CN100349895C - Pyrrolopyridazine derivatives - Google Patents
Pyrrolopyridazine derivatives Download PDFInfo
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- CN100349895C CN100349895C CNB2003801101353A CN200380110135A CN100349895C CN 100349895 C CN100349895 C CN 100349895C CN B2003801101353 A CNB2003801101353 A CN B2003801101353A CN 200380110135 A CN200380110135 A CN 200380110135A CN 100349895 C CN100349895 C CN 100349895C
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Abstract
The invention relates to compound of the formula (I) or its salt, in which R<1>, R<2>, R<3 >and R<4 >are as defined in the description, their use of as medicament, the process for their preparation and use for the treatment of PDE-IV or TNF-alpha mediated diseases.
Description
Technical field
The present invention relates to suppress new pyrrole and the pyridazine derivatives and the pharmacologically acceptable salt thereof of phosphodiesterase IN (PDE IV) enzymic activity and tumor necrosis factor-alpha (TNF-α) generation.
Background technology
Known ring gland glycosides phosplate (adenosine 3 ', 5 '-the ring phosplate, " cAMP " or " ring AMP ") as intracellular second messenger, it is the media of first messenger's (hormone, neurotransmitter or increta) and cellular response.The first messenger stimulates the enzyme of being responsible for synthetic cAMP, and cAMP gets involved many functions then, as metabolism, contraction or secretion.When cAMP specific cyclic nucleotide phosphodiesterase, particularly phosphodiesterase-4 (PDE4 or PDE-IV) were decomposed, the effect of cAMP stopped.PDE-IV finds in many tissues, comprises central nervous system, heart, vascular smooth muscle, tracheal smooth muscle, spinal cord line, lymph etc.Use the PDE-IV inhibitor will produce beneficial effect to the incorrect activity of tracheal smooth muscle and multiple inflammatory cell to the evaluation of cAMP level.
The subject matter of using the PDE-IV inhibitor to relate to is the vomiting side effect, and it is observed in some candidate compounds, as people such as C.Burnouf described in (Ann.Rep.InMed.Chem., 33:91-109 (1998)).Burnouf has recorded and narrated the extensive difference of the seriousness of the adverse side effect that all cpds demonstrates.
Some have PDE-IV, and to suppress active condensed heterocyclic derivates be known, for example in WO03/016279, WO03/018579, WO03/000679 etc.But, still need to have the new compound of the inhibition PDE-IV of minimal side effect.Though some Pyrrolopyridazine compounds with hydroxymethyl glutaryl (HMG) CoA reductase active are known, for example in WO91/18903, having PDE-IV, to suppress active Pyrrolopyridazine compound be unknown.
Disclosure of the present invention
The present invention relates to new pyrrole and pyridazine derivatives.
Compound of the present invention suppresses cAMP phosphodiesterase enzyme, particularly phosphodiesterase-4 enzyme, and suppresses the generation of tumor necrosis factor-alpha (TNF-α), seroglycoid.
Therefore, an object of the present invention is to provide and have strong phosphodiesterase-4 (PDE IV) suppresses active and the generation of tumour necrosis factor (TNF) is had strongly inhibited active new and useful Pyrrolopyridazine compound and pharmacologically acceptable salt thereof.
Another object of the present invention provides the method that is used to prepare this Pyrrolopyridazine compound and salt thereof.
Further purpose of the present invention provides the pharmaceutical composition that comprises described Pyrrolopyridazine compound or its pharmacologically acceptable salt.
Further purpose of the present invention provides described Pyrrolopyridazine compound or its pharmacologically acceptable salt purposes as medicine, described medicine is used for preventing and treating the PDE-IV and the TNF adjusting disease of humans and animals, brings out organ damage etc. as chronic inflammatory diseases, specific autoimmune disease, septicemia.
Target Pyrrolopyridazine compound of the present invention is new, and can be represented by following general formula (I):
Wherein
R
1Be (1) carboxyl or protection carboxyl,
(2)-CONR
5R
6，
(3) hydroxyl or lower alkoxy,
(4) amino, optional ring (rudimentary) alkylamino that replaces by lower alkoxy or single-or two (rudimentary) alkylamino,
(5) three halogen (rudimentary) alkyl,
(6) three halogen (rudimentary) alkyl sulphonyl oxygen base or arlysulfonylaminos,
(7) replace or do not replace low alkyl group,
(8) replace or do not replace lower aryl, or
(9) replace or do not replace rudimentary heterocyclic group,
R
2Be R
7Or-(A
1) p-X-A
2-R
7,
Wherein
P is 0 or 1 integer;
A
1Be (C
1-C
2) alkylidene group or-CH=CH-;
A
2Be-(CH
2) n-or-(CH=CH) m-[wherein n can be 1 to 3 integer for 1 to 6 integer and m];
X be singly-bound ,-O-,-NR
8,-C (=O)-,-C (=NR
9)-or hydroxyl (C
1-C
2) alkylidene group [R wherein
8Be hydrogen or low alkyl group, and R
9Be to replace or the unsubstituted N of containing heterocyclic group]; And
R
7Be
(1) hydrogen,
(2) replacement or unsubstituting aromatic yl,
(3) replace or do not replace rudimentary heterocyclic group,
(4) carboxyl, protection carboxyl or CONR
10R
11,
(5) acyl group or halo carbonyl,
(6) cyano group,
(7) amino, protection is amino or single-or two (rudimentary) alkylamino,
(8) hydroxyl, aryloxy, acyloxy or the optional lower alkoxy that replaces by hydroxyl or acyloxy,
(9) lower alkylthio, low alkyl group sulfinyl or low alkyl group alkylsulfonyl, or
(10)-O-R
12，
Or
R
1And R
2Be combined together to form low-grade alkylidene or rudimentary alkylene group group, optional interrupt and optionally condense with phenyl ring by amino or alkylsulfonyl, and optional by low alkyl group, hydroxyl, oxo and lower alkoxy replacement,
R
3Be to replace or unsubstituting aromatic yl, or replacement or unsubstituting heterocycle group,
R
4Be hydrogen, halogen, cyano group, formamyl, acyl group, thiocyano, lower alkylthio, low-grade alkenyl, hydroxyl (rudimentary) alkyl, three halogen (rudimentary) alkyl or low alkyl group,
R
5, R
6, R
10And R
11Represent independently of one another hydrogen, low alkyl group alkylsulfonyl, heterocyclic group or optional by hydroxyl, alkoxyl group, sulfo group, carboxyl or protection carboxyl or-R
17The low alkyl group that replaces,
Or selectively, R
5With R
6Or R
10With R
11Represent to contain the N heterocyclic group with the nitrogen-atoms that they were keyed to, and
R
12And R
17Independently of one another for derived from the protection of therefrom removing hydroxyl or the group of protection sugar, or its pharmacologically acceptable salt, or its prodrug.
The suitable pharmacologically acceptable salt of target compound (I) is conventional non-toxic salt, and can comprise alkali or acid salt, as with the salt of mineral alkali, for example an alkali metal salt (as sodium salt, sylvite etc.), alkaline earth salt (as calcium salt, magnesium salts etc.), ammonium salt; With the salt of organic bases, organic amine salt (as triethylamine salt, pyridinium salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexyl amine salt, N, N '-diphenyl-methyl ethylene amine salt etc.) for example; Inorganic acid addition salt (example hydrochloric acid salt, hydrobromate, vitriol, phosphoric acid salt etc.); Organic carboxyl acid or sulfonic acid addition salt (as formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, mesylate, benzene sulfonate, tosylate etc.); Salt (as arginic acid salt, aspartate, glutaminate etc.) with alkalescence or acidic amino acid.
" prodrug " expression has can chemistry or the derivative of the target compound (I) of metabolic degradation group, and it has pharmaceutical activity after chemistry or bio-transformation.
The preferred embodiment of target compound (I) is as follows:
Wherein
R
1Be (1) carboxyl or esterifying carboxyl group (more preferably ethoxy carbonyl),
(2)-CONR
5R
6[R wherein
5And R
6Represent low alkyl group independently of one another, or selectively, R
5And R
6Represent to contain saturated 5 yuan or 6 yuan of heteromonocyclic group groups of 1 to 2 nitrogen-atoms with the nitrogen-atoms that they were keyed to.] (more preferably dimethylamino formyl radical or 1-pyrrolidyl carbonyl),
(3) hydroxyl or lower alkoxy,
(4) amino, optional ring (rudimentary) alkylamino that replaces by lower alkoxy or single-or two (rudimentary) alkylamino,
(5) three halogen (rudimentary) alkyl,
(6) three halogen (rudimentary) alkyl sulphonyl oxygen base or arlysulfonylaminos,
(7) the optional low alkyl group that replaces by following group: (i) halogen; (ii) carboxyl; (iii) protect carboxyl; (iv) cyano group; (v) formamyl; (vi)-OCONR
15R
16[R wherein
15And R
16Represent hydrogen, aryl or the optional low alkyl group that replaces by aryl independently of one another, or R
15And R
16Represent to contain 1 to 2 nitrogen-atoms and also optional saturated 5 yuan or 6 yuan of heteromonocyclic group groups that contain Sauerstoffatom with the nitrogen-atoms that they were keyed to.] (more preferably dimethylamino formyl radical oxygen base, methyl-phenyl amino methanoyl, morpholinyl carbonyl oxygen base or pyrrolidyl ketonic oxygen base); (vii) lower alkylthio; (viii) low alkyl group alkylsulfonyl; (ix) low alkyl group alkylsulfonyl oxygen base; (x) low alkyl group sulfuryl amino; (xi) singly-or two (rudimentary) alkylamino, optional by hydroxyl, lower alkoxy, aryloxy or replacement or unsubstituting aromatic yl replacement; (xii) amino; (xiii) amide group (more preferably as the lower alkane acyl amino of kharophen, as the aroylamino of benzoyl-amido or as the heterocycle carbonylamino of pyrazinyl carbonylamino); (xiv) protection is amino, as phthalic imidine, phenmethyl amino or elementary alkoxy carbonyl amino; (xv) hydroxyl; (xvi) the acyloxy lower alkane acyloxy of acetoxyl group (more preferably as); (xvii) ring (rudimentary) alkoxyl group; (xviii) aryloxy; (xix) replacement or unsubstituting aromatic yl (more preferably phenyl); (xx) contain 1 to 3 nitrogen-atoms and also optional saturated or unsaturated 5 yuan or the 6 yuan of heteromonocyclic group groups that contains Sauerstoffatom or sulphur atom (more preferably piperazinyl, morpholinyl, _ oxazolidinyl, thio-morpholinyl, piperidyl, pyrrolidyl or triazolyl), optionally replace by low alkyl group, hydroxyl (rudimentary) alkyl, aryl or oxo; Or (xxi) lower alkoxy; optional by following group replacement: carboxyl, protection carboxyl, hydroxyl, protection hydroxyl, lower alkoxy, ring (rudimentary) alkyl, replacement or unsubstituting aromatic yl (the more preferably optional phenyl that replaces by cyano group, carboxyl, protection carboxyl or formamyl), optional saturated or unsaturated 5 yuan or the 6 yuan of heteromonocyclic group groups (more preferably pyridyl, pyrazinyl or piperazinyl) that contain 1 to 2 nitrogen-atoms by the low alkyl group replacement, or-CONR
13R
14[R wherein
13And R
14Represent hydrogen or the optional low alkyl group that replaces by aryl independently of one another, or R
13And R
14Represent to contain 1 to 2 nitrogen-atoms and also optional saturated 5 yuan or 6 yuan of heteromonocyclic group groups that contain Sauerstoffatom with the nitrogen-atoms that they were keyed to.] (more preferably formamyl, methylamino formyl radical, phenmethyl formamyl or morpholinyl carbonyl),
(8) aryl (more preferably phenyl), optional by the substituting group base replacement that is selected from halogen, or
(9) saturated or unsaturated 5 yuan or 6 yuan of heteromonocyclic group groups (more preferably pyrrolidyl, pyrryl, _ azoles base, different _ the azoles base, thiazolyl, furyl, thienyl, pyridyl) are optionally replaced by low alkyl group or halogen,
R
2Be R
7Or-(A
1) p-X-A
2-R
7
Wherein
P is 0 or 1,
A
1Be (C
1-C
2) alkylidene group or-CH=CH-;
A
2Be-(CH
2) n-or-(CH=CH) m-[wherein n can be 1 to 3 integer for 1 to 6 integer and m];
X be singly-bound ,-O-,-NR
8-,-C (=O)-,-C (=NR
9)-or hydroxyl (C
1-C
2) alkylidene group; [R wherein
8Be hydrogen or low alkyl group, and R
9Be to replace or substituted azole base not, as 2-ethyl-5-(4-fluoro benzoyl) pyrryl]
R
7Be
(1) hydrogen,
(2) aryl (more preferably phenyl), optional by the lower alkoxy replacement,
(3) contain the unsaturated heteromonocyclic group group (more preferably pyridyl) of 1 to 2 nitrogen-atoms,
(4) carboxyl, esterifying carboxyl group (more preferably elementary alkoxy carbonyl) or-CONR
10R
11[R wherein
10And R
11Represent independently of one another hydrogen, low alkyl group alkylsulfonyl, as the unsaturated heteromonocyclic group group that contains 1 to 2 nitrogen-atoms of pyridyl or optional by hydroxyl, alkoxyl group, carboxyl, protection carboxyl, sulfo group or-R
17The low alkyl group that replaces, or selectively, R
10And R
11Represent to contain 1 to 2 nitrogen-atoms and also optional saturated 5 yuan or 6 yuan of heteromonocyclic group groups that contain Sauerstoffatom with the nitrogen-atoms that they were keyed to, as morpholinyl.]，
(5) acyl group (lower alkane acyl group for example is as formyl radical or ethanoyl, and the heterocycle carbonyl, as the pyridyl carbonyl) or halo carbonyl,
(6) cyano group,
(7) amino, protection amino, as elementary alkoxy carbonyl amino, or single-or two (rudimentary) alkylamino,
(8) hydroxyl, aryloxy, acyloxy or the optional lower alkoxy that replaces by hydroxyl or acyloxy (as the lower alkane acyloxy),
(9) lower alkylthio, low alkyl group sulfinyl or low alkyl group alkylsulfonyl, or
(10)-O-R
12，
Or
R
1And R
2Be combined together to form low-grade alkylidene or rudimentary alkylene group group, optional by amino or alkylsulfonyl interruption, and optional by low alkyl group, hydroxyl, oxo and lower alkoxy replacement,
It is expressed from the next:
Can comprise following various structure:
R
3Be (1) aryl (more preferably phenyl or naphthyl), optional replace by at least a substituting group that is selected from following group: (i) halogen, (ii) carboxyl is (iii) protected carboxyl, (iv) cyano group, (v)-CONR
15R
16[R wherein
15And R
16Represent hydrogen, the optional low alkyl group that replaces by hydroxyl independently of one another], (vi) low alkyl group, (vii) ring (rudimentary) alkyl, (viii) hydroxyl (rudimentary) alkyl, (ix) lower alkoxy, (x) three halogen (rudimentary) alkyl (xi) contains unsaturated 5 yuan or 6 yuan of heteromonocyclic group groups of 1 to 2 Sauerstoffatom and 1 to 2 nitrogen-atoms, as _ the azoles base, (xii) low alkyl group alkylsulfonyl, (xiii) nitro, (xiv) sulphonamide and (xv) protection sulphonamide; Or
(2) be selected from pyridyl; pyrazinyl; _ azoles base; different _ the azoles base; furyl; thienyl; quinolyl; the heterocyclic group of benzofuryl and benzothienyl; wherein said heterocyclic group is optional to be replaced by at least a substituting group that is selected from following group: (i) low alkyl group; (ii) encircle (rudimentary) alkyl; (iii) lower alkoxy; (iv) acyl group; as the lower alkane acyl group; (it is v) amino, (vi) single-or two (rudimentary) alkylamino, (vii) protection is amino; as elementary alkoxy carbonyl amino; (viii) cyano group, (ix) carboxyl, (x) protection carboxyl; as ethoxy carbonyl or methoxycarbonyl, (xi)-CONR
15R
16[R wherein
15And R
16Represent hydrogen, the optional low alkyl group that replaces by hydroxyl independently of one another], (xii) low-grade alkenyl, optional by lower alkoxy replacement, (xiii) halogen, (xiv) lower alkylthio and (xv) hydroxyl;
R
4Be hydrogen, halogen, cyano group, formamyl, lower alkane acyl group, thiocyanate ion, lower alkylthio, low-grade alkenyl, hydroxyl (rudimentary) alkyl, three halogen (rudimentary) alkyl or low alkyl group, and
R
12And R
17Be group independently of one another derived from the protection of therefrom removing hydroxyl or unprotected sugar such as semi-lactosi,
Or its pharmacologically acceptable salt.
The compound of preferred formula (I) is wherein:
R
1Be (1) single-or two (rudimentary) alkylamino,
(2) aryl, as phenyl,
(3) contain 1 to 2 heteroatomic saturated or unsaturated 5 yuan to 6 yuan heteromonocyclic group group that are selected from nitrogen, oxygen or sulphur atom (more preferably pyrrolidyl, pyrryl, _ azoles base, different _ the azoles base, thiazolyl, furyl, thienyl, pyridyl etc.), or
(4) low alkyl group, choose wantonly by lower alkoxy or contain 1 to 2 and also choose saturated 5 yuan or 6 yuan of heteromonocyclic group groups (more preferably piperazinyl or the morpholinyl) replacement that also contains Sauerstoffatom wantonly, wherein lower alkoxy is optional is replaced by ring (rudimentary) alkyl or unsaturated 5 yuan to the 6 yuan heteromonocyclic group groups (more preferably pyridyl) that contain 1 to 2 nitrogen-atoms
R
2Be R
7Or-A
2-R
7, wherein
A
2Be-(CH
2) n-or-(CH=CH) m-[wherein n be can be 1 or 2 integer for 2 to 6 integer and m], and
R7 is hydrogen, low alkyl group alkylsulfonyl, carboxyl, protection carboxyl or unsaturated 5 yuan to the 6 yuan heteromonocyclic group groups (more preferably pyridyl) that contain 1 to 2 nitrogen-atoms,
R
3Be (1) aryl, optional by low alkyl group, ring (rudimentary) alkyl, halogen, cyano group or formamyl replacement; Or
(2) contain the unsaturated annelated heterocycles group (more preferably quinolyl) of 1 to 2 nitrogen-atoms; Or contain unsaturated 5 yuan to the 6 yuan heteromonocyclic group groups (more preferably 3-pyridyl and 4-pyridyl) of at least one nitrogen-atoms, replace by low alkyl group, ring (rudimentary) alkyl or halogen, and
R
4It is low alkyl group.
The compound of most preferred formula (I) is wherein:
R
1It is phenyl, contain 1 to 2 and be selected from nitrogen, heteroatomic saturated or unsaturated 5 yuan to the 6 yuan heteromonocyclic group groups of oxygen or sulphur atom (more preferably pyrryl, different _ the azoles base, furyl, thienyl etc.) or the optional low alkyl group that replaces by lower alkoxy or contain 1 to 2 nitrogen-atoms and also optional saturated or unsaturated 5 yuan or the 6 yuan of heteromonocyclic group groups (more preferably piperazinyl or morpholinyl) that contain Sauerstoffatom replace, wherein lower alkoxy is optional is replaced by ring (rudimentary) alkyl or unsaturated 5 yuan to the 6 yuan heteromonocyclic group groups (more preferably pyridyl) that contain at least one nitrogen-atoms
R
2Be-(CH
2) n-R
7, wherein n can be 2 to 5 integer, and R
7Be carboxyl or protection carboxyl,
R
3Be (1) phenyl, optional by low alkyl group, ring (rudimentary) alkyl, lower alkoxy, halogen, cyano group or formamyl replacement; Or (2) contain unsaturated 5 yuan to the 6 yuan heteromonocyclic group groups (more preferably 3-pyridyl and 4-pyridyl) of at least one nitrogen-atoms, replace by low alkyl group, ring (rudimentary) alkyl, lower alkoxy, formamyl or halogen, and R
4It is low alkyl group.
The particular compound of preferred formula (I) is:
(1) 3-[7-ethyl-2-methyl-3-(4-pyridyl)-pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile,
(2) 3-[7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile,
(3) 4-[7-ethyl-2-methyl-3-(methyl sulphonyl)-pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile,
(4) 3-[7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzamide,
(5) 5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] Valeric acid ethylester,
(6) 2-{[4-(3-chloro-phenyl-)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] methyl }-1, ammediol,
(7) 3-[4-(3-chloro-phenyl-)-7-ethyl-2-phenyl-pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid,
(8) 5-[7-ethyl-2-methyl-4-(6-quinolyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(9) 5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] valeric acid,
(10) 5-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(11) 5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(12) 3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid,
(13) 5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(4-morpholinyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(14) (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-the 2-ethyl propenoate,
(15) 6-{4-[4-(aminocarboxyl) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } caproic acid,
(16) 3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid,
(17) 4-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid,
(18) methyl 5-[2-[(cyclohexyl methoxyl group)]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(19) methyl 5-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(4-pyridyl methoxyl group)] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid,
(20) methyl 4-{4-(5-chloro-3-pyridyl)-7-ethyl-2-[(4-pyridyl methoxyl group)] pyrrolo-[1,2-b] pyridazine-3-yl } butyric acid,
(21) 4-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(4-morpholinyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid,
(22) 4-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid,
(23) 5-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid, or
(24) methyl 5-{4-(3-cyano-phenyl)-7-ethyl-2-[(4-pyridyl methoxyl group)] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid,
Or its pharmacologically acceptable salt.
The particular compound of preferred formula (I) is:
(1) 5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] Valeric acid ethylester,
(2) 3-[4-(3-chloro-phenyl-)-7-ethyl-2-phenyl-pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid,
(3) 5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] valeric acid,
(4) 5-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(5) 5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(6) 3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid,
(7) 5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(4-morpholinyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(8) 6-{4-[4-(aminocarboxyl) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } caproic acid,
(9) 3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid,
(10) 4-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid,
(11) methyl 5-[2-[(cyclohexyl methoxyl group)]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid and
(12) methyl 5-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(4-pyridyl methoxyl group)] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid,
(13) 4-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid, or
(14) 5-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
Or its pharmacologically acceptable salt.
Target compound of the present invention (I) can prepare by the following method.
Method 1
(II) or its salt (I) or its salt
Method 2
(I-a) or its salt (I-b) or its salt
Method 3
(I-c) or its salt (I-d) or its salt
Method 4
Or hydroxyl (I-e) or its salt (I-d) or its salt,
On reactive derivative
Method 5
(I-e) or its salt (I-g) or its salt
Method 6
(I-b) or its salt (I-h) or its salt
Method 7
(I-i) or its salt (I-j) or its salt
Method 8
(I-k) or its salt
Or carboxyl (I-j) or its salt,
Reactive derivative
Method 9
(I-l) or its salt (I-m) or its salt
Method 10
(I-i) or its salt (I-n) or its salt
Method 11
(I-n) or its salt (I-o) or its salt
Method 12
(V) or its salt (I) or its salt
Method 13
(I-p) or its salt (I-q) or its salt
Method 14
(I-r) or its salt (I-s) or its salt
Method 15
(I-t) or its salt
Method 16
(I-u) or (I-v) on its salt or the hydroxyl or its salt
Reactive derivative
Method 17
(I-w) or its salt (T-x) or its salt
Method 18
(I-h) or its salt (I-y) or its salt
Method 19
(I-z) or its salt (I-aa) or its salt
Method 20
(I-ab) or its salt (I-ac) or its salt
Method 21
(I-ad) or its salt (I-ae) or its salt
Method 22
(I-af) or its salt (I-ag) or its salt
Method 23
(I-a) or its salt (I-ah) or its salt
Method 24
(I-ai) or its salt (I-aj) or its salt
Method 25
(I-z) or its salt (I-ak) or its salt
Method 26
(I-al) or its salt (I-am) or its salt
Method 27
Method 28
(I-an) or its salt (I-ao) or its salt
Method 29
(I-an) or its salt (I-ap) or its salt
Method 30
(I-aq) or its salt (I-ar) or its salt
Method 31
(I-u) or its salt (I-as) or its salt
Method 32
(I-as) or its salt (I-at) or its salt
Method 33
(I-au) or its salt (I-av) or its salt
Method 34
(I-av) or its salt (I-aw) or its salt
Method 35
Method 36
Method 37
(I) or its salt
Method 38
(I-az) or its salt
Method 39
(I-z) or its salt (I-ba) or its salt
Method 40
(I-r) or its salt (I-bb) or its salt
R wherein
1, R
2, R
3And R
4Each above freely definition,
R
1 aWith above R with protection carboxy moiety
1It is identical,
R
1 bWith above R with carboxy moiety
1It is identical,
R
1 cBe-CONR
5R
6,
R
1 dBe formamyl (rudimentary) alkyl,
R
1 eBe amino, single-or two (rudimentary) alkylamino, lower alkoxy (rudimentary) alkylamino, nitrogen heterocyclic ring group, amino (rudimentary) alkyl, list-or two (rudimentary) alkylamino (rudimentary) alkyl, lower alkoxy (rudimentary) alkylamino (rudimentary) alkyl, nitrogen heterocyclic ring (rudimentary) alkyl
R
1 fBe lower alkylthio (rudimentary) alkyl,
R
1 gBe low alkyl group alkylsulfonyl (rudimentary) alkyl,
R
1 hBe trifluoro-methanesulfonyl oxy or trifluoro-methanesulfonyl oxy (rudimentary) alkyl,
R
1 iBe lower alkoxy or lower alkoxy (rudimentary) alkyl,
R
1 jBe hydroxyl or hydroxyl (rudimentary) alkyl,
R
2 aBe elementary alkoxy carbonyl,
R
2 bWith above R with protection carboxy moiety
2It is identical,
R
2 cWith above R with carboxy moiety
2It is identical,
R
2 dWith above R with carbamyl base section
2It is identical,
R
2 cWith above R with protection hydroxylic moiety
2It is identical,
R
2 fWith above R with hydroxylic moiety
2It is identical,
R
2 gWith above R with methylol part
2It is identical,
R
2 hBe-OR
12,
R
2 iBe elementary alkoxy carbonyl or low alkyl group alkylsulfonyl,
R
2 jBe as above R
2In the replacement mentioned or do not replace low-grade alkenyl, wherein said low-grade alkenyl is rudimentary 1-alkene-1-base,
R
2 kWith above R with hydroxyl (rudimentary) moieties
2It is identical,
R
2 lWith above R with oxo (rudimentary) moieties
2It is identical,
R
2 mWith above R with the amino part of protection
2It is identical,
R
2 nWith above R with amino part
2It is identical,
R
2 oWith above R with protection hydroxylic moiety
2It is identical,
R
2 pWith above R with hydroxyl (rudimentary) alkylamino (rudimentary) moieties
2It is identical,
R
2 qWith above R with alkoxy carbonyl (rudimentary) moieties
2It is identical,
R
2 rWith above R with elementary alkoxy carbonyl methyl carbonyl moiety
2It is identical,
R
3 aWith above R with cyano group part
3It is identical,
R
3 bWith above R with carbamyl base section
3It is identical,
R
3 cWith above R with carboxy moiety
3It is identical,
R
3 dWith above R with protection sulphonamide part
3It is identical,
R
3 cWith above R with sulphonamide part
3It is identical,
R
3 fHave-CONR with above
10R
11The R of part
3It is identical,
R
3 gWith above R with halogen heterocyclic moiety
3It is identical,
R
3 hWith above R with alkoxyl group heterocycle, thio alkoxy heterocycle or hydroxylic moiety
3It is identical,
R
3 iWith above R with 1-(rudimentary) alkoxyl group (rudimentary) alkene-1-base heterocyclic moiety
3It is identical,
R
3 jWith above R with lower alkane acyl group heterocyclic moiety
3It is identical,
R
3 kWith above R with amino methyl heterocyclic moiety
3It is identical,
R
3 lHas a single-or R of two (rudimentary) alkylamino heterocyclic moiety with above
3It is identical,
R
3 mWith above R with (rudimentary) alkene-1-base heterocyclic group or 1-(rudimentary) alkoxyl group-1-(rudimentary) alkene-1-base-heterocyclic moiety
3It is identical,
R
4 aBe halogen,
R
4 bBe formyl radical,
R
4 cBe rudimentary 1-alkene-1-base,
R
4 dBe low alkyl group,
R
12Be low alkyl group or derived from the protection of therefrom removing hydroxyl or the group of protection sugar, X is a leavings group, and
Formula
Group be the low-grade alkylidene that partly interrupts and replace by oxo group by imido grpup.
Initial compounds of the present invention (II) can prepare according to conventional methods or with the similar fashion among preparation example as described below and/or the embodiment.
The Pyrrolopyridazine part of the on the other hand compound (I) that should note also can exist with tautomeric form, and this tautomeric equilibrium can be represented by for example following formula.
R wherein
1, R
2, R
3And R
4Each above freely definition.
More than two kinds of tautomerism isomer all be included in the scope of the present invention, but for simplicity, in this specification sheets and claim, target compound (I) is represented by a kind of expression formula of the possible tautomeric form of Pyrrolopyridazine ring.
At the above of this specification sheets with in recording and narrating subsequently, following detailed explanation is done in the suitable example and the explanation of the various definition that are included in the scope of the present invention.
Unless otherwise prescribed, term " lower " means has 1 to 6, the group of preferred 1 to 4 carbon atom.
Suitable " low alkyl group " and " low alkyl group part " can comprise straight chain or the branched-alkyl with 1 to 6 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, tert-pentyl, hexyl etc., and wherein preferred example can be C
1-C
4Alkyl.
Suitable " low-grade alkenyl " can comprise vinyl, 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-methyl ethylene, 1-ethyl vinyl, 1-(or 2-) methyl isophthalic acid-(or 2-) propenyl, 1-(or 2-) ethyl-1-(or 2-) propenyl, 1-(or 2-or 3-) methyl isophthalic acid-(or 2-or 3-) butenyl etc., wherein preferred example can be C
2-C
4Alkenyl.
Suitable " low-grade alkynyl " can comprise ethynyl, 1-proyl, propargyl, 1-methyl propargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexin base etc.
Suitable " low-grade alkylidene " can comprise straight chain or sub-branched alkyl, and as methylene radical, ethylidene, trimethylene, tetramethylene, pentamethylene, six hexylidenes, methyl methylene radical, ethyl ethylidene, propylidene etc., wherein preferred example can be C
1-C
4Alkylidene group, and most preferred can be methylene radical.
Hydroxyl (C
1-C
2) example of alkylidene group is hydroxyl methylene radical, (methylol) methylene radical or 1-(or 2-) hydroxy ethylene.
Suitable " lower alkoxy " can comprise methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, pentyloxy, uncle's pentyloxy, hexyloxy etc.
Suitable " halogen " reaches " halogen part " can comprise fluorine, bromine, chlorine and iodine.
Suitable " three halogen (rudimentary) alkyl " can comprise trichloromethyl, trifluoromethyl, three chloroethyls, three bromomethyl etc.
Suitable " single-or two (rudimentary) alkylamino " can comprise the amino that replaces by one or two low alkyl group, as methylamino, ethylamino, dimethylamino etc.
The example of " list that is replaced by lower alkoxy-or two (rudimentary) alkylamino " can be methoxymethyl amino, methoxy ethyl amino, methoxy ethyl (methyl) is amino, methoxy ethyl (ethyl) is amino, two (methoxy ethyls) are amino, ethoxyl methyl is amino, ethoxyethyl group amino etc.
Suitable " lower alkylthio " can comprise conventional alkylthio, as methylthio group, ethylmercapto group, rosickyite base, butylthio etc.
Suitable " low alkyl group sulfinyl " can comprise conventional alkyl sulfinyl, as methyl sulfinyl, ethylsulfinyl-1 base, propyl group sulfinyl, butyl sulfinyl etc.
Suitable " low alkyl group alkylsulfonyl " can comprise conventional alkyl sulphonyl, as methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, butyl alkylsulfonyl etc.
Suitable " three halogen (rudimentary) alkyl sulphonyl oxygen base " can comprise the alkylsulfonyl oxygen base group that is replaced by three halogen (rudimentary) alkyl, as trifluoromethyl sulfonyl oxygen base, trifluoroethyl alkylsulfonyl oxygen base, trichloromethyl alkylsulfonyl oxygen base etc.
Suitable " protection carboxyl " and " protection carboxy moiety " can comprise esterifying carboxyl group etc.
The suitable example of described ester can be such as lower alkyl esters (as methyl esters, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, the tert-butyl ester, pentyl ester, tert-pentyl ester, own ester etc.);
Low-grade alkenyl ester (as vinyl ester, allyl ester etc.);
Low-grade alkynyl ester (as ethynyl ester, proyl ester etc.);
Lower alkoxy (rudimentary) alkyl ester (as methoxyl group methyl esters, oxyethyl group methyl esters, isopropoxy methyl esters, 1-methoxyl group ethyl ester, 1-ethoxy ethyl ester etc.);
Lower alkylthio (rudimentary) alkyl ester (as methylthiomethyl ester, ethylmercapto group methyl esters, ethylmercapto group ethyl ester, isopropoxy sulfenyl methyl esters etc.);
Single (or two or three) halogen (rudimentary) alkyl esters (as 2-iodo-ethyl ester, 2,2,2-trifluoro ethyl ester etc.); Lower alkane acyloxy (rudimentary) alkyl ester (as acetoxyl group methyl esters, propionyloxy methyl esters, butyryl acyloxy methyl esters, valeryl oxomethyl ester, new pentane acyloxy methyl esters, hexylyloxy methyl esters, 1-acetoxyl group ethyl ester, 2-acetoxyl group ethyl ester, 2-propionyloxy ethyl ester etc.);
Elementary alkoxy carbonyl oxygen base (rudimentary) alkyl ester (as methoxycarbonyl oxygen base methyl esters, ethoxy carbonyl oxygen base methyl esters, propoxycarbonyl oxygen base methyl esters, 1-(or 2-)-[methoxycarbonyl oxygen base] ethyl ester, 1-(or 2-)-[ethoxy carbonyl oxygen base] ethyl ester, 1-(or 2-)-[propoxycarbonyl oxygen base] ethyl ester, 1-(or 2-)-[isopropoxy carbonyl oxygen base] ethyl ester etc.);
Lower alkyl alkylsulfonyl (rudimentary) alkyl ester (as methylsulfonyl methyl esters, 2-methylsulfonyl ethyl ester etc.);
Elementary alkoxy carbonyl oxygen base (rudimentary) alkyl ester (as methoxycarbonyl oxygen base methyl esters, ethoxy carbonyl oxygen base methyl esters, propoxycarbonyl oxygen base methyl esters, tert-butoxycarbonyl oxygen base methyl esters, 1-(or 2-) methoxycarbonyl oxygen base ethyl ester, 1-(or 2-) ethoxy carbonyl oxygen base ethyl ester, 1-(or 2-) isopropoxy carbonyl oxygen base ethyl ester etc.);
Phthalidylidene (rudimentary) alkyl ester;
(5-low alkyl group-2-oxo-1, the 3-Dioxol-4-yl) (rudimentary) alkyl ester is [as (5-methyl-2-oxo-1, the 3-Dioxol-4-yl) methyl esters, (5-ethyl-2-oxo-1, the 3-Dioxol-4-yl) methyl esters, (5-propyl group-2-oxo-1,3-Dioxol-4-yl) ethyl ester etc.];
Single (or two or three) aryl (rudimentary) alkyl ester, list (or two or three) phenyl (rudimentary) alkyl ester that for example can have one or more suitable substituent is (as benzyl esters, 4-methoxybenzyl ester, 4-oil of mirbane methyl ester, styroyl ester, trityl ester, benzhydryl ester, two (p-methoxy-phenyl) methyl ester, 3,4-dimethoxy benzyl esters, 4-hydroxyl-3,5-di-t-butyl benzyl esters etc.); The aryl ester that can have one or more suitable substituent, for example replacement or unsubstituted phenyl ester are (as phenylester, tolyl ester, tert-butyl-phenyl ester, 3,5-dimethylphenyl ester, 2,4,6-trimethylphenyl ester, cumyl ester, 4-chloro-phenyl-ester, 4-p-methoxy-phenyl ester etc.);
Three (rudimentary) alkyl silyl ester (as trimethyl silyl ester, triethylsilyl ester etc.);
Three (rudimentary) alkyl silyl ester (rudimentary) alkyl ester (as 2-trimethyl silyl ethyl ester etc.);
Or the like, wherein preferred example can be a lower alkyl esters, i.e. elementary alkoxy carbonyl (as ethoxy carbonyl etc.).
Term " protection is amino " expression is keyed to the amino of amido protecting group.The example of this amido protecting group comprises elementary alkoxy carbonyl (as methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl etc.); Low-grade alkenyl oxygen base carbonyl (as vinyl oxygen base carbonyl, allyl group oxygen base carbonyl etc.); Optional aryl (rudimentary) alkoxy carbonyl that replaces (as phenmethyl oxygen base carbonyl etc.); Phthalic imidine; Or the like.The other example of amido protecting group is known in organic synthesis; and record and narrate second edition in T.W.Greene and P.G.M.Wuts " Protective Groups inOrganic Synthesis "; John Wiley and Sons; New York; N.Y., the document is introduced the present invention as a reference.
Term " protection sulphonamide " is illustrated in the sulfamyl that has above-mentioned amido protecting group on the nitrogen-atoms.Preferred amido protecting group is aryl (rudimentary) alkoxy carbonyl (as phenmethyl oxygen base carbonyl etc.) etc.
Suitable " acyl group " and " acyl moiety " can comprise aliphatic acyl radical, and be called aromatic acyl contain the aromatic ring acyl group, or be called the heterocyclic acyl that contains of heterocyclic acyl.
The suitable example of described acyl group can illustrate as follows:
Aliphatic acyl radical for example
Rudimentary or higher alkane acyl group (as formyl radical, ethanoyl, propionyl, butyryl radicals, 2-methylpropionyl, pentanoyl, 2,2-dimethyl propylene acyl group, caproyl, oenanthyl, capryloyl, nonanoyl, decanoyl, undecanoyl, lauroyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecane acyl group, octadecanoyl, nonadecane acyl group, eicosane acyl group etc.); Wherein preferred " lower alkane acyl group " can comprise straight chain or branched alkane acyl group, as formyl radical, ethanoyl, propionyl, butyryl radicals etc.
Rudimentary or senior alkenoyl (as acryl, 2-(or 3-)-crotonoyl, 2-(or 3-or 4-) pentenoyl, 2-(or 3-or 4-or 5-)-hexenoyl etc.);
Lower alkanols two enoyl-s (as heptadiene acyl group, hexadiene acyl group etc.);
Ring (rudimentary) alkyl-carbonyl (as cyclopropyl carbonyl, cyclopentylcarbonyl, cyclohexyl-carbonyl etc.);
Low alkyl group glyoxylyl (as methylglyoxal acyl, ethylhexanal acyl, propyl group glyoxylyl etc.);
Lower alkoxy glyoxylyl (as methoxyl group glyoxylyl, oxyethyl group glyoxylyl, propoxy-glyoxylyl etc.); Or the like;
Aromatic acyl for example
Aroyl (as benzoyl, toluyl, naphthoyl base etc.);
Aryl (rudimentary) alkanoyl [for example phenyl (rudimentary) alkanoyl (as phenyl acetyl, phenyl propionyl, phenyl butyryl radicals, phenyl isobutyryl, phenyl pentanoyl, phenyl caproyl etc.), naphthyl (rudimentary) alkanoyl (as naphthyl ethanoyl, naphthyl propionyl, naphthyl acyl group etc.) etc.];
Aryl (rudimentary) alkenoyl [for example phenyl (rudimentary) alkenoyl (as phenyl acryloyl, phenyl crotonoyl, phenyl methyl acryl, phenyl pentenoyl, phenyl hexenoyl etc.), naphthyl (rudimentary) alkenoyl (as naphthyl acryl, naphthyl enoyl-etc.) etc.];
Aryloxy (rudimentary) alkanoyl (as phenoxy group ethanoyl, phenoxy group propionyl etc.);
Aryl glyoxylyl (as phenyl glyoxylyl, naphthyl glyoxylyl etc.);
Heterocyclic acyl for example
The heterocycle carbonyl;
Heterocycle (rudimentary) alkanoyl (as heterocycle ethanoyl, heterocycle propionyl, heterocycle butyryl radicals, heterocycle pentanoyl, heterocycle caproyl etc.);
Heterocycle (rudimentary) alkenoyl (as heterocycle acryl, heterocycle crotonoyl, heterocyclic pentene acyl group, heterocycle hexenoyl etc.);
The heterocycle glyoxylyl; Heterocycle oxidation carbonyl; Or the like;
Wherein suitable " heterocyclic moiety " can comprise and as described belowly contain saturated or unsaturated, the monocycle of at least one heteroatoms such as oxygen, sulphur, nitrogen-atoms etc. or encircle heterocyclic group more, and preferred " heterocycle carbonyl " can comprise the carbonyl that replaced by heterocyclic group as described below such as pyrrolidyl carbonyl, pyridyl carbonyl, pyrazinyl carbonyl etc.
That suitable " halo carbonyl " can comprise is chloroformyl, bromine carbonyl etc.
Suitable " ring (rudimentary) alkyl " and " ring (rudimentary) moieties " can comprise the cycloalkyl with 3 to 7 carbon atoms, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
Suitable " aryl " and " aryl moiety " can comprise C
6-C
10Aryl is as phenyl, naphthyl etc.
Suitable " heterocyclic moiety " can comprise saturated or unsaturated, the monocycle that contains at least one heteroatoms such as oxygen, sulphur, nitrogen-atoms etc. or encircle heterocyclic group more.
Preferred heterocyclic group can be the heterocyclic group such as following group:
(1) contains unsaturated 3 to 8 yuan (more preferably 5 yuan or 6 yuan) heteromonocyclic group groups of 1 to 4 nitrogen-atoms, for example pyrryl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridine base, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl are (as 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazyl (as 1H-tetrazyl, 2H-tetrazyl etc.) etc.;
(2) contain saturated 3 to 8 yuan (more preferably 5 yuan or 6 yuan) heteromonocyclic group group, for example pyrrolidyl, imidazolidyl, piperidyl, piperazinyls etc. of 1 to 4 nitrogen-atoms;
(3) contain the unsaturated annelated heterocycles group of 1 to 4 nitrogen-atoms, for example indyl, pseudoindolyl, indolinyl, indolizine base, benzimidazolyl-, quinolyl, tetrahydric quinoline group are (as 1,2,3,4-tetrahydric quinoline group etc.), isoquinolyl, indazolyl, benzotriazole base, benzo pyrimidyl (as benzo [b] pyrimidyl etc.) etc.;
(4) contain unsaturated 3 to 8 yuan (more preferably 5 yuan or 6 yuan) heteromonocyclic group groups of 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms, for example _ the azoles base, different _ the azoles base, _ di azoly (as 1,2,4-_ di azoly, 1,3,4-_ di azoly, 1,2,5-_ di azoly etc.) etc.;
(5) contain saturated 3 to 8 yuan (more preferably 5 yuan or 6 yuan) heteromonocyclic group group, for example morpholinyl, Sydney ketone groups (sydnonyl) etc. of 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms;
(6) contain the unsaturated annelated heterocycles group of 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms, for example benzo _ azoles base, benzo _ di azoly etc.;
(7) contain unsaturated 3 to 8 yuan (more preferably 5 yuan or 6 yuan) heteromonocyclic group groups of 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms, for example thiazolyl, isothiazolyl, thiadiazolyl group are (as 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,5-thiadiazolyl group etc.), dihydro thiazinyl etc.;
(8) contain saturated 3 to 8 yuan (more preferably 5 yuan or 6 yuan) heteromonocyclic group groups of 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms, for example thiazolidyl etc.;
(9) contain unsaturated 3 to 8 yuan (more preferably 5 yuan or 6 yuan) heteromonocyclic group groups, for example thienyl, dihydro dithia cyclohexadienyl (dihydrodithiinyl), dihydro two thionyl etc. of 1 to 2 sulphur atom;
(10) contain the unsaturated annelated heterocycles group of 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms, for example benzothiazolyl, diazosulfide base etc.;
(11) contain unsaturated 3 to 8 yuan (more preferably 5 yuan or 6 yuan) heteromonocyclic group groups of 1 Sauerstoffatom, for example furyl etc.;
(12) contain the unsaturated annelated heterocycles group of 1 to 2 Sauerstoffatom, for example benzodioxole base (as methylenedioxyphenyl base etc.), benzofuryl etc.;
(13) contain unsaturated 3 to 8 yuan (more preferably 5 yuan or 6 yuan) heteromonocyclic group groups of 1 Sauerstoffatom and 1 to 2 sulphur atom, for example dihydro oxathiin base etc.;
(14) contain the unsaturated annelated heterocycles group of 1 to 2 sulphur atom, for example benzothienyl (as benzo [b] thienyl etc.), benzo dithia cyclohexadienyl (benzodithiinyl) etc.;
(15) contain the unsaturated annelated heterocycles group of a Sauerstoffatom and 1 to 2 sulphur atom, for example benzo oxathiin base etc.; Or the like.
Suitable " heterocyclic group " and " heterocyclic moiety " in the term " heterocycle carbonyl " can be with reference to aforesaid group.
Suitable " containing the N heterocyclic group " and " containing the N heterocyclic moiety " can be with reference to aforesaid groups, and wherein heterocyclic group contains at least one nitrogen-atoms, as 1-pyrrolidyl, morpholinyl etc.
Group derived from sugar can be derived from for example group of following sugar: Glycerose; Aldose is as erythrose, threose, arabinose, ribose, wood sugar, lyxose, glucose, seminose or semi-lactosi; Ketose is as fructose or sorbose; Or disaccharides, as maltose, lactose or sucrose.
The protecting group that is used for the hydroxyl of above-mentioned sugar is an aliphatic acyl radical, as formyl radical or ethanoyl; Cyclic ether group is as tetrahydrochysene-2-furyl or tetrahydrochysene-2-pyranyl; 1-alkoxyethyl group is as 1-methoxy ethyl or 1-ethoxyethyl group; And silyl-group, as trimethyl silyl, triethylsilyl or t-butyldimethylsilyl.
Be suitable for R
1" replace or do not replace low alkyl group " can comprise straight chain or branching low alkyl group (as methyl, sec.-propyl, neo-pentyl etc.), optionally replace by following group:
(1) halogen (as fluorine, bromine etc.), (2) carboxyl, (3) protection carboxyl (for example esterifying carboxyl group such as ethoxy carbonyl etc.), (4) cyano group, (5) formamyl, (6)-OCONR
15R
16[R wherein
15And R
16Represent hydrogen, aryl or the optional low alkyl group that replaces by aryl independently of one another, or R
13And R
14Represent to contain 1 to 2 nitrogen-atoms and also optional saturated 5 yuan or 6 yuan of heteromonocyclic group groups that contain Sauerstoffatom with the nitrogen-atoms that they were keyed to.] (more preferably dimethylamino formyl radical oxygen base, methyl-phenyl amino methanoyl, morpholinyl carbonyl oxygen base, pyrrolidyl ketonic oxygen base etc.); (7) lower alkylthio (as methylthio group etc.), (8) low alkyl group alkylsulfonyl (as methyl sulphonyl etc.), (9) low alkyl group alkylsulfonyl oxygen base (as methyl sulphonyl oxygen base etc.), (10) low alkyl group sulfuryl amino (as methyl sulphonyl amino etc.), (11) singly-or two (rudimentary) alkylamino, optional by hydroxyl, lower alkoxy, acyloxy (as phenoxy group etc.) or replacement or unsubstituting aromatic yl (as phenmethyl amino etc.), (12) amino; (13) amide group is (more preferably such as the lower alkane acyl amino of kharophen; aroylamino such as benzoyl-amido; or such as heterocycle carbonylamino of pyrazinyl carbonylamino etc.); (14) protection is amino (as methoxycarbonyl amino; phthalic imidine etc.); (15) hydroxyl; (16) acyloxy (more preferably lower alkane acyloxy such as acetoxyl group etc.); (17) ring (rudimentary) alkoxyl group; (18) aryloxy (as phenoxy group etc.); (19) replacement or unsubstituting aromatic yl (more preferably phenyl); (20) contain 1 to 3 nitrogen-atoms and also optional saturated or unsaturated 5 yuan or the 6 yuan of heteromonocyclic group groups that contains Sauerstoffatom or sulphur atom (more preferably piperidyl; morpholinyl; _ oxazolidinyl; thio-morpholinyl; piperidyl; pyrrolidyl or triazolyl); optional by low alkyl group; hydroxyl (rudimentary) alkyl; aryl or oxo replace; (21) lower alkoxy is (as methoxyl group; oxyethyl group; isopropoxy etc.); optional by following group replacement: carboxyl; the protection carboxyl (as tert-butoxycarbonyl etc.); hydroxyl; the protection hydroxyl (as tetrahydrochysene-2H-pyrans-2-base oxygen base etc.); ring (rudimentary) alkyl is (as cyclopropyl; cyclohexyl etc.); replacement or unsubstituting aromatic yl are (for example optional by cyano group; carboxyl; the phenyl that protection carboxyl or formamyl replace is as phenyl; 2-or 3-or 4-cyano-phenyl; 2-or 3-or 4-carboxyl phenyl; 2-or 3-or 4-(methoxycarbonyl) phenyl; 2-or 3-or 4-formamyl phenyl etc.); optional by rudimentary (more preferably 2-or 3-or 4-pyridyl; pyrazinyl or 4-methylpiperazine base) saturated or unsaturated 5 yuan or 6 yuan of heterocyclic groups of containing 1 to 2 nitrogen-atoms of replacing are (as 2-or 3-or 4-pyridyl; pyrazinyl etc.); or-CONR
13R
14[R wherein
13And R
14Be hydrogen or the optional low alkyl group that replaces by aryl independently of one another, or R
13And R
14Represent to contain the N heterocyclic group with the nitrogen-atoms that they were keyed to] (as morpholino carbonyl, dimethylamino formyl radical etc.) etc.
Suitable " replacing or unsubstituting aromatic yl " can comprise C
6-C
10Aryl (as phenyl, naphthyl etc.), optional by the substituting group replacement that is selected from following group: (1) halogen (as fluorine, chlorine etc.), (2) carboxyl, (3) protection carboxyl, (4) cyano group, (5)-CONR
15R
16[R wherein
15And R
16Represent hydrogen independently of one another; the optional low alkyl group that replaces by hydroxyl] (as formamyl; hydroxyethylamino formyl radical etc.); (6) low alkyl group (as methyl etc.); (7) ring (rudimentary) alkyl (as cyclopropyl etc.); (8) lower alkoxy (as methoxyl group etc.); (9) three halogen (rudimentary) alkyl (as trifluoromethyl etc.); (10) heterocyclic group; as _ the azoles base; (11) low alkyl group alkylsulfonyl (as methyl sulphonyl etc.), (12) nitro, (13) amino; (14) sulphonamide; (15) protection sulphonamide, as aryl (rudimentary) alkoxy carbonyl sulphonamide, or the like.
Wherein,
Be used for R
1The preferred embodiment of " replace or unsubstituting aromatic yl " be aryl, optionally replace (as phenyl, 4-fluorophenyl etc.) by the substituting group that is selected from halogen;
Be used for R
3The preferred embodiment of " replace or unsubstituting aromatic yl " be aryl, optionally replace by the substituting group that is selected from following group: (1) halogen, (2) carboxyl, (3) are the protection carboxyl of esterifying carboxyl group (as benzyloxycarbonyl etc.) for example, (4) cyano group, (5)-CONR
15R
16[R wherein
15And R
16Represent hydrogen, the optional low alkyl group that replaces by hydroxyl independently of one another]; (6) low alkyl group, (7) ring (rudimentary) alkyl, (8) lower alkoxy; (9) three halogen (rudimentary) alkyl; (10) heterocyclic group, (11) low alkyl group alkylsulfonyl, (12) nitro; (13) amino; (14) sulphonamide and (15) protection sulphonamide, or the like.(for example phenyl, 2-naphthyl, 2-or 3-chloro-phenyl-, 2,3-or 2,4-or 3,4-or 3,5-dichlorophenyl, 3-or 4-fluorophenyl, 3-or 4-cyano-phenyl, 3-or 4-formamyl phenyl, 4-sulfamyl phenyl, 4-(benzyloxycarbonyl sulfamyl) phenyl, 3-carboxyl phenyl, 3-(N-(2-hydroxyethyl) formamyl) phenyl, 3-nitrophenyl, 3-trifluoromethyl, 3-methyl sulphonyl phenyl, 3-(5-_ azoles base) phenyl, 3-p-methoxy-phenyl, 3-aminomethyl phenyl etc.); With
Be used for R
7The preferred embodiment of " replace or unsubstituting aromatic yl " be aryl, optionally replace (as phenyl, 2-or 3-or 4-p-methoxy-phenyl etc.) by lower alkoxy.
Suitable " replacing or the unsubstituting heterocycle group " can comprise above-mentioned heterocyclic group (more preferably pyridyl; pyrazinyl; _ azoles base; different _ the azoles base; furyl; thienyl; quinolyl; benzofuryl and benzothienyl); optional replace by the substituting group that is selected from following group: (1) low alkyl group (as methyl etc.); (2) ring (rudimentary) alkyl (as cyclopropyl etc.); (3) lower alkoxy (as methoxyl group etc.); (4) acyl group (for example lower alkane acyl group such as ethanoyl etc.); (5) amino; (6) single-or two (rudimentary) alkylamino (as dimethylamino etc.); (7) protection amino (for example elementary alkoxy carbonyl amino as tert-butoxycarbonyl amino etc.); (8) cyano group; (9) carboxyl; (10) protection carboxyl (as benzyloxycarbonyl etc.), (11)-CONR
15R
16[R wherein
15And R
16Represent hydrogen, the optional low alkyl group that replaces by hydroxyl independently of one another] (as formamyl, hydroxyethylamino formyl radical etc.); (12) the optional low-grade alkenyl (as vinyl, 1-vinyl ethyl ether base etc.) that replaces by lower alkoxy; (13) halogen (as chlorine, bromine etc.); (14) lower alkylthio; (15) hydroxyl, or the like.
Wherein,
Be used for R
1The preferred embodiment of " replace or unsubstituting heterocycle group " be the optional heterocyclic group that replaces by low alkyl group or halogen (as 2-pyridyl, 5-bromo-3-pyridyl, 1-methyl-2-pyrryl, 1-pyrryl, 1-pyrrolidyl, 3-methyl-2-thienyl, 2-thienyl, 2-or 3-furyl, 2-thiazolyl, 5-_ azoles base, 5-methyl-different _ azoles base, 3,5-dimethyl-4-is different _ azoles base etc.); With
Be used for R
3The preferred embodiment of " replace or unsubstituting heterocycle group " be heterocyclic group; optional by at least a substituting group replacement that is selected from following group: (1) low alkyl group; (2) ring (rudimentary) alkyl; (3) lower alkoxy; (4) acyl group; as the lower alkane acyl group; (5) amino; (6) singly-or two (rudimentary) alkylamino; (7) protection is amino; as elementary alkoxy carbonyl amino; (8) cyano group; (9) carboxyl; (10) protection carboxyl such as esterifying carboxyl group (as benzyloxycarbonyl); (11) formamyl; (12) low-grade alkenyl; choose wantonly and replace by lower alkoxy; (13) halogen; (14) lower alkylthio; (15) hydroxyl is (as 3-or 4-pyridyl; the 2-pyrazinyl; 6-methoxyl group-2-pyrazinyl; 4-or 5-_ azoles base; the 2-benzofuryl; the 2-benzothienyl; 3-or 6-quinolyl; 2-chloro-4-pyridyl; 5-bromo-3-pyridyl; 5-chloro-2-thienyl; 5; 6-two chloro-2-pyridyl; 4-chloro-2-pyridyl; 5-cyano group-3-pyridyl; 5-carboxyl-3-pyridyl; 5-formamyl-3-pyridyl; 5-(benzyloxycarbonyl)-3-pyridyl; 5-(tert-butoxycarbonyl amino)-3-pyridyl; 5-amino-3-pyridyl; 2-methoxyl group-4-pyridyl; 3-methoxyl group-5-is different _ the azoles base; 2-methylthio group 4-pyridyl; 2-hydroxyl-4-pyridyl; 5-methyl-3-pyridyl; 5-ethyl-3-pyridyl; 5-methyl-3-is different _ the azoles base; 5-vinyl-3-pyridyl; 2-vinyl-4-pyridyl; 5-ethanoyl-3-pyridyl; 2-dimethylamino-4-pyridyl; 5-(1-vinyl ethyl ether base)-3-pyridyl; 2-oxo-1,2-dihydro-4-pyridyl; or 2-methylthio group 4-pyridyl etc.).
R
1And R
2Be combined together to form low-grade alkylidene or rudimentary alkylene group group, optional by amino or alkylsulfonyl interruption, and optional by low alkyl group, hydroxyl, oxo and lower alkoxy replacement, it is represented by following structural formula:
Above structural formula can comprise array structure down:
Suitable " replacing or unsubstituting aromatic yl (rudimentary) alkenyl " can comprise C
6-C
10Aryl (rudimentary) alkenyl, optional by halogen replacement (as 2-phenyl vinyl, 2-(2-or 3-chloro-phenyl-) vinyl etc.).
Lower alkoxy that suitable " leavings group " can comprise acidic residues, as above exemplify etc.
Above method can be carried out according to the ordinary method described in preparation example and/or the embodiment or with similar approach.In above method, annelated heterocycles formation method (as method 1 and method 12) is important for enforcement of the present invention, now explains in more detail.
According to method 1; Pyrrolopyridazine compound (I) can be by making 1-amino-2-acyl pyrroline derivative (II) or its salt and compound (III) or its salt; in the presence of the acid catalyst of catalytic amount; prepared in reaction in inert solvent is preferably followed by physics (as the Dean-Stark trap) or chemistry (as molecular sieve) method and is removed the water of generation.Suitable acid catalyst is for example tosic acid, methylsulfonic acid, hydrochloric acid, trifluoroacetic acid etc.Suitable inert solvent is for example benzene, toluene, tetrahydrofuran (THF) etc.
Another kind of one-tenth ring method is recorded and narrated in method 12, Pyrrolopyridazine compound (I) also can be by prepared in reaction under the condition that makes 1-amino-pyrroles derivative (V) or its salt and beta-diketo derivative or its salt described method 1 before being similar in the method, so reaction conditions can reference method 1.
Compound of the present invention can be purified by the conventional method of purification of any organic compound that is used to purify, as recrystallization method, column chromatography, tlc, high performance liquid chromatography etc.Compound can be differentiated by ordinary method, as NMR spectrography, mass spectroscopy, IR spectrography, elemental microanalysis method and fusing point method of masurement.
The acceptable acid addition salts of target and initial compounds can be with reference to for compound (I) example person in the method 1 to 40.
New Pyrrolopyridazine compound (I) and pharmacologically acceptable salt thereof have the strongly inhibited activity at phosphodiesterase iii (PDE III) hardly, but have active and for the strongly inhibited activity of tumour necrosis factor (TNF) at the strongly inhibited of phosphodiesterase IN (PDE IV).
That is to say that Pyrrolopyridazine compound and pharmacologically acceptable salt thereof are the selective depressants of phosphodiesterase IN (PDEIV) and for the selective depressant of the generation of tumour necrosis factor (TNF).
Therefore, this new Pyrrolopyridazine compound (I) and pharmacologically acceptable salt thereof can be used for prevention and treatment PDE-IV and TNF and regulate disease, as chronic inflammatory diseases (as rheumatoid arthritis, osteoarthritis, pulmonary emphysema, chronic capillary bronchitis, allergic rhinitis etc.), osteoporosis, the rejection that causes by transplanting, asthma, chronic obstructive pulmonary disease (COPD), eosinophilia, fibrotic disease is (as cystic fibrosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis etc.), (viral alcohols, drug-induced) acute and fulminant hepatitis, liver fat sex change (alcohols and non-monohydric aliphatic liver), chronic (virus and non-virus) hepatitis, liver cirrhosis, autoimmune hepatitis, pancreatitis, ephritis, endotoxin shock, specific autoimmune disease [ankylosing spondylitis for example, the autoimmunization encephalomyelitis, the autoimmunization hemopathy is (as hemolytic anemia, aplastic anemia, PRCA, essential thrombocytopenia etc.), systemic lupus erythematosus (SLE), polychondritis, scleroderma, the Wegener granulomatosis, dermatomyositis, chronic active hepatitis (Wilson disease etc.), myasthenia gravis, spontaneous sprue, the autoimmunization inflammatory bowel is (as ulcerative colitis, Crohn disease etc.), endocrine ophthalmopathy, the Grave disease, sarcoidosis, multiple sclerosis, Charcot's cirrhosis, juvenile diabete (type i diabetes), Reiter syndrome, non-infect eye uveitis, autoimmunization keratitis is (as keratoconjunctivitis sicca, vernal keratoconjunctivitis etc.), interstitial pulmonary fibrosis, psoriatic arthritis etc.], the tetter relevant with the PDE-IV enzyme is (as psoriasis and other optimum or neoplasm tetter, atopic dermatitis and urticaria), neurodegenerative disorders is as Parkinson's disease, senile dementia, acute and chronic multiple sclerosis, carcinemia, virus infection, the AIDS emaciation, thrombosis etc.
For drug treatment, compound (I) or its prodrug or its salt can be individually dosed or preferably with the form of mixtures administration of drug excipient or carrier.
Activeconstituents of the present invention can use with the form of for example solid-state, semi-solid state or liquid pharmaceutical preparation, it contains compound (I) as activeconstituents, forms mixture with the organic or inorganic carrier or the vehicle that are applicable in the outside (part), intestines, intravenously, intramuscular, non-enteron aisle or internal secretion are used.Activeconstituents can be prepared with the conventional nontoxic pharmaceutically acceptable carrier that for example is used for ointment, emulsion, ointment, tablet, particle, capsule, suppository, solution (as salt solution), emulsion, suspension (as sweet oil), aerosol, pill, powder, syrup, injection, tablet, paste, perfume, washing lotion, buccal tablet, sublingual tablet, nasal drop and any other service form.Operable carrier is that water, wax, glucose, lactose, Sudan Gum-arabic, gelatin, mannitol, starch paster, Magnesium Trisilicate, talcum, W-Gum, Keratin sulfate, paraffin, colloided silica, yam starch, urea and other are applicable to the carrier of making preparation, it can be solid-state, semi-solid state or liquid state, and can make used additives, stablizer, thickening material and tinting material and spices in addition.Active compound is included in the pharmaceutical composition with the significant quantity that the process of foundation disease or situation are enough to produce required effect.
Activeconstituents can be mixed with the preparation that for example is used for oral, injection, external application, sucks and be applied to mucous membrane.
In addition, compound of the present invention can be treated compound with other and is used in combination.Especially, PDE4 of the present invention suppresses combination of compounds and can advantageously be used in combination with following compound: i) leukotrienes receptor antagonist, ii) leukotrienes biosynthesis inhibitor, iii) COX-2 selective depressant, iv) Statins, v) NSAIDs, vi) M2/M3 antagonist, vii) corticosteroid, viii) Hi (histamine) receptor antagonist, ix) beta 2 adrenoreceptor stimulant, x) Interferon, rabbit, xi) be used for the antiviral of hepatitis C virus (HCV), as proteinase inhibitor, the helicase inhibitor, AG14361 etc., xii) be used for the antiviral of hepatitis B virus, as lamivudine (lamivudine), xiii) ursodesoxycholic acid, xiv) glycyrrhizin, xv) human growth factor (HGF), xvi) aminosallcylic acid is as the Whitfield's ointment sulfapyridine, mesalazine (mesalazin) etc., xvii) steroide, as dehydrogenation skin sterol method ester (farnesylate), xviii) immunosuppressor is as imuran, Ismipur, tacrolimus (tacrolimus) etc.
