.5 Hz), 3.35 (3H, s), 3.92 (3H, s), 4.46 (2H ,d, J = 5.9 Hz), 4.61 (2H, s), 6.33 (IH ,d, J = 4.4 Hz), 6.69 (IH, br), 6.76 (IH, d, J = 4.4 Hz), 7.21 (2H ,d, J = 8.4 Hz), 6.96-7.99 (3H, m), 8.66 (IH, m), 8.75 (IH, m) ESI (m/z): 537 and 539 (M+H)

Example 18

Methyl ({ [4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo [ 1 ,2-b]pyridazin-3 - yl] carbonyl} amino)(phenyl)acetate ¹H-NMR (CDCl₃) δ 1.38 (3H ,t, J = 7.5 Hz), 3.05 (2H, q, J = 7.5 Hz), 3.303H, s), 3.70 (3H, s), 4.55 (IH ,d ,J = 10.8 Hz), 4.77 (IH, d, J = 10.8 Hz), 5.55 (IH, d_? J = 7.6 Hz), 6.34 (IH, d, J = 4.3 Hz), 6.76 (IH, d, J = 4.4 Hz), 7.22-7.36 (5H, m), 7.49 (IH, br), 7.95 (IH ,m), 8.63 (IH, m), 8.69 (IH, m)

Example 19

4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)-N-(4-methylbenzyl)pyrrolo[l,2- b]pyridazine-3-carboxamide

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J = 7 Hz), 2.33 (3H, s), 3.05 (2H, q, J = 7 Hz), 3.34

(3H, s), 4.36 (2H, d, J = 6 Hz), 4.60 (2H, s), 6.33 (IH, d, J = 4 Hz), 6.51 (IH, t, J = 6 Hz), 6.75 (IH, d, J = 4 Hz), 7.00 (2H, d, J = 8 Hz), 7.10 (2H, d, J = 8 Hz), 7.97

(IH, dd, J = 2, 2 Hz), 8.66 (IH, d, J = 2 Hz), 8.75 (IH, d, J = 2 Hz) MS (m/z) 493 (M+l) Example 20

4-(5-Bromo-3-pyridinyl)-N-(2,3-dihydro-lH-inden-2-yl)-7-ethyl-2-

(methoxymethyl)pyrrolo[l,2-b]pyridazine-3-carboxamide

¹H-NMR (CDCl₃) δ 1.36 (3H, t, J = 7 Hz), 2.64 (2H, dd, J = 15, 4 Hz), 3.05 (2H, q, J = 7 Hz), 3.25 (2H, dd, J = 15, 4 Hz), 3.36 (3H, s), 4.61 (2H, s), 4.66-4.76 (IH, m),

6.32 (IH, d, J = 4 Hz), 6.44-6.50 (IH, m), 6.74 (IH, d, J = 4 Hz), 7.12-7.24 (4H, m), 7.99 (IH, dd, J = 2, 2 Hz), 8.66 (IH, d, J = 2 Hz), 8.78 (IH, d, J = 2 Hz) MS (m/z) 505 (M+l)

Example 21

4-(5-Bromo-3-pyridinyl)-N-(cyclohexylmethyl)-7-ethyl-2-(methoxymethyl)pyrrolo[l,2- b]pyridazine-3-carboxamide

¹H-NMR (CDCl₃) δ 0.71-0.86 (2H, m), 1.10-1.72 (9H, m), 1.38 (3H, t, J = 7 Hz),

3.01-3.11 (4H, m), 3.47 (3H, s), 4.65 (2H, s), 6.15 (IH, t, J = 6 Hz), 6.34 (IH, d, J = 4 Hz), 6.75 (IH, d, J = 4 Hz), 8.01 (IH, dd, J = 2, 2 Hz), 8.70 (IH, d, J = 2 Hz),

8.76 (IH, d, J = 2 Hz) MS (m/z) 486 (M+l)

Example 22 4-(5-Bromo-3-pyridinyl)-7-ethyl-N-(2-methoxybenzyl)-2-(methoxymethyl)pyrrolo[l,2- b]pyridazine-3-carboxamide

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J = 7 Hz), 3.05 (2H, q, J = 7 Hz), 3.34 (3H, s), 3.75 (3H, s), 4.40 (2H, d, J = 6 Hz), 4.62 (2H, s), 6.30 (IH, d, J = 4 Hz), 6.49 (IH, t, J = 6 Hz), 6.72 (IH, d, J = 4 Hz), 6.80 (IH, d, J = 8 Hz), 6.90 (IH, dd, J = 8, 8 Hz), 7.14 (IH, dd, J = 8, 2 Hz), 7.25 (IH, dd, J = 8, 8 Hz), 7.89 (IH, dd, J = 2, 2 Hz),

8.50 (IH, d, J = 2 Hz), 8.56 (IH, d, J = 2 Hz)

Example 23

4-(5-Bromo-3-pyridinyl)-7-ethyl-N-(3-methoxybenzyl)-2-(methoxymethyl)pyrrolo[l,2- b]pyridazine-3-carboxamide

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J = 7 Hz), 3.05 (2H, q, J = 7 Hz), 3.34 (3H, s), 3.80 (3H, s), 4.40 (2H, d, J = 6 Hz), 4.61 (2H, s), 6.32 (IH, d, J = 4 Hz), 6.59 (IH, t, J =

