AU2003294183B2

AU2003294183B2 - Pyrrolopyridazine derivatives

Info

Publication number: AU2003294183B2
Application number: AU2003294183A
Authority: AU
Inventors: Yoshito Abe; Kenichiro Imamura; Makoto Inoue; Tsuyoshi Mizutani; Kazuhiko Ohne; Mitsuaki Okumura; Kozo Sawada; Yuki Sawada
Original assignee: Astellas Pharma Inc
Current assignee: Astellas Pharma Inc
Priority date: 2003-01-09
Filing date: 2003-12-26
Publication date: 2009-06-18
Anticipated expiration: 2023-12-26
Also published as: AU2003294183A1

Description

WO 2004/063197 PCT/JP2003/017091 DESCRIPTION PYRROLOPYRIDAZINE DERIVATIVES 5 TECHNICAL FIELD This invention relates to new pyrrolopyridazine derivatives and pharmaceutically acceptable salts thereof which inhibit enzymatic activity of phosphodiesterase IV (PDE IV) and production of tumor necrosis factor-a (TNF-a). 10 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 cellar responses. The first messenger stimulates the enzyme responsible for synthesis of cAMP, 15 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 phosphosiesterase-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 20 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 25 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, W003/018579, W003/000679 and the like. However, there remains a need for novel compounds that inhibit PDE-IV with 30 minimal side effects. Although some pyrrolopyridazine derivatives having the inhibitory activity of hydroxymethylglutaryl (HMG) CoA reductase have been known, for example, in W091/18903, pyrrolopyridazine derivatives having the inhibitory activity of PDE-IV have not been known. 1 P\WPDOCS\Di\SPEC1 DHT\12569331 Astellas AU 1i SOPAdoc-2005/2009 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-a (TNF-a), a serum glycoprotein. Accordingly, this invention seeks 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). This invention further seeks to provide processes for preparation of the pyrrolopyridazine derivatives and salts thereof. This invention also seeks to provide a pharmaceutical composition comprising said pyrrolopyridazine derivatives or a pharmaceutically acceptable salt thereof. This invention still further seeks 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 invention subject of this application is set out in the claims that follow. These and other aspects and embodiments are described below. Pyrrolopyridazine derivatives can be represented by the following general formula (I):

R

1 R2 N I I (I)

R

4

R

3 in which R' is (1) carboxy or protected carboxy, (2) -CONR 5 R , (3) hydroxy or lower alkoxy, 2 WO 2004/063197 PCT/JP2003/017091 (4) amino, cyclo(lower)alkylamino or mono- or di(lower)alkylamino optionally substituted by lower alkoxy, (5) trihalo(lower)alkyl, (6) trihalo(lower)alkylsulfonyloxy or arylsulfonylamino, 5 (7) substituted or unsubstituted lower alkyl, (8) substituted or unsubstituted aryl, or (9) substituted or unsubstituted heterocyclic group,

R

2 is R 7 or -(A')p-X-A 2

-R

7 , wherein 10 p is integer of 0 or 1; A' is (C-C 2 )alkylene or -CH=CH-;

A

2 is -(CH 2 )n- or -(CH=CH)m- [wherein n is integer which may range from 1 to 6 and m is integer which may range from 1 to 3]; X is single bond, -0-, -NR 8 -, -C(=0)-, -C(=NR 9 )- or hydroxy(C-C 2 )alkylene 15 (wherein R8 is hydrogen or lower alkyl, and R 9 is substituted or unsubstituted N containing heterocyclic group]; and

R

7 is (1) hydrogen, (2) substituted or unsubstituted aryl, 20 (3) substituted or unsubstituted heterocyclic group, (4) carboxy, protected carboxy or CONR' R1, (5) acyl or halocarbonyl, (6) cyano, (7) amino, protected amino, or mono- or di(lower)alkylamino, 25 (8) hydroxy, aryloxy, acyloxy or lower alkoxy optionally substituted by hydroxy or acyloxy, (9) lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl, or (10) -0-R, or 30 R' and R 2 are combined together to form lower alkylene or lower alkenylen group, which is optionally interrupted by amino or sulfonyl and optionally fuse with benzene ring, and also is optionally substituted by the group consisting of lower alkyl, hydroxy, oxo and lower alkoxy, 3 P:\WPDOCS\DHT\SPECI DHT12569331 AsII AU Is SOPAdoc-20/05/2009

R

3 is substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group,

R

4 is hydrogen, halogen, cyano, carbamoyl, acyl, thiocyanate, lower alkylthio, lower alkenyl, hydroxyl(lower)alkyl, trihalo(lower)alkyl or lower alkyl,

R

5 , R 6 , R' 0 and R" each independently represents hydrogen, lower alkylsulfonyl, heterocyclic group or lower alkyl optionally substituted by hydroxy, alkoxy, sulfo, carboxy, protected carboxy or -R or alternatively R and R or R' and R", together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group, and R1 2 and R 17 are each independently a group derived from protected or unprotected sugar by removal of the hydroxy group therefrom, or a pharmaceutically acceptable salt thereof, or prodrug thereof. Suitable pharmaceutically acceptable salts of 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 compound (I) having a chemically or metabolically degradable group, which became pharmaceutically active after chemo- or biotransformation. Preferred embodiments of compound (I) are as follows. RI R2 I I ( I) N R 3 4 WO 2004/063197 PCT/JP2003/017091 in which R' is (1) carboxy or esterified carboxy (more preferably, ethoxycarbonyl), (2) -CONR R 6 [wherein R 5 and R 6 each independently represents lower alkyl, or alternatively R 5 and R 6 , together with nitrogen atom to which 5 they are attached represents saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s).] (more preferably, dimethylcarbamoyl or 1-pyrrolidinylcarbonyl), (3) hydroxy or lower alkoxy, (4) amino, cyclo(lower)alkylamino, or mono- or di(lower)alkylamino 10 optionally substituted by lower alkoxy, (5) trihalo(lower)alkyl, (6) trihalo(lower)alkylsulfonyloxy or arylsulfonylamino, (7) lower alkyl optionally substituted by (i) halogen; (ii) carboxy; (iii) protected carboxy; (iv) cyano; (v) carbamoyl; (vi) -OCONR1 5 R1 6 15 [wherein R1 5 and R1 6 each independently represents hydrogen, aryl or 15 16 lower alkyl optionally substituted by aryl, or R and R , together with the nitrogen atom to which they are attached, represents saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom.] (more 20 preferably, dimethylcarbamoyloxy, methyl-phenylcarbamoyloxy, morpholinylcarbonyloxy or pyrrolidinylcarnbonyloxy); (vii) lower alkylthio; (viii) lower alkylsulfonyl; (ix) lower alkylsulfonyloxy; (x) lower alkylsulfonylamino; (xi) mono- or di(lower)alkylamino optionally substituted by hydroxy, lower alkoxy, aryloxy, or 25 substituted or unsubstituted aryl; (xii) amino; (xiii) acylamino (more preferably, lower alkanoylamino such as acetylamino, aroylamino such as benzoylamino, or heterocycliccarbonylamino such as pyrazinylcarbonylamino); (xiv) protected amino such as phthalimide, benzylamino or lower alkoxycarbonylamino; (xv) hydorxy; (xvi) 30 acyloxy (more preferably, lower alkanoyloxy such as acetyloxy); (xvii) cyclo(lower)alkyloxy; (xviii) aryloxy; (xix) substituted or unsubstituted aryl (more preferably, phenyl); (xx) saturated or unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 5 WO 2004/063197 PCT/JP2003/017091 3 nitrogen atom(s) and also optionally containing oxygen atom or sulfur atom (more preferably, piperazinyl, morpholinyl, oxazolidinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or triazolyl) optionally substituted by lower alkyl, hydroxy(lower)alkyl, aryl or oxo; or (xxi) 5 lower alkoxy optionally substituted by carboxy, protected carboxy, hydroxy, protected hydroxy, lower alkoxy, cyclo(lower)alkyl, substituted or unsubstituted aryl (more preferably, phenyl optionally substituted by cyano, carboxy, protected carboxy or carbamoyl), saturated or unsaturated 5- or 6-membered heteromonocyclic group 10 containing 1 to 2 nitrogen atom(s) (more preferably, pyridinyl, pyrazinyl or piperazinyl) optionally substituted by lower alkyl, or CONR"R1 4 [wherein R1 3 and R1 4 each independently represents hydrogen or lower alkyl optionally substituted by aryl, or R' and R' 4 , together with the nitrogen atom to which they are attached, represents 15 saturated 5- or 6-membered heteromonocyclic group containing I to 2 nitrogen atom(s) and also optionally containing oxygen atom.] (more preferably, carbamoyl, methylcarbamoyl, benzylcarbamoyl or morpholinylcarbonyl), (8) aryl (more preferably, phenyl) optionally substituted by the 20 substituent(s) selected from the group consisting of halogen, or (9) saturated or unsaturated 5- or 6-membered heteromonocyclic group (more preferably, pyrrolidinyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, furanyl, thienyl, pyridinyl) optionally substituted by lower alkyl or halogen, 25 R 2 is R 7 or -(A')p-X-A-R' wherein p is 0 or 1, A' is (CI-C 2 )alkylene or -CH=CH-; A2 is -(CH 2 )n- or -(CH=CH)m- [wherein n is integer which may range from 1 30 to 6 and m is integer which may range from 1 to 3]; X is single bond, -0-, -NR"-, -C(=0)-, -C(=NR 9 )- or hydroxy(C-C 2 )alkylene; [wherein R 8 is hydrogen or lower alkyl, and R 9 is substituted or unsubstituted pyrrolyl such as 2-ethyl-5-(4-fluorobenzoyl)pyrrolyl] 6 WO 2004/063197 PCT/JP2003/017091

R

7 is (1) hydrogen, (2) aryl (more preferably, phenyl) optionally substituted by lower alkoxy, (3) unsaturated heteromonocyclic group containing 1 to 2 nitrogen atom(s), 5 (more preferably, pyridinyl), (4) carboxy, esterified carboxy (more preferably, lower alkoxycarbonyl) or CONR' 0 R" [wherein R' 0 and R" each independently represents hydrogen, lower alkylsulfonyl, unsaturated heteromonocyclic group containing 1 to 2 nitrogen atom(s) such as pyridinyl or lower alkyl optionally substituted by 10 hydroxy, alkoxy, carboxy, protected carboxy, sulfo or -R4, or alternatively

R'

0 and R' 1 , together with the nitrogen atom to which they are attached, represents saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom such as morpholinyl.], 15 (5) acyl (e.g. lower alkanoyl such as formyl or acetyl, and heterocycliccarbonyl such as pyridinylcarbonyl) or halocarbonyl, (6) cyano, (7) amino, protected amino such as lower alkoxycarbonylamino, or mono- or di(lower)alkylamino, 20. (8) hydroxy, aryloxy, acyloxy or lower alkoxy optionally substituted by hydroxy or acyloxy (e.g. lower alkanoyloxy), (9) lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl, or (10) -O-R 2 , or 25 R1 and R 2 are combined together to form lower alkylene or lower alkenylen group which is optionally interrupted by amino or sulfonyl and also is optionally substituted by the group consisting of lower alkyl, hydroxy, oxo and lower alkoxy, which is represented by the following fonula: R1 30 R2 that may include the following ones; 7 WO 2004/063197 PCT/JP2003/017091

H

3 C

CH

3

CH

3 O 5 CH 3 0 NH so 2 10 0 OMe 15 HO 0 H 3 CO S0 2 S02 ,02 25 R 3 is (1) aryl (more preferably, phenyl or naphthyl) optionally substituted by at least one substituent(s) selected from the group consisting of (i) halogen, (ii) carboxy, (iii) protected carboxy, (iv) cyano, (v) -CONR 5 Ri 6 [wherein R1 5 and R 16 each independently represents hydrogen, lower alkyl optionally substituted by hydroxy], (vi) lower alkyl, (vii) cyclo(lower)alkyl, (viii) hydroxy(lower)alkyl, 30 (ix) lower alkoxy, (x) trihalo(lower)alkyl, (xi) unsaturated 5- or 6-membered heteromonocyclic group containing I to 2 oxygen atom(s) and I to 2 nitrogen atom(s) such as oxazolyl, (xii) lower alkylsulfonyl, (xiii) nitro, (xiv) sulfamoyl, and (xv) protected sulfamoyl; or (2) heterocyclic group selected from the group consisting of pyridinyl, pyrazinyl, 35 oxazolyl, isooxazolyl, furanyl, thienyl, quinolyl, benzofuranyl and benzothienyl, wherein said heterocyclic group is optionally substituted by at least one substituent(s) selected from the group consisting of (i) lower alkyl, (ii) 8 WO 2004/063197 PCT/JP2003/017091 cyclo(lower)alkyl, (iii) lower alkoxy, (iv) acyl such as lower alkanoyl, (v) amino, (vi) mono- or di(lower)alkylamino, (vii) protected amino such as lower alkoxycarbonylamino, (viii) cyano, (ix) carboxy, (x) protected carboxy such as ethoxycarbonyl or methoxycarbonyl, (xi) -CONR"R 16 [wherein Ri 5 and R1 6 5 each independently represents hydrogen, lower alkyl optionally substituted by hydroxy], (xii) lower alkenyl optionally substituted by lower alkoxy, (xiii) halogen, (xiv) lower alkylthio and (xv) hydroxy;

R

4 is hydrogen, halogen, cyano, carbamoyl, lower alkanoyl, thiocyanate, lower alkylthio, lower alkenyl, hydroxyl(lower)alkyl, trihalo(lower)alkyl or lower alkyl, and 10 R1 2 and R1 7 are each independently a group derived from protected or unprotected sugar such as galactose by removal of the hydroxy group therefrom, or a pharmaceutically acceptable salt thereof. More preferred compounds of formula (I) are those in which: 15 R 1 is (1) mono- or di(lower)alkylamino, (2) aryl such as phenyl, (3) satulated or unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 2 hetero atom(s) selected from nitrogen, oxygen or sulfur atom(s) (more preferably, pyrrolidinyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, furanyl, thienyl, 20 pyridinyl, etc), or (4) lower alkyl optionally substituted by lower alkoxy or saturated 5- or 6 membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom (more preferably, piperazinyl or morpholinyl), wherein lower alkoxy is optionally substituted by cyclo(lower)alkyl or unsaturated 25 5 to 6 membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) (more preferably, pyridinyl), R2 is R 7 or 2

-R

7 , wherein A2 is -(CH 2 )n- or -(CH=CH)m- [wherein n is integer which may range 2 to 6 and m is integer of 1 or 2, and 30 R 7 is hydrogen, lower alkylsulfonyl, carboxy, protected carboxy or unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) (more preferably, pyridinyl),

R

3 is (1) aryl optionally substituted by lower alkyl, cyclo(lower)alkyl, halogen, cyano or 9 WO 2004/063197 PCT/JP2003/017091 carbamoyl; or (2) unsaturated condensed heterocyclic group containing 1 to 2 nitrogen atom(s) (more preferably, quinolinyl); or unsaturated 5 to 6 membered heteromonocyclic group containing at least one nitrogen atom(s) (more preferably, 3-pyridinyl and 5 4-pyridinyl) substituted by lower alkyl, cyclo(lower)alkyl or halogen, and

R

4 is lower alkyl. Most preferred compounds of formula (I) are those in which: R' is phenyl, satulated or unsaturated 5 to 6 membered heteromonocyclic group 10 containing 1 to 2 hetero atom(s) selected from nitrogen, oxygen or sulfur atom(s) (more preferably, pyrrolyl, isooxazolyl, furanyl, thienyl, etc.) or lower alkyl optionally substituted by lower alkoxy or saturated or saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom (more preferably, piperazinyl or morpholinyl), wherein 15 lower alkoxy is optionally substituted by cyclo(lower)alkyl or unsaturated 5 to 6 membered heteromonocyclic group containing at least one nitrogen atom(s) (more preferably, pyridinyl), R2 is -(CH 2 )n-R 7 , wherein n is integer which may range 2 to 5, and R7 is carboxy or protected carboxy, 20 R is (1) phenyl optionally substituted by lower alkyl, cyclo(lower)alkyl, lower alkoxy, halogen, cyano or carbamoyl; or (2) unsaturated 5 to 6 membered heteromonocyclic group containing at least one nitrogen atom(s) (more preferably, 3-pyridinyl and 4-pyridinyl) substituted by lower alkyl, cyclo(lower)alkyl, lower alkoxy, carbamoyl or halogen, and 25 R4 is lower alkyl. Preferred concrete compound of formula (I) is: (1) 3-[7-Ethyl-2-methyl-3-(4-pyridinyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile, (2) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile, 30 (3) 4-[7-Ethyl-2-methyl-3-(methylsulfonyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile, (4) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide, (5) Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate, (6) 2-{[4-(3-Chlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methyl}-1,3 10 WO 2004/063197 PCT/JP2003/017091 propanediol, (7) 3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-yllpropanoic acid, (8) 5-[7-Ethyl-2-methyl-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid, (9) 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic 5 acid, (10) 5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid, (11) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid, 10 (12) 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoic acid, (13) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2 b]pyridazin-3-yl]pentanoic acid, (14) Ethyl (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl] 15 2-propenoate, (15) 6-{ 4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl}hexanoic acid (16) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo(1,2-b]pyridazin-3 yl]propanoic acid, 20 (17) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoic acid, (18) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 b]pyridazin-3-yl]pentanoic acid, (19) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 25 b]pyridazin-3-yl}pentanoic acid. (20) 4-{4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 blpyridazin-3-yl}butanoic acid, (21) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2 b]pyridazin-3-yl]butanoic acid, 30 (22) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoic acid, (23) 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid, or 11 WO 2004/063197 PCT/JP2003/017091 (24) 5-{ 4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoic acid, or a pharmaceutically acceptable salt thereof. 5 More preferred concrete compound of formula (I) is: (1) Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate, (2) 3 -[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid, (3) 5-[ 4 -(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid, 10 (4) 5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid, (5) 5-[ 4 -(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid, (6) 3

-[

7 -Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 15 yl]propanoic acid, (7) 5

-[

4

-(

5 -Bromo- 3 -pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2 b]pyridazin-3-yllpentanoic acid, (8) 6 -{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl}hexanoic acid 20 (9) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoic acid, (10) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 y]]butanoic acid, (11) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 25 b]pyridazin-3-yl]pentanoic acid, and (12) 5-{ 7 -ethyl- 4 -(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoic acid, (13) 4

-[

4 -(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo(1,2-b]pyridazin-3 yl]butanoic acid, or 30 (14) 5-[ 4 -(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid, or a pharmaceutically acceptable salt thereof. 12 P:\WPDOCS\D1i1TSPECI DHT\12569331 Ascllas AU Ist SOPA.doc-20/05/2009 Compound (I) of the present invention can be prepared by the following processes Process I 0 R1

NH

2 0 R2 R2 I -R1 N/ RN R3 /4 R 3 (III) I N or a salt thereof

R

4

R

3 \ / (II) or a salt thereof (I) or a salt thereof Process 2 RI R1 N/ R2 Hydrolysis N/

R

4 R3

R

4

R

3 a b (I-a) or a salt thereof (I-b) or a salt thereof Process 3 R1 Removal of the Ri a carboxy-protective b N/ R2 group in Ra N/ aN N N

R

4

R

3

R

4 R \ / \ / (I-c) or a salt thereof (I-d) or a salt thereof Process 4

R

1 b Rl

R

2 C N/ R2 I I AmidationN H R4 N R3 \ / (I-d) or a salt thereof, or a reactive derivative (I-e) or a salt thereof at the carboxy group 13 WO 2004/063197 PCT/JP2003/017091 Process 5 R1 d A a R2A N a Cyclization N N R4 /I3 5R 3

R

4 R3 5 \R/ (I-e) or a salt thereof (I-g) or a salt thereof Process 6 10 RI R1 N R2 Hydrolysis N R2

R

4 N

R

4 N \ / c 15 (I-b) or a salt thereof (I-h) or a salt thereof Process 7 R1 Removal of the R1 2 carboxy-protective N group in R 2 R2 b NC 20 R0_ N R3 R N

R

3 ~ R3 (I-i) or a salt thereof (I-j) or a salt thereof 25 Process 8 R1 R1 R2 R NC Amidation N/ d I I_ _ _ _ _ I I

R

4 RN R3 30 (I-j) or a salt thereof, (I-k) or a salt thereof or a reactive derivative at the carboxy group 14 WO 2004/063197 PCT/JP2003/017091 Process 9

R

1 R2 Removal of the R 1 N e hydroxy-protective I group in R 2 R2 5 R 4 N e N R 3 I I R4_ N R3 (I-1) or a salt thereof (I-m) or a salt thereof 10 Process 10

R

1 R1 N/ b Reduction R NN R4 N R 3 R4 N R3 \ / R 15 (I-i) or a salt thereof (I-n) or a salt thereof Process 11 R1 R 1 20 R 2 X-R12 R2 N 9 (IV) N/ h N

R

4

R

3 N \ / R 3 (I-n) or a salt thereof (I-o) or a salt thereof 25 Process 12 R1

R

2 NH2 O R1

R

4 N R2 R0 R3 N/ 30 | | N (VI) or R 4

R

3 a salt thereof (V) or a salt thereof (I) or a salt thereof 15 WO 2004/063197 PCT/JP2003/017091 Process 13 R1 R1 R2 N/ R2 halogenation R2 5 N

R

3

R

4 R -\ / a3 (I-p) or a salt thereof (I-q) or a salt thereof 10 Process 14 R1 Removal of the R1 R2 amino-protective N- group in R 3 R2

R

4 N R 3 15 \ / d R3 e (I-r) or a salt thereof (I-s) or a salt thereof Process 15 20 0 NR OH 0 cyclization R2 RR3 NN_______ R43R 4 R3 (VI) 25 (I-t) or a salt thereof Process 16 Rl R2 e N/ Reaction with R2 30 amines N R 4 RN ~

R

3

R

4 3N \ I \ I3 (I-u) or a salt thereof or a reactive derivative (I-v) or a salt thereof at the hydroxy-group 16 WO 2004/063197 PCT/JP2003/017091 Process 17 Ri Reaction with RI compounds having N CHO activated methylene N moiety N N 5 R 4

R

3 R4 / R 3 (I-w) or a salt thereof (I-x) or a salt thereof 10 Process 18 R1 R1 R2 amidation R2 N/ N/ N N

R

4

R

3

R

4 R3 c f 15 (I-h) or a salt thereof (I-y) or a salt thereof Process 19 20 R2 alcohol or thioalcohol R2 N/ or a salt thereof N I I I I N N R N R 3

R

4

R

3 9 h 25 (I-z) or a salt thereof (I-aa) or a salt thereof Process 20 R1 R1 30N R2 Solvolysis N R2 N I N

R

4 R3 R4 R3 (I-ab) or a salt thereof (I-ac) or a salt thereof 17 WO 2004/063197 PCT/JP2003/017091 Process 21 Rl Rl f g N/ R2 oxidation N NN 5 R_ R 3 R_ R3 (I-ad) or a salt thereof (I-ae) or a salt thereof 10 Process 22 R1 R1 R2 R2 N k oxidation N/ 1 __N __ R N

R

3

R

4 R3 15 (I-af) or a salt thereof (I-ag) or a salt thereof Process 23 R1 R1 20 N R2 Reduction N R2

R

4 N R 3

R

4 N R 3 a X k (I-a) or a salt thereof (I-ah) or a salt thereof 25 Process 24 R1 removal of the R1 R2 amino protective R2 N group N/ n 30 1 1 1 | N N

R

4

R

3

R

4 R3 \ / \ I (I-ai) or a salt thereof (I-aj) or a salt thereof 18 WO 2004/063197 PCT/JP2003/017091 Process 25 R1 R1 N/ R2 amines N/ R4 R3 R4 R3 R4 R3 5 g _0 R 5 \1 (I-z) or a salt thereof (I-ak) or a salt thereof Process 26 10 0 R1 a SO2CH3 SO2

N/C

3 Cyclization N N N R4 R3 R 4

R

3 \ /I 15 (I-al) or a salt thereof (I-am) or a salt thereof Process 27 0 HO 20 N

SO

2 Reduction So 2 N/ R4 R 3

R

4 N R4I R3 (I am) or a salt thereof (I-an) or a salt thereof 25 Process 28 HO

SO

2 So 2 30 lower alkyl halide N R 4 __ _ _ - I

R

4 N

R

3 \ I (I-an) or a salt thereof (I-ao) or a salt thereof 19 WO 2004/063197 PCT/JP2003/017091 Process 29 HO lower alkyl-O N/ 2 lower alkyl halide N 2 5 R4 N R3 R4 NY R3 5\ N (I-an) or a salt thereof (I-ap) or a salt thereof 10 Process 30 R1 R 1 COOH COCl N Oxalyl chloride N N 01 R4 R3 R4 R3 \/\ / 15 (I-aq) or a salt thereof (I-ar) or a salt thereof Process 31 20 Rj R1 J Trifluoromethane h N/ R2 sulfonic anhydride R2 R4 I I _ _ _ _ I I

R

4

R

3

R

4 R3 _ I \ / 25 (I-u) or a salt thereof (I-as) or a salt thereof Process 32 R R 30 R2 R2 alkylationN R4 R 3

R

4

R

3 \ I \ I (I-as) or a salt thereof (I-at) or a salt thereof 20 WO 2004/063197 PCT/JP2003/017091 Process 33 R1 lower alkyl R1 R2 triphenylphosphonium R2 N halide N 5 R4 R 3 R4 R 3 b3 c (I-au) or a salt thereof (I-av) or a salt thereof 10 Process 34 R1 R1 N / 2 Reduction N / N N R4 R 3

R

4

R

3 c d 15 (I-av) or a salt thereof (I-aw) or a salt thereof Process 35 20 Introduction of R 1 hydroxy-protective R2 group

R

4 - R 3

R

4 N R3 (I-af) or a salt thereof (I-ax) or a salt thereof 25 Process 36 R1 R1 / R21 Reaction with amines R2 N N R4 R 3

R

4 R3 (I-ag) or a salt thereof (I-ay) or a salt thereof 21 WO 2004/063197 PCT/JP2003/017091 Process 37 R1

NH

2 O O R2 R1 R R3 0 CH 3 (VIII) R4 R 3 (II)\I (I) or a salt thereof 10 Process 38 R4 RI R2

NH

2 O O q R1 N N3 I O C NO/

R

4

R

3 0 3 15 (IX) R 4 R3 (I-az) or a salt thereof Process 39 20 tri (lower) alkyl R1 (lower alken-1-yl)tin R1 R2 or tri(lower)alkyl- R2 N /(1- (lower )alkyl- N/ I (lower alken-1-yl)tinI , 4 N R3 er R 4

NR

3 \g/ / m 25 (I-z) or a salt thereof (I-ba) or a salt thereof Process 40 R1 R1 magnesium 30 N / bis(3-(lower)alkoxy- N R 3I N 3-oxopropanoate) r R,4 N, R3 R4_ N R3 \ /\ I (I-r) or a salt thereof (I-bb) or a salt thereof 22 WO 2004/063197 PCT/JP2003/017091 wherein R 1 , R 2 , R 3 and R 4 are each as defined above, R',a is the same as above R' having protected carboxy moiety, Rlb is the same as above R1 having carboxy moiety, R'c is -CONRR 6 , 5 Rld is carbamoyl(lower)alkyl, R', is amino, mono- or di(lower)alkylamino-, lower alkoxy(lower)alkylamino, nitrogen-containing heterocyclic group, amino(lower)alkyl, mono- or di(lower)alkylamino(lower)alkyl, lower alkoxy(lower)alkylamino(lower)alkyl, nitrogen-containing 10 heterocyclic(lower)alkyl, R f is lower alkylthio(lower)alkyl, R g is lower alkylsulfonyl(lower)alkyl, R h is trifluoromethanesulfonyloxy or trifluoromethanesulfonyloxy(lower)alkyl, R I is lower alkoxy or lower alkoxy(lower)alkyl, 15 R'j is hydroxy or hydroxy(lower)alkyl, Ra is lower alkoxycarbonyl, R 2 b is the same as above R 2 having protected carboxy moiety,

R

2 c is the same as above R2 having carboxy moiety, Rd is the same as above R 2 having carbamoyl moiety, 20 R 2 e is the same as above R 2 having protected hydroxy moiety,

R

2 f is the same as above R 2 having hydroxy moiety,

R

2 a is the same as above R 2 having hydroxymethyl moiety, Rh is -OR',

R

2 is lower alkoxycarbonyl or lower alkylsulfonyl, 25 R 2 j is substituted or unsubstituted lower alkenyl as mentioned in the above R 2 , wherein said lower alkenyl is lower 1-alken-1-yl,

R

2 is the same as above R 2 having hydroxy(lower)alkyl moiety, R is the same as above R 2 having oxo(lower)alkyl moiety, R2m is the same as above R2 having protected amino moiety, 30 R 2 is the same as above R2 having amino moiety,

R

2 , is the same as above R 2 having protected hydroxy moiety,

R

2 , is the same as above R 2 having hydroxy(lower)alkylamino(lower)alkyl moiety,

R

2 q is the same as above R 2 having lower alkoxycarbonyl(lower)alkyl moiety, 23 WO 2004/063197 PCT/JP2003/017091 R is the same as above R2 having lower alkoxycarbonylmethylcarbonyl moiety, Ra is the same as above R 3 having cyano moiety,

R

3 b is the same as above R 3 having carbamoyl moiety, Rc is the same as above R 3 having carboxy moiety, 5 R 3 d is the same as above R 3 having protected sulfamoyl moiety,

R

3 e is the same as above R 3 having sulfamoyl moiety,

R

3 f is the same as above R 3 having -CONR"R" moiety,

R

3 g is the same as above R 3 having haloheterocyclic moiety,

R

3 h is the same as above R 3 having alkoxyheterocyclic, thioalkoxyheterocyclic or 10 hydroxy moiety,

R

3 is the same as above R? having 1-(lower)alkoxy(lower)alken-1-ylheterocyclic moiety, Rj is the same as above R 3 having lower alkanoylheterocyclic moiety,

R

3 k is the same as above R 3 having aminomethylheterocyclic moiety, 15 R 3 1 is the same as above R 3 having mono- or di(lower)alkylaminoheterocyclic moiety,

R

3 m is the same as above R 3 having (lower)alken-1-ylheterocyclic group or 1 (lower)alkoxy- 1 -(lower)alken- 1 -yl-heterocyclic moiety,

R

4 , is halogen, 20 R 4 b is formyl,

R

4 e is lower I -alken-1 -yl,

R

4 d is lower alkyl, R1 2 is lower alkyl or a group derived from protected or unprotected sugar by removal of the hydroxy group therefrom, 25 X is a leaving group, and a group of the formula: ( is lower alkylene interrupted by imino moiety and substituted by oxo groups. The starting compound (1I) of the present invention can be prepared according to 30 a conventional manner or in a similar manner as described in the following Preparations and/or Examples. Another point to be noted is that the pyrrolopyridazine moiety of the compound 24 P\WPDOCS \HT\SPECI DI1\I2569331 Astls AU Ist SOPAdoc.-2005/2009 (I) can also exist in the tautomeric form, and such tautomeric equilibrium can be represented, for example, by the following formula. OH 0 R2 R2 N/ HN R4 NR3 p N3 wherein R' R 2 , R 3 and R 4 are each as defined above. Both of the above tautomeric isomers are included within the scope of the present invention, and in the present specification and claims, however, compound (I) is represented for convenience' 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. The term "lower" is used to intend a group having 1 to 6, preferably I to 4, carbon atom(s), unless otherwise provided. Suitable "lower alkyl" and "lower alkyl moiety" may include 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 C-C 4 alkyl. Suitable "lower alkenyl" may include vinyl(ethenyl), 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)hexenyl, 1-methylvinyl, 1-ethylvinyl, 1-(or 2-)methyl-1-(or 2-)propenyl, 1-(or 2-)ethyl-1-(or 2-)propenyl, 1-(or 2 or 3-)methyl-1 -(or 2- or 3-)butenyl, and the like, in which more preferable example may be C 2

-C

4 alkenyl. Suitable "lower alkynyl" may include ethynyl, 1-propynyl, propargyl, 1 methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5 hexynyl, and the like. 25 WO 2004/063197 PCT/JP2003/017091 Suitable "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 C 1

-C

4 alkylene and the most preferable one may be methylene. 5 Example of hydroxy(CI-C 2 )alkylene is hydroxymethylene, (hydroxymethyl)methylene or 1-(or 2-)hydroxyethylene. Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like. Suitable "halogen" and "halogen moiety" may include fluorine, bromine, chlorine 10 and iodine. 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. 15 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, 20 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. 25 Suitable "trihalo(lower)alkylsulfonyloxy" may include sulfonyloxy group substituted by trihalo(lower)alkyl such as trifluoromethylsulfonyloxy, trifluoroethylsulfonyloxy, trichloromethylsulfonyloxy, and the like. Suitable "protected carboxy" and "protected carboxy moiety" may include esterified carboxy and the like. 30 And suitable example of said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.); lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); 26 WO 2004/063197 PCT/JP2003/017091 lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); lower alkoxy(lower)alkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.); lower alkylthio(lower)alkyl ester (e.g., methylthiomethyl ester, ethylthiomethyl ester, 5 ethylthioethyl ester, isopropoxythiomethyl ester, etc.); mono(or di or tri)halo(lower)alkyl ester (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 10 hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, 1-(or 2-) [methoxycarbonyloxy]ethyl ester, 1-(or 2-)-[ethoxycarbonyloxy]ethyl ester, 1-(or 2-) 15 [propoxycarbonyloxy]ethyl ester, 1-(or 2-)-[isopropoxycarbonyloxy]ethyl ester, etc.); lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2-mesylethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycarbonyl oxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester, 1-(or 2 20 )ethoxycarbonyloxyethyl ester, 1-(or 2-)-isopropoxycarbonyloxyethyl ester, etc.); phthalidylidene(lower)alkyl ester; (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g., (5-methyl-2-oxo-1,3 dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo 1,3-dioxol-4-yl)ethyl ester, etc.]; 25 mono(or di or tri)aryl(lower)alkyl ester, for example, mono(or di or tri)phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4 hydroxy-3,5-di-t-butylbenzyl ester, etc.); 30 aryl ester which may have one or more suitable substituent(s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.); tri(lower)alkylsilyl ester (e.g. trimethylsilyl ester, triethylsilyl ester, etc.); 27 WO 2004/063197 PCT/JP2003/017091 tri(lower)alkylsilyl(lower)alkyl ester (e.g. 2-trimethylsilylethyl ester, etc.); and the like, in which more preferable example may be lower alkyl ester, i.e., lower alkoxycarbonyl (e.g. ethoxycarbonyl, etc.). The term "protected amino" means an amino group bonded to the amino 5 protecting group. Example of such amino-protectnig group include lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.); lower alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.); optionally substituted aryl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.); phthalimide; and the like. Further example of amino-protecting group are well-known in organic synthesis and are 10 described by T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," Second Edition, John Wiley and Sons, New York, N.Y., which is herein incorporated by reference. The term "protected sulfamoyl" means sulfamoyl group having the amino protecting group mentioned above on the nitrogen atom. A preferred amino-protecting 15 group is aryl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.); 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: 20 Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.); in which preferable 25 "lower alkanoyl" may include straight or branched one such as formyl, acetyl, propionyl, butyryl, and the like. lower or higher 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.); 30 cyclo(lower)alkylcarbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.); lower alkylglyoxyloyl (e.g., methylglyoxyloyl, ethylglyoxyloyl, propylglyoxyloyl, etc.); lower alkoxyglyoxyloyl (e.g., methoxyglyoxyloyl, ethoxyglyoxyloyl, propoxyglyoxyloyl, 28 WO 2004/063197 PCT/JP2003/017091 etc.); or the like; Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); 5 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, 10 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 15 heterocycliccarbonyl; heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.); heterocyclic(lower)alkenoyl(e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); 20 heterocyclicglyoxyloyl; heterocyclicoxycarbonyl; or the like; in which suitable "heterocyclic moiety" may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like, as mentioned below and preferable "heterocyclic carbonyl" may include carbonyl group substituted by heterocyclic group as mentioned 25 below such as pyrrolidinylcarbonyl, pyridinylcarbonyl, pyrazinylcarbonyl, and the like.. Syitable "halocarbonyl" may include chlorocarbonyl, bromocarbonyl, and the like. Suitable "cyclo(lower)alkyl" and "cyclo(lower)alkyl moeity" may include one having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. 30 Suitable "aryl" and "aryl moiety" may include C 6

-C

1 0 aryl such as phenyl, naphthyl and the like. Suitable "heterocyclic moiety" may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, 29 WO 2004/063197 PCT/JP2003/017091 sulfur, nitrogen atom and the like. Preferable heterocyclic group may be heterocyclic group such as (1) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, 5 pyrazolyl, pyridinyl, dihydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; (2) saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, 10 piperidyl, piperazinyl, etc.; (3) unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, tetrahydroquinolyl (e.g., 1,2,3,4-tetrahydroquinolyl, etc.), isoquinolyl, indazolyl, benzotriazolyl, benzopyrimidinyl (e.g., benzo[b]pyrimidinyl, etc.), etc.; 15 (4) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and I to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5 oxadiazolyl, etc.), etc.; (5) saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic 20 group containing 1 to 2 oxygen atom(s) and I to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.; (6) unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.; (7) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic 25 group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4 thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.; (8) saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, 30 thiazolidinyl, etc.; (9) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.; 30 WO 2004/063197 PCT/JP2003/017091 (10) unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.; (11) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, furanyl, etc.; 5 (12) unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s), for example, benzodioxolyl (e.g. methylenedioxyphenyl, etc.), benzofuranyl, etc.; (13) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.; 10 (14) unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl (e.g., benzo[b]thienyl, etc.), benzodithiinyl, etc.; (15) unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like. Suitable "heterocyclic group" and "heterocyclic moiety" in the terms 15 "heterocycliccarbonyl" can be referred to the ones as mentioned above. Suitable "N-containing heterocyclic group" and "N-containing heterocyclic moiety" can be referred to the ones as mentioned above, wherein the heterocyclic group is containing at least one nitrogen atom such as 1-pyrrolidiny], morpholinyl and the like. A group derived from a sugar may be the group derived from, for example, 20 glyceraldehydes; an aldose such as erythrose, threose, arabinose, ribose, xylose, lyxose, glucose, mannose or galactose; a ketose such as fructose or sorbose; or a discccharide such as maltose, lactose or sucrose. Protecting groups for the hydroxy group of the above-mentioned sugars are an aliphatic acyl group, such as formyl, or acetyl; a cyclic ether group such as tetrahydro-2 25 furanyl or tetrahydro-2-pyranyl; a 1-alkoxyethyl group such as 1-methoxyethyl or 1 ethoxyethyl; and a silyl group such as trimethylsilyl, triethylsilyl or t-butyldimethylsilyl. Suitable "substituted or unsubstituted lower alkyl" for RI may include straight or branched lower alkyl (e.g. methyl, isopropyl, neopentyl, etc.) optionally substituted by; 30 (1) halogen (e.g. fluoro, bromo, etc.), (2) carboxy, (3) protected carboxy (e.g. esterified carboxy such as ethoxycarbonyl, etc.), (4) cyano, (5) carbamoyl, (6) -OCONR1 5 R16 [wherein R 15 and R1 6 each independently represents hydrogen, aryl or lower alkyl optionally substituted by aryl, or R 3 and R , together with the nitrogen atom to which 31 WO 2004/063197 PCT/JP2003/017091 they are attached, represents saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom.] (more preferably, dimethylcarbamoyloxy, methyl-phenylcarbamoyloxy, morpholinylcarbonyloxy, pyrrolidinylcambonyloxy, etc); (7) lower alkylthio (e.g. 5 methylthio, etc.), (8) lower alkylsulfonyl (e.g. methylsulfonyl, etc.), (9) lower alkylsulfonyloxy (e.g. methylsulfonyoxyl, etc.), (10) lower alkylsulfonylamino (e.g. methylsulfonylamino, etc.), (11) mono- or di(lower)alkylamino optionally substituted by hydroxy, lower alkoxy, acyloxy (e.g. phenoxy, etc.), or substituted or unsubstituted aryl (e.g. benzylamino, etc.), (12) amino; (13) acylamino (more preferably, lower 10 alkanoylamino such as acetylamino, aroylamino such as benzoylamino, or heterocycliccarbonylamino such as pyrazinylcarbonylamino, or the like), (14) protected amino (e.g., methoxycarbonylamino, phthalimide, etc.), (15) hydroxy, (16) acyloxy (more preferably, lower alkanoyloxy such as acetyloxy, or the like), (17) cyclo(lower)alkyloxy, (18) aryloxy (e.g. phenoxy, etc.) (19) substituted or unsubstituted aryl (more preferably, 15 phenyl), (20) saturated or unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 3 nitrogen atom(s) and also optionally containing oxygen atom or sulfur atom (more preferably, piperazinyl, morpholinyl, oxazolidinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or triazolyl) optionally substituted by lower alkyl, hydroxy(lower)alkyl, aryl or oxo, (21) lower alkoxy (e.g. methoxy, ethoxy, iso-propoxy, 20 etc.) optionally substituted by carboxy, protected carboxy (e.g. tert-butoxycarbonyl, etc.), hydroxy, protected hydroxy (e.g. tetrahydro-2H-pyran-2-yloxy, etc.), cyclo(lower)alkyl (e.g. cyclopropyl, cyclohexyl, etc.), substituted or unsubstituted aryl (e.g. phenyl optionally substituted by cyano, carboxy, protected carboxy or carbamoyl, such as phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-carboxyphenyl, 2-, 3- or 4-(methoxycarbonyl)phenyl, 25 2-, 3- or 4-carbamoylphenyl, etc.), saturated or unsaturated 5- or 6-membered heterocyclic group containing 1 to 2 nitrogen atom(s) optionally substituted by lower (more preferably, 2-, 3- or 4-pyridinyl, pyrazinyl or 4-methylpiperazinyl)(e.g. 2-, 3- or 4 pyridinyl, pyrazinyl, etc.), or -CONR"R 14 [wherein R 1 3 and R' 4 each independently hydrogen or lower alkyl optionally substituted by aryl, or R and R , together with the 30 nitrogen atom to which they are attached, represents N-containing heterocyclic group] (e.g. morpholinocarbonyl, dimethylcarbamoyl, etc.), and the like. Suitable "substituted or unsubstituted aryl" may include C 6

-C

10 aryl (e.g. phenyl, naphthyl, etc.) optionally substituted by the substituent(s) selected from the group 32 WO 2004/063197 PCT/JP2003/017091 consisting of (1) halogen (e.g. fluoro, chloro, etc.), (2) carboxy, (3) protected carboxy, (4) cyano, (5) -CONR1 5 R1 6 [wherein R1 5 and R 6 are each independently represents hydrogen, lower alkyl optionally substituted by hydroxy) (e.g. carbamoyl, hydroxyethylcarbamoyl, etc.), (6) lower alkyl (e.g. methyl, etc.), (7) cyclo(Jower)alkyl (e.g. cyclopropyl, etc) (8) 5 lower alkoxy (e.g. methoxy, etc.), (9) trihalo(lower)alkyl (e.g. trifluoromethyl, etc.), (10) heterocyclic group such as oxazolyl, (11) lower alkylsulfonyl (e.g. methylsulfonyl, etc.), (12) nitro, (13) amino, (14) sulfamoyl, and (15) protected sulfamoyl such as ar(lower)alkoxycarbonylsulfamoyl, and the like. In which, 10 preferable example of "substituted or unsubstituted aryl" for R1 is aryl optionally substituted by the substituent(s) selected from the group consisting of halogen (e.g. phenyl, 4-fluorophenyl, etc.); preferable example of "substituted or unsubstituted aryl" for R 3 is aryl optionally substituted by the substituent(s) selected from the group consisting of (1) halogen, (2) 15 carboxy, (3) protected carboxy such as esterified carboxy (e.g. benzyloxycarbonyl, etc,), (4) cyano, (5) -CONR 15

R

2 6 [wherein R1 5 and R1 6 are each independently represents hydrogen, lower alkyl optionally substituted by hydroxy], (6) lower alkyl, (7) cyclo(lower)alkyl, (8) lower alkoxy, (9) trihalo(lower)alkyl, (10) heterocyclic group, (11) lower alkylsulfonyl, (12) nitro, (13) amino, (14) sulfamoyl, and (15) protected sulfamoyl, 20 and the like. (e.g. phenyl, 2-naphthyl, 2- or 3-chlorophenyl, 2,3-, 2,4-, 3,4- or 3,5 dichlorophenyl, 3- or 4-fluorophenyl, 3- or 4-cyanophenyl, 3- or 4-carbamoylphenyl, 4 sulfamoylphenyl, 4 -(benzyloxycarbonylsulfamoyl)phenyl, 3-carboxyphenyl, 3-(N-(2 hydroxyethyl)carbamoyl)phenyl, 3-nitrophenyl, 3-trifluoromethylphenyl, 3 methylsulfonylphenyl, 3-(5-oxazolyl)phenyl, 3-methoxyphenyl, 3-methylphenyl, etc.); 25 and preferable example of "substituted or unsubstituted aryl" for R 7 is aryl optionally substituted by lower alkoxy (e.g. phenyl, 2-, 3- or 4-methoxyphenyl, etc.). Suitable "substituted or unsubstituted heterocyclic group" may include heterocyclic group mentioned above (more preferably, pyridinyl, pyrazinyl, oxazolyl, 30 isooxazolyl, furanyl, thienyl, quinolinyl, benzofuranyl and benzothienyl), which is optionally substituted by the substituent(s) selected from the group consisting of (1) lower alkyl (e.g. methyl, etc.), (2) cyclo(lower)alkyl (e.g. cyclopropyl, etc.) (3) lower alkoxy (e.g. methoxy, etc.), (4) acyl (e.g. lower alkanoyl such as acetyl, etc.), (5) amino, 33 WO 2004/063197 PCT/JP2003/017091 (6) mono- or di(lower)alkylamino (e.g. dimethylamino, etc.), (7) protected amino (e.g. lower alkoxycarbonylamino such as tert-butoxycarbonylamino, etc.), (8) cyano, (9) carboxy, (10) protected carboxy (e.g. benzyloxycarbonyl, etc.), (11) -CONR 5 R1 6 [wherein R 5 and R1 6 are each independently represents hydrogen, lower alkyl optionally 5 substituted by hydroxy] (e.g. carbamoyl, hydroxyethylcarbamoyl, etc.), (12) lower alkenyl optionally substituted by lower alkoxy (e.g. vinyl, 1-ethoxyvinyl, etc.), (13) halogen (e.g. chloro, bromo, etc.), (14) lower alkylthio, (15) hydroxy, and the like. In which, preferable example of "substituted or unsubstituted heterocyclic group" for R1 is 10 heterocyclic group optionally substituted by lower alkyl or halogen (e.g. 2-pyridinyl, 5 blomo-3-pyridinyl, 1-methyl-2-pyrrolyl, 1-pyrrolyl, 1-pyrrolidinyl, 3-methyl-2-thienyl, 2 thienyl, 2- or 3-furanyl, 2-thiazolyl, 5-oxazolyl, 5-methyl-isooxazolyl, 3,5-dimethyl-4 isoxazolyl, etc.); and preferable example of "substituted or unsubstituted heterocyclic group" for R 3 is 15 heterocyclic group optionally substituted by at least one substituent(s) selected from the group consisting of (1) lower alkyl, (2) cyclo(lower)alkyl, (3) lower alkoxy, (4) acyl such as lower alkanoyl, (5) amino, (6) mono- or di(lower)alkylamino, (7) protected amino such as lower alkoxycarbonylamino, (8) cyano, (9) carboxy, (10) protected carboxy such as esterified carboxy (e.g. benzyloxycarbonyl), (11) carbamoyl, (12) lower alkenyl 20 optionally substituted by lower alkoxy, (13) halogen, (14) lower alkylthio, and (15) hydroxy (e.g. 3- or 4-pyridyl, 2-pyrazinyl, 6-methoxy-2-pyrazinyl, 4- or 5-oxazolyl, 2 benzofuranyl, 2-benzothienyl, 3- or 6-quinolinyl, 2-chloro-4-pyridyl, 5-bromo-3-pyridyl, 5-chloro-2-thienyl, 5,6-dichloro-2-pyridyl, 4-chloro-2-pyridyl, 5-cyano-3-pyridyl, 5 carboxy-3-pyridinyl, 5-carbamoyl-3-pyridyl, 5-(benzyloxycarbonyl)-3-pyridyl, 5-(tert 25 butoxycarbonylamino)-3-pyridinyl, 5-amino-3-pyridinyl, 2-methoxy-4-pyridyl, 3 methoxy-5-isoxazolyl, 2-methylthio-4-pyridinyl, 2-hydroxy-4-pyridyl, 5-methyl-3-pyridyl, 5-ethyl-3-pyridyl, 5-methyl-3-isoxazolyl, 5-vinyl-3-pyridyl, 2-vinyl-4-pyridyl, 5-acetyl-3 pyridyl, 2-dimethylamino-4-pyridyl, 5-(1-ethoxyvinyl)-3-pyridyl, 2-oxo-1,2-dihydro-4 pyridyl, or 2-methylthio-4-pyridyl, etc.). 30 R1 and R 2 are combined together to form lower alkylene or lower alkenylen group which is optionally interrupted by amino or sulfonyl and also is optionally substituted by the group consisting of lower alkyl, hydroxy, oxo and lower alkoxy, which is represented 34 WO 2004/063197 PCT/JP2003/017091 by the following formula: R1 5R2 The above formula may include following ones;

H

3 C

CH

3

CH

3 0 O 10

CH

3 0 NH

SO

2 15 OMe 20 HO 0 H 3 CO

SO

2 S0 2

SO

2 30 Suitable "substituted or unsubstituted aryl(lower)alkenyl" may include C 6 -C 1 0 aryl(lower)alkenyl which is optionally substituted by halogen (e.g. 2-phenylvinyl, 2-(2- or 3-chlorophenyl)vinyl, etc.). 35 Suitable "leaving group" may include acid residue, lower alkoxy as exemplified above, and the like. The above Processes can be carried out according to a conventional manner such 35 P WPDOCS\DHTSPECI DHhl2569331 AsIas AU Isa SOPA-doc-2/5/2009 as the one described in Preparations and/or Examples, or in a similar manner thereto. Among the above Processes, fused heterocyclic ring forming processes (such as Process I and Process 12) are important for carrying out of this invention and are explained in more detail. According to the Process 1, pyrrolopyridazine derivatives (I) can be prepared by reacting the 1-amino-2-acylpyrrole derivative (II) or a salt thereof and the compound (III) or a salt thereof in the presence of a catalytic amount of acid catalyst in an inert solvent, preferably with concomitant removal of the water being produced by physical (e.g. Dean Stark trap) or chemical (e.g. molecular sieves) means. Suitable acid catalyst is, for example p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, trifluoroacetic acid and so on. Suitable inert solvent is, for example, benzene, toluene, tetrahydrofuran and the like. Another ring forming process is descried in Process 12, in this process pyrrolopyridazine derivatives (I) can be also prepared reacting 1-aminopyrole derivative (V) or a salt thereof and @-diketone derivative or a salt thereof under the similar condition before mentioned Process 1, and therefore the reaction conditions can be referred to those of the Process 1. 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. Suitable salts of the compounds of formula I and the starting compounds in Processes 1 to 40 can be referred to the ones as exemplified for the compound (1). The new pyrrolopyridazine derivatives (I) and pharmaceutically acceptable salts thereof hardly possess a strong inhibitory activity against phosphodiesterase III (PDE III), 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 36 WO 2004/063197 PCT/JP2003/017091 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 5 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, 10 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 15 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 20 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, acute and 25 chronic multiple sclerosis, cancer cachexia, viral infection, AIDS cachexia, thrombosis, and the like. For therapeutic administration, the compound (1), or its prodrug, or a salt thereof can be administered alone or in the form of a mixture, preferably, with a pharmaceutical 30 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 37 WO 2004/063197 PCT/JP2003/017091 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 5 (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, 10 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. 15 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 20 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, 25 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, 30 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 38 WO 2004/063197 PCT/JP2003/017091 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, 5 500 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 (1) and a 10 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) 15 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 IM 20 leupeptin, 100 pM PMSF, 20 ptM 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 200g 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 25 same component as homogenizing buffer without DOC. The dialysate of enzyme preparation was stored at -20*C until assay. PDE4, activity was estimated with a Phosphodiesterase [ 3 H]cAMP SPA Enzyme Assay System (Amersham Pharmacia Biotech), using a 96 well Opti-plate. Reactions were initiated by addition of 0.025 tCi/well of [ 3 H]cAMP to the enzyme mixture 30 containing 50 mM Tris-HCl (pH 7.5), 8.3 mM MgCl 2 , 1.7 mM EGTA, and various concentrations of the test compound or vehicle. CI-930 (10 tM in final), a specific PDE3, inhibitor, was also added in the reaction mixture. After incubation at 30'C for 15 minutes, 50 VL of SPA beads suspension was added to each well. The well-plate was then shaken 39 WO 2004/063197 PCT/JP2003/017091 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. 5 IC 50 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 10 compound-treated tubes, respectively. 2. Test results The following table illustrates the inhibitory activity on PDE-IV of the representative compound of formula (I): 15 Example Compound name IC50 (pM) 198 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2- <1 methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid (b) Inhibition on TNF-alpha production in human mononuclear cells 20 1. Test method (1) Human peripheral blood mononuclear cells (PBMCs) preparation Blood (30 ml for each person) was collected from the median cubital vein of healthy volunteer was divided 15 mL each in heparin containing conical tube and the same volume of RPMI1640 was added to each tube. Diluted blood was then piled up to 25 20 mL of Ficoll-Paque PLUS (Amersham Pharmacia Biotech) in polystyrene centrifuge tube. After centrifugation at 1,600rpm for 30 minutes, cells gathering in the center area of the gradient were collected by capillary and washed with 40 mL of RPMI1640 in several times with centrifugation at 1,200 rpm for 10 minutes. PBMC finally precipitated were suspended in RPMI1640 containing 1% fetal bovine serum and antibiotics. After 30 cell counting, final suspension at 3 x 10 6 cells/mL in culture medium was prepared. 40 WO 2004/063197 PCT/JP2003/017091 (2) TNF-alpha production from stimulated PBMCs Human PBMCs prepared by the density gradient method using Ficoll-Paque PLUS were suspended in the culture medium mentioned above with the concentration of 5 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 CO 2 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 g/mL. After 24 hours, the supernatant of each well by centrifugation at 1,700 rpm for 10 minutes was 10 stored at -80*C until assay. TNF-alpha levels in the medium were measured by ELISA. The IC 50 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. 15 2. Test results Example Compound name IC50 (nM) 198 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2- <100 methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid 41 WO 2004/063197 PCT/JP2003/017091 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 5 be limitations on the scope of the instant invention in any way, and they should not 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 10 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. 15 The abbreviations, symbols and terms used in the Preparations, Examples and Formulae have the following meanings. DMF NN-dimethylformamide EtOAc or AcOEt Ethyl acetate THF Tetrahydrofuran 20 Et3N Triethylamine MeOH Methanol EtOH Ethanol BuOH Butanol DCM Dichloromethane 25 Pd/C Palladium on carbon powder Preparation a To a suspension of 2-pyridinethiol (17 g) in tetrahydrofuran (200 mL) was added triethylamine (15.5 g) in an ice-water bath under N 2 . To this was added a solution of 4 30 cyanobenzoyl chloride (25.3 g) in tetrahydrofuran (80 mL) below 10'C over 30 minutes. After 15 minutes, the bath was removed and the mixture was stirred overnight at ambient temperature. The mixture was concentrated in vacuo. The residue was partitioned between chloroform and water. The organic layer was washed with saturated sodium 42 WO 2004/063197 PCT/JP2003/017091 bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue (38 g) was triturated with isopropyl ether to give S-(2-pyridinyl) 4 cyanobenzenecarbothioate (32.5 g) as a pale brown solid. 5 S-(2-Pyridinyl) 4-cyanobenzenecarbothioate NMR (CDCl 3 , 6): 7.38 (1H, t, J=7Hz), 7.72 (1H, d, J=8Hz), 7.75-7.87 (3H, m), 8.11 (2H, d, J=8Hz), 8.71 (1H, d, J=2Hz) MS (ESI*): m/z 241 (M+H) 10 The following compound(s) was(were) obtained in substantially the same manner as that of Preparation 1. Preparation 2 S-(2-Pyridinyl) 2-chloro-4-pyridinecarbothioate 15 NMR (CDCl 3 , 6): 7.40 (1H, m), 7.65-7.75 (2H, m), 7.75-7.90 (2H, m), 8.62 (1H, d, J=5Hz), 8.70 (1H, m) Preparation 4 S-(2-Pyridinyl) 3-cyanobenzenecarbothioate 20 NMR (CDCI 3 , 6): 7.39 (1H, m), 7.66 (1H, t, J=8Hz), 7.72 (1H, t, J=8Hz), 7.83 (1H, m), 7.91 (1H, d, J=8Hz), 8.24 (1H, d, J=8Hz), 8.29 (1H, s), 8.71 (1H, m) MS (ESI'): m/z 241 (M+H) Preparation 5 25 S-(2-Pyridinyl) 3-methoxybenzenecarbothioate NMR (CDCI 3 , 6): 3.87 (3H, s), 7.16 (1H, m), 7.32-7.44 (2H, m), 7.51 (111, m), 7.63 (1H, d, J=8Hz), 7.71-7.83 (2H, m), 8.69 (1H, m) Preparation 6 30 S-(2-Pyridinyl) 4-pyridinecarbothioate NMR (CDCI 3 , 6): 7.35-7.43 (1H, m), 7.73 (1H, d, J=8Hz), 7.77-7.88 (3H, m), 8.70 (1H, d, J=7Hz), 8.85 (2H, d, J=8Hz) 43 WO 2004/063197 PCT/JP2003/017091 MS (ESI): m/z 217 Preparation 7 S-(2-Pyridinyl) 2-pyrazinecarbothioate 5 NMR (CDCl 3 , 6): 7.38 (1H, m), 7.71 (1H, d, J=8Hz), 7.82 (1H, m), 8.73 (2H, m), 8.86 (111, m), 9.17 (1H, s) Preparation 8 S-(2-Pyridinyl) 3-pyridinecarbothioate 10 NMR (CDCl 3 , 8): 7.37 (1H, m), 7.46 (1H, m), 7.73 (1H, m), 7.83 (1H, m), 8.27 (1H, m), 8.68 (1H, m), 8.84 (1H, m), 9.23 (1H, m) Preparation 9 To a solution of 2-ethyl-1H-pyrrole in toluene (120 mL) was added dropwise IM 15 methylmagnesium bromide in tetrahydrofuran (170 mL) in a dry ice-acetone bath below -60*C over 30 minutes. Then the mixture was stirred in an ice-water bath for 40 minutes. To this reaction mixture was added S-(2-pyridinyl) 4-cyanobenzenecarbothioate (15.2 g) portionwise over 10 minutes in a dryice-acetone bath. After 1.5 hours stirring, saturated ammonium chloride (100 mL) was added therein and the reaction mixture was allowed to 20 ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with IN sodium hydroxide (100 mL) twice, water, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with isopropyl ether to give 4-[(5-ethyl-1H-pyrrol-2-yl)carbonyljbenzonitrile (12.7 g) as a pale yellow solid. 25 4-[(5-Ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile NMR (CDCl 3 , 8): 1.32 (3H, t, J=8Hz), 2.75 (2H, q, J=8Hz), 6.11 (1H, d, J=5Hz), 6.76 (111, d, J=5Hz), 7.77 (21H, d, J=8Hz), 7.94 (2H, d, J=8Hz), 9.49 (1H, br s) MS (ESI'): m/z 225 (M+H) 30 The following compound was obtained in substantially the same manner as that of Preparation 9. 44 WO 2004/063197 PCT/JP2003/017091 Preparation 10 (2E)-1-(5-Ethyl-1H-pyrrol-2-yl)-3-phenyl-2-propen-1 -one NMR (CDC1 3 , 6): 1.31 (311, t, J=7Hz), 2.73 (2H, q, J=7Hz), 6.10 (1H, m), 7.02 (1H, m), 7.27 (1H, d, J=16Hz), 7.35-7.43 (3H, m), 7.63 (211, m), 7.79 (11H, d, J=16Hz) 5 MS (ESI'): m/z 226 (M+H) Preparation 11 To a solution of 4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]-benzonitrile (12.5 g) in N,N-dimethylformamide (63 mL) was added 60% sodium hydride in oil (2.68 g) in an 10 ice-water bath under N 2 . After 30 minutes, to the mixture was added 1-(aminooxy)-2,4 dinitrobenzene (13.3 g). After 2 hours, the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water (100 mL) 3 times, 1N sodium hydroxide (100 mL), and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified 15 by flash silica gel chromatography (silica gel, 500 mL) eluted with hexane-chloroform = 1-2, 1-5, and 1-10 followed by triturated with isopropyl ether to give 4-[(1-amino-5 ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (8.1 g, 60.7%) as an yellow solid. The mixed fraction and the mother layer (7 g) were repurified by flash silica gel chromatography (silica gel, 200 mL) eluted with hexane-chloroform = 2-1 and 1-1 followed by triturated 20 with isopropyl ether to give 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (2.0 g, 15%) as a pale yellow solid. 4-[(1 -Amino-5-ethyl-1 H-pyrrol-2-yl)carbonyl] -benzonitrile NMR (CDCl 3 , 8): 1.29 (311, t, J=81Hz), 2.77 (2H, q, J=8Hz), 5.75 (2H, br s), 5.94 (1H, 25 d, J=51z), 6.59 (11H, d, J=5Hz), 7.76 (2H, d, J=8Hz), 7.85 (211, d, J=8Hz) MS (ESI*): m/z 240 (M+H) The following compounds were obtained in substantially the same manner as that of Preparation 11. 30 Preparation 12 (1 -Amino-5-ethyl-1H-pyrrol-2-yl)(2-chloro-4-pyridinyl)methanone NMR (CDCl 3 , 6): 1.29 (3H, t, J=71Hz), 2.77 (2H, q, J=7Hz), 5.71 (2H, s), 5.96 (11H, d, 45 WO 2004/063197 PCT/JP2003/017091 J=4Hz), 6.63 (1H, d, J=4Hz), 7.50 (1H, d, J=4Hz), 7.61 (1H, s), 8.52 (1H, d, J=4Hz) MS: (m/z) 250 (M+H) 5 Preparation 13 3-[(1 -Amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-benzonitrile NMR (CDCl 3 , 6): 1.29 (3H, t, J=7Hz), 2.77 (2H, q, J=7Hz), 5.74 (2H, s), 5.94 (1H, d, J=5Hz), 6.59 (1H, d, J=5Hz), 7.59 (1H, t, J=8Hz), 7.82 (1H, d, J=8Hz), 8.00 (1H, d, J=8Hz), 8.06 (1H, s) 10 Preparation 14 (2E)-1 -(1 -Amino-5-ethyl-1H-pyrrol-2-yl)-3-phenyl-2-propen-1 -one NMR (CDC1 3 , 5): 1.28 (3H, t, J=7Hz), 2.73 (2H, q, J=7Hz), 5.93 (1H, d, J=5Hz), 6.99 (1H, d, J=5Hz), 7.30 (1H, d, J=16Hz), 7.37-7.43 (3H, m), 7.62 (2H, m), 7.74 15 (1H, d, J=16Hz) MS (ESI+): m/z 241 (M+H) Preparation 15 (1 -Amino-5-ethyl-1H-pyrrol-2-yl)(3-methoxyphenyl)-methanone 20 NMR (CDCl 3 , 6): 1.26 (3H, t, J=7Hz), 2.75 (2H, q, J=7Hz), 3.86 (3H, s), 5.79 (2H, s), 5.89 (1H, d, J=4Hz), 6.67 (1H, d, J=4Hz), 7.07 (1H, m), 7.29-7.40 (3H, m) MS (ESI*): m/z 245 Preparation 16 25 (1-Amino-5-ethyl-1H-pyrrol-2-yl)(4-pyridinyl)methanone NMR (CDCl 3 , 6): 1.29 (3H, t, J=7Hz), 2.77 (2H, q, J=7Hz), 5.76 (2H, s), 5.94 (1H, d, J=4Hz), 6.63 (1H, d, J=4Hz), 7.58 (2H, d, J=7Hz), 8.75 (2H, d, J=7Hz) MS (ESI*): m/z 216 30 Preparation 17 (1-Amino-5-ethyl-1H-pyrrol-2-yl)(2-pyrazinyl)methanone NMR (CDCI 3 , 8): 1.29 (3H, t, J=7Hz), 2.77 (2H, q, J=7Hz), 5.79 (2H, s), 5.98 (1H, d, 46 WO 2004/063197 PCT/JP2003/017091 J=4Hz), 7.27 (1H, d, J=4Hz), 8.63 (1H, m), 8.71 (1H, m), 9.17 (1H, m) Preparation 18 (1-Amino-5-ethyl-1H-pyrrol-2-yl)(3-pyridinyl)methanone 5 NMR (CDCI 3 , 6): 1.29 (3H, t, J=7Hz), 2.77 (2H, q, J=7Hz), 5.78 (2H, s), 5.94 (1H, d, J=4Hz), 6.65 (1H, d, J=4Hz), 7.39 (1H, m), 8.06 (1H, m), 8.74 (1H, m), 8.99 (1H, m) Preparation 19 10 (1-Amino-5-ethyl-1H-pyrrol-2-yl)(5-bromo-3-pyridinyl)-methanone NMR (CDCl 3 , 6): 1.29 (3H, t, J=7Hz), 2.76 (2H, q, J=7Hz), 5.72 (2H, s), 5.96 (1H, m), 6.65 (1H, m), 8.19 (1H, m), 8.70 (1H, m), 8.89 (1H, m) Preparation 20 15 To a solution of tert-butyl 3-oxobutanoate (20.0 g) in tetrahydrofuran (200 mL) was added 60% sodium hydride in oil (5.56 g) portionwise over 20 minutes in an ice water bath under N 2 . After 40 minutes, to the mixture was added ethyl 5-iodopentanoate (35.6 g) at the temperature. After 15 minutes, the mixture was stirred at ambient temperature. After 1 hour, the reaction mixture was heated at 50*C for 24 hours. The 20 cooled mixture was partitined between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 1 L) eluting with hexane-ethyl acetate = 50 1, 20-1, 10-1, and 8-1 to give 1-tert-butyl 7-ethyl 2-acetylheptanedioate (27.3 g, 75.4%) 25 as colorless oil. 1-tert-Butyl 7-ethyl 2-acetylheptanedioate NMR (CDCl 3 , 6): 1.20-1.38 (5H, m), 1.46 (9H, s), 1.54-1.71 (2H, m), 1.75-1.87 (2H, m), 2.12 (3H, s), 2.30 (2H, t, J=8Hz), 3.30 (12H, t, J=8Hz), 4.11 (2H, q, J=8Hz) 30 The following compounds were obtained in substantially the same manner as that of Preparation 20. 47 WO 2004/063197 PCT/JP2003/017091 Preparation 21 1-tert-Butyl 9-ethyl 2-acetylnonanedioate NMR (CDCl 3 , 5): 1.23-1.33 (9H, m), 1.46 (9H, s), 1.55 (2H, m), 1.77 (2H, m), 2.21 (3H, s), 2.28 (2H, t, J=7Hz), 3.27 (1H, t, J=7Hz), 4.12 (2H, q, J=7Hz) 5 MS (ESI*): m/z 315 (M+H) Preparation 22 tert-Butyl 2-acetylhexanoate NMR (CDCl 3 , 5): 0.90 (3H, t, J=8Hz), 1.28-1.40 (4H, m), 1.46 (9H, s), 1.73-1.89 10 (2H, m), 2.22 (311, s), 3.30 (1H, t, J=8Hz) Preparation 23 1-tert-Butyl 8-ethyl 2-acetyloctanedioate NMR (CDCI 3 , 6): 1.21-1.33 (7H, m), 1.46 (9H, s), 1.54-1.69 (2H, m), 1.74-1.85 (2H, 15 m), 2.21 (3H, s), 2.28 (2H, t, J=8Hz), 3.29 (1H, t, J=8Hz), 4.12 (2H, q, J=8Hz) Preparation 24 To a suspension of magnesium chloride (1.33 g) in dichloromethane (40 mL) was added 1-tert-butyl 7-ethyl 2-acetylheptanedioate (4.0 g) at ambient temperature under N 2 . 20 To this mixture was added dropwise pyridine (2.26 mL) in an ice-water bath. Then the mixture was stirred at ambient temperature for 40 minutes. To the reaction mixture was added a solution of 3-cyanobenzoyl chloride (3.01 g) in dichloromethane (6 mL) dropwise over 2 minutes. The reaction mixture was stirred at ambient temperature for 2 hours. To the mixture was added 1N hydrogen chloride and ethyl acetate in an ice-water 25 bath. The organic layer was washed with 1N hydrogen chloride, water, and brine, dried over magnesium sulfate, and evaporated in vacuo to give a solid. The residue was purified by flash silica gel chromatography (silica gel, 300 mL) eluting with hexane-ethyl acetate = 10-1, 8-1, 5-1, and 3-1 to give 1-tert-butyl 7-ethyl 2-acetyl-2-(3 cyanobenzoyl)heptanedioate (4.23 g, 72.9%) as colorless oil. 30 1-tert-Butyl 7-ethyl 2-acetyl-2-(3-cyanobenzoyl)-heptanedioate NMR (CDCI 3 , 6): 1.25 (311, t, J=8Hz), 1.28-1.40 (11H, m), 1.63-1.75 (2H, m), 2.19 48 WO 2004/063197 PCT/JP2003/017091 2.28 (2H, m), 2.32 (2H, t, J=8Hz), 2.45 (3H, s), 4.11 (2H, q, J=8Hz), 7.56 (1H, t, J=8Hz), 7.80 (2H, dd, J=8, 1Hz), 7.95 (2H, dd, J=8, 1Hz), 8.06 (1H, br s) MS (ESI*): m/z 416 (M+H) 5 The following compounds were obtained in substantially the same manner as that of Preparation 24. Preparation 25 Ethyl 2-isobutyryl-4-methyl-3-oxopentanoate NMR (300 MHz, CDCl 3 , 8): 1.10-1.23 (12H, m), 1.30-1.43 (3H, m), 2.91-3.10 (2H, 10 m),4.21-4.36 (2H, m) Preparation 26 Ethyl 2-(2-chlorobenzoyl)-4-methyl-3-oxopentanoate NMR (300 MHz, CDCl 3 , 6): 0.79 (3H, t, J=7.5Hz),1.22 (6H, d, J=7.5Hz), 3.36-3.54 15 (1H, m), 3.88 (2H, q, J=7.5Hz), 7.26-7.44 (4H, m) Preparation 27 Ethyl 4-methyl-2-(2-naphthoyl)-3-oxopentanoate NMR (300 MHz, CDC1 3 , 6): 0.76-1.03 (3H, m), 1.10-1.30 (6H, m), 2.56-2.71 (1/2H, 20 m), 2.88-3.04 (1/6H, m), 3.20-3.35 (1/3H, m), 3.72-4.336 (3H, m), 7.50-7.68 (2+1/3H, m), 7.82-8.01 (3+2/3H, m), 8.09 (1/3H, s), 8.35 (1/2H, s), 8.41 (1/6H, s) MS (ES+): m/e 313.45 Preparation 28 25 1-tert-Butyl 7-ethyl 2-acetyl-2-[3-(trifluoromethyl)benzoyl]heptanedioate NMR (CDCl 3 , 6): 1.24 (3H, t, J=7Hz), 1.32 (9H, s), 1.36-1.75 (4H, m), 2.15-2.36 (4H, m), 2.45 (3H, s), 4.11 (2H, q, J=7Hz), 7.56 (1H, t, J=8Hz), 7.79 (1H, d, J=8Hz), 7.93 (1H, d, J=8Hz), 8.04 (1H, s) 30 Preparation 29 1-tert-Butyl 7-ethyl 2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyl]heptanedioate NMR (CDCI 3 , 8): 1.24 (3H, t, J=7Hz), 1.27-1.42 (2H, m), 1.34 (9H, s), 1.65-1.77 49 WO 2004/063197 PCT/JP2003/017091 (2H, m), 2.16-2.35 (4H, m), 2.39 (3H, s), 2.43 (3H, s), 4.10 (2H, q, J=7Hz), 7.87 (1H, s), 8.56 (1H, s), 8.73 (1H, s) MS (ESI+): m/z 406 (M+H) 5 Preparation 30 1-tert-Butyl 7-ethyl 2-(methoxyacetyl)-2-[(3-methoxy Sisoxazolyl)carbonyl]heptanedioate NMR (CDCl 3 , 8): 1.25 (3H, t, J=7Hz), 1.39 (9H, s), 1.35-1.50 (2H, m), 1.64-1.75 (2H, m), 2.15-2.23 (2H, m), 2.32 (2H, t, J=7Hz), 3.40 (3H, s), 4.01 (3H, s), 4.12 10 (2H, q, J=7Hz), 4.57 (2H, s), 6.54 (1H, s) Preparation 31 1-tert-Butyl 7-ethyl 2-acetyl-2-[3-(1,3-oxazol-5-yl)benzoyl]heptanedioate NMR (CDCL 3 , 8): 1.23 (3H, t, J=7Hz), 1.33 (9H, s), 1.30-1.43 (2H, m), 1.62-1.76 15 (2H, m), 2.17-2.35 (4H, m), 2.44 (3H, s), 4.09 (2H, q, J=7Hz), 7.42 (1H, s), 7.48 (1H, t, J=8Hz), 7.69 (1H, d, J=8Hz), 7.82 (1H, d, J=8Hz), 7.94 (1H, s), 8.09 (1H, m) Preparation 32 20 1-tert-Butyl 7-ethyl 2-acetyl-2-(3,4-dichlorobenzoyl)heptanedioate NMR (CDCI 3 , 8): 1.23 (3H, t, J=7Hz), 1.30-1.43 (2H, m), 1.35 (9H, s), 1.63-1.74 (2H, m), 2.15-2.34 (4H, m), 2.41 (3H, s), 4.10 (2H, q, J=7Hz), 7.48 (1H, d, J=8Hz), 7.56 (1H, dd, J=2, 8Hz), 7.88 (1H, d, J=2Hz) 25 Preparation 33 1-tert-Butyl 7-ethyl 2-acetyl-2-[(4-chloro-2-pyridinyl)carbonyl]heptanedioate NMR (CDCI 3 , 8): 1.23-1.30 (3H, m), 1.25 (9H, s), 1.40-1.58 (2H, m), 1.65-1.77 (2H, m), 2.10-2.21 (2H, m), 2.35 (2H, t, J=7Hz), 2.61 (3H, s), 4.12 (2H, q, J=7Hz), 7.39 (1H, m), 8.04 (1H, m), 8.43 (1H, d, J=5Hz) 30 MS (ESI*): m/z 426 (M+H) Preparation 34 50 WO 2004/063197 PCT/JP2003/017091 1-tert-Butyl 7-ethyl 2-[(5-chloro-2-thienyl)carbonyl]-2-(methoxyacetyl)heptanedioate NMR (CDC1 3 , 8): 1.23 (3H, t, J=7Hz), 1.25-1.40 (2H, m), 1.41 (9H, s), 1.62-1.74 (2H, m), 2.26-2.37 (4H, m), 3.37 (3H, s), 4.11 (2H, q, J=7Hz), 4.30 (1H, d, J=17Hz), 4.42 (1H, d, J=17Hz), 6.92 (1H, d, J=4Hz), 7.39 (IH, d, J=4Hz) 5 Preparation 35 I-tert-Butyl 7-ethyl 2-acetyl-2-[(6-methoxy-2-pyrazinyl)carbonyl]heptanedioate NMR (CDCL 3 , 6): 1.24 (3H, t, J=7Hz), 1.26 (9H, s), 1.38-1.49 (2H, m), 1.66-1.80 (2H, m), 2.14-2.26 (2H, m), 2.33 (2H, t, J=7Hz), 2.57 (3H, s), 3.90 (3H, s), 4.12 10 (2H, q, J=7Hz), 8.37 (1H, s), 8.83 (1H, s) Preparation 36 1-tert-Butyl 7-ethyl 2-acetyl-2-(1-benzofuran-2-ylcarbonyl)heptanedioate NMR (CDCJ 3 , 6): 1.23 (3H, t, J=7Hz), 1.33 (9H, s), 1.38-1.55 (2H, m), 1.64-1.77 15 (2H, m), 2.23-2.36 (4H, m), 2.49 (3H, s), 4.08 (2H, q, J=7Hz), 7.32 (1H, m), 7.46 (2H, m), 7.54 (1H, s), 7.71 (1H, d, J=8Hz) Preparation 37 1-tert-Butyl 7-ethyl 2-acetyl-2-(1-benzothien-2-ylcarbonyl)heptanedioate 20 NMR (CDC1 3 , 5): 1.23 (3H, t, J=7Hz), 1.30-1.45 (2H, m), 1.39 (9H, s), 1.62-1.75 (2H, m), 2.25-2.38 (4H, m), 2.40 (3H, s), 4.10 (2H, q, J=7Hz), 7.36-7.51 (2H, m), 7.76 (1H, s), 7.82-7.88 (2H, m) Preparation 38 25 1-tert-Butyl 7-ethyl 2-acetyl-2-(1,3-oxazol-5-ylcarbonyl)heptanedioate NMR (CDCI 3 , 6): 1.24 (3H, t, J=7Hz), 1.30-1.45 (2H, m), 1.38 (9H, s), 1.63-1.77 (2H, m), 2.15-2.27 (2H, m), 2.30 (2H, t, J=7Hz), 2.43 (3H, s), 4.10 (2H, q, J=7Hz), 7.80 (1H, s), 7.93 (11H, s) 30 Preparation 39 1-tert-Butyl 7-ethyl 2-acetyl-2-benzoylheptanedioate NMR (CDCl 3 , 6): 1.26 (3H, t, J=7Hz), 1.20-1.40 (2H, m), 1.32 (9H, s), 1.60-1.73 51 WO 2004/063197 PCT/JP2003/017091 (2H, m), 2.26-2.38 (4H, m), 2.40 (3H, s), 4.12 (2H, q, J=7Hz), 7.36-7.78 (5H, m) Preparation 40 1-tert-Butyl 7-ethyl 2-acetyl-2-(6-quinolinylcarbonyl)heptanedioate 5 NMR (CDCl 3 , 8): 1.21 (3Ht, J=7Hz), 1.30 (9H, s), 1.32-1.47 (2H, m), 1.64-1.77 (2H, m), 2.26-2.38 (4H, m), 2.46 (3H, s), 4.08 (2H, q, J=7Hz), 7.48 (1H, m), 8.04 (IH, dd, J=2 Hz, 8Hz), 8.13 (1H, d, J=8Hz), 8.23 (1H, d, J=8Hz), 8.28 (1H, d, J=2Hz), 9.00 (1H, m) MS (ESI): m/z 442 (M+H) 10 Preparation 41 1-tert-Butyl 9-ethyl 2-acetyl-2-[4-({ [(benzyloxy)carbonyl]amino}sulfonyl)benzoyl] nonanedioate NMR (CDC1 3 , 8): 1.23-1.37 (11H, m), 1.60 (9H, s), 2.15-2.31 (4H, m), 2.46 (3H, s), 15 4.12 (2H, q, J=7Hz), 5.10 (2H, s), 7.26-7.40 (5H, m), 7.65 (1H, s, br), 7.84 (2H, d, J=9Hz), 8.06 (2H, d, J=9Hz) Preparation 42 1-tert-Butyl 7-ethyl 2-acetyl-2-(2-chloroisonicotinoyl)heptanedioate 20 NMR (CDCI 3 , 5): 1.20-1.40 (14H, m), 1.61-1.75 (2H, m), 2.19-2.28 (2H, m), 2.20 (2H, t, J=8Hz), 2.31 (2H, t, J=8Hz), 2.46 (3H, s), 4.11 (2H, q, J=8Hz), 7.41 (1H, dd, J =7, 1Hz), 7.55 (1H, d, J=lHz), 8.50 (1H, d, J=7Hz) Preparation 43 25 1-tert-Butyl 7-ethyl 2 -acetyl-2-[3-(methylsulfonyl)benzoyl]heptanedioate NMR (CDCI 3 , 8): 1.24 (3H, t, J=8Hz), 1.27-1.40 (11H, m), 1.61-1.75 (2H, m), 2.19 2.35 (4H, m), 2.46 (3H, s), 3.07 (3H, s), 4.10 (2H, q, J=8Hz), 7.65 (1H, t, J=8Hz), 7.99 (1H, dd, J=8, 1Hz), 8.09 (2H, br d, J=8Hz), 8.34 (1H, br s) 30 Preparation 44 1-tert-Butyl 7-ethyl 2 -acetyl-2-(3-nitrobenzoyl)heptanedioate NMR (CDCI 3 , 8): 1.30-1.39 (12H, m), 1.61-1.75 (2H, m), 2.19-2.35 (4H, m), 52 WO 2004/063197 PCT/JP2003/017091 2.47(3H, s), 4.10 (2H, q, J=8Hz), 7.63 (1H, t, J=8Hz), 8.09 (1H, br d, J=8Hz), 8.39 (IH, br d, J=8Hz), 8.60 (1H, br s) Preparation 45 5 tert-Butyl 2-acetyl-2-(4-cyanobenzoyl)hexanoate NMR (CDCI 3 , 5): 0.90 (311, t, J=8Hz), 1.20-1.44 (13H, m), 2.15-2.25 (2H, m), 2.45 (3H, s), 7.70 (21, d, J=8Hz), 7.83 (2H, d, J=8Hz) Preparation 46 10 1-tert-Butyl 7-ethyl 2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyljheptanedioate NMR (CDCI 3 , 5): 1.25 (3H, t, J=7Hz), 1.36 (91H, s), 1.32-1.45 (2H, m), 1.65-1.77 (2H, m), 2.18-2.28 (21, m), 2.32 (2H, t, J=711z), 2.45 (311, s), 4.11 (2H, q, J=7Hz), 8.20 (1H, m), 8.80 (21, m) MS: (m/z) 470,472 (M+H) 1s Preparation 47 1-tert-Butyl 7-ethyl 2-(2-chloroisonicotinoyl)-2-[(methylthio)acetyl]heptanedioate NMR (CDCl 3 , 5): 1.24 (3H, t, J=7Hz), 1.37 (911, s), 1.23-1.45 (2H, m), 1.63-1.77 (2H, m), 2.05 (3H, s), 2.16-2.28 (2H, m), 2.32 (211, t, J=7Hz), 3.16 (111, d, 20 J=17Hz), 4.07 (11, d, J=17Hz), 4.11 (2H, q, J=7Hz), 7.68 (111, d, J=5Hz), 7.87 (11H, s), 8.49 (1H, d, J=5Hz) Preparation 48 Ethyl 2-(4-fluorobenzoyl)-3-oxobutanoate 25 NMR (CDCl 3 , 6): (mixture of tautomers) 0.97 and 1.02 (31H, t, J=7Hz), 2.07 and 2.42 (31H, s), 4.01 and 4.13 (211, q, J=7Hz), 7.06-7.18, 7.56, and 7.85 (411, m) MS (ESI*): m/z 275 (M+H) Preparation 49 30 1-tert-Butyl 8-ethyl 2-acetyl-2-(3-cyanobenzoyl)octanedioate NMR (CDCI 3 , 8): 1.21-1.46 (16H, m), 1.56-1.70 (2H, m), 2.15-2.25 (2H, m), 2.29 (211, t, J=8Hz), 2.45 (311, s), 4.12 (211, q, J=8Hz), 7.56 (11H, t, J=8Hz), 7.80 (2H, 53 WO 2004/063197 PCT/JP2003/017091 dd, J=8, 1Hz), 7.95 (2H, dd, J=8, 1Hz), 8.05 (1H, br s) Preparation 50 1-tert-Butyl 7-ethyl 2-acetyl-2-[(6-chloro-2-pyridinyl)carbonyl]heptanedioate 5 NMR (CDCl 3 , 8): 1.25 (3H, t, J=7Hz), 1.27 (9H, s), 1.20-1.78 (4H, m), 2.08 (2H, t, J=7Hz), 2.26-2.40 (2H, m), 2.69 (3H, s), 4.12 (2H, q, J=7Hz), 7.43 (1H, d, J=8Hz), 7.81 (1H, t, J=8Hz), 7.96 (1H, d, J=8Hz) MS (ESI*): m/z 426 10 Preparation 51 1-tert-Butyl 7-ethyl 2-acetyl-2-(3-methoxybenzoyl)heptanedioate NMR (CDCl 3 , 6): 1.25 (3H, m), 1.34 (9H, s), 1.20-1.92 (4H, m), 2.10-2.38 (4H, m), 2.41 (3H, s), 3.84 (3H, s), 4.04-4.22 (2H, m), 7.08 (1H, br), 7.23-7.40 (3H, m) 15 Preparation 52 1-tert-Butyl 7-ethyl 2-acetyl-2-(3,5-dichlorobenzoyl)heptanedioate NMR (CDCl 3 , 5): 1.24 (3H, t, J=7Hz), 1.26-1.40 (2H, m), 1.36 (9H, s), 1.63-1.76 (2H, m), 2.15-2.36 (4H, m), 2.43 (3H, s), 4.10 (2H, q, J=7Hz), 7.51 (1H, m), 7.60 (2H, m) 20 Preparation 53 1-tert-Butyl 7-ethyl 2-acetyl-2-[(5-chloro-2-thienyl)carbonyl]heptanedioate NMR (CDCJ 3 , 5): 1.23 (3H, t, J=7Hz), 1.40 (9H, s), 1.30-1.90 (4H, m), 2.20-2.35 (4H, m), 2.38 (3H, s), 4.11 (2H, q, J=7Hz), 6.91 (1H, d, J=4Hz), 7.32 (1H, d, 25 J=4Hz) Preparation 54 1-tert-Butyl 7-ethyl 2-acetyl-2-(3-fluorobenzoyl)heptanedioate NMR (CDCl 3 , 6): 1.23 (3H, t, J=7Hz), 1.35 (9H, s), 1.35-1.45 (2H, m), 1.64-1.74 30 (2H, m), 2.16-2.35 (4H, m), 2.42 (3H, s), 4.09 (2H, q, J=7Hz), 7.24 (1H, m), 7.35-7.43 (1H, m), 7.46-7.53 (2H, m) 54 WO 2004/063197 PCT/JP2003/017091 Preparation 55 1-tert-Butyl 7-ethyl 2-acetyl-2-(3-quinolinylcarbonyl)heptanedioate NMR (CDCl 3 , 6): 1.22 (3H, t, J=7Hz), 1.33 (9H, s), 1.33-1.53 (2H, m), 1.65-1.78 (2H, m), 2.25-2.43 (4H, m), 2.47 (3H, s), 4.08 (2H, q, J=7Hz), 7.63 (1H, t, 5 J=8Hz), 7.81-7.87 (1H, t, J=8Hz), 7.91 (1H, d, J=8Hz), 8.56 (1H, m), 9.24 (1H, m) MS (ESI*): m/z 442 Preparation 56 10 1-tert-Butyl 7-ethyl 2-acetyl-2-isonicotinoylheptanedioate NMR (CDCl 3 , 8): 1.23 (3H, t, J=7Hz), 1.31 (9H, s), 1.30-1.45 (2H, m), 1.65-1.76 (2H, m), 2.18-2.28 (2H, m), 2.31 (2H, t, J=7Hz), 2.45 (3H, s), 4.10 (2H, q, J=7Hz), 7.52 (2H, d, J=7Hz), 8.75 (2H, d, J=7Hz) 15 Preparation 57 1-tert-Butyl 7-ethyl 2-acetyl-2-[(3-methoxy-5-isoxazolyl)carbonyl]heptanedioate NMR (CDCl 3 , 6): 1.25 (3H, t, J=7Hz), 1.39 (9H, s), 1.35-1.50 (2H, m), 1.62-1.75 (2H, m), 2.11-2.23 (2H, m), 2.33 (2H, t, J=7Hz), 2.49 (3H, s), 4.01 (3H, s), 4.11 (2H, q, J=7Hz), 6.53 (1H, s) 20 Preparation 58 1-tert-Butyl 7-ethyl 2-acetyl-2-[(5-methyl-3-isoxazolyl)carbonyl]heptanedioate NMR (CDCl 3 , 6): 1.24 (3H, t, J=7Hz), 1.31-1.48 (2H, m), 1.37 (9H, s), 1.63-1.75 (2H, m), 2.18-2.26 (2H, m), 2.31 (2H, t, J=7Hz), 2.47 (3H, s), 2.50 (3H, s), 4.11 25 (2H, q, J=7Hz), 6.38 (1H, s) Preparation 59 1-tert-Butyl 7-ethyl 2-(2-chloroisonicotinoyl)-2-(methoxyacetyl)heptanedioate NMR (CDCl 3 , 6): 1.24 (3H, t, J=7Hz), 1.32-1.45 (2H, m), 1.36 (9H, s), 1.64-1.78 30 (2H, m), 2.16-2.28 (2H, m), 2.31 (2H, t, J=7Hz), 3.36 (3H, s), 4.11 (2H, q, J=7Hz), 4.25 (1H, d, J=17Hz), 4.39 (1H, d, J=17Hz), 7.39 (1H, d, J=5Hz), 7.54 (1H, s), 8.50 (1H, d, J=5Hz) 55 WO 2004/063197 PCT/JP2003/017091 MS (ESI*): m/z 456 Preparation 60 1-tert-Butyl 7-ethyl 2 -(methoxyacetyl)-2-(3-methoxybenzoyl)heptanedioate 5 NMR (CDCI 3 , 8): 1.22 (3H, t, J=7Hz), 1.25-1.33 (2H, m), 1.34 (9H, s), 1.60-1.75 (2H, m), 2.15-2.40 (4H, m), 3.38 (3H, s), 3.83 (3H, s), 4.08 (2H, q, J=7Hz), 4.39 (1H, d, J=17Hz), 4.55 (1H, d, J=17Hz), 7.07 (1H, m), 7.26-7.34 (3H, m) MS (ESI*): m/z 451 10 Preparation 61 1-tert-Butyl 7-ethyl 2 -(methoxyacetyl)-2-(6-quinolinylcarbonyl)heptanedioate NMR (CDCl 3 , 6): 1.25 (3H, t, J=7Hz), 1.32 (9H, s), 1.30-1.50 (2H, m), 1.65-1.78 (2H, m), 2.26-2.44 (4H, m), 3.38 (3H, s), 4.11 (2H, q, J=7Hz), 4.38 (1H, d, J=17Hz), 4.57 (1H, d, J=17Hz), 7.47 (1H, m), 8.03 (1H, d, J=8Hz), 8.13 (1H, d, 15 J=8Hz), 8.28 (1H, d, J=8Hz), 8.27 (1H, s), 9.01 (1H, m) MS (ESI): m/z 472 Preparation 62 1-tert-Butyl 7-ethyl 2 -(methoxyacetyl)-2-(3-pyridinylcarbonyl)heptanedioate 20 NMR (CDCI 3 , 5): 1.23 (3H, t, J=7Hz), 1.30-1.47 (2H, m), 1.35 (9H, s), 1.63-1.78 (2H, m), 2.22-2.38 (4H, m), 3.37 (3H, s), 4.10 (2H, q, J=7Hz), 4.32 (1H, d, J=17Hz), 4.45 (1H, d, J=17Hz), 7.37 (1H, m), 8.03 (1H, m), 8.73 (1H, m), 8.92 (1H, m) 25 Preparation 63 1-tert-Butyl 7-ethyl 2

-(

3 -chlorobenzoyl)-2-(methoxyacetyl)heptanedioate NMR (CDCl 3 , 6): 1.25 (3H, t, J=7Hz), 1.35 (9H, s), 1.20-1.50 (2H, m), 1.60-1.73 (2H, m), 2.25-2.35 (4H, m), 3.37 (3H, s), 4.12 (2H, q, J=7Hz), 4.35 (1H, d, J=17Hz), 4.50 (1H, d, J=17Hz), 7.34 (1H, m), 7.48 (1H, d, J=8Hz), 7.59 (1H, d, 30 J=8Hz), 7.73 (1H, m) Preparation 64 56 WO 2004/063197 PCT/JP2003/017091 1-tert-Butyl 7-ethyl 2 -acetyl- 2