Can comprise such as livestocks such as milk cow, horses with the Mammals of the present invention's treatment, such as domestic animals such as dog, cat, mouse, and human, and preferred human.
The dosage of the treatment significant quantity of compound (I) is according to the age and the change of illness state of each individual patient, and the compound (I) that is about 0.01mg, 0.1mg, 1mg, 10mg, 50mg, 100mg, 250mg, 500mg and 1000mg for the average single dose of human patients can be effective to treat above-mentioned disease.Usually, every day can be with the amount administration between 0.01mg/ health and the about 1000mg/ health.
In order to prove the effectiveness of Pyrrolopyridazine compound of the present invention (I) and pharmacologically acceptable salt thereof, for example understand the pharmacology test data of the representative compounds of Pyrrolopyridazine compound (I) hereinafter.
(a) inhibition of U937 phosphodiesterase IN (PDE IV)
1. test method:
With the U937 cell washing of cultivating twice, and in phosphate buffered saline (PBS) (PBS), gather with cell scraper.After the centrifugal treating, cell granulations is suspended in the homogenizing buffer reagent (0.5% deoxycholate salt [DOC] among the PBS, 5mM 2 mercapto ethanol, 1 μ M leupeptin, 100 μ MPMSF, 20 μ M tolysulfonyl-L-Methionin-chloromethyl ketone [TLCK]).Then cell suspension is planted somewhat with sonic treatment, and with the glass with 20 strokes-teflon homogenizer homogenizing.With homogenate centrifugal 30 minutes with 200g, and with supernatant liquor with 100,000xg is super centrifugal 90 minutes (4 ℃) further.Final supernatant liquor is dialysed with respect to the dialysis buffer agent as the same composition homogenizing buffer reagent that does not have DOC.At-20 ℃ of dialyzates that store zymins until analyzing.
With phosphodiesterase [3H] cAMP SPA Enzyme Assay System (AmershamPharmacia Biotech), use 96 orifice plates (96 well Opti-plate) to estimate the PDE4 activity.By to containing 50mM Tris-HCl (pH 7.5), 8.3mM MgCl
2, add in the test compound of 1.7mM EGTA and various concentration or the enzyme mixture of vehicle 0.025 μ Ci/ hole [
3H] the cAMP initiation reaction.CI-930 (final 10 μ M), a kind of special P DE3 inhibitor also is added into reaction mixture.After 30 ℃ are cultivated 15 minutes, in each hole, add 50 μ LSPA particle suspension liquids.With dull and stereotyped mixing tank orifice plate was shaken 20 minutes then.Measure radioactivity in each hole with TopCounter.
Test compound is dissolved in 100% methyl-sulphoxide (DMSO) and is diluted to the respective concentration that final solution contains 1%v/v DMSO.
IC with contrast
50Value is compared, and is used for the IC of the test compound of PDE4 enzymic activity
50Value is to be determined by the regression analysis to the log-logit conversion value of the inhibition per-cent in the test tube of compound treatment.Suppressing per-cent calculates with following formula: suppress (%)={ 1-(C-B)/(A-B) } x100; The mean value of the radioactivity counting (dpm) of A, B and C test tube that represent respectively to contrast, barren and compound treatment wherein.
2. test-results
Following table is for example understood the inhibition activity of the representative compounds of formula (I) for PDE-IV:
| Embodiment | The compound title | IC 50(μM) |
| 198 | 6-{4-[4-(aminocarboxyl) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } caproic acid | ＜1 |
(b) the TNF-α that suppresses among the human monocyte produces
1. test method
(1) human peripheral blood mononuclear cell (PBMCs) preparation
Collection blood (everyone 30 milliliters) of ancon vein in the healthy volunteer is divided equally with 15mL in containing the taper test tube of Vitrum AB, and in each test tube, added the RPMI1640 of equal volume.Then with the 20mL Ficoll-Paque PLUS (Amersham Pharmacia Biotech) in the blood adding polystyrene centrifuge tube of dilution.Under 1600rpm, after the centrifugal treating 30 minutes, be collected in gradient central zone aggregating cells with kapillary, and wash several times, under 1200rpm centrifugal 10 minutes with 40mLRPMI1640.Last sedimentary PBMC is suspended in and contains among 1% foetal calf serum and the antibiotic RPMI1640.After the cell counting, in developing medium with 3 * 10
6Cell/mL prepares final suspension.
(2) by stimulating PBMCs to produce TNF-α
Using the human PBMCs of Ficoll-Paque PLUS preparation to be suspended in above-mentioned concentration by density gradient method is 3 * 10
6In the developing medium of cell/mL, and 0.5mL suspension is broadcast in each hole of 24 hole culture dish.Cell adds 0.25mL medicine enriched material or vehicle at CO with 0.25mL LPS when cultivating beginning
2Cultivated 24 hours in the thermostat container.The ultimate density of LPS in the developing medium is 1 μ g/mL.After 24 hours, will store until analysis down at-80 ℃ with the supernatant liquor in each centrifugal 10 minutes hole of 1700rpm.With the TNF-alpha levels in the ELISA measuring media.
IC with those vehicle processing
50Value is compared, the PBMC Chinese traditional medicine pair cell that the regression analysis of the horizontal relative value of cytokine in the hole by being used for drug treating is evaluated at LPS the to stimulate plain IC that produces that lives
50Value.
2. test-results
| Embodiment | The compound title | IC 50(nM) |
| 198 | 6-{4-[4-(aminocarboxyl) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } caproic acid | ＜100 |
Implement best mode of the present invention
Provide following examples further to illustrate the details that is used to prepare compound of the present invention.Do not wish that these embodiment limit the scope of the invention by any way, and should so not explain them yet.In addition, the compound of describing in following examples is not considered to only form a kind of compound of indication of the present invention, and any combination itself of these compounds or its part can form a kind of compound.Those of ordinary skills are understood that easily the condition of following preparation process and the known variant of technology can be used to prepare these compounds.
By to currently known methods, method is applied or improves preparation starting raw material and intermediate described in reference example or its tangible chemical equivalent.
The abbreviation, symbol and the term that are used for preparation example, embodiment and chemical formula have following implication.
DMF N, dinethylformamide
EtOAc or AcOEt ethyl acetate
The THF tetrahydrofuran (THF)
The Et3N triethylamine
MeOH methyl alcohol
EtOH ethanol
The BuOH butanols
The DCM methylene dichloride
Palladium on the Pd/C carbon dust
Preparation example 1
At N
2Under ice-water bath in, in the suspension of 2-pyridine mercaptan (17g) in tetrahydrofuran (THF) (200mL), add triethylamine (15.5g).Wherein adding 4-cyano-benzoyl chloride (25.3g) in the tetrahydrofuran (THF) (80mL) through 30 fens clockwise below 10 ℃.After 15 minutes, remove to bathe and mixture at room temperature stirred and spend the night.With the mixture vacuum concentration.Resistates is distributed between chloroform and water.With saturated sodium bicarbonate and salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.Resistates (38g) and isopropyl ether are ground, obtain light brown solid 4-cyano group benzene carbothioic acid carbothiolic acid S-(2-pyridyl) ester (32.5g).
4-cyano group benzene carbothioic acid carbothiolic acid S-(2-pyridyl) ester
NMR(CDCl
3，δ)：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)
Following compound is to obtain with preparation example 1 essentially identical mode.
Preparation example 2
2-chloro-4-pyridine carbothioic acid carbothiolic acid S-(2-pyridyl) ester
NMR(CDCl
3，δ)：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 example 4
3-cyano group benzene carbothioic acid carbothiolic acid S-(2-pyridyl) ester
NMR(CDCl
3，δ)：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 example 5
3-anisole carbothioic acid carbothiolic acid S-(2-pyridyl) ester
NMR(CDCl
3，δ)：3.87(3H，s)，7.16(1H，m)，7.32-7.44(2H，m)，7.51(1H，m)，7.63(1H，d，J＝8Hz)，7.71-7.83(2H，m)，8.69(1H，m)
Preparation example 6
4-pyridine carbothioic acid carbothiolic acid S-(2-pyridyl) ester
NMR(CDCl
3，δ)：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)
MS(ESI
+)：m/z 217
Preparation example 7
2-pyrazine carbothioic acid carbothiolic acid S-(2-pyridyl) ester
NMR(CDCl
3，δ)：7.38(1H，m)，7.71(1H，d，J＝8Hz)，7.82(1H，m)，8.73(2H，m)，8.86(1H，m)，9.17(1H，s)
Preparation example 8
3-pyridine carbothioic acid carbothiolic acid S-(2-pyridyl) ester
NMR(CDCl
3，δ)：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 example 9
In dry ice-propanone is bathed, in the 1M methylmagnesium-bromide that in the solution of 30 fens clockwise 2-ethyl-1H-pyrroles in toluene (120mL), drips below-60 ℃ in the tetrahydrofuran (THF) (170mL).Then with mixture ice-stirred in water bath 40 minutes.In the dry ice-propanone water-bath, added 4-cyano group benzene carbothioic acid carbothiolic acid S-(2-pyridyl) ester (15.2g) in this reaction mixture of clockwise through 10 minutes in batches.After stirring 1.5 hours, add saturated ammonium chloride (100mL) therein and make reaction mixture reach room temperature.Mixture is distributed between ethyl acetate and water.With 1N sodium hydroxide (100mL) washing organic layer twice, water and salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.Resistates and isopropyl ether are ground, obtain light yellow solid 4-[(5-ethyl-1H-pyrroles-2-yl) carbonyl] benzonitrile (12.7g).
4-[(5-ethyl-1H-pyrroles-2-yl) carbonyl] benzonitrile
NMR(CDCl
3，δ)：1.32(3H，t，J＝8Hz)，2.75(2H，q，J＝8Hz)，6.11(1H，d，J＝5Hz)，6.76(1H，d，J＝5Hz)，7.77(2H，d，J＝8Hz)，7.94(2H，d，J＝8Hz)，9.49(1H，br s)
MS(ESI
+)：m/z 225(M+H)
Following compound is to obtain with preparation example 9 essentially identical modes.
Preparation example 10
(2E)-1-(5-ethyl-1H-pyrroles-2-yl)-3-phenyl-2-propylene-1-ketone
NMR(CDCl
3，δ)：1.31(3H，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(2H，m)，7.79(1H，d，J＝16Hz)
MS(ESI
+)：m/z 226(M+H)
Preparation example 11
At N
2Under ice-water-bath in, to 4-[(5-ethyl-1H-pyrroles-2-yl) carbonyl]-benzonitrile (12.5g) is at N, adds the sodium hydride (2.68g) in 60% oil in the solution in the dinethylformamide (63mL).After 30 minutes, in mixture, add 1-(amino oxygen base)-2,4-dinitrobenzene (13.3g).After 2 hours, mixture is distributed between ethyl acetate and water.Use the ethyl acetate extraction water layer.The organic layer that water (100mL) washing merges 3 times, with 1N sodium hydroxide (100mL) and salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.By flash distillation silica gel chromatography (silica gel, 500mL) purification resistates grind with isopropyl ether subsequently, obtain yellow solid 4-[(1-amino-5-ethyl-1H-pyrroles-2-yl) carbonyl with hexane-chloroform=1-2,1-5 and 1-10 drip washing] benzonitrile (8.1g, 60.7%).By flash distillation silica gel chromatography (silica gel with hexane-chloroform=2-1 and 1-1 drip washing, 200mL) mixing part and female layer (7g) are carried out repurified, grind with isopropyl ether subsequently, obtain light yellow solid 4-[(1-amino-5-ethyl-1H-pyrroles-2-yl) carbonyl] benzonitrile (2.0g, 15%).
4-[(1-amino-5-ethyl-1H-pyrroles-2-yl) carbonyl]-benzonitrile
NMR(CDCl
3，δ)：1.29(3H，t，J＝8Hz)，2.77(2H，q，J＝8Hz)，5.75(2H，br s)，5.94(1H，d，J＝5Hz)，6.59(1H，d，J＝5Hz)，7.76(2H，d，J＝8Hz)，7.85(2H，d，J＝8Hz)
MS(ESI
+)：m/z 240(M+H)
Following compound is to obtain with preparation example 11 essentially identical modes.
Preparation example 12
(1-amino-5-ethyl-1H-pyrroles-2-yl) (2-chloro-4-pyridyl) ketone
NMR(CDCl
3，δ)：1.29(3H，t，J＝7Hz)，2.77(2H，q，J＝7Hz)，5.71(2H，s)，5.96(1H，d，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)
Preparation example 13
3-[(1-amino-5-ethyl-1H-pyrroles-2-yl) carbonyl]-benzonitrile
NMR(CDCl
3，δ)：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)
Preparation example 14
(2E)-1-(1-amino-5-ethyl-1H-pyrroles-2-yl)-3-phenyl-2-propylene-1-ketone
NMR(CDCl
3，δ)：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(1H，d，J＝16Hz)
MS(ESI
+)：m/z 241(M+H)
Preparation example 15
(1-amino-5-ethyl-1H-pyrroles-2-yl) (3-p-methoxy-phenyl)-ketone
NMR(CDCl
3，δ)：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 example 16
(1-amino-5-ethyl-1H-pyrroles-2-yl) (4-pyridyl) ketone
NMR(CDCl
3，δ)：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
Preparation example 17
(1-amino-5-ethyl-1H-pyrroles-2-yl) (2-pyrazinyl) ketone
NMR(CDCl
3，δ)：1.29(3H，t，J＝7Hz)，2.77(2H，q，J＝7Hz)，5.79(2H，s)，5.98(1H，d，J＝4Hz)，7.27(1H，d，J＝4Hz)，8.63(1H，m)，8.71(1H，m)，9.17(1H，m)
Preparation example 18
(1-amino-5-ethyl-1H-pyrroles-2-yl) (3-pyridyl) ketone
NMR(CDCl
3，δ)：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 example 19
(1-amino-5-ethyl-1H-pyrroles-2-yl) (5-bromo-3-pyridyl)-ketone
NMR(CDCl
3，δ)：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 example 20
At N
2Under ice-water-bath in, in the solution of 20 fens clockwise 3-ketobutyric acid tert-butyl esters (20.0g) in tetrahydrofuran (THF) (200mL), add 60% sodium hydride (5.56g) in the oil in batches.After 40 minutes, in mixture, add 5-iodine Valeric acid ethylester (35.6g) in this temperature.After 15 minutes, at room temperature stir the mixture.After 1 hour, reaction mixture was heated 24 hours at 50 ℃.The refrigerative mixture is distributed between ethyl acetate and water.Use the ethyl acetate extraction water layer.The organic layer that water and salt water washing merge, by dried over mgso, and evaporation in a vacuum.(silica gel, 1L) purification resistates obtain water white oil 2-ethanoyl pimelic acid 1-tertiary butyl 7-ethyl ester (27.3g, 75.4%) by the flash distillation silica gel chromatography with hexane-ethyl acetate=50-1,20-1,10-1 and 8-1 drip washing.
2-ethanoyl pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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)
Following compound is to obtain with preparation example 20 essentially identical modes.
Preparation example 21
2-ethanoyl nonane diacid 1-tertiary butyl 9-ethyl ester
NMR(CDCl
3，δ)：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)
MS(ESI
+)：m/z 315(M+H)
Preparation example 22
2-ethanoyl hecanoic acid t-butyl ester
NMR(CDCl
3，δ)：0.90(3H，t，J＝8Hz)，1.28-1.40(4H，m)，1.46(9H，s)，1.73-1.89(2H，m)，2.22(3H，s)，3.30(1H，t，J＝8Hz)
Preparation example 23
2-ethanoyl suberic acid 1-tertiary butyl 8-ethyl ester
NMR(CDCl
3，δ)：1.21-1.33(7H，m)，1.46(9H，s)，1.54-1.69(2H，m)，1.74-1.85(2H，m)，2.21(3H，s)，2.28(2H，t，J＝8Hz)，3.29(1H，t，J＝8Hz)，4.12(2H，q，J＝8Hz)
Preparation example 24
At room temperature N
2In the suspension of magnesium chloride (1.33g) in methylene dichloride (40mL), add 2-ethanoyl pimelic acid 1-tertiary butyl 7-ethyl ester (4.0g) down.In ice-water-bath, in this mixture, drip pyridine (2.26mL).At room temperature stirred the mixture then 40 minutes.3-cyano-benzoyl chloride (3.01g) in 2 fens clockwise reaction mixtures in the drip dichloromethane (6mL).At room temperature stirred reaction mixture is 2 hours.In ice-water-bath, in mixture, add 1N hydrogenchloride and ethyl acetate.With 1N hydrogenchloride, water and salt water washing organic layer, by dried over mgso, and evaporation obtains solid in a vacuum.(silica gel, 300mL) purification resistates obtain water white oil 2-ethanoyl-2-(3-cyano group benzoyl) pimelic acid 1-tertiary butyl 7-ethyl ester (4.23g, 72.9%) by the flash distillation silica gel chromatography with hexane-ethyl acetate=10-1,8-1,5-1 and 3-1 drip washing.
2-ethanoyl-2-(3-cyano group benzoyl)-pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：1.25(3H，t，J＝8Hz)，1.28-1.40(11H，m)，1.63-1.75(2H，m)，2.19-2.28(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)
Following compound is to obtain with preparation example 24 essentially identical modes.
Preparation example 25
2-isobutyryl-4-methyl-3-oxopentanoic acid ethyl ester
NMR(300MHz，CDCl
3，δ)：1.10-1.23(12H，m)，1.30-1.43(3H，m)，2.91-3.10(2H，m)，4.21-4.36(2H，m)
Preparation example 26
2-(2-chlorobenzene formacyl)-4-methyl-3-oxopentanoic acid ethyl ester
NMR(300MHz，CDCl
3，δ)：0.79(3H，t，J＝7.5Hz)，1.22(6H，d，J＝7.5Hz)，3.36-3.54(1H，m)，3.88(2H，q，J＝7.5Hz)，7.26-7.44(4H，m)
Preparation example 27
4-methyl-2-(2-naphthoyl base)-3-oxopentanoic acid ethyl ester
NMR(300MHz，CDCl
3，δ)：0.76-1.03(3H，m)，1.10-1.30(6H，m)，2.56-2.71(1/2H，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 example 28
2-ethanoyl-2-[3-(trifluoromethyl) benzoyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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)
Preparation example 29
2-ethanoyl-2-[(5-methyl-3-pyridyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.27-1.42(2H，m)，1.34(9H，s)，1.65-1.77(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)
Preparation example 30
2-(methoxyl group ethanoyl)-2-[(3-methoxyl group-5 is different _ the azoles base) and carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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(2H，q，J＝7Hz)，4.57(2H，s)，6.54(1H，s)
Preparation example 31
2-ethanoyl-2-[3-(1,3-_ azoles-5-yl) benzoyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.33(9H，s)，1.30-1.43(2H，m)，1.62-1.76(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 example 32
2-ethanoyl-2-(3,4-dichloro-benzoyl base) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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)
Preparation example 33
2-ethanoyl-2-[(4-chloro-2-pyridyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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)
MS(ESI
+)：m/z 426(M+H)
Preparation example 34
2-[(5-chloro-2-thienyl) carbonyl]-2-(methoxyl group ethanoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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(1H，d，J＝4Hz)
Preparation example 35
2-ethanoyl-2-[(6-methoxyl group-2-pyrazinyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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(2H，q，J＝7Hz)，8.37(1H，s)，8.83(1H，s)
Preparation example 36
2-ethanoyl-2-(1-cumarone-2-base carbonyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.33(9H，s)，1.38-1.55(2H，m)，1.64-1.77(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 example 37
2-ethanoyl-2-(1-thionaphthene-2-base carbonyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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 example 38
2-ethanoyl-2-(1,3-_ azoles-5-base carbonyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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(1H，s)
Preparation example 39
2-ethanoyl-2-benzoyl pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：1.26(3H，t，J＝7Hz)，1.20-1.40(2H，m)，1.32(9H，s)，1.60-1.73(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 example 40
2-ethanoyl-2-(6-quinolyl carbonyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：1.21(3H，t，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(1H，dd，J＝2Hz，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)
Preparation example 41
2-ethanoyl-2-[4-({ [(benzyloxy) carbonyl] amino } alkylsulfonyl) benzoyl] nonane diacid 1-tertiary butyl 9-ethyl ester
NMR(CDCl
3，δ)：1.23-1.37(11H，m)，1.60(9H，s)，2.15-2.31(4H，m)，2.46(3H，s)，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 example 42
2-ethanoyl-2-(the different nicotinoyl of 2-chlorine) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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＝1Hz)，8.50(1H，d，J＝7Hz)
Preparation example 43
2-ethanoyl-2-[3-(methyl sulphonyl) benzoyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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)
Preparation example 44
2-ethanoyl-2-(3-nitro benzoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：1.30-1.39(12H，m)，1.61-1.75(2H，m)，2.19-2.35(4H，m)，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(1H，br d，J＝8Hz)，8.60(1H，br s)
Preparation example 45
2-ethanoyl-2-(4-cyano group benzoyl) caproic acid uncle fourth salt
NMR(CDCl
3，δ)：0.90(3H，t，J＝8Hz)，1.20-1.44(13H，m)，2.15-2.25(2H，m)，2.45(3H，s)，7.70(2H，d，J＝8Hz)，7.83(2H，d，J＝8Hz)
Preparation example 46
2-ethanoyl-2-[(5-bromo-3-pyridyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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：(m/z)470，472(M+H)
Preparation example 47
2-(the different nicotinoyl of 2-chlorine)-2-[(methylthio group) ethanoyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.37(9H，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(2H，t，J＝7Hz)，3.16(1H，d，J＝17Hz)，4.07(1H，d，J＝17Hz)，4.11(2H，q，J＝7Hz)，7.68(1H，d，J＝5Hz)，7.87(1H，s)，8.49(1H，d，J＝5Hz)
Preparation example 48
2-(4-fluoro benzoyl)-ethyl 3-oxobutanoate
NMR (CDCl
3, δ): (mixture of tautomer) 0.97 and 1.02 (3H, t, J=7Hz), 2.07 and 2.42 (3H, s), 4.01 and 4.13 (2H, q, J=7Hz), 7.06-7.18,7.56 and 7.85 (4H, m)
MS(ESI
+)：m/z 275(M+H)
Preparation example 49
2-ethanoyl-2-(3-cyano group benzoyl) suberic acid 1-tertiary butyl 8-ethyl ester
NMR(CDCl
3，δ)：1.21-1.46(16H，m)，1.56-1.70(2H，m)，2.15-2.25(2H，m)，2.29(2H，t，J＝8Hz)，2.45(3H，s)，4.12(2H，q，J＝8Hz)，7.56(1H，t，J＝8Hz)，7.80(2H，dd，J＝8，1Hz)，7.95(2H，dd，J＝8，1Hz)，8.05(1H，br s)
Preparation example 50
2-ethanoyl-2-[(6-chloro-2-pyridyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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
Preparation example 51
2-ethanoyl-2-(3-anisoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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)
Preparation example 52
2-ethanoyl-2-(3,5-dichloro-benzoyl base) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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)
Preparation example 53
2-ethanoyl-2-[(5-chloro-2-thienyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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，J＝4Hz)
Preparation example 54
2-ethanoyl-2-(3-fluoro benzoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.35(9H，s)，1.35-1.45(2H，m)，1.64-1.74(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)
Preparation example 55
2-ethanoyl-2-(3-quinolyl carbonyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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，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 example 56
The different nicotinoyl pimelic acid of 2-ethanoyl-2-1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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)
Preparation example 57
2-ethanoyl-2-[(3-methoxyl group-5-is different _ the azoles base) and carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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)
Preparation example 58
2-ethanoyl-2-[(5-methyl-3-is different _ the azoles base) and carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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(2H，q，J＝7Hz)，6.38(1H，s)
Preparation example 59
2-(the different nicotinoyl of 2-chlorine)-2-[(methoxyl group ethanoyl)] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.32-1.45(2H，m)，1.36(9H，s)，1.64-1.78(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)
MS(ESI
+)：m/z 456
Preparation example 60
2-(methoxyl group ethanoyl)-2-(3-anisoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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
Preparation example 61
2-(methoxyl group ethanoyl)-2-(6-quinolyl carbonyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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，J＝8Hz)，8.28(1H，d，J＝8Hz)，8.27(1H，s)，9.01(1H，m)
MS(ESI
+)：m/z 472
Preparation example 62
2-(methoxyl group ethanoyl)-2-(3-pyridyl carbonyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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)
Preparation example 63
2-(3-chlorobenzene formacyl)-2-(methoxyl group ethanoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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，J＝8Hz)，7.73(1H，m)
Preparation example 64
2-ethanoyl-2-(3-methyl benzoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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)
MS(ESI
+)：m/z 405
Preparation example 67
2-(methoxyl group ethanoyl)-2-[(5-methyl-3-pyridyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.36(9H，s)，1.30-1.45(2H，m)，1.62-1.76(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 example 68
2-ethanoyl-2-[(5-bromo-3-pyridyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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
Preparation example 69
2-[(5-bromo-3-pyridyl) carbonyl]-2-(methoxyl group ethanoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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，J＝17Hz)，4.40(1H，d，J＝17Hz)，8.18(1H，m)，8.80(2H，m)
MS(ESI
+)：m/z 500，502
Preparation example 70
2-ethanoyl-2-[(5,6-two chloro-3-pyridyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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)
Preparation example 71
2-(methoxyl group ethanoyl)-2-[(5-methyl-3-pyridyl) carbonyl] hexanodioic acid 1-tertiary butyl 6-ethyl ester
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.36(9H，s)，1.60-1.80(2H，m)，2.20-2.45(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 example 72
2-(methoxyl group ethanoyl)-2-[(5-methyl-3-pyridyl) carbonyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
NMR(CDCl
3，δ)：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
Preparation example 73
2-ethanoyl-2-[(5-methyl-3-pyridyl) carbonyl] hexanodioic acid 1-tertiary butyl 6-ethyl ester
NMR(CDCl
3，δ)：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)，8.73(1H，s)
MS(ESI
+)：m/z 392
Preparation example 74
2-ethanoyl-2-[(5-methyl-3-pyridyl) carbonyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
NMR(CDCl
3，δ)：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
Preparation example 75
2-ethanoyl-2-[(5-bromo-3-pyridyl) carbonyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.37(9H，s)，2.40(2H，t，J＝7Hz)，2.59(2H，t，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 example 76
2-(3-cyano group benzoyl)-2-(methoxyl group ethanoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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)
Preparation example 77
The 2-[(acetoxyl group) ethanoyl]-2-[(5-bromo-3-pyridyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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(1H，m)，8.81(2H，m)
Preparation example 78
In ice-water-bath, in 2-ethanoyl-2-(3-cyano group benzoyl) pimelic acid 1-tertiary butyl 7-ethyl ester (4.2g), add trifluoroacetic acid (20mL).After 30 minutes, remove ice-water-bath and reaction mixture is at room temperature stirred.After 1 hour, enriched mixture.Resistates is dissolved in toluene, and evaporation in a vacuum, water white oil 6-(3-cyano group benzoyl)-7-oxo ethyl octylate (3.20g, 100.4%) obtained.
6-(3-cyano group benzoyl)-7-oxo ethyl octylate
NMR(CDCl
3，δ)：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(2H，dd，J＝8，1Hz)，8.20(2H，dd，J＝8，1Hz)，8.26(1H，br s)
MS(ESI
-)：m/z 314(M-H)
Following compound is to obtain with preparation example 78 essentially identical modes.
Preparation example 79
7-oxo-6-[3-(trifluoromethyl) benzoyl] ethyl octylate
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.32-1.43(2H，m)，1.62-1.77(2H，m)，1.96-2.17(2H，m)，2.17(3H，s)，2.30(2H，t，J＝7Hz)，4.11(2H，q，J＝7Hz)，4.44(1H，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 example 80
6-[(5-methyl-3-pyridyl) carbonyl]-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.26(3H，t，J＝7Hz)，1.27-1.44(2H，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(2H，q，J＝7Hz)，4.42(1H，t，J＝7Hz)，8.03(1H，s)，8.63(1H，s)，8.98(1H，s)
MS(ESI
+)：m/z 306(M+H)
Preparation example 81
8-methoxyl group-6-[(3-methoxyl group-5-is different _ the azoles base)] carbonyl]-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.34-1.47(2H，m)，1.65-1.74(2H，m)，1.83-2.03(2H，m)，2.29(2H，t，J＝7Hz)，3.31(3H，s)，4.05(5H，s)，4.11(2H，q，J＝7Hz)，4.51(1H，t，J＝7Hz)，6.56(1H，s)
MS(ESI
+)：m/z 342(M+H)
Preparation example 82
6-[3-(1,3-_ azoles-5-yl) benzoyl]-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.33-1.46(2H，m)，1.63-1.77(2H，m)，1.95-2.17(2H，m)，2.17(3H，s)，2.30(2H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.46(1H，t，J＝7Hz)，7.47(1H，s)，7.56(1H，t，J＝8Hz)，7.85-7.96(2H，m)，7.98(1H，s)，8.27(1H，m)
Preparation example 83
6-(3,4-dichloro-benzoyl base)-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.30-1.43(2H，m)，1.60-1.74(2H，m)，1.91-2.14(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 example 84
6-[(4-chloro-2-pyridyl) carbonyl]-7-oxo ethyl octylate
NMR(CDCl
3，δ)：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＝2Hz，5Hz)，8.04(1H，d，J＝2Hz)，8.57(1H，d，J＝5Hz)
MS(ESI
+)：m/z 326(M+H)
Preparation example 85
6-[(5-chloro-2-thienyl) carbonyl]-8-methoxyl group-7-oxo ethyl octylate
NMR(CDCl
3，δ)：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，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 example 86
6-[(6-methoxyl group-2-pyrazinyl) carbonyl]-7-oxo ethyl octylate
NMR(CDCl
3，δ)：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)
Preparation example 87
6-(1-cumarone-2-base carbonyl)-7-oxo ethyl octylate
NMR(CDCl
3，δ)：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，J＝8Hz)
MS(ESI
+)：m/z 895(M+H)
Preparation example 88
6-(1-benzothienyl-2-carbonyl)-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.35-1.48(2H，m)，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(1H，t，J＝7Hz)，7.38-7.53(2H，m)，7.82-7.93(2H，m)，8.05(1H，s)
Preparation example 89
6-(1,3-_ azoles-5-base carbonyl)-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.30-1.43(2H，m)，1.65-1.78(2H，m)，1.92-2.10(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 example 90
6-benzoyl-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.29-1.42(2H，m)，1.60-1.75(2H，m)，1.92-2.12(2H，m)，2.14(3H，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 example 91
7-oxo-6-(6-quinolyl carbonyl) ethyl octylate
NMR(CDCl
3，δ)：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(1H，d，J＝8Hz)，8.28(1H，dd，J＝2Hz，8Hz)，8.32(1H，d，J＝8Hz)，8.51(1H，d，J＝2Hz)，9.05(1H，m)
MS(ESI
+)：m/z 342(M+H)
Preparation example 92
8-[4-({ [(benzyloxy) carbonyl] amino } alkylsulfonyl) benzoyl]-9-oxo ethyl decylate
NMR(CDCl
3，δ)：1.23-1.37(9H，m)，1.55-1.68(11H，s)，2.01(2H，m)，2.18(3H，s)，2.29(2H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.39(1H，t，J＝7Hz)，5.11(2H，s)，7.30-7.49(5H，m)，7.74(1H，s，br)，8.04-8.13(4H，m)
MS(ESI
-)：m/z 530(M-H)
Preparation example 93
7-(1,3-_ azoles-5-yl)-7-oxoheptanoate
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.41(2H，m)，1.76(2H，m)，2.03(2H，m)，2.31(2H，m)，3.20(2H，m)，4.10(2H，q，J＝7Hz)，7.94(1H，s)，8.10(1H，s)
Preparation example 94
6-[3-(methyl sulphonyl) benzoyl]-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.24(3H，t，J＝8Hz)，1.59-1.64(2H，m)，1.91-2.15(2H，m)，2.18(3H，s)，2.30(2H，t，J＝8Hz)，3.11(3H，s)，4.10(2H，q，J＝8Hz)，4.45(1H，t，J＝8Hz)，7.23(1H，t，J＝8Hz)，8.17(1H，dd，J＝8，1Hz)，8.25(2H，br d，J＝8Hz)，8.53(1H，br s)
MS(ESI
+)：m/z 369(M+H)
Preparation example 95
6-(the different nicotinoyl of 2-chlorine)-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.25(3H，t，J＝8Hz)，1.30-1.40(2H，m)，1.60-1.71(2H，m)，1.90-2.14(2H，m)，2.27(3H，s)，2.25-2.74(2H，m)，4.11(2H，q，J＝8Hz)，4.32(1H，t，J＝8Hz)，7.15(1H，dd，J＝7，1Hz)，7.76(1H，d，J＝1Hz)，8.09(1H，d，J＝7Hz)
MS(ESI
+)：m/z 326(M+H)
Preparation example 96
6-(3-nitro benzoyl)-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.24(3H，t，J＝8Hz)，1.29-1.41(2H，m)，1.60-1.74(2H，m)，1.91-2.16(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(1H，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)
Preparation example 97
4-(2-ethanoyl caproyl) benzonitrile
NMR(CDCl
3，δ)：0.90(3H，t，J＝8Hz)，1.18-1.44(4H，m)，1.90-2.12(2H，m)，2.17(3H，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 example 98
6-[(5-bromo-3-pyridyl) carbonyl]-7-oxo ethyl octylate
NMR(CDCl
3，δ)：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(3H，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：(m/z)370，372(M+H)
Preparation example 99
6-(the different nicotinoyl of 2-chlorine)-8-(methylthio group)-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.34-1.47(2H，m)，1.60-1.77(2H，m)，1.92(3H，s)，1.93-2.05(2H，m)，2.30(2H，t，J＝7Hz)，3.19(1H，d，J＝17Hz)，3.26(1H，d，J＝17Hz)，4.11(2H，q，J＝7Hz)，4.68(1H，t，J＝7Hz)，7.72(1H，d，J＝5Hz)，7.86(1H，s)，8.57(1H，d，J＝5Hz)
MS：(m/z)370(M-H)，372(M+H)
Preparation example 100
7-(3-cyano group benzoyl)-8-oxo ethyl pelargonate
NMR(CDCl
3，δ)：1.21-1.44(7H，m)，1.55-1.69(2H，m)，1.89-2.15(2H，m)，2.17(3H，s)，2.29(2H，t，J＝8Hz)，4.12(2H，q，J＝8Hz)，4.39(1H，t，J＝8Hz)，7.64(1H，t，J＝8Hz)，7.87(1H，dd，J＝8，1Hz)，8.20(1H，dd，J＝8，1Hz)，8.27(1H，br s)
MS(ESI
+)：m/z 330(M+H)
Preparation example 101
6-[(6-chloro-2-pyridyl) carbonyl]-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.26(3H，t，J＝7Hz)，1.36-1.52(2H，m)，1.63-1.75(2H，m)，1.77-2.06(2H，m)，2.29(2H，t，J＝7Hz)，2.45(3H，s)，4.12(2H，q，J＝7Hz)，4.82(1H，t，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
Preparation example 102
6-(3-anisoyl)-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.30-1.43(2H，m)，1.60-1.77(2H，m)，1.92-2.12(2H，m)，2.15(3H，s)，2.31(2H，t，J＝7Hz)，3.88(3H，s)，4.12(2H，q，J＝7Hz)，4.42(1H，t，J＝7Hz)，7.14(1H，dd，J＝2Hz，8Hz)，7.40(1H，t，J＝8Hz)，7.46-7.58(2H，m)
MS(ESI
+)：m/z 321
Preparation example 103
6-(3,5-dichloro-benzoyl base)-7-oxo ethyl octylate
NMR(CDCl
3，δ)：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(3H，s)，2.30(2H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.32(1H，t，J＝7Hz)，7.58(1H，m)，7.82(2H，m)
Preparation example 104
6-[(5-chloro-2-thienyl) carbonyl]-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，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＝4Hz)，7.58(1H，d，J＝4Hz)
Preparation example 105
6-(3-fluoro benzoyl)-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.24(3H，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(2H，t，J＝7Hz)，4.11(2H，q，J＝7Hz)，4.37(1H，t，J＝7Hz)，7.26-7.33(1H，m)，7.43-7.52(1H，m)，7.63-7.68(1H，m)，7.76(1H，d，J＝8Hz)
MS(ESI
+)：m/z 309
Preparation example 106
7-oxo-6-(3-quinolyl carbonyl) ethyl octylate
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.35-1.47(2H，m)，1.63-1.77(2H，m)，1.98-2.18(2H，m)，2.20(3H，s)，2.31(2H，t，J＝7Hz)，4.10(2H，q，J＝7Hz)，4.55(1H，t，J＝7Hz)，7.66(1H，t，J＝8Hz)，7.87(1H，t，J＝8Hz)，7.97(1H，d，J＝8Hz)，8.18(1H，d，J＝8Hz)，8.78(1H，d，J＝2Hz)，9.43(1H，d，J＝2Hz)
MS(ESI
+)：m/z 342
Preparation example 107
The different nicotinoyl of 6--7-oxo ethyl octylate
NMR(CDCl
3，δ)：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(2H，m)，4.11(2H，q，J＝7Hz)，4.38(1H，t，J＝7Hz)，7.74(2H，m)，8.83(2H，m)
Preparation example 108
6-[(3-methoxyl group-5-is different _ the azoles base)] carbonyl]-7-oxo ethyl octylate
NMR(CDCl
3，δ)：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)，4.33(1H，t，J＝7Hz)，6.56(1H，s)
MS(ESI
+)：m/z 312
Preparation example 109
6-[(5-methyl-3-is different _ the azoles base) and carbonyl]-7-oxo ethyl octylate
NMR(CDCl
3，δ)：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(2H，m)，2.29(3H，s)，2.49(3H，s)，4.11(2H，q，J＝7Hz)，4.64(1H，m)，6.39(1H，s)
MS(ESI
+)：m/z 296
Preparation example 110
6-(the different nicotinoyl of 2-chlorine)-8-methoxyl group-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.24(3H，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(3H，s)，3.89(1H，d，J＝17Hz)，4.00(1H，d，J＝17Hz)，4.10(2H，q，J＝7Hz)，458(1H，t，J＝7Hz)，7.66(1H，d，J＝5Hz)，7.78(1H，s)，8.60(1H，d，J＝5Hz)
MS(ESI
+)：m/z 356，MS(ESI
-)：m/z 354
Preparation example 111
8-methoxyl group-6-(3-anisoyl)-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.30-1.43(2H，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(2H，q，J＝7Hz)，4.66(1H，t，J＝7Hz)，7.13(1H，m)，7.39(1H，m)，7.45-7.55(2H，m)
Preparation example 112
8-methoxyl group-7-oxo-6-(6-quinolyl carbonyl) ethyl octylate
NMR(CDCl
3，δ)：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(2H，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(1H，m)，9.02(1H，m)
MS(ESI
+)：m/z 372
Preparation example 113
8-methoxyl group-7-oxo-6-(3-pyridine carbonyl) ethyl octylate
NMR(CDCl
3，δ)：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，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 example 114
6-(3-chlorobenzene formacyl)-8-methoxyl group-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.23(3H，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(2H，t，J＝7Hz)，3.25(3H，s)，3.93(1H，d，J＝17Hz)，4.02(1H，d，J＝17Hz)，4.12(2H，q，J＝7Hz)，4.63(1H，t，J＝7Hz)，7.43(1H，t，J＝8Hz)，7.57(1H，d，J＝8Hz)，7.83(1H，d，J＝8Hz)，7.94(1H，s)
Preparation example 115
6-(3-methyl benzoyl)-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.29-1.42(2H，m)，1.60-1.73(2H，m)，1.90-2.06(2H，m)，2.13(3H，s)，2.28(2H，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)
Preparation example 118
8-methoxyl group-6-[(5-methyl-3-pyridyl)] carbonyl]-7-oxo ethyl octylate
NMR(CDCl
3，δ)：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(1H，d，J＝17Hz)，4.12(2H，q，J＝7Hz)，4.67(1H，t，J＝7Hz)，8.03(1H，s)，8.63(1H，s)，8.98(1H，s)
MS(ESI
+)：m/z 336
Preparation example 119
6-[(5-bromo-3-pyridyl) carbonyl]-7-oxo ethyl octylate
NMR(CDCl
3，δ)：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(3H，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
Preparation example 120
6-[(5-bromo-3-pyridyl) carbonyl]-8-methoxyl group-7-oxo ethyl octylate
NMR(CDCl
3，δ)：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(2H，t，J＝7Hz)，3.25(3H，s)，3.93(1H，d，J＝17Hz)，4.02(1H，d，J＝17Hz)，4.10(2H，q，J＝7Hz)，4.63(1H，t，J＝7Hz)，8.38(1H，m)，8.88(1H，m)，9.07(1H，m)
MS(ESI
+)：m/z 400，402
Preparation example 121
6-[(5,6-two chloro-3-pyridyl) carbonyl]-7-oxo ethyl octylate
NMR(CDCl
3，δ)：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(3H，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)
Preparation example 122
7-methoxyl group-5-[(5-methyl-3-pyridyl) carbonyl]-the 6-oxoheptanoate
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.60-1.75(2H，m)，1.78-1.95(1H，m)，1.95-2.12(1H，m)，2.32(2H，t，J＝7Hz)，2.44(3H，s)，3.25(3H，s)，3.94(1H，d，J＝18Hz)，4.02(1H，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
Preparation example 123
6-methoxyl group-4-[(5-methyl-3-pyridyl) carbonyl]-5-oxo ethyl hexanoate
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，2.08-2.55(4H，m)，2.44(3H，s)，3.23(3H，s)，3.94(1H，d，J＝18Hz)，4.01(1H，d，J＝18Hz)，4.12(2H，q，J＝7Hz)，4.88(1H，m)，8.12(1H，s)，8.64(1H，s)，9.04(1H，s)
MS(ESI
+)：m/z 308
Preparation example 124
5-[(5-methyl-3-pyridyl) carbonyl]-the 6-oxoheptanoate
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.60-1.75(2H，m)，1.96-2.13(2H，m)，2.18(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(1H，s)
MS(ESI
+)：m/z 292
Preparation example 125
4-[(5-methyl-3-pyridyl) carbonyl]-5-oxo ethyl hexanoate
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，2.20(3H，s)，2.26-2.48(4H，m)，2.43(3H，s)，4.13(2H，q，J＝7Hz)，4.62(1H，t，J＝7Hz)，8.08(1H，s)，8.64(1H，s)，9.02(1H，s)
MS(ESI
+)：m/z 278
Preparation example 126
4-[(5-bromo-3-pyridyl) carbonyl]-5-oxo ethyl hexanoate
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，2.26(3H，s)，2.30(2H，t，J＝7Hz)，2.43(2H，t，J＝7Hz)，4.15(2H，q，J＝7Hz)，8.65(1H，s)，8.94(1H，s)，9.22(1H，s)
Preparation example 127
6-(3-cyano group benzoyl)-8-methoxyl group-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.19-1.43(12H，m)，1.57-1.70(2H，m)，1.80(1H，m)，1.99(1H，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＝8Hz)，7.87(1H，dd，J＝8，1Hz)，8.18(1H，dd，J＝8，1Hz)，8.25(1H，br s)
Preparation example 128
8-(acetoxyl group)-6-[(5-bromo-3-pyridyl) carbonyl]-7-oxo ethyl octylate
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.37(2H，m)，1.67(2H，m)，1.98-2.06(5H，m)，2.30(2H，t，J＝7Hz)，4.11(2H，q，J＝7Hz)，4.47(1H，t，J＝7Hz)，4.66(d，J＝17Hz)，4.74(d，J＝17Hz)，8.37(1H，m)，8.88(1H，m)，9.06(1H，m)
Preparation example 129
In ice-methanol bath under nitrogen atmosphere (9 ℃), through 3 fens clockwise Meldrum acid (30g, 0.208mol) add in the solution in methylene dichloride (420mL) pyridine (33.7mL, 0.416mol).In this mixture, dripping the solution of methoxyacetyl chloride (24.8g) in methylene dichloride (180mL) under this temperature through 1 hour.After the adding, reaction mixture stirred under this temperature 1 hour and at room temperature stirred 2 hours.(600mL) makes the mixture quenching with 1N hydrochloric acid.Separate organic layer and use the dichloromethane extraction water layer.Organic layer with the salt water washing merges by dried over mgso, and evaporates in a vacuum, obtains dark orange oil 5-(methoxyl group ethanoyl)-2,2-dimethyl-1,3-two _ alkane-4,6-diketone (38.1g, 84.7%).
5-(methoxyl group ethanoyl)-2,2-dimethyl-1,3-two _ alkane-4,6-diketone
NMR(CDCl
3，δ)：1.75(6H，s)，3.53(3H，s)，4.87(2H，s)
Preparation example 130
With 5-(methoxyl group ethanoyl)-2,2-dimethyl-1,3-two _ alkane-4,6-diketone (38g) solution in the trimethyl carbinol (120mL) and toluene (120mL) refluxed 2 hours under nitrogen atmosphere.Evaporating mixture obtains brown oil (32.5g) in a vacuum.Resistates is dissolved in hexane-ethyl acetate=2-1 (200mL) and to wherein adding silica gel (65g).After at room temperature stirring 30 minutes, filtering mixt is also used hexane-ethyl acetate=2-1 (200mL) washing.Filtrate is concentrated in a vacuum, obtain light yellow oil 4-methoxyl group-3-ketobutyric acid tert-butyl ester (30.1g, 91.0%).
4-methoxyl group-3-ketobutyric acid the tert-butyl ester
NMR(CDCl
3，δ)：1.50(9H，s)，3.41(2H，s)，3.43(3H，s)，4.08(2H，s)
Preparation example 131
Add salt of wormwood (1.38g) to 3-formyl radical phenylformic acid (500mg) and tolysulfonyl ylmethyl isocyanide (715mg) in the mixture in methyl alcohol (20mL), and mixture was heated 2 hours under refluxing.After the evaporating solvent, resistates is distributed between ethyl acetate and water.Separate water layer and use the 1N hcl acidifying.Precipitation that collection obtains and water, methyl alcohol and ether washing obtain colourless amorphous powder 3-(1,3-_ azoles-5-yl) phenylformic acid (484mg).
3-(1,3-_ azoles-5-yl) phenylformic acid
NMR(DMSO-d
6，δ)：7.63(1H，t，J＝8Hz)，7.84(1H，s)，7.89-8.02(2H，m)，8.25(1H，m)，8.50(1H，s)，13.22(1H，br)
MS(ESI
+)：m/z 188(M-H)
Preparation example 132
With 1-(3-chloro-phenyl-)-1,3-dimethyl diketone (500mg), 5-(iodomethyl)-2,2-dimethyl-1,3-two _ alkane (716mg) and the mixture of salt of wormwood (351mg) in methyl-sulphoxide (2.5mL) at room temperature stirred 14 hours and stirred 7 hours down at 40 ℃.Mixture is distributed between ethyl acetate (20mL) and water (10mL).(10 * 2mL) and salt water washing organic layer, by dried over mgso, and evaporation obtains brown oil to water in a vacuum.Obtain yellow oil 1-(3-chloro-phenyl-)-2-[(2,2-dimethyl-1,3-two _ alkane-5-yl with ethyl acetate-hexane=1-10 to the flash distillation silica gel column chromatography of 2-5 drip washing) methyl]-1,3 dimethyl diketone (614mg).
1-(3-chloro-phenyl-)-2-[(2,2-dimethyl-1,3-two _ alkane-5-yl) methyl]-1, the 3-dimethyl diketone
NMR(CDCl
3，δ)：1.39(6H，s)，1.70(1H，m)，1.91-2.15(2H，m)，2.16(3H，s)，3.61(2H，m)，3.88(2H，m)，4.46(1H，t，J＝7Hz)，7.44(1H，t，J＝9Hz)，7.57(1H，m)，7.86(1H，d，J＝9Hz)，7.96(1H，m)
Following compound is to obtain with preparation example 132 essentially identical modes.
Preparation example 133
2-(1,3-_ azoles-5-base carbonyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：1.26(3H，t，J＝7Hz)，1.32-1.38(11H，m)，1.67(2H，m)，1.97(2H，m)，2.30(2H，m)，3.86(1H，t，J＝7Hz)，4.11(2H，q，J＝7Hz)，7.86(1H，s)，8.03(1H，s)
Preparation example 134
2-[(3,5-dimethyl-4-is different _ the azoles base) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.33-1.41(11H，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，J＝7Hz)
Preparation example 135
In the suspension of magnesium chloride (1.46g) in tetrahydrofuran (THF) (10mL), add the 3-oxo-solution of 4-phenylbutyrate (2.0g) in tetrahydrofuran (THF) (10mL), and mixture is cooled to 0 ℃, add pyridine (2.5mL) then.Mixture was stirred 30 minutes at 20 ℃, add the solution of 4-fluorobenzoyl chloride (2.44g) in tetrahydrofuran (THF) (10mL) at 0 ℃ then.After 20 ℃ are stirred 2 hours, mixture is distributed between 0.5N hydrochloric acid and ethyl acetate.Separate organic layer, water and salt water washing are by dried over mgso and evaporation.By on silica gel, resistates being carried out chromatographic separation, obtain oily 2-(4-fluoro benzoyl)-3-oxo-4-phenylbutyrate (2.15g) with ethyl acetate and hexane (1: 5) mixture drip washing.
2-(4-fluoro benzoyl)-3-oxo-4-phenylbutyrate
(mixture of tautomer, too complicated) so that be difficult to point out
Preparation example 136
With 1-(4-fluorophenyl) butane-1,3-diketone (1.0g), salt of wormwood (3.42g) and bromination tetrabutylammonium (20mg) mixture in toluene (10mL) refluxed 3 hours.Be cooled to after 20 ℃, in mixture, add ethyl bromoacetate (0.74mL).After 20 ℃ of placements are spent the night, mixture is distributed between ethyl acetate and 0.5N hydrochloric acid.Separate organic layer, water and salt water washing are by dried over mgso and evaporation.By on silica gel, resistates being carried out chromatographic separation, obtain oily 3-(4-fluoro benzoyl)-ethyl 4-oxopentanoate (964mg) with ethyl acetate and hexane (1: 5) mixture drip washing.
3-(4-fluoro benzoyl)-ethyl 4-oxopentanoate
NMR(CDCl
3，δ)：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 example 137
With 1-(4-fluorophenyl) butane-1,3-diketone (1.0g), salt of wormwood (3.84g) and bromination tetrabutylammonium (90mg) mixture in toluene (20mL) refluxed 3 hours, added 6-bromocaproic acid ethyl ester (1.18mL) then.After 100 ℃ are stirred 3 hours, mixture is distributed between ethyl acetate and 0.5N hydrochloric acid.Separate organic layer, water and salt water washing are by dried over mgso and evaporation.By on silica gel, resistates being carried out chromatographic separation, obtain oily 7-(4-fluoro benzoyl)-8-oxo ethyl pelargonate (983mg) with ethyl acetate and hexane (1: 5) mixture drip washing.
7-(4-fluoro benzoyl)-8-oxo ethyl pelargonate
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.25-1.45(4H，m)，1.55-1.70(2H，m)，1.90-2.10(2H，m)，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 example 138
At 20 ℃ with pentane-2,4-diketone (5.0g), 7-bromine oil of cognac (11.1g), salt of wormwood (13.8g) and cesium carbonate (1.63g) mixture in acetonitrile (150ml) and methyl-sulphoxide (30ml) mixture stirs and spends the night, add pentane-2 then, 4-diketone (5g).After 20 ℃ of stirrings are spent the night, mixture is distributed between ethyl acetate and 0.5N hydrochloric acid.Separate organic layer, water and salt water washing are by dried over mgso and evaporation.By on silica gel, resistates being carried out chromatographic separation, obtain oily 8-ethanoyl-9-oxo ethyl decylate (5.5g) with ethyl acetate and hexane (1: 5) mixture drip washing.
7-ethanoyl-8-oxo ethyl pelargonate
(mixture of tautomer, too complicated) so that be difficult to point out
Preparation example 139
Add pyridine (2.15mL) to 7-ethanoyl-8-oxo ethyl pelargonate (4.0g) and magnesium chloride (1.27g) in the mixture in methylene dichloride (70ml) at 0 ℃.Mixture was stirred 1 hour at 20 ℃, add the solution of 4-cyano-benzoyl chloride (2.87g) in methylene dichloride (10mL) then.After 20 ℃ are stirred 3 hours, mixture is distributed between ether and 1N hydrochloric acid.Separate organic layer, water and salt water washing are by dried over mgso and evaporation.By on silica gel, using ethyl acetate and hexane (1: 5) mixture drip washing, obtain oily 7-ethanoyl-7-(4-cyano group benzoyl)-8-oxo ethyl pelargonate (3.52g) to the resistates chromatographic separation.
2-ethanoyl-2-(4-cyano group benzoyl) suberic acid 1-tertiary butyl 8-ethyl ester
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.25-1.45(4H，m)，1.30(9H，s)，1.55-1.70(2H，m)，2.20(2H，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 example 140
7-ethanoyl-7-(4-cyano group benzoyl)-8-oxo ethyl pelargonate (3.5g) is dissolved in trifluoroacetic acid (12.6ml), and mixture was stirred 15 minutes at 20 ℃.Mixture is distributed between ethyl acetate and water.Separate organic layer, MgSO is passed through in water, sodium bicarbonate aqueous solution and salt water washing
4(sal epsom) dry and evaporation obtains oily 7-(4-cyano group benzoyl)-8-oxo ethyl pelargonate (2.25g).
7-(4-cyano group benzoyl)-8-oxo ethyl pelargonate
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.25-1.45(4H，m)，1.55-1.70(2H，m)，1.80-2.10(2H，m)，2.16(3H，s)，2.28(2H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.40(1H，t，J＝7Hz)，7.80(2H，t，J＝9Hz)，8.07(2H，d，J＝9Hz)
Preparation example 141
Mixture in glycol dimethyl ether (50mL) refluxed 5 minutes with 4-(amino-sulfonyl) methyl benzoate (5.10g) and salt of wormwood (6.55g).After the cooling mixture, with chlorine carbonic acid benzyl ester (benzyl chloridocarbonate) (5.25g) solution in glycol dimethyl ether (30mL) refluxed 1 hour with the mixture that obtains.Make the reaction quenching by adding 1N hydrochloric acid (100mL).With ethyl acetate (200mL) extraction mixture, and with salt water washing organic layer, by dried over mgso, and evaporation, obtain light yellow oil, when placing, it solidifies.Abrasive solid in diisopropyl ether (30mL) obtains white powder 4-({ [(benzyloxy) carbonyl] amino } alkylsulfonyl) methyl benzoate (3.38g).
4-({ [(benzyloxy) carbonyl] amino } alkylsulfonyl) methyl benzoate
NMR(CDCl
3，δ)：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 example 142
Suspension in methyl alcohol (40mL) stirred 35 minutes with 4-({ [(benzyloxy) carbonyl] amino } alkylsulfonyl) methyl benzoate (3.38g) and 85% potassium hydroxide (1.28g).With the methyl alcohol evaporation, and in mixture, add 1N hydrochloric acid (20mL).Collect the white crystal that forms by filtering, and water and diisopropyl ether washing, and dry under vacuum.Obtain white crystal 4-({ [(benzyloxy) carbonyl] amino } alkylsulfonyl) phenylformic acid (2.92g).
4-({ [(benzyloxy) carbonyl] amino } alkylsulfonyl) phenylformic acid
NMR(DMSO-d
6，δ)：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(ESI
-)：m/z 334(M-H)
Preparation example 143
In ice-methanol bath (7 to-2 ℃), in the suspension of 5 fens clockwise 3-cyano group benzene carbothioic acid carbothiolic acid S-(2-pyridyl) esters (2.40g) in toluene (10mL), add titanium chloride (1.99g).After stirring 10 minutes, added the 2-ethyl-solution (4 to 0 ℃) of 1H-pyrroles (1.00g) in toluene (10mL) through 5 minutes.The heterogeneous mixture that stirring at room temperature obtains 1.5 hours.Add ethyl acetate (20mL) and water (20mL), and by celite (celite) filtering mixt.Filtrate is diluted with ethyl acetate (80mL) and water (30mL), and water (30mL), 1N sodium hydroxide (50mL) and salt solution (50mL) washing organic extract liquid, and by dried over mgso, and evaporation obtains dark crystal (2.46g).In diisopropyl ether (10mL), grind crystal, obtain brown crystal 3-[(5-ethyl-1H-pyrroles-2-yl) carbonyl] benzonitrile (1.57g, 70.1%).
3-[(5-ethyl-1H-pyrroles-2-yl) carbonyl] benzonitrile
NMR(CDCl
3，δ)：1.33(3H，t，J＝7Hz)，2.75(2H，q，J＝7Hz)，6.12(1H，m)，6.78(1H，m)，7.60(1H，t，J＝8Hz)，7.82(1H，d，J＝8Hz)，8.07(1H，d，J＝8Hz)，8.14(1H，s)，9.50(1H，s，br)
Preparation example 144
In the suspension of magnesium chloride (3.01g) in tetrahydrofuran (THF) (30mL), add the 3-ketobutyric acid tert-butyl ester (5.00g).Cooling mixture in ice bath.Then, added pyridine (5.00g) through 15 minutes.After at room temperature stirring 1 hour, the mixture that cooling obtains in ice bath.Added the solution of 2-chloro-benzoyl chloride (4.98g) in tetrahydrofuran (THF) (30mL) through 15 minutes.At room temperature stirred the mixture 1 hour.Make the reaction quenching by adding 1N hydrochloric acid (65mL).Filtering mixt, and solvent evaporated.With ethyl acetate (150mL) extracted residues.Water (100mL), saturated sodium bicarbonate (100mL) and salt water washing extraction liquid, by dried over mgso, and evaporation obtains yellow oil 2-(3-chlorobenzene formacyl)-3-ketobutyric acid tert-butyl ester (8.82g).
2-(3-the fluoro benzoyl)-3-ketobutyric acid tert-butyl ester
NMR (CDCl
3, δ): tautomers mixture: 1.20 and 1.27 (9H, s), 2.16 and 2.44 (3H, s), 7.33-7.71 (4H, m), 13.66 (1H, s)
Preparation example 145
In ice bath with 2-(3-the chlorobenzene formacyl)-solution stirring of the 3-ketobutyric acid tert-butyl ester (8.82g) in trifluoroacetic acid (40mL) 1 hour.Remove volatile matter in a vacuum, and resistates is distributed between ethyl acetate (150mL) and saturated sodium bicarbonate.With salt water washing organic layer, by dried over mgso, and evaporation obtains greenish orange yellow crystals 1-(3-chloro-phenyl-)-1,3-dimethyl diketone (5.33g).
1-(3-chloro-phenyl-)-1, the 3-dimethyl diketone
NMR(CDCl
3，δ)：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 example 146
In ice bath (6 to 20 ℃), in 30 fens clockwise 2-(trimethyl silyl) ethanol (20.5g) and the mixture of pyridine (18.7g) in methylene dichloride (40mL), add (10.0g) solution in methylene dichloride (20mL) of oxalyl dichloro (ethanedioyl dichloride).Remove ice bath, and mixture was stirred 0.5 hour.Filtering mixt, and filtrate distributed between ethyl acetate (200mL) and 1N hydrochloric acid (200mL).With saturated sodium bicarbonate and salt water washing organic layer, by dried over mgso, and evaporation obtains light yellow oil oxalic acid two [2-(trimethyl silyl) ethyl] ester (25.1g).
Oxalic acid two [2-(trimethyl silyl) ethyl] ester
NMR(CDCl
3，δ)：0.08(18H，s)，1.12(4H，m)，4.38(4H，m)
Preparation example 147
In the suspension of dimethyl sulfone (7.00g) in ether (50mL), add uncle's fourth potassium oxide (8.76g).In the mixture that obtains, add oxalic acid two [2-(trimethyl silyl) ethyl] ester (23.8g).The mixture that stirring at room temperature obtains 36 hours.Mixture is distributed between ethyl acetate (100mL) and 1N hydrochloric acid (50mL).With salt water washing organic layer, by dried over mgso, and evaporation obtains dark orange oil.Obtain light brown oil 3-(methyl sulphonyl)-2-oxo propionic acid 2-(trimethyl silyl) ethyl ester (8.37g) with ethyl acetate-hexane=1-25 to the flash distillation silica gel column chromatography of 8-5 drip washing.
3-(methyl sulphonyl)-2-oxo propionic acid 2-(trimethyl silyl) ethyl ester
NMR(CDCl
3，δ)：0.08(9H，s)，1.14(2H，m)，3.11(3H，s)，4.43(4H，m)，4.56(2H，s)
MS(ESI
-)：m/z 265(M-H)
Preparation example 148
At room temperature with 4-oxo-4-phenylbutyric acid (5.00g), ethanol (2.59g), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (6.46g) and 4-(dimethylamino) pyridine (171mg) at N, mixture in the dinethylformamide (25mL) stirred 1.5 hours.Mixture is distributed between ethyl acetate (100mL) and 1N hydrochloric acid (75mL), and water (75 * 3mL), saturated sodium bicarbonate (75mL) and salt solution (75mL) washing organic layer, by dried over mgso, and evaporation obtains water white oil 4-oxo-4-phenylbutyrate (4.19g).
4-oxo-4-phenylbutyrate
NMR(CDCl
3，δ)：1.27(3H，t，J＝7Hz)，2.76(2H，t，J＝7Hz)，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)
Following compound is to obtain with preparation example 148 essentially identical modes.
Preparation example 149
5-oxo-5-phenylpentanoic acid ethyl ester
NMR(CDCl
3，δ)：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＝9Hz)，7.97(2H，d，J＝9Hz)
MS(ESI
+)：m/z 221(M+H)
Preparation example 150
At room temperature 2-benzoyl pimelinketone (1.00g), sodium ethylate (404mg) mixture in ethanol (5mL) was stirred 3.5 hours.Make the reaction quenching by adding 1N hydrochloric acid (1mL).Solvent evaporated, and resistates distributed between ethyl acetate and water.With salt water washing organic layer, by dried over mgso, and evaporation obtains brown oil 7-oxo-7-phenyl oil of cognac (1.33g).
7-oxo-7-phenyl oil of cognac
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.42(2H，m)，1.63-1.81(4H，m)，2.32(2H，t，J＝7Hz)，2.98(2H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，7.47(2H，t，J＝9Hz)，7.54(1H，d，J＝7Hz)，7.95(2H，d，J＝9Hz)
Preparation example 151
Under nitrogen, in the solution of 7-chloro-7-oxygen oil of cognac (1.31g) in methylene dichloride (25mL), add 2-(the trimethyl silyl)-solution of 1,3-thiazoles (500mg) in methylene dichloride (5mL).After stirring 3 hours, make the reaction quenching by adding saturated sodium bicarbonate (5mL).Mixture is distributed between ethyl acetate (30mL) and saturated sodium bicarbonate (30mL), and with salt water washing organic layer, by dried over mgso, and evaporation obtains water white oil.Obtain water white oil 7-oxo-7-(1,3-thiazoles-2-yl) oil of cognac (778mg) with ethyl acetate-hexane=1-10 to the flash distillation silica gel column chromatography of 2-5 drip washing.
7-oxo-7-(1,3-thiazoles-2-yl) oil of cognac
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.44(2H，m)，1.64-1.85(4H，m)，2.32(2H，t，J＝7Hz)，3.17(2H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，7.66(1H，d，J＝3Hz)，8.00(1H，d，J＝3Hz)
MS(ESI
+)：m/z 256(M+H)
Preparation example 152
In the 7-methoxyl group-solution of 7-oxo enanthic acid (1.00g) in methylene dichloride (10mL), add the solution of trifluoroacetic anhydride (1.33g) in methylene dichloride (2mL).After stirring 0.5 hour, add the solution of 1-methyl isophthalic acid H-pyrroles (1.49g) in methylene dichloride (2mL).Mixture was at room temperature stirred 2 hours 40 minutes and stirred 2 hours down at 35 ℃.Mixture is distributed between ethyl acetate and saturated sodium bicarbonate.With salt water washing organic layer, by dried over mgso, and evaporation obtains brown oil.Obtain water white oil 7-(1-methyl isophthalic acid H-pyrroles-2-yl)-7-oxo Methylheptanoate (615mg) with ethyl acetate-hexane=1-20 to the flash distillation silica gel column chromatography of 4-5 drip washing.