6 Hz), 6.68-6.72 (2H, m), 6.75 (IH, d, J = 4 Hz), 6.80 (IH, d, J = 8 Hz), 7.22 (IH, dd, J = 8, 8 Hz), 7.99 (IH, dd, J = 2, 2 Hz), 8.66 (IH, d, J = 2 Hz), 8.74 (IH, d, J = 2 Hz)

Example 24 4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)-N-phenylpyrrolo[l,2-b]pyridazine- 3-carboxamide

¹H-NMR (CDCl₃) δ 1.42 (3H, t, J = 7 Hz), 3.10 (2H, q, J = 7 Hz), 3.54 (3H, s), 4.72 (2H, s), 6.40 (IH, d, J = 4 Hz), 6.81 (IH, d, J = 4 Hz), 7.14 (IH, dd, J = 8, 8 Hz), 7.32 (2H, dd, J = 8, 8 Hz), 7.42 (IH, d, J = 8 Hz), 8.07 (IH, dd, J = 2, 2 Hz), 8.52 (IH, br s), 8.72 (IH, d, J = 2 Hz), 8.74 (IH, d, J = 2 Hz)

MS (m/z) 465 (M+l)

Example 25

N-Benzyl-4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[l,2-b]pyridazine- 3-carboxamide

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J = 7 Hz), 3.05 (2H, q, J = 7 Hz), 3.33 (3H, s), 4.42 (2H, d, J = 6 Hz), 4.60 (2H, s), 6.33 (IH, d, J = 4 Hz),, 6.59 (IH, t, J = 6 Hz), 6.75 (IH, d, J = 4 Hz), 7.13 (2H, d, J = 8 Hz), 7.25-7.34 (3H, m), 8.00 (IH, dd, J = 2 Hz), 8.66 (IH, d, J = 2 Hz), 8.75 (IH, d, J = 2 Hz)

Example 26

4-(5-Bromo-3-pyridinyl)-7-ethyl-N-(4-methoxybenzyl)-2-(methoxymethyl)pyrrolo[l,2- b]pyridazine-3-carboxamide

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J = 7 Hz), 3.05 (2H, q, J = 7 Hz), 3.34 (3H, s), 3.80 (3H, s), 4.35 (2H, d, J = 6 Hz), 4.60 (2H, s), 6.33 (IH, d, J = 4 Hz), 6.51 (IH, t, J =

6 Hz), 6.75 (IH, d, J = 4 Hz), 6.82 (2H, d, J = 8 Hz), 7.05 (2H, d, J = 8 Hz), 7.99 (IH, dd, J = 2, 2 Hz), 8.66 (IH, d, J = 2 Hz), 8.75 (IH, d, J = 2 Hz)

Example 27 4-(5-Bromo-3-pyridinyl)-N-(3,4-dimethoxybenzyl)-7-ethyl-2-

(methoxymethyl)pyrrolo [ l,2-b]pyridazine-3 -carboxamide

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J = 7 Hz), 3.05 (2H, q, J = 7 Hz), 3.32 (3H, s), 3.87

(3H, s), 3.88 (3H, s), 4.35 (2H, d, J = 6 Hz), 4.59 (2H, s), 6.33 (IH, d, J = 4 Hz), 6.60 (IH, t, J = 6 Hz), 6.69 (IH, dd, J = 8, 2 Hz), 6.72-6.82 (3H, m), 7.99 (IH, dd, J = 2, 2 Hz), 8.66 (IH, d, J = 2 Hz), 8.72 (IH, d, J = 2 Hz)

Example 28 4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)-N- [4-

(trifluoromethyl)benzyl]pyrrolo[l,2-b]pyridazine-3-carboxamide

¹H-NMR (CDCl₃) δ 1.40 (3H, t, J = 7 Hz), 3.07 (2H, q, J = 7 Hz), 3.37 (3H, s), 4.47 (2H, d, J = 6 Hz), 4.62 (2H, s), 6.34 (IH, d, J = 4 Hz), 6.70 (IH, t, J = 6 Hz), 6.76 (IH, d, J = 4 Hz), 7.25 (2H, d, J = 8 Hz), 7.56 (2H, d, J = 8 Hz), 7.97 (IH, dd, J = 2, 2 Hz), 8.66 (IH, d, J = 2 Hz), 8.73 (IH, d, J = 2 Hz)

MS (m/z) 547 (M+l).

Example 29

4-(5-Bromo-3-pyridinyl)-N-(2,3-dichlorobenzyl)-7-ethyl-2-(methoxymethyl)pyrrolo[l,2- b]pyridazine-3-carboxamide

¹H-NMR (CDCl₃) δ 1.40 (3H, t, J = 7 Hz), 3.05 (2H, q, J = 7 Hz), 3.37 (3H, s), 4.51 (2H, d, J = 6 Hz), 4.63 (2H, s), 6.32 (IH, d, J = 4 Hz), 6.65 (IH, t, J = 6 Hz), 6.75 (IH, d, J = 4 Hz), 7.20-7.25 (2H, m), 7.42 (IH, dd, J = 8, 2 Hz), 7.90 (IH, dd, J = 2, 2 Hz), 8.55 (IH, d, J = 2 Hz), 8.67 (IH, d, J = 2 Hz) MS (m/z) 547 (M+l)

Example 30

4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)-N-(3-pyridinylmethyl)pyrrolo[l,2- b]pyridazine-3-carboxamide ¹H-NMR (CDCl₃) δ 1.38 (3H, t, J = 7 Hz), 3.05 (2H, q, J = 7 Hz), 3.35 (3H, s), 4.42