-(

3 -methylbenzoyl)heptanedioate , NMR (CDCl 3 , 6): 1.25 (3H, t, J=7Hz), 1.30-1.40 (2H, m), 1.33 (9H, s), 1.60-1.72 (2H, m), 2.10-2.38 (4H, m), 2.21 (3H, s), 2.39 (3H, s), 4.10 (2H, q, J=7Hz), 7.26 7.36 (2H, m), 7.48-7.62 (2H, m) 5 MS (ESI*): m/z 405 Preparation 67 1-tert-Butyl 7-ethyl 2 -(methoxyacetyl)-2-[(5-methyl-3-pyridinyl)carbonyl]heptanedioate NMR (CDCl 3 , 5): 1.25 (3H, t, J=7Hz), 1.36 (9H, s), 1.30-1.45 (2H, m), 1.62-1.76 10 (2H, m), 2.20-2.36 (4H, m), 2.40 (3H, s), 3.38 (3H, s), 4.10 (2H, q, J=7Hz), 4.34 (1H, d, J=17Hz), 4.49 (1H, d, J=17Hz), 7.86 (1H, s), 8.56 (1H, s), 8.73 (1H, s) MS (ESI*): m/z 436 Preparation 68 15 1-tert-Butyl 7-ethyl 2 -acetyl- 2 -[(5-bromo-3-pyridinyl)carbonyl]heptanedioate NMR (CDCI 3 , 5): 1.25 (3H, t, J=7Hz), 1.36 (9H, s), 1.32-1.45 (2H, m), 1.65-1.77 (2H, m), 2.18-2.28 (2H, m), 2.32 (2H, t, J=7Hz), 2.45 (3H, s), 4.11 (2H, q, J=7Hz), 8.20 (1H, m), 8.80 (2H, m) MS (ESI*): m/z 470,472 20 Preparation 69 1-tert-Butyl 7-ethyl 2 -[(5-bromo-3-pyridinyl)carbonyl]- 2 -(methoxyacetyl)heptanedioate NMR (CDCl 3 , 6): 1.24 (3H, t, J=7Hz), 1.30-1.44 (2H, m), 1.37 (9H, s), 1.65-1.77 (2H, m), 2.18-2.36 (4H, m), 3.36 (3H, s), 4.10 (2H, q, J=7Hz), 4.28 (1H, d, 25 J=17Hz), 4.40 (1H, d, J=17Hz), 8.18 (1H, m), 8.80 (2H, m) MS (ESI*): m/z 500,502 Preparation 70 1-tert-Butyl 7-ethyl 2-acetyl-2-[(5, 6 -dichloro-3-pyridinyl)carbonyl]heptanedioate 30 NMR (CDCl 3 , 6): 1.24 (3H, t, J=7Hz), 1.25-1.40 (2H, m), 1.38 (9H, s), 1.65-1.75 (2H, m), 2.18-2.27 (2H, m), 2.28-2.37 (2H, m), 2.44 (3H, s), 4.12 (2H, q, J=7Hz), 8.13 (1H, d, J=2Hz), 8.57 (1H, d, J=2Hz) 57 WO 2004/063197 PCT/JP2003/017091 Preparation 71 1-tert-Butyl 6-ethyl 2-(methoxyacetyl)-2-[(5-methyl-3-pyridinyl)carbonyl]hexanedioate NMR (CDCl 3 , 8): 1.24 (3H, t, J=7Hz), 1.36 (9H, s), 1.60-1.80 (2H, m), 2.20-2.45 5 (4H, m), 2.39 (3H, s), 3.38 (3H, s), 4.12 (2H, q, J=7Hz), 4.38 (1H, d, J=18Hz), 4.50 (1H, d, J=18Hz), 7.87 (1H, s), 8.55 (1H, s), 8.73 (1H, s) MS (ESI'): m/z 422 Preparation 72 10 1-tert-Butyl 5-ethyl 2-(methoxyacetyl)-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate NMR (CDC1 3 , 8): 1.24 (3H, t, J=7Hz), 1.37 (9H, s), 2.23-2.70 (4H, m), 2.39 (3H, s), 3.37 (3H, s), 4.12 (2H, q, J=7Hz), 4.32 (1H, d, J=18Hz), 4.43 (1H, d, J=18Hz), 7.84 (1H, s), 8.55 (1H, s), 8.73 (1H, s) MS (ESI*): m/z 408 15 Preparation 73 1-tert-Butyl 6-ethyl 2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyl]hexanedioate NMR (CDCl 3 , 8): 1.24 (3H, t, J=7Hz), 1.34 (9H, s), 1.60-1.75 (2H, m), 2.20-2.39 (4H, m), 2.39 (3H, s), 2.46 (3H, s), 4.11 (2H, q, J=7Hz), 7.87 (1H, s), 8.56 (1H, s), 20 8.73 (1H, s) MS (ESI*): m/z 392 Preparation 74 1-tert-Butyl 5-ethyl 2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate 25 NMR (CDC1 3 , 8): 1.24 (3H, t, J=7Hz), 1.36 (9H, s), 2.39 (3H, s), 2.44 (3H, s), 2.35 2.47 (2H, m), 2.56-2.70 (2H, m), 4.11 (2H, q, J=7Hz), 7.88 (1H, s), 8.56 (1H, s), 8.74 (1H, s) MS (ESI*): m/z 378 30 Preparation 75 1-tert-Butyl 5-ethyl 2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]pentanedioate NMR (CDCI 3 , 8): 1.24 (3H, t, J=7Hz), 1.37 (9H, s), 2.40 (2H, t, J=7Hz), 2.59 (2H, t, 58 WO 2004/063197 PCT/JP2003/017091 J=7Hz), 2.46 (3H, s), 4.13 (2H, q, J=7Hz), 8.20 (1H, t, J=3Hz), 8.81 (2H, dd, J=7, 3Hz) Preparation 76 5 1-tert-Butyl 7-ethyl 2-(3-cyanobenzoyl)-2-(methoxyacetyl)heptanedioate NMR (CDCl 3 , 8): 1.20-1.41 (14H, m), 1.60-1.74 (2H, m), 2.27-2.34 (4H, m), 3.37 (83H, s), 4.10 (2H, q, J=8Hz), 4.29 (1H, d, J=16Hz), 4.46 (1H, d, J=16Hz), 7.55 (1H, t, J=8Hz), 7.80 (1H, dd, J=8, 1Hz), 7.93 (1H, dd, J=8, 1Hz), 8.04 (1H, br s) 10 Preparation 77 1-tert-Butyl 7-ethyl 2-[(acetyloxy)acetyl]-2-[(5-bromo-3 pyridinyl)carbonyl]heptanedioate NMR (CDCI 3 , 8): 1.22-1.28 (5H, m), 1.36 (9H, s), 1.68 (2H, m), 2.14 (3H, s), 2.32 (2H, m), 4.11 (2H, q, J=7Hz), 5.07 (1H, d, J=18Hz), 5.34 (1H, d, J=18Hz), 8.21 15 (1H, m), 8.81 (2H, m) Preparation 78 To 1-tert-butyl 7-ethyl 2-acetyl-2-(3-cyanobenzoyl) heptanedioate (4.2 g) was added trifluoroacetic acid (20 mL) in an ice-water bath. After 20 30 minutes, the bath was removed and the reaction mixture was stirred at ambient temperature. After 1 hour, the mixture was concentrated. The residue was dissolved in toluene and was evaporated in vacuo to give ethyl 6-(3-cyanobenzoyl)-7-oxooctanoate (3.20 g, 100.4%) as colorless oil. 25 Ethyl 6-(3-cyanobenzoyl)-7-oxooctanoate NMR (CDCl 3 , 8): 1.25 (3H, t, J=8Hz), 1.28-1.40 (2H, m), 1.60-1.74 (2H, m), 1.91 2.14 (2H, m), 2.17 (3H, s), 2.31 (2H, t, J=8Hz), 4.11 (2H, q, J=8Hz), 4.39 (1H, t, J=8Hz), 7.64 (1H, t, J=8Hz), 7.87 (211, dd, J=8, 1Hz), 8.20 (2H, dd, J=8, 1Hz), 8.26 (1H, br s) 30 MS (EST): m/z 314 (M-H) The following compounds were obtained in substantially the same manner as that 59 WO 2004/063197 PCT/JP2003/017091 of Preparation 78. Preparation 79 Ethyl 7-oxo-6-[3-(trifluoromethyl)benzoyl]octanoate NMR (CDCl 3 , 8): 1.24 (3H, t, J=7Hz), 1.32-1.43 (2H, m), 1.62-1.77 (2H, m), 1.96 5 2.17 (2H, m), 2.17 (3H, s), 2.30 (2H, t, J=7Hz), 4.11 (21H, q, J=7Hz), 4.44 (11-1, t, J=7Hz), 7.64 (1H, t, J=8Hz), 7.86 (1H, d, J=8Hz), 8.15 (1H, d, J=8Hz), 8.24 (1H, s) Preparation 80 10 Ethyl 6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate NMR (CDCl 3 , 6): 1.26 (3H, t, J=7Hz), 1.27-1.44 (21, m), 1.65-1.75 (2H, m), 1.90 2.12 (2H, m), 2.17 (3H, s), 2.25-2.34 (2H, m), 2.43 (3H, s), 4.10 (211, q, J=7H1z), 4.42 (111, t, J=7Hz), 8.03 (1H, s), 8.63 (1H, s), 8.98 (1H, s) MS (ESI*): m/z 306 (M+H) 15 Preparation 81 Ethyl 8-methoxy-6-[(3-methoxy-5-isoxazolyl)carbonyl]-7-oxooctanoate NMR (CDCl 3 , 6): 1.25 (3H, t, J=7Hz), 1.34-1.47 (2H, m), 1.65-1.74 (2H, m), 1.83 2.03 (211, m), 2.29 (2H, t, J=7Hz), 3.31 (3H, s), 4.05 (5H, s), 4.11 (2H, q, J=7Hz), 20 4.51 (11H, t, J=7Hz), 6.56 (111, s) MS (ESI*): m/z 342 (M+H) Preparation 82 Ethyl 6-[3-(1,3-oxazol-5-yl)benzoyl]-7-oxooctanoate 25 NMR (CDCl 3 , 6): 1.23 (3H, t, J=711z), 1.33-1.46 (211, m), 1.63-1.77 (2H, m), 1.95 2.17 (21, m), 2.17 (3H, s), 2.30 (211, t, J=7Hz), 4.12 (2H, q, J=7Hz), 4.46 (1H, t, J=7Hz), 7.47 (111, s), 7.56 (1H, t, J=8Hz), 7.85-7.96 (2H, m), 7.98 (1H, s), 8.27 (1H, m) 30 Preparation 83 Ethyl 6-(3,4-dichlorobenzoyl)-7-oxooctanoate NMR (CDCl 3 , 6): 1.24 (3H, t, J=7Hz), 1.30-1.43 (2H, m), 1.60-1.74 (211, m), 1.91 60 WO 2004/063197 PCT/JP2003/017091 2.14 (2H, m), 2.14 (3H, s), 2.30 (2H, t, J=7Hz), 4.11 (2H, q, J=7Hz), 4.34 (1H, t, J=7Hz), 7.57 (1H, d, J=8Hz), 7.78 (1H, dd, J=2, 8Hz), 8.06 (1H, d, J=2Hz) Preparation 84 5 Ethyl 6-[(4-chloro-2-pyridinyl)carbonyl]-7-oxooctanoate NMR (CDC1 3 , 6): 1.25 (3H, t, J=7Hz), 1.34-1.48 (2H, m), 1.62-1.77 (2H, m), 1.80 2.10 (2H, m), 2.31 (2H, t, J=7Hz), 2.34 (3H, s), 4.12 (2H, q, J=7Hz), 4.83-4.92 (1H, m), 7.49 (1H, dd, J=2 Hz, 5Hz), 8.04 (1H, d, J=2Hz), 8.57 (1H, d, J=5Hz) MS (ESI'): m/z 326 (M+H) 10 Preparation 85 Ethyl 6-[(5-chloro-2-thienyl)carbonyl]-8-methoxy-7-oxooctanoate NMR (CDCI 3 , 6): 1.24 (3H, t, J=7Hz), 1.32-1.42 (2H, m), 1.60-1.73 (2H, m), 1.84 2.06 (2H, m), 2.28 (2H, t, J=7Hz), 3.30 (3H, s), 3.97 (1H, d, J=17Hz), 4.06 (1H, d, 15 J=17Hz), 4.11 (2H, q, J=7Hz), 4.40 (1H, t, J=7Hz), 6.99 (1H, d, J=4Hz), 7.56 (1H, d, J=4Hz) Preparation 86 Ethyl 6-[(6-methoxy-2-pyrazinyl)carbonyl]-7-oxooctanoate 20 NMR (CDCI 3 , 6): 1.25 (3H, t, J=7Hz), 1.34-1.48 (2H, m), 1.60-1.78 (2H, m), 1.88 2.08 (2H, m), 2.31 (3H, s), 2.32 (2H, t, J=7Hz), 4.01 (3H, s), 4.11 (2H, q, J=7Hz), 4.62 (1H, t, J=7Hz), 8.44 (1H, s), 8.81 (1H, s) MS (ESI*): m/z 323 (M+H) 25 Preparation 87 Ethyl 6-(1-benzofuran-2-ylcarbonyl)-7-oxooctanoate NMR (CDCl 3 , 8): 1.23 (3H, t, J=7Hz), 1.34-1.48 (2H, m), 1.62-1.76 (2H, m), 1.93 2.19 (2H, m), 2.24 (3H, s), 2.30 (2H, t, J=7Hz), 4.10 (2H, q, J=7Hz), 4.37 (1H, t, J=7Hz), 7.34 (1H, t, J=8Hz), 7.51 (1H, t, J=8Hz), 7.56-7.65 (2H, m), 7.73 (1H, d, 30 J=8Hz) MS (ESI*): m/z 895 (M+H) 61 WO 2004/063197 PCT/JP2003/017091 Preparation 88 Ethyl 6-(1-benzothien-2-ylcarbonyl)-7-oxooctanoate NMR (CDC1 3 , 6): 1.23 (3H, t, J=7Hz), 1.35-1.48 (211, n), 1.60-1.80 (2H, m), 1.95 2.17 (2H, m), 2.19 (3H, s), 2.30 (2H, t, J=7Hz), 4.10 (2H, q, J=7Hz), 4.36 (11H, t, 5 J=7Hz), 7.38-7.53 (2H, m), 7.82-7.93 (2H, m), 8.05 (1H, s) Preparation 89 Ethyl 6-(1,3-oxazol-5-ylcarbonyl)-7-oxooctanoate NMR (CDCI 3 , 6): 1.25 (3H, t, J=7Hz), 1.30-1.43 (2H, m), 1.65-1.78 (2H, m), 1.92 10 2.10 (2H, m), 2.21 (3H, s), 2.32 (2H, t, J=7Hz), 4.11 (3H, m), 7.88 (1H, s), 8.05 (1H, s) Preparation 90 Ethyl 6-benzoyl-7-oxooctanoate 15 NMR (CDC1 3 , 6): 1.24 (3H, t, J=7Hz), 1.29-1.42 (21H, m), 1.60-1.75 (211, m), 1.92 2.12 (2H, m), 2.14 (311, s), 2.29 (2H, t, J=7Hz), 4.10 (2H, q, J=7Hz), 4.43 (1H, t, J=7Hz), 7.42-7.53 (2H, m), 7.55-7.64 (1H, m), 7.98 (2H, d, J=8Hz) Preparation 91 20 Ethyl 7-oxo-6-(6-quinolinylcarbonyl)octanoate NMR (CDCl 3 , 5): 1.23 (3H, t, J=7Hz), 1.36-1.48 (2H, m), 1.65-1.78 (2H, m), 2.00 2.18 (2H, m), 2.18 (3H, s), 2.30 (2H, t, J=7Hz), 4.10 (2H, q, J=7Hz), 4.58 (1H, t, J=8Hz), 7.54 (1H, m), 8.18 (11H, d, J=8Hz), 8.28 (1H, dd, J=2 Hz, 8Hz), 8.32 (111, d, J=8Hz), 8.51 (1H, d, J=2Hz), 9.05 (111, m) 25 MS (ESI*): m/z 342 (M+H) Preparation 92 Ethyl 8-[4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoyl]-9-oxodecanoate NMR (CDCl 3 , 5): 1.23-1.37 (9H, m), 1.55-1.68 (11H, s), 2.01 (211, m), 2.18 (31H, s), 30 2.29 (2H, t, J=7Hz), 4.12 (21H, q, J=7Hz), 4.39 (1H, t, J=7Hz), 5.11 (2H, s), 7.30 7.49 (5H, m), 7.74 (111, s, br), 8.04-8.13 (411, m) MS (ESI~): m/z 530 (M-H) 62 WO 2004/063197 PCT/JP2003/017091 Preparation 93 Ethyl 7-(1,3-oxazol-5-yl)-7-oxoheptanoate NMR (CDC1 3 , 5): 1.25 (3H, t, J=7Hz), 1.41 (2H, m), 1.76 (2H, m), 2.03 (21, m), 5 2.31 (2H, m), 3.20 (2H, m), 4.10 (2H, q, J=7Hz), 7.94 (1H, s), 8.10 (1H, s) Preparation 94 Ethyl 6-[3-(methylsulfonyl)benzoyl]-7-oxooctanoate NMR (CDC1 3 , 6): 1.24 (3H, t, J=8Hz), 1.59-1.64 (2H, m), 1.91-2.15 (21H, m), 2.18 10 (311, s), 2.30 (2H, t, J=8Hz), 3.11 (3H, s), 4.10 (2H, q, J=8Hz), 4.45 (11H, t, J=8Hz), 7.23 (11, t, J=8Hz), 8.17 (1H, dd, J=8, 1Hz), 8.25 (2H, br d, J=8Hz), 8.53 (1H1, br s) MS (ESI*): m/z 369 (M+H) 15 Preparation 95 Ethyl 6-(2-chloroisonicotinoyl)-7-oxooctanoate NMR (CDCI 3 , 8): 1.25 (3H, t, J=8Hz), 1.30-1.40 (2H, n), 1.60-1.71 (2H, m), 1.90 2.14 (2H, in), 2.27 (3H, s), 2.25-2.74 (2H, m), 4.11 (2H, q, J=8Hz), 4.32 (11, t, J=8Hz), 7.15 (1H, dd, J=7, 1Hz), 7.76 (1H, d, J=lHz), 8.09 (1H, d, J=7Hz) 20 MS (ESI*): m/z 326 (M+H) Preparation 96 Ethyl 6-(3-nitrobenzoyl)-7-oxooctanoate NMR (CDC1 3 , 5): 1.24 (31, t, J=8Hz), 1.29-1.41 (2H, m), 1.60-1.74 (2H, m), 1.91 25 2.16 (2H, m), 2.19 (3H, s), 2.30 (2H, t, J=8Hz), 4.11 (2H, q, J=8Hz), 4.46 (1H, t, J=8Hz), 7.71 (11, t, J=8Hz), 8.30 (1H, br d, J=8Hz), 8.45 (4H, br d, J=8Hz), 8.80 (1H, br s) MS (ESI*): m/z 337 (M+H) 30 Preparation 97 4-(2-Acetylhexanoyl)benzonitrile NMR (CDCI 3 , 5): 0.90 (3H, t, J=8Hz), 1.18-1.44 (4H, m), 1.90-2.12 (211, m), 2.17 63 WO 2004/063197 PCT/JP2003/017091 (314, s), 4.40 (1H, t, J=8Hz), 7.80 (2H, d, J=8Hz), 8.08 (2H, d, J=8Hz) MS (ESI): m/z 242 (M-H) Preparation 98 5 Etbyl 6-[(5-bromo-3-pyridinyl)carbonyl]-7-oxooctanoate NMR (CDC1 3 , 8): 1.25 (3H, t, J=7Hz), 1.32-1.43 (2H, m), 1.60-1.76 (2H, m), 1.96 2.15 (2H, m), 2.19 (314, s), 2.30 (2H, t, J=7Hz), 4.12 (2H, q, J=714z), 4.36 (1H, t, J=7Hz), 8.37 (114, s), 8.87 (114, br), 9.07 (114, br) MS: (m/z) 370,372 (M+H) 10 Preparation 99 Ethyl 6-(2-chloroisonicotinoyl)-8-(methylthio)-7-oxooctanoate NMR (CDCl 3 , 5): 1.24 (3H, t, J=7Hz), 1.34-1.47 (214, m), 1.60-1.77 (2H, m), 1.92 (314, s), 1.93-2.05 (2H, m), 2.30 (2H, t, J=7Hz), 3.19 (1H, d, J=171Hz), 3.26 (114, d, 15 J=17Hz), 4.11 (2H, q, J=71z), 4.68 (1H, t, J=7Hz), 7.72 (114, d, J=5Hz), 7.86 (1H, s), 8.57 (1H, d, J=5Hz) MS: (m/z) 370 (M-H), 372 (M+H) Preparation 100 20 Ethyl 7-(3-cyanobenzoyl)-8-oxononanoate NMR (CDCl 3 , 5): 1.21-1.44 (71, m), 1.55-1.69 (21, m), 1.89-2.15 (2H, m), 2.17 (3H, s), 2.29 (21, t, J=814z), 4.12 (2H, q, J=8Hz), 4.39 (1H, t, J=8Hz), 7.64 (11, t, J=81z), 7.87 (114, dd, J=8, 1Hz), 8.20 (1H, dd, J=8, 1Hz), 8.27 (114, br s) MS (ESI*): m/z 330 (M+H) 25 Preparation 101 Ethyl 6-[(6-chloro-2-pyridinyl)carbonyl]-7-oxooctanoate NMR (CDCl 3 , 8): 1.26 (314, t, J=7Hz), 1.36-1.52 (214, m), 1.63-1.75 (214, m), 1.77 2.06 (2H, m), 2.29 (214, t, J=71z), 2.45 (3H, s), 4.12 (2H, q, J=714z), 4.82 (1H, t, 30 J=7Hz), 7.51 (1H, d, J=8Hz), 7.82 (1H, t, J=8Hz), 7.97 (1H, d, J=8Hz) MS (ESI*): m/z 326 64 WO 2004/063197 PCT/JP2003/017091 Preparation 102 Ethyl 6-(3-methoxybenzoyl)-7-oxooctanoate NMR (CDCl 3 , 6): 1.25 (3H, t, J=7Hz), 1.30-1.43 (2H, m), 1.60-1.77 (2H,m), 1.92 2.12 (211, m), 2.15 (3H, s), 2.31 (2H, t, J=7Hz), 3.88 (3H, s), 4.12 (2H, q, J=7Hz), 5 4.42 (1H, t, J=711z), 7.14 (111, dd, J=2Hz, 8Hz), 7.40 (1H, t, J=8Hz), 7.46-7.58 (2H, m) MS (ESI*): m/z 321 Preparation 103 10 Ethyl 6-(3,5-dichlorobenzoyl)-7-oxooctanoate NMR (CDCI 3 , 8): 1.23 (3H, t, J=7Hz), 1.32-1.42 (2H, m), 1.63-1.75 (2H, m), 1.90 2.12 (2H, m), 2.16 (311, s), 2.30 (2H, t, J=7Hz), 4.12 (2H, q, J=7Hz), 4.32 (1H, t, J=7Hz), 7.58 (111, m), 7.82 (2H, m) 15 Preparation 104 Ethyl 6-[(5-chloro-2-thienyl)carbonyl]-7-oxooctanoate NMR (CDCl 3 , 6): 1.24 (3H, t, J=71z), 1.30-1.40 (2H, m), 1.62-1.74 (2H, m), 1.90 2.12 (2H, m), 2.16 (3H, s), 2.29 (2H, t, J=7Hz), 4.13 (2H, q, J=7Hz), 4.14 (1H, m), 6.98 (1H, d, J=411z), 7.58 (1H, d, J=4Hz) 20 Preparation 105 Ethyl 6-(3-fluorobenzoyl)-7-oxooctanoate NMR (CDCl 3 , 6): 1.24 (311, t, J=7Hz), 1.28-1.42 (2H, m), 1.60-1.75 (2H, m), 1.90 2.13 (2H, m), 2.14 (3H, s), 2.29 (211, t, J=7Hz), 4.11 (2H, q, J=7Hz), 4.37 (1H, t, 25 J=71z), 7.26-7.33 (111, m), 7.43-7.52 (1H, m), 7.63-7.68 (111, m), 7.76 (1H, d, J=8Hz) MS (ESI+): m/z 309 Preparation 106 30 Ethyl 7-oxo-6-(3-quinolinylcarbonyl)octanoate NMR (CDCl 3 , 6): 1.23 (311, t, J=71z), 1.35-1.47 (211, m), 1.63-1.77 (211, m), 1.98 2.18 (2H, m), 2.20 (311, s), 2.31 (2H, t, J=7Hz), 4.10 (2H, q, J=7Hz), 4.55 (11H, t, 65 WO 2004/063197 PCT/JP2003/017091 J=7Hz), 7.66 (111, t, J=8Hz), 7.87 (1H, t, J=8Hz), 7.97 (1H, d, J=8Hz), 8.18 (111, d, J=8Hz), 8.78 (111, d, J=2Hz), 9.43 (1H, d, J=2Hz) MS (ESI*): m/z 342 5 Preparation 107 Ethyl 6-isonicotinoyl-7-oxooctanoate NMR (CDCl 3 , 8): 1.24 (3H, t, J=7Hz), 1.26-1.45 (2H, m), 1.60-1.75 (2H, m), 1.94 2.07 (2H, m), 2.17 (3H, s), 2.27-2.35 (21, m), 4.11 (2H, q, J=71z), 4.38 (1H, t, J=7Hz), 7.74 (211, m), 8.83 (2H, m) 10 Preparation 108 Ethyl 6-[(3-methoxy-5-isoxazolyl)carbonyl]-7-oxooctanoate NMR (CDCl 3 , 5): 1.25 (3H, t, J=7Hz), 1.33-1.45 (2H, m), 1.60-1.80 (2H, m), 1.88 2.05 (2H, m), 2.28 (3H, s), 2.30-2.45 (2H, m), 4.03 (3H, s), 4.11 (2H, q, J=7Hz), 15 4.33 (111, t, J=7Hz), 6.56 (1H, s) MS (ESI*): m/z 312 Preparation 109 Ethyl 6-[(5-methyl-3-isoxazolyl)carbonyl]-7-oxooctanoate 20 NMR (CDCI 3 , 5): 1.24 (3H, t, J=7Hz), 1.32-1.44 (2H, m), 1.61-1.74 (2H, m), 1.85 2.07 (2H, m), 2.26-2.38 (211, m), 2.29 (3H, s), 2.49 (3H, s), 4.11 (2H, q, J=7Hz), 4.64 (11, m), 6.39 (1H, s) MS (ESI*): m/z 296 25 Preparation 110 Ethyl 6-(2-chloroisonicotinoyl)-8-methoxy-7-oxooctanoate NMR (CDCl 3 , 5): 1.24 (311, t, J=7Hz), 1.28-1.43 (2H, m), 1.66 (2H, t, J=7Hz), 1.73 1.86 (1H, m), 1.93-2.07 (1H, m), 2.73 (2H, t, J=7Hz), 3.23 (311, s), 3.89 (1H, d, J=1711z), 4.00 (1H, d, J=17Hz), 4.10 (211, q, J=7Hz), 4.58 (111, t, J=7Hz), 7.66 30 (1H, d, J=5Hz), 7.78 (1H, s), 8.60 (1H1, d, J=5Hz) MS (ESI*): m/z 356, MS (ESI-): m/z 354 66 WO 2004/063197 PCT/JP2003/017091 Preparation 111 Ethyl 8-methoxy-6-(3-methoxybenzoyl)-7-oxooctanoate NMR (CDC1 3 , 6): 1.24 (3H, t, J=7Hz), 1.30-1.43 (211, m), 1.60-1.73 (2H, m), 1.79 2.04 (2H, m), 2.28 (2H, t, J=7Hz), 3.27 (3H, s), 3.87 (3H, s), 4.00 (2H, m), 4.12 5 (2H, q, J=7Hz), 4.66 (1H, t, J=7Hz), 7.13 (111, m), 7.39 (111, m), 7.45-7.55 (211, m) Preparation 112 Ethyl 8-methoxy-7-oxo-6-(6-quinolinylcarbonyl)octanoate 10 NMR (CDCl 3 , 6): 1.24 (3H, t, J=7Hz), 1.34-1.47 (2H, m), 1.60-1.75 (2H, m), 1.86 2.10 (2H, m), 2.27 (2H, t, J=7Hz), 3.24 (3H, s), 4.02-4.10 (211, m), 4.12 (2H, q, J=7Hz), 4.83 (1H, t, J=7Hz), 7.48-7.55 (1H, m), 8.16-8.33 (3H, m), 8.49 (111, m), 9.02 (1H, m) MS (ESI*): m/z 372 15 Preparation 113 Ethyl 8-methoxy-7-oxo-6-(3-pyridinylcarbonyl)octanoate NMR (CDC1 3 , 8): 1.23 (3H, t, J=7Hz), 1.31-1.45 (2H, m), 1.60-1.73 (2H, m), 1.75 2.08 (2H, m), 2.28 (2H, t, J=7Hz), 3.24 (3H, s), 3.94 (1H, d, J=17Hz), 4.00 (1H, d, 20 J=17Hz), 4.10 (2H, q, J=7Hz), 4.67 (1H, t, J=7Hz), 7.44 (1H, m), 8.22 (1H, m), 8.81 (1H, d, J=5Hz), 9.18 (1H, m) MS (ESI*): m/z 322 Preparation 114 25 Ethyl 6-(3-chlorobenzoyl)-8-methoxy-7-oxooctanoate NMR (CDC1 3 , 8): 1.23 (31H, t, J=7Hz), 1.30-1.44 (2H, m), 1.60-1.74 (2H, m), 1.75 1.92 (1H, m), 1.94-2.10 (1H, m), 2.28 (211, t, J=7Hz), 3.25 (3H, s), 3.93 (1H, d, J=17Hz), 4.02 (1H, d, J=17Hz), 4.12 (211, q, J=7Hz), 4.63 (111, t, J=7Hz), 7.43 (11H, t, J=8Hz), 7.57 (1H, d, J=8Hz), 7.83 (1H, d, J=8Hz), 7.94 (1H, s) 30 Preparation 115 Ethyl 6-(3-methylbenzoyl)-7-oxooctanoate 67 WO 2004/063197 PCT/JP2003/017091 NMR (CDCl 3 , 6): 1.24 (3H, t, J=7Hz), 1.29-1.42 (2H, mn), 1.60-1.73 (2H, m), 1.90 2.06 (2H, m), 2.13 (311, s), 2.28 (21H, t, J=7Hz), 2.42 (3H, s), 4.10 (2H, q, J=7Hz), 4.42 (1H, t, J=7Hz), 7.31-7.43 (2H, m), 7.73-7.78 (2H, m) 5 Preparation 118 Ethyl 8-methoxy-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate NMR (CDCI 3 , 8): 1.23 (3H, t, J=7Hz), 1.30-1.47 (2H, m), 1.60-1.74 (2H, m), 1.75 1.93 (1H, m), 1.93-2.08 (1H, m), 2.26 (2H, t, J=7Hz), 2.43 (3H, s), 3.25 (3H, s), 3.95 (1H, d, J=17Hz), 4.03 (11H, d, J=17Hz), 4.12 (2H, q, J=7Hz), 4.67 (1H, t, 10 J=7Hz), 8.03 (1H, s), 8.63 (11H, s), 8.98 (1H, s) MS (ESI*): m/z 336 Preparation 119 Ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-7-oxooctanoate 15 NMR (CDCl 3 , 8): 1.25 (3H, t, J=7Hz), 1.32-1.43 (2H, m), 1.60-1.76 (2H, m), 1.96 2.15 (211, m), 2.19 (31H, s), 2.30 (2H, t, J=7Hz), 4.12 (2H, q, J=7Hz), 4.36 (1H, t, J=7Hz), 8.37 (1H, s), 8.87 (1H, br), 9.07 (1H, br) MS (ESI*): m/z 370,372 20 Preparation 120 Ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-8-methoxy-7-oxooctanoate NMR (CDCI 3 , 6): 1.23 (3H, t, J=7Hz), 1.30-1.47 (2H, m), 1.60-1.72 (2H, m), 1.75 1.93 (1H, m), 1.95-2.08 (1H, m), 2.27 (211, t, J=7Hz), 3.25 (3H, s), 3.93 (111, d, J=17Hz), 4.02 (1H, d, J=17Hz), 4.10 (2H, q, J=7Hz), 4.63 (1H, t, J=7Hz), 8.38 25 (111, m), 8.88 (1H, m), 9.07 (111, m) MS (ESI*): m/z 400,402 Preparation 121 Ethyl 6-[(5,6-dichloro-3-pyridinyl)carbonyl]-7-oxooctanoate 30 NMR (CDC1 3 , 6): 1.24 (3H, t, J=7Hz), 1.30-1.43 (2H, m), 1.60-1.77 (2H, m), 1.95 2.17 (2H, m), 2.19 (31H, s), 2.30 (2H, t, J=7Hz), 4.11 (2H, q, J=7Hz), 4.32 (1H, t, J=7Hz), 8.31 (1H, d, J=2Hz), 8.82 (1H, d, J=2Hz) 68 WO 2004/063197 PCT/JP2003/017091 Preparation 122 Ethyl 7-methoxy-5-[(5-methyl-3-pyridinyl)carbonyl]-6-oxoheptanoate NMR (CDCl 3 , 8): 1.23 (3H, t, J=7Hz), 1.60-1.75 (2H, m), 1.78-1.95 (1H, m), 1.95 5 2.12 (1H, m), 2.32 (2H, t, J=7Hz), 2.44 (3H, s), 3.25 (3H, s), 3.94 (1H, d, J=18Hz), 4.02 (111, d, J=18Hz), 4.12 (2H, q, J=7Hz), 4.69 (1H, t, J=7Hz), 8.04 (1H, s), 8.63 (1H, s), 9.00 (1H, s) MS (ESI): m/z 322 10 Preparation 123 Ethyl 6-methoxy-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate NMR (CDCl 3 , 6): 1.24 (3H, t, J=7Hz), 2.08-2.55 (4H, m), 2.44 (311, s), 3.23 (3H, s), 3.94 (111, d, J=18Hz), 4.01 (111, d, J=1811z), 4.12 (21H, q, J=7Hz), 4.88 (1H, m), 8.12 (11, s), 8.64 (1H, s), 9.04 (1H, s) 15 MS (ESI*): m/z 308 Preparation 124 Ethyl 5-[(5-methyl-3-pyridinyl)carbonyl]-6-oxoheptanoate NMR (CDCl 3 , 8): 1.25 (311, t, J=7Hz), 1.60-1.75 (211, m), 1.96-2.13 (2H, m), 2.18 20 (3H, s), 2.36 (2H, t, J=7Hz), 2.43 (3H, s), 4.12 (2H, q, J=7Hz), 4.43 (1H, t, J=7Hz), 8.04 (1H, s), 8.63 (1H, s), 8.97 (111, s) MS (ESI*): m/z 292 Preparation 125 25 Ethyl 4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate NMR (CDCI 3 , 5): 1.25 (3H, t, J=7Hz), 2.20 (311, s), 2.26-2.48 (4H, m), 2.43 (3H, s), 4.13 (211, q, J=7Hz), 4.62 (1H, t, J=7Hz), 8.08 (11, s), 8.64 (11, s), 9.02 (1H, s) MS (ESI*): m/z 278 30 Preparation 126 Ethyl 4-[(5-bromo-3-pyridinyl)carbonyl]-5-oxohexanoate NMR (CDCl 3 , 6): 1.25 (311, t, J=7Hz), 2.26 (3H, s), 2.30 (2H, t, J=711z), 2.43 (2H, t, 69 WO 2004/063197 PCT/JP2003/017091 J=7Hz), 4.15 (2H, q, J=7Hz), 8.65(1H, s), 8.94 (1H, s), 9.22(1H, s) Preparation 127 Ethyl 6-(3-cyanobenzoyl)-8-methoxy-7-oxooctanoate 5 NMR (CDC1 3 , 5): 1.19-1.43 (12H, m), 1.57-1.70 (2H, m), 1.80 (1 H, m), 1.99 (11H, m), 2.28 (2H, t, J=8Hz), 3.24 (3H, s), 3.91 (1H, d, J=16Hz), 4.01 (1H, d, J=16Hz), 4.09 (2H, q, J=8Hz), 4.65 (1H, t, J=8Hz), 7.64 (1H, t, J=81Hz), 7.87 (1H, dd, J=8, 1Hz), 8.18 (11H, dd, J=8, 1Hz), 8.25 (1H, br s) 10 Preparation 128 Ethyl 8-(acetyloxy)-6-[(5-bromo-3-pyridinyl)carbonyl]-7-oxooctanoate NMR (CDCl 3 , 8): 1.25 (3H, t, J=71z), 1.37 (2H, m), 1.67 (2H, m), 1.98-2.06 (5H, m), 2.30 (2H, t, J=7Hz), 4.11 (211, q, J=7Hz), 4.47 (11H, t, J=7Hz), 4.66 (d, J=1711z), 4.74 (d, J=17Hz), 8.37 (1H, m), 8.88 (111, m), 9.06 (11H, m) 15 Preparation 129 To a solution of Meldrum's acid (30 g, 0.208 mol) in dichloromethane (420 mL) was added pyridine (33.7 mL, 0.416 mol) over 3 minutes in an ice-methanol bath under nitrogen atmosphere (-9'C). To this mixture was added dropwise a solution of 20 methoxyacetyl chloride (24.8 g) in dichloromethane (180 mL) over 1 hour period at the temperature. After addition, the reaction mixture was stirred at the temperature for 1 hour and at ambient temperature for 2 hours. The mixture was quenched with IN hydrochoric acid (600 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, 25 dried over magnesium sulfate, and evaporated in vacuo to give 5-(methoxyacetyl)-2,2 dimethyl-1,3-dioxane-4,6-dione as dark orange oil (38.1 g, 84.7%). 5-(Methoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione NMR (CDCI 3 , 5): 1.75 (6H, s), 3.53 (311, s), 4.87 (2H, s) 30 Preparation 130 A solution of 5-(methoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (38 g) in 70 WO 2004/063197 PCT/JP2003/017091 tert-butanol (120 mL) and toluene (120 mL) was refluxed for 2 hours under nitrogen atmosphere. The mixture was evaporated in vacuo to give brown oil (32.5 g). The residue was dissolved in hexane-ethyl acetate = 2-1 (200 mL) and was added silica gel (65 g) therein. After stirring for 30 minutes at ambient temperature, the mixture was 5 filtered and washed with hexane-ethyl acetate = 2-1 (200 mL). The filtrate was concentrated in vacuo to give tert-butyl 4-methoxy-3-oxobutanoate as pale yellow oil (30.1 g, 91.0%). tert-Butyl 4-methoxy-3-oxobutanoate 10 NMR (CDCl 3 , 8): 1.50 (9H, s), 3.41 (2H, s), 3.43 (3H, s), 4.08 (2H, s) Preparation 131 To a mixture of 3-formylbenzoic acid (500 mg) and p-toluenesulfonylmethyl isocyanide (715 mg) in methanol (20 mL) was added potassium carbonate (1.38 g) and 15 the mixture was heated under reflux for 2 hours. After evaporation of solvent, the residue was partitioned between ethyl acetate and water. The aqueous layer was separated and acidified with IN hydrochloric acid. The resulting precipitates were collected and washed with water, methanol and ether to give 3-(1,3-oxazol-5-yl)benzoic acid as a colorless amorphous powder (484 mg). 20 3-(1,3-Oxazol-5-yl)benzoic acid NMR (DMSO-d 6 , 5): 7.63 (1H, t, J=811z), 7.84 (1H, s), 7.89-8.02 (2H, m), 8.25 (1H, m), 8.50 (IH, s), 13.22 (1H, br) MS (ESI*): m/z 188 (M-H) 25 Preparation 132 A mixture of 1-(3-chlorophenyl)-1,3-butanedione (500 mg), 5-(iodomethyl)-2,2 dimethyl-1,3-dioxane (716 mg), and potassium carbonate (351 mg) in dimethylsulfoxide (2.5 mL) was stirred for 14 hours at room temperature and 7 hours at 40*C. The mixture 30 was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with water (10 x 2 mL) and brine, dried over magnesium sulfate, and evaporated to give a brown oil. Flash silica gel column chromatography eluting with ethyl acetate hexane = 1-10 to 2-5 afforded 1-(3-chlorophenyl)-2-[(2,2-dimethyl-1,3-dioxan-5 71 WO 2004/063197 PCT/JP2003/017091 yl)methyl]-1,3-butanedione as an yellow oil (614 mg). 1-(3-Chlorophenyl)-2-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-1,3-butanedione NMR (CDCL 3 , 5): 1.39 (6H, s), 1.70 (1H, m), 1.91-2.15 (2H, m), 2.16 (311, s), 3.61 5 (2H, m), 3.88 (2H, m), 4.46 (IH, t, J=7Hz), 7.44 (1H, t, J=911z), 7.57 (1H, m), 7.86 (1H, d, J=9Hz), 7.96 (1H, m) The following compounds were obtained in substantially the same manner as that of Preparation 132. 10 Preparation 133 1-tert-Butyl 7-ethyl 2-(1,3-oxazol-5-ylcarbonyl)heptanedioate NMR (CDCL 3 , 8): 1.26 (3H, t, J=7Hz), 1.32-1.38 (11H, m), 1.67 (2H, m), 1.97 (211, m), 2.30 (2H, m), 3.86 (1H, t, J=7Hz), 4.11 (2H, q, J=7Hz), 7.86 (1H, s), 8.03 (111, s) 15 Preparation 134 1-tert-Butyl 7-ethyl 2-[(3,5-dimethyl-4-isoxazolyl)carbonyl]heptanedioate NMR (CDCI 3 , 8): 1.25 (3H, t, J=7Hz), 1.33-1.41 (111H, m), 1.64 (2H, m), 1.93 (2H, m), 2.30 (2H, m), 2.47 (3H, s), 2.69 (2H, s), 3.79 (1H, t, J=7Hz), 4.12 (2H, q, 20 J=7Hz) Preparation 135 To a suspensin of magnesium chloride (1.46 g) in tetrahydrofuran (10 ml) was added a solution of ethyl 3-oxo-4-phenylbutanoate (2.0 g) in tetrahydrofuran (10 ml) and 25 the mixture was cooled to 0*C, then pyridine (2.5 ml) was added. The mixture was stirred at 20'C for 30 minutes, then a solution of 4-fluorobenzoyl chloride (2.44 g) in tetrahydrofuran (10 ml) was added at 0 0 C. After stirring at 20'C for 2 hours, the mixure was partitoned between 0.5N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. 30 The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 2 -(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate (2.15 g) as an oil. 72 WO 2004/063197 PCT/JP2003/017091 Ethyl 2-(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate (mixture of tautomers, too complicated to be assigned) Preparation 136 5 A mixture of 1-(4-fluorophenyl)butane-1,3-dione (1.0 g), potassium carbonate (3.42 g), and tetrabutylammonium bromide (20 mg) in toluene (10 ml) was refluxed for 3 hours. After cooling to 20'C, ethyl bromoacetate (0.74 ml) was added to the mixture. After being allowed to stand at 20'C overnight, the mixture was partitoned between ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water 10 and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 3-(4-fluorobenzoyl)-4-oxopentanoate (964 mg) as an oil. Ethyl 3-(4-fluorobenzoyl)-4-oxopentanoate 15 NMR (CDCI 3 , 6): 1.23 (3H, t, J=7Hz), 2.18 (3H, s), 3.01 (2H, d, J=7Hz), 4.12 (2H, q, J=7Hz), 4.95 (1H, d, J=7Hz), 7.18 (2H, dt, J=2, 7Hz), 8.07 (2H, ddd, J=2, 5, 7Hz) Preparation 137 A mixture of 1-(4-fluorophenyl)butane-1,3-dione (1.0 g), potassium carbonate 20 (3.84 g), and tetrabutylammonium bromide (90 mg) in toluene (20 ml) was refluxed for 3 hours, then ethyl 6-bromohexanoate (1.18 ml) was added. After stirring at 100*C for 3 hours, the mixture was partitoned between ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of 25 ethyl acetate and hexane (1:5) to give ethyl 7-(4-fluorobenzoyl)-8-oxononanoate (983 mg) as an oil. Ethyl 7-(4-fluorobenzoyl)-8-oxononanoate NMR (CDC1 3 , 8): 1.24 (3H, t, J=7Hz), 1.25-1.45 (4H, m), 1.55-1.70 (2H, in), 1.90 30 2.10 (2H, in), 2.13 (3H, s), 2.27 (2H, t, J=7Hz), 4.11 (2H, q, J=7Hz), 4.37 (1H, t, J=7Hz), 7.16 (2H, t, J=9Hz), 8.02 (2H, dd, J=5, 9Hz) Preparation 138 73 WO 2004/063197 PCT/JP2003/017091 A mixture of pentane-2,4-dione (5.0 g), ethyl 7-bromoheptanoate (11.1 g), potassium carbonate (13.8 g), and cesium carbonate (1.63 g) in a mixture of acetonitrile (150 ml) and dimethylsulfoxide (30 ml) was stirred at 20'C overnight, then pentane-2, 4 dione (5 g) was added. After stirring at 20'C overnight, the mixture Was partitoned 5 between ethyl acetate and 05N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 8-acetyl-9-oxodecanoate (5.5 g) as an oil. 10 Ethyl 7-acetyl-8-oxononanoate (mixture of tautomers, too complicated to be assigned) Preparation 139 To a mixture of ethyl 7-acetyl-8-oxononanoate (4.0 g) and magnesium chloride 15 (1.27 g) in dichloromethane (70 ml) was added pyridine (2.15 ml) at 0*C. The mixture was stirred at 20*C for 1 hour, then a solution of 4-cyanobenzoyl chloride (2.87 g) in dichloromethane (10 ml) was added. After stirring for 3 hours at 20'C, the mixture was partitioned between ether and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue 20 was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 7-acetyl-7-(4-cyanobenzoyl)-8-oxononanoate (3.52 g) as an oil. 1-tert-Butyl 8-ethyl 2-acetyl-2-(4-cyanobenzoyl)octanedioate NMR (CDCl 3 , 5): 1.24 (3H, t, J=7Hz), 1.25-1.45 (4H, m), 1.30 (9H, s), 1.55-1.70 25 (2H, m), 2.20 (211, t, J=7Hz), 2.28 (2H, t, J=7Hz), 2.44 (3H, s), 4.12 (2H, q, J=7Hz), 7.72 (2H, t, J=9Hz), 7.83 (2H, d, J=9Hz) Preparation 140 Ethyl 7-acetyl-7-(4-cyanobenzoyl)-8-oxononanoate (3.5 g) was dissolved in 30 trifluoroacetic acid (12.6 ml) and the mixture was stirred at 20'C for 15 minutes. The mixture was partitoned between ethyl acetate and water. The organic layer was separated, washed with water, aqueous sodium bicarbonate and brine, dried over MgSO4 (magnesium sulfate), and evaporated to give ethyl 7-(4-cyanobenzoyl)-8-oxononanoate 74 WO 2004/063197 PCT/JP2003/017091 (2.25 g) as an oil. Ethyl 7-(4-cyanobenzoyl)-8-oxononanoate NMR (CDCl 3 ,S): 1.25 (3H, t, J=7Hz), 1.25-1.45 (4H, m), 1.55-1.70 (2H, m), 1.80 5 2.10 (2H, m), 2.16 (3H, s), 2.28 (2H, t, J=7Hz), 4.12 (2H, q, J=7Hz), 4.40 (11, t, J=7Hz), 7.80 (2H, t, J=9Hz), 8.07 (2H, d, J=9Hz) Preparation 141 A mixture of methyl 4-(aminosulfonyl)benzoate (5.10 g) and potassium carbonate 10 (6.55 g) in dimethoxyethane (50 mL) was refluxed for 5 minutes. After cooling the mixture, a solution of benzyl chloridocarbonate (5.25 g) in dimethoxyethane (30 mL), and the resulting mixture was refluxed for 1 hour. The reaction was quenched by adding IN hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (200 mL), and the organic layer was washed with brine, dried over magnesium sulfate, and 15 evaporated to give a pale yellow oil, which was solidified upon standing. The solid was triturated in diisopropyl ether.(30 mL) to give methyl 4 ({[(benzyloxy)carbonyl]amino}sulfonyl)benzoate as a white powder (3.38 g). Methyl 4-({ [(benzyloxy)carbonyl]amino}sulfonyl)benzoate 20 NMR (CDCl 3 , 8): 3.98 (3H, s), 5.10 (2H, s), 7.22 (2H, m), 7.34 (3H, m), 7.64 (1H, s, br), 8.08 (2H, d, J=9Hz), 8.16 (2H, d, J=9Hz) Preparation 142 A suspension of methyl 4-({[(benzyloxy)carbonyl]amino} 25 sulfonyl)benzoate (3.38 g) and 85% pottasium hydroxide (1.28 g) in methanol (40 mL) was stirred for 35 minutes. Methanol was evaporated off, and to the mixture was added IN hydrochloric acid (20 mL). A white crystal was formed, which was collected by filtration and washed with water and diisopropyl ether, and dried under vacuum. 4 ({ [(Benzyloxy)carbonyl]amino}sulfonyl)benzoic acid was obtained as a white crystal 30 (2.92 g). 4-({[(Benzyloxy)carbonyllamino}sulfonyl)benzoic acid 75 WO 2004/063197 PCT/JP2003/017091 NMR (DMSO-d 6 , 6): 5.06 (2H, s), 7.25 (2H, m), 7.33 (3H, m), 8.00 (2H, d, J=9Hz), 8.15 (2H, d, J=9Hz) MS (EST): m/z 334 (M-H) 5 Preparation 143 To a suspension of S-(2-pyridinyl) 3-cyanobenzenecarbothioate (2.40 g) in toluene (10 mL) was added titanium chloride (1.99 g) under an ice-methanol bath over 5 minutes (-7 to -2'C). After stirring for 10 minutes, a solution of 2-ethyl-1H-pyrrole (1.00 g) in toluene (10 mL) was added over 5 minutes (-4 to 0 0 C). The resulting heterogeneous 10 mixture was stirred for 1.5 hours at room temperature. Ethyl acetate (20 mL) and water (20 mL) were added, and the mixture was filtered through celite. The filtrate was diluted with ethyl acetate (80 mL) and water (30 mL), and organic extract was washed with water (30 mL), IN sodium hydroxide (50 mL), and brine (50 mL), dried over magnesium sulfate, and evaporated to give a dark colored crystal (2.46 g). The crystal was triturated 15 in diisopropyl ether (10 mL) to give 3-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile as a brown crystal (1.57 g, 70.1%). 3-[(5-Ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile NMR (CDCl 3 , 5): 1.33 (3H, t, J=7Hz), 2.75 (2H, q, J=7Hz), 6.12 (1H, m), 6.78 (1H, 20 m), 7.60 (1H, t, J=8Hz), 7.82 (111, d, J=8Hz), 8.07 (1H, d, J=8Hz), 8.14 (1H, s), 9.50 (1H, s, br) Preparation 144 To a suspension of magnesium chloride (3.01 g) in tetrahydrofuran (30 mL) was 25 added tert-butyl 3-oxobutanoate (5.00 g). The mixture was cooled under an ice-bath. Then, pyridine (5.00 g) was added over 15 minutes. After stirring for 1 hour at room temperature, the resulting mixture was cooled under the ice-bath. A solution of 2 chlorobenzoyl chloride (4.98 g) in tetrahydrofuran (30 mL) was added over 15 minutes. The mixture was stirred for 1 hour at room temperature. The reaction was quenched by 30 adding iN hydrochloric acid (65 mL). The mixture was filtered, and the solvent was evaporated off. The residue was extracted with ethyl acetate (150 mL). The extract was washed with water (100 mL), saturated sodium bicarbonate (100 mL), and brine, dried over magnesium sulfate, and evaporated to give tert-butyl 2-(3-chlorobenzoyl)-3 76 WO 2004/063197 PCT/JP2003/017091 oxobutanoate as an yellow oil (8.82 g). tert-Butyl 2-(3-chlorobenzoyl)-3-oxobutanoate NMR (CDCI 3 , 6): mixture of tautomers: 1.20 and 1.27 (9H, s), 2.16 and 2.44 (3H, s), 5 7.33-7.71 (4H, m), 13.66 (1H, s) Preparation 145 A solution of tert-butyl 2-(3-chlorobenzoyl)-3-oxobutanoate (8.82 g) in trifluoroacetic acid (40 mL) was stirred for 1 hour under an ice-bath. The volatile was 10 removed in vacuo, and the residue was partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give 1-(3-chlorophenyl)-1,3-butanedione as a pale orange crystal (5.33 g). 15 1-(3-Chlorophenyl)-1,3-butanedione NMR (CDCl 3 , 5): 2.21 (3H, s), 6.14 (1H, s), 7.38 (1H, t, J=9Hz), 7.48 (1H, d, J=9Hz), 7.75 (1H, d, J=9Hz), 7.85 (1H, s) Preparation 146 20 To a mixture of 2-(trimethylsilyl)ethanol (20.5 g) and pyridine (18.7 g) in dichloromethane (40 mL) was added a solution of ethanedioyl dichloride (10.0 g) in dichloromethane (20 mL) over 30 minutes under an ice-bath (6 to 20*C). The bath was removed, and the mixture was stirred for 0.5 hour. The mixture was filtered, and the filtrate was partitioned between ethyl acetate (200 mL) and 1N hydrochloric acid (200 25 mL). The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated to give bis[2-(trimethylsilyl)ethyl] oxalate as a pale yellow oil (25.1 g). bis[2-(Trimethylsilyl)ethyl]oxalate 30 NMR (CDCl 3 , 8): 0.08 (18H, s), 1.12 (4H, m), 4.38 (414, m) Preparation 147 77 WO 2004/063197 PCT/JP2003/017091 To a suspension of dimethyl sulfone (7.00 g) in diethyl ether (50 mL) was added potassium tert-butoxide (8.76 g). To the resulting mixture was added bis[2 (trimethylsilyl) ethyl]oxalate (23.8 g). The resulting mixture was stirred for 36 hours at room 5 temperature. The mixture was partitioned between ethyl acetate (100 mL) and IN hydrochloric acid (50 mL). The organic layer was washed with brine, dried over magnesium sufate, and evaporated to give a dark orange oil. Flash silica gel column chromatography eluting with ethyl acetate-hexane = 1-25 to 8-5 afforded 2 (trimethylsilyl)ethyl 3-(methylsulfonyl)-2-oxopropanoate as a pale brown oil (8.37 g). 10 2-(Trimethylsilyl)ethyl 3-(methylsulfonyl)-2-oxopropanoate NMR (CDCl 3 , 8): 0.08 (9H, s), 1.14 (2H, m), 3.11 (3H, s), 4.43 (4H, m), 4.56 (2H, s) MS (EST): m/z 265 (M-H) 15 Preparation 148 A mixture of 4-oxo-4-phenylbutanoic acid (5.00 g), ethanol (2.59 g), 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.46 g), and 4 (dimethylamino)pyridine (171 mg) in N,N-dimethylformamide (25 mL) was stirred for 20 1.5 hours at room temperature. The mixture was partitioned between ethyl acetate (100 mL) and IN hydrochloric acid (75 mL), and the organic layer was washed with water (75 x 3 mL), saturated sodium bicarbonate (75 mL), and brine (75 mL), dried over magnesium sulfate, and evaporated to give ethyl 4-oxo-4-phenylbutanoate as a colorless oil (4.19 g). 25 Ethyl 4-oxo-4-phenylbutanoate NMR (CDCl 3 , 8): 1.27 (3H, t, J=7Hz), 2.76 (2H, t, J=71z), 3.32 (2H, t, J=7Hz), 4.16 (2H, q, J=7Hz), 7.47 (2H, t, J=9Hz), 7.55 (1H, d, J=9Hz), 7.98 (2H, d, J=9Hz) MS (ESI+): m/z 207 (M+H) 30 The following compound was obtained in substantially the same manner as that of Preparation 148. 78 WO 2004/063197 PCT/JP2003/017091 Preparation 149 Ethyl 5-oxo-5-phenylpentanoate NMR (CDCl 3 , 5): 1.26 (3H, t, J=7Hz), 2.08 (2H, m), 2.44 (2H, t, J=7Hz), 3.06 (2H, t, J=7Hz), 4.14 (2H, q, J=7Hz), 7.46 (2H, t, J=9Hz), 7.56 (1H, d, J=911z), 7.97 (211, 5 d, J=9Hz) MS (ESI*): m/z 221 (M+H) Preparation 150 A mixture of 2-benzoylcyclohexanone (1.00 g), sodium ethoxide (404 mg) in 10 ethanol (5 mL) was stirred for 3.5 hours at room temperature. The reaction was quenched by adding 1N hydrochloric acid (1 mL). The solvent was evaporated off, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give ethyl 7-oxo-7 phenylheptanoate as a brown oil (1.33 g). 15 Ethyl 7-oxo-7-phenylheptanoate NMR (CDCl 3 , 5): 1.25 (311, t, J=7Hz), 1.42 (211, m), 1.63-1.81 (411, m), 2.32 (2H, t, J=7Hz), 2.98 (211, t, J=711z), 4.12 (2H, q, J=7Hz), 7.47 (21H, t, J=9Hz), 7.54 (1H, d, J=7Hz), 7.95 (2H, d, J=9Hz) 20 Preparation 151 To a solution of ethyl 7-chloro-7-oxoheptanoate (1.31 g) in dichloromethane (25 mL) was added a solution of 2-(trimethylsilyl)-1,3-thiazole (500 mg) in dichloromethane (5 mL) under nitrogen. After stirring for 3 hours, the reaction was quenched by adding 25 saturated sodium bicarbonate (5 mL). The mixture was partitioned between ethyl acetate (30 mL) and saturated sodium bicarbonate (30 mL), and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give a colorless oil. Flash silica gel column chromatography eluting with ethyl acetate-hexane = 1-10 to 2-5 afforded ethyl 7-oxo-7-(1,3-thiazol-2-yl)heptanoate as a colorless oil (778 mg). 30 Ethyl 7-oxo-7-(1,3-thiazol-2-yl)heptanoate NMR (CDCI 3 , 5): 1.25 (311, t, J=7Hz), 1.44 (211, m), 1.64-1.85 (4H, m), 2.32 (2H, t, 79 WO 2004/063197 PCT/JP2003/017091 J=711z), 3.17 (2H, t, J=7Hz), 4.12 (2H, q, J=7Hiz), 7.66 (1H, d, J=3Hz), 8.00 (1H, d, J=3Hz) MS (ESI*): m/z 256 (M+H) 5 Preparation 152 To a solution of 7-methoxy-7-oxoheptanoic acid (1.00 g) in dichloromethane (10 mL) was added a solution of trifluoroacetic anhydride (1.33 g) in dichloromethane (2 mL). After stirring for 0.5 hour, a solution of 1-methyl-1H-pyrrole (1.49 g) in dichloromethane (2 mL) was added. The mixture was stirred for 2 hours 40 minutes at 10 room temperature and 2 hours at 35*C. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give a brmown oil. Flash silica gel column chromatography eluting with ethyl acetate-hexane = 1-20 to 4-5 afforded methyl 7-(1-methyl-1H-pyrrol-2-yl)-7-oxoheptanoate as a colorless oil (615 mg). 15 Methyl 7-(1-methyl-1H-pyrrol-2-yl)-7-oxoheptanoate NMR (CDCl 3 , 5): 1.34 (2H, m), 1.61-1.77 (4H, m), 2.32 (2H, t, J=7Hz), 2.77 (2H, t, J=7Hz), 3.66 (3H, s), 3.94 (3H, s), 6.13 (1H, m), 6.79 (1H, m), 6.93 (1H, m) MS (ESI*): m/z 238 (M+H) 20 Preparation 153 To a suspension of 4-({[(benzyloxy)carbonyl]amino} sulfonyl)benzoic acid (2.90 g) in dichloromethane (30 mL) was added N,N dimethylformamide (19.0 mg) and followed by oxalyl chloride (1.15 g) under an ice-bath. 25 The mixture was stirred for 0.5 hour at room temperature and refluxed for 1 hour. The resulting mixture was refluxed further for 5 minutes after adding oxalyl chloride (439 mg). The volatile was evaporated off to give a white solid. The solid was triturated in diisopropyl ether to give benzyl [4-(chlorocarbonyl)phenyl]sulfonylcarbamate as a white powder (2.40 g), which was used for the next reaction without further purification. 30 Benzyl [4-(chlorocarbonyl)phenyl]sulfonylcarbamate Preparation 154 80 WO 2004/063197 PCT/JP2003/017091 To a solution of tert-butyl 4-(methylthio)-3-oxobutanoate (5.00 g) and potassium carbonate (3.72 g) in dimethylformamide (25 mL) was added ethyl 5-iodopentanoate (6.89 g) and the mixture was stirred at ambient temperature for 15 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, 5 washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1 - 10:1) to give 1-tert-butyl 7-ethyl 2 [(methylthio)acetyl]heptanedioate as colorless oil (5.88 g). 10 1-tert-butyl 7-ethyl 2-[(methylthio)acetyl]heptanedioate NMR (CDCl 3 , 8): 1.25 (3H, t, J=7Hz), 1.30-1.42 (2H, m), 1.45 (9H, s), 1.63-1.74 (2H, m), 1.81-1.93 (211, m), 2.05 (3H, s), 2.30 (2H, t, J=7Hz), 3.23 (11, d, J=17Hz), 3.38 (1H, d, J=17Hz), 3.74 (111, t, J=7Hz), 4.11 (2H, q, J=7Hz) 15 Preparation 155 To a suspension of hydroxylamine hydrochloride (29.4 g) in dichloromethane (200 mL) was added diisopropylethylamine (54.6 g) over 3 minutes in a methanol-ice bath under a nitrogen atmosphere. A white precipitate was formed upon the addition. After stirring for 1 hour under the bath, a solution of diphenylphosphinic chloride (20.0 20 g) in dichloromethane (20 mL) was added over 60 minutes. A white crystal was formed upon the addition. The mixture was warmed to 0 0 C over 1 hour with stirring. The reaction was quenched by adding water (200 mL) over 3 minutes. After stirring the mixture for 0.5 hour, the crystal was collected by filtration. The crystal was washed with water (50 x 3 mL) followed by diisopropyl ether (50 x 3 mL). The collected crystal was 25 dried overnight in the air and 3 hours under a reduced pressure with slight warming (4 C) to give a crude product. The crude product was triturated in EtOH (ethanol) to give (aminooxy)(diphenyl)phosphine oxide as a white crystal (15.3 g). (Aminooxy)(diphenyl)phosphine oxide 30 NMR (CDCl 3 , 8): 7.54-7.58 (6H, m), 7.74-7.83 (4H, m), 8.20-8.33 (2H, m) Preparation 156 81 WO 2004/063197 PCT/JP2003/017091 To a solution of 1-(1H-pyrrol-2-yl)ethanone (5.00 g) in tetrahydrofuran (100 mL) was added potassium tert-butoxide (6.17 g) in a water bath under a nitrogen atmosphere. After stirring for 1 hour, (aminooxy)(diphenyl)phosphine oxide (12.8 g) was added over 2 hours. After stirring for 2 hours at room temperature, water (4 mL) was added over 3 5 minutes to give a clear solution. The solvent was evaporated off, and the residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (25 x 5 mL), and the combined organic extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give a brown oil (6.01 g). The oil was dissolved in diisopropyl ether (30 mL), and to the solution was 10 added hexane (15 mL) to afford a pale yellow crystal. After stirring for 1 hour, the crystal was removed by filtration. The filtrate was evaporated to give a brown oil (5.69 g). The oil was dissolved in ethyl acetate (45.5 mL), the solution was cooled under an ice-bath. To the cooled solution was added 4N hydrogen chloride in ethyl acetate (11.5 mL) over 15 minutes to afford a pale brown precipitate. After stirring the mixture for 0.5 15 hour under the bath, the precipitate was collected by filtration and washed with ethyl acetate (5 x 3 mL) to give a pale brown powder (5.33 g). The powder was suspended in ethyl acetate (37 mL) and warmed to 3C. The suspension was stirred for 1 hour at room temperature. The powder was collected by filtration and washed with ethyl acetate (5 x 3 mL) to give i-(1-amino-1H-pyrrol-2-yl)ethanone hydrochloride as a pale brown powder 20 (5.25 g). 1-(1-Amino-1H-pyrrol-2-yl)ethanone hydrochloride NMR (CDCl 3 , 6): 2.37 (3H, s), 5.22 (2H, s, br), 6.07 (1H, m), 6.99 (1H, m), 7.15 (1H, m) 25 Preparation 157 Under a nitrogen atmosphere, hydrazine monohydrate (530 g) was added to ethanol (1.7 L) over 55 minutes. To the mixture was added 1-(1-amino-1H-pyrrol-2 yl)ethanone hydrochloride (170 g) over 20 minutes. The mixture was stirred for 10 30 minutes at room temperature and heated to refluxing temperature over 55 minutes, and refluxed for 15 minutes. After cooling the mixture under a water bath, water (1.7 L) was added to the mixture (30 to 31'C). Ethanol was evaporated off, and the resulting mixture was extracted with chloroform (0.85 x 4 mL). The combined organic extract was washed 82 WO 2004/063197 PCT/JP2003/017091 with brine (1.3 L). The brine was extracted with chloroform (0.85 L). The combined organic extract was dried over anhydrous magnesium sulfate, and evaporated to give (1E)-1-(1-amino- 1H-pyrrol-2-yl)ethanone hydrazone as a brown crystal (112 g). 5 (1E)-1 -(1 -Amino-1H-pyrrol-2-yl)ethanone hydrazone NMR (CDCl 3 , 8): 2.10 (3H, s), 5.11 (2H, s, br), 5.83 (2H, s, br), 5.98 (1H, m), 6.25 (1H, m), 6.79 (1H, m) MS (ESI*): m/z 139 (M+H) 10 Preparation 158 To a suspension of (1E)-1-(1-amino-1H-pyrrol-2-yl)ethanone hydrazone (110 g) in toluene (1.1 L) was added potassium tert-butoxide (93.8 g) over 5 minutes under a nitrogen atmosphere, and the mixture was heated to refluxing temperature over 45 minutes. After refluxing for 15 minutes, the mixture was cooled to room temperature and 15 partitioned between ethyl acetate (1.1 L) and water (1.1 L). The aqueous layer was extracted with ethyl acetate (1.1 L) again. The combined organic extract was was washed with brine (1.1 L), and the brine was extracted with ethyl acetate (0.5 L). All the organic layer was combined, dried over anhydrous magnesium sulfate, and evaporated to give 2 ethyl-1H-pyrrol-1 -amine as a brown oil (94.4 g). 20 2-Ethyl-1H-pyrrol-1-amine NMR (CDCl 3 , 8): 1.26 (3H, t, J=7Hz), 21.62 (2H, q, J=7Hz), 4.53 (2H, s, br), 5.80 (1H, m), 5.99 (111, m), 6.67 (1H, m) 25 Preparation 159 To a suspension of tert-butyl 4-methoxy-3-oxobutanoate (3.09 g) and potassium carbonate (2.50 g) in dimethylformamide (20 mL) was added ethyl 5-iodopentanoate (4.62 g) and the mixture was stirred at ambient temperature for 15 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, 30 washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1 - 5:1) to give 1-tert-butyl 7-ethyl 2 (methoxyacetyl)heptanedioate as colorless oil (4.33 g). 83 WO 2004/063197 PCT/JP2003/017091 1-tert-Butyl 7-ethyl 2-(methoxyacetyl)heptanedioate NMR (CDCl 3 , 6): 1.25 (3H, t, J=7Hz), 1.30-1.44 (2H, m), 1.45 (9H, s), 1.60-1.73 (2H, m), 1.80-1.93 (2H, m), 2.29 (2H, t, J=7Hz), 3.41 (3H, s), 3.47 (1H, t, J=7Hz), 5 4.02 (4H, m) MS: (m/z) 317 (M+H) The following compounds were obtained in substantially the same manner as that of Preparation 159. 10 Preparation 160 1-tert-Butyl 6-ethyl 2-(methoxyacetyl)hexanedioate NMR (CDCl 3 , 5): 1.25 (3H, t, J=7Hz), 1.46 (91, s), 1.52-1.73 (2H, m), 1.82-1.94 (2H, m), 2.33 (2H, t, J=7Hz), 3.42 (311, s), 3.50 (1H, t, J=7Hz), 4.10 (2H, s), 4.12 (211, q, J=7Hz) 15 Preparation 161 1-tert-Butyl 5-ethyl 2-(methoxyacetyl)pentanedioate NMR (CDCl 3 , 6): 1.26 (3H, t, J=7Hz), 1.47 (9H, s), 2.10-2.25 (2H, m), 2.37 (2H, t, J=7Hz), 3.42 (3H, s), 3.62 (1H, t, J=7Hz), 4.12 (2H, s), 4.13 (211, q, J=7Hz) 20 Preparation 162 1-tert-Butyl 6-ethyl 2-acetylhexanedioate NMR (CDCl 3 , 5): 1.26 (3H, t, J=7Hz), 1.47 (9H, s), 1.57-1.75 (2H, m), 1.79-1.93 (2H, m), 2.23 (3H, s), 2.33 (2H, t, J=7Hz), 3.33 (1H, t, J=7Hz), 4.12 (2H, q, 25 J=7Hz) MS (ESI*): m/z 273 Preparation 163 1-tert-Butyl 5-ethyl 2-acetylpentanedioate 30 NMR (CDC1 3 , 5): 1.26 (311, t, J=7Hz), 1.47 (9H, s), 2.08-2.22 (2H, m), 2.24 (3H, s), 2.33-2.42 (211, m), 3.45 (1H, t, J=7Hz), 4.13 (2H, q, J=7Hz) 84 WO 2004/063197 PCT/JP2003/017091 Preparation 164 To a solution of 2-ethyl-1H-pyrrole (7.00 g) in tetrahydrofuran (14 mL) was added 0.93 M ethyl magnesium bromide (198 mL) under an ice-bath. The mixture was stirred for 1 hour at room temperature. Then the resulting solution was added to a 5 suspension of 5-bromonicotinoyl chloride (22.3 g) in tetrahydrofuran (110 mL) over 50 minutes under an ice-bath. After stirring for 15 minutes under the bath, the reaction was quenched by adding saturated ammonium chloride (30 mL). The mixture was partitioned between ethyl acetate (350 mL) and water (350 mL). The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated to 10 give a dark colored gum (33.9 g). The gum was dispersed in ethyl acetate/hexane (1:3, 150 mL) in the presence of silica gel (150 mL). The mixture was filtered, and the filtrate was concentrated to give an yellow crystal (20.6 g). Flash silica gel column chromatography eluting with ethyl acetate-hexane = 1-20 to 4-5 afforded (5-bromo-3 pyridinyl)(5-ethyl-1H-pyrrol-2-yl)methanone as a pale yellow solid (7.11 g). 15 (5-Bromo-3-pyridinyl)(5-ethyl-1H-pyrrol-2-yl)methanone NMR (CDCl 3 , 6): 1.33 (3H, t, J=7Hz), 2.75 (2H, q, J=7Hz), 6.14 (1H, m), 6.83 (1H, m), 8.27 (1H, m), 8.82 (1H, m), 8.98 (1H, m) MS (ESI*): m/z 279 (M+H) 20 Preparation 165 To a solution of tert-butyl 4-(acetyloxy)-3-oxobutanoate (30.0 g) and ethyl 5 iodopentanoate (35.5 g) in N,N-dimethylformamide (150 mL) was added potassium carbonate (19.2 g) at room temperature. After stirring for 4 hours, the mixture was 25 quenched by adding 1N hydrochloric acid (140 mL) under an ice-bath. The mixture was partitioned between ethyl acetate (450 mL) and water (300 mL). The organic extract was washed with water (500 mL, three times) and brine, dried over magnesium sulfate, and evaporated to give a brown oil containing 1-tert-butyl 7-ethyl 2 [(acetyloxy)acetyl]heptanedioate (63.4 g, 43% wt purity). 30 1-tert-Butyl 7-ethyl 2-[(acetyloxy)acetyl]heptanedioate NMR (CDCl 3 , 6): 1.20-1.37 (5H, m), 1.46 (9H, s), 1.63 (2H, m), 1.85 (2H, m), 2.17 (3H, s), 2.30 (2H, t, J=7Hz), 3.39 (1H, t, J=7Hz), 4.11 82H, q, J=7Hz), 4.73 (1H, 85 WO 2004/063197 PCT/JP2003/017091 d, J=17Hz), 4.82 (1H, d, J=17Hz) Preparation 166 To a solution of ethyl thiophene (2.00 g) and ethyl 7-chloro-7-oxoheptanoate 5 (5.39 g) in dichloromethane (20 mL) was added 1 M tin chloride in dichloromethane (38.9 mL) over 0.5 hour under an ice-bath (5 to 8'C). After stirring for 0.5 hour, the mixture was stirred for 0.5 hour at room temperature. The mixture was poured into ice water (100 mL), and extracted with ethyl acetate (100 mL). The organic extract was washed with water (100 mL) and brine, dried over magnesium sulfate, and evaporated to 10 give a brown oil. Flash silica gel column chromatography eluting with ethyl acetate hexane = 1-10 to 3-10 afforded ethyl 7-oxo-7-(2-thienyl)heptanoate as a brown oil (5.79 g). Ethyl 7-oxo-7-(2-thienyl)heptanoate 15 NMR (CDCI 3 , 6): 1.25 (3H, t, J=7Hz), 1.42 (2H, m), 1.63-1.72 (4H, m), 2.31 (2H, t, J=7Hz), 2.91 (2H, t, J=7Hz), 4.12 (2H, q, J=7Hz), 7.13 (1H, m), 7.612 (1H, m), 7.70 (1H, m) The following compounds were obtained in substantially the same manner as 20 those of Preparations 129 and 130. Preparation 167 tert-Butyl 3-(3,5-dimethyl-4-isoxazolyl)-3-oxopropanoate NMR (CDCl 3 , 8): 1.47 (9H, s), 2.46 (3H, s), 2.68 (3H, s), 3.68 (2H, s) 25 Preparation 168 Ethyl 4-methyl-3-oxopentanoate NMR (CDCl 3 , 8): 1.14 (6H, d, J=7Hz), 1.28 (3H, t, J=7Hz), 2.71 (1H, quintet, J=7Hz), 3.50 (s, 2H), 4.19 (2H, q, J=7Hz), 7.06-7.18, 7.56, and 7.85 (4H, m) 30 Preparation 169 86 WO 2004/063197 PCT/JP2003/017091 tert-Butyl 4-(methylthio)-3-oxobutanoate NMR (CDC1 3 , 6): 1.47 (9H, s), 2.07 (3H, s), 3.31 (211, s), 3.58 (2H, s) Preparation 170 5 tert-Butyl 3-(1,3-oxazol-5-yl)-3-oxopropanoate NMR (CDC1 3 , 6): (a mixture of keto- and enol-form); keto-form: 1.45 (9H, s), 3.77 (2H, s), 7.85 (1H, s), 8.04 (11, s); enol-form: d 1.45 (9H, s), 5.54 (111, s), 7.53 (1H, s), 7.91 (1H, s) 10 The following compounds were obtained in substantially the same manner as that of Preparation 143. Preparation 171

(

2 -Chloro-4-pyridiny)(5-ethyl-1H-pyrrol-2-yl)methanone NMR (CDCl 3 , 6): 1.32 (3H, t, J=7Hz), 2.74 (2H, q, J=7Hz), 6.13 (1H, m), 6.79 (111, 15 m), 7.56 (1H, d, J=5Hz), 7.69 (1H, s), 8.54 (1H, d, J=511z), 9.40 (1H, br) Preparation 172 (5-Ethyl-1H-pyrrol-2-y1)(3-methoxyphenyl)methanone NMR (CDCl 3 , 6): 1.32 (3H, t, J=711z), 2.74 (211, q, J=7Hz), 3.87 (3H, s), 6.08 (111, 20 m), 6.83 (1H, m), 7.08 (1H, dd, J=2 Hz, 8Hz), 7.33-7.42 (2H, m), 7.47 (1H, d, J=8Hz), 9.58 (1H, br) MS (ESI*): m/z 230 Preparation 173 25 (5-Ethyl-1H-pyrrol-2-yl)(4-pyridinyl)methanone NMR (CDC1 3 , 6): 1.32 (3H, t, J=7Hz), 2.72 (2H, q, J=7Hz), 6.13 (1H, m), 6.81 (1H, m), 7.65 (2H, d, J=7Hz), 8.77 (21, d, J=71Hz), 9.39 (1H, br) Preparation 174 30 (5-Ethyl-1H-pyrrol-2-yl)(2-pyrazinyl)methanone NMR (CDC1 3 , 6): 1.33 (3H, t, J=7Hz), 2.77 (2H, q, J=7Hz), 6.14 (1H, m), 7.51 (111, m), 8.65 (1H, m), 8.74 (1H, m), 9.36 (1H, br) 87 WO 2004/063197 PCT/JP2003/017091 Preparation 175 (5-Ethyl-1H-pyrrol-2-yl)(3-pyridinyl)methanone NMR (CDC1 3 , 6): 1.33 (3H, t, J=7Hz), 2.76 (211, q, J=7Hz), 6.12 (1H, m), 6.81 (1H, 5 m), 7.42 (1H, m), 8.13 (1H, m), 8.76 (1H, m), 9.08 (1H, m), 9.36 (1H, br) Preparation 176 A mixture of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbony1]benzonitrile (300 mg), methanesulfonylacetic acid (208 mg), 1-( 3 -dimethylaminopropyl)-3-ethylcarbodiimide 10 hydrochloride (361 mg), and 1-hydroxybenzotriazole (254 mg) in N,N dimethylformamide (1 mL) was stirred for 1.5 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water two times, saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and evaporated to give a pale brown solid. Flash silica gel column chromatography eluting with ethyl 15 acetate-hexane = 1/2 to 1/0 afforded N-[2-(3-cyanobenzoyl)-5-ethyl-1H-pyrrol-1-yl]-2 (methylsulfonyl)acetamide as a pale brown foam, which was solidified upon standing (505 mg). N-[2-(3-Cyanobenzoy)-5-ethyl-1H-pyrrol-1 -yl]-2-(methylsulfonyl)acetamide 20 NMR (CDC1 3 , 8): 1.29 (3H, t, J=7Hz), 2.62 (2H, q, J=7 Hz,), 3.28 (311, s), 4.15 (2H, s), 6.12 (111, d, J=5Hz), 6.75 (1H, d, J=511z), 7.58 (1H, t, J=91z), 7.82 (1H, d, J=9Hz), 8.01 (1H, d, J=9Hz), 8.06 (1H, s) The following compound was obtained in substantially the same manner as that of 25 Preparation 176. Preparation 177 Ethyl 3-{[2-(4-cyanobenzoy)-5-ethyl-1H-pyrrol-1-yl]amino}-3-oxopropanoate NMR (CDCl 3 , 6): 1.20-1.37 (6H, m), 2.56 (2H, q, J=7Hz), 3.57 (2H, s), 4.30 (211, q, J=7Hz), 6.06 (1H, d, J=5Hz), 6.68 (1H, d, J=5Hz), 7.54 (211, d, J=9Hz), 7.84 (2H, 30 d, J=9Hz) Example 1 88 WO 2004/063197 PCT/JP2003/017091 To a solution of 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (100 mg) in toluene (1 mL) were added 1-(4-methoxyphenyl)acetone (103 mg) and p-toluene sulfonic acid monohydrate (16 mg) at ambient temperature. The reaction mixture was heated at 80*C for 3 hours. The mixture was evaporated in vacuo. The residue was 5 purified by flash silica gel column chromatography eluting with hexane-ethyl acetate 20-1 and 15-1 to give 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin 4-yl]benzonitrile (31 mg, 20.2%) as an yellow solid. 4-[7-Ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile 10 NMR (CDCl 3 , 8): 1.40 (3H, t, J=8Hz), 2.31 (3H, s), 3.16 (2H, q, J=8Hz), 3.77 (3H, s), 6.10 (1H, d, J=5Hz), 6.60 (1H, d, J=5Hz), 6.75 (2H, d, J=8Hz), 6.93 (2H, d, J=8Hz), 7.33 (2H, d, J=8Hz), 7.53 (2H, d, J=8Hz) MS (ESI*): m/z 368 (M+H) 15 The following compounds were obtained in substantially the same manner as that of Example 1. Example 2 Ethyl 4-(4-cyanophenyl)-2-(2-ethoxy-2-oxoethyl)-7-ethylpyrrolo[1,2-b]pyridazine-3 carboxylate 20 NMR (CDCl 3 , 8): 0.84 (31H, t, J=7Hz), 1.28 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 3.04 (2H, q, J=7Hz), 3.93 (2H, q, J=7Hz), 4.13 (3H, s), 4.19 (2H, q, J=7Hz), 6.24 (111, d, J=5Hz), 6.62 (1H, d, J=5Hz), 7.13 (21H, d, J=9Hz), 7.76 (2H, d, J=9Hz) Example 3 25 Ethyl 4-(4-cyanophenyl)-7-ethyl-2-(trifluoromethyl)pyrrolo[1,2-b]pyridazine-3 carboxylate NMR (CDCl 3 , 6): 1.08 (3H, t, J=7Hz), 1.41 (3H, t, J=7Hz), 3.11 (2H, q, J=7Hz), 4.11 (2H, q, J=7Hz), 6.43 (IH, d, J=5Hz), 6.93 (111, d, J=5Hz), 7.62 (2H, d, J=9Hz), 7.80 (211, d, J=9Hz) 30 Example 4 4-[7-Ethyl-2-methyl-3-(3-pyridinylcarbonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile 89 WO 2004/063197 PCT/JP2003/017091 NMR (CDC1 3 , 6): 1.43 (t, J=7 Hz, 3H), 2.47 (s, 3H), 3.09 (q, J=7 Hz, 2 H), 6.35 (d, J=5 Hz, 1H), 6.74 (d, J=5 Hz, 1H), 7.23 (1H, m), 7.48 (2H, d, J=9Hz), 7.55 (2H, d, J=9Hz), 7.93 (1H, m), 8.62 (1H, m), 8.74 (1H, m) 5 Example 5 3-[7-Ethyl-2-methyl-3-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile NMR (CDC1 3 , 5): 1.42 (3H, t, J=7Hz), 2.32 (3H, s), 3.08 (2H, q, J=7Hz), 6.15 (1H, d, J=5Hz), 6.67 (1H, d, J=5Hz), 7.00 (21, d, J=9Hz), 7.37 (211, m), 7.57 (2H, m), 8.50 (2H, d, J=9Hz) 10 Example 6 4-(3-Benzyl-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile NMR (CDCI 3 , 6): 1.40 (3H, t, J=8Hz), 2.35 (3H, s), 3.04 (2H, q, J=8Hz), 3.83 (3H, s), 5.94 (1H, d, J=5Hz), 6.57 (111, d, J=5Hz), 6.98 (2H, d, J=8Hz), 7.14-7.30 (3H, m), 15 7.46 (2H, d, J=8Hz), 7.68 (2H, d, J=8Hz) MS (ESI*): m/z 352 (M+H) Example 7 4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazine-3-carbonitrile 20 mp: 172-173*C NMR (CDCl3, 8): 1.41 (3H, t, J8Hz), 3.10 (2H, q, J=8Hz), 6.65 (IH, d, J=5Hz), 6.88 (1H, d, J=5Hz), 7.47-7.64 (61, m), 7.70 (1H, br s), 7.81-7.90 (2H, m) Example 8 25 3-(3-Ethyl-7,7,9,9-tetramethyl-6,7,8,9-tetrahydropyrrolo[1,2-b]cinnolin- 10 yl)benzonitrile NMR (CDCl 3 , 6): 1.00-1.15 (12H, m), 1.37 (3H, t, J=8Hz), 2.81 (3H, s), 3.00 (2H, q, J=8Hz), 3.82 (2H, t, J=5Hz), 5.46 (1H, d, J=5Hz), 6.46 (111, d, J=5Hz), 7.50-7.65 (3H, m), 7.72 (1H, m) 30 Example 9 3-(3-Ethyl-9-oxo-6,7,8,9-tetrahydropyrrolo[1,2-b]cinnolin-10-yl)benzonitrile 90 WO 2004/063197 PCT/JP2003/017091 NMR (CDCI 3 , 6): 1.40 (3H, t, J=8Hz), 2.08-2.22 (2H, m), 2.60 (2H, t, J=7Hz), 3.00 3.15 (4H, m), 6.26 (1H, d, J=5Hz), 6.74 (1H, d, J=5Hz), 7.49-7.61 (3H, m), 7.74 (1H, m) MS (ESI*): m/z 316 (M+H) 5 Example 10 3-(6-Ethyl-1-oxo-2, 3 -dihydro-1H-cyclopenta[e]pyrrolo[1,2-b]pyridazin-9-yl)benzonitrile mp: 150-154'C NMR (CDCI3, 5): 1.43 (3H, t, J=8Hz), 2.75 (2H, t, J=7Hz), 3.10 (2H, q, J=8Hz), 3.24 10 (2H, t, J=7Hz), 6.67 (1H, d, J=5Hz), 6.87 (1H, d, J=5Hz), 7.60 (1H, t, J=8Hz), 7.75-7.90 (3H, m) MS (ESI*): m/z 324 (M+Na) Example 11 15 3 -(7-Ethyl-2-neopentylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile NMR (CDCI 3 , 8): 1.05 (9H, s), 1.39 (3H, t, J=8Hz), 2.68 (2H, s), 3.04 (2H, q, J=8Hz), 6.36 (1H, s), 6.48 (1H, d, J=5Hz), 6.67 (1H, d, J=5Hz), 7.51 (1H, t, J=8Hz), 7.75 (1H, br d, J=8Hz), 7.92-8.01 (2H, m) MS (ESI*): m/z 318 (M+H) 20 Example 12 3 -[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile NMR (CDC1 3 , 6): 1.44 (3H, t, J=8Hz), 3.11 (2H, q, J=8Hz), 6.52-6.60 (2H, m), 6.74 (1H, d, J=5Hz), 6.98 (1H, s), 7.09 (1H, d, J=5Hz), 7.56-7.68 (2H, m), 7.78 (1H, 25 dd, J=8, 1Hz), 7.96-8.08 (2H, m) MS (ESI*): m/z 314 (M+H) Example 13 4