7-(1-methyl isophthalic acid H-pyrroles-2-yl)-7-oxo Methylheptanoate
NMR(CDCl
3，δ)：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)
Preparation example 153
In ice bath, in 4-({ [(benzyloxy) carbonyl] amino } alkylsulfonyl) suspension of phenylformic acid (2.90g) in methylene dichloride (30mL), add N, dinethylformamide (19.0mg) and oxalyl chloride subsequently (1.15g).At room temperature mixture was stirred 0.5 hour and refluxed 1 hour.Adding oxalyl chloride (439mg) further refluxes the mixture that obtains 5 minutes afterwards.Evaporate volatile matter and obtain white solid.Abrasive solid obtains white powder [4-(chloroformyl) phenyl] sulfonylcarbamic acid benzyl ester (2.40g) in diisopropyl ether, and further not purifying is used for next step reaction.
[4-(chloroformyl) phenyl] sulfonylcarbamic acid benzyl ester
Preparation example 154
Add 5-iodo Valeric acid ethylester (6.89g) to 4-(methylthio group)-3-ketobutyric acid tert-butyl ester (5.00g) and salt of wormwood (3.72g) in the solution in dimethyl formamide (25mL), and mixture was at room temperature stirred 15 hours.Mixture is distributed between ethyl acetate and water.Separate organic layer, water and salt water washing, by dried over mgso, and evaporation in a vacuum.By mixture (20: 1-10: 1) the silica gel column chromatography purification resistates of drip washing obtains water white oil 2-[(methylthio group) ethanoyl with hexane and ethyl acetate] pimelic acid 1-tertiary butyl 7-ethyl ester (5.88g).
The 2-[(methylthio group) ethanoyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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(2H，m)，2.05(3H，s)，2.30(2H，t，J＝7Hz)，3.23(1H，d，J＝17Hz)，3.38(1H，d，J＝17Hz)，3.74(1H，t，J＝7Hz)，4.11(2H，q，J＝7Hz)
Preparation example 155
Add diisopropylethylamine (54.6g) in oxammonium hydrochloride (29.4g) suspension in the methyl alcohol ice bath under nitrogen atmosphere in 3 minutes clockwise methylene dichloride (200mL).White precipitate forms along with adding.After in the methyl alcohol ice bath, stirring 1 hour, diphenyl phosphinyl chloride (20.0g) solution that added in the methylene dichloride (20mL) through 60 minutes.White crystal forms along with adding.Under agitation through 1 hour with mixture heating up to 0 ℃.The water (200mL) that adds by 3 minutes makes the reaction quenching.After stirring the mixture 0.5 hour, collect crystal by filtering.Water (50 * 3mL), use diisopropyl ether (50 * 3mL) washing crystals subsequently.The crystal collected through air-dry overnight, and in mild heat (4 ℃) decompression drying 3 hours down, is obtained crude product.In EtOH (ethanol), grind crude product, obtain white crystal (amino oxygen base) (phenylbenzene) phosphine oxide (15.3g).(amino oxygen base) (phenylbenzene) phosphine oxide
NMR(CDCl
3，δ)：7.54-7.58(6H，m)，7.74-7.83(4H，m)，8.20-8.33(2H，m)
Preparation example 156
Under nitrogen atmosphere, in the solution of 1-(1H-pyrroles-2-yl) ethyl ketone (5.00g) in tetrahydrofuran (THF) (100mL), add uncle's fourth potassium oxide (6.17g) in the water-bath.After stirring 1 hour, added (amino oxygen base) (phenylbenzene) phosphine oxide (12.8g) through 2 hours.After at room temperature stirring 2 hours, added water (4mL), obtain clear solution through 3 minutes.Solvent evaporated, and resistates distributed between ethyl acetate (50mL) and water (50mL).(25 * 5mL) aqueous layer extracted, and the organic extract liquid that merges with the salt water washing, by anhydrous magnesium sulfate drying, and evaporation obtains brown oil (6.01g) with ethyl acetate.Oil is dissolved in diisopropyl ether (30mL), and in solution, adds hexane (15mL), obtain pale yellow crystals.After stirring 1 hour, by removing by filter crystal.Evaporated filtrate obtains brown oil (5.69g).Oil is dissolved in ethyl acetate (45.5mL), cooling solution in ice bath.The 4N hydrogenchloride (11.5mL) that added in the clockwise refrigerative solution in the ethyl acetate through 15 minutes obtains the light brown precipitation.After stirring the mixture in ice bath 0.5 hour, (5 * 3mL) washings obtain light brown powder (5.33g) by filtering collecting precipitation and using ethyl acetate.Make powder suspension in ethyl acetate (37mL) and be heated to 3 ℃.At room temperature stirred suspension is 1 hour.(5 * 3mL) washings obtain light brown powder 1-(1-amino-1H-pyrroles-2-yl) acetophenone hydrochloride (5.25g) by filtering the collection powder and using ethyl acetate.1-(1-amino-1H-pyrroles-2-yl) acetophenone hydrochloride
NMR(CDCl
3，δ)：2.37(3H，s)，5.22(2H，s，br)，6.07(1H，m)，6.99(1H，m)，7.15(1H，m)
Preparation example 157
In nitrogen atmosphere, in 55 minutes clockwise ethanol (1.7L), add a hydrazine hydrate (530g).Added 1-(1-amino-1H-pyrroles-2-yl) acetophenone hydrochloride (170g) in the clockwise mixture through 20 minutes.At room temperature stirred the mixture 10 minutes, and be heated to reflux temperature, refluxed 15 minutes through 55 minutes.In water-bath, after the cooling mixture, in mixture (30 to 31 ℃), add entry (1.7L).Evaporate ethanol, and (0.85 * 4mL) extracts the mixture that obtains with chloroform.Organic extract liquid with salt solution (1.3L) washing merging.With chloroform (0.85L) extraction salt solution.By the organic extract liquid of anhydrous magnesium sulfate drying merging, and evaporation obtains brown crystal (1E)-1-(1-amino-1H-pyrroles-2-yl) ethyl ketone hydrazone (112g).
(1E)-1-(1-amino-1H-pyrroles-2-yl) ethyl ketone hydrazone
NMR(CDCl
3，δ)：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)
Preparation example 158
In nitrogen atmosphere, in the suspension of 5 fens clockwise (1E)-1-(1-amino-1H-pyrroles-2-yl) ethyl ketone hydrazones (110g) in toluene (1.1L), add uncle's fourth potassium oxide (93.8g), and mixture heating up is arrived reflux temperature through 45 minutes.After refluxing 15 minutes, distribute with the mixture cool to room temperature and between ethyl acetate (1.1L) and water (1.1L).With ethyl acetate (1.1L) aqueous layer extracted once more.Wash the organic extract liquid that merges with salt solution (1.1L), and extract salt solution with ethyl acetate (0.5L).Merge all organic layers, by anhydrous magnesium sulfate drying, and evaporation obtains brown oil 2-ethyl-1H-pyrroles-1-amine (94.4g).
2-ethyl-1H-pyrroles-1-amine
NMR(CDCl
3，δ)：1.26(3H，t，J＝7Hz)，21.62(2H，q，J＝7Hz)，4.53(2H，s，br)，5.80(1H，m)，5.99(1H，m)，6.67(1H，m)
Preparation example 159
Add 5-iodine Valeric acid ethylester (4.62g) to 4-methoxyl group-3-ketobutyric acid tert-butyl ester (3.09g) and salt of wormwood (2.50g) in the suspension in dimethyl formamide (20mL), and mixture was at room temperature stirred 15 hours.Mixture is distributed between ethyl acetate and water.Separate organic layer, water and salt water washing, by dried over mgso, and evaporation in a vacuum.(20: 1-5: 1) the silica gel column chromatography purification resistates of drip washing obtains water white oil 2-(methoxyl group ethanoyl) pimelic acid 1-tertiary butyl 7-ethyl ester (4.33g) by the mixture with hexane and ethyl acetate.
2-(methoxyl group ethanoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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)，4.02(4H，m)
MS：(m/z)317(M+H)
Following compound is to obtain with preparation example 159 essentially identical modes.
Preparation example 160
2-(methoxyl group ethanoyl) hexanodioic acid 1-tertiary butyl 6-ethyl ester
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.46(9H，s)，1.52-1.73(2H，m)，1.82-1.94(2H，m)，2.33(2H，t，J＝7Hz)，3.42(3H，s)，3.50(1H，t，J＝7Hz)，4.10(2H，s)，4.12(2H，q，J＝7Hz)
Preparation example 161
2-(methoxyl group ethanoyl) pentanedioic acid 1-tertiary butyl 5-ethyl ester
NMR(CDCl
3，δ)：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(2H，q，J＝7Hz)
Preparation example 162
2-ethanoyl hexanodioic acid 1-tertiary butyl 6-ethyl ester
NMR(CDCl
3，δ)：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，J＝7Hz)
MS(ESI
+)：m/z 273
Preparation example 163
2-ethanoyl pentanedioic acid 1-tertiary butyl 5-ethyl ester
NMR(CDCl
3，δ)：1.26(3H，t，J＝7Hz)，1.47(9H，s)，2.08-2.22(2H，m)，2.24(3H，s)，2.33-2.42(2H，m)，3.45(1H，t，J＝7Hz)，4.13(2H，q，J＝7Hz)
Preparation example 164
In ice bath, in the 2-ethyl-solution of 1H-pyrroles (7.00g) in tetrahydrofuran (THF) (14mL), add 0.93M ethyl-magnesium-bromide (198mL).At room temperature stirred the mixture 1 hour.In ice bath, the solution that obtains is added the suspension of 5-bromine nicotinoyl chlorine (22.3g) in tetrahydrofuran (THF) (110mL) then through 50 minutes.After in ice bath, stirring 15 minutes, make the reaction quenching by adding saturated ammonium chloride (30mL).Mixture is distributed between ethyl acetate (350mL) and water (350mL).With saturated sodium bicarbonate and salt water washing organic layer, by dried over mgso, and evaporation obtains dark glue (33.9g).In the presence of silica gel (150mL), with glue be scattered in ethyl acetate/hexane (1: 3,150mL).Filtering mixt, and with the concentrated yellow crystals (20.6g) that obtains of filtrate.With flash distillation silica gel column chromatography acquisition light yellow solid (5-bromo-3-pyridyl) (5-ethyl-1H-pyrroles-2-yl) ketone (7.11g) of ethyl acetate-hexane=1-20 to 4-5 drip washing.
(5-bromo-3-pyridyl) (5-ethyl-1H-pyrroles-2-yl) ketone
NMR(CDCl
3，δ)：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)
Preparation example 165
At room temperature to 4-(acetoxyl group)-3-ketobutyric acid tert-butyl ester (30.0g) and 5-iodine Valeric acid ethylester (35.5g) at N, add salt of wormwood (19.2g) in the solution in the dinethylformamide (150mL).After stirring 4 hours, make the mixture quenching by in ice bath, adding 1N hydrochloric acid (140mL).Mixture is distributed between ethyl acetate (450mL) and water (300mL).Water (500mL, three times) and salt water washing organic extract liquid, by dried over mgso, and evaporation obtains containing the 2-[(acetoxyl group) ethanoyl] brown oil of pimelic acid 1-tertiary butyl 7-ethyl ester (63.4g, 43% pure weight).
The 2-[(acetoxyl group) ethanoyl] pimelic acid 1-tertiary butyl 7-ethyl ester
NMR(CDCl
3，δ)：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，d，J＝17Hz)，4.82(1H，d，J＝17Hz)
Preparation example 166
In ice bath (5 to 8 ℃), added the 1M tin chloride in the methylene dichloride (38.9mL) in the solution in methylene dichloride (20mL) to ethylthiophene (2.00g) and 7-chloro-7-oxygen oil of cognac (5.39g) through 0.5 hour.After stirring 0.5 hour, at room temperature stirred the mixture 0.5 hour.Pour mixture into frozen water (100mL), and extract with ethyl acetate (100mL).Water (100mL) and salt water washing organic extract liquid, by dried over mgso, and evaporation obtains brown oil.Obtain brown oil 7-oxo-7-(2-thienyl) oil of cognac (5.79g) with ethyl acetate-hexane=1-10 to the flash distillation silica gel column chromatography of 3-10 drip washing.
7-oxo-7-(2-thienyl) oil of cognac
NMR(CDCl
3，δ)：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)
Following compound is to obtain with preparation example 129 and 130 essentially identical modes.
Preparation example 167
3-(3,5-dimethyl-4-is different _ the azoles base)-the 3-oxo propionic acid tert-butyl ester
NMR(CDCl
3，δ)：1.47(9H，s)，2.46(3H，s)，2.68(3H，s)，3.68(2H，s)
Preparation example 168
4-methyl-3-oxopentanoic acid ethyl ester
NMR (CDCl
3, δ): 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)
Preparation example 169
4-(the methylthio group)-3-ketobutyric acid tert-butyl ester
NMR(CDCl
3，δ)：1.47(9H，s)，2.07(3H，s)，3.31(2H，s)，3.58(2H，s)
Preparation example 170
3-(1,3-_ azoles-5-the yl)-3-oxo propionic acid tert-butyl ester
NMR (CDCl
3, δ): (mixture of keto-acid and enol form); Keto-acid: 1.45 (9H, s), 3.77 (2H, s), 7.85 (1H, s), 8.04 (1H, s); Enol form: d 1.45 (9H, s), 5.54 (1H, s), 7.53 (1H, s), 7.91 (1H, s)
Following compound is to obtain with preparation example 143 essentially identical modes.
Preparation example 171
(2-chloro-4-pyridyl) (5-ethyl-1H-pyrroles-2-yl) ketone
NMR(CDCl
3，δ)：1.32(3H，t，J＝7Hz)，2.74(2H，q，J＝7Hz)，6.13(1H，m)，6.79(1H，m)，7.56(1H，d，J＝5Hz)，7.69(1H，s)，8.54(1H，d，J＝5Hz)，9.40(1H，br)
Preparation example 172
(5-ethyl-1H-pyrroles-2-yl) (3-p-methoxy-phenyl) ketone
NMR(CDCl
3，δ)：1.32(3H，t，J＝7Hz)，2.74(2H，q，J＝7Hz)，3.87(3H，s)，6.08(1H，m)，6.83(1H，m)，7.08(1H，dd，J＝2Hz，8Hz)，7.33-7.42(2H，m)，7.47(1H，d，J＝8Hz)，9.58(1H，br)
MS(ESI
+)：m/z 230
Preparation example 173
(5-ethyl-1H-pyrroles-2-yl) (4-pyridyl) ketone
NMR(CDCl
3，δ)：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(2H，d，J＝7Hz)，9.39(1H，br)
Preparation example 174
(5-ethyl-1H-pyrroles-2-yl) (2-pyrazinyl) ketone
NMR(CDCl
3，δ)：1.33(3H，t，J＝7Hz)，2.77(2H，q，J＝7Hz)，6.14(1H，m)，7.51(1H，m)，8.65(1H，m)，8.74(1H，m)，9.36(1H，br)
Preparation example 175
(5-ethyl-1H-pyrroles-2-yl) (3-pyridyl) ketone
NMR(CDCl
3，δ)：1.33(3H，t，J＝7Hz)，2.76(2H，q，J＝7Hz)，6.12(1H，m)，6.81(1H，m)，7.42(1H，m)，8.13(1H，m)，8.76(1H，m)，9.08(1H，m)，9.36(1H，br)
Preparation example 176
With 3-[(1-amino-5-ethyl-1H-pyrroles-2-yl) carbonyl] benzonitrile (300mg), methylsulfonyl acetate (208mg), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (361mg) and I-hydroxybenzotriazole (254mg) are at N, and the mixture in the dinethylformamide (1mL) stirred 1.5 hours.Mixture is distributed between ethyl acetate and water.Wash organic layer twice with water, with saturated sodium bicarbonate and salt water washing organic layer, by dried over mgso, and evaporation obtains the light brown solid.With ethyl acetate-hexane=1/2 solidified light brown foams N-[2-(3-cyano group benzoyl)-5-ethyl-1H-pyrroles-1-yl when the flash distillation silica gel column chromatography of 1/0 drip washing obtains placing]-2-(methyl sulphonyl) ethanamide (505mg).
N-[2-(3-cyano group benzoyl)-5-ethyl-1H-pyrroles-1-yl]-2-(methyl sulphonyl) ethanamide
NMR(CDCl
3，δ)：1.29(3H，t，J＝7Hz)，2.62(2H，q，J＝7Hz，)，3.28(3H，s)，4.15(2H，s)，6.12(1H，d，J＝5Hz)，6.75(1H，d，J＝5Hz)，7.58(1H，t，J＝9Hz)，7.82(1H，d，J＝9Hz)，8.01(1H，d，J＝9Hz)，8.06(1H，s)
Following compound is to obtain with preparation example 176 essentially identical modes.
Preparation example 177
3-{[2-(4-cyano group benzoyl)-5-ethyl-1H-pyrroles-1-yl] amino }-3-oxo ethyl propionate
NMR(CDCl
3，δ)：1.20-1.37(6H，m)，2.56(2H，q，J＝7Hz)，3.57(2H，s)，4.30(2H，q，J＝7Hz)，6.06(1H，d，J＝5Hz)，6.68(1H，d，J＝5Hz)，7.54(2H，d，J＝9Hz)，7.84(2H，d，J＝9Hz)
Embodiment 1
At room temperature, to 4-[(1-amino-5-ethyl-1H-pyrroles-2-yl) carbonyl] add 1-(4-p-methoxy-phenyl) acetone (103mg) and tosic acid monohydrate (16mg) in the solution of benzonitrile (100mg) in toluene (1mL).Reaction mixture was heated 3 hours at 80 ℃.Evaporating mixture in a vacuum.Flash distillation silica gel column chromatography purification resistates by with hexane-ethyl acetate=20-1 and 15-1 drip washing obtains also [1,2-b] pyridazine-4-yl of yellow solid 4-[7-ethyl-3-(4-p-methoxy-phenyl)-2-methylpyrrole] benzonitrile (31mg, 20.2%).
4-[7-ethyl-3-(4-p-methoxy-phenyl)-2-methylpyrrole is [1,2-b] pyridazine-4-yl also] benzonitrile
NMR(CDCl
3，δ)：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)
Following compound is to obtain in mode substantially the same manner as Example 1.
Embodiment 2
4-(4-cyano-phenyl)-2-(2-oxyethyl group-2-oxoethyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-ethyl formate also
NMR(CDCl
3，δ)：0.84(3H，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(1H，d，J＝5Hz)，6.62(1H，d，J＝5Hz)，7.13(2H，d，J＝9Hz)，7.76(2H，d，J＝9Hz)
Embodiment 3
4-(4-cyano-phenyl)-7-ethyl-2-(trifluoromethyl) pyrrolo-[1,2-b] pyridazine-3-ethyl formate
NMR(CDCl
3，δ)：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(1H，d，J＝5Hz)，6.93(1H，d，J＝5Hz)，7.62(2H，d，J＝9Hz)，7.80(2H，d，J＝9Hz)
Embodiment 4
4-[7-ethyl-2-methyl-3-(3-pyridine carbonyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile
NMR(CDCl
3，δ)：1.43(t，J＝7Hz，3H)，2.47(s，3H)，3.09(q，J＝7Hz，2H)，6.35(d，J＝5Hz，1H)，6.74(d，J＝5Hz，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)
Embodiment 5
3-[7-ethyl-2-methyl-3-(4-pyridyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile
NMR(CDCl
3，δ)：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(2H，d，J＝9Hz)，7.37(2H，m)，7.57(2H，m)，8.50(2H，d，J＝9Hz)
Embodiment 6
4-(3-benzyl-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-4-yl also) benzonitrile
NMR(CDCl
3，δ)：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(1H，d，J＝5Hz)，6.98(2H，d，J＝8Hz)，7.14-7.30(3H，m)，7.46(2H，d，J＝8Hz)，7.68(2H，d，J＝8Hz)
MS(ESI
+)：m/z 352(M+H)
Embodiment 7
4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-nitrile also
mp：172-173℃
NMR(CDCl3，δ)：1.41(3H，t，J＝8Hz)，3.10(2H，q，J＝8Hz)，6.65(1H，d，J＝5Hz)，6.88(1H，d，J＝5Hz)，7.47-7.64(6H，m)，7.70(1H，br s)，7.81-7.90(2H，m)
Embodiment 8
3-(3-ethyl-7,7,9,9-tetramethyl--6,7,8,9-Pyrrolidine be [1,2-b] cinnolines-10-yl also) benzonitrile
NMR(CDCl
3，δ)：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(1H，d，J＝5Hz)，7.50-7.65(3H，m)，7.72(1H，m)
Embodiment 9
3-(3-ethyl-9-oxo-6,7,8,9-Pyrrolidine be [1,2-b] cinnolines-10-yl also) benzonitrile
NMR(CDCl
3，δ)：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)
Embodiment 10
3-(6-ethyl-1-oxo-2,3-dihydro-1H-ring penta [e] pyrrolo-[1,2-b] pyridazine-9-yl) benzonitrile
mp：150-154℃
NMR(CDCl3，δ)：1.43(3H，t，J＝8Hz)，2.75(2H，t，J＝7Hz)，3.10(2H，q，J＝8Hz)，3.24(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)
Embodiment 11
3-(7-ethyl-2-neo-pentyl pyrrolo-[1,2-b] pyridazine-4-yl) benzonitrile
NMR(CDCl
3，δ)：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)
Embodiment 12
3-[7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile
NMR(CDCl
3，δ)：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，dd，J＝8，1Hz)，7.96-8.08(2H，m)
MS(ESI
+)：m/z 314(M+H)
Embodiment 13
4-[7-ethyl-2-methyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile
NMR(CDCl
3，δ)：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)
Embodiment 13-2
4-{7-ethyl-2-[(methyl sulphonyl) methyl] pyrrolo-[1,2-b] pyridazine-4-yl } benzonitrile
NMR(CDCl
3，δ)：1.39(3H，t，J＝8Hz)，2.96-3.09(5H，m)，4.44(2H，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，J＝8Hz)
MS(ESI
+)：m/z 340(M+H)
Embodiment 15
3-[7-ethyl-2-methyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile
NMR(CDCl
3，δ)：1.39(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)，7.54-7.63(3H，m)，7.77(1H，m)
Embodiment 16
At room temperature to 4-[7-ethyl-3-(4-p-methoxy-phenyl)-2-methylpyrrole also [1,2-b] pyridazine-4-yl] benzonitrile (22mg) is at N, adds 1N sodium hydroxide (0.12mL) and 30% hydrogen peroxide (0.07mL) in the solution in the dinethylformamide (1mL).After stirring 1 hour, reaction mixture is distributed between ethyl acetate and water.Wash organic layer with water three times, and with salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.By flash distillation silica gel column chromatography (silica gel with hexane-ethyl acetate=5-1 and 0-1 drip washing, 30mL) purification resistates, obtain also [1,2-b] pyridazine-4-yl of yellow solid 4-[7-ethyl-3-(4-p-methoxy-phenyl)-2-methylpyrrole] benzamide (18mg, 78.0%).
4-[7-ethyl-3-(4-p-methoxy-phenyl)-2-methylpyrrole is [1,2-b] pyridazine-4-yl also] benzamide
NMR(CDCl
3，δ)：1.41(3H，t，J＝8Hz)，2.31(3H，s)，3.17(2H，q，J＝8Hz)，3.77(3H，s)，5.61(0.2H，br s)，6.O2(0.4H，br s)，6.13(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，6.75(2H，d，J＝8Hz)，6.95(2H，d，J＝8Hz)，7.31(2H，d，J＝8Hz)，7.68(2H，d，J＝8Hz)
MS(ESI
+)：m/z 386(M+H)
Following compound is to obtain in mode substantially the same manner as Example 16.
Embodiment 17
3-[2-(dimethylamino)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzamide
NMR(CDCl
3，δ)：1.32(3H，t，J＝7Hz)，2.90(6H，s)，2.95(2H，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)，7.90(1H，s)，7.94-8.06(2H，m)
MS(ESI
+)：m/z 387(M+H)
Embodiment 18
3-(7-ethyl-2-neo-pentyl pyrrolo-[1,2-b] pyridazine-4-yl) benzamide
NMR(CDCl
3，δ)：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(1H，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(1H，br s)
MS(ESI
+)：m/z 336(M+H)
Embodiment 19
3-[7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzamide
NMR(CDCl
3，δ)：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(1H，d，J＝5Hz)，7.02(1H，s)，7.06(1H，d，J＝5Hz)，7.55-7.65(2H，m)，7.79-7.98(2H，m)，8.02(1H，br s)
MS(ESI
+)：m/z 332(M+H)
Embodiment 20
5-[2-({ [4-(aminocarboxyl) benzyl] oxygen base } methyl)-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(DMSO-d
6，δ)：1.27-1.45(7H，m)，1.99(2H，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(1H，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(1H，m)
Embodiment 21
At room temperature in 6-(3-cyano group the benzoyl)-solution of 7-oxo ethyl octylate (3.18g) in toluene (30mL), add 2-ethyl-1H-pyrroles-1-amine (1.17g) and tosic acid monohydrate (96mg).With reaction mixture refluxed 1 hour.Evaporating mixture in a vacuum.By flash distillation silica gel chromatography (silica gel with hexane-ethyl acetate=20-1,15-1 and 10-1 drip washing, 200mL) purification resistates, obtain also [1,2-b] pyridazine-3-yl of yellow oil 5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole] Valeric acid ethylester (3.29g, 83.8%).
5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：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)，6.51(1H，d，J＝5Hz)，7.57-7.67(3H，m)，7.75(1H，m)
Following compound is to obtain in mode substantially the same manner as Example 21.
Embodiment 22
2,4-di-isopropyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate
NMR(300MHz，CDCl
3，δ)：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
Embodiment 23
4-(2-chloro-phenyl-)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate
NMR(300 MHz，CDCl
3，δ)：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，m)，7.45-7.55(1H，m)，7.75-7.81(1H，m)
Embodiment 24
2-sec.-propyl-4-(2-naphthyl) pyrrolo-[1,2-b] pyridazine-3-ethyl formate
NMR(300MHz，CDCl
3，δ)：0.78(3H，t，J＝7.5Hz)，1.38(6H，d，J＝7.5Hz)，3.24-3.35(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
Embodiment 25
5-{7-ethyl-2-methyl-4-[3-(trifluoromethyl) phenyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
NMR(CDCl
3，δ)：1.22(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.59(4H，m)，2.14(2H，t，J＝7Hz)，2.38-2.46(2H，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(3H，m)，7.71(1H，d，J＝8Hz)
MS(ESI
+)：m/z 433(M+H)
Embodiment 26
5-[7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.38-1.60(4H，m)，2.18(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(2H，q，J＝7Hz)，5.87(1H，d，J＝4Hz)，6.51(1H，d，J＝4Hz)，7.50(1H，s)，8.59(1H，s)，8.53(1H，s)
MS(ESI
+)：m/z 380(M+H)
Embodiment 27
5-[7-ethyl-4-(3-methoxyl group-5-different _ azoles base)-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.55-1.64(2H，m)，1.64-1.80(2H，m)，2.33(2H，t，J＝7Hz)，2.74-2.85(2H，m)，3.03(2H，q，J＝7Hz)，3.43(3H，s)，4.08(3H，s)，4.12(2H，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)
Embodiment 28
5-{7-ethyl-2-methyl-4-[3-(1,3-_ azoles-5-yl) phenyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
NMR(CDCl
3，δ)：1.20(3H，t，J＝7Hz)，1.35(3H，t，J＝7Hz)，1.40-1.63(4H，m)，2.17(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＝4Hz)，7.33(1H，d，J＝8Hz)，7.39(1H，s)，7.53(1H，t，J＝8Hz)，7.66(1H，m)，7.74(1H，d，J＝8Hz)，7.93(1H，s)
Embodiment 29
5-[4-(3, the 4-dichlorophenyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：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(2H，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，dd，J＝2Hz，8Hz)，7.46(1H，d，J＝2Hz)，7.56(1H，d，J＝8Hz)
MS(ESI
+)：m/z 433(M+H)
Embodiment 30
5-[4-(4-chloro-2-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.44-1.67(4H，m)，2.15-2.26(2H，m)，2.42-2.56(2H，m)，2.56(3H，s)，3.01(2H，q，J＝7Hz)，4.10(2H，q，J＝7Hz)，5.95(1H，d，J＝3Hz)，6.54(1H，d，J＝3Hz)，7.40(1H，dd，J＝2Hz，4Hz)，7.54(1H，d，J＝2Hz)，8.67(1H，d，J＝4Hz)
MS(ESI
+)：m/z 400(M+H)
Embodiment 31
5-[4-(5-chloro-2-thienyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：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)
Embodiment 32
5-[7-ethyl-4-(6-methoxyl group-2-pyrazinyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.52-1.68(4H，m)，2.23(2H，t，J＝7Hz)，2.48-2.55(2H，m)，2.56(3H，s)，3.02(2H，q，J＝7Hz)，3.98(3H，s)，4.09(2H，q，J＝7Hz)，6.03(1H，d，J＝4Hz)，6.55(1H，d，J＝4Hz)，8.30(1H，s)，8.33(1H，s)
MS(ESI
+)：m/z 397(M+H)
Embodiment 33
5-[4-(1-cumarone-2-yl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.62-1.83(4H，m)，2.33(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＝7Hz)，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(ESI
+)：m/z 405(M+H)
Embodiment 34
5-[4-(1-thionaphthene-2-yl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：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(3H，m)，7.81-7.92(2H，m)
Embodiment 35
5-[7-ethyl-2-methyl-4-(1,3-_ azoles-5-yl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.53-1.66(2H，m)，1.66-1.83(2H，m)，2.34(2H，t，J＝7Hz)，2.56(3H，s)，2.62-2.73(2H，m)，3.02(2H，q，J＝7Hz)，4.13(2H，q，J＝7Hz)，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)
Embodiment 36
5-(7-ethyl-2-methyl-4-phenylpyrrole is [1,2-b] pyridazine-3-yl also) Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.60(4H，m)，2.15(2H，t，J＝7Hz)，2.41-2.48(2H，m)，2.55(3H，s)，3.02(2H，q，J＝7Hz)，4.08(2H，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)
Embodiment 37
5-[7-ethyl-2-methyl-4-(6-quinolyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.18(3H，t，J＝7Hz)，1.39(3H，t，J＝7Hz)，1.39-1.55(4H，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，J＝7Hz)，5.86(1H，d，J＝4Hz)，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)
Embodiment 38
7-{4-[4-({ [(benzyloxy) carbonyl] amino } alkylsulfonyl) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } oil of cognac
NMR(CDCl
3，δ)：1.12-1.23(7H，m)，1.33-1.51(7H，s)，2.17(2H，t，J＝7Hz)，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(1H，d，J＝5Hz)，6.52(1H，d，J＝5Hz)，7.29-7.38(5H，m)，7.49(2H，d，J＝9Hz)，7.87(1H，s，br)，8.11(2H，d，J＝9Hz)
MS(ESI
+)：m/z 606(M+H)
MS(ESI
-)：m/z 604(M-H)
Embodiment 39
2-{[4-(3-chloro-phenyl-)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] methyl }-1, ammediol
NMR(CDCl
3，δ)：1.26(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.64-1.82(3H，m)，2.59(3H，s)，3.02(2H，q，J＝7Hz)，3.45(2H，m)，3.63(2H，m)，4.12(2H，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)
Embodiment 40
5-{7-ethyl-2-methyl-4-[3-(methyl sulphonyl) phenyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
NMR(CDCl
3，δ)：1.22(3H，t，J＝8Hz)，1.33-1.57(7H，m)，2.18(2H，t，J＝8Hz)，2.35-2.45(2H，m)，2.56(3H，s)，3.01(2H，q，J＝8Hz)，3.12(3H，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)
MS(ESI
+)：m/z 443(M+H)
Embodiment 41
5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，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(1H，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)
Embodiment 42
5-[7-ethyl-2-methyl-4-(3-nitrophenyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.21(3H，t，J＝8Hz)，1.34-1.59(7H，m)，2.17(2H，t，J＝8Hz)，2.37-2.47(2H，m)，2.57(3H，s)，3.01(2H，q，J＝8Hz)，4.08(2H，q，J＝8Hz)，5.81(1H，d，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)
Embodiment 43
4-(4-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-ethyl formate also
NMR(CDCl
3，δ)：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)
Embodiment 44
4-(3-butyl-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-4-yl also) benzonitrile
NMR(CDCl
3，δ)：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，d，J＝8Hz)，7.77(2H，d，J＝8Hz)
MS(ESI
+)：m/z 318(M+H)
Embodiment 45
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.65(4H，m)，2.21(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(1H，m)，8.53(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz)
MS：(m/z)444，446(M+H)
Embodiment 46
5-{4-(2-chloro-4-pyridyl)-7-ethyl-2-[(methylthio group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
NMR(CDCl
3，δ)：1.24(3H，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(1H，d，J＝4Hz)，6.57(1H，d，J＝4Hz)，7.27(1H，m)，7.38(1H，s)，8.53(1H，d，J＝4Hz)
MS：(m/z)446(M+H)
Embodiment 47
6-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl hexanoate
NMR(CDCl
3，δ)：1.15-1.29(5H，m)，1.32-1.61(7H，m)，2.20(2H，t，J＝8Hz)，2.33-2.43(2H，m)，2.56(3H，s)，3.01(2H，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(1H，m)
MS(ESI
+)：m/z 404(M+H)
Embodiment 48
5-[4-(6-chloro-2-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.46-1.65(4H，m)，2.22(2H，t，J＝7Hz)，2.46-2.57(2H，m)，2.54(3H，s)，3.00(2H，q，J＝7Hz)，4.09(2H，q，J＝7Hz)，5.95(1H，d，J＝4Hz)，6.51(1H，d，J＝4Hz)，7.38-7.47(2H，m)，7.80(1H，t，J＝8Hz)
MS(ESI
+)：m/z 400
Embodiment 49
5-[7-ethyl-4-(3-p-methoxy-phenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：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(3H，s)，4.08(2H，q，J＝7Hz)，5.91(1H，d，J＝4Hz)，6.49(1H，d，J＝4Hz)，6.87-6.99(3H，m)，7.37(1H，t，J＝8Hz)
MS(ESI
+)：m/z 395
Embodiment 50
5-[4-(3, the 5-dichlorophenyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：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(2H，t，J＝7Hz)，2.38-2.48(2H，m)，2.54(3H，s)，3.00(2H，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)
MS(ESI
+)：m/z 433
Embodiment 51
5-[4-(5-chloro-2-thienyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.46-1.58(2H，m)，1.60-1.74(2H，m)，2.28(2H，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(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 405
Embodiment 52
5-[7-ethyl-4-(3-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.39(3H，t，J＝7Hz)，1.38-1.50(2H，m)，1.50-1.63(2H，m)，2.17(2H，t，J＝7Hz)，2.39-2.48(2H，m)，2.54(3H，s)，3.03(2H，q，J＝7Hz)，4.09(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 383
Embodiment 53
5-[7-ethyl-2-methyl-4-(3-quinolyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.18(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.40-1.60(4H，m)，2.16(2H，t，J＝7Hz)，2.44-2.56(2H，m)，2.59(3H，s)，3.04(2H，q，J＝7Hz)，4.03(2H，q，J＝7Hz)，5.89(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，7.62(1H，t，J＝8Hz)，7.80(1H，t，J＝8Hz)，7.90(1H，d，J＝8Hz)，8.21(2H，m)，8.90(1H，d，J＝2Hz)
MS(ESI
+)：m/z 416
Embodiment 54
5-[7-ethyl-2-methyl-4-(4-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.40-1.64(4H，m)，2.19(2H，t，J＝7Hz)，2.38-2.52(2H，m)，2.55(3H，s)，3.02(2H，q，J＝7Hz)，4.09(2H，q，J＝7Hz)，5.83(1H，d，J＝4Hz)，6.51(1H，d，J＝4Hz)，7.29(2H，m)，8.72(2H，m)
MS(ESI
+)：m/z 366
Embodiment 55
5-[7-ethyl-4-(3-methoxyl group-5-different _ azoles base)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.55-1.82(4H，m)，2.33(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＝4Hz)，6.58(1H，d，J＝4Hz)
Embodiment 56
5-[7-ethyl-2-methyl-4-(5-methyl-3-different _ azoles base) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.50-1.75(4H，m)，2.29(2H，t，J＝7Hz)，2.55(6H，s)，2.56-2.65(2H，m)，2.99(2H，q，J＝7Hz)，4.11(2H，q，J＝7Hz)，6.16(1H，d，J＝4Hz)，6.22(1H，s)，6.54(1H，d，J＝4Hz)
MS(ESI
+)：m/z 370
Embodiment 57
5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.36-1.63(4H，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(1H，d，J＝4Hz)，7.26(1H，m)，7.37(1H，s)，8.53(1H，d，J＝5Hz)
MS(ESI
+)：m/z 430
Embodiment 58
5-[7-ethyl-2-(methoxymethyl)-4-(3-p-methoxy-phenyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.22(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.63(4H，m)，2.16(2H，t，J＝7Hz)，2.54-2.65(2H，m)，3.04(2H，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(3H，m)，7.38(1H，t，J＝8Hz)
MS(ESI
+)：m/z 425
Embodiment 59
5-[7-ethyl-2-(methoxymethyl)-4-(6-quinolyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：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(2H，m)，3.07(2H，q，J＝7Hz)，3.48(3H，s)，4.02(2H，q，J＝7Hz)，4.66(2H，s)，5.90(1H，d，J＝4Hz)，6.56(1H，d，J＝4Hz)，7.45-7.50(1H，m)，7.72(1H，dd，J＝2Hz，8Hz)，7.86(1H，d，J＝2Hz)，8.16-8.24(2H，m)，8.98(1H，m)
Embodiment 60
5-[7-ethyl-2-(methoxymethyl)-4-(3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.22(3H，t，J＝7Hz)，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＝4Hz)，6.58(1H，d，J＝4Hz)，7.42(1H，m)，7.71(1H，m)，8.62(1H，m)，8.70(1H，m)
MS(ESI
+)：m/z 396
Embodiment 61
5-[4-(3-chloro-phenyl-)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.58(4H，m)，2.17(2H，t，J＝7Hz)，2.51-2.62(2H，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(2H，m)
Embodiment 62
5-[7-ethyl-2-methyl-4-(3-aminomethyl phenyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.60(4H，m)，2.16(2H，t，J＝7Hz)，2.40(3H，s)，2.40-2.50(2H，m)，2.54(3H，s)，3.03(2H，q，J＝7Hz)，4.08(2H，q，J＝7Hz)，5.90(1H，d，J＝4Hz)，6.49(1H，d，J＝4Hz)，7.10-7.15(2H，m)，7.24(1H，m)，7.33(1H，m)
MS：(m/z)379(M+H)
Embodiment 65
5-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.60(4H，m)，2.18(2H，t，J＝7Hz)，2.42(3H，s)，2.48-2.63(2H，m)，3.05(2H，q，J＝7Hz)，3.46(3H，s)，4.08(2H，q，J＝7Hz)，4.62(2H，s)，5.90(1H，d，J＝4Hz)，6.57(1H，d，J＝4Hz)，7.51(1H，s)，8.41(1H，s)，8.53(1H，s)
MS(ESI
+)：m/z 410
Embodiment 66
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.65(4H，m)，2.21(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(1H，m)，8.53(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz)
MS(ESI
+)：m/z 444，446
Embodiment 67
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.63(4H，m)，2.19(2H，t，J＝7Hz)，2.50-2.66(2H，m)，3.03(2H，q，J＝7Hz)，3.46(3H，s)，4.10(2H，q，J＝7Hz)，4.62(2H，s)，5.91(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.88(1H，m)，8.55(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz)
MS(ESI
+)：m/z 474，476
Embodiment 68
5-[4-(5,6-two chloro-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.36-1.60(4H，m)，2.23(2H，t，J＝7Hz)，2.37-2.50(2H，m)，2.55(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＝4Hz)，7.81(1H，d，J＝2Hz)，8.30(1H，d，J＝2Hz)
MS(ESI
+)：m/z 434
Embodiment 69
4-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
NMR(CDCl
3，δ)：1.37(3H，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)，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
Embodiment 70
3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
NMR(CDCl
3，δ)：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)，4.65(2H，s)，5.91(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.51(1H，s)，8.41(1H，s)，8.52(1H，s)
Embodiment 71
4-[7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
NMR(CDCl
3，δ)：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＝4Hz)，7.51(1H，s)，8.41(1H，d，J＝2Hz)，8.53(1H，d，J＝2Hz)
MS(ESI
+)：m/z 366
Embodiment 72
3-[7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，2.30-2.43(2H，m)，2.42(3H，s)，2.58(3H，s)，2.76-2.86(2H，m)，3.02(2H，q，J＝7Hz)，4.10(2H，q，J＝7Hz)，5.87(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，7.48(1H，s)，8.40(1H，d，J＝2Hz)，8.53(1H，d，J＝2Hz)
MS(ESI
+)：m/z 352
Embodiment 73
3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl propionate
NMR(CDCl
3，δ)：1.21(3H，t，J＝7Hz)，1.39(2H，t，J＝7Hz)，2.35(2H，t，J＝7Hz)，2.58(3H，s)，2.74-2.83(2H，m)，3.01(2H，q，J＝7Hz)，4.08(2H，q，J＝7Hz)，5.89(1H，d，J＝4Hz)，6.55(1H，d，J＝4Hz)，7.87(1H，s)，8.53(1H，s)，8.79(1H，s)
MS：(m/z)416(M
+)，418(M
+-2)，85(bp)
Embodiment 74
5-[4-(3-cyano-phenyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝8Hz)，1.32-1.55(5H，m)，2.16(2H，t，J＝8Hz)，2.46-2.57(2H，m)，3.03(2H，q，J＝8Hz)，3.46(3H，s)，4.09(1H，q，J＝8Hz)，4.62(2H，s)，5.34(1H，d，J＝5Hz)，6.57(1H，d，J＝5Hz)，7.59-7.64(2H，m)，7.68(1H，br s)，7.75(1H，m)
MS(ESI
+)：420(M+H)
Embodiment 75
The 5-[2-[(acetoxyl group) methyl]-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.34-1.55(7H，m)，2.11-2.22(5H，m)，2.47(2H，m)，3.02(2H，q，J＝7Hz)，4.09(2H，q，J＝7Hz)，5.29(2H，s)，5.94(1H，d，J＝5Hz)，6.63(1H，d，J＝5Hz)，7.88(1H，m)，8.56(1H，m)，8.79(1H，m)
Embodiment 76
To 5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] add 1N sodium hydroxide (4.62mL) in the solution of Valeric acid ethylester (1.20g) in ethanol (12mL), and at room temperature stirred 2 hours.With reaction mixture 1N hydrogenchloride acidifying, and between ethyl acetate and water, distribute.Water and salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.(silica gel, 100mL) purification resistates obtain yellow solid (846mg) by the flash distillation silica gel chromatography with hexane-ethyl acetate=3-1,2-1 and 1-1 drip washing.With solid recrystallization from hexane-ethyl acetate (5-1), obtain also [1,2-b] pyridazine-3-yl of pale yellow crystals 5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole] valeric acid (795mg, 71.4%).
5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
mp：109-110℃
NMR(CDCl3，δ)：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)
Following compound is to obtain with embodiment 76 essentially identical modes.
Embodiment 77
3-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] propionic acid
NMR(CDCl
3，δ)：1.36(3H，t，J＝7 H)，1.56(2H，m)，2.03(2H，m)，2.79(2H，m)，3.01(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)
Embodiment 78
5-{7-ethyl-2-methyl-4-[3-(trifluoromethyl) phenyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
NMR(CDCl
3，δ)：1.37(3H，t，J＝7Hz)，1.40-1.62(4H，m)，2.22(2H，t，J＝7Hz)，2.38-2.46(2H，m)，2.56(3H，s)，3.02(2H，q，J＝7Hz)，5.84(1H，d，J＝4Hz)，6.51(1H，d，J＝4Hz)，7.53-7.64(3H，m)，7.72(1H，d，J＝8Hz)
MS(ESI
+)：m/z403(M-H)，405(M+H)
Embodiment 79
5-[7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：1.37(3H，t，J＝7Hz)，1.45-1.67(4H，m)，2.22(2H，t，J＝7Hz)，2.42(3H，s)，2.35-2.48(2H，m)，2.56(3H，s)，3.02(2H，q，J＝7Hz)，5.83(1H，d，J＝4Hz)，6.51(1H，d，J＝4Hz)，7.53(1H，s)，8.39(1H，s)，8.53(1H，s)
MS(ESI
+)：m/z 352(M+H)
Embodiment 80
5-[7-ethyl-4-(3-methoxyl group-5-different _ azoles base)-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：1.36(3H，t，J＝7Hz)，1.58-1.83(4H，m)，2.38(2H，t，J＝7Hz)，2.74-2.85(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)
Embodiment 81
5-{7-ethyl-2-methyl-4-[3-(1,3-_ azoles-5-yl) phenyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
NMR(CDCl
3，δ)：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(1H，s)，7.53(1H，t，J＝8Hz)，7.65(1H，s)，7.73(1H，d，J＝8Hz)，7.93(1H，s)
MS(ESI
+)：m/z 402(M-H)，404(M+H)
Embodiment 82
5-[4-(3, the 4-dichlorophenyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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＝2Hz，8Hz)，7.45(1H，d，J＝2Hz)，7.56(1H，d，J＝8Hz)
MS(ESI
+)：m/z 403(M-H)，405(M+H)
Embodiment 83
5-[4-(4-chloro-2-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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＝2Hz，7Hz)，7.53(1H，d，J＝2Hz)，8.67(1H，d，J＝7Hz)
MS(ESI
+)：m/z 372(M+H)
Embodiment 84
5-[4-(5-chloro-2-thienyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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)，6.60(1H，d，J＝4Hz)，6.97(2H，m)
MS(ESI
+)：m/z 405(M-H)，407(M+H)
Embodiment 85
5-[7-ethyl-4-(6-methoxyl group-2-pyrazinyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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)
Embodiment 86
5-[4-(1-cumarone-2-yl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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，J＝4Hz)，7.16(1H，s)，7.26-7.43(2H，m)，7.57(1H，d，J＝8Hz)，7.68(1H，d，J＝8Hz)
Embodiment 87
5-[4-(1-thionaphthene-2-yl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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)
Embodiment 88
5-[7-ethyl-2-methyl-4-(1,3-_ azoles-5-yl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.52(1H，s)，8.13(1H，s)
MS(ESI
+)：m/z 328(M+H)
Embodiment 89
5-(7-ethyl-2-methyl-4-phenylpyrrole is [1,2-b] pyridazine-3-yl also) valeric acid
NMR(CDCl
3，δ)：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)
Embodiment 90
5-[7-ethyl-2-methyl-4-(6-quinolyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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，J＝4Hz)，7.49(1H，m)，7.73(1H，dd，J＝2Hz，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)
Embodiment 91
7-{4-[4-(amino-sulfonyl) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } enanthic acid
NMR(CDCl
3，δ)：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(1H，d，J＝5Hz)，6.52(1H，d，J＝5Hz)，7.52(2H，d，J＝9Hz)，8.04(2H，d，J＝9Hz)
MS(ESI
+)：m/z 444(M+H)
Embodiment 92
({ [4-(3-chloro-phenyl-)-7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-3-yl] carbonyl } amino) acetate
NMR(CDCl
3，δ)：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)
Embodiment 93
5-{7-ethyl-2-methyl-4-[3-(methyl sulphonyl) phenyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
NMR(CDCl
3，δ)：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)
Embodiment 94
5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
mp：139-140℃
NMR(CDCl3，δ)：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，br d，J＝7Hz)，7.36(1H，br s)，8.53(1H，d，J＝7Hz)
MS(ESI
+)：m/z 372(M+H)
Embodiment 95
5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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＝10Hz)，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)
Embodiment 96
5-[7-ethyl-2-methyl-4-(3-nitrophenyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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，m)
Embodiment 97
{ [7-ethyl-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl] methoxyl group } acetate
NMR(CDCl
3，δ)：1.33-1.45(9H，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)
Embodiment 98
5-[4-(5-ethanoyl-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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)，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)
Embodiment 99
5-{4-(2-chloro-4-pyridyl)-7-ethyl-2-[(methylthio group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
NMR(CDCl
3，δ)：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)
Embodiment 100
5-{4-(2-chloro-4-pyridyl)-7-ethyl-2-[(methyl sulphonyl) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
NMR(CDCl
3，δ)：1.37(3H，t，J＝7Hz)，1.45-1.65(4H，m)，2.29(2H，t，J＝7Hz)，2.56-2.67(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(1H，s)，8.56(1H，d，J＝5Hz)
MS：(m/z)448(M-H)，450(M+H)
Embodiment 101
5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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)，7.31(1H，d，J＝5Hz)，7.39-7.53(6H，m)，8.55(1H，d，J＝5Hz)
Embodiment 102
5-[4-(6-chloro-2-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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
Embodiment 103
5-[7-ethyl-4-(3-p-methoxy-phenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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)
MS(ESI
+)：m/z 367，MS(ESI
-)：m/z 365
Embodiment 104
5-[4-(3, the 5-dichlorophenyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：1.37(3H，t，J＝7Hz)，1.42-1.53(2H，m)，1.53-1.66(2H，m)，2.27(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
Embodiment 105
5-[4-(5-chloro-2-thienyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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
Embodiment 106
5-[7-ethyl-4-(3-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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/z353
Embodiment 107
5-[7-ethyl-2-methyl-4-(3-quinolyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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，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
Embodiment 108
5-[7-ethyl-2-methyl-4-(4-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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，J＝7Hz)
Embodiment 109
5-[7-ethyl-4-(3-methoxyl group-5-different _ azoles base)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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(1H，d，J＝4Hz)，6.57(1H，d，J＝4Hz)
Embodiment 110
5-[7-ethyl-4-(3-p-methoxy-phenyl)-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：1.06-1.33(4H，m)，1.36(3H，t，J＝7Hz)，1.91(2H，t，J＝7Hz)，2.42-2.53(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
Embodiment 111
5-[7-ethyl-2-methyl-4-(5-methyl-3-different _ azoles base) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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
Embodiment 112
5-[7-ethyl-2-phenyl-4-(4-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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)
Embodiment 113
5-[7-ethyl-2-phenyl-4-(2-pyrazinyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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)，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
Embodiment 114
5-[7-ethyl-2-phenyl-4-(3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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(ESI
+)：m/z 400，MS(ESI
-)：m/z 398
Embodiment 115
5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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 embodiment 116
5-[7-ethyl-2-(methoxymethyl)-4-(3-p-methoxy-phenyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：1.37(3H，t，J＝7Hz)，1.40-1.62(4H，m)，2.19(2H，t，J＝7Hz)，2.55-2.66(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
Embodiment 117
5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-(2-thienyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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)
MS(ESI
+)：m/z 440
Embodiment 118
5-[7-ethyl-2-(methoxymethyl)-4-(6-quinolyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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(ESI
-)：m/z 416
Embodiment 119
5-[7-ethyl-2-(methoxymethyl)-4-(3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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(1H，d，J＝4Hz)，7.48(1H，m)，7.78(1H，m)，8.62(1H，m)，8.69(1H，m)
MS(ESI
+)：m/z 368
Embodiment 120
5-[4-(3-chloro-phenyl-)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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)
Embodiment 121
5-[7-ethyl-2-methyl-4-(3-aminomethyl phenyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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
Embodiment 124
5-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：1.37(3H，t，J＝7Hz)，1.44-1.65(4H，m)，2.16-2.26(2H，m)，2.43(3H，s)，2.47-2.69(2H，m)，3.03(2H，q，J＝7Hz)，3.45(3H，s)，4.63(2H，m)，5.88(1H，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
Embodiment 125
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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，J＝4Hz)，7.88(1H，m)，8.53(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz)
MS(ESI
+)：m/z 416，418
Embodiment 126
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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)
MS(ESI
+)：m/z 446，448
Embodiment 127
5-[4-(5,6-two chloro-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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
Embodiment 128
5-[7-ethyl-2-methyl-4-(5-vinyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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＝11Hz)，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＝11Hz，17Hz)，7.77(1H，m)，8.47(1H，d，J＝2Hz)，8.68(1H，d，J＝2Hz)
MS(ESI
+)：m/z 364
Embodiment 129
5-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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(1H，d，J＝11Hz)，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＝11Hz，18Hz)，7.78(1H，s)，8.48(1H，s)，8.68(1H，s)
MS(ESI
+)：m/z 394(M+H)，MS(ESI
-)：m/z 392
Embodiment 130
5-[4-(5-ethanoyl-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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(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(ESI
-)：m/z 408
Embodiment 131
4-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
NMR(CDCl
3，δ)：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)
MS(ESI
+)：m/z 368
Embodiment 132
3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
NMR(CDCl
3，δ)：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(ESI
+)：m/z 354
Embodiment 133
4-[7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
NMR(CDCl
3，δ)：1.37(3H，t，J＝7Hz)，1.70-1.88(2H，m)，2.22-2.32(2H，m)，2.45(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
Embodiment 134
3-[7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
NMR(CDCl
3，δ)：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)
MS(ESI
+)：m/z 324，MS(ESI
-)：m/z 322
Embodiment 135
3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] propionic acid
mp：181-182℃
NMR(CDCl3，δ)：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)
Embodiment 136
5-[4-(3-cyano-phenyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NNMR(CDCl
3，δ)：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，J＝5Hz)，7.59-7.64(2H，m)，7.68(1H，br s)，7.75(1H，m)
MS(ESI
+)：392(M+H)
Embodiment 136-2
5-[4-[3-(aminocarboxyl) phenyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR (CDCl
3, δ): (5H is with H for 1.30-1.70
2O is overlapping), and 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=10Hz), 4.77 (1H, d, J=10Hz), 5.80 (1H, d, J=5Hz), 6.55 (1H, d, J=5Hz), 7.43-7.50 (2H, m), 7.58 (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)
Embodiment 137
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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)
Embodiment 138
5-[7-ethyl-4-(5-ethyl-3-pyridyl)-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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)
Embodiment 139
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(2-thienyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：1.25-1.48(7H，m)，2.12(2H，t，J＝7Hz)，2.62(2H，m)，3.03(2H，q，J＝7Hz)，5.93(1H，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)
Embodiment 140
The 5-[2-[(benzyloxy) methyl]-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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(1H，m)
Embodiment 141
5-(4-(5-bromo-3-pyridyl)-2-{[(4-cyano group benzyl) oxygen base] methyl }-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also) valeric acid
NMR(CDCl
3，δ)：1.35-1.56(7H，m)，2.18(2H，m)，2.57(2H，m)，3.03(2H，q，J＝7Hz)，4.69(2H，s)，4.74(2H，s)，5.92(1H，d，J＝5Hz)，6.62(1H，d，J＝5Hz)，7.47(2H，d，J＝8Hz)，7.64(2H，d，J＝8Hz)，7.88(1H，s)，8.54(1H，m)，8.79(1H，m)
Embodiment 142
The 5-[2-[(benzylamino) methyl]-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：1.20-1.49(7H，m)，2.17(2H，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(1H，m)，8.49(1H，m)，8.75(1H，m)
Embodiment 143
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(4-morpholinyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：1.20-1.38(5H，m)，1.49(4H，m)，2.24(2H，q，J＝7Hz)，2.59(4H，m)，3.01(2H，q，J＝7Hz)，3.70(4H，m)，5.88(1H，d，J＝5Hz)，6.55(1H，d，J＝5Hz)，7.90(1H，m)，8.55 81H，m)，8.78(1H，m)
Embodiment 144
From 5-[4-(5-cyano group-3-pyridyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] 5-{4-[5-(the aminocarboxyl)-3-pyridyl of Valeric acid ethylester]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } valeric acid
NMR(CDCl
3，δ)：1.10-1.70(4H，m)，1.37(3H，t，J＝7Hz)，2.24-2.77(4H，m)，2.59(3H，s)，3.02(2H，q，J＝7Hz)，5.77(1H，d，J＝4Hz)，6.52(1H，d，J＝4Hz)，7.57(1H，br)，7.97(1H，br)，8.07(1H，s)，8.68(1H，s)，9.18(1H，s)
MS(ESI
+)：m/z 381
Embodiment 145
5-[4-[5-(aminocarboxyl)-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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)
MS(ESI
+)：m/z 411
Embodiment 146
Under 2 ℃ of nitrogen, (the 1.1mol/L solution in the hexane 15mL), and stirred the mixture under uniform temp 30 minutes to drip lithium two (trimethyl silyl) acid amides in the solution of 4-phosphono Ba Dousuan triethyl (2.13g) in tetrahydrofuran (THF) (20mL).In mixture, drip 4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1, the 2-b] pyridazine-solution of 3-formaldehyde (1.2g) in tetrahydrofuran (THF) (20mL).After 2 ℃ are stirred 3 hours, mixture is poured in the saturated aqueous ammonium chloride, and used the ethyl acetate extraction mixture.Water, salt water washing organic layer are by anhydrous magnesium sulfate drying and concentrated.(eluent: 3% ethyl acetate in the normal hexane) purification resistates obtains the title compound (1.06g) into yellow crystals by silica gel column chromatography.
(2E, 4E)-5-[4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-2, the 4-pentanedioic acid diethyl ester
NMR (300 MHz, CDCl
3, δ): 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=16,11Hz), 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)
MS(ESI
+)：m/z 379(M+H)
Following compound is to obtain with embodiment 146 essentially identical modes.
Embodiment 147
(2E)-3-[7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-the 2-ethyl propionate
NMR(CDCl
3，δ)：1.25(3H，t，J＝7Hz)，1.40(6H，d，J＝7Hz)，3.38(1H，m)，4.16(2H，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(ESI
-)：m/z 385(M-H)
Embodiment 148
(2E)-3-[7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-the 2-vinyl cyanide
NMR(CDCl
3，δ)：1.41(6H，d，J＝7Hz)，3.28(1H，m)，4.99，(1H，d，J＝15Hz)，6.24(1H，d，J＝5Hz)，6.76(1H，d，J＝15Hz)，7.17-7.27(2H，m)，7.30-7.40(3H，m)
MS(ESI
-)：m/z 340(M+H)
Embodiment 149
To (2E, 4E)-5-[4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-2, drip N-chloro-succinimide (106mg) in the solution of 4-pentanedioic acid diethyl ester (300mg) in tetrahydrofuran (THF) (3mL) and acetate (1mL).At room temperature stirred the mixture 24 hours.The mixture that obtains is concentrated and between saturated sodium bicarbonate aqueous solution and ethyl acetate, distribute.With salt water washing organic layer, by anhydrous magnesium sulfate drying and concentrated.(eluent: 1% ethyl acetate in the normal hexane) purification resistates obtains the title compound (110mg) into oil by silica gel column chromatography.(2E, 4E)-5-[7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-2, the 4-pentanedioic acid diethyl ester
NMR (300MHz, CDCl
3, δ): 1.28 (3H, t, J=7Hz), 1.40 (6H, d, J=7Hz), 3.33 (1H, quintet, J=7Hz), 4.19 (2H, quartets, J=7Hz), 5.64 (1H, d, J=16Hz), 5.94 (1H, dd, J=16,11Hz), 6.18 (1H, d, J=4.4Hz), 6.71 (1H, d, J=4.4Hz), 6.79 (1H, d, J=16Hz), and 7.13-7.23 (3H, m), 7.32-7.37 (2H, m)
Following compound is to obtain with embodiment 149 essentially identical modes.
Embodiment 151
7-chloro-4-(2-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate
NMR(300MHz，CDCl
3，δ)：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
Embodiment 152
7-chloro-2-sec.-propyl-4-(2-naphthyl) pyrrolo-[1,2-b] pyridazine-3-ethyl formate
NMR(300MHz，CDCl
3，δ)：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)，7.50-7.60(3H，m)，7.81-8.00(4H，m)
Embodiment 153
To (2E, 4E)-5-[7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-2, add 1N sodium hydroxide solution (0.5mL) in the solution of 4-glutarate (82mg) in ethanol (2mL), and at room temperature stirred the mixture 12 hours.With the mixture vacuum concentration that obtains, and resistates is water-soluble, use the 1N hcl acidifying, and use ethyl acetate extraction.Water, salt water washing organic layer are by anhydrous magnesium sulfate drying and concentrated.(eluent: 50% ethyl acetate in the normal hexane) purification resistates obtains the title compound (14mg) into brown amorphous solid, by the aqueous ethanolic solution recrystallization by silica gel column chromatography.
(2E, 4E)-5-[7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-2, the 4-pentadienoic acid
NMR (300MHz, CDCl
3, δ): 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)
Embodiment 154
To 5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-(2-thienyl) pyrrolo-[1,2-b] pyridazine-3-yl] add 28% methanol solution of sodium methylate (536mg) in the mixture of Valeric acid ethylester (130mg) in toluene (5mL), and with mixture heating 2 hours under refluxing.With 1N hydrochloric acid solution is acidified to pH 4, and uses chloroform extraction.Separate organic layer, by dried over mgso, and evaporation in a vacuum.Add 1N sodium hydroxide solution (1mL) in the resistates in ethanol (5mL), and 60 ℃ of heated mixt 1 hour.With 1N hydrochloric acid solution is acidified to pH 4, and uses chloroform extraction.Separate organic layer, use the salt water washing, by dried over mgso, and evaporation in a vacuum.Silica gel column chromatography purification resistates by with hexane and ethyl acetate mixture (1: 1) drip washing obtains yellow powder 5-[7-ethyl-4-(2-methoxyl group-4-pyridyl)-2-(2-thienyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid (50.0mg).
5-[7-ethyl-2-methyl-4-(2-methoxyl group-4-pyridyl)-2-(2-thienyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：1.30-1.48(4H，m)，1.38(3H，t，J＝7Hz)，2.13(2H，t，J＝7Hz)，2.58-2.69(2H，m)，3.02(2H，q，J＝7Hz)，4.02(3H，s)，5.96(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，6.78(1H，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)
Following compound is to obtain with embodiment 154 essentially identical modes.
Embodiment 155
5-[7-ethyl-4-(2-methoxyl group-4-pyridyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：1.31-1.64(7H，m)，2.25(2H，t，J＝8Hz)，2.43(2H，br t，J＝8Hz)，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(1H，br s)，6.93(1H，br d，J＝7Hz)，8.30(1H，d，J＝7Hz)
MS(ESI
+)：m/z 368(M+H)
Embodiment 155-2
5-[7-ethyl-2-methyl-4-(2-oxo-1,2-dihydro-4-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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(1H，br d，J＝7Hz)，6.84(1H，brs)，7.70(1H，br d，J＝7Hz)
MS(ESI
+)：m/z 354(M+H)
Following compound is to obtain with embodiment 154 essentially identical modes.