(2H, d, J = 6 Hz), 4.58 (2H, s), 6.35 (IH, d, J = 4 Hz), 6.72-6.80 (3H, m), 7.50 (IH, d, J = 7 Hz), 7.97-8.02 (IH, m), 8.47-8.50 (IH, m), 8.55 (IH, d, J = 8 Hz), 8.64 (IH, d, J = 2 Hz), 8.76 (IH, d, J = 2 Hz) MS (m/z) 480 (M+l)

Example 31 4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)-N-(4-pyridinylmethyl)pyrrolo[l,2- b]pyridazine-3-carboxamide ¹H-NMR (CDCl₃) δ 1.40 (3H, t, J = 7 Hz), 3.06 (2H, q, J =7 Hz), 3.40 (3H, s), 4.43 (2H, d, J = 6 Hz), 4.64 (2H₅ s), 6.36 (IH, d, J = 4 Hz), 6.72-6.80 (3H, m), 7.06 (2H, d, J = 6 Hz), 7.98 (IH, dd, J = 2, 2 Hz), 8.54 (2H, d, J = 6 Hz), 8.68 (IH, d, J = 2 Hz), 8.76 (IH, d, J = 2 Hz) 5 MS (m/z) 480 (M+l)

Example 32

4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)-N-(2-phenylethyl)pyrrolo[l,2- b]pyridazine-3-carboxamide 0 ¹H-NMR (CDCl₃) δ 1.37 (3H, t, J = 7 Hz), 2.70 (2H, t, J = 6 Hz), 3.05 (2H, q, J = 7 Hz), 3.38 (3H, s), 3.54 (2H, dt, J = 6, 6 Hz), 4.59 (2H, s), 6.28 (IH, t, J = 6 Hz), 6.36 (IH, d, J = 4 Hz), 6.74 (IH, d, J = 4 Hz), 7.08 (2H, d, J = 8 Hz), 7.21-7.31 (3H, m), 8.01 (IH, dd, J = 2, 2 Hz), 8.68 (IH, d, J = 2 Hz), 8.76 (IH, d, J = 2 Hz) MS (m/z) 493 (M+l) 5

Example 33

N-Benzyl-4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[l,2-b]pyridazine-3-carboxamide ¹H-NMR (CDCl₃) δ 1.40 (3H, t, J = 7 Hz), 3.10 (2H, q, J = 7 Hz), 4.16 (2H, d, J = 6 Hz), 5.53 (IH, t, J = 6 Hz), 6.37 (IH, d, J = 4 Hz), 6.72-6.77 (3H, m), 7.16-7.20 O (3H, m), 7.37-7.52 (6H, m), 7.60 (IH, s), 7.71-7.77 (2H, m)

Example 34

4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)-N-(3-methylphenyl)pyrrolo[l,2- b]pyridazine-3-carboxamide 5 ¹H-NMR (CDCl₃) δ 1.41 (3H, t, J = 7 Hz), 2.34 (3H, s), 3.10 (2H, q, J = 7 Hz), 3.53 (3H, s), 4.71 (2H, s), 6.41 (IH, d, J = 4 Hz), 6.30 (IH, d, J = 4 Hz), 6.95 (IH, d, J = 8 Hz), 7.20 (2H, d, J = 8 Hz), 8.08 (IH, br s), 8.45 (IH, br s), 8.72 (IH, br s), 8.75 (IH, br s)

0 Example 35

N-Benzyl-4-(3-chlorophenyl)-7-ethyl-2-(3-furyl)pyrrolo[l,2-b]pyridazine-3-carboxamide ¹H-NMR (CDCl₃) δ 1.40 (3H, t, J = 7 Hz), 3.09 (2H, q, J = 7 Hz), 4.30 (2H, d, J = 6 Hz), 5.70 (IH, t, J = 6 Hz), 6.33 (IH, d, J = 4 Hz), 6.72 (IH, d, J = 4 Hz), 6.76- 6.81 (2H, m), 6.96 (IH, d, J = 2 Hz), 7.16-7.25 (3H, m), 7.40 (IH, d, J = 8 Hz), , 7.45-7.50 (3H, m), 7.60 (IH, s), 7.95 (IH, s)

Example 36

4-(Bicyclo[2.2.1]hept-2-ylmethyl)-7-ethyl-N-(4-methoxybenzyl)-2- (methoxymethyl)pyrrolo[l,2-b]pyridazme-3-carboxamide

¹H-NMR (CDCl₃) δ 0.80-1.41 (HH, πi), 1.82-1.96 (2H, m), 2.17-2.23 (IH, m), 2.84- 2.92 (2H, m), 3.00 (2H, q, J = 7 Hz), 3.28 (3H, s), 3.81 (3H, s), 4.49 (2H, s), 4.52 (IH, d, J = 7 Hz), 4.61 (IH, d, J = 7 Hz), 6.61 (IH, d, J = 4 Hz), 6.68 (IH, d, J = 4

Hz), 6.84 (IH, br s), 6.90 (2H, d, J = 8 Hz), 7.34 (2H, d, J = 8 Hz)

Example 37

4-(5-Bromo-3-pyridinyl)-7-ethyl-N-(4-methoxybenzyl)-2-(methoxymethyl)-N- methylpyrrolo[l,2-b]pyridazine-3¹-carboxamide major isomer