-[

7 -Ethyl-2-methyl-3-(methylsulfonyl)pyrrolo[1,2-blpyridazin-4-yl]benzonitrile 30 NMR (CDC1 3 , 5): 1.38 (3H, t, J=8Hz), 2.89 (3H, s), 3.00-3.11 (5H, m), 6.09 (1H, d, J=5Hz), 6.73 (1H, d, J=5Hz), 7.45 (2H, d, J=8Hz), 7.76 (2H, d, J=8Hz) MS (ESI*): m/z 340 (M+H) 91 WO 2004/063197 PCT/JP2003/017091 Example 13-2 4-{ 7-Ethyl-2-[(methylsulfonyl)methyl]pyrrolo[1,2-b]pyridazin-4-yl}benzonitrile NMR (CDCI 3 , 5): 1.39 (3H, t, J=8Hz), 2.96-3.09 (511, m), 4.44 (21H, s), 6.63 (1H, d, J=5Hz), 6.71 (1H, s), 6.81 (1H, d, J=5Hz), 7.79 (2H, d, J=8Hz), 7.85 (2H, d, 5 J=8Hz) MS (ESI*): m/z 340 (M+H) Example 15 3-[7-Ethyl-2-methyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile 10 NMR (CDCl 3 , 6): 1.39 (31H, t, J=8Hz), 2.89 (311, s), 3.00-3.11 (5H, m), 6.09 (111, d, J=5Hz), 6.73 (1H, d, J=5Hz), 7.54-7.63 (3H, m), 7.77 (1H, m) Example 16 To a solution of 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2 15 b]pyridazin-4-yl]benzonitrile (22 mg) in N,N-dimethylfornamide (1 mL) were added 1N sodium hydroxide (0.12 mL) and 30% hydrogen peroxide (0.07 mL) at ambient temperature. After 1 hour stirring, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash 20 silica gel column chromatography (silica gel, 30 mL) eluting with hexane-ethyl acetate = 5-1 and 0-1 to give 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4 yl]benzamide (18 mg, 78.0%) as an yellow solid. 4-[7-Ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yljbenzamide 25 NMR (CDCI 3 , 6): 1.41 (311, t, J=8Hz), 2.31 (3H, s), 3.17 (2H, q, J=8Hz), 3.77 (311, s), 5.61 (0.2H, br s), 6.02 (0.4H, br s), 6.13 (11H, d, J=5Hz), 6.60 (11H, d, J=51Hz), 6.75 (2H, d, J=8Hz), 6.95 (2H, d, J=81z), 7.31 (2H, d, J=8Hz), 7.68 (21, d, J=8Hz) MS (ESI*): m/z 386 (M+H) 30 The following compound was obtained in substantially the same manner as that of Example 16. 92 WO 2004/063197 PCT/JP2003/017091 Example 17 3-[2-(Dimethylamino)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide NMR (CDCl 3 , 8): 1.32 (3H, t, J=7Hz), 2.90 (6H, s), 2.95 (211, q, J=7Hz), 3.36 (3H, s), 6.21 (1H, d, J=5Hz), 6.79 (1H, d, J=5Hz), 7.44 (1H, s, br), 7.52-7.56 (2H, m), 5 7.90 (1H, s), 7.94-8.06 (2H, m) MS (ESI*): m/z 387 (M+H) Example 18 3-(7-Ethyl-2-neopentylpyrrolo[1,2-b]pyridazin-4-yl)benzamide 10 NMR (CDCl 3 , 5): 1.05 (9H, s), 1.39 (3H, t, J=8Hz), 2.68 (2H, s), 3.04 (2H, q, J=8Hz), 5.70 (1H, br s), 6.11 (111, br s), 6.41 (1H, s), 6.52 (1H, d, J=5Hz), 6.65 (1H, d, J=5Hz), 7.59 (1H, t, J=8Hz), 7.85-7.93 (2H, m), 8.15 (111, br s) MS (ESI*): m/z 336 (M+H) 15 Example 19 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide NMR (CDCI 3 , 5): 1.43 (3H, t, J=8Hz), 3.10 (2H, q, J=8Hz), 5.70 (1H, br s), 6.13 (1H, br s), 6.53-6.60 (2H, m), 6.71 (111, d, J=5Hz), 7.02 (111, s), 7.06 (1H, d, J=5Hz), 7.55-7.65 (2H, m), 7.79-7.98 (2H, m), 8.02 (1H, br s) 20 MS (ESI"): m/z 332 (M+H) Example 20 5-[2-({[4-(Aminocarbonyl)benzyl]oxy}methyl)-4-(5-bromo-3-pyridinyl)-7 ethylpyrrolol,2-b]pyridazin-3-yl]pentanoic acid 25 NMR (DMSO-d 6 , 6): 1.27-1.45 (7H, m), 1.99 (211, m), 2.96 (2H, m), 3.40 (2H, m), 4.67 (2H, s), 4.72 (2H, s), 5.88 (1H, d, J=5Hz), 6.67 (111, d, J=5Hz), 7.35 (1H, s, br), 7.44 (2H, d, J=8Hz), 7.86 (2H, d, J=8Hz), 7.96 (1H, s, br), 8.21 (1H, m), 8.60 (1H, m), 8.86 (111, m) 30 Example 21 To a solution of ethyl 6-(3-cyanobenzoyl)-7-oxooctanoate (3.18 g) in toluene (30 mL) was added 2-ethyl-1H-pyrrol-1-amine (1.17 g) and p-toluenesulfonic acid 93 WO 2004/063197 PCT/JP2003/017091 monohydrate (96 mg) at ambient temperature. The reaction mixture was refluxed for 1 hour. The mixture was evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 200 mL) eluting with hexane-ethyl acetate = 20-1, 15-1, and 10-1 to give ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 5 yl]pentanoate (3.29 g, 83.8%) as an yellow oil. Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yljpentanoate NMR (CDCI 3 , 5): 1.23 (3H, t, J=8Hz), 1.32-1.58 (7H, m), 2.18 (2H, t, J=8Hz), 2.35 2.45 (2H, m), 3.01 (2H, q, J=8Hz), 4.10 (2H, q, J=8Hz), 5.79 (1H, d, J=5Hz), 10 6.51 (1H, d, J=5Hz), 7.57-7.67 (3H, m), 7.75 (1H, m) The following compounds were obtained in substantially the same manner as that of Example 21. Example 22 15 Ethyl 2,4-diisopropylpyrrolo[1,2-b]pyridazine-3-carboxylate NMR (300 MHz, CDCl 3 , 6): 1.32 (6H, d, J=7.5Hz), 1.39 (3H, t, J=7.5Hz), 1.46 (6H, d, J=7.5Hz), 2.91-3.05 (1H, m), 3.05-3.20 (1H, m), 4.38 (2H, q, J=7.5Hz), 6.64 6.68 (1H, m), 6.76-6.80 (1H, m), 7.65-7.68 (1H, m) MS (ES+) m/e 275.33 20 Example 23 Ethyl 4-(2-chlorophenyl)-2-isopropylpyrrolo[ 1,2-b]pyridazine-3-carboxylate NMR (300 MHz, CDCl 3 , 6): 0.89 (3H, t, J=7.5Hz), 1.30-1.40 (6H, m), 3.36-3.51 (1H, m), 4.00 (2H, q, J=7.5Hz), 6.10-6.18 (1H, m), 6.75-6.84 (1H, m), 7.28-7.45 (3H, 25 m), 7.45-7.55 (1H, m), 7.75-7.81 (1H, m) Example 24 Ethyl 2-isopropyl-4-(2-naphthyl)pyrrolo[1,2-b]pyridazine-3-carboxylate NMR (300 MHz, CDCl 3 , 6): 0.78 (3H, t, J=7.5Hz), 1.38 (6H, d, J=7.5Hz), 3.24-3.35 30 (1H, m), 3.95 (2H, q, J=7.5Hz), 6.36-6.40 (1H, m), 6.80-6.85 (1H, m), 7.50-7.54 (3H, m), 7.78-7.82 (1H, m), 7.82-8.00 (4H, m) MS (ES+) m/e 359.56 94 WO 2004/063197 PCT/JP2003/017091 Example 25 Ethyl 5 -{7-ethyl-2-methyl-4-[3-(trifluoromethyl)phenyl]pyrrolo[1,2-b]pyridazin-3 yl}pentanoate 5 NMR (CDC1 3 , 8): 1.22 (3H, t, J=7Hz), 1.37 (311, t, J=7Hz), 1.40-1.59 (4H, m), 2.14 (2H, t, J=7Hz), 2.38-2.46 (21H, m), 2.55 (3H, s), 3.01 (2H, q, J=7Hz), 4.10 (2H, q, J=7Hz), 5.83 (1H, d, J=4Hz), 6.51 (1H, d, J=4Hz), 7.53-7.64 (311, m), 7.71 (1H, d, J=8Hz) MS (ESI*): m/z 433 (M+H) 10 Example 26 Ethyl 5-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate NMR (CDCI 3 , 5): 1.23 (3H, t, J=7Hz), 1.37 (3H, t, J=711z), 1.38-1.60 (4H, m), 2.18 15 (2H, t, J=7Hz), 2.42 (3H, s), 2.38-2.50 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=7Hz), 4.09 (211, q, J=711z), 5.87 (1H, d, J=411z), 6.51 (IH, d, J=4Hz), 7.50 (1H, s), 8.39 (111, s), 8.53 (111, s) MS (ESI*): m/z 380 (M+H) 20 Example 27 Ethyl 5-[7-ethyl-4-(3-methoxy-5-isoxazolyl)-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin 3-yl]pentanoate NMR (CDCI 3 , 8): 1.25 (3H, t, J=7Hz), 1.36 (3H, t, J=7Hz), 1.55-1.64 (21H, m), 1.64 1.80 (2H, m), 2.33 (211, t, J=7Hz), 2.74-2.85 (2H, m), 3.03 (211, q, J=7Hz), 3.43 25 (3H, s), 4.08 (311, s), 4.12 (21H, q, J=7Hz), 4.62 (2H, s), 6.28 (1H, s), 6.38 (1H, d, J=4Hz), 6.65 (1H, d, J=4Hz) MS (ESI*): m/z 416 (M+H) Example 28 30 Ethyl 5-{7-ethyl-2-methyl-4-[3-(1,3-oxazol-5-yl)phenyl]pyrrolo[1,2-b]pyridazin-3 yl}pentanoate NMR (CDCl 3 , 6): 1.20 (311, t, J=7Hz), 1.35 (3H, t, J=7Hz), 1.40-1.63 (4H, m), 2.17 95 WO 2004/063197 PCT/JP2003/017091 (2H, t, J=7Hz), 2.44-2.57 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7Hz), 4.05 (2H, q, J=7Hz), 5.89 (1H, d, J=4Hz), 6.50 (1H, d, J=411z), 7.33 (1H, d, J=8Hz), 7.39 (111, s), 7.53 (1H, t, J=8Hz), 7.66 (1H, m), 7.74 (1H, d, J=8Hz), 7.93 (1H, s) 5 Example 29 Ethyl 5-[4-(3,4-dichlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCl 3 , 6): 1.24 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.38-1.48 (2H, m), 1.50 1.65 (2H, m), 2.20 (211, t, J=7Hz), 2.38-2.47 (2H, m), 2.54 (3H, s), 3.00 (2H, q, J=7Hz), 4.12 (2H, q, J=7Hz), 5.87 (1H, d, J=4Hz), 6.51 (1H, d, J=4Hz), 7.19 (1H, 10 dd, J=2 Hz, 8Hz), 7.46 (1H, d, J=2Hz), 7.56 (1H, d, J=8Hz) MS (ESI+): m/z 433 (M+H) Example 30 Ethyl 5-[4-(4-chloro-2-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 15 yl]pentanoate NMR (CDCI 3 , 6): 1.24 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.44-1.67 (411, m), 2.15 2.26 (2H, m), 2.42-2.56 (211, m), 2.56 (311, s), 3.01 (2H, q, J=7Hz), 4.10 (2H, q, J=7Hz), 5.95 (1H, d, J=3Hz), 6.54 (1H, d, J=311z), 7.40 (1H, dd, J=2 Hz, 4Hz), 7.54 (111, d, J=2Hz), 8.67 (1H, d, J=4Hz) 20 MS (ESI+): m/z 400 (M+H) Example 31 Ethyl 5-[4-(5-chloro-2-thienyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate 25 NMR (CDCI 3 , 6): 1.25 (3H, t, J=7Hz), 1.36 (3H, t, J=7Hz), 1.48-1.74 (4H, m), 2.28 (2H, t, J=7Hz), 2.68-2.77 (2H, m), 3.02 (2H, q, J=7Hz), 3.44 (3H, s), 4.12 (2H, q, J=7Hz), 4.60 (2H, s), 6.25 (1H, d, J=4Hz), 6.60 (1H, d, J=4Hz), 6.97 (2H, m) MS (ESI*): m/z 435 (M+H) 30 Example 32 Ethyl 5-[7-ethyl-4-(6-methoxy-2-pyrazinyl)-2-methylpyrrolo[1,2-b]pyridazin-3 yl]pentanoate 96 WO 2004/063197 PCT/JP2003/017091 NMR (CDCl 3 , 6): 1.23 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.52-1.68 (4H, m), 2.23 (21-, t, J=7Hz), 2.48-2.55 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7Hz), 3.98 (311, s), 4.09 (2H, q, J=7Hz), 6.03 (11, d, J=4Hz), 6.55 (111, d, J=4Hz), 8.30 (1H, s), 8.33 (1H,s) 5 MS (ESI*): m/z 397 (M+H) Example 33 Ethyl 5-[4-(1-benzofuran-2-yl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCI 3 , 5): 1.23 (3H, t, J=7Hz), 1.38 (3H, t, J=711z), 1.62-1.83 (4H, m), 2.33 10 (2H, t, J=7Hz), 2.57 (3H, s), 2.69-2.78 (2H, m), 3.03 (2H, q, J=7Hz), 4.12 (2H, q, J=711z), 6.48 (1H, d, J=4Hz), 6.59 (1H, d, J=4Hz), 7.15 (1H, s), 7.26-7.42 (2H, m), 7.57 (1H, d, J=8Hz), 7.68 (1H, d, J=8Hz) MS (ESIr): m/z 405 (M+H) 15 Example 34 Ethyl 5-[4-(1-benzothien-2-yl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCl 3 , 8): 1.21 (3H, t, J=7Hz), 1.35 (3H, t, J=7Hz), 1.52-1.69 (4H, m), 2.23 (2H, t, J=7Hz), 2.56 (3H, s), 2.61-2.70 (2H, m), 3.02 (2H, q, J=7Hz), 4.07(2H, q, J=7Hz), 6.21 (1H, d, J=4Hz), 6.53 (1H, d, J=4Hz), 7.35-7.43 (311, m), 7.81-7.92 20 (2H, m) Example 35 Ethyl 5-[7-ethyl-2-methyl-4-(1,3-oxazol-5-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCl 3 , 6): 1.25 (3H, t, J=711z), 1.36 (3H, t, J=7Hz), 1.53-1.66 (2H, m), 1.66 25 1.83 (2H, m), 2.34 (211, t, J=7Hz), 2.56 (3H, s), 2.62-2.73 (2H, m), 3.02 (2H, q, J=7Hz), 4.13 (2H, q, J=711z), 6.42 (1H, d, J=4Hz), 6.58 (1H, d, J=4Hz), 7.50 (1H, s), 8.10 (1H, s) MS (ESI*): m/z 356 (M+H) 30 Example 36 Ethyl 5-(7-ethyl-2-methyl-4-phenylpyrrolo[1,2-b]pyridazin-3-yl)pentanoate NMR (CDCl 3 , 6): 1.23 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.40-1.60 (4H, m), 2.15 97 WO 2004/063197 PCT/JP2003/017091 (2H, t, J=7Hz), 2.41-2.48 (2H, m), 2.55 (3H, s), 3.02 (2H, q, J=7Hz), 4.08 (211, q, J=7Hz), 5.88 (1H, d, J=4Hz), 6.48 (1H, d, J=4Hz), 7.31-7.34 (2H, m), 7.40-7.49 (3H, m) MS (ESI*): m/z 365 (M+H) 5 Example 37 Ethyl 5-[7-ethyl-2-methyl-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yljpentanoate NMR (CDCl 3 , 5): 1.18 (3H, t, J=7Hz), 1.39 (3H, t, J=7Hz), 1.39-1.55 (41, m), 2.14 (2H, d, J=7Hz), 2.44-2.55 (2H, m), 2.58 (3H, s), 3.03 (2H, q, J=7Hz), 4.03 (2H, q, 10 J=7Hz), 5.86 (1H, d, J=411z), 6.51 (1H, d, J=4Hz), 7.45-7.52 (1H, m), 7.69 (1H, dd, J=2Hz, 8Hz), 7.84 (1H, d, J=2Hz), 8.20 (2H, d, J=8Hz), 9.00 (1H, m) Example 38 Ethyl 7-{ 4-[4-({ [(benzyloxy)carbonyl]amino}sulfonyl)phenyl]-7-ethyl-2 15 methylpyrrolo[1,2-b]pyridazin-3-yl}heptanoate NMR (CDCl 3 , 8): 1.12-1.23 (7H, m); 1.33-1.51 (7H, s), 2.17 (2H, t, J=711z), 2.35 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7Hz), 4.11 (2H, q, J=7Hz), 5.17 (2H, s), 5.78 (111, d, J=5Hz), 6.52 (1H, d, J=511z), 7.29-7.38 (5H, m), 7.49 (2H, d, J=911z), 7.87 (11, s, br), 8.11 (211, d, J=9Hz) 20 MS (ESI*): m/z 606 (M+H) MS (ESI~): m/z 604 (M-H) Example 39 2-{ [4-(3-Chlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methyl}-1,3 25 propanediol NMR (CDCl 3 , 6): 1.26 (311, t, J=7Hz), 1.38 (3H, t, J=7Hz), 1.64-1.82 (311, m), 2.59 (3H, s), 3.02 (21H, q, J=7Hz), 3.45 (211, m), 3.63 (2H, m), 4.12 (211, q, J=7Hz), 5.93 (1H, d), J=5Hz), 6.53 (1H, d, J=5Hz), 7.28 (1H, m), 7.42-7.44 (3H, m) 30 Example 40 Ethyl 5-{ 7-ethyl-2-methyl-4-[3-(methylsulfonyl)phenyl]pyrrolo[1,2-b]pyridazin-3 yl}pentanoate 98 WO 2004/063197 PCT/JP2003/017091 NMR (CDCl3, 6): 1.22 (3H1, t, J=8Hz), 1.33-1.57 (7H, m), 2.18 (2H, t, J=z8Hz), 2.35 2.45 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8Hz), 3.12 (311, s), 4.08 (2H, q, J=8Hz), 5.80 (1H, d, J=5Hz), 6.51 (1H, d, J=5Hz), 7.64-7.74 (2H, m), 7.96 (1H, br s), 8.04 (1H, m) 5 MS (ESI*): m/z 443 (M+H) Example 41 Ethyl 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yllpentanoate 10 NMR (CDCl 3 , 8): 1.23 (31, t, J=8Hz), 1.30-1.62 (7H, m), 2.21 (2H, t, J=8Hz), 2.35 2.45 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=8Hz), 4.10 (2H, q, J=8Hz), 5.85 (1H1, d, J=5Hz), 6.53 (1H, d, J=5Hz), 7.24 (1H, dd, J=7, 1Hz), 7.35 (1H, br s), 8.53 (1H, d, J=7Hz) MS (ESI*): m/z 400 (M+H) 15 Example 42 Ethyl 5-[7-ethyl-2-methyl-4-(3-nitrophenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCI 3 , 6): 1.21 (3H, t, J=8Hz), 1.34-1.59 (7H, m), 2.17 (2H, t, J=8Hz), 2.37 2.47 (211, m), 2.57 (31, s), 3.01 (2H, q, J=8Hz), 4.08 (2H, q, J=8Hz), 5.81 (11H, d, 20 J=5Hz), 6.52 (1H, d, J=5Hz), 7.64-7.74 (2H, m), 8.25 (1H, br s), 8.33 (1H, m) MS (ESI+): m/z 410 (M+H) Example 43 Ethyl 4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate 25 NMR (CDCI 3 , 6): 0.98 (3H, t, J=8Hz), 2.55 (3H, s), 4.05 (2H, q, J=8Hz), 6.35 (1H, m), 6.81 (1H, m), 7.12-7.22 (2H, m), 7.41-7.50 (2H, m), 7.76 (1H, m) MS (ESI*): m/z 359 (M+H) Example 44 30 4-(3-Butyl-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile NMR (CDCI 3 , 6): 0.78 (3H, t, J=8Hz), 1.12-1.43 (7H, m), 2.31-2.40 (2H, m), 2.56 (3H, s), 3.00 (2H, q, J=8Hz), 5.79 (1H, d, J=5Hz), 6.50 (1H, d, J=5Hz), 7.47 (2H, 99 WO 2004/063197 PCT/JP2003/017091 d, J=81z), 7.77 (2H, d, J=8Hz) MS (ESI*): m/z 318 (M+H) Example 45 5 Ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yllpentanoate NMR (CDC1 3 , 5): 1.24 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.40-1.65 (411, m), 2.21 (2H, t, J=7Hz), 2.37-2.49 (2H, m), 2.56 (3H, s), 3.00 (21H, q, J=7Hz), 4.10 (2H, q, J=7Hz), 5.87 (1H, d, J=4Hz), 653 (11, d, J=4Hz), 7.85 (1H, m), 8.53 (11, d, 10 J=2Hz), 8.77 (1H, d, J=2Hz) MS: (m/z) 444,446 (M+H) Example 46 Ethyl 5-4-(2-chloro-4-pyridinyl)-7-ethyl-2-[(methylthio)methyl pyrrolo[1,2-b]pyridazin 15 3-yl}pentanoate NMR (CDCl 3 , 6): 1.24 (311, t, J=7Hz), 1.36 (3H, t, J=7Hz), 1.40-1.63 (4H, m), 2.18 (3H, s), 2.20 (2H, t, J=7Hz), 2.48-2.58 (2H, m), 3.02 (2H, q, J=7Hz), 3.81 (2H, s), 4.10 (2H, q, J=7Hz), 5.89 (111, d, J=4Hz), 6.57 (1H, d, J=4Hz), 7.27 (11, m), 7.38 (111, s), 8.53 (11, d, J=4Hz) 20 MS: (m/z) 446 (M+H) Example 47 Ethyl 6-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate NMR (CDC1 3 , 8): 1.15-1.29 (51H, m), 1.32-1.61 (7H, m), 2.20 (2H, t, J=8Hz), 2.33 25 2.43 (2H, m), 2.56 (3H, s), 3.01 (211, q, J=8Hz), 4.10 (2H, q, J=8Hz), 5.79 (1H, d, J=5Hz), 6.51 (1H, d, J=5Hz), 7.57-7.67 (3H, m), 7.75 (11H, m) MS (ESI*): m/z 404 (M+H) Example 48 30 Ethyl 5-[4-(6-chloro-2-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl]pentanoate NMR (CDCI 3 , 5): 1.23 (3H, t, J=71z), 1.36 (3H, t, J=7Hz), 1.46-1.65 (411, m), 2.22 100 WO 2004/063197 PCT/JP2003/017091 (2H, t, J=7Hz), 2.46-2.57 (2H, m), 2.54 (3H, s), 3.00 (211, q, J=7Hz), 4.09 (2H, q, J=7Hz), 5.95 (1H, d, J=4Hz), 6.51 (111, d, J=4Hz), 7.38-7.47 (2H, m), 7.80 (1H, t, J=8Hz) MS (ESI*): m/z 400 5 Example 49 Ethyl 5-[7-ethyl-4-(3-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCI 3 , 8): 1.23 (3H, t, J=7Hz), 1.36 (3H, t, J=7Hz), 1.40-1.62 (4H, m), 2.17 (2H, t, J=7Hz), 2.43-2.52 (2H, m), 2.54 (3H, s), 3.00 (2H, q, J=7Hz), 3.83 (31H, s), 10 4.08 (211, q, J=7Hz), 5.91 (11H, d, J=4Hz), 6.49 (1H, d, J=4Hz), 6.87-6.99 (3H, m), 7.37 (111, t, J=8Hz) MS (ESI*): m/z 395 Example 50 15 Ethyl 5-[4-(3,5-dichlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCl 3 , 6): 1.23 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.39-1.52 (2H, m), 1.52 1.64 (2H, m), 2.22 (211, t, J=7Hz), 2.38-2.48 (2H, m), 2.54 (3H, s), 3.00 (211, q, J=7Hz), 4.10 (2H, q, J=7Hz), 5.88 (1H, d, J=4Hz), 6.51 (1H, d, J=4Hz), 7.25 (2H, m), 7.45 (1H, m) 20 MS (ESI*): m/z 433 Example 51 Ethyl 5-[4-(5-chloro-2-thienyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCl 3 , 6): 1.25 (31H, t, J=7Hz), 1.36 (311, t, J=7Hz), 1.46-1.58 (2H, m), 1.60 25 1.74 (2H, m), 2.28 (21H, t, J=7Hz), 2.53 (3H, s), 2.56-2.66 (2H, m), 2.98 (2H, q, J=7Hz), 4.12 (2H, q, J=7Hz), 6.20 (11H, d, J=411z), 6.53 (1H, d, J=4Hz), 6.94 (111, d, J=4Hz), 6.98 (1H, d, J=4Hz) MS (ESI*): m/z 405 30 Example 52 Ethyl 5-[7-ethyl-4-(3-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCI 3 , 8): 1.23 (3H, t, J=7Hz), 1.39 (3H, t, J=7Hz), 1.38-1.50 (211, m), 1.50 101 WO 2004/063197 PCT/JP2003/017091 1.63 (2H, m), 2.17 (2H, t, J=7Hz), 2.39-2.48 (21H, m), 2.54 (3H, s), 3.03 (211, q, J=7Hz), 4.09 (2H, q, J=711z), 5.88 (11, d, J=4Hz), 6.50 (111, d, J=4Hz), 7.03-7.16 (3H, m), 7.38-7.47 (1H, m) MS (ESI*): m/z 383 5 Example 53 Ethyl 5-[7-ethyl-2-methyl-4-(3-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCI 3 , 5): 1.18 (3H, t, J=7Hz), 1.38 (311, t, J=7Hz), 1.40-1.60 (4H, m), 2.16 (2H, t, J=7Hz), 2.44-2.56 (2H, m), 2.59 (311, s), 3.04 (2H, q, J=7Hz), 4.03 (211, q, 10 J=7Hz), 5.89 (1H, d, J=4Hz), 6.53 (1H, d, J=4Hz), 7.62 (1H, t, J=811z), 7.80 (1H, t, J=8Hz), 7.90 (111, d, J=8H1z), 8.21 (211, m), 8.90 (1H, d, J=2Hz) MS (ESI'): m/z 416 Example 54 15 Ethyl 5-[7-ethyl-2-methyl-4-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDC1 3 , 8): 1.23 (3H, t, J=711z), 1.38 (3H, t, J=7Hz), 1.40-1.64 (41H, m), 2.19 (2H, t, J=7Hz), 2.38-252 (211, m), 2.55 (311, s), 3.02 (2H, q, J=7Hz), 4.09 (2H, q, J=7Hz), 5.83 (111, d, J=4Hz), 6.51 (1H, d, J=4Hz), 7.29 (2H, m), 8.72 (2H, m) MS (ESI*): m/z 366 20 Example 55 Ethyl 5-[7-ethyl-4-(3-methoxy-5-isoxazolyl)-2-methylpyrrolo[1,2-b]pyridazin-3 yl]pentanoate NMR (CDCI 3 , 6): 1.25 (3H, t, J=7Hz), 1.36 (3H, t, J=7Hz), 1.55-1.82 (4H, m), 2.33 25 (2H, t, J=7Hz), 2.55 (3H, s), 2.62-2.72 (2H, m), 2.99 (2H, q, J=7Hz), 4.08 (3H, s), 4.12 (2H, q, J=7Hz), 6.26 (1H, s), 6.34 (1H, d, J=411z), 6.58 (1H, d, J=4Hz) Example 56 Ethyl 5-[7-ethyl-2-methyl-4-(5-methyl-3-isoxazolyl)pyrrolo[1,2-b]pyridazin-3 30 yl]pentanoate NMR (CDCI 3 , 8): 1.25 (3H, t, J=7Hz), 1.36 (311, t, J=7Hz), 1.50-1.75 (4H, m), 2.29 (211, t, J=7Hz), 2.55 (6H, s), 2.56-2.65 (2H, m), 2.99 (2H, q, J=7Hz), 4.11 (2H, q, 102 WO 2004/063197 PCT/JP2003/017091 J=7Hz), 6.16 (1H, d, J=4Hz), 6.22 (1H, s), 6.54 (1H, d, J=4Hz) MS (ESI*): m/z 370 Example 57 5 Ethyl 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate NMR (CDCI 3 , 6): 1.23 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.36-1.63 (411, m), 2.20 (2H, t, J=7Hz), 2.48-2.63 (2H, m), 3.03 (2H, q, J=7Hz), 3.45 (3H, s), 4.09 (2H, q, J=7Hz), 4.62 (2H, s), 5.89 (1H, d, J=4Hz), 6.60 (11, d, J=4Hz), 7.26 (1H, m), 10 7.37 (1H, s), 8.53 (1H, d, J=5Hz) MS (ESI*): m/z 430 Example 58 Ethyl 5-[7-ethyl-2-(methoxymethyl)-4-(3-methoxyphenyl)pyrrolo[1,2-b]pyridazin-3 15 yl]pentanoate NMR (CDCI 3 , 8): 1.22 (3H, t, J=7Hz), 1.37 (311, t, J=71z), 1.40-1.63 (4H, m), 2.16 (2H, t, J=7Hz), 2.54-2.65 (2H, m), 3.04 (211, q, J=7Hz), 3.45 (3H, s), 3.83 (3H, s), 4.08 (2H, q, J=7Hz), 4.62 (2H, s), 5.96 (1H, d, J=4Hz), 6.56 (1H, d, J=4Hz), 6.87 7.00 (311, m), 7.38 (1H, t, J=8Hz) 20 MS (ESI*): m/z 425 Example 59 Ethyl 5-[7-ethyl-2-(methoxymethyl)-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate 25 NMR (CDCI 3 , 5): 1.17 (3H, t, J=7Hz), 1.43 (3H, t, J=7Hz), 1.36-1.58 (4H, m), 2.10 (2H, m), 2.56-2.68 (21, m), 3.07 (211, q, J=7Hz), 3.48 (3H, s), 4.02 (2H, q, J=7Hz), 4.66 (211, s), 5.90 (1H, d, J=4Hz), 6.56 (111, d, J=4Hz), 7.45-7.50 (111, m), 7.72 (1H, dd, J=2 Hz, 8Hz), 7.86 (1H, d, J=2Hz), 8.16-8.24 (211, m), 8.98 (1H, m) 30 Example 60 Ethyl 5-[7-ethyl-2-(methoxymethyl)-4-(3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 103 WO 2004/063197 PCT/JP2003/017091 yl]pentanoate NMR (CDCl 3 , 5): 1.22 (3H, t, J=711z), 1.38 (3H, t, J=7Hz), 1.40-1.60 (4H, m), 2.17 (2H, t, J=7Hz), 2.52-2.64 (2H, m), 3.04 (2H, q, J=7Hz), 3.46 (3H, s), 4.10 (2H, q, J=7Hz), 4.63 (2H, s), 5.89 (1H, d, J=411z), 6.58 (1H, d, J=4Hz), 7.42 (1H, m), 5 7.71 (1H, m), 8.62 (1H, m), 8.70 (1H, m) MS (ESI*): m/z 396 Example 61 Ethyl 5-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 10 yl]pentanoate NMR (CDCl 3 , 6): 1.23 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.40-1.58 (4H, m), 2.17 (21H, t, J=7Hz), 2.51-2.62 (211, m), 3.03 (2H, q, J=7Hz), 3.45 (3H, s), 4.08 (2H, q, J=7Hz), 4.61 (2H, s), 5.92 (1H, d, J=4Hz), 6.56 (1H, d, J=4Hz), 7.25 (1H, m), 7.37 (1H, s), 7.42 (211, m) 15 Example 62 Ethyl 5-[7-ethyl-2-methyl-4-(3-methylphenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCI 3 , 5): 1.23 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.40-1.60 (4H, m), 2.16 (2H, t, J=711z), 2.40 (311, s), 2.40-2.50 (2H, m), 2.54 (3H, s), 3.03 (2H, q, J=71z), 20 4.08 (2H, q, J=7Hz), 5.90 (1H, d, J=4Hz), 6.49 (111, d, J=4Hz), 7.10-7.15 (2H, m), 7.24 (1H, m), 7.33 (1H, m) MS: (m/z) 379 (M+H) Example 65 25 Ethyl 5-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate NMR (CDCl 3 , 8): 1.23 (31H, t, J=7Hz), 1.37 (311, t, J=7Hz), 1.40-1.60 (411, m), 2.18 (2H, t, J=711z), 2.42 (3H, s), 2.48-2.63 (211, m), 3.05 (2H, q, J=7Hz), 3.46 (3H, s), 4.08 (211, q, J=7Hz), 4.62 (211, s), 5.90 (1H, d, J=4Hz), 6.57 (1H, d, J=4Hz), 7.51 30 (11H, s), 8.41 (1H, s), 8.53 (111, s) MS (ESI*): m/z 410 104 WO 2004/063197 PCT/JP2003/017091 Example 66 Ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl]pentanoate NMR (CDCl 3 , 5): 1.24 (3H, t, J=7Hz), 1.37 (3H, t, J=711z), 1.40-1.65 (4H, m), 2.21 5 (2H, t, J=7Hz), 2.37-2.49 (2H, m), 2.56 (3H, s), 3.00 (2H, q, J=7Hz), 4.10 (2H, q, J=7Hz), 5.87 (1H, d, J=4Hz), 6.53 (1H, d, J=4Hz), 7.85 (111, m), 8.53 (1H, d, J=2Hz), 8.77 (1H, d, J=2Hz) MS (ESI*): m/z 444,446 10 Example 67 Ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate NMR (CDCl 3 , 6): 1.23 (3H, t, J=7Hz), 1.37 (311, t, J=7Hz), 1.40-1.63 (4H, m), 2.19 (211, t, J=7Hz), 2.50-2.66 (2H, m), 3.03 (2H, q, J=7Hz), 3.46 (3H, s), 4.10 (2H, q, 15 J=71Hz), 4.62 (2H, s), 5.91 (1H, d, J=4Hz), 6.60 (1H, d, J=4Hz), 7.88 (11H, m), 8.55 (1H, d, J=2Hz), 8.77 (1H, d, J=2Hz) MS (ESI*): m/z 474,476 Example 68 20 Ethyl 5-[4-(5,6-dichloro-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl]pentanoate NMR (CDCI 3 , 5): 1.24 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.36-1.60 (4H, m), 2.23 (211, t, J=7Hz), 2.37-2.50 (211, m), 2.55 (311, s), 3.02 (211, q, J=711z), 4.12 (211, q, J=7Hz), 5.87 (1H, d, J=4Hz), 6.53 (1H, d, J=4Hz), 7.81 (1H, d, J=2Hz), 8.30 (11H, 25 d, J=2Hz) MS (ESI*): m/z 434 Example 69 Ethyl 4-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 30 yl]butanoate NMR (CDCl 3 , 6): 1.37 (311, t, J=7Hz), 1.65-1.78 (2H, m), 2.16-2.25 (2H, m), 2.42 (3H, s), 2.53-2.65 (2H, m), 3.04 (2H, q, J=7Hz), 3.46 (3H, s), 4.12 (2H, q, J=7Hz), 105 WO 2004/063197 PCT/JP2003/017091 4.67 (2H, m), 5.91 (1H, d, J=4Hz), 6.58 (1H, d, J=4Hz), 7.53 (1H, s), 8.43 (1H, s), 8.54 (1H, s) MS (ESI): m/z 396 5 Example 70 Ethyl 3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoate NMR (CDCI 3 , 8): 1.25 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 2.35-2.55 (2H, m), 2.42 (3H, s), 2.84-2.96 (2H, m), 3.04 (2H, q, J=7Hz), 3.46 (3H, s), 4.08 (2H, q, J=7Hz), 10 4.65 (2H, s), 5.91 (1H, d, J=411z), 6.61 (1H, d, J=4Hz), 7.51 (1H, s), 8.41 (1H, s), 8.52 (1H, s) Example 71 Ethyl 4-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 15 yllbutanoate NMR (CDC1 3 , 8): 1.20 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.66-1.82 (2H, m), 2.16 2.28 (2H, m), 2.42 (3H, s), 2.44-2.53 (2H, m), 2.59 (3H, s), 3.02 (2H, q, J=7Hz), 4.12 (2H, q, J=7Hz), 5.87 (1H, d, J=4Hz), 6.53 (1H, d, J=411z), 7.51 (1H, s), 8.41 (1H, d, J=2Hz), 8.53 (111, d, J=2Hz) 20 MS (ESI+): m/z 366 Example 72 Ethyl 3-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yllpropanoate 25 NMR (CDCI 3 , 6): 1.24 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 2.30-2.43 (2H, m), 2.42 (3H, s), 2.58 (311, s), 2.76-2.86 (2H, m), 3.02 (211, q, J=7Hz), 4.10 (211, q, J=7Hz), 5.87 (1H, d, J=4Hz), 6.53 (1H, d, J=4Hz), 7.48 (IH, s), 8.40 (1H, d, J=2Hz), 8.53 (1H, d, J=2Hz) MS (ESI*): m/z 352 30 Example 73 Ethyl 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 106 WO 2004/063197 PCT/JP2003/017091 yl]propanoate NMR (CDCl 3 , 6): 1.21 (3H, t, J=7Hz), 1.39 (2H, t, J=7Hz), 2.35 (2H, t, J=7Hz), 2.58 (311, s), 2.74-2.83 (2H, m), 3.01 (211, q, J=7Hz), 4.08 (2H, q, J=7Hz), 5.89 (11H, d, J=4Hz), 6.55 (11H, d, J=4Hz), 7.87 (1H, s), 8.53 (11H, s), 8.79 (1H, s) 5 MS: (m/z) 416 (M+), 418 (M+-2), 85(bp) Example 74 Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate 10 NMR (CDCI 3 , 6): 1.23 (3H, t, J=8Hz), 1.32-1.55 (5H, m), 2.16 (211, t, J=8Hz), 2.46 2.57 (211, m), 3.03 (211, q, J=8Hz), 3.46 (311, s), 4.09 (111, q, J=8Hz), 4.62 (211, s), 5.34 (1H, d, J=51Hz), 6.57 (11H, d, J=51Hz), 7.59-7.64 (2H, m), 7.68 (1H, br s), 7.75 (1H, m) MS (ESI*): 420 (M+H) 15 Example 75 Ethyl 5-[2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin 3-yl]pentanoate NMR (CDCI 3 , 6): 1.23 (3H, t, J=7z), 1.34-1.55 (71H, m), 2.11-2.22 (5H, m), 2.47 20 (211, m), 3.02 (21H, q, J=711z), 4.09 (21H, q, J=7Hz), 5.29 (2H, s), 5.94 (1H, d, J=5Hz), 6.63 (1H, d, J=5Hz), 7.88 (111, m), 8.56 (1H, m), 8.79 (1Hl, m) Example 76 To a solution of ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2 25 b]pyridazin-3-yl]pentanoate (1.20 g) in ethanol (12 mL) was added IN sodium hydroxide (4.62 mL) and was stirred at ambient temperature for 2 hours. The reaction mixture was acidified with IN hydrogen chloride and was partitined between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica 30 gel, 100 mL) eluted with hexane-ethyl acetate= 3-1, 2-1, and 1-1 to give an yellow solid (846 mg). The solid was recrystallized from hexane-ethyl acetate (5-1) to give 5-[4-(3 cyanophenyl)-7-ethyl-2-methylpyrrolo(1,2-b]pyridazin-3-yl]pentanoic acid as a pale 107 WO 2004/063197 PCT/JP2003/017091 yellow crystals (795 mg, 71.4%). 5-[4-(3-Cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid mp: 109-110*C 5 NMR (CDCl3, 8): 1.33-1.60 (7H, m), 2.42 (2H, t, J=8Hz), 2.34-2.48 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8Hz), 5.80 (1H, d, J=5Hz), 6.52 (1H, d, J=5Hz), 7.56-7.64 (2H, m), 7.66 (1H, br s), 7.76 (1H, m) MS (ESI*): m/z 362 (M-H) 10 The following compounds were obtained in substantially the same manner as that of Example 76. Example 77 3-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoic acid NMR (CDCl 3 , 5): 1.36 (3H, t, J=7 H), 1.56 (2H, m), 2.03 (2H, m), 2.79 (2H, m), 3.01 15 (2H, q, J=7Hz), 6.01 (1H, d, J=5Hz), 6.63 (1H, d, J=5Hz), 7.27 (1H, m), 7.40 7.53 (8H, m) Example 78 5-{7-Ethyl-2-methyl-4-[3-(trifluoromethyl)phenyl]pyrrolo[1,2-b]pyridazin-3 20 yl}pentanoic acid NMR (CDCl 3 , 5): 1.37 (3H, t, J=7Hz), 1.40-1.62 (411, m), 2.22 (211, t, J=7Hz), 2.38 2.46 (2H, m), 2.56 (3H, s), 3.02 (2H, q, 1=7Hz), 5.84 (1H, d, J=4Hz), 6.51 (1H, d, J=4Hz), 7.53-7.64 (3H, m), 7.72 (11H, d, J=8Hz) MS (ESI*): m/z 403 (M-H), 405 (M+H) 25 Example 79 5-[7-Ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 5): 1.37 (3H, t, J=7Hz), 1.45-1.67 (4H, m), 2.22 (211, t, J=7Hz), 2.42 (3H, s), 2.35-2.48 (2H, m), 2.56 (3H, s), 3.02 (211, q, J=7Hz), 5.83 (1H, d, J=4Hz), 30 6.51 (1H, d, J=4Hz), 7.53 (111, s), 8.39 (1H, s), 8.53 (1H, s) MS (ESI*): m/z 352 (M+H) 108 WO 2004/063197 PCT/JP2003/017091 Example 80 5-[7-Ethyl-4-(3-rnethoxy-5-isoxazolyl)-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid NMR (CDCI 3 , 6): 1.36 (3H, t, J=7Hz), 1.58-1.83 (4H, m), 2.38 (2H, t, J=7Hz), 2.74 5 2.85 (2H, m), 3.03 (2H, q, J=7Hz), 3.43 (3H, s), 4.08 (3H, s), 4.62 (2H, s), 6.28 (1H, s), 6.41 (1H, d, J=4Hz), 6.67 (1H, d, J=4Hz) MS (ESI'): m/z 386 (M-H), 388 (M+H) Example 81 10 5-{7-Ethyl-2-methyl-4-[3-(1,3-oxazol-5-yl)phenyl]pyrrolo[1,2-b]pyridazin-3 yl}pentanoic acid NMR (CDCl 3 , 5): 1.38 (3H, t, J=7Hz), 1.45-1.65 (4H, m), 2.21 (2H, t, J=7Hz), 2.43 2.53 (2H, m), 2.56 (3H, s), 3.03 (2H, q, J=7Hz), 5.89 (1H, d, J=4Hz), 6.51 (1H, d, J=4Hz), 7.32 (1H, d, J=8Hz), 7.39 (IH, s), 7.53 (1H, t, J=8Hz), 7.65 (1H, s), 7.73 15 (1H, d, J=8Hz), 7.93 (1H, s) MS (ESI*): m/z 402 (M-H), 404 (M+H) Example 82 5-[4-(3,4-Dichlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 20 NMR (CDCl 3 , 6): 1.37 (3H, t, J=7Hz), 1.42-1.65 (4H, m), 2.27 (2H, t, J=7Hz), 2.38 2.48 (2H, m), 2.54 (3H, s), 3.02 (2H, q, J=7Hz), 5.87 (1H, d, J=4Hz), 6.51 (1H, d, J=4Hz), 7.19 (1H, dd, J=2 Hz, 8Hz), 7.45 (1H, d, J=2Hz), 7.56 (1H, d, J=8Hz) MS (ESI*): m/z 403 (M-H), 405 (M+H) 25 Example 83 5-[4-(4-Chloro-2-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCI 3 , 6): 1.36 (3H, t, J=7Hz), 1.47-1.66 (4H, m), 2.24 (2H, t, J=7Hz), 1.45 2.56 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=7Hz), 5.94 (1H, d, J=4Hz), 6.53 (1H, d, J=4Hz), 7.39 (1H, dd, J=2 Hz, 7Hz), 7.53 (1H, d, J=2Hz), 8.67 (1H, d, J=7Hz) 30 MS (ESI*): m/z 372 (M+H) Example 84 109 WO 2004/063197 PCT/JP2003/017091 5-[4-(5-Chloro-2-thienyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid NMR (CDCl 3 , 6): 1.36 (3H, t, J=7Hz), 1.52-1.74 (4H, m), 2.33 (2H, t, J=7Hz), 2.69 2.78 (2H, m), 3.01 (2H, q, J=7Hz), 3.44 (3H, s), 4.60 (2H, s), 6.25 (1H, d, J=4Hz), 5 6.60 (1H, d, J=4Hz), 6.97 (2H, m) MS (ESI*): m/z 405 (M-H), 407 (M+H) Example 85 5-[7-Ethyl-4-(6-methoxy-2-pyrazinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic 10 acid NMR (CDCI 3 , 5): 1.37 (3H, t, J=7Hz), 1.55-1.69 (4H, m), 2.28 (2H, m), 2.52 (2H, m), 2.56 (3H, s), 3.03 (2H, q, J=7Hz), 3.97 (3H, s), 6.03 (1H, d, J=4Hz), 6.54 (1H, d, J=4Hz), 8.30 (1H, s), 8.32 (1H, s) MS (ESI*): m/z 369 (M+H) 15 Example 86 5-[4-(1-Benzofuran-2-yl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCI 3 , 6): 1.39 (3H, t, J=7Hz), 1.66-1.86 (4H, m), 2.34-2.47 (2H, m), 2.58 (3H, s), 2.69-2.85 (2H, m), 3.03 (2H, q, J=7Hz), 6.47 (1H, d, J=4Hz), 6.61 (1H, d, 20 J=4Hz), 7.16 (1H, s), 7.26-7.43 (2H, m), 7.57 (1H, d, J=8Hz), 7.68 (1H, d, J=8Hz) Example 87 5-[4-(1-Benzothien-2-yl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 25 NMR (CDCI 3 , 6): 1.37 (3H, t, J=7Hz), 1.53-1.73 (4H, m), 2.30 (2H, t, J=7Hz), 2.56 (3H, s), 2.62-2.73 (2H, m), 3.02 (2H, q, J=7Hz), 6.19 (1H, d, J=4Hz), 6.53 (1H, d, J=4Hz), 7.34-7.45 (3H, m), 7.79-7.93 (2H, m) Example 88 30 5-[7-Ethyl-2-methyl-4-(1,3-oxazol-5-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 6): 1.37 (3H, t, J=7Hz), 1.57-1.70 (2H, m), 1.70-1.88 (2H, m), 2.43 (2H, t, J=7Hz), 2.56 (3H, s), 2.66-2.75 (2H, m), 3.02 (2H, q, J=7Hz), 6.41 (1H, d, 110 WO 2004/063197 PCT/JP2003/017091 J=4Hz), 6.60 (1H, d, J=4Hz), 7.52 (1H, s), 8.13 (1H, s) MS (ESI*): m/z 328 (M+H) Example 89 5 5-(7-Ethyl-2-methyl-4-phenylpyrrolo[1,2-b]pyridazin-3-yl)pentanoic acid NMR (CDCI 3 , 6): 1.37 (3H, t, J=7Hz), 1.40-1.62 (4H, m), 2.20 (2H, t, J=7Hz), 2.43 2.52 (2H, m), 2.54 (3H, s), 3.01 (2H, q, J=7Hz), 5.89 (1H, d, J=4Hz), 6.48 (1H, d, J=4Hz), 7.33 (2H, m), 7.38-7.52 (3H, m) MS (ESI*): m/z 337 (M+H) 10 Example 90 5-[7-Ethyl-2-methyl-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 6): 1.39 (3H, t, J=7Hz), 1.47-1.61 (4H, m), 2.14-2.23 (2H, m), 2.44 2.55 (2H, m), 2.59 (3H, s), 3.05 (2H, q, J=7Hz), 5.86 (1H, d, J=4Hz), 6.51 (1H, d, 15 J=4Hz), 7.49 (1H, m), 7.73 (1H, dd, J=2 Hz, 8Hz), 7.85 (1H, d, J=2Hz), 8.23 (2H, m), 8.97 (1H, m) MS (ESI*): m/z 386 (M-H), 388 (M+H) Example 91 20 7-{4-[4-(Aminosulfonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}heptanoic acid NMR (CDC1 3 , 8): 0.98 (2H, m), 1.17-1.48 (9H, m), 2.27 (2H, t, J=7Hz), 2.36 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7Hz), 5.06 (2H, s, br), 5.84 (IH, d, J=5Hz), 6.52 (1H, d, J=5Hz), 7.52 (2H, d, J=9Hz), 8.04 (2H, d, J=9Hz) 25 MS (ESIi): m/z 444 (M+H) Example 92 ({ [4-(3-Chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-3 yl]carbonyl}amino)acetic acid 30 NMR (CDCI 3 , 6): 1.41 (3H, t, J=7Hz), 3.07 (2H, q, J=7Hz), 3.95 (2H, d, J=5Hz), 6.02 (1H, t, br, 5Hz), 6.37 (1H, d, J=5Hz), 6.50 (1H, m), 6.75 (1H, d, J=5Hz), 7.01 (1H, d, J=7Hz), 7.37-7.45 (3H, m), 7.51 (1H, m), 7.55 (1H, m) 111 WO 2004/063197 PCT/JP2003/017091 Example 93 5 -{7-Ethyl-2-methyl-4-[3-(methylsulfonyl)phenyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid 5 NMR (CDCl 3 , 6): 1.30-1.59 (7H, m), 2.22 (2H, t, J=8Hz), 2.33-2.49 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8Hz), 3.12 (3H, s), 5.80 (1H, d, J=5Hz), 6.50 (1H, d, J=5Hz), 7.63-7.74 (2H, m), 7.95 (1H, br s), 8.03 (1H, br d, J=8Hz) MS (ESI*): m/z 415 (M+H) 10 Example 94 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid mp: 139-140*C NMR (CDCl3, 6): 1.32-1.64 (7H, m), 2.28 (2H, t, J=8Hz), 2.36-2.46 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=8Hz), 5.85 (1H, d, J=5Hz), 6.52 (1H, d, J=5Hz), 7.24 (1H, 15 br d, J=7Hz), 7.36 (1H, br s), 8.53 (1H, d, J=7Hz) MS (ESI*): m/z 372 (M+H) Example 95 5-[7-Ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yllpentanoic acid 20 NMR (CDCI 3 , 5): 1.36 (3H, t, J=8Hz), 1.40-1.62 (4H, m), 2.25 (2H, t, J=8Hz), 2.35 2.47 (2H, m), 2.56 (3H, s), 3.00 (2H, q, J=8Hz), 5.54 (1H, d, J=lOHz), 5.86 (1H, d, J=5Hz), 6.23 (1H, d, J=16Hz), 6.51 (1H, d, J=5Hz), 6.88 (1H, dd, J=16, 10Hz), 7.20 (1H, dd, J=6, 1Hz), 7.38 (1H, br s), 8.70 (1H, d, J=6Hz) 25 Example 96 5-[7-Ethyl-2-methyl-4-(3-nitrophenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 6): 1.37 (3H, t, J=8Hz), 1.41-1.59 (4H, m), 2.23 (2H, t, J=8Hz), 2.37 2.47 (2H, m), 2.57 (3H, s), 3.02 (2H, q, J=8Hz), 5.81 (1H, d, J=5Hz), 6.51 (1H, d, J=5Hz), 7.63-7.74 (2H, m), 8.25 (1H, br s), 8.32 (1H, n) 30 Example 97 {[7-Ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methoxy} acetic 112 WO 2004/063197 PCT/JP2003/017091 acid NMR (CDCI 3 , 6): 1.33-1.45 (9 H, m), 3.04 (2H, q, J=8Hz), 3.43 (1H, m), 4.01 (2H, s), 4.45 (2H, s), 6.09 (1H, d, J=5Hz), 6.58 (1H, d, J=5Hz), 7.13-7.22 (2H, m), 7.40-7.49 (2H, m) 5 Example 98 5-[4-(5-Acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDC1 3 , 8): 1.37 (3H, t, J=7Hz), 1.43-1.63 (4H, m), 2.23 (2H, t, J=7Hz), 2.35 2.48 (2H, m), 2.57 (3H, s), 2.69 (3H, s), 3.03 (2H, q, J=7Hz), 5.80 (1H, d, J=4Hz), 10 6.53 (1H, d, J=4Hz), 8.26 (1H, m), 8.78 (1H, d, J=2Hz), 9.23 (1H, d, J=2Hz) MS: (m/z) 378 (M-H), 380 (M+H) Example 99 5-{4-(2-Chloro-4-pyridinyl)-7-ethyl-2-[(methylthio)methyl]pyrrolo[1,2-b]pyridazin-3 15 yl}pentanoic acid NMR (CDCI 3 , 5): 1.36 (3H, t, J=7Hz), 1.42-1.65 (4H, m), 2.18 (3H, s), 2.28 (2H, t, J=7Hz), 2.48-2.60 (2H, m), 3.02 (2H, q, J=7Hz), 3.81 (2H, s), 5.89 (1H, d, J=4Hz), 6.57 (1H, d, J=4Hz), 7.27 (1H, m), 7.38 (1H, s), 8.53 (1H, d, J=5Hz) MS: (m/z) 416 (M-H), 418 (M+H) 20 Example 100 5-{4-(2-Chloro-4-pyridinyl)-7-ethyl-2-[(methylsulfonyl)methyl]pyrrolo[1,2-b]pyridazin 3-yl}pentanoic acid NMR (CDC1 3 , 8): 1.37 (3H, t, J=7Hz), 1.45-1.65 (4H, m), 2.29 (2H, t, J=7Hz), 2.56 25 2.67 (2H, m), 2.98 (2H, q, J=7Hz), 3.13 (3H, s), 4.54 (2H, s), 5.98 (1H, d, J=4Hz), 6.69 (1H, d, J=4Hz), 7.27 (1H, m), 7.38 (1-H, s), 8.56 (1H, d, J=5Hz) MS: (m/z) 448 (M-H), 450 (M+H) Example 101 30 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCI 3 , 6): 1.03-1.45 (4H, m), 1.36 (3H, t, J=7Hz), 1.97 (2H, t, J=7Hz), 2.36 2.48 (2H, m), 3.02 (2H, q, J=7Hz), 5.96 (1H, d, J=4Hz), 6.64 (1H, d, J=4Hz), 113 WO 2004/063197 PCT/JP2003/017091 7.31 (1H, d, J=5Hz), 7.39-7.53 (6H, m), 8.55 (1H, d, J=5Hz) Example 102 5-[4-(6-Chloro-2-pyridinyl)-7-ethyl-2-methylpyrrolo-[1,2-b]pyridazin-3-yl]pentanoic acid 5 NMR (CDC1 3 , 6): 1.36 (3H, t, J=7Hz), 1.56-1.73 (4H, m), 2.29 (2H, t, J=7Hz), 2.46 2.56 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7Hz), 5.96 (1H, d, J=4Hz), 6.53 (1H, d, J=4Hz), 7.38-7.48 (2H, m), 7.78 (1H, t, J=8Hz) MS (ESI*): m/z 372 (M+H), MS (ESI~): m/z 370 10 Example 103 5-[7-Ethyl-4-(3-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCL 3 , 8): 1.37 (3H, t, J=7Hz), 1.46-1.63 (4H, m), 2.22 (2H, t, J=7Hz), 2.44 2.53 (2H, m), 2.54 (3H, s), 3.01 (2H, q, J=7Hz), 3.82 (3H, s), 5.92 (1H, d, J=4Hz), 6.49 (1H, d, J=4Hz), 6.87-7.01 (3H, m), 7.37 (1H, t, J=8Hz) 15 MS (ESI*): m/z 367, MS (ESI~): m/z 365 Example 104 5-[4-(3,5-Dichlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 8): 1.37 (3H, t, J=7Hz), 1.42-1.53 (2H, m), 1.53-1.66 (2H, m), 2.27 20 (2H, t, J=7Hz), 2.41-2.49 (2H, m), 2.54 (3H, s), 3.01 (2H, q, J=7Hz), 5.88 (1H, d, J=4Hz), 6.52 (1H, d, J=4Hz), 7.26 (2H, m), 7.45 (1H, m) MS (ESI*): m/z 405, MS (ESI): m/z 403 Example 105 25 5-[4-(5-Chloro-2-thienyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 8): 1.36 (3H, t, J=7Hz), 1.48-1.62 (2H, m), 1.62-1.73 (2H, m), 2.34 (2H, t, J=7Hz), 2.53 (3H, s), 2.58-2.67 (2H, m), 2.99 (2H, q, J=7Hz), 6.20 (1H, d, J=4Hz), 6.53 (1H, d, J=4Hz), 6.94 (1H, d, J=4Hz), 6.98 (1H, d, J=4Hz) MS (ESI): m/z 377, MS (ESI-): m/z 375 30 Example 106 5-[7-Ethyl-4-(3-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 114 WO 2004/063197 PCT/JP2003/017091 NMR (CDCI 3 , 6): 1.37 (3H, t, J=7Hz), 1.40-1.64 (4H, m), 2.23 (2H, t, J=7Hz), 2.41 2.49 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=7Hz), 5.88 (1H, d, J=4Hz), 6.50 (1H, d, J=4Hz), 7.03-7.16 (3H, m), 7.38-7.47 (1H, m) MS (ESI'): m/z 355, MS (ESI~): m/z 353 5 Example 107 5-[7-Ethyl-2-methyl-4-(3-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 6): 1.39 (3H, t, J=7Hz), 1.47-1.65 (4H, m), 2.20-2.30 (2H, m), 2.45 2.53 (2H, m), 2.59 (3H, s), 3.05 (2H, q, J=7Hz), 5.87 (1H, d, J=4Hz), 6.53 (1H, d, 10 J=4Hz), 7.62 (1H, t, J=8Hz), 7.79 (1H, t, J=8Hz), 7.87 (1H, d, J=8Hz), 8.21 (2H, m), 8.88 (1H, d, J=2Hz) MS (ESI*): m/z 388, MS (ESI): m/z 386 Example 108 15 5-[ 7 -Ethyl-2-methyl-4-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCI 3 , 6): 1.37 (3H, t, J=7Hz), 1.40-1.70 (4H, m), 2.20-2.30 (2H, m), 2.37 2.53 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=7Hz), 5.84 (1H, d, J=4Hz), 6.51 (1H, d, J=4Hz), 7.39 (2H, d, J=7Hz), 8.74 (2H, d, 1=7Hz) 20 Example 109 5-[ 7 -Ethyl-4-(3-methoxy-5-isoxazolyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDC1 3 , 5): 1.36 (3H, t, J=7Hz), 1.57-1.84 (4H, m), 2.41 (2H, t, J=7Hz), 2.55 (3H, s), 2.63-2.72 (2H, m), 3.02 (2H, q, J=7Hz), 4.08 (3H, s), 6.27 (1H, s), 6.34 25 (1H, d, J=4Hz), 6.57 (1H, d, J=4Hz) Example 110 5-[7-Ethyl-4-(3-methoxyphenyl)-2-phenylpyrrolofl, 2 -b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 6): 1.06-1.33 (4H, m), 1.36 (3H, t, J=7Hz), 1.91 (2H, t, J=7Hz), 2.42 30 2.53 (2H, m), 3.01 (2H, q, J=7Hz), 3.83 (3H, s), 6.03 (1H, d, J=4Hz), 6.59 (1H, d, J=4Hz), 6.93-7.02 (3H, m), 7.36-7.54 (6H, m) MS (ESI*): m/z 429 115 WO 2004/063197 PCT/JP2003/017091 Example 111 5-[7-Ethyl-2-methyl-4-(5-methyl-3-isoxazolyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 5 NMR (CDCl 3 , 8): 1.36 (3H, t, J=7Hz), 1.52-1.77 (4H, m), 2.35 (2H, t, J=7Hz), 2.55 (6H, s), 2.56-2.67 (2H, m), 3.01 (2H, q, J=7Hz), 6.16 (1H, d, J=4Hz), 6.23 (1H, s), 6.54 (1H, d, J=4Hz) MS (ESI*): m/z 342, MS (ESI~): m/z 340 10 Example 112 5-[7-Ethyl-2-phenyl-4-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 6): 1.11-1.33 (4H, m), 1.36 (3H, t, J=7Hz), 1.99 (2H, t, J=7Hz), 2.38 2.50 (2H, m), 3.03 (2H, q, J=7Hz), 5.94 (1H, d, J=4Hz), 6.63 (1H, d, J=4Hz), 7.38-7.56 (7H, m), 8.74 (2H, d, J=6Hz) 15 Example 113 5-[7-Ethyl-2-phenyl-4-(2-pyrazinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 6): 1.10-1.33 (4H, m), 1.36 (3H, t, J=7Hz), 1.95 (2H, t, J=7Hz), 2.45 2.57 (2H, m), 3.02 (2H, q, J=7Hz), 6.05 (1H, d, J=4Hz), 6.66 (1H, d, J=4Hz), 20 7.40-7.55 (5H, m), 8.67 (1H, d, J=3Hz), 8.77 (1H, s), 8.85 (1H, s) MS (ESI*): m/z 401, MS (ESI~): m/z 399 Example 114 5-[7-Ethyl-2-phenyl-4-(3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 25 NMR (CDCl 3 , 6): 1.05-1.30 (4H, m), 1.36 (3H, t, J=7Hz), 1.95 (2H, t, J=7Hz), 2.35 2.48 (2H, m), 3.02 (2H, q, J=7Hz), 5.94 (1H, d, J=4Hz), 6.62 (1H, d, J=4Hz), 7.40-7.55 (6H, m), 7.76-7.83 (1H, m), 8.65-8.72 (2H, m) MS (ESIr): m/z 400, MS (ESI): m/z 398 30 Example 115 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yljpentanoic acid 116 WO 2004/063197 PCT/JP2003/017091 NMR (CDCl 3 , 6): 1.37 (3H, t, J=7Hz), 1.42-1.64 (4H, m), 2.27 (2H, t, J=7Hz), 2.48 2.62 (2H, m), 3.04 (2H, q, J=7Hz), 3.45 (3H, s), 4.62 (2H, s), 5.90 (1H, d, J=4Hz), 6.61 (1H, d, J=4Hz), 7.27 (1H, m), 7.38 (1H, s), 8.53 (1H, d, J=5Hz) MS (ESI*): m/z 402 5 Example 116 5-[7-Ethyl-2-(methoxymethyl)-4-(3-methoxyphenyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid NMR (CDCl 3 , 6): 1.37 (3H, t, J=7Hz), 1.40-1.62 (4H, m), 2.19 (2H, t, J=7Hz), 2.55 10 2.66 (2H, m), 3.03 (2H, q, J=7Hz), 3.45 (3H, s), 3.82 (3H, s), 4.62 (2H, s), 5.96 (1H, d, J=4Hz), 6.56 (1H, d, J=4Hz), 6.87-7.00 (3H, m), 7.37 (1H, t, J=8Hz) MS (ESI*): m/z 397, MS (ESI): m/z 395 Example 117 15 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 6): 1.20-1.50 (4H, m), 1.38 (3H, t, J=7Hz), 2.15 (2H, t, J=7Hz), 2.55 2.68 (2H, m), 3.04 (2H, q, J=7Hz), 5.93 (1H, d, J=4Hz), 6.64 (1H, d, J=4Hz), 7.13 (1H, t, J=5Hz), 7.28 (1H, d, J=5Hz), 7.35-7.47 (3H, m), 8.54 (1H, d, J=5Hz) 20 MS (ESI*): m/z 440 Example 118 5-[7-Ethyl-2-(methoxymethyl)-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 25 NMR (CDCI 3 , 8): 1.39 (3H, t, J=7Hz), 1.45-1.60 (4H, m), 2.16 (2H, m), 2.55-2.75 (2H, m), 3.07 (2H, q, J=7Hz), 3.47 (3H, s), 4.66 (2H, s), 5.89 (1H, d, J=4Hz), 6.57 (1H, d, J=4Hz), 7.45-7.53 (1H, m), 7.72 (1H, d, J=8Hz), 7.86 (1H, s), 8.22 (2H, m), 8.94 (1H, m) MS (ESI*): m/z 418, MS (ESr): m/z 416 30 Example 119 5-[7-Ethyl-2-(methoxymethyl)-4-(3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic 117 WO 2004/063197 PCT/JP2003/017091 acid NMR (CDCI 3 , 6): 1.38 (3H, t, J=7Hz), 1.45-1.64 (4H, m), 2.22 (2H, t, J=7Hz), 2.48 2.68 (2H, m), 3.06 (2H, q, J=7Hz), 3.46 (3H, s), 4.63 (2H, s), 5.89 (1H, d, J=4Hz), 6.58 (111, d, J=4Hz), 7.48 (1H, m), 7.78 (1H, m), 8.62 (1H, m), 8.69 (1H, m) 5 MS (ESI*): m/z 368 Example 120 5-[4-(3-Chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-blpyridazin-3-yl]pentanoic acid 10 NMR (CDCl 3 , 6): 1.37 (3H, t, J=7Hz), 1.45-1.63 (4H, m), 2.23 (2H, t, J=7Hz), 2.53 2.63 (2H, m), 3.04 (2H, q, J=7Hz), 3.45 (3H, s), 4.63 (2H, s), 5.93 (1H, d, J=4Hz), 6.58 (1H, d, J=4Hz), 7.25 (1H, m), 7.36 (1H, s), 7.42 (2H, m) Example 121 15 5-[7-Ethyl-2-methyl-4-(3-methylphenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCI 3 , 6): 1.23-1.63 (4H, m), 1.37 (3H, t, J=7Hz), 2.22 (2H, t, J=7Hz), 2.40 (3H, s), 2.40-2.49 (2H, m), 2.54 (3H, s), 3.02 (2H, q, J=7Hz), 5.89 (1H, d, J=4Hz), 6.48 (1H, d, J=4Hz), 7.10-7.14 (2H, m), 7.23-7.27 (1H, m), 7.32-7.38 (1H, m) MS (ESI*): m/z 351 20 Example 124 5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid NMR (CDCl 3 , 6): 1.37 (3H, t, J=7Hz), 1.44-1.65 (4H, m), 2.16-2.26 (2H, m), 2.43 25 (3H, s), 2.47-2.69 (2H, m), 3.03 (2H, q, J=7Hz), 3.45 (3H, s), 4.63 (2H, m), 5.88 (iH, d, J=4Hz), 6.57 (1H, d, J=4Hz), 7.56 (1H, s), 8.42 (1H, s), 8.53 (1H, s) MS (ESI*): m/z 382, MS (ESI~): m/z 380 Example 125 30 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 8): 1.37 (3H, t, J=7Hz), 1.45-1.67 (4H, m), 2.27 (2H, t, J=7Hz), 2.38 2.52 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7Hz), 5.87 (1H, d, J=4Hz), 6.53 (1H, d, 118 WO 2004/063197 PCT/JP2003/017091 J=4Hz), 7.88 (1H, m), 8.53 (1H, d, J=2Hz), 8.77 (1H, d, J=2Hz) MS (ESI*): m/z 416, 418 Example 126 5 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo(1,2-b]pyridazin-3 yl]pentanoic acid NMR (CDCl 3 , 5): 1.37 (3H, t, J=7Hz), 1.45-1.65 (4H, m), 2.25 (2H, t, J=7Hz), 2.49 2.68 (2H, m), 3.03 (2H, q, J=7Hz), 3.45 (3H, s), 4.63 (2H, s), 5.91 (1H, d, J=4Hz), 6.62 (1H, d, J=4Hz), 7.89 (1H, m), 8.51 (1H, s), 8.79 (1H, m) 10 MS (ESI+): m/z 446,448 Example 127 5-[4-(5,6-Dichloro-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 15 NMR (CDCl 3 , 6): 1.37 (3H, t, J=7Hz), 1.43-1.68 (4H, m), 2.29 (2H, t, J=7Hz), 2.38 2.52 (2H, m), 2.57 (3H, s), 3.02 (2H, q, J=7Hz), 5.87 (1H, d, J=4Hz), 6.53 (1H, d, J=4Hz), 7.81 (1H, d, J=2Hz), 8.31 (1H, d, J=2Hz) MS (ESI*): m/z 406, MS (ESI-): m/z 404 20 Example 128 5-[7-Ethyl-2-methyl-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 6): 1.37 (3H, t, J=7Hz), 1.45-1.68 (4H, m), 2.23 (2H, t, J=7Hz), 2.38 2.53 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7Hz), 5.46 (1H, d, J=1lHz), 5.86 (1H, d, J=4Hz), 5.89 (1H, d, J=17Hz), 6.52 (1H, d, J=4Hz), 6.72-6.83 (1H, dd, J=11 25 Hz, 17Hz), 7.77 (1H, m), 8.47 (1H, d, J=2Hz), 8.68 (1H, d, J=2Hz) MS (ESI*): m/z 364 Example 129 5-[7-Ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[ 1,2-b]pyridazin-3 30 ylpentanoic acid NMR (CDCl 3 , 6): 1.37 (3H, t, J=7Hz), 1.45-1.65 (4H, m), 2.22 (2H, t, J=7Hz), 2.45 2.73 (2H, m), 3.04 (2H, q, J=7Hz), 3.46 (3H, s), 4.63 (2H, m), 5.44 (111, d, 119 WO 2004/063197 PCT/JP2003/017091 J=llHz), 5.87 (1H, d, J=18Hz), 5.92 (1H, d, J=4Hz), 6.57 (1H, d, J=4Hz), 6.72 6.83 (1H, dd, J=11 Hz, 18Hz), 7.78 (1H, s), 8.48 (1H, s), 8.68 (1H, s) MS (ESI*): m/z 394 (M+H), MS (ESIT): m/z 392 5 Example 130 5-[ 4 -(5-Acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid NMR (CDC1 3 , 8): 1.38 (3H, t, J=7Hz), 1.44-1.60 (4H, m), 2.22 (2H, t, J=7Hz), 2.50 2.63 (2H, m), 2.69 (3H, s), 3.02 (2H, q, J=7Hz), 3.46 (3H, s), 4.64 (2H, s), 5.86 10 (1H, d, J=4Hz), 6.59 (1H, d, J=4Hz), 8.29 (1H, m), 8.79 (1H, d, J=2Hz), 9.23 (1H, d, J=2Hz) MS (ESI*): m/z 410, MS (EST): m/z 408 Example 131 15 4

-[

7 -Ethyl- 2 -(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoic acid NMR (CDCl 3 , 5): 1.38 (3H, t, J=7Hz), 1.70-1.87 (2H, m), 2.26 (2H, t, J=7Hz), 2.45 (3H, s), 2.53-2.81 (2H, m), 3.06 (2H, q, J=7Hz), 3.46 (3H, s), 4.66 (2H, m), 5.90 (1H, d, J=4Hz), 6.59 (1H, d, J=4Hz), 7.61 (1H, s), 8.43 (1H, s), 8.46 (1H, s) 20 MS (ESI*): m/z 368 Example 132 3

-[

7 -Ethyl- 2 -(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoic acid 25 NMR (CDCI 3 , 5): 1.37 (3H, t, J=7Hz), 2.30-2.60 (2H, m), 2.42 (3H, s), 2.77-3.13 (2H, m), 3.05 (2H, q, J=7Hz), 3.47 (3H, s), 4.66 (2H, s), 5.91 (1H, d, J=4Hz), 6.60 (1H, d, J=4Hz), 7.58 (1H, s), 8.42 (1H, s), 8.54 (1H, s) MS (ESl*): m/z 354 30 Example 133 4

-[

7 -Ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid NMR (CDCl 3 , 5): 1.37 (3H, t, J=7Hz), 1.70-1.88 (2H, m), 2.22-2.32 (2H, m), 2.45 120 WO 2004/063197 PCT/JP2003/017091 (3H, s), 2.50-2.62 (2H, m), 2.59 (3H, s), 3.02 (2H, q, J=7Hz), 5.86 (1H, d, J=4Hz), 6.53 (1H, d, J=4Hz), 7.60 (1H, s), 8.42 (2H, m) MS (ESI*): m/z 338, MS (ESI-): m/z 336 5 Example 134 3-[7-Ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid NMR (CDC1 3 , 8): 1.37 (3H, t, J=7Hz), 2.42 (3H, s), 2.40-2.53 (2H, m), 2.59 (3H, s), 2.82 (2H, t, J=7Hz), 3.03 (2H, q, J=7Hz), 5.86 (1H, d, J=4Hz), 6.53 (1H, d, J=4Hz), 7.57 (1H, s), 8.38 (1H, s), 8.52 (1H, s) 10 MS (ESI*): m/z 324, MS (ESI-): m/z 322 Example 135 3-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoic acid mp: 181-182*C 15 NMR (CDCl3, 8): 1.38(2H, t, J=7Hz), 2.4(2H, t, J=7Hz), 2.58(3H, s), 2.74-2.85(2H, m), 3.01(2H, q, J=7Hz), 5.89(1H, d, J=4Hz), 6.55(1H, d, J=4Hz), 7.87(1H, s), 8.54(1H, s), 8.77(1H, s) MS: (m/z) 388 (M+), 390(M++2), 114(bp) 20 Example 136 5-[4-(3-Cyanophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NNMR (CDCI 3 , 6): 1.30-1.57 (5H, m), 2.21 (2H, t, J=8Hz), 2.47-2.57 (2H, m), 3.03 (2H, q, J=8Hz), 3.45 (3H, s), 4.62 (2H, s), 5.84 (1H, d, J=5Hz), 6.57 (1H, d, 25 J=5Hz), 7.59-7.64 (2H, m), 7.68 (1H, br s), 7.75 (1H, m) MS (ESI*): 392 (M+H) Example 136-2 5-[4-[3-(Aminocarbonyl)phenyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 30 NMR (CDCI 3 , 6): 1.30-1.70 (5H, overlappoed with H20), 2.20-2.50 (4H, m), 2.80 2.93 (2H, m), 3.03 (2H, q, J=8Hz), 3.46 (3H, s), 4.54 (1H, d, J=lOHz), 4.77 (1H, d, J=1OHz), 5.80 (1H, d, J=5Hz), 6.55 (1H, d, J=5Hz), 7.43-7.50 (2H, m), 7.58 121 WO 2004/063197 PCT/JP2003/017091 (1H, t, J=8Hz), 7.77 (1H, br s), 7.88 (1H, br s), 7.99 (1H, br d, J=8Hz) MS (ESI*): 410 (M+H) Example 137 5 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCI 3 , 8): 1.06-1.26 (4H, m), 1.36 (3H, t, J=7Hz), 1.94 (2H, t, J=7Hz), 2.40 (2H, m), 2.99 (2H, q, J=7Hz), 5.96 (1H, d, J=5Hz), 6.63 (1H, d, J=5Hz), 7.40 7.52 (5H, m), 7.93 (1H, s), 8.59 (1H, s), 8.77 (1H, s) 10 Example 138 5-[7-Ethyl-4-(5-ethyl-3-pyridinyl)-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 8): 1.05-1.42 (10H, m), 1.92 (2H, m), 2.41 (2H, m), 2.75 (2H, q, J=7Hz), 3.01 (2H, q, J=7Hz), 5.93 (1H, d, J=5Hz), 6.55 (1H, d, J=5Hz), 7.37-7.54 (5H, m), 7.62 (1H, m), 8.45 (1H, m), 8.52 (1H, m) 15 Example 139 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCI 3 , 8): 1.25-1.48 (7H, m), 2.12 (2H, t, J=7Hz), 2.62 (2H, m), 3.03 (2H, q, 20 J=7Hz), 5.93 (iH, d, J=5Hz), 6.64 (1H, d, J=5Hz), 7.14 (1H, m), 7.37 (1H, d, J=5Hz), 7.43 (1H, d, J=5Hz), 7.92 (1H, s) 8.58 (1H, m), 8.79 (1H, m) MS (ESI*): m/z 484 (M+H) Example 140 25 5-[2-[(Benzyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid NMR (CDCI 3 , 6): 1.23 (3H, t, J=7Hz), 1.34-1.48 (5H, m), 2.09 (2H, m), 2.53 (2H, m), 3.04 (2H, q, J=7Hz), 4.07 (2H, J=7Hz), 4.65 (2H, s), 4.72 (2H, s), 5.90 (1H, d, J=5Hz), 6.60 (1H, d, J=5Hz), 7.29-7.38 (5H, m), 7.86 (1H, s), 8.54 (1H, m), 8.77 30 (1H,m) Example 141 122 WO 2004/063197 PCT/JP2003/017091 5-(4-(5-Bromo-3-pyridinyl)-2-{ [(4-cyanobenzyl)oxy]methyl}-7-ethylpyrrolo[1,2 b]pyridazin-3-yl)pentanoic acid NMR (CDCl 3 , 8): 1.35-1.56 (7H, m), 2.18 (2H, m), 2.57 (2H, m), 3.03 (211, q, J=7Hz), 4.69 (2H, s), 4.74 (211, s), 5.92 (111, d, J=5Hz), 6.62 (1H, d, J=5Hz), 7.47 5 (2H, d, J=8Hz), 7.64 (2H, d, J=811z), 7.88 (1H, s), 8.54 (1H, m), 8.79 (1H, m) Example 142 5-[2-[(Benzylamino)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 10 NMR (CDCl 3 , 8): 1.20-1.49 (7H, m), 2.17 (211, m), 2.32 (2H, m), 3.04 (2H, q, J=7Hz), 4.29 (4H, s), 5.94 (1H, d, J=5Hz), 6.51 (1H, s, br), 6.12 (1H, d, J=5Hz), 7.27-7.36 (3H, m), 7.48 (2H, m), 7.84 (111, m), 8.49 (1H, m), 8.75 (1H, m) Example 143 15 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid NMR (CDCI 3 , 6): 1.20-1.38 (5H, m), 1.49 (4H, m), 2.24 (2H, q, J=7Hz), 2.59 (4H, m), 3.01 (211, q, J=7Hz), 3.70 (4H, m), 5.88 (111, d, J=5Hz), 6.55 (1H, d, J=5Hz), 7.90 (111, m), 8.55 81H, m), 8.78 (1H, m) 20 Example 144 5-{ 4-[5-(Aninocarbonyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl}pentanoic acid from ethyl 5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b] pyridazin-3-yl]pentanoate 25 NMR (CDCI 3 , 6): 1.10-1.70 (4H, m), 1.37 (3H, t, J=7Hz), 2.24-2.77 (4H, m), 2.59 (3H, s), 3.02 (211, q, J=7Hz), 5.77 (1H, d, J=4Hz), 6.52 (1H, d, J=41z), 7.57 (111, br), 7.97 (1H, br), 8.07 (1H, s), 8.68 (1H, s), 9.18 (1H, s) MS (ESI*): m/z 381 30 Example 145 5-[4-[5-(Aminocarbonyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2 b]pyridazin-3-yl]pentanoic acid , 123 WO 2004/063197 PCT/JP2003/017091 NMR (CDCJ 3 , 6): 1.16-1.72 (4H, m), 1.37 (3H, t, J=7Hz), 2.25-2.50 (3H, m), 2.83 2.97 (1H, m), 3.04 (2H, q, J=7Hz), 3.47 (3H, s), 4.56 (1H, d, J=17Hz), 4.77 (1H, d, J=17Hz), 5.81 (1H, d, J=4Hz), 6.58 (1H, d, J=4Hz), 7.52 (1H, br), 7.82 (1H, br), 8.11 (1H, m), 8.70 (1H, d, J=2Hz), 9.18 (1H, d, J=2Hz) 5 MS (ESI*): m/z 411 Example 146 To a solution of triethyl 4-phosphonocrotonate (2.13 g) in tetrahydrofuran (20 mL) was added dropwise lithium bis(trimethylsilyl)amide (1.1mol/L solution in hexanes, 10 15mL) at 2*C under nitrogen, and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of 4-(4-fluorophenyl)-2 isopropylpyrrolo[1,2-b]pyridazine-3-carbaldehyde (1.2 g) in tetrahydrofuran (20 mL). After being stirred for 3 hours at 2"C, the mixture was poured into saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer 15 was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent; 3% ethyl acetate in n-hexane) to give the title compound (1.06 g) as an yellow crystals. Ethyl (2E,4E)-5-[4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2,4 20 pentadienoate NMR (300 MHz, CDCl 3 , 6): 1.28(3H, t, J=7Hz), 1.35(6H, d, J=7Hz), 3.30(1H, quintet, J=7Hz), 4.19(2H, quartet, J=7Hz), 5.63(1H, d, J=16Hz), 5.94(1H, dd, J=16,1lHz), 6.16(1H, dd, J=4.4,1.5Hz), 6.76(1H, dd, J=4.4,2.6Hz), 6.78(1H, d, J=16Hz), 7.11-7.23(3H, m), 7.33-7.40(2H, m), 7.72(1H, dd, J=2.6,1.5Hz) 25 MS (ESI): m/z 379 (M+H) The following compounds were obtained in substantially the same manner as that of Example 146. Example 147 30 Ethyl (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2 propenoate NMR (CDCl 3 , 6): 1.25 (3H, t, J=7Hz), 1.40 (6H, d, J=7Hz), 3.38 (1H, m), 4.16 (2H, 124 WO 2004/063197 PCT/JP2003/017091 q, J=7Hz), 5.57 (1H, d, J=15Hz), 6.25 (1H, d, J=5Hz), 6.74 (1H, d, J=5Hz), 7.15 (1H, d, J=8.5Hz), 7.29 (1H, d, J=8.5Hz), 7.33 (1H, d, J=8.5Hz), 7.35 (1H, d, J=8.5Hz), 7.63 (1H, d, J=15Hz) MS (EST): m/z 385 (M-H) 5 Example 148 (2E)-3-[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2 propenenitrile NMR (CDCl 3 , 6): 1.41 (6H, d, J=7Hz), 3.28 (1H, m), 4.99 (1H, d, J=15Hz), 6.24 (1H, 10 d, J=5Hz), 6.76 (1H, d, J=15Hz), 7.17-7.27 (2H, m), 7.30-7.40 (3H, m) MS (EST): m/z 340 (M+H) Example 149 To a solution of ethyl (2E,4E)-5-[4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2 15 b]pyridazin-3-yl]-2,4-pentadienoate (300 mg) in tetrahydrofuran (3 mL) and acetic acid (1mL) was added dropwise N-chlorosuccinimide (106 mg). The mixture was stirred at ambient temperature for 24 hours. The resulting mixture was concentrated and partitioned between saturated aqueous sodium hydrogencarbonate and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and 20 concentrated. The residue was purified by silica gel column chromatography (eluent; 1% ethyl acetate in n-hexane) to give the title compound (110mg) as an oil. Ethyl ( 2

E,

4 E)-5-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl] 2,4-pentadienoate 25 NMR (300 MHz, CDCl 3 , 6): 1.28(3H, t, J=7Hz), 1.40(6H, d, J=7Hz), 3.33(1H, quintet, J=7Hz), 4.19(2H, quartet, J=7Hz), 5.64(1H, d, J=16Hz), 5.94(1H, dd, J=16,llHz), 6.18(1H, d, J=4.4Hz), 6.71(1H, d, J=4.4Hz), 6.79(1H, d, J=16Hz), 7.13-7.23(3H, m), 7.32-7.37(2H, m) 30 The following compounds were obtained in substantially the same manner as that of Example 149. Example 151 Ethyl 7-chloro-4-(2-chlorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate 125 WO 2004/063197 PCT/JP2003/017091 NMR (300 MHz, CDC1 3 , 6): 0.89 (3H, t, J=7.5Hz), 1.41 (6H, d, J=7.5Hz), 3.41-3.56 (1H, m), 4.00 (2H, q, J=7.5Hz), 6.16 (1H, d, J=5Hz), 6.76 (1H, d, J=5Hz), 7.25 7.53 (4H, m) MS (ES+): m/e 377.44 5 Example 152 Ethyl 7-chloro-2-isopropyl-4-(2-naphthyl)pyrrolo[1,2-b]pyridazine-3-carboxylate NMR (300 MHz, CDC1 3 , 8): 0.78 (3H, t, J=7.5Hz), 1.43 (6H, d, J=7.5Hz), 3.29-3.41 (1H, m), 3.95 (2H,.q, J=7.5Hz), 6.40 (1H, d, J=5Hz), 6.79 (1H, d, J=5Hz), 7.50 10 7.60 (3H, m), 7.81-8.00 (4H, m) Example 153 To a solution of ethyl (2E,4E)-5-[7-chloro-4-(4-fluorophenyl)-2 isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2,4-pentadienoate( 8 2 mg) in ethanol (2 mL) was 15 added 1N sodium hydroxide solution (0.5 mL), and the mixture was stirred at ambient temperature for 12 hours. The resulting mixture was concentrated in vacuo, and the residue was dissolved in water, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column 20 chromatography (eluent; 50% ethyl acetate in n-hexane) to give the title compound (14mg) as a brown amorphous solid, which was recrystallized from aqueous ethanol. (2E,4E)-5-[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2,4 pentadienoic acid 25 NMR (300 MHz, CDCl 3 , 6): 1.40 (6H, d, J=7Hz), 1.30-1.90 (1H, br),.3.34 (1H, quintet, J=7Hz), 5.64 (1H, d, J=16Hz), 5.98 (1H, dd, J=16,11Hz), 6.19 (1H, d, J=4.4Hz), 6.72 (1H, d, J=4.4Hz), 6.84 (1H, d, J=16Hz), 7.14-7.37 (5H, m) MS(ESI): m/z 383 (M-H) 30 Example 154 To a mixture of ethyl 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2 b]pyridazin-3-yl]pentanoate (130 mg) in toluene (5 mL) was added 28% sodium 126 WO 2004/063197 PCT/JP2003/017091 methylate metanol solution (536 mg) and the mixture was heated under reflux for 2 hours. The solution was acidified to pH 4 with 1N hydrochloric acid and extracted with chloroform. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. To the residue in ethanol (5 mL) was added 1N sodium hydroxide 5 solution (1 mL) and the mixture was heated at 60*C for 1 hour. The solution was acidified to pH 4 with 1N hydrochloric acid and extracted with chloroform. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (1:1) to give 5-[7-ethyl-4-(2-methoxy-4-pyridinyl)-2 10 (2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid as an yellow powder (50.0 mg). 5-[7-Ethyl-4-(2-methoxy-4-pyridinyl)-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid NMR (CDCI 3 , 8): 1.30-1.48 (4H, m), 1.38 (3H, t, J=71Hz), 2.13 (2H, t, J=7Hz), 2.58 15 2.69 (2H, m), 3.02 (211, q, J=7Hz), 4.02 (3H, s), 5.96 (1H, d, J=41Hz), 6.61 (1H, d, J=4Hz), 6.78 (111, s), 6.90 (1H, d, J=5Hz), 7.12 (1H, m), 7.34 (1H, m), 7.42 (1H, d, J=5Hz), 8.29 (1H, d, J=5Hz) The following compounds were obtained in substantially the same manner as that 20 of Example 154. Example 155 5-[7-Ethyl-4-(2-methoxy-4-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCI 3 , 8): 1.31-1.64 (7H, m), 2.25 (2H, t, J=8Hz), 2.43 (2H, br t, J=8Hz), 25 2.54 (3H, s), 3.00 (2H, q, J=8Hz), 4.04 (3H, s), 5.60 (1H, br s), 5.90 (1H, d, J=5Hz), 6.51 (1H, d, J=5Hz), 6.81 (11H, br s), 6.93 (1H, br d, J=7Hz), 8.30 (1H, d, J=7Hz) MS (ESI*): m/z 368 (M+H) 30 Example 155-2 5-[7-Ethyl-2-methyl-4-(2-oxo-1,2-dihydro-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 127 WO 2004/063197 PCT/JP2003/017091 NMR (CDCl 3 , 6): 1.29-1.67 (7H, m), 2.29 (2H, t, J=8Hz), 2.35-2.60 (5H, m), 3.00 (2H, q, J=8Hz), 5.94 (1H, d, J=5Hz), 6.54 (1H, d, J=5Hz), 6.64 (111, br d, J=7Hz), 6.84 (1H, br s), 7.70 (1H, br d, J=7Hz) MS (ESI*): m/z 354 (M+H) 5 The following compounds were obtained in substantially the same manner as that of Example 154. Example 156 5-[7-Ethyl-4-(2-methoxy-4-pyridinyl)-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic 10 acid NMR (CDCl 3 , 5): 1.08-1.30 (4H, m), 1.36 (3H, t, J=7Hz), 1.95 (2H, t, J=7Hz), 2.48 2.53 (211, m), 3.03 (2H, q, J=7Hz), 4.01 (3H, s), 6.02 (1H, d, J=411z), 6.63 (111, d, J=4Hz), 6.82 (1H, s), 6.94 (11H, d, J=5Hz), 7.42-7.54 (5H, m), 8.29 (1H, d, J=5Hz) 15 MS (ESI*): m/z 430 Example 157 5-[7-Ethyl-2-(methoxymethyl)-4-(2-methoxy-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 20 NMR (CDCl 3 , 6): 1.37 (3H, t, J=7Hz), 1.40-1.64 (4H, m), 2.24 (211, t, J=7Hz), 2.53 2.64 (211, m), 3.03 (2H, q, J=7Hz), 3.45 (3H, s), 4.01 (3H, s), 4.61 (2H, s), 5.94 (1H, d, J=4Hz), 6.58 (1H, d, J=4Hz), 6.77 (1H, s), 6.89 (1H, d, J=5Hz), 8.28 (1H, d, J=5Hz) MS (ESI*): m/z 398, MS (ESI-): m/z 396 25 Example 158 To a solution of ethyl 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2 b]pyridazin-3-yl]pentanoate (120 mg) in toluene (5 mL) and tetrahydrofuran (10 mL) was added sodium thiomethoxide (91.0 mg) and the mixture was heated under reflux for 4 30 hours. The solution was acidfied with 1N hydrochloric acid and extracted with chloroform. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column 128 WO 2004/063197 PCT/JP2003/017091 chromatography eluting with a mixture of hexane and ethyl acetate (10:1 - 3:1) to give 5-{7-ethyl-4-[2-(methylthio)-4-pyridinyl]-2-phenylpyrrolo [1,2-b]pyridazin-3-yl}pentanoic acid as an yellow powder (85.0 mg). 5 5-{7-Ethyl-4-[2-(methylthio)-4-pyridinyl]-2-phenylpyrrolo[1,2-b]pyridazin-3 yl}pentanoic acid NMR (CDCl 3 , 8): 1.07-1.17 (2H, m), 1.17-1.30 (2H, m), 1.36 (3H, t, J=7Hz), 1.97 (2H, t, J=7Hz), 2.38-2.48 (2H, m), 2.61 (3H, s), 3.02 (2H, q, J=7Hz), 5.98 (1H, d, J=4Hz), 6.63 (1H, d, J=4Hz), 7.03 (1H, dd, J=1 Hz, 5Hz), 7.25 (1H, m), 7.43-7.55 10 (5H, m), 8.57 (1H, d, J=5Hz) MS (ESI*): m/z 446 (M+H) Example 159 A mixture of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (3.00 g), 15 ethyl 6-benzoylhexanoate (5.07 g), and trifluoromethanesulfonic acid (376 mg) in toluene (60 mL) was refluxed for 1 hour and 20 minutes with Dean-Stark equipment. The mixture was partitioned between ethyl acetate (60 mL) and water (60 mL), and the organic layer was washed with saturated sodium bicarbonate (60 mL) and brine (60 mL), dried over magnesium sulfate, and evaporated to give a dark colored oil. Flash silica gel 20 column chromatography eluting with acetone = 1-100 to 7-100 afforded ethyl 5-[4-(3 cyanophenyl)-7-ethyl-2-phenylpyrrolo [1,2-b]pyridazin-3-yl]pentanoate as an orange oil (4.45 g, 78.6%). Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate 25 NMR (CDCl 3 , 6): 1.01-1.27 (7H, m), 1.36 (3H, t, J=7Hz), 1.86 (2H, t, J=7Hz), 2.40 (2H, m), 3.02 (2H, q, J=7Hz), 4.02 (2H, q, J=7Hz), 5.90 (1H, d, J=5Hz), 6.61 (1H, d, J=5Hz), 7.44-7.53 (5H, s), 7.60-7.69 (2H, m), 7.74-7.79 (2H, m) The following compound was obtained in substantially the same manner as that of 30 Example 159. Example 160 Ethyl 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate 129 WO 2004/063197 PCT/JP2003/017091 NMR (CDCI 3 , 6): 1.21 (3H, t, J=7Hz), 1.38 (3H, t, J=7Hz), 1.25-1.48 (4H, m), 2.07 (2H, t, J=7Hz), 2.57-2.68 (2H, m), 3.04 (2H, q, J=7Hz), 4.12 (2H, q, J=7Hz), 5.93 (1H, d, J=4Hz), 6.64 (1H, d, J=4Hz), 7.12 (1H, m), 7.28 (111, dd, J=1 Hz, 5Hz), 7.37 (1H, m), 7.41 (1H, s), 7.45 (1H, d, J=5Hz), 8.55 (1H, d, J=5Hz) 5 MS: (m/z) 468 (M+H) Example 161 Ethyl 5-[ 4

-(

2 -chloro- 4 -pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 yl]pentanoate 10 NMR (CDCI 3 , 8): 1.05-1.17 (2H, m), 1.19-1.30 (2H, m), 1.28 (3H, t, J=7Hz), 1.36 (3H, t, J=7Hz), 1.91 (2H, t, J=7Hz), 2.38-2.48 (2H, m), 3.02 (2H, q, J=7Hz), 4.12 (2H, q, J=7Hz), 5.96 (1H, d, J=4Hz), 6.64 (1H, d, J=4Hz), 7.31 (1H, dd, J=2 Hz, 5Hz), 7.41-7.54 (6H, m), 8.56 (1H, d, J=5Hz) MS (ESI*): m/z 462 (M+H) 15 Example 162 Ethyl [ 4

-(

3 -chlorophenyl)-7-ethyl-2-phenylpyrrolo[ 1,2-b]pyridazin-3-yl]acetate NMR (CDCI 3 , 5): 1.08 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 3.03 (2H, q, J=7Hz), 3.36 (2H, s), 3.93 (2H, q, J=7Hz), 6.09 (1H, d, J=5Hz), 6.66 (1H, d, J=5Hz), 7.33 (1H, 20 m), 7.41-7.50 (8H, m) MS (ESI*): m/z 419 (M+H) Example 163 Ethyl 4

-(

3 -chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carboxylate 25 NMR (CDCI 3 , 6): 1.06 (3H, t, J=7Hz), 1.41 (3H, t, J=7Hz), 3.08 (2H, q, J=7Hz), 4.09 (2H, q, J=7Hz), 6.34 (1H, d, J=5Hz), 6.53 (1H, m), 6.74 (1H, d, J=5Hz), 6.97 (1H, m), 7.39-7.46 (3H, m), 752 (2H, m) MS (ESI*): m/z 395 (M+H) 30 Example 164 Ethyl 4

-(

3 -chlorophenyl)-7-ethyl-2-(2-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylate NMR (CDCl 3 , 8): 0.94 (3H, m), 1.41 (3H, m), 3.08 (2H, q, J=7Hz), 3.11 (2H, m), 130 WO 2004/063197 PCT/JP2003/017091 4.00 (2H, m), 6.36 (1H, m), 6.76 (1H, m), 7.26-7.55 (411, m), 7.84 (1H, m), 8.15 (1H, m), 8.57 (111, m) MS (ESI*): m/z 406 (M+H) 5 Example 165 Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-(1,3-thiazol-2-yl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate NMR (CDCl 3 , 6): 1.21 (3H, t, J=7Hz), 1.33-1.50 (7H, m), 2.14 (211, t, J=7Hz), 2.46 (2H, m), 2.97 (2H, q, J=7Hz), 3.06 (2H, q, J=7Hz), 4.05 (2H, q, J=7Hz), 5.88 (1H, 10 d, J=5Hz), 6.67 (1H, d, J=5Hz), 7.43 (1H, d, J=3Hz), 7.64-7.67 (2H, m), 7.70 (1H, m), 7.78 (1H, m), 7.93 (111, d, J=3Hz) Example 166 Methyl 5-[4-(3-cyanophenyl)-7-ethyl-2-(1-methyl-1H-pyrrol-2-yl)pyrrolo[1,2 15 b]pyridazin-3-yl]pentanoate NMR (CDC1 3 , 5): 1.04 (211, m), 1.21-1.41 (5H, m), 1.99 (2H, t, J=7Hz), 2.46 (2H, m), 3.02 (2H, q, J=7Hz), 3.60 (3H, s), 3.68 (311, s), 5.89 (1H, d, J=5Hz), 6.23 (1H, m), 6.35 (1H, m), 6.62 (111, d, J=5Hz), 6.76 (1H, m), 7.62-7.79 (411, m) 20 Example 167 Ethyl 3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoate NMR (CDCl 3 , 6): 1.08 (3H, t, J=711z), 1.37 (31H, t, J=7Hz), 2.02 (2H, m), 2.80 (211, m), 3.02 (2H, q, J=71z), 3.89 (2H, q, J=7Hz), 6.01 (1H, d, J=5Hz), 6.63 (111, d, J=51z), 7.31 (1H, m), 7.41-7.54 (8H, m) 25 Example 168 Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-(1,3-oxazol-5-yl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate NMR (CDCl 3 , 6): 1.17-1.49 (1011, m), 2.08 (2H, t, J=711z), 2.57 (211, m), 3.03 (2H, q, 30 J=71Hz), 4.06 (2H, q, J=7Hz), 5.91 (1H, d, J=5Hz), 6.66 (111, d J=5Hz), 7.55 (11H, s), 7.62-7.68 (3H, m), 7.78 (111, m), 8.04 (1H, s) 131 WO 2004/063197 PCT/JP2003/017091 Example 169 Ethyl 5-[7-ethyl-4-(3-methoxyphenyl)-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCl 3 , 6): 1.05-1.29 (4H, m), 1.18 (3H, t, J=7Hz), 1.36 (3H, t, J=7Hz), 1.86 (211, t, J=7Hz), 2.42-2.52 (2H, m), 3.02 (2H, q, J=7Hz), 3.84 (3H, s), 4.02 (2H, q, 5 J=7Hz), 6.02 (111, d, J=4Hz), 6.60 (1H, d, J=4Hz), 6.95-7.02 (3H, m), 7.36-7.56 (6H, m) Example 170 Ethyl 5-[7-ethyl-2-phenyl-4-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate 10 NMR (CDCI 3 , 5): 1.04-1.29 (4H, m), 1.19 (3H, t, J=7Hz), 1.36 (3H, t, J=7Hz), 1.88 (2H, t, J=7Hz), 2.38-2.48 (2H, m), 3.02 (2H, q, J=7Hz), 4.04 (2H, q, J=7Hz), 5.95 (1H, d, J=4Hz), 6.62 (1H, d, J=4Hz), 7.36 (2H, m), 7.42-7.54 (5H, m), 8.76 (2H, m) 15 Example 171 Ethyl 5-[7-ethyl-2-phenyl-4-(2-pyrazinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCI 3 , 6): 1.10-1.32 (4H, m), 1.18 (3H, t, J=7Hz), 1.36 (3H, t, J=7Hz), 1.90 (2H, t, J=7Hz), 2.45-2.55 (2H, m), 3.02 (211, q, J=7Hz), 4.02 (211, q, J=7Hz), 6.05 (1H, d, J=4Hz), 6.66 (1H, d, J=4Hz), 7.43-7.56 (5H, m), 8.66 (1H, m), 8.77 (1H, 20 m), 8.86 (1H, m) Example 172 Ethyl 5-[7-ethyl-2-phenyl-4-(3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCl 3 , 6): 1.04-1.30 (4H, m), 1.18 (3H, t, J=7Hz), 1.37 (311, t, J=7Hz), 1.87 25 (2H, t, J=7Hz), 2.38-2.50 (2H, m), 3.02 (211, q, J=7Hz), 4.01 (211, q, J=7Hz), 5.96 (1H, d, J=4Hz), 6.63 (111, d, J=4Hz), 7.42-7.55 (6H, m), 7.77 (11H, m), 8.66-8.73 (2H, m) Example 173 30 Ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 yl]pentanoate NMR (CDCl 3 , 6): 1.12-1.28 (7H, m), 1.36 (3H, t, J=7Hz), 1.89 (211, t, J=7Hz), 2.43 132 WO 2004/063197 PCT/JP2003/017091 (2H, m), 3.01 (2H, m), 4.02 (2H, q, J=7Hz), 5.97 (111, d, J=5Hz), 6.65 (1H, d, J=5Hz), 7.43-7.55 (5H, m), 7.93 (1H, m), 8.61 (11H, m), 8.79 (1H, m) Example 174 5 Ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate NMR (CDCI 3 , 8): 1.16-1.46 (10H, m), 1.57 (2H, t, J=7Hz), 2.62 (2H, m), 2.30 (2H, m), 3.03 (211, q, J=7Hz), 4.05 (2H, q, J=7Hz), 5.93 (1H, d, J=51Hz), 6.63 (1H, d, J=5Hz), 7.36 (1H, m), 7.44 (1H, m), 7.91 (1H, m) 10 Example 175 To a solution of ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2 b]pyridazin-3-yl]pentanoate (1.00 g) in dimethylsulfoxide (20 mL) was added iN sodium hydroxide (5.31 mL) over 1.5 hours. The reaction was quenched by adding IN 15 hydrochloric acid (6 mL) under an ice-bath. The mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with water (50 x 2 mL) and brine, dried over magnesium sulfate, and evaporated. Flash silica gel column chromatography eluting with ethyl acetate-hexane = 1/3 to 1/1 afforded 5-[4-(3 cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid as an yellow 20 solid (668 mg). 5-[4-(3-Cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 6): 1.03-1.25 (4H, m), 1.36 (3H, t, J=7Hz), 1.93 (2H, t, J=7Hz), 2.39 (2H, m), 3.02 (2H, q, J=7Hz), 5.91(1H, d, J=5Hz), 6.63 (1H, d, J=5Hz), 7.26-7.53 25 (5H, s), 7.56-7.69 (2H, m), 7.72-7.79 (2H, m) MS (ESI*): m/z 424 (M+H) The following compounds were obtained in substantially the same manner as that of Example 175. 30 Example 176 5-[4-(3-Cyanophenyl)-7-ethyl-2-(1,3-thiazol-2-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 133 WO 2004/063197 PCT/JP2003/017091 NMR (CDCI 3 , 6): 1.20-1.52 (7H, m), 2.19 (2H, m), 2.98 (2H, m), 3.04 (2H, q, J=7Hz), 4.05 (211, q, J=7Hz), 5.38 (1H, d, J=5Hz), 6.67 (11, d, J=5Hz), 7.43 (1H, d, J=3Hz), 7.60-7.64 (2H, m), 7.67 (111, m), 7.76 (111, m), 7.92 (1H, d, J=3Hz) MS (ESI*): m/z 431 (M+H) 5 Example 177 5-[4-(3-Cyanophenyl)-7-ethyl-2-(1-methyl-1H-pyrrol-2-yl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid NMR (CDCl 3 , 8): 1.12 (21, m), 1.23-1.41 (5H, m), 2.04 (2H, t, J=7Hz), 2.48 (2H, m), 10 3.02 (2H, q, J=7Hz), 3.68(3H, s), 5.90 (1H, d, J=5Hz), 6.22 (1H, m), 6.35 (1H, m), 6.62 (1H, d, J=5Hz), 6.75 (1H, m), 7.57-7.789 (4H, m) MS (ESI*): m/z 427 (M+H) Example 178 15 5-[4-(3-Cyanophenyl)-7-ethyl-2-(1,3-oxazol-5-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 8): 1.31-1.49 (7H, m), 2.17 (21, t, J=7Hz), 2.57 (2H, m), 3.04 (2H, q, J=7Hz), 5.42 (1H, d, J=5Hz), 6.67 (111, d, J=5Hz), 7.56 (1H, s), 7.64 (2H, m), 7.67 (11, s), 7.78 (1H, m), 8.07 (111, s) 20 Example 179 5-[4-(3-Cyanophenyl)-2-(3,5-dimethyl-4-isoxazolyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid NMR (CDCl 3 , 6): 1.04-1.30 (7H, m), 1.97 (2H, t, J=7Hz), 2.26-2.35 (511, m), 2.41 25 (3H, s), 3.00 (211, q, J=7Hz), 4.06 (211, q, J=7Hz), 5.97 (1H, d, J=5Hz), 6.68 (111, d, J=5Hz), 7.61-7.68 (211, m), 7.73 (1H, s), 7.79 (1H, m) Example 180 A solution of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (120 mg), 30 1-tert-butyl 7-ethyl 2-[(3,5-dimethyl-4-isoxazolyl)carbonyl]heptanedioate (203 mg), and toluenesulfonic acid monohydrate (3.76 mg) in toluene (1 mL) was refluxed for 1 hour. Additional p-toluenesulfonic acid monohydrate (14.5 mg) was added, and the mixture 134 WO 2004/063197 PCT/JP2003/017091 was refluxed for 1 hour. The mixture was stirred further for 0.5 hour after adding trifluoromethanesulfonic acid (3.76 mg). The mixture was partitioned between ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL). The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. Flash silica gel 5 column chromatography eluting with ethyl acetate-hexane = 1/40 to 2/5 afforded ethyl 5 [4-(3-cyanophenyl)-2-(3,5-dimethyl-4-isoxazolyl)-7-ethylpyrrolo [1,2-b]pyridazin-3-yl]pentanoate as an yellow gum (75.7 mg, 19.1%). Ethyl 5-[4-(3-cyanophenyl)-2-(3,5-dimethyl-4-isoxazolyl)-7-ethylpyrrolo[1,2 10 b]pyridazin-3-yl]pentanoate NMR (CDC1 3 , 6): 1.04-1.30 (7H, m), 1.97 (2H, t, J=7Hz), 2.26-2.35 (5H, m), 2.41 (3H, s), 3.00 (2H, q, J=7Hz), 4.06 (2H, q, J=7Hz), 5.97 (1H, d, J=5Hz), 6.68 (1H, d, J=5Hlz), 7.61-7.68 (2H, m), 7.73 (1H, s), 7.79 (1H, m) 15 Example 181 To a solution of N-[2-(3-cyanobenzoyl)-5-ethyl-1H-pyrrol-1-yl]-2 (methylsulfonyl)acetamide (2.70 g) in tetrahydrofuran (30 mL) was added sodium hydride (601 mg, 60% in oil) under an ice-bath. After stirring for 40 minutes, the reaction was quenched by adding IN hydrochloric acid (15 mL). The mixture was 20 extracted with ethyl acetate (50 mL), and the extract was washed with water (50 x 2 mL) and brine (50 mL), dried over magnesium sulfate, and evaporated to give a brownish yellow solid (3.36 g). The solid was triturated in diisopropyl ether (20 mL) to give 3-[7 ethyl-3-(methylsulfonyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4-yl]benzonitrile as an yellow powder (2.31 g, 90.1%). 25 3-[7-Ethyl-3-(methylsulfonyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4 yl]benzonitrile NMR (CDCI 3 , 5): 1.37 (3H, t, J=7Hz), 2.46-3.07 (511, m), 6.81 (111, d, J=5Hz), 6.70 (1H, d, J=5Hz), 7.60-7.69 (3H, m), 7.83 (1H, d, J=9Hz) 30 The following compound was obtained in substantially the same manner as that of Example 181. Example 182 135 WO 2004/063197 PCT/JP2003/017091 Ethyl 4-(4-cyanophenyl)-7-ethyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3 carboxylate NMR (CDCI 3 , 5): 0.78 (3H, t, J=711z), 1.36 (311, t, J=7Hz), 3.02 (2H, q, J=7Hz), 4.02 (2H, q, J=7Hz), 6.15 (1H, d, J=5Hz), 6.64 (1H, d, J=5Hz), 7.42 (2H, d, J=9Hz), 5 7.77 (2H, d, J=9Hz), 11.74 (1H, s, br) MS (ESI*): m/z 336 (M+H) Example 183 To a solution of 3-[7-ethyl-3-(methylsulfonyl)-2-oxo-1,2-dihydropyrrolo[1,2 10 b]pyridazin-4-yl]benzonitrile (1.30 g) and triethylamine (578 mg) in dichloromethane (18 mL) was added trifluoromethanesulfonic anhydride (1.61 g) under an ice-bath over 30 minutes (3 to 7*C). After stirring for 0.5 hour, the reaction was quenched by adding water (100 mL). The mixture was partitioned between ethyl acetate (200 mL) containing chloroform (200 mL) and iN hydrochloric acid (50 mL). An insoluble yellow solid was 15 collected by filtration (0.542 g). The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give a dark yellow solid (1.27 g). Both the solid was combined, and triturated in diisopropyl ether (30 mL) to give 4-(3-cyanophenyl)-7 ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-2-yl trifluoromethanesulfonate as a brownish yellow powder (1.67 g, 92.6%). 20 4-(3-Cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-2-yl trifluoromethanesulfonate NMR (CDCI 3 , 6): 1.39 (3H, t, J=7Hz), 3.02 (2H, q, J=7 Hz,), 3.22 (3H, s), 6.40 (1H, d, J=5Hz), 6.93 (1H, d, J=5Hz), 7.63 (3H, m), 7.82 (1H, m) 25 Example 184 A mixture of 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2 blpyridazin-2-yl trifluoromethanesulfonate (150 mg) and pyrrolidine (45.6 mg) in tetrahydrofuran (1 mL) was refluxed for 1.5 hours. The mixture was partitioned between 30 ethyl acetate (20 mL) and IN hydrochloric acid (10 mL). The organic extract was washed with brine, dried over magnesium sulfate, and evaporated to give a dark colored solid. Flash silica gel column chromatography eluting with ethyl acetate-hexane = 1-4 to 1-2 afforded 3-[7-ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinyl) 136 WO 2004/063197 PCT/JP2003/017091 pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile as an yellow oil, which was crystalyzed upon standing (112 mg, 89.6%). 3-[7-Ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile 5 NMR (CDCl 3 , 6): 1.38 (3H, t, J=7Hz), 1.99 (4H, m), 3.99 (2H, q, J=7Hz), 3.22 (3H, s), 3.42-3.70 (4H, m), 6.28 (1H, d, J=5Hz), 6.68 (1H, d, J=5Hz), 7.57 (1H, t, J=9Hz), 7.69- 7.78 (3H, m) MS (ESI*): m/z 395 (M+H) 10 The following compounds were obtained in substantially the same manner as that of Example 184. Example 185 3-[2-(Dimethylamino)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4 yl]benzonitrile 15 NMR (CDCl 3 , 6): 1.39 (3H, t, J=7Hz), 2.97 (6H, s), 3.02 (2H, q, J=7H1z), 3.26 (3H, s), 6.28 (1H, d, J=5Hz), 6.69 (1H, d, J=5Hz), 7.57 (1H, t, J=9Hz), 7.66- 7.79 (3H, m) MS (ESI*): m/z 369 (M+H) Example 186 20 3-[7-Ethyl-2-[(2-methoxyethyl)amino]-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4 yl]benzonitrile NMR (CDCl 3 , 6): 1.35 (3H, t, J=7Hz), 2.96 (2H, q, J=7Hz), 3.07 (3H, s), 3.43 (3H, s), 3.61-3.73 (4H, m), 5.96 (1H, d, J=5Hz), 6.51 (111, d, J=5Hz), 6.75 (1H, m, br), 7.51- 7.60 (3H, m), 7.74 (11H, m) 25 MS (ESI*): m/z 399 (M+H) Example 187 A mixture of ethyl 2-(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate (1.4 g), 1H pyrrol-1-amine (350 mg), and p-toluenesulfonic acid monohydrate (41 mg) in ethanol (10 30 ml) was refluxed for 5 hours. The mixture was partioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of 137 WO 2004/063197 PCT/JP2003/017091 ethyl acetate and hexane (1:4) to give ethyl 2-benzyl-4-(4-fluorophenyl)pyrrolo[1,2 b]pyridazine-3-carboxylate (828 mg) as an oil. Ethyl 2-benzyl-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate 5 NMR (CDCI 3 , 5): 0.70 (3H, t, J=7Hz), 3.71 (2H, q, J=7Hz), 4.29 (2H, s), 6.37 (11H, dd, J=1, 4Hz), 6.85 (1H, dd, J=2, 4Hz), 7.10-7.30 (7H, m), 7.38-7.46 (211, m), 7.83 (1H, dd, 1, 2Hz) Example 188 10 To a solution of ethyl 2-benzyl-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3 carboxylate (730 mg) in tetrahydrofuran (10 ml) was added N-chlorosuccinimide (260 mg) and the mixture was stirred at 20'C for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with aqueous sodium thiosulfate, water and brine, dried over magnesium sulfate, and evaporated. The 15 residue was purified by silica gel column chromatograpy eluting with a mixture of toluene and ethyl acetate (10:1) to give ethyl 2-benzyl-7-chloro-4-(4 fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (285 mg) as an yellow oil. Ethyl 2-benzyl-7-chloro-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate 20 NMR (CDCI 3 , 5): 0.69 (3H, t, J=7Hz), 3.70 (2H, q, J=7Hz), 4.37 (211, s), 6.39 (1H, d, J=4Hz), 6.82 (1H, d, J=4Hz), 7.10-7.30 (7H, m), 7.35-7.45 (211, m) Example 189 A mixture of ethyl 3-(4-fluorobenzoyl)-4-oxopentanoate (800 mg), 1H-pyrrol-1 25 amine (265 mg), and p-toluenesulfonic acid monohydrate (31 mg) in ethanol (5 ml) was refluxed for 5 hours. The mixture was partioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl [4-(4-fluorophenyl)-2-methylpyrrolo[l,2 30 b]pyridazin-3-yl]acetate (1.09 g) as an oil. Ethyl [4-(4-fluorophenyl)-2-methylpyrrolo[ 1,2-b]pyridazin-3-yl]acetate 138 WO 2004/063197 PCT/JP2003/017091 NMR (CDCl 3 , 5): 1.25 (3H, t, J=7Hz), 2.45 (3H, s), 3.45 (2H, s), 4.16 (2H, q, J=7Hz), 6.03 (1H, dd, J=1, 4Hz), 6.72 (1H, dd, J=2, 4Hz), 7.17 (2H, dt, J=2, 7Hz), 7.40 (2H, ddd, J=2, 5, 7Hz), 7.68 (1H, dd, J=1, 2Hz) 5 Example 190 To a solution of ethyl [ 4

-(

4 -fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3 yl]acetate (100 mg) in tetrahydrofuran (2 ml) was added N-chlorosuccinimide (43 mg) and the mixture was stirred at 20'C for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with aqueous ethyl 10 acetate, water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatograpy eluting with a mixture of toluene and ethyl acetate (10:1) to give ethyl [7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2 b]pyridazin-3-yl]acetate (34 mg) as an yellow oil. 15 Ethyl [7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl] acetate NMR (CDCl 3 , 6): 1.25 (3H, t, J=7Hz), 2.54 (3H, s), 3.47 (2H, s), 4.16 (2H, q, J=7Hz), 6.05 (1H, d, J=4Hz), 6.68 (1H, d, J=4Hz), 7.18 (2H, dt, J=2, 7Hz), 7.38 (2H, ddd, J=2, 5, 7Hz) 20 Example 191 To a solution of ethyl [7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2 b]pyridazin-3-yljacetate (300 mg) in tetrahydrofuran (4 ml) was added 1N sodium hydroxide (1.7 ml), followed by methanol (2 ml). After standing at 20*C overnight, the mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic 25 layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was triturated with ether to give [7-chloro-4-(4-fluorophenyl)-2 methylpyrrolo[1,2-b]pyridazin-3-yl]acetic acid (250 mg) as an yellow powder.