Embodiment 156
5-[7-ethyl-4-(2-methoxyl group-4-pyridyl)-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：1.08-1.30(4H，m)，1.36(3H，t，J＝7Hz)，1.95(2H，t，J＝7Hz)，2.48-2.53(2H，m)，3.03(2H，q，J＝7Hz)，4.01(3H，s)，6.02(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，6.82(1H，s)，6.94(1H，d，J＝5Hz)，7.42-7.54(5H，m)，8.29(1H，d，J＝5Hz)
MS(ESI
+)：m/z 430
Embodiment 157
5-[7-ethyl-2-(methoxymethyl)-4-(2-methoxyl group-4-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：1.37(3H，t，J＝7Hz)，1.40-1.64(4H，m)，2.24(2H，t，J＝7Hz)，2.53-2.64(2H，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
Embodiment 158
To 5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-phenylpyrrole also [1,2-b] pyridazine-3-yl] add sulfo-sodium methylate (91.0mg) in the solution of Valeric acid ethylester (120mg) in toluene (5mL) and tetrahydrofuran (THF) (10mL), and with mixture heating 4 hours under refluxing.With the solution acidifying, and use chloroform extraction with 1N hydrochloric acid.Separate organic layer, use the salt water washing, by dried over mgso, and evaporation in a vacuum.By with the mixture of hexane and ethyl acetate (10: 1-3: 1) the silica gel column chromatography purification resistates of drip washing obtains yellow powder 5-{7-ethyl-4-[2-(methylthio group)-4-pyridyl]-2-phenylpyrrole [1,2-b] pyridazine-3-yl also valeric acid (85.0mg).
5-{7-ethyl-4-[2-(methylthio group)-4-pyridyl]-2-phenylpyrrole [1,2-b] pyridazine-3-yl also } valeric acid
NMR(CDCl
3，δ)：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＝1Hz，5Hz)，7.25(1H，m)，7.43-7.55(5H，m)，8.57(1H，d，J＝5Hz)
MS(ESI
+)：m/z 446(M+H)
Embodiment 159
With Dean-Stark equipment with 3-[(1-amino-5-ethyl-1H-pyrroles-2-yl) carbonyl] benzonitrile (3.00g), 6-benzoyl ethyl hexanoate (5.07g) and the mixture of trifluoromethanesulfonic acid (376mg) in toluene (60mL) refluxed 1 hour 20 minutes.Mixture is distributed between ethyl acetate (60mL) and water (60mL), and wash organic layer with saturated sodium bicarbonate (60mL) and salt solution (60mL), by dried over mgso, and evaporation obtains dark oil.Obtain also [1,2-b] pyridazine-3-yl of orange-yellow oil 5-[4-(3-cyano-phenyl)-7-ethyl-2-phenylpyrrole with acetone=1-100 to the flash distillation silica gel column chromatography of 7-100 drip washing] Valeric acid ethylester (4.45g, 78.6%).
5-[4-(3-cyano-phenyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：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)
Following compound is to obtain with embodiment 159 essentially identical modes.
Embodiment 160
5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-(2-thienyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：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(1H，dd，J＝1Hz，5Hz)，7.37(1H，m)，7.41(1H，s)，7.45(1H，d，J＝5Hz)，8.55(1H，d，J＝5Hz)
MS：(m/z)468(M+H)
Embodiment 161
5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：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＝2Hz，5Hz)，7.41-7.54(6H，m)，8.56(1H，d，J＝5Hz)
MS(ESI
+)：m/z 462(M+H)
Embodiment 162
[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl acetate
NMR(CDCl
3，δ)：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，m)，7.41-7.50(8H，m)
MS(ESI
+)：m/z 419(M+H)
Embodiment 163
4-(3-chloro-phenyl-)-7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-3-ethyl formate
NMR(CDCl
3，δ)：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)
Embodiment 164
4-(3-chloro-phenyl-)-7-ethyl-2-(2-pyridyl) pyrrolo-[1,2-b] pyridazine-3-ethyl formate
NMR(CDCl
3，δ)：0.94(3H，m)，1.41(3H，m)，3.08(2H，q，J＝7Hz)，3.11(2H，m)，4.00(2H，m)，6.36(1H，m)，6.76(1H，m)，7.26-7.55(4H，m)，7.84(1H，m)，8.15(1H，m)，8.57(1H，m)
MS(ESI
+)：m/z 406(M+H)
Embodiment 165
5-[4-(3-cyano-phenyl)-7-ethyl-2-(1,3-thiazoles-2-yl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.21(3H，t，J＝7Hz)，1.33-1.50(7H，m)，2.14(2H，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，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(1H，d，J＝3Hz)
Embodiment 166
5-[4-(3-cyano-phenyl)-7-ethyl-2-(1-methyl isophthalic acid H-pyrroles-2-yl) pyrrolo-[1,2-b] pyridazine-3-yl] methyl valerate
NMR(CDCl
3，δ)：1.04(2H，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(3H，s)，5.89(1H，d，J＝5Hz)，6.23(1H，m)，6.35(1H，m)，6.62(1H，d，J＝5Hz)，6.76(1H，m)，7.62-7.79(4H，m)
Embodiment 167
3-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl propionate
NMR(CDCl
3，δ)：1.08(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，2.02(2H，m)，2.80(2H，m)，3.02(2H，q，J＝7Hz)，3.89(2H，q，J＝7Hz)，6.01(1H，d，J＝5Hz)，6.63(1H，d，J＝5Hz)，7.31(1H，m)，7.41-7.54(8H，m)
Embodiment 168
5-[4-(3-cyano-phenyl)-7-ethyl-2-(1,3-_ azoles-5-yl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.17-1.49(10H，m)，2.08(2H，t，J＝7Hz)，2.57(2H，m)，3.03(2H，q，J＝7Hz)，4.06(2H，q，J＝7Hz)，5.91(1H，d，J＝5Hz)，6.66(1H，d J＝5Hz)，7.55(1H，s)，7.62-7.68(3H，m)，7.78(1H，m)，8.04(1H，s)
Embodiment 169
5-[7-ethyl-4-(3-p-methoxy-phenyl)-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.05-1.29(4H，m)，1.18(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.86(2H，t，J＝7Hz)，2.42-2.52(2H，m)，3.02(2H，q，J＝7Hz)，3.84(3H，s)，4.02(2H，q，J＝7Hz)，6.02(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，6.95-7.02(3H，m)，7.36-7.56(6H，m)
Embodiment 170
5-[7-ethyl-2-phenyl-4-(4-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：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)
Embodiment 171
5-[7-ethyl-2-phenyl-4-(2-pyrazinyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：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(2H，q，J＝7Hz)，4.02(2H，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，m)，8.86(1H，m)
Embodiment 172
5-[7-ethyl-2-phenyl-4-(3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.04-1.30(4H，m)，1.18(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.87(2H，t，J＝7Hz)，2.38-2.50(2H，m)，3.02(2H，q，J＝7Hz)，4.01(2H，q，J＝7Hz)，5.96(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.42-7.55(6H，m)，7.77(1H，m)，8.66-8.73(2H，m)
Embodiment 173
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.12-1.28(7H，m)，1.36(3H，t，J＝7Hz)，1.89(2H，t，J＝7Hz)，2.43(2H，m)，3.01(2H，m)，4.02(2H，q，J＝7Hz)，5.97(1H，d，J＝5Hz)，6.65(1H，d，J＝5Hz)，7.43-7.55(5H，m)，7.93(1H，m)，8.61(1H，m)，8.79(1H，m)
Embodiment 174
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(2-thienyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.16-1.46(10H，m)，1.57(2H，t，J＝7Hz)，2.62(2H，m)，2.30(2H，m)，3.03(2H，q，J＝7Hz)，4.05(2H，q，J＝7Hz)，5.93(1H，d，J＝5Hz)，6.63(1H，d，J＝5Hz)，7.36(1H，m)，7.44(1H，m)，7.91(1H，m)
Embodiment 175
Through 1.5 hours to 5-[4-(3-cyano-phenyl)-7-ethyl-2-phenylpyrrole [1,2-b] pyridazine-3-yl also] add 1N sodium hydroxide (5.31mL) in the solution of Valeric acid ethylester (1.00g) in methyl-sulphoxide (20mL).Make the reaction quenching by in ice bath, adding 1N hydrochloric acid (6mL).Mixture is distributed between ethyl acetate (50mL) and water (50mL).Water (50 * 2mL) and salt water washing organic layer, by dried over mgso, and evaporation.Obtain also [1,2-b] pyridazine-3-yl of yellow solid 5-[4-(3-cyano-phenyl)-7-ethyl-2-phenylpyrrole with ethyl acetate-hexane=1/3 to the flash distillation silica gel column chromatography of 1/11 drip washing] valeric acid (668mg).
5-[4-(3-cyano-phenyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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(5H，s)，7.56-7.69(2H，m)，7.72-7.79(2H，m)
MS(ESI
+)：m/z 424(M+H)
Following compound is to obtain with embodiment 175 essentially identical modes.
Embodiment 176
5-[4-(3-cyano-phenyl)-7-ethyl-2-(1,3-thiazoles-2-yl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：1.20-1.52(7H，m)，2.19(2H，m)，2.98(2H，m)，3.04(2H，q，J＝7Hz)，4.05(2H，q，J＝7Hz)，5.38(1H，d，J＝5Hz)，6.67(1H，d，J＝5Hz)，7.43(1H，d，J＝3Hz)，7.60-7.64(2H，m)，7.67(1H，m)，7.76(1H，m)，7.92(1H，d，J＝3Hz)
MS(ESI
+)：m/z 431(M+H)
Embodiment 177
5-[4-(3-cyano-phenyl)-7-ethyl-2-(1-methyl isophthalic acid H-pyrroles-2-yl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：1.12(2H，m)，1.23-1.41(5H，m)，2.04(2H，t，J＝7Hz)，2.48(2H，m)，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)
Embodiment 178
5-[4-(3-cyano-phenyl)-7-ethyl-2-(1,3-_ azoles-5-yl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：1.31-1.49(7H，m)，2.17(2H，t，J＝7Hz)，2.57(2H，m)，3.04(2H，q，J＝7Hz)，5.42(1H，d，J＝5Hz)，6.67(1H，d，J＝5Hz)，7.56(1H，s)，7.64(2H，m)，7.67(1H，s)，7.78(1H，m)，8.07(1H，s)
Embodiment 179
5-[4-(3-cyano-phenyl)-2-(3,5-dimethyl-4-is different _ azoles base)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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＝5Hz)，7.61-7.68(2H，m)，7.73(1H，s)，7.79(1H，m)
Embodiment 180
With 3-[(1-amino-5-ethyl-1H-pyrroles-2-yl) carbonyl] benzonitrile (120mg), 2-[(3,5-dimethyl-4-is different _ the azoles base) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester (203mg) and the solution of toluenesulphonic acids monohydrate (3.76mg) in toluene (1mL) refluxed 1 hour.Add tosic acid monohydrate (14.5mg) in addition, and mixture was refluxed 1 hour.Adding trifluoromethanesulfonic acid (3.76mg) further stirred the mixture 0.5 hour afterwards.Mixture is distributed between ethyl acetate (20mL) and saturated sodium bicarbonate (10mL).With salt water washing organic layer, by dried over mgso, and evaporation.Obtain also [1,2-b] pyridazine-3-yl of yellow glue 5-[4-(3-cyano-phenyl)-2-(3,5-dimethyl-4-is different _ azoles base)-7-N-ethyl pyrrole N-with ethyl acetate-hexane=1/40 to the flash distillation silica gel column chromatography of 2/5 drip washing] Valeric acid ethylester (75.7mg, 19.1%).
5-[4-(3-cyano-phenyl)-2-(3,5-dimethyl-4-is different _ azoles base)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：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＝5Hz)，7.61-7.68(2H，m)，7.73(1H，s)，7.79(1H，m)
Embodiment 181
In ice bath, to N-[2-(3-cyano group benzoyl)-5-ethyl-1H-pyrroles-1-yl]-add sodium hydride (601mg, in the oil 60%) in the solution of 2-(methyl sulphonyl) ethanamide (2.70g) in tetrahydrofuran (THF) (30mL).After stirring 40 minutes, make the reaction quenching by adding 1N hydrochloric acid (15mL).With ethyl acetate (50mL) extraction mixture, and water (50 * 2mL) and salt solution (50mL) washing extraction liquid, by dried over mgso, and evaporate and obtain pale brown look solid (3.36g).Abrasive solid in diisopropyl ether (20mL) obtains yellow powder 3-[7-ethyl-3-(methyl sulphonyl)-2-oxo-1, and the 2-pyrrolin is [1,2-b] pyridazine-4-yl also] benzonitrile (2.31g, 90.1%).3-[7-ethyl-3-(methyl sulphonyl)-2-oxo-1,2-pyrrolin be [1,2-b] pyridazine-4-yl also] benzonitrile
NMR(CDCl
3，δ)：1.37(3H，t，J＝7Hz)，2.46-3.07(5H，m)，6.81(1H，d，J＝5Hz)，6.70(1H，d，J＝5Hz)，7.60-7.69(3H，m)，7.83(1H，d，J＝9Hz)
Following compound is to obtain with embodiment 181 essentially identical modes.
Embodiment 182
4-(4-cyano-phenyl)-7-ethyl-2-oxo-1,2-pyrrolin be [1,2-b] pyridazine-3-ethyl formate also
NMR(CDCl
3，δ)：0.78(3H，t，J＝7Hz)，1.36(3H，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)，7.77(2H，d，J＝9Hz)，11.74(1H，s，br)
MS(ESI
+)：m/z 336(M+H)
Embodiment 183
In ice bath (3 to 7 ℃); through 30 fens clockwise 3-[7-ethyl-3-(methyl sulphonyl)-2-oxos-1; the 2-pyrrolin is [1,2-b] pyridazine-4-yl also] add trifluoromethanesulfanhydride anhydride (1.61g) in benzonitrile (1.30g) and the solution of triethylamine (578mg) in methylene dichloride (18mL).After stirring 0.5 hour, make the reaction quenching by adding water (100mL).Mixture is distributed between ethyl acetate that contains chloroform (200mL) (200mL) and 1N hydrochloric acid (50mL).Collect insoluble yellow solid (0.542g) by filtering.With salt water washing organic layer, by dried over mgso, and evaporation obtains dark yellow solid (1.27g).Two kinds of solids are mixed, and in diisopropyl ether (30mL), grind, obtain pale brown toner end trifluoromethanesulfonic acid 4-(3-cyano-phenyl)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-2-base ester (1.67g, 92.6%).
Trifluoromethanesulfonic acid 4-(3-cyano-phenyl)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-2-base ester
NMR(CDCl
3，δ)：1.39(3H，t，J＝7Hz)，3.02(2H，q，J＝7Hz，)，3.22(3H，s)，6.40(1H，d，J＝5Hz)，6.93(1H，d，J＝5Hz)，7.63(3H，m)，7.82(1H，m)
Embodiment 184
Trifluoromethanesulfonic acid 4-(3-cyano-phenyl)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-2-base ester (150mg) and the mixture of tetramethyleneimine (45.6mg) in tetrahydrofuran (THF) (1mL) were refluxed 1.5 hours.Mixture is distributed between ethyl acetate (20mL) and 1N hydrochloric acid (10mL).With salt water washing organic extract liquid, by dried over mgso, and evaporation obtains dark solid.With ethyl acetate-hexane=1-4 crystalline yellow oil 3-[7-ethyl-3-(methyl sulphonyl)-2-(1-pyrrolidyl)-pyrrolo-[1,2-b] pyridazine-4-yl when the flash distillation silica gel column chromatography of 1-2 drip washing obtains placing] benzonitrile (112mg, 89.6%).
3-[7-ethyl-3-(methyl sulphonyl)-2-(1-pyrrolidyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile
NMR(CDCl
3，δ)：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)
Following compound is to obtain with embodiment 184 essentially identical modes.
Embodiment 185
3-[2-(dimethylamino)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile
NMR(CDCl
3，δ)：1.39(3H，t，J＝7Hz)，2.97(6H，s)，3.02(2H，q，J＝7Hz)，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)
Embodiment 186
3-[7-ethyl-2-[(2-methoxy ethyl) amino]-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile
NMR(CDCl
3，δ)：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(1H，d，J＝5Hz)，6.75(1H，m，br)，7.51-7.60(3H，m)，7.74(1H，m)
MS(ESI
+)：m/z 399(M+H)
Embodiment 187
2-(4-fluoro benzoyl)-3-oxo-4-phenylbutyrate (1.4g), 1H-pyrroles-1-amine (350mg) and tosic acid monohydrate (41mg) mixture in ethanol (10ml) was refluxed 5 hours.Mixture is distributed between ethyl acetate and water.Separate organic layer, use the salt water washing, by dried over mgso, and evaporation.By on silica gel, resistates being carried out chromatographic separation, obtain oily 2-benzyl-4-(4-fluorophenyl) pyrrolo-[1,2-b] pyridazine-3-ethyl formate (828mg) with ethyl acetate and hexane (1: 4) mixture drip washing.
2-benzyl-4-(4-fluorophenyl) pyrrolo-[1,2-b] pyridazine-3-ethyl formate
NMR(CDCl
3，δ)：0.70(3H，t，J＝7Hz)，3.71(2H，q，J＝7Hz)，4.29(2H，s)，6.37(1H，dd，J＝1，4Hz)，6.85(1H，dd，J＝2，4Hz)，7.10-7.30(7H，m)，7.38-7.46(2H，m)，7.83(1H，dd，1，2Hz)
Embodiment 188
In 2-benzyl-4-(4-fluorophenyl) pyrrolo-[1, the 2-b] pyridazine-solution of 3-ethyl formate (730mg) in tetrahydrofuran (THF) (10mL), add N-chloro-succinimide (260mg), and under 20 ℃, stirred the mixture 2 hours.Mixture is distributed between ethyl acetate and water.Separate organic layer, with sodium thiosulfate solution, water and salt water washing, by dried over mgso, and evaporation.Silica gel column chromatography purification resistates by with toluene and ethyl acetate (10: 1) mixture drip washing obtains yellow oil 2-benzyl-7-chloro-4-(4-fluorophenyl) pyrrolo-[1,2-b] pyridazine-3-ethyl formate (285mg).
2-benzyl-7-chloro-4-(4-fluorophenyl) pyrrolo-[1,2-b] pyridazine-3-ethyl formate
NMR(CDCl
3，δ)：0.69(3H，t，J＝7Hz)，3.70(2H，q，J＝7Hz)，4.37(2H，s)，6.39(1H，d，J＝4Hz)，6.82(1H，d，J＝4Hz)，7.10-7.30(7H，m)，7.35-7.45(2H，m)
Embodiment 189
3-(4-fluoro benzoyl)-ethyl 4-oxopentanoate (800mg), 1H-pyrroles-1-amine (265mg) and tosic acid monohydrate (31mg) mixture in ethanol (5ml) was refluxed 5 hours.Mixture is distributed between ethyl acetate and water.Separate organic layer, use the salt water washing, by dried over mgso, and evaporation.By on silica gel, resistates being carried out chromatographic separation, obtain oil [4-(4-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl acetate (1.09g) with ethyl acetate and hexane (1: 4) mixture drip washing.
[4-(4-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl acetate
NMR(CDCl
3，δ)：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)
Embodiment 190
In [4-(4-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl acetate (100mg) solution in tetrahydrofuran (THF) (2mL), add N-chloro-succinimide (43mg), and under 20 ℃, stirred the mixture 2 hours.Mixture is distributed between ethyl acetate and water.Separate organic layer, with the ethyl acetate aqueous solution, water and salt water washing, by dried over mgso, and evaporation.Silica gel column chromatography purification resistates by with toluene and ethyl acetate (10: 1) mixture drip washing obtains yellow oil [7-chloro-4-(4-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl acetate (34mg).
[7-chloro-4-(4-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl acetate
NMR(CDCl
3，δ)：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)
Embodiment 191
In the solution of [7-chloro-4-(4-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl acetate (300mg) in tetrahydrofuran (THF) (4m L), add 1N sodium hydroxide solution (1.7mL), add methyl alcohol (2mL) subsequently.After 20 ℃ of placements were spent the night, mixture distributed between 1N hydrochloric acid and ethyl acetate.Separate organic layer, water and salt water washing, by dried over mgso, and evaporation.Resistates and ether are ground, obtain yellow powder [7-chloro-4-(4-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] acetate (250mg).
[7-chloro-4-(4-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] acetate
NMR(CDCl
3，δ)：2.57(3H，s)，3.54(2H，s)，6.06(1H，d，J＝4Hz)，6.69(1H，d，J＝4Hz)，7.19(2H，t，J＝7Hz)，7.38(2H，dd，J＝5，7Hz)
Embodiment 192
To [7-chloro-4-(4-fluorophenyl)-2-methylpyrrole also [1,2-b] pyridazine-3-yl] add 1 in the solution of acetate (220mg) in tetrahydrofuran (THF) (10mL), 1 '-carbonyl dimidazoles (18mg), and under 20 ℃, stirred the mixture 1 hour, add two (3-oxyethyl group-3-oxo-propionic acid) magnesium (109mg) then.20 ℃ stir the mixture spend the night after, add two (3-oxyethyl group-3-oxo-propionic acid) magnesium (109mg).After stirring 3 hours, mixture is distributed between 1N hydrochloric acid and ethyl acetate.Separate organic layer, water and salt water washing, by dried over mgso, and evaporation.By on silica gel, resistates being carried out chromatographic separation with ethyl acetate and hexane (1: 5) mixture drip washing, obtain oil production (237mg), itself and ethyl acetate are ground and wash with isopropyl ether, obtain also [1,2-b] pyridazine-3-yl of yellow powder 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrole]-ethyl 3-oxobutanoate (212mg).
4-[7-chloro-4-fluorophenyl)-2-methylpyrrole [1,2-b] pyridazine-3-base [ethyl 3-oxobutanoate also
mp 116-118℃
NMR(CDCl
3，δ)：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)，7.28(2H，dd，J＝5，7Hz)
Embodiment 193
At 0 ℃ to 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrole [1,2-b] pyridazine-3-yl also]-add sodium borohydride (23.4mg) in the solution of 3-oxo-ethyl butyrate (160mg) in methyl alcohol (5mL), and under uniform temp, stirred the mixture 1 hour.Mixture is distributed between 1N hydrochloric acid and ethyl acetate.Separate organic layer, water and salt water washing, by dried over mgso, and evaporation.By preparation thin-layer chromatography purification resistates with ethyl acetate and hexane (1: 3) mixture drip washing, and grind with ethyl acetate, obtain also [1,2-b] pyridazine-3-yl of yellow powder 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrole]-ethyl 3-hydroxybutanoate (95mg).
4-[7-chloro-4-fluorophenyl]-2-methylpyrrole [1,2-b] pyridazine-3-yl also]-ethyl 3-hydroxybutanoate
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，2.18-2.38(2H，m)，2.67(3H，s)，2.70-2.852H，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(2H，t，J＝7Hz)，7.30-7.45(2H，m)
Embodiment 194
To 4-[7-chlorine 4-(4-fluorophenyl)-2-methylpyrrole [1,2-b] pyridazine-3-yl also]-add 1N sodium hydroxide (0.27mL) in the solution of ethyl 3-hydroxybutanoate (52mg) in tetrahydrofuran (THF) (1mL), add methyl alcohol (1mL) subsequently.After 20 ℃ of placements are spent the night, mixture is distributed between 1N hydrochloric acid and ethyl acetate.Separate organic layer, water and salt water washing, by dried over mgso, and evaporation obtains also [1,2-b] pyridazine-3-yl of yellow oil 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrole]-3-hydroxybutyric acid (45mg).
4-[7-chlorine (4-(4-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also]-the 3-hydroxybutyric acid
NMR(CDCl
3，δ)：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)
Embodiment 195
7-(4-fluoro benzoyl)-8-oxo ethyl pelargonate (300mg), (1-amino-5-ethyl-1H-pyrroles-2-yl) (4-fluorophenyl) ketone (216mg) and tosic acid monohydrate (35.4mg) mixture in ethanol (6mL) was refluxed 5 hours.Mixture is distributed between ethyl acetate and water.Separate organic layer, use the salt water washing, by dried over mgso, and evaporation.By on silica gel, resistates being carried out chromatographic separation with ethyl acetate and hexane (1: 4) mixture drip washing, obtain oily 6-[7-ethyl-2,4-two (4-fluorophenyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl hexanoate (83mg) and 6-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrole [1,2-b] pyridazine-3-yl also] ethyl hexanoate (40mg).
6-[7-ethyl-2,4-two (4-fluorophenyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl hexanoate
NMR(CDCl
3，δ)：0.85-1.00(2H，m)，1.00-1.10(2H，m)，1.16-1.30(2H，m)，1.21(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，2.00(2H，t，J＝7Hz)，2.40(2H，t，J＝7Hz)，3.01(2H，q，J＝7Hz)，4.06(2H，q，J＝7Hz)，5.97(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.12-7.24(4H，m)，7.38(2H，dd，J＝5，9Hz)，7.50(2H，dd，J＝5，9Hz)
6-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl hexanoate
NMR(CDCl
3，δ)：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(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)
Embodiment 196
(1-amino-5-ethyl-1H-pyrroles-2-yl) (4-fluorophenyl) ketone (500mg), 8-ethanoyl-9-oxo ethyl decylate (678mg) and tosic acid monohydrate (82mg) mixture in ethanol (5mL) was refluxed 2 hours.Mixture is distributed between ethyl acetate and 1N hydrochloric acid.Separate organic layer, water and salt water washing, by dried over mgso, and evaporation.By with the silica gel of toluene drip washing with the resistates chromatographic separation, obtain oily 6-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrole also [1,2-b] pyridazine-3-yl] ethyl hexanoate (130mg) and yellow crystals [5-ethyl-1-((1E)-and 1-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrole [1,2-b] pyridazine-3-yl also] ethylidene } amino)-1H-pyrroles-2-yl] (4-fluorophenyl)-ketone (70mg).
[5-ethyl-1-((1E)-and 1-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrole [1,2-b] pyridazine-3-yl also] ethylidene } amino)-1H-pyrroles-2-yl] (4-fluorophenyl) ketone
NMR(CDCl
3，δ)：1.13(3H，t，J＝7Hz)，1.39(3H，t，J＝7Hz)，1.80-2.00(2H，m)，1.91(3H，s)，2.86(3H，s)，3.06(2H，q，J＝7Hz)，5.97(1H，d，J＝4Hz)，6.11(1H，d，J＝4Hz)，6.62(2H，t，J＝4Hz)，7.11(4H，t，J＝9Hz)，7.48(2H，dd，J＝5，9Hz)，7.82(2H，dd，J＝5，9Hz)
6-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl hexanoate
NMR(CDCl
3，δ)：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(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)
Embodiment 197
7-(4-cyano group benzoyl)-8-oxo ethyl pelargonate (2.2g), 2-ethyl-1H-pyrroles-1-amine (809mg) and tosic acid monohydrate (64mg) mixture in toluene (40mL) was refluxed 20 minutes.Mixture is distributed between ethyl acetate and 1N hydrochloric acid.Separate organic layer, water and salt water washing, by dried over mgso, and evaporation.By with the silica gel of ethyl acetate and hexane (1: 5) mixture drip washing with the resistates chromatographic separation, obtain product, itself and hexane are ground, obtain also [1,2-b] pyridazine-3-yl of yellow crystals 6-[4-(4-cyano-phenyl)-7-ethyl-2-methylpyrrole] ethyl hexanoate (2.21g).
6-[4-(4-cyano-phenyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl hexanoate
NMR(CDCl
3，δ)：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)
Embodiment 198
To 6-[4-(4-cyano-phenyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] add 2N potassium hydroxide (7.4mL) in the solution of ethyl hexanoate (1.5g) in tetrahydrofuran (THF) (15ml), add methyl alcohol (7.4mL) subsequently.Stirred 2 hours and after 60 ℃ are stirred 3 hours, mixture was distributed between 1N hydrochloric acid and ethyl acetate at 50 ℃.Filtering-depositing also washs with ethyl acetate.Organic layer and washings are merged, water and salt water washing, by dried over mgso, and evaporation.Resistates and ethyl acetate are ground, and filtering-depositing.By silica gel column chromatography purification filtrate, obtain also [1,2-b] pyridazine-3-yl of yellow crystals 6-[4-(4-cyano-phenyl)-7-ethyl-2-methylpyrrole with the isopropyl ether grinding with ethyl acetate and hexane (1: 1) mixture drip washing] caproic acid (650mg).Two kinds of precipitations are merged, and, obtain yellow crystals 6-{4-[4-(aminocarboxyl) phenyl from re-crystallizing in ethyl acetate]-7-ethyl-2-methylpyrrole also [1,2-b} pyridazine-3-yl } caproic acid (550mg, 37.6%).
6-[4-(4-cyano-phenyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] caproic acid
NMR(CDCl
3，δ)：1.15-1.30(2H，m)，1.35-1.45(2H，m)，1.38(3H，t，J＝7Hz)，1.45-1.60(2H，m)，2.26(2H，t，J＝7Hz)，2.38(2H，t，J＝7Hz)，2.56(3H，s)，3.02(2H，q，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-(aminocarboxyl) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } caproic acid
NMR(CDCl
3，δ)：1.1-1.20(2H，m)，1.29(3H，t，J＝7Hz)，1.30-1.45(4H，m)，2.10(2H，t，J＝7Hz)，2.37(2H，t，J＝7Hz)，2.51(3H，s)，2.92(2H，q，J＝7Hz)，5.73(1H，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)
Embodiment 199
At room temperature, to 3-[(1-amino-5-ethyl-1H-pyrroles-2-yl) carbonyl] add 2,4-diacetylmethane (837mg) and tosic acid monohydrate (32mg) in the solution of benzonitrile (200mg) in toluene (6mL).With reaction mixture refluxed 1 hour.By with the flash distillation silica gel column chromatography of hexane-ethyl acetate=10-1 drip washing (silica gel, 80mL) purification resistates, obtain yellow solid 3-(3-ethanoyl-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-4-yl also] benzonitrile (63mg, 24.8%).3-(3-ethanoyl-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-4-yl also) benzonitrile
NMR(CDCl
3，δ)：1.39(3H，t，J＝8Hz)，1.95(3H，s)，2.50(3H，s)，3.04(2H，q，J＝8Hz)，6.27(1H，d，J＝5Hz)，6.69(1H，d，J＝5Hz)，7.59-7.72(2H，m)，7.76-7.84(2H，m)
MS(ESI
+)：m/z 304(M+H)
Embodiment 200
In dry ice-propanone is bathed to (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-drip the 1.5M diisobutylaluminium hydride (0.277mL) in the toluene (24mL) in the solution of 2-ethyl propionate (50mg) in toluene.After the adding, 2 hours (10 ℃) stir the mixture., and filter the reaction mixture quenching with sodium tartrate, potassium by celite.Separate organic layer, by dried over mgso, and evaporation in a vacuum.By flash distillation silica gel chromatography (silica gel with hexane-ethyl acetate=10-1,5-1 and 3-1 drip washing, 40mL) purification resistates, obtain yellow solid (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-2-propylene-1-alcohol (30mg).
(2E)-3-[7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-2-propylene-1-alcohol
NMR(CDCl
3，δ)：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)
Following compound is to obtain with embodiment 200 essentially identical modes.
Embodiment 201
[4-(4-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] methyl alcohol
NMR(CDCl
3，δ)：1.45(1H，t，J＝5Hz)，2.65(3H，s)，4.47(2H，d，J＝5Hz)，6.13(1H，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)
Embodiment 202
[7-ethyl-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl] methyl alcohol
NMR(CDCl
3，δ)：1.31-1.46(10H，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)
Embodiment 203
2-{[7-ethyl-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl] methoxyl group } ethanol
NMR(CDCl
3，δ)：1.30-1.45(9H，m)，3.04(2H，q，J＝8Hz)，3.35(1H，m)，3.46(2H，t，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)
Embodiment 204
Under nitrogen atmosphere in the ice-water-bath, to (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-2-propylene-1-alcohol (30mg) is at N, adds 60% sodium hydride (3.8mg) in the oil in the solution in the dinethylformamide (1mL).After 20 minutes, under this temperature, in mixture, add methyl-iodide (18.5mg).After 15 minutes, at room temperature stirred reaction mixture is 5 hours.Reaction mixture is distributed between ethyl acetate and water.Wash organic layer with water three times, and with salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.By p-TLC (the purification resistates of hexane-ethyl acetate=10-1) obtains brown oil 7-chloro-4-(4-fluorophenyl)-2-sec.-propyl-3-[(1E)-3-methoxyl group-1-propenyl] pyrrolo-[1,2-b] pyridazine (3.5mg, 10.2%).
7-chloro-4-(4-fluorophenyl)-2-sec.-propyl-3-[(1E)-3-methoxyl group-1-propenyl] pyrrolo-[1,2-b] pyridazine
NMR(CDCl
3，δ)：1.38(3H，t，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)
Embodiment 205
In methyl-sulphoxide (0.5mL), add 60% sodium hydride (27mg) in the oil, and 60 ℃ of heating 40 minutes.At room temperature in this mixture, add (3-carboxyl propyl group) (triphenyl) bromide phosphine (124mg) and stirred 40 minutes.At room temperature to wherein adding 7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-formaldehyde (40mg).After 4 hours,, and between ethyl acetate and water, distribute reaction mixture 1N hydrogenchloride acidifying.Wash organic layer with water three times, and with salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.By p-TLC (the purification resistates of hexane-ethyl acetate=1-1) obtains yellow oil (4E)-5-[7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-4-pentenoic acid (21mg, E: Z=16: 1,56.3%).
(4E)-5-[7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-the 4-pentenoic acid
NMR(CDCl
3，δ)：1.40(6H，d，J＝7Hz)，2.20-2.37(4H，m)，3.25(1H，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).
MS(ESI
-)：m/z 385(M-H)
Embodiment 206
At room temperature in 7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-formaldehyde solution (40mg), add 1N sodium hydroxide (19.3mg) and acetone (0.425mL).After 8 hours, reaction mixture is distributed between ethyl acetate and water.Water and salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.By p-TLC (the purification resistates of hexane-ethyl acetate=5-1) obtains yellow solid (3E)-4-[7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-3-butene-2-ketone (33mg).
(3E)-4-[7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-3-butene-2-ketone
NMR(CDCl
3，δ)：1.40(6H，d，J＝7Hz)，2.13(3H，s)，3.38(1H，m)，5.89(1H，d，J＝15Hz)，6.23(1H，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)
Embodiment 207
In bathing, dry ice-propanone uses nitrogen purging 4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1, the 2-b] pyridazine-solution of 3-ethyl formate (100mg) in tetrahydrofuran (THF) (1mL).In mixture, add 2,2 '-Diisopropyl azodicarboxylate (0.5mg).After 5 minutes, add 1,3-two bromo-5,5-dimethyl-2,4-imidazolidimedione (43.8mg).The mixture that obtains is stirred 3 hours (78 to-30 ℃).Add water (5mL), and use the ethyl acetate extraction mixture.With salt water washing organic extract liquid, by anhydrous magnesium sulfate drying, and evaporation obtains yellow glue.Obtain yellow glue 7-bromo-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate product (90.0mg, 72.5%) with toluene-hexane=1-5 to the flash distillation silica gel column chromatography of 2-3 drip washing.
7-bromo-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate
NMR (CDCl
3, δ): 0.98 (3H, t, J=7Hz), 1.40 (6H, d, J=7Hz), 3.31 (1H, septets, J=7Hz), 4.05 (2H, q, J=7Hz), 6.39 (1H, d, J=5Hz), 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)
Embodiment 208
Under 60 ℃ the suspension of sodium hydride (74.4mg) in methyl-sulphoxide (1.4mL) was being stirred 1 hour.At room temperature mixture is added in the solution in methyl-sulphoxide (1.0mL) of methyltriphenylphospbromide bromide _ (1.11g).After stirring 0.5 hour, in mixture, add 4-(4-fluorophenyl)-7-formyl radical 2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate (500mg).After stirring 15 hours, mixture is distributed between ethyl acetate (20mL) and water (5mL).Water and salt water washing organic layer by anhydrous magnesium sulfate drying, and obtain orange coloring agent.With the ethyl acetate-hexane=1-7 yellow glue 4-(4-fluorophenyl) of solidified-2-sec.-propyl-7-vinyl pyrrole [1,2-b] pyridazine-3-ethyl formate (361mg, 72.6%) also when the flash distillation silica gel column chromatography of 3-1 drip washing obtains placing.
4-(4-fluorophenyl)-2-sec.-propyl-7-vinyl pyrrole is [1,2-b] pyridazine-3-ethyl formate also
NMR (CDCl
3, δ): 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), 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)
Embodiment 209
To 7-{4-[4-({ [(benzyloxy) carbonyl] amino } alkylsulfonyl) phenyl]-7-ethyl-2-methylpyrrole also [1; 2-b] pyridazine-3-yl } add 10% palladium on the gac (1.6mg) in the solution of oil of cognac (169mg) in ethanol (2mL), and at hydrogen pressure (3kg/cm
2) stirred 2 hours down.Filter the mixture that obtains by celite, and filtrate concentrating obtained yellow glue.Preparation silica gel thin-layer chromatography with ethyl acetate-hexane=1-1 drip washing obtains yellow glue 7-{4-[4-(amino-sulfonyl) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } oil of cognac (76.8mg, 58.4%).
7-{4-[4-(amino-sulfonyl) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } oil of cognac
NMR(CDCl
3，δ)：1.07-1.25(7H，m)，1.30-1.46(7H，m)，2.18(2H，t，J＝7Hz)，2.36(2H，m)，2.55(3H，s)，3.00(2H，q，J＝7Hz)，4.12(2H，q，J＝7Hz)，5.21(2H，s)，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)
Embodiment 210
Also add 1N potassium hydroxide in the solution of [1,2-b] pyridazine-3-ethyl formate (77.9mg) in ethanol (0.5mL)-tetrahydrofuran (THF) (0.5mL) to 4-(4-cyano-phenyl)-2-(2-oxyethyl group-2-oxoethyl)-7-N-ethyl pyrrole N-.The solution that stirring at room temperature obtains 2.5 hours.Adding 1N potassium hydroxide (0.04mL) further stirred the mixture 1 hour afterwards.Make the reaction quenching by adding 1N hydrochloric acid (0.23mL).Evaporate volatile matter, and the resistates that obtains is distributed between ethyl acetate (10mL) and 1N hydrochloric acid (6mL).With salt water washing organic layer, and evaporation obtains yellow solid [4-(4-cyano-phenyl)-3-(ethoxy carbonyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-2-yl also] acetate (67.7mg, 93.4%).
[4-(4-cyano-phenyl)-3-(ethoxy carbonyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-2-yl also] acetate
NMR(CDCl
3，δ)：0.84(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，3.05(2H，q，J＝7Hz)，3.93(2H，q，J＝7Hz)，4.18(3H，s)，6.27(1H，d，J＝5Hz)，6.74(1H，d，J＝5Hz)，7.52(2H，d，J＝9Hz)，7.76(2H，d，J＝9Hz)
MS(ESI
+)：m/z 378(M+H)
Embodiment 211
In ice bath, also add 60% sodium hydride (4.50mg) in [1, the 2-b] pyridazine-solution of 3-ethyl formate (35.0mg) in tetrahydrofuran (THF) (1mL) to 2-(2-amino-2-oxoethyl)-4-(4-cyano-phenyl)-7-N-ethyl pyrrole N-.The mixture that stirring obtains 1 hour.Make the reaction quenching by adding 1N HCl (4mL).With ethyl acetate (10mL) extraction mixture, and water and salt water washing organic layer, by dried over mgso, and evaporation.Preparation silica gel thin-layer chromatography with ethyl chloride imitation-carbinol=10-1 drip washing obtains yellow solid 4-(the 4-tetrahydropyridine is [3,4-e] pyrrolo-[1,2-b] pyridazine-10-yl also for 7-ethyl-1,3-dioxo-1,2,3) benzonitrile (3.86mg, 12.6%).
4-(the 4-tetrahydropyridine is [3,4-e] pyrrolo-[1,2-b] pyridazine-10-yl also for 7-ethyl-1,3-oxo-1,2,3) benzonitrile
NMR(CDCl
3，δ)：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)
Embodiment 212
At room temperature in methyl alcohol (1mL), add 60% sodium hydride (6.51mg).Then trifluoromethanesulfonic acid 4-(3-cyano-phenyl)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-2-base ester (70.0mg) is added mixture.The mixture that obtains was at room temperature stirred 2 hours and stirred 1 hour down at 50 ℃.Mixture is distributed between ethyl acetate and water.With salt water washing organic layer, by dried over mgso, and evaporation.Preparation silica gel thin-layer chromatography with ethyl acetate-hexane=1-1 drip washing obtains yellow solid 3-[7-ethyl-2-methoxyl group-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile (1.92mg, 3.7%).
3-[7-ethyl-2-methoxyl group-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile
NMR(CDCl
3，δ)：1.38(3H，t，J＝7Hz)，3.01(2H，q，J＝7Hz，)，3.24(3H，s)，4.18(3H，s)，6.12(1H，d，J＝5Hz)，6.63(1H，d，J＝5Hz)，7.53-7.64(3H，m)，7.76(1H，m)
Embodiment 213
In 4-(3-cyano-phenyl)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1, the 2-b] pyridazine-solution of 2-ethyl formate (92.6mg) in tetrahydrofuran (THF) (1mL) and ethanol (0.5mL), add 1N sodium hydroxide (0.349mL).The mixture that stirring at room temperature obtains 3 hours.The mixture that the further afterwards stirring of interpolation 1N sodium hydroxide (0.1mL) obtains 40 minutes.Adding 1N sodium hydroxide (0.1mL) further stirred the mixture 1.5 hours afterwards.Make the reaction quenching by adding 1N hydrochloric acid (1mL), and mixture is distributed between ethyl acetate (20mL) and water (10mL).With salt water washing organic layer, by dried over mgso, and evaporation obtains reddish oil.Flash distillation silica gel column chromatography with ethyl acetate-hexane=1-1 drip washing obtains red foam 3-(6-ethyl-1,1-two oxo bridges-3-oxo-2,3-pyrrolin be [1,2-b] thieno-[2,3-e] pyridazine-9-yl also) benzonitrile (52.4mg, 64.0%).
3-(6-ethyl-1,1-two oxo bridges-3-oxo-2,3-pyrrolin be [1,2-b] thieno-[2,3-e] pyridazine-9-yl also) benzonitrile
NMR(CDCl
3，δ)：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(2H，m)
MS(ESI
+)：m/z 352(M+H)
Embodiment 214
In ice bath, to 3-(6-ethyl-1,1-two oxo bridges-3-oxo-2,3-pyrrolin also [1,2-b] thieno-[2,3-e] pyridazine-9-yl) add the solution of 1M borine-tetrahydrofuran complex in tetrahydrofuran (THF) (0.487mL) in the solution of benzonitrile (60.0mg) in tetrahydrofuran (THF) (0.2mL).After stirring 1 hour, make the reaction quenching by adding 1N hydrochloric acid (1mL).Mixture is distributed between ethyl acetate (20mL) and water (10mL), and use salt water washing, drying, and evaporation obtains yellow foam 3-(6-ethyl-3-hydroxyl-1,1-two oxo bridges-2,3-pyrrolin also [1,2-b] thieno-[2,3-e] pyridazine-9-yl) benzonitrile (576mg, 99.8%).
3-(6-ethyl-3-hydroxyl-1,1-two oxo bridges-2,3-pyrrolin be [1,2-b] thieno-[2,3-e] pyridazine-9-yl also) benzonitrile
NMR(CDCl
3，δ)：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(2H，m)
Embodiment 215
In ice bath, in 3-(6-ethyl-3-hydroxyl-1,1-two oxo bridges-2,3-pyrrolin be [1,2-b] thieno-[2, the 3-e] pyridazine-9-yl also) solution of benzonitrile (54.0mg) in tetrahydrofuran (THF) (1mL), add 60% sodium hydride (6.69mg).After stirring 0.5 hour, add methyl-iodide (25.9mg), and at room temperature stirred the mixture 3 hours 20 minutes.Adding methyl-iodide (25.9mg) stirs mixture 6 hours afterwards again.Add 60% sodium hydride (3.0mg) and methyl-iodide (25.9mg) further stirred the mixture 1 hour afterwards.Mixture is distributed between ethyl acetate and 1N hydrochloric acid, and with salt water washing organic layer, by dried over mgso, and evaporation obtains yellow oil.Preparation silica gel thin-layer chromatography with ethyl acetate-hexane=1-2 drip washing obtains 3-(6-ethyl-1,1-two oxo bridge pyrrolo-es [1,2-b] thieno-s [2,3-c] pyridazine-9-yl) benzonitrile (5.9mg, 10.5%, yellow solid) and 3-(6-ethyl-3-methoxyl group-1,1-two oxo bridges-2,3-pyrrolin also [1,2-b] thieno-[2,3-e] pyridazine-9-yl) benzonitrile (16.8mg, 30.0%, orange coloring agent).
3-(6-ethyl-1,1-two oxo bridge pyrrolo-es [1,2-b] thieno-s [2,3-e] pyridazine-9-yl) benzonitrile
NMR(CDCl
3，δ)：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(1H，d，J＝7Hz)，7.72(1H，t，J＝9Hz)，7.87(1H，d，J＝9Hz)，8.11-8.16(2H，m)
3-(6-ethyl-3-methoxyl group-1,1-two oxo bridges-2,3-pyrrolin be [1,2-b] thieno-[2,3-e] pyridazine-9-yl also) benzonitrile
NMR(CDCl
3，δ)：1.42(3H，t，J＝7Hz)，3.12(2H，q，J＝7Hz)，3.67(3H，s)，3.73(2H，m)，5.02(1H，m)，6.74(1H，d，J＝5Hz)，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)
Embodiment 216
With the Dean-Stark condenser with 3-[(1-amino-5-ethyl-1H-pyrroles-2-yl) carbonyl] benzonitrile (1.00g), 3-(methyl sulphonyl)-ethyl 2-oxopropanoate (1.34g) and the mixture of tosic acid monohydrate (79.5mg) in toluene (20mL) refluxed 1 hour.Remove volatile matter in a vacuum.Obtain orange-yellow foam intermediate imines (1.38g, 67.7%) with ethyl acetate-hexane=1-10 to the flash distillation silica gel column chromatography of 9-15 drip washing.Foam is dissolved in N-methylmorpholine (10mL), and 130 ℃ of following stirred solutions 1 hour.Mixture is distributed between ethyl acetate (50mL) and water (30mL).(30 * 2mL) and salt water washing organic layer, by dried over mgso, and evaporation obtains dark orange solids to water.Abrasive solid in diisopropyl ether (10mL) obtains yellow powder 4-(3-cyano-phenyl)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-2-formic acid 2-(trimethyl silyl) ethyl ester (1.11g, 67.7%).
4-(3-cyano-phenyl)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-2-formic acid 2-(trimethyl silyl) ethyl ester
NMR(CDCl
3，δ)：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(1H，d，J＝5Hz)，7.50-7.67(3H，m)，7.82(1H，m)
MS(ESI
+)：m/z 470(M+H)
Following compound is to obtain with embodiment 216 essentially identical modes.
Embodiment 217
4-(3-cyano-phenyl)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-2-ethyl formate
NMR(CDCl
3，δ)：1.39(3H，t，J＝7Hz)，1.47(3H，t，J＝7Hz)，3.10(2H，q，J＝7Hz)，3.21，(3H，s)，4.51(2H，q，J＝7Hz)，6.30(1H，d，J＝5Hz)，6.90(1H，d，J＝5Hz)，7.61-7.67(3H，m)，7.72(1H，m)
Embodiment 218
In ice bath with 4-(3-cyano-phenyl)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1, the 2-b] pyridazine-solution stirring of 2-formic acid 2-(trimethyl silyl) ethyl ester (1.09) in trifluoroacetic acid (5mL) 1.5 hours.Make the reaction quenching by adding water (20mL).Form yellow crystals once adding entry, collected by filtering.Water (5mL) and hexane (3mL) washing crystal obtain 4-(3-cyano-phenyl)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1, the 2-b] pyridazine-2-formic acid (756mg, 88.2%) as yellow crystals.
4-(3-cyano-phenyl)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-2-formic acid
NMR(CDCl
3，δ)：1.41(2H，m)，3.10(2H，q，J＝7Hz)，3.30(3H，s)，6.36(1H，d，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)
Embodiment 219
At room temperature with 4-(3-cyano-phenyl)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1; 2-b] pyridazine-2-formic acid (40.0mg), dimethylamine hydrochloride (12.4mg), 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (25.2mg) and I-hydroxybenzotriazole (21.9mg) are at N, and the mixture in the dinethylformamide (1mL) stirred 3 hours.Mixture is distributed between ethyl acetate (20mL) and 1N hydrochloric acid (10mL).Water (10 * 3mL), saturated sodium bicarbonate (10mL) and salt water washing organic layer; by dried over mgso, and evaporation obtains yellow solid 4-(3-cyano-phenyl)-7-ethyl-N, N-dimethyl-3-(methyl sulphonyl) pyrrolo-[1; 2-b] pyridazine-2-methane amide (43.4mg, 101%).
4-(3-cyano-phenyl)-7-ethyl-N, N-dimethyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-2-methane amide
NMR(CDCl
3，δ)：1.38(2H，m)，3.07(2H，q，J＝7Hz)，3.12(3H，s)，3.18(3H，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)
Embodiment 220
Mixture in ethanol (3mL) and water (2mL) mixture refluxed 2.5 hours with 4-(3-chloro-phenyl-)-7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-3-ethyl formate (450mg) and 85% potassium hydroxide (3.01g).In ice bath, make the reaction mixture cooling, and make the reaction mixture quenching by adding concentrated hydrochloric acid (5mL).Mixture is distributed between ethyl acetate (20mL) and water (10mL), and with salt water washing organic layer, by dried over mgso, and evaporation obtains yellow solid (388mg).Abrasive solid in hexane obtains yellow powder 4-(3-chloro-phenyl-)-7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-3-formic acid (361mg, 86.4%).
4-(3-chloro-phenyl-)-7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-3-formic acid
NMR(CDCl
3，δ)：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)
Embodiment 221
At room temperature, add oxalyl chloride (157mg) in the solution of dinethylformamide (1.39mg) in methylene dichloride (3mL) to 4-(3-chloro-phenyl-)-7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-3-formic acid (358mg) and N.After stirring 30 minutes, remove volatile matter in a vacuum, and, obtain yellow glue 4-(3-chloro-phenyl-)-7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-3-formyl chloride (396mg, 106%) resistates and methylbenzene azeotropic three times.
4-(3-chloro-phenyl-)-7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-3-formyl chloride
NMR(CDCl
3，δ)：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＝5Hz)，7.06(1H，d，J＝7Hz)，7.38-7.55(4H，m)，7.63(1H，m)
Embodiment 222
In ice bath, add 4-(3-chloro-phenyl-)-7-ethyl-2-(2-furyl) pyrrolo-[1, the 2-b] pyridazine-solution of 3-formyl chloride (40.0mg) in methylene dichloride (0.5mL) in the solution in methylene dichloride (0.5mL) to methyl aminoacetate hydrochloride (26.1mg) and triethylamine (42.0mg).Mixture is distributed between ethyl acetate (20mL) and 1N hydrochloric acid (10mL), and with salt solution (10mL) washing organic layer, pass through dried over mgso, and evaporation obtains yellow glue ({ [4-(3-chloro-phenyl-)-7-ethyl-2-(3-furyl) pyrrolo-[1,2-b] pyridazine-3-yl] carbonyl } amino) methyl acetate (50.6mg, 111%).
({ [4-(3-chloro-phenyl-)-7-ethyl-2-(3-furyl) pyrrolo-[1,2-b] pyridazine-3-yl] carbonyl } amino) methyl acetate
NMR(CDCl
3，δ)：1.41(3H，t，J＝7Hz)，3.10(2H，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(1H，m)
MS(ESI
+)：m/z 438(M+H)
Following compound is to obtain with embodiment 222 essentially identical modes.
Embodiment 223
4-(3-chloro-phenyl-)-7-ethyl-2-(2-furyl)-N, N-two (2-hydroxyethyl) pyrrolo-[1,2-b] pyridazine-3-methane amide
NMR(CDCl
3，δ)：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(2H，m)，7.71(1H，m)
MS(ESI
+)：m/z 454(M+H)
Embodiment 224
To 3-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole also [1,2-b] pyridazine-3-yl] add triethylamine (25.2mg) in the solution of propionic acid (100mg) in two _ alkane (0.5mL), add the solution of pivalyl chloride (30.1mg) in two _ alkane (0.5mL) subsequently.Form white precipitate.After at room temperature stirring 40 minutes, by removing by filter precipitation, and wash with two _ alkane (2mL).In the washings that merges, add the solution of 2-ammonia ethyl sulfonic acid (38.6mg) in 1N sodium hydroxide (0.247mL).The mixture that stirring at room temperature obtains 1 hour.Mixture is distributed between ethyl acetate (15mL) and water (5mL).With salt water washing organic layer, by dried over mgso, and evaporation.Obtain yellow solid 2-({ 3-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] propionyl } amino) ethyl sulfonic acid (104mg, 82.0%) with the preparation silica gel thin-layer chromatography of chloroform-methanol=5-1 drip washing.
2-({ 3-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole also [1,2-b] pyridazine-3-base [propionyl } amino) ethyl sulfonic acid
NMR(CDCl
3，δ)：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)
Embodiment 225
At room temperature with 3-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole also [1; 2-b] pyridazine-3-yl] propionic acid (100mg), PIVALIC ACID CRUDE (25) (2R; 3R; 4S; 5S; 6R)-2-amino-3; 5-two [(2; 2-dimethyl propylene acyl group) oxygen base]-6-{[(2; 2-dimethyl propylene acyl group) oxygen base] methyl } tetrahydrochysene-2H-pyrans-4-base ester (255mg), 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (0.494mmol) and I-hydroxybenzotriazole (66.7mg) be at N, the solution stirring in the dinethylformamide (1mL) 1 hour.Mixture is distributed between ethyl acetate (20mL) and 1N hydrochloric acid (10mL).Water (10 * 3mL), saturated sodium bicarbonate (10mL) and salt water washing organic layer, by dried over mgso, and evaporation obtains yellow foam (339mg).Obtain yellow foam PIVALIC ACID CRUDE (25) (2R with ethyl acetate-hexane=1-10 to the flash distillation silica gel column chromatography of 2-5 drip washing; 3R; 4S; 5S, 6R)-2-(3-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] and propionyl } amino)-3; 5-two [(2; 2-dimethyl propylene acyl group) oxygen base]-6-{[(2,2-dimethyl propylene acyl group) the oxygen base] methyl } tetrahydrochysene-2H-pyrans-4-base ester (240mg, 108%).
PIVALIC ACID CRUDE (25) (2R, 3R, 4S; 5S, 6R)-2-(3-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] and propionyl } amino)-3; 5-two [(2,2-dimethyl propylene acyl group) oxygen base]-6-{[(2,2-dimethyl propylene acyl group) the oxygen base] methyl } tetrahydrochysene-2H-pyrans-4-base ester
NMR(CDCl
3，δ)：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(1H，d，J＝5Hz)，7.29(1H，m)，7.40-7.59(8H，m)
Embodiment 226
In ice bath, in [4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl acetate (114mg) solution in tetrahydrofuran (THF) (2mL), add the 1M diisobutylaluminium hydride in the toluene (0.816mL).After at room temperature stirring 1 hour, add 1M diisobutylaluminium hydride (0.41mL) in addition.Make the reaction quenching by adding 1N hydrochloric acid (1mL) after 1 hour.Mixture is distributed between ethyl acetate (20mL) and 1N hydrochloric acid (10mL), and filter by celite.Water (10mL) and salt water washing organic layer, by dried over mgso, and evaporation obtains yellow glue.With ethyl acetate-hexane=1-20 crystalline yellow oil 2-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole [1,2-b] pyridazine-3-yl also when the flash distillation silica gel column chromatography of 2-50 drip washing obtains placing] ethanol (107mg, 104%).
2-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] ethanol
NMR(CDCl
3，δ)：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＝5Hz)，6.63(1H，d，J＝5Hz)，7.34(1H，m)，7.41-7.55(8H，m)
Embodiment 227
In ice bath to 2-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole also [1; 2-b] pyridazine-3-yl] ethanol (105mg), 2; 3; 4, add silver trifluoromethanesulfonate (3.58mg) in 6-four-O-ethanoyl-β-D-galactosyl bromide (299mg), the mixture of silver carbonate (154mg) in toluene (2mL).After 40 minutes, add 2,3,4,6-four-O-ethanoyl-β-D-galactosyl bromide (114mg), silver carbonate (229mg), and stirred the mixture 50 minutes.Add 2,3,4,6-four-O-ethanoyl-β-D-galactosyl bromide (114mg), silver carbonate (154mg) further stirred the mixture 50 minutes afterwards.By the celite filtering mixt, and filtrate distributed between ethyl acetate and water.With salt water washing organic layer, by dried over mgso, and evaporation obtains yellow glue.Obtain yellow glue acetate (2R with ethyl acetate-hexane=1-10 to the flash distillation silica gel column chromatography of 7/10 drip washing, 3R, 4S, 5S, 6R)-4,5-two (acetoxyl group)-6-[(acetoxyl group) methyl]-2-{2-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole [1,2-b] pyridazine-3-yl also] oxyethyl group } tetrahydrochysene-2H-pyrans-3-base ester (115mg, 58.4%).
Acetate (2R, 3R, 4S, 5S, 6R)-4,5-two (acetoxyl group)-6-[(acetoxyl group) methyl]-2-{2-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole [1,2-b] pyridazine-3-yl also] oxyethyl group } tetrahydrochysene-2H-pyrans-3-base ester
NMR (CDCl
3, δ): 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 (1H, 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 (1H, d, J=3Hz), 6.02 (1H, d, J=5Hz), 6.64 (1H, d, J=5Hz), 7.31 (1H, m), 7.41-7.56 (8H, m)
Embodiment 228
At room temperature to acetate (2R, 3R, 4S, 5S, 6R)-4,5-two (acetoxyl group)-6-[(acetoxyl group) methyl]-2-{2-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole [1,2-b] pyridazine-3-yl also] oxyethyl group } add sodium methylate (0.86mg) in the tetrahydrochysene-2H-pyrans-solution of 3-base ester (113mg) in methyl alcohol (2mL).After stirring 2 hours, solvent evaporated, and mixture distributed between ethyl acetate (20mL) and water (10mL).With salt water washing organic layer, by dried over mgso, and evaporation obtains yellow foam (77.3mg).Milled foam in hexane obtains yellow powder (2R, 3R, 4S, 5R, 6R)-2-{2-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole [1,2-b] pyridazine-3-yl also] oxyethyl group }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (48.3mg, 89.7%).(2R, 3R, 4S, 5R, 6R)-and 2-{2-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole [1,2-b] pyridazine-3-yl also] oxyethyl group }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4, the 5-triol
NMR(CDCl
3，δ)：1.36(3H，t，J＝7Hz)，1.92(1H，m)，2.06(1H，m)，2.56(1H，s，br)，2.76-2.92(3H，m)，3.02(2H，q，J＝7Hz)，3.24(2H，m)，3.38-3.50(3H，m)，3.63-3.84(3H，m)，2.41(1H，s，br)，6.01(1H，d，J＝5Hz)，6.63(1H，d，J＝5Hz)，7.32(1H，m)，7.41-7.57(8H，m)
Following compound is to obtain with embodiment 228 essentially identical modes.
Embodiment 229
3-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also]-N-[(2R, 3R, 4S, 5R, 6R)-3,4, and 5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl] propionic acid amide
NMR(CDCl
3，δ)：1.38(3H，t，J＝7Hz)，1.97(2H，m)，2.83(2H，m)，3.01(2H，q，J＝7Hz)，3.31-3.52(3H，m)，3.61-3.76(2H，m)，3.88(1H，m)，4.63(1H，d，J＝9Hz)，6.01(1H，d，J＝5Hz)，6.64(1H，d，J＝5Hz)，7.34(1H，m)，7.42-7.59(8H，m)
Embodiment 230
Derive from the 5-[2-[(acetoxyl group) methyl]-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] 5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methylol) pyrrolo-[1, the 2-b] pyridazine-3-yl of Valeric acid ethylester] Valeric acid ethylester
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.34-1.50(5H，m)，1.54(2H，m)，2.19(2H，t，J＝7Hz)，2.37(2H，m)，3.02(2H，q，J＝7Hz)，3.71(1H，t，J＝5Hz)，4.10(2H，q，J＝7Hz)，4.86(2H，d，J＝5Hz)，5.97(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.88(1H，m)，8.55(1H，m)，8.79(1H，m)
Embodiment 231
At room temperature to 5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] valeric acid (50mg) is at N, add 1,1 in the solution in the dinethylformamide (1mL) '-carbonyl dimidazoles (33.6mg).After stirring 1 hour, in mixture, add Toluidrin (19.7mg) and 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (31.6mg).50 ℃ of following heated mixt 2 hours.Reaction mixture is distributed between ethyl acetate and water.With water layer 1N hydrogenchloride acidifying, and use ethyl acetate extraction.Wash organic layer 3 times with water and with salt water washing organic layer, by anhydrous magnesium sulfate drying, and evaporation obtains yellow solid in a vacuum.Resistates by the IPE crystallization, is obtained yellow solid (45mg).With solid recrystallization from ethanol, obtain also [1,2-b] pyridazine-3-yl of yellow solid N-{5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole] pentanoyl } Toluidrin (25mg).
N-{5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] pentanoyl } Toluidrin
NMR(CDCl
3，δ)：1.33-1.61(7H，m)，2.21(2H，t，J＝8Hz)，2.40(2H，t，J＝8Hz)，2.55(3H，s)，3.00(2H，q，J＝8Hz)，3.29(3H，s)，5.80(1H，d，J＝5Hz)，6.52(1H，d，J＝5Hz)，7.58-7.67(3H，m)，7.76(1H，m)，7.86(1H，br s)
MS(ESI
+)：m/z 439(M+H)
Embodiment 232
In ice-water-bath to 5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] add lithium borohydride (5mg) in the solution of Valeric acid ethylester (45mg) in tetrahydrofuran (THF) (1mL).Stirred reaction mixture at room temperature then.After 2 hours, to wherein adding lithium borohydride (5mg) again and stirring and spend the night.Reaction mixture is distributed between ethyl acetate and water.With salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.By p-TLC (the purification resistates of hexane-ethyl acetate=1-1), obtain yellow oil 3-[7-ethyl-3-(6-hydroxyl hexyl)-2-methylpyrrole also [1,2-b] pyridazine-4-yl] benzonitrile (26mg, 64.5%) and yellow solid 6-{4-[3-(amino methyl) phenyl]-7-ethyl-2-methylpyrrole also [1,2-b] pyridazine-3-yl }-1-hexanol (13mg, 31.9%).
3-[7-ethyl-3-(6-hydroxyl hexyl)-2-methylpyrrole is [1,2-b] pyridazine-4-yl also] benzonitrile
NMR(CDCl
3，δ)：1.15-1.53(11H，m)，2.32-2.41(2H，m)，2.56(3H，s)，3.01(2H，q，J＝8Hz)，3.58(2H，br t，J＝8Hz)，5.58(1H，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-(amino methyl) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also }-the 1-hexanol
NMR(CDCl
3，δ)：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(2H，m)，4.25(2H，br s)，5.31(1H，d，J＝5Hz)，6.49(1H，d，J＝5Hz)，7.28-7.40(3H，m)，7.51(1H，t，J＝8Hz)
MS(ESI
+)：m/z 366(M+H)
Embodiment 233
At room temperature to 6-{4-[4-(aminocarboxyl) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } add 1N sodium hydroxide (1.5mL) in the suspension of caproic acid (590mg) in water (3mL).After 5 hours, mixture becomes clear solution.By the membrane filter filtering solution, water (0.4mL * 3) washing, and lyophilize 15 hours obtain buff powder 6-{4-[4-(aminocarboxyl) phenyl]-7-ethyl-2-methylpyrrole also [1,2-b] pyridazine-3-yl } caproic acid sodium salt (612mg, 98.2%).