¹H-NMR (CDCl₃) δ 1.38 (3H, t, J = 7 Hz), 2.50 (3H, s), 3.05 (2H, q, J = 7 Hz), 3.36 (3H, s), 3.80 (3H, s), 4.27 (IH, d, J = 14 Hz), 4.40 (IH, d, J = 11 Hz), 4.60 (IH, d, . J = 14 Hz), 4.86 (IH, d, J = 11 Hz), 6.32 (IH, d, J = 4 Hz), 6.72 (IH, d, J = 4 Hz), 6.79 (2H, d, J = 8 Hz), 6.95 (IH, d, J = 8 Hz), 8.07 (IH, dd, J = 2 Hz), 8.75 (IH, d,

J = 2, 2 Hz), 8.77 (IH, d, J = 2 Hz) minor isomer

¹H-NMR (CDCl₃) δ 1.38 (3H, t, J = 7 Hz), 2.74 (3H, s), 3.05 (2H, q, J = 7 Hz), 3.45

(3H, s), 3.77 (3H, s), 4.25 (IH, d, J = 14 Hz), 4.42 (IH, d, J = 11 Hz), 4.50 (IH, d, J = 14 Hz), 4.90 (IH, d, J = 11 Hz), 6.40 (IH, d, J = 4 Hz), 6.64-6.82 (5H, m), 8.05

(IH, dd, J = 2, 2 Hz), 8.82 (IH, d, J = 2 Hz), 8.84 (IH, d, J = 2 Hz)

Example 38

4-(5-Bromo-3-pyridmyl)-2-[(cyclohexyloxy)methyl]-7-ethyl-N-(4- methoxybenzyl)pyrrolo[l,2-b]pyridazine-3-carboxamide

¹H-NMR (CDCl₃) δ 0.86-1.76 (13H, m), 2.85 (2H, q, J = 7 Hz), 3.34-3.46 (IH, m), 3.80 (3H, s), 3.90 (2H, s), 4.44 (2H, d, J = 6 Hz), 6.25 (IH, d, J = 4 Hz), 6.64 (IH, d, J = 4 Hz), 6.86-6.95 (3H, m), 7.24 (2H, d, J = 8 Hz), 8.12 (IH, dd, J = 2, 2 Hz), 8.76 (IH, d, J = 2 Hz), 8.81 (IH, d, J = 2 Hz)

Example 39

To a solution of 7-ethyl-N-(4-methoxybenzyl)-2-methyl-4-(4- piperidinylmethyl)pyrrolo[l,2-b]pyridazine-3-carboxamide (20.0 mg) and acetic anhydride (7.28 mg) in dichloromethane (1 mL) was added 4-(dimethylamino)pyridine (1.16 mg). The mixture was stirred for 5 h at room temperature. The mixture was partitioned between CHC13 and 1 N HCl. The organic layer was washed with water, satd. NaHCO₃, and brine, dried over MgSO₄, and evaporated. Preparative thin layer silica gel chromatography (CHCB-MeOH = 15-1) afforded 4-[(l-acetyl-4-piperidinyl)methyl]-7- ethyl-N-(4-methoxybenzyl)-2-methylpyrrolo[l,2-b]pyridazine-3-carboxamideas an yellow foam (19.0 mg).

¹H-NMR (CDCl₃) δ 1.10 (2H ,m), 1.34 (3H, t, J = 7.5 Hz), 1.53 (2H, m), 1.97 (IH, m), 2.41 (IH, m), 2.45 (3H, s), 21.62 (2H, m), 2.68 (2H, m), 2.85 (IH, m), 2.96 (2H, q, J = 7.5 Hz), 3.67 (IH ,M), 3.81 (IH ,s), 4.53-4.56 (3H, m), 5.96 (IH, m), 6.46 (IH, d, J = 4.4 Hz), 6.59 (IH, d, J = 4.3 Hz), 6.89 (2H, d, J = 8.8 Hz), 7.30 (2H ,d, J = 8.8 Hz) _. :

ESI (m/z): 463 (M+H)

Example 40

To a solution of 4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyi)-N-4- piperidinylpyrrolo[l,2-b]pyridazine-3-carboxamide (20.0 mg), cyclopropylacetic acid (4.74 mg), and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (10.6 mg) in N,N- dimethylformamide (1 mL) was added 4-(dimethylamino)pyridine (1.03 mg). The mixture was stirred for 4 h at room temperature. The mixture was partitioned between EtOAc and 1 N HCl. The organic layer was washed with water (two times) satd. NaHCO₃ and brine, dried over MgSO₄, and evaporated. Preparative thin layer silica gel column chromatography(CHC13-MeOH = 10-1) afforded 4-(5-bromo-3-pyridinyl)-N-[l- (cyclopropylcarbonyl)-4-piperidinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[l,2- b]pyridazine-3-carboxamide as an yellow gum (9.5 mg).

¹H-NMR (CDCl₃) δ 0.16 (2H, m), 0.56 (2H, m), 1.02 (IH, m), 1.20 (2H, m), 1.38 (3H ,t, J = 7.5 Hz), 1.85 (2H, m), 2.25 (2H, d, J = 6.7 Hz), 2.75 (2H, m), 3.06 (2H, q, J = 7.5 Hz), 3.13 (IH, m), 3.46 (3H ,s), 3.74 (IH, m), 4.01 (IH, m), 4.48 (IH, m), 4.61 (IH, d,J = 11.0 Hz), 4.66 (IH, d, J = 11.0 Hz), 6.32 (IH, d, br, J = 7.7 Hz), 6.38 (IH, d, J = 4.3 Hz), 6.77 (IH, d, J = 4.4 Hz), 8.01 (IH, m), 8.67 (IH, m), 8.77 (IH, m)