[

7 -Chloro-4-(4-fluorophenyl)-2-methylpyrrolo[ 1,2-b]pyridazin-3-yl] acetic acid 30 NMR (CDCI 3 , 6): 2.57 (3H, s), 3.54 (2H, s), 6.06 (111, d, J=4Hz), 6.69 (1H, d, J=4Hz), 7.19 (2H, t, J=711z), 7.38 (211, dd, J=5, 7Hz) 139 WO 2004/063197 PCT/JP2003/017091 Example 192 To a solution of [7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3 yl]acetic acid (220 mg) in tetrahydrofuran (10 ml) was added 1,1'-carbonyldiimidazole (18 mg) and the mixture was stirred at 20'C for 1 hour, then magnesium bis(3-ethoxy-3 5 oxo-propanoate) (109 mg) was added. After the mixture was stirred overnight at 20*C, magnesium bis(3-ethoxy-3-oxo-propanoate) (109 mg) was added. After stirring for 3 hours, the mixture was partitioned between IN hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of 10 ethyl acetate and hexane (1:5) to give the product (237 mg) as an oil, which was triturated with ethyl acetate and washed with isopropyl ether to give ethyl 4-[7-chloro-4-(4 fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-oxobutanoate (212 mg) as an yellow powder. 15 Ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3 oxobutanoate mp 116-118 0 C NMR (CDCI 3 , 5): 1.25 (3H, t, J=7Hz), 2.46 (3H, s), 3.40 (2H, s), 3.75 (2H, s), 4.16 (2H, q, J=7Hz), 6.04 (1H, d, J=4Hz), 6.68 (1H, d, J=4Hz), 7.20 (2H, t, J=7Hz), 20 7.28 (2H, dd, J=5, 7Hz) Example 193 To a solution of ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2 b)pyridazin-3-yl]-3-oxo-butanoate (160 mg) in methanol (5 ml) was added sodium 25 borohydride (23.4 mg) at 0*C and the mixture was stirred at the same temperature for I hour. The mixture was partitioned between IN hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by preparative thin-layer chromatograpy eluting with a mixture of ethyl acetate and hexane (1:3) and triturated with ethyl acetate 30 to give ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3 hydroxybutanoate (95 mg) as an yellow powder. Ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3 140 WO 2004/063197 PCT/JP2003/017091 hydroxybutanoate NMR (CDCl 3 , 6): 1.23 (3H, t, J=7Hz), 2.18-2.38 (2H, m), 2.67 (3H, s), 2.70-2.85 (2H, m), 4.03 (1H, m), 4.09 (2H, q, J=7Hz), 5.96 (1H, d, J=4Hz), 6.65 (1H, d, J=4Hz), 7.19 (211, t, J=7Hz), 7.30-7.45 (2H, m) 5 Example 194 To a solution of ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo(1,2 b]pyridazin-3-yl]-3-hydroxybutanoate (52 mg) in tetrahydrofuran (1 ml) was added 1N sodium hydroxide (0.27 ml), followed by methanol (1 ml). After standing at 20'C 10 overnight, the mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated to give 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2 b]pyridazin-3-yl]-3-hydroxybutanoic acid (45 mg) as an yellow oil. 15 4-[7-Chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3 hydroxybutanoic acid NMR (CDCl 3 , 8): 2.125-2.45 (2H, m), 2.66 (3H, s), 2.70-2.88 (2H, m), 4.02 (1H, m), 5.97 (1H, d, J=4Hz), 6.65 (1H, d, J=4Hz), 7.20 (2H, t, J=7Hz), 7.30-7.45 (2H, m) 20 Example 195 A mixture of ethyl 7-(4-fluorobenzoyl)-8-oxononanoate (300 mg), (1-amino-5 ethyl-1H-pyrrol-2-yl)(4-fluorophenyl)methanone (216 mg), and p-toluenesulfonic acid monohydrate (35.4 mg) in ethanol (6 ml) was refluxed for 5 hours. The mixture was partioned between ethyl acetate and water. The organic layer was separated, washed with 25 brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 6-[7 ethyl-2,4-bis(4-fluorophenyl)pyrrolo[1,2-b]pyridazin-3-yllhexanoate (83 mg) and ethyl 6 [7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate (40 mg) as an oil. 30 Ethyl 6-[7-ethyl-2,4-bis(4-fluorophenyl)pyrrolo[1,2-b]pyridazin-3-yl]hexanoate NMR (CDCl 3 , 8): 0.85-1.00 (2H, m), 1.00-1.10 (2H, m), 1.16-1.30 (211, m), 1.21 (3H, 141 WO 2004/063197 PCT/JP2003/017091 t, J=7Hz), 1.36 (311, t, J=7Hz), 2.00 (2H, t, J=7Hz), 2.40 (2H, t, J=7Hz), 3.01 (2H, q, J=711z), 4.06 (2H, q, J=7Hz), 5.97 (111, d, J=4Hz), 6.61 (111, d, J=4Hz), 7.12 7.24 (411, m), 7.38 (2H, dd, J=5, 9Hz), 7.50 (2H, dd, J=5, 9Hz) 5 Ethyl 6-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[ 1,2-b]pyridazin-3-yl]hexanoate NMR (CDCl 3 , 5): 1.15-1.30 (2H, m), 1.23 (3H, t, J=7Hz), 1.35-1.45 (211, m), 1.37 (311, t, J=7Hz), 1.45-1.55 (211, m), 2.18 (2H, t, J=711z), 2.40 (2H, t, J=7Hz), 2.54 (3H, s), 3.01 (2H, q, J=7Hz), 4.10 (2H, q, J=7Hz), 5.85 (1H, d, J=4Hz), 6.49 (1H, d, J=4Hz), 7.16 (2H, t, J=911z), 7.32 (2H, dd, J=5, 9Hz) 10 Example 196 A mixture of (1 -amino-5-ethyl-1H-pyrrol-2-yl)(4-fluorophenyl)methanone (500 mg), ethyl 8-acetyl-9-oxodecanoate (678 mg), and p-toluenesulfonic acid monohydrate (82 mg) in ethanol (5 ml) was refluxed for 2 hours. The mixture was partioned between 15 ethyl acetate and IN hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with toluene to give ethyl 6-[7-ethyl-4-(4 fluorophenyl)-2-methylpyrrolo[1,2-eb]pyridazin-3-yl]hexanoate (130 mg) as an oil and [5-ethyl-1-({ (1E)-1-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3 20 yl] ethylidene}amino)-1H-pyrrol-2-yl] (4-fluorophenyl) methanone (70 mg) as an yellow crystal. [5-Ethyl-1-({ (1E)-i-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3 yl]ethylidene} Iamino)-1H-pyrrol-2-yl] (4-fluorophenyl)methanone 25 NMR (CDCl 3 , 6): 1.13 (3H, t, J=7Hz), 1.39 (3H, t, J=7Hz), 1.80-2.00 (211, m), 1.91 (3H, s), 2.86 (311, s), 3.06 (2H, q, J=7Hz), 5.97 (1H, d, J=4Hz), 6.11 (111, d, J=4Hz), 6.62 (2H, t, J=4Hz), 7.11 (4H, t, J=9Hz), 7.48 (211, dd, J=5, 9Hz) , 7.82 (211, dd, J=5, 9Hz) 30 Ethyl 6-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate NMR (CDCl 3 , 6): 1.15-1.30 (2H, m), 1.23 (3H, t, J=7Hz), 1.35-1.45 (2H, m), 1.37 (3H, t, J=7Hz), 1.45-1.55 (2H, m), 2.18 (2H, t, J=7Hz), 2.40 (2H, t, J=7Hz), 2.54 142 WO 2004/063197 PCT/JP2003/017091 (3H, s), 3.01 (2H, q, J=7Hz), 4.10 (2H, q, J=7Hz), 5.85 (1H, d, J=4Hz), 6.49 (1H, d, J=4Hz), 7.16 (2H, t, J=9Hz), 7.32 (2H, dd, J=5, 9Hz) Example 197 5 A mixture of ethyl 7-(4-cyanobenzoyl)-8-oxononanoate (2.2 g), 2-ethyl-1H pyrrol-1-amine (809 mg), and p-toluenesulfonic acid monohydrate (64 mg) in toluene (40 ml) was refluxed for 20 minutes. The mixture was partioned between ethyl acetate and iN hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on 10 silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give the product, which was triturated with hexane to give ethyl 6-[4-(4-cyanophenyl)-7-ethyl-2 methylpyrrolo-[1,2-b]pyridazin-3-yl]hexanoate (2.21 g) as an yellow crystals. Ethyl 6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate 15 NMR (CDC 3 , S): 1.15-1.25 (2H, m), 1.25 (3H, t, J=7Hz), 1.30-1.45 (2H, m), 1.38 (3H, t, J=7Hz), 1.45-1.65 (2H, m), 2.19 (2H, t, J=7Hz), 2.38 (2H, t, J=7Hz), 2.56 (3H, s), 3.02 (2H, q, J=7Hz), 4.12 (2H, q, J=7Hz), 5.80 (1H, d, J=4Hz), 6.51 (1H, d, J=4Hz), 7.48 (2H, t, J=9Hz), 7.78 (2H, d, J=9Hz) 20 Example 198 To a solution of ethyl 6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2 b]pyridazin-3-yl]hexanoate (1.5 g) in tetrahydrofuran (15 ml) was added 2N potassium hydroxide (7.4 ml), followed by methanol (7.4 ml). After stirring at 50*C for 2 hours and 60'C for 3 hours, the mixture was partitioned between IN hydrochloric acid and ethyl 25 acetate. The precipitates were filtered and washed with ethyl acetate. The organic layer and the washings were combined, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was triturated with ethyl acetate and the precipitates were filtered. The filtrate was purified by silica gel column chromatograpy eluting with a mixture of ethyl acetate and hexane (1:1) and triturated with isopropyl ether to give 6-[4 30 (4-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoic acid (650 mg) as an yellow crystals. The two precipitates were combined and recrystallized from ethyl acetate to give 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin 3-yl}hexanoic acid (550 mg, 37.6%) as an yellow crystals. 143 WO 2004/063197 PCT/JP2003/017091 6-[4-(4-Cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoic acid NMR (CDCI 3 , 6): 1.15-1.30 (2H, m), 1.35-1.45 (2H, m), 1.38 (311, t, J=7Hz), 1.45 1.60 (21H, m), 2.26 (211, t, J=7Hz), 2.38 (2H, t, J=7Hz), 2.56 (3H, s), 3.02 (2H, q, 5 J=7Hz), 5.80 (1H, d, J=4Hz), 6.51 (1H, d, J=4Hz), 7.48 (2H, t, J=9Hz), 7.79 (2H, d, J=9Hz) 6-{4-[4-(Aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid 10 NMR (CDCl 3 , 6): 1.1-1.20 (2H, m), 1.29 (3H, t, J=7Hz), 1.30-1.45 (4H, m), 2.10 (211, t, J=7Hz), 2.37 (211, t, J=7Hz), 2.51 (3H, s), 2.92 (2H, q, J=7Hz), 5.73 (11H, d, J=4Hz), 6.51 (1H, d, J=4Hz), 7.45 (2H, t, J=9Hz), 7.47 (1H, s), 7.80 (2H, d, J=9Hz), 8.09 (1H, s) 15 Example 199 To a solution of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (200 mg) in toluene (6 mL) was added 2,4-pentanedione (837 mg) and p-toluenesulfonic acid monohydrate (32 mg) at ambient temperature. The reaction mixture was refluxed for 1 hour. The residue was purified by flash silica gel chromatography (silica gel, 80 mL) 20 eluted with hexane-ethyl acetate = 10-1 to give 3-(3-acetyl-7-ethyl-2-methylpyrrolo[1,2 b]pyridazin-4-yl)benzonitrile (63 mg, 24.8%) as an yellow solid. 3-(3-Acetyl-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile NMR (CDCl 3 , 8): 1.39 (311, t, J=8Hz), 1.95 (3H, s), 2.50 (31H, s), 3.04 (2H, q, J=8Hz), 25 6.27 (1H, d, J=5Hz), 6.69 (11H, d, J=5Hz), 7.59-7.72 (2H, m), 7.76-7.84 (2H, m) MS (ESI*): m/z 304 (M+H) Example 200 To a solution of ethyl (2E)-3-[7-chloro-4-(4-fluorophenyl)-2 30 isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propenoate (50 mg) in toluene was added dropwise 1.5 M diisobutylalminum hydride (0.277 mL) in toluene (24 mL) in a dryice acetone bath. After addition, the mixture was stirred for 2 hours (-10'C). The reaction 144 WO 2004/063197 PCT/JP2003/017091 mixture was quenched with sodium, potassium-tartarate and was filtered through Celite. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 40 mL) eluted with hexane-ethyl acetate = 10-1, 5-1, and 3-1 to give (2E)-3-[7-chloro-4-(4 5 fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propen-1-ol as an yellow solid (30 mg). (2E)-3-[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propen 1-01 10 NMR (CDCl 3 , 6): 1.38 (6H, d, J=7Hz), 3.31 (1H, m), 4.05-4.11 (2H, m), 5.48 (1H, dt, J=15, 6Hz), 6.11 (1H, d, J=5Hz), 6.45 (1H, d, J=15Hz), 6.68 (1H, d, J=5Hz), 7.08-7.18 (2H, m), 7.29-7.40 (2H, m) MS (ESI): m/z 345 (M+H) 15 The following compounds were obtained in substantially the same manner as that of Example 200. Example 201 [4-(4-Fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methanol NMR (CDCl 3 , 6): 1.45 (1H, t, J=5Hz), 2.65 (3H, s), 4.47 (2H, d, J=5Hz), 6.13 (1H, 20 m), 6.73 (1H, m), 7.14-7.28 (2H, m), 7.43-7.51 (2H, m), 7.70 (1H, m) MS (ESI*): m/z 257 (M+H) Example 202 [7-Ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methanol 25 NMR (CDCl 3 , 6): 1.31-1.46 (10 H, m), 3.04 (2H, q, J=8Hz), 3.46 (1H, m), 4.49 (2H, d, J=5Hz), 6.05 (1H, d, J=5Hz), 6.56 (1H, d, J=5Hz), 7.12-7.22 (2H, m), 7.41 7.50 (2H, m) MS (ESI'): m/z 313 (M+H) 30 Example 203 2-{ [7-Ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo [1,2-b]pyridazin-3-yl]methoxy}ethanol NMR (CDCl 3 , 8): 1.30-1.45 (9 H, m), 3.04 (2H, q, J=8Hz), 3.35 (1H, m), 3.46 (2H, t, 145 WO 2004/063197 PCT/JP2003/017091 J=6Hz), 3.69 (2H, br t, J=8Hz), 4.30 (2H, s), 6.07 (1H, d, J=5Hz), 6.55 (1H, d, J=5Hz), 7.11-7.22 (2H, m), 7.41-7.51 (2H, m) MS (ESI*): m/z 357 (M+H) 5 Example 204 To a solution of (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2 b]pyridazin-3-yl]-2-propen-1-ol (30 mg) in N,N-dimethylformamide (1 mL) was added 60% sodium hydride in oil (3.8 mg) in an ice-water bath under nitrogen atmosphere. After 20 minutes, to the mixture was added methyl iodide (18.5 mg) at the temperature. 10 After 15 minutes, the reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate = 10-1) to give 7 -chloro- 4

-(

4 -fluorophenyl)-2-isopropyl-3-[(1E)-3-methoxy-1-propenyl]pyrrolo[1,2 15 b]pyridazine as a brown oil (3.5 mg, 10.2 %). 7-Chloro-4-(4-fluorophenyl)-2-isopropyl-3-[(1E)-3-methoxy-1-propenyl]pyrrolo[1,2 b]pyridazine NMR (CDCl 3 , 8): 1.38 (3H, t, J=7Hz), 3.31 (1H, m), 4.05-4.11 (2H, m), 5.48 (1H, dt, 20 J=15, 6Hz), 6.11 (1H, d, J=5Hz), 6.45 (1H, d, J=15Hz), 6.68 (1H, d, J=5Hz), 7.08-7.18 (2H, m), 7.29-7.40 (2H, m) MS (ESI~): in/z 345 (M+H) Example 205 25 To dimethylsulfoxide (0.5 mL) was added 60% sodium hydride in oil (27 mg) and was heated at 60*C for 40 minutes. To this mixture was added (3 carboxypropyl)(triphenyl)phosphonium bromide (124 mg) at ambient temperature and was stirred for 40 minutes. 7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2 b]pyridazine-3-carbaldehyde (40 mg) was added therein at ambient temperature. After 4 30 hours, the reaction mixture was acidified with 1N hydrogen chloride and was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate = 1-1) to give (4E)-5-[7-chloro-4-(4 146 WO 2004/063197 PCT/JP2003/017091 fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-4-pentenoic acid as an yellow oil (21 mg, E:Z=16:1, 56.3%). (4E)-5-[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-4 5 pentenoic acid NMR (CDCl 3 , 8): 1.40 (6H, d, J=7Hz), 2.20-2.37 (4H, m), 3.25 (11H, m), 5.30 (0.94H, dt, J=15, 7Hz), 5.01 (0.06H, m), 6.09 (1H, d, J=5Hz), 6.24 (0.94H, d, J=15Hz), 6.84 (0.06H, d, J=10Hz), 6.67 (0.94H, d, J=5Hz), 6.70 (0.06H, d, J=5Hz), 7.07 7.17 (2H, m), 7.26-7.35 (2H, m). 10 MS (ESI~): m/z 385 (M-H) Example 206 To a solution of 7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine 3-carbaldehyde (40 mg) was added 1N sodium hydroxide (19.3 mg) and acetone (0.425 15 mL) at ambient temperature. After 8 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate = 5-1) to give (3E)-4-[7-chloro-4-(4-fluorophenyl)-2 isopropylpyrrolo[1,2-b] 20 pyridazin-3-yl]-3-buten-2-one as an yellow solid (33 mg). (3E)-4-[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-3-buten-2 one NMR (CDCI 3 , 6): 1.40 (6H, d, J=7Hz), 2.13 (3H, s), 3.38 (1H, m), 5.89(1H, d, 25 J=15Hz), 6.23 (111, d, J=5Hz), 6.75 (1H, d, J=5Hz), 7.13-7.23 (2H, m), 7.30-7.39 (2H, m), 7.49 (1H, d, J=15Hz) Example 207 A solution of ethyl 4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3 30 carboxylate (100 mg) in tetrahydrofuran (1 mL) was purged with nitrogen gas under a dryice-acetone bath. To the mixture was added 2,2'-azobisisobutyronitrile (0.5 mg) was added to the mixture. After 5 minutes, was added 1,3-dibromo-5,5-dimethyl-2,4 imidazolidinedione (43.8 mg). The resulting mixture was stirred for 3 hours (-78 to 147 WO 2004/063197 PCT/JP2003/017091 30'C). Water (5 mL) was added, and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give an yellow gum. Flash silica gel column chromatography eluting with toluene-hexane = 1-5 to 2-3 afforded ethyl 7-bromo-4-(4-fluorophenyl)-2 5 isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate product as an yellow gum (90.0 mg, 72.5%). Ethyl 7-bromo-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate NMR (CDCl 3 , 8): 0.98 (3H, t, J=7Hz), 1.40 (6H, d, J=7Hz), 3.31 (1H, septet, J=7Hz), 10 4.05 (2H, q, J=7Hz), 6.39 (1H, d, J=5H1z), 6.87 (1H, d, J=5Hz), 7.16 (2H, t, J=9Hz), 7.45 (2H, dd, J=4 and 9Hz) MS (ESI*): m/z 405 (M+H) Example 208 15 A suspension of sodium hydride (74.4 mg) in dimethylsulfoxide (1.4 mL) was stirred for 1 hour at 60*C. The mixture was added to a solution of methyl triphenylphosphonium bromide (1.11 g) in dimethylsulfoxide (1.0 mL) at room temperature. After stirring for 0.5 hour, the mixture was added ethyl 4-(4-fluorophenyl) 7-formyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (500 mg). After stirring for 20 15 hours, the mixture was partitioned between ethyl acetate (20 mL) and water (5 mL). The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated to give an orange gum. Flash silica gel column chromatography eluting with ethyl acetate-hexane = 1-7 to 3-1 afforded ethyl 4-(4-fluorophenyl)-2 isopropyl-7-vinylpyrrolo[1,2-b]pyridazine-3-carboxylate an yellow gum, which was 25 solidified upon standing (361 mg, 72.6%). Ethyl 4-(4-fluorophenyl)-2-isopropyl-7-vinylpyrrolo[1,2-b]pyridazine-3-carboxylate NMR (CDC1 3 , 6): 0.97 (3H, t, J=7Hz), 1.38 (6H, d, J=7Hz), 3.32 (1H, septet, J=7Hz), 4.03 (2H, q, J=7Hz), 5.35 (1H, dd, J=2 and 12Hz), 6.11 (1H, dd, J=2 and 18Hz), 30 6.34 (1H, d, J=5Hz), 6.99 (1H, d, J=5Hz), 7.16 (1H, t, J=9Hz), 7.25 (1H, dd, J=12 and 18Hz), 7.45 (2H, d, J=4 and 9Hz) 148 WO 2004/063197 PCT/JP2003/017091 Example 209 To a solution of ethyl 7-{4-[4-({[(benzyloxy)carbonyl amino}sulfonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}heptanoate (169 mg) in ethanol (2 mL) was added 10% palladium on activated carbon (1.6 mg), and the 5 mixture was stirred under hydrogen pressure (3 kg/cm2) for 2 hours. The resulting mixture was filtered through celite, and the filtrate was concentrated to give an yellow gum. Preparative silica gel thin layer chromatography eluting with ethyl acetate-hexane = 1-1 afforded ethyl 7-{4-[4-(aminosulfonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2 b]pyridazin-3-yl}heptanoate as an yellow gum (76.8 mg, 58.4%). 10 Ethyl 7-{4-[4-(aminosulfonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl}heptanoate NMR (CDCl 3 , 6): 1.07-1.25 (7H, m), 1.30-1.46 (711, m), 2.18 (2H, t, J=7Hz), 2.36 (2H, in), 2.55 (3H, s), 3.00 (21H, q, J=7Hz), 4.12 (2H, q, J=7Hz), 5.21 (2H, s), 15 5.82 (1H, d, J=5Hz), 6.50 (1H, d, J=5Hz), 7.52 (2H, d, J=9Hz), 8.05 (2H, d, J=9Hz) MS (ESI*): m/z 472 (M+H) Example 210 20 To a solution of ethyl 4-(4-cyanophenyl)-2-(2-ethoxy-2-oxoethyl)-7 ethylpyrrolo[1,2-b]pyridazine-3-carboxylate (77.9 mg) in ethanol (0.5 mL) tetrahydrofuran (0.5 mL) was added IN potassium hydroxide. The resulting solution was stirred for 2.5 hours at room temperature. The mixture was stirred for futher 1 hour after adding IN potassium hydroxide (0.04 mL). The reaction was quenched by adding iN 25 hydrochloric acid (0.23 mL). The volatile was evaporated off, and the resulting residue was partitioned between ethyl acetate (10 mL) and IN hydrochloric acid (6 mL). The organic layer was washed with brine, dried, and evaporated to give [4-(4-cyanophenyl)-3 (ethoxycarbonyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl] acetic acid as an yellow solid (67.7 mg, 93.4%). 30 [4-(4-Cyanophenyl)-3-(ethoxycarbonyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]acetic acid NMR (CDCl 3 , 6): 0.84 (3H, t, J=7Hz), 1.38 (3H, t, J=7Hz), 3.05 (2H, q, J=7Hz), 3.93 (211, q, J=711z), 4.18 (31, s), 6.27 (1H, d, J=5Hz), 6.74 (1H, d, J=5Hz), 7.52 (2H, 149 WO 2004/063197 PCT/JP2003/017091 d, J=9Hz), 7.76 (2H, d, J=9Hz) MS (ESI*): m/z 378 (M+H) Example 211 5 To a solution of ethyl 2-(2-amino-2-oxoethyl)-4-(4-cyanophenyl)-7 ethylpyrrolo[1,2-b]pyridazine-3-carboxylate (35.0 mg) in tetrahydrofuran (1 mL) was added 60% sodium hydride (4.50 mg) under an ice-bath. The resulting mixture was stirred for 1 hour. The reaction was quenched by adding 1N HCI (4 mL). The mixture was extracted with ethyl acetate (10 mL), and the organic layer was washed with water 10 and brine, dried over magnesium sulfate, and evaporated. Preparative silica gel thin layer chromatography eluting with ethyl chloroform-methanol = 10-1 afforded 4-(7-ethyl-1,3 dioxo-1,2,3,4-tetrahydropyrido[3,4-e]pyrrolo[1,2-b] pyridazin-10-yl)benzonitrile as an yellow solid (3.86 mg, 12.6%). 15 4-(7-Ethyl-1,3-dioxo-1,2,3,4-tetrahydropyrido[3,4-e]pyrrolo[1,2-b]pyridazin-10 yl)benzonitrile NMR (CDCl 3 , 8): 1.40 (3H, t, J=7Hz), 3.08 (2H, q, J=7Hz), 4.16 (3H, s), 6.38 (1H, d, J=5Hz), 6.85 (1H, d, J=5Hz), 7.46 (2H, d, J=9Hz), 7.78 (2H, d, J=9Hz), 7.92 (1H, s, br) 20 Example 212 To methanol (1 mL) was added 60% sodium hydride (6.51 mg) at room temperature. Then, 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2 b]pyridazin-2-yl trifluoromethanesulfonate (70.0 mg) was added to the mixture. The 25 resulting mixture was stirred for 2 hours at room temperature and 1 hour at 50'C. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. Preparative silica gel thin layer chromatography eluting with ethyl acetate-hexane = 1-1 afforded 3-[7-ethyl-2 methoxy-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile as an yellow solid 30 (1.92 mg, 3.7%). 3-[7-Ethyl-2-methoxy-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile NMR (CDCI 3 , 5): 1.38 (3H, t, J=7Hz), 3.01 (2H, q, J=7Hz,), 3.24 (3H, s), 4.18 (3H, 150 WO 2004/063197 PCT/JP2003/017091 s), 6.12 (1H, d, J=5Hz), 6.63 (1H, d, J=5Hz), 7.53-7.64 (3H, m), 7.76 (1H, m) Example 213 To a solution of ethyl 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2 5 b]pyridazine-2-carboxylate (92.6 mg) in tetrahydrofuran (1 mL) and ethanol (0.5 mL) was added IN sodium hydroxide (0.349 mL). The resulting mixture was stirred for 3 hours at room temperature. The resulting mixture was stirred further for 40 minutes after adding iN sodium hydroxide (0.1 mL). The mixture was stirred further for 1.5 hours after adding IN sodium hydroxide (0.1 mL). The reaction was quenched by adiding IN 10 hydrochloric acid (1 mL), and the mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give a red oil. Flash silica gel column chromatography eluting with ethyl acetate-hexane = 1-1 afforded 3-(6-ethyl-1,1-dioxido-3-oxo-2,3 dihydropyrrolo[1,2-b]thieno[2,3-e] 15 pyridazin-9-yl)benzonitrile as a red foam (52.4 mg, 64.0%). 3-(6-Ethyl-1,1-dioxido-3-oxo-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9 yl)benzonitrile NMR (CDCI 3 , 5): 1.45 (3H, t, J=7Hz), 3.21, (3H, s), 4.28 (2H, s), 6.91 (1H, d, J=5Hz), 7.26 (1H, d, J=5Hz), 7.75 (1H, t, J=9Hz), 7.91 (1H, d, J=9Hz), 8.08-8.16 20 (2H,m) MS (ESI*): m/z 352 (M+H) Example 214 To a solution of 3-(6-ethyl-1,1-dioxido-3-oxo-2,3-dihydropyrrolo[1,2 25 b]thieno[2,3-e]pyridazin-9-yl)benzonitrile (60.0 mg) in tetrahydrofuran (0.2 mL) was added 1 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (0.487 mL) under an ice-bath. After stirring for 1 hour, the reaction was quenched by adding iN hydrochloric acid (1 mL). The mixture was partitioned between ethyl acetate (20 mL) and water (10 mL), and the organic layer was washed with brine, dried, and evaporated to 30 give 3-(6-ethyl-3-hydroxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin 9-yl) benzonitrile as an yellow foam (576 mg, 99.8%). 151 WO 2004/063197 PCT/JP2003/017091 3-(6-Ethyl-3-hydroxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9 yl)benzonitrile NMR (CDC1 3 , 5): 1.45 (3H, t, J=7Hz), 3.21, (3H, s), 4.28 (2H, s), 6.91 (1H, d, J=5Hz), 7.26 (1H, d, J=5Hz), 7.75 (1H, t, J=9Hz), 7.91 (1H, d, J=9Hz), 8.08-8.16 5 (2H, m) Example 215 To a solution of 3-(6-ethyl-3-hydroxy-1,1-dioxido-2,3-dihydropyrrolo[1,2 b]thieno[2,3-e]pyridazin-9-yl)benzonitrile (54.0 mg) in tetrahydrofuran (1 mL) was added 10 60% sodium hydride (6.69 mg) under an ice-bath. After stirring for 0.5 hour, methyl iodide (25.9 mg) was added, and the mixture was stirred for 3 hours 20 minutes at room temperature. The mixture was stirred for another 6 hours after adding mehtyl iodide (25.9 mg). The mixture was further stirred for 1 hour after adding 60% sodium hydride (3.0 mg) and methyl iodide (25.9 mg). The mixture was partitioned between ethyl acetate 15 and 1N hydrochloric acid, and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give an yellow oil. Preparative silica gel thin layer chromatography eluting with ethyl acetate-hexane = 1-2 afforded 3-(6-ethyl-1,1 dioxidopyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile (5.9 mg, 10.5%, an yellow solid) and 3-(6-ethyl-3-methoxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3 20 e]pyridazin-9-yl)benzonitrile (16.8 mg, 30.0%, an orange gum). 3-(6-Ethyl-1,1-dioxidopyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile NMR (CDCl 3 , 5): 1.40 (3H, t, J=7Hz), 3.07 (2H, q, J=7Hz), 6.68 (1H, d, J=5Hz), 6.82 (1H, d, J=5Hz), 7.02 (1H, d, J=7Hz), 7.37 (111, d, J=7Hz), 7.72 (1H, t, 25 J=9Hz), 7.87 (1H, d, J=9Hz), 8.11-8.16 (2H, m) 3-(6-Ethyl-3-methoxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9 yl)benzonitrile NMR (CDCl 3 , 5): 1.42 (3H, t, J=7Hz), 3.12 (2H, q, J=7Hz), 3.67 (3H, s), 3.73 (2H, 30 m), 5.02 (1H, m), 6.74 (1H, d, J=51Hz), 6.97 (1H, d, J=5Hz), 7.70 (1H, t, J=9Hz), 7.85 (1H, d, J=9Hz), 8.04-8.13 (2H, m) MS (ESI*): m/z 368 (M+H) 152 WO 2004/063197 PCT/JP2003/017091 Example 216 A mixture of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (1.00 g), ethyl 3-(methylsulfonyl)-2-oxopropanoate (1.34 g), and p-toluenesulfonic acid 5 monohydrate (79.5 mg) in toluene (20 mL) was refluxed for 1 hour with Dean-Stark condenser. The volatile was removed in vacuo. Flash silica gel column chromatography eluting with ethyl acetate-hexane = 1-10 to 9-15 afforded the intermediate imine (1.38 g, 67.7%) as an orange foam. The foam was dissolved in N-methylmorpholine (10 mL), and the solution was stirred for 1 hour at 130'C. The mixture was partitioned between 10 ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with water (30 x 2 mL) and brine, dried over magnesium sulfate, and evaporated to give a dark orange solid. The solid was triturated in diisopropyl ether (10 mL) to give 2-(trimethylsilyl)ethyl 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylate as an yellow powder (1.11 g, 67.7%). 15 2-(Trimethylsilyl)ethyl 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2 b]pyridazine-2-carboxylate NMR (CDCl 3 , 8): 0.12 (9H, s), 1.22 (2H, m), 1.39 (3H, t, J=7Hz), 3.09 (2H, q, J=7Hz), 3.23 (3H, s), 4.53 (2H, m), 6.30 (1H, d, J=5Hz), 6.89 (11H, d, J=5Hz), 20 7.50-7.67 (3H, m), 7.82 (1H, m) MS (ESI*): m/z 470 (M+H) The following compound was obtained in substantially the same manner as that of Example 216. 25 Example 217 Ethyl 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2 carboxylate NMR (CDCl 3 , 6): 1.39 (311, t, J=7Hz), 1.47 (3H, t, J=7Hz), 3.10 (2H, q, J=7Hz), 3.21, (311, s), 4.51 (2H, q, J=7Hz), 6.30 (1H, d, J=5Hz), 6.90 (111, d, J=5Hz), 7.61-7.67 30 (311, m), 7.72 (1H, m) Example 218 A solution of 2-(trimethylsilyl)ethyl 4-(3-cyanophenyl)-7-ethyl-3 153 WO 2004/063197 PCT/JP2003/017091 (methylsulfonyl)pyrrolo[1, 2 -b]pyridazine-2-carboxylate (1.09 ) in trifluoroacetic acid (5 mL) was stirred for 1.5 hours under an ice-bath. The reaction was quenched by adding water (20 mL). An yellow crystal was formed upon the addition, which was collected by filtration. The crystal was washed with water (5 mL) and hexane (3 mL) to give 4-(3 5 cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylic acid as an yellow crystal (756 mg, 88.2%). 4

-(

3 -Cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylic acid NMR (CDCI 3 , 6): 1.41 (211, m), 3.10 (2H, q, J=7Hz), 3.30 (3H, s), 6.36 (1H, d, 10 J=5Hz), 6.94 (1H, d, J=5Hz), 7.53-7.67 (3H, m), 7.82 (1H, m) MS (ESI*): m/z 370 (M+H) Example 219 A mixture of 4

-(

3 -cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2 15 b]pyridazine-2-carboxylic acid (40.0 mg), diemthylamine hydrochloride (12.4 mg), 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide (25.2 mg), and 1-hydroxybenzotriazole (21.9 mg) in N,N-dimethylfornamide (1 mL) was stirred for 3 hours at room temperature. The mixture was partitioned between ehtyl acetate (20 mL) and 1N hydrochloric acid (10 mL). The organic layer was washed with water (10 x 3 mL), saturated sodium bicarbonate(10 20 mL), and brine, dried over magnesium sulfate, and evaporated to give 4-(3-cyanophenyl) 7-ethyl-N,N-dimethyl-3-(methylsulfonyl)pyrrolo[1,2-blpyridazine-2-carboxamide as an yellow solid (43.4 mg, 101%). 4

-(

3 -Cyanophenyl)-7-ethyl-N,N-dimethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2 25 carboxamide NMR (CDCl 3 , 5): 1.38 (2H, m), 3.07 (2H, q, J=7Hz), 3.12 (3H, s), 3.18 (31H, s), 3.27 (3H, s), 6.27 (1H, d, J=5Hz), 6.85 (1H, d, J=5Hz), 7.57-7.67 (3H, m), 7.81 (1H, m) MS (ESI*): m/z 397 (M+H) 30 Example 220 A mixture of ethyl 4

-(

3 -chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2 b]pyridazine-3-carboxylate (450 mg) and 85% potassium hydroxide (3.01 g) in a mixture 154 WO 2004/063197 PCT/JP2003/017091 of ethanol (3 mL) and water (2 mL) was refluxed for 2.5 hours. The reaction mixture was cooled under an ice-bath, and quenched by adding concentrated hydrochloric (5 mL). The mixture was partitioned between ethyl acetate (20 mL) and water (10 mL), and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated to 5 give an yellow solid (388 mg). The solid was triturated in hexane to give 4-(3 chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid as an yellow powder (361 mg, 86.4%). 4-(3-Chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo(1,2-b]pyridazine-3-carboxylic acid 10 NMR (CDCl 3 , 8): 1.41 (3H, t, J=7Hz), 3.08 (2H, q, J=7Hz), 6.37 (1H, d, J=5Hz), 6.55 (1H, m), 6.76 (1H, d, J=5Hz), 7.02 (1H, d, J=3Hz), 7.40-7.55 (5H, m) MS (ESI*): m/z 367 (M+H) Example 221 15 To a solution of 4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3 carboxylic acid (358 mg,) and N,N-dimethylformamide (1.39 mg) in dichloromethane (3 mL) was added oxalyl chloride (157 mg) at room temperature. After stirring for 30 minutes, the volatile was removed in vacuo, and the residue was azeotroped with toluene three times to afford 4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3 20 carbonyl chloride as an yellow gum (396 mg, 106%). 4-(3-Chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carbonyl chloride NMR (CDCl 3 , 8): 1.42 (3H, t, J=7Hz), 3.10 (2H, q, J=7Hz), 6.45 (1H, d, J=5Hz), 6.59 (1H, m), 6.82 (1H, d, J=511z), 7.06 (1H, d, J=7Hz), 7.38-7.55 (4H, m), 7.63 25 (1H,m) Example 222 To a solution of methyl aminoacetate hydrochloride (26.1 mg) and triethylamine (42.0 mg) in dichloromethane (0.5 mL) was added a solution of 4-(3-chlorophenyl)-7 30 ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carbonyl chloride (40.0 mg) in dichloromethane (0.5 mL) under an ice-bath. The mixture was partitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (10 mL), and the organic layer was washed with brine (10 mL), dried over magnesium sulfate, and evaporated to give methyl ({ [4-(3 155 WO 2004/063197 PCT/JP2003/017091 chlorophenyl)-7-ethyl-2-(3-furyl)pyrrolo[1,2-b]pyridazin-3-yl]carbonyl}amino)acetate as an yellow gum (50.6 mg, 111%). Methyl ({ [4-(3-chlorophenyl)-7-ethyl-2-(3-furyl)pyrrolo[1,2-b]pyridazin-3 5 yl]carbonyllamino)acetate NMR (CDCl 3 , 8): 1.41 (311, t, J=7Hz), 3.10 (211, q, J=7Hz), 3.69 (3H, s), 3.95 (2H, d, J=5Hz), 6.01 (1H, t, br, 5Hz), 6.35 (1H, d, J=5Hz), 6.51 (1H, m), 6.75 (1H, d, J=5Hz), 7.01 (1H, d, J=7Hz), 7.37-7.48 (3H, m), 7.53 (1H, m), 7.58 (11H, m) MS (ESI*): m/z 438 (M+H) 10 The following compound was obtained in substantially the same manner as that of Example 222. Example 223 4-(3-Chlorophenyl)-7-ethyl-2-(2-furyl)-N,N-bis(2-hydroxyethyl)pyrrolo[1,2 15 b]pyridazine-3-carboxamide NMR (CDCl 3 ., 5): 1.42 (3H, t, J=7Hz), 2.35-2.72 (4H, m), 3.08 (2H, d, J=5Hz), 3.20 3.63 (4H, m), 3.82 (2H, m), 6.40 (1H, t, br, 5Hz), 6.54 (1H, m), 6.75 (1H, d, J=5Hz), 7.04 (1H, d, J=3Hz), 7.40-7.48 (2H, m), 7.53-7.60 (211, m), 7.71 (1H, m) MS (ESI*): m/z 454 (M+H) 20 Example 224 To a solution of 3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 yl]propanoic acid (100 mg) in dioxane (0.5 mL) was added triethylamine (25.2 mg) followed by a solution of pivaloyl chloride (30.1 mg) in dioxane (0.5 mL). A white 25 precipitate was formed. After stirring for 40 minutes at room temperature, the precipitate was removed by filtration, and washed with dioxane (2 mL). To the combined washing was added a solution of 2-aminoethanesulfonic acid (38.6 mg) in IN sodium hydroxide (0.247 mL). The resulting mixture was stirred for 1 hour at room temperature. The mixture was partitioned between ethyl acetate (15 mL) and water (5 mL). The organic 30 layer was washed with brine, dried over magnesium sulfate, and evaporated. Preparative silica gel thin layer chromatography eluting with chloroform-methanol = 5-1 afforded 2 ({ 3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo [1,2-b]pyridazin-3-yl]propanoyl}amino)ethanesulfonic acid as an yellow solid (104 mg, 156 WO 2004/063197 PCT/JP2003/017091 82.0%). 2-({3-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 yl]propanoyl}amino)ethanesulfonic acid 5 NMR (CDCI 3 , 6): 1.27 (5H, m), 2.59 (4H, m), 2.90-3.14 (4H, m), 5.96 (1H, m), 6.06 (1H, m), 7.06-7.40 (9H, m) Example 225 A solution of 3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 10 yl]propanoic acid (100 mg), (2R,3R,4S,5S,6R)-2-amino-3,5-bis[(2,2 dimethylpropanoyl) oxy]-6-{ [(2,2-dimethylpropanoyl)oxy]methyl}tetrahydro-2H-pyran-4-yl pivalate (255 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.494 mmol), and 1 hydroxybenzotriazole (66.7 mg) in N,N-dimethylformamide (1 mL) was stirred for 1 15 hour at room temperature. The mixture was partitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (10 mL). The organic layer was washed with water (10 x 3 mL), saturated sodium bicarbonate (10 mL), and brine, dried over magnesium sulfate, and evaporated to give an yellow foam (339 mg). Flash silica gel column chromatography eluting with ethyl acetate-hexane = 1-10 to 2-5 afforded 20 (2R,3R,4S,5S,6R)-2-({ 3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 yl]propanoyl}amino)-3,5-bis[(2,2-dimethylpropanoyl)oxy]-6-{ [(2,2-dimethylpropanoyl) oxy]methyl}tetrahydro-2H-pyran-4-yl pivalate an yellow foam (240 mg, 108%). (2R,3R,4S,5S,6R)-2-({ 3-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 25 yl]propanoyl}amino)-3,5-bis[(2,2-dimethylpropanoyl)oxy]-6-{[(2,2 dimethylpropanoyl)oxy]methyl}tetrahydro-2H-pyran-4-yl pivalate NMR (CDC1 3 , 8): 0.97-1.26 (36H, m), 1.35 (3H, t, J=7Hz), 1.83 (2H, m), 2.81 (2H, m), 3.01 (2H, q, J=7Hz), 3.87-4.16 (3H, m), 4.90-5.27 (3H, m), 5.36-5.51 (2H, m), 6.01 (1H, d, J=5Hz), 6.52 (1H4, d, J=5Hz), 7.29 (1H1, m), 7.40-7.59 (8H, m) 30 Example 226 To a solution of ethyl [4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2 b]pyridazin-3-yl]acetate (114 mg) in tetrahydrofuran (2 mL) was added 1 M 157 WO 2004/063197 PCT/JP2003/017091 diisobutyl aluminum hydride in toluene (0.816 mL) under an ice-bath. After stirring for 1 hour at room temperature, additional 1 M diisobutylaluminum hydride (0.41 mL) was added. The reaction was quenched by adding 1N hydrochloric acid (1 mL) after 1 hour. The mixture was partitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (10 5 mL), and filtered through celite. The organic layer was washed with water (10 mL) and brine, dried over magnesium sulfate, and evaporated to give an yellow gum. Flash silica gel column chromatography eluting with ethyl acetate-hexane = 1-20 to 2-50 afforded 2 [4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[ 1,2-b]pyridazin-3-yl]ethanol as an yellow oil, which was crystalyzed upon standing (107 mg, 104%). 10 2-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethanol NMR (CDCl 3 , 8): 1.37 (3H, t, J=7Hz), 2.77 (2H, t, J=7Hz), 3.01 (2H, q, J=7Hz), 3.26 (2H, m), 3.26 (2H, m), 6.00 (1H, d, J=511z), 6.63 (1H, d, J=5Hz), 7.34 (1H, m), 7.41-7.55 (8H, m) 15 Example 227 To a mixture of 2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 yl]ethanol (105 mg), 2,3,4,6-tetra-O-acetyl-beta-D-galactosyl bromide (299 mg), silver carbonate (154 mg) in toluene (2 mL) was added silver triflate (3.58 mg) under an ice 20 bath. After 40 minutes, 2,3,4,6-tetra-O-acetyl-beta-D-galactosyl bromide (114 mg), silver carbonate (229 mg) was added, and the mixture was stirred for 50 minutes. The mixtrure was further stirred for 50 minutes after adding 2,3,4,6-tetra-O-acetyl-beta-D galactosyl bromide (114 mg), silver carbonate (154 mg). The mixture was filtered through celite, and the filtrate was paritiotned between ethyl acetate and water. The 25 organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give an yellow gum. Flash silica gel column chromatography eluting with ethyl acetate hexane = 1-10 to 7/10 afforded (2R,3R,4S,5S,6R)-4,5-bis(acetyloxy)-6 [(acetyloxy)methyl]-2-{2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pydidazin-3 yl]ethoxy}tetrahydro-2H-pyran-3-yl acetate as an yellow gum (115 mg, 58.4%). 30 (2R,3R,4S,5S,6R)-4,5-bis(Acetyloxy)-6-[(acetyloxy)methyl]-2-{ 2-[4-(3 chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}tetrahydro-2H pyran-3-yl acetate 158 WO 2004/063197 PCT/JP2003/017091 NMR (CDCl 3 , 8): 1.35 (3H, t, J=7Hz), 1.70 (3H, m), 1.94 (3H, s), 2.04 (3H, s), 2.11 (3H, s), 2.78 (2H, m), 3.01 (2H, q, J=7Hz), 3.10 (111, m), 3.46 (1H, m), 3.62 (1H, t, J=6Hz), 3.79 (1H, d, J=8Hz), 3.98 (2H, m), 4.83 (1H, dd, J=3 and 10Hz), 4.97 (1H, dd, J=8 and 10Hz), 5.28 (111, d, J=3Hz), 6.02 (1H, d, J=51Hz), 6.64 (1H, d, 5 J=5Hz), 7.31 (1H, m), 7.41-7.56 (8H, m) Example 228 To a solution of (2R,3R,4S,5S,6R)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]-2 { 2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}tetrahydro 10 2H-pyran-3-yl acetate (113 mg) in methanol (2 mL) was added sodium methoxide (0.86 mg) at room temperature. After stirring for 2 hours, the solvent was evaporated off, and the mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give an yellow foam (77.3 mg). The foam was triturated in hexane to give 15 (2R,3R,4S,5R,6R)-2-{2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 yl]ethoxy}-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol as an yellow powder (48.3 mg, 89.7%). (2R,3R,4S,5R,6R)-2-{2-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 20 yl]ethoxy}-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol NMR (CDCl 3 , 8): 1.36 (3H, t, J=7Hz), 1.92 (1H, m), 2.06 (1H, m), 2.56 (111, s, br), 2.76-2.92 (311, m), 3.02 (2H, q, J=7Hz), 3.24 (211, m), 3.38-3.50 (3H, m), 3.63 3.84 (3H, m), 2.41 (111, s, br), 6.01 (1H, d, J=5Hz), 6.63 (111, d, J=5Hz), 7.32 (1H, m), 7.41-7.57 (8H, m) 25 The following compounds were obtained in substantially the same manner as that of Example 228. Example 229 3-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N 30 [(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2 yl]propanamide NMR (CDC1 3 , 8): 1.38 (3H, t, J=7Hz), 1.97 (2H, m), 2.83 (211, m), 3.01 (2H, q, 159 WO 2004/063197 PCT/JP2003/017091 J=7Hz), 3.31-3.52 (3H, m), 3.61-3.76 (2H, m), 3.88 (1H, m), 4.63 (111, d, J=9Hz), 6.01 (111, d, J=5Hz), 6.64 (1H, d, J=5Hz), 7.34 (111, m), 7.42-7.59 (8H, m) Example 230 5 Ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate from ethyl 5-[2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7 ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCl 3 , 6): 1.24 (3H, t, J=711z), 1.34-1.50 (5H, m), 1.54 (21H, m), 2.19 (2H, t, J=7Hz), 2.37 (2H, m), 3.02 (211, q, J=7Hz), 3.71 (111, t, J=5Hz), 4.10 (211, q, 10 J=7Hz), 4.86 (2H, d, J=5Hz), 5.97 (1H, d, J=5Hz), 6.60 (111, d, J=5Hz), 7.88 (1H, m), 8.55 (111, m), 8.79 (111, m) Example 231 To a solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 15 yl]pentanoic acid (50 mg) in N,N-dimethylfornamide (1 mL) was added 1,1 carbonyldiimidazole (33.6 mg) at ambient temperature. After 1 hour stirring, to the mixture was added methanesulfonamide (19.7 mg) and 1,8-diazabicyclo[5.4.0]undec-7 ene (31.6 mg). The mixture was heated at 50'C for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 1N 20 hydrogen chloride and was extracted with ethyl acetate. The organic layer was washed with water 3 times and brine, dried over magnesium sulfate, and evaporated in vacuo to give an yellow solid. The residue was crystallized from IPE to give yellow solid (45 mg). The solid was recrystallized from ethanol to give N-{5-[4-(3-cyanophenyl)-7-ethyl-2 methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoyl}methanesulfonamide (25 mg,) as an 25 yellow solid. N-{5-[4-(3-Cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl]pentanoyl}methanesulfonamide NMR (CDCl 3 , 6): 1.33-1.61 (7H, m), 2.21 (211, t, J=8Hz), 2.40 (211, t, J=8Hz), 2.55 30 (311, s), 3.00 (211, q, J=8Hz), 3.29 (3H, s), 5.80 (1H, d, J=5Hz), 6.52 (111, d, J=5Hz), 7.58-7.67 (3H, m), 7.76 (1H, m), 7.86 (111, br s) MS (ESI*): m/z 439 (M+H) 160 WO 2004/063197 PCT/JP2003/017091 Example 232 To a solution of ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2 b]pyridazin-3-yl]pentanoate (45 mg) in tetrahydrofuran (1 mL) was added lithium borohydride (5 mg) in an ice-water bath. Then the reaction mixture was stirred at 5 ambient temperature. After 2 hours, another lithium borohydride (5 mg) was added therein and was stirred overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and was evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate = 1-1) to give 3-[7-ethyl-3-(6-hydroxyhexyl)-2-methylpyrrolo[1,2-b]pyridazin-4 10 yl]benzonitrile (26 mg, 64.5%) as an yellow oil and 6-{4-[3-(aminomethyl)phenyl]-7 ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}-1-hexanol (13 mg, 31.9%) as a yello solid. 3-[7-Ethyl-3-(6-hydroxyhexyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile NMR (CDCl 3 , 8): 1.15-1.53 (11H, m), 2.32-2.41 (2H, m), 2.56 (3H, s), 3.01 (2H, q, 15 J=8Hz), 3.58 (2H, br t, J=8Hz), 5.58 (11, br t, J=8Hz), 5.79 (1H, d, J=5Hz), 6.51 (1H, d, J=5Hz), 7.57-7.63 (2H, m), 7.65 (1H, br s), 7.75 (1H, m) MS (ESI*): m/z 362 (M+H) ' 6-{4-[3-(Aminomethyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}-1-hexanol 20 NMR (CDCI 3 , 6): 1.03-1.43 (11H, m), 2.41 (2H, t, J=8Hz), 2.55 (3H, s), 3.01 (2H, q, J=8Hz), 3.39-3.61 (2H, m), 3.88-4.04 (21H, m), 4.25 (2H, br s), 5.31 (1H, d, J=5Hz), 6.49 (1H, d, J=5Hz), 7.28-7.40 (311, m), 7.51 (1H, t, J=8Hz) MS (ESI*): m/z 366 (M+H) 25 Example 233 To a suspension of 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2 b]pyridazin-3-yl}hexanoic acid (590 mg) in water (3 mL) was added 1N sodium hydroxide (1.5 mL) at ambient temperature. After 5 hours, the mixure became clear solution. The solution was filtered through membrane filter, washed with water (0.4 mL 30 x3), and was freezedried for 15 hours to give 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2 methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid sodium salt (612 mg, 98.2%) as a pale yellow powder. 161 WO 2004/063197 PCT/JP2003/017091 6-{4-[4-(Aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid sodium salt NMR (DMSO-d 6 , 6): 1.10-1.15 (2H, m), 1.20-1.40 (7H, m), 1.74 (2H, t, J=8Hz), 2.25-2.38 (211, m), 2.50 (3H, s), 2.91 (2H, q, J=8Hz), 5.72 (1H, d, J=5Hz), 6.50 5 (1H, d, J=5Hz), 7.39-7.46 (3H, m), 7.97 (2H, d, J=8Hz), 8.26 (1H, br s) Example 234 A solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid (100 mg), triethylamime (29.4 mg), and diphenylphosphoryl azide (79.9 10 mg) in tert-butanol (2 mL) was heated at 80'C for 8 hours. The cooled reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate = 3-1) to give tert-butyl 4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2 15 b]pyridazin-3-yl]butylcarbamate (28 mg, 23.4%) as an yellow oil. tert-Butyl 4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl]butylcarbamate NMR (CDCl 3 , 5): 1.27-1.47 (14H, m), 2.34-2.45 (2H, m), 2.55 (31, s), 2.91-3.02 20 (4H, m), 4.39 (1H, br s), 5.79 (1H, d, J=5Hz), 6.51 (11H, d, J=5Hz), 7.56-7.67 (311, m), 7.75 (1H, m) MS (ESI'): m/z 433 (M+H) Example 235 25 To tert-butyl 4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl]butylcarbamate (25 mg) was added 4N hydrogen chloride in ethyl acetate (1 mL) at ambient temperature. After 1 hour, the mixture was evaporated in vacuo. The residue was triturated with isopropyl ether to give 3-[3-(4-aminobutyl)-7-ethyl-2 methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile hydrochloride as dark green amorphous 30 (18 mg). 3-[3-(4-Aminobutyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile hydrochloride 162 WO 2004/063197 PCT/JP2003/017091 NMR (CDC1 3 , 5): 1.27-1.47 (14H, m), 2.34-2.45 (2H, m), 2.55 (3H, s), 2.91-3.02 (411, m), 4.39 (1H, br s), 5.79 (111, d, J=5Hz), 6.51 (111, d, J=5Hz), 7.56-7.67 (3H, m), 7.75 (11, m) MS (ESI*): m/z 333 (M+H) 5 Example 236 To lithium chloride (16.5 mg) was added a solution of ethyl 5-[4-(2-chloro-4 pyridinyl)-7-ethyl-2 methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (65 mg) and tributyl(vinyl)stannane (56.7 10 mg) in dioxane (1 mL) and tetrakis(triphenylphosphine)palladium(0) (1.9 mg). The mixture was refluxed. After 4 hours, tributyl(vinyl)stannane (50 mg) and tetrakis(triphenylphosphine)palladium(O) (1.9 mg) was added. After refluxed over night, the reaction mixture was quenched with potassium fluoride (1.8 mmol) in H20. The mixture was filtered through Celite and was washed with ethyl acetate. The organic layer 15 was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 50 mL) eluted with hexane-ethyl acetate = 5-1 and 3-1 to give ethyl 5-[7-ethyl-2 methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (18 mg, 28.3%) as an yellow oil. 20 Ethyl 5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate NMR (CDCl 3 , 6): 1.15-1.70 (10H, m), 2.18 (211, t, J=8Hz), 2.36-2.46 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=8Hz), 4.08 (2H, q, J=8Hz), 5.54 (111, d, J=lOHz), 5.86 (1H, d, J=5Hz), 6.25 (1H, d, J=16Hz), 6.51 (1H, d, J=5Hz), 6.87 (1H, dd, J=16, 10Hz), 25 7.16 (1H, dd, J=6, 1Hz), 7.33 (1H, br s), 8.70 (111, d, J=6Hz) MS (ESI*): m/z 392 (M+H) The following compounds were obtained in substantially the same manner as that of Example 236. 30 Example 237 Ethyl 5-{ 4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl}pentanoate 163 WO 2004/063197 PCT/JP2003/017091 NMR (CDCl 3 , 6): 1.23 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.42 (3H, t, J=7Hz), 1.40-1.60 (4H, m), 2.20 (2H, t, J=7Hz), 2.38-2.52 (2H, m), 2.56 (3H, s), 3.03 (2H, q, J=7Hz), 3.96 (2H, q, J=7Hz), 4.09 (2H, q, J=7Hz), 4.34 (1H4, d, J=2Hz), 4.76 (iH, d, J=2Hz), 5.87 (1H, d, J=4Hz), 6.52 (1H, d, J=4Hz), 7.89 (1H, m), 8.53 (1H1, 5 d, J=2Hz), 8.93 (1H, d, J=2Hz) MS: (m/z) 436 (M+H) Example 238 Ethyl 5-[7-ethyl-2-methyl-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate 10 NMR (CDCl 3 , 8): 1.22 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.40-1.65 (4H, m), 2.18 (2H, t, J=7Hz), 2.40-2.53 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7Hz), 4.08 (2H, q, J=7Hz), 5.43 (1, d, J=11Hz), 5.88 (1H, d, J=4HIz), 5.89 (1H, d, J=18Hz), 6.52 (1H1, d, J=4Hz), 6.71-6.83 (1H, dd, J=11 Hz, 18H1z), 7.73 (1H, m), 8.47 (1H, d, J=2Hz), 8.68 (1H, d, J=2Hz) 15 Example 239 Ethyl 5-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate NMR (CDCl 3 , 6): 1.22 (3H, t, J=7nz), 1.38 (3H, t, J=7H1z), 1.40-1.60 (4H, m), 2.17 20 (2H, t, J=7Hz), 2.52-2.65 (2H, m), 3.04 (2H, q, J=7Hz), 3.46 (3H, s), 4.08 (2H, q, J=7Hz), 4.63 (2H, s), 5.43 (1H4, d, J=11H1z), 5.88 (111, d, J=18H1z), 5.91 (1H-, d, J=4Hz), 6.58 (1, d, J=4Hlz), 6.71-6.83 (1H, dd, J=11 Hz, 18Hz), 7.75 (111, m), 8.49 (1H, d, J=2Hz), 8.71 (iH, d, J=2Hz) 25 Example 240 Ethyl 5-[4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2 b]pyridazin-3-yl]pentanoate NMR (CDCl 3 , 8): 1.22 (3n, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.42 (3H, t, J=7Hz), 1.40-1.63 (4H, m), 2.18 (2H, t, J=7Hz), 2.51-2.63 (2H, m), 3.03 (2H, q, J=7Hz), 30 3.47 (3n, s), 3.93 (2H, q, J=7Hz), 4.12 (2H, q, J=7Hz), 4.35 (1H, d, J=3Hz), 4.63 (2H, s), 4.77 (1H, d, J=3nz), 5.92 (1H, d, J=4Hz), 6.58 (1H, d, J=4Hz), 7.92 (1H, m), 8.53 (1H, d, J=2Hz), 8.93 (1H, d, J=2Hz) 164 WO 2004/063197 PCT/JP2003/017091 MS (ESI*): m/z 466 Example 241 Ethyl 5-[7-ethyl-2-phenyl-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-blpyridazin-3-yl]pentanoate 5 NMR (CDCl 3 , 6): 1.15-1.31 (711, m), 1.37 (3H, t, J=7Hz), 1.87 (2H, t, J=7Hz), 2.43 (2H, m), 3.01 (2H, q, J=7Hz), 3.98 (2H, q, J=7Hz), 5.45 (1H, d, J=11Hz), 5.88 (111, d, J=18Hz), 5.98 (1H, d, J=5Hz), 6.62 (1H, d, J=5Hz), 6.78 (1H, dd, J=11 and 18Hz), 7.44-7.55 (5H, m), 7.81 (1H, m), 8.55 (1H, m), 8.72 (1H, m) 10 Example 242 A solution of 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2 b]pyridazin-3-yl]pentanoic acid (50 mg) in dioxane (1.5 mL) in a sealed tube was added 50% dimethylamine in water (1.5 mL). The mixture was heated at 175"C overnight. The cooled reaction mixture was concentrated in vacuo. The residue was dissolved in water 15 (1 mL) and the pH was adjusted to 7-8. The mixture was extracted with chloroform three times. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 50 mL) eluted with chloroform-ethyl acetate = 1-1 and chloroform-methanol = 20-1 to give yellow oil (43 mg). The oil was crystallized from isopropyl ether to give 5-{4-[2-(dimethylamino) 20 4-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid as an yellow solid (27 mg, 52.8%). 5-{4-[2-(Dimethylamino)-4-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl}pentanoic acid 25 NMR (CDCl 3 , 8): 1.36 (3H, t, J=8Hz), 1.40-1.65 (411, m), 2.25 (2H, t, J=8Hz), 1.86 1.96 (2H, m), 2.55 (3H, s), 3.00 (211, q, J=8Hz), 4.08 (211, q, J=8Hz), 5.54 (1H, d, J=lOHz), 5.86 (1H, d, J=5Hz), 6.25 (1H, d, J=16Hz), 6.51 (1H, d, J=5Hz), 6.87 (1H, dd, J=16, 10Hz), 7.16 (111, dd, J=6, 1Hz), 7.33 (1H, br s), 8.70 (1H, d, J=6Hz) 30 Example 243 To a suspension of 7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2 b]pyridazine-3-carbaldehyde (40 mg) in ethanol (1 mL) was added 2-aminoethanol (11.8 165 WO 2004/063197 PCT/JP2003/017091 mg), sodium cyanoborohydride (12.1 mg), and acetic acid (1 drop) in an ice-water bath. After 10 minutes, the mixture was stirred at ambient temperature. After 2 hours, sodium cyanoborohydride (11.8 mg) was added and the reaction mixture was acidified to pH4 with acetic acid (5 drops). After stirring overnight, the reaction mixture was partitioned 5 between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, water, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (chloroform-methanol = 10-1) to give'2-({ [7-chloro 4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methyl}amino)ethanol as pale yellow oil (21 mg). 10 2-({ [7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3 yl]methyl}amino)ethanol NMR (CDCl 3 , 6): 1.43 (6H, d, J=7Hz), 2.65 (211, t, J=7Hz), 3.42 (1H, m), 3.53 (2H, t, J=7Hz), 3.59 (2H, s), 6.01 (1H, d, J=5Hz), 6.77 (1H, d, J=5Hz), 7.14-7.24 (2H, 15 m), 7.35-7.44 (2H, m) MS (ESI*): m/z 362 (M+H) Example 244 To a solution of [4-(4-fluorophenyl)-2-methylpyrrolo 20 [1,2-b]pyridazin-3-yl]methanol (505 mg) and triethylamine (997 mg) in dichloromethane (4 mL) and dimethyl sulfoxide (2 mL) was added sulfur trioxide pyridine complex (941 mg) in an ice-water bath under nitrogen. After 30 minutes, the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated to about 1/3 volume. The mixture was partitioned between ethyl acetate and water. The organic layer 25 was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 30 mL) eluted with hexane-chloroform = 3-1 and 2-1 to give 4-(4-fluorophenyl)-2 methylpyrrolo[1,2-b]pyridazine-3-carbaldehyde as an yelow solid (340 mg, 67.9%). 30 4-(4-Fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazine-3-carbaldehyde NMR (CDCI 3 , 8): 2.77 (3H, s), 6.50 (1H, m), 6.86 (1H, m), 7.20-7.30 (2H, m), 7.44 7.54 (2H, m), 8.89 (1H, br s), 9.79 (1H, s) 166 WO 2004/063197 PCT/JP2003/017091 Example 245 A mixture of ethyl 4-(4-fluorophenyl)-2-isopropyl-7-vinylpyrrolo[1,2 b]pyridazine-3-carboxylate (8.9 g) and 10% palladium on carbon (900 mg) in ethanol (180 mL) was stirred under hydrogen atomosphere (3.5 atm) at ambient temperature. 5 After 10 hours, the mixture was stood overnight. To the mixture was added 10% palladium on carbon (900 mg) and was stirred under hydrogen atomosphere (3.5 atm) at ambient temperature. After 12 hours, the mixture was stood overnight. To the mixture was added 10% palladium on carbon (900 mg) and was stirred under hydrogen atomosphere (3.5 atm) at ambient temperature for 8 hours. The mixture was filtered 10 through Celite. The filtrate was concentrated in vacuo to give ethyl 7-ethyl-4-(4 fluorophenyl)-2-isopropylpyrrolo [1,2-b]pyridazine-3-carboxylate as an yellow oil (9.0 g, 100.5%). Ethyl 7-ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate 15 NMR (CDCI 3 , 5): 0.96 (3H, t, J=8Hz), 1.38 (3H, t, J=8Hz), 3.05 (2H, q, J=8Hz), 4.01 (2H, q, J=8Hz), 6.27 (1H, d, J=5Hz), 6.64 (1H, d, J=5Hz), 7.10-7.19 (2H, m), 7.41-7.49 (2H, m) MS (ESI*): m/z 362 (M +H) 20 The following compounds were obtained in substantially the same manner as that of Example 245. Example 246 5-[7-Ethyl-4-(5-ethyl-3-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid from 5-[7-ethyl-2-methyl-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic 25 acid NMR (CDCl 3 , 8): 1.30 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.45-1.65 (4H, m), 2.22 (2H, m), 2.35-2.50 (2H, m), 2.56 (3H, s), 2.75 (2H, q, J=7Hz), 3.00 (2H, q, J=7Hz), 5.84 (1H, d, J=4Hz), 6.52 (1H, d, J=4Hz), 7.57 (1H, s), 8.42 (1H, d, J=2Hz), 8.53 (1H, d, J=2Hz) 30 MS (ESI*): m/z 366 (M+H), MS (EST): m/z 364 Example 247 5-[7-Ethyl-4-(5-ethyl-3-pyridinyl)-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 167 WO 2004/063197 PCT/JP2003/017091 yl]pentanoic acid NMR (CDCl 3 , 6): 1.30 (3H, t, J=:7Hz), 1.37 (3H, t, J=7Hz), 1.45-1.64 (4H, m), 2.17 (2H, m), 2.45-2.67 (2H, m), 2.73 (2H, q, J=7Hz), 3.04 (2H, q, J=7Hz), 3.45 (3H, s), 4.62 (2H, m), 5.89 (1H, d, J=4H1z), 6.58 (11H, d, J=4Hz), 7.59 (111, s), 8.44 (1H, 5 s), 8.54 (11H, s) MS (ESI*): m/z 396 Example 248 Ethyl 5-[7-ethyl-4-(5-ethyl -3-pyridinyl)-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate 10 NMR (CDCl 3 , 6): 1.04-1.23 (7H, m), 1.32 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.86 (2H, t, J=7Hz), 2.42 (2H, m), 2.74 (2H, q, J=7Hz), 3.01 (2H, q, J=7Hz), 3.99 (2H, q, J=7Hz), 5.97 (1H, d, J=5Hz), 6.62 (1H, d, J=5Hz), 7.45-7.53 (5H, m), 7.60 (1H, m), 8.50 (1H, m), 8.56 (1H, m) 15 Example 249 To a solution of 3-(7-ethyl-2-neopentylpyrrolo[1,2-b]pyridazin-4-yl)benzamide (35 mg) in ethanol (1 mL) was added water (0.2 mL) and potassium hydroxide (68.9 mg) at ambient temperature. The reaction mixture was heated at 60'C. After 2 hours, potassium hydroxide (100 mg) was added. After 5 hours, potassium hydroxide (100 mg) 20 was added. After 12 hours, the mixture was acidified with IN hydrogen chloride. The precipitate was filtered, washed with water and ethyl acetate to give 3-(7-ethyl-2 neopentylpyrrolo [1,2-b]pyridazin-4-yl)benzoic acid as an yellow solid (19 mg, 54.1%). 25 3-(7-Ethyl-2-neopentylpyrrolo[1,2-bjpyridazin-4-yl)benzoic acid NMR (CDCI 3 , 6): 1.05 (9H, s), 1.39 (3H, t, J=8Hz), 2.69 (211, s), 3.04 (211, q, J=8Hz), 6.42 (1H, s), 6.54 (1H, d, J=5Hz), 6.65 (11H, d, J=5Hz), 7.62 (111, t, J=8Hz), 7.97 (1H, d, J=8Hz), 8.21 (1H, d, J=8Hz), 8.46 (1H, br s) MS (ESI*): m/z 337 (M+H) 30 The following compound was obtained in substantially the same manner as that of Example 249. 168 WO 2004/063197 PCT/JP2003/017091 Example 250 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid NMR (CDCl 3 , 5): 1.44 (3H, t, J=8Hz), 3.11 (2H, q, J=8Hz), 6.56 (1H, m), 6.61 (1H, d, J=5Hz), 6.72 (1H, d, J=5Hz), 7.03 (1H, br s), 7.07 (1H, d, J=5Hz), 7.55-7.69 5 (2H, m), 8.03 (1H, br d, J=8Hz), 8.23 (1HB, br d, J=8Hz), 8.52 (11H, br s) Example 251 A solution of ethyl 5-{4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2 methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate (190 mg) in methanol (5 mL) and IN 10 hydrochloric acid (5 mL) was stirred at ambient temperature for 2 hours. The solution was diluted with brine and extracted with chloroform. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1 - 2:1) to give ethyl 5-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2 15 b]pyridazin-3-yl]pentanoate as an yellow oil (160 mg). Ethyl 5-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl]pentanoate NMR (CDCl 3 , 8): 1.24 (3H, t, J=7Hz), 1.38 (3H, t, J=7Hz), 1.40-1.60 (4H, m), 2.19 20 (2H, t, J=7Hz), 2.36-2.47 (2H, m), 2.57 (3H, s), 2.70 (3H, s), 3.02 (2H, q, J=7Hz), 4.08 (2H, q, J=7Hz), 5.81 (1H, d, J=4Hz), 6.53 (11H, d, J=4Hz), 8.23 (1H, m), 8.78 (1H, d, J=2Hz), 9.23 (1H, d, J=2Hz) MS: (m/z) 408 (M+H) 25 The following compound was obtained in substantially the same manner as that of Example 251. Example 252 Ethyl 5-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 y]pentanoate 30 NMR (CDCl 3 , 8): 1.24 (3H, t, J=7Hz), 1.38 (3H, t, J=7Hz), 1.40-1.59 (4H, m), 2.17 (2H, t, J=7Hz), 2.50-2.63 (21H, m), 2.70 (311, s), 3.03 (2H, q, J=7Hz), 3.46 (3H, s), 4.12 (21H, q, J=7Hz), 4.63 (2H, s), 5.86 (11H, d, J=4Hz), 6.59 (111, d, J=4Hz), 8.26 169 WO 2004/063197 PCT/JP2003/017091 (1H, m), 8.79 (1H, d, J=2Hz), 9.24 (1H, d, J=2Hz) MS (ESI*): m/z 438 Example 253 5 To a solution of ethyl 5-{4-(2-chloro-4-pyridinyl)-7-ethyl-2 [(methylthio)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate (139 mg) in tetrahydrofuran (4 mL) and water (1 mL) was added oxone (287 mg) and the mixture was stirred at ambient temperature for 4 hours. The solution was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with saturated 10 sodium bicarbonate solution, sodium thiosulfate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1 - 1:1) to give ethyl 5-{4-(2-chloro-4-pyridinyl)-7-ethyl-2-[(methylsulfonyl)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoate as an yellow oil (124 mg). 15 Ethyl 5-{ 4-(2-chloro-4-pyridinyl)-7-ethyl-2-[(methylsulfonyl)methyl]pyrrolo(1,2 b]pyridazin-3-yl}pentanoate NMR (CDCI 3 , 8): 1.24 (31H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.40-1.63 (4H, m), 2.21 (2H, t, J=7Hz), 2.57-2.68 (211, m), 3.02 (2H, q, J=7Hz), 3.12 (3H, s), 4.10 (2H, q, 20 J=7Hz), 4.53 (2H, s), 5.98 (1H, d, J=4Hz), 6.68 (1H, d, J=4Hz), 7.27 (1H, m), 7.38 (1H, s), 8.56 (111, d, J=5Hz) Example 254 A mixture of ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2 25 b]pyridazin-3-yl]pentanoate (167 mg) and copper(I) cyanide (37 mg) in 1-methyl-2 pyrrolidinone (3 mL) was stirred at 170"C for 4 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl 30 acetate (20:1 - 5:1) to give ethyl 5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2 b]pyridazin-3-yl]pentanoate as an yellow oil (88 mg). Ethyl 5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl]pentanoate 170 WO 2004/063197 PCT/JP2003/017091 NMR (CDCl 3 , 6): 1.24 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.40-1.62 (4H, m), 2.21 (2H, t, J=7Hz), 2.35-2.47 (2H, m), 2.57 (3H, s), 3.02 (2H, q, J=7Hz), 4.12 (2H, q, J=7Hz), 5.79 (1H, d, J=4Hz), 6.54 (1H, d, J=4Hz), 7.98 (iH, m), 8.80 (1H, d, J=2Hz), 8.97 (1H, d, J=2Hz) 5 MS (ESI'): m/z 391. The following compounds were obtained in substantially the same manner as that of Example 254. Example 255 10 5-[4-(5-Cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 8): 1.37 (3H, t, J=7Hz), 1.40-1.67 (4H, m), 2.28 (2H, m), 2.37-2.47 (2H, m), 2.57 (3H, s), 3.01 (2H, q, J=7Hz), 5.80 (iH, d, J=4H1z), 6.55 (1H, d, J=4Hz), 8.01 (1H, s), 8.81 (iH, br), 8.98 (1H, br) 15 Example 256 Ethyl 5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate NMR (CDCl 3 , 6): 1.23 (3H, t, J=7Hz), 1.37 (3H, t, J=7Hz), 1.40-1.60 (4H, m), 2.19 (2H, t, J=7Hz), 2.49-2.60 (2H, m), 3.04 (2H, q, J=7Hz), 3.46 (3H, s), 4.12 (2H, q, 20 J=7Hz), 4.63 (2H, s), 5.84 (1H, d, J=4Hz), 6.63 (iH, d, J=4Hz), 8.02 (1H, m), 8.83 (111, d, J=2Hz), 8.98 (1H, d, J=2Hz) Example 257 5-[4-(5-Cyano-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 25 yl]pentanoic acid NMR (CDCl 3 , 6): 1.38 (31, t, J=7Hz), 1.40-1.65 (4H, m), 2.27 (21, t, J=71z), 2.48 2.64 (2H, m), 3.03 (2H, q, J=7Hz), 3.46 (3H, s), 4.64 (2H, s), 5.84 (1H, d, J=4Hz), 6.62 (1H, d, J=4Hz), 8.03 (1H, s), 8.82 (1H, s), 8.97 (114, s) 30 Example 258 5-[4-(5-Cyano-3-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid NMR (CDCl 3 , 8): 1.06-1.24 (4H, m), 1.36 (3H, t, J=7Hz), 1.94 (2H, t, J=714z), 2.38 171 WO 2004/063197 PCT/JP2003/017091 (2H, m), 2.99 (2H, q, J=71Hz), 5.88 (1H, d, J=5Hz), 6.64 (1H, d, J=5Hz), 7.44 7.52 (511, m), 8.06 (1H, s), 8.87 (11H, s), 8.98 (1H, s) MS (ESI*): m/z 425 (M+H) 5 Example 259 To a suspension of lithium aluminum hydride (98.8 mg) in tetrahydrofuran (10 mL) was added ethyl 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo(1,2-b]pyridazin-3 yl]pentanoate (600 mg) in tetrahydrofuran (10 mL) under ice-water cooling and the mixture was stirred at 0*C for 2 hours. The reaction was quenched with saturated 10 potassium sodium tartrate solution and the insolubles were filtereed off and washed with ethyl acetate. The filtrates were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1 - 2:1) to give 5-[4-(3 chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol as an yellow oil 15 (478 mg). 5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol NMR (CDCl 3 , 8): 0.90-1.22 (6H, m), 1.27 (11, t, J=7Hz), 1.36 (31, t, J=7Hz), 2.37 2.47 (211, m), 3.02 (2H, q, J=7Hz), 3.29-3.41 (2H, n), 5.97 (1H, d, J=4Hz), 6.61 20 (1H, d, J=4Hz), 7.32 (111, m), 7.40-7.55 (8H, m) Example 260 To a solution of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 yl]-1-pentanol (63.0 mg) and triethylamine (22.8 mg) in dichloromethane (3 mL) was 25 added methanesulfonyl chloride (18.9 mg) under ice-water cooling and the mixture was stirred at 0 0 C for 1 hour. The solution was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was added to sodium cyanide (14.7 mg) in dimethylformamide (2 mL) and the mixture was stirred at 60'C for 5 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, 30 washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1 - 5:1) to give 6-[4-(3-chlorophenyl)-7-ethyl-2 phenylpyrrolo[1,2-b] 172 WO 2004/063197 PCT/JP2003/017091 pyridazin-3-yl]hexanenitrile as an yellow oil (58.5 mg). 6-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]hexanenitrile NMR (CDCI 3 , 8): 1.00-1.15 (4H, m), 1.17-1.28 (211, m), 1.36 (3H, t, J=7Hz), 1.98 5 (2H, t, J=7Hz), 2.38-2.47 (2H, m), 3.03 (2H, q, J=7Hz), 5.99 (1H, d, J=4Hz), 6.62 (11, d, J=4Hz), 7.32 (111, m), 7.38-7.56 (8H, m) MS (ESI*): m/z 428 Example 261 10 A mixture of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 yl]-l-pentanol (65 mg), trimethyloxonium tetrafluoroborate (27.5 mg) and 2,6-di-t-butyl 4-methylpyridine (47.8 mg) in 1,2-dichloroethane (3 mL) was stirred at ambient temperature for 4 hours. The solution was washed with water, 1N hydrochloric acid, water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, 15 and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1 - 5:1) to give 4-(3-chlorophenyl) 7-ethyl-3-(5-methoxypentyl)-2-phenylpyrrolo[1,2-b]pyridazine as an yellow oil (60 mg). 4-(3-chlorophenyl)-7-ethyl-3-(5-methoxypentyl)-2-phenylpyrrolo[1,2-b]pyridazine 20 NMR (CDCI 3 , 8): 00.90-1.32 (6H, m), 1.36 (3H, t, J=7Hz), 2.37-2.47 (2H, m), 3.03 (2H, q, J=7Hz), 3.08 (2H, t, J=7Hz), 3.31 (3H, s), 5.97 (1H, d, J=4Hz), 6.61 (1H, d, J=4Hz), 7.27-7.33 (1H, m), 7.38-7.53 (8H, m) MS (ESI*): m/z 433 25 Example 262 To a solution of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 yl]-1-pentanol (55 mg) and triethylamine (19.9 mg) in dichloromethane (3 mL) was added methanesulfonyl chloride (16.5 mg) under ice-water cooling and the mixture was stirred at 0*C for 1 hour. The solution was washed with brine, dried over magnesium 30 sulfate, and evaporated in vacuo. To the residue in 1,2-dichloroethane (3 mL) was added 2 M dimethylamine in tetrahydrofuran (3 mL) and the mixture was stirred at 60*C for 120 hours. The solution was diluted with chloroform, washed with brine, dried over 173 WO 2004/063197 PCT/JP2003/017091 magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1 - 5:1) to give 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N,N-dimethyl 1-pentanamine as an yellow oil (38 mg). 5 N-{5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentyl}-N,N dimethylamine NMR (CDCI 3 , 6): 0.86-0.97 (2H, m), 1.02-1.15 (4H, m), 1.36 (3H, t, J=7Hz), 1.97 2.04 (2H, m), 2.11 (6H, s), 2.37-2.47 (2H, m), 3.02 (2H, q, J=71z), 5.97 (1H, d, 10 J=4Hz), 6.61 (1H, d, J=4Hz), 7.31 (1H, n), 7.39-7.54 (8H, m) MS (ESI'): m/z 446 Example 263 To a stirred solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2 15 b]pyridazin-3-yl]pentanoic acid (60 mg) in dichloromethane (2 ml) was added 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35.3 mg) and 2 animopyridine (20 mg) and the reaction mixture was stirred for 10 minutes. 4 Dimethylaminopyridine (2 mg) was added and the reaction mixture was stirred at room temperature for 15 hours. The mixture was diluted with water and extracted with ethyl 20 acetate. The organic layer was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of ethyl acetate and n-hexane (1:2) to give 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-(2 pyridinyl)pentanamide(55.7mg) as an yellow amorphous. 25 5-[4-(3-Cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-(2 pyridinyl)pentanamide mp: 67-70*C NMR (CDC13, 8): 1.12 (2H, quintet, J=7Hz), 1.30 (2H, quintet, J=7Hz), 1.36 (3H, t, 30 J=7Hz), 1.95 (2H, t, J=7Hz), 2.43 (2H, q, J=7Hz), 3.02 (2H, q, J=7Hz), 5.90 (1H, d, J=4Hz), 6.62 (1H, d, J=4Hz), 7.00-7.05 (1H, m.), 7.43-7.54 (5H, m), 7.59-7.77 (6H, m), 8.11 (1H, d, J=7.5Hz), 8.24 (1H, d, J=4Hz) MS: (m/z) 499 (M+), 45 (bp) 174 WO 2004/063197 PCT/JP2003/017091 The following compounds were obtained in substantially the same manner as that of Example 263. Example 264 5 5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-(2 pyridinyl)pentanamide NMR (CDCl 3 , 5): 1.15 (2H, quintet, J=7Hz), 1.24(2H, quintet, J=7Hz), 1.36(3H, t, J=7Hz), 1.91(2H, t, J=71z), 2.45(2H, t, J=7Hz), 3.00(2H, q, J=7Hz), 5.97(1H, d, J=5Hz), 6.60(1H, d, J=4Hz), 7.00(1H, t, J=71Hz), 7.30(1H, s), 7.38-7.53(7H, m), 10 7.65-7.73(2H, m), 8.11(1H, d, J=7Hz), 8.25(1H, d, J=5Hz) MS: (m/z) 509 (M++H), 74 (bp) Example 265 N-{5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 15 yl]pentanoyl}methanesulfonamide NMR (CDCI 3 , 5): 1.08 (2H, quintet, J=7Hz), 1.23 (211, quintet, J=7Hz), 1.36 (3H, t, J=7Hz), 1.85 (211, t, J=7Hz), 2.44 (211, t, J=7Hz), 3.02 (2H, q, J=7Hz), 3.21 (3H, s), 5.99 (1H, d, J=41Hz), 6.62 (11, d, J=41Hz), 7.30-7.33 (11H, m), 7.43-7.55 (8H, m) 20 Example 266 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-(2 pyridinyl)pentanamide NMR (CDCI 3 , 5): 1.12 (21H, quintet, J=7Hz), 1.27 (21H, quintet, J=7Hz), 1.36 (3H, t, 25 J=7Hz), 1.97 (2H, t, J=7Hz), 2.45 (211, t, J=7Hz), 3.01 (211, q, J=7Hz), 5.95 (11H, d, J=5Hz), 6.63 (111, d, J=4Hz), 7.01 (1H, t, J=7Hz), 7.31 (111, d, J=7Hz), 7.41 7.53 (611, m), 7.68 (1H, ddd, J=7,7,lHz), 7.77 (1H, s), 8.12 (1H, d, J=7.5Hz), 8.24 (111, d, J=5Hz), 8.53 (1H, d, J=6Hz) MS: (m/z) 510 (M++H), 80 (bp) 30 Example 267 N-{5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 175 WO 2004/063197 PCT/JP2003/017091 yl]pentanoyl}methanesulfonamide mp: 124-125'C NMR (CDCI3, 8): 1.37 (3H, t, J=7Hz), 1.43-1.49 (2H, m), 1.55-1.65 (2H, m), 2.23 (2H, t, J=7Hz), 2.34-2.48 (2H, m), 2.55 (3H, s), 3.01 (2H, q, J=7Hz), 3.28 (3H, s), 5 5.87 (1H, d, J=4Hz), 6.53 (1H, d, J=4Hz), 7.09 (1H, s), 7.40 (1H, s), 8.53 (1H, s), 8.77 (1H, s) MS: (m/z) 493(M+), 491 (M+-2), 137 (bp) Example 268 10 To a solution of ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2 (hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (100.0 mg) and (bromomethyl)benzene (111 mg) in N,N-dimethylformamide (1 mL) was added 60% sodium hydride (17.4 mg) under an ice-bath. After stirring for 2.5 hour, the reaction was quenched by adding IN hydrochloric acid (1 mL), and the mixture was partitioend 15 between ethyl acetate (10 mL) and water (5 mL). The organic layer was washed with IN hydrochloric acid (5 mL), water (5 mL, three times), and brine, dried over magnesium sulfate, and evaporated. Flash silica gel column chromatography eluting with ethyl acetate-hexane = 1/40 to 20/40 afforded ethyl 5-[2-[(benzyloxy)methyl]-4-(5-bromo-3 pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow gum (47.7 mg, 20 39.9%). Ethyl 5-[2-[(benzyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin 3-yl]pentanoate NMR (CDCI 3 , 6): 1.23 (311, t, J=7Hz), 1.34-1.48 (511, m), 2.09 (2H, m), 2.53 (2H, m), 25 3.04 (211, q, J=7Hz), 4.07 (2H, J=7Hz), 4.65 (2H, s), 4.72 (2H, s), 5.90 (1H, d, J=5Hz), 6.60 (1H, d, J=5Hz), 7.29-7.38 (5H, m), 7.86 (111, s), 8.54 (111, m), 8.77 (1H, m) The following compound was obtained in substantially the same manner as that of 30 Example 268. Example 269 Ethyl 5-(4-(5-bromo-3-pyridinyl)-2-{ [(4-cyanobenzyl)oxy]methyl}-7-ethylpyrrolo[1,2 b]pyridazin-3-yl)pentanoate 176 WO 2004/063197 PCT/JP2003/017091 NMR (CDCl 3 , 5): 1.23 (311, J=7Hz), 1.35-1.55 (7H, m), 2.12 (2H, t, J=7Hz), 2.57 (2H, m), 3.02 (2H, q, J=7Hz), 4.07 (2H, q, J=7H1z), 4.49 (211, s), 4.76 (2H, s), 5.93 (1H, d, J=7Hz), 6.62 (1H, d, J=7Hz), 7.48 (2H, d, J=8Hz), 7.65 (2H, d, J=8Hz), 7.86 (1H, m), 8.54 (11H, m), 8.78 (111, m) 5 Example 270 To a solution of ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2 (hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (200 mg) and triethylamine (65.9 mg) in dichloromethane (2 mL) was added methanesulfonyl chloride (54.7 mg) 10 under an ice-bath. After stirring for 1 hour, the reaction was quenched by adding iN hydrochloric acid (1 mL). The mixrure was partitioned between ethyl acetate (20 mL) and IN hydrochloric acid (5 mL). The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated to give ethyl 5-(4 (5-bromo-3-pyridinyl)-7-ethyl-2-{ [(methylsulfonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin 15 3-yl)pentanoate as an yellow gum (247 mg). Ethyl 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{ [(methylsulfonyl)oxy]methyl}pyrrolo[1,2 b]pyridazin-3-yl)pentanoate NMR (CDCI 3 , 8): 1.22 (3H, t, J=7Hz), 1.34-1.65 (711, m), 2.20 (211, t, J=7Hz), 2.55 20 (21H, m), 3.02 (2H, q, J=7Hz), 3.15 (31H, s), 4.07 (211, q, J=7Hz), 5.42 (2H, s), 5.99 (1H, d, J=5Hz), 6.68 (1H, d, J=5Hz), 7.87 (1H, m), 8.54 (1H, m), 8.81 (1H, m) Example 271 25 A mixture of ethyl 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2 { [(methylsulfonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate (50.0 mg), benzylamine (29.8 mg) in dichloromathane (1 mL) was stirred for 20 hour at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, and evaporated. Preparative thin layer 30 chromatography eluting with ethyl acetate-hexane = 1:2 afforded ethyl 5-[2 [(benzylamino)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 yl]pentanoate as an yellow gum (19.1 mg). 177 WO 2004/063197 PCT/JP2003/017091 Ethyl 5-[2-[(benzylamino)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2 b]pyridazin-3-yl]pentanoate NMR (CDCl 3 , 5): 1.23 (311, t, J=7Hz), 1.30-1.50 (7H, m), 2.13 (2H, t, J=7Hz), 2.42 (2H, m), 3.03 (2H, q, J=711z), 3.96 (4H, m), 4.09 (211, q, J=7Hz), 5.89 (1H, d, 5 J=5Hz), 6.57 (1H, d, J=511z), 7.23-7.42 (5H, m), 7.86 (1H, m), 8.53 (1H, m), 8.77 (1H, m) The following compound was obtained in substantially the same manner as that of Example 271. 10 Example 272 Ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2 b]pyridazin-3-yl]pentanoate NMR (CDCl 3 , 8): 1.23 (3H, t, J=7Hz), 1.31-1.56 (7H, m), 2.19 (2H, t, J=7Hz), 2.45 2.65 (611, m), 3.02 (211, q, J=7Hz), 3.60-3.75 (6H, m), 4.09 (21, q, J=711z), 5.88 15 (1H, d, J=5Hz), 6.57 (1H, d, J=5Hz), 7.89 (1H, m), 8.55 (1H, m), 8.78 (1H, m) Example 273 To a solution of (7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin 3-yl)methanol (40 mg) in N,N-dimethylformamide (1 mL) was added 40% sodium 20 hydride in oil (5.5 mg) in an ice-water bath. After 20 minutes, to the mixture was added 2-bromoethyl acetate (31 mg) at the temperature. After 15 minutes, the reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was 25 purified by p-TLC (hexane-ethyl acetate = 10-1) to give [7-chloro-4-(4-fluorophenyl)-2 isopropylpyrrolo[1,2-b]pyridazin-3-yl]methyl acetate as a pale yellow solid (42 mg). [7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methyl acetate NMR (CDCl 3 , 6): 1.41 (6H, d, J=8Hz), 2.06 (311, s), 3.21 (1H, m), 4.92 (2H, s), 6.14 30 (1H, d, J=5Hz), 6.72 (1H, d, J=5Hz), 7.13-7.24 (2H, m), 7.34-7.43 (21H, m) MS (ESI*): m/z 361 (M+H) 178 WO 2004/063197 PCT/JP2003/017091 The following compound was obtained in substantially the same manner as that of Preparation 20. Example 274 Ethyl {[7-ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3 5 yl]methoxy}acetate NMR (CDCl 3 , 6): 1.25 (3H, t, J=8Hz), 1.30-1.45 (9 H, m), 3.04 (2H, q, J=8Hz), 3.51 (1H, m), 3.97 (2H, s), 4.15 (2H, q, J=8Hz), 4.40 (2H, s), 6.06 (1H, d, J=5Hz), 6.56 (1H, d, J=5Hz), 7.11-7.22 (2H, m), 7.41-7.51 (2H, m) MS (ESI*): m/z 399 (M+H) 10 The following compound was obtained in substantially the same manner as that of Preparation 276. Example 275 Ethyl 2-(2-amino-2-oxoethyl)-4-(4-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazine-3 15 carboxylate NMR (CDCI 3 , 5): 0.84 (3H, t, J=7Hz), 1.38 (3H, t, J=7Hz), 3.06 (2H, q, J=7Hz), 3.96 (2H, q, J=7Hz), 4.02 (3H, s), 5.41 (1H, s, br), 6.09 (1H, s, br), 6.28 (1H, d, J=5Hz), 6.75 (1H, d, J=5Hz), 7.53 (2H, d, J=9Hz), 7.77 (2H, d, J=9Hz) MS (ESI*): m/z 753 (2M + H) 20 Example 276 A mixture of 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2 b]pyridazine-2-carboxylic acid (40.0 mg), pyrrolidine (10.8 mg), 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.1 mg), and 1 25 hydroxybenzotriazole (21.9 mg) in NN-dimethylformamide (1 mL) was stirred for 6 hour at room temperature. The mixture was partitioned between ethyl acetate (20 mL) and IN hydrochloric acid (10 mL). The organic layer was washed with water (10 mL) three times, saturated sodium bicarbonate (10 mL), and brine, dried, and evaporated to give 3-[7-ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinylcarbonyl)pyrrolo[1,2-b]pyridazin-4 30 yl]benzonitrile as an yellow solid (35.6 mg). 3-[7-Ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinylcarbonyl)pyrrolo[1,2-b]pyridazin-4 yl]benzonitrile 179 WO 2004/063197 PCT/JP2003/017091 NMR (CDCl 3 , 5): 1.38 (2H, m), 1.99 (4H, m), 3.07 (2H, q, J=7Hz), 3.23 (3H, s), 3.59 (2H, t, J=7Hz), 3.68 (2H, t, J=7Hz), 6.27 (1H, d, J=5Hz), 6.83 (1H, d, J=5Hz), 7.57-7.66 (3H, m), 7.79 (1H, m) MS (ESI*): m/z 423 (M+H) 5 Example 277 To a solution of 3-[7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid (40 mg) in NN-dimethylformamide (4 mL) was added 1-(3-dimethylaminopropyl)-3 ethylcarbodiimide hydrochloride (30 mg), 1-hydroxybenzotriazole (24 mg), and 2 10 aminoethanol (15 mg) at ambient temperature. After stirring overnight, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with water 3 times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel column chromatography (silica gel, 40 mL) eluted with chloroform-methanol = 50-1 and 20-1 to 15 give an yellow solid (42 mg). The solid was triturated with isopropyl ether to give 3-[7 ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]-N-(2-hydroxyethyl)benzamide as an yellow solid (35 mg). 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]-N-(2-hydroxyethyl)benzamide 20 NMR (CDCI 3 , 5): 1.43 (3H, t, J=8Hz), 2.39-2.49 (2H, m), 3.10 (2H, q, J=8Hz), 3.60 3.74 (2H, m), 3.80-3.94 (2H, m), 6.53-6.86 (4H, m), 7.00 (1H, s), 6.61 (1H, d, J=5Hz), 6.72 (1H, d, J=5Hz), 7.03 (1H, br s), 7.07 (111, d, J=5Hz), 7.55-7.65 (2H, m), 7.86-7.97 (2H, m), 8.17 (1H, br s) MS (ESI*): m/z 376 (M+H) 25 The following compounds were obtained in substantially the same manner as that of Example 283. Example 278 5-[4-(3-Cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N 30 methylpentanamide mp: 60'C NMR (CDCl3, 8): 1.02-1.12 (2H, m), 1.17-1.25 (2H, m), 1.36 (3H, t, J=7Hz), 1.73 (2H, t, J=7Hz), 2.40( 2H, t, J=7Hz), 2.71 (3H, d, J=7Hz), 3.03 (2H, q, J=7Hz), 180 WO 2004/063197 PCT/JP2003/017091 5.09 (1H, broad s), 5.90 (1H, d, J=4Hz), 6.63 1H, d, J=4Hz), 7.45-7.55 (5H, m), 7.60-7.78 (4H, m) MS: (m/z) 437 (M++H), 115 (bp) 5 Example 279 4-(3-Chlorophenyl)-7-ethyl-3-[5-(4-morpholinyl)-5-oxopentyl]-2-phenylpyrrolo[1,2 b]pyridazine mp: 55-58*C NMR (CDC13, 5): 1.05-1.14 (2H, m), 1.17-1.23 (2H, m), 1.35 (3H, t, J=7Hz), 1.84 10 (2H, t, J=7Hz), 2.45 (2H, t, J=7Hz), 3.02 (2H, q, J=7Hz), 3.24 (2H, t, J=6Hz), 3.50 (2H, t, J=6Hz), 3.55-3.62 (4H, m), 5.99 (1H, d, J=4Hz), 6.62 (1H, d, J=4Hz), 7.30-7.35 (1H, m), 7.40-7.55 (8H, m) MS: (m/z) 502 (M++H), 115 (bp) 15 Example 280 5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N methylpentanamide mp: 70-72'C NMR (CDCI3, 5): 1.06 (2H, quintet, J=7Hz), 1.22 (2H, quintet, J=7Hz), 1.36 (3H, t, 20 J=7Hz), 1.72 (2H, t, J=7Hz), 2.43 (2H, t, J=7Hz), 2.70 (3H, d, J=7Hz), 3.03 (2H, q, J=7Hz), 5.08 (1H, broad s), 5.99 (1H, d, J=4Hz), 6.61 (1H, d, J=4Hz), 7.29 7.33 (1H, m), 7.41-7.55 (8H, m) MS: (m/z) 446 (M++H), 115 (bp) 25 Example 281 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N methylpentanamide NMR (CDCI 3 , 5): 1.07 (2H, quintet, J=7Hz), 1.23 (2H, quintet, J=7Hz), 1.36(3H, t, J=7Hz), 1.74 (2H, t, J=7Hz), 2.41 (2H, t, J=7Hz), 2.71 (3H, d, J=7Hz), 3.02 (2H, 30 q, J=7Hz), 5.10 (1H, broad s), 5.95 (1H, d, J=4Hz), 6.64 (1H, d, J=4Hz), 7.31 (1H, d, J=7Hz), 7.42 (1H, s), 7.46-7.52 (1H, m), 7.41-7.55 (1H, d, J=7Hz) MS: (m/z) 447 (M++H), 115 (bp) 181 WO 2004/063197 PCT/JP2003/017091 Example 282 3-{7-Ethyl-3-[5-(4-morpholinyl)-5-oxopentyl]-2-phenylpyrrolo[1,2-b]pyridazin-4 yl}benzonitrile from 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 5 yl]pentanoic acid mp: 66-69'C NMR (CDCI3, 6): 1.04-1.12 (2H, m), 1.17-1.23 (2H, m), 1.36 (3H, t, J=7Hz), 1.84 (2H, t, J=7Hz), 2.42 (2H, t, J=7Hz), 3.03 (2H, q, J=7Hz), 3.23 (2H, t, J=6Hz), 3.50 (2H, t, J=6Hz), 3.55-3.63 (4H, m), 5.90 (1H, d, J=4Hz), 6.63 (1H, d, J=4Hz), 10 7.43-7.55 (5H, m), 7.60-7.78 (4H, m) MS: (m/z) 493 (M++H), 126 (bp) Example 283 To a solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 15 yl]pentanoic acid (50 mg) in NN-dimethylformamide (1 mL) was added 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35 mg) and 1 hydroxybenzotriazole (28 mg) at ambient temperature. After 30 minutes, to the mixture was added morpholine (24 mg). After 5 hours, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed 20 with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel column chromatography (silica gel, 40 mL) eluted with hexane-ethyl acetate = 3-1, 2-1, 1-1, 1-3, and 0-1 to give 3-{7-ethyl-2-methyl 3-[5-(4-morpholinyl)-5-oxopentyl]pyrrolo[1,2-b]pyridazin-4-yl}benzonitrile as an yellow gum (53 mg). 25 3-{7-Ethyl-2-methyl-3-[5-(4-morpholinyl)-5-oxopentyl]pyrrolo[1,2-b]pyridazin-4 yl}benzonitrile NMR (CDCl 3 , 6): 1.15-1.61 (7H, m), 2.18 (2H, t, J=8Hz), 2.41 (2H, t, J=8Hz), 2.56 (3H, s), 3.00 (211, q, J=8Hz), 3.82 (2H, t, J=5Hz), 3.51-3.68 (6H, m), 5.78 (1H, d, 30 J=5Hz), 6.50 (1H, d, J=5Hz), 7.56-7.67 (3H, m), 7.74 (1H, m) MS (ESI*): m/z 431 (M+H) The following compound was obtained in substantially the same manner as that of 182 WO 2004/063197 PCT/JP2003/017091 Example 283. Example 284 5-[4-(3-Cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanamide NMR (CDCI 3 , 8): 1.31-1.61 (7H, m), 2.11 (2H, t, J=8Hz), 2.40 (2H, t, J=8Hz), 2.56 5 (3H, s), 3.00 (2H, q, J=8Hz), 5.36 (2H, br s), 5.79 (1H, d, J=5Hz), 6.50 (1H, d, J=5Hz), 7.56-7.67 (31, m), 7.75 (1H, m) MS (ESI*): m/z 361 (M+H) Preparation 178 10 To a suspension of 60% sodium hydride (8.79 g) in tetrahydrofuran (500 mL) was addded cyclohexanol (10 g) and the mixture was stirred at 0 0 C for 0.5 hour. To the mixture was added bromoacetic acid (13.9 g) under ice-water cooling and the mixture was heated under reflux for 2 hours. After adding water to the mixture and organic solvent was evaporated in vacuo. The aqueous solution was diluted with water, washed 15 with ether, acidified with 1 N hydrochloric acid, and extracted with ether. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo to give (cyclohexyloxy)acetic acid as colorless oil (13.3 g). (cyclohexyloxy)acetic acid 20 'H NMR (CDC 3 ) 8 1.18-1.47 (5H, m), 1.52-1.63 (111, m), 1.72-1.85 (2H, m), 1.90 2.03 (2H, m), 3.36-3.47 (1H, m), 4.13 (2H, s). The following compound(s) was(were) obtained in substantially the same manner as that of Preparation 178. 25 Preparation 179 isopropoxyacetic acid 'H NMR (CDCl 3 ) 8 1.24 (611, d, J= 7 Hz), 3.68-3.82 (1H, m), 4.11 (2H, s). The following compound(s) was(were) obtained in substantially the same manner 30 as that of Preparation 129 and Preparation 130. Preparation 180 tert-butyl 4-(benzyloxy)-3-oxobutanoate 'H NMR (CDCl 3 ) 8 1.44 (9H, s), 3.45 (2H, s), 4.14 (2H, s), 4.60 (211, s), 7.28-7.40 183 WO 2004/063197 PCT/JP2003/017091 (51H, m). Preparation 181 tert-butyl 4-(cyclohexyloxy)-3-oxobutanoate 5 'H NMR (CDCI 3 ) 8 1.18-1.43 (511, m), 1.47 (9H, s), 1.53-1.63 (11H, m), 1.69-1.85 (2H, m), 1.87-1.97 (2H, m), 3.24-3.38 (1H, m), 3.46 (2H, s), 4.11 (2H, s). Preparation 182 tert-butyl 4-isopropoxy-3-oxobutanoate 10 'H NMR (CDCl 3 ) 8 1.20 (6H, d, J= 7 Hz), 1.47 (9H, s), 3.45 (211, s), 3.60-3.70 (111, m), 4.08 (2H, s). The following compound(s) was(were) obtained in substantially the same manner as that of Preparation 159. 15 Preparation 183 1-tert-butyl 4-ethyl 2-acetylsuccinate 'H NMR (CDCl 3 ) 6 1.25 (311, t, J= 7 Hz), 1.47 (9H, s), 2.35 (3H, s), 3.08 (2H, m), 3.93 (1H, m), 4.12 (2H, q, J= 7 Hz). 20 Preparation 184 1-tert-butyl 7-ethyl 2-[(benzyloxy)acetyl]heptanedioate 'H NMR (CDCl 3 ) 6 1.25 (311, t, J= 7 Hz), 1.30-1.50 (2H, m), 1.40 (9H, s), 1.56-1.72 (2H, m), 1.75-1.95 (2H, m), 2.28 (2H, t, J= 7 Hz), 3.52 (1H, t, J= 7 Hz), 4.11 (2H, q, J= 7 Hz), 4.16 (2H, s), 4.59 (2H, s), 7.27-7.40 (5H, m). 25 Preparation 185 1-tert-butyl 5-ethyl 2-[(benzyloxy)acetyl]pentanedioate 'H NMR (CDC 3 ) 6 1.25 (3H, t, J= 7 Hz), 1.41 (9H, s), 2.10-2.23 (2H, m), 2.36 (2H, t, J= 7 Hz), 3.66 (1H, t, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.18 (2H, s), 4.60 (2H, s), 30 7.26-7.38 (5H, m). Preparation 186 1-tert-butyl 7-ethyl 2-[(cyclohexyloxy)acetyl]heptanedioate 184 WO 2004/063197 PCT/JP2003/017091 IH NMR (CDCl 3 ) 8 1.25 (3H, t, J= 7 Hz), 1.44 (9H, s), 1.15-1.92 (16H, m), 2.29 (2H, t, J= 7 Hz), 3.24-3.38 (1H, m), 3.56 (1H, t, J= 7 Hz), 4.12 (41H, m), Preparation 187 5 1-tert-butyl 7-ethyl 2-(isopropoxyacetyl)heptanedioate 'H NMR (CDCl 3 ) 8 1.20 (6H, d, J= 7 Hz), 1.25 (3H, t, J= 7 Hz), 1.25-1.45 (2H, m), 1.45 (9H, s), 1.60-1.72 (2H, m), 1.75-1.95 (2H, m), 2.29 (2H, t, J= 7 Hz), 3.54 (1H, t, J= 7 Hz), 3.60-3.68 (1H, m), 4.11 (2H, s), 4.12 (2H, q, J= 7 Hz). MS (ESI*): m/z 345. 10 The following compound(s) was(were) obtained in substantially the same manner as that of Preparation 20. Preparation 188 1-tert-butyl 5-ethyl 2-[(cyclohexyloxy)acetyl]pentanedioate 15 'H NMR (CDCl 3 ) 8 1.26 (3H, t, J= 7 Hz), 1.45 (9H, s), 1.18-1.62 (6H, m), 1.66-1.78 (2H, m), 1.84-1.98 (2H, m), 2.10-2.23 (2H, m), 2.38 (2H, t, J= 7 Hz), 3.25-3.38 (1H, m), 3.69 (1H, t, J= 7 Hz), 4.12 (211, q, J= 7 Hz), 4.15 (2H, s). MS (ESI*): m/z 357. 20 Preparation 189 To a suspension of 60% sodium hydride (527 mg) in dimethylformamide (20 mL) was added 3,5-pyridinedicarboxylic acid (2.00 g) under ice-water cooling and the mixture was stirred at 0 'C for 1 hour. To the mixture was added (bromomethyl)benzene (2.05 g) and the mixture was stirred at 60 0 C for 2 hours. The mixture was partitioned between 25 ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with ethyl acetate to give 5-[(benzyloxy)carbonyl]nicotinic acid as a pale yellow powder (722 mg). 5-[(benzyloxy)carbonyl]nicotinic acid 'H NMR (DMSO-d 6 ) 8 5.42 (2H, s), 7.34-7.54 (5H, m), 8.63 (1H, m), 9.23-9.34 (211, 30 m). The following compound(s) was(were) obtained in substantially the same manner as that of Preparation 24. 185 WO 2004/063197 PCT/JP2003/017091 Preparation 190 1-tert-butyl 4-ethyl 2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyllsuccinate 'H NMR (CDCI 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.40 (9H, s), 2.38 (311, s), 2.45 (3H, s), 3.20 (2H, m), 4.13 (2H, q, J= 7 Hz), 7.88 (1H, s), 8.57 (1H, s), 8.74 (1H, s). 5 MS (ESI*): m/z 363. Preparation 191 ethyl 2-[(5-methyl-3-pyridinyl)carbonyl]-3-oxobutanoate 'H NMR (CDCl 3 ) 8 0.96 (3H, t, J= 7 Hz), 2.15 (3H, s), 2.45 (3H, s), 4.03 (2H, q, J= 7 10 Hz), 4.12 (1H, t, J= 7 Hz), 7.89 (11H, s), 8.54 (1H, s), 8.72 (1H, s). MS (ESI*): m/z 250. Preparation 192 1-tert-butyl 6-ethyl 2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]hexanedioate 15 1H NMR (CDCl 3 ) 8 1.25 (3H, t, J= 7 Hz), 1.36 (9H, s), 1.60-1.73(2H, m), 2.23-2.35 (2H, m), 2.38 (211, t, J= 7 Hz), 2.48 (311, s), 4.12 (2H, q, J= 7 Hz), 8.20 (1H, m), 8.78 (11H, m), 8.81 (11H, m). Preparation 193 20 1-tert-butyl 5-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2-(methoxyacetyl)pentanedioate 'H NMR (CDCl 3 ) 8 1.25 (3H, t, J= 7 Hz), 1.39 (9H, s), 2.40-2.47 (2H, m), 2.55-2.67 (2H, m), 3.36 (3H, s), 4.12 (2H, q, J= 7 Hz), 4.27 (1H, d, J= 17 Hz), 4.40 (1H, d, J= 17 Hz), 8.21 (1H, m), 8.79 (111, d, J= 2 Hz), 8.82 (1H, d, J= 2 Hz). MS (ESI*): m/z 472 474. 25 Preparation 194 1-tert-butyl 7-ethyl 2-acetyl-2-({5-[(benzyloxy)carbonyl]-3 pyridinyl}carbonyl)heptanedioate 'H NMR (CDC 3 ) 6 1.23 (3H, t, J= 7 Hz), 1.20-1.40 (2H, m), 1.32 (9H, s), 1.65-1.76 30 (2H, m), 2.19-2.26 (2H, m), 2.32 (2H, t, J= 7 Hz), 2.44 (3H, s), 4.12 (2H, q, J= 7 Hz), 5.41 (2H, s), 7.35-7.48 (5H, m), 8.62 (1H, m), 9.07 (1H, d, J= 2 Hz), 9.33 (1H,d,J=2Hz). MS (ESI*): m/z 526. 186 WO 2004/063197 PCT/JP2003/017091 Preparation 195 1-tert-butyl 7-ethyl 2-[(benzyloxy)acetyl]-2-[(5-methyl-3 pyridinyl)carbonyl]heptanedioate 5 'H NMR (CDCl 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.20-1.46 (2H, m), 1.32 (9H, s), 1.60-1.74 (2H, m), 2.10-2.36 (4H, m), 2.35 (3H, s), 4.10 (2H, q, J= 7 Hz), 4.38 (1H, d, J= 18 Hz), 4.53 (1H, d, J= 18 Hz), 4.54 (2H, m), 7.27-7.40 (5H, m), 7.79 (1H, m), 8.54 (1H, d, J= 2 Hz), 8.72 (1H, d, J= 2 Hz). MS (ESI*): m/z 512. 10 Preparation 196 1-tert-butyl 5-ethyl 2-[(benzyloxy)acetyl]-2-[(5-methyl-3 pyridinyl)carbonyl]pentanedioate 'H NMR (CDC 3 ) 8 1.26 (3H, t, J= 7 Hz), 1.34 (9H, s), 2.35 (3H, s), 2.40-2.72 (4H, 15 m), 4.12 (2H, q, J= 7 Hz), 4.38 (1H, d, J= 17 Hz), 4.50 (1H, d, J= 17 Hz), 4.53 (2H, m), 7.25-7.38 (5H, m), 7.81 (1H, s), 8.54 (1H, s), 8.73 (1H, s). MS (ESI*): m/z 484. Preparation 197 20 1-tert-butyl 7-ethyl 2-[(cyclohexyloxy)acetyl]-2-[(5-methyl-3 pyridinyl)carbonyl]heptanedioate 'H NMR (CDC 3 ) 8 1.25 (3H, t, J= 7 Hz), 1.16-1.55 (10H, m), 1.37 (9H, s), 1.60-1.76 (2H, m), 1.78-1.90 (2H, m), 2.15-2.28 (2H, m), 2.31 (2H, t, J= 7 Hz), 2.39 (3H, s), 3.17-3.29 (1H, m), 4.12 (2H, q, J= 7 Hz), 4.34 (1H, d, J= 18 Hz), 4.44 (1H, d, J= 25 18 Hz), 7.86 (1H, s), 8.56 (1H, s), 8.76 (1H, s). MS (ESI*): m/z 504. Preparation 198 1-tert-butyl 7-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2 30 [(cyclohexyloxy)acetyl]heptanedioate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.39 (9H, s), 1.16-1.88 (14H, m), 2.15-2.40 (4H, m), 3.16-3.28 (1H, m), 4.10 (2H, q, J= 7 Hz), 4.28 (1H, d, J= 18 Hz), 4.38 (1H, d, J= 18 Hz), 8.20 (1H, m), 8.78 (1H, d, J= 2 Hz), 8.84 (1H, d, J= 2 Hz). 187 WO 2004/063197 PCT/JP2003/017091 MS (ESI*): m/z 568 570. Preparation 199 1-tert-butyl 5-ethyl 2-[(cyclohexyloxy)acetyl]-2-[(5-methyl-3 5 pyridinyl)carbonyl]pentanedioate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.15-1.38 (4H, m), 1.39 (9H, s), 1.45-1.75 (4H, m), 1.76-1.93 (2H, m), 2.39 (3H, s), 2.45-2.75 (4H, m), 3.17-3.30 (1H, m), 4.12 (2H, q, J= 7 Hz), 4.32 (1H, d, J= 17 Hz), 4.41 (1H, d, J= 17 Hz), 7.88 (1H, s), 8.55 (1H, s), 8.77 (1H, s). 10 MS (ESI): m/z 476. Preparation 200 1-tert-butyl 5-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2 [(cyclohexyloxy)acetyl]pentanedioate 15 'H NMR (CDCl 3 ) 8 1.26 (3H, t, J= 7 Hz), 1.15-1.35 (4H, m), 1.40 (9H, s), 1.40-1.65 (2H, m), 1.65-1.75 (2H, m), 1.75-1.92 (2H, m), 2.35-2.85 (4H, m), 3.16-3.32 (1H, m), 4.12 (2H, q, J= 7 Hz), 4.28 (1H, d, J= 17 Hz), 4.35 (1H, d, J= 17 Hz), 8.22 (1H, t, J= 2 Hz), 8.78 (1H, d, J= 2 Hz), 8.87 (1H, d, J= 2 Hz). MS (ESI*): m/z 540 542. 20 Preparation 201 1-tert-butyl 7-ethyl 2-(isopropoxyacetyl)-2-[(5-methyl- 3 pyridinyl)carbonyl]heptanedioate 'H NMR (CDCl 3 ) 8 1.12 (6H, d, J= 7 Hz), 1.23 (3H, t, J= 7 Hz), 1.30-1.55 (2H, m), 25 1.37 (9H, s), 1.63-1.77 (2H, m), 2.19-2.28 (2H, m), 2.28 (2H, t, J= 7 Hz), 2.39 (3H, s), 3.53-3.64 (1H, m), 4.10 (2H, q, J= 7 Hz), 4.31 (1H, d, J= 18 Hz), 4.42 (1H, d, J= 18 Hz), 7.86 (1H, s), 8.55 (1H, s), 8.74 (1H, s). MS (ESI*): m/z 464. 30 Preparation 202 1-tert-butyl 7-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2-(isopropoxyacetyl)heptanedioate 'H NMR (CDCl 3 ) 8 1.10 (6H, d, J= 7 Hz), 1.24 (3H, t, J= 7 Hz), 1.39 (9H, s), 1.18 1.48 (2H, m), 1.64-1.77 (2H, m), 2.18-2.37 (4H, m), 3.52-3.64 (1H, m), 4.12 (2H, 188 WO 2004/063197 PCT/JP2003/017091 q, J= 7 Hz), 4.25 (1H, d, J= 17 Hz), 4.36 (1H, d, J= 17 Hz), 8.19 (1H, t, J= 2 Hz), 8.77 (1H, d, J= 2 Hz), 8.83 (1H, d, J= 2 Hz). MS (ESI+): m/z 528 530. 5 Preparation 203 1-tert-butyl 7-ethyl 2-[(acetyloxy)acetyl]-2-[(5-methyl-3 pyridinyl)carbonyl]heptanedioate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.33 (9H, s), 1.20-1.42 (2H, m), 1.63-1.74 (2H, m), 2.14 (3H, s), 2.27-2.38 (4H, m), 2.40 (3H, s), 4.10 (2H, q, J= 7 Hz), 5.08 10 (1H, d, J= 18 Hz), 5.36 (1H, d, J= 18 Hz), 7.84 (1H, s), 8.56 (1H, s), 8.75 (1H, s). MS (ESI*): m/z 464. The following compound(s) was(were) obtained in substantially the same manner as that of Preparation 78. 15 Preparation 204 ethyl 3-[(5-methyl-3-pyridinyl)carbonyl]-4-oxopentanoate 'H NMR (CDCl 3 ) 8 1.23 (3H, t, J= 7 Hz), 2.21 (3H, s), 2.44 (3H, s), 3.03 (2H, t, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.96 (1H, t, J= 7 Hz), 8.08 (1H, s), 8.66 (1H, s), 9.03 (IH, s). 20 MS (ESI*): m/z 264. Preparation 205 ethyl 5-[(5-bromo-3-pyridinyl)carbonyl]-6-oxoheptanoate 'H NMR (CDCl 3 ) 8 1.25 (3H, t, J= 7 Hz), 1.60-1.78 (2H, m), 1.98-2.12 (2H, m), 2.20 25 (3H, s), 2.36 (2H, t, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.39 (1H, t, J= 7 Hz), 8.38 (1H, m), 8.87 (1H, d, J= 2 Hz), 9.08 (1H, d, J= 2 Hz). Preparation 206 ethyl 4-[(5-bromo-3-pyridinyl)carbonyl]-6-methoxy-5-oxohexanoate 30 'H NMR (CDCl 3 ) 8 1.25 (3H, t, J= 7 Hz), 2.04-2.16 (1H, m), 2.20-2.34 (1H, m), 2.40-2.48 (2H, m), 3.22 (3H, s), 3.93 (1H, d, J= 17 Hz), 4.00 (1H, d, J= 17 Hz), 4.12 (2H, q, J= 7 Hz), 4.85 (1H, m), 8.47 (1H, m), 8.88 (1H, s), 9.16 (1H, s). MS (ESI*): m/z 372 374. 189 WO 2004/063197 PCT/JP2003/017091 Preparation 207 benzyl 5-(2-acetyl-7-ethoxy-7-oxoheptanoyl)nicotinate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.30-1.43 (2H, m), 1.65-1.75 (2H, m), 5 1.93-2.15 (2H, m), 2.19 (3H, s), 2.29 (2H, t, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.44 (1H, t, J= 7 Hz), 5.43 (2H, s), 7.35-7.50 (5H, m), 8.81 (1H, m), 9.28 (1H, d, J= 2 Hz), 9.39 (1H, d, J= 2 Hz). MS (ESI*): m/z 426. 10 Preparation 208 ethyl 8-(benzyloxy)-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate 'H NMR (CDC 3 ) 6 1.22 (3H, t, J= 7 Hz), 1.30-1.43 (2H, m), 1.60-1.69 (2H, m), 1.73-1.86 (1H, m), 1.95-2.08 (1H, m), 2.25 (2H, t, J= 7 Hz), 2.34 (3H, s), 4.05 (2H, s), 4.07 (211, q, J= 7 Hz), 4.35-4.45 (2H, m), 4.69 (111, t, J= 7 Hz), 7.09 (211, 15 m), 7.17-7.25 (3H, m), 7.93 (1H, s), 8.58 (1H, d, J= 2 Hz), 8.94 (1H, d, J= 2 Hz). MS (ESI+): m/z 412. Preparation 209 ethyl 6-(benzyloxy)-4-[(5-methyl-3-pyridinyl)carbonyl)-5-oxohexanoate 20 'H NMR (CDCl 3 ) 8 1.23 (31H, t, J= 7 Hz), 2.07-2.35 (2H, m), 2.34 (3H, s), 2.38-2.48 (2H, m), 4.05 (2H, s), 4.12 (2H, q, J= 7 Hz), 4.34 (1H, d, J= 17 Hz), 4.41 (1H, d, J= 17 Hz), 4.90 (111, m), 7.03 (2H, m), 7.15-7.25 (3H, m), 8.00 (1H, s), 8.57 (111, s), 9.02 (1H, s). MS (ESI*): m/z 384. 25 Preparation 210 ethyl 8-(cyclohexyloxy)-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate 'H NMR (CDCl 3 ) 8 0.91-1.70 (12H, m), 1.23 (3H, t, J= 7 Hz), 1.70-1.85 (2H, m), 1.96-2.04 (2H, m), 2.27 (2H, t, J= 7 Hz), 2.43 (31, s), 3.14-3.28 (1H, m), 4.00 30 (2H, s), 4.12 (2H, q, J= 7 Hz), 4.76 (111, t, J= 7 Hz), 8.04 (1H, s), 8.62 (1H, s), 9.00 (1H, s). MS (ESI'): m/z 404. 190 WO 2004/063197 PCT/JP2003/017091 Preparation 211 ethyl 6 -[(5-bromo-3-pyridinyl)carbonyl)-8-(cyclohexyloxy)-7-oxooctanoate 'H NMR (CDCI 3 ) 8 0.95-1.87 (14H, m), 1.23 (3H, t, J= 7 Hz), 1.96-2.07 (2H, m), 2.28 (211, t, J= 7 Hz), 3.16-3.27 (111, m), 3.96-4.07 (2H, m), 4.12 (2H, q, J= 7 Hz), 5 4.72 (111, t, J= 7 Hz), 8.38 (1H, m), 8.87 (1H, d, J= 2 Hz), 9.08 (1H, d, J= 2 Hz). MS (ESI*): m/z 468 470. Preparation 212 ethyl 6-(cyclohexyloxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate 10 'H NMR (CDCl 3 ) 8 0.88-1.25 (5H, m), 1.24 (3H, t, J= 7 Hz), 1.40-1.83 (5H, m), 2.04-2.14 (1H, m), 2.18-2.34 (1H, m), 2.42 (2H, m), 2.44 (3H, s), 3.13-3.27 (1H, m), 4.00 (2H, s), 4.12 (2H, q, J= 7 Hz), 4.93 (111, m), 8.13 (1H, s), 8.63 (1H, d, J= 2 Hz), 9.07 (1H, d, J= 2 Hz). MS (ESI*): m/z 376. 15 Preparation 213 ethyl 4 -[(5-bromo-3-pyridinyl)carbonyl]-6-(cyclohexyloxy)-5-oxohexanoate 'H NMR (CDC 3 ) 8 0.88-1.85 (10H, m), 1.25 (31H, t, J= 7 Hz), 2.02-2.14 (1H, m), 2.18-2.34 (1H, n), 2.40-2.50 (2H, m), 3.15-3.27 (111, m), 3.97 (111, d, J= 17 Hz), 20 4.02 (1H, d, J= 17 Hz), 4.13 (2H, q, J= 7 Hz), 4.87-4.95 (1H, m), 8.48 (111, t, J= 2 Hz), 8.88 (1H, d, J= 2 Hz), 9.19 (111, d, J= 2 Hz). MS (ESI*): m/z 440 442. Preparation 214 25 ethyl 8-isopropoxy-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate 'H NMR (CDCI 3 ) 8 0.86 (311, d, J= 7 Hz), 1.02 (3H, d, J= 7 Hz), 1.23 (3H, t, J= 7 Hz), 1.30-1.48 (2H, m), 1.60-1.72 (2H, m), 1.72-1.88 (1H, m), 1.95-2.07 (1H, m), 2.27 (2H, t, J= 7 Hz), 2.43 (3H, s), 3.44-3.54 (1H, m), 3.95 (1H, d, J= 18 Hz), 4.03 (1H, d, J= 18 Hz), 4.08 (2H, q, J= 7 Hz), 4.73 (1H, t, J= 7 Hz), 8.06 (11, s), 30 8.63 (1H, s), 9.02 (1H, s). MS (ESI*): m/z 364. Preparation 215 191 WO 2004/063197 PCT/JP2003/017091 ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-8-isopropoxy-7-oxooctanoate 'H NMR (CDCl 3 ) 8 0.88 (3H, d, J= 7 Hz), 1.03 (3H, t, J= 7 Hz), 1.23 (3H, t, J= 7 Hz), 1.20-1.46 (2H, m), 1.58-1.72 (2H, m), 1.73-1.87 (1H, m), 1.95-2.07 (1H, m), 2.27 (2H, t, J= 7 Hz), 3.46-3.58 (1H, m), 3.94 (1H, d, J= 17 Hz), 4.03 (1H, d, J= 17 5 Hz), 4.10 (2H, q, J= 7 Hz), 4.68 (1H, t, J= 7 Hz), 8.40 (1H, t, J= 2 Hz), 8.86 (1H, d, J= 2 Hz), 9.08 (1H, d, J= 2 Hz). MS (ESI*): m/z 428 430. Preparation 216 10 ethyl 8-(acetyloxy)-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.37-1.47 (2H, m), 1.60-1.77 (2H, m), 2.01 (3H, s), 1.97-2.08 (2H, m), 2.29 (2H, t, J= 7 Hz), 2.44 (3H, s), 4.10 (2H, q, J= 7 Hz), 4.52 (1H, t, J= 7 Hz), 4.68 (1H, d, J= 18 Hz), 4.76 (1H, d, J= 18 Hz), 8.04 (1H, s), 8.66 (1H, s), 8.98 (1H, s). 15 MS (ESI*): m/z 364. The following compound(s) was(were) obtained in substantially the same manner as that of Example 21. Example 285 20 ethyl [7-ethyl -2-methyl -4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]acetate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 2.40 (3H, s), 2.50 (3H, s), 3.02 (2H, q, J= 7 Hz), 3.44 (2H, s), 4.14 (2H, q, J= 7 Hz), 5.98 (1H, d, J= 4 Hz), 6.56 (1H, d, J= 4 Hz), 7.55 (1H, s), 8.45 (1H, s), 8.54 (1H, s). MS (ESI+): m/z 338. 25 Example 286 yl 7-ethyl -2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylate 'H NMR (CDC 3 ) 8 0.96 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 2.41 (3H, s), 2.61 (3H, s), 3.04 (2H, q, J= 7 Hz), 4.05 (2H, q, J= 7 Hz), 6.30 (1H, d, J= 4 Hz), 6.67 30 (1H, d, J= 4 Hz), 7.58 (1H, s), 8.48 (1H, d, J= 2 Hz), 8.51 (1H, d, J= 2 Hz). MS (ESI*): m/z 324. Example 287 192 WO 2004/063197 PCT/JP2003/017091 ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoate 'H NMR (CDCl 3 ) 8 1.21 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.67-1.78 (2H, m), 2.22 (2H, t, J= 7 Hz), 2.42-2.54 (2H, m), 2.59 (3H, s), 3.01 (2H, q, J= 7 Hz), 4.06 (2H, q, J= 7 Hz), 5.87 (1H, d, J= 4 Hz), 6.53 (1H, d, J= 4 Hz), 7.87 (1H, m), 8.54 5 (1H, d, J= 2 Hz), 8.77 (1H, d, J= 2 Hz). MS (ESI*): m/z 430 432. Example 288 ethyl 3