6-{4-[4-(aminocarboxyl) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } the caproic acid sodium salt
NMR(DMSO-d
6，δ)：1.10-1.15(2H，m)，1.20-1.40(7H，m)，1.74(2H，t，J＝8Hz)，2.25-2.38(2H，m)，2.50(3H，s)，2.91(2H，q，J＝8Hz)，5.72(1H，d，J＝5Hz)，6.50(1H，d，J＝5Hz)，7.39-7.46(3H，m)，7.97(2H，d，J＝8Hz)，8.26(1H，br s)
Embodiment 234
Under 80 ℃ with 5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] valeric acid (100mg), triethylamine (29.4mg) and the solution heating of diphenyl phosphoryl azide (79.9mg) in the trimethyl carbinol (2mL) 8 hours.The refrigerative reaction mixture is distributed between ethyl acetate and water.Use the ethyl acetate extraction water layer.Organic layer with the salt water washing merges by dried over mgso, and evaporates in a vacuum.By p-TLC (the purification resistates of hexane-ethyl acetate=3-1) obtains also [1,2-b] pyridazine-3-yl of yellow oil 4-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole] butyl t-butyl carbamate (28mg, 23.4%).
4-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] the butyl t-butyl carbamate
NMR(CDCl
3，δ)：1.27-1.47(14H，m)，2.34-2.45(2H，m)，2.55(3H，s)，2.91-3.02(4H，m)，4.39(1H，br s)，5.79(1H，d，J＝5Hz)，6.51(1H，d，J＝5Hz)，7.56-7.67(3H，m)，7.75(1H，m)
MS(ESI
+)：m/z 433(M+H)
Embodiment 235
At room temperature to 4-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] add the 4N hydrogenchloride in the ethyl acetate (1mL) in the butyl t-butyl carbamate (25mg).After 1 hour, evaporating mixture in a vacuum.Resistates and isopropyl ether are ground, obtain also [1,2-b] pyridazine-4-yl of deep green amorphous substance 3-[3-(the amino butyl of 4-)-7-ethyl-2-methylpyrrole] benzonitrile hydrochloride (18mg).
3-[3-(the amino butyl of 4-)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-4-yl also] the benzonitrile hydrochloride
NMR(CDCl
3，δ)：1.27-1.47(14H，m)，2.34-2.45(2H，m)，2.55(3H，s)，2.91-3.02(4H，m)，4.39(1H，br s)， 5.79(1H，d，J＝5Hz)，6.51(1H，d，J＝5Hz)，7.56-7.67(3H，m)，7.75(1H，m)
MS(ESI
+)：m/z 333(M+H)
Embodiment 236
In lithium chloride (16.5mg), adding also [1,2-b] pyridazine-3-yl of 5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole] Valeric acid ethylester (65mg) and solution and four (triphenyl phosphine) palladium (0) of tributyl (vinyl) stannic hydride (56.7mg) in two _ alkane (1mL) are (1.9mg).Mixture is refluxed.After 4 hours, add tributyl (vinyl) stannic hydride (50mg) and four (triphenyl phosphine) palladium (O) (1.9mg).After backflow is spent the night, at H
2Make the reaction mixture quenching with Potassium monofluoride (1.8mmol) among the O.Wash by the celite filtering mixt and with ethyl acetate.Separate organic layer, water and salt water washing, by dried over mgso, and evaporation in a vacuum.By flash distillation silica gel chromatography (silica gel with hexane-ethyl acetate=5-1 and 3-1 drip washing, 50mL) purification resistates, obtain yellow oil 5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester (18mg, 28.3%).
5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.15-1.70(10H，m)，2.18(2H，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(1H，d，J＝10Hz)，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(1H，dd，J＝6，1Hz)，7.33(1H，br s)，8.70(1H，d，J＝6Hz)
MS(ESI
+)：m/z 392(M+H)
Following compound is to obtain with embodiment 236 essentially identical modes.
Embodiment 237
5-{4-[5-(1-vinyl ethyl ether base)-3-pyridyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } Valeric acid ethylester
NMR(CDCl
3，δ)：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(1H，d，J＝2Hz)，4.76(1H，d，J＝2Hz)，5.87(1H，d，J＝4Hz)，6.52(1H，d，J＝4Hz)，7.89(1H，m)，8.53(1H，d，J＝2Hz)，8.93(1H，d，J＝2Hz)
MS：(m/z)436(M+H)
Embodiment 238
5-[7-ethyl-2-methyl-4-(5-vinyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：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(1H，d，J＝11Hz)，5.88(1H，d，J＝4Hz)，5.89(1H，d，J＝18Hz)，6.52(1H，d，J＝4Hz)，6.71-6.83(1H，dd，J＝11Hz，18Hz)，7.73(1H，m)，8.47(1H，d，J＝2Hz)，8.68(1H，d，J＝2Hz)
Embodiment 239
5-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.22(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.40-1.60(4H，m)，2.17(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(1H，d，J＝11Hz)，5.88(1H，d，J＝18Hz)，5.91(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，6.71-6.83(1H，dd，J＝11Hz，18Hz)，7.75(1H，m)，8.49(1H，d，J＝2Hz)，8.71(1H，d，J＝2Hz)
Embodiment 240
5-[4-[5-(1-vinyl ethyl ether base)-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.22(3H，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)，3.47(3H，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＝3Hz)，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)
Embodiment 241
5-[7-ethyl-2-phenyl-4-(5-vinyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR (CDCl
3, δ): 1.15-1.31 (7H, 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 (1H, d, J=18Hz), 5.98 (1H, d, J=5Hz), 6.62 (1H, d, J=5Hz), 6.78 (1H, dd, J=11 and l8Hz), 7.44-7.55 (5H, m), 7.81 (1H, m), 8.55 (1H, m), 8.72 (1H, m)
Embodiment 242
In the sealing test tube to 5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] add 50% dimethylamine (1.5mL) in the entry in the solution of valeric acid (50mg) in two _ alkane (1.5mL).Spend the night at 175 ℃ of following heated mixt.The refrigerative reaction mixture is concentrated in a vacuum.With resistates water-soluble (1mL) and regulate pH to 7-8.With chloroform extraction mixture three times.By the dried over mgso organic layer, and evaporation in a vacuum.(silica gel, 50mL) purification resistates obtain yellow oil (43mg) by the flash distillation silica gel chromatography with chloroform-ethyl acetate=1-1 and chloroform-methanol=20-1 drip washing.Oil from the isopropyl ether crystallization, is obtained yellow solid 5-{4-[2-(dimethylamino)-4-pyridyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } valeric acid (27mg, 52.8%).
5-{4-[2-(dimethylamino)-4-pyridyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } valeric acid
NMR(CDCl
3，δ)：1.36(3H，t，J＝8Hz)，1.40-1.65(4H，m)，2.25(2H，t，J＝8Hz)，1.86-1.96(2H，m)，2.55(3H，s)，3.00(2H，q，J＝8Hz)，4.08(2H，q，J＝8Hz)，5.54(1H，d，J＝10Hz)，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(1H，dd，J＝6，1Hz)，7.33(1H，br s)，8.70(1H，d，J＝6Hz)
Embodiment 243
In ice-water-bath, in 7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1, the 2-b] pyridazine-suspension of 3-formaldehyde (40mg) in ethanol (1mL), add 2-monoethanolamine (11.8mg), sodium cyanoborohydride (12.1mg) and acetate (1).After 10 minutes, at room temperature stir the mixture.After 2 hours, add sodium cyanoborohydride (11.8mg) and reaction mixture is acidified to pH4 with acetate (5).After stirring is spent the night, reaction mixture is distributed between ethyl acetate and water.With saturated sodium bicarbonate, water and salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.(the purification resistates of chloroform-methanol=10-1) obtains light yellow oil 2-({ [7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl] methyl } amino) ethanol (21mg) by p-TLC.
2-({ [7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl] methyl } amino) ethanol
NMR(CDCl
3，δ)：1.43(6H，d，J＝7Hz)，2.65(2H，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，m)，7.35-7.44(2H，m)
MS(ESI
+)：m/z 362(M+H)
Embodiment 244
Under nitrogen in the ice-water-bath, add sulfur trioxide pyridine complex (941mg) to [4-(4-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] methyl alcohol (505mg) and triethylamine (997mg) in the solution in methylene dichloride (4mL) and methyl-sulphoxide (2mL).After 30 minutes, at room temperature stirred the mixture 2 hours.Reaction mixture is concentrated to about 1/3 volume.Mixture is distributed between ethyl acetate and water.Wash organic layer with water three times, and with salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.(silica gel, 30mL) purification resistates obtain also [1,2-b] pyridazine-3-formaldehyde (340mg, 67.9%) of yellow solid 4-(4-fluorophenyl)-2-methylpyrrole by the flash distillation silica gel chromatography with hexane-chloroform=3-1 and 2-1 drip washing.4-(4-fluorophenyl)-2-methylpyrrole is [1,2-b] pyridazine-3-formaldehyde also
NMR(CDCl
3，δ)：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)
Embodiment 245
At room temperature in the hydrogen atmosphere (3.5 normal atmosphere) with 4-(4-fluorophenyl)-2-sec.-propyl-7-vinyl pyrrole also the mixture of 10% palladium (900mg) in ethanol (180mL) on [1,2-b] pyridazine-3-ethyl formate and the carbon stir.After 10 hours, the mixture placement is spent the night.In mixture, add 10% palladium (900mg) and the middle stirring of hydrogen atmosphere (3.5 normal atmosphere) at room temperature on the carbon.After 12 hours, the mixture placement is spent the night.10% palladium (900mg) that adds in mixture on the carbon also at room temperature stirred 8 hours in the hydrogen atmosphere (3.5 normal atmosphere).By the celite filtering mixt.Concentrated filtrate obtains yellow oil 7-ethyl-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate (9.0g, 100.5%) in a vacuum.
7-ethyl-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate
NMR(CDCl
3，δ)：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)
Following compound is to obtain with embodiment 245 essentially identical modes.
Embodiment 246
Derive from 5-[7-ethyl-2-methyl-4-(5-vinyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] 5-[7-ethyl-4-(5-ethyl-3-the pyridyl)-2-methylpyrrole of valeric acid [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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)
MS(ESI
+)：m/z 366(M+H)，MS(ESI
-)：m/z 364
Embodiment 247
5-[7-ethyl-4-(5-ethyl-3-pyridyl)-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：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＝4Hz)，6.58(1H，d，J＝4Hz)，7.59(1H，s)，8.44(1H，s)，8.54(1H，s)
MS(ESI
+)：m/z 396
Embodiment 248
5-[7-ethyl-4-(5-ethyl-3-pyridyl)-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：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)
Embodiment 249
At room temperature in 3-(7-ethyl-2-neo-pentyl pyrrolo-[1, the 2-b] pyridazine-4-yl) solution of benzamide (35mg) in ethanol (1mL), add entry (0.2mL) and potassium hydroxide (68.9mg).At 60 ℃ of reacting by heating mixtures.After 2 hours, add potassium hydroxide (100mg).After 5 hours, add potassium hydroxide (100mg).After 12 hours, use 1N hydrogenchloride with the mixture acidifying.Filtering-depositing, water and ethyl acetate washing obtain yellow solid 3-(7-ethyl-2-neo-pentyl pyrrolo-[1,2-b] pyridazine-4-yl) phenylformic acid (19mg, 54.1%).
3-(7-ethyl-2-neo-pentyl pyrrolo-[1,2-b] pyridazine-4-yl) phenylformic acid
NMR(CDCl
3，δ)：1.05(9H，s)，1.39(3H，t，J＝8Hz)，2.69(2H，s)，3.04(2H，q，J＝8Hz)，6.42(1H，s)，6.54(1H，d，J＝5Hz)，6.65(1H，d，J＝5Hz)，7.62(1H，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)
Following compound is to obtain with embodiment 249 essentially identical modes.
Embodiment 250
3-[7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-4-yl] phenylformic acid
NMR(CDCl
3，δ)：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(2H，m)，8.03(1H，br d，J＝8Hz)，8.23(1H，br d，J＝8Hz)，8.52(1H，br s)
Embodiment 251
At room temperature with 5-{4-[5-(1-vinyl ethyl ether base)-3-pyridyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } solution stirring of Valeric acid ethylester (190mg) in methyl alcohol (5mL) and 1N hydrochloric acid (5mL) 2 hours.With solution with salt solution dilution with use chloroform extraction.Separate organic layer, by dried over mgso, and evaporation in a vacuum.By with hexane and ethyl acetate (10: 1-2: 1) the silica gel column chromatography purification resistates of mixture drip washing obtains also [1,2-b] pyridazine-3-yl of yellow oil 5-[4-(5-ethanoyl-3-pyridyl)-7-ethyl-2-methylpyrrole] Valeric acid ethylester (160mg).
5-[4-(5-ethanoyl-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.24(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.40-1.60(4H，m)，2.19(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(1H，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)
Following compound is to obtain with embodiment 251 essentially identical modes.
Embodiment 252
5-[4-(5-ethanoyl-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：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(2H，m)，2.70(3H，s)，3.03(2H，q，J＝7Hz)，3.46(3H，s)，4.12(2H，q，J＝7Hz)，4.63(2H，s)，5.86(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，8.26(1H，m)，8.79(1H，d，J＝2Hz)，9.24(1H，d，J＝2Hz)
MS(ESI
+)：m/z 438
Embodiment 253
To 5-{4-(2-chloro-4-pyridyl)-7-ethyl-2-[(methylthio group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } add oxone (287mg) in the solution of Valeric acid ethylester (139mg) in tetrahydrofuran (THF) (4mL) and water (1mL) and at room temperature stirred the mixture 4 hours.With solution with water dilution and use ethyl acetate extraction.Separate organic layer, with saturated sodium bicarbonate solution, hypo solution and salt water washing, by dried over mgso, and evaporation in a vacuum.By using hexane and ethyl acetate (10: 1-1: 1) the silica gel column chromatography purification resistates of mixture drip washing; obtain yellow oil 5-{4-(2-chloro-4-pyridyl)-7-ethyl-2-[(methyl sulphonyl) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester (124mg).
5-{4-(2-chloro-4-pyridyl)-7-ethyl-2-[(methyl sulphonyl) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
NMR(CDCl
3，δ)：1.24(3H，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(2H，m)，3.02(2H，q，J＝7Hz)，3.12(3H，s)，4.10(2H，q，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(1H，d，J＝5Hz)
Embodiment 254
Under 170 ℃ with 5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] Valeric acid ethylester (167mg) and cupric cyanide (I) (37mg) mixture in 1-Methyl-2-Pyrrolidone (3mL) stirred 4 hours.Mixture is distributed between ethyl acetate and water.Separate organic layer, water and salt water washing, by dried over mgso, and evaporation in a vacuum.By with hexane and ethyl acetate (20: 1-5: 1) the silica gel column chromatography purification resistates of mixture drip washing obtains also [1,2-b] pyridazine-3-yl of yellow oil 5-[4-(5-cyano group-3-pyridyl)-7-ethyl-2-methylpyrrole] Valeric acid ethylester (88mg).
5-[4-(5-cyano group-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：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(1H，m)，8.80(1H，d，J＝2Hz)，8.97(1H，d，J＝2Hz)
MS(ESI
+)：m/z 391.
Following compound is to obtain with embodiment 254 essentially identical modes.
Embodiment 255
5-[4-(5-cyano group-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：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(1H，d，J＝4Hz)，6.55(1H，d，
Embodiment 256
5-[4-(5-cyano group-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：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，J＝7Hz)，4.63(2H，s)，5.84(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，8.02(1H，m)，8.83(1H，d，J＝2Hz)，8.98(1H，d，J＝2Hz)
Embodiment 257
5-[4-(5-cyano group-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
NMR(CDCl
3，δ)：1.38(3H，t，J＝7Hz)，1.40-1.65(4H，m)，2.27(2H，t，J＝7Hz)，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(1H，s)
Embodiment 258
5-[4-(5-cyano group-3-pyridyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
NMR(CDCl
3，δ)：1.06-1.24(4H，m)，1.36(3H，t，J＝7Hz)，1.94(2H，t，J＝7Hz)，2.38(2H，m)，2.99(2H，q，J＝7Hz)，5.88(1H，d，J＝5Hz)，6.64(1H，d，J＝5Hz)，7.44-7.52(5H，m)，8.06(1H，s)，8.87(1H，s)，8.98(1H，s)
MS(ESI
+)：m/z 425(M+H)
Embodiment 259
Under ice-water cooling, in the suspension of lithium aluminium hydride (98.8mg) in tetrahydrofuran (THF) (10mL), add 5-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole [1, the 2-b] pyridazine-3-yl also in the tetrahydrofuran (THF) (10mL)] Valeric acid ethylester (600mg) and under 0 ℃, stirring the mixture 2 hours.Make the reaction quenching with saturated sodium tartrate potassium solution, wash with the insolubles elimination and with ethyl acetate.Use the salt solution wash filtrate, by dried over mgso, and evaporation in a vacuum.By with hexane and ethyl acetate (10: 1-2: 1) the silica gel column chromatography purification resistates of mixture drip washing obtains also [1,2-b] pyridazine-3-yl of yellow oil 5-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole]-1-amylalcohol (478mg).
5-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also]-1-amylalcohol NMR (CDCl
3, δ): 0.90-1.22 (6H, m), 1.27 (1H, t, J=7Hz), 1 36 (3H, t, J=7Hz), 2.37-2.47 (2H, m), 3.02 (2H, q, J=7Hz), 3.29-3.41 (2H, m), 5.97 (1H, d, J=4Hz), 6.61 (1H, d, J=4Hz), 7.32 (1H, m), 7.40-7.55 (8H, m)
Embodiment 260
Under ice-water cooling to 5-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole [1,2-b] pyridazine-3-yl also]-add methylsulfonyl chloride (18.9mg) in 1-amylalcohol (63.0mg) and the solution of triethylamine (22.8mg) in methylene dichloride (3mL) and under 0 ℃, stirred the mixture 1 hour.Use the salt solution washing soln, by dried over mgso, and evaporation in a vacuum.Resistates is added in the sodium cyanide (14.7mg) in the dimethyl formamide (2mL), and under 60 ℃, stirred the mixture 5 hours.Mixture is distributed between ethyl acetate and water.Separate organic layer, water and salt water washing, by dried over mgso, and evaporation in a vacuum.By with hexane and ethyl acetate (20: 1-5: 1) the silica gel column chromatography purification resistates of mixture drip washing obtains also [1,2-b] pyridazine-3-yl of yellow oil 6-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole] own nitrile (58.5mg).
6-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] own nitrile
NMR(CDCl
3，δ)：1.00-1.15(4H，m)，1.17-1.28(2H，m)，1.36(3H，t，J＝7Hz)，1.98(2H，t，J＝7Hz)，2.38-2.47(2H，m)，3.03(2H，q，J＝7Hz)，5.99(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.32(1H，m)，7.38-7.56(8H，m)
MS(ESI
+)：m/z 428
Embodiment 261
At room temperature with 5-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole also [1,2-b] pyridazine-3-yl]-1-amylalcohol (65mg), Tetrafluoroboric acid trimethylammonium oxygen _ salt (27.5mg) and 2,6-two-tertiary butyl-4-picoline (47.8mg) is 1, and the mixture in the 2-ethylene dichloride (3mL) stirred 4 hours.Water, 1N hydrochloric acid, water, saturated sodium bicarbonate solution and salt solution washing soln, by dried over mgso, and evaporation in a vacuum.(20: 1-5: 1) the silica gel column chromatography purification resistates of mixture drip washing obtains also [1,2-b] pyridazine (60mg) of yellow oil 4-(3-chloro-phenyl-)-7-ethyl-3-(5-methoxyl group amyl group)-2-phenylpyrrole by using hexane and ethyl acetate.
4-(3-chloro-phenyl-)-7-ethyl-3-(5-methoxyl group amyl group)-2-phenylpyrrole is [1,2-b] pyridazine also
NMR(CDCl
3，δ)：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
Embodiment 262
Under ice-water cooling to 5-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole [1,2-b] pyridazine-3-yl also]-add methylsulfonyl chloride (16.5mg) in 1-amylalcohol (55mg) and the solution of triethylamine (19.9mg) in methylene dichloride (3mL) and under 0 ℃, stirred the mixture 1 hour.Use the salt solution washing soln, by dried over mgso, and evaporation in a vacuum.To 1, add the 2M dimethylamine in the tetrahydrofuran (THF) (3mL) in the resistates in the 2-ethylene dichloride (3mL) and under 60 ℃, stirred the mixture 120 hours.Solution is diluted with chloroform, use the salt water washing, by dried over mgso, and evaporation in a vacuum.By with hexane and ethyl acetate (20: 1-5: 1) the silica gel column chromatography purification resistates of mixture drip washing obtains also [1,2-b] pyridazine-3-yl of yellow oil 5-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole]-N, N-dimethyl-1-amylamine (38mg).
N-{5-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] amyl group }-N, N dimethylamine
NMR(CDCl
3，δ)：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＝7Hz)，5.97(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.31(1H，m)，7.39-7.54(8H，m)
MS(ESI
+)：m/z 446
Embodiment 263
To 5-[4-(3-cyano-phenyl)-7-ethyl-2-phenylpyrrole also [1,2-b] pyridazine-3-yl] add 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (35.3mg) and 2-aminopyridine (20mg) in the stirred solution of valeric acid (60mg) in methylene dichloride (2ml), and stirred reaction mixture 10 minutes.Add 4-Dimethylamino pyridine (2mg) and stirred reaction mixture 15 hours at room temperature.With the mixture dilute with water and use ethyl acetate extraction.Water, salt water washing organic layer are by dried over mgso and concentrated in a vacuum.By flash distillation column chromatography purification resistates with ethyl acetate and normal hexane (1: 2) mixture drip washing, obtain also [1,2-b] pyridazine-3-yl of yellow amorphous substance 5-[4-(3-cyano-phenyl)-7-ethyl-2-phenylpyrrole]-N-(2-pyridyl) valeramide (55.7mg).
5-[4-(3-cyano-phenyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also]-N-(2-pyridyl) valeramide
mp：67-70℃
NMR (CDCl3, δ): 1.12 (2H, quintet, J=7Hz), 1.30 (2H, quintet, J=7Hz), 1.36 (3H, t, 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)
Following compound is to obtain with embodiment 263 essentially identical modes.
Embodiment 264
5-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also]-N-(2-pyridyl) valeramide
NMR (CDCl
3, δ): 1.15 (2H, quintet, J=7Hz), 1.24 (2H, quintet, J=7Hz), 1.36 (3H, t, J=7Hz), 1.91 (2H, t, J=7Hz), 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=7Hz), 7.30 (1H, s), 7.38-7.53 (7H, m), 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)
Embodiment 265
N-{5-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] pentanoyl } Toluidrin
NMR (CDCl
3, δ): 1.08 (2H, quintet, J=7Hz), 1.23 (2H, quintets, J=7Hz), 1.36 (3H, t, J=7Hz), 1.85 (2H, t, J=7Hz), 2.44 (2H, t, J=7Hz), 3.02 (2H, q, J=7Hz), 3.21 (3H, s), 5.99 (1H, d, J=4Hz), 6.62 (1H, d, J=4Hz), and 7.30-7.33 (1H, m), 7.43-7.55 (8H, m)
Embodiment 266
5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also]-N-(2-pyridyl) valeramide
NMR (CDCl
3, δ): 1.12 (2H, quintet, J=7Hz), 1.27 (2H, quintet, J=7Hz), 1.36 (3H, t, J=7Hz), 1.97 (2H, t, J=7Hz), 2.45 (2H, t, J=7Hz), 3.01 (2H, q, J=7Hz), 5.95 (1H, d, J=5Hz), 6.63 (1H, d, J=4Hz), 7.01 (1H, t, J=7Hz), 7.31 (1H, d, J=7Hz), and 7.41-7.53 (6H, m), 7.68 (1H, ddd, J=7,7,1Hz), 7.77 (1H, s), 8.12 (1H, d, J=7.5Hz), 8.24 (1H, d, J=5Hz), 8.53 (1H, d, J=6Hz)
MS：(m/z)510(M++H)，80(bp)
Embodiment 267
N-{5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] pentanoyl } Toluidrin
mp：124-125℃
NMR(CDCl3，δ)：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)，5.87(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)
Embodiment 268
In ice bath to 5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester (100.0mg) and (brooethyl) benzene (111mg) is at N, adds 60% sodium hydride (17.4mg) in the solution in the dinethylformamide (1mL).After stirring 2.5 hours, make the reaction quenching by adding 1N hydrochloric acid (1mL), and mixture is distributed between ethyl acetate (10mL) and water (5mL).With 1N hydrochloric acid (5mL), water (5mL, three times) and salt water washing organic layer, by dried over mgso, and evaporation.Obtain yellow glue 5-[2-[(benzyloxy with ethyl acetate-hexane=1/40 to the flash distillation silica gel column chromatography of 20/40 drip washing) methyl]-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] Valeric acid ethylester (47.7mg, 39.9%).The 5-[2-[(benzyloxy) methyl]-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：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(1H，m)
Following compound is to obtain with embodiment 268 essentially identical modes.
Embodiment 269
5-(4-(5-bromo-3-pyridyl)-2-{[(4-cyano group benzyl) oxygen base] methyl }-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also) Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，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＝7Hz)，4.49(2H，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(1H，m)，8.78(1H，m)
Embodiment 270
In ice bath to 5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-yl] add methylsulfonyl chloride (54.7mg) in Valeric acid ethylester (200mg) and the solution of triethylamine (65.9mg) in methylene dichloride (2mL).After stirring 1 hour, make the reaction quenching by adding 1N hydrochloric acid (1mL).Mixture is distributed between ethyl acetate (20mL) and 1N hydrochloric acid (5mL).With saturated sodium bicarbonate and salt water washing organic layer; pass through dried over mgso; and evaporation obtains yellow glue 5-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[(methyl sulphonyl) oxygen base] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) Valeric acid ethylester (247mg).
5-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[(methyl sulphonyl) oxygen base] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) Valeric acid ethylester
NMR(CDCl
3，δ)：1.22(3H，t，J＝7Hz)，1.34-1.65(7H，m)，2.20(2H，t，J＝7Hz)，2.55(2H，m)，3.02(2H，q，J＝7Hz)，3.15(3H，s)，4.07(2H，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)
Embodiment 271
At room temperature with 5-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[(methyl sulphonyl) oxygen base] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) Valeric acid ethylester (247mg), benzylamine (29.8mg) mixture in methylene dichloride (1mL) stirred 20 hours.Mixture is distributed between ethyl acetate and water.With salt water washing organic layer, dry and evaporation.Preparation thin-layer chromatography with ethyl acetate-hexane=drip washing in 1: 2 obtains yellow glue 5-[2-[(benzylamino) methyl]-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] Valeric acid ethylester (19.1mg).
The 5-[2-[(benzylamino) methyl]-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.30-1.50(7H，m)，2.13(2H，t，J＝7Hz)，2.42(2H，m)，3.03(2H，q，J＝7Hz)，3.96(4H，m)，4.09(2H，q，J＝7Hz)，5.89(1H，d，J＝5Hz)，6.57(1H，d，J＝5Hz)，7.23-7.42(5H，m)，7.86(1H，m)，8.53(1H，m)，8.77(1H，m)
Following compound is to obtain with embodiment 271 essentially identical modes.
Embodiment 272
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(4-morpholinyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
NMR(CDCl
3，δ)：1.23(3H，t，J＝7Hz)，1.31-1.56(7H，m)，2.19(2H，t，J＝7Hz)，2.45-2.65(6H，m)，3.02(2H，q，J＝7Hz)，3.60-3.75(6H，m)，4.09(2H，q，J＝7Hz)，5.88(1H，d，J＝5Hz)，6.57(1H，d，J＝5Hz)，7.89(1H，m)，8.55(1H，m)，8.78(1H，m)
Embodiment 273
In ice-water-bath to (7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl) methyl alcohol (40mg) at N, add 40% sodium hydride (5.5mg) in the oil in the solution in the dinethylformamide (1mL).After 20 minutes, under this temperature, in mixture, add acetate 2-bromine ethyl ester (31mg).After 15 minutes, at room temperature stirred reaction mixture is 5 hours.Reaction mixture is distributed between ethyl acetate and water.Wash organic layer with water three times, and with salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.(the purification resistates of hexane-ethyl acetate=10-1) obtains light yellow solid acetate [7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl] methyl esters (42mg) by p-TLC.
Acetate [7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl] methyl esters
NMR(CDCl
3，δ)：1.41(6H，d，J＝8Hz)，2.06(3H，s)，3.21(1H，m)，4.92(2H，s)，6.14(1H，d，J＝5Hz)，6.72(1H，d，J＝5Hz)，7.13-7.24(2H，m)，7.34-7.43(2H，m)
MS(ESI
+)：m/z 361(M+H)
Following compound is to obtain with preparation example 20 essentially identical modes.
Embodiment 274
{ [7-ethyl-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl] methoxyl group } ethyl acetate
NMR(CDCl
3，δ)：1.25(3H，t，J＝8Hz)，1.30-1.45(9H，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)
Following compound is to obtain with preparation example 276 essentially identical modes.
Embodiment 275
2-(2-amino-2-oxoethyl)-4-(4-cyano-phenyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-ethyl formate also
NMR(CDCl
3，δ)：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)
Embodiment 276
At room temperature with 4-(3-cyano-phenyl)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1; 2-b] pyridazine-2-formic acid (40.0mg), tetramethyleneimine (10.8mg), 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (31.1mg) and I-hydroxybenzotriazole (21.9mg) are at N, and the mixture in the dinethylformamide (1mL) stirred 6 hours.Mixture is distributed between ethyl acetate (20mL) and 1N hydrochloric acid (10mL).Water (10mL) washing organic layer three times; with saturated sodium bicarbonate (10mL) and salt water washing organic layer; drying, and evaporation obtains yellow solid 3-[7-ethyl-3-(methyl sulphonyl)-2-(1-pyrrolidyl carbonyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile (35.6mg).3-[7-ethyl-3-(methyl sulphonyl)-2-(1-pyrrolidyl carbonyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile
NMR(CDCl
3，δ)：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)
Embodiment 277
At room temperature to 3-[7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-4-yl] phenylformic acid (40mg) is at N, adds 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (30mg), I-hydroxybenzotriazole (24mg) and 2-monoethanolamine (15mg) in the solution in the dinethylformamide (4mL).After stirring is spent the night, reaction mixture is distributed between ethyl acetate and saturated sodium bicarbonate.Wash organic layer with water 3 times, and with salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.(silica gel, 40mL) purification resistates obtain yellow solid (42mg) by the flash distillation silica gel column chromatography with chloroform-methanol=50-1 and 20-1 drip washing.Solid and isopropyl ether are ground, obtain yellow solid 3-[7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-4-base-N-(2-hydroxyethyl) benzamide (35mg).
3-[7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-4-yl]-N-(2-hydroxyethyl) benzamide
NMR(CDCl
3，δ)：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(1H，d，J＝5Hz)，7.55-7.65(2H，m)，7.86-7.97(2H，m)，8.17(1H，brs)
MS(ESI
+)：m/z 376(M+H)
Following compound is to obtain with embodiment 283 essentially identical modes.
Embodiment 278
5-[4-(3-cyano-phenyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also]-N-methylpent acid amides
mp：60℃
NMR (CDCl3, δ): 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), 5.09 (1H, broad peak s), 5.90 (1H, d, J=4Hz), 6.63 1H, d, J=4Hz), and 7.45-7.55 (5H, m), 7.60-7.78 (4H, m)
MS：(m/z)437(M
++H)，115(bp)
Embodiment 279
4-(3-chloro-phenyl-)-7-ethyl-3-[5-(4-morpholinyl)-5-oxo amyl group]-2-phenylpyrrole [1,2-b] pyridazine also
mp：55-58℃
NMR(CDCl3，δ)：1.05-1.14(2H，m)，1.17-1.23(2H，m)，1.35(3H，t，J＝7Hz)，1.84(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)
Embodiment 280
5-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also]-N-methylpent acid amides
mp：70-72℃
NMR (CDCl3, δ): 1.06 (2H, quintet, J=7Hz), 1.22 (2H, quintets, J=7Hz), 1.36 (3H, t, 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 peak 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)
Embodiment 281
5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also]-N-methylpent acid amides
NMR (CDCl
3, δ): 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, q, J=7Hz), 5.10 (1H, broad peak s), 5.95 (1H, d, J=4Hz), 6.64 (1H, d, J=4Hz), 7.31 (1H, d, J=7Hz), 7.42 (1H, s), and 7.46-7.52 (1H, m), 7.41-7.55 (1H, d, J=7Hz)
MS：(m/z)447(M
++H)，115(bp)
Embodiment 282
Derive from also [1,2-b] pyridazine-3-yl of 5-[4-(3-cyano-phenyl)-7-ethyl-2-phenylpyrrole] 3-{7-ethyl-3-[5-(4-the morpholinyl)-5-oxo amyl group of valeric acid]-2-phenylpyrrole [1,2-b] pyridazine-4-yl also } benzonitrile
mp：66-69℃
NMR(CDCl3，δ)：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)，7.43-7.55(5H，m)，7.60-7.78(4H，m)
MS：(m/z)493(M
++H)，126(bp)
Embodiment 283
At room temperature to 5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole also [1,2-b] pyridazine-3-yl] valeric acid (50mg) is at N, adds 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (35mg) and I-hydroxybenzotriazole (28mg) in the solution in the dinethylformamide (1mL).After 30 minutes, in mixture, add morpholine (24mg).After 5 hours, reaction mixture is distributed between ethyl acetate and saturated sodium bicarbonate.Wash organic layer with water three times, and with salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.By flash distillation silica gel column chromatography purification resistates with hexane-ethyl acetate=3-1,2-1,1-1,1-3 and 0-1 drip washing, obtain yellow glue 3-{7-ethyl-2-methyl-3-[5-(4-morpholinyl)-5-oxo amyl group] pyrrolo-[1,2-b] pyridazine-4-yl } benzonitrile (53mg).
3-{7-ethyl-2-methyl-3-[5-(4-morpholinyl)-5-oxo amyl group] pyrrolo-[1,2-b] pyridazine-4-yl } benzonitrile
NMR(CDCl
3，δ)：1.15-1.61(7H，m)，2.18(2H，t，J＝8Hz)，2.41(2H，t，J＝8Hz)，2.56(3H，s)，3.00(2H，q，J＝8Hz)，3.82(2H，t，J＝5Hz)，3.51-3.68(6H，m)，5.78(1H，d，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)
Following compound is to obtain with embodiment 283 essentially identical modes.
Embodiment 284
5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeramide
NMR(CDCl
3，δ)：1.31-1.61(7H，m)，2.11(2H，t，J＝8Hz)，2.40(2H，t，J＝8Hz)，2.56(3H，s)，3.00(2H，q，J＝8Hz)，5.36(2H，brs)，5.79(1H，d，J＝5Hz)，6.50(1H，d，J＝5Hz)，7.56-7.67(3H，m)，7.75(1H，m)
MS(ESI
+)：m/z 361(M+H)
Preparation example 178
In the suspension of 60% sodium hydride (8.79g) in tetrahydrofuran (THF) (500mL), add hexalin (10g), and mixture was stirred 0.5 hour down at 0 ℃.Under ice-water cooling, in mixture, add bromoacetic acid (13.9g) and with mixture heating 2 hours under refluxing.In mixture, add after the entry, evaporate organic solvent in a vacuum.With aqueous solution dilute with water,, use the 1N hcl acidifying, and extract with ether with the ether washing.Separate organic layer, by dried over mgso, and evaporation obtains water white oil (cyclohexyloxy) acetate (13.3g) in a vacuum.
(cyclohexyloxy) acetate
1H NMR (CDCl
3) δ 1.18-1.47 (5H, m), 1.52-1.63 (1H, m), 1.72-1.85 (2H, m), 1.90-2.03 (2H, m), 3.36-3.47 (1H, m), 4.13 (2H, s).
Following compound is to obtain with preparation example 178 essentially identical modes.
Preparation example 179
Isopropoxy acetate
1H NMR(CDCl
3)δ1.24(6H，d，J＝7Hz)，3.68-3.82(1H，m)，4.11(2H，s).
Following compound is to obtain with preparation example 129 and preparation example 130 essentially identical modes.
Preparation example 180
4-(the benzyloxy)-3-ketobutyric acid tert-butyl ester
1H NMR(CDCl
3)δ1.44(9H，s)，3.45(2H，s)，4.14(2H，s)，4.60(2H，s)，7.28-7.40(5H，m).
Preparation example 181
4-(the cyclohexyloxy)-3-ketobutyric acid tert-butyl ester
1H NMR(CDCl
3)δ1.18-1.43(5H，m)，1.47(9H，s)，1.53-1.63(1H，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 example 182
4-isopropoxy-3-ketobutyric acid the tert-butyl ester
1H NMR(CDCl
3)δ1.20(6H，d，J＝7 Hz)，1.47(9H，s)，3.45(2H，s)，3.60-3.70(1H，m)，4.08(2H，s).
Following compound is to obtain with preparation example 159 essentially identical modes.
Preparation example 183
2-ethanoyl succsinic acid 1-tertiary butyl 4-ethyl ester
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.47(9H，s)，2.35(3H，s)，3.08(2H，m)，3.93(1H，m)，4.12(2H，q，J＝7Hz).
Preparation example 184
The 2-[(benzyloxy) ethanoyl] pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，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＝7Hz)，3.52(1H，t，J＝7Hz)，4.11(2H，q，J＝7Hz)，4.16(2H，s)，4.59(2H，s)，7.27-7.40(5H，m).
Preparation example 185
The 2-[(benzyloxy) ethanoyl] pimelic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.41(9H，s)，2.10-2.23(2H，m)，2.36(2H，t，J＝7Hz)，3.66(1H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.18(2H，s)，4.60(2H，s)，7.26-7.38(5H，m).
Preparation example 186
The 2-[(cyclohexyloxy) ethanoyl] pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.44(9H，s)，1.15-1.92(16H，m)，2.29(2H，t，J＝7Hz)，3.24-3.38(1H，m)，3.56(1H，t，J＝7Hz)，4.12(4H，m)，
Preparation example 187
2-(isopropoxy ethanoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.20(6H，d，J＝7Hz)，1.25(3H，t，J＝7Hz)，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＝7Hz)，3.54(1H，t，J＝7Hz)，3.60-3.68(1H，m)，4.11(2H，s)，4.12(2H，q，J＝7Hz).
MS(ESI
+)：m/z 345.
Following compound is to obtain with preparation example 20 essentially identical modes.
Preparation example 188
The 2-[(cyclohexyloxy) ethanoyl] pimelic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ1.26(3H，t，J＝7Hz)，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＝7Hz)，3.25-3.38(1H，m)，3.69(1H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.15(2H，s).
MS(ESI
+)：m/z 357.
Preparation example 189
Under ice-water cooling, in the suspension of 60% sodium hydride (527mg) in dimethyl formamide (20mL), add 3,5-dinicotinic acid (2.00g), and mixture stirred 1 hour down at 0 ℃.In mixture, add (brooethyl) benzene (2.05g) and mixture is descended stirring 2 hours at 60 ℃.Mixture is distributed between ethyl acetate and water.Water and salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.Resistates and ethyl acetate are ground, obtain buff powder 5-[(benzyloxy) carbonyl] nicotinic acid (722mg).
The 5-[(benzyloxy) carbonyl] nicotinic acid
1H NMR(DMSO-d
6)δ5.42(2H，s)，7.34-7.54(5H，m)，8.63(1H，m)，9.23-9.34(2H，m).
Following compound is to obtain with preparation example 24 essentially identical modes.
Preparation example 190
2-ethanoyl-2-[(5-methyl-3-pyridyl) carbonyl] succsinic acid 1-tertiary butyl 4-ethyl ester
1HNMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.40(9H，s)，2.38(3H，s)，2.45(3H，s)，3.20(2H，m)，4.13(2H，q，J＝7Hz)，7.88(1H，s)，8.57(1H，s)，8.74(1H，s).
MS(ESI
+)：m/z 363.
Preparation example 191
2-[(5-methyl-3-pyridyl) carbonyl]-ethyl 3-oxobutanoate
1HNMR(CDCl
3)δ0.96(3H，t，J＝7Hz)，2.15(3H，s)，2.45(3H，s)，4.03(2H，q，J＝7Hz)，4.12(1H，t，J＝7Hz)，7.89(1H，s)，8.54(1H，s)，8.72(1H，s).
MS(ESI
+)：m/z 250.
Preparation example 192
2-ethanoyl-2-[(5-bromo-3-pyridyl) carbonyl] hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.36(9H，s)，1.60-1.73(2H，m)，2.23-2.35(2H，m)，2.38(2H，t，J＝7Hz)，2.48(3H，s)，4.12(2H，q，J＝7Hz)，8.20(1H，m)，8.78(1H，m)，8.81(1H，m).
Preparation example 193
2-[(5-bromo-3-pyridyl) carbonyl]-2-(methoxyl group ethanoyl) pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，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＝7Hz)，4.27(1H，d，J＝17Hz)，4.40(1H，d，J＝17Hz)，8.21(1H，m)，8.79(1H，d，J＝2Hz)，8.82(1H，d，J＝2Hz).
MS(ESI
+)：m/z 472 474.
Preparation example 194
2-ethanoyl-2-(the 5-[(benzyloxy) carbonyl]-the 3-pyridyl } carbonyl) pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.20-1.40(2H，m)，1.32(9H，s)，1.65-1.76(2H，m)，2.19-2.26(2H，m)，2.32(2H，t，J＝7Hz)，2.44(3H，s)，4.12(2H，q，J＝7Hz)，5.41(2H，s)，7.35-7.48(5H，m)，8.62(1H，m)，9.07(1H，d，J＝2Hz)，9.33(1H，d，J＝2Hz).
MS(ESI
+)：m/z 526.
Preparation example 195
The 2-[(benzyloxy) ethanoyl]-2-[(5-methyl-3-pyridyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，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＝7Hz)，4.38(1H，d，J＝18Hz)，4.53(1H，d，J＝18Hz)，4.54(2H，m)，7.27-7.40(5H，m)，7.79(1H，m)，8.54(1H，d，J＝2Hz)，8.72(1H，d，J＝2Hz).
MS(ESI
+)：m/z 512.
Preparation example 196
The 2-[(benzyloxy) ethanoyl]-2-[(5-methyl-3-pyridyl) carbonyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ1.26(3H，t，J＝7Hz)，1.34(9H，s)，2.35(3H，s)，2.40-2.72(4H，m)，4.12(2H，q，J＝7Hz)，4.38(1H，d，J＝17Hz)，4.50(1H，d，J＝17Hz)，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 example 197
The 2-[(cyclohexyloxy) ethanoyl]-2-[(5-methyl-3-pyridyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，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＝7Hz)，2.39(3H，s)，3.17-3.29(1H，m)，4.12(2H，q，J＝7Hz)，4.34(1H，d，J＝18Hz)，4.44(1H，d，J＝18Hz)，7.86(1H，s)，8.56(1H，s)，8.76(1H，s).
MS(ESI
+)：m/z 504.
Preparation example 198
2-[(5-bromo-3-pyridyl) carbonyl]-the 2-[(cyclohexyloxy) ethanoyl] pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，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＝7Hz)，4.28(1H，d，J＝18Hz)，4.38(1H，d，J＝18Hz)，8.20(1H，m)，8.78(1H，d，J＝2Hz)，8.84(1H，d，J＝2Hz).
MS(ESI
+)：m/z 568 570.
Preparation example 199
The 2-[(cyclohexyloxy) ethanoyl]-2-[(5-methyl-3-pyridyl) carbonyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，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＝7Hz)，4.32(1H，d，J＝17Hz)，4.41(1H，d，J＝17Hz)，7.88(1H，s)，8.55(1H，s)，8.77(1H，s).
MS(ESI
+)：m/z 476.
Preparation example 200
2-[(5-bromo-3-pyridyl) carbonyl]-the 2-[(cyclohexyloxy) ethanoyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ1.26(3H，t，J＝7Hz)，1.15-135(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＝7Hz)，4.28(1H，d，J＝17Hz)，4.35(1H，d，J＝17Hz)，8.22(1H，t，J＝2Hz)，8.78(1H，d，J＝2Hz)，8.87(1H，d，J＝2Hz).
MS(ESI
+)：m/z 540 542.
Preparation example 201
2-(isopropoxy ethanoyl)-2-[(5-methyl-3-pyridyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.12(6H，d，J＝7Hz)，1.23(3H，t，J＝7Hz)，1.30-1.55(2H，m)，1.37(9H，s)，1.63-1.77(2H，m)，2.19-2.28(2H，m)，2.28(2H，t，J＝7Hz)，2.39(3H，s)，3.53-3.64(1H，m)，4.10(2H，q，J＝7Hz)，4.31(1H，d，J＝18Hz)，4.42(1H，d，J＝18Hz)，7.86(1H，s)，8.55(1H，s)，8.74(1H，s).
MS(ESI
+)：m/z 464.
Preparation example 202
2-[(5-bromo-3-pyridyl) carbonyl]-2-(isopropoxy ethanoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.10(6H，d，J＝7Hz)，1.24(3H，t，J＝7Hz)，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，q，J＝7Hz)，4.25(1H，d，J＝17Hz)，4.36(1H，d，J＝17Hz)，8.19(1H，t，J＝2Hz)，8.77(1H，d，J＝2Hz)，8.83(1H，d，J＝2Hz).
MS(ESI
+)：m/z 528 530.
Preparation example 203
The 2-[(acetoxyl group) ethanoyl]-2-[(5-methyl-3-pyridyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，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＝7Hz)，5.08(1H，d，J＝18Hz)，5.36(1H，d，J＝18Hz)，7.84(1H，s)，8.56(1H，s)，8.75(1H，s).
MS(ESI
+)：m/z 464.
Following compound is to obtain with preparation example 78 essentially identical modes.
Preparation example 204
3-[(5-methyl-3-pyridyl) carbonyl]-ethyl 4-oxopentanoate
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，2.21(3H，s)，2.44(3H，s)，3.03(2H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.96(1H，t，J＝7Hz)，8.08(1H，s)，8.66(1H，s)，9.03(1H，s).
MS(ESI
+)：m/z 264.
Preparation example 205
5-[(5-bromo-3-pyridyl) carbonyl]-the 6-oxoheptanoate
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.60-1.78(2H，m)，1.98-2.12(2H，m)，2.20(3H，s)，2.36(2H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.39(1H，t，J＝7Hz)，8.38(1H，m)，8.87(1H，d，J＝2Hz)，9.08(1H，d，J＝2Hz).
Preparation example 206
4-[(5-bromo-3-pyridyl) carbonyl]-6-methoxyl group-5-oxo ethyl hexanoate
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，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＝17Hz)，4.00(1H，d，J＝17Hz)，4.12(2H，q，J＝7Hz)，4.85(1H，m)，8.47(1H，m)，8.88(1H，s)，9.16(1H，s).
MS(ESI
+)：m/z 372 374.
Preparation example 207
5-(2-ethanoyl-7-oxyethyl group-7-oxo oenanthyl) Pykaryl
1HNMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，1.30-1.43(2H，m)，1.65-1.75(2H，m)，1.93-2.15(2H，m)，2.19(3H，s)，2.29(2H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.44(1H，t，J＝7Hz)，5.43(2H，s)，7.35-7.50(5H，m)，8.81(1H，m)，9.28(1H，d，J＝2Hz)，9.39(1H，d，J＝2Hz).
MS(ESI
+)：m/z 426.
Preparation example 208
8-(benzyloxy)-6-[(5-methyl-3-pyridyl) carbonyl]-7-oxo ethyl octylate
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，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＝7Hz)，2.34(3H，s)，4.05(2H，s)，4.07(2H，q，J＝7Hz)，4.35-4.45(2H，m)，4.69(1H，t，J＝7Hz)，7.09(2H，m)，7.17-7.25(3H，m)，7.93(1H，s)，8.58(1H，d，J＝2Hz)，8.94(1H，d，J＝2Hz).
MS(ESI
+)：m/z 412.
Preparation example 209
6-(benzyloxy)-4-[(5-methyl-3-pyridyl) carbonyl]-5-oxo ethyl hexanoate
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，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＝7Hz)，4.34(1H，d，J＝17Hz)，4.41(1H，d，J＝17Hz)，4.90(1H，m)，7.03(2H，m)，7.15-7.25(3H，m)，8.00(1H，s)，8.57(1H，s)，9.02(1H，s).
MS(ESI
+)：m/z 384.
Preparation example 210
8-(cyclohexyloxy)-6-[(5-methyl-3-pyridyl) carbonyl]-7-oxo ethyl octylate
1H NMR(CDCl
3)δ0.91-1.70(12H，m)，1.23(3H，t，J＝7Hz)，1.70-1.85(2H，m)，1.96-2.04(2H，m)，2.27(2H，t，J＝7Hz)，2.43(3H，s)，3.14-3.28(1H，m)，4.00(2H，s)，4.12(2H，q，J＝7Hz)，4.76(1H，t，J＝7Hz)，8.04(1H，s)，8.62(1H，s)，9.00(1H，s).
MS(ESI
+)：m/z 404.
Preparation example 211
6-[(5-bromo-3-pyridyl) carbonyl]-8-(cyclohexyloxy)-7-oxo ethyl octylate
1H NMR(CDCl
3)δ0.95-1.87(14H，m)，1.23(3H，t，J＝7Hz)，1.96-2.07(2H，m)，2.28(2H，t，J＝7Hz)，3.16-3.27(1H，m)，3.96-4.07(2H，m)，4.12(2H，q，J＝7Hz)，4.72(1H，t，J＝7Hz)，8.38(1H，m)，8.87(1H，d，J＝2Hz)，9.08(1H，d，J＝2Hz).
MS(ESI
+)：m/z 468 470.
Preparation example 212
6-(cyclohexyloxy)-4-[(5-methyl-3-pyridyl) carbonyl]-5-oxo ethyl hexanoate
1H NMR(CDCl
3)δ0.88-1.25(5H，m)，1.24(3H，t，J＝7Hz)，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＝7Hz)，4.93(1H，m)，8.13(1H，s)，8.63(1H，d，J＝2Hz)，9.07(1H，d，J＝2Hz).
MS(ESI
+)：m/z 376.
Preparation example 213
4-[(5-bromo-3-pyridyl) carbonyl]-6-(cyclohexyloxy)-5-oxo ethyl hexanoate
1H NMR(CDCl
3)δ0.88-1.85(10H，m)，1.25(3H，t，J＝7Hz)，2.02-2.14(1H，m)，2.18-2.34(1H，m)，2.40-2.50(2H，m)，3.15-3.27(1H，m)，3.97(1H，d，J＝17Hz)，4.02(1H，d，J＝17Hz)，4.13(2H，q，J＝7Hz)，4.87-4.95(1H，m)，8.48(1H，t，J＝2Hz)，8.88(1H，d，J＝2Hz)，9.19(1H，d，J＝2Hz).
MS(ESI
+)：m/z 440 442.
Preparation example 214
8-isopropoxy-6-[(5-methyl-3-pyridyl)) carbonyl]-7-oxo ethyl octylate
1H NMR(CDCl
3)δ0.86(3H，d，J＝7Hz)，1.02(3H，d，J＝7Hz)，1.23(3H，t，J＝7Hz)，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＝7Hz)，2.43(3H，s)，3.44-3.54(1H，m)，3.95(1H，d，J＝18Hz)，4.03(1H，d，J＝18Hz)，4.08(2H，q，J＝7Hz)，4.73(1H，t，J＝7Hz)，8.06(1H，s)，8.63(1H，s)，9.02(1H，s).
MS(ESI
+)：m/z 364.
Preparation example 215
6-[(5-bromo-3-pyridyl) carbonyl]-8-isopropoxy-7-oxo ethyl octylate
1H NMR(CDCl
3)δ0.88(3H，d，J＝7Hz)，1.03(3H，t，J＝7Hz)，1.23(3H，t，J＝7Hz)，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＝7Hz)，3.46-3.58(1H，m)，3.94(1H，d，J＝17Hz)，4.03(1H，d，J＝17Hz)，4.10(2H，q，J＝7Hz)，4.68(1H，t，J＝7Hz)，8.40(1H，t，J＝2Hz)，8.86(1H，d，J＝2Hz)，9.08(1H，d，J＝2Hz).
MS(ESI
+)：m/z 428 430.
Preparation example 216
8-(acetoxyl group)-6-[(5-methyl-3-pyridyl) carbonyl]-7-oxo ethyl octylate
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，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＝7Hz)，2.44(3H，s)，4.10(2H，q，J＝7Hz)，4.52(1H，t，J＝7Hz)，4.68(1H，d，J＝18Hz)，4.76(1H，d，J＝18Hz)，8.04(1H，s)，8.66(1H，s)，8.98(1H，s).
MS(ESI
+)：m/z 364.
Following compound is to obtain in mode substantially the same manner as Example 21.
Embodiment 285
[7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl acetate
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，2.40(3H，s)，2.50(3H，s)，3.02(2H，q，J＝7Hz)，3.44(2H，s)，4.14(2H，q，J＝7Hz)，5.98(1H，d，J＝4Hz)，6.56(1H，d，J＝4Hz)，7.55(1H，s)，8.45(1H，s)，8.54(1H，s).
MS(ESI
+)：m/z 338.
Embodiment 286
7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-ethyl formate
1H NMR(CDCl
3)δ0.96(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，2.41(3H，s)，2.61(3H，s)，3.04(2H，q，J＝7Hz)，4.05(2H，q，J＝7Hz)，6.30(1H，d，J＝4Hz)，6.67(1H，d，J＝4Hz)，7.58(1H，s)，8.48(1H，d，J＝2Hz)，8.51(1H，d，J＝2Hz).
MS(ESi
+)：m/z 324.
Embodiment 287
4-[4-(5-bromo-3-pyridyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] ethyl butyrate
1H NMR(CDCl
3)δ1.21(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.67-1.78(2H，m)，2.22(2H，t，J＝7Hz)，2.42-2.54(2H，m)，2.59(3H，s)，3.01(2H，q，J＝7Hz)，4.06(2H，q，J＝7Hz)，5.87(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，7.87(1H，m)，8.54(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
MS(ESI
+)：m/z 430 432.
Embodiment 288
3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(CDCl
3)δ1.20(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，2.42(2H，t，J＝7Hz)，2.85-2.97(2H，m)，3.06(2H，q，J＝7Hz)，3.46(3H，s)，4.08(2H，q，J＝7Hz)，4.65(2H，s)，5.94(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.87(1H，m)，8.54(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
MS(ESI
+)：m/z 446 448.
Embodiment 289
The 4-[2-[(acetoxyl group) methyl]-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] ethyl butyrate
1H NMR(CDCl
3)δ1.20(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，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＝7Hz)，4.05(2H，q，J＝7Hz)，5.32(2H，s)，5.95(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.88(1H，m)，8.55(1H，m)，8.78(1H，m).
MS(ESI
+)：m/z 488 490.
Embodiment 290
5-[3-(5-oxyethyl group-5-oxo amyl group)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-4-yl also] Pykaryl
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.33-1.60(4H，m)，2.18(2H，t，J＝7Hz)，2.35-2.47(2H，m)，2.56(3H，s)，3.03(2H，q，J＝7Hz)，4.10(2H，q，J＝7Hz)，5.42(2H，s)，5.82(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，7.36-7.47(5H，m)，8.33(1H，m)，8.77(1H，d，J＝2Hz)，9.33(1H，d，J＝2Hz).
MS(ESI
+)：m/z 500.
Embodiment 291
The 5-[2-[(benzyloxy) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.20-1.50(4H，m)，2.06(2H，t，J＝7Hz)，2.42(3H，s)，2.47-2.63(2H，m)，3.05(2H，q，J＝7Hz)，4.08(2H，q，J＝7Hz)，4.64(2H，s)，4.73(2H，s)，5.90(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.27-7.39(5H，m)，751(1H，s)，8.41(1H，d，J＝2Hz)，8.53(1H，d，J＝2Hz).
Embodiment 292
The 3-[2-[(benzyloxy) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(CDCl
3)δ1.16(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，2.36(2H，t，J＝7Hz)，2.42(3H，s)，2.80-3.00(2H，m)，3.06(2H，q，J＝7Hz)，4.03(2H，q，J＝7Hz)，4.65(2H，s)，4.75(2H，s)，5.92(1H，d，J＝2Hz)，6.59(1H，d，J＝2Hz)，7.26-7.38(5H，m)，7.48(1H，s)，8.40(1H，d，J＝2Hz)，8.53(1H，d，J＝2Hz).
MS (ESI
+)：m/z 458.
Embodiment 293
The 5-[2-[(cyclohexyloxy) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.20-1.60(10H，m)，1.25(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.70-1.83(2H，m)，1.96-2.07(2H，m)，2.15(2H，t，J＝7Hz)，2.43(3H，s)，2.53-2.68(2H，m)，3.04(2H，q，J＝7Hz)，3.42-3.53(1H，m)，4.08(2H，q，J＝7Hz)，4.69(2H，s)，5.88(1H，d，J＝4Hz)，6.55(1H，d，J＝4Hz)，7.53(1H，s)，8.42(1H，d，J＝2Hz)，8.53(1H，d，J＝2Hz).
Embodiment 294
5-{4-(5-bromo-3-pyridyl)-2-[(cyclohexyloxy) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } Valeric acid ethylester
1H NMR(CDCl
3)δ1.22-1.62(10H，m)，1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.73-1.86(2H，m)，1.98-2.07(2H，m)，2.18(2H，t，J＝7Hz)，2.53-2.70(2H，m)，3.03(2H，q，J＝7Hz)，3.42-3.56(1H，m)，4.12(2H，q，J＝7Hz)，4.69(2H，s)，5.88(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.88(1H，m)，8.54(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
Embodiment 295
The 3-[2-[(cyclohexyloxy) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(CDCl
3)δ1.19(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，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(3H，s)，2.84-2.98(2H，m)，3.03(2H，q，J＝7Hz)，3.45-3.56(1H，m)，4.06(2H，q，J＝7Hz)，4.71(2H，s)，5.89(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.50(1H，s)，8.42(1H，s)，8.53(1H，s).
MS(ESI
+)：m/z 450.
Embodiment 296
3-{4-(5-bromo-3-pyridyl)-2-[(cyclohexyloxy) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } ethyl propionate
1H NMR(CDCl
3)δ1.20(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.15-1.60(6H，m)，1.73-1.85(2H，m)，1.97-2.08(2H，m)，2.45(2H，t，J＝7Hz)，2.83-2.97(2H，m)，3.05(2H，q，J＝7Hz)，3.42-3.56(1H，m)，4.08(2H，q，J＝7Hz)，4.71(2H，s)，5.90(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.86(1H，t，J＝2Hz)，8.53(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
MS(ESI
+)：m/z 514 516.
Embodiment 297
5-[7-ethyl-2-(isopropoxy methyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.26(6H，d，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.38-1.62(4H，m)，2.17(2H，t，J＝7Hz)，2.43(3H，s)，2.53-2.68(2H，m)，3.03(2H，q，J＝7Hz)，3.76-3.88(1H，m)，4.08(2H，q，J＝7Hz)，4.66(2H，s)，5.88(1H，d，J＝4Hz)，6.57(1H，d，J＝4Hz)，7.52(1H，s)，8.42(1H，s)，8.53(1H，s).
MS(ESI
+)：m/z 438.
Embodiment 298
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(isopropoxy methyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.25(6H，d，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.37-1.64(4H，m)，2.15(2H，t，J＝7Hz)，2.54-2.72(2H，m)，3.02(2H，q，J＝7Hz)，3.75-3.87(1H，m)，4.09(2H，q，J＝7Hz)，4.66(2H，s)，5.89(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.88(1H，m)，8.55(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
MS(ESI
+)：m/z 502 504.
Embodiment 299
The 5-[2-[(acetoxyl group) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.30-1.58(4H，m)，2.13(2H，t，J＝7Hz)，2.18(3H，s)，2.44(3H，s)，2.40-2.55(2H，m)，3.02(2H，q，J＝7Hz)，4.08(2H，q，J＝7Hz)，5.29(2H，s)，5.93(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.52(1H，s)，8.42(1H，s)，8.53(1H，s).
MS(ESI
+)：m/z 438.
Following compound is to obtain with embodiment 236 essentially identical modes.
Embodiment 300
4-{4-[5-(1-vinyl ethyl ether base)-3-pyridyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } ethyl butyrate
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.41(3H，t，J＝7Hz)，1.68-1.80(2H，m)，2.22(2H，t，J＝7Hz)，2.44-2.54(2H，m)，2.59(3H，s)，3.03(2H，q，J＝7Hz)，3.95(2H，q，J＝7Hz)，4.10(2H，q，J＝7Hz)，4.36(1H，d，J＝3Hz)，4.77(1H，d，J＝3Hz)，5.88(1H，d，J＝4Hz)，6.52(1H，d，J＝4Hz)，7.92(1H，m)，8.53(1H，d，J＝2Hz)，8.93(1H，d，J＝2Hz).
MS(ESI
+)：m/z 422.
Embodiment 301
3-[4-[5-(1-vinyl ethyl ether base)-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(CDCl
3)δ1.19(3H，t，J＝7Hz)，1.26(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，2.42(2H，t，J＝7Hz)，2.84-2.97(2H，m)，3.07(2H，q，J＝7Hz)，3.47(3H，s)，3.97(2H，q，J＝7Hz)，4.08(2H，q，J＝7Hz)，4.36(1H，d，J＝3Hz)，4.66(2H，s)，4.77(1H，d，J＝3Hz)，5.95(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.92(1H，m)，8.54(1H，d，J＝2Hz)，8.95(1H，d，J＝2Hz).
MS(ESI
+)：m/z 438.
Embodiment 302
3-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(CDCl
3)δ1.18(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，2.40(2H，t，J＝7Hz)，2.84-2.98(2H，m)，3.03(2H，q，J＝7Hz)，3.47(3H，s)，4.04(2H，q，J＝7Hz)，4.65(2H，s)，5.46(1H，d，J＝11Hz)，5.87(1H，d，J＝18Hz)，5.94(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，6.72-6.83(1H，dd，J＝11Hz，18Hz)，7.74(1H，m)，8.49(1H，d，J＝2Hz)，8.72(1H，d，J＝2Hz).
MS(ESI
+)：m/z 394.
Embodiment 303
4-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] methyl-butyrate
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.65-1.78(2H，m)，2.23(2H，t，J＝7Hz)，2.54-2.70(2H，m)，3.05(2H，q，J＝7Hz)，3.47(3H，s)，3.58(3H，s)，4.67(2H，s)，5.46(1H，d，J＝11Hz)，5.88(1H，d，J＝18Hz)，5.93(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，6.73-6.83(1H，dd，J＝11Hz，18Hz)，7.77(1H，m)，8.51(1H，d，J＝2Hz)，8.71(1H，d，J＝2Hz).
MS(ESI
+)：m/z 394.
Embodiment 304
4-[4-[5-(1-vinyl ethyl ether base)-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] methyl-butyrate
1H NMR(CDCl
3)δ1.26(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.67-1.82(2H，m)，2.22(2H，t，J＝7Hz)，2.53-2.67(2H，m)，3.04(2H，q，J＝7Hz)，3.47(3H，s)，3.58(3H，s)，3.95(2H，q，J＝7Hz)，4.34(1H，d，J＝2Hz)，4.67(2H，s)，4.77(1H，d，J＝2Hz)，5.93(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，7.92(1H，m)，8.54(1H，d，J＝2Hz)，8.95(1H，d，J＝2Hz).
MS(ESI
+)：m/z 438.
Embodiment 305
3-{4-[5-(1-vinyl ethyl ether base)-3-pyridyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } ethyl propionate
1H NMR(CDCl
3)δ1.19(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.44(3H，t，J＝7Hz)，2.33-2.43(2H，m)，2.58(3H，s)，2.76-2.87(2H，m)，3.03(2H，q，J＝7Hz)，3.96(2H，q，J＝7Hz)，4.06(2H，q，J＝7Hz)，4.36(1H，d，J＝2Hz)，4.77(1H，d，J＝2Hz)，5.91(1H，d，J＝4Hz)，6.54(1H，d，J＝4Hz)，7.91(1H，m)，8.53(1H，d，J＝2Hz)，8.96(1H，d，J＝2Hz).