The following compound(s) was(were) obtained in a similar manner to that of

Example 40. Example 41

4-(5-Bromo-3-pyridinyl)-N-{[l-(cyclopropylcarbonyl)-4-piperidinyl]methyl}-7-ethyl-2- (methoxymethyl)pyrrolo[l,2-b]pyridazine-3-carboxamide ¹H-NMR (CDCl₃) δ 0.17 (2H, m), 0.55 (2H, m), 0.94-1.07 (3H, m), 1.38 (3H, t, J = 7.5 Hz), 1.48 (IH, m), 2.25 (2H, d, J = 6.7 Hz), 2.49 (2H, m), 2.94 (2H, m), 3.02- 3.10 (3H, m), 3.19 (IH, m), 3.46 (3H, s), 3.80 (2H, m), 4.61 (2H, m), 6,64 (2H, s), 8.33 (IH, m), 8.35 (IH, d, J = 4.4 Hz), 8.76 (IH, d, J = 4.4 Hz), 8.02 (IH, m), 8.70 (IH, m), 8.76 (IH, m)

Example 42

To a solution of 4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)-N-4- piperidinylpyrrolo[l,2-b]pyridazine-3-carboxamide (20.0 mg) in dichloromethane (1 mL) was added methanesulfonyl chloride (6.3 mg) followed by pyridine (5.02 mg) in an ice bath under a nitrogen atmosphere. After stirring for 4 h at room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with satd. NaHCO₃ and brine, dried over MgSO₄, and evaporated. Preparative thin layer silica gel column chromatography(CHC13-MeOH = 10-1) afforded 4-(5-bromo-3-pyridinyl)-7- ethyl-2-(methoxymethyl)-N-[l-(methylsulfonyl)-4-piperidinyl]pyrrolo[l,2-b]pyridazine- 3-carboxamide as an yellow solid (9.5 mg).

¹H-NMR (CDCl₃ + CD₃OD) δ 2.38 (5H, m), 1.83 (2H, m), 2.74-2.73 (2H, m), 2.78 (3H, s), 3.06 (2H, q, J = 7.5 Hz), 3.46 (3H, s), 3.17 (2H, m), 3.88 (IH, m), 4.65 (2H, m), 6.37 (IH ,d, J = 4.4 Hz), 6.78 (IH, d, J = 4.4 Hz), 6.93 (IH, br), 8.05 (IH, m), 8.68 (IH, m), 8.77 (IH, m)

The following compound(s) was(were) obtained in a similar manner to that of Example 42. Example 43 4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)-N-{[l-(methylsulfonyl)-4- piperidinyl]methyl}pyrrolo[l,2-b]pyridazine-3-carboxamide

¹H-NMR (CDCl₃) δ 1.22 (2H, m), 1.38 (3H, t, J = 7.5 Hz), 1.53 (IH, m), 2.60 (2H, m),

2.78 (3H, s), 3.06 (2H, m), 3.16 (2H, m), 3.46 (3H, s), 3.76 (2H, m), 4.64 (2H, s), 6.33 (IH, m), 6.34 (IH, d, J = 4.4 Hz), 6.76 (IH, d, J = 4.4 Hz), 8.02 (IH, m), 8.69

(IH, m), 8.77 (IH, m)

Example 44

A solution of tert-butyl 4-[(7-ethyl-3-{[(4-methoxybenzyl)amino]carbonyl}-2- methylpyrrolo[l,2-b]pyridazin-4-yl)methyl]-l-piperidinecarboxylate (130 mg) in trifluoroacetic acid (1 mL) was stirred for 1 h at room temperature. The volatile was evaporated in vacuo. The residue was partitioned between EtOAc and satd. NaHCO₃. The organic layer was washed with satd. NaHCO₃ and brine, dried over MgSO₄, and evaporated to give 7-ethyl-N-(4-methoxybenzyl)-2-methyl-4-(4- piperidinylmethyl)pyrrolo[l,2-b]pyridazine-3-carboxamideas a pale yellow foam (97.8 mg).

¹H-NMR (CDCl₃) δ 1.27 (2H, m), 1.34 (3H, t, J = 7.5 Hz), 1.60 (2H, m), 1.91 (IH, m), 2.45 (3H, s), 2.54 (2H, m), 2.67 (2H, d, J = 7.3 Hz), 2.96 (2H, q, J = 7.5 Hz), 3.09 (2H, m), 3.81 (3H, s), 4.55 (2H, d, J = 5.9 Hz), 5.91 (IH, br), 6.48 (IH, d, J = 4.3 Hz), 6.59 (IH ,d, J = 4.4 Hz), 6.91 (2H, d, J = 8.5 Hz), 7.31 (2H, d, J = 8.4 Hz)

The following compound(s) was(were) obtained in a similar manner to that of Preparation 30. Example 45 4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)-N-4-piperidinylpyrrolo[l,2- b]pyridazine-3-carboxamide

¹H-NMR (CDCl₃) δ 1.25-1.34 (2H, m), 1.37 (3H, t, J = 7.5 Hz), 1.80-2.04 (2H, m), 2.70 (2H, m), 3.02-3.10 (4H, m), 3.47 (3H, m), 3.91 (IH, m), 4.64 (2H, s), 6.27 (IH, d, br, J = 7.7 Hz), 6.36 (IH, d, J = 4.4 Hz), 6.76 (IH, d, J = 4.4 Hz), 8.02 (IH, t, J = 2.0 Hz), 8.68 (IH, d ,J = 1.9 Hz), 8.76 (IH, d, J = 2.1 Hz)