-[

4 -(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 10 yl]propanoate 'H NMR (CDCl 3 ) 8 1.20 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 2.42 (2H, t, J= 7 Hz), 2.85-2.97 (2H, m), 3.06 (2H, q, J= 7 Hz), 3.46 (3H, s), 4.08 (2H, q, J= 7 Hz), 4.65 (2H, s), 5.94 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.87 (1H, m), 8.54 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). 15 MS (ESI*): m/z 446 448. Example 289 ethyl 4 -[2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 yl]butanoate 20 'H NMR (CDCl 3 ) 8 1.20 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.60-1.75 (2H, m), 2.17 (3H, s), 2.10-2.28 (2H, m), 2.45-2.60 (2H, m), 3.02 (2H, q, J= 7 Hz), 4.05 (2H, q, J= 7 Hz), 5.32 (2H, s), 5.95 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.88 (IH, m), 8.55 (1H, m), 8.78 (1H, m). MS (ESI*): m/z 488 490. 25 Example 290 benzyl 5-[ 3 -(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4 yl]nicotinate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.33-1.60 (4H, m), 30 2.18 (2H, t, J= 7 Hz), 2.35-2.47 (2H, m), 2.56 (3H, s), 3.03 (2H, q, J= 7 Hz), 4.10 (2H, q, J= 7 Hz), 5.42 (2H, s), 5.82 (1H, d, J= 4 Hz), 6.53 (1H, d, J= 4 Hz), 7.36 7.47 (5H, m), 8.33 (1H, m), 8.77 (1H, d, J= 2 Hz), 9.33 (1H, d, J= 2 Hz). MS (ESI*): m/z 500. 193 WO 2004/063197 PCT/JP2003/017091 Example 291 ethyl 5-[2-[(benzyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin 3-yl]pentanoate 5 1H NMR (CDCl 3 ) 8 1.22 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.20-1.50 (4H, m), 2.06 (2H, t, J= 7 Hz), 2.42 (3H, s), 2.47-2.63 (2H, m), 3.05 (2H, q, J= 7 Hz), 4.08 (2H, q, J= 7 Hz), 4.64 (2H, s), 4.73 (2H, s), 5.90 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.27-7.39 (511, m), 7.51 (1H, s), 8.41 (111, d, J= 2 Hz), 8.53 (1H, d, J= 2 Hz). 10 Example 292 ethyl 3-[2-[(benzyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin 3-yl]propanoate 'H NMR (CDCl 3 ) 8 1.16 (3H, t, J= 7 Hz), 1.38 (311, t, J= 7 Hz), 2.36 (2H, t, J= 7 Hz), 15 2.42 (3H, s), 2.80-3.00 (2H, m), 3.06 (211, q, J= 7 Hz), 4.03 (211, q, J= 7 Hz), 4.65 (2H, s), 4.75 (2H, s), 5.92 (1H, d, J= 2 Hz), 6.59 (1H, d, J= 2 Hz), 7.26-7.38 (5H, m), 7.48 (111, s), 8.40 (1H, d, J= 2 Hz), 8.53 (11H, d, J= 2 Hz). MS (ESI*): m/z 458. 20 Example 293 ethyl 5-[2-[(cyclohexyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 b]pyridazin-3-yl]pentanoate 'H NMR (CDC 3 ) 8 1.20-1.60 (10H, m), 1.25 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.70-1.83 (2H, m), 1.96-2.07 (211, m), 2.15 (2H, t, J= 7 Hz), 2.43 (3H, s), 2.53 25 2.68 (2H, m), 3.04 (2H, q, J= 7 Hz), 3.42-3.53 (1H, m), 4.08 (211, q, J= 7 Hz), 4.69 (2H, s), 5.88 (1H, d, J= 4 Hz), 6.55 (1H, d, J= 4 Hz), 7.53 (1H, s), 8.42 (1H, d, J= 2 Hz), 8.53 (111, d, J= 2 Hz). Example 294 30 ethyl 5-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-ethylpyrrolo[1,2 b]pyridazin-3-yl}pentanoate 1H NMR (CDCl 3 ) 8 1.22-1.62 (10H, m), 1.23 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.73-1.86 (2H, m), 1.98-2.07 (211, m), 2.18 (211, t, J= 7 Hz), 2.53-2.70 (211, m), 194 WO 2004/063197 PCT/JP2003/017091 3.03 (2H, q, J= 7 Hz), 3.42-3.56 (1H, m), 4.12 (2H, q, J= 7 Hz), 4.69 (2H, s), 5.88 (1H, d, J= 4 Hz), 6.58 (111, d, J= 4 Hz), 7.88 (1H, m), 8.54 (1H, d, J= 2 Hz), 8.77 (1H, d, J= 2 Hz). 5 Example 295 ethyl 3-[2-[(cyclohexyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 b]pyridazin-3-yl]propanoate 'H NMR (CDCl 3 ) 5 1.19 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.16-1.45 (4H, m), 1.52-1.65 (2H, m), 1.73-1.83 (2H, m), 1.98-2.07 (2H, m), 2.35-2.47 (2H, m), 2.42 10 (3H, s), 2.84-2.98 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.45-3.56 (1H, m), 4.06 (2H, q, J= 7 Hz), 4.71 (2H, s), 5.89 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.50 (1H, s), 8.42 (111, s), 8.53 (1H1, s). MS (ESI*): m/z 450. 15 Example 296 ethyl 3-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-ethylpyrrolo[1,2 b]pyridazin-3-yl}propanoate 1H NMR (CDC 3 ) 8 1.20 (311, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.15-1.60 (611, m), 1.73-1.85 (211, m), 1.97-2.08 (2H, m), 2.45 (2H, t, J= 7 Hz), 2.83-2.97 (2H, m), 20 3.05 (211, q, J= 7 Hz), 3.42-3.56 (111, m), 4.08 (2H, q, J= 7 Hz), 4.71 (211, s), 5.90 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.86 (1H, t, J= 2 Hz), 8.53 (1H, d, J= 2 Hz), 8.77 (1Hl, d, J= 2 Hz). MS (ESI*): m/z 514 516. 25 Example 297 ethyl 5-[7-ethyl-2-(isopropoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin 3-yl]pentanoate 'H NMR (CDC 3 ) 5 1.23 (311, t, J= 7 Hz), 1.26 (6H, d, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.38-1.62 (4H, m), 2.17 (2H, t, J= 7 Hz), 2.43 (3H, s), 2.53-2.68 (211, m), 3.03 30 (211, q, J= 7 Hz), 3.76-3.88 (111, m), 4.08 (2H, q, J= 7 Hz), 4.66 (2H, s), 5.88 (1H, d, J= 4 Hz), 6.57 (1H, d, J= 4 Hz), 7.52 (1H, s), 8.42 (1H, s), 8.53 (1H, s). MS (ESI+): m/z 438. 195 WO 2004/063197 PCT/JP2003/017091 Example 298 ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isopropoxymethyl)pyrrolo(1,2-b]pyridazin-3 yl]pentanoate 'H NMR (CDC 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.25 (6H, d, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 5 1.37-1.64 (4H, m), 2.15 (2H, t, J= 7 Hz), 2.54-2.72 (2H, m), 3.02 (2H, q, J= 7 Hz), 3.75-3.87 (1H, m), 4.09 (2H, q, J= 7 Hz), 4.66 (2H, s), 5.89 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.88 (1H, m), 8.55 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). MS (ESI*): m/z 502 504. 10 Example 299 ethyl 5-[2-[(acetyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin 3-yl]pentanoate 'H N MR (CDCl 3 ) 5 1.23 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.30-1.58 (4H, m), 2.13 (2H, t, J= 7 Hz), 2.18 (3H, s), 2.44 (3H, s), 2.40-2.55 (2H, m), 3.02 (2H, q, 15 J= 7 Hz), 4.08 (2H, q, J= 7 Hz), 5.29 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.52 (1H, s), 8.42 (1H, s), 8.53 (1H, s). MS (ESI*): m/z 438. The following compound(s) was(were) obtained in substantially the same manner 20 as that of Example 236. Example 300 ethyl 4-{4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl}butanoate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.41 (3H, t, J= 7 Hz), 25 1.68-1.80 (2H, m), 2.22 (2H, t, J= 7 Hz), 2.44-2.54 (2H, m), 2.59 (3H, s), 3.03 (2H, q, J= 7 Hz), 3.95 (2H, q, J= 7 Hz), 4.10 (2H, q, J= 7 Hz), 4.36 (1H, d, J= 3 Hz), 4.77 (1H, d, J= 3 Hz), 5.88 (1H, d, J= 4 Hz), 6.52 (1H, d, J= 4 Hz), 7.92 (1H, m), 8.53 (1H, d, J= 2 Hz), 8.93 (1H, d, J= 2 Hz). MS (ESI*): m/z 422. 30 Example 301 ethyl 3-[4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2 b]pyridazin-3-yl]propanoate 196 WO 2004/063197 PCT/JP2003/017091 'H NMR (CDC 3 ) b 1.19 (3H, t, J= 7 Hz), 1.26 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 2.42 (2H, t, J= 7 Hz), 2.84-2.97 (2H, m), 3.07 (2H, q, J= 7 Hz), 3.47 (3H, s), 3.97 (2H, q, J= 7 Hz), 4.08 (2H, q, J= 7 Hz), 4.36 (1H, d, J= 3 Hz), 4.66 (2H, s), 4.77 (1H, d, J= 3 Hz), 5.95 (1H, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.92 (1H, m), 8.54 5 (1H, d, J= 2 Hz), 8.95 (1H, d, J= 2 Hz). MS (ESI*): m/z 438. Example 302 ethyl 3-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 10 yl]propanoate 'H NMR (CDC 3 ) 8 1.18 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 2.40 (2H, t, J= 7 Hz), 2.84-2.98 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.47 (3H, s), 4.04 (2H, q, J= 7 Hz), 4.65 (2H, s), 5.46 (1H, d, J= 11 Hz), 5.87 (1H, d, J= 18 Hz), 5.94 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 6.72-6.83 (1H, dd, J= 11 Hz, 18 Hz), 7.74 (1H, m), 8.49 15 (1H, d, J= 2 Hz), 8.72 (1H, d, J= 2 Hz). MS (ESI*): m/z 394. Example 303 methyl 4-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 20 yl]butanoate 'H NMR (CDC1 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.65-1.78 (2H, m), 2.23 (2H, t, J= 7 Hz), 2.54-2.70 (2H, m), 3.05 (2H, q, J= 7 Hz), 3.47 (3H, s), 3.58 (3H, s), 4.67 (2H, s), 5.46 (1H, d, J= 11 Hz), 5.88 (1H, d, J= 18 Hz), 5.93 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 6.73-6.83 (1H, dd, J= 11 Hz, 18 Hz), 7.77 (1H, m), 8.51 (1H, d, J= 2 25 Hz), 8.71 (1H, d, J= 2 Hz). MS (ESI*): m/z 394. Example 304 methyl 4-[4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2 30 b]pyridazin-3-yl]butanoate 1H NMR (CDC 3 ) 8 1.26 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.67-1.82 (2H, m), 2.22 (2H, t, J= 7 Hz), 2.53-2.67 (2H, m), 3.04 (2H, q, J= 7 Hz), 3.47 (3H, s), 3.58 (3H, s), 3.95 (2H, q, J= 7 Hz), 4.34 (1H, d, J= 2 Hz), 4.67 (2H, s), 4.77 (1H, d, J= 197 WO 2004/063197 PCT/JP2003/017091 2 Hz), 5.93 (1H, d, J= 4 Hz), 6.59 (1H, d, J= 4 Hz), 7.92 (1H, m), 8.54 (1H, d, J= 2 Hz), 8.95 (1H, d, J= 2 Hz). MS (ESI*): m/z 438. 5 Example 305 ethyl 3-{4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl}propanoate 'H NMR (CDCl 3 ) 8 1.19 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.44 (3H, t, J= 7 Hz), 2.33-2.43 (2H, in), 2.58 (3H, s), 2.76-2.87 (2H, n), 3.03 (2H, q, J= 7 Hz), 3.96 10 (2H, q, J= 7 Hz), 4.06 (2H, q, J= 7 Hz), 4.36 (1H, d; J= 2 Hz), 4.77 (1H, d, J= 2 Hz), 5.91 (1H, d, J= 4 Hz), 6.54 (1H, d, J= 4 Hz), 7.91 (1H, n), 8.53 (1H, d, J= 2 Hz), 8.96 (1H, d, J= 2 Hz). MS (ESI): m/z 408. 15 The following compound(s) was(were) obtained in substantially the same manner as that of Example 251. Example 306 ethyl 4-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoate 'H NMR (CDCl 3 ) 8 1.19 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.66-1.82 (2H, m), 20 2.21 (2H, t, J= 7 Hz), 2.41-2.51 (2H, m), 2.60 (3H, s), 2.69 (3H, s), 3.03 (2H, q, J= 7 Hz), 4.03 (2H, q, J= 7 Hz), 5.83 (1H, d, J= 4 Hz), 6.53 (1H, d, J= 4 Hz), 8.25 (1H, m), 8.79 (1H, d, J= 2 Hz), 9.25 (1H, d, J= 2 Hz). MS (ESI*): m/z 394. 25 Example 307 ethyl 3-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoate 'H NMR (CDCl 3 ) 8 1.18 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 2.41 (2H, t, J= 7 Hz), 2.70 (3H, s), 2.83-2.96 (2H, m), 3.06 (2H, q, J= 7 Hz), 3.47 (3H, s), 4.03 (2H, q, 30 J= 7 Hz), 4.66 (2H, s), 5.88 (1H, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 8.26 (1H, m), 8.79 (1H, d, J= 2 Hz), 9.25 (1H, d, J= 2 Hz). Example 308 198 WO 2004/063197 PCT/JP2003/017091 methyl 4-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoate 'H NMR (CDCl 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.64-1.80 (2H, m), 2.20 (2H, t, J= 7 Hz), 2.53-2.65 (2H, m), 2.70 (3H, s), 3.05 (211, q, J= 7 Hz), 3.47 (3H, s), 3.57 (3H, s), 5 4.67 (2H, s), 5.87 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 8.27 (1H, s), 8.81 (1, d, J= 2 Hz), 9.26 (1H, d, J= 2 Hz). MS (ESI*): m/z 410. Example 309 10 ethyl 3-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl]propanoate 'H NMR (CDCl 3 ) 8 1.19 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 2.33-2.42 (2H, m), 2.59 (3H, s), 2.69 (3H, s), 2.75-2.83 (2H, m), 3.02 (2H, q, J= 7 Hz), 4.05 (2H, q, J= 7 Hz), 5.83 (1H, d, J= 4 Hz), 6.53 (1H, d, J= 4 Hz), 8.25 (1H, m), 8.78 (1H, d, 15 J= 2 Hz), 9.26 (1H, d, J= 2 Hz). MS (ESI*): m/z 380. Example 310 A mixture of benzyl 5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2 20 b]pyridazin-4-yl]nicotinate (330 mg) and 10% palladium on carbon (33 mg) in methanol (10 mL) was stirred under 4 atm hydrogen atmosphere at ambient temperature for 2 hours. The catalysts were filterred off and washed with chloroform. The filtrates were evaporated in vacuo to give 5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2 b]pyridazin-4-yl]nicotinic acid as yellow oil (272 mg). 25 5 -[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyolo[1,2-b]pyridazin-4-yl]nicotinic acid 'H NMR (CDCl 3 ) 8 1.21 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.35-1.63 (4H, m), 2.19 (2H, t, J= 7 Hz), 2.38-2.49 (2H, m), 2.57 (3H, s), 3.03 (2H, q, J= 7 Hz), 4.11 (2H, q, J= 7 Hz), 5.85 (1H, d, J= 4 Hz), 6.53 (1H, d, J= 4 Hz), 8.40 (1H, m), 8.83 30 (1H, d, J= 2 Hz), 9.37 (1H, d, J= 2 Hz). MS (ESI-): m/z 408, MS (ESI*): m/z410. Example 311 199 WO 2004/063197 PCT/JP2003/017091 To a solution of 5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2 b]pyridazin-4-yl]nicotinic acid (235 mg) and triethylamine (87.1 mg) in t-butanol (10 mL) was added diphenylphosphoryl azide (237 mg) and the mixture was heated under reflux for 2 hours. After evaporation of solvent, the residue was partitioned between 5 ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1 - 2:1) to give ethyl 5-(4-{5-[(tert-butoxycarbonyl)amino]-3-pyridinyl}-7-ethyl-2 methylpyrrolo[1,2-b]pyridazin-3-yl)pentanoate as yellow oil (190 mg). 10 ethyl 5-(4-{5-[(tert-butoxycarbonyl)amino]-3-pyridinyl}-7-ethyl-2-methylpyrrolo[1,2 b]pyridazin-3-yl)pentanoate 'H NMR (CDC 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.42-1.67 (4H, m), 1.52 (9H, s), 2.19-2.28 (2H, m), 2.38-2.50 (2H, m), 2.55 (3H, s), 3.03 (2H, q, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 5.92 (1H, d, J= 4 Hz), 6.53 (1H, d, J= 4 Hz), 6.93 (1H, 15 br), 7.87 (1H, s), 8.30 (1H, d, J= 2 Hz), 8.70 (1H, d, J= 2 Hz). MS (ESI*): m/z 481. Example 312 A solution of ethyl 5-(4-{5-[(tert-butoxycarbonyl)amino]-3-pyridinyl}-7-ethyl-2 20 methylpyriolo[1,2-b]pyridazin-3-yl)pentanoate (190 mg) in 2 N hydrogen chloride ethyl acetate solution (4 mL) was stirred at ambient temperature for 2 hours. After evaporation of solvent, the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel 25 column chromatography eluting with a mixture of chloroform and methanol (100:1 20:1) to give ethyl 5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin 3-yl]pentanoate as yellow oil (140 mg). ethyl 5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 30 yl]pentanoate 'H NMR (CDCl 3 ) 6 1.24 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.40-1.65 (4H, m), 2.23 (2H, t, J= 7 Hz), 2.45 (2H, t, J= 7 Hz), 2.54 (3H, s), 3.03 (2H, q, J= 7 Hz), 3.97 (2H, br), 4.12 (2H, q, J= 7 Hz), 5.94 (1H, d, J= 4 Hz), 6.53 (1H, d, J= 4 Hz), 200 WO 2004/063197 PCT/JP2003/017091 7.02 (1H, m), 8.02 (1H, d, J= 2 Hz), 8.17 (1H, d, J= 2 Hz). MS (ESI*): m/z 381 (M+H). Example 313 5 To a solution of ethyl 5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2 b]pyridazin-3-yl]pentanoate (55 mg), 37% formaldehyde solution (277 mg) and sodium cyanoborohydride (27.3 mg) in acetnitrile (1 mL) and methanol (1 mL) was added acetic acid (2 drops) and the mixture was stirred at ambient temperature for 2 hours. The solution was diluted with saturated sodium bicarbonate solution and extracted with 10 chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-{4-[5-(dimethylamino)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl}pentanoate as yellow oil (36.5 mg). 15 ethyl 5-{ 4-[5-(dimethylamino)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl}pentanoate 'H NMR (CDCl 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.40-1.63 (4H, m), 2.19 (2H, t, J= 7 Hz), 2.40-2.53 (2H, m), 2.55 (3H, s), 3.02 (6H, s), 3.03 (2H, q, 20 J= 7 Hz), 4.09 (2H, q, J= 7 Hz), 5.93 (1H, d, J= 4 Hz), 6.50 (1H, d, J= 4 Hz), 6.96 (1H, m), 7.95 (1H, d, J= 2 Hz), 8.20 (1H, d, J= 2 Hz). MS (ESI*): m/z 409. The following compound(s) was(were) obtained in substantially the same manner 25 as that of Example 245. Example 314 3-[7-ethyl-4-(5-ethyl-3-pyridinyl)-2-(methoxymethyl)pyrrolo[ 1,2-b]pyridazin-3 yl]propanoic acid 'H NMR (CDCl 3 ) 8 1.29 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 2.45-2.58 (2H, m), 30 2.73 (2H, q, J= 7 Hz), 2.82-3.02 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.47 (3H, s), 4.67 (2H, s), 5.91 (1H, d, J= 4 Hz), 6.59 (1H, d, J= 4 Hz), 7.58 (1H, m), 8.43 (1H, d, J= 2 Hz), 8.53 (1H, d, J= 2 Hz). MS (ESI): m/z 366, MS (ESI'): m/z 368. 201 WO 2004/063197 PCT/JP2003/017091 Example 315 4-[7-ethyl-4-(5-ethyl-3-pyridinyl)-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoic acid 5 'H NMR (CDCl 3 ) 8 1.31 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.69-1.85 (2H, m), 2.20-2.31 (2H, m), 2.52-2.75 (2H, m), 2.77 (2H, q, J= 7 Hz), 3.06 (2H, q, J= 7 Hz), 3.46 (3H, s), 4.60-4.80 (2H, m), 5.91 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.61 (1H, s), 8.44-8.53 (2H, m). MS (ESI*): m/z 382. 10 The following compound(s) was(were) obtained in substantially the same manner as that of Example 228. Example 316 methyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3 15 yl]butanoate 1H NMR (CDC 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.65-1.79 (2H, m), 2.25 (2H, t, J= 7 Hz), 2.39-2.53 (2H, m), 3.06 (2H, q, J= 7 Hz), 3.61 (3H, s), 4.90 (2H, s), 5.96 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.88 (1H, m), 8.55 (1H, d, J= 2 Hz), 8.79 (1H, d, J= 2 Hz). 20 MS (ESI+): m/z 432 434. Example 317 ethyl 5-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate 25 'H NMR (CDCl 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.35-1.60 (4H, m), 2.17 (2H, t, J= 7 Hz), 2.35-2.45 (2H, m), 2.43 (3H, s), 3.04 (2H, q, J= 7 Hz), 3.83 (1H, t, J= 7 Hz), 4.10 (2H, q, J= 7 Hz), 4.85 (2H, d, J= 7 Hz), 5.96 (1H, d, J= 4 Hz), 6.57 (1H, d, J= 4 Hz), 7.50 (1H, s), 8.42 (1H, s), 8.54 (1H, s). MS (ESI*): m/z 396. 30 The following compound(s) was(were) obtained in substantially the same manner as that of Example 268. Example 318 202 WO 2004/063197 PCT/JP2003/017091 methyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoate 'H NMR (CDC 3 ) 6 1.37 (3H, t, J= 7 Hz), 1.65-1.79 (2H, m), 2.24 (2H, t, J= 7 Hz), 2.52-2.70 (2H, m), 3.04 (211, q, J= 7 Hz), 3.46 (3H, s), 3.60 (311, s), 4.76 (211, s), 5 5.93 (1H, d, J= 4 Hz), 6.62 (1H1, d, J= 4 Hz), 7.88 (1H, m), 8.56 (1H, d, J= 2 Hz), 8.79 (1H, d, J= 2 Hz). MS (ESI*): m/z 446 448. Example 319 10 ethyl 5-[ 2 -[(2-tert-butoxy-2-oxoethoxy)methyl]-7-ethyl-4-(5-methyl-3 pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate 'H NMR (CDC 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.30-1.60 (4H, m), 1.47 (911, s), 2.17 (211, t, J= 7 Hz), 2.43 (3H, s), 2.58-2.72 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.08 (2H, s), 4.12 (2H, q, J= 7 Hz), 4.81 (2H, s), 5.91 (1H, d, J= 4 Hz), 15 6.58 (111, d, J= 4 Hz), 7.53 (1H, s), 8.43 (1H, s), 8.53 (1H, s). MS (ESI*): m/z 510. Example 320 ethyl 5-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 20 b]pyridazin-3-yljpentanoate 'H NMR (CDCl 3 ) 8 0.20-0.32 (2H, m), 0.53-0.63 (2H, m), 1.07-1.20 (1H, m), 1.22 (3H, t, J= 7 Hz), 1.37 (311, t, J= 7 Hz), 1.40-1.60 (411, m), 2.15 (2H, t, J= 7 Hz), 2.43 (311, s), 2.53-2.68 (2H, m), 3.02 (2H, q, J= 7 Hz), 3.41 (2H, d, J= 7 Hz), 4.08 (2H, q, J= 7 Hz), 4.70 (2H, s), 5.89 (111, d, J= 4 Hz), 6.56 (111, d, J= 4 Hz), 7.52 25 (1H, s), 8.43 (1H, s), 8.53 (1H, s). MS (ESI*): m/z 450. Example 321 ethyl 5-[ 2 -[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 30 b]pyridazin-3-yl]pentanoate 1H NMR (CDC1 3 ) 6 0.88-1.05 (2H, m), 1.16-1.35 (4H, m), 1.25 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.38-1.59 (4H, m), 1.60-1.87 (5H, m), 2.16 (2H, t, J= 7 Hz), 2.43 (311, s), 2.54-2.67 (211, m), 3.03 (2H, q, J= 7 Hz), 3.35 (2H, d, J= 7 Hz), 4.10 (2H, 203 WO 2004/063197 PCT/JP2003/017091 q, J= 7 Hz), 4.64 (2H, s), 5.89 (1H, d, J= 4 Hz), 6.56 (1H, d, J= 4 Hz), 7.52 (1H, s), 8.43 (1H, d, J= 2 Hz), 8.53 (1H, d, J= 2 Hz). MS (ESI*): m/z 492. 5 Example 322 ethyl 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoate 'H NMR (CDCl 3 ) 8 1.22 (3H, t, J= 7 Hz), 1.39 (3H, t, J= 7 Hz), 1.35-1.54 (4H, m), 2.12 (2H, t, J= 7 Hz), 2.43 (3H, s), 2.50-2.63 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.08 10 (21H, q, J= 7 Hz), 4.66 (2H, s), 4.76 (211, s), 5.92 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 7.28 (1H, m), 7.52 (1H, s), 7.72 (1H, d, J= 8 Hz), 8.42 (111, d, J= 2 Hz), 8.54 (2H, m), 8.62 (1H,d, J= 2 Hz). MS (ESI+): m/z 487. 15 Example 323 ethyl 5-{ 7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoate 'H NMR (CDCl 3 ) 8 1.21 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.36-1.54 (4H, m), 2.12 (2H, t, J= 7 Hz), 2.42 (3H, s), 2.56-2.68 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.08 20 (2H, q, J= 7 Hz), 4.77 (2H, s), 4.85 (2H, s), 5.92 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.22 (1H, m), 7.43-7.54 (2H, m), 7.66-7.74 (1H, m), 8.42 (1H, d, J= 2 Hz), 8.54 (1H, d, J= 2 Hz), 8.57 (1H, d, J= 5 Hz). MS (ESI*): m/z 487. 25 Example 324 ethyl 5-{ 7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoate 'H NMR (CDC 3 ) 8 1.22 (3H, t, J= 7 Hz), 1.39 (3H, t, J= 7 Hz), 1.38-1.57 (4H, m), 2.12 (2H, t, J= 7 Hz), 2.43 (3H, s), 2.52-2.68 (2H, m), 3.05 (2H, q, J= 7 Hz), 4.08 30 (2H, q, J= 7 Hz), 4.66 (211, s), 4.77 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 2 Hz), 7.28 (2H, d, J= 7 Hz), 7.52 (1H, s), 8.42 (1H, d, J= 2 Hz), 8.53 (iH, d, J= 2 Hz), 8.58 (2H, d, J= 7 Hz). MS (ESI*): m/z 487. 204 WO 2004/063197 PCT/JP2003/017091 Example 325 ethyl 5-{7-ethyl-4-(5-methyl- 3 -pyridinyl)-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoate 5 'H NMR (CDC 3 ) 8 1.22 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.38-1.57 (4H, m), 2.13 (2H, t, J= 7 Hz), 2.43 (311, s), 2.52-2.68 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.07 (2H, q, J= 7 Hz), 4.82 (2H, s), 4.88 (2H, m), 5.92 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 7.52 (1H, s), 8.43 (111, d, J= 2 Hz), 8.48-8.57 (311, m), 8.75 (1H, m). MS (ESI'): m/z 488. 10 Example 326 ethyl 5-[ 4

-(

3 -cyanophenyl)-2-(ethoxymethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 yl]pentanoate 'H NMR (CDC 3 ) 8 1.18-1.29 (6H, m), 1.34-1.53 (7H, m), 2.14 (2H, t, J = 7 Hz), 15 2.52 (2H, m), 3.02 (211, q, J= 7 Hz), 3.53 (2H, q, J = 7 Hz), 4.07 (2H, q, J = 7 Hz), 4.66 (1H, s), 5.73 (1J, d, J = 5 Hz), 6.56 (1H, d, J = 5 Hz), 7.60 (2H, m), 7.67 (1H, s), 7.75 (11H, m) Example 327 20 ethyl 5-[2-[(benzyloxy)methyl]-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2-blpyridazin-3 yl]pentanoate 'H NMR (CDCl 3 ) 8 1.22 (3H, t, J = 7 Hz), 1.30-1.46 (7H, m), 2.06 (2H, t, J = 7 Hz), 2.51 (2H, m), 3.02 (211, q, J = 7 Hz), 4.07 (2H, q, J = 7 Hz), 4.64 (3H, s), 4.72 (3H, s), 5.83 (111, d, J = 5 Hz), 6.57 (1H, d, J = 5 Hz), 7.25-7.38 (5H, m), 7.57 25 (2H, d, J = 9 Hz), 7.65 (11H, s), 7.74 (1H, m). Example 328 methyl 4-({ [ 4