MS(ESI
+)：m/z 408.
Following compound is to obtain with embodiment 251 essentially identical modes.
Embodiment 306
4-[4-(5-ethanoyl-3-pyridyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] ethyl butyrate
1H NMR(CDCl
3)δ1.19(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.66-1.82(2H，m)，2.21(2H，t，J＝7Hz)，2.41-2.51(2H，m)，2.60(3H，s)，2.69(3H，s)，3.03(2H，q，J＝7Hz)，4.03(2H，q，J＝7Hz)，5.83(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，8.25(1H，m)，8.79(1H，d，J＝2Hz)，9.25(1H，d，J＝2Hz).
MS(ESI
+)：m/z 394.
Embodiment 307
3-[4-(5-ethanoyl-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(CDCl
3)δ1.18(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，2.41(2H，t，J＝7Hz)，2.70(3H，s)，2.83-2.96(2H，m)，3.06(2H，q，J＝7Hz)，3.47(3H，s)，4.03(2H，q，J＝7Hz)，4.66(2H，s)，5.88(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，8.26(1H，m)，8.79(1H，d，J＝2Hz)，9.25(1H，d，J＝2Hz).
Embodiment 308
4-[4-(5-ethanoyl-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] methyl-butyrate
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.64-1.80(2H，m)，2.20(2H，t，J＝7Hz)，2.53-2.65(2H，m)，2.70(3H，s)，3.05(2H，q，J＝7Hz)，3.47(3H，s)，3.57(3H，s)，4.67(2H，s)，5.87(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，8.27(1H，s)，8.81(1H，d，J＝2Hz)，9.26(1H，d，J＝2Hz).
MS(ESI
+)：m/z 410.
Embodiment 309
3-[4-(5-ethanoyl-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl propionate
1H NMR(CDCl
3)δ1.19(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，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＝7Hz)，4.05(2H，q，J＝7Hz)，5.83(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，8.25(1H，m)，8.78(1H，d，J＝2Hz)，9.26(1H，d，J＝2Hz).
MS(ESI
+)：m/z 380.
Embodiment 310
At room temperature, with 5-[3-(5-oxyethyl group-5-oxo amyl group)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-4-yl also] the mixture of 10% palladium (33mg) in methyl alcohol (10mL) on Pykaryl (330mg) and the carbon stirred 2 hours under 4 normal atmosphere hydrogen atmosphere.The elimination catalyzer also washs with chloroform.Evaporated filtrate obtains also [1,2-b] pyridazine-4-yl of yellow oil 5-[3-(5-oxyethyl group-5-oxo amyl group)-7-ethyl-2-methylpyrrole in a vacuum] nicotinic acid (272mg).5-[3-(5-oxyethyl group-5-oxo amyl group)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-4-yl also] nicotinic acid
1H NMR(CDCl
3)δ1.21(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.35-1.63(4H，m)，2.19(2H，t，J＝7Hz)，2.38-2.49(2H，m)，2.57(3H，s)，3.03(2H，q，J＝7Hz)，4.11(2H，q，J＝7Hz)，5.85(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，8.40(1H，m)，8.831H，d，J＝2Hz)，9.37(1H，d，J＝2Hz).
MS(ESI
-)：m/z 408，MS(ESI
+)：m/z410.
Embodiment 311
To 5-[3-(5-oxyethyl group-5-oxo amyl group)-7-ethyl-2-methylpyrrole also [1; 2-b] pyridazine-4-yl] add diphenyl phosphoryl azide (237mg) in nicotinic acid (235mg) and the solution of triethylamine (87.1mg) in the trimethyl carbinol (10mL), and under refluxing heated mixt 2 hours.After the evaporating solvent, resistates is distributed between ethyl acetate and water.Separate organic layer, use the salt water washing, by dried over mgso, and evaporation in a vacuum.By using hexane and ethyl acetate (20: 1-2: 1) the silica gel column chromatography purification resistates of mixture drip washing, obtain yellow oil 5-(4-{5-[(tert-butoxycarbonyl) amino]-the 3-pyridyl }-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also) Valeric acid ethylester (190mg).
5-(4-{5-[(tert-butoxycarbonyl) amino]-the 3-pyridyl }-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also) Valeric acid ethylester
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，1.37(3H，t，J＝7hz)，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＝7Hz)，4.12(2H，q，J＝7Hz)，5.92(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，6.93(1H，br)，7.87(1H，s)，8.30(1H，d，J＝2Hz)，8.70(1H，d，J＝2Hz).
MS(ESI
+)：m/z 481.
Embodiment 312
At room temperature with 5-(4-{5-[(tert-butoxycarbonyl) amino]-the 3-pyridyl }-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also) solution stirring of Valeric acid ethylester (190mg) in 2N hydrogenchloride ethyl acetate solution (4mL) 2 hours.After the evaporating solvent, resistates is distributed between ethyl acetate and saturated sodium bicarbonate solution.Separate organic layer, use the salt water washing, by dried over mgso, and evaporation in a vacuum.By with chloroform and methyl alcohol (100: 1-20: 1) the silica gel column chromatography purification resistates of mixture drip washing obtains also [1,2-b] pyridazine-3-yl of yellow oil 5-[4-(5-amino-3-pyridyl)-7-ethyl-2-methylpyrrole] Valeric acid ethylester (140mg).
5-[4-(5-amino-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.65(4H，m)，2.23(2H，t，J＝7Hz)，2.45(2H，t，J＝7Hz)，2.54(3H，s)，3.03(2H，q，J＝7Hz)，3.97(2H，br)，4.12(2H，q，J＝7Hz)，5.94(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，7.02(1H，m)，8.02(1H，d，J＝2Hz)，8.17(1H，d，J＝2Hz).
MS(ESI
+)：m/z 381(M+H).
Embodiment 313
To 5-[4-(5-amino-3-pyridyl)-7-ethyl-2-methylpyrrole also [1,2-b] pyridazine-3-yl] add acetate (2) in Valeric acid ethylester (55mg), 37% formaldehyde solution (277mg) and the solution of sodium cyanoborohydride (27.3mg) in acetonitrile (1mL) and methyl alcohol (1mL), and at room temperature stirred the mixture 2 hours.Dilute this solution with saturated sodium bicarbonate solution, and use chloroform extraction.With salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.Preparation silica gel column chromatography purification resistates by with chloroform and methyl alcohol (20: 1) mixture drip washing obtains yellow oil 5-{4-[5-(dimethylamino)-3-pyridyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } Valeric acid ethylester (36.5mg).
5-{4-[5-(dimethylamino)-3-pyridyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.63(4H，m)，2.19(2H，t，J＝7Hz)，2.40-2.53(2H，m)，2.55(3H，s)，3.02(6H，s)，3.03(2H，q，J＝7Hz)，4.09(2H，q，J＝7Hz)，5.93(1H，d，J＝4Hz)，6.50(1H，d，J＝4Hz)，6.96(1H，m)，7.95(1H，d，J＝2Hz)，8.20(1H，d，J＝2Hz).
MS(ESI
+)：m/z 409.
Following compound is to obtain with embodiment 245 essentially identical modes.
Embodiment 314
3-[7-ethyl-4-(5-ethyl-3-pyridyl)-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
1H NMR(CDCl
3)δ1.29(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，2.45-2.58(2H，m)，2.73(2H，q，J＝7Hz)，2.82-3.02(2H，m)，3.03(2H，q，J＝7Hz)，3.47(3H，s)，4.67(2H，s)，5.91(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，7.58(1H，m)，8.43(1H，d，J＝2Hz)，8.53(1H，d，J＝2Hz).
MS(ESI
-)：m/z 366，MS(ESI
+)：m/z 368.
Embodiment 315
4-[7-ethyl-4-(5-ethyl-3-pyridyl)-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
1H NMR(CDCl
3)δ1.31(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.69-1.85(2H，m)，2.20-2.31(2H，m)，2.52-2.75(2H，m)，2.77(2H，q，J＝7Hz)，3.06(2H，q，J＝7Hz)，3.46(3H，s)，4.60-4.80(2H，m)，5.91(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.61(1H，s)，8.44-8.53(2H，m).
MS(ESI
+)：m/z 382.
Following compound is to obtain with embodiment 228 essentially identical modes.
Embodiment 316
4-[4-(5-bromo-3-pyridyl]-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-yl] methyl-butyrate
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.65-1.79(2H，m)，2.25(2H，t，J＝7Hz)，2.39-2.53(2H，m)，3.06(2H，q，J＝7Hz)，3.61(3H，s)，4.90(2H，s)，5.96(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.88(1H，m)，8.55(1H，d，J＝2Hz)，8.79(1H，d，J＝2Hz).
MS(ESI
+)：m/z 432 434.
Embodiment 317
5-[7-ethyl-2-(methylol)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.35-1.60(4H，m)，2.17(2H，t，J＝7Hz)，2.35-2.45(2H，m)，2.43(3H，s)，3.04(2H，q，J＝7Hz)，3.83(1H，t，J＝7Hz)，4.10(2H，q，J＝7Hz)，4.85(2H，d，J＝7Hz)，5.96(1H，d，J＝4Hz)，6.57(1H，d，J＝4Hz)，7.50(1H，s)，8.42(1H，s)，8.54(1H，s).
MS(ESI
+)：m/z 396.
Following compound is to obtain with embodiment 268 essentially identical modes.
Embodiment 318
4-[4-(5-bromo-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] methyl-butyrate
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.65-1.79(2H，m)，2.24(2H，t，J＝7Hz)，2.52-2.70(2H，m)，3.04(2H，q，J＝7Hz)，3.46(3H，s)，3.60(3H，s)，4.76(2H，s)，5.93(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.88(1H，m)，8.56(1H，d，J＝2Hz)，8.79(1H，d，J＝2Hz).
MS(ESI
+)：m/z 446 448.
Embodiment 319
5-[2-[(2-tert.-butoxy-2-oxo oxyethyl group) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.30-1.60(4H，m)，1.47(9H，s)，2.17(2H，t，J＝7Hz)，2.43(3H，s)，2.58-2.72(2H，m)，3.03(2H，q，J＝7Hz)，4.08(2H，s)，4.12(2H，q，J＝7Hz)，4.81(2H，s)，5.91(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.53(1H，s)，8.43(1H，s)，8.53(1H，s).
MS(ESI
+)：m/z 510.
Embodiment 320
The 5-[2-[(cyclo propyl methoxy) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ0.20-0.32(2H，m)，0.53-0.63(2H，m)，1.07-1.20(1H，m)，1.22(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.60(4H，m)，2.15(2H，t，J＝7Hz)，2.43(3H，s)，2.53-2.68(2H，m)，3.02(2H，q，J＝7Hz)，3.41(2H，d，J＝7Hz)，4.08(2H，q，J＝7Hz)，4.70(2H，s)，5.89(1H，d，J＝4Hz)，6.56(1H，d，J＝4Hz)，7.52(1H，s)，8.43(1H，s)，8.53(1H，s).
MS(ESI
+)：m/z 450.
Embodiment 321
5-[2-[(cyclohexyl methoxyl group) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ0.88-1.05(2H，m)，1.16-1.35(4H，m)，1.25(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.38-1.59(4H，m)，1.60-1.87(5H，m)，2.16(2H，t，J＝7Hz)，2.43(3H，s)，2.54-2.67(2H，m)，3.03(2H，q，J＝7Hz)，3.35(2H，d，J＝7Hz)，4.10(2H，q，J＝7Hz)，4.64(2H，s)，5.89(1H，d，J＝4Hz)，6.56(1H，d，J＝4Hz)，7.52(1H，s)，8.43(1H，d，J＝2Hz)，8.53(1H，d，J＝2Hz).
MS(ESI
+)：m/z 492.
Embodiment 322
5-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(3-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.39(3H，t，J＝7Hz)，1.35-1.54(4H，m)，2.12(2H，t，J＝7Hz)，2.43(3H，s)，2.50-2.63(2H，m)，3.03(2H，q，J＝7Hz)，4.08(2H，q，J＝7Hz)，4.66(2H，s)，4.76(2H，s)，5.92(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.28(1H，m)，7.52(1H，s)，7.72(1H，d，J＝8Hz)，8.42(1H，d，J＝2Hz)，8.54(2H，m)，8.62(1H，d，J＝2Hz).
MS(ESI
+)：m/z 487.
Embodiment 323
5-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(2-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
1H NMR(CDCl
3)δ1.21(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.36-1.54(4H，m)，2.12(2H，t，J＝7Hz)，2.42(3H，s)，2.56-2.68(2H，m)，3.03(2H，q，J＝7Hz)，4.08(2H，q，J＝7Hz)，4.77(2H，s)，4.85(2H，s)，5.92(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.22(1H，m)，7.43-7.54(2H，m)，7.66-7.74(1H，m)，8.42(1H，d，J＝2Hz)，8.54(1H，d，J＝2Hz)，8.57(1H，d，J＝5Hz).
MS(ESI
+)：m/z 487.
Embodiment 324
5-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.39(3H，t，J＝7Hz)，1.38-1.57(4H，m)，2.12(2H，t，J＝7Hz)，2.43(3H，s)，2.52-2.68(2H，m)，3.05(2H，q，J＝7Hz)，4.08(2H，q，J＝7Hz)，4.66(2H，s)，4.77(2H，s)，5.93(1H，d，J＝4Hz)，6.60(1H，d，J＝2Hz)，7.28(2H，d，J＝7Hz)，7.52(1H，s)，8.42(1H，d，J＝2Hz)，8.53(1H，d，J＝2Hz)，8.58(2H，d，J＝7Hz).
MS(ESI
+)：m/z 487.
Embodiment 325
5-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(2-pyrazinyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.38-1.57(4H，m)，2.13(2H，t，J＝7Hz)，2.43(3H，s)，2.52-2.68(2H，m)，3.03(2H，q，J＝7Hz)，4.07(2H，q，J＝7Hz)，4.82(2H，s)，4.88(2H，m)，5.92(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.52(1H，s)，8.43(1H，d，J＝2Hz)，8.48-8.57(3H，m)，8.75(1H，m).
MS(ESI
+)：m/z 488.
Embodiment 326
5-[4-(3-cyano-phenyl)-2-(ethoxyl methyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
1H NMR(CDCl
3)δ1.18-1.29(6H，m)，1.34-1.53(7H，m)，2.14(2H，t，J＝7Hz)，2.52(2H，m)，3.02(2H，q，J＝7Hz)，3.53(2H，q，J＝7Hz)，4.07(2H，q，J＝7Hz)，4.66(1H，s)，5.73(1J，d，J＝5Hz)，656(1H，d，J＝5Hz)，7.60(2H，m)，7.67(1H，s)，7.75(1H，m)
Embodiment 327
The 5-[2-[(benzyloxy) methyl]-4-(3-cyano-phenyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] Valeric acid ethylester
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.30-1.46(7H，m)，2.06(2H，t，J＝7Hz)，2.51(2H，m)，3.02(2H，q，J＝7Hz)，4.07(2H，q，J＝7Hz)，4.64(3H，s)，4.72(3H，s)，5.83(1H，d，J＝5Hz)，6.57(1H，d，J＝5Hz)，7.25-7.38(5H，m)，757(2H，d，J＝9Hz)，7.65(1H，s)，7.74(1H，m).
Embodiment 328
4-({ [4-(3-cyano-phenyl)-3-(5-oxyethyl group-5-oxo amyl group)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-2-yl also] methoxyl group } methyl) methyl benzoate
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.32-1.49(7H，m)，2.01(2H，t，J＝7Hz)，2.52(2H，m)，3.02(2H，t，J＝7Hz)，3.92(3H，s)，4.07(2H，t，J＝7Hz)，4.69(2H，s)，4.75(2H，s)，6.84(1H，d，J＝5Hz)，6.59(1H，d，J＝5Hz)，7.43(2H，d，J＝9Hz)，7.60(2H，m)，7.65(1H，s)，7.75(1H，m)，8.02(2H，d，J＝9Hz).
Embodiment 329
At room temperature with 5-[2-[(2-tert.-butoxy-2-oxo oxyethyl group) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] solution stirring of Valeric acid ethylester (60mg) in trifluoroacetic acid (2m L) 2 hours, and evaporation obtains brown oil { [3-(5-oxyethyl group-5-oxo amyl group)-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-2-yl] methoxyl group } acetate (55mg) in a vacuum.
{ [3-(5-oxyethyl group-5-oxo amyl group)-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-2-yl] methoxyl group } acetate
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.35-1.60(4H，m)，2.23(2H，t，J＝7Hz)，2.50-2.58(2H，m)，2.67(3H，s)，3.03(2H，q，J＝7Hz)，4.08(2H，q，J＝7Hz)，4.30(2H，s)，4.87(2H，s)，5.86(1H，d，J＝4Hz)，6.67(1H，d，J＝4Hz)，8.15(1H，s)，8.69(1H，s)，8.85(1H，s).
MS(ESI
-)：m/z 452，MS(ESI
+)：m/z 454.
Embodiment 330
To { [3-(5-oxyethyl group-5-oxo amyl group)-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-2-yl] methoxyl group } add morpholine (12.7mg) in acetate (55mg), 1-ethyl-3-(3 '-dimethylamino-propyl) carbodiimide hydrochloride (34.9mg) and the solution of I-hydroxybenzotriazole (24.6mg) in dimethyl formamide (2mL), and at room temperature stirred the mixture 1 hour.Mixture is distributed between ethyl acetate and water.Separate organic layer, with saturated sodium bicarbonate solution, water and salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.By using ethyl acetate and methyl alcohol (50: 1-20: 1) the silica gel column chromatography purification resistates of mixture drip washing, obtain yellow oil 5-(7-ethyl-4-(5-methyl-3-pyridyl)-2-{[2-(4-morpholinyl)-2-oxo oxyethyl group] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) Valeric acid ethylester (50mg).
5-(7-ethyl-4-(5-methyl-3-pyridyl)-2-{[2-(4-morpholinyl)-2-oxo oxyethyl group] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) Valeric acid ethylester
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.63(4H，m)，2.15(2H，t，J＝7Hz)，2.43(3H，s)，2.54-2.68(2H，m)，3.02(2H，q，J＝7Hz)，3.48-3.57(2H，m)，3.63-3.78(6H，m)，4.08(2H，q，J＝7Hz)，4.30(2H，s)，4.78(2H，s)，5.93(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.52(1H，s)，8.43(1H，d，J＝2Hz)，8.54(1H，d，J＝2Hz).
MS(ESI
+)：m/z 523.
Following compound is to obtain with embodiment 330 essentially identical modes.
Embodiment 331
5-[7-ethyl-2-{[2-(methylamino)-2-oxo oxyethyl group] methyl }-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.38-1.62(4H，m)，2.18(2H，t，J＝7Hz)，2.44(3H，s)，2.48-2.62(2H，m)，2.88(3H，d，J＝7Hz)，3.03(2H，q，J＝7Hz)，4.11(2H，q，J＝7Hz)，4.13(2H，s)，4.77(2H，s)，5.94(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，6.79(1H，br)，7.53(1H，s)，8.44(1H，s)，8.56(1H，s).
MS(ESI
+)：m/z 467.
Following compound is to obtain with embodiment 271 essentially identical modes.
Embodiment 332
The 5-[2-[(benzylamino) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.30-1.50(2H，m)，1.60-1.85(2H，m)，2.12(2H，t，J＝7Hz)，2.30-2.45(2H，m)，2.42(3H，s)，3.03(2H，q，J＝7Hz)，3.96(2H，s)，3.98(2H，s)，4.08(2H，q，J＝7Hz)，5.87(1H，d，J＝4Hz)，6.54(1H，d，J＝4Hz)，7.27-7.43(5H，m)，7.48(1H，s)，8.38(1H，d，J＝2Hz)，8.53(1H，d，J＝2Hz).
MS(ESI
+)：m/z 485.
Embodiment 333
At room temperature with 5-[7-ethyl-2-(methylol)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester (100mg), 1H-isoindole-1,3 (2H) diketone (44.6mg), diisopropyl azodiformate (76.7mg) and the mixture of triphenyl phosphine (99.5mg) in tetrahydrofuran (THF) (2mL) stirred 1 hour.After the evaporating solvent, by using hexane and ethyl acetate (20: 1-1: 1) the silica gel column chromatography purification resistates of mixture drip washing, obtain yellow oil 5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester (107mg).
5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ0.89(3H，t，J＝7Hz)，1.26(3H，t，J＝7Hz)，1.20-1.40(2H，m)，1.53-1.75(2H，m)，2.24(2H，t，J＝7Hz)，2.44(3H，s)，2.47(2H，q，J＝7Hz)，2.50-2.64(2H，m)，4.12(2H，q，J＝7Hz)，5.10(2H，s)，5.85(1H，d，J＝4Hz)，6.43(1H，d，J＝4Hz)，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.
Embodiment 334
With 5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] heating 2 hours under refluxing of Valeric acid ethylester (107mg) and the mixture of a hydrazine hydrate (51.1mg) in ethanol (2mL).After the evaporating solvent, resistates is distributed between chloroform and saturated sodium bicarbonate solution.Separate organic layer, use the salt water washing, by dried over mgso, and evaporation obtains yellow oil 5-[2-(amino methyl)-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl in a vacuum] Valeric acid ethylester (67.6mg).
5-[2-(amino methyl)-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.38-1.62(4H，m)，2.14(2H，t，J＝7Hz)，2.42(3H，s)，2.38-2.56(2H，m)，3.04(2H，q，J＝7Hz)，4.06(2H，s)，4.08(2H，q，J＝7Hz)，5.90(1H，d，J＝4Hz)，6.55(1H，d，J＝4Hz)，7.51(1H，s)，8.41(1H，s)，8.53(1H，s).
MS(ESI
+)：m/z 395.
Embodiment 335
With 5-[2-(amino methyl)-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester (67.6mg) and the mixture of diacetyl oxide (19.2mg) in methylene dichloride (3mL) at room temperature stirred 1 hour.Solution is diluted with chloroform, with saturated sodium bicarbonate solution and salt water washing, by dried over mgso, and evaporation in a vacuum.By preparation silica gel column chromatography purification resistates with chloroform and methyl alcohol (20: 1) mixture drip washing, obtain yellow oil 5-[2-[(kharophen) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester (70mg).
The 5-[2-[(kharophen) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.40(3H，t，J＝7Hz)，1.40-1.63(4H，m)，2.12(2H，m)，2.15(3H，s)，2.43(3H，s)，2.40-2.53(2H，m)，3.03(2H，q，J＝7Hz)，4.10(2H，q，J＝7Hz)，4.66(2H，m)，5.94(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，6.85(1H，br)，7.50(1H，s)，8.40(1H，d，J＝2Hz)，8.54(1H，d，J＝2Hz).
MS(ESI
+)：m/z 437.
Embodiment 336
Under ice-water cooling, to 5-[2-(amino methyl)-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] add methylsulfonyl chloride (34.8mg) in Valeric acid ethylester (80mg) and the solution of pyridine (1mL) in methylene dichloride (2mL), and at room temperature stirred the mixture 1 hour.Solution is diluted with chloroform, with saturated sodium bicarbonate solution and salt water washing, by dried over mgso, and evaporation in a vacuum.By preparation silica gel column chromatography purification resistates with chloroform and methyl alcohol (20: 1) mixture drip washing; obtain yellow oil 5-(7-ethyl-4-(5-methyl-3-pyridyl)-2-{[(methyl sulphonyl) amino] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) Valeric acid ethylester (62.8mg).
5-(7-ethyl-4-(5-methyl-3-pyridyl)-2-{[(methyl sulphonyl) amino] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.39(3H，t，J＝7Hz)，1.40-1.62(4H，m)，2.19(2H，t，J＝7Hz)，2.44(3H，s)，2.38-2.51(2H，m)，3.02(2H，q，J＝7Hz)，3.06(3H，s)，4.08(2H，q，J＝7Hz)，4.58(2H，s)，5.63(1H，br)，5.97(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.50(1H，s)，8.41(1H，d，J＝2Hz)，8.54(1H，d，J＝2Hz).
MS(ESI
+)：m/z 473.
Embodiment 337
At room temperature with 5-[2-(amino methyl)-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester (75mg), phenylformic acid (27.9mg), 1-ethyl-3-(3 '-dimethylamino-propyl) carbodiimide hydrochloride (54.7mg) and the mixture of I-hydroxybenzotriazole (38.5mg) in dimethyl formamide (2mL) stirred 2 hours.Mixture is distributed between ethyl acetate and water.Separate organic layer, with saturated sodium bicarbonate solution, water and salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.By preparation silica gel column chromatography purification resistates with chloroform and methyl alcohol (20: 1) mixture drip washing; obtain yellow oil 5-[2-[(benzoyl-amido) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester (60mg).
The 5-[2-[(benzoyl-amido) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.42(3H，t，J＝7Hz)，1.42-1.65(4H，m)，2.17(2H，t，J＝7Hz)，2.44(3H，s)，2.44-2.58(2H，m)，3.06(2H，q，J＝7Hz)，4.08(2H，q，J＝7Hz)，4.86(2H，m)，5.96(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.46-7.59(4H，m)，7.78(1H，br)，7.91-7.97(2H，m)，8.44(1H，d，J＝2Hz)，8.56(1H，d，J＝2Hz).
MS(ESI
+)：m/z 499.
Following compound is to obtain with embodiment 337 essentially identical modes.
Embodiment 338
5-(7-ethyl-4-(5-methyl-3-pyridyl)-2-[[(2-pyrazine carbonyl) amino] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.41(3H，t，J＝7Hz)，1.42-1.64(4H，m)，2.18(2H，t，J＝7Hz)，2.44(3H，s)，2.47-2.59(2H，m)，3.08(2H，q，J＝7Hz)，4.09(2H，q，J＝7Hz)，4.89(2H，d，J＝7Hz)，5.96(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.53(1H，s)，8.43(1H，d，J＝2Hz)，8.55(1H，d，J＝2Hz)，8.62(1H，m)，8.79(1H，m)，9.15(1H，br)，9.46(1H，m).
MS(ESI
+)：m/z 501.
Embodiment 339
Under ice-water cooling, to 5-[2-(amino methyl)-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] add methyl-chlorocarbonate (34.8mg) in Valeric acid ethylester (80mg) and the solution of pyridine (1mL) in methylene dichloride (2mL), and at room temperature stirred the mixture 2 hours.After the evaporating solvent, resistates is distributed between ethyl acetate and water.Separate organic layer, with saturated sodium bicarbonate solution and salt water washing, by dried over mgso, and evaporation in a vacuum.By preparation silica gel column chromatography purification resistates with chloroform and methyl alcohol (20: 1) mixture drip washing, obtain yellow oil 5-[7-ethyl-2-{[(methoxycarbonyl) amino] methyl }-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester (70mg).
5-[7-ethyl-2-{[(methoxycarbonyl) amino] methyl }-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.39(3H，t，J＝7Hz)，1.40-1.63(4H，m)，2.19(2H，t，J＝7Hz)，2.44(3H，s)，2.40-2.55(2H，m)，3.03(2H，q，J＝7Hz)，3.07(3H，s)，4.12(2H，q，J＝7Hz)，4.57(2H，m)，5.72(1H，br)，5.97(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.51(1H，s)，8.41(1H，s)，8.56(1H，s).
Embodiment 340
In ice bath to 5-[4-(3-cyano-phenyl)-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-yl] add methylsulfonyl chloride (20.9mg) in Valeric acid ethylester (70.0mg) and the solution of triethylamine (18.5mg) in methylene dichloride (1mL).After stirring 1 hour, in mixture, add 1-methylpiperazine (27.0mg).Mixture was stirred in ice bath 0.5 hour and at room temperature stir and spend the night.Mixture is distributed between ethyl acetate and water.With salt water washing organic layer, by dried over mgso, and evaporation.Preparation silica gel thin-layer chromatography (chloroform-methanol=20-1) obtain yellow glue 5-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(4-methyl isophthalic acid-piperazinyl) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester (52.4mg, 63.5%).
5-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(4-methyl isophthalic acid-piperazinyl) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
1H NMR(CDCl
3)：1.23(3H，t，J＝7Hz)，1.33-1.60(7H，m)，2.16(2H，t，J＝7Hz)，2.29(3H，s)，2.34-2.65(6H，m)，3.00(2H，q，J＝7Hz)，3.54(2H，s)，4.08(2H，q，J＝7Hz)，5.86(1H，d，J＝5Hz)，6.55(1H，d，J＝5Hz9，7.87(1H，m)，8.54(1H，m)，8.77(1H，m).
Embodiment 341
Through 40 fens clockwise 5-[4-(3-cyano-phenyl)-7-ethyl-2-(methylol) pyrrolo-es [1,2-b] pyridazine-3-yl] Valeric acid ethylester (300mg, 0.652mmol) and tetrabromomethane (432mg, 1.30mmol) add in the solution in tetrahydrofuran (THF) (3mL) triphenylphosphine (308mg, 1.17mmol).Mixture is concentrated, and it is last with the resistates chromatographic separation at flash distillation silica gel column chromatography (ethyl acetate-hexane=1-8 is to 1-5), obtain also [1,2-b] pyridazine-3-yl of yellow glue 5-[2-(brooethyl)-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-] Valeric acid ethylester (229mg, 50.4%).
5-[2-(brooethyl)-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.41-1.50(4H，m)，2.19(2H，t，J＝7Hz)，2.58(2H，m)，3.01(2H，q，J＝7Hz)，4.08(2H，q，J＝7Hz)，4.66(2H，s)，5.94(1H，d，J＝5Hz)，6.63(1H，d，J＝5Hz)，7.88(1H，m)，8.55(1H，m)，8.79(1H，m).
Embodiment 342
At room temperature with 5-[2-(brooethyl)-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] Valeric acid ethylester (70.0mg) and potassium cyanide (13.1mg) are at N, and the mixture in the dinethylformamide (1mL) stirred 28 hours.Mixture is distributed between ethyl acetate and water.Wash organic layer (twice) with water, with salt water washing organic layer, by dried over mgso, and evaporation obtains yellow glue 5-[4-(5-bromo-3-pyridyl)-2-(cyano methyl)-7-N-ethyl pyrrole N-also [1,2-b] pyridazine-3-yl] Valeric acid ethylester (28.8mg, 45.9%).
5-[4-(5-bromo-3-pyridyl)-2-(cyano methyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，1.46-1.65(7H，m)，2.22(2H，t，J＝7Hz)，2.48(2H，m)，3.04(2H，q，J＝7Hz)，3.98(2H，s)，4.10(2H，q，J＝7Hz)，5.98(1H，d，J＝5Hz)，6.65(1H，d，J＝5Hz)，7.88(1H，m)，8.55(1H，m)，8.81(1H，m).
Following compound is to obtain with embodiment 76 essentially identical modes.
Embodiment 343
[7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] acetate
1H NMR(CDCl
3)δ1.36(3H，t，J＝7Hz)，2.45(3H，s)，2.56(3H，s)，3.02(2H，q，J＝7Hz)，3.28(1H，d，J＝17Hz)，3.53(1H，d，J＝17Hz)，5.91(1H，d，J＝4Hz)，6.52(1H，d，J＝4Hz)，7.71(1H，s)，8.47(1H，s)，8.59(1H，s).
MS(ESI
-)：m/z 308，MS(ESI
+)：m/z 310.
Embodiment 344
4-[4-(5-bromo-3-pyridyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] butyric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.65-1.85(2H，m)，2.31(2H，t，J＝7Hz)，2.45-2.63(2H，m)，2.59(3H，s)，3.03(2H，q，J＝7Hz)，5.88(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，7.90(1H，s)，8.53(1H，s)，8.75(1H，s).
MS(ESI
-)：m/z 400 402，MS(ESI
+)：m/z 402 404.
Embodiment 345
4-[4-(5-ethanoyl-3-pyridyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] butyric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.68-1.82(2H，m)，2.26(2H，t，J＝7Hz)，2.45-2.58(2H，m)，2.60(3H，s)，2.70(3H，s)，3.03(2H，q，J＝7Hz)，5.83(1H，d，J＝4Hz)，6.54(1H，d，J＝4Hz)，8.28(1H，m)，8.77(1H，d，J＝2Hz)，9.19(1H，d，J＝2Hz).
Embodiment 346
3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，2.49(2H，t，J＝7Hz)，2.80-3.00(2H，m)，3.05(2H，q，J＝7Hz)，3.46(3H，s)，4.66(2H，s)，5.94(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.88(1H，s)，8.55(1H，s)，8.77(1H，s).
MS(ESI
-)：m/z 416 418，MS(ESI
+)：m/z 418 420.
Embodiment 347
3-[4-(5-ethanoyl-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，2.48(2H，t，J＝7Hz)，2.68(3H，s)，2.85-2.97(2H，m)，3.05(2H，q，J＝7Hz)，3.47(3H，s)，4.67(2H，s)，5.88(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，8.27(1H，m)，8.78(1H，d，J＝2Hz)，9.23(1H，d，J＝2Hz).
MS(ESI
-)：m/z 380，MS(ESI
+)：m/z 382.
Embodiment 348
3-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，2.46-2.58(2H，m)，2.83-3.03(2H，m)，3.05(2H，q，J＝7Hz)，3.47(3H，s)，4.68(2H，s)，5.46(1H，d，J＝11Hz)，5.88(1H，d，J＝18Hz)，5.93(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，6.68-6.82(1H，dd，J＝11Hz，18Hz)，7.78(1H，m)，8.47(1H，d，J＝2Hz)，8.68(1H，d，J＝2Hz).
MS(ESI
-)：m/z 364，MS(ESI
+)：m/z 366.
Embodiment 349
4-[4-(5-bromo-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.68-1.82(2H，m)，2.29(2H，t，J＝7Hz)，2.55-2.75(2H，m)，3.04(2H，q，J＝7Hz)，3.45(3H，s)，4.64(2H，s)，5.93(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.91(1H，m)，8.56(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
MS(ESI
-)：m/z 430 432，MS(ESI
+)：m/z 432 434.
Embodiment 350
4-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.72-1.87(2H，m)，2.26(2H，t，J＝7Hz)，2.53-2.80(2H，m)，3.06(2H，q，J＝7Hz)，3.46(3H，s)，4.68(2H，m)，5.47(1H，d，J＝11Hz)，5.88(1H，d，J＝18Hz)，5.93(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，6.72-6.83(1H，dd，J＝11Hz，18Hz)，7.81(1H，m)，8.50(1H，d，J＝2Hz)，8.63(1H，d，J＝2Hz).
MS(ESI
-)：m/z 378，MS(ESI
+)：m/z 380.
Embodiment 351
4-[4-(5-ethanoyl-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.66-1.83(2H，m)，2.26(2H，t，J＝7Hz)，2.55-2.70(2H，m)，2.70(3H，s)，3.05(2H，q，J＝7Hz)，3.46(3H，s)，4.67(2H，s)，5.88(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，8.29(1H，m)，8.80(1H，d，J＝2Hz)，9.22(1H，d，J＝2Hz).
MS(ESI
-)：m/z 394，MS(ESI
+)：m/z 396.
Embodiment 352
5-[4-(5-amino-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
1H NMR(CDCl
3)δ1.34(3H，t，J＝7Hz)，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＝7Hz)，5.06(2H，br)，5.86(1H，d，J＝4Hz)，5.98(1H，d，J＝4Hz)，7.45(1H，s)，7.84(1H，s)，8.58(1H，s).
MS(ESI
-)：m/z 351，MS(ES
+)：m/z 353.
Embodiment 353
5-{4-[5-(dimethylamino)-3-pyridyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } valeric acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，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＝7Hz)，3.06(6H，s)，5.88(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，7.13(1H，s)，7.90(1H，s)，8.14(1H，m).
MS(ESI
+)：m/z 381.
Embodiment 354
3-[4-(5-ethanoyl-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] propionic acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，2.40-2.53(2H，m)，2.60(3H，s)，2.68(3H，s)，2.83(2H，t，J＝7Hz)，3.03(2H，q，J＝7Hz)，5.83(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，8.27(1H，m)，8.78(1H，d，J＝2Hz)，9.22(1H，d，J＝2Hz).
MS(ESI
-)：m/z 350，MS(ESI
+)：m/z 352.
Embodiment 355
The 5-[2-[(benzyloxy) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(CDCl
3)δ137(3H，t，J＝7Hz)，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＝7Hz)，4.63(2H，s)，4.74(2H，m)，5.88(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.27-7.42(5H，m)，7.53(1H，s)，8.40(1H，s)，8.53(1H，s).
MS(ESI
+)：m/z 458.
Embodiment 356
The 3-[2-[(benzyloxy) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，2.40(3H，s)，2.40-2.54(2H，m)，2.80-3.08(2H，m)，3.06(2H，q，J＝7Hz)，4.65(2H，s)，4.77(2H，m)，5.89(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.26-7.42(5H，m)，7.54(1H，s)，8.39(1H，d，J＝2Hz)，8.48(1H，d，J＝2Hz).
MS(ESI
-)：m/z 428，MS(ESI
+)：m/z 430.
Embodiment 357
The 5-[2-[(cyclohexyloxy) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(CDCl
3)δ1.20-1.45(6H，m)，1.36(3H，t，J＝7Hz)，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＝7Hz)，3.42-3.54(1H，m)，4.72(2H，m)，5.87(1H，d，J＝4Hz)，6.54(1H，d，J＝4Hz)，7.55(1H，s)，8.41(1H，s)，8.53(1H，s).
MS(ESI
-)：m/z 448，MS(ESI
+)：m/z 450.
Embodiment 358
5-{4-(5-bromo-3-pyridyl)-2-[(cyclohexyloxy) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } valeric acid
1H NMR(CDCl
3)δ1.18-1.60(10H，m)，1.36(3H，t，J＝7Hz)，1.70-1.80(2H，m)，1.95-2.05(2H，m)，2.22(2H，t，J＝7Hz)，2.50-2.70(2H，m)，3.03(2H，q，J＝7Hz)，3.42-3.53(1H，m)，4.68(2H，s)，5.89(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.88(1H，s)，8.54(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
MS(ESI
+)：m/z 514 516.
Embodiment 359
The 3-[2-[(cyclohexyloxy) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
1H NMR(CDCl
3)δ1.20-1.45(5H，m)，1.37(3H，t，J＝7Hz)，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＝7Hz)，3.44-3.66(1H，m)，4.73(2H，s)，5.88(1H，d，J＝4Hz)，6.57(1H，d，J＝4Hz)，7.55(1H，s)，8.40(1H，s)，8.51(1H，s).
MS(ESI
+)：m/z 422.
Embodiment 360
3-{4-(5-bromo-3-pyridyl)-2-[(cyclohexyloxy) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } propionic acid
1H NMR(CDCl
3)δ1.18-1.47(5H，m)，1.37(3H，t，J＝7Hz)，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＝7Hz)，3.44-3.57(1H，m)，4.73(2H，s)，5.91(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.88(1H，t，J＝2Hz)，8.55(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
MS(ESI
-)：m/z 484 486，MS(ESI
+)：m/z 486 488.
Embodiment 361
5-[7-ethyl-2-(isopropoxy methyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(CDCl
3)δ1.25(6H，d，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.44-1.63(4H，m)，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＝7Hz)，3.75-3.87(1H，m)，4.67(2H，s)，5.87(1H，d，J＝4Hz)，6.56(1H，d，J＝4Hz)，7.55(1H，s)，8.41(1H，s)，8.53(1H，s).
MS(ESI
-)：m/z 408，MS(ESI
+)：m/z 410.
Embodiment 362
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(isopropoxy methyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(CDCl
3)δ1.25(6H，d，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.45-1.65(4H，m)，2.23(2H，t，J＝7Hz)，2.50-2.60(2H，m)，3.03(2H，q，J＝7Hz)，3.75-3.85(1H，m)，4.66(2H，s)，5.89(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.89(1H，m)，8.54(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
MS(ESI
+)：m/z 474 476.
Embodiment 363
5-[7-ethyl-2-(methylol)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.40-1.65(4H，m)，2.22(2H，t，J＝7Hz)，2.33-2.45(2H，m)，2.43(3H，s)，3.03(2H，q，J＝7Hz)，4.87(2H，s)，5.94(1H，d，J＝4Hz)，6.57(1H，d，J＝4Hz)，7.56(1H，s)，8.43(1H，s)，8.54(1H，s).
MS(ESI
-)：m/z 366，MS(ESI
+)：m/z 368.
Embodiment 364
5-(7-ethyl-4-(5-methyl-3-pyridyl)-2-{[2-(4-morpholinyl)-2-oxo oxyethyl group] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) valeric acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.40-1.63(4H，m)，2.22(2H，t，J＝7Hz)，2.43(3H，s)，2.50-2.72(2H，m)，3.03(2H，q，J＝7Hz)，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＝4Hz)，6.59(1H，d，J＝4Hz)，7.53(1H，s)，8.42(1H，s)，8.53(1H，s).
MS(ESI
-)：m/z 493，MS(ESI
+)：m/z 495.
Embodiment 365
5-[7-ethyl-2-{[2-(methylamino)-2-oxo oxyethyl group] methyl }-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.40-1.65(4H，m)，2.22(2H，t，J＝7Hz)，2.44(3H，s)，2.45-2.64(2H，m)，2.87(3H，m)，3.03(2H，q，J＝7Hz)，4.13(2H，s)，4.74(2H，m)，5.93(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，6.83(1H，br)，7.57(1H，s)，8.42(1H，s)，8.53(1H，s).
MS(ESI
-)：m/z 437，MS(ESI
+)：m/z 439.
Embodiment 366
The 5-[2-[(cyclo propyl methoxy) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(CDCl
3)δ0.23-0.33(2H，m)，0.55-0.64(2H，m)，1.07-1.22(1H，m)，1.36(3H，t，J＝7Hz)，1.45-1.68(4H，m)，2.19(2H，t，J＝7Hz)，2.43(3H，s)，2.50-2.75(2H，m)，3.02(2H，q，J＝7Hz)，3.40(2H，d，J＝7Hz)，4.70(2H，m)，5.87(1H，d，J＝4Hz)，6.56(1H，d，J＝4Hz)，7.57(1H，s)，8.40(1H，s)，8.54(1H，s).
MS(ESI
+)：m/z 422.
Embodiment 367
5-[2-[(cyclohexyl methoxyl group) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(CDCl
3)δ0.87-1.04(2H，m)，1.10-1.82(13H，m)，1.37(3H，t，J＝7Hz)，2.18(2H，t，J＝7Hz)，2.43(3H，s)，2.47-2.72(2H，m)，3.03(2H，q，J＝7Hz)，3.33(2H，d，J＝7Hz)，4.63(2H，m)，5.87(1H，d，J＝4Hz)，6.56(1H，d，J＝4Hz)，7.56(1H，s)，8.42(1H，s)，8.53(1H，s).
MS(ESI
-)：m/z 462，MS(ESI
+)：m/z 464.
Embodiment 368
5-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(3-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.35-1.57(4H，m)，2.13(2H，t，J＝7Hz)，2.42(3H，s)，2.47-2.66(2H，m)，3.03(2H，q，J＝7Hz)，4.68(2H，s)，4.77(2H，m)，5.90(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，7.28-7.36(1H，m)，7.53(1H，s)，7.73(1H，d，J＝8Hz)，8.41(1H，d，J＝2Hz)，8.53(2H，m)，8.63(1H，s).
MS(ESI
-)：m/z 457，MS(ESI
+)：m/z 459.
Embodiment 369
5-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(2-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.45-1.65(4H，m)，2.23(2H，t，J＝7Hz)，2.41(3H，s)，2.48-2.74(2H，m)，3.03(2H，q，J＝7Hz)，4.80(2H，s)，4.82(2H，m)，5.88(1H，d，J＝4Hz)，6.57(1H，d，J＝4Hz)，7.26(1H，m)，7.47-7.53(2H，m)，7.69-7.77(1H，m)，8.42(1H，d，J＝2Hz)，8.50(1H，d，J＝2Hz)，8.58(1H，d，J＝7Hz).
MS(ESI
-)：m/z 457，MS(ESI
+)：m/z 459.
Embodiment 370
5-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.40-1.62(4H，m)，2.16(2H，t，J＝7Hz)，2.43(3H，s)，2.48-2.71(2H，m)，3.02(2H，q，J＝7Hz)，4.68(2H，s)，4.79(2H，m)，5.91(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.32(2H，d，J＝7Hz)，7.54(1H，s)，8.42(1H，d，J＝2Hz)，8.54(1H，d，J＝2Hz)，8.55(2H，d，J＝7Hz).
MS(ESI
-)：m/z 457，MS(ESI
+)：m/z 459.
Embodiment 371
5-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(2-pyrazinyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.45-1.62(4H，m)，2.18(2H，t，J＝7Hz)，2.43(3H，s)，2.48-2.73(2H，m)，3.03(2H，q，J＝7Hz)，4.83(2H，s)，4.88(2H，m)，5.90(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，7.54(1H，s)，8.42(1H，s)，8.48-8.563H，m)，8.76(1H，s).
MS(ESI
-)：m/z 458，MS(ESI
+)：m/z 460.
Embodiment 372
The 5-[2-[(benzylamino) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(DMSO-d
6)δ1.33(3H，t，J＝7Hz)，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＝7Hz)，4.37(2H，s)，4.46(2H，s)，5.92(1H，d，J＝4Hz)，6.68(1H，d，J＝4Hz)，7.40-7.52(3H，m)，7.56-7.67(3H，m)，8.36(1H，d，J＝2Hz)，8.57(1H，d，J＝2Hz).
MS(ESI
+)：m/z 457.
Embodiment 373
The 5-[2-[(kharophen) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(CDCl
3)δ1.40(3H，t，J＝7Hz)，1.40-1.64(4H，m)，2.16(3H，s)，2.23(2H，t，J＝7Hz)，2.35-2.50(2H，m)，2.43(3H，s)，3.03(2H，q，J＝7Hz)，4.63-4.72(2H，m)，5.92(1H，d，J＝4Hz)，6.57(1H，d，J＝4Hz)，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.
Embodiment 374
5-(7-ethyl-4-(5-methyl-3-pyridyl)-2-{[(methyl sulphonyl) amino] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) valeric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.46-1.66(4H，m)，2.23(2H，t，J＝7Hz)，2.44(3H，s)，2.39-2.53(2H，m)，3.03(2H，q，J＝7Hz)，3.05(3H，s)，4.57(2H，s)，5.72(1H，br)，5.96(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.54(1H，s)，8.41(1H，d，J＝2Hz)，8.55(1H，d，J＝2Hz).
MS(ESI
-)：m/z 443，MS(ESI
+)：m/z 445.
Embodiment 375
The 5-[2-[(benzoyl-amido) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(CDCl
3)δ1.42(3H，t，J＝7Hz)，1.50-1.68(4H，m)，2.25(2H，t，J＝7Hz)，2.44(3H，s)，2.40-2.60(2H，m)，3.07(2H，q，J＝7Hz)，4.89(2H，m)，5.95(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.46-7.60(4H，m)，7.83(1H，br)，7.93(2H，d，J＝8Hz)，8.44(1H，d，J＝2Hz)，8.56(1H，d，J＝2Hz).
MS(ESI
-)：m/z 469，MS(ESI
+)：m/z 471.
Embodiment 376
5-(7-ethyl-4-(5-methyl-3-pyridyl)-2-{[(2-pyrazine carbonyl) amino] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) valeric acid
1H NMR(CDCl
3)δ1.41(3H，t，J＝7Hz)，1.51-1.72(4H，m)，2.24(2H，t，J＝7Hz)，2.44(3H，s)，2.45-2.58(2H，m)，3.10(2H，q，J＝7Hz)，4.90(2H，m)，5.94(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，7.55(1H，s)，8.43(1H，s)，8.53(1H，s)，8.62(1H，m)，8.79(1H，d，J＝2Hz)，9.20(1H，br)，9.45(1H，d，J＝2Hz).
MS(ESI
-)：m/z 471，MS(ESI
+)：m/z 473.
Embodiment 377
5-[7-ethyl-2-{[(methoxycarbonyl) amino] methyl }-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.45-1.65(4H，m)，2.23(2H，t，J＝7Hz)，2.40-2.53(2H，m)，2.44(3H，s)，3.02(2H，q，J＝7Hz)，3.05(3H，s)，4.58(2H，s)，5.69(1H，br)，5.96(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.53(1H，s)，8.41(1H，d，J＝2Hz)，8.54(1H，d，J＝2Hz).
Embodiment 378
In 7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1, the 2-b] pyridazine-solution of 3-ethyl formate (682mg) in ethanol (20mL), add potassium hydroxide (5g) solution (10mL), and under refluxing heated mixt 1 hour.Solution is acidified to pH 3-4 and with salt solution dilution with 1N hydrochloric acid, and with twice of chloroform extraction.Separate organic layer, by dried over mgso, and evaporation in a vacuum.Crude product and ethyl acetate are ground, obtain yellow powder 7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-formic acid (590mg).
7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-formic acid
1H NMR(CDCl
3)δ1.39(3H，t，J＝7Hz)，2.44(3H，s)，2.69(3H，s)，3.05(2H，q，J＝7Hz)，6.29(1H，d，J＝4Hz)，6.67(1H，d，J＝4Hz)，7.97(1H，s)，8.41(1H，s)，8.58(1H，s).
MS(ESI
-)m/z 294，MS(ESI
+)：m/z 296.
Following compound is to obtain with embodiment 175 essentially identical modes.
Embodiment 379
5-[4-(3-cyano-phenyl)-2-(ethoxyl methyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] valeric acid
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.34-1.53(7H，m)，2.20(2H，t，J＝7Hz)，2.53(2H，m)，3.03(2H，q，J＝7Hz)，3.62(2H，q，J＝7Hz)，4.66(2H，s)，5.33(1H，d，J＝5Hz)，6.57(1H，d，J＝5Hz)，7.60(2H，m)，7.66(1H，s)，7.74(1H，m)
Embodiment 380
The 5-[2-[(benzyloxy) methyl]-4-(3-cyano-phenyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] valeric acid
1H NMR(CDCl
3)δ1.30-1.46(7H，m)，2.11(2H，t，J＝7Hz)，2.50(2H，m)，3.02(2H，q，J＝7Hz)，4.64(3H，s)，4.71(3H，s)，5.83(1H，d，J＝5Hz)，6.56(1H，d，J＝5Hz)，7.25-7.34(5H，m)，7.57(2H，d，J＝9Hz)，7.65(1H，s)，7.74(1H，m).
MS(ESI
+)：m/z 468(M+H)
Embodiment 381
4-({ [3-(4-carboxybutyl)-4-(3-cyano-phenyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-2-yl also] methoxyl group } methyl) phenylformic acid
1H-NMR(CDCl
3)δ1.05-1.43(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＝8Hz).
MS(ESI
+)：m/z 510(M-H)
Embodiment 381-2
4-([(4-[3-(formamyl) phenyl]-3-(4-carboxybutyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-2-yl also] methoxyl group } methyl) phenylformic acid
1H-NMR(CDCl
3)δ1.20-1.45(7H，m)，2.03(2H，m)，2.52(2H，m)，3.03(2H，q，J＝7Hz)，4.69(2H，s)，4.73(2H，s)，5.36(1H，d，J＝5Hz)，6.57(1H，d，J＝5Hz)，7.39-7.60(4H，m)，7.77(1H，s)，7.93(1H，d，J＝8Hz)，7.98(2H，d，J＝8Hz).
MS(ESI
+)：m/z 528(M-H)
Following compound is to obtain with embodiment 77 essentially identical modes.
Embodiment 382
5-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(4-methyl isophthalic acid-piperazinyl) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
1H NMR(CDCl
3)δ1.34(3H，t，J＝7Hz)，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＝5Hz)，6.56(1H，d，J＝5Hz)，7.87(1H，m)，8.54(1H，m)，8.76(1H，m).
Embodiment 383
5-[4-(5-bromo-3-pyridyl)-2-(cyano methyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] valeric acid
1H NMR(CDCl
3)δ1.35-1.60(7H，m)，2.27(2H，m)，2.46(2H，m)，3.03(2H，q，J＝7Hz)，3.98(2H，s)，3.97(1H，d，J＝5Hz)，6.65(1H，d，J＝5Hz)，7.90(1H，m)，8.54(1H，s，br)，8.79(1H，s，br).
Embodiment 384
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(CDCl
3)δ1.35-1.60(7H，m)，2.22(2H，t，J＝7Hz)，2.38(2H，m)，3.02(2H，q，J＝7Hz)，4.86(2H，s)，5.95(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.88(1H，m)，8.54(1H，s，br)，8.79(1H，s，br).
Embodiment 385
To 7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] add 2-monoethanolamine (17.4mg) in pyridazine-3-formic acid (70mg), 1-ethyl-3-(3 '-dimethylamino-propyl) carbodiimide hydrochloride (68.2mg) and the solution of I-hydroxybenzotriazole (48mg) in dimethyl formamide (2mL), and at room temperature stirred the mixture 1 hour.Mixture is distributed between ethyl acetate and water.Separate organic layer, with saturated sodium bicarbonate solution, water and salt water washing organic layer, by dried over mgso, and evaporation in a vacuum.By using chloroform and methyl alcohol (50: 1-10: 1) the silica gel column chromatography purification resistates of mixture drip washing.Crude product and isopropyl ether are ground, obtain yellow powder 7-ethyl-N-(2-hydroxyethyl)-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-methane amide (47mg).
7-ethyl-N-(2-hydroxyethyl)-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-methane amide
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，2.39(3H，s)，2.57(3H，s)，3.02(2H，q，J＝7Hz)，3.33(2H，m)，3.45(2H，m)，6.03(1H，br)，6.31(1H，d，J＝4Hz)，6.66(1H，d，J＝4Hz)，7.71(1H，s)，8.47(1H，s)，8.58(1H，s).
MS(ESI
-)：m/z 337，MS(ESI
+)：m/z 339.
Following compound is to obtain with embodiment 385 essentially identical modes.
Embodiment 386
N-normal-butyl-7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-methane amide
1H NMR(CDCl
3)δ0.80(3H，t，J＝7Hz)，0.96-1.08(2H，m)，1.08-1.25(2H，m)，1.38(3H，t，J＝7Hz)，2.40(3H，s)，2.56(3H，s)，3.03(2H，q，J＝7Hz)，3.16(2H，m)，5.36(1H，br)，6.31(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.69(1H，s)，8.53(1H，s)，8.62(1H，s).
MS(ESI
+)：m/z 351.
Embodiment 387
3-({ [7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] carbonyl } amino) ethyl propionate
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，138(3H，t，J＝7Hz)，2.21(2H，t，J＝7Hz)，2.40(3H，s)，2.55(3H，s)，3.03(2H，q，J＝7Hz)，3.43(2H，q，J＝7Hz)，4.04(2H，q，J＝7Hz)，6.08(1H，br)，6.30(1H，d，J＝4Hz)，6.65(1H，d，J＝4Hz)，7.67(1H，s)，8.50(1H，d，J＝1Hz)，8.60(1H，d，J＝1Hz).
MS(ESI
+)：m/z 395.
Following compound is to obtain with preparation example 176 essentially identical modes.
Embodiment 388
4-(5-bromo-3-pyridyl)-7-ethyl-2-methyl-3-[3-(4-morpholinyl)-3-oxopropyl] pyrrolo-[1,2-b] pyridazine
1H NMR(CDCl
3)δ：
1H NMR(CDCl
3)δ：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，J＝1Hz)，8.54(1H，d，J＝1Hz)，8.77(1H，d，J＝1Hz)
MS(m/z)457(M
+)，459(M++2)，115(bp)
mp.178-180℃
Embodiment 389
3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also]-the N-methyl propanamide
1H NMR(CDCl
3)δ：
1H NMR(CDCl
3)δ：1.38(3H，t，J＝7Hz)，2.20(2H，t，J＝7Hz)，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＝4Hz)，7.86(1H，t，J＝1Hz)，8.53(1H，d，J＝1Hz)，8.78(1H，d，J＝1Hz)
MS(m/z)401(M
++1)，403(M
++1)，115(bp)
mp.172-174℃
Following compound is to obtain with embodiment 263 essentially identical modes.
Embodiment 390
N-{3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] propionyl } Toluidrin
1H NMR(CDCl
3)δ：1.36(3H，t，J＝7Hz)，2.33-2.45(2H，m)，2.58(3H，s)，2.84-2.95(2H，m)，3.01(2H，q，J＝7Hz)，3.26(3H，s)，5.89(1H，d，J＝4Hz)，6.56(1H，d，J＝4Hz)，7.90(1H，s)，8.50(1H，s)，8.77(1H，s)
MS(m/z)465(M+，bp)，467(M+-2，bp)
mp.196.5-197.5℃
Following compound is to obtain with embodiment 224 essentially identical modes.
Embodiment 391
2-[{3-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] propionyl } (methyl) amino] ethyl sulfonic acid
1H NMR(CDCl
3)δ1.32(3H，t，J＝7Hz)，1.90 2H，m)，2.26(3H，s)，2.57-2.2.78(4H，m)，2.98(2H，q，J＝7Hz)，3.31(2H，m)，6.00(1H，d，J＝5Hz)，6.61(1H，d，J＝5Hz)，7.20-7.52(5H，m).
Following compound is to obtain with preparation example 20 essentially identical modes.
Preparation example 217
2-(isobutoxy ethanoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(300MHz，CDCl
3)δ0.95(6H，d，J＝7Hz)，1.27(3H，t，J＝7Hz)，1.31-1.41(2H，m)，1.46(9H，s)，1.66(2H，tt，J＝7，7Hz)，1.75-1.98(3H，m)，2.31(2H，t，J＝8Hz)，3.26(2H，d，J＝7Hz)，3.56(1H，t，J＝7Hz)，4.06-4.17(4H，m).
Preparation example 218
2-(isobutoxy ethanoyl) hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(300MHz，CDCl
3)δ0.93(6H，d，J＝7Hz)，1.25(3H，t，J＝7Hz)，1.45(9H，s)，1.59-1.69(2H，m)，1.80-1.95(3H，m)，2.32(2H，t，J＝7Hz)，2.25(2H，d，J＝7Hz)，3.57(1H，t，J＝7Hz)，4.10(2H，s)，4.12(2H，q，J＝7Hz).
Following compound is to obtain with preparation example 24 essentially identical modes.
Preparation example 219
2-ethanoyl-2-(the different nicotinoyl of 2-chlorine) hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(CDCl
3)δ1.26(3H，t，J＝7Hz)，1.34(9H，s)，1.60-1.73(2H，m)，2.22-2.32(2H，m)，2.39(2H，t，J＝7Hz)，2.49(3H，s)，4.12(2H，q，J＝7Hz)，7.43(1H，d，J＝5Hz)，7.57(1H，s)，8.50(1H，d，J＝5Hz).
MS(ESI
+)：m/z 412.
Preparation example 220
2-ethanoyl-2-(the different nicotinoyl of 2-chlorine) pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.72-1.84(2H，m)，2.33(2H，t，J＝7Hz)，2.47-2.57(2H，m)，2.58(3H，s)，3.03(2H，q，J＝7Hz)，5.88(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，7.27(1H，m)，7.38(1H，s)，8.53(1H，d，J＝5Hz).
MS(ESI
-)：m/z 356，MS(ESI
+)：m/z 358.
Preparation example 221
2-(2-chloroisonicotinic acid base)-2-(phenyl acetyl) pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，1.35(9H，s)，1.63-1.76(2H，m)，2.22-2.37(4H，m)，3.93(1H，d，J＝17Hz)，4.12(2H，q，J＝7Hz)，4.29(1H，d，J＝17Hz)，7.22(2H，d，J＝8Hz)，7.26-7.36(4H，m)，7.50(1H，s)，8.42(1H，d，J＝5hz).
MS(ESI
+)：m/z 502.
Preparation example 222
2-[2-(2-methoxyl group-2-oxo oxyethyl group) ethyl]-2-[(5-methyl-3-pyridyl) carbonyl]-the 3-ketobutyric acid tert-butyl ester
1H NMR(CDCl
3)δ1.33(9H，s)，2.39(3H，s)，2.47(3H，s)，2.62(2H，t，J＝7Hz)，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 example 223
2-ethanoyl-2-[(5-bromo-3-pyridyl) carbonyl] succsinic acid 1-tertiary butyl 4-ethyl ester
1H NMR(CDCl
3)δ1.27(3H，t，J＝7Hz)，1.41(9H，s)，2.45(3H，s)，3.22(2H，m)，4.12(2H，q，J＝7Hz)，8.22(1H，m)，8.80(1H，m)，8.82(1H，m).
MS(ESI
+)：m/z 428 430.
Preparation example 224
The 2-[(acetoxyl group) ethanoyl]-2-[(5-methyl-3-pyridyl) carbonyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，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＝7Hz)，5.12(1H，d，J＝18Hz)，5.34(1H，d，J＝18Hz)，7.85(1H，s)，8.58(1H，s)，8.78(1H，s).
MS(ESI
+)：m/z 436.
Preparation example 225
The 2-[(acetoxyl group) ethanoyl]-2-[(5-methyl-3-pyridyl) carbonyl] hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，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＝7Hz)，5.13(1H，d，J＝18Hz)，5.40(1H，d，J＝18Hz)，7.86(1H，s)，8.57(1H，s)，8.78(1H，s).
MS(ESI
+)：m/z 450.
Preparation example 226
The 2-[(acetoxyl group) ethanoyl]-2-(3-cyano group benzoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，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＝7Hz)，5.06(1H，d，J＝18Hz)，5.42(1H，d，J＝18Hz)，7.57(1H，t，J＝8Hz)，7.81(1H，d，J＝8Hz)，7.92(1H，d，J＝8Hz)，8.09(1H，s).
Preparation example 227
The 2-[(acetoxyl group) ethanoyl]-2-[(5-bromo-3-pyridyl) carbonyl] hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，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＝7Hz)，5.12(1H，d，J＝17Hz)，5.42(1H，d，J＝17Hz)，8.23(1H，m)，8.81(1H，m)，8.83(1H，m).
Preparation example 228
The 2-[(acetoxyl group) ethanoyl]-2-[(5-bromo-3-pyridyl) carbonyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.37(9H，s)，2.14(3H，s)，2.41-2.51(2H，m)，2.66(2H，t，J＝7Hz)，4.13(2H，q，J＝7Hz)，5.11(1H，d，J＝18Hz)，5.33(1H，d，J＝18Hz)，8.22(1H，m)，8.82(2H，m).
MS(ESI
+)：m/z 500 502.
Preparation example 229
2-[(cyclohexyl methoxyl group) ethanoyl]-2-[(5-methyl-3-pyridyl) carbonyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ0.80-0.98(2H，m)，1.00-1.32(3H，m)，1.23(3H，t，J＝7Hz)，1.38(9H，s)，1.46-1.62(6H，m)，2.39(3H，s)，2.40-2.72(4H，m)，3.19(2H，d，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.31(1H，d，J＝17Hz)，4.39(1H，d，J＝17Hz)，7.88(1H，s)，8.56(1H，s)，8.77(1H，s).
MS(ESI
+)：m/z 490.
Preparation example 230
2-[(5-bromo-3-pyridyl) carbonyl]-2-[(cyclohexyl methoxyl group) ethanoyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ0.78-0.98(2H，m)，1.10-1.33(3H，m)，1.25(3H，t，J＝7Hz)，1.40(9H，s)，1.38-1.83(6H，m)，2.35-2.75(4H，m)，3.22(2H，d，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.25(1H，d，J＝17Hz)，4.37(1H，d，J＝17Hz)，8.22(1H，s)，8.78(1H，s)，8.86(1H，s).
MS(ESI
+)：m/z 554 556.
Preparation example 231
2-[(5-bromo-3-pyridyl) carbonyl]-2-[(cyclohexyl methoxyl group) ethanoyl] hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(CDCl
3)δ0.80-0.97(2H，m)，1.12-1.35(3H，m)，1.25(3H，t，J＝7Hz)，1.39(9H，s)，1.46-1.80(10H，m)，2.22-2.45(2H，m)，3.20(2H，d，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.30(1H，d，J＝17Hz)，4.38(1H，d，J＝17Hz)，8.22(1H，s)，8.78(1H，s)，8.85(1H，s).