ESI (m/z): 944 and 946 (2M+H)

Example 46 4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)-N-(4-piperidinylmethyl)pyrrolo[l,2- b]pyridazine-3-carboxamide

¹H-NMR (CDCl₃) δ 0.99 (2H, m), 1.31 (5H, m), 2.50 (3H ,s), 2.86 (2H, m), 299 (2H, q, J = 7.5 Hz), 3.07 (2H, m), 3.30 (3H, s), 4.55 (2H, s), 6.31 (IH, d, J = 4.4 Hz), 6.82 (IH, d, J = 4.3 Hz), 8.13 (IH, m), 8.30 (IH, br), 8.64 (IH, m), 8.85 (IH, m).

ESI (m/z): 487 (M+H)

Example 47

To a solution of methyl 4-[({[4-(5-bromo-3-pyridinyl)-7-ethyl-2- (methoxymethyl)pyrrolo[l,2-b]pyridazm-3-yl]carbonyl}amino)methyl]benzoate (22.0 mg) in mathanol-tetrahydrofuran (1-1, 1 mL) was added 1 N NaOH (0.15 niL) at 40°C. The mixture was stirred for 1 h at 60°C. The reaction was quenched by adding 1 N HCl to afford 4-[({[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[l,2- b]pyridazin-3-yl]carbonyl}amino)methyl]benzoic acid as yellow crystals. The crystals were collected by filtration, washed with water, and dried in the air (21.6 mg).

¹H-NMR (CDCl₃) δ 1.32 (3H, t, J = 7.5 Hz), 3.00 (2H ,q, J = 7.5 Hz), 3.29 (3H, s), 4.27 (2H, d, J = 6.0 Hz), 4.58 (2H ,s), 6.30 (IH, d, J = 4.4 Hz), 6.82 (IH, d, J = 4.3 Hz), 7.00 (2H, d, J = 8.2 Hz), 7.78 (2H, d, J = 8.0 Hz), 8.09 (IH, m), 8.61 (IH, m), 8.75 (IH ,t, br, J = 6.1 Hz), 8.81 (IH, m)

The following compound(s) was(were) obtained in a similar manner to that of Example 47. Example 48

({[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[l,2-b]pyridazin-3- yl]carbonyl}amino)(phenyl)acetic acid

¹H-NMR (CDCl₃) δ 2.15 (3H, t, J = 7.5 Hz), 3.82 (2H, q, J = 7.5 Hz), 4.01 (3H, s), 5.35 (IH, d, J = 10.8 Hz), 5.44 (IH ,d, J = 108 Hz), 6.28 (IH, s), 7.11 (IH, m), 7.54 (IH, m), 8.04-8.13 (5H, m), 8.81 (IH, m), 9.43 (2H, m)

Example 49

To a solution of N-benzyl-4-(5-bromo-3-pyridinyl)-7-ethyl-2- (methoxymethyl)pyrrolo[l,2-b]pyridazine-3-carboxamide (26 mg) in 1,4-dioxane (1.2 mL) and water (0.3mL) was added trimethylboroxine (6.81 mg), tetrakis(triphenylphosphine) palladium (12.5 mg) and K2CO₃ (37.5 mg) at room temperature. Then the mixture was stirred at 110 "C for 8 hours. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous MgSO₄, and evaporated in vacuo. The residue was purified by preparative thin layer silica gel chromatography (eluent; hexne-EtOAc = 1-1) to give N- benzyl-7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[l,2-b]pyridazine-3- carboxamide as yellow crystals (12 mg).

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J = 7 Hz), 2.35 (3H, s), 3.05 (2H, q, J = 7 Hz), 3.35

(3H, s), 4.37 (2H, d, J = 6 Hz), 4.64 (2H, s), 6.27 (IH, t, J = 6 Hz), 6.33 (IH, d, J = 4 Hz), 6.72 (IH, d, J = 4 Hz), 7.02-7.06 (2H, m), 7.23-7.28 (3H, m), 7.64 (IH, br s), 8.52 (IH, d, J = 2 Hz), 8.57 (IH, d, J = 2 Hz) MS (m/z) 415 (M+l)

The following compound(s) was(were) obtained in a similar manner to that of Example 49. Example 50

N-Benzyl-4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[l,2- b]pyridazine-3-carboxamide

¹H-NMR (CDCl₃) δ 0.70-0.76 (2H, m), 1.04-1.10 (2H, m), 1.37 (3H, t, J = 7 Hz), 1.89-1.96 (IH, m), 3.05 (2H, q, J = 7 Hz), 3.33 (3H, s), 4.46 (2H, d, J = 6 Hz)^

4.63 (2H, s), 6.14-6.21 (IH, m), 6.34 (IH, d, J = 4 Hz), 6.72 (IH, d, J = 4 Hz), 7.00-7.05 (2H, m)i 7.23-7.31 (3H, m), 7.44 (IH, dd, J = 2, 2 Hz), 8.51 (IH, d, J = 2 Hz), 8.56 (IH, d, J = 2 Hz)