-(

3 -cyanophenyl)-3-(5-ethoxy-5-oxopentyl)-7-ethylpyrrolo[1,2-b]pyridazin 2-yl]methoxy}methyl)benzoate 30 'H NMR (CDCI 3 ) 8 1.22 (3H, t, J = 7 Hz), 1.32-1.49 (7H, m), 2.01 (211, t, J = 7 Hz), 2.52 (2H, m), 3.02 (2H, t, J = 7 Hz), 3.92 (311, s), 4.07 (211, t, J = 7 Hz), 4.69 (211, s), 4.75 (2H, s), 6.84 (11H, d, J = 5 Hz), 6.59 (11H, d, J = 5 Hz), 7.43 (2H, d, J = 9 Hz), 7.60 (211, m), 7.65 (1H, s), 7.75 (1H, m), 8.02 (211, d, J = 9 Hz). 205 WO 2004/063197 PCT/JP2003/017091 Example 329 A solution of ethyl 5-[2-[(2-tert-butoxy-2-oxoethoxy)methyl]-7-ethyl-4-(5 methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (60 mg) in tifluoroacetic acid 5 (2 mL) was stirred at ambient temperature for 2 hours, and evaporated in vacuo to give { [3-(5-ethoxy-5-oxopentyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-2 yl]methoxy}acetic acid as brown oil (55 mg). {[3-(5-ethoxy-5-oxopentyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-2 10 yl]methoxy} acetic acid 'H NMR (CDCl 3 ) 8 1.25 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.35-1.60 (4H, m), 2.23 (2H, t, J= 7 Hz), 2.50-2.58 (2H, m), 2.67 (3H, s), 3.03 (2H, q, J= 7 Hz), 4.08 (2H, q, J= 7 Hz), 4.30 (2H, s), 4.87 (2H, s), 5.86 (1H, d, J= 4 Hz), 6.67 (1H, d, J= 4 Hz), 8.15 (1H, s), 8.69 (1H, s), 8.85 (1H, s). 15 MS (ESI~): m/z 452, MS (ESI*): m/z 454. Example 330 To a solution of {[3-(5-ethoxy-5-oxopentyl)-7-ethyl-4-(5-methyl-3 pyridinyl)pyrrolo[1,2-b]pyridazin-2-yl] methoxy}acetic acid (55 mg), 1-ethyl-3-(3' 20 dimethylaminopropyl)carbodiimide hydrochloride (34.9 mg) and 1-hydroxybenotriazole (24.6 mg) in dimethylformamide (2 mL) was added morpholine (12.7 mg) and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and 25 evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of ethyl acetate and methanol (50:1 - 20:1) to give ethyl 5-(7-ethyl 4-(5-methyl-3-pyridinyl)-2-{ [2-(4-morpholinyl)-2-oxoethoxy]methyl}pyrrolo[1,2 b]pyridazin-3-yl)pentanoate as yellow oil (50 mg). 30 ethyl 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[2-(4-morpholinyl)-2 oxoethoxy)methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate . 'H NMR (CDC 3 ) 5 1.22 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.40-1.63 (4H, m), 2.15 (2H, t, J= 7 Hz), 2.43 (3H, s), 2.54-2.68 (2H, m), 3.02 (2H, q, J= 7 Hz), 3.48 206 WO 2004/063197 PCT/JP2003/017091 3.57 (21H, m), 3.63-3.78 (6H, m), 4.08 (2H, q, J= 7 Hz), 4.30 (2H, s), 4.78 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 7.52 (1H, s), 8.43 (1H, d, J= 2 Hz), 8.54 (1H, d, J= 2 Hz). MS (ESI*): m/z 523. 5 The following compound(s) was(were) obtained in substantially the same manner as that of Example 330. Example 331 ethyl 5-[7-ethyl-2-{ [2-(methylamino)-2-oxoethoxy]methyl}-4-(5-methyl-3 10 pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate 'H NMR (CDC 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.38-1.62 (414, m), 2.18 (2H, t, J= 7 Hz), 2.44 (3H, s), 2.48-2.62 (2H, m), 2.88 (3H, d, J= 7 Hz), 3.03 (2H, q, J= 7 Hz), 4.11 (2H, q, J= 7 Hz), 4.13 (2H, s), 4.77 (2H, s), 5.94 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 6.79 (1H, br), 7.53 (1H, s), 8.44 (1H, s), 8.56 (1H, s). 15 MS (ESI*): m/z 467. The following compound(s) was(were) obtained in substantially the same manner as that of Example 271. Example 332 20 ethyl 5-[2-[(benzylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 b]pyridazin-3-yl]pentanoate 'H NMR (CDC 3 ) 8 1.22 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.30-1.50 (2H, m), 1.60-1.85 (2H, m), 2.12 (2H, t, J= 7 Hz), 2.30-2.45 (2H, m), 2.42 (3H, s), 3.03 (2H, q, J= 7 Hz), 3.96 (2H, s), 3.98 (28, s), 4.08 (2H, q, J= 7 Hz), 5.87 (1H, d, J= 25 4 Hz), 6.54 (1H, d, J= 4 Hz), 7.27-7.43 (5H, m), 7.48 (1H, s), 8.38 (1H, d, J= 2 Hz), 8.53 (1H, d, J= 2 Hz). MS (ESI+): m/z 485. Example 333 30 A mixture of ethyl 5-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3 pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (100 mg), 1H-isoindole-1,3(2H) dione (44.6 mg) diisopropyl azodicarboxylate (76.7 mg) and triphenylphosphine (99.5 mg) in tetrahydrofuran (2 mL) was stirred at ambient temperature for 1 hour. After evaporation 207 WO 2004/063197 PCT/JP2003/017091 of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1 - 1:1) to give ethyl 5-[2-[(1,3-dioxo-1,3 dihydro-2H-isoindol-2-yl)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 b]pyridazin-3-yl]pentanoate as yellow oil (107 mg). 5 ethyl 5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7-ethyl-4-(5-methyl-3 pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate 'H NMR (CDC 3 ) 5 0.89 (3H, t, J= 7 Hz), 1.26 (3H, t, J= 7 Hz), 1.20-1.40 (2H, m), 1.53-1.75 (2H, m), 2.24 (2H, t, J= 7 Hz), 2.44 (3H, s), 2.47 (2H, q, J= 7 Hz), 2.50 10 2.64 (2H, m), 4.12 (2H, q, J= 7 Hz), 5.10 (2H, s), 5.85 (1H, d, J= 4 Hz), 6.43 (111, d, J= 4 Hz), 7.51 (1H, s), 7.78 (2H, m), 7.96 (2H, m), 8.43 (1H, s), 8.55 (1H, s). MS (ESI*): m/z 525. Example 334 15 A mixture of ethyl 5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7 ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (107 mg) and hydrazine monohydrate (51.1 mg) in ethanol (2 mL) was heated under reflux for 2 hours. After evaporation of solvent, the residue was partitioned between chloroform and saturated sodium bicarbonate solution. The organic layer was separated, washed with 20 brine, dried over magnesium sulfate, and evaporated in vacuo to give ethyl 5-[2 (aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (67.6 mg). ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 25 yl]pentanoate 'H NMR (CDCl 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.38-1.62 (4H, m), 2.14 (21H, t, J= 7 Hz), 2.42 (3H, s), 2.38-2.56 (2H, m), 3.04 (2H, q, J= 7 Hz), 4.06 (2H, s), 4.08 (2H, q, J= 7 Hz), 5.90 (1H, d, J= 4 Hz), 6.55 (1H, d, J= 4 Hz), 7.51 (1H, s), 8.41 (1H, s), 8.53 (111, s). 30 MS (ESI*): m/z 395. Example 335 A mixture of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3 208 WO 2004/063197 PCT/JP2003/017091 pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (67.6 mg) and acetic anhydride (19.2 mg) in dichloromethane (3 mL) was stirred at ambient temperature for 1 hour. The solution was diluted with chloroform, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was 5 purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-[2-[(acetylamino)methyl]-7-ethyl-4-(5 methyl-3-pyridinyl)pyrrolo[1,2-blpyridazin-3-yl]pentanoate as yellow oil (70 mg). ethyl 5-[2-[(acetylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 10 b]pyridazin-3-yl]pentanoate 'H NMR (CDCl 3 ) 8 1.22 (3H, t, J= 7 Hz), 1.40 (3H, t, J= 7 Hz), 1.40-1.63 (411, m), 2.12 (2H, m), 2.15 (3H, s), 2.43 (3H, s), 2.40-2.53 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.10 (2H, q, J= 7 Hz), 4.66 (2H, m), 5.94 (111, d, J= 4 Hz), 6.59 (1H, d, J= 4 Hz), 6.85 (1H, br), 7.50 (1H, s), 8.40 (1H, d, J= 2 Hz), 8.54 (1H, d, J= 2 Hz). 15 MS (ESI*): m/z 437. Example 336 To a solution of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3 pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (80 mg) and pyridine (1 mL) in 20 dichloromethane (2 mL) was added methanesulfonyl chloride (34.8 mg) under ice-water cooling and the mixture was stirred at ambient temperature for 1 hour. The solution was diluted with chloroform, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and 25 methanol (20:1) to give ethyl 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2 { [(methylsulfonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate as yellow oil (62.8 mg) ethyl 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{ [(methylsulfonyl)amino]methyl}pyrrolo[1,2 30 b]pyridazin-3-yl)pentanoate 'H NMR (CDCl 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.39 (3H, t, J= 7 Hz), 1.40-1.62 (411, m), 2.19 (2H, t, J= 7 Hz), 2.44 (3H, s), 2.38-2.51 (2H, m), 3.02 (211, q, J= 7 Hz), 3.06 (3H, s), 4.08 (2H, q, J= 7 Hz), 4.58 (2H, s), 5.63 (11H, br), 5.97 (1H, d, J= 4 Hz), 209 WO 2004/063197 PCT/JP2003/017091 6.61 (1H, d, J= 4 Hz), 7.50 (11H, s), 8.41 (1H, d, J= 2 Hz), 8.54 (1H, d, J= 2 Hz). MS (ESI*): m/z 473. Example 337 5 A mixture of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3 pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (75 mg), benzoic acid (27.9 mg), 1 ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (54.7 mg) and 1 hydroxybenotriazole (38.5 mg) in dimethylformamide (2 mL) was stirred at ambient temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. 10 The organic layer was separated, washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-[2-[(benzoylamino)methyl]-7-ethyl-4-(5 methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (60 mg). 15 ethyl 5-[2-[(benzoylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 b]pyridazin-3-yl]pentanoate 'H NMR (CDC 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.42 (3H, t, J= 7 Hz), 1.42-1.65 (4H, m), 2.17 (2H, t, J= 7 Hz), 2.44 (3H, s), 2.44-2.58 (2H, m), 3.06 (2H, q, J= 7 Hz), 4.08 20 (2H, q, J= 7 Hz), 4.86 (2H, m), 5.96 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 7.46 7.59 (4H, m), 7.78 (1H, br), 7.91-7.97 (2H, m), 8.44 (1H, d, J= 2 Hz), 8.56 (1H, d, J= 2 Hz). MS (ESI*): m/z 499. 25 The following compound(s) was(were) obtained in substantially the same manner as that of Example 337. Example 338 ethyl 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{{(2 pyrazinylcarbonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate 30 'H NMR (CDCl 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.41 (31-1, t, J= 7 Hz), 1.42-1.64 (4H, m), 2.18 (2H, t, J= 7 Hz), 2.44 (3H, s), 2.47-2.59 (2H, m), 3.08 (2H, q, J= 7 Hz), 4.09 (2H, q, J=7 Hz), 4.89 (2H, d, J= 7 Hz), 5.96 (1H, d, J= 4 Hz), 6.60 (IH, d, J= 4 Hz), 7.53 (1H, s), 8.43 (1H, d, J= 2 Hz), 8.55 (IH, d, J= 2 Hz), 8.62 (IH, m), 8.79 210 WO 2004/063197 PCT/JP2003/017091 (1H, m), 9.15 (1H, br), 9.46 (1H, m). MS (ESI'): m/z 501. Example 339 5 To a solution of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3 pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (80 mg) and pyridine (1 mL) in dichloromethane (2 mL) was added methyl chloridocarbonate (34.8 mg) under ice-water cooling and the mixture was stirred at ambient temperature for 2 hours. After evaporation of solvent, the residue was partitioned between ethyl acetate and water. 10 The organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-[7-ethyl-2-{[(methoxycarbonyl)amino]methyl}- 4 -(5 methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (70 mg). 15 ethyl 5-[7-ethyl-2-{ [(methoxycarbonyl)amino]methyl}-4-(5-methyl-3 pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate 'H NMR (CDC 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.39 (3H, t, J= 7 Hz), 1.40-1.63 (4H, m), 2.19 (2H, t, J= 7 Hz), 2.44 (3H, s), 2.40-2.55 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.07 20 (3H, s), 4.12 (2H, q, J= 7 Hz), 4.57 (2H, m), 5.72 (1H, br), 5.97 (1H, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.51 (1H, s), 8.41 (1H, s), 8.56 (1H, s). Example 340 To a solution of ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2 25 (hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (70.0 mg) and triethyl amine (18.5 mg) in dichloromethane (1 mL) was added methanesulfonyl chloride (20.9 mg) under an ice bath. After stirring for 1 hour, to the mixture was added 1-methylpiperazine (27.0 mg). The mixture was stirred for 0.5 hour under an ice bath and overnight at room temperature. The mixture was partitioned between ethyl acetate and water. The organic 30 layer was washed with brine, dried over magnesium sulfate, and evaporated. Preparative silicagel thin layer chromatography (chloroform-methanol = 20-1) afforded ethyl 5-{4-(5 bromo-3-pyridinyl)-7-ethyl-2-[(4-methyl-1-piperazinyl)methyl]pyrrolo[1,2-b]pyridazin-3 yl}pentanoate as an yellow gum (52.4 mg, 63.5%). 211 WO 2004/063197 PCT/JP2003/017091 ethyl 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-methyl-1-piperazinyl)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoate 'H NMR (CDC1 3 ): 1.23 (3H, t, J = 7 Hz), 1.33-1.60 (7 H, m), 2.16 (2H, t, J = 7 Hz), 5 2.29 (3H, s), 2.34-2.65 (6H, m), 3.00 (2H, q, J = 7 Hz), 3.54 (2H, s), 4.08 (2H, q, J = 7 Hz), 5.86 (1H, d, J = 5 Hz), 6.55 (1H, d, J = 5 Hz9, 7.87 (1H, m), 8.54 (1H, m), 8.77 (1H, m). Example 341 10 To a solution of ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2 (hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (300 mg, 0.652 mmol) and tetrabromomethane (432 mg, 1.30 mmol) in tetrahydrofuran (3 mL) was added triphenylphosphine (308 mg, 1.17 mmol) over 40 minutes. The mixture was concentrated, and the residue was chromatographed on a flash silica gel column 15 chromatography (ethyl acetate-hexane = 1-8 to 1-5) to afford ethyl 5-[2-(bromomethyl) 4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow gum (229 mg, 50.4%). ethyl 5-[2-(bromomethyl)-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 20 yl]pentanoate 'H NMR (CDCl 3 ) 8 1.23 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.41-1.50 (4H, m), 2.19 (2H, t, J = 7 Hz), 2.58 (2H, m), 3.01 (2H, q, J = 7 Hz), 4.08 (2H, q, J = 7 Hz), 4.66 (2H, s), 5.94 (1H, d, J = 5 Hz), 6.63 (1H, d, J = 5 Hz), 7.88 (1H, m), 8.55 (1H, m), 8.79 (1H, m). 25 Example 342 A mixture of ethyl 5-[2-(bromomethyl)-4-(5-bromo-3-pyridinyl)-7 ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (70.0 mg) and potassium cyanide (13.1 mg) in N,N-dimethylformamide (1 mL) was stirred for 28 hours at room temperature. The 30 mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (two times), brine, dried over magnesium sulfate, and evaporated to give ethyl 5-[4-(5-bromo-3-pyridinyl)-2-(cyanomethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 yl]pentanoate as an yellow gum (28.8 mg, 45.9%). 212 WO 2004/063197 PCT/JP2003/017091 ethyl 5-[4-(5-bromo-3-pyridinyl)-2-(cyanomethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 yl]pentanoate 'H NMR (CDCl 3 ) 8 1.24 (3H,t, J= 7 Hz), 1.46-1.65 (7H, m), 2.22 (2H, t, J = 7 Hz), 5 2.48 (2H, m), 3.04 (2H, q, J = 7 Hz), 3.98 (2H, s), 4.10 (2H, q, J = 7 Hz), 5.98 (1H, d, J = 5 Hz), 6.65 (1H, d, J = 5 Hz), 7.88 (1H, m), 8.55 (1H, m), 8.81 (11H, m). The following compound(s) was(were) obtained in substantially the same manner 10 as that of Example 76. Example 343 [7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo [1,2-b]pyridazin-3-yl] acetic acid 'H NMR (CDC 3 ) 8 1.36 (3H, t, J= 7 Hz), 2.45 (3H, s), 2.56 (311, s), 3.02 (2H, q, J= 7 Hz), 3.28 (111, d, J= 17 Hz), 3.53 (1H, d, J= 17 Hz), 5.91 (1H, d, J= 4 Hz), 6.52 15 (1H, d, J= 4 Hz), 7.71 (111, s), 8.47 (1H, s), 8.59 (111, s). MS (ESI~): m/z 308, MS (ESI*): m/z 310. Example 344 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoic acid 20 'H NMR (CDC3) 8 1.38 (3H, t, J= 7 Hz), 1.65-1.85 (2H, m), 2.31 (2H, t, J= 7 Hz), 2.45-2.63 (2H, m), 2.59 (311, s), 3.03 (211, q, J= 7 Hz), 5.88 (1H, d, J= 4 Hz), 6.53 (111, d, J= 4 Hz), 7.90 (111, s), 8.53 (111, s), 8.75 (1H, s). MS (ESI-): m/z 400 402, MS (ESI*): m/z 402 404. 25 Example 345 4-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoic acid 1H NMR (CDCl 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.68-1.82 (2H, m), 2.26 (211, t, J= 7 Hz), 2.45-2.58 (2H, m), 2.60 (3H, s), 2.70 (3H, s), 3.03 (2H, q, J= 7 Hz), 5.83 (11, d, J= 4 Hz), 6.54 (111, d, J= 4 Hz), 8.28 (1H, m), 8.77 (1H, d, J= 2 Hz), 9.19 (1H, d, 30 J= 2 Hz). Example 346 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 213 WO 2004/063197 PCT/JP2003/017091 yl]propanoic acid 'H NMR (CDCl 3 ) 8 1.37 (3H, t, J= 7 Hz), 2.49 (2H, t, J= 7 Hz), 2.80-3.00 (2H, m), 3.05 (2H, q, J= 7 Hz), 3.46 (3H, s), 4.66 (2H, s), 5.94 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.88 (1H, s), 8.55 (1H, s), 8.77 (1H, s). 5 MS (ESI): m/z 416 418, MS (ESI*): m/z 418 420. Example 347 3-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoic acid 10 'H NMR (CDCl 3 ) 8 1.38 (3H, t, J= 7 Hz), 2.48 (2H, t, J= 7 Hz), 2.68 (3H, s), 2.85 2.97 (2H, m), 3.05 (2H, q, J= 7 Hz), 3.47 (3H, s), 4.67 (2H, s), 5.88 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 8.27 (1H, m), 8.78 (1H, d, J= 2 Hz), 9.23 (1H, d, J= 2 Hz). MS (ESI): m/z 380, MS (ESI*): m/z 382. 15 Example 348 3-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoic acid 'H NMR (CDCl 3 ) 6 1.38 (3H, t, J= 7 Hz), 2.46-2.58 (2H, i), 2.83-3.03 (2H, m), 3.05 20 (2H, q, J= 7 Hz), 3.47 (3H, s), 4.68 (2H, s), 5.46 (1H, d, J= 11 Hz), 5.88 (1H, d, J= 18 Hz), 5.93 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 6.68-6.82 (1H, dd, J= 11 Hz, 18 Hz), 7.78 (1H, m), 8.47 (1H, d, J= 2 Hz), 8.68 (1H, d, J= 2 Hz). MS (ESI~): m/z 364, MS (ESI*): m/z 366. 25 Example 349 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoic acid 'H NMR (CDCl 3 ) 6 1.37 (3H, t, J= 7 Hz), 1.68-1.82 (2H, m), 2.29 (2H, t, J= 7 Hz), 2.55-2.75 (2H, m), 3.04 (2H, q, J= 7 Hz), 3.45 (3H, s), 4.64 (2H, s), 5.93 (1H, d, 30 J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.91 (1H, m), 8.56 (1H, d, J= 2 Hz), 8.77 (1H, d, J= 2 Hz). MS (ESI-): m/z 430 432, MS (ESI*): n/z 432 434. 214 WO 2004/063197 PCT/JP2003/017091 Example 350 4-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoic acid 'H NMR (CDCl 3 ) 5 1.38 (3H, t, J= 7 Hz), 1.72-1.87 (2H, m), 2.26 (2H, t, J= 7 Hz), 5 2.53-2.80 (2H, m), 3.06 (2H, q, J= 7 Hz), 3.46 (3H, s), 4.68 (2H, m), 5.47 (1H, d, J= 11 Hz), 5.88 (1H, d, J= 18 Hz), 5.93 (1H, d, J= 4 Hz), 6.59 (1H, d, J= 4 Hz), 6.72-6.83 (1H, dd, J= 11 Hz, 18 Hz), 7.81 (1H, m), 8.50 (1H, d, J= 2 Hz), 8.63 (1H, d, J= 2 Hz). MS (ESI-): m/z 378, MS (ESI*): m/z 380. 10 Example 351 4-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoic acid 'H NMR (CDC 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.66-1.83 (2H, m), 2.26 (2H, t, J= 7 Hz), 15 2.55-2.70 (2H, m), 2.70 (3H, s), 3.05 (2H, q, J= 7 Hz), 3.46 (3H, s), 4.67 (2H, s), 5.88 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz),8.29 (1H, m), 8.80 (1H, d, J= 2 Hz), 9.22 (1H, d, J= 2 Hz). MS (ESI): m/z 394 , MS (ESI*): m/z 396. 20 Example 352 5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 'H NMR (CDCl 3 ) 8 1.34 (3H, t, J= 7 Hz), 1.44-1.65 (4H, m), 2.16-2.32 (2H, m), 2.34-2.46 (2H, m), 2.53 (3H, s), 3.02 (2H, q, J= 7 Hz), 5.06 (2H, br), 5.86 (1H, d, J= 4 Hz), 5.98 (1H, d, J= 4 Hz), 7.45 (1H, s), 7.84 (1H, s), 8.58 (1H, s). 25 MS (ESI~): m/z 351, MS (ESI*): m/z 353. Example 353 5-{4-[5-(dimethylamino)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl}pentanoic acid 30 'H NMR (CDC 3 ) 8 1.37 (3H, t, J= 7 Hz), 1.40-1.70 (4H, m), 2.23 (2H, m), 2.36-2.50 (2H, m), 2.56 (3H, s), 3.03 (2H, q, J= 7 Hz), 3.06 (6H, s), 5.88 (1H, d, J= 4 Hz), 6.53 (1H, d, J= 4 Hz), 7.13 (1H, s), 7.90 (1H, s), 8.14 (1H, m). MS (ESI+): m/z 381. 215 WO 2004/063197 PCT/JP2003/017091 Example 354 3-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo(1,2-b]pyridazin-3-yl]propanoic acid 'H NMR (CDCl 3 ) 8 1.37 (3H, t, J= 7 Hz), 2.40-2.53 (2H, m), 2.60 (3H, s), 2.68 (3H, 5 s), 2.83 (2H, t, J= 7 Hz), 3.03 (2H, q, J= 7 Hz), 5.83 (1H, d, J= 4 Hz), 6.53 (1H, d, J= 4 Hz), 8.27 (1H, m), 8.78 (1H, d, J= 2 Hz), 9.22 (1H, d, J= 2 Hz). MS (ESF): m/z 350, MS (ESI*): m/z 352. Example 355 10 5-[2-[(benzyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 'H NMR (CDCI 3 ) 8 1.37 (3H, t, J= 7 Hz), 1.35-1.55 (4H, m), 2.05-2.20 (2H, m), 2.42 (3H, s), 2.40-2.70 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.63 (2H, s), 4.74 (2H, m), 5.88 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.27-7.42 (5H, m), 7.53 (1H, s), 8.40 (1H, 15 s), 8.53 (1H, s). MS (ESI*): m/z 458. Example 356 3-[2-[(benzyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 20 yl]propanoic acid 'H NMR (CDC1 3 ) 8 1.38 (3H, t, J= 7 Hz), 2.40 (3H, s), 2.40-2.54 (2H, m), 2.80-3.08 (2H, m), 3.06 (2H, q, J= 7 Hz), 4.65 (2H, s), 4.77 (2H, m), 5.89 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.26-7.42 (5H, m), 7.54 (1H, s), 8.39 (1H, d, J= 2 Hz), 8.48 (1H, d, J= 2 Hz). 25 MS (ESF): m/z 428, MS (ESI*): m/z 430. Example 357 5-[2-[(cyclohexyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo(1,2-b]pyridazin-3 yl]pentanoic acid 30 'H NMR (CDC1 3 ) 8 1.20-1.45 (6H, m), 1.36 (3H, t, J= 7 Hz), 1.45-1.63 (4H, m), 1.70-1.83 (2H, m), 1.95-2.08 (2H, m), 2.14-2.28 (2H, m), 2.42 (3H, s), 2.46-2.60 (1H, m), 2.60-2.75 (1H, m), 3.03 (2H, q, J= 7 Hz), 3.42-3.54 (1H, m), 4.72 (2H, m), 5.87 (1H, d, J= 4 Hz), 6.54 (1H, d, J= 4 Hz), 7.55 (1H, s), 8.41 (1H, s), 8.53 216 WO 2004/063197 PCT/JP2003/017091 (1H, s). MS (ESI): m/z 448, MS (ESI*): m/z 450. Example 358 5 5- 4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3 yl}pentanoic acid 1 H NMR (CDCl 3 ) 8 1.18-1.60 (10H, m), 1.36 (3H, t, J= 7 Hz), 1.70-1.80 (2H, m), 1.95-2.05 (2H, m), 2.22 (2H, t, J= 7 Hz), 2.50-2.70 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.42-3.53 (1H, m), 4.68 (2H, s), 5.89 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.88 10 (1H, s), 8.54 (1H, d, J= 2 Hz), 8.77 (1H, d, J= 2 Hz). MS (ESI*): m/z 514 516. Example 359 3-[2-[(cyclohexyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 15 yl]propanoic acid 'H NMR (CDC 3 ) 8 1.20-1.45 (5H, m), 1.37 (3H, t, J= 7 Hz), 1.50-1.60 (1H, m), 1.72-1.84 (2H, m), 1.96-2.08 (2H, m), 2.42 (3H, s), 2.48-2.62 (2H, m), 2.80-3.10 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.44-3.66 (1H, m), 4.73 (2H, s), 5.88 (1H, d, J= 4 Hz), 6.57 (1H, d, J= 4 Hz), 7.55 (1H, s), 8.40 (1H, s), 8.51 (1H, s). 20 MS (ESI+): m/z 422. Example 360 3-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)iethyl]-7-ethylpyrrolo[1,2-b]pyridazin-3 yl}propanoic acid 25 'H NMR (CDCl 3 ) 8 1.18-1.47 (5H, m), 1.37 (3H, t, J= 7 Hz), 1.52-1.63 (1H, m), 1.72-1.85 (2H, m), 1.97-2.07 (2H, m), 2.48-2.62 (2H, m), 2.80-3.10 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.44-3.57 (1H, m), 4.73 (2H, s), 5.91 (1H, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.88 (1H, t, J= 2 Hz), 8.55 (1H, d, J= 2 Hz), 8.77 (1H, d, J= 2 Hz). MS (ESI~): m/z 484 486, MS (ESI*): m/z 486 488. 30 Example 361 5-[7-ethyl-2-(isopropoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[l,2-b]pyridazin-3 yl]pentanoic acid 217 WO 2004/063197 PCT/JP2003/017091 'H NMR (CDC13) 5 1.25 (6H, d, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.44-1.63 (4H, in), 2.15-2.27 (2H, m), 2.43 (3H, s), 2.47-2.60 (1H, m), 2.60-2.73 (1H, m), 3.03 (2H, q, J= 7 Hz), 3.75-3.87 (1H, m), 4.67 (2H, s), 5.87 (1H, d, J= 4 Hz), 6.56 (1H, d, J= 4 Hz), 7.55 (1H, s), 8.41 (1H, s), 8.53 (1H, s). 5 MS (EST): m/z 408, MS (ESI*): m/z 410. Example 362 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isopropoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 10 'H NMR (CDC 3 ) 5 1.25 (6H, d, J= 7 Hz), 1.36 (3H, t, J= 7 Hz), 1.45-1.65 (4H, m), 2.23 (2H, t, J= 7 Hz), 2.50-2.60 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.75-3.85 (1H, m), 4.66 (2H, s), 5.89 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.89 (1H, m), 8.54 (1H, d, J= 2 Hz), 8.77 (1H, d, J= 2 Hz). MS (ESI*): m/z 474 476. 15 Example 363 5--[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 'H NMR (CDC1 3 ) 5 1.38 (3H, t, J= 7 Hz), 1.40-1.65 (4H, m), 2.22 (2H, t, J= 7 Hz), 20 2.33-2.45 (2H, m), 2.43 (3H, s), 3.03 (2H, q, J= 7 Hz), 4.87 (2H, s), 5.94 (1H, d, J= 4 Hz), 6.57 (1H, d, J= 4 Hz), 7.56 (1H, s), 8.43 (1H, s), 8.54 (1H, s). MS (EST): m/z 366, MS (ESI*): m/z 368. Example 364 25 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[2-(4-morpholinyl)-2 oxoethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoic acid 'H NMR (CDC 3 ) 5 1.37 (3H, t, J= 7 Hz), 1.40-1.63 (4H, m), 2.22 (2H, t, J= 7 Hz), 2.43 (3H, s), 2.50-2.72 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.51 (2H, m), 3.57-3.75 (6H, m), 4.32 (2H, s), 4.70-4.86 (2H, m), 5.90 (1H, d, J= 4 Hz), 6.59 (1H, d, J= 4 30 Hz), 7.53 (1H, s), 8.42 (1H, s), 8.53 (1H, s). MS (EST): m/z 493, MS (ESI+): m/z 495. Example 365 218 WO 2004/063197 PCT/JP2003/017091 5-[7-ethyl-2-{[2-(methylamino)-2-oxoethoxy]methyl}-4-(5-methyl-3 pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 'H NMR (CDCl 3 ) 8 1.37 (3H, t, J= 7 Hz), 1.40-1.65 (4H, m), 2.22 (2H, t, J= 7 Hz), 2.44 (3H, s), 2.45-2.64 (2H, m), 2.87 (3H, m), 3.03 (2H, q, J= 7 Hz), 4.13 (2H, s), 5 4.74 (2H, m), 5.93 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 6.83 (1H, br), 7.57 (1H, s), 8.42 (1H, s), 8.53 (1H, s). MS (ESIT): m/z 437, MS (ESI'): m/z 439. Example 366 10 5-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 b]pyridazin-3-yl]pentanoic acid 'H NMR (CDCl 3 ) 6 0.23-0.33 (2H, m), 0.55-0.64 (2H, m), 1.07-1.22 (1H, m), 1.36 (3H, t, J= 7 Hz), 1.45-1.68 (4H, m), 2.19 (2H, t, J= 7 Hz), 2.43 (3H, s), 2.50-2.75 (2H, m), 3.02 (2H, q, J= 7 Hz), 3.40 (2H, d, J= 7 Hz), 4.70 (2H, m), 5.87 (1H, d, 15 J= 4 Hz), 6.56 (1H, d, J= 4 Hz), 7.57 (1H, s), 8.40 (1H, s), 8.54 (1H, s). MS (ESI*): m/z 422. Example 367 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 20 b]pyridazin-3-yl]pentanoic acid 'H NMR (CDC 3 ) 6 0.87-1.04 (2H, m), 1.10-1.82 (13H, m), 1.37 (3H, t, J= 7 Hz), 2.18 (2H, t, J= 7 Hz), 2.43 (3H, s), 2.47-2.72 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.33 (2H, d, J= 7 Hz), 4.63 (2H, m), 5.87 (1H, d, J= 4 Hz), 6.56 (1H, d, J= 4 Hz), 7.56 (1H, s), 8.42 (1H, s), 8.53 (1H, s). 25 MS (ESIF): m/z 462, MS (ESI*): m/z 464. Example 368 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoic acid 30 'H NMR (CDC 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.35-1.57 (4H, m), 2.13 (2H, t, J= 7 Hz), 2.42 (3H, s), 2.47-2.66 (2H, m), 3.03 (2H, q, J= 7 Hz),4.68 (2H, s), 4.77 (2H, m), 5.90 (1H, d, J= 4 Hz), 6.59 (1H, d, J= 4 Hz), 7.28-7.36 (1H, m), 7.53 (1H, s), 7.73 (1H, d, J= 8 Hz), 8.41 (1H, d, J= 2 Hz), 8.53 (2H, m), 8.63 (1H, s). 219 WO 2004/063197 PCT/JP2003/017091 MS (ESI-): m/z 457, MS (ESI+): m/z 459. Example 369 5-{ 7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2 5 b]pyridazin-3-yl}pentanoic acid 'H NMR (CDCl 3 ) 8 1.37 (3H, t, J= 7 Hz), 1.45-1.65 (4H, m), 2.23 (2H, t, J= 7 Hz), 2.41 (3H, s), 2.48-2.74 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.80 (2H, s), 4.82 (2H, m), 5.88 (1H, d, J= 4 Hz), 6.57 (1H, d, J= 4 Hz), 7.26 (1H, m), 7.47-7.53 (2H, m), 7.69-7.77 (1H, m), 8.42 (1H, d, J= 2 Hz), 8.50 (1H, d, J= 2 Hz), 8.58 (1H, d, J= 7 10 Hz). MS (ESI~): m/z 457, MS (ESI*): m/z 459. Example 370 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 15 b]pyridazin-3-yl}pentanoic acid 'H NMR (CDCl 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.40-1.62 (4H, m), 2.16 (2H, t, J= 7 Hz), 2.43 (3H, s), 2.48-2.71 (2H, m), 3.02 (2H, q, J= 7 Hz), 4.68 (2H, s), 4.79 (2H, m), 5.91 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 7.32 (2H, d, J= 7 Hz), 7.54 (1H, s), 8.42 (1H, d, J= 2 Hz), 8.54 (1H, d, J= 2 Hz), 8.55 (2H, d, J= 7 Hz). 20 MS (ESI-): m/z 457, MS (ESI*): m/z 459. Example 371 5-{ 7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoic acid 25 'H NMR (CDCI 3 ) 8 1.37 (3H, t, J= 7 Hz), 1.45-1.62 (4H, m), 2.18 (2H, t, J= 7 Hz), 2.43 (3H, s), 2.48-2.73 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.83 (2H, s), 4.88 (2H, m), 5.90 (1H, d, J= 4 Hz), 6.59 (1H, d, J= 4 Hz), 7.54 (1H, s), 8.42 (1H, s), 8.48-8.56 (3H, m), 8.76 (1H, s). MS (ESI-): m/z 458, MS (ESI*): m/z 460. 30 Example 372 5-[2-[(benzylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 220 WO 2004/063197 PCT/JP2003/017091 'H NMR (DMSO-d 6 ) 8 1.33 (3H, t, J= 7 Hz), 1.28-1.48 (4H, m), 2.03-2.13 (2H, m), 2.30-2.45 (2H, m), 2.40 (3H, s), 3.06 (2H, q, J= 7 Hz), 4.37 (2H, s), 4.46 (2H, s), 5.92 (1H, d, J= 4 Hz), 6.68 (1H, d, J= 4 Hz), 7.40-7.52 (3H, m), 7.56-7.67 (3H, m), 8.36 (1H, d, J= 2 Hz), 8.57 (1H, d, J= 2 Hz). 5 MS (ESI*): m/z 457. Example 373 5-[2-[(acetylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 10 'H NMR (CDCl 3 ) 8 1.40 (3H, t, J= 7 Hz), 1.40-1.64 (4H, m), 2.16 (3H, s), 2.23 (2H, t, J= 7 Hz), 2.35-2.50 (2H, m), 2.43 (3H, s), 3.03 (2H, q, J= 7 Hz), 4.63-4.72 (2H, m), 5.92 (1H, d, J= 4 Hz), 6.57 (1H, d, J= 4 Hz), 6.88-6.97 (1H, br), 7.53 (1H, s), 8.41 (1H, s), 8.53 (1H, s). MS (ESI-): m/z 407, MS (ESI*): m/z 409. 15 Example 374 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{ [(methylsulfonyl)amino]methyl}pyrrolo[1,2 b]pyridazin-3-yl)pentanoic acid 'H NMR (CDCl 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.46-1.66 (4H, m), 2.23 (2H, t, J= 7 Hz), 20 2.44 (3H, s), 2.39-2.53 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.05 (3H, s), 4.57 (2H, s), 5.72 (1H, br), 5.96 (1H, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.54 (1H, s), 8.41 (1H, d, J= 2 Hz), 8.55 (1H, d, J= 2 Hz). MS (ESI~): m/z 443, MS (ESI*): m/z 445. 25 Example 375 5-[2-[(benzoylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 'H NMR (CDCl 3 ) 8 1.42 (3H, t, J= 7 Hz), 1.50-1.68 (4H, m), 2.25 (2H, t, J= 7 Hz), 2.44 (3H, s), 2.40-2.60 (2H, m), 3.07 (2H, q, J= 7 Hz), 4.89 (2H, m), 5.95 (1H, d, 30 J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.46-7.60 (4H, m), 7.83 (1H, br), 7.93 (2H, d, J= 8 Hz), 8.44 (1H, d, J= 2 Hz), 8.56 (1H, d, J= 2 Hz). MS (ESI~): m/z 469, MS (ESI*): m/z 471. 221 WO 2004/063197 PCT/JP2003/017091 Example 376 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(2-pyrazinylcarbonyl)amino]methyl}pyrrolo[1,2 b]pyridazin-3-yl)pentanoic acid 'H NMR (CDC 3 ) 8 1.41 (3H, t, J= 7 Hz), 1.51-1.72 (4H, m), 2.24 (2H, t, J= 7 Hz), 5 2.44 (3H, s), 2.45-2.58 (2H, m), 3.10 (211, q, J= 7 Hz), 4.90 (2H, m), 5.94 (1H, d, J= 4 Hz), 6.59 (11H, d, J= 4 Hz), 7.55 (1H, s), 8.43 (1H, s), 8.53 (1H, s), 8.62 (1H, m), 8.79 (1H, d, J= 2 Hz), 9.20 (1H, br), 9.45 (1H, d, J= 2 Hz). MS (ESI-): m/z 471, MS (ESI*): m/z 473. 10 Example 377 5-[7-ethyl-2-{ [(methoxycarbonyl)amino]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 b]pyridazin-3-yl]pentanoic acid 1 H NMR (CDCl 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.45-1.65 (411, m), 2.23 (211, t, J= 7 Hz), 2.40-2.53 (2H, m), 2.44 (3H, s), 3.02 (2H, q, J= 7 Hz), 3.05 (311, s), 4.58 (2H, s), 15 5.69 (1H, br), 5.96 (1H, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.53 (1H, s), 8.41 (1H, d, J= 2 Hz), 8.54 (1H, d, J= 2 Hz). Example 378 To a solution of ethyl 7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 20 b]pyridazine-3-carboxylate (682 mg) in ethanol (20 mL) was added potassium hydroxide (5 g) solution (10 mL) and the mixture was heated under reflux for 1 hour. The solution was acidified with 1 N hydrochloric acid to pH 3-4 and diluted with brine, and extracted with chloroform twice. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The crude produt was triturated with ethyl acetate to give 7 25 ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid as a yellow powder (590 mg) 7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid 'H NMR (CDCl 3 ) 6 1.39 (3H, t, J= 7 Hz), 2.44 (311, s), 2.69 (3H, s), 3.05 (2H, q, J= 7 30 Hz), 6.29 (111, d, J= 4 Hz), 6.67 (1H, d, J= 4 Hz), 7.97 (11H, s), 8.41 (111, s), 8.58 (111, s). MS (ESI~): m/z 294 , MS (ESI*): m/z 296. 222 WO 2004/063197 PCT/JP2003/017091 The following compound(s) was(were) obtained in substantially the same manner as that of Example 175. Example 379 5-[4-(3-cyanophenyl)-2-(ethoxymethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic 5 acid 'H NMR (CDCl 3 ) 8 1.25 (3H, t, J = 7 Hz), 1.34-1.53 (7H, m), 2.20 (2H, t, J = 7 Hz), 2.53 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.62 (2H, q, J = 7 Hz), 4.66 (2H, s), 5.33 (1H, d, J = 5 Hz), 6.57 (1H, d, J = 5 Hz), 7.60 (2H, m), 7.66 (1H, s), 7.74 (IH, m) 10 Example 380 5-[2-[(benzyloxy)methyl]-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 'H NMR (CDC 3 ) 8 1.30-1.46 (7H, m), 2.11 (2H, t, J = 7 Hz), 2.50 (2H, m), 3.02 (2H, q, J = 7 Hz), 4.64 (3H, s), 4.71 (3H, s), 5.83 (1H, d, J = 5 Hz), 6.56 (1H, d, J = 5 15 Hz), 7.25-7.34 (5H, m), 7.57 (2H, d, J = 9 Hz), 7.65 (1H, s), 7.74 (1H, m). MS (ESI*): m/z 468 (M + H) Example 381 4-({[3-(4-carboxybutyl)-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-2 20 yl]methoxy}methyl)benzoic acid 'H-NMR (CDCl 3 ) 8 1.05-1.43 (7H, m), 1.92 (2H, m), 2.31 (2H, m), 3.04 (2H, m), 4.65 (2H, s), 4.72 (2H, s), 5.82 (1H, m), 6.58 (1H, m), 7.46-7.77 (6H, m), 8.09 (2H, d, J = 8 Hz). MS (ESI*): m/z 510 (M - H) 25 Example 381-2 4-({[4-[3-(carbamoyl)phenyl]-3-(4-carboxybutyl)-7-ethylpyrrolo[1,2-b]pyridazin-2 yl]methoxy}methyl)benzoic acid 'H-NMR (CDC 3 ) 8 1.20-1.45 (7H, m), 2.03 (2H, m), 2.52 (2H, m), 3.03 (2H, q, J = 7 Hz), 4.69 (2H, s), 4.73 (2H, s), 5.36 (1H, d, J = 5 Hz), 6.57 (1H, d, J = 5 Hz), 30 7.39-7.60 (4H, m), 7.77 (1H, s), 7.93 (1H, d, J = 8 Hz), 7.98 (2H, d, J = 8 Hz). MS (ESI*): m/z 528 (M - H) The following compound(s) was(were) obtained in substantially the same manner 223 WO 2004/063197 PCT/JP2003/017091 as that of Example 77. Example 382 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-methyl-1-piperazinyl)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoic acid 5 'H NMR (CDCl 3 ) 5 1.34 (3H, t, J= 7 Hz), 1.38-1.59 (4H, m), 2.22 (2H, m), 2.43 2.60 (5H, m), 2.83-3.04 (8H, m), 3.74 (3H, s), 5.88 (1H, d, J = 5 Hz), 6.56 (1H1, d, J = 5 Hz), 7.87 (1H, m), 8.54 (1H, m), 8.76 (1H, m). Example 383 10 5-[4-(5-bromo-3-pyridinyl)-2-(cyanomethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 'H NMR (CDC 3 ) 8 1.35-1.60 (7H, m), 2.27 (2H, m), 2.46 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.98 (2H, s), 3.97 (1H, d, J = 5 Hz), 6.65 (1H, d, J = 5 Hz), 7.90 (1H, m), 8.54 (1H, s, br), 8.79 (1H, s, br). 15 Example 384 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 'H NMR (CDCl 3 ) 8 1.35-1.60 (7H, m), 2.22 (2H, t, J = 7 Hz), 2.38 (2H, m), 3.02 (2H, 20 q, J = 7 Hz), 4.86 (2H, s), 5.95 (1H, d, J = 5 Hz), 6.60 (1H, d, J = 5 Hz), 7.88 (1H, m), 8.54 (1H, s, br), 8.79 (1H, s, br). Example 385 To a solution of 7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 25 b]pyridazine-3-carboxylic acid (70 mg), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (68.2 mg) and 1-hydroxybenotriazole (48 mg) in dimethylformamide (2 mL) was added 2-aminoethanol (17.4 mg) and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, 30 water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (50:1 - 10:1). The crude product was triturated with isopropylether to give 7-ethyl-N-(2-hydroxyethyl)-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine 224 WO 2004/063197 PCT/JP2003/017091 3-carboxamide as a yellow powder (47 mg). 7-ethyl-N-(2-hydroxyethyl)-2-methyl-4-(5-methyl- 3 -pyridinyl)pyrrolo[1,2-b]pyridazine 3-carboxamide 5 1H NMR (CDCl 3 ) 8 1.38 (3H, t, J= 7 Hz), 2.39 (3H, s), 2.57 (3H, s), 3.02 (2H, q, J= 7 Hz), 3.33 (2H, m), 3.45 (2H, m), 6.03 (1H, br), 6.31 (1H, d, J= 4 Hz), 6.66 (1H, d, J= 4 Hz), 7.71 (1H, s), 8.47 (1H, s), 8.58 (1H, s). MS (ESI~): m/z 337, MS (ESI*): m/z 339. 10 The following compound(s) was(were) obtained in substantially the same manner as that of Example 385. Example 386 N-butyl-7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3 carboxamide 15 'H NMR (CDCl 3 ) 6 0.80 (3H, t, J= 7 Hz), 0.96-1.08 (2H, m), 1.08-1.25 (211, m), 1.38 (3H, t, J= 7 Hz), 2.40 (311, s), 2.56 (3H, s), 3.03 (2H, q, J= 7 Hz), 3.16 (2H, m), 5.36 (1H, br), 6.31 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.69 (1H, s), 8.53 (1H, s), 8.62 (1H, s). MS (ESI*): m/z 351. 20 Example 387 ethyl 3-({[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]carbonyl}amino)propanoate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 2.21 (2H, t, J= 7 Hz), 25 2.40 (3H, s), 2.55 (3H, s), 3.03 (2H, q, J= 7 Hz), 3.43 (2H, q, J= 7 Hz), 4.04 (2H, q, J= 7 Hz), 6.08 (1H, br), 6.30 (1H, d, J= 4 Hz), 6.65 (1H, d, J= 4 Hz), 7.67 (1H, s), 8.50 (1H, d, J= 1 Hz), 8.60 (1H, d, J= 1 Hz). MS (ESI*): m/z 395. 30 The following compound(s) was(were) obtained in substantially the same manner as that of Preparation 176. Example 388 4-(5-bromo-3-pyridinyl)-7-ethyl-2-methyl-3-[3-(4-morpholinyl)-3-oxopropyl]pyrrolo[1,2 225 WO 2004/063197 PCT/JP2003/017091 b]pyridazine 'H NMR(CDCl3) 6:H NMR(CDCl 3 ) 6:1.37(3H, t, J=7Hz), 2.41(2H, t, J=7Hz), 2.60(3H, s), 2.72-2.82(2H, m), 3.01(2H, q, J=7Hz), 3.19(2H, t, J=5Hz), 3.55(4H, t, J=5Hz), 3.63(2H, t, J=5Hz), 5.89(1H, d, J=4Hz), 6.55(1H, d, J=4Hz), 7.87(1H, t, 5 J=1Hz), 8.54(1H, d, J=lHz), 8.77(1H, d, J=lHz) MS(m/z) 457(M*), 459(M++2), 115(bp) mp. 178-1809C Example 389 10 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-N methylpropanamide 'H NMR(CDCl 3 ) 6:'H NMR(CDCl 3 ) 6:1.38(3H, t, J=7Hz), 2.20(2H, t, J=71z), 2.60(3H, s), 2.75(3H, d, J=6Hz), 2.78-2.89(2H, m), 3.01(2H, q, J=7Hz), 5.21 5.27(1H, m), 5.88(1H, d, J=4Hz), 6.54(1H, d, J=411z), 7.86(1H, t, J=1Hz), 15 8.53(111, d, J=lHz), 8.78(1H, d, J=1Hz) MS(m/z) 401(M++1), 403(M++1), 115(bp) mp. 172-174C The following compound(s) was(were) obtained in substantially the same manner as 20 that of Example 263. Example 390 N-{3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl]propanoyl}methanesulfonamide 'H NMR(CDCl 3 ) 6:1.36(3H, t, J=7Hz), 2.33-2.45(2H, m), 2.58(3H, s), 2.84-2.95(2H, 25 m), 3.01(2H, q, J=7Hz), 3.26(3H,s), 5.89(1H, d, J=4Hz), 6.56(1H, d, J=41z), 7.90(1H, s), 8.50(1H, s), 8.77(1H, s) MS(m/z) 465(M+, bp), 467(M+-2, bp) mp. 196.5-197.59C 30 The following compound(s) was(were) obtained in substantially the same manner as that of Example 224. Example 391 226 WO 2004/063197 PCT/JP2003/017091 2-[{3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-blpyridazin-3 yl]propanoyl} (methyl)amino]ethanesulfonic acid 'H NMR (CDCl 3 ) 6 1.32 (3H, t, J = 7 Hz), 1.90 2H, m), 2.26 (3H, s), 2.57-2.2.78 (4H, m), 2.98 (2H, q, J = 7 Hz), 3.31 (2H, m), 6.00 (1H, d, J = 5 Hz), 6.61 (1H, d, J = 5 5 Hz), 7.20-7.52 (5H, m). The following compound(s) was(were) obtained in a similar manner to that of Preparation 20. Preparation 217 10 1-tert-butyl 7-ethyl 2-(isobutoxyacetyl)heptanedioate 'H NMR (300 MHz, CDCl 3 ) 8 0.95 (6H, d, J = 7 Hz), 1.27 (3H, t, J = 7 Hz), 1.31 1.41 (2H, m), 1.46 (9H, s), 1.66 (2H, tt, J = 7, 7 Hz), 1.75-1.98 (3H, m), 2.31 (2H, t, J = 8 Hz), 3.26 (2H, d, J = 7 Hz), 3.56 (1H, t, J = 7 Hz), 4.06-4.17 (4H, m). 15 Preparation 218 1-tert-butyl 6-ethyl 2-(isobutoxyacetyl)hexanedioate 'H NMR (300 MHz, CDCl 3 ) 8 0.93 (6H, d, J = 7 Hz), 1.25 (3H, t, J = 7 Hz), 1.45 (9H, s), 1.59-1.69 (2H, m), 1.80-1.95 (3H, m), 2.32 (2H, t, J = 7 Hz), 2.25 (2H, d, J = 7 Hz), 3.57 (1H, t, J = 7 Hz), 4.10 (2H, s), 4.12 (2H, q, J = 7 Hz). 20 The following compound(s) was(were) obtained in a similar manner to that of Preparation 24. Preparation 219 1-tet-butyl 6-ethyl 2-acetyl-2-(2-chloroisonicotinoyl)hexanedioate 25 'H NMR (CDCl 3 ) 6 1.26 (3H, t, J= 7 Hz), 1.34 (9H, s), 1.60-1.73 (2H, m), 2.22-2.32 (2H, m), 2.39 (2H, t, J= 7 Hz), 2.49 (3H, s), 4.12 (2H, q, J= 7 Hz), 7.43 (1H, d, J= 5 Hz), 7.57 (1H, s), 8.50 (1H, d, J= 5 Hz). MS (ESI*): m/z 412. 30 Preparation 220 1-tert-butyl 5-ethyl 2-acetyl-2-(2-chloroisonicotinoyl)pentanedioate 'H NMR (CDCl 3 ) 8 1.37 (3H, t, J= 7 Hz), 1.72-1.84 (2H, m), 2.33 (2H, t, J= 7 Hz), 2.47-2.57 (2H, m), 2.58 (3H, s), 3.03 (2H, q, J= 7 Hz), 5.88 (1H, d, J= 4 Hz), 6.53 227 WO 2004/063197 PCT/JP2003/017091 (1H, d, J= 4 Hz), 7.27 (1H, m), 7.38 (1H, s), 8.53 (1H, d, J= 5 Hz). MS (ESI): m/z 356, MS (ESI*): m/z 358. Preparation 221 5 1-tert-butyl 7-ethyl 2-(2-chloroisonicotinoyl)-2-(phenylacetyl)heptanedioate 'H NMR (CDC 3 ) 6 1.24 (3H, t, J= 7 Hz), 1.35 (9H, s), 1.63-1.76 (2H, m), 2.22-2.37 (4H, m), 3.93 (1H, d, J= 17 Hz), 4.12 (2H, q, J= 7 Hz), 4.29 (1H, d, J= 17 Hz), 7.22 (2H, d, J= 8 Hz), 7.26-7.36 (4H, m), 7.50 (1H, s), 8.42 (1H, d, J= 5 Hz). MS (ESI*): m/z 502. 10 Preparation 222 tert-butyl 2-[2-(2-methoxy-2-oxoethoxy)ethyl]-2-[(5-methyl-3-pyridinyl)carbonyl]-3 oxobutanoate 'H NMR (CDC 3 ) 6 1.33 (9H, s), 2.39 (3H, s), 2.47 (3H, s), 2.62 (2H, t, J= 7 Hz), 15 3.66 (2H, m), 3.70 (3H, s), 3.90 (2H, s), 7.87 (1H, s), 8.56 (1H, s), 8.75 (1H, s). MS (ESI*): m/z 394. Preparation 223 1-tert-butyl 4-ethyl 2-acetyl--2-[(5-bromo-3-pyridinyl)carbonyl]succinate 20 'H NMR (CDCl 3 ) 6 1.27 (3H, t, J= 7 Hz), 1.41 (9H, s), 2.45 (3H, s), 3.22 (2H, m), 4.12 (2H, q, J= 7 Hz), 8.22 (1H, m), 8.80 (1H, m), 8.82 (1H, m). MS (ESI*): m/z 428 430. Preparation 224 25 1-tert-butyl 5-ethyl 2-[(acetyloxy)acetyl]-2-[(5-methyl-3 pyridinyl)carbonyl]pentanedioate 'H NMR (CDCl 3 ) 6 1.23 (3H, t, J= 7 Hz), 1.35 (9H, s), 2.14 (3H, s), 2.40 (3H, s), 2.40-2.48 (2H, m), 2.62-2.70 (2H, m), 4.12 (2H, q, J= 7 Hz), 5.12 (1H, d, J= 18 Hz), 5.34 (1H, d, J= 18 Hz), 7.85 (1H, s), 8.58 (1H, s), 8.78 (1H, s). 30 MS (ESI*): m/z 436. Preparation 225 1-tert-butyl 6-ethyl 2-[(acetyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]hexanedioate 228 WO 2004/063197 PCT/JP2003/017091 'H NMR (CDC 3 ) 6 1.24 (3H, t, J= 7 Hz), 1.34 (9H, s), 1.60-1.75 (2H, m), 2.14 (3H, s), 2.26-2.39 (4H, m), 2.40 (3H, s), 4.12 (2H, q, J= 7 Hz), 5.13 (1H, d, J= 18 Hz), 5.40 (1H, d, J= 18 Hz), 7.86 (1H, s), 8.57 (1H, s), 8.78 (1H, s). MS (ESI'): m/z 450. 5 Preparation 226 1-tert-butyl 7-ethyl 2-[(acetyloxy)acetyl]-2-(3-cyanobenzoyl)heptanedioate 'IH NMR (CDC 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.32 (9H, s), 1.26-1.46 (2H, m), 1.66-1.77 (2H, m), 2.14 (3H, s), 2.26-2.38 (4H, m), 4.12 (2H, q, J= 7 Hz), 5.06 (1H, d, J= 10 18 Hz), 5.42 (1H, d, J= 18 Hz), 7.57 (1H, t, J= 8 Hz), 7.81 (IH, d, J= 8 Hz), 7.92 (1H, d, J= 8 Hz), 8.09 (1H, s). Preparation 227 1-tert-butyl 6-ethyl 2-[(acetyloxy)acetyl]-2-[(5-bromo-3-pyridinyl)carbonyl]hexanedioate 15 'H NMR (CDCI 3 ) 8 1.25 (3H, t, J= 7 Hz), 1.36 (9H, s), 1.60-1.74 (2H, m), 1.85-1.96 (2H, m), 2.14 (3H, s), 2.28-2.42 (2H, m), 4.12 (2H, q, J= 7 Hz), 5.12 (1H, d, J= 17 Hz), 5.42 (1H, d, J= 17 Hz), 8.23 (1H, m), 8.81 (1H, m), 8.83 (1H, m). Preparation 228 20 1-tert-butyl 5-ethyl 2-[(acetyloxy)acetyl]-2-[(5-bromo-3-pyridinyl)carbonyl]pentanedioate 'H NMR (CDC 3 ) 6 1.25 (3H, t, J= 7 Hz), 1.37 (9H, s), 2.14 (3H, s), 2.41-2.51 (2H, m), 2.66 (2H, t, J= 7 Hz), 4.13 (2H, q, J= 7 Hz), 5.11 (1H, d, J= 18 Hz), 5.33 (1H, d, J= 18 Hz), 8.22 (1H, m), 8.82 (2H, m). MS (ESI+): m/z 500 502. 25 Preparation 229 1-tert-butyl 5-ethyl 2-[(cyclohexylmethoxy)acetyl]-2-[(5-methyl-3 pyridinyl)carbonyl]pentanedioate 'H NMR (CDC 3 ) 8 0.80-0.98 (2H, m), 1.00-1.32 (3H, m), 1.23 (3H, t, J= 7 Hz), 1.38 30 (9H, s), 1.46-1.62 (6H, m), 2.39 (3H, s), 2.40-2.72 (4H, m), 3.19 (2H, d, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.31 (1H, d, J= 17 Hz), 4.39 (1H, d, J= 17 Hz), 7.88 (1H, s), 8.56 (1H, s), 8.77 (1H, s). MS (ESI*): m/z 490. 229 WO 2004/063197 PCT/JP2003/017091 Preparation 230 1-tert-butyl 5-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2 [(cyclohexylmethoxy)acetylpentanedioate 5 'H NMR (CDCl 3 ) 8 0.78-0.98 (2H, m), 1.10-1.33 (3H, m), 1.25 (3H, t, J= 7 Hz), 1.40 (9H, s), 1.38-1.83 (6H, m), 2.35-2.75 (4H, m), 3.22 (2H, d, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.25 (1H, d, J= 17 Hz), 4.37 (1H, d, J= 17 Hz), 8.22 (1H, s), 8.78 (1H, s), 8.86 (1H, s). MS (ESI*): m/z 554 556. 10 Preparation 231 1-tert-butyl 6-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2 [(cyclohexylmethoxy)acetyl]hexanedioate 'H NMR (CDCl 3 ) 8 0.80-0.97 (2H, m), 1.12-1.35 (3H, m), 1.25 (3H, t, J= 7 Hz), 1.39 15 (9H, s), 1.46-1.80 (10H, m), 2.22-2.45 (2H, m), 3.20 (2H, d, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.30 (1H, d, J= 17 Hz), 4.38 (1H, d, J= 17 Hz), 8.22 (1H, s), 8.78 (1H, s), 8.85 (1H, s). MS (ESI 4 ): m/z 568 570. 20 Preparation 232 1-tert-butyl 6-ethyl 2-[(cyclopropylmethoxy)acetyl]-2-[(5-methyl-3 pyridinyl)carbonyl]hexanedioate 'H NMR (CDCl 3 ) 8 0.16-0.28 (2H, m), 0.48-0.59 (2H, m), 0.98-1.12 (1H, m), 1.24 (3H, t, J= 7 Hz), 1.37 (9H, s), 1.55-1.80 (4H, m), 2.18-2.40 (2H, m), 2.39 (3H, s), 25 3.31 (2H, m), 4.12 (2H, q, J= 7 Hz), 4.38 (1H, d, J= 17 Hz), 4.53 (1H, d, J= 17 Hz), 7.88 (1H, s), 8.55 (1H, d, J= 2 Hz), 8.75 (1H, d, J= 2 Hz). MS (ESI*): m/z 462. Preparation 233 30 1-tert-butyl 5-ethyl 2-[(cyclopropylmethoxy)acetyl]-2-[(5-methyl-3 pyridinyl)carbonyl]pentanedioate 'H NMR (CDC 3 ) 8 0.15-0.23 (2H, m), 0.48-0.56 (2H, m), 0.95-1.10 (1H, m), 1.24 (3H, t, J= 7 Hz), 1.39 (9H, s), 2.39 (3H, s), 2.40-2.68 (4H, m), 3.28 (2H, m), 4.12 230 WO 2004/063197 PCT/JP2003/017091 (2H, q, J= 7 Hz), 4.36 (1H, d, J= 17 Hz), 4.48 (IH, d, J= 17 Hz), 7.88 (1H, s), 8.55 (iH, s), 8.75 (1H, s). MS (ESI*): m/z 448. 5 Preparation 234 1-tert-butyl 5-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(2 methoxyethoxy)acetyl]pentanedioate IH NMR (CDCl 3 ) 8 1.26 (3H, t, J= 7 Hz), 1.46 (9H, s), 2.15-2.25 (2H, m), 2.42-2.72 (2H, m), 3.38 (3H, s), 3.48-3.72 (4H, m), 4.12 (2H, q, J= 7 Hz), 4.43 (1H, d, J= 10 17 Hz), 4.58 (1H, d, J= 17 Hz), 8.22 (1H, s), 8.78 (1H, s), 8.82 (1H, s). MS (ESI*): m/z 516 518. Preparation 235 tert-butyl 2-[(5-bromo-3-pyridinyl)carbonyl]-3-oxobutanoate 15 'H NMR (CDCl 3 ) 8 1.22, 1.30 (9H, s), 2.22, 2.45 (3H, s), 7.96, 8.13 (1H, s), 8.66, 8.76-8.80 (2H, m). Preparation 236 1-tert-butyl 6-ethyl 2 -[(acetyloxy)acetyl]-2-[(5-chloro-3-pyridinyl)carbonyl]hexanedioate 20 'H NMR (300 MHz, CDC 3 ) 8 1.25 (3H, t, J = 7 Hz), 1.36 (9H, s), 1.63-1.71 (2H, m), 2.14 (3H, s), 2.27-2.40 (4H, m), 4.13 (2H, q, J = 7 Hz), 5.11 (1H, d, J = 18 Hz), 5.38 (1H, d, J = 18 Hz), 8.07 (1H, dd, J = 2 Hz), 8.71 (1H, d, J = 2 Hz), 8.80 (1H, d,J=2Hz). 25 Preparation 237 1-tert-butyl 7-ethyl 2-[(5-chloro-3-pyridinyl)carbonyl]-2 [(cyclopropylmethoxy)acetyl]heptanedioate 'H NMR (300 MHz, CDCl 3 ) 6 0.15-0.20 (2H, m), 0.49-0.58 (2H, m), 0.95-1.04 (1H, m), 1.24 (3H, t, J = 7 Hz), 1.38 (9H, s), 1.68 (2H, tt, J = 7, 7 Hz), 2.14-2.33 (4H, 30 m), 3.26-3.29 (2H, m), 4.07-4.19 (4H, m), 4.31 (1H, d, J = 17 Hz), 4.45 (1H, d, J = 17 Hz), 8.05 (1H, dd, J = 2 Hz), 8.68 (1H, d, J = 2 Hz), 8.78 (iH, d, J = 2 Hz). Preparation 238 231 WO 2004/063197 PCT/JP2003/017091 1-tert-butyl 6-ethyl 2 -[(5-chloro-3-pyridinyl)carbonyl]-2 [(cyclopropylmethoxy)acetyl]hexanedioate 'H NMR (300 MHz, CDC 3 ) 8 0.14-0.21 (2H, m), 0.49-0.55 (2H, m), 0.92-1.04 (1H, m), 1.25 (3H, t, J = 7 Hz), 1.39 (9H, s), 1.62-1.74 (2H, m), 1.82-1.90 (2H, m), 5 2.21-2.33 (2H, m), 3.27-3.31 (2H, m), 4.12 (2H, q, J = 7 Hz), 4.34 (11H, d, J = 18 Hz), 4.46 (1H, d, J = 18 Hz), 8.07 (1H, dd, J = 2, 2 Hz), 8.68 (1H, d, J = 2 Hz), 8.80 (1H,d,J = 2Hz). Preparation 239 10 1-tert-butyl 7-ethyl 2 -[(5-bromo-3-pyridinyl)carbonyl]-2-(isobutoxyacetyl)heptanedioate 1H NMR (300 MHz, CDCl 3 ) 6 0.85 (6H, d, J = 7 Hz), 1.24 (3H, t, J = 7 Hz), 1.38 (9H, s), 1.67 (2H, t, J = 7 Hz), 1.75-1.93 (3H, m), 2.24-2.33 (4H, m), 3.17 (2H, d, J = 7 Hz), 4.11 (2H, q, J = 7 Hz), 4.28 (1H, d, J = 17 Hz), 4.38 (1H, d, J = 17 Hz), 8.20 (11H, dd, J = 2, 2 Hz), 8.79 (11H, d, J = 2 Hz), 8.84 (11H, d, J = 2 Hz). 15 Preparation 240 1-tert-butyl 5-ethyl 2 -[(5-chloro- 3 -pyridinyl)carbonyl]-2-(isobutoxyacetyl)pentanedioate lH NMR (300 MHz, CDC 3 ) 6 0.84 (6H, d, J = 7 Hz), 1.24 (3H, t, J = 7 Hz), 1.39 (9H, s), 1.80 (1H, qt, J = 7 Hz), 2.34-2.71 (4H, m), 3.17 (2H, d, J = 7 Hz), 4.12 (2H, q, 20 J = 7 Hz), 4.28 (1H, d, J = 18 Hz), 4.36 (1H, d, J = 18 Hz), 8.07 (1H, s), 8.69 (1H, s), 8.83 (11H, s). Preparation 241 1-tert-butyl 5-ethyl 2 -[(acetyloxy)acetyl]-2-(3-chlorobenzoyl)pentanedioate 25 'H NMR (300 MHz, CDC 3 ) 6 1.24 (3H, t, J = 7 Hz), 1.34 (9H, s), 2.14 (3H, s), 2.35 2.44 (2H, m), 2.60-2.68 (2H, m), 4.11 (2H, q, J = 7 Hz), 5.11 (1H, d, J = 18 Hz), 5.35 (1H, d, J = 18 Hz), 7.38 (1H, dd, J = 8, 8 Hz), 7.53 (1H, d, J = 8 Hz), 7.60 (1H, d, J = 8 Hz), 7.79 (1H, s). 30 Preparation 242 1-tert-butyl 6-ethyl 2 -[(5-bromo- 3 -pyridinyl)carbonyl]-2-(isobutoxyacetyl)hexanedioate 'H NMR (300 MHz, CDC 3 ) 8 0.85 (6H, d, J = 7 Hz), 1.25 (3H, t, J = 7 Hz), 1.39 (9H, s), 1.59-1.72 (2H, m), 1.80 (1H, qt, J = 7,7Hz), 2.19-2.39 (4H, m), 3.18 (2H, d, J 232 WO 2004/063197 PCT/JP2003/017091 = 7 Hz), 4.12 (2H, q, J = 7 Hz), 4.31 (1H, d, J = 17 Hz), 4.40 (1H, d, J = 17 Hz), 8.22 (1H, dd, J = 2, 2 Hz), 8.79 (1H, d, J = 2 Hz), 8.85 (1H, d, J = 2 Hz). Preparation 243 5 tert-butyl 3-(5-brorno-3-pyridinyl)-2-[(5-bromo-3-pyridinyl)carbonyl]-3-oxopropanoate 'H NMR (CDCl 3 ) 8 1.05 (9H, s), 7.86 (2H, s), 8.46 (2H, s), 8.61 (2H, s). MS (ESI~): m/z 481 483 485. Preparation 244 10 1-tert-butyl 6-ethyl 2-[(acetyloxy)acetyl]-2-(3-chlorobenzoyl)hexanedioate 'H NMR (CDC 3 ) 8 1.24 (3H, t, J = 8 Hz), 1.33 (9H, s), 1.56-1.72 (2H, m), 2.15 (3H, s), 2.20-2.41 (4H, m), 4.11 (2H, q, J = 8 Hz), 5.13 (1H, d, J = 18 Hz), 5.40 (1H, d, J = 18 Hz), 7.38 (1H, t, J = 8 Hz), 7.52 (1H, br d, J = 8 Hz), 7.60 (1H, br d, J = 8 Hz), 7.79 (1H, br s). 15 Preparation 245 1-tert-butyl 7-ethyl 2-(methoxyacetyl)-2-[(5-methoxy-3-pyridinyl)carbonyl]heptanedioate 'H NMR (CDCl 3 ) 8 1.23 (3H, t, J = 8 Hz), 1.27-1.43 (11H, m), 1.60-1.74 (2H, m), 2.15-2.34 (4H, m), 3.37 (3H, s), 3.90 (3H, s), 4.10 (2H, q, J = 8 Hz), 4.35 (1H, d, 20 J = 18 Hz), 4.48 (1H, d, J = 18 Hz), 7.58 (IH, m), 8.43 (1H, d, J = 3 Hz), 8.50 (1H, d, J = 1 Hz). MS (ESI*): m/z 452 (M + H). Preparation 246 25 1-tert-butyl 7-ethyl 2-acetyl-2-[(5-methoxy-3-pyridinyl)carbonyl]heptanedioate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J = 8 Hz), 1.27-1.40 (11H, m), 1.60-1.74 (2H, m), 2.15-2.34 (4H, m), 2.44 (3H, s), 3.89 (3H, s), 4.10 (2H, q, J = 8 Hz), 7.61 (1H, m), 8.43 (1H, d, J = 3 Hz), 8.49 (1H, d, J = 1 Hz). MS (ESI*): m/z 422 (M + H). 30 Preparation 247 1-tert-butyl 5-ethyl 2-(methoxyacetyl)-2-[(5-methoxy-3-pyridinyl)carbonyl]pentanedioate 'H NMR (CDC 3 ) 8 1.24 (3H, t, J = 8 Hz), 1.38 (9H, s), 2.36-2.48 (2H, m), 2.53-2.67 233 WO 2004/063197 PCT/JP2003/017091 (2H, m), 3.37 (3H, s), 3.90 (3H, s), 4.11 (2H, q, J = 8 Hz), 4.33 (1H, d, J = 18 Hz), 4.45 (1H, d, J = 18 Hz), 7.59 (1H, m), 8.43 (1H, d, J = 3 Hz), 8.51 (1H, d, J = 1 Hz). MS (ESI*): m/z 446 (M + + Na). 5 Preparation 248 I-tert-butyl 6-ethyl 2-(methoxyacetyl)-2-[(5-methoxy-3-pyridinyl)carbonyl]hexanedioate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J = 8 Hz), 1.37 (9H, s), 1.52-1.75 (2H, m), 2.18-2.39 (4H, m), 3.38 (3H, s), 3.90 (3H, s), 4.11 (2H, q, J = 8 Hz), 4.37 (1H, d, J = 18 Hz), 10 4.51 (1H, d, J = 18 Hz), 7.60 (1H, m), 8.43 (1H, d, J = 3 Hz), 8.50 (1H, d, J = 1 Hz). MS (ESI+): m/z 438 (M + H). Preparation 249 15 1-tert-butyl 7-ethyl 2-(methoxyacetyl)-2-(5-pyrimidinylcarbonyl)heptanedioate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J = 8 Hz), 1.30-1.44 (11H, m), 1.62-1.75 (2H, m), 2.16-2.35 (4H, m), 3.35 (3H, s), 4.11 (2H, q, J = 8 Hz), 4.20 (1H, d, J = 18 Hz), 4.33 (1H, d, J = 18 Hz), 9.01 (2H, s), 9.31 (1H, s). MS (ESI*): m/z 423 (M + H). 20 Preparation 250 1-tert-butyl 6-ethyl 2-[(5-chloro-3-pyridinyl)carbonyl]-2-(methoxyacetyl)hexanedioate 'H NMR (CDCl 3 ) 8 1.26 (3H, t, J = 8 Hz), 1.39 (9H, s), 1.57-1.74 (2H, m), 1.78 (2H, br t, J = 8 Hz), 2.23-2.41 (2H, m), 3.38 (3H, s), 4.14 (2H, q, J = 8 Hz), 4.33 (1H, d, 25 J = 18 Hz), 4.45 (1H, d, J = 18 Hz), 8.07 (1H, m), 8.71 (1H, br s), 8.80 (1H, br s). MS (ESI'): m/z 442 (M + H). Preparation 251 1-tert-butyl 5-ethyl 2-[(5-chloro-3-pyridinyl)carbonyl]-2-(methoxyacetyl)pentanedioate 30 'H NMR (CDCl 3 ) 8 1.25 (3H, t, J = 8 Hz), 1.39 (9H, s), 2.37-2.48 (2H, m), 2.53-2.65 (2H, m), 3.36 (3H, s), 4.13 (2H, q, J = 8 Hz), 4.26 (1H, d, J = 18 Hz), 4.40 (1H, d, J = 18 Hz), 8.06 (1H, br s), 8.70 (1H, br s), 8.80 (1H, br s). MS (ESI*): m/z 428 (M + H). 234 WO 2004/063197 PCT/JP2003/017091 Preparation 252 1-tert-butyl 7-ethyl 2-[(5-chloro-3-pyridinyl)carbonyl]-2-(methoxyacetyl)heptanedioate 'H NMR (CDC 3 ) 8 1.24 (3H, t, J = 8 Hz), 1.31-1.48 (11H, m), 1.55-1.75 (2H, m), 5 2.15-2.35 (4H, m), 3.36 (3H, s), 4.10 (2H, q, J = 8 Hz), 4.27 (111, d, J = 18 Hz), 4.43 (1H, d, J = 18 Hz), 8.03 (1H, t, J = 2 Hz), 8.69 (1H, d, J = 2 Hz), 8.77 (1H, d, J = 2 Hz). MS (ESI*): m/z 456 (M + H). 10 Preparation 253 methyl 4-(acetyloxy)-2-[(5-bromo-3-pyridinyl)carbonyl]-3-oxobutanoate 'H NMR (CDC 3 ) 6 2.21 (3H, s), 3.58 (3H, br s), 4.87 (1H, br s), 5.19 (2H, br s), 7.98 (1H, br s), 8.58 (1H, br s), 8.79 (1H, br s). MS (ESI*): m/z 358,360 (M + H). 15 Preparation 254 tert-butyl 2-(2-{2-[2-(acetyloxy)ethoxy]ethoxy}ethyl)-2-[(5-methyl-3 pyridinyl)carbonyl]-3-oxobutanoate 'H-NMR (CDCl 3 ) 8 1.32 (9H, s), 2.07 (3H, s), 2.38 (3H, s), 2.45 (31H, s), 2.57 (2H, t, 20 J = 7 Hz), 3.43 (4H, m), 3.57 (4H, m), 4.16 (2H, m), 7.84 (11H, m), 8.53 (1H, m), 8.75 (1H, m). Preparation 255 1-tert-butyl 6-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2-(methoxyacetyl)hexanedioate 25 'H NMR (CDC 3 ) 6 1.26 (3H, t, J= 7 Hz), 1.39 (911, s), 1.55-1.75 (2H, m), 2.23-2.45 (4H, m), 3.38 (311, s), 4.12 (2H, q, J= 7 Hz), 4.34 (1H, d, J= 18 Hz), 4.47 (1H, d, J= 18 Hz), 8.22 (111, m), 8.81 (1H, d, J= 2 Hz), 8.83 (1H, d, J= 2 Hz). MS (ESI*): m/z 486 488. 30 Preparation 256 ethyl 2-(2-chloroisonicotinoyl)-3-oxobutanoate 'H NMR (CDCl 3 ) 8 0.91-1.00 (3H, m), 2.24 (1.2H, s), 2.48 (1.811, s), 4.02 (1.2H, q, J = 8 Hz), 4.10 (0.8H, q J = 8 Hz), 7.24 (0.6H, m), 7.39 (0.6H, s), 7.45 (0.4H, m), 235 WO 2004/063197 PCT/JP2003/017091 7.54 (1H, s), 8.49 (1H, m). MS (ESI*): m/z 298 (M + H). The following compound(s) was(were) obtained in a similar manner to that of 5 Prepatration 78. Preparation 257 ethyl 5-(2-chloroisonicotinoyl)-6-oxoheptanoate 'H NMR (CDCl 3 ) 8 1.25 (3H, t, J= 7 Hz), 1.60-1.73 (2H, m), 1.98-2.10 (2H, m), 2.20 (3H, s), 2.35 (2H, t, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.37 (1H, t, J= 7 Hz), 7.67 10 (1H, d, J= 5 Hz), 7.77 (11H, s), 8.59 (1H, d, J= 5 Hz). MS (ESI*): m/z 312. Preparation 258 ethyl 4-(2-chloroisonicotinoyl)-5-oxohexanoate 15 'H NMR (CDC 3 ) 8 1.26 (3H, t, J= 7 Hz), 2.21 (311, s), 2.22-2.35 (211, m), 2.36-2.47 (211, m), 4.12 (2H, q, J= 7 Hz), 4.57 (111, t, J= 7 Hz), 7.76 (1H, dd, J= 2 Hz, 5 Hz), 7.83 (1H, d, J= 2 Hz), 8.61 (1H, d, J= 5 Hz). MS (ESI*): m/z 298. 20 Preparation 259 ethyl 6-(2-chloroisonicotinoyl)-7-oxo-8-phenyloctanoate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.20-1.38 (2H, m), 1.60-1.72 (211, m), 1.95-2.06 (211, m), 2.28 (2H, t, J= 7 Hz), 3.71 (1H, d, J= 17 Hz), 3.80 (1H, d, J= 17 Hz), 4.12 (2H, q, J= 7 Hz), 4.41 (11H, t, J= 7 Hz), 7.10 (21H, m), 7.20-7.33 (4H, 25 m), 7.39 (1H, s), 8.42 (1H, d, J= 5 Hz). Preparation 260 methyl ({3-[(5-methyl-3-pyridinyl)carbonyl]-4-oxopentyl}oxy)acetate 'H NMR (CDCl 3 ) 8 2.23 (3H, s), 2.23-2.40 (2H, m), 2.44 (3H, s), 3.58 (2H, m), 3.71 30 (311, s), 4.02 (2H, s), 4.89 (1H, t, J= 7 Hz), 8.12 (111, s), 8.64 (11H, s), 9.07 (1H, s). MS (ESI*): m/z 294. Preparation 261 236 WO 2004/063197 PCT/JP2003/017091 methyl (4-oxo-4-phenylbutoxy)acetate 'H NMR (CDCl 3 ) 6 2.04-2.16 (2H, m), 3.15 (2H, t, J= 7 Hz), 3.64 (2H, t, J= 7 Hz), 3.73 (3H, s), 4.09 (2H, s), 7.46 (2H, t, J= 8 Hz), 7.56 (1H, t, J= 8 Hz), 7.99 (2H, d, J= 8 Hz). 5 MS (ESI*): m/z 237. The following compound(s) was(were) obtained in a similar manner to that of Preparation 78. Preparation 262 10 ethyl 3-[(5-bromo-3-pyridinyl)carbonyll-4-oxopentanoate 'H NMR (CDCl 3 ) 6 1.24 (3H, t, J= 7 Hz), 2.22 (3H, s), 2.97-3.17 (2H, m), 4.12 (2H, q, J= 7 Hz), 4.91 (1H, m), 8.41 (1H, m), 8.88 (1H, m), 9.12 (1H, m). MS (ESI*): m/z 328 330. 15 Preparation 263 ethyl 6-(acetyloxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate 'H NMR (CDC 3 ) 8 1.25 (3H, t, J= 7 Hz), 1.98 (3H, s), 2.23-2.34 (2H, m), 2.40-2.50 (2H, m), 2.45 (3H, s), 4.12 (2H, q, J= 7 Hz), 4.69 (2H, m), 4.82 (1H, t, J= 7 Hz), 8.14 (1H, s), 8.67 (1H, s), 9.07 (1H, s). 20 MS (ESI*): m/z 336. Preparation 264 ethyl 7-(acetyloxy)-5-[(5-methyl-3-pyridinyl)carbonyl]-6-oxoheptanoate 'H NMR (CDCl 3 ) 8 1.25 (3H, t, J= 7 Hz), 1.60-1.80 (2H, m), 2.02 (3H, s), 1.97-2.13 25 (2H, m), 2.35 (2H, t, J= 7 Hz), 2.45 (3H, s), 4.12 (2H, q, J= 7 Hz), 4.56 (1H, t, J= 7 Hz), 4.69 (1H, d, J= 17 Hz), 4.78 (1H, d, J= 17 Hz), 8.06 (1H, s), 8.66 (1H, s), 9.00 (1H, s). MS (ESI*): m/z 350. 30 Preparation 265 ethyl 8-(acetyloxy)-6-(3-cyanobenzoyl)-7-oxooctanoate 'H NMR (CDC1 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.35-1.50 (2H, m), 1.60-1.78 (2H, m), 2.04 (3H, s), 2.00-2.12 (2H, m), 2.29 (2H, t, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.49 (1H, 237 WO 2004/063197 PCT/JP2003/017091 t, J= 7 Hz), 4.68 (1H, d, J= 17 Hz), 4.75 (1H, d, J= 17 Hz), 7.66 (111, t, J= 8 Hz), 7.88 (1H, d, J= 8 Hz), 8.16 (1H, d, J= 8 Hz), 8.26 (111, s). MS (ESI~): m/z 372. 5 Preparation 266 ethyl 7-(acetyloxy)-5-[(5-bromo-3-pyridinyl)carbonyl]-6-oxoheptanoate 'H NMR (CDC1 3 ) 6 1.25 (3H, t, J= 7 Hz), 1.60-1.82 (2H, m), 2.04 (3H, s), 2.03-2.15 (2H, m), 2.35 (2H, t, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.51 (11H, t, J= 7 Hz), 4.70 (111, d, J= 17 Hz), 4.75 (11, d, J= 17 Hz), 8.39 (1H, m), 8.88 (1H, s), 9.07 (1H, s). 10 MS (ESI~): m/z 414 416, MS (ESI+): m/z 414 416. Preparation 267 ethyl 6-(acetyloxy)-4-[(5-bromo-3-pyridinyl)carbonyl]-5-oxohexanoate 'H NMR (CDC 3 ) 6 1.26 (3H, t, J= 7 Hz), 2.00 (31H, s), 2.22-2.36 (2H, m), 2.43-2.53 15 (2H, m), 4.13 (211, q, J= 7 Hz), 4.70 (2H, m), 4.80 (1H, t, J= 7 Hz), 8.48 (11H, s), 8.90 (111, s), 9.19 (1H, s). MS (ESI*): m/z 400 402. Preparation 268 20 ethyl 6-(cyclohexylmethoxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate 'H NMR (CDC 3 ) 6 0.60-0.82 (2H, m), 0.93-1.10 (3H, m), 1.12-1.65 (6H, m), 1.25 (311, t, J= 7 Hz), 2.07-2.17 (1H, m), 2.22-2.35 (111, m), 2.42 (211, m), 2.44 (3H, s), 3.05-3.23 (2H, m), 3.96 (211, s), 4.12 (2H, q, J= 7 Hz), 4.92 (1H, m), 8.16 (1H, s), 8.66 (1H, s), 9.08 (1H, s). 25 MS (ESI*): m/z 390. Preparation 269 ethyl 4-[(5-bromo-3-pyridinyl)carbonyl]-6-(cyclohexylmethoxy)-5-oxohexanoate 'H NMR (CDC 3 ) 6 0.63-0.84 (2H, m), 0.93-1.88 (3H, m), 1.25 (311, t, J= 7 Hz), 30 1.35-1.90 (6H, m), 2.02-2.14 (111, m), 2.20-2.36 (111, m), 2.44 (2H, t, J= 7 Hz), 3.04-3.20 (211, m), 3.95 (211, s), 4.13 (2H, q, J= 7 Hz), 4.85-4.93 (1H, m), 8.50 (111, m), 8.88 (1H, d, J= 2 Hz), 9.20 (1H, d, J= 2 Hz). MS (ESI*): m/z 454 456. 238 WO 2004/063197 PCT/JP2003/017091 Preparation 270 ethyl 5-[(5-bromo-3-pyridinyl)carbonyl]-7-(cyclohexylmethoxy)-6-oxoheptanoate 'H NMR (300 MHz, CDC 3 ) 5 0.75-0.86 (2H, n), 0.95-1.15 (3H, m), 1.24 (3H, t, J= 5 7 Hz), 1.40-1.90 (10H, m), 2.36 (2H, t, J= 7 Hz), 3.12 (2H, q, J= 7 Hz), 3.97 (2H, s), 4.12 (2H, q, J= 7 Hz), 4.71 (1H, t, J= 7 Hz), 8.41 (1H, s), 8.88 (1H, s), 9.12 (IH, s). MS (ESI*): m/z 468 470. 10 Preparation 271 ethyl 7-(cyclopropylmethoxy)-5-[(5-methyl-3-pyridinyl)carbonyll-6-oxoheptanoate 'H NMR (CDCl 3 ) 5 -0.08-0.00 (1H, m), 0.00-0.15 (1H, m), 0.28-0.49 (2H, m), 0.72 0.87 (1H, m), 1.23 (3H, t, J= 7 Hz), 1.58-2.13 (4H, m), 2.32 (2H, t, J= 7 Hz), 2.44 (3H, s), 3.10-3.26 (2H, m), 4.02 (2H, m), 4.12 (2H, q, J= 7 Hz), 4.77 (1H, t, J= 7 15 Hz), 8.07 (1H, s), 8.63 (1H, s), 9.03 (1H, s). MS (ESI+): m/z 362. Preparation 272 ethyl 6-(cyclopropylmethoxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate 20 'H NMR (CDCl 3 ) 5 -0.08-0.00 (1H, m), 0.00-0.13 (1H, m), 0.23-0.47 (2H, m), 0.68 0.84 (1H, m), 1.24 (3H, t, J= 7 Hz), 2.03-2.17 (1H, m), 2.22-2.36 (1H, m), 2.40 (2H, m), 2.44 (3H, s), 3.12 (2H, m), 3.98 (1H, d, J= 17 Hz), 4.06 (1H, d, J= 17 Hz), 4.12 (2H, q, J= 7 Hz), 4.93 (1H, m), 8.12 (1H, s), 8.65 (1H, s), 9.08 (1H, s). MS (ESI*): m/z 348. 25 Preparation 273 ethyl 4-[(5-bromo-3-pyridinyl)carbonyl]-6-(2-methoxyethoxy)-5-oxohexanoate 'H NMR (CDCl 3 ) 5 1.25 (3H, t, J= 7 Hz), 1.90-2.37 (2H, m), 2.43 (2H, t, J= 7 Hz), 3.18 (3H, s), 3.16-3.73 (4H, m), 4.06 (2H, q, J= 7 Hz), 4.10-4.24 (2H, m), 4.86 30 4.93 (1H, m), 8.51 (1H, m), 8.87 (IH, d, J= 2 Hz), 9.20 (1H, d, J= 2 Hz). MS (ESI~): m/z 414 416, MS (ESI*): m/z 416 418. Preparation 274 239 WO 2004/063197 PCT/JP2003/017091 1-(5-bromo-3-pyridinyl)-1,3-butanedione 1H NMR (CDC1 3 ) 8 2.25 (3H, s), 6.18 (1H, s), 8.31 (1H, s), 8.78 (1H, s), 8.96 (1H, s). MS (ESI'): m/z 242 244. 5 Preparation 275 ethyl 7-(acetyloxy)-5-[(5-chloro-3-pyridinyl)carbonyl]-6-oxoheptanoate H NMR (300 MHz, CDCl 3 ) 5 1.25 (3H, t, J = 7 Hz), 1.60-1.70 (4H, m), 2.04 (3H, s), 2.35 (2H, t, J = 6 Hz), 4.12 (2H, q, J = 7 Hz), 4.52 (111, t, J = 7 Hz), 4.69 (1H, d, J = 18 Hz), 4.78 (1H, d, J = 18 Hz), 8.24 (1H, s), 8.78 (1H, s), 9.05 (1H, s). 10 Preparation 276 ethyl 6-[(5-chloro-3-pyridinyl)carbonyl]-8-(cyclopropylmethoxy)-7-oxooctanoate 'H NMR (300 MHz, CDC 3 ) 8 -0.09-0.11 (2H, m), 0.25-0.35 (1H, m), 0.37-0.46 (1H, m), 0.70-0.79 (1H, m), 1.24 (3H, t, J = 7 Hz), 1.29-1.41 (2H, m), 1.64 (2H, t, J = 15 7 Hz), 1.72-1.84 (1H, m), 1.96-2.08 (1H, m), 2.28 (2H, t, J = 7 Hz), 3.12 (1H, dd, J = 10, 7 Hz), 3.21 (1H, dd, J = 10, 7 Hz), 3.97 (1H, d, J = 12 Hz), 4.05 (1H, d, J = 12 Hz), 4.11 (2H, q, J = 7 Hz), 4.70 (1H, t, J = 7 Hz), 8.26 (1H, dd, J = 2, 2 Hz), 8.77 (1H, dd, J = 2 Hz), 9.09 (1H, dd, J = 2 Hz). 20 Preparation 277 ethyl 5-[(5-chloro-3-pyridinyl)carbonyl]-7-(cyclopropylmethoxy)-6-oxoheptanoate 'H NMR (300 MHz, CDC 3 ) 8 -0.07-0.09 (2H, m), 0.24-0.46 (2H, m), 0.68-0.79 (1H, m), 1.23 (3H, t, J = 7 Hz), 1.47-1.84 (3H, m), 1.98-2.10 (1H, m), 2.33 (2H, t, J = 7 Hz), 3.12 (1H, dd, J = 10, 7 Hz), 3.21 (1H, dd, J = 10, 7 Hz), 3.97 (1H, d, J = 17 25 Hz), 4.06 (1H, d, J = 17 Hz), 4.10 (2H, q, J = 7 Hz), 4.73 (1H, t, J = 6 Hz), 8.27 (1H, dd, J = 2, 2 Hz), 8.77 (1H, d, J = 2 Hz), 9.10 (1H, d, J = 2 Hz). Preparation 278 ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-8-isobutoxy-7-oxooctanoate 30 'H NMR (300 MHz, CDCl 3 ) 8 0.72 (3H, d, J = 7 Hz), 0.77 (3H, d, J = 7 Hz), 1.24 (3H, t, J = 7 Hz), 1.30-1.42 (2H, m), 1.54-1.70 (3H, m), 1.75-1.87 (1H, m), 1.95 2.08 (1H, m), 2.28 (2H, t, J = 8 Hz), 3.10 (1H, dd, J = 9, 7 Hz), 3.14 (1H, dd, J = 9, 7 Hz), 3.98 (2H, s), 4.11 (2H, q, J = 7 Hz), 4.70 (1H, t, J = 6 Hz), 8.39 (1H, dd, 240 WO 2004/063197 PCT/JP2003/017091 J = 2 Hz), 8.87 (1H, d, J = 2 Hz), 9.08 (1H, d, J = 2 Hz). Preparation 279 ethyl 4-[(5-chloro-3-pyridinyl)carbonyl]-6-isobutoxy-5-oxohexanoate 5 1H NMR (300 MHz, CDC1 3 ) b 0.68 (3H, d, J = 7 Hz), 0.72 (3H, d, J = 7 Hz), 1.25 (3H, t , J = 7 Hz), 1.52 (1H, qt, J = 7, 7 Hz), 2.02-2.13 (1H, m), 2.20-2.32 (1H, m), 2.44 (2H, t, J = 7 Hz), 3.07 (1H, dd, J = 9, 7 Hz), 3.12 (1H, dd, J = 9, 7 Hz), 3.98 (2H, s), 4.14 (2H, q, J = 7 Hz), 4.90 (1H, d, J = 9 Hz), 4.92 (11H, d, J = 9 Hz), 8.34 (1H, dd, J = 2 Hz), 8.78 (11H, d, J = 2 Hz), 9.15 (11H, d, J = 2 Hz). 10 Preparation 280 ethyl 6-(acetyloxy)-4-(3-chlorobenzoyl)-5-oxohexanoate 'H NMR (300 MHz, CDCl 3 ) 8 1.26 (3H, t, J = 7 Hz), 1.95 (3H, s), 2.20-2.29 (2H, m), 2.41-2.47 (2H, m), 4.15 (2H, q, J = 7 Hz), 4.64 (11H, d, J = 17 Hz), 4.71 (1H, d, J 15 = 17 Hz), 4.78 (1H, t, J = 6 Hz), 7.48 (1H, dd, J = 8, 8 Hz), 7.60 (1H, d, J = 8 Hz), 7.96 (1H, d, J = 8 Hz), 8.04 (1H, s). Preparation 281 ethyl 5-[(5-bromo-3-pyridinyl)carbonyl]-7-isobutoxy-6-oxoheptanoate 20 'H NMR (300 MHz, CDC 3 ) 8 0.72 (311, d, J = 7 Hz), 0.77 (3H, d, J = 7 Hz), 1.23 (3H, t, J = 7 Hz), 1.61-1.73 (3H, m), 1.77-1.88 (1H, n), 1.98-2.10 (1H, m), 2.33 (2H, t, J = 7 Hz), 3.10 (1H, dd, J = 9, 7 Hz), 3.15 (1H, dd, J = 9, 7 Hz), 3.99 (2H, s), 4.11 (2H, q, J = 7 Hz), 4.73 (1H, t, J = 7 Hz), 8.40 (1H, dd, J = 2, 2 Hz), 8.87 (1H, d, J = 2 Hz), 9.10 (1H, d, J = 2 Hz). 25 Preparation 282 1,3-bis(5-bromo-3-pyridinyl)-1,3-propanedione 1H NMR (DMSO-d 6 ) 8 7.60 (1H, s), 8.78 (2H, s), 8.88 (2H, s), 9.30 (2H, s). 30 Preparation 283 ethyl 7-(acetyloxy)-5-(3-chlorobenzoyl)-6-oxoheptanoate 'H NMR (CDC 3 ) 8 1.24 (3H, t, J = 8 Hz), 1.57-1.75 (2H, m), 1.90-2.12 (5H, m), 2.34 (2H, t, J = 8 Hz), 4.11 (2H, q, J = 8 Hz), 4.52 (1H, t, J = 8 Hz), 4.71 (2H, q, J 241 WO 2004/063197 PCT/JP2003/017091 = 8 Hz), 4.65 (1H, d, J = 16 Hz), 4.75 (1H, d, J = 16 Hz), 7.43 (1H, t, J = 8 Hz), 7.60 (1H, br d, J = 8 Hz), 7.84 (1H, br d, J = 8 Hz), 7.96 (1H, br s). Preparation 284 5 ethyl 8-methoxy-6-[(5-methoxy-3-pyridinyl)carbonyl]-7-oxooctanoate 'H NMR (CDC 3 ) 8 1.23 (3H, t, J = 8 Hz), 1.27-1.43 (2H, m), 1.55-1.70 (2H, m), 1.84 (1H, m), 2.00 (1H, m), 2.27 (2H, d, J = 8 Hz), 3.26 (3H, s), 3.92 (3H, s), 3.98 (2H, d, J = 5 Hz), 4.10 (2H, q, J = 8 Hz), 4.67 (1H, t, J = 8 Hz), 7.71 (1H, in), 8.50 (1H, d, J = 3 Hz), 8.78 (1H, br s). 10 MS (ESI*): m/z 352 (M + H). Preparation 285 ethyl 6-[(5-methoxy-3-pyridinyl)carbonyl]-7-oxooctanoate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J = 8 Hz), 1.27-1.41 (2H, m), 1.60-1.73 (2H, m), 15 1.90-2.14 (2H, m), 2.18 (3H, s), 2.24-2.84 (2H, m), 3.26 (3H, s), 3.92 (3H, s), 4.10 (2H, q, J = 8 Hz), 4.40 (1H, t, J = 8 Hz), 7.71 (1H, m), 8.51 (1H, d, J = 3 Hz), 8.78 (1H, br s). Preparation 286 20 ethyl 6-methoxy-4-[(5-methoxy-3-pyridinyl)carbonyl]-5-oxohexanoate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J = 8 Hz), 2.10 (1H, m), 2.25 (1H, m), 2.38-2.47 (2H, m), 3.24 (3H, s), 3.94 (3H, s), 3.95 (1H, d, J = 16 Hz), 4.00 (1H, d, J = 16 Hz), 4.12 (2H, q, J = 8 Hz), 4.38 (1H, m), 7.83 (1H, m), 8.52 (1H, d, J = 3 Hz), 8.87 (1H, d, J = 1 Hz). 25 MS (ESI*): m/z 346 (M+ + Na). Preparation 287 ethyl 7-methoxy-5-[(5-methoxy-3-pyridinyl)carbonyl]-6-oxoheptanoate 'H NMR (CDCl 3 ) 8 1.23 (3H, t, J = 8 Hz), 1.54-1.74 (2H, m), 1.84 (1H, m), 2.02 (1H, 30 m), 2.32 (2H, d, J = 8 Hz), 3.26 (3H, s), 3.92 (3H, s), 3.99 (2H, d, J = 5 Hz), 4.10 (2H, q, J = 8 Hz), 4.70 (1H, t, J = 8 Hz), 7.71 (1H, m), 8.51 (1H, d, J = 3 Hz), 8.79 (1H, br s). MS (ESI*): m/z 338 (M + H). 242 WO 2004/063197 PCT/JP2003/017091 Preparation 288 ethyl 8-methoxy-7-oxo-6-(5-pyrimidinylcarbonyl)octanoate 'H NMR (CDC 3 ) 8 1.23 (3H, t, J = 8 Hz), 1.25-1.45 (2H, m), 1.55-1.70 (2H, m), 5 1.81 (1H, m), 2.03 (1H, m), 2.28 (2H, t, J = 8 Hz), 3.24 (3H, s), 3.92 (1H, d, J = 18 Hz), 4.01 (1H, d, J = 18 Hz), 4.10 (2H, q, J = 8 Hz), 9.26 (2H, s), 9.40 (11H, s). MS (ESI): m/z 323 (M + H). Preparation 289 10 ethyl 5-[(5-chloro-3-pyridinyl)carbonyl]-7-methoxy-6-oxoheptanoate 1H NMR (CDCl 3 ) 8 1.24 (3H, t, J = 8 Hz), 1.52-1.74 (2H, m), 1.83 (1H, m), 2.02 (1H, m), 2.34-2.40 (2H, m), 3.25 (3H, s), 3.92 (1H, d, J = 16 Hz), 4.01 (1H, d, J = 16 Hz), 4.11 (2H, q, J = 8 Hz), 4.68 (1H, t, J = 8 Hz), 8.23 (1H, br s), 8.78 (1H, br s), 9.05 (1H, br s). 15 MS (ESI*): m/z 342 (M + H). Preparation 290 ethyl 4- [(5-chloro-3-pyridinyl)carbonyl]-6-methoxy-5-oxohexanoate 'H NMR (CDC 3 ) 8 1.25 (3H, t, J = 8 Hz), 2.09 (1H, m), 2.25 (1H, m), 2.38-2.49 (2H, 20 m), 3.22 (3H, s), 3.91 (1H, d, J = 18 Hz), 4.00 (1H, d, J = 18 Hz), 4.14 (2H, q, J = 8 Hz), 4.85 (1H, m), 8.33 (1H, br s), 8.78 (1H, br s), 9.14 (1H, br s). MS (ESI*): m/z 328 (M+ H). Preparation 291 25 ethyl 6-[(5-chloro-3-pyridinyl)carbonyl]-8-methoxy-7-oxooctanoate 'H NMR (CDC 3 ) 8 1.23 (3H, t, J = 8 Hz), 1.27-1.43 (2H, m), 1.50-1.71 (2H, m), 1.82 (1H, m), 2.00 (1H, m), 2.27 (2H, d, J = 8 Hz), 3.25 (3H, s), 3.92 (1H, d, J = 16 Hz), 4.02 (1H, d, J = 16 Hz), 4.10 (2H, q, J = 8 Hz), 4.63 (1H, t, J = 8 Hz), 8.23 (1H, br s), 8.78 (1H, br s), 9.03 (1H, br s). 30 MS (ESI*): m/z 356 (M + H). Preparation 292 2-[2-({ 3-[(5-methyl-3-pyridinyl)carbonyl]-4-oxopentyl} oxy)ethoxy] ethyl acetate 243 WO 2004/063197 PCT/JP2003/017091 trifluoroacetate 'H-NMR (CDCl 3 ) 5 2.06 (3H, s), 2.28 (3H, s), 2.33 (2H, m), 2.65 (3H, s), 3.47-3.67 (8H, m), 4.17 (2H, m), 4.71 (1H, t, J = 7 Hz), 8.66 (1H, m), 8.88 (1H, m), 9.31 (1H, m). 5 Preparation 293 ethyl 5-[(5-bromo-3-pyridinyl)carbonyl]-7-methoxy-6-oxoheptanoate 'H NMR (CDC 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.56-1.73 (2H, m), 1.77-1.92 (111, m), 1.96-2.10 (1H, m), 2.32 (2H, t, J= 7 Hz), 3.25 (311, s), 3.92 (1H, d, J= 17 Hz), 10 4.02 (1H, d, J= 17 Hz), 4.12 (211, q, J= 7 Hz), 4.67 (111, t, J= 7 Hz), 8.39 (IH, m), 8.87 (1H, d, J= 2 Hz), 9.09 (1H, d, J= 2 Hz). MS (ESI*): m/z 386 388. The following compound(s) was(were) obtained in a similar manner to that of 15 Preparation 129 and 130. Preparation 294 tert-butyl 3-oxo-4-phenylbutanoate 'H NMR (CDCl 3 ) 5 1.46 (9H, s), 3.37 (211, s), 3.82 (2H, s), 7.21 (2H, d, J= 8 Hz), 7.25-7.37 (311, m). 20 Preparation 295 tert-butyl 3-oxo-3-phenylpropanoate 'H NMR (CDC 3 ) 5 1.43 (9H, s), 3.81 (2H, s), 7.40-7.52 (2H, m), 7.56-7.63 (111, m), 7.94 (211, d, J= 8 Hz). 25 Preparation 296 tert-butyl 4-(cyclohexylmethoxy)-3-oxobutanoate 1H NMR (CDC 3 ) 5 0.89-1.07 (2H, m), 1.13-1.40 (311, m), 1.47 (9H, s), 1.60-1.83 (6H, m), 3.28 (2H, d, J= 7 Hz), 3.45 (2H, s), 4.06 (2H, s). 30 Preparation 297 tert-butyl 4 -(cyclopropylmethoxy)-3-oxobutanoate 'H NMR (CDC 3 ) 5 0.20-0.28 (2H, m), 0.55-0.64 (2H, m), 1.03-1.17 (1H, m), 1.47 244 WO 2004/063197 PCT/JP2003/017091 (9H, s), 3.36 (2H, d, J= 7 Hz), 3.45 (2H, s), 4.15 (2H, s). Preparation 298 tert-butyl 4-(2-methoxyethoxy)-3-oxobutanoate 5 'H NMR (CDC 3 ) 6 1.47 (9H, s), 3.38 (3H, s), 3.44 (2H, s), 3.57 (2H, m), 3.70 (2H, m), 4.20 (2H, s). Preparation 299 tert-butyl 4-isobutoxy-3-oxobutanoate 10 'H NMR (300 MHz, CDCl 3 ) 8 0.93 (6H, d, J = 7 Hz), 1.45 (9H, s), 1.91 (1H, qt, J = 7, 7 Hz), 3.26 (2H, d, J = 7 Hz), 3.45 (2H, s), 4.07 (2H, s). Preparation 300 tert-butyl 3-(3-methyl-2-thienyl)-3-oxopropanoate 15 'H-NMR (CDCl 3 ) 8 1.47 (9H, s), 2.57 (3H, s), 3.79 (2H, s), 6.96 (1H, d, J = 5 Hz), 7.44 (1H, d, J = 5 Hz). Preparation 301 tert-butyl 3-(5-methyl-3-isoxazolyl)-3-oxopropanoate 20 'H-NMR (CDCl 3 ) 6 1.475-1.57 (9H, m), 2.49 (3H, m), 3.95 (2H, s), 6.40 (1H, s). The following compound(s) was(were) obtained in a similar manner to that of Preparation 132. Preparation 302 25 ethyl (2E)-5-(3-cyanobenzoyl)-6-oxo-2-heptenoate 'H-NMR (CDC 3 ) 8 1.28 (3H, t, J = 7 Hz), 2.20 (3H, s), 2.88 (2H, m), 4.16 (2H, q, J = 7 Hz), 4.54 (1H, t, J = 7 Hz), 5.88 (1H, d, J = 16 Hz), 6.82 (1H, dt, J = 7 and 16 Hz), 7.65 (1H, t, J = 8Hz), 7.89 (1H, d, J = 8 Hz), 8.20 (1H, d, J = 8 Hz), 8.27 (1H, s). 30 MS (ESI*): m/z 300.14 (M + H) Preparation 303 1-tert-butyl 7-ethyl 2-[(3-methyl-2-thienyl)carbonyl]heptanedioate 245 WO 2004/063197 PCT/JP2003/017091 'H-NMR (CDCl 3 ) 8 1.25 (3H, t, J = 7 Hz), 1.35-1.51 (11H, m), 1.65 (2H, m), 1.96 (2H, m), 2.30 (2H, t, J = 7 Hz), 2.58 (3H, s), 3.94 (1H, t, J = 7 Hz), 4.12 (2H, q, J = 7 Hz),6.97 (1H, d, J = 5 Hz), 7.44 (1H, d, J = 5 Hz). 5 Preparation 304 1-tert-butyl 7-ethyl 2-[(5-methyl-3-isoxazolyl)carbonyl]heptanedioate 'H-NMR (CDCl 3 ) 8 11.24 (3H, t, J = 7 Hz), 1.39 (9H, s), 1.67 (2H, m), 1.98 (2H, m), 2.49 (3H, s), 4.10 (211, q, J = 7 Hz), 4.26 (111, t, J = 7 Hz), 6.37 (111, s). 10 The following compound(s) was(were) obtained in a similar manner to that of Preparation 152. Preparation 305 methyl 7-oxo-7-(2-thienyl)heptanoate 'H-NMR (CDCl 3 ) 8 1.41 (2H, m), 1.63-1.82 (4H, m), 2.33 (2H, t, J = 7 Hz), 2.91 (2H, 15 t, J = 7 Hz), 3.67 (3H, s), 1.73 (111, m), 7.62 (11, m), 7.70 (1H, m). The following compound(s) was(were) obtained in a similar manner to that of Preparation 153. Preparation 306 20 5-methoxynicotinoyl chloride hydrochloride Preparation 307 5-pyrimidinecarbonyl chloride hydrochloride 25 Preparation 308 5-chloronicotinoyl chloride hydrochloride Preparation 309 - methyl 2-bromo-4-(chlorocarbonyl)benzoate 30 The following compound(s) was(were) obtained in a similar manner to that of Praparation 159. Preparation 310 246 WO 2004/063197 PCT/JP2003/017091 1-tert-butyl 7-ethyl 2-(phenylacetyl)heptanedioate 'H NMR (CDCIs) 6 1.24 (3H, t, J= 7 Hz), 1.18-1.50 (2H, m), 1.46 (9H, s), 1.50-1.75 (2H, m), 1.75-1.88 (2H, m), 2.24 (2H, t, J= 7 Hz), 3.47 (1H, t, J= 7 Hz), 3.81 (2H, s), 4.10 (2H, q, J= 7 Hz), 7.20 (2H, d, J= 8 Hz), 7.25-7.37 (3H, m). 5 Preparation 311 tert-butyl 2-[2-(2-methoxy-2-oxoethoxy)ethyl]-3-oxobutanoate 'H NMR (CDCl 3 ) 8 1.46 (9H, s), 2.04-2.23 (2H, m), 2.29 (3H, s), 3.54 (2H, t, J= 7 Hz), 3.69 (1H, t, J= 7 Hz), 3.74 (3H, s), 4.04 (2H, s). 10 Preparation 312 tert-butyl 2-benzoyl-4-(2-methoxy-2-oxoethoxy)butanoate 'H NMR (CDCl 3 ) 8 1.34 (9H, s), 2.26-2.40 (2H, m), 3.55-3.67 (2H, m), 3.70 (3H, s), 4.04 (2H, s), 4.57 (1H, t, J= 7 Hz), 7.47 (2H, t, J= 8 Hz), 7.56 (1H, m), 8.01 (2H, 15 d, J= 8 Hz). Preparation 313 1-tert-butyl 6-ethyl 2-[(acetyloxy)acetyl]hexanedioate 'H NMR (CDC 3 ) 6 1.25 (3H, t, J= 7 Hz), 1.48 (9H, s), 1.60-1.73 (2H, m), 1.82-1.95 20 (2H, m), 2.17 (3H, s), 2.32 (2H, t, J= 7 Hz), 3.43 (1H, t, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.72 (1H, d, J= 17 Hz), 4.83 (11H, d, J= 17 Hz). Preparation 314 1-tert-butyl 5-ethyl 2-[(cyclohexylmethoxy)acetyl]pentanedioate 25 'H NMR (CDCl 3 ) 8 0.85-1.06 (2H, m), 1.13-1.34 (3H, m), 1.26 (3H, t, J= 7 Hz), 1.45 (9H, s), 1.60-1.85 (6H, m), 2.08-2.23 (2H, m), 2.36 (2H, t, J= 7 Hz), 3.27 (2H, d, J= 7 Hz), 3.67 (1H, t, J= 7 Hz), 4.10 (2H, s), 4.12 (2H, q, J= 7 Hz). Preparation 315 30 1-tert-butyl 6-ethyl 2-[(cyclohexylmethoxy)acetyl]hexanedioate 'H NMR (CDC 3 ) 6 0.88-1.06 (2H, n), 1.12-1.34 (3H, m), 1.25 (3H, t, J= 7 Hz), 1.45 (9H, s), 1.54-1.94 (10H, m), 2.32 (2H, t, J= 7 Hz), 3.27 (2H, d, J= 7 Hz), 3.56 (1H, t, J= 7 Hz), 4.09 (2H, s), 4.11 (2H, q, J= 7 Hz). 247 WO 2004/063197 PCT/JP2003/017091 MS (ESI*): m/z 385. Preparation 316 1-tert-butyl 6-ethyl 2-[(cyclopropylmethoxy)acetyl]hexanedioate 5 'H NMR (CDCl 3 ) 8 0.22-0.33 (2H, m), 0.54-0.64 (2H, m), 1.04-1.18 (1H, m), 1.25 (3H, t, J= 7 Hz), 1.45 (9H, s), 1.60-1.73 (2-1, m), 1.83-1.95 (2H, m), 2.33 (2H, t, J= 7 Hz), 3.33 (2H, d, J= 7 Hz), 3.53 (1H, t, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.18 (2H, m). MS (ESI*): m/z 343. 10 Preparation 317 1-tert-butyl 5-ethyl 2-[(cyclopropylmethoxy)acetyl]pentanedioate 'H NMR (CDCIs) 8 0.20-0.35 (2H, m), 0.56-0.64 (2H, m), 1.04-1.16 (1H, m), 1.26 (3H, t, J= 7 Hz), 1.45 (9H, s), 2.12-2.24 (2H, m), 2.38 (2H, t, J= 7 Hz), 3.36 (2H, 15 m), 3.65 (1H, t, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.19 (2H, s). Preparation 318 1-tert-butyl 5-ethyl 2-[(2-methoxyethoxy)acetyl]pentanedioate 'H NMR (CDCl 3 ) 8 1.25 (3H, t, J= 7 Hz), 1.46 (9H, s), 2.10-2.23 (2H, m), 2.38 (2H, t, 20 J= 7 Hz), 3.37 (3H, s), 3.60 (2H, m), 3.62 (1H, t, J= 7 Hz), 3.70 (2H, m), 4.12 (2H, q, J= 7 Hz), 4.23 (1H, d, J= 17 Hz), 4.30 (1H, d, J= 17 Hz). MS (ESI+): m/z 333. Preparation 319 25 1-tert-butyl 5-ethyl 2-(isobutoxyacetyl)pentanedioate 'H NMR (300 MHz, CDC 3 ) 6 0.93 (6H, d, J = 7 Hz), 1.26 (3H, t, J = 7 Hz), 1.45 (9H, s), 1.91 (1H, qt, J = 7, 7 Hz), 2.13 (2H, m), 2.37 (2H, t, J = 7 Hz), 3.25 (2H, d, J = 7 Hz), 3.67 (1H, t, J = 7 Hz), 4.12 (2H, s), 4.13 (2H, q, J 7 Hz). 30 The following compound(s) was(were) obtained in a similar manner to that of Preparation 164. Preparation 320 methyl 2-bromo-4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate 248 WO 2004/063197 PCT/JP2003/017091 'H-NMR (CDCI 3 ) 6 1.32 (3H, t, J = 7 Hz), 2.72 (211, q, J = 7 Hz), 3.97 (3H, s), 6.10 (1H, m), 6.77 (1H, m), 7.81 (1H, d, J = 8 Hz), 7.85 (1H, d, J = 8 Hz), 8.11 (1H, s), 9.32 (1H, s, br). 5 The following compound(s) was(were) obtained in a similar manner to that of Preparation 165. Preparation 321 tert-butyl 2-(2-{ 2-[2-(acetyloxy)ethoxy]ethoxy}ethyl)-3-oxobutanoate 'H-NMR (CDC 3 ) 8 1.46 (9H, s), 2.00-2.17 (5H, m), 2.25 (3H, s), 3.45-3.70 (10H, m), 10 4.22 (2H, m). The following compound(s) was(were) obtained in a similar manner to that of Preparation 178. Preparation 322 15 isobutoxyacetic acid 'H NMR (300 MHz, CDCl 3 ) 8 0.94 (6H, d, J = 7 Hz), 1.93 (IH, qt, J = 7, 7 Hz), 3.34 (21H, d, J = 7 Hz), 4.12 (21, s). Preparation 323 20 To a suspension of 60% NaH (2.66 g) in DMF (20 mL) was added methyl hydroxyacetate (5.00 g) under ice-water cooling, and the mixture was stirred at 0 'C for 0.5 hour. To this was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (12.8 g) under ice water cooling, and the mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, 25 washed with water and brine, dried over MgSO 4 , and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (10:1 - 3:1) to give methyl [2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]acetate pale yellow oil (4.45 g). 30 methyl [2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]acetate 'H NMR (CDC 3 ) 8 1.48-1.95 (6H, m), 3.46-3.57 (2H, m), 3.64-3.75 (2H, m), 3.76 (3H, s), 3.82-3.97 (2H, m), 4.20 (2H, s), 4.66 (1H, m). 249 WO 2004/063197 PCT/JP2003/017091 Preparation 324 A mixture of methyl [2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]acetate (1.07 g) and pyridinium p-toluenesulfonate (24.6 mg) in MeOH (10 mL) was heated under reflux for 2 hours. After evaporation of solvent, the residue was purified by silica gel column 5 chromatography eluting with a mixture of hexane and AcOEt (10:1 - 1:3) to give methyl (2-hydroxyethoxy)acetate as colorless oil (555 mg). methyl (2-hydroxyethoxy)acetate 'H NMR (CDCl 3 ) 8 3.69 (2H, m), 3.76 (2H, m), 3.78 (3H, s), 4.16 (2H, s). 10 Preparation 325 To solution of methyl (2-hydroxyethoxy)acetate (540 mg), imidazole (411 mg) and triphenylphosphine (1.37 g) in ether (2 mL) and CH 3 CN (1 mL) was added iodine (1.43 g) under ice-water cooling and the mixture was stirred at 0 0 C for 2 hours. After 15 insolubles were filterred off, the filtrates were diluted with AcOEt, washed with aq Na 2

SO

3 solution and brine, dried over MgSO 4 , and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1 - 5:1) to give methyl (2-iodoethoxy)acetate as colorless oil (898 mg). 20 methyl (2-iodoethoxy)acetate 'H NMR (CDC 3 ) 8 3.30 (2H, t, J= 7 Hz), 3.77 (3H, s), 3.84 (2H, t, J= 7 Hz), 4.17 (2H, s). Preparation 326 25 To a suspension of 60% NaH (1.02 g) in THF (50 mL) was added tert-butyl 4 (acetyloxy)-3-oxobutanoate (5.00 g) under ice-water cooling and the mixture was stirred at 0 'C for 0.5 hour. To this added ethyl 3-iodopropanoate (5.54 g) and the mixture was stirred at 50 0 C for 8 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, washed with brine, dried over MgSO 4 , and evaporated in 30 vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1 - 3:1) to give 1-tert-butyl 5-ethyl 2 [(acetyloxy)acetyl]pentanedioate as yellow oil (4.27 g). 250 WO 2004/063197 PCT/JP2003/017091 1-tert-butyl 5-ethyl 2-[(acetyloxy)acetyl]pentanedioate 'H NMR (CDC 3 ) 8 1.26 (3H, t, J= 7 Hz), 1.46 (9H, s), 2.14-2.24 (2H, m), 2.17 (3H, s), 2.36 (2H, t, J= 7 Hz), 3.60 (1H, t, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.73 (1H, d, J= 18 Hz), 4.83 (IH, d, J= 18 Hz). 5 Preparation 327 To a solution of benzyl 4-thiomorpholinecarboxylate (4.8 g) in methanol (30 mL) and H 2 0 (20 mL) was added oxone (16.2 g) under ice water cooling and the mixture was stirred at ambient temperature for 2 hours. The solution was evaporated in vacuo and 10 partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and brine, dried over MgSO 4 and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and EtOAc to give benzyl 4-thiomorpholinecarboxylate 1,1-dioxide as a colorless solid (3.8 g). 15 benzyl 4-thiomorpholinecarboxylate 1,1-dioxide 'H NMR (300 MHz, CDC 3 ) b 3.02 (4H, br s), 4.01 (4H, t, J = 5 Hz), 5.16 (2H, s), 7.33-7.40 (5H, m). 20 Preparation 328 To a solution of thiomorpholine (2 g) in 1N NaOH (11.6 mL) was added benzyl chloridocarbonate (1.66 mL) under ice water cooling and the mixture was stirred at ambient temperature for 2 hours. The solution was neutrolized with IN HCl and extracted with EtOAc twice. The combined organic layer was washed with water and 25 brine, dried over MgSO 4 and evaporated in vacuo. The residue was purified by silica gel column chromatography to give benzyl 4-thiomorpholinecarboxylate as a colorless solid (4.8 g). benzyl 4-thiomorpholinecarboxylate 30 1H NMR (300 MHz, CDCl 3 ) 8 2.59 (4H, br s), 3.77 (4H, t, J = 5 Hz), 5.14 (2H, s), 7.30-7.41 (5H, m). Preparation 329 251 WO 2004/063197 PCT/JP2003/017091 To a solution of benzyl 4-thiomorpholinecarboxylate 1,1-dioxide (3.8 g) in methanol (32 mL) and 1,4-dioxane (8 mL) was added Palladium, 10 wt. % on activated carbon (380 mg) at ambient temperature. The mixture was stirred at ambient temperature for 4 hours under H 2 (3.4 atom). The mixture was filtered and evaporated in vacuo to 5 give thiomorpholine 1,1-dioxide as a colorless solid (2.22 g). thiomorpholine 1,1-dioxide 'H NMR (300 MHz, CDC 3 ) 8 3.03 (4H, t, J = 5 Hz), 3.33 (4H, t, J = 5 Hz). MS (m/z) 136 (M+H). 10 Preparation 330 To a suspension of [(5-chloro-4-mercapto-6-methyl-3-pyridinyl)oxy]acetic acid (10 g) in dichloromethane (100 mL) was added Et3N (14 mL) in ice-MeOH bath. To this was added trifluoromethanesulfonic anhydride (14.3 mL) dropwise below 10*C over 30 15 min. After 2 hours the mixture was partitioned between CHC1 3 and water. The aqueous layer was extracted with CHCl 3 twice. The combined organic layer was dried over MgSO 4 and evaporated in vacuo to give brown oil. The residue was purified by silica gel column chromatography (silica gel, 100 mL) eluted with hexane-EtOAc = 15-1 and 10-1 to give 5-chloro-3-pyridinyl trifluoromethanesulfonate (15.8 g) as a pale brown oil. 20 5-chloro-3-pyridinyl trifluoromethanesulfonate H NMR (300 MHz, CDCl 3 ) 8 7.69 (11H, dd, J = 4, 4 Hz), 8.52 (1H, d, J = 4 Hz), 8.65 (1H, d, J = 4 Hz). 25 Preparation 331 To ethanol (66 mL) and DMF (66 mL) was added Et3N (29.4 mL), 1,3 propanediylbis(diphenylphosphine) (3.48 g) and palladium acetate (1.9 g) in ice-water bath. To this was added 5-chloro-3-pyridinyl trifluoromethanesulfonate (22.1 g) at the temperature. The mixture was stirred at 501C for 4 hours under CO (1 atom). The mixture 30 was partitioned betwwen EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water three times, dried over MgSO 4 and evaporated in vacuo. The residue was purified by silica gel column chromatography (silica gel, 200 mL) eluted with hexane-EtOAc = 15-1 and 10-1 to give ethyl 5 252 WO 2004/063197 PCT/JP2003/017091 chloronicotinate (10.5 g) as a pale brown oil. ethyl 5-chloronicotinate 'H NMR (300 MHz, CDC] 3 ) 8 1.42 (3H, t, J = 7 Hz), 4.43 (2H, q, J = 7 Hz), 8.28 (1H, 5 dd, J = 3, 3 Hz), 8.74 (1H, d, J = 3 Hz), 9.09 (1H, d, J= 3 Hz). Preparation 332 To 5-chloronicotinate (10.5 g) was added 1N NaOH (84.9 mL) at ambient temperature. The mixture was heated at 609C for 1 hour. The reaction mixture was 10 adjusted to pH 4-5 with HCL. The precipitate was filtered to give 5-chloronicotinic acid (6.9 g) a colorless solid. 'H NMR (300 MHz, DMSO-d 6 ) 8 8.30 (1H, dd, J = 3 Hz), 8.88 (1H, d, J = 3 Hz), 9.01 (1H, d, J = 3 Hz), 13.8 (111, br s). 15 5-chloronicotinic acid 'H NMR (300 MHz, DMSO-d 6 ) 8 8.30 (1H, dd, J = 3, 3 Hz), 8.88 (1H, d, J = 3 Hz), 9.01 (11H, d, J = 3 Hz), 13.8 (11H, br s). The following compound(s) was(were) obtained in a similar manner to that of 20 Preparation 332. Preparation 333 5-methoxynicotinic acid 'H NMR (DMSO-d 6 ) 8 3.87 (3H, s), 7.73 (111, m), 8.48 (1H, d, J = 3 Hz), 8.65 (1H, d, J = 1 Hz). 25 MS (ESI*): m/z 154 (M + H). Preparation 334 , 5-pyrimidinecarboxylic acid 'H NMR (DMSO-d 6 ) 8 9.20 (211, s), 9.37 (1H, s). 30 MS (ESI*): m/z 148 (M+ + Na). Preparation 335 To a solution of diisopropylamine (5.41 g) in THF (30 mL) was added 1.5 M n 253 WO 2004/063197 PCT/JP2003/017091 butyllithium hexane solution (35 mL) under dryice acetone cooling and the mixture was stirred at -78 0 C for 10 minutes. To this was added tert-butyl acetate (5.87 g) under dryice acetone cooling and the mixture was stirred at -78 0 C for 10 minutes and added dropwise to a solution of 5-bromonicotinic acid (3.00 g) and N, N-carbonyldiimidazole 5 (2.65 g) in THF (30 mL) under dryice acetone cooling. The mixture was stirred at -78 0 C for 0.5 hour. The mixture was partitioned between ethyl acetate and aq NH 4 Cl solution. The organic layer was separated, washed with aq NaHCO 3 solution and brine, dried over MgSO 4 , and evaporated in vacuo. The residue was triturated with isopropyl ether to give tert-butyl 3-(5-bromo-3-pyridinyl)-3-oxopropanoate as a colorless powder (3.71 g). 10 tert-butyl 3-(5-bromo-3-pyridinyl)-3-oxopropanoate Enol form: 'H NMR (CDC 3 ) 8 1.54 (911, s), 5.62 (111, s), 8.19 (1H, m), 8.72 (1H, d, J= 2 Hz), 8.86 (1H, d, J= 2 Hz). Keto form: 'H NMR (CDC 3 ) 8 1.44 (9H, s), 3.90 (2H, s), 8.37 (1H, m), 8.86 (11H, d, 15 J= 2 Hz), 9.03 (1H, d, J= 2 Hz). MS (ESI'): m/z 300 302. Preparation 336 To a suspension of NaH in DMF (50 mL) which was washed with hexane 3 times 20 was added methyl 5-hydroxynicotinate (10.2 g) portionwise below 101C in an ice-water bath under nitrogen atmosphere. After 30 min, methyl iodide (4.56 mL) was added dropwise therein. The precipitate appeared and the mixture was hard to be stirred. DMF (30 mL) was added. After 20 min, the mixture was stirred at ambient temperature for 3 h. The reaction mixture was quenched with MeOH and was concentrated in vacuo. To the 25 residue was added CHC1 3 , sat. NaHCO 3 , and brine. The organic layer was separated and the aqueous layer was extracted with CHCl 3 . The combined organic layer was dried over MgSO 4 and was evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 200 mL) eluted with hexane-AcOEt = 5-1 and 3-1 to give methyl 5-methoxynicotinate (3.47 g) as a pale brown solid 30 methyl 5-methoxynicotinate 'H NMR (CDCI 3 ) 8 3.91 (3H, s), 3.96 (3H, s), 7.76 (111, m), 8.47 (1H, d, J = 3 Hz), 254 WO 2004/063197 PCT/JP2003/017091 8.83 (1H, d, J = 1 Hz). MS (ESI+): m/z 168 (M + H). Preparation 337 5 To a solution of methyl 2-bromo-4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate (330 mg) in N,N-dimethylformamide (5 mL) was added 60% sodium hydride in oil (58.4 mg) in an ice-bath over 5 miutes. After stirring for 1 hour, (aminooxy)(diphenyl)phosphine oxide (340 mg) was added portionwise over 40 minutes. The resulting mixture was stirred for 1 hour in the bath. The reaction was quenched by 10 adding water (10 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (two times) and brine, dried over magnesium sulfate, and evaporated. The residue was dissolved in ethyl acetatec-hexane (1-5), and to the solution was added silicagel. The mixture was filtered, and the filtrate was evaporated to give methyl 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-2 15 bromobenzoate as an orange solid (310 mg). methyl 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-2-bromobenzoate 1 H-NMR (CDCl 3 ) 8 1.29 (3H, t, J = 7 Hz), 2.76 (2H, q, J = 7 Hz), 3.97 (3H, s), 5.73 (2H, s, br), 5.93 (1H, d, J = 5 Hz), 6.62 (1H, d, J = 5 Hz), 7.73 (1H, d, J = 8 Hz), 20 7.84 (1H, d, J = 8 Hz), 8.02 (1H, s). Preparation 338 To a solution of dimethyl 2-bromoterephthalate (1.04 g) in methanol (10 mL) was added 1 N sodium hydroxide (5.71 mL) at room temperature. After stirring for 1.5 hour, 25 the reaction was quenched by adding 1 N hydrochloric acid (7 mL). White crystals were formed. Water (10 mL) was added to aid crystalyzation. The crystals were collected by filtration, washed with water, and dried in the air. 3-Bromo-4-(methoxycarbonyl)benzoic acid was obtained as white crystals (532 mg). 30 3-bromo-4-(methoxycarbonyl)benzoic acid 'H-NMR (DMSO-d 6 ) 6 3.89 (3H, s), 7.87 (1H, d, J = 8 Hz), 8.01 (1H, d, J = 8 Hz), 8.17 (1H, s). 255 WO 2004/063197 PCT/JP2003/017091 Preparation 339 A mixture of 2-[2-(2-chloroethoxy)ethoxy]ethyl acetate (6.23 g) and sodium iodide (22.2 g) in acetone (60 mL) was refluxed for 4 hours. The mixture was further refluxed for 4 hours after adding sodium iodide (11.0 g). The solvent was evaporated off, 5 and the residue was partitioend between EtOAc (50 mL) and water (50 mL). The aqueous layer was washed with 10% sodium thiosulfate and brine, dried over MgSO 4 , and evaporated to give 2-[2-(2-iodoethoxy)ethoxy]ethyl acetate as a pale yellow oil (9.74 g). 10 2-[2-(2-iodoethoxy)ethoxy]ethyl acetate 'H-NMR (CDCl 3 ) 6 2.09 (3H, s), 3.27 (2H, t, J = 7 Hz), 3.65-3.78 (8H, m), 4.24 (2H, m). Preparation 340 15 A solution of 1-tert-butyl 7-ethyl 2-[(5-methyl-3 isoxazolyl)carbonyl]heptanedioate (126 mg) in trifluoroacetic acid (1 mL) was stirred for 1.5 hour at room temperature. The volatile was evaporated off, and azeotroped with toluene to give 7-ethoxy-2-[(5-methyl-3-isoxazolyl)carbonyl]-7-oxoheptanoic acid as a pale orange oil (106 mg). 20 7-ethoxy-2-[(5-methyl-3-isoxazolyl)carbonyl]-7-oxoheptanoic acid 'H-NMR (CDCl 3 ) 8 1.24 (3H, t, J = 7 Hz), 1.41 (2H, m), 1.65 (2H, m), 2.02 (2H, m), 2.30 (2H, m), 2.50 (3H, s), 2.55 (1H, s, br), 4.10 (2H, q, J = 7 Hz), 4.47 (1H, t, J = 7 Hz), 6.40 (1H, s). 25 MS (ESI'): m/z 296.22 (M-H) and 593.52 (2M-H) Preparation 341 To a suspension of dimethyl sulfone (5.43 g) in tetrahydrofuran (10 mL) was addded 1.59 M n-butyl lithium (36.3 mL) in a dryice-acetone bath under a nitrogen 30 atmosphere. After stirring for 0.5 hour, a solution of methyl methoxyacetate (2.00 g) in tetrahydrofuran (5 mL) was added. The resulting mixture was stirred for 2 hours in the bath and allowed to warm to room temperature over 2 hours. The mixture was partitioned between EtOAc and 4 N hydrochloric acid. The reaction was quenched by 256 WO 2004/063197 PCT/JP2003/017091 adding 4 N hydrochloric acid in EtOAc (15 mL). The mixture was partitioned between EtOAc (100 mL) and brine (100 mL). The aqueous layer was washed with EtOAc (100 mL, five times). The organic layer was combined, and the combined extracts were dried over MgSO 4 , and evaporated. Flash silicagel column chromatography (EtOAc-hexane = 5 50-200 to 300-100) afforded 2-(methylsulfonyl)-1-methoxyethanone as a colorless oil (2.24 g). 1-methoxy-3-(methylsulfonyl)acetone 'H-NMR (CDCl 3 ) 8 2.99 (311, s), 3.08 (2H, s), 3.47 (3H, s), 4.19 (2H, s). 10 The following compound(s) was(were) obtained in a similar manner to that of Example 1. Example 392 ethyl 4-[3-bromo-4-(methoxycarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine 15 3-carboxylate H-NMR (CDCl 3 ) 8 0.98 (3H, t, J = 7 Hz), 1.38 (3H, t, J = 7 Hz), 2.61 (3H, s), 3.04 (2H, q, J = 7 Hz), 3.98 (3H, s), 4.05 (2H, q, J = 7 Hz), 6.29 (111, d, J = 5 Hz), 6.67 (1H, d, J = 7 Hz), 7.44 (1H, d, J = 8 Hz), 7.76 (11H, s), 7.89 (1H, d, J = 8 Hz). 20 Example 393 3-[7-ethyl-2-(methoxymethyl)-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4 yl]benzonitrile 'H-NMR (CDC 3 ) 8 1.38 (311, t, J = 7 Hz), 2.98 (21H, q, J = 7 Hz), 3.18 (3H, s), 3.45 (3H, s), 4.59 (2H, s), 6.25 (1H, d, J = 5 Hz), 6.71 (1H, d, J = 5 Hz), 7.65 (11H, t, J 25 = 8 Hz), 7.78 (1H, d, J = 8 Hz), 7.94 (1H, d, J = 8 Hz), 7.99 (1H, s). MS (ESI'): m/z 370 (M + H) The following compound(s) was(were) obtained in a similar manner to that of Example 16. 30 Example 394 5-{ 4-[3-(aminocarbonyl)phenyl]-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid 'H-NMR (CDCl 3 ) 8 1.02 (4H, m), 1.28 (31H, t, J = 7 Hz), 1.70 (211, m), 2.37 (2H, m), 257 WO 2004/063197 PCT/JP2003/017091 2.92 (2H, q, J = 7 Hz), 5.87 (1H, d, J = 5 Hz), 6.66 (1H, d, J = 5 Hz), 7.46-7.67 (5H, m), 7.96-8.08 (3H, m). The following compound(s) was(were) obtained in a similar manner to that of 5 Example 21. Example 395 ethyl 4-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-bjpyridazin-3-yl]butanoate 'H NMR (CDC 3 ) 8 1.21 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.65-1.78 (2H, m), 2.22 (2H, t, J= 7 Hz), 2.40-2.52 (2H, m), 2.58 (3H, s), 3.03 (2H, q, J= 7 Hz), 4.05 10 (2H, q, J= 7 Hz), 5.86 (1H, d, J= 4 Hz), 6.53 (1H1, d, J= 4 Hz), 7.25 (1H, d, J= 5 Hz), 7.36 (1H, s), 8.53 (1H, d, J= 5 Hz). MS (ESI*): m/z 386 . Example 396 15 ethyl 3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl]propanoate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 2.30-2.39 (2H, m), 2.57 (3H, s), 2.74-2.83 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 5.88 (1H, d, J= 4 Hz), 6.55 (1H, d, J= 4 Hz), 7.24 (1H, d, J= 5 Hz), 7.35 (1H, s), 8.53 20 (1H, d, J= 5 Hz). MS (ESI*): m/z 372. Example 397 ethyl 5-[2-benzyl-4-(2-chloro-4-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 25 yl]pentanoate 'H NMR (CDCl 3 ) 6 1.23 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.30-1.50 (4H, m), 2.10 (2H, t, J= 7 Hz), 2.23-2.35 (2H, m), 3.04 (2H, q, J= 7 Hz), 4.09 (2H, q, J= 7 Hz), 4.21 (2H, s), 5.88 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.14-7.32 (7H, m), 8.50 (1H, d, J= 5 Hz). 30 Example 398 methyl { 2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]ethoxy} acetate 258 WO 2004/063197 PCT/JP2003/017091 IH NMR (CDCl 3 ) 8 1.37 (3H, t, J= 7 Hz), 2.42 (3H, s), 2.61 (3H, s), 2.78-2.88 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.46-3.57 (2H, m), 3.71 (3H, s), 3.95 (2H, s), 5.87 (1H, d, J= 4 Hz), 6.52 (1H, d, J= 4 Hz), 7.54 (1H, s), 8.43 (1H, d, J= 2 Hz), 8.53 (1H, d, J= 2 Hz). 5 MS (ESI*): m/z 368. Example 399 ethyl [4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl] acetate 1H NMR (CDCl 3 ) 8 1.26 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 2.51 (3H, s), 3.03 10 (2H, q, J= 7 Hz), 3.43 (2H, s), 4.12 (2H, q, J= 7 Hz), 5.99 (1H, d, J= 4 Hz), 6.58 (111, d, J= 4 Hz), 7.94 (1H, m), 8.58 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). MS (ESI*): m/z 402 404. Example 400 15 ethyl 3-[2-[(acetyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin 3-yl]propanoate 1H NMR (CDC1 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 2.16 (311, s), 2.32 2.42 (2H, m), 2.44 (3H, s), 2.77-2.90 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 5.31 (2H, s), 5.96 (111, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.53 (1H, s), 20 8.42 (1H, d, J=2 Hz), 8.55 (111, d, J= 2 Hz). MS (ESI'): m/z 410. Example 401 ethyl 4-[2-[(acetyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin 25 3-yl]butanoate 1H NMR (CDC 3 ) 8 1.25 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.64-1.78 (2H, m), 2.10-2.23 (2H, m), 2.17 (3H, s), 2.43 (3H, s), 2.43-2.58 (211, m), 3.02 (2H, q, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 5.33 (211, s), 5.93 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 7.53 (1H, s), 8.43 (111, s), 8.55 (1H, s). 30 MS (ESI*): m/z 424. Example 402 ethyl 5-[2-[(acetyloxy)methyl]-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2-b)pyridazin-3 259 WO 2004/063197 PCT/JP2003/017091 yl]pentanoate H NMR (CDC 3 ) 5 1.24 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.40-1.60 (4H, m), 2.16 (2H, t, J= 7 Hz), 2.17 (3H, s), 2.40-252 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 5.29 (2H, s), 5.88 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.60 5 7.68 (3H, m), 7.75-7.83 (1H, m). MS (ESI*): m/z 448. Example 403 ethyl 4-[2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 10 yl]butanoate 'H NMR (CDC 3 ) 8 1.22 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.65-1.82 (2H, m), 2.17 (3H, s), 2.21 (2H, t, J= 7 Hz), 2.45-2.63 (2H, m), 3.02 (2H, q, J= 7 Hz), 4.05 (2H, q, J= 7 Hz), 5.33 (2H, s), 5.95 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.90 (1H, m), 8.57 (1H, d, J= 2 Hz), 8.80 (1H, d, J= 2 Hz). 15 MS (ESI*): m/z 488 490. Example 404 ethyl 3-[2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 yl]propanoate 20 'H NMR (CDCl 3 ) 5 1.23 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 2.16 (3H, s), 2.36 (2H, t, J= 7 Hz), 2.77-2.95 (2H, m), 3.02 (2H, q, J= 7 Hz), 4.06 (2H, q, J= 7 Hz), 5.31 (2H, s), 5.96 (1H, d, J= 4 Hz), 6.64 (1H, d, J= 4 Hz), 7.88 (1H, s), 8.56 (1H, m), 8.80 (1H, m). MS (ESI): m/z 474 476. 25 Example 405 ethyl 3-[2-[(cyclohexylinethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 b]pyridazin-3-yl]propanoate 'H NMR (CDCl 3 ) 5 0.88-1.06 (2H, m), 1.19 (3H, t, J= 7 Hz), 1.15-1.36 (3H, rn), 1.37 30 (3H, t, J= 7 Hz), 1.58-1.85 (6H, m), 2.42 (2H, in), 2.43 (3H, s), 2.83-2.97 (2H, M), 3.05 (2H, q, J= 7 Hz), 3.38 (2H, d, J= 7 Hz), 4.06 (2H, q, J= 7 Hz), 4.66 (2H, s), 5.91 (1H, d, J= 4 Hz), 6.58 (IH, d, J= 4 Hz), 7.52 (1H, s), 8.42 (1H, d, J= 2 Hz), 8.54 (1H, d, J= 2 Hz). 260 WO 2004/063197 PCT/JP2003/017091 Example 406 ethyl 3-{ 4-(5-bromo-3-pyridinyl)-2-[(cyclohexylmethoxy)methyl]-7-ethylpyrrolo[1,2 b]pyridazin-3-yl}propanoate 5 'H NMR (CDCl 3 ) 8 0.85-1.06 (2H, m), 1.20 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.16-1.46 (311, m), 1.55-1.84 (6H, m), 2.43 (2H, t, J= 7 Hz), 2.82-3.00 (2H, m), 3.06 (2H, q, J= 7 Hz), 3.37 (2H, d, J= 7 Hz), 4.06 (2H, q, J= 7 Hz), 4.66 (2H, s), 5.93 (111, d, J= 4 Hz), 6.62 (11H, d, J= 4 Hz), 7.87 (1H, m), 8.55 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). 10 MS (ESI*): m/z 528 530. Example 407 ethyl 4-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexylmethoxy)methyl]-7-ethylpyrrolo[1,2 15 b]pyridazin-3-yl}butanoate 'H NMR (CDC 3 ) 8 0.87-1.06 (2H, m), 1.21 (311, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.16-1.46 (311, m), 1.50-1.85 (811, m), 2.23 (2H, t, J= 7 Hz), 2.55-2.75 (2H, m), 3.04 (211, q, J= 7 Hz), 3.38 (211, d, J= 7 Hz), 4.08 (2H, q, J= 7 Hz), 4.67 (2H, s), 5.92 (11H, d, J= 4 Hz), 6.60 (111, d, J= 4 Hz), 7.89 (1H, m), 8.56 (11H, d, J= 2 Hz), 20 8.79 (1H, d, J= 2 Hz). MS (ESI*): m/z 542 544. Example 408 ethyl 4-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 25 b]pyridazin-3-yl]butanoate 1H NMR (CDC 3 ) 6 0.22-0.32 (21H, m), 0.53-0.65 (211, m), 1.10-1.20 (1H, m), 1.19 (3H, t, J= 7 Hz), 1.37 (311, t, J= 7 Hz), 1.65-1.80 (211, m), 2.14-2.30 (2H, m), 2.43 (311, s), 2.57-2.74 (2H, m), 3.05 (2H, q, J= 7 Hz), 3.43 (211, d, J= 7 Hz), 4.03 (2H, q, J= 7 Hz), 4.74 (211, s), 5.90 (111, d, J= 4 Hz), 6.57 (1H, d, J= 4 Hz), 7.53 (1H, 30 s), 8.43 (1H, s), 8.54 (1H, s). MS (ESI*): m/z 436. Example 409 261 WO 2004/063197 PCT/JP2003/017091 ethyl 3-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 b]pyridazin-3-yl]propanoate 'H NMR (CDC 3 ) 8 0.22-0.32 (2H, m), 0.54-0.63 (2H, m), 1.10-1.20 (1H, m), 1.21 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 2.40-2.50 (2H, m), 2.43 (3H, s), 2.86-2.98 5 (2H, m), 3.05 (2H, q, J= 7 Hz), 3.42 (2H, d, J= 7 Hz), 4.06 (2H, q, J= 7 Hz), 4.71 (2H, s), 5.92 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 7.52 (1H, s), 8.42 (1H, s), 8.54 (1H, s). MS (BSI*): m/z 422. 10 Example 410 ethyl 3-{ 4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-methoxyethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}propanoate 'H NMR (CDC 3 ) 8 1.20 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 2.44 (2H, t, J= 7 Hz), 2.82-2.98 (2H, m), 3.05 (2H, q, J= 7 Hz), 3.38 (3H, s), 3.58 (2H, m), 3.76 (2H, m), 15 4.05 (2H, q, J= 7 Hz), 4.76 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.87 (1H, m), 8.54 (1H, s), 8.79 (1H, s). MS (ESI*): m/z 490 492. Example 411 20 4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine 'H NMR (CDC 3 ) 8 1.39 (3H, t, J= 7 Hz), 2.54 (3H, s), 3.04 (2H, q, J= 7 Hz), 6.39 (1H, s), 6.51 (1H, d, J= 4 Hz), 6.67 (1H, d, J= 4 Hz), 8.17 (1H, m), 8.76 (iH, d, J= 2 Hz), 8.86 (1H, d, J= 2 Hz). MS (ESI*): m/z 316 318. 25 Example 412 ethyl 4-[2-[(acetyloxy)methyl]-4-(5-chloro-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 yl]butanoate 'H NMR (300 MHz, CDCl 3 ) 5 1.20 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.70 (2H, 30 tt, J = 7, 7 Hz), 2.17 (3H, s), 2.20 (2H, t, J = 7 Hz), 2.45-2.54 (2H, m), 3.02 (2H, q, J = 7 Hz), 4.04 (2H, q, J = 7 Hz), 5.33 (2H, s), 5.94 (IH, d, J = 4 Hz), 6.63 (1H, d, J = 4 Hz), 7.74 (11H, dd, J = 2, 2 Hz), 8.53 (11H, d, J = 2 Hz), 8.70 (1H, d, J = 2 Hz). 262 WO 2004/063197 PCT/JP2003/017091 Example 413 ethyl 5-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2 b]pyridazin-3-yl}pentanoate 5 'H NMR (300 MHz, CDCl 3 ) 8 0.23-0.26 (2H, m), 0.54-0.59 (2H, m), 1.07-1.16 (IH, m), 1.23 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.41-1.56 (4H, m), 2.17 (2H, t, J = 7 Hz), 2.53-2.64 (2H, m), 3.03 (2H, q, J =7 Hz), 3.41 (2H, d, J = 7 Hz), 4.09 (2H, q, J = 7 Hz), 4.70 (2H, s), 5.90 (1H, d, J= 5 Hz), 6.58 (1H, d, J = 5 Hz), 7.72 (1H, s), 8.51 (1H, s), 8.68 (1H, s). 10 Example 414 ethyl 4 -{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2 b]pyridazin-3-yl}butanoate 'H NMR (300 MHz, CDCl 3 ) 8 0.24 (2H, dt, J = 7, 7 Hz), 0.56 (2H, dt, J = 7, 7 Hz), 15 1.07-1.15 (1H, m), 1.20 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.72 (2H, tt, J = 7, 7 Hz), 2.21 (2H, t, J = 7 Hz), 2.55-2.66 (2H, m), 3.02 (2H, q, J = 7 Hz), 3.43 (2H, d, J = 7 Hz), 4.04 (2H, q, J = 7 Hz), 4.73 (2H, s), 5.91 (1H, d, J = 5 Hz), 6.59 (1H, d, J = 5 Hz), 7.74 (1H, dd, J = 2, 2 Hz), 8.52 (1H, d, J = 2 Hz), 8.68 (1H, d, J = 2 Hz). 20 Example 415 ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate 'H NMR (300 MHz, CDCl 3 ) 6 0.92 (6 H, d, J = 7 Hz), 1.26 (3H, t, J = 7 Hz), 1.34 25 (3H, t, J = 7 Hz), 1.38-1.56 (4H, m), 1.92 (1H, qt, J= 7, 7 Hz), 2.15 (2H, t, J = 7 Hz), 2.51-2.63 (2H, m), 3.03 (2H, q, J = 7 Hz), 3.33 (2H, d, J = 7 Hz), 4.09 (2H, q, J = 7 Hz), 4.65 (2H, s), 5.90 (1H, d, J =7 Hz), 6.59 (1H, d, J =7 Hz), 7.88 (1H, dd, J = 2, 2 Hz), 8.55 (1H, d, J = 2 Hz), 8.77 (1H, d, J = 2 Hz). 30 Example 416 ethyl 3-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoate 'H NMR (300 MHz, CDCl 3 ) 6 0.92 (6H, d, J = 7 Hz), 1.19 (3H, t, J = 7 Hz), 1.37 (3H, 263 WO 2004/063197 PCT/JP2003/017091 t, J = 7 Hz), 1.91 (11H, qt, J = 7, 7 Hz), 2.41 (2H, t, J = 8 Hz), 2.84-2.94 (2H, m), 3.03 (2H, q, J = 7 Hz), 3.35 (2H, d, J = 7 H), 4.05 (2H, q, J = 7 Hz), 4.68 (2H, s), 5.92 (1H, d, J = 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.72 (11H, dd, J = 2, 2 Hz), 8.51 (1H, d,J=2Hz), 8.69 (1H,d,J = 2Hz). 5 Example 417 ethyl 3-[2-[(acetyloxy)methyl]-4-(3-chlorophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 yl]propanoate 'H NMR (300 MHz, CDC 3 ) 8 1.19 (3H, t, J = 7 Hz), 1.36 (3H, t, J = 7 Hz), 2.15 (3H, 10 s), 2.33 (2H, t, J = 8 Hz), 2.82 (2H, t, J = 8 Hz), 3.02 (2H, q, J = 7 Hz), 4.06 (2H, q, J = 7 Hz), 5.31 (2H, s), 5.97 (1H, d, J = 4 Hz), 6.61 (1H, d, J = 4 Hz), 7.23-7.26 (1H, m), 7.37 (1H, s), 7.44-7.46 (2H, m). Example 418 15 ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoate 'H NMR (300 MHz, CDC 3 ) 8 0.92 (61H, d, J = 7 Hz), 1.20 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.71 (2H, tt, J = 8,8Hz), 1.91 (1H, qt, J = 7,7 Hz), 2.20 (2H, t, J = 8 Hz), 2.56-2.66 (2H, m), 3.03 (2H, q, J = 7 Hz), 3.34 (2H, d, J = 7 Hz), 4.05 (2H, q, 20 J = 7 Hz), 4.69 (2H, s), 5.91 (1H, d, J = 5 Hz), 6.60 (1H, d, J = 5 Hz), 7.89 (1H, s), 8.56 (1H, d, J = 2 Hz), 8.78 (1H, d, J = 2 Hz). Example 419 2,4-bis(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazine 25 'H NMR (CDC 3 ) 8 1.45 (3H, t, J= 7 Hz), 3.14 (2H, q, J= 7 Hz), 6.66 (1H, d, J= 4 Hz), 6.86 (1H, d, J= 4 Hz), 6.91 (1H, s), 8.23 (1H, m), 8.48 (1H, m), 8.77 (1H, m), 8.83 (1H, m), 8.94 (1H, d, J= 2 Hz), 9.18 (1H, d, J= 2 Hz). Example 420 30 ethyl 4-[2-[(acetyloxy)methyl]-4-(3-chlorophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3 yl]butanoate 'H NMR (CDCl 3 ) 8 1.19 (3H, t, J = 8 Hz), 1.34 (3H, t, J = 8 Hz), 1.63-1.76 (2H, m), 2.10-2.22 (5H, m), 2.45-2.55 (2H, m), 3.01 (2H, q, J = 8 Hz), 4.04 (2H, q, J = 8 264 WO 2004/063197 PCT/JP2003/017091 Hz), 5.32 (2H, s), 5.95 (111, d, J = 5 Hz), 6.59 (iH, d, J = 5 Hz), 7.21-7.29 (1H, overlappled with CDCl 3 ), 7.36 (1H, br s), 7.38-7.46 (2H, m). MS (ESI*): m/z 443 (M + H). 5 Example 421 ethyl 5-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate 'H NMR (CDC 3 ) 8 1.23 (3H, t, J = 8 Hz), 1.33-1.60 (711, n), 1.55-1.70 (2H, m), 2.17 (2H, t, J = 8 Hz), 2.46-2.64 (2H, m), 3.04 (2H, d, J = 8 Hz), 3.46 (311, s), 10 3.90 (3H, s), 4.09 (2H, q, J = 8 Hz), 4.62 (2H, s), 5.93 (1H, d, J = 5 Hz), 6.59 (11H, d, J = 5 Hz), 7.23 (1H, m), 8.22 (1H, d, J = 1 Hz), 8.40 (1H, d, J = 3 Hz). MS (ESI*): m/z 426 (M + H). Example 422 15 ethyl 5-[7-ethyl-4-(5-methoxy-3-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3 yl]pentanoate 'H NMR (CDCl 3 ) 6 1.23 (3H, t, J = 8 Hz), 1.33-1.62 (7H, m), 2.18 (2H, t, J = 8 Hz), 2.38-2.49 (2H, m), 2.56 (3H, s), 3.01 (211, q, J = 8 Hz), 3.90 (3H, s), 4.08 (2H, q, J = 8 Hz), 5.89 (1H, d, J = 5 Hz), 6.51 (1H, d, J = 5 Hz), 7.21 (1H, m), 8.21 (1H, 20 d,J=1Hz),8.40(1H,d,J=3 Hz). MS (ESI*): m/z 396 (M + H). Example 423 ethyl 3-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 25 yl]propanoate 'H NMR (CDC 3 ) 6 1.20 (311, t, J = 8 Hz), 1.38 (311, t, J = 8 Hz), 2.40 (2H, t, J = 8 Hz), 2.81-2.96 (2H, m), 3.04 (2H, d, J = 8 Hz), 3.47 (3H, s), 3.90 (3H, s), 4.05 (2H, q, J = 8 Hz), 4.65 (211, s), 5.96 (111, d, J = 5 Hz), 6.60 (111, d, J = 5 Hz), 7.21 (1H, m), 8.23 (111, br s), 8.40 (1H, d, J = 3 Hz). 30 MS (ESI+): m/z 398 (M + H). Example 424 ethyl 4-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyiidinyl)pyrrolo[1,2-b]pyridazin-3 265 WO 2004/063197 PCT/JP2003/017091 yl]butanoate 'H NMR (CDC 3 ) 8 1.20 (3H, t, J = 8 Hz), 1.38 (3H, t, J = 8 Hz), 1.64-1.79 (2H, m), 2.14-2.24 (2H, m), 2.53-2.66 (2H, m), 3.04 (2H, d, J = 8 Hz), 3.47 (3H, s), 3.90 (3H, s), 4.04 (2H, q, J = 8 Hz), 4.67 (2H, br s), 5.94 (1H, d, J = 5 Hz), 6.59 (1H, d, 5 J = 5 Hz), 7.23 (1H, m), 8.22 (1H, d, J = 1 Hz), 8.40 (1H, d, J = 3 Hz). MS (ESI*): m/z 412 (M + H). Example 425 ethyl 5-[7-ethyl-2-(methoxymethyl)-4-(5-pyrimidinyl)pyrrolo[1,2-b]pyridazin-3 10 yl]pentanoate 1 H NMR (CDCl 3 ) 8 1.23 (3H, t, J = 8 Hz), 1.30-1.62 (7H, m), 2.19 (2H, t, J = 8 Hz), 2.46-2.60 (2H, m), 3.04 (2H, d, J = 8 Hz), 3.47 (3H, s), 3.90 (3H, s), 4.09 (2H, q, J = 8 Hz), 4.63 (2H, s), 5.90 (1H, d, J = 5 Hz), 6.61 (1H, d, J = 5 Hz), 8.80 (2H, s), 9.34 (1H, s). 15 MS (ESI*): m/z 397 (M + H). Example 426 ethyl 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoate 20 'H NMR (CDC1 3 ) 6 1.21 (3H, t, J = 8 Hz), 1.37 (3H, t, J = 8 Hz), 1.62-1.76 (2H, m), 2.21 (2H, t, J = 8 Hz), 2.49-2.67 (2H, m), 3.04 (2H, d, J = 8 Hz), 3.46 (3H, s), 4.06 (2H, q, J = 8 Hz), 4.67 (2H, br s), 5.92 (1H, d, J = 5 Hz), 6.61 (1H, d, J = 5 Hz), 7.74 (1H, m), 8.53 (1H, d, J = 1 Hz), 8.69 (1H, d, J = 2 Hz). MS (ESI*): m/z 414 (M - H). 25 Example 427 ethyl 3-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoate 'H NMR (CDC1 3 ) 8 1.20 (3H, t, J = 8 Hz), 1.38 (3H, t, J = 8 Hz), 2.40 (2H, t, J = 8 30 Hz), 2.82-2.94 (2H, m), 3.04 (2H, d, J = 8 Hz), 3.47 (3H, s), 4.06 (2H, q, J = 8 Hz), 4.65 (2H, s), 5.93 (1H, d, J = 5 Hz), 6.67 (1H, d, J = 5 Hz), 7.73 (1H, br s), 8.51 (1H, br s), 8.70 (1H, br s). MS (ESI*): m/z 402 (M + H). 266 WO 2004/063197 PCT/JP2003/017091 Example 428 ethyl 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate 5 'H NMR (CDC 3 ) 6 1.23 (3H, t, J = 8 Hz), 1.34-1.60 (7H, m), 2.19 (2H, t, J = 8 Hz), 2.47-2.64 (2H, m), 3.04 (2H, d, J = 8 Hz), 3.46 (3H, s), 4.10 (2H, q, J = 8 Hz), 4.62 (2H, s), 5.90 (1H, d, J = 5 Hz), 6.60 (1H, d, J = 5 Hz), 7.73 (1H, m), 8.51 (1H, br s), 8.68 (1H, br s). MS (ESI*): m/z 426 (M + H). 10 Example 429 methyl 2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazine 3-carboxylate mp 122-123 deg. 15 'H NMR (CDC 3 ) 6 1.38 (311, t, J = 8 Hz), 2.12 (3H, s), 3.06 (2H, t, J = 8 Hz), 3.61 (311, s), 5.43 (211, s), 6.37 (111, d, J = 5 Hz), 6.78 (1H, d, J = 5 Hz), 7.93 (1H, t, J = 1 Hz), 8.57 (1H, d, J = 1 Hz), 8.78 (111, d, J = 1 Hz). MS (ESI*): m/z 432,434 (M + H). 20 Example 430 2-(2-{ 2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]ethoxy}ethoxy)ethyl acetate 'H-NMR (CDC 3 ) 6 1.37 (3H, t ,J = 7 Hz), 2.05 (311, s), 2.42 (3H, s), 2.59 (311, s), 2.75 (21H, m), 3.00 (2H, q, J = 7 Hz), 3.39-3.48 (4H, m), 3.54 (211, m), 3.63 (2H, 25 m), 4.16 (2H, m), 5.86 (1H, d, J = 5 Hz), 6.52 (1H, d, J = 5 Hz), 7.50 (1H, m), 8.43 (1H, m), 8.52 (1H, m). Example 431 ethyl (2E)-4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-2 30 butenoate 'H-NMR (CDCl 3 ) 6 1.27 (3H, t, J = 7 Hz), 1.36 (311, t, J = 7 Hz), 2.49 (3H, s), 3.02 (2H, q, J = 7 Hz), 3.30 (2H, m), 4.16 (211, q, J = 7 Hz), 5.58 (111, d, J = 16 Hz), 5.90 (1H, d, J = 5 Hz), 6.56 (111, d, J = 5 Hz), 6.97 (111, dt, J = 7 and 16 Hz), 7.58 267 WO 2004/063197 PCT/JP2003/017091 (2H, m), 7.65 (1H, s), 7.75 (1H, m). Example 432 ethyl 4