MS(ESI
+)：m/z 568 570.
Preparation example 232
The 2-[(cyclo propyl methoxy) ethanoyl]-2-[(5-methyl-3-pyridyl) carbonyl] hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(CDCl
3)δ0.16-0.28(2H，m)，0.48-0.59(2H，m)，0.98-1.12(1H，m)，1.24(3H，t，J＝7Hz)，1.37(9H，s)，1.55-1.80(4H，m)，2.18-2.40(2H，m)，2.39(3H，s)，3.31(2H，m)，4.12(2H，q，J＝7Hz)，4.38(1H，d，J＝17Hz)，4.53(1H，d，J＝17Hz)，7.88(1H，s)，8.55(1H，d，J＝2Hz)，8.75(1H，d，J＝2Hz).
MS(ESI
+)：m/z 462.
Preparation example 233
The 2-[(cyclo propyl methoxy) ethanoyl]-2-[(5-methyl-3-pyridyl) carbonyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ0.15-0.23(2H，m)，0.48-0.56(2H，m)，0.95-1.10(1H，m)，1.24(3H，t，J＝7Hz)，1.39(9H，s)，2.39(3H，s)，2.40-2.68(4H，m)，3.28(2H，m)，4.12(2H，q，J＝7Hz)，4.36(1H，d，J＝17Hz)，4.48(1H，d，J＝17Hz)，7.88(1H，s)，8.55(1H，s)，8.75(1H，s).
MS(ESI
+)：m/z 448.
Preparation example 234
2-[(5-bromo-3-pyridyl) carbonyl]-the 2-[(2-methoxy ethoxy) ethanoyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ1.26(3H，t，J＝7Hz)，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＝7Jz)，4.43(1H，d，J＝17Hz)，458(1H，d，J＝17Hz)，8.22(1H，s)，8.78(1H，s)，8.82(1H，s).
MS(ESI
+)：m/z 516 518.
Preparation example 235
2-[(5-bromo-3-pyridyl) carbonyl]-the 3-ketobutyric acid tert-butyl ester
1H NMR(CDCl
3)δ1.22，1.30(9H，s)，2.22，2.45(3H，s)，7.96，8.13(1H，s)，8.66，8.76-8.80(2H，m).
Preparation example 236
The 2-[(acetoxyl group) ethanoyl]-2-[(5-chloro-3-pyridyl) carbonyl] hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(300MHz，CDCl
3)δ1.25(3H，t，J＝7Hz)，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＝7Hz)，5.11(1H，d，J＝18Hz)，5.38(1H，d，J＝18Hz)，8.07(1H，dd，J＝2Hz)，8.71(1H，d，J＝2Hz)，8.80(1H，d，J＝2Hz).
Preparation example 237
2-[(5-chloro-3-pyridyl) carbonyl]-the 2-[(cyclo propyl methoxy) ethanoyl] pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(300MHz，CDCl
3)δ0.15-0.20(2H，m)，0.49-0.58(2H，m)，0.95-1.04(1H，m)，1.24(3H，t，J＝7Hz)，1.38(9H，s)，1.68(2H，tt，J＝7，7Hz)，2.14-2.33(4H，m)，3.26-3.29(2H，m)，4.07-4.19(4H，m)，4.31(1H，d，J＝17Hz)，4.45(1H，d，J＝17Hz)，8.05(1H，dd，J＝2Hz)，8.68(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
Preparation example 238
2-[(5-chloro-3-pyridyl) carbonyl]-the 2-[(cyclo propyl methoxy) ethanoyl] hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(300MHz，CDCl
3)δ0.14-0.21(2H，m)，0.49-0.55(2H，m)，0.92-1.04(1H，m)，1.25(3H，t，J＝7Hz)，1.39(9H，s)，1.62-1.74(2H，m)，1.82-1.90(2H，m)，2.21-2.33(2H，m)，3.27-3.31(2H，m)，4.12(2H，q，J＝7Hz)，4.34(1H，d，J＝18Hz)，4.46(1H，d，J＝18Hz)，8.07(1H，dd，J＝2，2Hz)，8.68(1H，d，J＝2Hz)，8.80(1H，d，J＝2Hz).
Preparation example 239
2-[(5-bromo-3-pyridyl) carbonyl]-2-(isobutoxy ethanoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(300MHz，CDCl
3)δ0.85(6H，d，J＝7Hz)，1.24(3H，t，J＝7Hz)，1.38(9H，s)，1.67(2H，t，J＝7Hz)，1.75-1.93(3H，m)，2.24-2.33(4H，m)，3.17(2H，d，J＝7Hz)，4.11(2H，q，J＝7Hz)，4.28(1H，d，J＝17Hz)，4.38(1H，d，J＝17Hz)，8.20(1H，dd，J＝2，2Hz)，8.79(1H，d，J＝2Hz)，8.84(1H，d，J＝2Hz).
Preparation example 240
2-[(5-chloro-3-pyridyl) carbonyl]-2-(isobutoxy ethanoyl) pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(300MHz，CDCl
3)δ0.84(6H，d，J＝7Hz)，1.24(3H，t，J＝7Hz)，1.39(9H，s)，1.80(1H，qt，J＝7Hz)，2.34-2.71(4H，m)，3.17(2H，d，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.28(1H，d，J＝18Hz)，4.36(1H，d，J＝18Hz)，8.07(1H，s)，8.69(1H，s)，8.83(1H，s).
Preparation example 241
The 2-[(acetoxyl group) ethanoyl]-2-(3-chlorobenzene formacyl) pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(300MHz，CDCl
3)δ1.24(3H，t，J＝7Hz)，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＝7Hz)，5.11(1H，d，J＝18Hz)，5.35(1H，d，J＝18Hz)，7.38(1H，dd，J＝8，8Hz)，7.53(1H，d，J＝8Hz)，7.60(1H，d，J＝8Hz)，7.79(1H，s).
Preparation example 242
2-[(5-bromo-3-pyridyl) carbonyl]-2-(isobutoxy ethanoyl) hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(300MHz，CDCl
3)δ0.85(6H，d，J＝7Hz)，1.25(3H，t，J＝7Hz)，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＝7Hz)，4.12(2H，q，J＝7Hz)，4.31(1H，d，J＝17Hz)，4.40(1H，d，J＝17Hz)，8.22(1H，dd，J＝2，2Hz)，8.79(1H，d，J＝2Hz)，8.85(1H，d，J＝2Hz).
Preparation example 243
3-(5-bromo-3-pyridyl)-2-[(5-bromo-3-pyridyl) carbonyl]-the 3-oxo propionic acid tert-butyl ester
1H NMR(CDCl
3)δ1.05(9H，s)，7.86(2H，s)，8.46(2H，s)，8.61(2H，s).
MS(ESI
-)：m/z 481 483 485.
Preparation example 244
The 2-[(acetoxyl group) ethanoyl]-2-(3-chlorobenzene formacyl) hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(CDCl
3)δ1.24(3H，t，J＝8Hz)，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＝8Hz)，5.13(1H，d，J＝18Hz)，5.40(1H，d，J＝18Hz)，7.38(1H，t，J＝8Hz)，7.52(1H，br d，J＝8Hz)，7.60(1H，br d，J＝8Hz)，7.79(1H，br s).
Preparation example 245
2-(methoxyl group ethanoyl)-2-[(5-methoxyl group-3-pyridyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.23(3H，t，J＝8Hz)，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＝8Hz)，4.35(1H，d，J＝18Hz)，4.48(1H，d，J＝18Hz)，7.58(1H，m)，8.43(1H，d，J＝3Hz)，8.50(1H，d，J＝1Hz).
MS(ESI
+)：m/z 452(M+H).
Preparation example 246
2-ethanoyl-2-[(5-methoxyl group-3-pyridyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.24(3H，t，J＝8Hz)，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＝8Hz)，7.61(1H，m)，8.43(1H，d，J＝3Hz)，8.49(1H，d，J＝1Hz).
MS(ESI
+)：m/z 422(M+H).
Preparation example 247
2-(methoxyl group ethanoyl)-2-[(5-methoxyl group-3-pyridyl) carbonyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ1.24(3H，t，J＝8Hz)，1.38(9H，s)，2.36-2.48(2H，m)，2.53-2.67(2H，m)，3.37(3H，s)，3.90(3H，s)，4.11(2H，q，J＝8Hz)，4.33(1H，d，J＝18Hz)，4.45(1H，d，J＝18Hz)，7.59(1H，m)，8.43(1H，d，J＝3Hz)，8.51(1H，d，J＝1Hz).
MS(ESI
+)：m/z 446(M++Na).
Preparation example 248
2-(methoxyl group ethanoyl)-2-[(5-methoxyl group-3-pyridyl) carbonyl] hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(CDCl
3)δ1.24(3H，t，J＝8Hz)，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＝8Hz)，4.37(1H，d，J＝18Hz)，4.51(1H，d，J＝18Hz)，7.60(1H，m)，8.43(1H，d，J＝3Hz)，8.50(1H，d，J＝1Hz).
MS(ESI+)：m/z 438(M+H).
Preparation example 249
2-(methoxyl group ethanoyl)-2-(5-pyrimidyl carbonyl) pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.24(3H，t，J＝8Hz)，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＝8Hz)，4.20(1H，d，J＝18Hz)，4.33(1H，d，J＝18Hz)，9.01(2H，s)，9.31(1H，s).
MS(ESI
+)：m/z 423(M+H).
Preparation example 250
2-[(5-chloro-3-pyridyl) carbonyl]-2-(methoxyl group ethanoyl) hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(CDCl
3)δ1.26(3H，t，J＝8Hz)，1.39(9H，s)，1.57-1.74(2H，m)，1.78(2H，br t，J＝8Hz)，2.23-2.41(2H，m)，3.38(3H，s)，4.14(2H，q，J＝8Hz)，4.33(1H，d，J＝18Hz)，4.45(1H，d，J＝18Hz)，8.07(1H，m)，8.71(1H，br s)，8.80(1H，br s).
MS(ESI
+)：m/z 442(M+H).
Preparation example 251
2-[(5-chloro-3-pyridyl) carbonyl]-2-(methoxyl group ethanoyl) pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ1.25(3H，t，J＝8Hz)，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＝8Hz)，4.26(1H，d，J＝18Hz)，4.40(1H，d，J＝18Hz)，8.06(1H，br s)，8.70(1H，br s)，8.80(1H，br s).
MS(ESI
+)：m/z 428(M+H).
Preparation example 252
2-[(5-chloro-3-pyridyl) carbonyl]-2-(methoxyl group ethanoyl) pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.24(3H，t，J＝8Hz)，1.31-1.48(11H，m)，1.55-1.75(2H，m)，2.15-2.35(4H，m)，3.36(3H，s)，4.10(2H，q，J＝8Hz)，4.27(1H，d，J＝18Hz)，4.43(1H，d，J＝18Hz)，8.03(1H，t，J＝2Hz)，8.69(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
MS(ESI
+)：m/z 456(M+H).
Preparation example 253
4-(acetoxyl group)-2-[(5-bromo-3-pyridyl) carbonyl]-3-ketobutyric acid methyl esters
1H NMR(CDCl
3)δ2.21(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).
Preparation example 254
2-(2-{2-[2-(acetoxyl group) oxyethyl group] oxyethyl group } ethyl)-2-[(5-methyl-3-pyridyl) carbonyl]-the 3-ketobutyric acid tert-butyl ester
1H-NMR(CDCl
3)δ1.32(9H，s)，2.07(3H，s)，2.38(3H，s)，2.45(3H，s)，2.57(2H，t，J＝7Hz)，3.43(4H，m)，3.57(4H，m)，4.16(2H，m)，7.84(1H，m)，8.53(1H，m)，8.75(1H，m).
Preparation example 255
2-[(5-bromo-3-pyridyl) carbonyl]-2-(methoxyl group ethanoyl) hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(CDCl
3)δ1.26(3H，t，J＝7Hz)，1.39(9H，s)，1.55-1.75(2H，m)，2.23-2.45(4H，m)，3.38(3H，s)，4.12(2H，q，J＝7Hz)，4.34(1H，d，J＝18Hz)，4.47(1H，d，J＝18Hz)，8.22(1H，m)，8.81(1H，d，J＝2Hz)，8.83(1H，d，J＝2Hz).
MS(ESI
+)：m/z 486 488.
Preparation example 256
2-(the different nicotinoyl of 2-chlorine)-ethyl 3-oxobutanoate
1H NMR(CDCl
3)δ0.91-1.00(3H，m)，2.24(1.2H，s)，2.48(1.8H，s)，4.02(1.2H，q，J＝8Hz)，4.10(0.8H，q J＝8Hz)，7.24(0.6H，m)，7.39(0.6H，s)，7.45(0.4H，m)，7.54(1H，s)，8.49(1H，m).
MS(ESI
+)：m/z 298(M+H).
Following compound is to obtain with preparation example 78 essentially identical modes.
Preparation example 257
5-(the different nicotinoyl of 2-chlorine)-6-oxoheptanoate
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.60-1.73(2H，m)，1.98-2.10(2H，m)，2.20(3H，s)，2.35(2H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.37(1H，t，J＝7Hz)，7.67(1H，d，J＝5Hz)，7.77(1H，s)，8.59(1H，d，J＝5Hz).
MS(ESI
+)：m/z 312.
Preparation example 258
4-(the different nicotinoyl of 2-chlorine)-5-oxo ethyl hexanoate
1H NMR(CDCl
3)δ1.26(3H，t，J＝7Hz)，2.21(3H，s)，2.22-2.35(2H，m)，2.36-2.47(2H，m)，4.12(2H，q，J＝7Hz)，4.57(1H，t，J＝7Hz)，7.76(1H，dd，J＝2Hz，5Hz)，7.83(1H，d，J＝2Hz)，8.61(1H，d，J＝5Hz).
MS(ESI
+)：m/z 298.
Preparation example 259
6-(2-chloroisonicotinic acid base)-7-oxo-8-phenyl ethyl octylate
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，1.20-1.38(2H，m)，1.60-1.72(2H，m)，1.95-2.06(2H，m)，2.28(2H，t，J＝7Hz)，3.71(1H，d，J＝17Hz)，3.80(1H，d，J＝17Hz)，4.12(2H，q，J＝7Hz)，4.41(1H，t，J＝7Hz)，7.10(2H，m)，7.20-7.33(4H，m)，7.39(1H，s)，8.42(1H，d，J＝5Hz).
Preparation example 260
(3-[(5-methyl-3-pyridyl) carbonyl]-4-oxo amyl group } the oxygen base) methyl acetate
1H NMR(CDCl
3)δ2.23(3H，s)，2.23-2.40(2H，m)，2.44(3H，s)，3.58(2H，m)，3.71(3H，s)，4.02(2H，s)，4.89(1H，t，J＝7Hz)，8.12(1H，s)，8.64(1H，s)，9.07(1H，s).
MS(ESI
+)：m/z 294.
Preparation example 261
(4-oxo-4-phenyl butoxy) methyl acetate
1H NMR(CDCl
3)δ2.04-2.16(2H，m)，3.15(2H，t，J＝7Hz)，3.64(2H，t，J＝7Hz)，3.73(3H，s)，4.09(2H，s)，7.46(2H，t，J＝8Hz)，7.56(1H，t，J＝8Hz)，7.99(2H，d，J＝8Hz).
MS(ESI
+)：m/z 237.
Following compound is to obtain with preparation example 78 essentially identical modes.
Preparation example 262
3-[(5-bromo-3-pyridyl) carbonyl]-ethyl 4-oxopentanoate
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，2.22(3H，s)，2.97-3.17(2H，m)，4.12(2H，q，J＝7Hz)，4.91(1H，m)，8.41(1H，m)，8.88(1H，m)，9.12(1H，m).
MS(ESI
+)：m/z 328 330.
Preparation example 263
6-(acetoxyl group)-4-[(5-methyl-3-pyridyl) carbonyl]-5-oxo ethyl hexanoate
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，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＝7Hz)，4.69(2H，m)，4.82(1H，t，J＝7Hz)，8.14(1H，s)，8.67(1H，s)，9.07(1H，s).
MS(ESI
+)：m/z 336.
Preparation example 264
7-(acetoxyl group)-5-[(5-methyl-3-pyridyl) carbonyl]-the 6-oxoheptanoate
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.60-1.80(2H，m)，2.02(3H，s)，1.97-2.13(2H，m)，2.35(2H，t，J＝7Hz)，2.45(3H，s)，4.12(2H，q，J＝7Hz)，4.56(1H，t，J＝7Hz)，4.69(1H，d，J＝17Hz)，4.78(1H，d，J＝17Hz)，8.06(1H，s)，8.66(1H，s)，9.00(1H，s).
MS(ESI
+)：m/z 350.
Preparation example 265
8-(acetoxyl group)-6-(3-cyano group benzoyl)-7-oxo ethyl octylate
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，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＝7Hz)，4.12(2H，q，J＝7Hz)，4.49(1H，t，J＝7Hz)，4.68(1H，d，J＝17Hz)，4.75(1H，d，J＝17Hz)，7.66(1H，t，J＝8Hz)，7.88(1H，d，J＝8Hz)，8.16(1H，d，J＝8Hz)，8.26(1H，s).
MS(ESI
-)：m/z 372.
Preparation example 266
7-(acetoxyl group)-5-[(5-bromo-3-pyridyl) carbonyl]-the 6-oxoheptanoate
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.60-1.82(2H，m)，2.04(3H，s)，2.03-2.15(2H，m)，2.35(2H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.51(1H，t，J＝7Hz)，4.70(1H，d，J＝17Hz)，4.75(1H，d，J＝17Hz)，8.39(1H，m)，8.88(1H，s)，9.07(1H，s).
MS(ESI
-)：m/z 414 416，MS(ESI
+)：m/z 414 416.
Preparation example 267
6-(acetoxyl group)-4-[(5-bromo-3-pyridyl) carbonyl]-5-oxo ethyl hexanoate
1H NMR(CDCl
3)δ1.26(3H，t，J＝7Hz)，2.00(3H，s)，2.22-2.36(2H，m)，2.43-2.53(2H，m)，4.13(2H，q，J＝7Hz)，4.70(2H，m)，4.80(1H，t，J＝7Hz)，8.48(1H，s)，8.90(1H，s)，9.19(1H，s).
MS(ESI
+)：m/z 400 402.
Preparation example 268
6-(cyclohexyl methoxyl group)-4-[(5-methyl-3-pyridyl) carbonyl]-5-oxo ethyl hexanoate
1H NMR(CDCl
3)δ0.60-0.82(2H，m)，0.93-1.10(3H，m)，1.12-1.65(6H，m)，1.25(3H，t，J＝7Hz)，2.07-2.17(1H，m)，2.22-2.35(1H，m)，2.42(2H，m)，2.44(3H，s)，3.05-3.23(2H，m)，3.96(2H，s)，4.12(2H，q，J＝7Hz)，4.92(1H，m)，8.16(1H，s)，8.66(1H，s)，9.08(1H，s).
MS(ESI
+)：m/z 390.
Preparation example 269
4-[(5-bromo-3-pyridyl) carbonyl]-6-(cyclohexyl methoxyl group)-5-oxo ethyl hexanoate
1H NMR(CDCl
3)δ0.63-0.84(2H，m)，0.93-1.88(3H，m)，1.25(3H，t，J＝7Hz)，1.35-1.90(6H，m)，2.02-2.14(1H，m)，2.20-2.36(1H，m)，2.44(2H，t，J＝7Hz)，3.04-3.20(2H，m)，3.95(2H，s)，4.13(2H，q，J＝7Hz)，4.85-4.93(1H，m)，8.50(1H，m)，8.88(1H，d，J＝2Hz)，9.20(1H，d，J＝2Hz).
MS(ESI
+)：m/z 454 456.
Preparation example 270
5-[(5-bromo-3-pyridyl) carbonyl]-7-(cyclohexyl methoxyl group)-6-oxoheptanoate
1H NMR(300MHz，CDCl
3)δ0.75-0.86(2H，m)，0.95-1.15(3H，m)，1.24(3H，t，J＝7Hz)，1.40-1.90(10H，m)，2.36(2H，t，J＝7Hz)，3.12(2H，q，J＝7Hz)，3.97(2H，s)，4.12(2H，q，J＝7Hz)，4.71(1H，t，J＝7Hz)，8.41(1H，s)，8.88(1H，s)，9.12(1H，s).
MS(ESI
+)：m/z 468 470.
Preparation example 271
7-(cyclo propyl methoxy)-5-[(5-methyl-3-pyridyl) carbonyl]-the 6-oxoheptanoate
1H NMR(CDCl
3)δ-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＝7Hz)，1.58-2.13(4H，m)，2.32(2H，t，J＝7Hz)，2.44(3H，s)，3.10-3.26(2H，m)，4.02(2H，m)，4.12(2H，q，J＝7Hz)，4.77(1H，t，J＝7Hz)，8.07(1H，s)，8.63(1H，s)，9.03(1H，s).
MS(ESI
+)：m/z 362.
Preparation example 272
6-(cyclo propyl methoxy)-4-[(5-methyl-3-pyridyl) carbonyl]-5-oxo ethyl hexanoate
1H NMR(CDCl
3)δ-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＝7Hz)，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＝17Hz)，4.06(1H，d，J＝17Hz)，4.12(2H，q，J＝7Hz)，4.93(1H，m)，8.12(1H，s)，8.65(1H，s)，9.08(1H，s).
MS(ESI
+)：m/z 348.
Preparation example 273
4-[(5-bromo-3-pyridyl) carbonyl]-6-(2-methoxy ethoxy)-5-oxo ethyl hexanoate
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.90-2.37(2H，m)，2.43(2H，t，J＝7Hz)，3.18(3H，s)，3.16-3.73(4H，m)，4.06(2H，q，J＝7Hz)，4.10-4.24(2H，m)，4.86-4.93(1H，m)，8.51(1H，m)，8.87(1H，d，J＝2Hz)，9.20(1H，d，J＝2Hz).
MS(ESI
-)：m/z 414 416，MS(ESI
+)：m/z 416 418.
Preparation example 274
1-(5-bromo-3-pyridyl)-1, the 3-dimethyl diketone
1H NMR(CDCl
3)δ2.25(3H，s)，6.18(1H，s)，8.31(1H，s)，8.78(1H，s)，8.96(1H，s).
MS(ESI
+)：m/z 242 244.
Preparation example 275
7-(acetoxyl group)-5-[(5-chloro-3-pyridyl) carbonyl]-the 6-oxoheptanoate
1H NMR(300MHz，CDCl
3)δ1.25(3H，t，J＝7Hz)，1.60-1.70(4H，m)，2.04(3H，s)，2.35(2H，t，J＝6Hz)，4.12(2H，q，J＝7Hz)，4.52(1H，t，J＝7Hz)，4.69(1H，d，J＝18Hz)，4.78(1H，d，J＝18Hz)，8.24(1H，s)，8.78(1H，s)，9.05(1H，s).
Preparation example 276
6-[(5-chloro-3-pyridyl) carbonyl]-8-(cyclo propyl methoxy)-7-oxo ethyl octylate
1H NMR(300MHz，CDCl
3)δ-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＝7Hz)，1.29-1.41(2H，m)，1.64(2H，t，J＝7Hz)，1.72-1.84(1H，m)，1.96-2.08(1H，m)，2.28(2H，t，J＝7Hz)，3.12(1H，dd，J＝10,7Hz)，3.21(1H，dd，J＝10,7Hz)，3.97(1H，d，J＝12Hz)，4.05(1H，d，J＝12Hz)，4.11(2H，q，J＝7Hz)，4.70(1H，t，J＝7Hz)，8.26(1H，dd，J＝2,2Hz)，8.77(1H，dd，J＝2Hz)，9.09(1H，dd，J＝2Hz).
Preparation example 277
5-[(5-chloro-3-pyridyl) carbonyl]-7-(cyclo propyl methoxy)-6-oxoheptanoate
1H NMR(300MHz，CDCl
3)δ-0.07-0.09(2H，m)，0.24-0.46(2H，m)，0.68-0.79(1H，m)，1.23(3H，t，J＝7Hz)，1.47-1.84(3H，m)，1.98-2.10(1H，m)，2.33(2H，t，J＝7Hz)，3.12(1H，dd，J＝10，7Hz)，3.21(1H，dd，J＝10，7Hz)，3.97(1H，d，J＝17Hz)，4.06(1H，d，J＝17Hz)，4.10(2H，q，J＝7Hz)，4.73(1H，t，J＝6Hz)，8.27(1H，dd，J＝2,2Hz)，8.77(1H，d，J＝2Hz)，9.10(1H，d，J＝2Hz).
Preparation example 278
6-[(5-bromo-3-pyridyl) carbonyl]-8-isobutoxy-7-oxo ethyl octylate
1H NMR(300MHz，CDCl
3)δ0.72(3H，d，J＝7Hz)，0.77(3H，d，J＝7Hz)，1.24(3H，t，J＝7Hz)，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＝8Hz)，3.10(1H，dd，J＝9，7Hz)，3.14(1H，dd，J＝9,7Hz)，3.98(2H，s)，4.11(2H，q，J＝7Hz)，4.70(1H，t，J＝6Hz)，8.39(1H，dd，J＝2Hz)，8.87(1H，d，J＝2Hz)，9.08(1H，d，J＝2Hz).
Preparation example 279
4-[(5-chloro-3-pyridyl) carbonyl]-6-isobutoxy-5-oxo ethyl hexanoate
1H NMR(300MHz，CDCl
3)δ0.68(3H，d，J＝7Hz)，0.72(3H，d，J＝7Hz)，1.25(3H，t，J＝7Hz)，1.52(1H，qt，J＝7,7Hz)，2.02-2.13(1H，m)，2.20-2.32(1H，m)，2.44(2H，t，J＝7Hz)，3.07(1H，dd，J＝9,7Hz)，3.12(1H，dd，J＝9,7Hz)，3.98(2H，s)，4.14(2H，q，J＝7Hz)，4.90(1H，d，J＝9Hz)，4.92(1H，d，J＝9Hz)，8.34(1H，dd，J＝2Hz)，8.78(1H，d，J＝2Hz)，9.15(1H，d，J＝2Hz).
Preparation example 280
6-(acetoxyl group)-4-(3-chlorobenzene formacyl)-5-oxo ethyl hexanoate
1H NMR(300MHz，CDCl
3)δ1.26(3H，t，J＝7Hz)，1.95(3H，s)，2.20-2.29(2H，m)，2.41-2.47(2H，m)，4.15(2H，q，J＝7Hz)，4.64(1H，d，J＝17Hz)，4.71(1H，d，J＝17Hz)，4.78(1H，t，J＝6Hz)，7.48(1H，dd，J＝8,8Hz)，7.60(1H，d，J＝8Hz)，7.96(1H，d，J＝8Hz)，8.04(1H，s).
Preparation example 281
5-[(5-bromo-3-pyridyl) carbonyl]-7-isobutoxy-6-oxoheptanoate
1H NMR(300MHz，CDCl
3)δ0.72(3H，d，J＝7Hz)，0.77(3H，d，J＝7Hz)，1.23(3H，t，J＝7Hz)，1.61-1.73(3H，m)，1.77-1.88(1H，m)，1.98-2.10(1H，m)，2.33(2H，t，J＝7Hz)，3.10(1H，dd，J＝9,7Hz)，3.15(1H，dd，J＝9,7Hz)，3.99(2H，s)，4.11(2H，q，J＝7Hz)，4.73(1H，t，J＝7Hz)，8.40(1H，dd，J＝2,2Hz)，8.87(1H，d，J＝2Hz)，9.10(1H，d，J＝2Hz).
Preparation example 282
1,3-two (5-bromo-3-pyridyl)-1,3-propanedione
1H NMR(DMSO-d
6)δ7.60(1H，s)，8.78(2H，s)，8.88(2H，s)，9.30(2H，s).
Preparation example 283
7-(acetoxyl group)-5-(3-chlorobenzene formacyl)-6-oxoheptanoate
1H NMR(CDCl
3)δ1.24(3H，t，J＝8Hz)，1.57-1.75(2H，m)，1.90-2.12(5H，m)，2.34(2H，t，J＝8Hz)，4.11(2H，q，J＝8Hz)，4.52(1H，t，J＝8Hz)，4.71(2H，q，J＝8Hz)，4.65(1H，d，J＝16Hz)，4.75(1H，d，J＝16Hz)，7.43(1H，t，J＝8Hz)，7.60(1H，br d，J＝8Hz)，7.84(1H，br d，J＝8Hz)，7.96(1H，br s).
Preparation example 284
8-methoxyl group-6-[(5-methoxyl group-3-pyridyl) carbonyl]-7-oxo ethyl octylate
1H NMR(CDCl
3)δ1.23(3H，t，J＝8Hz)，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＝8Hz)，3.26(3H，s)，3.92(3H，s)，3.98(2H，d，J＝5Hz)，4.10(2H，q，J＝8Hz)，4.67(1H，t，J＝8Hz)，7.71(1H，m)，8.50(1H，d，J＝3Hz)，8.78(1H，br s).
MS(ESI
+)：m/z 352(M+H).
Preparation example 285
6-[(5-methoxyl group-3-pyridyl) carbonyl]-7-oxo ethyl octylate
1H NMR(CDCl
3)δ1.24(3H，t，J＝8Hz)，1.27-1.41(2H，m)，1.60-1.73(2H，m)，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＝8Hz)，4.40(1H，t，J＝8Hz)，7.71(1H，m)，8.51(1H，d，J＝3Hz)，8.78(1H，br s).
Preparation example 286
6-methoxyl group-4-[(5-methoxyl group-3-pyridyl) carbonyl]-5-oxo ethyl hexanoate
1H NMR(CDCl
3)δ1.24(3H，t，J＝8Hz)，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＝16Hz)，4.00(1H，d，J＝16Hz)，4.12(2H，q，J＝8Hz)，4.38(1H，m)，7.83(1H，m)，8.52(1H，d，J＝3Hz)，8.87(1H，d，J＝1Hz).
MS(ESI
+)：m/z 346(M++Na).
Preparation example 287
7-methoxyl group-5-[(5-methoxyl group-3-pyridyl) carbonyl]-the 6-oxoheptanoate
1H NMR(CDCl
3)δ1.23(3H，t，J＝8Hz)，1.54-1.74(2H，m)，1.84(1H，m)，2.02(1H，m)，2.32(2H，d，J＝8Hz)，3.26(3H，s)，3.92(3H，s)，3.99(2H，d，J＝5Hz)，4.10(2H，q，J＝8Hz)，4.70(1H，t，J＝8Hz)，7.71(1H，m)，8.51(1H，d，J＝3Hz)，8.79(1H，br s).
MS(ESI
+)：m/z 338(M+H).
Preparation example 288
8-methoxyl group-7-oxo-6-(5-pyrimidyl carbonyl) ethyl octylate
1H NMR(CDCl
3)δ1.23(3H，t，J＝8Hz)，1.25-1.45(2H，m)，1.55-1.70(2H，m)，1.81(1H，m)，2.03(1H，m)，2.28(2H，t，J＝8Hz)，3.24(3H，s)，3.92(1H，d，J＝18Hz)，4.01(1H，d，J＝18Hz)，4.10(2H，q，J＝8Hz)，9.26(2H，s)，9.40(1H，s).
MS(ESI
+)：m/z 323(M+H).
Preparation example 289
5-[(5-chloro-3-pyridyl) carbonyl]-7-methoxyl group-6-oxoheptanoate
1H NMR(CDCl
3)δ1.24(3H，t，J＝8Hz)，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＝16Hz)，4.01(1H，d，J＝16Hz)，4.11(2H，q，J＝8Hz)，4.68(1H，t，J＝8Hz)，8.23(1H，br s)，8.78(1H，br s)，9.05(1H，br s).
MS(ESI
+)：m/z 342(M+H).
Preparation example 290
4-[(5-chloro-3-pyridyl) carbonyl]-6-methoxyl group-5-oxo ethyl hexanoate
1H NMR(CDCl
3)δ1.25(3H，t，J＝8Hz)，2.09(1H，m)，2.25(1H，m)，2.38-2.49(2H，m)，3.22(3H，s)，3.91(1H，d，J＝18Hz)，4.00(1H，d，J＝18Hz)，4.14(2H，q，J＝8H2)，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 example 291
6-[(5-chloro-3-pyridyl) carbonyl]-8-methoxyl group-7-oxo ethyl octylate
1H NMR(CDCl
3)δ1.23(3H，t，J＝8Hz)，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＝8Hz)，3.25(3H，s)，3.92(1H，d，J＝16Hz)，4.02(1H，d，J＝16Hz)，4.10(2H，q，J＝8Hz)，4.63(1H，t，J＝8Hz)，8.23(1H，br s)，8.78(1H，br s)，9.03(1H，br s).
MS(ESI
+)：m/z 356(M+H).
Preparation example 292
Acetate 2-[2-(3-[(5-methyl-3-pyridyl) carbonyl]-4-oxo amyl group } the oxygen base) oxyethyl group] the ethyl ester trifluoroacetate
1H-NMR(CDCl
3)δ2.06(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＝7Hz)，8.66(1H，m)，8.88(1H，m)，9.31(1H，m).
Preparation example 293
5-[(5-bromo-3-pyridyl) carbonyl]-7-methoxyl group-6-oxoheptanoate
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.56-1.73(2H，m)，1.77-1.92(1H，m)，1.96-2.10(1H，m)，2.32(2H，t，J＝7Hz)，3.25(3H，s)，3.92(1H，d，J＝17Hz)，4.02(1H，d，J＝17Hz)，4.12(2H，q，J＝7Hz)，4.67(1H，t，J＝7Hz)，8.39(1H，m)，8.87(1H，d，J＝2Hz)，9.09(1H，d，J＝2Hz).
MS(ESI
+)：m/z 386 388.
Following compound is to obtain with preparation example 129 and 130 essentially identical modes.
Preparation example 294
3-oxo-4-phenylbutyric acid the tert-butyl ester
1H NMR(CDCl
3)δ1.46(9H，s)，3.37(2H，s)，3.82(2H，s)，7.21(2H，d，J＝8Hz)，7.25-7.37(3H，m).
Preparation example 295
3-oxo-3-phenylpropionic acid the tert-butyl ester
1H NMR(CDCl
3)δ1.43(9H，s)，3.81(2H，s)，7.40-7.52(2H，m)，7.56-7.63(1H，m)，7.94(2H，d，J＝8Hz).
Preparation example 296
4-(cyclohexyl the methoxyl group)-3-ketobutyric acid tert-butyl ester
1H NMR(CDCl
3)δ0.89-1.07(2H，m)，1.13-1.40(3H，m)，1.47(9H，s)，1.60-1.83(6H，m)，3.28(2H，d，J＝7Hz)，3.45(2H，s)，4.06(2H，s).
Preparation example 297
4-(the cyclo propyl methoxy)-3-ketobutyric acid tert-butyl ester
1H NMR(CDCl
3)δ0.20-0.28(2H，m)，0.55-0.64(2H，m)，1.03-1.17(1H，m)，1.47(9H，s)，3.36(2H，d，J＝7Hz)，3.45(2H，s)，4.15(2H，s).
Preparation example 298
4-(2-the methoxy ethoxy)-3-ketobutyric acid tert-butyl ester
1H NMR(CDCl
3)δ1.47(9H，s)，3.38(3H，s)，3.44(2H，s)，3.57(2H，m)，3.70(2H，m)，4.20(2H，s).
Preparation example 299
4-isobutoxy-3-ketobutyric acid the tert-butyl ester
1H NMR(300MHz，CDCl
3)δ0.93(6H，d，J＝7Hz)，1.45(9H，s)，1.91(1H，qt，J＝7，7Hz)，3.26(2H，d，J＝7Hz)，3.45(2H，s)，4.07(2H，s).
Preparation example 300
3-(3-methyl-2-the thienyl)-3-oxo propionic acid tert-butyl ester
1H-NMR(CDCl
3)δ1.47(9H，s)，2.57(3H，s)，3.79(2H，s)，6.96(1H，d，J＝5Hz)，7.44(1H，d，J＝5Hz).
Preparation example 301
3-(5-methyl-3-different _ azoles the base)-3-oxo propionic acid tert-butyl ester
1H-NMR(CDCl
3)δ1.475-1.57(9H，m)，2.49(3H，m)，3.95(2H，s)，6.40(1H，s).
Following compound is to obtain with preparation example 132 essentially identical modes.
Preparation example 302
(2E)-5-(3-cyano group benzoyl)-6-oxo-2-heptenoic acid ethyl ester
1H-NMR(CDCl
3)δ1.28(3H，t，J＝7Hz)，2.20(3H，s)，2.88(2H，m)，4.16(2H，q，J＝7Hz)，4.54(1H，t，J＝7Hz)，5.88(1H，d，J＝16Hz)，6.82(1H，dt，J＝7 and 16Hz)，7.65(1H，t，J＝8Hz)，7.89(1H，d，J＝8Hz)，8.20(1H，d，J＝8Hz)，8.27(1H，s).
MS(ESI
+)：m/z 300.14(M+H)
Preparation example 303
2-[(3-methyl-2-thienyl) carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
1H-NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.35-1.51(11H，m)，1.65(2H，m)，1.96(2H，m)，2.30(2H，t，J＝7Hz)，2.58(3H，s)，3.94(1H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，6.97(1H，d，J＝5Hz)，7.44(1H，d，J＝5Hz).
Preparation example 304
2-[(5-methyl-3-is different _ the azoles base) and carbonyl] pimelic acid 1-tertiary butyl 7-ethyl ester
1H-NMR(CDCl
3)δ11.24(3H，t，J＝7Hz)，1.39(9H，s)，1.67(2H，m)，1.98(2H，m)，2.49(3H，s)，4.10(2H，q，J＝7Hz)，4.26(1H，t，J＝7Hz)，6.37(1H，s).
Following compound is to obtain with preparation example 152 essentially identical modes.
Preparation example 305
7-oxo-7-(2-thienyl) Methylheptanoate
1H-NMR(CDCl
3)δ1.41(2H，m)，1.63-1.82(4H，m)，2.33(2H，t，J＝7Hz)，2.91(2H，t，J＝7Hz)，3.67(3H，s)，1.73(1H，m)，7.62(1H，m)，7.70(1H，m).
Following compound is to obtain with preparation example 153 essentially identical modes.
Preparation example 306
5-methoxyl group nicotinoyl chlorine hydrochloride
Preparation example 307
5-pyrimidine formyl chloride hydrochloride
Preparation example 308
5-chloronicotinoyl chloride hydrochloride
Preparation example 309
2-bromo-4-(chloroformyl) methyl benzoate
Following compound is to obtain with preparation example 159 essentially identical modes.
Preparation example 310
2-(phenyl acetyl) pimelic acid 1-tertiary butyl 7-ethyl ester
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，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＝7Hz)，3.47(1H，t，J＝7Hz)，3.81(2H，s)，4.10(2H，q，J＝7Hz)，7.20(2H，d，J＝8Hz)，7.25-7.37(3H，m).
Preparation example 311
2-[2-(2-methoxyl group-2-oxo oxyethyl group) ethyl]-the 3-ketobutyric acid tert-butyl ester
1H NMR(CDCl
3)δ1.46(9H，s)，2.04-2.23(2H，m)，2.29(3H，s)，3.54(2H，t，J＝7Hz)，3.69(1H，t，J＝7Hz)，3.74(3H，s)，4.04(2H，s).
Preparation example 312
2-benzoyl-4-(2-methoxyl group-2-oxo oxyethyl group) tert-butyl acetate
1H NMR(CDCl
3)δ1.34(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＝7Hz)，7.47(2H，t，J＝8Hz)，7.56(1H，m)，8.01(2H，d，J＝8Hz).
Preparation example 313
The 2-[(acetoxyl group) ethanoyl] hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.48(9H，s)，1.60-1.73(2H，m)，1.82-1.95(2H，m)，2.17(3H，s)，2.32(2H，t，J＝7Hz)，3.43(1H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.72(1H，d，J＝17Hz)，4.83(1H，d，J＝17Hz).
Preparation example 314
2-[(cyclohexyl methoxyl group) ethanoyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ0.85-1.06(2H，m)，1.13-1.34(3H，m)，1.26(3H，t，J＝7Hz)，1.45(9H，s)，1.60-1.85(6H，m)，2.08-2.23(2H，m)，2.36(2H，t，J＝7Hz)，3.27(2H，d，J＝7Hz)，3.67(1H，t，J＝7Hz)，4.10(2H，s)，4.12(2H，q，J＝7Hz).
Preparation example 315
2-[(cyclohexyl methoxyl group) ethanoyl] hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(CDCl
3)δ0.88-1.06(2H，m)，1.12-1.34(3H，m)，1.25(3H，t，J＝7Hz)，1.45(9H，s)，1.54-1.94(10H，m)，2.32(2H，t，J＝7Hz)，3.27(2H，d，J＝7Hz)，3.56(1H，t，J＝7Hz)，4.09(2H，s)，4.11(2H，q，J＝7Hz).
MS(ESI
+)：m/z 385.
Preparation example 316
The 2-[(cyclo propyl methoxy) ethanoyl] hexanodioic acid 1-tertiary butyl 6-ethyl ester
1H NMR(CDCl
3)δ0.22-0.33(2H，m)，0.54-0.64(2H，m)，1.04-1.18(1H，m)，1.25(3H，t，J＝7Hz)，1.45(9H，s)，1.60-1.73(2H，m)，1.83-1.95(2H，m)，2.33(2H，t，J＝7Hz)，3.33(2H，d，J＝7Hz)，3.53(1H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.18(2H，m).
MS(ESI
+)：m/z 343.
Preparation example 317
The 2-[(cyclo propyl methoxy) ethanoyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ0.20-0.35(2H，m)，0.56-0.64(2H，m)，1.04-1.16(1H，m)，1.26(3H，t，J＝7Hz)，1.45(9H，s)，2.12-2.24(2H，m)，2.38(2H，t，J＝7Hz)，3.36(2H，m)，3.65(1H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.19(2H，s).
Preparation example 318
The 2-[(2-methoxy ethoxy) ethanoyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.46(9H，s)，2.10-2.23(2H，m)，2.38(2H，t，J＝7Hz)，3.37(3H，s)，3.60(2H，m)，3.62(1H，t，J＝7Hz)，3.70(2H，m)，4.12(2H，q，J＝7Hz)，4.23(1H，d，J＝17Hz)，4.30(1H，d，J＝17Hz).
MS(ESI
+)：m/z 333.
Preparation example 319
2-(isobutoxy ethanoyl) pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(300MHz，CDCl
3)δ0.93(6H，d，J＝7Hz)，1.26(3H，t，J＝7Hz)，1.45(9H，s)，1.91(1H，qt，J＝7，7Hz)，2.13(2H，m)，2.37(2H，t，J＝7Hz)，3.25(2H，d，J＝7Hz)，3.67(1H，t，J＝7Hz)，4.12(2H，s)，4.13(2H，q，J＝7Hz).
Following compound is to obtain with preparation example 164 essentially identical modes.
Preparation example 320
2-bromo-4-[(5-ethyl-1H-pyrroles-2-yl) carbonyl] methyl benzoate
1H-NMR(CDCl
3)δ1.32(3H，t，J＝7Hz)，2.72(2H，q，J＝7Hz)，3.97(3H，s)，6.10(1H，m)，6.77(1H，m)，7.81(1H，d，J＝8Hz)，7.85(1H，d，J＝8Hz)，8.11(1H，s)，9.32(1H，s，br).
Following compound is to obtain with preparation example 165 essentially identical modes.
Preparation example 321
2-(2-{2-[2-(acetoxyl group) oxyethyl group] oxyethyl group } ethyl)-the 3-ketobutyric acid tert-butyl ester
1H-NMR(CDCl
3)δ1.46(9H，s)，2.00-2.17(5H，m)，2.25(3H，s)，3.45-3.70(10H，m)，4.22(2H，m).
Following compound is to obtain with preparation example 178 essentially identical modes.
Preparation example 322
Isobutoxy acetate
1H NMR(300MHz，CDCl
3)δ0.94(6H，d，J＝7Hz)，1.93(1H，qt，J＝7，7Hz)，3.34(2H，d，J＝7Hz)，4.12(2H，s).
Preparation example 323
Under ice-water cooling, in the suspension of 60%NaH (2.66g) in DMF (20mL), add hydroxy methyl acetate (5.00g), and mixture was stirred 0.5 hour down at 0 ℃.Under ice-water cooling, to wherein adding 2-(2-bromine oxethyl) tetrahydrochysene-2H-pyrans (12.8g), and at room temperature stirred the mixture 2 hours.Mixture is distributed between AcOEt and water.Separate organic layer, MgSO is passed through in water and salt water washing
4Drying, and evaporation in a vacuum.(10: 1-3: 1) the silica gel column chromatography purification resistates of mixture drip washing obtains light yellow oil [2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) oxyethyl group] methyl acetate (4.45g) by using hexane and AcOEt.[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) oxyethyl group] methyl acetate
1HNMR(CDCl
3)δ1.48-1.95(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).
Preparation example 324
Will [2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) oxyethyl group] methyl acetate (1.07g) and the tosic acid pyridine _ (24.6mg) mixture in MeOH (10mL) heated 2 hours under refluxing.After the evaporating solvent, (10: 1-1: 3) the silica gel column chromatography purification resistates of mixture drip washing obtains water white oil (2-hydroxyl-oxethyl) methyl acetate (555mg) by using hexane and AcOEt.
(2-hydroxyl-oxethyl) methyl acetate
1H NMR(CDCl
3)δ3.69(2H，m)，3.76(2H，m)，3.78(3H，s)，4.16(2H，s).
Preparation example 325
Under ice-water cooling, to (2-hydroxyl-oxethyl) methyl acetate (540mg), imidazoles (411mg) and triphenylphosphine (1.37g) at ether (2mL) and CH
3Add iodine (1.43g) in the solution among the CN (1mL), and under 0 ℃, stirred the mixture 2 hours.After the elimination insolubles, filtrate is diluted with AcOEt, use Na
2S0
3MgS0 is passed through in the aqueous solution and salt water washing
4Drying, and evaporation in a vacuum.(20: 1-5: 1) the silica gel column chromatography purification resistates of mixture drip washing obtains water white oil (2-iodine oxyethyl group) methyl acetate (898mg) by using hexane and AcOEt.
(2-iodine oxyethyl group) methyl acetate
1H NMR(CDCl
3)δ3.30(2H，t，J＝7Hz)，3.77(3H，s)，3.84(2H，t，J＝7Hz)，4.17(2H，s).
Preparation example 326
Under ice-water cooling, in the suspension of 60%NaH (1.02g) in THF (50mL), add 4-(acetoxyl group)-3-ketobutyric acid tert-butyl ester (5.00g), and mixture was stirred 0.5 hour down at 0 ℃.To wherein adding 3-iodopropionic acid ethyl ester (5.54g), and under 50 ℃, stirred the mixture 8 hours.Mixture is distributed between AcOEt and water.Separate organic layer, use the salt water washing, pass through MgSO
4Drying, and evaporation in a vacuum.By using hexane and AcOEt (20: 1-3: 1) the silica gel column chromatography purification resistates of mixture drip washing obtains yellow oil 2-[(acetoxyl group) ethanoyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester (4.27g).
The 2-[(acetoxyl group) ethanoyl] pentanedioic acid 1-tertiary butyl 5-ethyl ester
1H NMR(CDCl
3)δ1.26(3H，t，J＝7Hz)，1.46(9H，s)，2.14-2.24(2H，m)，2.17(3H，s)，2.36(2H，t，J＝7Hz)，3.60(1H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.73(1H，d，J＝18Hz)，4.83(1H，d，J＝18Hz).
Preparation example 327
Under frozen water cooling, to 4-thiomorpholine formic acid benzyl ester (4.8g) at methyl alcohol (30mL) and H
2Add oxone (16.2g) in the solution among the O (20mL), and at room temperature stirred the mixture 2 hours.Solution is evaporated in a vacuum, and between EtOAc and water, distribute.Use the EtOAc aqueous layer extracted.The organic layer that water and salt water washing merge passes through MgSO
4Drying, and evaporation in a vacuum.Silica gel column chromatography purification resistates by with hexane and the drip washing of EtOAc mixture obtains colorless solid 4-thiomorpholine formic acid benzyl ester 1,1-dioxide (3.8g).
4-thiomorpholine formic acid benzyl ester 1, the 1-dioxide
1H NMR(300MHz，CDCl
3)δ3.02(4H，br s)，4.01(4H，t，J＝5Hz)，5.16(2H，s)，7.33-7.40(5H，m).
Preparation example 328
Under the frozen water cooling, in the solution of thiomorpholine (2g) in 1N NaOH (11.6mL), add chlorocarbonic acid benzyl ester (1.66mL), and at room temperature stirred the mixture 2 hours.Solution is used 1N HCl neutralization and used the EtOAc extracting twice.The organic layer that water and salt water washing merge passes through MgSO
4Drying, and evaporation in a vacuum.By silica gel column chromatography purification resistates, obtain colorless solid 4-thiomorpholine formic acid benzyl ester (4.8g).
4-thiomorpholine formic acid benzyl ester
1H NMR(300MHz，CDCl
3)δ2.59(4H，br s)，3.77(4H，t，J＝5Hz)，5.14(2H，s)，7.30-7.41(5H，m).
Preparation example 329
At room temperature to 4-thiomorpholine formic acid benzyl ester 1,1-dioxide (3.8g) adds the palladium (380mg) of 10wt% on the gac in methyl alcohol (32mL) and 1 in the solution in 4-two _ alkane (8mL).At H
2Under (3.4 normal atmosphere), at room temperature stirred the mixture 4 hours.Filtering mixt and evaporation in a vacuum obtain colorless solid thiomorpholine 1,1-dioxide (2.22g).Thiomorpholine 1, the 1-dioxide
1H NMR(300MHz，CDCl
3)δ3.03(4H，t，J＝5Hz)，3.33(4H，t，J＝5Hz).
MS(m/z)136(M+H).
Preparation example 330
In bathing, ice-MeOH in [(5-chloro-4-sulfydryl 6-methyl-3-pyridyl) oxygen base] acetate (10g) suspension in methylene dichloride (100mL), adds Et3N (14mL).Below 10 ℃, wherein drip trifluoromethanesulfanhydride anhydride (14.3mL) through 30 fens clockwise.After 2 hours with mixture at CHCl
3And distribute between the water.Use CHCl
3Twice of aqueous layer extracted.The organic layer that merges is passed through MgSO
4Drying, and evaporation obtains brown oil in a vacuum.(silica gel, 100mL) purification resistates obtain light brown oil trifluoromethanesulfonic acid 5-chloro-3-pyridyl ester (15.8g) by the silica gel column chromatography with hexane-EtOAc=15-1 and 10-1 drip washing.
Trifluoromethanesulfonic acid 5-chloro-3-pyridyl ester
1H NMR(300MHz，CDCl
3)δ7.69(1H，dd，J＝4，4Hz)，8.52(1H，d，J＝4Hz)，8.65(1H，d，J＝4Hz).
Preparation example 331
Add Et3N (29.4mL), 1 in ice-water-bath in ethanol (66mL) and DMF (66mL), 3-glyceryl two (diphenylphosphine) (3.48g) and acid chloride (1.9g).Under this temperature to wherein adding trifluoromethanesulfonic acid 5-chloro-3-pyridyl ester (22.1g).Under CO (1 normal atmosphere), under 50 ℃, stirred the mixture 4 hours.Mixture is distributed between EtOAc and water.Use the EtOAc aqueous layer extracted.Wash the organic layer three times of merging with water, pass through MgSO
4Drying, and evaporation in a vacuum.(silica gel, 200mL) purification resistates obtain light brown oil 5-chlorine apellagrin ethyl ester (10.5g) by the silica gel column chromatography with hexane-EtOAc=15-1 and 10-1 drip washing.5-chlorine apellagrin ethyl ester
1H NMR(300MHz，CDCl
3)δ1.42(3H，t，J＝7Hz)，4.43(2H，q，J＝7Hz)，8.28(1H，dd，J＝3，3Hz)，8.74(1H，d，J＝3Hz)，9.09(1H，d，J＝3Hz).
Preparation example 332
At room temperature in 5-chlorine apellagrin ester (10.5g), add 1N NaOH (84.9mL).60 ℃ of following heated mixt 1 hour.With HCl reaction mixture is adjusted to pH 4-5.Filtering-depositing obtains colorless solid 5-chlorine apellagrin (6.9g).
1H NMR(300MHz，DMSO-d
6)δ8.30(1H，dd，J＝3Hz)，8.88(1H，d，J＝3Hz)，9.01(1H，d，J＝3Hz)，13.8(1H，br s).
The 5-chlorine apellagrin
1H NMR(300MHz，DMSO-d
6)δ8.30(1H，dd，J＝3，3Hz)，8.88(1H，d，J＝3Hz)，9.01(1H，d，J＝3Hz)，13.8(1H，br s).
Following compound is to obtain with preparation example 332 essentially identical modes.
Preparation example 333
5-methoxyl group nicotinic acid
1H NMR(DMSO-d
6)δ3.87(3H，s)，7.73(1H，m)，8.48(1H，d，J＝3Hz)，8.65(1H，d，J＝1Hz).
MS(ESI
+)：m/z 154(M+H).
Preparation example 334
The 5-pyrimidinecarboxylic acid
1H NMR(DMSO-d
6)δ9.20(2H，s)，9.37(1H，s).
MS(ESI
+)：m/z 148(M++Na).
Preparation example 335
Under the dry ice-propanone cooling, in the solution of Diisopropylamine (5.41g) in THF (30mL), add 1.5M n-Butyl Lithium hexane solution (35mL), and under-78 ℃, stirred the mixture 10 minutes.Under dry ice-propanone cooling to wherein adding tert.-butyl acetate (5.87g), and under-78 ℃, stirred the mixture 10 minutes, under the dry ice acetone cooling, be added drop-wise to 5-bromo-nicotinic acid (3.00g) and N then, in the solution of N-carbonyl dimidazoles (2.65g) in THF (30mL).Under-78 ℃, stirred the mixture 0.5 hour.With mixture at ethyl acetate and NH
4Distribute between the Cl aqueous solution.Separate organic layer, use NaHCO
3MgSO is passed through in the aqueous solution and salt water washing
4Drying, and evaporation in a vacuum.Resistates and isopropyl ether are ground, obtain colourless powder 3-(5-bromo-3-pyridyl)-3-oxo propionic acid tert-butyl ester (3.71g).
3-(5-bromo-3-the pyridyl)-3-oxo propionic acid tert-butyl ester
Enol form:
1H NMR (CDCl
3) δ 1.54 (9H, s), 5.62 (1H, s), 8.19 (1H, m), 8.72 (1H, d, J=2Hz), 8.86 (1H, d, J=2Hz).
Keto-acid:
1H NMR (CDCl
3) δ 1.44 (9H, s), 3.90 (2H, s), 8.37 (1H, m), 8.86 (1H, d, J=2Hz), 9.03 (1H, d, J=2Hz).
MS(ESI
+)：m/z 300 302.
Preparation example 336
Under nitrogen atmosphere, in ice-water-bath below 10 ℃, in the suspension of NaH in DMF (50mL), add 5-hydroxy niacin methyl esters (10.2g) with hexane wash 3 times in batches.After 30 minutes, to wherein dripping methyl-iodide (4.56mL).Precipitation and mixture occurring is difficult to stir.Add DMF (30mL).After 20 minutes, at room temperature stirred the mixture 3 hours.Make the reaction mixture quenching with MeOH, and concentrate in a vacuum.In resistates, add CHCl
3, saturated NaHCO
3And salt solution.Separate organic layer and use CHCl
3Aqueous layer extracted.The organic layer that merges is passed through MgSO
4Drying, and evaporation in a vacuum.(silica gel, 200mL) purification resistates obtain light brown solid 5-methoxyl group nicotinic acid methyl ester (3.47g) by the flash distillation silica gel chromatography with hexane-AcOEt=5-1 and 3-1 drip washing.
5-methoxyl group nicotinic acid methyl ester
1H NMR(CDCl
3)δ3.91(3H，s)，3.96(3H，s)，7.76(1H，m)，8.47(1H，d，J＝3Hz)，8.83(1H，d，J＝1Hz).
MS(ESI
+)：m/z 168(M+H).
Preparation example 337
In ice bath through 5 fens clockwise 2-bromo-4-[(5-ethyl-1H-pyrroles-2-yls) carbonyl] methyl benzoate (330mg) is at N, adds 60% sodium hydride (58.4mg) in the oil in the solution in the dinethylformamide (5mL).After stirring 1 hour, through 40 minutes portion-wise addition (amino oxygen base) (phenylbenzene) phosphine oxides (340mg).The mixture that stirring obtains in ice bath 1 hour.Make the reaction quenching by adding water (10mL).Mixture is distributed between ethyl acetate and water.Wash organic layer (twice) with water, with salt water washing organic layer, by dried over mgso, and evaporation.Resistates is dissolved in ethyl acetate-hexane (1-5), and in solution, adds silica gel.Filtering mixt, and evaporated filtrate obtains orange/yellow solid 4-[(1-amino-5-ethyl-1H-pyrroles-2-yl) carbonyl]-2-methyl-bromobenzoate (310mg).
4-[(1-amino-5-ethyl-1H-pyrroles-2-yl) carbonyl]-the 2-methyl-bromobenzoate
1H-NMR(CDCl
3)δ1.29(3H，t，J＝7Hz)，2.76(2H，q，J＝7Hz)，3.97(3H，s)，5.73(2H，s，br)，5.93(1H，d，J＝5Hz)，6.62(1H，d，J＝5Hz)，7.73(1H，d，J＝8Hz)，7.84(1H，d，J＝8Hz)，8.02(1H，s).
Preparation example 338
At room temperature in the solution of 2-bromo terephthalic acid dimethyl ester (1.04g) in methyl alcohol (10mL), add 1N sodium hydroxide (5.71mL).After stirring 1.5 hours, make the reaction quenching by adding 1N hydrochloric acid (7mL).Form white crystal.Add water (10mL) with help crystallisation.Collect crystal by filtering, wash with water, and at air drying.Obtain white crystal 3-bromo-4-(methoxycarbonyl) phenylformic acid (532mg).
3-bromo-4-(methoxycarbonyl) phenylformic acid
1H-NMR(DMSO-d
6)δ3.89(3H，s)，7.87(1H，d，J＝8Hz)，8.01(1H，d，J＝8Hz)，8.17(1H，s).
Preparation example 339
With acetate 2-[2-(2-chloroethoxy) oxyethyl group] ethyl ester (6.23g) and sodium iodide (22.2g) mixture in acetone (60mL) refluxed 4 hours.Adding sodium iodide (11.0g) refluxes mixture 4 hours afterwards again.Solvent evaporated, and resistates distributed between EtOAc (50mL) and water (50mL).With 10% Sulfothiorine and salt solution washing water layer, pass through MgSO
4Drying, and evaporation obtains light yellow oil acetate 2-[2-(2-iodine oxyethyl group) oxyethyl group] ethyl ester (9.74g).Acetate 2-[2-(2-iodine oxyethyl group) oxyethyl group] ethyl ester
1H-NMR(CDCl
3)δ2.09(3H，s)，3.27(2H，t，J＝7Hz)，3.65-3.78(8H，m)，4.24(2H，m).
Preparation example 340
At room temperature with 2-[(5-methyl-3-different _ the azoles base) carbonyl] solution stirring of pimelic acid 1-tertiary butyl 7-ethyl ester (126mg) in trifluoroacetic acid (1mL) 1.5 hours.Evaporate volatile matter, and and methylbenzene azeotropic, obtain light orange oil 7-oxyethyl group-2-[(5-methyl-3-different _ the azoles base) carbonyl]-7-oxo enanthic acid (106mg).
7-oxyethyl group-2-[(5-methyl-3-is different _ the azoles base) and carbonyl]-7-oxo enanthic acid
1H-NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，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＝7Hz)，4.47(1H，t，J＝7Hz)，6.40(1H，s).
MS(ESI
+)：m/z 296.22(M-H)and 593.52(2M-H)
Preparation example 341
Under nitrogen atmosphere, in bathing, dry ice-propanone in the suspension of dimethyl sulfone (5.43g) in tetrahydrofuran (THF) (10mL), adds 1.59M n-Butyl Lithium (36.3mL).After stirring 0.5 hour, add the solution of methoxy menthyl acetate (2.00g) in tetrahydrofuran (THF) (5mL).In dry ice-propanone is bathed, stirred the mixture that obtains 2 hours, and be heated room temperature through 2 hours.Mixture is distributed between EtOAc and 4N hydrochloric acid.Make the reaction quenching by the 4N hydrochloric acid (15mL) that adds among the EtOAc.Mixture is distributed between EtOAc (100mL) and salt solution (100mL).With EtOAc (100mL, five times) washing water layer.Merge organic layer, pass through MgSO
4The organic layer that extraction merges, and evaporation.Flash distillation silica gel column chromatography (EtOAc-hexane=50-200 is to 300-100) obtains water white oil 2-(methyl sulphonyl)-1-methoxyl group ethyl ketone (2.24g).
1-methoxyl group-3-(methyl sulphonyl) acetone
1H-NMR(CDCl
3)δ2.99(3H，s)，3.08(2H，s)，3.47(3H，s)，4.19(2H，s).
Following compound is to obtain in mode substantially the same manner as Example 1.
Embodiment 392
4-[3-bromo-4-(methoxycarbonyl) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-ethyl formate also
1H-NMR(CDCl
3)δ0.98(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，2.61(3H，s)，3.04(2H，q，J＝7Hz)，3.98(3H，s)，4.05(2H，q，J＝7Hz)，6.29(1H，d，J＝5Hz)，6.67(1H，d，J＝7Hz)，7.44(1H，d，J＝8Hz)，7.76(1H，s)，7.89(1H，d，J＝8Hz).
Embodiment 393
3-[7-ethyl-2-(methoxymethyl)-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile
1H-NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，2.98(2H，q，J＝7Hz)，3.18(3H，s)，3.45(3H，s)，4.59(2H，s)，6.25(1H，d，J＝5Hz)，6.71(1H，d，J＝5Hz)，7.65(1H，t，J＝8Hz)，7.78(1H，d，J＝8Hz)，7.94(1H，d，J＝8Hz)，7.99(1H，s).
MS(ESI
+)：m/z 370(M+H)
Following compound is to obtain in mode substantially the same manner as Example 16.
Embodiment 394
5-{4-[3-(aminocarboxyl) phenyl]-7-ethyl-2-phenylpyrrole [1,2-b] pyridazine-3-yl also } valeric acid
1H-NMR(CDCl
3)δ1.02(4H，m)，1.28(3H，t，J＝7Hz)，1.70(2H，m)，2.37(2H，m)，2.92(2H，q，J＝7Hz)，5.87(1H，d，J＝5Hz)，6.66(1H，d，J＝5Hz)，7.46-7.67(5H，m)，7.96-8.08(3H，m).
Following compound is to obtain in mode substantially the same manner as Example 21.
Embodiment 395
4-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl butyrate
1H NMR(CDCl
3)δ1.21(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.65-1.78(2H，m)，2.22(2H，t，J＝7Hz)，2.40-2.52(2H，m)，2.58(3H，s)，3.03(2H，q，J＝7Hz)，4.05(2H，q，J＝7Hz)，5.86(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，7.25(1H，d，J＝5Hz)，7.36(1H，s)，8.53(1H，d，J＝5Hz).
MS(ESI
+)：m/z 386.
Embodiment 396
3-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl propionate
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，2.30-2.39(2H，m)，2.57(3H，s)，2.74-2.83(2H，m)，3.03(2H，q，J＝7Hz)，4.12(2H，q，J＝7Hz)，5.88(1H，d，J＝4Hz)，6.55(1H，d，J＝4Hz)，7.24(1H，d，J＝5Hz)，7.35(1H，s)，8.53(1H，d，J＝5Hz).