The following compound(s) was(were) obtained in a similar manner to that of

Example 1. Example 51 tert-Butyl 4-({[4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[l,2-b]pyridazin-3- yl] carbonyl} amino)- 1 -piperidinecarboxylate ¹H-NMR (CDCl₃) δ 1.21 (2H, m), 1.39 (3H, t, J = 7.5 Hz), 1.44 (9H, s), 1.75 (2H, m), 2.81 (2H, m), 3.07 (2H, q, J = 7.5 Hz), 3.88-3.99 (3H, m), 5.02 (IH, d, br, J = 8.1 Hz), 6.41 (IH, d, J = 4.4 Hz), 6.80 (IH, d, J = 4.4 Hz), 8.01 (IH, m), 8.43 (IH, s),

8.70 (IH, d, J = 1.9 Hz), 8.84 (IH, d, J = 2.1 Hz) Example 52 tert-Butyl 4-[({[7-gthyl-2-methyl-4-(tetrahydro-2H-pyran-4-ylmethyl)pyrrolo[l,2- b]pyridazin-3-yl]carbonyl}amino)methyl]-l-piperidinecarboxylate ¹H-NMR (CDCl₃) δ 1.23 (2H, m), 1.36-1.58 (17H, m), 1.75 (2H, m), 2.07 (IH, m), 2.47 (3H, s), 2.68-2.77 (4H, m), 2.98 (2H, q, J = 7.5 Hz), 3.30 (2H, m), 3.36 (2H, m), 3.91 (2H₅ m), 4.14 (2H, m), 5.74 (IH, m), 6.51 (IH, d, J = 4.3 Hz), 6.61 (IH, d, J = 4.3 Hz)

Example 53 tert-Butyl 4-({ [7-ethyl-2-methyl-4-(tetrahydro-2H-pyran-4-ylmethyl)pyrrolo[l,2- b]pyridazin-3-yl] carbonyl} amino)- 1 -piperidinecarboxylate

¹H-NMR (CDCl₃) δ 1.35 (3H, t, J = 7.5 Hz), 1.75-1.45 (4H ,m), 1.47 (9H, s), 1.56

(2H ,m), 2.04-2.08 (3H, m), 2.47 (3H, s), 2.73 (2H, d, J = 7.2 Hz), 2.92 (2H, m), 2.97 (2H, q, J = 7.5 Hz), 3.30 (2H, m), 3.92 (2H ,m), 4.07-4.19 (3H ,m), 5.56 (IH, d, br, J = 8 Hz), 6.52 (IH, d, J = 4.3 Hz), 6.61 (IH, d, J = 4.3 Hz)

Example 54

4-(5-Bromo-3-pyridinyl)-7-ethyl-N-(4-methylbenzyl)pyrrolo[l,2-b]pyridazine-3- carboxamide

¹H-NMR (CDCl₃) δ 1.39 (3H, t, J = 7.5 Hz), 2.34 (3H, s), 3.06 (2H, q, J = 7.5 Hz), 4.36 (2H, d, J = 5.4 Hz), 5.42 (IH, m), 6.35 (IH, d, J = 4.4 Hz), 6.78 (IH, d, J = 4.4 Hz), 6.92 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz), 7.95 (IH, m), 8.46 (IH, s), 8.64 (IH, m), 8.73 (IH, m)

Claims

C LA I M S

1. A compound of the formula:

in which

R¹ Is (1) hydrogen,

(2) carboxy or protected carboxy,

(3) -CONR⁶R⁷,

(4) hydroxy or lower alkoxy, (5) amino, cyclo(lower)alkylamino or mono- or di(lower)alkylamino optionally substituted by lower alkoxy,

(6) trihalo(lower)alkyl,

(7) trihalo(lower)alkylsulfonyloxy or arylsulfonylamino,

(8) substituted or unsubstituted lower alkyl, (9) substituted or unsubstituted aryl,

(10) substituted or unsubstituted heteroaryl, or

(11) substituted or unsubstituted heterocyclyl, R² is -(CH₂)_q- Y- R⁸

[wherein q is O, 1, 2 or 3,

Y is bond, -O- or -CH(R⁹)- (wherein R⁹ is carboxy or protected carboxy), and R⁸ is (1) substituted or unsubstituted aryl, (2) substituted or unsubstituted heteroaryl, (3) substituted or unsubstituted heterocyclyl, or (4) substituted or unsubstituted cyclo(lower)alkyl, R³ is hydrogen or lower alkyl, or alternatively R and R , together with the nitrogen atom to which they are attached, represent substituted or unsubstituted azaheterocyclyl group],

R⁴ is (1) substituted or unsubstituted aryl, (2) substituted or unsubstituted heteroaryl, or

(3) lower alkyl substituted by (a) substituted or unsubstituted cyclo(lower)alkyl, or (b) substituted or unsubstituted heterocyclyl,

R⁵ is lower alkyl, and R⁶ and R⁷ each independently represents hydrogen, lower alkylsulfonyl, heteroaryl or lower alkyl optionally substituted by hydroxy, alkoxy, sulfo, carboxy or protected carboxy, or alternatively R⁶ and R⁷ together with the nitrogen atom to which they are attached, represent substituted or unsubstituted azaheterocyclyl, or a pharmaceutically acceptable salt thereof, or prodrug thereof.