-[

4 -(5-bromo- 3 -pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 5 yl]butanoate 'H NMR (300 MHz, CDC 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.65-1.78 (2H, m), 2.23 (2H, t, J= 7 Hz), 2.54-2.72 (2H, m), 3.04 (2H, q, J= 7 Hz), 3.46 (3H, s), 4.06 (2H, q, J= 7 Hz), 4.66 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.89 (1H, m), 8.55 (1H, d, J= 2 Hz), 8.77 (1H, d, J= 2 Hz). 10 MS (ESI*): m/z 460 462. Example 433 ethyl 4 -(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate 'H NMR (CDCl 3 ) 8 0.99 (3H, t, J = 8 Hz), 1.38 (3H, t, J = 8 Hz), 2.63 (3H, s), 3.05 15 (2H, q, J = 8 Hz), 4.07 (2H, q, J = 8 Hz), 6.27 (1H, d, J = 5 Hz), 6.70 (1H, d, J = 5 Hz), 7.30 (1H, dd, J = 5, 1 Hz), 7.41 (1H, br s), 8.49 (1H, d, J = 5 Hz). MS (ESI*): m/z 344 (M + H). The following compound(s) was(were) obtained in a similar manner to that of 20 Example 76. Example 434 4

-[

4 -(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoic acid 'H NMR (CDCl 3 ) 8 1.37 (3H, t, J= 7 Hz), 1.72-1.84 (2H, m), 2.33 (2H, t, J= 7 Hz), 2.47-2.57 (2H, m), 2.58 (3H, s), 3.03 (2H, q, J= 7 Hz), 5.88 (1H, d, J= 4 Hz), 6.53 25 (1H, d, J= 4 Hz), 7.27 (1H, m), 7.38 (1H, s), 8.53 (1H, d, J= 5 Hz). MS (ESI-): m/z 356, MS (ESI*): m/z 358. Example 435 3

-[

4 -(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoic acid 30 'H NMR (CDC 3 ) 8 1.37 (3H, t, J= 7 Hz), 2.36-2.47 (2H, m), 2.58 (3H, s), 2.76-2.88 (2H, m), 3.03 (2H, q, J= 7 Hz), 5.89 (1H, d, J= 4 Hz), 6.55 (1H, d, J= 4 Hz), 7.25 (1H, d, J= 5 Hz), 7.35 (1H, s), 8.53 (1H, d, J= 5 Hz). 268 WO 2004/063197 PCT/JP2003/017091 Example 436 4-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]butanoic acid 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.30-1.42 (2H, m), 1.35 (9H, s), 1.63-1.76 (2H, m), 2.22-2.37 (4H, m), 3.93 (1H, d, J= 17 Hz), 4.12 (2H, q, J= 7 Hz), 4.29 5 (1H, d, J= 17 Hz), 7.22 (2H, d, J= 8 Hz), 7.26-7.36 (4H, m), 7.50 (1H, s), 8.42 (1H, d, J= 5 Hz). MS (EST): m/z 418, MS (ESI*): m/z 420. Example 437 10 3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoic acid 'H NMR (CDCl 3 ) 8 1.36 (3H, t, J= 7 Hz), 2.06 (2H, t, J= 7 Hz), 2.78 (2H, t, J= 7 Hz), 3.04 (2H, q, J= 7 Hz), 5.99 (1H, d, J= 4 Hz), 6.67 (1H, d, J= 4 Hz), 7.28 (1H, d, J= 5 Hz), 7.41 (1H, s), 7.45-7.55 (5H, m), 8.53 (1H, d, J= 5 Hz). MS (ESI): m/z 404, MS (ESI'): m/z 406. 15 Example 438 5-[2-benzyl-4-(2-chloro-4-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 'H NMR (CDCl 3 ) 8 1.16-1.32 (2H, m), 1.39 (3H, t, J= 7 Hz), 1.38-1.53 (2H, m), 2.15 (2H, t, J= 7 Hz), 2.30-2.40 (2H, m), 3.06 (2H, q, J= 7 Hz), 4.21 (2H, s), 5.88 (1H, 20 d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.18-7.35 (7H, m), 8.49 (1H, d, J= 5 Hz). MS (EST): m/z 446, MS (ESI*): m/z 448. Example 439 { 2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy} acetic 25 acid 'H NMR (CDCI) 8 1.37 (3H, t, J= 7 Hz), 2.44 (3H, s), 2.59 (3H, s), 2.74-2.92 (2H, m), 3.02 (2H, q, J= 7 Hz), 3.54-3.66 (2H, m), 3.93 (2H, m), 5.82 (1H, d, J= 4 Hz), 6.53 (1H, d, J= 4 Hz), 7.63 (1H, s), 8.52 (1H, s), 8.56 (1H, s). 30 Example 440 {2-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy} acetic acid 'H NMR (CDC 3 ) 8 1.37 (3H, t, J= 7 Hz), 2.80 (2H, t, J= 7 Hz), 3.03 (2H, q, J= 7 Hz), 269 WO 2004/063197 PCT/JP2003/017091 3.20 (2H, t, J= 7 Hz), 3.72 (3H, s), 6.01 (1H, d, J= 4 Hz), 6.67 (1H, d, J= 4 Hz), 7.42 (1H, d, J= 5 Hz), 7.45-7.60 (6H, m), 8.57 (1H, d, J= 5 Hz). Example 441 5 [4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl] acetic acid 'H NMR (CDCl 3 ) 5 1.37 (3H, t, J= 7 Hz), 2.55 (3H, s), 2.97-3.10 (2H, m), 3.30-3.62 (2H, m), 5.97 (1H, m), 6.57 (1H, m), 8.03 (1H, s), 8.69 (1H, s), 8.77 (1H, s). MS (ESI*): m/z 374 376. 10 Example 442 3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}propanoic acid 'H NMR (CDCl 3 ) 5 1.38 (3H, t, J= 7 Hz), 2.33-2.50 (2H, m), 2.42 (3H, s), 2.80-3.00 (2H, m), 3.06 (2H, q, J= 7 Hz), 4.72 (2H, s), 4.83 (2H, s), 5.92 (1H, d, J= 4 Hz), 15 6.62 (1H, d, J= 4 Hz), 7.36 (2H, d, J= 7 Hz), 7.55 (1H, s), 8.41 (1H, s), 8.44 (2H, d, J= 7 Hz), 8.53 (1H, s). MS (ESI*): m/z 429 431. Example 443 20 3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyrazinylmethoxy)methyl]pyfrolo[l,2 b]pyridazin-3-yl}propanoic acid 'H NMR (CDCl 3 ) 5 1.38 (3H, t, J= 7 Hz), 2.42 (3H, s), 2.40-2.55 (2H, m), 2.83-3.12 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.84 (2H, s), 4.91 (2H, m), 5.92 (1H, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.57 (1H, s), 8.42 (1H, s), 8.48-8.55 (3H, m), 8.76 (1H, s). 25 MS (ESI*): m/z 432. Example 444 3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}propanoic acid 30 'H NMR (CDCl 3 ) 5 1.37 (3H, t, J= 7 Hz), 2.43 (3H, s), 2.50-2.60 (2H, m), 2.88-3.05 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.81 (2H, s), 4.87 (2H, s), 5.82 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.27 (1H, m), 7.48 (1H, d, J= 8 Hz), 7.56 (1H, s), 7.77 (1H, t, J= 8 Hz), 8.43 (1H, s), 8.54 (2H, n). 270 WO 2004/063197 PCT/JP2003/017091 Example 445 4-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methylpyrrolo[1,2 b]pyridazin-3-yl}butanoic acid 5 'H NMR (CDCl 3 ) 5 1.40 (3H, t, J= 7 Hz), 1.70-1.85 (2H, m), 2.16-2.31 (2H, m), 2.44 (3H, s), 2.53-2.83 (2H, m), 3.05 (2H, q, J= 7 Hz), 4.72 (2H, s), 4.83-4.98 (2H, m), 5.92 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.30 (2H, d, J= 7 Hz), 7.57 (1H, s), 8.38-8.55 (4H, m). MS (EST): m/z 443, MS (ESI*): m/z 445. 10 Example 446 5-{ 4 -(5-bromo- 3 -pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoic acid 'H NMR (CDCl 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.40-1.63 (4H, m), 2.20 (2H, t, J= 7 Hz), 15 2.52-2.68 (2H, m), 3.04 (2H, q, J= 7 Hz), 4.69 (2H, s), 4.78 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.35 (2H, d, J= 6 Hz), 7.88 (1H, m), 8.54 (2H, d, J= 6 Hz), 8.55 (1H, m), 8.79 (11H, m). Example 447 20 5-{ 4 -(5-bromo- 3 -pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoic acid 'H NMR (CDCl 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.40-1.62 (4H, m), 2.17 (2H, t, J= 7 Hz), 2.50-2.67 (2H, m), 3.04 (2H, q, J= 7 Hz), 4.69 (2H, s), 4.76 (2H, s), 5.92 (1H, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.32-7.38 (1H, m), 7.77 (1H, d, J= 8 Hz), 7.88 25 (1H, m), 8.55 (2H, m), 8.65 (1H, m), 8.78 (1H, m). MS (EST): m/z 521 523, MS (ESI*): m/z 523 525. Example 448 5-{ 4 -(5-bromo- 3 -pyridinyl)-7-ethyl-2-[(2-pyridinylmethoxy)methyllpyrrolo[1,2 30 b]pyridazin-3-yl}pentanoic acid 'H NMR (CDC1 3 ) 6 1.37 (3H, t, J= 7 Hz), 1.48-1.67 (4H, m), 2.26 (2H, t, J= 7 Hz), 2.53-2.75 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.82 (2H, s), 4.83 (2H, s), 5.90 (1H, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.26-7.34 (1H, m), 7.53 (1H, d, J= 8 Hz), 7.75 271 WO 2004/063197 PCT/JP2003/017091 7.83 (1H, m), 7.87 (1H, m), 8.55 (1H, d, J= 2 Hz), 8.62 (11, m), 8.77 (1H, d, J= 2 Hz). MS (ESI*): m/z 523 525. 5 Example 449 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoic acid 'H NMR (CDC 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.45-1.64 (4H, m), 2.23 (2H, t, J= 7 Hz), 2.53-2.72 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.83 (2H, s), 4.87 (2H, s), 5.93 (1H, d, 10 J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.88 (1H, m), 8.53 (3H, m), 8.77 (2H, m). MS (EST): m/z 522 524, MS (ESI+): m/z 524 526. Example 450 4

-{

4 -(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 15 b]pyridazin-3-yl}butanoic acid 'H NMR (CDCl 3 ) 8 1.39 (3H, t, J= 7 Hz), 1.69-1.84 (2H, m), 2.27 (2H, t, J= 7 Hz), 2.56-2.80 (2H, m), 3.02 (2H, q, J= 7 Hz), 4.73 (2H, s), 4.92 (2H, m), 5.94 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.31 (2H, d, J= 6 Hz), 7.90 (1H, m), 8.46 (2H, d, J= 6 Hz), 8.57 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). 20 MS (EST): m/z 507 509, MS (ESI*): m/z 509 511. Example 451 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}butanoic acid 25 'H NMR (CDC 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.66-1.83 (2H, m), 2.26 (2H, t, J= 7 Hz), 2.53-2.77 (2H, m), 3.04 (2H, q, J= 7 Hz), 4.71 (2H, s), 4.86 (2H, m), 5.92 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.33 (1H, m), 7.78 (1H, d, J= 8 Hz), 7.90 (1H, m), 8.50 (IH, m), 8.56 (1H, d, J= 2 Hz), 8.60 (1H, s), 8.78 (1H, d, J= 2 Hz). MS (ESI'): m/z 509 511. 30 Example 452 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}butanoic acid 272 WO 2004/063197 PCT/JP2003/017091 H NMR (CDC 3 ) 6 1.37 (3H, t, J= 7 Hz), 1.70-1.85 (2H, m), 2.23-2.34 (2H, m), 2.57-2.76 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.81 (2H, s), 4.90 (2H, m), 5.91 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.28 (1H, m), 7.49 (1H, d, J= 7 Hz), 7.77 (IH, t, J= 8 Hz), 7.88 (1H, m), 8.55 (1H, d, J= 2 Hz), 8.57 (1H, m), 8.74 (1H, d, J= 2 Hz). 5 MS (ESI*): m/z 509 511. Example 453 4

-{

4 -(5-bromo-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2 b]pyridazin-3-yl}butanoic acid 10 'H NMR (CDC 3 ) 8 0.22 (2H, m), 0.57 (2H, m), 1.07-1.22 (1H, m), 1.37 (3H, t, J= 7 Hz), 1.72-1.87 (2H, m), 2.28 (2H, t, J= 7 Hz), 2.58-2.77 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.41 (2H, d, J= 7 Hz), 4.72 (2H, s), 5.92 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 7.93 (1H, m), 8.56 (1H, d, J= 2 Hz), 8.77 (1H, d, J= 2 Hz). MS (ESI): m/z 470 472, MS (ESI*): m/z 472 474. 15 Example 454 4-{4-(5-bromo- 3 -pyridinyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}butanoic acid 'H NMR (CDC 3 ) 5 1.38 (3H, t, J= 7 Hz), 1.68-1.83 (2H, m), 2.27 (2H, t, J= 7 Hz), 20 2.56-2.78 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.84 (2H, s), 4.92 (2H, m), 5.94 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.91 (1H, m), 8.51 (2H, m), 8.56 (1H, d, J= 2 Hz), 8.76 (2H, m). MS (EST): m/z 508 510, MS (ESI*): m/z 510 512. 25 Example 455 3

-{

4 -(5-bromo- 3 -pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}propanoic acid 'H NMR (CDC 3 ) 8 1.39 (3H, t, J= 7 Hz), 2.38 (2H, t, J= 7 Hz), 2.83-2.98 (2H, m), 3.07 (2H, q, J= 7 Hz), 4.74 (2H, s), 4.83 (2H, s), 5.95 (1H, d, J= 4 Hz), 6.65 (1H, 30 d, J= 4 Hz), 7.38 (2H, d, J= 6 Hz), 7.88 (1H, s), 8.43 (2H, d, J= 6 Hz), 8.55 (1H, s), 8.78 (11H, s). MS (ESI-): m/z 493 495, MS (ESI*): m/z 495 497. 273 WO 2004/063197 PCT/JP2003/017091 Example 456 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-hydroxyethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}butanoic acid 'H NMR (CDC 3 ) 8 1.37 (3H, t, J= 7 Hz), 1.68-1.83 (2H, m), 2.28 (2H, t, J= 7 Hz), 5 2.53-2.76 (2H, m), 3.02 (2H, q, J= 7 Hz), 3.75 (2H, m), 3.79 (2H, m), 4.78 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.90 (1H, s), 8.56 (1H, s), 8.78 (1H, s). MS (ESI~): m/z 460 462, MS (ESI*): m/z 462 464. 10 Example 457 3-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 b]pyridazin-3-yl]propanoic acid 'H NMR (CDC 3 ) 5 0.88-1.06 (2H, m), 1.10-1.36 (3H, m), 1.37 (3H, t, J= 7 Hz), 1.58-1.85 (6H, m), 2.42 (3H, s), 2.48-2.60 (2H, m), 2.80-3.02 (2H, m), 3.04 (2H, 15 q, J= 7 Hz), 3.39 (2H, d, J= 7 Hz), 4.67 (2H, m), 5.89 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.57 (1H, s), 8.42 (1H, s), 8.53 (1H, s). MS (ESI~): m/z 434, MS (ESI*): m/z 436. Example 458 20 3-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexylmethoxy)methyl]-7-ethylpyrrolo[1,2 b]pyridazin-3-yl}propanoic acid 'H NMR (CDC1 3 ) 8 0.88-1.05 (2H, m), 1.10-1.36 (3H, m), 1.37 (3H, t, J= 7 Hz), 1.56-1.83 (6H, m), 2.51 (2H, t, J= 7 Hz), 2.80-3.07 (2H, m), 3.06 (2H, q, J= 7 Hz), 3.37 (2H, d, J= 7 Hz), 4.67 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 25 7.89 (1H, m), 8.55 (1H, s), 8.79 (1H, s). MS (EST): m/z 498 500, MS (ESI*): m/z 500 502. Example 459 4-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexylmethoxy)methyl]-7-ethylpyrrolo[1,2 30 b]pyridazin-3-yl}butanoic acid 'H NMR (CDC1 3 ) 8 0.86-1.03 (2H, m), 1.10-1.35 (3H, m), 1.37 (3H, t, J= 7 Hz), 1.60-1.82 (8H, m), 2.28 (2H, t, J= 7 Hz), 2.55-2.76 (2H, m), 3.05 (2H, q, J= 7 Hz), 3.36 (2H, d, J= 7 Hz), 4.67 (2H, s), 5.92 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 274 WO 2004/063197 PCT/JP2003/017091 7.91 (1H, m), 8.55 (1H, d, J= 2 Hz), 8.76 (1H, d, J= 2 Hz). MS (EST): m/z 512 514, MS (ESI*): m/z 514 516. Example 460 5 4-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 b]pyridazin-3-yl]butanoic acid 'H NMR (CDCl 3 ) 8 0.22-0.32 (2H, m), 0.55-0.63 (2H, m), 1.10-1.22 (1H, m), 1.37 (3H, t, J= 7 Hz), 1.73-1.86 (2H, m), 2.20-2.35 (2H, m), 2.46 (3H, s), 2.55-2.86 (2H, m), 3.04 (2H, q, J= 7 Hz), 3.43 (2H, d, J= 7 Hz), 4.70-4.85 (2H, m), 5.88 10 (1H, d, J= 4 Hz), 6.57 (1H, d, J= 4 Hz), 7.62 (1H, s), 8.42 (1H, s), 8.46 (1H, s). MS (ESI*): m/z 408. Example 461 3-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 15 b]pyridazin-3-yl]propanoic acid 'H NMR (CDCl 3 ) 8 0.23-0.35 (2H, m), 0.54-0.65 (2H, m), 1.08-1.24 (1H, m), 1.37 (3H, t, J= 7 Hz), 2.43 (3H, s), 2.50-2.65 (2H, m), 2.70-3.05 (2H, m), 3.04 (2H, q, J= 7 Hz), 3.44 (2H, d, J= 7 Hz), 4.74 (2H, s), 5.89 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.56 (1H, s), 8.42 (1H, s), 8.53 (IH, s). 20 MS (EST): m/z 392, MS (ESI*): m/z 394. Example 462 3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-methoxyethoxy)methyllpyrrolo[1,2 b]pyridazin-3-yl}propanoic acid 25 'H NMR (CDC 3 ) 8 1.37 (3H, t, J= 7 Hz), 2.48-2.62 (2H, m), 2.83-3.02 (2H, m), 3.02 (2H, q, J= 7 Hz), 3.37 (31H, s), 3.60 (2H, m), 3.73 (2H, m), 4.75 (2H, s), 5.92 (1H, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.89 (1H, m), 8.55 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). MS (EST): m/z 460 462, MS (ESI*): m/z 462 464. 30 Example 463 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{ [(4-morpholinylcarbonyl)oxy]methyl}pyrrolo[1,2 b]pyridazin-3-yl)pentanoic acid 275 WO 2004/063197 PCT/JP2003/017091 'H NMR (CDCl 3 ) 8 1.37 (3H, t, J= 7 Hz), 1.35-1.65 (4H, m), 2.23 (211, t, J= 7 Hz), 2.40-2.56 (2H, m), 3.02 (2H, q, J= 7 Hz), 3.48-3.57 (4H, m), 3.60-3.78 (4H, m), 5.33 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.89 (1H, m), 8.56 (iH, d, J= 2 Hz), 8.79 (1H, d, J= 2 Hz). 5 Example 464 5-[4-(5-bromo-3-pyridinyl)-2-({ [(dimethylamino)carbonyl]oxy}methyl)-7 ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 1 H NMR (CDCl 3 ) 8 1.36 (3H, t, J= 7 Hz), 1.45-1.65 (4H, m), 2.22 (2H, t, J= 7 Hz), 10 2.42-2.57 (2H, m), 2.97 (6H, s), 3.03 (2H, q, J= 7 Hz), 5.30 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.89 (iH, s), 8.54 (iH, s), 8.78 (1H, s). MS (ESI*): m/z 503 505. Example 465 15 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(1-pyrrolidinylcarbonyl)oxy]methyl}pyrrolo[1,2 b]pyridazin-3-yl)pentanoic acid 'H NMR (CDCl 3 ) 8 1.36 (3H, t, J= 7 Hz), 1.40-1.63 (4H, m), 1.82-1.97 (4H, m), 2.23 (2H, t, J= 7 Hz), 2.43-2.58 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.37-3.52 (4H, m), 5.31 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 7.88 (1H, m), 8.54 (1H, 20 d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). MS (ESI-): m/z 527 529, MS (ESI*): m/z 529 531. Example 466 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2 25 [({ [methyl(phenyl)amino]carbonyl}oxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid 'H NMR (CDCl 3 ) 6 1.38 (3H, t, J= 7 Hz), 1.40-1.58 (4H, m), 2.18 (2H, t, J= 7 Hz), 2.32-2.53 (2H, m), 3.04 (2H, q, J= 7 Hz), 3.37 (3H, s), 5.36 (2H, s), 5.92 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.16-7.40 (5H, m), 7.87 (1H, s), 8.52 (iH, s), 30 8.79 (1H, s). Example 467 4-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(4-morpholinylcarbonyl)oxy]methyl}pyrrolo[1,2 276 WO 2004/063197 PCT/JP2003/017091 b]pyridazin-3-yl)butanoic acid 'H NMR (CDC 3 ) 8 1.37 (3H, t, J= 7 Hz), 1.65-1.84 (2H, m), 2.27 (2H, t, J= 7 Hz), 2.45-2.68 (2H, m), 3.04 (2H, q, J= 7 Hz), 3.53 (4H, m), 3.69 (4H, m), 5.36 (2H, s), 5.95 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.91 (1H, m), 8.55 (1H, d, J= 2 Hz), 5 8.78 (1H, d, J= 2 Hz). Example 468 4-[4-(5-bromo-3-pyridinyl)-2-({ [(dimethylamino)carbonyl]oxy}methyl)-7 ethylpyrrolo[1,2-b]pyridazin-3-yl]butanoic acid 10 'H NMR (CDCl3) 6 1.36 (3H, t, J= 7 Hz), 1.66-1.82 (2H, m), 2.27 (2H, t, J= 7 Hz), 2.46-2.68 (2H, m), 2.97 (6H, s), 3.04 (2H, q, J= 7 Hz), 5.33 (2H, s), 5.94 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.92 (1H, m), 8.56 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). 15 Example 469 3-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7 ethylpyrrolo[1,2-b]pyridazin-3-yl]propanoic acid 'H NMR (CDCl 3 ) 8 1.36 (3H, t, J= 7 Hz), 2.45 (2H, t, J= 7 Hz), 2.82-2.96 (2H, m), 2.97 (6H, s), 3.03 (2H, q, J= 7 Hz), 5.33 (2H, s), 5.96 (IH, d, J= 4 Hz), 6.63 (1H, 20 d, J= 4 Hz), 7.89 (1H, m), 8.55 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). MS (ESI~): m/z 473 475, MS (ESI'): m/z 475 477. Example 470 5-{ 4-(5-bromo-3-pyridinyl)-2-[(1,1-dioxido-4-thiomorpholinyl)methyl-7 25 ethylpyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid 'H NMR (300 MHz, CDC1 3 ) 6 1.36 (3H, t, J = 7 Hz), 1.42-1.56 (4H, m), 2.26 (2H, t, J = 7 Hz), 2.48-2.61 (2H, m), 3.01 (2H, q, J = 7 Hz), 3.10 (4H, t, J = 6 Hz), 3.19 (4H, t, J = 6 Hz), 3.85 (2H, s), 5.92 (1H, d, J = 4 Hz), 6.61 (1H, d, J = 4 Hz), 7.89 (1H, dd, J = 2, 2 Hz), 8.56 (1H, d, J = 2 Hz), 8.78 (1H, d, J = 2 Hz). 30 MS (m/z) 550 (M+H). Example 471 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2-b]pyridazin 277 WO 2004/063197 PCT/JP2003/017091 3 -yl]pentanoic acid 'H NMR (300 MHz, CDC 3 ) 6 1.37 (3H, t, J = 7 Hz), 1.43-1.58 (4H, m), 2.24 (2H, t, J = 7 Hz), 2.49-2.61 (2H, m), 2.66 (4H, t, J = 4 Hz), 2.86 (4H, t, J = 4 Hz), 3.02 (2H, q, J = 7 Hz), 3.68 (2H, s), 5.89 (1H, d, J = 5 Hz), 6.58 (1H, d, J = 5 Hz), 7.90 5 (1H, s), 8.56 (11H, s), 8.79 (11H, s). MS (m/z) 518 (M+H). Example 472 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[4-(2-hydroxyethyl)-1 10 piperazinyl]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoic acid 'H NMR (300 MHz, CDC 3 ) 6 1.34 (3H, t, J = 7 Hz), 1.41-1.57 (4H, m), 2.21 (2H, t, J = 6 Hz), 2.43-2.57 (2H, m), 2.80-2.84 (4H, m), 2.91-3.00 (6H, m), 3.65 (2H, s), 3.83 (2H, m), 5.88 (1H, d, J = 5 Hz), 6.57 (1H, d, J = 5 Hz), 7.88 (1H, s), 8.55 (1H, s), 8.77 (1H, s). 15 MS (m/z) 545 (M+H). Example 473 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2-b]pyridazin 3-yl]butanoic acid 20 'H NMR (300 MHz, CDCl 3 ) 6 1.37 (3H, t, J = 7 Hz), 1.72 (2H, tt, J = 7,7 Hz), 2.26 (2H, t, J = 7 Hz), 2.53-2.68 (6H, m), 2.87-2.90 (4H, m), 3.02 (2H, q, J = 7 Hz), 3.72 (2H, s), 5.91 (1H, d, J = 4 Hz), 6.59 (1H, d, J = 4 Hz), 7.78 (11H, dd, J = 2, 2 Hz), 8.52 (1H, d, J = 2 Hz), 8.68 (11H, d, J = 2 Hz). MS (m/z) 460 (M+H). 25 Example 474 4-{ 4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}butanoic acid 'H NMR (300 MHz, CDC 3 ) 8 1.38 (3H, t, J = 7 Hz), 1.73 (2H, tt, J = 7,7 Hz), 2.25 30 (2H, t, J = 7 Hz), 2.57-2.73 (2H, m), 3.04 (2H, q, J = 7 Hz), 4.72 (2H, s), 4.89 (2H, s), 5.93 (1H, d, J =5 Hz), 6.63 (1H, d, J =5 Hz), 7.31 (2H, d, J = 6 Hz), 7.76 (1H, dd, J = 2, 2 Hz), 8.46 (2H, d, J = 6 Hz), 8.53 (11H, d, J = 2 Hz), 8.67 (11H, d, J = 2 Hz). 278 WO 2004/063197 PCT/JP2003/017091 MS (m/z) 465 (M+H). Example 475 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3 5 yl]butanoic acid 'H NMR (300 MHz, CDCl 3 ) 8 1.37 (3H, t, J = 7 Hz), 1.73 (2H, tt, J = 7,7 Hz), 2.26 (2H, t, J = 7 Hz), 2.54-2.72 (6H, m), 3.03 (2H, q, J = 7 Hz), 3.66-3.73 (6H, m), 5.90 (1H, d, J = 4 Hz), 6.59 (1H, d, J = 4 Hz), 7.79 (1H, s), 8.53 (1H, s), 8.67 (1H, s). 10 MS (m/z) 443 (M+H). Example 476 5-{ 4 -(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2 b]pyridazin-3-yl}pentanoic acid 15 'H NMR (300 MHz, CDC 3 ) 6 0.24 (2H, dt, J = 7, 7 Hz), 0.57 (2H, dt, J = 7,7 Hz), 1.07-1.17 (1H, m), 1.38 (3H, t, J = 7 Hz), 1.45-1.61 (4H, m), 2.23 (2H, t, J = 7 Hz), 2.52-2.66 (2H, m), 3.02 (2H, q, J = 7 Hz), 3.41 (2H, d, J = 7 Hz), 4.70 (2H, s), 5.90 (1H, d, J = 4 Hz), 6.59 (1H, d, J = 4 Hz), 7.74 (1H, dd, J = 2, 2 Hz), 8.52 (1H, d, J = 2 Hz), 8.68 (1H, d, J = 2 Hz). 20 MS (m/z) 442 (M+H). Example 477 4-{ 4-(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2 b]pyridazin-3-yl}butanoic acid 25 'H NMR (300 MHz, CDC 3 ) 6 0.23 (2H, dt, J = 6, 6 Hz), 0.56 (2H, dt, J = 6, 6 Hz), 1.05-1.17 (11H, m), 1.37 (3H, t, J = 7 Hz), 1.75 (2H, tt, J = 7, 7 Hz), 2.28 (2H, t, J = 7 Hz), 2.57-2.70 (2H, m), 3.03 (2H, q, J = 7 Hz), 3.42 (2H, d, J = 7 Hz), 4.73 (2H, s), 5.91 (11H, d, J = 5 Hz), 6.60 (1H, d, J = 5 Hz), 7.77 (11H, dd, J = 2, 2 Hz), 8.52 (1H, d, J = 2 Hz), 8.66 (1H, d, J = 2 Hz). 30 MS (m/z) 428 (M+H). Example 478 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3 279 WO 2004/063197 PCT/JP2003/017091 yl]pentanoic acid 'H NMR (300 MHz, CDC 3 ) 8 0.93 (6H, d, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.42 1.59 (4H, m), 1.92 (1H, qt, J = 7, 7 Hz), 2.24 (2H, t, J = 7 Hz), 2.48-2.69 (2H, m), 3.03 (2H, q, J = 7 Hz), 3.33 (2H, d, J = 7 Hz), 4.66 (2H, s), 5.91 (1H, d, J = 4 Hz), 5 6.60 (1H, d, J = 4 Hz), 7.90 (1H, dd, J = 2,2 Hz), 8.56 (1H, d, J = 2 Hz), 8.77 (1H, d,J =2Hz). MS (m/z) 489 (M+H). Example 479 10 3

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4 -(5-chloro-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoic acid 'H NMR (300 MHz, CDCl 3 ) 8 0.92 (6H, d, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.91 (1H, qt, J = 7, 7 Hz), 2.49 (2H, t, J = 8 Hz), 2.82-2.98 (2H, m), 3.03 (2H, q, J = 7 Hz), 3.35 (2H, d, J = 7 Hz), 4.69 (2H, s), 5.92 (1H, d, J = 4 Hz), 6.61 (1H, d, J = 4 Hz), 15 7.72 (1H, dd, J = 2, 2 Hz), 8.51 (1H, d, J = 2 Hz), 8.69 (11H, d, J = 2 Hz). MS (m/z) 416 (M+H). Example 480 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-norpholinylmethyl)pyrrolo[1,2-b]pyridazin-3 20 yl]propanoic acid 'H NMR (300 MHz, CDC 3 ) 8 1.36 (3H, t, J = 7 Hz), 2.55 (2H, t, J = 8 Hz), 2.66 (4H, br s), 2.79-2.97 (2H, m), 3.02 (2H, q, J = 7 Hz), 3.70-3.74 (6H, m), 5.92 (1H, d, J = 4 Hz), 6.61 (11H, d, J = 4 Hz), 7.90 (11H, dd, J = 2, 2 Hz), 8.55 (11H, d, J = 2 Hz), 8.79 (1H, d, J = 2 Hz). 25 MS (m/z) 474 (M+H). Example 481 4

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4 -(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoic acid 30 'H NMR (300 MHz, CDCl 3 ) 8 1.36 (3H, t, J = 7 Hz), 1.73 (2H, tt, J = 7, 7 Hz), 2.26 (2H, t, J = 7 Hz), 2.57-2.70 (6H, m), 3.02 (2H, q, J = 7 Hz), 3.69 (6H, m), 5.90 (1H, d, J = 4 Hz), 6.58 (1H, d, J = 4 Hz), 7.93 (1H, dd, J = 2, 2 Hz), 8.57 (1H, d, J =2 Hz), 8.77 (1H, d, J = 2 Hz). 280 WO 2004/063197 PCT/JP2003/017091 MS (m/z) 488 (M+H). Example 482 4-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylamino)methyl]-7-ethylpyrrolo[1,2 5 b]pyridazin-3-yl}butanoic acid 'H NMR (300 MHz, CDCl 3 ) 6 0.54-0.60 (2H, m), 0.74-0.79 (2H, m), 1.38 (3H, t, J 7 Hz), 1.65 (2H, tt, J = 6, 6 Hz), 2.21 (2H, t, J = 6 Hz), 2.45-2.55 (2H, m), 3.03 (2H, q, J = 7 Hz), 4.30 (2H, s), 5.04 (1H, br s), 5.93 (1H, d, J = 5 Hz), 6.60 (1H, d, J = 5 Hz), 7.73 (1H, dd, J = 2,2 Hz), 8.52 (1H, d, J = 2 Hz), 8.69 (1H, d, J = 2 10 Hz). MS (m/z) 413 (M+H). Example 483 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(2-phenoxyethyl)amino]methyl}pyrrolo[l,2 15 b]pyridazin-3-yl)pentanoic acid 'H NMR (300 MHz, CDCl 3 ) 8 1.36 (3H, t, J = 7 Hz), 1.42-1.56 (4H, m), 2.22 (2H, br s), 2.34-2.48 (2H, m), 3.03 (2H, q, J = 7 Hz), 3.38-3.43 (2H, br s), 4.23-4.50 (4H, m), 5.93 (1H, d, J = 4 Hz), 6.60 (1H, d, J = 4 Hz), 6.89-6.97 (3H, m), 7.23-7.30 (2H, m), 7.85 (1H, s), 8.52 (1H, s), 8.78 (1H, s). 20 MS (m/z) 552 (M+H). Example 484 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{ [(2 hydroxyethyl)(methyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoic acid 25 lH NMR (300 MHz, CDCI 3 ) 6 1.36 (3H, t, J = 7 Hz), 1.34-1.54 (4H, m), 2.15-2.26 (2H, m), 2.33-2.52 (2H, m), 2.98 (2H, q, J = 7 Hz), 3.16 (3H, s), 3.59-3.72 (2H, m), 3.99-4.10 (2H, m), 4.70 (2H, s), 5.94 (1H, d, J = 4 Hz), 6.59 (1H, d, J = 4 Hz), 7.85 (1H, s), 8.51 (1H, s), 8.73 (1H, s). MS (m/z) 490 (M+H). 30 Example 485 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(1-piperidinylmethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 281 WO 2004/063197 PCT/JP2003/017091 'H NMR (300 MHz, CDCL 3 ) 8 1.36 (3H, t, J = 7 Hz), 1.39-1.51 (6H, m), 1.62-1.71 (4H, m), 2.19 (2H, t, J = 6 Hz), 2.52-2.65 (2H, m), 2.78-2.91 (4H, m), 3.10 (2H, q, J = 7 Hz), 3.65 (2H, s), 5.89 (1H, d, J = 5 Hz), 6.58 (1H, d, J = 5 Hz), 7.88 (1H, s), 8.55 (1H, s), 8.76 (1H, s). 5 MS (m/z) 500 (M+H). Example 486 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2-b]pyridazin 3-yl]propanoic acid 10 1 H NMR (300 MHz, CDC 3 ) 6 1.37 (3H, t, J = 7 Hz), 2.52 (2H, t, J = 8 Hz), 2.68 (4H, t, J = 5 Hz), 2.81-2.95 (6H, m), 3.02 (2H, q, J = 7 Hz), 3.74 (2H, s), 5.92 (1H, d, J = 5 Hz), 6.61 (1H, d, J = 5 Hz), 7.89 (1H, dd, J = 2, 2 Hz), 8.55 (1H, d, J = 2 Hz), 8.79 (1H, d, J = 2 Hz). MS (m/z) 490 (M+H). 15 Example 487 3-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{ [4-(2-hydroxyethyl)-1 piperazinyl]methyl}pyrrolo[1,2-b]pyridazin-3-yl)propanoic acid 'H NMR (300 MHz, DMSO-d 6 ) 8 1.32 (3H, t, J = 7 Hz), 2.40-2.56 (12H, m), 2.58 20 2.65 (2H, m), 2.94 (2H, q, J = 7 Hz), 3.52 (2H, t, J = 5 Hz), 3.67 (2H, s), 5.83 (1H, d, J = 5 Hz), 6.62 (1H, d, J = 5 Hz), 8.25 (1H, dd, J = 2, 2 Hz), 8.63 (1H, d, J = 2 Hz), 8.86 (1H, d, J = 2 Hz). MS (m/z) 517 (M+H). 25 Example 488 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoic acid 'H NMR (300 MHz, CDC 3 ) 6 0.91 (6H, d, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.74 (2H, tt, J = 8, 8 Hz), 1.91 (1H, qt, J = 7, 7 Hz), 2.27 (2H, t, J = 8 Hz), 2.56-2.73 (2H, 30 m), 3.03 (2H, q, J = 7 Hz), 3.33 (2H, d, J = 7 Hz), 4.68 (2H, s), 5.92 (1H, d, J = 5 Hz), 6.60 (1H, d, J = 5 Hz), 7.92 (1H, dd, J = 7,7 Hz), 8.56 (1H, d, J = 2 Hz), 8.77 (1H, d, J = 2 Hz). MS (m/z) 475 (M+H). 282 WO 2004/063197 PCT/JP2003/017091 Example 489 5-[2-{ [2-(benzylamino)-2-oxoethoxy]methyl}-7-ethyl-4-(5-methyl-3 pyridinyl)pyrrolo[1,2-b]pyridazin-3-y]]pentanoic acid 5 'H NMR (CDCl 3 ) 8 1.33 (3H, t, J= 7 Hz), 1.39-1.60 (4H, m), 2.15 (2H, t, J= 7 Hz), 2.42 (3H, s), 2.40-2.58 (2H, m), 2.95 (2H, q, J= 7 Hz), 4.19 (2H, s), 4.50 (2H, d, J= 7 Hz), 4.75 (2H, m), 5.91 (1H, d, J= 4 Hz), 6.59 (1H, d, J= 4 Hz), 7.07 (1H, br), 7.22-7.34 (5H, m), 7.54 (1H, s), 8.40 (1H, s), 8.53 (1H, s). MS (EST): m/z 513, MS (ESI*): m/z 515. 10 Example 490 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(phenylsulfonyl)amino]methyl}pyrrolo[1,2 b]pyridazin-3-yl)pentanoic acid 'H NMR (CDCl 3 ) 8 1.36 (3H, t, J= 7 Hz), 1.23-1.60 (4H, m), 2.19 (2H, t, J= 7 Hz), 15 2.28-2.46 (2H, m), 2.42 (3H, s), 2.97 (2H, q, J= 7 Hz), 4.37 (2H, m), 5.89 (1H, d, J= 4 Hz), 5.90 (1H, m), 6.57 (1H, d, J= 4 Hz), 7.42-7.53 (4H, m), 7.90 (2H, d, J= 8 Hz), 8.34 (1H, s), 8.53 (1H, s). MS (EST): m/z 505, MS (ESI*): m/z 507. 20 Example 491 5-[ 4 -(5-bromo-3-pyridinyl)-7-ethyl-2-(1-pyrrolidinylmethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 'H NMR (300 MHz, CDC 3 ) 6 1.35 (3H, t, J = 7 Hz), 1.39-1.57 (4H, m), 1.79-1.88 (4H, m), 2.18 (2H, t, J = 7 Hz), 2.84-2.89 (6H, m), 3.00 (2H, q, J = 7 Hz), 3.89 25 4.02 (2H, m), 5.88 (1H, d, J = 5 Hz), 6.56 (1H, d, J =5 Hz), 7.87(11H, s), 8.55 (1H1, s), 8.75 (1H, s). MS (m/z) 486 (M+H). Example 492 30 3

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4 -(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid 'H NMR (CDC 3 ) 8 1.37 (3H, t, J = 8 Hz), 2.39-2.48 (2H, m), 2.83-2.94 (2H, m), 3.03 (2H, q, J = 8 Hz), 3.45 (3H, s), 4.65 (2H, s), 5.95 (1H, d, J = 5 Hz), 6.60 (1H, 283 WO 2004/063197 PCT/JP2003/017091 d, J = 5 Hz), 7.24 (1H, m), 7.35 (1H, br s), 7.40-7.46 (2H, m). MS (ESI+): m/z 373 (M + H). Example 493 5 4-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid 'H NMR (CDC1 3 ) 5 1.37 (3H, t, J = 8 Hz), 1.64-1.78 (2H, m), 2.24 (2H, t, J = 8 Hz), 2.56-2.66 (2H, m), 3.04 (2H, q, J = 8 Hz), 3.45 (3H, s), 4.65 (2H, s), 5.94 (1H, d, J = 5 Hz), 6.59 (1H, d, J = 5 Hz), 7.21-7.29 (1H, overlappled with CDCl 3 ), 7.36 10 (1H, br s), 7.39-7.46 (2H, m). MS (ESI*): m/z 387 (M + H). Example 494 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-phenyl-1-piperazinyl)methyl]pyrrolo[1,2 15 b]pyridazin-3-yl}pentanoic acid 'H NMR (300 MHz, CDCl 3 ) 5 1.37 (3H, t, J = 7 Hz), 1.41-1.61 (4H, m), 2.22 (2H, t, J = 7 Hz), 2.49-2.67 (2H, m), 2.76 (4H, t, J = 5 Hz), 3.03 (2H, q, J = 7 Hz), 3.20 (4H, t, J = 5 Hz), 3.73 (2H, s), 5.89 (1H, d, J = 5 Hz), 6.58 (1H, d, J = 5 Hz), 6.85 (11H, dd, J = 8, 8 Hz), 6.93 (2H, J = 8 Hz), 7.25 (2H, J = 8 Hz), 7.90 (1H, dd, J = 2, 20 2 Hz), 8.56 (1H, d, J = 2 Hz), 8.77 (1H, d, J = 2 Hz). Example 495 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{ [(2-methoxyethyl)amino]methyl}pyrrolo[1,2 b]pyridazin-3-yl)pentanoic acid 25 'H NMR (300 MHz, CDCl 3 ) 6 1.28 (3H, t, J = 7 Hz), 1.32-1.43 (4H, m), 2.03-2.17 (2H, m), 2.23-2.41 (2H, m), 2.49-2.88 (2H, m), 2.98 (2H, q, J = 7 Hz), 3.37 (3H, s), 3.89-3.99 (2H, m), 4.51 (2H, s), 5.91 (1H, d, J = 5 Hz), 6.57 (1H, d, J = 5 Hz), 7.82 (1H, s), 8.47 (1H, s), 8.72 (1H, s). 30 Example 496 5-[7-ethyl-2-(methoxymethyl)-4-(5-nethoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid mp 111-112cC 284 WO 2004/063197 PCT/JP2003/017091 'H NMR (CDC 3 ) 8 1.37 (3H, t, J = 8 Hz), 1.41-1.60 (4H, m), 2.21 (2H, br t, J = 8 Hz), 2.30-2.70 (2H, m), 3.04 (2H, d, J = 8 Hz), 3.46 (3H, s), 3.90 (3H, s), 4.63 (2H, br d, J = 5 Hz), 5.92 (1H, d, J = 5 Hz), 6.58 (2H, d, J = 8 Hz), 7.25 (1H, m), 8.22 (1H, d, J = 1 Hz), 8.40 (1H, d, J = 3 Hz). 5 MS (ESI*): m/z 398 (M + H). Example 497 5-[ 7 -ethyl-4-(5-methoxy-3-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 10 mp 133-1341C 'H NMR (CDCl 3 ) 6 1.37 (3H, t, J = 8 Hz), 1.40-1.62 (7H, m), 2.24 (2H, t, J = 8 Hz), 2.35-2.49 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J = 8 Hz), 3.89 (3H, s), 5.87 (1H, d, J = 5 Hz), 6.51 (1H, d, J = 5 Hz), 7.23 (1H, m), 8.20 (1H, d, J = 1 Hz), 8.39 (1H, d, J = 3 Hz). 15 MS (ESI*): m/z 369 (M + H). Example 498 3

-[

7 -ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoic acid 20 mp 164-1659C 'H NMR (CDC 3 ) 8 1.37 (3H, t, J = 8 Hz), 2.44-2.54 (2H, m), 2.80-3.00 (2H, m), 3.04 (2H, d, J = 8 Hz), 3.47 (3H, s), 3.89 (3H, s), 4.66 (2H, br s), 5.95 (1H, d, J = 5 Hz), 6.60 (1H, d, J = 5 Hz), 7.25 (1H, m), 8.22 (1H, d, J = 1 Hz), 8.38 (1H, d, J = 3 Hz). 25 MS (ESI*): m/z 370 (M + H). Example 499 4 -[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoic acid 30 mp 140-1411C 'H NMR (CDCl 3 ) 8 1.38 (3H, t, J = 8 Hz), 1.68-1.82 (2H, m), 2.25 (2H, t, J = 8 Hz), 2.52-2.75 (2H, m), 3.04 (2H, d, J = 8 Hz), 3.46 (3H, s), 3.92 (3H, s), 4.65 (2H, br 285 WO 2004/063197 PCT/JP2003/017091 d, J = 7 Hz), 5.94 (1H, d, J = 5 Hz), 6.59 (1H, d, J = 5 Hz), 7.29 (1H, m), 8.23 (1H, d, J = 1 Hz), 8.37 (1H, d, J = 3 Hz). MS (ESI*): m/z 384 (M + H). 5 Example 500 5-[7-ethyl-2-(methoxymethyl)-4-(5-pyrimidinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 'H NMR (CDC 3 ) 8 1.38 (3H, t, J = 8 Hz), 1.40-1.64 (4H, m), 2.25 (2H, t, J = 8 Hz), 2.49-2.61 (2H, m), 3.04 (2H, d, J = 8 Hz), 3.47 (3H, s), 4.65 (2H, s), 5.91 (1H, d, 10 J = 5 Hz), 6.62 (1H, d, J = 5 Hz), 8.82 (2H, s), 9.32 (1H, s). MS (ESI*): m/z 369 (M + H). Example 501 4

-[

4 -(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 15 yl]butanoic acid mp 112-1139C 'H NMR (CDCl 3 ) 8 1.38 (3H, t, J = 8 Hz), 1.66-1.79 (2H, m), 2.28 (2H, t, J = 8 Hz), 2.52-2.71 (2H, m), 3.05 (2H, d, J = 8 Hz), 3.46 (3H, s), 4.66 (2H, br s), 5.92 (1H, d, J = 5 Hz), 6.61 (1H, d, J = 5 Hz), 7.77 (1H, m), 8.53 (1H, d, J = 1 Hz), 8.67 20 (1H, d, J = 2 Hz). MS (ESI*): m/z 388 (M + H). Example 502 3

-[

4 -(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 25 yl]propanoic acid mp 159-160'C 'H NMR (CDC 3 ) 8 1.38 (3H, t, J = 8 Hz), 2.47 (2H, br t, J = 8 Hz), 2.79-2.98 (2H, m), 3.04 (2H, d, J = 8 Hz), 3.47 (3H, s), 4.66 (2H, s), 5.93 (1H, d, J = 5 Hz), 6.67 (1H, d, J = 5 Hz), 7.74 (1H, m), 8.51 (1H, d, J = 1 Hz), 8.68 (1H, d, J = 3 Hz). 30 MS (ESI*): m/z 374,376 (M + H). Example 503 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 286 WO 2004/063197 PCT/JP2003/017091 yl]pentanoic acid mp 118-119'C 'H NMR (CDCl 3 ) 5 1.37 (3H, t, J = 8 Hz), 1.40-1.62 (7H, m), 2.24 (2H, t, J = 8 Hz), 2.45-2.64 (2H, m), 3.04 (2H, d, J = 8 Hz), 3.45 (3H, s), 4.63 (2H, s), 5.91 (1H, d, 5 J = 5 Hz), 6.60 (1H, d, J = 5 Hz), 7.74 (1H, m), 8.51 (1H, d, J = 1 Hz), 8.67 (1H, d,J =2Hz). MS (ESI*): m/z 402,404 (M + H). Example 504 10 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4H-1,2,4-triazol-4-ylmethyl)pyrrolo[1,2 b]pyridazin-3-yl]butanoic acid 'H-NMR (CDCl 3 ) 5 1.36 (3H, t, J = 7 Hz), 1.60 (2H, m), 2.32 (2H, m), 2.46 (2H, m), 3.01 (2H, q, J = 7 Hz), 5.75 (2H, m), 5.97 (1H, d, J = 5 Hz), 6.66 (1H, d, J = 5 Hz), 7.87 (1H, m), 7.97 (1H, s), 8.53 (1H, s), 8.65 (1H, s), 8.69 (1H, s). 15 Example 505 4-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylamino)methyl]-7-ethylpyrrolo[1,2 b]pyridazin-3-yllbutanoic acid 'H-NMR (CDC 3 ) 5 0.56 (2H, m), 0.75 (2H, m), 1.38 (3H, t, J = 7 Hz), 1.65 (2H, m), 20 2.21 (2H, m), 2.50 (2H, m), 3.01 (2H,q, J = 7 Hz), 3.27 (3H, br), 4.29 (2H, s), 5.93 (1H, d, J = 5 Hz), 6.60 (1H, d, J = 5 Hz), 7.98 (1H, m), 8.55 (1H, m), 8.78 (1H, m). MS (ESI*) m/z: 457 and 459 (M + H) 25 Example 506 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-oxo-1,3-oxazolidin-3-yl)methyl]pyrrolo[1,2 b]pyridazin-3-yl}butanoic acid 'H-NMR (CDCl 3 ) 5 1.37 (3H, t, J = 7 Hz), 1.68 (2H, m), 2.31 (2H, in), 2.53 (2H, m), 2.98 (2H, q, J = 7 Hz), 3.77 (2H, m), 4.42 (2H, t J = 7 Hz), 4.67 (2H, m), 5.94 30 (1H, d, J = 5 Hz), 6.63 (1H, d, J = 5 Hz), 7.89(1H, m), 8.55 (1H, m), 8.78 (IH, m). Example 507 2-bromo-4-[3-(ethoxycarbonyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzoic 287 WO 2004/063197 PCT/JP2003/017091 acid 'H-NMR (CDC 3 ) 8 1.00 (3H, t, J = 7 Hz), 1.38 (3H, t, J = 7 Hz), 2.62 (3H, s), 3.04 (2H, q, J = 7 Hz), 4.06 (2H, q, J = 7 Hz), 6.29 (1H, d, J = 5 Hz), 6.68 (1H, d, J = 5 Hz), 7.49 (2H, dd, J = 2 and 8 Hz), 7.82 (1H, d, J = 2 Hz), 8.07 (1H, d, J = 8 Hz). 5 MS (ESI*) m/z: 431 and 433 (M + H) Example 508 5-[4-(3-cyanophenyl)-7-ethyl-2-(phenoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 10 'H-NMR (CDCl 3 ) 5 1.25-1.49 (7H, m), 2.15 (2H, m), 2.54 (2H, m), 3.02 (2H, q, J= 7 Hz), 5.23 (2H, s), 5.86 (1H, d, J = 5 Hz), 6.60 (1H, d, J = 5 Hz), 6.98 (1H, t, J =8 Hz), 7.06 (2H, d, J = 8 Hz), 7.28 (2H, t, J = 8 Hz), 7.60 (2H, m), 7.67 (1H, s), 7.77 (1H, m). 15 Example 509 5-[4-(3-cyanophenyl)-7-ethyl-2-(3-methyl-2-thienyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 'H-NMR (CDCl 3 ) 8 1.14-1.28 (4H, m), 1.37 (3H, t, J = 7 Hz), 2.01 (2H, t, J = 7 Hz), 2.23 (3H, s), 2.40 (2H, m), 3.02 (2H, q, J = 7 Hz), 5.92 (1J, d, J = 5 Hz)(, 6.64 20 (1H, d, J = 5 Hz), 6.94 (1J, d, J = 5 Hz), 7.33 (1H, d, J = 5 Hz), 7.57-7.66 (2H, m), 7.73-7.76 (2H, m). Example 510 (2E)-4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-2-butenoic acid 25 'H-NMR (CDC 3 ) 8 1.38 (3H, t, J = 7 Hz), 2.55 (3H, s), 3.03 (2H, q, J = 7 Hz), 3.09 (2H, d, J = 7 Hz), 5.45 (1H, dt, J = 7 and 16 Hz), 6.05 (1H, d, J = 5 Hz), 6.25 (1H, d, J = 16 Hz), 6.57 (1H, d, J = 5 Hz), 7.55 (1H, t, J = 8 Hz), 7.66+-7.72 (3H, m). MS (ESI*): m/z 345 (M+H) 30 Example 511 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoic acid 'H NMR (CDC1 3 ) 5 1.37 (3H, t, J= 7 Hz), 1.68-1.84 (2H, m), 2.28 (2H, t, J= 7 Hz), 288 WO 2004/063197 PCT/JP2003/017091 2.56-2.74 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.46 (3H, s), 4.66 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.92 (1H, m), 8.57 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). MS (EST): m/z 430 432, MS (ESI*): m/z 432 434. 5 The following compound(s) was(were) obtained in a similar manner to that of Example 159. Example 512 ethyl 4-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]butanoate 10 'H NMR (CDC 3 ) 8 1.26 (3H, t, J= 7 Hz), 1.36 (3H, t, J= 7 Hz), 1.35-1.45 (2H, m), 1.88 (2H, t, J= 7 Hz), 2.43-2.55 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 5.98 (11, d, J= 4 Hz), 6.65 (111, d, J= 4 Hz), 7.33 (1H, d, J= 5 Hz), 7.42-7.55 (6H, m), 8.55 (1H, d, J= 5 Hz). MS (ESI+): m/z 448. 15 Example 513 ethyl 3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 yl]propanoate 'H NMR (CDC 3 ) 8 1.09 (3H, t, J= 7 Hz), 1.36 (3H, t, J= 7 Hz), 1.98-2.08 (2H, m), 20 2.75-2.85 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.92 (2H, q, J= 7 Hz), 6.00 (1H, d, J= 4 Hz), 6.67 (1H, d, J= 4 Hz), 7.32 (1H, d, J= 5 Hz), 7.42 (111, s), 7.43-7.57 (5H, m), 8.55 (1H, d, J= 5 Hz). MS (ESI*): m/z 434. 25 Example 514 methyl { 2-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 yl]ethoxy} acetate 1H NMR (CDCl 3 ) 5 1.36 (311, t, J= 7 Hz), 2.73-2.85 (2H, t, J= 7 Hz), 3.03 (2H, t, J= 7 Hz), 3.15 (2H, t, J= 7 Hz), 3.74 (2H, s), 4.09 (3H, s), 6.02 (1H, d, J= 4 Hz), 6.67 30 (1H, d, J= 4 Hz), 7.39 (1H, m), 7.42-7.60 (6H, m), 8.53 (1H, d, J= 5 Hz). MS (ESI*): m/z 450. Example 515 289 WO 2004/063197 PCT/JP2003/017091 ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-(3-methyl-2-thienyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate 'H-NMR (CDC 3 ) 5 1.09-1.26 (7H, m), 1.36 (3H, t, J = 7 Hz), 1.93 (2H, t, J = 7 Hz), 2.23 (3H, s), 2.39 (2H, m), 3.03 (2H, q, J = 7 Hz), 4.03 (2H, q, J = 7 Hz), 5.93 5 (1H, d, J = 5 Hz), 6.64 (1H, d, J = 7 Hz), 6.96 (1H, d, J = 5 Hz), 7.33 (1H, d, J = 5 Hz), 7.60-7.67 (2H, m), 7.72-7.79 (2H, m). Example 516 methyl 5-[4-(3-cyanophenyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3 10 yl]pentanoate 'H-NMR (CDC 3 ) 8 1.21-1.47 (7H, m), 2.04 (211, t, J = 7 Hz), 2.60 (2H, m), 3.05 (2H, q, J = 7 Hz), 3.61 (3H, s), 5.37 (1H, d, J = 5 Hz), 6.63 (1H, d, J = 5 Hz), 7.13 (1H, m), 7.36 (1H, m), 7.44 (111, m), 7.62-7.78 (4H, m). 15 Example 517 ethyl 3-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoate 'H-NMR (CDC 3 ) 8 1.08 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.98 (2H, m), 2.75 (2H, m), 3.02 (2H, q, J = 7 Hz), 3.89 (2H, q, J = 7 Hz), 5.93 (1H, d, J = 5 Hz), 6.63 (1H, d, J = 5 Hz), 7.41-7.55 (5H, m), 7.57-7.78 (4H, m). 20 MS (ESI*): m/z 424 (M + H) Example 518 ethyl 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate 'H-NMR (CDC 3 ) 5 1.02-1.25 (711, m), 1.37 (311, t, J = 7 Hz), 1.88 (21, t, J = 7 Hz), 25 2.43 (2H, m), 3.01 (2H, q, J = 7 Hz), 4.00 (2H, q, J = 7 Hz), 5.96 (1H, d, J = 5 Hz), 6.60 (1H, d, J = 5 Hz), 7.29 (1H, m), 7.37-7.54 (8H, m). MS (ESI*): m/z 461 Example 519 30 4-(5-bromo-3-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazine-3-carbonitrile 1 H NMR (CDC1 3 ) 5 1.42 (311, t, J = 8 Hz), 3.12 (2H, t, J = 8 Hz), 6.65 (1H, d, J = 5 Hz), 6.94 (1H, d, J = 5 Hz), 7.51-7.59 (3H, m), 7.83-7.91 (211, m), 8.19 (111, m), 8.85-8.92 (2H, m). 290 WO 2004/063197 PCT/JP2003/017091 MS (ESI*): m/z 403,405 (M + H). The following compound(s) was(were) obtained in a similar manner to that of Example 175. 5 Example 520 5-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3 yl}pentanoic acid 'H NMR (CDC 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.36-1.57 (4H, m), 2.16 (2H, t, J= 7 Hz), 2.51-2.62 (2H, m), 3.03 (211, q, J= 7 Hz), 4.69 (2H, s), 4.78 (2H, s), 5.87 (1H, d, 10 J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.35 (2H, d, J= 5 Hz), 7.61 (2H, d, J= 5 Hz), 7.67 (1H, s), 7.77 (1H, m), 8.54 (2H, d, J= 5 Hz). MS (ESI~): m/z 467, MS (ESI*): m/z 469. Example 521 15 5-{4-[3-(aminocarbonyl)phenyl]-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoic acid 1H NMR (CDCl 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.47-1.68 (4H, m), 2.15-2.40 (2H, m), 2.40-2.56 (111, m), 2.82-2.96 (111, m), 3.05 (2H, q, J= 7 Hz), 4.68 (2H, s), 4.72 (1H, d, J= 17 Hz), 4.93 (1H, d, J= 17 Hz), 5.83 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 20 Hz), 7.31 (2H, d, J= 5 Hz), 7.39 (1H, br), 7.45 (1H, d, J= 8 Hz), 7.58 (1H, t, J= 8 Hz), 7.69 (1H, br), 7.77 (1H, br), 7.98 (1H, d, J= 8 Hz), 8.57 (2H, d, J= 5 Hz). MS (ESI): m/z 485, MS (ESI 4 ): m/z 487. Example 522 25 5-{4-(3-cyanophenyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3 yl}pentanoic acid 'H NMR (CDCl 3 ) 8 1.38 (3H, t, J= 7 Hz), 1.30-1.57 (4H, m), 2.18 (2H, m), 2.48-2.65 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.83 (2H, s), 4.85 (211, s), 5.86 (11, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.61 (2H, d, J= 5 Hz), 7.68 (1H, s), 7.77 (1H, m), 8.53 (2H, 30 d, J= 5 Hz), 8.76 (1H, s). MS (ESI): m/z 468, MS (ESI*): m/z 470. Example 523 291 WO 2004/063197 PCT/JP2003/017091 5-{4-(3-cyanophenyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1 ,2-b]pyridazin-3 yl}pentanoic acid 'H NMR (CDC 3 ) 5 1.38 (3H, t, J= 7 Hz), 1.38-1.57 (4H, m), 2.15 (2H, t, J= 7 Hz), 2.49-2.62 (2H, m), 3.04 (211, q, J= 7 Hz), 4.69 (2H, s), 4.76 (2H, s), 5.85 (1H, d, 5 J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.33 (1H, m), 7.62 (2H, m), 7.67 (11H, s), 7.73 7.82 (2H, m), 8.53 (1H, d, J= 5 Hz), 8.67 (1H, s). MS (ESI): m/z 467, MS (ESI*): m/z 469. Example 524 10 5-[4-(3-cyanophenyl)-7-ethyl-2-(5-methyl-3-isoxazolyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid 'H-NMR (CDCl 3 ) 8 1.34-1.52 (7H, m), 2.17 (2H, t, J = 7 Hz), 2.53 (311, s), 2.77 (2H, m), 3.03 (211, q, J = 7 Hz), 5.89 (1H, d, J = 5 Hz), 6.54 (1H, s), 6.67 (1H, d, J = 5 Hz), 7.63 (2H, m), 7.68 (1H, s), 7.78 (1H, m). 15 Example 525 5-[4-(3-cyanophenyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 'H-NMR (CDC1 3 ) 5 1.23-1.42 (7H, m), 2.07 (2H, t, J = 7 Hz), 2.58 (2H, m), 3.03 (211, q, J = 7 Hz), 5.87 (1H, d, J = 5 hz), 6.56 (111, d, J = 5 Hz), 7.13 (11H, m), 7.36 (1H, 20 m), 7.43 (111, d, J = 5 Hz), 7.62 (2H, m), 7.70 (1H, s), 7.76 (11H, m). Example 526 3-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoic acid 'H-NMR (CDC 3 ) 5 1.36 (311, t, J = 7 Hz), 1.99 (211, m), 2.75 (211, m), 3.00 (2H, q, J 25 = 7 Hz), 5.93 (1H, d, J = 5 Hz), 6.63 (111, d, J = 5 Hz), 7.42-7.55 (5H, m), 7.57 7.78 (4H, m). Example 527 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 30 1 H-NMR (CDC 3 ) 5 1.03-1.25 (4H, m), 1.36 (3H, t, J = 7 Hz), 1.90 (2H, t, J = 7 Hz), 2.41 (211, m), 3.00 (2H, q, J = 7 Hz), 5.97 (1H, d, J = 5 Hz), 6.59 (1H, d, J = 5 Hz), 7.28 (1H, m), 7.35-7.54 (811, in). MS (ESI*): m/z 433 (M+H) 292 WO 2004/063197 PCT/JP2003/017091 The following compound(s) was(were) obtained in a similar manner to that of Example 180. Example 528 5 ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-(5-methyl-3-isoxazolyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate 'H-NMR (CDCl 3 ) 8 1.22 (3H, t, J = 7 Hz), 1.32-1.46 (5H, m), 1.72 (2H, m), 2.10 (2H, t, J = 7 Hz), 2.54 (3H, s), 2.78 (2H, m), 3.03 (2H, q, J = 7 Hz), 4.06 (2H, q, J = 7 Hz), 5.89 (1H, d, J = 5 Hz), 6.54 (1H, s), 6.66 (1H, d, J = 5 Hz), 7.62 (2H, m), 10 7.67 (1H, s), 7.77 (1H, m). The following compound(s) was(were) obtained in a similar manner to that of Preparation 176. Example 529 15 ethyl 4-[4-(aminocarbonyl)-3-bromophenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3 carboxylate 'H-NMR (CDCl 3 ) b 1.03 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 2.60 (3H, s), 3.03 (2H, q, J = 7 Hz), 4.07 (2H, q, J = 7 Hz), 5.83 (1H, s, br), 6.19 (1H, s, br), 6.28 (1H, d, J = 5 Hz), 6.67 (1H, d, J = 5 Hz), 7.46 (1H, d, J = 8 Hz), 7.72 (1H, s), 7.77 20 (1H,d,J=8Hz). The following compound(s) was(were) obtained in a similar manner to that of Example 184. Example 530 25 3-[2-(cyclopentylamino)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4 yl]benzonitrile 'H-NMR (CDCl 3 ) 8 1.36 (3H, t, J = 7 Hz), 1.51-1.80 (6H, m), 2.15 (2H, m), 2.96 (2H, q, J = 7 Hz), 3.05 (3H, s), 4.27 (1H, m), 5.94 (1H, d, J = 5 Hz), 6.47-6.53 (2H, m), 7.53-7.59 (3H, m), 7.74 (1H, m). 30 Example 531 3-[7-ethyl-2-(methylamino)-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile 'H-NMR (CDC1 3 ) 5 1.37 (3H, t, J = 7 Hz), 2.94-3.07 (8H, m), 5.95 (1H, d, J = 5 Hz), 293 WO 2004/063197 PCT/JP2003/017091 6.50 (2H, m), 7.54-7.59 (3H, m), 7.74 (1H, n). The following compound(s) was(were) obtained in a similar manner to that of Example 225. 5 Example 532 (2R,3R,4S,5S,6R)-2-({3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2 (methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoyl}amino)-6-{[(2,2 dimethylpropanoyl)oxy]methyl}tetrahydro-2H-pyran-3,4,5-triyl tris(2,2 dimethylpropanoate) 10 'H-NMR (CDC 3 ) 8 1.07 (911, s), 1.11 (9H, s), 1.16 (9H, s), 1.18 (9H, s), 1.37 (3H, t, J = 7 Hz), 2.23 (2H, m), 2.84 (21, m), 3.03 (2H, q, J = 7 Hz), 3.48 (311, s), 3.91 4.21 (3H, m), 4.62-4.67 (2H, m), 5.00-5.26 (311, m), 5.43 (2H, m), 5.91 (1H, d, J = 5 Hz), 6.55 (1H, m, br), 6.62 (1H, d, J = 5 Hz), 7.84 (111, m), 8.51 (1H, m), 8.77 (111, in). 15 The following compound(s) was(were) obtained in a similar manner to that of Example 226. Example 533 [4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-3-yl]methanol 20 'H-NMR (CDCl 3 ) 6 1.40 (3H, t, J =7 Hz), 2.53 (1H, t, J = 7 Hz), 3.07 (2H, q, J = 7 Hz), 4.48 (2H, m), 6.23 (1H, d, J = 5 Hz), 6.62 (11H, m), 6.71 (11H, d, J = 5 Hz), 7.10 (111, d, J = 5 Hz), 7.46-7.52 (311, in), 7.61 (1H, m), 7.64 (111, m). Example 534 25 [4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methanol 'H NMR (CDC 3 ) 6 1.38 (311, t, J = 8 Hz), 3.05 (211, q, J = 8 Hz), 3.45-3.55 (4H, m), 4.40 (2H, br d, J = 7 Hz), 4.77 (211, br s), 6.22 (1H, d, J = 5 Hz), 6.70 (1H, d, J = 5 Hz), 8.11 (11H, m), 8.74 (1H, br s), 8.80 (1H, d, J = 2 Hz). MS (ESI*): m/z 302 (M + H). 30 The following compound(s) was(were) obtained in a similar manner to that of Example 227. Example 535 294 WO 2004/063197 PCT/JP2003/017091 (2R,3S,4S,5R,6R)-2-[(acetyloxy)methyl]-6-({ 5-[4-(3-cyanophenyl)-7-ethyl-2 phenylpyrrolo[1,2-b]pyridazin-3-yl]pentyl}oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate 'H-NMR (CDCl 3 ) 8 0.82-1.18 (6H, m), 1.37 (3H, t, J = 7 Hz), 1.92-2.17 (14H, m), 2.35 (2H, m), 3.01 (2H, q, J = 7 Hz), 3.16 (111, m), 3.62 (1H, m), 3.85 (1H, m), 5 4.11 (2H, m), 4.10 (2H, m), 4.30 (1H, d, J = 8.1 Hz), 4.96 (1H, m), 5.11 (1H, m), 5.35 (1H, m), 5.90 (1H, d, J = 5 Hz), 6.62 (1H, d, J = 5 Hz), 7.44-7.53 (5H, m), 7.60-7.80 (4H, m). The following compound(s) was(were) obtained in a similar manner to that of 10 Example 228. Example 536 ethyl 3-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoate 'H NMR (CDCl 3 ) 6 1.19 (3H, t, J= 7 Hz), 1.39 (3H, t, J= 7 Hz), 2.33 (2H, t, J= 7 Hz), 15 2.43 (3H, s), 2.70-2.82 (2H, in), 3.04 (2H, q, J= 7 Hz), 3.71 (1H, t, J= 5 Hz), 4.05 (2H, q, J= 7 Hz), 4.89 (21H, d, J= 5 Hz), 5.98 (11H, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.52 (111, s), 8.42 (1H, d, J= 2 Hz), 8.56 (111, d, J= 2 Hz). MS (ESI*): m/z 368. 20 Example 537 ethyl 4-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoate 'H NMR (CDCl 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.39 (3H, t, J= 7 Hz), 1.62-1.78 (2H, m), 2.16-2.28 (2H, m), 2.36-2.53 (2H, m), 2.44 (3H, s), 3.06 (2H, q, J= 7 Hz), 3.86 25 (1H, t, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.90 (2H, m), 5.96 (11H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 7.53 (1H, s), 8.44 (1H, s), 8.56 (1H, s). MS (ESI*): m/z 382. Example 538 30 ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoate 'H NMR (CDC 3 ) 6 1.26 (311, t, J= 7 Hz), 1.39 (3H, t, J= 7 Hz), 1.46-1.65 (4H, m), 2.16 (2H, t, J= 7 Hz), 2.32-2.44 (2H, m), 3.04 (2H, q, J= 7 Hz), 4.12 (2H, q, J= 7 295 WO 2004/063197 PCT/JP2003/017091 Hz), 4.86 (2H, s), 5.91 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 7.58-7.68 (3H, m), 7.75-7.82 (1H, m). MS (ESI+): m/z 406. 5 Example 539 ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoate 'H NMR (CDC 3 ) 8 1.25 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.64-1.79 (2H, m), 2.23 (2H, t, J= 7 Hz), 2.42-2.53 (2H, m), 3.04 (2H, q, J= 7 Hz), 4.10 (2H, q, J= 7 10 Hz), 4.91 (2H, s), 5.97 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.89 (1H, m), 8.56 (1H, d, J= 2 Hz), 8.80 (1H, d, J= 2 Hz). MS (ESI*): m/z 446 448. Example 540 15 ethyl 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoate 'H NMR (CDCl 3 ) 8 1.20 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 2.32 (2H, m), 2.68 2.90 (2W, m), 3.03 (2H, q, J= 7 Hz), 4.10 (2H, m), 4.89 (2H, s), 6.03 (1H, m), 6.65 (1H, m), 7.90 (1H, m), 8.58 (1H, m), 8.83 (1H, m). 20 MS (ESI*): m/z 432 434. Example 541 ethyl 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoate 25 'H NMR (300 MHz, CDCl 3 ) 8 1.22 (3H, t, J = 7 Hz), 1.38 (3H, t, J = 7 Hz), 1.67 (2H, tt, J = 7, 7 Hz), 2.20 (2H, t, J = 7 Hz), 2.37-2.79 (2H, m), 3.04 (2H, q, J = 7 Hz), 3.77 (1H, t, J = 4 Hz), 4.07 (2H, q, J = 7 Hz), 4.91 (2H, d, J = 4 Hz), 5.96 (1H, d, J = 4 Hz), 6.61 (1H, d, J = 4 Hz), 7.73 (1H, dd, J = 2,2 Hz), 8.52 (1H, d, J = 2 Hz), 8.70 (1H, d, J = 2 Hz). 30 Example 542 ethyl 3-[4-(3-chlorophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3 yljpropanoate 296 WO 2004/063197 PCT/JP2003/017091 'H NMR (300 MHz, CDCl 3 ) 8 1.20 (3H, t, J = 7 Hz), 1.38 (3H, t, J = 7 Hz), 2.31 (2H, t, J = 8 Hz), 2.85 (2H, t, J = 8 Hz), 3.04 (2H, q, J = 7 Hz), 3.69-3.75 (1H, br s), 4.06 (2H, q, J = 7 Hz), 4.88 (2H, s), 6.00 (1H, d, J = 4 Hz), 6.59 (1H, d, J = 4 Hz), 7.23-7.26 (1H, m), 7.36 (1H, s), 7.44-7.46 (2H, m). 5 Example 543 ethyl 4-[4-(3-chlorophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-bjpyridazin-3 yl]butanoate 'H NMR (CDCl 3 ) 6 1.21 (3H, t, J = 8 Hz), 1.38 (3H, t, J = 8 Hz), 1.57 (3H, s), 1.59 10 1.74 (2H, m), 2.20 (2H, t, J = 8 Hz), 2.37-2.47 (2H, m), 3.03 (2H, q, J = 8 Hz), 3.84 (1H, t, J = 5 Hz), 4.06 (2H, q, J = 8 Hz), 4.39 (2H, d, J = 5 Hz), 5.32 (2H, s), 5.96 (1H, d, J = 5 Hz), 6.56 (1H, d, J 5 Hz), 7.21-7.29 (1H, overlappled with

CDC

3 ), 7.36 (1H, br s), 7.39-7.47 (2H, m). 15 Example 544 9-(5-bromo-3-pyridinyl)-6-ethyl-1H,3H-furo [3,4-elpyrrolo[1,2-b]pyridazin- 1-one 'H NMR (CDCl 3 ) 8 1.42 (3H, t, J = 8 Hz), 3.11 (2H, q, J = 8 Hz), 5.32 (2H, s), 6.87 (1H, d, J = 5 Hz), 6.99 (1H, d, J = 5 Hz), 8.20 (1H, m), 8.83-8.87 (2H, m). MS (ESI*): m/z 358, 360 (M + H). 20 4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid 'H NMR (CDCI 3 -CD30D) 8 1.40 (3H, t, J = 8 Hz), 3.09 (2H, q, J = 8 Hz), 4.93 (2H, s), 6.34 (1H, d, J = 5 Hz), 6.79 (1H, d, J = 5 Hz), 7.96 (1H, m), 8.55 (1H, br s), 25 8.73 (1H, br s). MS (ESI*): m/z 376, 378 (M + H). Example 545 30 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]-N [(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2 yl]propanamide 'H-NMR (DMSO-d 6 ) 6 1.30 (3H, t ,J = 7 Hz), 2.21 (1H, m), 2.96 (2H, q, J = 7 Hz), 297 WO 2004/063197 PCT/JP2003/017091 3.25-3.45 (811, m), 3.66 (1H, m), 4.40 (1H, m), 4.55-4.67 (5H, m), 4.75 (1H, m), 5.85 (1H, d, J = 5 Hz), 6.66 (1H, d, J = 5 Hz), 8.23 (1H, m), 8.33 (1H, d, br, J = 7 Hz), 8.61 (1H, m), 8.84 (1H, m). 5 Example 546 3-[7-ethyl-2-phenyl-3-(5-{ [(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6 (hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}pentyl)pyrrolo[1,2-b]pyridazin-4 yl]benzonitrile 1 H-NMR (CDCl 3 ) 8 0.85-1.38 (6H, m), 1.46 (3H, t, J = 7 Hz), 2.13 (2H, m), 2.38 (211, 10 m), 2.65 (1H, m), 2.73 (111, m), 3.02 (2H, q, J = 7 Hz), 3.23 (1H, m), 3.48-3.70 (4H, m), 3.80-4.01 (3H, m), 4.13 (1H, m), 5.90 (1H, d, J = 5 Hz), 663 (1H, d, J 5 Hz), 7.42-7.55 (5H, m), 7.60-7.79 (4H, m). The following compound(s) was(were) obtained in a similar manner to that of 15 Example 235. Example 547