2. The compound of claim 1, wherein

R¹ is (1) lower alkyl optionally substituted by (i) cyclo(lower)alkyloxy or (ii) lower alkoxy optionally substituted by cyclo(lower)alkyl or aryl, (2) aryl,

(3) a radical of aromatic monocyclic ring system comprising 5 or 6 ring atoms and containing one to three heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by lower alkyl or lower alkoxy, or (4) a radical of saturated monocyclic ring system comprising 5 or 6 ring atoms and containing one to three heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulfur, R² is -(CH₂)_q- Y- ^R8 [wherein q is 0, 1 or 2,

Y is bond, -O- or -CH(R⁹)- (wherein R⁹ is carboxy or protected carboxy), and R⁸ is (1) aryl optionally substituted by at least one substituent selected from the group consisting of halogen, lower alkyl, trihalo(lower)alkyl, lower alkoxy, carboxy, protected carboxy, cyano, CONR¹⁰R¹¹, and SO₂NR¹⁰R¹¹ [in which R¹⁰ and R¹¹ represent each independently hydrogen or lower alkyl], (2) a radical of aromatic monocyclic ring system comprising 5 or 6 ring atoms and containing one to three heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by at least one substituent selected from the group consisting of halogen, lower alkoxy, cyano, carboxy, protected carboxy and CONR¹⁰R¹¹ [in which R¹⁰ and R¹¹ represent each independently hydrogen or lower alkyl], (3) a radical of saturated monocyclic ring system comprising 5 or 6 ring atoms and containing one to three heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by lower alkyl, aryl, acyl, lower alkylsulfonyl or protected carboxy, or (4) cyclo(lower)alkyl], R³ is hydrogen or lower alkyl, or alternatively R² and R³, together with the nitrogen atom to which they are attached, represent saturated monocyclic ring system comprising 5 or 6 ring atoms and containing at least one nitrogen atom optionally substituted by lower alkyl, aryl or acyl, R⁴ is (1) aryl optionally substituted by halogen, cyano or carbamoyl,

(2) a radical of aromatic monocyclic ring system comprising 5 or 6 ring atoms and containing one to three heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, lower alkyl, lower alkenyl, cyclo(lower)alkyl or acyl, or

(3) lower alkyl substituted by (a) cyclo(lower)alkyl, or (b) a radical of saturated monocyclic ring system comprising 5 or 6 ring atoms and containing one to three heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by acyl or protected carboxy,

R⁵ is lower alkyl.

3. The compound of claim 1, wherein

R¹ is (1) lower alkyl optionally substituted by (i) cyclo(lower)alkyloxy or (ii) lower alkoxy,

(2) phenyl,

(3) heteroaryl optionally substituted by lower alkyl or lower alkoxy, said heteroaryl is selected from furanyl, oxazolyl, isooxazolyl, thiophenyl and thiazolyl, or (4) pyrrolidinyl or morpholyl,

R² is -(CH₂)_q-Y- R⁸ [wherein q is 0, 1 or 2, Y is bond, -O- or -CH(R⁹)- (wherein R⁹ is carboxy or protected carboxy), and R⁸ is (1) aryl optionally substituted by at least one substituent selected from the group consisting of halogen, lower alkyl, trihalo(lower)alkyl, lower alkoxy, carboxy, protected carboxy and sulfamoyl, said aryl is selected from phenyl or indanyl, (2) pyridinyl, (3) piperidinyl optionally substituted by acyl, lower alkylsulfonyl or protected carboxy, or (4) cyclo(lower)alkyl], R is hydrogen or lower alkyl, or alternatively R² and R³, together with the nitrogen atom to which they are attached, represent piperidinyl optionally substituted by lower alkyl, phenyl or acyl, R⁴ is (1) phenyl optionally substituted by halogen, cyano or carbamoyl,

(2) pyridinyl optionally substituted by halogen, lower alkyl or cyclo(lower)alkyl,

(3) heterocyclyl optionally substituted by protected carboxy, said heterocyclyl is selected from piperidinyl or tetrahydropyranyl, or

(4) lower alkyl substituted by (a) cyclo(lower)alkyl, or (b) piperidinyl optionally substituted by acyl,

R⁵ is ethyl.

4. A pharmaceutical composition which comprises, as an active ingredient, a compound of Claim 1 in admixture with pharmaceutically acceptable carriers.

5. A pharmaceutical composition of claim 4, for inhibiting phosphodiesterase IV (PDE- IV) enzyme activity and/or inhibiting the production of tumor necrosis factor (TNF).

6. A pharmaceutical composition of claim 4, for prevention or treatment of diseases for which therapy by a PDE-IV inhibitor or TNF produxtion inhibitor is relevant.

7. A pharmaceutical composition of claim 4, for prevention or treatment of asthma, chronic obstructive pulmonary disease (COPD), fibrotic disease, acute and fulminant hepatitis, hepatic steatosis (alcoholic or non-alcoholic steatohepatitis), chronic (viral or non- viral) hepatitis, hepatic cirrhosis, autoimmune hepatitis, autoimmune inflammatory bowel disease, atopic dermatitis, Alzheimer's diseases, viral infection and depression.

8. A method of prevention or treatment of diseases for which therapy by a PDE-IV inhibitor or TNF synthesis inhibitor is relevant, comprising the step of administering an effective amount of the compound of claim 1.

9. A method of prevention or treatment of asthma, chronic obstructive pulmonary disease (COPD), fibrotic disease, acute and fulminant hepatitis, hepatic steatosis

(alcoholic or non-alcoholic steatohepatitis), chronic (viral or non-viral) hepatitis, hepatic cirrhosis, autoimmune hepatitis, autoimmune inflammatory bowel disease, atopic dermatitis, Alzheimer's diseases, viral infection or depression, comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound of claim 1.

10. A use of a compound of claim 1 in the manufacture of a medicament for prevention or treatment of diseases for which therapy by a PDE-IV inhibitor or TNF synthesis inhibitor is relevant.