N-(

2 -aminoethyl)-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2 b]pyridazin-3-yl]propanamide 'H-NMR (CDC 3 ) 8 1.37 (311, t, J = 7 Hz), 2.29 (2H, m), 2.72-3.07 (6H, m), 3.33 (2H, 20 q, J = 7 Hz), 3.49 (3H, s), 4.68 (211, s), 5.93 (1H, d, J = 5 Hz), 6.06 (11H, m, br), 6.62 (1H, d, J = 5 Hz), 7.89 (1H, m), 8.55 (11H, m), 8.77 (111, m). MS (ESI+) m/z: 460 and 462 (M + H) The following compound(s) was(were) obtained in a similar manner to that of 25 Example 268. Example 548 ethyl 3 -{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}propanoate 'H NMR (CDC 3 ) 8 1.15 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 2.37 (211, t, J= 7 Hz), 30 2.43 (311, s), 2.86-3.01 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.99 (2H, q, J= 7 Hz), 4.68 (2H, s), 4.81 (211, s), 5.95 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.27 (211, d, J= 7 Hz), 7.51 (111, s), 8.43 (111, s), 8.56 (1H, s), 8.57 (2H, d, J= 7 Hz). MS (ESI*): m/z 459. 298 WO 2004/063197 PCT/JP2003/017091 Example 549 ethyl 3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}propanoate 5 'H NMR (CDCl 3 ) 8 1.16 (31, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 2.39 (2H, t, J= 7 Hz), 2.43 (3H, s), 2.88-3.03 (2H, m), 3.04 (2H, q, J= 7 Hz), 4.01 (2H, q, J= 7 Hz), 4.83 (2H, s), 4.90 (211, s), 5.94 (1H, d, J= 4 Hz), 6.63 (11H, d, J= 4 Hz), 7.53 (1H, s), 8.42 (111, m), 8.48-8.55 (3H, m), 8.76 (11H, s). MS (ESI*): m/z 460. 10 Example 550 ethyl 3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}propanoate 'H NMR (CDC 3 ) 8 1.15 (3H, t, J= 7 Hz), 1.38 (31H, t, J= 7 Hz), 2.40 (211, t, J= 7 Hz), 15 2.42 (3H, s), 2.88-3.00 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.99 (2H, q, J= 7 Hz), 4.79 (2H, s), 4.86 (2H, s), 5.92 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 7.16-7.23 (1H, m), 7.45-7.53 (2H, m), 7.68 (1H, m), 8.42 (1H, m), 8.53 (2H, m). MS (ESI*): m/z 459. 20 Example 551 ethyl 4-{ 7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}butanoate 'H NMR (CDC 3 ) 8 1.18 (311, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.60-1.80 (2H, m), 2.13-2.25 (2H, m), 2.43 (311, s), 2.53-2.76 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.03 25 (2H, q, J= 7 Hz), 4.68 (2H, s), 4.83 (2H, m), 5.92 (11H, d, J= 4 Hz), 6.61 (11H, d, J= 4 Hz), 7.27 (2H, d, J= 5 Hz), 7.53 (11H, s), 8.42 (1H, s), 8.53 (111, s), 8.55 (2H, d, J= 5 Hz). MS (ESI*): m/z 473. 30 Example 552 ethyl 5-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 bjpyridazin-3-yl}pentanoate 1H NMR (CDCl 3 ) 8 1.22 (31H, t, J= 7 Hz), 1.38 (31, t, J= 7 Hz), 1.35-1.57 (4H, m), 299 WO 2004/063197 PCT/JP2003/017091 2.11 (2H, t, J= 7 Hz), 2.53-2.65 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.03 (2H, q, J= 7 Hz), 4.67 (2H, s), 4.78 (2H, s), 5.87 (111, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.28 (2H, d, J= 5 Hz), 7.61 (2H, m), 7.66 (1H, s), 7.78 (1H, m), 8.58 (2H, d, J= 5 Hz). 5 MS (ESI): m/z 497. Example 553 ethyl 5-{4-(3-cyanophenyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoate 10 'H NMR (CDC 3 ) 8 1.22 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.35-1.58 (4H, m), 2.11 (211, t, J= 7 Hz), 2.55-2.65 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.10 (2H, q, J= 7 Hz), 4.82 (2H, s), 4.86 (2H, s), 5.86 (111, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 7.62 (2H, m), 7.67 (1H, s), 7.78 (1H, m), 8.51 (2H, m), 8.74 (1H, s). MS (ESI+): m/z 498. 15 Example 554 ethyl 5-{4-(3-cyanophenyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoate 'H NMR (CDC1 3 ) , 1.22 (3H, t, J= 7 Hz), 1.39 (3H, t, J= 7 Hz), 1.32-1.66 (4H, m), 20 2.10 (2H, t, J= 7 Hz), 2.48-2.60 (2H, m), 3.03 (2H, q, J= 7 Hz), 4.08 (2H, q, J= 7 Hz), 4.66 (2H, s), 4.75 (2H, s), 5.86 (1H, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.28 (1H, m), 7.58-7.63 (2H, m), 7.66 (1H, s), 7.66-7.80 (2H, m), 8.54 (111, m), 8.62 (1H, m). MS (ESI*): m/z 497. 25 Example 555 ethyl 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoate 'H NMR (CDCl 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.38 (31H, t, J= 7 Hz), 1.40-1.62 (4H, m), 30 2.16 (2H, t, J= 7 Hz), 2.53-2.71 (211, m), 3.05 (211, q, J= 7 Hz), 4.09 (2H, q, J= 7 Hz), 4.67 (2H, s), 4.78 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.63 (111, d, J= 4 Hz), 7.31 (2H, d, J= 5 Hz), 7.88 (1H, m), 8.56 (1H, d, J= 2 Hz), 8.58 (2H, d, J= 5 Hz), 8.79 (1H, d, J= 2 Hz). 300 WO 2004/063197 PCT/JP2003/017091 Example 556 ethyl 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoate 5 'H NMR (CDCl 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.40 (3H, t, J= 7 Hz), 1.30-1.60 (411, m), 2.15 (2H, t, J= 7 Hz), 2.50-2.68 (2H, m), 3.06 (2H, q, J= 7 Hz), 4.12 (2H, q, J= 7 Hz), 4.68 (211, s), 4.78 (211, s), 5.95 (111, m), 6.63 (1H, m), 7.24-7.38 (111, m), 7.75 (111, m), 7.89 (1H, m), 8.58 (2H, s), 8.64 (111, s), 8.80 (11, s). MS (ESI'): m/z 551 553. 10 Example 557 ethyl 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoate 'H NMR (CDC1 3 ) 8 1.24 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.40-1.58 (4H, m), 15 2.12 (2H, t, J= 7 Hz), 2.53-2.68 (211, m), 3.03 (2H, q, J= 7 Hz), 4.10 (2H, q, J= 7 Hz), 4.78 (2H, s), 4.84 (211, s), 5.92 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.22 (1H, m), 7.48 (1H, d, J= 8 Hz), 7.68-7.75 (111, m), 7.88 (1H, m), 8.57 (2H, m), 8.78 (1H, d, J= 2 Hz). 20 Example 558 ethyl 5-{ 4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoate 'H NMR (CDC 3 ) 8 1.22 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.40-1.62 (411, m), 2.15 (2H, t, J= 7 Hz), 2.53-2.72 (2H, m), 3.05 (2H, q, J= 7 Hz), 4.08 (2H, q, J= 7 25 Hz), 4.82 (2H, s), 4.86 (2H, s), 5.94 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.88 (1H, m), 8.52 (211, m), 8.55 (1H, d, J= 2 Hz), 8.74 (111, m), 8.79 (1H, d, J= 2 Hz). MS (ESI*): m/z 552 554. Example 559 30 ethyl 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[ 1,2 b]pyridazin-3-yl}butanoate 'H NMR (CDC 3 ) 6 1.19 (3H, t, J= 7 Hz), 1.38 (311, t, J= 7 Hz), 1.60-1.80 (211, m), 2.22 (211, t, J= 7 Hz), 2.55-2.74 (211, m), 3.05 (2H, q, J= 7 Hz), 4.06 (211, q, J= 7 301 WO 2004/063197 PCT/JP2003/017091 Hz), 4.69 (2H, s), 4.83 (2H, s), 5.96 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.30 (2H, d, J= 6 Hz), 7.88 (1H, m), 8.56 (2H, d, J= 6 Hz), 8.57 (1H, m), 8.80 (1H, m). MS (ESI*): m/z 537 539. 5 Example 560 ethyl 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}butanoate 'H NMR (CDC 3 ) 8 1.26 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.55-1.82 (2H, m), 2.18 (2H, t, J= 7 Hz), 2.52-2.72 (2H, m), 3.05 (2H, q, J= 7 Hz), 4.05 (2H, q, J= 7 10 Hz), 4.68 (2H, s), 4.83 (2H, s), 5.94 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.28 (1H, m), 7.73 (1H, d, J= 8 Hz), 7.88 (1H, m), 8.54 (2H, m), 8.62 (1H, s), 8.79 (1H, s) Example 561 15 ethyl 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylmethoxy)methyllpyrrolo[1,2 b]pyridazin-3-yl}butanoate 'H NMR (CDCl 3 ) 6 1.26 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.63-1.82 (2H, m), 2.18 (2H, t, J= 7 Hz), 2.55-2.75 (2H, m), 3.06 (2H, q, J= 7 Hz), 4.00 (2H, q, J= 7 Hz), 4.80 (2H, s), 4.88 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.22 20 (1H, m), 7.48 (1H, d, J= 8 Hz), 7.71 (1H, t, J= 8 Hz), 7.89 (1H, m), 8.55 (2H, m), 8.78 (1H, d, J= 2 Hz). MS (ESI*): m/z 537 539. Example 562 25 ethyl 4-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2 b]pyridazin-3-yl}butanoate 'H NMR (CDCl 3 ) 8 0.25 (2H, m), 0.60 (2H, m), 1.08-1.22 (1H, m), 1.22 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.69-1.82 (2H, m), 2.21 (2H, t, J= 7 Hz), 2.56-2.72 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.42 (2H, d, J= 7 Hz), 4.04 (2H, q, J= 7 Hz), 4.73 30 (2H, s), 5.91 (1H, d, J= 4 Hz), 6.59 (1H, d, J= 4 Hz), 7.89 (1H, m), 8.56 (1H, d, J= 2 Hz), 8.79 (1H, d, J= 2 Hz). MS (ESI*): m/z 500 502. 302 WO 2004/063197 PCT/JP2003/017091 Example 563 ethyl 4-{ 4-(5-brono-3-pyridinyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}butanoate 'H NMR (CDC1 3 ) 8 1.19 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 1.70-1.82 (2H, m), 5 2.23 (2H, t, J= 7 Hz), 2.56-2.76 (2H, m), 3.06 (2H, q, J= 7 Hz), 4.04 (2H, q, J= 7 Hz), 4.84 (2H, s), 4.95 (2H, m), 5.94 (1H, d, J= 4 Hz), 6.63 (11H, d, J= 4 Hz), 7.89 (1H, m), 8.50 (2H, m), 8.56 (1H, s), 8.74 (1H, s), 8.79 (1H, m). MS (ESI*): m/z 538 540. 10 Example 564 ethyl 3-{ 4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}propanoate 1H NMR (CDCl 3 ) 8 1.16 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 2.41 (2H, t, J= 7 Hz), 2.85-3.07 (2H, m), 3.06 (2H, q, J= 7 Hz), 4.02 (2H, q, J= 7 Hz), 4.68 (2H, s), 4.81 15 (2H, s), 5.95 (1H, d, J= 4 Hz), 6.65 (1H, d, J= 4 Hz), 7.31 (2H, d, J= 6 Hz), 7.87 (1H, m), 8.55 (1H, m), 8.56 (2H, d, J= 6 Hz), 8.79 (1H, d, J= 2 Hz). MS (ESI*): m/z 523 525. Example 565 20 ethyl 4-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{ [2-(tetrahydro-2H-pyran-2 yloxy)ethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)butanoate 'H NMR (CDC 3 ) 8 1.20 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.46-1.93 (8H, m), 2.21 (2H, t, J= 7 Hz), 2.55-2.76 (2H, m), 3.02 (2H, q, J= 7 Hz), 3.46-3.56 (1H, m), 3.60-3.68 (1H, m), 3.74-3.82 (2H, m), 3.83-3.96 (2H, m), 4.03 (2H, q, J= 7 Hz), 25 4.63 (1H, m), 4.77 (2H, s), 5.91 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 7.89 (1H, m), 8.56 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). Example 566 ethyl 4-{ 4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 30 b]pyridazin-3-yl}butanoate 'H NMR (300 MHz, CDCl 3 ) 6 1.19 (3H, t, J = 7 Hz), 1.38 (3H, t, J = 7 Hz), 1.70 (2H, t, J = 7 Hz), 2.19 (2H, t, J = 7 Hz), 2.55-2.67 (2H, m), 3.04 (2H, q, J = 7 Hz), 4.03 (2H, q, J = 7 Hz), 4.69 (2H, s), 4.83 (2H, s), 5.94 (1H, d, J = 5 Hz), 6.63 (1H, d, J 303 WO 2004/063197 PCT/JP2003/017091 = 5 Hz), 7.29 (2H, d, J= 6 Hz), 7.73 (IH, dd, J 2, 2 Hz), 8.52 (1H, d, J = 2 Hz), 8.58 (2H, d, J = 6 Hz), 8.69 (1H, d, J = 2 Hz). Example 567 5 ethyl 3-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoate 'H NMR (CDCl 3 ) 8 1.20 (3H, t, J = 8 Hz), 1.37 (3H, t, J = 8 Hz), 2.33-2.44 (2H, m), 2.84-2.94 (2H, m), 3.03 (2H, q, J = 8 Hz), 3.45 (3H, s), 4.05 (2H, q, J = 8 Hz), 4.64 (2H, s), 5.94 (1H, d, J = 5 Hz), 6.58 (1H, d, J = 5 Hz), 7.21-7.29 (1H, 10 overlappled with CDCl 3 ), 7.36 (1H, br s), 7.38-7.46 (2H, m). Example 568 ethyl 4-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoate 15 1H NMR (CDCl 3 ) 8 1.20 (3H, t, J = 8 Hz), 1.37 (3H, t, J = 8 Hz), 1.62-1.78 (2H, m), 2.14-2.28 (2H, m), 2.53-2.66 (2H, m), 3.04 (2H, q, J = 8 Hz), 3.46 (3H, s), 4.04 (2H, q, J = 8 Hz), 4.65 (2H, s), 5.93 (1H, d, J = 5 Hz), 6.58 (1H, d, J = 5 Hz), 7.21-7.29 (1H, overlappled with CDCl 3 ), 7.36 (1H, br s), 7.39-7.46 (2H, m). 20 The following compound(s) was(were) obtained in a similar manner to that of Example 272. Example 569 ethyl 5-{4-(5-bromo-3-pyridinyl)-2-[(1,1-dioxido-4-thiomorpholinyl)methyl]-7 ethylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate 25 'H NMR (300 MHz, CDC1 3 ) 8 1.23 (3H, t, J = 7 Hz), 1.36 (3H, t, J = 7 Hz), 1.39 1.53 (4H, m), 2.19 (2H, t, J = 7 Hz), 2.50-2.61 (2H, m), 3.00 (2H, q, J = 7 Hz), 3.10 (4H, t, J 6 Hz), 3.21 (4H, t, J = 6 Hz), 3.85 (2H, s), 4.10 (2H, q, J = 7 Hz), 5.92 (1H, d, J = 4 Hz), 6.61 (1H, d, J = 4 Hz), 7.88 (1H, dd, J = 2, 2 Hz), 8.55 (1H, d, J = 2 Hz), 8.80 (1H, d, J = 2 Hz). 30 Example 570 ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomoipholinylmethy)pyrrolo[1,2 b]pyridazin-3-yl]pentanoate 304 WO 2004/063197 PCT/JP2003/017091 'H NMR (300 MHz, CDC 3 ) 8 1.23 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.41 1.54 (4H, m), 2.19 (2H, t, J = 7 Hz), 2.50-2.61 (2H, m), 2.66 (4H, t, J = 4 Hz), 2.85 (4H, t, J = 4 Hz), 3.01 (2H, q, J = 7 Hz), 3.67 (2H, s), 4.10 (2H, q, J = 7 H), 5.88 (1H, d, J = 5 Hz), 6.57 (1H, d, J = 5 Hz), 7.88 (1H, dd, J = 2, 2 Hz), 8.55 (1H, 5 d, J = 2 Hz), 8.79 (1H, d, J = 2 Hz). Example 571 ethyl 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{ [4-(2-hydroxyethyl)-1 piperazinyl]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate 10 'H NMR (300 MHz, CDCl 3 ) 8 1.23 (3H, t, J = 7 Hz), 1.36 (3H, t, J = 7 Hz), 1.40 1.55 (4H, m), 2.18 (2H, t, J = 7 Hz), 2.48-2.66 (12H, m), 3.02 (2H, q, J = 7 Hz), 3.61 (2H, t, J = 5 Hz), 3.66 (2H, s), 4.10 (2H, q, J = 7 Hz), 5.88 (1H, d, J = 4 Hz), 6.57 (1H, d, J = 4 Hz), 7.88 (1H, dd, J = 2, 2 Hz), 8.55 (1H, d, J = 2 Hz), 8.78 (iH, d, J = 2 Hz). 15 Example 572 ethyl 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2 b]pyridazin-3-yl]butanoate 'H NMR (300 MHz, CDC 3 ) 8 1.21 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.70 (2H, 20 tt, J = 7, 7 Hz), 2.19 (2H, t, J = 7 Hz), 2.50-2.67 (6H, m), 2.86 (4H, t, J = 5 Hz), 3.02 (2H, q, J = 7 Hz), 3.70 (2H, s), 4.05 (2H, q, J = 5 Hz), 5.89 (1H, d, J = 4 Hz), 6.58 (1H, d, J = 4 Hz), 7.74 (1H, dd, J = 2, 2 Hz), 8.52 (1H, d, J = 2 Hz), 8.68 (1H, d,J=2Hz). 25 Example 573 ethyl 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2 b]pyridazin-3-yl]butanoate 'H NMR (300 MHz, CDC 3 ) 5 1.21 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.72 (2H, tt, J = 7, 7 Hz), 2.20 (2H, t, J = 7 Hz), 2.56-2.69 (6H, m), 3.02 (2H, q, J = 7 Hz), 30 3.68-3.71 (6H, m), 4.05 (2H, q, J = 7 Hz) 5.89 (1H, d, J = 4 Hz), 6.58 (1H, d, J = 4 Hz), 7.74 (1H, dd, J = 2, 2 Hz), 8.53 (1H, d, J = 2 Hz), 8.69 (1H, d, J = 2 Hz). Example 574 305 WO 2004/063197 PCT/JP2003/017091 ethyl 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2 b]pyridazin-3-yl]propanoate 'H NMR (300 MHz, CDCl 3 ) 6 1.21 (3H, t, J = 7 Hz), 1.34 (3H, t, J = 7 Hz), 2.47-2.54 (2H, m), 2.59 (4H, t, J = 5 Hz), 2.81-2.95 (2H, m), 3.02 (2H, q, J = 7 Hz), 3.67 5 (4H, t, J = 5 Hz), 3.69 (2H, s), 4.07 (2H, q, J = 7 Hz), 5.90 (1H, d, J = 4 Hz), 6.59 (1H, d, J =4 Hz), 7.88 (1H, dd, J = 2,2 Hz), 8.55 (1H, d, J = 2 Hz), 8.79 (1H, d, J =2 Hz). Example 575 10 ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2 blpyridazin-3-yl]butanoate 'H NMR (300 MHz, CDCl 3 ) 8 1.21 (3H, t, J = 7 Hz), 1.36 (3H, t, J = 7 Hz), 1.73 (2H, tt, J = 7, 7 Hz), 2.20 (2H, t, J = 7 Hz), 2.55-2.69 (6H, m), 3.02 (2H, q, J = 7 Hz), 3.69 (4H, t, J = 5 Hz), 4.05 (2H, q, J = 7 Hz), 5.89 (1H, d, J = 4 Hz), 6.58 (1H, d, 15 J = 4Hz),7.89 (1H,dd,J = 2,2Hz), 8.57 (1H, d,J = 2Hz),8.79 (1H,d,J = 2 Hz). Example 576 ethyl 4-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylamino)methyl]-7-ethylpyrrolo[1,2 20 b]pyridazin-3-yl}butanoate 'H NMR (300 MHz, CDC 3 ) 6 0.46-0.52 (4H, m), 1.21 (3H, t, J = 7 Hz), 1.38 (3H, t, J = 7 Hz), 1.71 (2H, tt, J = 8, 8 Hz), 2.21 (2H, t, J = 8 Hz), 2.32-2.39 (1H, m), 2.45-2.54 (2H, m), 3.04 (2H, q, J = 7 Hz), 4.06 (2H, q, J = 7 Hz), 4.07 (2H, s), 5.89 (1H, d, J = 4 Hz), 6.57 (1H, d, J = 4 Hz), 7.72 (1H, dd, J = 2, 2 Hz), 8.50 (1H, 25 d, J = 2 Hz), 8.68 (1H, d, J = 2 Hz). Example 577 ethyl 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{ [(2 phenoxyethyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate 30 'H NMR (300 MHz, CDCl 3 ) 5 1.23 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.40-1.56 (4H, m), 2.18 (2H, t, J = 8 Hz), 2.41-2.52 (2H, m), 3.04 (2H, q, J = 7 Hz), 3.19 (2H, t, J = 5 Hz), 4.07 (2H, s), 4.09 (2H, q, J = 7 Hz), 4.17 (2H, t, J = 5 Hz), 5.90 (1H, d, J = 4 Hz), 6.57 (1H, d, J = 4 Hz), 6.92-6.98 (3H, m), 7.29-7.32 (2H, m), 306 WO 2004/063197 PCT/JP2003/017091 7.86 (1H, dd, J = 2, 2 Hz), 8.54 (1H, d, J = 2 Hz), 8.78 (1H, d, J = 2 Hz). Example 578 ethyl 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{ [(2 5 hydroxyethyl)(methyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate 'H NMR (300 MHz, CDCl 3 ) 6 1.23 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.42-1.63 (4H, m), 2.20 (2H, t, J = 8 Hz), 2.38 (3H, s), 2.53-2.64 (2H, m), 2.75 (2H, t, J = 5 Hz), 3.02 (2H, q, J = 7 Hz), 3.66 (2H, t, J = 5 Hz), 3.77 (2H, s), 4.10 (2H, q, J = 7 Hz), 5.90 (1H, d, J = 4 Hz), 6.59 (1H, d, J = 4 Hz), 7.88 (1H, dd, J = 2, 2 Hz), 10 8.55 (1H, d, J = 2 Hz), 8.78 (1H, d, J = 2 Hz). Example 579 ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(1-piperidinylmethyl)pyrrolo[1,2-b]pyridazin 3-yl]pentanoate 15 1H NMR (300 MHz, CDCl 3 ) 8 1.23 (3H, t, J = 7 Hz), 1.36 (3H, t, J = 7 Hz), 1.42-1.58 (6H, m), 1.69 (4H, tt, J = 5, 5 Hz), 2.18 (2H, t, J = 8 Hz), 2.53-2.64 (2H, m), 3.02 (2H, q, J = 7 Hz), 3.19 (4H, t, J = 5 Hz), 3.60 (2H, s), 4.07 (2H, q, J = 7 Hz), 5.86 (1H, d, J = 5 Hz), 6.54 (1H, d, J = 5 Hz), 7.89 (1H, dd, J = 2,2 Hz), 8.56 (1H, d, J 2 Hz), 8.75 (1H, d, J = 2 Hz). 20 Example 580 ethyl 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2 b]pyridazin-3-yllpropanoate 1H NMR (300 MHz, CDC 3 ) 6 1.23 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 2.46 (2H, 25 t, J = 8 Hz), 2.64 (4H, t, J = 5 Hz), 2.86 (6H, m), 3.02 (2H, q, J = 7 Hz), 3.69 (2H, s), 4.06 (2H, q, J = 7 Hz), 5.91 (1H, d, J = 5 Hz), 6.60 (1H, d, J = 5 Hz), 7.88 (1H, dd, J = 2, 2 Hz), 8.56 (1H, d, J = 2 Hz), 8.80 (1H, d, J = 2 Hz). Example 581 30 ethyl 3-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[4-(2-hydroxyethyl)-1 piperazinyl]methyl}pyrrolo[1,2-b]pyridazin-3-yl)propanoate 'H NMR (300 MHz, CDC 3 ) 8 1.21 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 2.46-2.63 (12H, m), 2.80-2.94 (2H, m), 3.03 (2H, q, J = 7 Hz), 3.61 (2H, t, J = 5 Hz), 3.70 307 WO 2004/063197 PCT/JP2003/017091 (2H, s), 4.08 (2H, q, J = 7 Hz), 5.90 (IH, d, J = 5 Hz), 6.59 (1H, d, J = 5 Hz), 7.88 (1H, dd, J = 2,2 Hz), 8.56 (1H, d, J = 2 Hz), 8.79 (1H, d, J = 2 Hz). Example 582 5 ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(1-pyrrolidinylmethyl)pyrrolo[1,2 b]pyridazin-3-yl]pentanoate H NMR (300 MHz, CDC1 3 ) 8 1.23 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.40-1.55 (4H, m), 1.75-1.80 (4H, m), 2.19 (2H, t, J = 7 Hz), 2.54-2.66 (6H, m), 3.02 (2H, q, J = 7 Hz), 3.76-3.81 (2H, m), 4.10 (2H, q, J = 7 Hz), 5.87 (1H, d, J = 5 Hz), 6.55 10 (1H, d,J = 5 Hz), 7.89 (1H, dd, J = 2,2Hz), 8.56(11H, d, J = 2Hz), 8.77(11H, d, J =2 Hz). Example 583 ethyl 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-phenyl-1-piperazinyl)methyl]pyrrolo[1,2 15 b]pyridazin-3-yl}pentanoate 'H NMR (300 MHz, CDCl 3 ) 8 1.21 (3H, t, J = 7 Hz), 1.38 (3H, t, J = 7 Hz), 1.41-1.54 (4H, m), 2.17 (2H, t, J = 7 Hz), 2.53-2.68 (2H, m), 2.75 (4H, t, J = 5 Hz), 3.03 (2H, q, J = 7 Hz), 3.19 (4H, t, J = 5 Hz), 3.73 (2H, s), 4.07 (2H, q, J = 7 Hz), 5.89 (1H, d, J = 5 Hz), 6.58 (1H, d, J = 5 Hz), 6.85 (1H, dd, J = 8, 8 Hz), 6.93 (2H, J = 20 8 Hz), 7.25 (2H, J = 8 Hz), 7.89 (1H, dd, J = 2,2 Hz), 8.56 (1H, d, J = 2 Hz), 8.78 (1H, d, J = 2 Hz). Example 584 ethyl 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(2 25 methoxyethyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate 'H NMR (300 MHz, CDC 3 ) 6 1.23 (3H, t, J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.41-1.60 (4H, m), 2.19 (2H, t, J = 7 Hz), 2.43-2.52 (2H, m), 2.96 (2H, t, J = 5 Hz), 3.03 (211, q, J = 7 Hz), 3.40 (3H, s), 3.58 (2H, t, J = 5 Hz), 3.99 (2H, s), 4.10 (2H, q, J = 7 Hz), 5.89 (1H, d, J = 5 Hz), 6.56 (1H, d, J = 5 Hz), 7.87 (1H, dd, J = 2,2 Hz), 30 8.54 (1H, d, J= 2 Hz), 8.78 (1H, d, J = 2 Hz). The following compound(s) was(were) obtained in a similar manner to that of Example 385. 308 WO 2004/063197 PCT/JP2003/017091 Example 585 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]-N [2-hydroxy-1,1-bis(hydroxymethyl)ethyl]propanamide 'H-NMR (CDCI 3 ) 8 1.37 (3H, t, J = 7 Hz), 2.25-3.10 (611, m), 3.49 (3H, s), 3.58 (4H, 5 m), 3.81 (211, m), 4.55 (2H, s), 5.97 (11H, d, J = 5 Hz), 6.54 (1H, s), 6.64 (11H, d, J 5 Hz), 7.93 (111, m), 8.52 (1H, m), 8.78 (1H, m). Example 586 tert-butyl [2-({3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2 10 b]pyridazin-3-yl]propanoyl}amino)ethyl]carbamate 1 H-NMR (CDC 3 ) 8 1.37 (3H, t, J = 7 Hz), 1.43 (911, s), 2.26 (2H, m), 2.88 (2H, m), 3.04 (211, q, J = 7 Hz), 3.20 (2H, m), 3.28 (2H, m), 3.48 (3H, s), 4.67 (2H, s), 4.85 (11H, s, br), 5.93 (1H, d, J = 5 Hz), 6.20 (1H, s, br), 6.63 (111, d, J = 5 Hz), 7.88 (1H, m), 8.53 (1H, m), 8.79 (1H, m). 15 The following compound(s) was(were) obtained in a similar manner to that of Example 330. Example 587 ethyl 5-[2-{[2-(benzylamino)-2-oxoethoxy]methyl}-7-ethyl-4-(5-methyl-3 20 pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate 'H NMR (CDC 3 ) 6 1.22 (3H, t, J= 7 Hz), 1.34 (3H, t, J= 7 Hz), 1.33-1.55 (4H, m), 2.12 (2H, t, J= 7 Hz), 2.43 (3H, s), 2.40-2.56 (2H, m), 2.96 (2H, q, J= 7 Hz), 4.07 (2H, q, J= 7 Hz), 4.19 (211, s), 4.52 (2H, d, J= 7 Hz), 4.76 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.59 (111, d, J= 4 Hz), 7.06 (111, br), 7.23-7.38 (5H, m), 7.49 (1H, s), 8.40 25 (1H, s), 8.54 (1H, s). MS (ESI*): m/z 543. The following compound(s) was(were) obtained in a similar manner to that of Example 333. 30 Example 588 ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4H-1,2,4-triazol-4-ylmethyl)pyrrolo[1,2 b]pyridazin-3-yl]butanoate 'H-NMR (CDC 3 ) 8 1.22-1.34 (6H, m), 1.67 (2H, m), 2.23 (2H, m), 2.51 (211, m), 309 WO 2004/063197 PCT/JP2003/017091 2.98 (2H, q, J = 7 Hz), 4.21 (2H, q, J = 7 Hz), 5.67 (2H, m), 5.97 (111, d, J = 5 Hz), 6.63 (1H, d, J = 5 Hz), 7.85 (1H, m), 7.96 (1H, s), 8.34 (1H, s), 8.53 (1H, m), 8.79 (1H, m). 5 The following compound(s) was(were) obtained in a similar manner to that of Example 336. Example 589 ethyl 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(phenylsulfonyl)amino]methyl}pyrrolo[1,2 b]pyridazin-3-yl)pentanoate 10 'H NMR (CDCI 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.26-1.57 (4H, m), 2.16 (2H, t, J= 7 Hz), 2.33-2.46 (2H, m), 2.42 (3H, s), 2.98 (211, q, J= 7 Hz), 4.11 (2H, q, J= 7 Hz), 4.38 (2H, m), 5.91 (1H, br), 5.92 (1H, d, J= 4 Hz), 6.58 (1H, d, J= 4 Hz), 7.43-7.55 (4H, m), 7.93 (2H, d, J= 8 Hz), 8.33 (111, d, J= 2 Hz), 8.54 (1H, d, J= 2 Hz). 15 MS (ESI*): m/z 535. The following compound(s) was(were) obtained in a similar manner to that of Example 340. Example 590 20 ethyl 4-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylamino)methyl]-7-ethylpyrrolo[1,2 b]pyridazin-3-yl}butanoate 'H-NMR (CDC 3 ) 6 0.48 (4H, m), 1.19 (311, t, J = 7 Hz), 1.37 (311, t, J = 7 Hz), 1.70 (2H, t, J = 7 Hz), 2.22 (2H, m), 2.50 (211, m), 2.95-3.07 (3H, m), 3.96-4.12 (411, m), 5.90 (1H, d, J = 5 Hz), 6.57 (1H, d, J = 5 Hz), 7.88 (111, m), 8.54 (1H, m), 25 8.77 (1H, m). Example 591 To a suspension of LiAlH4 (113 mg) in THF (10 mL) was added ethyl [4-(5 bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[ 1,2-blpyridazin-3-yl] acetate (600 mg) under 30 ice-water cooling and the mixture was stirred at 0 *C for 2 hours. To the mixture was added potassium sodium tartrate solution and the insolubles were filterred off. After evaporation of solvent, the residue was partitioned between AcOEt and water. The organic layer was separated, washed with brine, dried over MgSO 4 , and evaporated in 310 WO 2004/063197 PCT/JP2003/017091 vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (5:1 - 1:1) to give 2-[4-(5-bromo-3-pyridinyl)-7-ethyl-2 methylpyrrolo[1,2-b]pyridazin-3-yl]ethanol as yellow oil (246 mg). 5 2-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]ethanol 'H NMR (CDC 3 ) 8 1.37 (3H, t, J= 7 Hz), 2.60 (3H, s), 2.72-2.84 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.65 (2H, t, J= 7 Hz), 5.89 (1H, d, J= 4 Hz), 6.55 (1H, d, J= 4 Hz), 7.91 (1IH, t, J= 2 Hz), 8.56 (11H, d, J= 2 Hz), 8.76 (1H, d, J= 2 Hz). MS (ESI*): m/z 360 362. 10 Example 592 A mixture of 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2 b]pyridazin-3-yl]propanoic acid (1.07 g), diphenylphosphoryl azide (1.14 g) and Et3N (0.576 mL) in BuOH (30 mL) was heated under reflux for 2 hours. After evaporation of 15 solvent, the residue was partitioned between AcOEt and water. The organic layer was separated, washed with aq NaHCO 3 solution and brine, dried over MgSO 4 , and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1 - 3:1) to give tert-butyl {2-[4-(5 bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]ethyl}carbamate as 20 yellow oil (450 mg). tert-butyl {2-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl]ethyl} carbam ate 'H NMR (CDC 3 ) 8 1.37 (9H, s), 1.37 (3H, t, J= 7 Hz), 2.64 (3H, s), 2.62-2.75 (2H, 25 m), 3.03 (2H, q, J= 7 Hz), 3.10-3.27 (2H, m), 4.40-4.52 (1H, m), 5.89 (1H, d, J= 4 Hz), 6.55 (1H, d, J= 4 Hz), 7.89 (1H, m), 8.53 (1H, m), 8.77 (1H, m). Example 593 To a suspension of 60% NaH (74 mg) in DMF (3 mL) was added ethyl 3-[4-(5 30 bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate (200 mg) under ice-water cooling, and the mixture was stirred at 0 0 C for 0.5 hour. To this was added 3-(bromomethyl)pyridine hydrobromide (234 mg) under ice-water cooling, and the mixture was stirred at ambient temperature for 2 hours. The mixture was 311 WO 2004/063197 PCT/JP2003/017091 partitioned between AcOEt and water. The aqueous layer was separated, acidified to pH 3-4 with HCI and extracted with AcOEt. The organic layer was washed with water and brine, dried over MgSO 4 , and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of CHCl 3 and MeOH (100:1 - 20:1) to 5 give 3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}propanoic acid as a yellow powder (110 mg). 3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}propanoic acid 10 'H NMR (CDCl 3 ) 8 1.39 (3H, t, J= 7 Hz), 2.41 (2H, t, J= 7 Hz), 2.80-2.98 (2H, m), 3.04 (2H, q, J= 7 Hz), 4.70 (2H, s), 4.83 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.32-7.38 (1H, m), 7.81 (1H, d, J= 8 Hz), 7.87 (1H, m), 8.52 (1H, d, J= 8 Hz), 8.53 (1H, d, J= 2 Hz), 8.63 (1H, s), 8.77 (1H, d, J= 2 Hz). 15 The following compound(s) was(were) obtained in a similar manner to that of Example 593. Example 594 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-methoxyethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}butanoic acid 20 1 H NMR (CDCl 3 ) 8 1.37 (3H, t, J= 7 Hz), 1.72-1.83 (2H, m), 2.28 (2H, t, J= 7 Hz), 2.60-2.77 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.39 (3H, s), 3.62 (2H, m), 3.77 (2H, m), 4.75 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.92 (1H, m), 8.56 (1H, d, J= 2 Hz), 8.77 (1H, d, J= 2 Hz). MS (ESIT): m/z 474 476, MS (ESI t ): m/z 476 478. 25 Example 595 3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}propanoic acid 1 H NMR (CDCl 3 ) 5 1.38 (3H, t, J= 7 Hz), 2.48-2.62 (2H, m), 2.98-3.10 (2H, m), 3.05 30 (2H, q, J= 7 Hz), 4.82 (2H, s), 4.88 (2H, s), 5.94 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.27 (1H, m), 7.48 (1H, d, J= 8 Hz), 7.77 (1H, t, J= 8 Hz), 7.90 (1H, m), 8.56 (2H, m), 8.80 (1H, m). MS (ESI*): m/z 495 497. 312 WO 2004/063197 PCT/JP2003/017091 Example 596 3-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2 b]pyridazin-3-yl}propanoic acid 5 'H NMR (CDCl 3 ) 5 0.25 (2H, m), 0.58 (21H, m), 1.12 (1H, m), 1.37 (3H, t, J= 7 Hz), 2.40-2.63 (2H, in), 2.85-3.05 (2H, m), 3.02 (2H, q, J= 7 Hz), 3.42 (2H, d, J= 7 Hz), 4.73 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.89 (1H, m), 8.55 (1H, d, J= 2 Hz), 8.77 (1H, d, J= 2 Hz). MS (EST): m/z 456 458, MS (ESI*): m/z 458 460. 10 Example 597 3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}propanoic acid 'H NMR (CDCl 3 ) 8 1.38 (3H, t, J= 7 Hz), 2.48 (2H, t, J= 7 Hz), 2.85-3.09 (2H, m), 15 3.06 (2H, q, J= 7 Hz), 4.84 (2H, s), 4.92 (2H, s), 5.96 (1H, d, J= 4 Hz), 6.65 (1H, d, J= 4 Hz), 7.90 (1H, m), 8.48-8.62 (3H, m), 8.77 (2H, m). Example 598 A mixture of ethyl 4-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{ [2-(tetrahydro-2H 20 pyran-2-yloxy)ethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)butanoate (89 mg) and pyridinium p-toluenesulfonate (0.8 mg) in MeOH (5 mL) was heated under reflux for 2 hours. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (10:1 - 1:1) to give ethyl 4 {4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-hydroxyethoxy)methyllpyrrolo[1,2-b]pyridazin 25 3-yl}butanoate as yellow oil (69 mg). ethyl 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-hydroxyethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}butanoate 1H NMR (CDCl 3 ) 8 1.22 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.69-1.84 (2H, m), 30 2.22 (2H, t, J= 7 Hz), 2.53-2.72 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.76 (2H, m), 3.83 (2H, m), 4.07 (2H, q, J= 7 Hz), 4.79 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.89 (1H, m), 8.56 (1H, d, J= 2 Hz), 8.79 (1H, d, J= 2 Hz). MS (ESI*): m/z 490 492. 313 WO 2004/063197 PCT/JP2003/017091 Example 599 To a suspension of 60% NaH (69.5 mg) in DMF (3 mL) was added ethyl 5-[4-(5 bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate 5 (200 mg) under ice-water cooling and the mixture was stirred at 0 'C for 0.5 hour. To this was added 4-moipholinecarbonyl chloride (659 mg) and the mixture was stirred at ambient temperature for 15 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, washed with water and brine, dried over MgSO 4 , and evaporated in vacuo. The residue was purified by silica gel column chromatography 10 eluting with a mixture of hexane and AcOEt (20:1 - 1:1) to give [4-(5-bromo-3 pyridinyl)-3-(5-ethoxy-5-oxopentyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methyl 4 morpholinecarboxylate as yellow oil (75 mg). [4-(5-bromo-3-pyridinyl)-3-(5-ethoxy-5-oxopentyl)-7-ethylpyrrolo[1,2-b]pyridazin-2 15 yl]methyl 4-morpholinecarboxylate 'H NMR (CDCl 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.40-1.60 (4H, m), 2.18 (2H, t, J= 7 Hz), 2.42-2.54 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.53-3.57 (4H, m), 3.63-3.78 (4H, m), 4.09 (2H, q, J= 7 Hz), 5.33 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.87 (1H, m), 8.54 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). 20 MS (ESI+): m/z 573 575. The following compound(s) was(were) obtained in a similar manner to that of Example 599. Example 600 25 ethyl 5-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7 ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate 'H NMR (CDCl 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.36 (3H, t, J= 7 Hz), 1.35-1.60 (4H, m), 2.17 (2H, t, J= 7 Hz), 2.44-2.57 (2H, m), 2.98 (6H, s), 3.03 (2H, q, J= 7 Hz), 4.09 (2H, q, J= 7 Hz), 5.30 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.87 30 (1H, m), 8.54 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). MS (ESI*): m/z 531 533. Example 601 314 WO 2004/063197 PCT/JP2003/017091 [4-(5-bromo-3-pyridinyl)-3-(5-ethoxy-5-oxopentyl)-7-ethylpyrrolo[1,2-b]pyridazin-2 yl]methyl 1-pyrrolidinecarboxylate 'H NMR (CDC 3 ) 8 1.23 (3H, t, J= 7 Hz), 1.36 (3H, t, J= 7 Hz), 1.38-1.60 (4H, m), 1.86-1.98 (4H, n), 2.17 (2H, t, J= 7 Hz), 2.44-2.57 (2H, m), 3.03 (2H, q, J= 7 Hz), 5 3.36-3.52 (4H, m), 4.11 (2H, q, J= 7 Hz), 5.32 (2H, s), 5.92 (1H, d, J= 4 Hz), 6.61 (1H, d, J= 4 Hz), 7.87 (1H, m), 8.55 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). Example 602 ethyl 5-{ 4-(5-bromo-3-pyridinyl)-7-ethyl-2 10 [({[methyl(phenyl)amino]carbonyl}oxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate 'H NMR (CDCl 3 ) 8 1.20 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.32-1.57 (4H, m), 2.13 (2H, t, J= 7 Hz), 2.33-2.48 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.38 (3H, s), 4.08 (2H, q, J= 7 Hz), 5.34 (2H, s), 5.92 (1H, d, J= 4 Hz), 6.60 (1H, d, J= 4 Hz), 7.20 7.38 (5H, m), 7.83 (1H, s), 8.49 (1H, s), 8.77 (1H, s). 15 Example 603 [4-(5-bromo-3-pyridinyl)-3-(4-ethoxy-4-oxobutyl)-7-ethylpyrrolo[l,2-b]pyridazin-2 yl]methyl 4-morpholinecarboxylate 'H NMR (CDCl 3 ) 8 1.20 (3H, t, J= 7 Hz), 1.37 (3H, t, J= 7 Hz), 1.63-1.80 (2H, m), 20 2.22 (2H, t, J= 7 Hz), 2.44-2.65 (2H, m), 3.03 (2H, q, J= 7 Hz), 3.54 (4H, m), 3.68 (4H, m), 4.05 (2H, q, J= 7 Hz), 5.37 (2H, s), 5.94 (1H, d, J= 4 Hz), 6.62 (1H, d, J= 4 Hz), 7.87 (1H, m), 8.55 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). MS (ESI*): m/z 559 561. 25 Example 604 ethyl 4-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)- 7 ethylpyrrolo[1,2-b]pyridazin-3-yl]butanoate 'H NMR (CDCl 3 ) 8 1.20 (3H, t, J= 7 Hz), 1.36 (3H, t, J= 7 Hz), 1.66-1.79 (2H, m), 2.20 (2H, t, J= 7 Hz), 2.46-2.62 (2H, m), 2.97 (6H, s), 3.03 (2H, q, J= 7 Hz), 4.04 30 (2H, q, J= 7 Hz), 5.34 (2H, s), 5.93 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.89 (1H, m), 8.56 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 2 Hz). MS (ESI+): m/z 517 519. 315 WO 2004/063197 PCT/JP2003/017091 Example 605 ethyl 3-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)- 7 ethylpyrrolo[1,2-b]pyridazin-3-yl]propanoate 'H NMR (CDC1 3 ) 8 1.20 (3H, t, J= 7 Hz), 1.36 (3H, t, J= 7 Hz), 2.37 (2H, t, J= 7 Hz), 5 2.82-2.93 (2H, m), 2.97 (6H, s), 3.03 (211, q, J= 7 Hz), 4.05 (211, q, J= 7 Hz), 5.32 (2H, s), 5.96 (1H, d, J= 4 Hz), 6.63 (1H, d, J= 4 Hz), 7.88 (1H, m), 8.54 (1H, d, J= 2 Hz), 8.78 (111, d, J= 2 Hz). Example 606 10 To a solution of sodium hydride (93.1 mg) in DMF (4 mL) was added ethyl 3-[4 (3-chlorophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate (150 mg) under ice water cooling and the mixture was stirred at this temperature for 1 hour. To this was added 4-(bromomethyl)pyridine hydrobromide (196 mg) and the mixture was stirred for 1 hour at ambient temperature. The reaction was quenched by adding water. 15 The mixture was extracted with CHC1 3 .The organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of CHCl 3 -MeOH = 30-1 to give 3-{4-(3 chlorophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3 yl}propanoic acid (18 mg) as a yellow solid. 20 3-{4-(3-chlorophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3 yl}propanoic acid 'H NMR (300 MHz, CDCl 3 ) 8 1.39 (3H, t, J = 7 Hz), 2.33 (2H, t, J = 7 Hz), 2.84-2.91 (2H, m), 3.04 (2H, q, J = 7 Hz), 4.73 (2H, s), 4.82 (2H, s), 5.96 (1H, d, J = 5 Hz), 25 6.62 (1H, d, J = 5 Hz), 7.23-7.26 (1H, m), 7.36-7.38 (3H, m), 7.42-7.44 (211, m), 8.41 (2H, d, J = 5 Hz). MS (m/z) 450 (M+H). The following compound(s) was(were) obtained in a similar manner to that of 30 Example 606. Example 607 3-{ 4-(3-chlorophenyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3 yl}propanoic acid 316 WO 2004/063197 PCT/JP2003/017091 'H NMR (300 MHz, CDCl 3 ) 8 1.39 (3H, t, J = 7 Hz), 2.32-2.38 (2H, m), 2.84-2.92 (2H, m), 3.04 (2H, q, J = 7 Hz), 4.70 (2H, s), 4.82 (2H, s), 5.94 (1H, d, J = 5 Hz), 6.60 (1H, d, J = 5 Hz), 7.21-7.24 (1H, m), 7.31-7.36 (2H, m), 7.40-7.42 (2H, m), 7.80 (2H, d, J = 8 Hz), 8.51 (1H, d, J = 5 Hz), 8.64 (1H, s). 5 Example 608 3-{4-(3-chlorophenyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3 yl}propanoic acid 'H NMR (300 MHz, CDC 3 ) 8 1.38 (3H, t, J = 7 Hz), 2.42 (2H, t, J = 7 Hz), 2.91-2.97 10 (2H, m), 3.03 (2H, q, J = 7 Hz), 4.83 (2H, s), 4.90 (2H, s), 5.96 (2H, d, J = 5 Hz), 6.62 (2H, d, J = 5 Hz), 7.23-7.26 (1H, m), 7.36 (1H, s), 7.43-7.44 (2H, m), 8.51 8.53 (2H, m), 8.75 (1H, s). Example 609 15 A solution of 5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin 3-yl]pentanoic acid (15 mg) in MeOH was added 10% Pd/C (2 mg). The mixture was stirred under under hydrogen atmosphere (1 atm) for 6 h. The reaction mixture was filtered through Celite and the filtrate was concentrarted in vacuo. The residue was triturated with hexane to give 5-[7-ethyl-4-(2-ethyl-4-pyridinyl)-2-methylpyrrolo[1,2 20 b]pyridazin-3-yl]pentanoic acid (14 mg) as an yellow solid. 5-[7-ethyl-4-(2-ethyl-4-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid 'H NMR (CDC 3 ) 8 1.29-1.64 (10H, m), 2.18-2.30 (2H, m), 2.45-2.48 (2H, m), 2.56 (3H, s), 2.91-3.06 (4H, m), 5.84 (1H, d, J = 5 Hz), 6.53 (1H, d, J = 16 Hz), 6.51 25 (1H, d, J = 5 Hz), 7.25-7.32 (2H, m), 8.69 (1H, br s). Example 610 To a solution of ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2 (hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate (70.0 mg) in toluene (1 mL) was 30 added tributylphosphine (0.098 mL), 1,3-oxazolidin-2-one (34.1 mg) in that order in an ice bath. After stirring for 5 minutes, to the mixture was added 1,1' (azodicarbonyl)dipiperidine (98.9 mg). The mixture was stirred for 10 minutes in the bath, and 8 hours at room temperature. Hexane (5 mL) was added, and the mixture was 317 WO 2004/063197 PCT/JP2003/017091 filtered. The filtrate was evaporated. Preparative thin layer chromatography (ethyl acetate-hexane = 1-1) afforded ethyl 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-oxo-1,3 oxazolidin-3-yl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate as an yellow gum (25.0 mg). 5 ethyl 4-{ 4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-oxo-1,3-oxazolidin-3 yl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate 'H-NMR (CDC 3 ) 8 1.20 (3H, t, J = 7 Hz), 1.369 (3H, t, J = 7 Hz), 1.65 (3H, t, J = 7 Hz), 2.25 (2H, t, J 7 Hz), 2.51 (2H, m), 2.99 (2H, q, J = 7 Hz), 3.79 (211, t, J = 7 10 Hz), 4.04 (2H, q, J = 7 Hz), 4.43 (211, t, J = 7 Hz), 4.69 (2H, m), 5.95 (111, d, J = 5 Hz), 6.61 (1H, d, J = 5 Hz), 7.87 (1H, m), 8.55 (1H, m), 8.80 (111, m). Example 611 To a solution of 2-bromo-4-[3-(ethoxycarbonyl)-7-ethyl-2-methylpyrrolo[1,2 15 b]pyridazin-4-yl]benzoic acid (50.0 mg) in tetrahydrofuran (1 mL) was added a solution of 1 M borane-tetrahydrofuran complex (0.348 mL) in an ice bath. After stirring for 2 hours at room temperature, additional solution of the borane-tetrahydrofuran complex (0.348 mL) was added. The mixture was stirred for 15 hours at room temperature. The mixture was parititioned between ethyl acetate and 1 N hydrochloric acid. The organic 20 layer was washed with water, saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and evaporated to give ethyl 4-[3-bromo-4-(hydroxymethyl)phenyl] 7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow oil (54.2 mg). ethyl 4-[3-bromo-4-(hydroxymethyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3 25 carboxylate 'H-NMR (CDCl 3 ) 5 0.99 (311, t, J = 7 Hz), 1.38 (311, t, J = 7 Hz), 2.59 (3H, s), 3.03 (211, q, J = 7 Hz), 4.07 (211, q, J = 7 Hz),4.82 (2H, s), 6.33 (11H, d, J = 5 Hz), 6.66 (1H, d, J = 5 Hz), 7.44 (111, d, J = 8 Hz), 7.58 (1H, d, J = 8 Hz), 7.67 (1H, s). 30 Example 612 To a solution of 2-(2-{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 b]pyridazin-3-yl]ethoxy}ethoxy)ethyl acetate (62.0 mg) in methanol (1 mL) was added potassium carbonate (22.2 mg). After stirring for 1.5 hour, The solvent was evaporated 318 WO 2004/063197 PCT/JP2003/017091 off. Preparative thin layer chromatography (CHCI 3 -MeOH = 20-1) affroded the desired product as an yellow gum (54.1 mg). The gum was dissolved in 1 N HCI (1 mL), and the solution was lyophilized to give a dark green gum, which was crystalyzed upon standing. The crystal was triturated in diisopropyl ether to give 2-(2-{2-[7-ethyl-2-methyl-4-(5 5 methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy}ethoxy)ethanol hydrochloride as an yellow powder (40.3 mg). 2-(2-{ 2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]ethoxy}ethoxy)ethanol hydrochloride 10 'H-NMR (DMSO-d 6 ): 1.29 (3H, t, J = 7 Hz), 2.51 (3H, s), 2.56 (3H, s), 2.62 (2H, m), 2.94 (2H, q, J = 7 Hz), 3.30-3.47 (10H, m), 5.84 (111, d, J = 5 Hz), 6.59 (1H, d, J = 5 Hz), 8.26 (1H, m), 8.77 (1H, m), 8..85 (1H, m). Example 613 15 A mixture of ethyl 5-[ 2 -(bromomethyl)-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2 b]pyridazin-3-yl]pentanoate (70.0 mg), phenol (21.1 mg), and pottassium carbonate (31.0 mg) in N,N-dimethylformamide was stirred for 2.5 hours at room temperature. The mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with water, saturated sodium bicarbonate, and brine, dried over 20 magnesium sulfate, and evaporated to give ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2 (phenoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow gum (77.5 mg, 108%). ethyl 5-[ 4

-(

3 -cyanophenyl)-7-ethyl-2-(phenoxymethyl)pyrrolo[1,2-b]pyridazin-3 25 yl]pentanoate 'H-NMR (CDCl 3 ) 5 1.21 (3H, t, J = 7 Hz), 1.35-1.53 (7H, m), 2.07 (2H, in), 2.54 (2H, m), 3.03 (2H, q, J = 7 Hz), 4.05 (2H, q, J = 7 Hz), 5.24 (2H, s), 5.86 (1H, d, J = 5 Hz), 6.65 (1H, d, J = 5 Hz), 6.80-7.01 (3H, m), 7.03 (2H, d, J = 9 Hz), 7.32 (2H, t, J = 9 Hz), 7.55-7.63 (2H, m), 7.67 (1H, s), 7.76 (1H, m). 30 MS (ESI*): m/z 482 (M + H) Example 614 A mixture of 4

-(

3 -cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2 319 WO 2004/063197 PCT/JP2003/017091 b]pyridazin-2-yl trifluoromethanesulfonate (50.0 mg), 3-furylboronic acid (23.6 mg), dichlorobis(triphenylphosphine)palladium (3.71 mg), and 2 N sodium carbonate (44.8 mg in 0.2 mL of water) in dioxane was stirred for 20 minutes at 859C. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried, 5 and evaporated. Preparative thin layer chromatography (EtOAc-hexane = 1-1) afforded 3-[7-ethyl-2-(2-furyl)-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile as an orange solid (11.5 mg). 3-[7-ethyl-2-(2-furyl)-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile 10 'H-NMR (CDCl 3 ) 8 1.40 (3H, t, J = 7 Hz), 3.10 (2H, q, J = 7 Hz), 3.20 (3H, s), 6.30 (1H, d, J = 5 Hz), 6.63 (1H, m), 6.87 (1H, d, J = 5 Hz), 6.95 (1H, m), 7.60-7.73 (4H, m), 8.79 (1H, m). Example 615 15 To a solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid(100 mg) in tetrahydrofurane (1 mL) was added I M borane tetrahydrofurane comples (0.708 mL,) in an ice bath under a nitrogen atmosphere. The mixture was stirred for 4 hours in the bath and 1 hour at room temperature. The reaction was quenched by adding 1 N hydrochloric acid (1 mL). The mixture was partitioned 20 between EtOAc (10 mL) and 1 N hydrochloric acid (5 mL). The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated. Preparative thin layer chromatography eluting with acetone-hexane = 1-2 afforded 3-[7-ethyl-3-(5 hydroxypentyl)-2-phenylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile as an yellow gum (104 mg). 25 3-[7-ethyl-3-(5-hydroxypentyl)-2-phenylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile 'H-NMR (CDCl 3 ) 8 0.98-1.17 (6H, m), 1.36 (3H, t, J = 7 Hz), 2.38 (2H, m), 2.58 (2H, m), 3.34 (2H, m), 5.89 (1H, d, J = 5 Hz), 6.62 (1H, d, J = 5 Hz), 7.45-7.53 (5H, m), 7.55-7.67 (4H, m). 30 MS (ESI+): m/z 410 (M + H) The following compound(s) was(were) obtained in a similar manner to that of Preparation 24. 320 WO 2004/063197 PCT/JP2003/017091 Preparation 343 ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-4-methoxy-3-oxobutanoate 'H NMR (CDC 3 ) 8 0.96-1.10 (3H, m), 3.23 (1.5H, s), 3.49 (1.5H, s), 4.00-4.34 (4H, m), 4.57 (1H, s), 8.00 (0.5H, br s), 8.23 (0.511, br s), 8.60-8.91 (2H, m). 5 Preparation 344 1-tert-butyl 8-ethyl 2 -acetyl- 2

-[(

6 -cyano-3-pyridinyl)carbonyl]octanedioate 'H NMR (CDC 3 ) 8 1.22-1.46 (16H, m), 1.55-1.70 (2H, m), 2.17-2.34 (4H, m), 2.48 (3H, s), 4.14 (2H, q, J = 8 Hz), 7.77 (11H, br d, J = 8 Hz), 8.17 (1H, dd, J = 8, 2 10 Hz), 8.97(1H, d, J = 2Hz). The following compound(s) was(were) obtained in a similar manner to that of Preparation 78. Preparation 345 15 ethyl 7-[(6-cyano-3-pyridinyl)carbonyl]-8-oxononanoate 'H NMR (CDCl 3 ) 6 1.20-1.45 (7H, m), 1.52-1.70 (2H, m), 1.92-2.14 (2H, m), 2.17 2.39 (5H, m), 4.11 (211, q, J = 8 Hz), 4.40 (1H, t, J = 8 Hz), 7.84 (1H, br d, J = 8 Hz), 8.39 (1H, m), 9.23 (1H, br s). 20 The following compound(s) was(were) obtained in a similar manner to that of Preparation 130. Preparation 346 ethyl 4-methoxy-3-oxobutanoate 'H NMR (CDCl 3 ) 8 1.28 (3H, t, J = 8 Hz), 3.42 (3H, s), 3.51 (2H, s), 4.09 (2H, s), 25 4.20 (2H, q, J = 8 Hz). The following compound(s) was(were) obtained in a similar manner to that of Preparation 338. Preparation 347 30 benzyl 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-5-bromobenzoate 'H-NMR (CDC 3 ) 6 1.28 (3H, t, J = 7 Hz), 2.75 (2H, q, J = 7Hz), 5.37 (2H, s), 5.73 (2H, s), 5.94 (1H, d, J = 5 Hz), 6.66 (1H, d, J = 5 Hz), 7.35-7.48 (5H, m), 7.99 (1H, s), 8.33 (1H, s), 8.38 (1H, s). 321 WO 2004/063197 PCT/JP2003/017091 The following compound(s) was(were) obtained in a similar manner to that of Preparation 321. Preparation 348 5 benzyl 3-bromo-5-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate 'H-NMR (CDCl 3 ) 8 1.29 (311, t, J = 7 Hz), 2.72 (211, q, J = 7 Hz), 5.37 (2H, s), 6.09 (1H, m), 6.78 (1H, m), 7.33-7.45 (5H, m), 8.15 (11H, s), 8.33 (111, s), 8.45 (1H, s). 10 The following compound(s) was(were) obtained in a similar manner to that of Preparation 310. Preparation 349 benzyl 3 -bromo-5-(chlorocarbonyl)benzoate 15 Preparation 350 To a solution of benzyl 3-bromo-5-iodobenzoate (1.00 g) in THF (10 mL) was added 0.76 M isopropyl magnesium bromide (3.16 mL) in an ice bath under a nitrogen atmosphere. After stirring for 0.5 hour, the mixture was poured onto dryice. The mixture was warmed to room temperature over 1 hour. The mixture was partitioned between 20 . EtOAc and 1 N HCL. The organic layer was washed with brine, dried over MgSO 4 , and evaporated. Flash silicagel column chromatography (chloroform-methanol = 50-0 to 50 2) afforded 3 -benzyloxycarbonyl-5-bromobenzoic acid as a white solid (273 mg). 3 -[(benzyloxy)carbonyl]-5-bromobenzoic acid 25 'H-NMR (DMSO-d 6 ) 8 5.39 (2H, s), 7.30-7.52 (51, m), 8.29 (2H, s), 8.43 (1H, s). Preparation 351 A mixture of 3-bromo-5-iodobenzoic aicd (5.00 g) and N,N-dimethylformamide (0.059 mL) in dichloromethane (50 mL) was added oxalyl chloride (1.47 mL) in an ice 30 bath under a nitrogen atmosphere. After stirring for 1 hour, the volatile was evaporated off. The residue was dissolved in dichloromethane (50 mL), and to the solution was added bensyl alcohol (1.82 g) followe by triethyl amine (3.2 mL) in the ice bath. The mixture was stirred for 2 hours at room temperature. The mixture was partitioned 322 WO 2004/063197 PCT/JP2003/017091 between EtOAc and water. The organic layer was washed with water (two times), satd. NaHCO 3 , and brine, dried over MgSO 4 and evaporated. Flash silicagel column hromatography (EtOAc-hexanes = 1/200 to 20/200) afforded benzyl 3-bromo-5 iodobenzoate as white crystals (5.95 g). 5 benzyl 3 -bromo-5-iodobenzoate 'H-NMR (CDC 3 ) 8 5.35 (3H, s), 7.35-7.68 (5H, m), 8.04 (1H, s), 8.16 (1H, m), 8.30 (1H, s). 10 The following compound(s) was(were) obtained in a similar manner to that of Example 1. Example 615 benzyl 3-bromo-5-[7-ethyl-2-methyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4 yl]benzoate 15 2 H-NMR (CDC 3 ) 8 1.38 (3H, t, J = 7 Hz), 2.88 (3H, s), 3.05 (3H, s), 3.06 (211, q, J = 7 Hz), 5.35 (2H, s), 6.15 (1H, d, J = 5 Hz), 6.72 (1H, d, J = 5 Hz), 7.33-7.45 (5H, m), 7.68 (111, m), 7.94 (1H, m), 8.28 (111, m). Example 616 20 4

-(

3 -cyanophenyl)-7-ethyl-2-phenylpyrrolo[1, 2 -b]pyridazine-3-carbonitrile 'H NMR (CDC 3 ) 8 1.42 (3H, t, J = 8 Hz), 3.12 (2H, q, J = 8 Hz), 6.60 (111, d, J = 5 Hz), 6.92 (1H, d, J = 5 Hz), 7.50-7.58 (3H, m), 7.73 (1H, t, J = 8 Hz), 7.82-7.91 (3H, m), 7.93-8.01 (2H, m). 25 Example 617 2 -tert-butyl-4-(3-chlorophenyl)-7-ethylpyrrolo[1, 2 -b]pyridazine-3-carbonitrile H NMR (CDCl 3 ) 8 1.38 (3H, t, J = 8 Hz), 1.60 (9H, s), 3.05 (2H, q, J = 8 Hz), 6.48 (1H, d, J = 5 Hz), 6.77 (111, d, J = 5 Hz), 7.45-7.54 (3H, m), 7.60 (111, br s). 30 The following compound(s) was(were) obtained in a similar manner to that of Preparation 78. Example 618 ethyl 6

-[

4

-(

6 -cyano- 3 -pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate 323 WO 2004/063197 PCT/JP2003/017091 'H NMR (CDC 3 ) 8 1.15-1.64 (12H, m), 2.21 (1H, t, J = 8 Hz), 2.32-2.44 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J = 8 Hz), 4.10 (2H, q, J =8 Hz), 5.79 (1H, d, J = 5 Hz), 6.54 (11-1, d, J = 5 Hz), 7.85 (1H, br s), 8.30 (1H, br d, J = 8 Hz), 8.72 (1H, br s). MS (ESI*): m/z 405 (M + H). 5 The following compound(s) was(were) obtained in a similar manner to that of Example 21. Example 619 ethyl 4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazine-3 10 carboxylate 'H NMR (CDCl 3 ) 8 1.04 (3H, t, J = 8 Hz), 1.38 (3H, t, J = 8 Hz), 3.06 (21H, q, J = 8 Hz), 3.39 (3H, s), 4.10 (2H, q, J = 8 Hz), 4.76 (2H, s), 6.33 (114, d, J = 5 Hz), 6.74 (114, d, J = 5 Hz), 7.96 (1H, br s), 8.61 (1H, br s), 8.78 (1H, d, J = 2 Hz). MS (ESI+): m/z 418,420 (M + H). 15 The following compound(s) was(were) obtained in a similar manner to that of Example 76. Example 620 3-bromo-5-[7-ethyl-2-methyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic 20 acid 'H-NMR (CDC 3 + CD30D) 8 1.38 (3H, t, J = 7 Hz), 2.86 (3H, s), 3.05 (3H, s), 3.06 (214, q, J = 7 Hz), 6.19 (114, d, J = 5 Hz), 6.71 (1H, d, J = 5 Hz), 7.53 (1H, s), 7.90 (114, s), 8.23 (114, s). 25 Example 621

(

2

E)-

3

-[

4 -(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]acrylic acid 1H NMR (CDC 3 ) 8 1.39 (3H, t, J = 8 Hz), 3.07 (2H, q, J = 8 Hz), 3.51 (3H, s), 4.65 (2H, s), 5.96 (1H, d, J = 15 Hz), 6.27 (1H, d, J = 5 Hz), 6.74 (114, d, J = 5 Hz), 30 7.68 (114, d, J = 15 Hz), 7.93 (1H, m), 8.57 (1H, d, J = 1 Hz), 8.70 (1H, d, J = 2 Hz). MS (ESI*): m/z 416, 418 (M + H). 324 WO 2004/063197 PCT/JP2003/017091 Example 622 6-[4-(6-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoic acid 'H NMR (CDC 3 ) 8 1.15-1.69 (9H, m),1.90-2.50 (4H, m), 2.56 (311, s), 3.01 (2H, q, J = 8 Hz), 5.80 (1H, d, J = 5 Hz), 6.51 (1H, d, J = 5 Hz), 7.84 (1-, dd, J = 8, 2 Hz), 5 8.28 (1H, d, J = 8 Hz), 8.51 (1H, d, J = 2 Hz). MS (ESI'): m/z 377 (M + H). Example 622-2 6-{4-[6-(aminocarbonyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo(1,2-b]pyridazin-3 yl}hexanoic acid 10 'H NMR (CDCl 3 ) 6 1.16-1.51 (9H, m), 2.10-2.24 (2H, m), 2.35-2.47 (2H, m), 2.58 (3H, s), 3.01 (2H, q, J = 8 Hz), 5.85 (1H, d, J = 5 Hz), 6.54 (1H, d, J = 5 Hz), 7.22 (1H, br s), 7.90 (1H, dd, J = 8, 1 Hz), 8.01 (1H, br s), 8.34 (1H, d, J = 8 Hz), 8.61 (1H, d, J= 1 Hz). MS (ESI*): m/z 395 (M + H). 15 The following compound(s) was(were) obtained in a similar manner to that of Example 147. Example 623 ethyl (2E)-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2 20 b]pyridazin-3-yl]acrylate 'H NMR (CDCl 3 ) 6 1.27 (3H, t, J = 8 Hz), 1.39 (3H, t, J = 8 Hz), 3.06 (2H, q, J = 8 Hz), 3.51 (3H, s), 4.17 (2H, q, J = 8 Hz), 4.64 (2H, s), 5.97 (1H, d, J = 15 Hz), 6.24 (1H, d, J = 5 Hz), 6.73 (1H, d, J = 5 Hz), 7.51 (1H, d, J = 15 Hz), 7.91 (1H, br s), 8.57 (1H, br s), 8.70 (1H, br s). 25 MS (ESI*): m/z 444,446 (M + H). The following compound(s) was(were) obtained in a similar manner to that of Example 200. Example 624 30 [4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]methanol 'H NMR (CDCl 3 ) 8 1.38 (3H, t, J = 8 Hz), 3.05 (2H, q, J = 8 Hz), 3.45-3.55 (4H, m), 4.40 (2H, br d, J = 7 Hz), 4.77 (2H, br s), 6.22 (1H, d, J = 5 Hz), 6.70 (1H, d, J = 325 WO 2004/063197 PCT/JP2003/017091 5 Hz), 8.11 (1H, m), 8.74 (1H, br s), 8.80 (1H, d, J = 2 Hz). MS (ESI*): m/z 376, 378 (M + H). The following compound(s) was(were) obtained in a similar manner to that of 5 Example 205. Example 625 (4E)-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-4 pentenoic acid 'H NMR (CDCl 3 ) 5 1.37 (3H, t, J = 8 Hz), 2.26-2.43 (4H, m), 2.50 (3H, s), 3.01 (2H, 10 q, J = 8 Hz), 5.40 (1H, dt, J = 15, 7 Hz), 6.05 (11H, d, J = 5 Hz), 6.20 (1H, d, J = 15 Hz), 6.56 (1H, d, J = 5 Hz), 7.28 (1H, br d, J = 5 Hz), 7.39 (111, br s), 8.47 (1H, br d, J = 5 Hz). MS (ESI*): m/z 370 (M + H). 15 Example 625-2 (4Z)-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-4 pentenoic acid 1H NMR (CDCl 3 ) 5 1.39 (3H, t, J = 8 Hz), 1.87-2.00 (2H, m), 2.12 (2H, t, J = 8 Hz), 2.42 (3H, s), 3.03 (2H, q, J = 8 Hz), 5.58 (111, dt, J = 10, 8 Hz), 6.17 (1H, d, J = 5 20 Hz), 6.26 (1H, br d, J = 10 Hz), 6.60 (111, d, J = 5 Hz), 7.35 (1H, br d, J = 5 Hz), 7.44 (1H, br s), 8.48 (111, br d, J = 5 Hz). MS (ESI*): m/z 370 (M + H). The following compound(s) was(were) obtained in a similar manner to that of 25 Example 220. Example 626 4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazine-3 carboxylic acid 'H NMR (CDCl 3 ) 8 1.39 (3H, t, J = 8 Hz), 3.06 (2H, q, J = 8 Hz), 3.44 (3H, s), 4.82 30 (211, s), 6.36 (111, d, J = 5 Hz), 6.77 (11H, d, J = 5 Hz), 8.09 (1H, br s), 8.65 (1H, br s), 8.72 (111, br s). MS (ESI*): m/z 390, 392 (M + H). 326 WO 2004/063197 PCT/JP2003/017091 Example 627 4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylic acid 'H NMR (CDC 3 ) 8 1.38 (3H, t, J = 8 Hz), 2.70 (3H, s), 3.06 (2H, q, J = 8 Hz), 6.26 (1H, d, J = 5 Hz), 6.72 (1H, d, J = 5 Hz), 7.32 (1H, dd, J = 5, 1 Hz), 7.43 (1H, br 5 s), 8.50 (1H, d, J = 5 Hz). MS (ESI*): m/z 316 (M + H). The following compound(s) was(were) obtained in a similar manner to that of Example 244. 10 Example 628 4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carbaldehyde 'H NMR (CDCl 3 ) 8 1.39 (3H, t, J = 8 Hz), 2.81 (3H, s), 3.09 (2H, q, J = 8 Hz), 6.43 (1, d, J = 5 Hz), 6.78 (1, d, J = 5 Hz), 7.34 (1H, br d, J = 5 Hz), 7.46 (1, br s), 8.56 (iH, d, J = 5 Hz), 9.76 (1H, s). 15 MS (ESI*): m/z 300 (M + H). Example 629 4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazine-3 carbaldehyde 20 'H NMR (CDC 3 ) 6 1.41 (3H, t, J = 8 Hz), 3.14 (2H, q, J = 8 Hz), 3.55 (3H, s), 4.94 (2H, s), 6.50 (1H, d, J = 5 Hz), 6.84 (1H, d, J = 5 Hz), 7.95 (1H, br s), 8.12 (1H, br s), 8.84 (1, br s), 9.85 (1H, s). MS (ESI+): m/z 374, 376 (M + H). 25 Example 630 A solution of phosphorus oxychloride (241 mg, 1.57 mmol) in N,N dimethylformamide (4 mL) was stirred for 10 min at room temperature. The resulting mixture was cooled to 0*C, and a solution of ethyl 4-(4-fluorophenyl)-2 isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (428 mg, 1.31 mmol) in N,N 30 dimethylformamide (0.7 mL) was added. The resulting mixture was warmed to 50'C, and stirred for 45 min. Since the startimg material was remained, a solution of phosphorus oxychloride (621 mg, 0.67 mmol) in N,N-dimethylformamide (0.2 mL) was added, and the mixture was stirred for 15 min. The resulting mixture was poured into 327 WO 2004/063197 PCT/JP2003/017091 ice-cooled water (10 mL), and extracted with ethyl acetate (30 mL). The organic layer was washed with water and saturated sodium bicarbonate. All the aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give a blue oil. Flash silica gel 5 column chromatography eluting with ethyl acetate-hexane = 1-20 to 1-10 afforded ethyl 4

-(

4 -fluorophenyl)-7-formyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow oil, which was crystalized upon standing (360 mg, 77.5%). 'H-NMR (CDCI 3 ) 8 1.02 (3H, t, J = 7 Hz), 1.41 (6H, d, J = 7 Hz), 3.29 (1H, septet, J 10 = 7 Hz,), 4.10 (2H, q, J = 7 Hz), 6.42 (1H, d, J = 5 Hz), 7.20 (2H, t, J = 9 Hz), 7.45 - 7.51 (3H, m), 10.56 (1H ,s). MS (ESI*): m/z 355 (M + H) Example 631 15 To a solution of N,N-dimethylacetamide (80.1 mg, 0.919 mmol) in dichloroethane (1 mL) was added phosphorus oxychloride (141 mg, 0.919 mmol) in dichloroethane (0.5 mL) at 0 0 C. After stirring for 0.5 h, a solution of ethyl 4-(4-fluorophenyl)-2 isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (200 mg, 0.613 mmol) in dichloroethane(0.5 mL) was added. The resulting mixture was stirred for 3 days at room 20 temperature. The mixture was partitioned between ethyl acetate (30 mL) and water (5 mL), and the organic layer was washed with saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, and evaporated to give an orange gum. Flash silica gel column chromatography eluting with ethyl acetate-hexane = 1-20 to 1-10 afforded ethyl 7-acetyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate as 25 an yellow gum (144 mg, 63.8%). 'H-NMR (CDC 3 ) 8 1.00 (311, t, J = 7 Hz), 1.41 (611, d, J = 7 Hz), 2.88 (3H, s), 3.09 (1H, septet, J = 7 Hz), 4.09 (2H, q, J = 7 Hz), 6.40 (1H, d, J = 5 Hz), 7.19 (2H, t, J = 9 Hz), 7.46 (211, dd, J = 3 and 9 Hz), 7.57 (2H, d, J = 7 Hz). 30 MS (ESI'): m/z 369 (M + H) Example 632 A solution of ethyl 4 -(4-fluorophenyl)-7-formyl-2-isopropylpyrrolo[1,2 328 WO 2004/063197 PCT/JP2003/017091 b]pyridazine-3-carboxylate (100 mg, 0.282 mmol) and sodium borohydride (10.7 mg, 0.282 mmol) in ethanol (1 mL) was stirred for 0.5 h under an ice bath. The mixture was partitioned between ethyl acetate (10 mL) and water (5 mL), and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporateed to give 5 ethyl 4-(4-fluorophenyl)-7-hydroxymethyl-2-isopropylpyrrolo[1,2-b]pyridazine-3 carboxylate as an yellow gum (89.1 mg, 89.1%). 1 H-NMR (CDC 3 ) 8 0.97 (3H, t, J = 7 Hz), 1.37 (6H, , J = 7 Hz), 3.25-3.37 (2H, m), 4.04 (2H, q, J = 7 Hz), 5.06 (1H, d, J = 7 Hz), 6.32 (1H, d, J = 5 Hz), 6.78 (1H, d, 10 J = 5 Hz), 7.19 (2H, t, J = 9 Hz), 7.46 (2H, d, J = 4 and 9 Hz). Example 633 To a solution of ethyl 4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3 carboxylate (80.0 mg, 0.245 mmol) and N,N-dimethylaminopyridine (29.9 mg, 0.245 15 mmol) in N,N-dimethylformamide (0.5 mL) was added 3,7-dinitro-5 (trifluoromethyl)dibenzo[b,d]thiophenium trifluoromethanesulfonate (120 mg, 0.245 mmol) at -20"C. The resulting mixture was stirred for 45 min at 0 0 C and 12 h at room temperatue. Water (5 mL) and ethyl acetate (10 mL) were added, and the resulting mixture was filtered. The organic layer was washed with brine, dried over anhydrous 20 magnesium sulfate, and evaporated to give a brown gum. Flash silica gel column chromatography eluting with toluene-hexane = 1-5 to 4-5 afforded ethyl 4-(4 fluorophenyl)-2-isopropyl-7-trifluoromethylpyrrolo[1,2-b]pyridazine-3-carboxylate product as an yellow gum (46.7 mg, 48.3%). 25 'H-NMR (CDCl 3 ) 8 1.00 (3H, t, J = 7 Hz), 1.38 (6H, d, J = 7 Hz), 3.26 (1H, septet, J = 7 Hz), 4.08 (2H, q, J = 7 Hz), 6.33 (1H, d, J = 5 Hz), 7.12 (1H, d, J = 5 Hz), 7.19 (2H, t, J = 9 Hz), 7.47 (2H, d, J = 4 and 9 Hz). MS (ESI*): m/z 395 (M + H) 30 Example 634 A solution of ethyl 4-(4-fluorophenyl)-7-formyl-2-isopropylpyrrolo1,2 b]pyridazine-3-carboxylate (200 mg, 0.564 mmol), hydroxylamine hydrochloride (51.0 mg, 0.734 mmol), and sodium formate (69.1 mg, 1.02 mmol) in formic acid (2 mL) were 329 WO 2004/063197 PCT/JP2003/017091 refluxed for 2 h. The mixture was evaporated to give a green gum. The gum was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate (5 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give a green gum. Flash silica gel column chromatography eluting with 5 ethyl acetate-hexane = 1-10 to 1-8 gave ethyl 7-cyano-4-(4-fluorophenyl)-2 isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow crystal (144 mg, 72.6%). 'H-NMR (CDC 3 ) 8 1.01 (3H, t, J = 7 Hz), 1.41 (611, d, J = 7 Hz), 3.26 (1H, septet, J = 7 Hz), 4.09 (211, q, J = 7 Hz), 6.36 (1H, d, J = 5 Hz), 7.20 (2H, t, J = 9 Hz), 7.28 10 (1H,d,J=5Hz),7.47(2H,d,J =4and9Hz). MS (ESI*): m/z 398 (M + HCOOH + H) Example 635 A solution of ethyl 7-cyano-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2 15 b]pyridazine-3-carboxylate (70.4 mg, 0.200 mmol) in sulfuric acid (1 mL) was stirred for 50 min at 70'C. The solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give a brown gum. Preparative silica gel thin layer chromatography eluting with ethyl acetate-hexane = 1-1 afforded ethyl 7-aminocarbonyl-4-(4-fluorophenyl)- 2 20 isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate as an orange solid (5.2 mg, 7.0%). 'H-NMR (CDC1 3 ) 8 0.99 (3H, t, J = 7 Hz), 1.41 (6H, d, J = 7 Hz), 3.41 (1H, septet, J = 7 Hz), 4.08 (211, q, J = 7 Hz), 5.93 (111, br s), 6.46 (111, d, J = 5 Hz), 7.45 (2H, t, J = 9 Hz), 7.28 (1H, d, J = 5 Hz), 8.90 (1H, br s). 25 Example 636 To a mixture of ethyl 4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3 carboxylate (100 mg, 0.306 mmol) and ammonium thiocyanate (28.0 mg, 0.368 mmol) in methanol (100 mL) was added cerium ammonium nitrate (386 mg, 0.705 mmol) under an 30 ice bath. The mixture was stirred for 30 min. The mixture was stirred for additional 10 min after adding ammonium thiocyanate (8.2 mg, 0.107 mmol). Water (5 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give a 330 WO 2004/063197 PCT/JP2003/017091 deep green gum. Flash silica gel column chromatography eluting with ethyl acetate hexane = 1-10 to 3-20 afforded ethyl ethyl 4-(4-fluorophenyl)-2-isopropyl-7 thiocyanatopyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow gum (89.6 mg, 82.3%). 5 'H-NMR (CDCl 3 ) 8 1.01 (3H, t, J = 7 Hz), 1.46 (6H, d, J = 7 Hz), 3.36 (1H, septet, J = 7 Hz), 4.08 (2H, q, J = 7 Hz), 6.23 (1H, d, J = 5 Hz), 7.14-7.22 (3H, m), 7.16 (2H, t, J = 9 Hz), 7.46 (2H, dd, J = 4 and 9 Hz). Example 637 10 To a solution of ethyl 4-(4-fluorophenyl)-2-isopropyl-7-thiocyanatopyrrolo[1,2 b]pyridazine-3-carboxylate (77.7 mg, 0.219 mmol) in methanol (0.7 mL) was added 85% potassium hydroxide (0.3 mg, 0.004 mmol) at room temperature. After stirring for 5 min, the mixture was partitioned between ethyl acetate (20 mL) and water (5 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and 15 evaporated to give an yellow gum. Preparative silica gel thin layer chromatography eluting with ethyl acetate-hexane = 1-7 afforded ethyl 4-(4-fluorophenyl)-2-isopropyl-7 (methylthio)pyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow gum (35.9 mg, 44.1%). 'H-NMR (CDC 3 ) 8 0.98 (3H, t, J = 7 Hz), 1.41 (6H, d, J = 7 Hz), 2.52 (3H, s), 3.32 20 (1H, septet, J = 7 Hz), 4.05 (2H, q, J = 7 Hz), 6.35 (1H, d, J = 5 Hz), 6.89 (1H, d, J = 5 Hz), 7.16 (2H, t, J = 9 Hz), 7.44 (2H, d, J = 4 and 9 Hz). MS (ESI*): m/z 373 (M + H) The following compound(s) was(were) obtained in a similar manner to that of 25 Example 1 Example 638 3-(9-ethyl-3-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-b]cinnolin-12-yl)benzonitrile 'H NMR (CDCl 3 ) 8 1.41 (3H, t, J = 8 Hz), 2.91-3.11 (6H, m), 3.78 (3H, s), 6.09 (1H, d, J = 5 Hz), 6.38 (1H, dd, J = 8, 3 Hz), 6.52 (1H, d, J = 8 Hz), 6.59 (1H, d, J = 5 30 Hz), 6.77 (1H, br s), 7.56 (1H, t, J = 8 Hz), 7.67 (1H, br d, J = 8 Hz), 7.70-7.77 (2H, m). Example 639 331 WO 2004/063197 PCT/JP2003/017091 4-(3-ethyl-6H-indeno [1,2-e]pyrrolo [1,2-b]pyridazin-1 1 -yl)benzonitrile 'H NMR (CDCl 3 ) 8 1.43 (3H, t, J = 8 Hz), 3.09 (2H, q, J = 8 Hz), 4.11 (3H, s), 6.14 (1H, d, J = 5 Hz), 6.64 (1H, d, J = 5 Hz), 6.71 (1H, d, J = 8 Hz), 7.07 (1H, t, J = 8 Hz), 7.20-7.30 (1H, overlapped with CDC1 3 ), 7.49 (1H, d, J = 8 Hz), 7.69 (2H, d, 5 J = 8 Hz), 7.88 (2H, d, J = 8 Hz). MS (ESI*): m/z 336 (M + H). The following compound(s) was(were) obtained in a similar manner to that of Preparation 24. 10 Preparation 352 ethyl 4-methoxy-2-[(5-methyl-3-pyridinyl)carbonyl]-3-oxobutanoate 'H NMR (CDC 3 ) 8 0.97, 1.26 (3H, t, J= 7 Hz), 2.40 (3H, s), 3.24,3.35,3.49 (3H, s), 3.98-4.20 (2H, m), 4.11, 4.20, 4.54 (2H, s), 5.70 (1H, s), 7.67, 7.92, 8.02, 8.50 8.66, 8.77, 8.89 (3H, m). 15 Preparation 353 ethyl 2-[(5-chloro-3-pyridinyl)carbonyl]-4-methoxy-3-oxobutanoate 'H NMR (CDCl 3 ) 8 1.00, 1.06, 1.28, 1.35 (3H, t, J= 7 Hz), 3.23, 3.43, 3.49 (3H, s), 4.05-4.33 (2H, m), 4.56 (2H, s), 7.85, 8.05, 8.22, 8.29, 8.58-8.82, 8.85,.9.01, 9.10 20 (3H, m). The following compound(s) was(were) obtained in a similar manner to that of Preparation 176. 25 Preparation 354 tert-butyl 3-bromo-5-({1-[(cyanoacetyl)amino]-5-ethyl-1H-pyrrol-2-yl}carbonyl)benzoate 'H-NMR (CDCl 3 ) 6 1.29 (34H, t, J = 7 Hz), 1.60 (9H, s), 2.61 (2H, q, J = 7 Hz), 3.64 (2H, s), 6.00 (1H, m), 6.80 (1H, m), 8.03 (1H, m), 8.26 (1H, m), 8.28 (1H, m). 30 Preparation 355 tert-butyl 3-bromo-5-[(5-ethyl-1 -{ [(methylsulfonyl)acetyl]amino} -1 H-pyrrol-2 yl)carbonyl]benzoate 'H-NMR (CDCl 3 ) 6 1.29 (3H, t, J = 7 Hz), 1.60 (9H, s), 2.60 (2H, q, J = 7 Hz), 2.92 332 WO 2004/063197 PCT/JP2003/017091 (3H, s), 4.04 (2H, s), 6.11 (IH, m), 6.78 (111, m), 8.03 (1H, m), 8.25 (1H, m), 8.27 (1H, m). The following compound(s) was(were) obtained in a similar manner to that of 5 Preparation 153. Preparation 356 tert-butyl 3-bromo-5-(chlorocarbonyl)benzoate The following compound(s) was(were) obtained in a similar manner to that of 10 Preparation 164. Preparation 357 tert-butyl 3-bromo-5-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate 1H-NMR (CDC 3 ) 8 1.32 (3H, t, J = 7 Hz), 1.61 (9H, s), 2.74 (2H, q, J =7Hz), 6.10 (1H, m), 6.80 (1H, m), 8.13 (1H, m), 8.26 (1H, m), 8.39 (1H, m), 9.34 (1H, s, br). 15 The following compound(s) was(were) obtained in a similar manner to that of Preparation 338. Preparation 358 tert-butyl 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-5-bromobenzoate 20 'H -NMR (CDC 3 ) 8 1.29 (3H, t, J = 7 Hz), 1.61 (9H, s), 2.76 (2H, q, J = 7 Hz), 5.74 (2H, s, br), 5.93 (1H, d, J = 5 Hz), 6.63 (1H, d, J = 5 Hz), 8.05 (1H, m), 8.25 (1H, m), 8.29 (1H, m). Preparation 359 25 To a solution of tert-butyl 3-bromo-5-iodobenzoate (4.00 g) in tetrahydrofuran (30 mL) was added 0.76 M isopropylmagnesium bromide (13.7 mL) in an ice-methanol bath under a nitrogen atmosphere. After stirring for 0.5 hour, the mixture was poured onto dryice. The mixture was warmed to room temperature over 1 hour. The mixture was partitioned between EtOAc and 1 N hydrochloric acid. The organic layer was back 30 extracted with 1 N sodium hydroxide (two times). The extract was acidified by adding concentrated hydrochloric acid, and extracted with chloroform (two times). The organic extract was washed with brine, dried over MgSO4, and evaporated to give 3-bromo-5 (tert-butoxycarbonyl)benzoic acid as a pale brown solid (529 mg). 333 WO 2004/063197 PCT/JP2003/017091 3-bromo-5-(tert-butoxycarbonyl)benzoic acid 'H -NMR (DMSO-d6) 6 1.57 (9H, s), 8.21 (1H, s), 8.25 (1H, s), 8.37 (1H, s). 5 Preparation 360 To a vigirously stirred suspension of poudered MgSO 4 (7.36 g) in dichloromethane (50 mL) was added sulfuric acid (0.758 mL) at room temperature. After stirring for 15 minutes, to the mixture was added 3-bromo-5-iodobenzoic acid (5.00 g) followed by tert-butanol (7.31 mL). The mixture was stirred for 3 days at room 10 temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with satd. NaHCO 3 and brine, dried over MgSO 4 , and evaporated to give tert-butyl 3-bromo-5-iodobenzoate as pale purple crystals (4.44 g). tert-butyl 3-bromo-5-iodobenzoate 15 'H-NMR (CDC 3 ) 8 1.58 (9H, s), 8.00 (1H, m), 8.06 (1H, m), 8.22 (1H, m). Preparation 361 To a suspension of lithium (316 mg) in ether (10 mL) was added cyclopropylbromide (2.50 g) in ether (10 mL) over 20 min in a methanol-ice bath under a 20 nitrogen atmosphere. The mixture was stirred for 0.5 hour in an ice bath. The mixture was cooled in a dryice-acetone bath. To the mixture was added a solution of triisopropoxyborane (5.05 g) in tetrahydrofuran (5 mL) over 15 minutes. The mixture was alowed to warme to room temperature over 2 hours. The reaction was quenced by adding hydrochloric acid. The organic solvent was evaporated off, and the residual 25 solution was extracted with ether (30 mL, five times). The combined extract was dried over MgSO 4 , and evaporated to give a white solid (968 mg). The solid was triturated in cold hexanes to give cyclopropylboronic acid as a white powder (789 mg). cyclopropylboronic acid 30 'H-NMR (DMSO-d 6 ) 5 -0.40 (1H, m), 0.32 (2H, m), 0.39 (2H, m), 7.28 (2H, s). The following compound(s) was(were) obtained in a similar manner to that of Example 21. 334 WO 2004/063197 PCT/JP2003/017091 Example 640 ethyl 7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3 carboxylate 'H NMR (CDC 3 ) 6 0.99 (3H, t, J= 7 Hz), 1.38 (3H, t, J= 7 Hz), 2.41 (3H, s), 3.06 5 (2H, q, J= 7 Hz), 3.38 (3H, s), 4.06 (2H, q, J= 7 Hz), 4.75 (2H, s), 6.33 (1H, d, J= 4 Hz), 6.71 (1H, d, J= 4 Hz), 7.61 (1H, s), 8.52 (IH, d, J= 2 Hz), 8.54 (IH, d, J= 2 Hz). MS (ESI): m/z 354. 10 Example 641 ethyl 4 -(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazine-3 carboxylate 'H NMR (300 MHz, CDC1 3 ) 8 1.04 (3H, t, J = 7 Hz), 1.38 (3H, t, J = 7 Hz), 3.06 (2H, q, J = 7 Hz), 3.39 (3H, s), 4.09 (2H, q, J = 7 Hz), 4.76 (2H, s), 6.33 (iH, d, J = 4 15 Hz), 6.75 (1H, d, J = 4 Hz), 7.81 (1H, dd, J = 2, 2 Hz), 8.57 (1H, d, J = 2 Hz), 8.68 (1H, d, J = 2 Hz). MS (m/z) 374 (M+1). The following compound(s) was(were) obtained in a similar manner to that of 20 Example 076. Example 642

(

2

E)-

3 -[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]acrylic acid 'H NMR (CDC 3 ) 8 1.39 (3H, t, J= 7 Hz), 2.43 (3H, s), 3.07 (2H, q, J= 7 Hz), 3.51 25 (3H, s), 4.65 (2H, s), 5.97 (1H, d, J= 16 Hz), 6.27 (1H, d, J= 4 Hz), 6.71 (iH, d, J= 4 Hz), 7.61 (iH, s), 7.72 (iH, d, J= 16 Hz), 8.46 (1H, d, J= 2 Hz), 8.57 (1H, d, J= 2 Hz). MS (ESI*): m/z 352. 30 Example 643

(

2

E)-

3 -[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]acrylic acid 'H NMR (300 MHz, CDC 3 ) 6 1.39 (3H, t, J = 7 Hz), 3.07 (2H, q, J = 7 Hz), 3.51 335 WO 2004/063197 PCT/JP2003/017091 (3H, s), 4.65 (2H, s), 5.97 (iH, d, J = 16 Hz), 6.27 (1H, d, J = 4 Hz), 6.75 (1H, d, J = 4 Hz), 7.69 (1H, d, J = 16 Hz), 7.78 (1H, dd, J = 2, 2 Hz), 8.54 (1H, d, J = 2 Hz), 8.71 (1H, d, J = 2 Hz). MS (m/z) 400 (M+1). 5 Example 644 4-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoic acid 1H-NMR (CDCl 3 ) 6 0.78 (2H, m), 1.10 (2H, m), 1.37 (3H, t, J = 7 Hz), 1.73 (2H, m), 10 1.98 (1H, m), 2.23 (2H, m), 2.62 (2H, m), 3.02 (2H, q, J = 7 Hz9, 3.46 (3H, s), 4.65 (2H, q, J = 7 Hz), 5.88 (1H, d, J = 5 Hz), 6.57 (1H, d, J = 5 Hz), 7.36 (1H, m), 8.41 (1H, m), 8.47 (1H, m). Example 645 15 5-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid H-NMR (CDC 3 ) 8 0.75 (2H, m), 1.08 (2H, m), 1.37 (3H, t, J = 7 Hz), 1.40-1.57 (4H, m), 1.96 (1H, m), 2.18 (2H, m), 2.51 (2H, m), 3.02 (2H, q, J = 7 Hz), 3.45 (3H, s), 4.61 (2H, m), 5.87 (1H, d, J = 5 Hz), 6.56 (1H, d, J = 5 Hz), 7.34 (1H, m), 8.39 20 (1H, m), 8.50 (1H, m). Example 646 3-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoic acid 25 'H-NMR (DMSO-d6) 8 0.76 (2H, m) ,1.08 (2H, m), 1.37 (3H, t, J = 7 Hz), 1.95 (1H, m), 2.48 (2H, m), 2.87 (2H, m), 3.02 (2H, q, J = 7 Hz), 3.47 (3H, s), 4.66 (2H, m), 5.90 (1H, d, J = 5 Hz), 6.59 (1H, d, J = 5 Hz), 7.35 (1H, m), 8.40 (1H, m), 8.48 (1H, m). 30 Example 647 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5 oxopentanoic acid 'H NMR (CDC 3 ) 8 1.38 (3H, t, J = 8 Hz), 1.73-1.85 (2H, m), 2.26 (2H, t, J = 8 Hz), 336 WO 2004/063197 PCT/JP2003/017091 2.36 (2H, t, J = 8 Hz), 2.46 (3H, s), 3.04 (2H, q, J = 8 Hz), 6.33 (1H, d, J = 5 Hz), 6.70 (1H, d, J = 5 Hz), 7.34 (1H, br d), 7.45(1H, br s), 8.53 (1H, d, J = 6 Hz). Example 648 5 (2E)-3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo [1,2-b]pyridazin-3-yl]acrylic acid 1H NMR (CDC 3 ) 8 1.38 (3H, t, J = 8 Hz), 2.67 (3H, s), 3.05 (211, q, J = 8 Hz), 5.79 (11H, d, J = 15 Hz), 6.19 (1H, d, J = 5 Hz), 6.67 (1H, d, J = 5 Hz), 7.24-7.29 (1H, overlappled with CDCl 3 ), 7.40 (1H, br s), 7.51 (1H, d, J = 15 Hz), 8.55 (11H, d, J = 10 5 Hz). The following compound(s) was(were) obtained in a similar manner to that of Example 146. Example 649 15 ethyl (2E)-3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 yl]acrylate 'H NMR (CDCI 3 ) 5 1.27 (311, t, J = 8 Hz), 1.38 (3H, t, J = 8 Hz), 2.65 (311, s), 3.04 (2H, q, J = 8 Hz), 4.17 (211, q, J = 8 Hz), 5.76 (11H, d, J = 15 Hz), 6.16 (11H, d, J = 5 Hz), 6.65 (1H, d, J = 5 Hz), 7.24-7.29 (111, overlappled with CDCI 3 ), 7.40 (1H, 20 br s), 7.53 (11H, d, J = 15 Hz), 8.53 (11H, d, J = 5 Hz). MS (ESI'): m/z 370 (M + H). The following compound(s) was(were) obtained in a similar manner to that of Example 181. 25 Example 650 tert-butyl 3-bromo-5-(3-cyano-7-ethyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4 yl)benzoate 'H-NMR (CDC 3 ) 8 1.36 (3H, t, J = 7 Hz), 2.94 (2H, q, J = 7 Hz), 6.57 (1H, d, J = 5 Hz), 6.72 (1H, d, J = 5 Hz), 7.94 (1H, m), 8.20 (1H, m), 8.38 (1H, m). 30 Example 651 tert-butyl 3-bromo-5-[7-ethyl-3-(methylsulfonyl)-2-oxo-1,2-dihydropyrrolo[1,2 b]pyridazin-4-yl]benzoate 337 WO 2004/063197 PCT/JP2003/017091 1H-NMR (CDC 3 ) 5 1.35 (3H, t, J= 7 Hz), 3.02 (2H, q, J = 7 Hz), 3.06 (3H, s), 6.24 (1H, d, J = 5 Hz), 6.70 (1H, d, J = 5 Hz), 7.23 (1H, m), 7.94 (1H, m), 8.25 (1H, m). 5 The following compound(s) was(were) obtained in a similar manner to that of Example 183. Example 652 tert-butyl 3-bromo-5-(3-cyano-7-ethyl-2-{ [(trifluoromethyl)sulfonylloxy}pyrrolo[1,2 b]pyridazin-4-yl)benzoate 10 1H-NMR (CDCl 3 ) 5 1.39 (3H, t, J = 7 Hz), 1.61 (9H, s), 3.02 (2H, q, J = 7 Hz), 6.81 (1H, d, J = 5 Hz), 700 (1H, d, J = 5 Hz), 7.96 (1H, m), 8.21 (1H, m), 8.33 (1H, m). Example 653 tert-butyl 3-bromo-5-(7-ethyl-3-(methylsulfonyl)-2 15 {[(trifluoromethyl)sulfonyl]oxy}pyrrolo[1,2-b]pyridazin-4-yl)benzoate 1H-NMR (CDC 3 ) 5 1.38 (3H, t, J = 7 Hz), 1.59 (9H, s), 3.01 (2H, q, J = 7 Hz), 3.22 (3H, s), 6.46 (1H, d, J = 5 Hz), 7.12 (1H, d, J = 5 Hz), 7.67 (1H, m), 7.90 (1H, m), 8.23 (1H, m). 20 The following compound(s) was(were) obtained in a similar manner to that of Example 184. Example 654 tert-butyl 3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4 yl]benzoate 25 'H-NMR (CDCl 3 ) 5 1.35 (3H, t, J = 7 Hz), 1.60 (9H, s), 2.01 (4H, m), 2.93 (2H, q, J = 7 Hz), 3.73 (4H, m), 6.32 (IH, d, J = 5 Hz), 6.58 (1H, d, J = 7 Hz), 7.86 (1H, m), 8.12 (1H, m), 8.24 (1H, m). Example 655 30 tert-butyl 3-bromo-5-[7-ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2 b]pyridazin-4-yl]benzoate 1H -NMR (CDC 3 ) 5 1.37 (3H, t, J = 7 Hz), 1.58 (9H, s), 1.99 (4H, m), 2.98 (2H, q, J = 7 Hz), 3.21 (3H, s), 3.52 (4H, m), 6.30 (1H, d, J = 5 Hz), 6.66 (1H, d, J = 5 Hz), 338 WO 2004/063197 PCT/JP2003/017091 7.76 (1H, m), 8.00 (1H, m), 8.19 (1H, m). The following compound(s) was(were) obtained in a similar manner to that of Example 147. 5 Example 656 ethyl (2E)-3-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2 b]pyridazin-3-yl] acryl ate 'H NMR (300 MHz, CDC 3 ) 8 1.27 (3H, t, J = 7 Hz), 1.39 (3H, t, J = 7 Hz), 3.07 (2H, q, J = 7 Hz), 3.51 (3H, s), 4.18 (2H, q, J = 7 Hz), 4.64 (2H, s), 5.97 (1H, d, J = 16 10 Hz), 6.24 (1H, d, J = 4 Hz), 6.72 (1H, d, J = 4 Hz), 7.61 (1H, d, J = 16 Hz), 7.76 (1H, dd, J = 2,2 Hz), 8.54 (1H, d, J = 2 Hz), 8.68 (1H, d, J = 2Hz). The following compound(s) was(were) obtained in a similar manner to that of Example 205. 15 Example 657 (4E)-5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]-4-pentenoic acid 'H NMR (300 MHz, CDCl 3 ) 8 1.38 (3H, t, J = 7 Hz), 2.25-2.41 (4H, m), 3.05 (2H, q, J = 7 Hz), 3.50 (3H, s), 4.57 (2H, s), 5.53 (1H, dd, J = 16, 7 Hz), 6.13 (1H, d, J = 20 4 Hz), 6.36 (1H, d, J = 16 Hz), 6.65 (1H, d, J = 4 Hz), 7.80 (1H, s), 8.54 (1H, br s), 8.62 (1H, br s). MS (m/z) 400 (M+1). The following compound(s) was(were) obtained in a similar manner to that of 25 Preparation 153. Example 658 4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carbonyl chloride The following compound(s) was(were) obtained in a similar manner to that of 30 Example 244. Example 659 7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3 carbaldehyde 339 WO 2004/063197 PCT/JP2003/017091 'H NMR (CDCI 3 ) 8 1.40 (3H, t, J= 7 Hz), 2.45 (3H, s), 3.12 (2H, q, J= 7 Hz), 3.56 (3H, s), 4.96 (2H, s), 6.51 (1H, d, J= 4 Hz), 6.80 (1H, d, J= 4 Hz), 7.62 (1H, s), 8.54 (1H, s), 8.61 (1H, s), 9.79 (1H, s). MS (ESI'): m/z 310. 5 Example 660 4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazine-3 carbaldehyde 'H NMR (300 MHz, CDC 3 ) 6 1.41 (3H, t, J = 7 Hz), 3.12 (2H, q, J = 7 Hz), 3.54 10 (3H, s), 4.94 (2H, s), 6.50 (1H, d, J = 4 Hz), 6.84 (1H, d, J = 4 Hz), 7.81 (1H, dd, J = 2,2 Hz), 8.59 (1H, d, J = 2 Hz), 8.74 (1H, d, J = 2 Hz), 9.85 (1H, s). The following compound(s) was(were) obtained in a similar manner to that of Example 533. 15 Example 661 [7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]methanol 'H NMR (CDCl 3 ) 8 1.38 (3H, t, J= 7 Hz), 2.43 (3H, s), 3.05 (2H, q, J= 7 Hz), 3.52 (3H, s), 4.37-4.51 (2H, br), 4.66-4.78 (2H, br), 6.20 (1H, d, J= 4 Hz), 6.67 (1H, d, 20 J= 4 Hz), 7.75 (1H, s), 8.54 (1H, s), 8.60 (1H, s). MS (ESI*): m/z 312. Example 662 [4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 25 yllmethanol 'H NMR (300 MHz, CDC 3 ) 8 1.38 (3H, t, J = 7 Hz), 3.05 (2H, q, J = 7 Hz), 3.53 (3H, s), 4.41 (2H, d, J = 6 Hz), 4.77 (2H, s), 6.22 (1H, d, J = 4 Hz), 6.70 (1H, d, J = 4 Hz), 7.97 (1H, dd, J = 2, 2 Hz), 8.69-8.71 (2H, m). MS (m/z) 332 (M+1). 30 Example 663 A mixture of 7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 b]pyridazine-3-carbaldehyde (48 mg) and ethyl (triphenylphosphoranylidene)acetate 340 WO 2004/063197 PCT/JP2003/017091 (56.8 mg) in THF (3 mL) was stirred at ambient temperature for 2 hours. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (5:1 - 2:1) to give ethyl (2E)-3-[7-ethyl-2 (methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[ 1,2-b]pyridazin-3-yl] acrylate as a 5 yellow powder (30 mg). ethyl (2E)-3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2 b]pyridazin-3-yl]acrylate 'H NMR (CDCI 3 ) 8 1.26 (3H, t, J= 7 Hz), 1.39 (3H, t, J= 7 Hz), 2.42 (3H, s), 3.07 (2H, q, J= 7 Hz), 3.51 (3H, s), 4.12 (2H, q, J= 7 Hz), 4.64 (2H, s), 5.97 (1H, d, J= 10 16 Hz), 6.24 (1H, d, J= 4 Hz), 6.70 (1H, d, J= 4 Hz), 7.55 (1H, s), 7.63 (1H, d, J= 16 Hz), 8.47 (1H, d, J= 2 Hz), 8.55 (1H, d, J= 2 Hz). MS (ESI*): m/z 380. Example 664 15 To a mixture of ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2 (methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate (75.0 mg), cyclopropylboronic acid (18.2 mg), tricyclohexylphosphine (4.57 mg), and potassium phosphate (104 mg) in toluene-water (1 mL-0.2 mL) was added palladium acetate (1.83 mg). The mixture was stirred for 2 hours at 100*C. The mixture was partitioned between EtOAc and water. 20 The organic layer was washed with brine, dried over MgSO 4 , and evaporated. Preparative silicagel thin layer chtomatography (EtOAc-hexanes = 1-3) afforded ethyl 4 [4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoateas an yellow gum (60.9 mg). ethyl 4-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[l1,2 25 b]pyridazin-3-yl]butanoate 'H-NMR (CDCI 3 ) 8 0.76 (2H, m), 1.07 (2H, m), 1.20 (3H, t, J= 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.68 (2H, m), 1.96 (1H, m), 2.17 (2H, m), 2.56 (2H, m), 3.02 (2H, q, J = 7 Hz), 3.46 (3H, s), 4.03 (2H, q, J = 7 Hz), 4.65 (2H, m), 5.90 (1H, d, J = 5 Hz), 6.57 (1H, d, J = 5 Hz), 7.30 (1H, m), 8.40 (1H, m), 8.51 (1H, m). 30 The following compound(s) was(were) obtained in a similar manner to that of Example 664. Example 665 341 WO 2004/063197 PCT/JP2003/017091 ethyl 5-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2 b]pyridazin-3-yl]penltanoate 'H-NMR (CDC 3 ) 8 0.76 (2H, m), 1.08 (2H, m), 1.23 (3H, t, J = 7 Hz), 1.35-1.57 (7H, m), 1.96 (1H, m), 2.16 (2H, t, J = 7 Hz), 2.53 (2H, m), 3.03 (2H, q, J = 7 Hz), 5 3.46 (3H, s), 4.08 (2H, q, J = 7 Hz), 4.62 (2H, s), 5.89 (1H, d, J = 5 Hz), 6.56 (1H, d, J = 5 Hz), 7.29 (1H, m), 8.40 (1H, m), 8.52 (1H, m). Example 666 ethyl 3-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2 10 b]pyridazin-3-yl]propanoate 'H-NMR (CDC 3 ) 6 0.76 (2H, m), 1.08 (2H, m), 1.19 (3H, t; J = 7 Hz), 1.37 (3H, t, J = 7 Hz), 1.97 (111, m), 2.38 (2H, m), 2.85 (2H, m), 3.02 (2H, q, J = 7 Hz), 3.46 (3H, s), 4.04 (2H, q, J = 7 Hz), 4.64 (2H, s), 5.92 (1H, d, J = 5 Hz), 6.59 (1H, d, J = 5 Hz), 7.29 (1H, m), 8.40 (1H, m), 8.53 (1H, m). 15 Example 667 tert-butyl 3-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]-5 cyclopropylbenzoate 'H-NMR (CDCl 3 ) 6 0.81 (2H, m), 1.03 (2H, m), 1.35 (3H, t, J = 7 Hz), 1.59 (9H, s), 20 1.94-2.08 (5H, m), 2.94 (2H, q, J = 7 Hz), 3.68-3.77 (4H, m), 6.35 (1H, j, J = 5 Hz), 6.55 (1H, d, J = 5 Hz), 7.43 (1H, s), 7.84 (1H, s), 7.97 (1H, s). Example 668 A solution of tert-butyl 3-bromo-5-[3-cyano-7-ethyl-2-(1 25 pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoate (16.0 mg) in trifluoroacetic acid (0.5 mL) was stirred for 0.5 hour at room temperature. The reaction was quenched by adding water. The mixture was neutralized by adding NaOH (pH = 3). The mixture was extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 , and evaporated to give a greenish yellow solid. The solid was triturated in hexanes-CHCl 3 30 (2-1) to afford 3-bromo-5-[3-cyano-7-ethyl-2-(l-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4 yl]benzoic acid as an yellow powder (10.8 mg). 3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid 342 WO 2004/063197 PCT/JP2003/017091 3 H-NMR (CDC 3 + CD 3 0D) 8 1.36 (3H, t, J = 7 Hz), 2.01 (4H, m), 2.94 (2H, q, J = 7 Hz), 3.72 (4H, m), 6.36 (1H, d, J = 5 Hz), 6.60 (1H, d, J = 5 Hz), 7.92 (1H, m), 8.23 (1H, m), 8.35 (1H, m). 5 The following compound(s) was(were) obtained in a similar manner to that of Example 668. Example 669 3-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]-5-cyclopropylbenzoic acid 10 'H-NMR (CDC 3 + CD 3 OD) 6 0.81 (2H, m), 1.05 (2H, m), 1.35 (3H, t, J = 7 Hz), 2.01 (5H, m), 2.94 (2H, q, J = 7 Hz), 7.73 (4H, m), 6.37 (1H, d, J = 5 Hz), 6.57 (1H, d, J = 5 Hz), 6.98 (1H, s), 7.90 (1H, s), 8.08 (1H,s). Example 670 15 3-bromo-5-[7-ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4 yl]benzoic acid 'H-NMR (CDCl 3 + CD30D) 8 1.37 (3H, t, J = 7 Hz), 1.98 (4H, m), 2.99 (2H, q, J = 7 Hz), 320 (3H, s), 3.56 (4H, m), 6.32 (1H, d, J = 5 Hz), 6.67 (1H, d, J = 5 Hz), 7.80 (1H, m), 8.08 (1H, m), 8.30 (1H, m). 20 Example 671 To a 3-necked frask containing Zn-Cu couple was added a solution of ethyl 4 iodobutanoate (369 mg) in toluene (3 mL) and N,N-dimethylacetamide (0.2 mL) at ambient temperature under N 2 . The mixture was stirred at the temperature for 1 h and 25 then at 60'C for 3 h. A suspension of tetrakis(triphenylphosphine)palladium (44 mg) in toluene (0.5 mL) was added and stirred for 5 min. After removal of an oil bath, the mixture was cooled in an ice-water bath. To this mixture was added a solution of 4-(2 chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carbonyl chloride (212 mg) in DCM (1 mL) dropwise. After 10 min, the reaction mixture was stirred at ambient 30 temperature for 2 h. The reaction mixture was partitioned between AcOEt and H 2 0. The organic layer was washed with sat. NaHCO 3 and brine, dried over MgSO 4 , and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 80 mL) eluted with hexane-AcOEt = 10-1 and 5-1 to give ethyl 5-[4-(2-chloro-4 343 WO 2004/063197 PCT/JP2003/017091 pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5-oxopentanoate as yellow amorphous (143 mg). ethyl 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5 oxopentanoate 5 'H NMR (CDCl 3 ) 8 1.23 (3H, t, J = 8 Hz), 1.38 (3H, t, J = 8 Hz), 1.71-1.84 (21H, m), 2.17 (3H, t, J = 8 Hz), 2.32 (31H, t, J = 8 Hz), 2.46 (3H, s), 3.04 (2H, q, J = 8 Hz), 4.06 (2H, q, J = 8 Hz), 6.32 (1H, d, J = 5 Hz), 6.70 (11H, d, J = 5 Hz), 7.32 (1H, dd, J = 5, 1), 7.46 (1H, br s), 8.53 (1H, d, J = 5 Hz). 10 Example 672 To a solution of 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2 b]pyridazin-3-yl]-5-oxopentanoic acid (47 mg) in EtOH (1 mL) was added sodium borohydride (5 mg) in an ice-water bath under N 2 . After 10 min, the mixture was stirred at ambient temperature. After 1 h, another odium borohydride (5 mg) was added. After 15 2 h, the reaction mixture was partitioned between CHC 3 and H20. The aqueous layer was extracted with CHC1 3 twice. The combined organic layer was dried over MgSO 4 and evaporated in vacuo. The residue was purified by p-TLC (CHCl 3 -MeOH = 10-1) to give 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5 hydroxypentanoic acid as yellow amorphous (28 mg). 20 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5 hydroxypentanoic acid 'H NMR (CDC 3 ) 8 1.36 (3H, t, J = 8 Hz), 1.46-1.83 (311, m), 1.95 (1H, m), 2.70 (3H, br s), 3.01 (2H, q, J = 8 Hz), 4.63 (11H, m), 5.85 (11, m), 6.55 (1H, d, J = 5 Hz), 7.18-7.29 (1H, overlapped with CDCl 3 ), 7.34 (1H, d, J = 2 Hz), 8.49 (1H, d, J = 5 25 Hz). 344 P:)WPDOCS\DHT\SPECI DHT\12569331 Asilas AU Is SOPAdoc-20105/2009 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as, an acknowledgement or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. 344a

Claims

1. A compound of the formula: R1 R2 I (I) N R4 R 3 in which R' is (1) mono- or di(lower)alkylamino, (2) phenyl, (3) saturated or unsaturated 5 to 6 membered heteromonocyclic group selected from the group consisting of pyrrolidinyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, furanyl, thienyl and pyridinyl, or (4) lower alkyl optionally substituted by (i) lower alkoxy or (ii) saturated 5- or 6 membered heteromonocyclic group selected from the group consisting of piperazinyl and morpholinyl, wherein lower alkoxy is optionally substituted by cyclo(lower)alkyl or pyridinyl, R 2 is R' or -A 2 -R', wherein A2 is -(CH2)n- or -(CH=CH)m- [wherein n is an integer from 2 to 6 and m is an integer of I or 2], and R 7 is hydrogen, lower alkyl sulfonyl, carboxy, esterified carboxy or pyridinyl, R 3 is (1) phenyl optionally substituted by lower alkyl, cyclo(lower)alkyl, lower alkoxy, halogen, cyano or carbamoyl; or (2) quinolinyl; or pyridinyl substituted by lower alkyl, cyclo(lower)alkyl, lower alkoxy, carbamoyl or halogen, and R 4 is lower alkyl, provided that Ethyl 4-(4-fluorophenyl)-2-isopropyl-7-methylpyrrolo[1,2-b] pyridazine-3 -carboxylate is excluded, or a pharmaceutically acceptable salt thereof, or prodrug thereof. 345 P:\WPDOCS\DtHSPECI DHT 12569331 Astells AU Isn SOPAdoc.20105/2009

2. A compound of claim 1, wherein R' is phenyl, pyrrolyl, isooxazolyl, furanyl, thienyl, lower alkyl optionally substituted by lower alkoxy, piperazinyl or morpholinyl, wherein lower alkoxy is optionally substituted by cyclo(lower)alkyl or pyridinyl, R 2 is -(CH2)n-R , wherein n is an integer from 2 to 5, and R' is carboxy or esterified carboxy, and R 3 is (1) phenyl optionally substituted by lower alkyl, cyclo(lower)alkyl, lower alkoxy, halogen, cyano or carbamoyl; or (2) pyridinyl substituted by lower alkyl, cyclo(lower)alkyl, lower alkoxy, carbamoyl or halogen.

3. A compound of claim 1, which is (1) 3-[7-Ethyl-2-methyl-3-(4-pyridinyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile, (2) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile, (3) 4-[7-Ethyl-2-methyl-3-(methylsulfonyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile, (4) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-y]]benzamide, (5) Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate, (6) 2-{[4-(3-Chlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methyl}-1,3 propanediol, (7) 3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid, (8) 5-[7-Ethyl-2-methyl-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid, (9) 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[ 1,2-b]pyridazin-3-yl]pentanoic acid, (10) 5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid, (11) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid, (12) 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoic acid, (13) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo(1,2 b]pyridazin-3-yllpentanoic acid, (14) Ethyl (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl] 2-propenoate, (15) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3 346 P \WPDOCS\DIMlSPECI DFM1I2569331 ASAIILSI AU I SOFA doc.20/05/2009 yllhexanoic acid (16) 3-[4-(5 -bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrroIo[1 ,2-b]pyridazin-3 yl]propanoic acid, (17) 4-[4-(5 -bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo(1 ,2-b~pyridazin-3 yl]butanoic acid, (18) 5-[2-{(cyclohexylmethoxy)methyll-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo [1,2 b]pyridazin-3-yl]pentanoic acid, (19) 5-{ 7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyidinylmethoxy)methyl]pyrrolo[1 ,2 blpyridazin-3-yllpentanoic acid, (20) 4-{4-(5-chloro-3-pyridinyl)-7-ethyl-2-[4-pyridinylmethoxy)methyl]pyrroloI1 ,2 b]pyridazin-3-yl I butanoic acid, (21) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrroloii1 2 blpyridazin-3-yIlbutanoic acid, (22) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1l,2-b]pyridazin-3 yl]butanoic acid, (23) 5-[4-(5-chloro-3-pyridiny)-7-ethyl-2-(metoxymethyl)pyrrolo[1 ,2-b]pyridazin-3 yljpentanoic acid, or (24) 5-f{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylmetoxy)metyl]pyrrolo[ 1,2 blpyridazin-3-yilpentanoic acid, or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1, which is (1) Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1 ,2-b~pyridazin-3-yllpentanoate, (2) 3-[4-(3-Ghloropheny)-7-ethyl-2-pheny-pyrolo[1 ,2-b]pyridaziri-3-yllpropafloic acid, (3) 5-[4-(2-Ciiloro-4-pyridinyl)-7-ethyl-2-methylpyrroloI I,2-b]pyridazin-3-yI~pentanoic acid, (4) 5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1 ,2-blpyridazin-3 yllpentanoic acid, (5) 5-[4-(5-B romo-3-pyridinyl)-7-ethyl-2-(methoxymethy)pyrrolo[1 ,2-bjpyridazin-3 yl]pentanoic acid, (6) 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyidinyl)pyToJo[I ,2-b]pyridazin-3 yljpropanoic acid, (7) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[ 1,2 347 P.\WPDOCS\DImSPECI DIM12569331 Astclas AU t SOPA do-20/05/2009 b]pyridazin-3-yl]pentanoic acid, (8) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpYrrolo[1,2-b]pyridazin-3 yl}hexanoic acid, (9) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]propanoic acid, (10) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(1ethoxymethyl)pyrrolo 1,2-b]pyridazin-3 yl]butanoic acid, (11) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl- 3 -pyridinyl)pyrrolo[1,2 b]pyridazin-3-yl]pentanoic acid, (12) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2 b]pyridazin-3-yl}pentanoic acid, (13) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2.-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]butanoic acid, or (14) 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3 yl]pentanoic acid, or a pharmaceutically acceptable salt thereof

5. A process for preparing a compound of claim 1 comprising (1) the reaction of a compound (II) of general formula NH 2 0 R 4 NR 3 [wherein R 3 and R 4 are as defined in claim I] or a salt thereof with a compound (111) of general formula 0 R 1 R2 [wherein R' and R 2 are as defined in claim 1] or a salt thereof to obtain a compound (I) of general formula 348 P:\WPDOCS\DHTlSPECI Dim12569331 Astela AU t SOPAdoc.-20/05/2009 R 1 R2 N R 4 R 3 [wherein R', R 2 , R 3 and R 4 are as defined in claim 1] or a salt thereof, or (2) the reaction of a compound (V) of general formula NH 2 N R 4 [wherein R 4 is as defined in claim 1] or a salt thereof with a compound (VI) of general formula R1 R2 0 0 R3 [wherein R', R 2 and R 3 are as defined in claim I] or a salt thereof to obtain a compound (I) of general formula R 1 R2 N/ I I N R 4 R 3 [wherein R', R 2 , R 3 and R 4 are as defined in claim 1] or a salt thereof.

6. A pharmaceutical composition which comprises, as an active ingredient, a compound of any one of Claims I to 4 in admixture with pharmaceutically acceptable carriers. 349 P \WPDOCS\DIfT\SPFCI DHT\12569331 AsteIla AU Ist SOPA doc-20/05/2009

7. A pharmaceutical composition of claim 6, for inhibiting phosphodiesterase TV (PDE-IV) enzyme activity and/or inhibiting the production of tumor necrosis factor (TNF).

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

9. A pharmaceutical composition of claim 6, 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 and viral infection.

10. 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 any one of Claims I to 4.

11. 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 or viral infection, comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound of any one of Claims 1 to 4.

12. A use of a compound of any one of Claims I to 4 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. 350