MS(ESI
+)：m/z 372.
Embodiment 397
5-[2-benzyl-4-(2-chloro-4-pyridyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.30-1.50(4H，m)，2.10(2H，t，J＝7Hz)，2.23-2.35(2H，m)，3.04(2H，q，J＝7Hz)，4.09(2H，q，J＝7Hz)，4.21(2H，s)，5.88(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.14-7.32(7H，m)，8.50(1H，d，J＝5Hz).
Embodiment 398
2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] and oxyethyl group } methyl acetate
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，2.42(3H，s)，2.61(3H，s)，2.78-2.88(2H，m)，3.03(2H，q，J＝7Hz)，3.46-3.57(2H，m)，3.71(3H，s)，3.95(2H，s)，5.87(1H，d，J＝4Hz)，6.52(1H，d，J＝4Hz)，7.54(1H，s)，8.43(1H，d，J＝2Hz)，8.53(1H，d，J＝2Hz).
MS(ESI
+)：m/z 368.
Embodiment 399
[4-(5-bromo-3-pyridyl]-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl acetate
1H NMR(CDCl
3)δ1.26(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，2.51(3H，s)，3.03(2H，q，J＝7Hz)，3.43(2H，s)，4.12(2H，q，J＝7Hz)，5.99(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.94(1H，m)，8.58(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
MS(ESI
+)：m/z 402 404.
Embodiment 400
The 3-[2-[(acetoxyl group) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，2.16(3H，s)，2.32-2.42(2H，m)，2.44(3H，s)，2.77-2.90(2H，m)，3.03(2H，q，J＝7Hz)，4.12(2H，q，J＝7Hz)，5.31(2H，s)，5.96(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.53(1H，s)，8.42(1H，d，J＝2Hz)，8.55(1H，d，J＝2Hz).
MS(ESI
+)：m/z 410.
Embodiment 401
The 4-[2-[(acetoxyl group) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.64-1.78(2H，m)，2.10-2.23(2H，m)，2.17(3H，s)，2.43(3H，s)，2.43-2.58(2H，m)，3.02(2H，q，J＝7Hz)，4.12(2H，q，J＝7Hz)，5.33(2H，s)，5.93(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.53(1H，s)，8.43(1H，s)，8.55(1H，s).
MS(ESI
+)：m/z 424.
Embodiment 402
The 5-[2-[(acetoxyl group) methyl]-4-(3-cyano-phenyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] Valeric acid ethylester
1HNMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.60(4H，m)，2.16(2H，t，J＝7Hz)，2.17(3H，s)，2.40-2.52(2H，m)，3.03(2H，q，J＝7Hz)，4.12(2H，q，J＝7Hz)，5.29(2H，s)，5.88(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.60-7.68(3H，m)，7.75-7.83(1H，m).
MS(ESI
+)：m/z 448.
Embodiment 403
The 4-[2-[(acetoxyl group) methyl]-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] ethyl butyrate
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.65-1.82(2H，m)，2.17(3H，s)，2.21(2H，t，J＝7Hz)，2.45-2.63(2H，m)，3.02(2H，q，J＝7Hz)，4.05(2H，q，J＝7Hz)，5.33(2H，s)，5.95(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.90(1H，m)，8.57(1H，d，J＝2Hz)，8.80(1H，d，J＝2Hz).
MS(ESI
+)：m/z 488 490.
Embodiment 404
The 3-[2-[(acetoxyl group) methyl]-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] ethyl propionate
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，2.16(3H，s)，2.36(2H，t，J＝7Hz)，2.77-2.95(2H，m)，3.02(2H，q，J＝7Hz)，4.06(2H，q，J＝7Hz)，5.31(2H，s)，5.96(1H，d，J＝4Hz)，6.64(1H，d，J＝4Hz)，7.88(1H，s)，8.56(1H，m)，8.80(1H，m).
MS(ESI
+)：m/z 474 476.
Embodiment 405
3-[2-[(cyclohexyl methoxyl group) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(CDCl
3)δ0.88-1.06(2H，m)，1.19(3H，t，J＝7Hz)，1.15-1.36(3H，m)，1.37(3H，t，J＝7Hz)，1.58-1.85(6H，m)，2.42(2H，m)，2.43(3H，s)，2.83-2.97(2H，m)，3.05(2H，q，J＝7Hz)，3.38(2H，d，J＝7Hz)，4.06(2H，q，J＝7Hz)，4.66(2H，s)，5.91(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.52(1H，s)，8.42(1H，d，J＝2Hz)，8.54(1H，d，J＝2Hz).
Embodiment 406
3-{4-(5-bromo-3-pyridyl)-2-[(cyclohexyl methoxyl group) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } ethyl propionate
1H NMR(CDCl
3)δ0.85-1.06(2H，m)，1.20(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.16-1.46(3H，m)，1.55-1.84(6H，m)，2.43(2H，t，J＝7Hz)，2.82-3.00(2H，m)，3.06(2H，q，J＝7Hz)，3.37(2H，d，J＝7Hz)，4.06(2H，q，J＝7Hz)，4.66(2H，s)，5.93(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.87(1H，m)，8.55(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
MS(ESI
+)：m/z 528 530.
Embodiment 407
4-{4-(5-bromo-3-pyridyl)-2-[(cyclohexyl methoxyl group) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } ethyl butyrate
1H NMR(CDCl
3)δ0.87-1.06(2H，m)，1.21(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.16-1.46(3H，m)，1.50-1.85(8H，m)，2.23(2H，t，J＝7Hz)，2.55-2.75(2H，m)，3.04(2H，q，J＝7Hz)，3.38(2H，d，J＝7Hz)，4.08(2H，q，J＝7Hz)，4.67(2H，s)，5.92(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.89(1H，m)，8.56(1H，d，J＝2Hz)，8.79(1H，d，J＝2Hz).
MS(ESI
+)：m/z 542 544.
Embodiment 408
The 4-[2-[(cyclo propyl methoxy) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H NMR(CDCl
3)δ0.22-0.32(2H，m)，0.53-0.65(2H，m)，1.10-1.20(1H，m)，1.19(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.65-1.80(2H，m)，2.14-2.30(2H，m)，2.43(3H，s)，2.57-2.74(2H，m)，3.05(2H，q，J＝7Hz)，3.43(2H，d，J＝7Hz)，4.03(2H，q，J＝7Hz)，4.74(2H，s)，5.90(1H，d，J＝4Hz)，6.57(1H，d，J＝4Hz)，7.53(1H，s)，8.43(1H，s)，8.54(1H，s).
MS(ESI
+)：m/z 436.
Embodiment 409
The 3-[2-[(cyclo propyl methoxy) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(CDCl
3)δ0.22-0.32(2H，m)，0.54-0.63(2H，m)，1.10-1.20(1H，m)，1.21(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，2.40-2.50(2H，m)，2.43(3H，s)，2.86-2.98(2H，m)，3.05(2H，q，J＝7Hz)，3.42(2H，d，J＝7Hz)，4.06(2H，q，J＝7Hz)，4.71(2H，s)，5.92(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.52(1H，s)，8.42(1H，s)，8.54(1H，s).
MS(ESI
+)：m/z 422.
Embodiment 410
3-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-methoxy ethoxy) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } ethyl propionate
1H NMR(CDCl
3)δ1.20(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，2.44(2H，t，J＝7Hz)，2.82-2.98(2H，m)，3.05(2H，q，J＝7Hz)，3.38(3H，s)，358(2H，m)，3.76(2H，m)，4.05(2H，q，J＝7Hz)，4.76(2H，s)，5.93(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.87(1H，m)，8.54(1H，s)，8.79(1H，s).
MS(ESI
+)：m/z 490 492.
Embodiment 411
4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine also
1H NMR(CDCl
3)δ1.39(3H，t，J＝7Hz)，2.54(3H，s)，3.04(2H，q，J＝7Hz)，6.39(1H，s)，6.51(1H，d，J＝4Hz)，6.67(1H，d，J＝4Hz)，8.17(1H，m)，8.76(1H，d，J＝2Hz)，8.86(1H，d，J＝2Hz).
MS(ESI
+)：m/z 316 318.
Embodiment 412
The 4-[2-[(acetoxyl group) methyl]-4-(5-chloro-3-pyridyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] ethyl butyrate
1H NMR(300MHz，CDCl
3)δ1.20(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.70(2H，tt，J＝7，7Hz)，2.17(3H，s)，2.20(2H，t，J＝7Hz)，2.45-2.54(2H，m)，3.02(2H，q，J＝7Hz)，4.04(2H，q，J＝7Hz)，5.33(2H，s)，5.94(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.74(1H，dd，J＝2，2Hz)，8.53(1H，d，J＝2Hz)，8.70(1H，d，J＝2Hz).
Embodiment 413
5-{4-(5-chloro-3-pyridyl)-2-[(cyclo propyl methoxy) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } Valeric acid ethylester
1H NMR(300MHz，CDCl
3)δ0.23-0.26(2H，m)，0.54-0.59(2H，m)，1.07-1.16(1H，m)，1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.41-1.56(4H，m)，2.17(2H，t，J＝7Hz)，2.53-2.64(2H，m)，3.03(2H，q，J＝7Hz)，3.41(2H，d，J＝7Hz)，4.09(2H，q，J＝7Hz)，4.70(2H，s)，5.90(1H，d，J＝5Hz)，6.58(1H，d，J＝5Hz)，7.72(1H，s)，8.51(1H，s)，8.68(1H，s).
Embodiment 414
4-{4-(5-chloro-3-pyridyl)-2-[(cyclo propyl methoxy) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } ethyl butyrate
1H NMR(300MHz，CDCl
3)δ0.24(2H，dt，J＝7，7Hz)，0.56(2H，dt，J＝7，7Hz)，1.07-1.15(1H，m)，1.20(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.72(2H，tt，J＝7，7Hz)，2.21(2H，t，J＝7Hz)，2.55-2.66(2H，m)，3.02(2H，q，J＝7Hz)，3.43(2H，d，J＝7Hz)，4.04(2H，q，J＝7Hz)，4.73(2H，s)，5.91(1H，d，J＝5Hz)，6.59(1H，d，J＝5Hz)，7.74(1H，dd，J＝2，2Hz)，8.52(1H，d，J＝2Hz)，8.68(1H，d，J＝2Hz).
Embodiment 415
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(isobutoxy methyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(300MHz，CDCl
3)δ0.92(6H，d，J＝7Hz)，1.26(3H，t，J＝7Hz)，134(3H，t，J＝7Hz)，1.38-1.56(4H，m)，1.92(1H，qt，J＝7，7Hz)，2.15(2H，t，J＝7Hz)，2.51-2.63(2H，m)，3.03(2H，q，J＝7Hz)，3.33(2H，d，J＝7Hz)，4.09(2H，q， J＝7Hz)，4.65(2H，s)，5.90(1H，d，J＝7Hz)，6.59(1H，d，J＝7Hz)，7.88(1H，dd，J＝2，2Hz)，8.55(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
Embodiment 416
3-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(isobutoxy methyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(300MHz，CDCl
3)δ0.92(6H，d，J＝7Hz)，1.19(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.91(1H，qt，J＝7，7Hz)，2.41(2H，t，J＝8Hz)，2.84-2.94(2H，m)，3.03(2H，q，J＝7Hz)，3.35(2H，d，J＝7H)，4.05(2H，q，J＝7Hz)，4.68(2H，s)，5.92(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.72(1H，dd，J＝2，2Hz)，8.51(1H，d，J＝2Hz)，8.69(1H，d，J＝2Hz).
Embodiment 417
The 3-[2-[(acetoxyl group) methyl]-4-(3-chloro-phenyl-)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] ethyl propionate
1H NMR(300MHz，CDCl
3)δ1.19(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，2.15(3H，s)，2.33(2H，t，J＝8Hz)，2.82(2H，t，J＝8Hz)，3.02(2H，q，J＝7Hz)，4.06(2H，q，J＝7Hz)，5.31(2H，s)，5.97(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.23-7.26(1H，m)，7.37(1H，s)，7.44-7.46(2H，m).
Embodiment 418
4-[4-(5-bromo-3-pyridyl]-7-ethyl-2-(isobutoxy methyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H NMR(300MHz，CDCl
3)δ0.92(6H，d，J＝7Hz)，1.20(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.71(2H，tt，J＝8，8Hz)，1.91(1H，qt，J＝7，7Hz)，2.20(2H，t，J＝8Hz)，2.56-2.66(2H，m)，3.03(2H，q，J＝7Hz)，3.34(2H，d，J＝7Hz)，4.05(2H，q，J＝7Hz)，4.69(2H，s)，5.91(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.89(1H，s)，8.56(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
Embodiment 419
2,4-two (5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine also
1H NMR(CDCl
3)δ1.45(3H，t，J＝7Hz)，3.14(2H，q，J＝7Hz)，6.66(1H，d，J＝4Hz)，6.86(1H，d，J＝4Hz)，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＝2Hz)，9.18(1H，d，J＝2Hz).
Embodiment 420
The 4-[2-[(acetoxyl group) methyl]-4-(3-chloro-phenyl-)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also] ethyl butyrate
1H NMR (CDCl
3) δ 1.19 (3H, t, J=8Hz), 1.34 (3H, t, J=8Hz), and 1.63-1.76 (2H, m), 2.10-2.22 (5H, m), 2.45-2.55 (2H, m), 3.01 (2H, q, J=8Hz), 4.04 (2H, q, J=8Hz), 5.32 (2H, s), 5.95 (1H, d, J=5Hz), 6.59 (1H, d, J=5Hz), (1H is with CDCl for 7.21-7.29
3Overlapping), 7.36 (1H, br s), 7.38-7.46 (2H, m).
MS(ESI
+)：m/z 443(M+H).
Embodiment 421
5-[7-ethyl-2-(methoxymethyl)-4-(5-methoxyl group-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1HNMR(CDCl
3)δ1.23(3H，t，J＝8Hz)，1.33-1.60(7H，m)，1.55-1.70(2H，m)，2.17(2H，t，J＝8Hz)，2.46-2.64(2H，m)，3.04(2H，d，J＝8Hz)，3.46(3H，s)，3.90(3H，s)，4.09(2H，q，J＝8Hz)，4.62(2H，s)，5.93(1H，d，J＝5Hz)，6.59(1H，d，J＝5Hz)，7.23(1H，m)，8.22(1H，d，J＝1Hz)，8.40(1H，d，J＝3Hz).
MS(ESI
+)：m/z 426(M+H).
Embodiment 422
5-[7-ethyl-4-(5-methoxyl group-3-pyridyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝8Hz)，1.33-1.62(7H，m)，2.18(2H，t，J＝8Hz)，2.38-2.49(2H，m)，2.56(3H，s)，3.01(2H，q，J＝8Hz)，3.90(3H，s)，4.08(2H，q，J＝8Hz)，5.89(1H，d，J＝5Hz)，6.51(1H，d，J＝5Hz)，7.21(1H，m)，8.21(1H，d，J＝1Hz)，8.40(1H，d，J＝3Hz).
MS(ESI
+)：m/z 396(M+H).
Embodiment 423
3-[7-ethyl-2-(methoxymethyl)-4-(5-methoxyl group-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(CDCl
3)δ1.20(3H，t，J＝8Hz)，1.38(3H，t，J＝8Hz)，2.40(2H，t，J＝8Hz)，2.81-2.96(2H，m)，3.04(2H，d，J＝8Hz)，3.47(3H，s)，3.90(3H，s)，4.05(2H，q，J＝8Hz)，4.65(2H，s)，5.96(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.21(1H，m)，8.23(1H，br s)，8.40(1H，d，J＝3Hz).
MS(ESI
+)：m/z 398(M+H).
Embodiment 424
4-[7-ethyl-2-(methoxymethyl)-4-(5-methoxyl group-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H NMR(CDCl
3)δ1.20(3H，t，J＝8Hz)，1.38(3H，t，J＝8Hz)，1.64-1.79(2H，m)，2.14-2.24(2H，m)，2.53-2.66(2H，m)，3.04(2H，d，J＝8Hz)，3.47(3H，s)，3.90(3H，s)，4.04(2H，q，J＝8Hz)，4.67(2H，brs)，5.94(1H，d，J＝5Hz)，6.59(1H，d，J＝5Hz)，7.23(1H，m)，8.22(1H，d，J＝1Hz)，8.40(1H，d，J＝3Hz).
MS(ESI
+)：m/z 412(M+H).
Embodiment 425
5-[7-ethyl-2-(methoxymethyl)-4-(5-pyrimidyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝8Hz)，1.30-1.62(7H，m)，2.19(2H，t，J＝8Hz)，2.46-2.60(2H，m)，3.04(2H，d，J＝8Hz)，3.47(3H，s)，3.90(3H，s)，4.09(2H，q，J＝8Hz)，4.63(2H，s)，5.90(1H，d，J＝5Hz)，6.61(1H，d，J＝5Hz)，8.80(2H，s)，9.34(1H，s).
MS(ESI
+)：m/z 397(M+H).
Embodiment 426
4-[4-(5-chloro-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H NMR(CDCl
3)δ1.21(3H，t，J＝8Hz)，1.37(3H，t，J＝8Hz)，1.62-1.76(2H，m)，2.21(2H，t，J＝8Hz)，2.49-2.67(2H，m)，3.04(2H，d，J＝8Hz)，3.46(3H，s)，4.06(2H，q，J＝8Hz)，4.67(2H，br s)，5.92(1H，d，J＝5Hz)，6.61(1H，d，J＝5Hz)，7.74(1H，m)，8.53(1H，d，J＝1Hz)，8.69(1H，d，J＝2Hz).
MS(ESI
+)：m/z 414(M-H).
Embodiment 427
3-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(CDCl
3)δ1.20(3H，t，J＝8Hz)，1.38(3H，t，J＝8Hz)，2.40(2H，t，J＝8Hz)，2.82-2.94(2H，m)，3.04(2H，d，J＝8Hz)，3.47(3H，s)，4.06(2H，q，J＝8Hz)，4.65(2H，s)，5.93(1H，d，J＝5Hz)，6.67(1H，d，J＝5Hz)，7.73(1H，br s)，8.51(1H，brs)，8.70(1H，br s).
MS(ESI
+)：m/z 402(M+H).
Embodiment 428
5-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝8Hz)，1.34-1.60(7H，m)，2.19(2H，t，J＝8Hz)，2.47-2.64(2H，m)，3.04(2H，d，J＝8Hz)，3.46(3H，s)，4.10(2H，q，J＝8Hz)，4.62(2H，s)，5.90(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.73(1H，m)，8.51(1H，br s)，8.68(1H，br s).
MS(ESI
+)：m/z 426(M+H).
Embodiment 429
The 2-[(acetoxyl group) methyl]-4-(5-bromo-3-pyridyl)-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-methyl-formiate also
mp 122-123℃
1H NMR(CDCl
3)δ1.38(3H，t，J＝8Hz)，2.12(3H，s)，3.06(2H，t，J＝8Hz)，3.61(3H，s)，5.43(2H，s)，6.37(1H，d，J＝5Hz)，6.78(1H，d，J＝5Hz)，7.93(1H，t，J＝1Hz)，8.57(1H，d，J＝1Hz)，8.78(1H，d，J＝1Hz).
MS(ESI
+)：m/z 432，434(M+H).
Embodiment 430
Acetate 2-(2-{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] oxyethyl group } oxyethyl group) ethyl ester
1H-NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，2.05(3H，s)，2.42(3H，s)，2.59(3H，s)，2.75(2H，m)，3.00(2H，q，J＝7Hz)，3.39-3.48(4H，m)，3.54(2H，m)，3.63(2H，m)，4.16(2H，m)，5.86(1H，d，J＝5Hz)，6.52(1H，d，J＝5Hz)，7.50(1H，m)，8.43(1H，m)，8.52(1H，m).
Embodiment 431
(2E)-4-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also]-the 2-butylene acetoacetic ester
1H-NMR (CDCl
3) δ 1.27 (3H, t, J=7Hz), 1.36 (3H, t, J=7Hz), 2.49 (3H, s), 3.02 (2H, q, J=7Hz), 3.30 (2H, m), 4.16 (2H, q, J=7Hz), 5.58 (1H, d, J=16Hz), 5.90 (1H, d, J=5Hz), 6.56 (1H, d, J=5Hz), 6.97 (1H, dt, J=7 and 16Hz), 7.58 (2H, m), 7.65 (1H, s), 7.75 (1H, m).
Embodiment 432
4-[4-(5-bromo-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H NMR(300MHz，CDCl
3)δ1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.65-1.78(2H，m)，2.23(2H，t，J＝7Hz)，2.54-2.72(2H，m)，3.04(2H，q，J＝7Hz)，3.46(3H，s)，4.06(2H，q，J＝7Hz)，4.66(2H，s)，5.93(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.89(1H，m)，8.55(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
MS(ESI
+)：m/z 460 462.
Embodiment 433
4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-ethyl formate also
1H NMR(CDCl
3)δ0.99(3H，t，J＝8Hz)，1.38(3H，t，J＝8Hz)，2.63(3H，s)，3.05(2H，q，J＝8Hz)，4.07(2H，q，J＝8Hz)，6.27(1H，d，J＝5Hz)，6.70(1H，d，J＝5Hz)，7.30(1H，dd，J＝5，1Hz)，7.41(1H，br s)，8.49(1H，d，J＝5Hz).
MS(ESI
+)：m/z 344(M+H).
Following compound is to obtain with embodiment 76 essentially identical modes.
Embodiment 434
4-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] butyric acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.72-1.84(2H，m)，2.33(2H，t，J＝7Hz)，2.47-2.57(2H，m)，2.58(3H，s)，3.03(2H，q，J＝7Hz)，5.88(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，7.27(1H，m)，7.38(1H，s)，8.53(1H，d，J＝5Hz).
MS(ESI
-)：m/z 356，MS(ESI
+)：m/z 358.
Embodiment 435
3-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] propionic acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，2.36-2.47(2H，m)，2.58(3H，s)，2.76-2.88(2H，m)，3.03(2H，q，J＝7Hz)，5.89(1H，d，J＝4Hz)，6.55(1H，d，J＝4Hz)，7.25(1H，d，J＝5Hz)，7.35(1H，s)，8.53(1H，d，J＝5Hz).
Embodiment 436
4-[4-(2-chloro-4-pyridyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] butyric acid
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，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＝17Hz)，4.12(2H，q，J＝7Hz)，4.29(1H，d，J＝17Hz)，7.22(2H，d，J＝8Hz)，7.26-7.36(4H，m)，7.50(1H，s)，8.42(1H，d，J＝5Hz).
MS(ESI
-)：m/z 418，MS(ESI
+)：m/z 420.
Embodiment 437
3-[4-(2-chloro-4-pyridyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] propionic acid
1H NMR(CDCl
3)δ1.36(3H，t，J＝7Hz)，2.06(2H，t，J＝7Hz)，2.78(2H，t，J＝7Hz)，3.04(2H，q，J＝7Hz)，5.99(1H，d，J＝4Hz)，6.67(1H，d，J＝4Hz)，7.28(1H，d，J＝5Hz)，7.41(1H，s)，7.45-7.55(5H，m)，8.53(1H，d，J＝5Hz).
MS(ESI
-)：m/z 404，MS(ESI
+)：m/z 406.
Embodiment 438
5-[2-benzyl-4-(2-chloro-4-pyridyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] valeric acid
1H NMR(CDCl
3)δ1.16-1.32(2H，m)，1.39(3H，t，J＝7Hz)，1.38-1.53(2H，m)，2.15(2H，t，J＝7Hz)，2.30-2.40(2H，m)，3.06(2H，q，J＝7Hz)，4.21(2H，s)，5.88(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.18-7.35(7H，m)，8.49(1H，d，J＝5Hz).
MS(ESI
-)：m/z 446，MS(ESI
+)：m/z 448.
Embodiment 439
2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] and oxyethyl group } acetate
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，2.44(3H，s)，2.59(3H，s)，2.74-2.92(2H，m)，3.02(2H，q，J＝7Hz)，3.54-3.66(2H，m)，3.93(2H，m)，5.82(1H，d，J＝4Hz)，6.53(1H，d，J＝4Hz)，7.63(1H，s)，8.52(1H，s)，8.56(1H，s).
Embodiment 440
2-[4-(2-chloro-4-pyridyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] and oxyethyl group } acetate
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，2.80(2H，t，J＝7Hz)，3.03(2H，q，J＝7Hz)，3.20(2H，t，J＝7Hz)，3.72(3H，s)，6.01(1H，d，J＝4Hz)，6.67(1H，d，J＝4Hz)，7.42(1H，d，J＝5Hz)，7.45-7.60(6H，m)，8.57(1H，d，J＝5Hz).
Embodiment 441
[4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] acetate
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，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.
Embodiment 442
3-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } propionic acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，2.33-2.50(2H，m)，2.42(3H，s)，2.80-3.00(2H，m)，3.06(2H，q，J＝7Hz)，4.72(2H，s)，4.83(2H，s)，5.92(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.36(2H，d，J＝7Hz)，7.55(1H，s)，8.41(1H，s)，8.44(2H，d，J＝7Hz)，8.53(1H，s).
MS(ESI
+)：m/z 429 431.
Embodiment 443
3-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(2-pyrazinyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } propionic acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，2.42(3H，s)，2.40-2.55(2H，m)，2.83-3.12(2H，m)，3.03(2H，q，J＝7Hz)，4.84(2H，s)，4.91(2H，m)，5.92(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.57(1H，s)，8.42(1H，s)，8.48-8.55(3H，m)，8.76(1H，s).
MS(ESI
+)：m/z 432.
Embodiment 444
3-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(2-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } propionic acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，2.43(3H，s)，2.50-2.60(2H，m)，2.88-3.05(2H，m)，3.03(2H，q，J＝7Hz)，4.81(2H，s)，4.87(2H，s)，5.82(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.27(1H，m)，7.48(1H，d，J＝8Hz)，7.56(1H，s)，7.77(1H，t，J＝8Hz)，8.43(1H，s)，8.54(2H，m).
Embodiment 445
4-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } butyric acid
1H NMR(CDCl
3)δ1.40(3H，t，J＝7Hz)，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＝7Hz)，4.72(2H，s)，4.83-4.98(2H，m)，5.92(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.30(2H，d，J＝7Hz)，7.57(1H，s)，8.38-8.55(4H，m).
MS(ESI
-)：m/z 443，MS(ESI
+)：m/z 445.
Embodiment 446
5-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.40-1.63(4H，m)，2.20(2H，t，J＝7Hz)，2.52-2.68(2H，m)，3.04(2H，q，J＝7Hz)，4.69(2H，s)，4.78(2H，s)，5.93(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.35(2H，d，J＝6Hz)，7.88(1H，m)，8.54(2H，d，J＝6Hz)，8.55(1H，m)，8.79(1H，m).
Embodiment 447
5-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(3-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.40-1.62(4H，m)，2.17(2H，t，J＝7Hz)，2.50-2.67(2H，m)，3.04(2H，q，J＝7Hz)，4.69(2H，s)，4.76(2H，s)，5.92(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.32-7.38(1H，m)，7.77(1H，d，J＝8Hz)，7.88(1H，m)，8.55(2H，m)，8.65(1H，m)，8.78(1H，m).
MS(ESI
-)：m/z 521 523，MS(ESI
+)：m/z 523 525.
Embodiment 448
5-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.48-1.67(4H，m)，2.26(2H，t，J＝7Hz)，2.53-2.75(2H，m)，3.03(2H，q，J＝7Hz)，4.82(2H，s)，4.83(2H，s)，5.90(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.26-7.34(1H，m)，7.53(1H，d，J＝8Hz)，7.75-7.83(1H，m)，7.87(1H，m)，8.55(1H，d，J＝2Hz)，8.62(1H，m)，8.77(1H，d，J＝2Hz).
MS(ESI
+)：m/z 523 525.
Embodiment 449
5-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-pyrazinyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.45-1.64(4H，m)，2.23(2H，t，J＝7Hz)，2.53-2.72(2H，m)，3.03(2H，q，J＝7Hz)，4.83(2H，s)，4.87(2H，s)，5.93(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.88(1H，m)，8.53(3H，m)，8.77(2H，m).
MS(ESI
-)：m/z 522 524，MS(ESI
+)：m/z 524 526.
Embodiment 450
4-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } butyric acid
1HNMR(CDCl
3)δ1.39(3H，t，J＝7Hz)，1.69-1.84(2H，m)，2.27(2H，t，J＝7Hz)，2.56-2.80(2H，m)，3.02(2H，q，J＝7Hz)，4.73(2H，s)，4.92(2H，m)，5.94(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.31(2H，d，J＝6Hz)，7.90(1H，m)，8.46(2H，d，J＝6Hz)，8.57(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
MS(ESI
-)：m/z 507 509，MS(ESI
+)：m/z 509 511.
Embodiment 451
4-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(3-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } butyric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.66-1.83(2H，m)，2.26(2H，t，J＝7Hz)，2.53-2.77(2H，m)，3.04(2H，q，J＝7Hz)，4.71(2H，s)，4.86(2H，m)，5.92(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.33(1H，m)，7.78(1H，d，J＝8Hz)，7.90(1H，m)，8.50(1H，m)，8.56(1H，d，J＝2Hz)，8.60(1H，s)，8.78(1H，d，J＝2Hz).
MS(ESI
+)：m/z 509 511.
Embodiment 452
4-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } butyric acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.70-1.85(2H，m)，2.23-2.34(2H，m)，2.57-2.76(2H，m)，3.03(2H，q，J＝7Hz)，4.81(2H，s)，4.90(2H，m)，5.91(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.28(1H，m)，7.49(1H，d，J＝7Hz)，7.77(1H，t，J＝8Hz)，7.88(1H，m)，8.55(1H，d，J＝2Hz)，8.57(1H，m)，8.74(1H，d，J＝2Hz).
MS(ESI
+)：m/z 509 511.
Embodiment 453
4-{4-(5-bromo-3-pyridyl)-2-[(cyclo propyl methoxy) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } butyric acid
1H NMR(CDCl
3)δ0.22(2H，m)，0.57(2H，m)，1.07-1.22(1H，m)，1.37(3H，t，J＝7Hz)，1.72-1.87(2H，m)，2.28(2H，t，J＝7Hz)，2.58-2.77(2H，m)，3.03(2H，q，J＝7Hz)，3.41(2H，d，J＝7Hz)，4.72(2H，s)，5.92(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.93(1H，m)，8.56(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
MS(ESI
-)：m/z 470 472，MS(ESI
+)：m/z 472 474.
Embodiment 454
4-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-pyrazinyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } butyric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.68-1.83(2H，m)，2.27(2H，t，J＝7Hz)，2.56-2.78(2H，m)，3.03(2H，q，J＝7Hz)，4.84(2H，s)，4.92(2H，m)，5.94(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.91(1H，m)，8.51(2H，m)，8.56(1H，d，J＝2Hz)，8.76(2H，m).
MS(ESI
-)：m/z 508 510，MS(ESI
+)：m/z 510 512.
Embodiment 455
3-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } propionic acid
1H NMR(CDCl
3)δ1.39(3H，t，J＝7Hz)，2.38(2H，t，J＝7Hz)，2.83-2.98(2H，m)，3.07(2H，q，J＝7Hz)，4.74(2H，s)，4.83(2H，s)，5.95(1H，d，J＝4Hz)，6.65(1H，d，J＝4Hz)，7.38(2H，d，J＝6Hz)，7.88(1H，s)，8.43(2H，d，J＝6Hz)，8.55(1H，s)，8.78(1H，s).
MS(ESI
-)：m/z 493 495，MS(ESI
+)：m/z 495 497.
Embodiment 456
4-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-hydroxyl-oxethyl) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } butyric acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.68-1.83(2H，m)，2.28(2H，t，J＝7Hz)，2.53-2.76(2H，m)，3.02(2H，q，J＝7Hz)，3.75(2H，m)，3.79(2H，m)，4.78(2H，s)，5.93(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.90(1H，s)，8.56(1H，s)，8.78(1H，s).
MS(ESI
-)：m/z 460 462，MS(ESI
+)：m/z 462 464.
Embodiment 457
3-[2-[(cyclohexyl methoxyl group) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
1H NMR(CDCl
3)δ0.88-1.06(2H，m)，1.10-1.36(3H，m)，1.37(3H，t，J＝7Hz)，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，q，J＝7Hz)，3.39(2H，d，J＝7Hz)，4.67(2H，m)，5.89(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.57(1H，s)，8.42(1H，s)，8.53(1H，s).
MS(ESI
-)：m/z 434，MS(ESI
+)：m/z 436.
Embodiment 458
3-{4-(5-bromo-3-pyridyl)-2-[(cyclohexyl methoxyl group) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } propionic acid
1H NMR(CDCl
3)δ0.88-1.05(2H，m)，1.10-1.36(3H，m)，1.37(3H，t，J＝7Hz)，1.56-1.83(6H，m)，2.51(2H，t，J＝7Hz)，2.80-3.07(2H，m)，3.06(2H，q，J＝7Hz)，3.37(2H，d，J＝7Hz)，4.67(2H，s)，5.93(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.89(1H，m)，8.55(1H，s)，8.79(1H，s).
MS(ESI
-)：m/z 498 500，MS(ESI
+)：m/z 500 502.
Embodiment 459
4-{4-(5-bromo-3-pyridyl)-2-[(cyclohexyl methoxyl group) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } butyric acid
1H NMR(CDCl
3)δ0.86-1.03(2H，m)，1.10-1.35(3H，m)，1.37(3H，t，J＝7Hz)，1.60-1.82(8H，m)，2.28(2H，t，J＝7Hz)，2.55-2.76(2H，m)，3.05(2H，q，J＝7Hz)，3.36(2H，d，J＝7Hz)，4.67(2H，s)，5.92(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.91(1H，m)，8.55(1H，d，J＝2Hz)，8.76(1H，d，J＝2Hz).
MS(ESI
-)：m/z 512 514，MS(ESI
+)：m/z 514 516.
Embodiment 460
The 4-[2-[(cyclo propyl methoxy) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
1H NMR(CDCl
3)δ0.22-0.32(2H，m)，0.55-0.63(2H，m)，1.10-1.22(1H，m)，1.37(3H，t，J＝7Hz)，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＝7Hz)，3.43(2H，d，J＝7Hz)，4.70-4.85(2H，m)，5.88(1H，d，J＝4Hz)，6.57(1H，d，J＝4Hz)，7.62(1H，s)，8.42(1H，s)，8.46(1H，s).
MS(ESI
+)：m/z 408.
Embodiment 461
The 3-[2-[(cyclo propyl methoxy) methyl]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
1H NMR(CDCl
3)δ0.23-0.35(2H，m)，0.54-0.65(2H，m)，1.08-1.24(1H，m)，1.37(3H，t，J＝7Hz)，2.43(3H，s)，2.50-2.65(2H，m)，2.70-3.05(2H，m)，3.04(2H，q，J＝7Hz)，3.44(2H，d，J＝7Hz)，4.74(2H，s)，5.89(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.56(1H，s)，8.42(1H，s)，8.53(1H，s).
MS(ESI
-)：m/z 392，MS(ESI
+)：m/z 394.
Embodiment 462
3-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-methoxy ethoxy) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } propionic acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，2.48-2.62(2H，m)，2.83-3.02(2H，m)，3.02(2H，q，J＝7Hz)，3.37(3H，s)，3.60(2H，m)，3.73(2H，m)，4.75(2H，s)，5.92(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.89(1H，m)，8.55(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
MS(ESI
-)：m/z 460 462，MS(ESI
+)：m/z 462 464.
Embodiment 463
5-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[(4-morpholinyl carbonyl) oxygen base] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) valeric acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.35-1.65(4H，m)，2.23(2H，t，J＝7Hz)，2.40-2.56(2H，m)，3.02(2H，q，J＝7Hz)，3.48-3.57(4H，m)，3.60-3.78(4H，m)，5.33(2H，s)，5.93(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.89(1H，m)，8.56(1H，d，J＝2Hz)，8.79(1H，d，J＝2Hz).
Embodiment 464
5-[4-(5-bromo-3-pyridyl)-2-({ [(dimethylamino) carbonyl] oxygen base } methyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] valeric acid
1H NMR(CDCl
3)δ1.36(3H，t，J＝7Hz)，1.45-1.65(4H，m)，2.22(2H，t，J＝7Hz)，2.42-2.57(2H，m)，2.97(6H，s)，3.03(2H，q，J＝7Hz)，5.30(2H，s)，5.93(1H，d， J＝4Hz)，6.62(1H，d，J＝4Hz)，7.89(1H，s)，8.54(1H，s)，8.78(1H，s).
MS(ESI
+)：m/z 503 505.
Embodiment 465
5-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[(1-pyrrolidyl carbonyl) oxygen base] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) valeric acid
1H NMR(CDCl
3)δ1.36(3H，t，J＝7Hz)，1.40-1.63(4H，m)，1.82-1.97(4H，m)，2.23(2H，t，J＝7Hz)，2.43-2.58(2H，m)，3.03(2H，q，J＝7Hz)，3.37-3.52(4H，m)，5.31(2H，s)，5.93(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.88(1H，m)，8.54(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
MS(ESI
-)：m/z 527 529，MS(ESI
+)：m/z 529 531.
Embodiment 466
5-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[({[methyl (phenyl) amino] carbonyl } the oxygen base) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.40-1.58(4H，m)，2.18(2H，t，J＝7Hz)，2.32-2.53(2H，m)，3.04(2H，q，J＝7Hz)，3.37(3H，s)，5.36(2H，s)，5.92(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.16-7.40(5H，m)，7.87(1H，s)，8.52(1H，s)，8.79(1H，s).
Embodiment 467
4-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[(4-morpholinyl carbonyl) oxygen base] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) butyric acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.65-1.84(2H，m)，2.27(2H，t，J＝7Hz)，2.45-2.68(2H，m)，3.04(2H，q，J＝7Hz)，3.53(4H，m)，3.69(4H，m)，5.36(2H，s)，5.95(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.91(1H，m)，8.55(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
Embodiment 468
4-[4-(5-bromo-3-pyridyl)-2-({ [(dimethylamino) carbonyl] oxygen base } methyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] butyric acid
1H NMR(CDCl
3)δ1.36(3H，t，J＝7Hz)，1.66-1.82(2H，m)，2.27(2H，t，J＝7Hz)，2.46-2.68(2H，m)，2.97(6H，s)，3.04(2H，q，J＝7Hz)，5.33(2H，s)，5.94(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.92(1H，m)，8.56(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
Embodiment 469
3-[4-(5-bromo-3-pyridyl)-2-({ [(dimethylamino) carbonyl] oxygen base } methyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] propionic acid
1H NMR(CDCl
3)δ1.36(3H，t，J＝7Hz)，2.45(2H，t，J＝7Hz)，2.82-2.96(2H，m)，2.97(6H，s)，3.03(2H，q，J＝7Hz)，5.33(2H，s)，5.96(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.89(1H，m)，8.55(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
MS(ESI
-)：m/z 473 475，MS(ESI
+)：m/z 475 477.
Embodiment 470
5-{4-(5-bromo-3-pyridyl)-2-[(1,1-dioxo-4-thio-morpholinyl) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } valeric acid
1H NMR(300MHz，CDCl
3)δ1.36(3H，t，J＝7Hz)，1.42-1.56(4H，m)，2.26(2H，t，J＝7Hz)，2.48-2.61(2H，m)，3.01(2H，q，J＝7Hz)，3.10(4H，t，J＝6Hz)，3.19(4H，t，J＝6Hz)，3.85(2H，s)，5.92(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.89(1H，dd，J＝2，2Hz)，8.56(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
MS(m/z)550(M+H).
Embodiment 471
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(4-thiomorpholine ylmethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(300MHz，CDCl
3)δ1.37(3H，t，J＝7Hz)，1.43-1.58(4H，m)，2.24(2H，t，J＝7Hz)，2.49-2.61(2H，m)，2.66(4H，t，J＝4Hz)，2.86(4H，t，J＝4Hz)，3.02(2H，q，J＝7Hz)，3.68(2H，s)，5.89(1H，d，J＝5Hz)，6.58(1H，d，J＝5Hz)，7.90(1H，s)，8.56(1H，s)，8.79(1H，s).
MS(m/z)518(M+H).
Embodiment 472
5-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[4-(2-hydroxyethyl)-1-piperazinyl] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) valeric acid
1H NMR(300MHz，CDCl
3)δ1.34(3H，t，J＝7Hz)，1.41-1.57(4H，m)，2.21(2H，t，J＝6Hz)，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＝5Hz)，6.57(1H，d，J＝5Hz)，7.88(1H，s)，8.55(1H，s)，8.77(1H，s).
MS(m/z)545(M+H).
Embodiment 473
4-[4-(5-chloro-3-pyridyl]-7-ethyl-2-(4-thiomorpholine ylmethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
1H NMR(300MHz，CDCl
3)δ1.37(3H，t，J＝7Hz)，1.72(2H，tt，J＝7，7Hz)，2.26(2H，t，J＝7Hz)，2.53-2.68(6H，m)，2.87-2.90(4H，m)，3.02(2H，q，J＝7Hz)，3.72(2H，s)，5.91(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，7.78(1H，dd，J＝2，2Hz)，8.52(1H，d，J＝2Hz)，8.68(1H，d，J＝2Hz).
MS(m/z)460(M+H).
Embodiment 474
4-{4-(5-chloro-3-pyridyl)-7-ethyl-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } butyric acid
1H NMR(300MHz，CDCl
3)δ1.38(3H，t，J＝7Hz)，1.73(2H，tt，J＝7，7Hz)，2.25(2H，t，J＝7Hz)，2.57-2.73(2H，m)，3.04(2H，q，J＝7Hz)，4.72(2H，s)，4.89(2H，s)，5.93(1H，d，J＝5Hz)，6.63(1H，d，J＝5Hz)，7.31(2H，d，J＝6Hz)，7.76(1H，dd，J＝2，2Hz)，8.46(2H，d，J＝6Hz)，8.53(1H，d，J＝2Hz)，8.67(1H，d，J＝2Hz).
MS(m/z)465(M+H).
Embodiment 475
4-[4-(5-chloro-3-pyridyl]-7-ethyl-2-(4-morpholinyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
1H NMR(300MHz，CDCl
3)δ1.37(3H，t，J＝7Hz)，1.73(2H，tt，J＝7，7Hz)，2.26(2H，t，J＝7Hz)，2.54-2.72(6H，m)，3.03(2H，q，J＝7Hz)，3.66-3.73(6H，m)，5.90(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，7.79(1H，s)，8.53(1H，s)，8.67(1H，s).
MS(m/z)443(M+H).
Embodiment 476
5-{4-(5-chloro-3-pyridyl)-2-[(cyclo propyl methoxy) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } valeric acid
1H NMR(300MHz，CDCl
3)δ0.24(2H，dt，J＝7，7Hz)，0.57(2H，dt，J＝7，7Hz)，1.07-1.17(1H，m)，1.38(3H，t，J＝7Hz)，1.45-1.61(4H，m)，2.23(2H，t，J＝7Hz)，2.52-2.66(2H，m)，3.02(2H，q，J＝7Hz)，3.41(2H，d，J＝7Hz)，4.70(2H，s)，5.90(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，7.74(1H，dd，J＝2，2Hz)，8.52(1H，d，J＝2Hz)，8.68(1H，d，J＝2Hz).
MS(m/z)442(M+H).
Embodiment 477
4-{4-(5-chloro-3-pyridyl)-2-[(cyclo propyl methoxy) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } butyric acid
1H NMR(300MHz，CDCl
3)δ0.23(2H，dt，J＝6，6Hz)，0.56(2H，dt，J＝6，6Hz)，1.05-1.17(1H，m)，1.37(3H，t，J＝7Hz)，1.75(2H，tt，J＝7，7Hz)，2.28(2H，t，J＝7Hz)，2.57-2.70(2H，m)，3.03(2H，q，J＝7Hz)，3.42(2H，d，J＝7Hz)，4.73(2H，s)，5.91(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.77(1H，dd，J＝2，2Hz)，8.52(1H，d，J＝2Hz)，8.66(1H，d，J＝2Hz).
MS(m/z)428(M+H).
Embodiment 478
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(isobutoxy methyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(300MHz，CDCl
3)δ0.93(6H，d，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.42-1.59(4H，m)，1.92(1H，qt，J＝7,7Hz)，2.24(2H，t，J＝7Hz)，2.48-2.69(2H，m)，3.03(2H，q，J＝7Hz)，3.33(2H，d，J＝7Hz)，4.66(2H，s)，5.91(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.90(1H，dd，J＝2,2Hz)，8.56(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
MS(m/z)489(M+H).
Embodiment 479
3-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(isobutoxy methyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
1H NMR(300MHz，CDCl
3)δ0.92(6H，d，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.91(1H，qt，J＝7,7Hz)，2.49(2H，t，J＝8Hz)，2.82-2.98(2H，m)，3.03(2H，q，J＝7Hz)，3.35(2H，d，J＝7Hz)，4.69(2H，s)，5.92(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.72(1H，dd，J＝2,2Hz)，8.51(1H，d，J＝2Hz)，8.69(1H，d，J＝2Hz).
MS(m/z)416(M+H).
Embodiment 480
3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(4-morpholinyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
1H NMR(300MHz，CDCl
3)δ1.36(3H，t，J＝7Hz)，2.55(2H，t，J＝8Hz)，2.66(4H，br s)，2.79-2.97(2H，m)，3.02(2H，q，J＝7Hz)，3.70-3.74(6H，m)，5.92(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.90(1H，dd，J＝2,2Hz)，8.55(1H，d，J＝2Hz)，8.79(1H，d，J＝2Hz).
MS(m/z)474(M+H).
Embodiment 481
4-[4-(5-bromo-3-pyridyl]-7-ethyl-2-(4-morpholinyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
1H NMR(300MHz，CDCl
3)δ1.36(3H，t，J＝7Hz)，1.73(2H，tt，J＝7,7Hz)，2.26(2H，t，J＝7Hz)，2.57-2.70(6H，m)，3.02(2H，q，J＝7Hz)，3.69(6H，m)，5.90(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.93(1H，dd，J＝2,2Hz)，8.57(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
MS(m/z)488(M+H).
Embodiment 482
4-{4-(5-chloro-3-pyridyl)-2-[(cyclopropyl amino) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } butyric acid
1H NMR(300MHz，CDCl
3)δ0.54-0.60(2H，m)，0.74-0.79(2H，m)，1.38(3H，t，J＝7Hz)，1.65(2H，tt，J＝6,6Hz)，2.21(2H，t，J＝6Hz)，2.45-2.55(2H，m)，3.03(2H，q，J＝7Hz)，4.30(2H，s)，5.04(1H，br s)，5.93(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.73(1H，dd，J＝2,2Hz)，8.52(1H，d，J＝2Hz)，8.69(1H，d，J＝2Hz).
MS(m/z)413(M+H).
Embodiment 483 (a)
5-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[(2-phenoxy group ethyl) amino] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) valeric acid
1H NMR(300MHz，CDCl
3)δ1.36(3H，t，J＝7Hz)，1.42-1.56(4H，m)，2.22(2H，brs)，2.34-2.48(2H，m)，3.03(2H，q，J＝7Hz)，3.38-3.43(2H，br s)，4.23-4.50(4H，m)，5.93(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，6.89-6.97(3H，m)，7.23-7.30(2H，m)，7.85(1H，s)，8.52(1H，s)，8.78(1H，s).
MS(m/z)552(M+H).
Embodiment 484
5-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[(2-hydroxyethyl) (methyl) amino] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) valeric acid
1H NMR(300MHz，CDCl
3)δ1.36(3H，t，J＝7Hz)，1.34-1.54(4H，m)，2.15-2.26(2H，m)，2.33-2.52(2H，m)，2.98(2H，q，J＝7Hz)，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＝4Hz)，6.59(1H，d，J＝4Hz)，7.85(1H，s)，8.51(1H，s)，8.73(1H，s).
MS(m/z)490(M+H).
Embodiment 485
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(piperidino methyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(300MHz，CDCl
3)δ1.36(3H，t，J＝7Hz)，1.39-1.51(6H，m)，1.62-1.71(4H，m)，2.19(2H，t，J＝6Hz)，2.52-2.65(2H，m)，2.78-2.91(4H，m)，3.10(2H，q，J＝7Hz)，3.65(2H，s)，5.89(1H，d，J＝5Hz)，6.58(1H，d，J＝5Hz)，7.88(1H，s)，8.55(1H，s)，8.76(1H，s).
MS(m/z)500(M+H).
Embodiment 486
3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(4-thiomorpholine ylmethyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
1H NMR(300MHz，CDCl
3)δ1.37(3H，t，J＝7Hz)，2.52(2H，t，J＝8Hz)，2.68(4H，t，J＝5Hz)，2.81-2.95(6H，m)，3.02(2H，q，J＝7Hz)，3.74(2H，s)，5.92(1H，d，J＝5Hz)，6.61(1H，d，J＝5Hz)，7.89(1H，dd，J＝2,2Hz)，8.55(1H，d，J＝2Hz)，8.79(1H，d，J＝2Hz).
MS(m/z)490(M+H).
Embodiment 487
3-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[4-(2-hydroxyethyl)-1-piperazinyl] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) propionic acid
1H NMR(300MHz，DMSO-d
6)δ1.32(3H，t，J＝7Hz)，2.40-2.56(12H，m)，2.58-2.65(2H，m)，2.94(2H，q，J＝7Hz)，3.52(2H，t，J＝5Hz)，3.67(2H，s)，5.83(1H，d，J＝5Hz)，6.62(1H，d，J＝5Hz)，8.25(1H，dd，J＝2,2Hz)，8.63(1H，d，J＝2Hz)，8.86(1H，d，J＝2Hz).
MS(m/z)517(M+H).
Embodiment 488
4-[4-(5-bromo-3-pyridyl]-7-ethyl-2-(isobutoxy methyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
1H NMR(300MHz，CDCl
3)δ0.91(6H，d，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.74(2H，tt，J＝8,8Hz)，1.91(1H，qt，J＝7,7Hz)，2.27(2H，t，J＝8Hz)，2.56-2.73(2H，m)，3.03(2H，q，J＝7Hz)，3.33(2H，d，J＝7Hz)，4.68(2H，s)，5.92(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.92(1H，dd，J＝7,7Hz)，8.56(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
MS(m/z)475(M+H).
Embodiment 489
5-[2-{[2-(benzylamino)-2-oxo oxyethyl group] methyl }-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(CDCl
3)δ1.33(3H，t，J＝7Hz)，1.39-1.60(4H，m)，2.15(2H，t，J＝7Hz)，2.42(3H，s)，2.40-2.58(2H，m)，2.95(2H，q，J＝7Hz)，4.19(2H，s)，4.50(2H，d，J＝7Hz)，4.75(2H，m)，5.91(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，7.07(1H，br)，7.22-7.34(5H，m)，7.54(1H，s)，8.40(1H，s)，8.53(1H，s).
MS(ESI
-)：m/z 513，MS(ESI
+)：m/z 515.
Embodiment 490
5-(7-ethyl-4-(5-methyl-3-pyridyl)-2-{[(benzenesulfonyl) amino] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) valeric acid
1H NMR(CDCl
3)δ1.36(3H，t，J＝7Hz)，1.23-1.60(4H，m)，2.19(2H，t，J＝7Hz)，2.28-2.46(2H，m)，2.42(3H，s)，2.97(2H，q，J＝7Hz)，4.37(2H，m)，5.89(1H，d，J＝4Hz)，5.90(1H，m)，6.57(1H，d，J＝4Hz)，7.42-7.53(4H，m)，7.90(2H，d，J＝8Hz)，8.34(1H，s)，8.53(1H，s).
MS(ESI
-)：m/z 505，MS(ESI
+)：m/z 507.
Embodiment 491
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(1-pyrrolidyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(300MHz，CDCl
3)δ1.35(3H，t，J＝7Hz)，1.39-1.57(4H，m)，1.79-1.88(4H，m)，2.18(2H，t，J＝7Hz)，2.84-2.89(6H，m)，3.00(2H，q，J＝7Hz)，3.89-4.02(2H，m)，5.88(1H，d，J＝5Hz)，6.56(1H，d，J＝5Hz)，7.87(1H，s)，8.55(1H，s)，8.75(1H，s).
MS(m/z)486(M+H).
Embodiment 492
3-[4-(3-chloro-phenyl-)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝8Hz)，2.39-2.48(2H，m)，2.83-2.94(2H，m)，3.03(2H，q，J＝8Hz)，3.45(3H，s)，4.65(2H，s)，5.95(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.24(1H，m)，7.35(1H，brs)，7.40-7.46(2H，m).
MS(ESI
+)：m/z 373(M+H).
Embodiment 493
4-[4-(3-chloro-phenyl-)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
1H NMR (CDCl
3) δ 1.37 (3H, t, J=8Hz), 1.64-1.78 (2H, m), 2.24 (2H, t, J=8Hz), 2.56-2.66 (2H, m), 3.04 (2H, q, J=8Hz), 3.45 (3H, s), 4.65 (2H, s), 5.94 (J=5Hz), 6.59 (J=5Hz), (1H is with CDCl for 7.21-7.29 for 1H, d for 1H, d
3Overlapping), 7.36 (1H, br s), 7.39-7.46 (2H, m).
MS(ESI
+)：m/z 387(M+H).
Embodiment 494
5-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(4-phenyl-peiperazinyl) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
1H NMR(300MHz，CDCl
3)δ1.37(3H，t，J＝7Hz)，1.41-1.61(4H，m)，2.22(2H，t，J＝7Hz)，2.49-2.67(2H，m)，2.76(4H，t，J＝5Hz)，3.03(2H，q，J＝7Hz)，3.20(4H，t，J＝5Hz)，3.73(2H，s)，5.89(1H，d，J＝5Hz)，6.58(1H，d，J＝5Hz)，6.85(1H，dd，J＝8,8Hz)，6.93(2H，J＝8Hz)，7.25(2H，J＝8Hz)，7.90(1H，dd，J＝2，2Hz)，8.56(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
Embodiment 495
5-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[(2-methoxy ethyl) amino] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) valeric acid
1H NMR(300MHz，CDCl
3)δ1.28(3H，t，J＝7Hz)，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＝7Hz)，3.37(3H，s)，3.89-3.99(2H，m)，4.51(2H，s)，5.91(1H，d，J＝5Hz)，6.57(1H，d，J＝5Hz)，7.82(1H，s)，8.47(1H，s)，8.72(1H，s).
Embodiment 496
5-[7-ethyl-2-(methoxymethyl)-4-(5-methoxyl group-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
mp 111-112℃
1H NMR(CDCl
3)δ1.37(3H，t，J＝8Hz)，1.41-1.60(4H，m)，2.21(2H，br t，J＝8Hz)，2.30-2.70(2H，m)，3.04(2H，d，J＝8Hz)，3.46(3H，s)，3.90(3H，s)，4.63(2H，br d，J＝5Hz)，5.92(1H，d，J＝5Hz)，6.58(2H，d，J＝8Hz)，7.25(1H，m)，8.22(1H，d，J＝1Hz)，8.40(1H，d，J＝3Hz).
MS(ESI
+)：m/z 398(M+H).
Embodiment 497
5-[7-ethyl-4-(5-methoxyl group-3-pyridyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
mp 133-134℃
1H NMR(CDCl
3)δ1.37(3H，t，J＝8Hz)，1.40-1.62(7H，m)，2.24(2H，t，J＝8Hz)，2.35-2.49(2H，m)，2.56(3H，s)，3.01(2H，q，J＝8Hz)，3.89(3H，s)，5.87(1H，d，J＝5Hz)，6.51(1H，d，J＝5Hz)，7.23(1H，m)，8.20(1H，d，J＝1Hz)，8.39(1H，d，J＝3Hz).
MS(ESI
+)：m/z 369(M+H).
Embodiment 498
3-[7-ethyl-2-(methoxymethyl)-4-(5-methoxyl group-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
mp 164-165℃
1H NMR(CDCl
3)δ1.37(3H，t，J＝8Hz)，2.44-2.54(2H，m)，2.80-3.00(2H，m)，3.04(2H，d，J＝8Hz)，3.47(3H，s)，3.89(3H，s)，4.66(2H，br s)，5.95(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.25(1H，m)，8.22(1H，d，J＝1Hz)，8.38(1H，d，J＝3Hz).
MS(ESI
+)：m/z 370(M+H).
Embodiment 499
4-[7-ethyl-2-(methoxymethyl)-4-(5-methoxyl group-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
mp 140-141℃
1H NMR(CDCl
3)δ1.38(3H，t，J＝8Hz)，1.68-1.82(2H，m)，2.25(2H，t，J＝8Hz)，2.52-2.75(2H，m)，3.04(2H，d，J＝8Hz)，3.46(3H，s)，3.92(3H，s)，4.65(2H，brd，J＝7Hz)，5.94(1H，d，J＝5Hz)，6.59(1H，d，J＝5Hz)，7.29(1H，m)，8.23(1H，d，J＝1Hz)，8.37(1H，d，J＝3Hz).
MS(ESI
+)：m/z 384(M+H).
Embodiment 500
5-[7-ethyl-2-(methoxymethyl)-4-(5-pyrimidyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝8Hz)，1.40-1.64(4H，m)，2.25(2H，t，J＝8Hz)，2.49-2.61(2H，m)，3.04(2H，d，J＝8Hz)，3.47(3H，s)，4.65(2H，s)，5.91(1H，d，J＝5Hz)，6.62(1H，d，J＝5Hz)，8.82(2H，s)，9.32(1H，s).
MS(ESI
+)：m/z 369(M+H).
Embodiment 501
4-[4-(5-chloro-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
mp 112-113℃
1H NMR(CDCl
3)δ1.38(3H，t，J＝8Hz)，1.66-1.79(2H，m)，2.28(2H，t，J＝8Hz)，2.52-2.71(2H，m)，3.05(2H，d，J＝8Hz)，3.46(3H，s)，4.66(2H，br s)，5.92(1H，d，J＝5Hz)，6.61(1H，d，J＝5Hz)，7.77(1H，m)，8.53(1H，d，J＝1Hz)，8.67(1H，d，J＝2Hz).
MS(ESI
+)：m/z 388(M+H).
Embodiment 502
3-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
mp 159-160℃
1H NMR(CDCl
3)δ1.38(3H，t，J＝8Hz)，2.47(2H，br t，J＝8Hz)，2.79-2.98(2H，m)，3.04(2H，d，J＝8Hz)，3.47(3H，s)，4.66(2H，s)，5.93(1H，d，J＝5Hz)，6.67(1H，d，J＝5Hz)，7.74(1H，m)，8.51(1H，d，J＝1Hz)，8.68(1H，d，J＝3Hz).
MS(ESI
+)：m/z 374，376(M+H).
Embodiment 503
5-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
mp 118-119℃
1H NM R(CDCl
3)δ1.37(3H，t，J＝8Hz)，1.40-1.62(7H，m)，2.24(2H，t，J＝8Hz)，2.45-2.64(2H，m)，3.04(2H，d，J＝8Hz)，3.45(3H，s)，4.63(2H，s)，5.91(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.74(1H，m)，8.51(1H，d，J＝1Hz)，8.67(1H，d，J＝2Hz).
MS(ESI
+)：m/z 402，404(M+H).
Embodiment 504
4-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(4H-1,2,4-triazole-4-ylmethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
1H-NMR(CDCl
3)δ1.36(3H，t，J＝7Hz)，1.60(2H，m)，2.32(2H，m)，2.46(2H，m)，3.01(2H，q，J＝7Hz)，5.75(2H，m)，5.97(1H，d，J＝5Hz)，6.66(1H，d，J＝5Hz)，7.87(1H，m)，7.97(1H，s)，8.53(1H，s)，8.65(1H，s)，8.69(1H，s).
Embodiment 505
4-{4-(5-bromo-3-pyridyl)-2-[(cyclopropyl amino) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } butyric acid
1H-NMR(CDCl
3)δ0.56(2H，m)，0.75(2H，m)，1.38(3H，t，J＝7Hz)，1.65(2H，m)，2.21(2H，m)，2.50(2H，m)，3.01(2H，q，J＝7Hz)，3.27(3H，br)，4.29(2H，s)，5.93(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.98(1H，m)，8.55(1H，m)，8.78(1H，m).
MS(ESI
+)m/z：457and459(M+H)
Embodiment 506
4-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-oxo-1,3-_ azoles alkane-3-yl) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } butyric acid
1H-NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.68(2H，m)，2.31(2H，m)，2.53(2H，m)，2.98(2H，q，J＝7Hz)，3.77(2H，m)，4.42(2H，t，J＝7Hz)，4.67(2H，m)，5.94(1H，d，J＝5Hz)，6.63(1H，d，J＝5Hz)，7.89(1H，m)，8.55(1H，m)，8.78(1H，m).
Embodiment 507
2-bromo-4-[3-(ethoxy carbonyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-4-yl also] phenylformic acid
1H-NMR (CDCl
3) δ 1.00 (3H, t, J=7Hz), 1.38 (3H, t, J=7Hz), 2.62 (3H, s), 3.04 (2H, q, J=7Hz), 4.06 (2H, q, J=7Hz), 6.29 (1H, d, J=5Hz), 6.68 (1H, d, J=5Hz), (7.49 2H, dd, J=2 and 8Hz), 7.82 (1H, d, J=2Hz), 8.07 (1H, d, J=8Hz).
MS (ESI
+) m/z:431 and 433 (M+H)
Embodiment 508
5-[4-(3-cyano-phenyl)-7-ethyl-2-(phenoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H-NMR(CDCl
3)δ1.25-1.49(7H，m)，2.15(2H，m)，2.54(2H，m)，3.02(2H，q，J＝7Hz)，5.23(2H，s)，5.86(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，6.98(1H，t，J＝8Hz)，7.06(2H，d，J＝8Hz)，7.28(2H，t，J＝8Hz)，7.60(2H，m)，7.67(1H，s)，7.77(1H，m).
Embodiment 509
5-[4-(3-cyano-phenyl)-7-ethyl-2-(3-methyl-2-thienyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H-NMR(CDCl
3)δ1.14-1.28(4H，m)，1.37(3H，t，J＝7Hz)，2.01(2H，t，J＝7Hz)，2.23(3H，s)，2.40(2H，m)，3.02(2H，q，J＝7Hz)，5.92(1J，d，J＝5Hz)(，6.64(1H，d，J＝5Hz)，6.94(1J，d，J＝5Hz)，7.33(1H，d，J＝5Hz)，7.57-7.66(2H，m)，7.73-7.76(2H，m).
Embodiment 510
(2E)-4-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also]-2-butylene acid
1H-NMR (CDCl
3) δ 1.38 (3H, t, J=7Hz), 2.55 (3H, s), 3.03 (2H, q, J=7Hz), 3.09 (2H, d, J=7Hz), 5.45 (1H, dt, J=7 and 16Hz), 6.05 (1H, d, J=5Hz), 6.25 (1H, d, J=16Hz), 6.57 (1H, d, J=5Hz), 7.55 (1H, t, J=8Hz), 7.66+-7.72 (3H, m).
MS(ESI
+)：m/z 345(M+H)
Embodiment 511
4-[4-(5-bromo-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.68-1.84(2H，m)，2.28(2H，t，J＝7Hz)，2.56-2.74(2H，m)，3.03(2H，q，J＝7Hz)，3.46(3H，s)，4.66(2H，s)，5.93(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.92(1H，m)，8.57(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
MS(ESI
-)：m/z 430 432，MS(ESI
+)：m/z 432 434.
Following compound is to obtain with embodiment 159 essentially identical modes.
Embodiment 512
4-[4-(2-chloro-4-pyridyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl butyrate
1H N MR(CDCl
3)δ1.26(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.35-1.45(2H，m)，1.88(2H，t，J＝7Hz)，2.43-2.55(2H，m)，3.03(2H，q，J＝7Hz)，4.12(2H，q，J＝7Hz)，5.98(JH，d，J＝4Hz)，6.65(1H，d，J＝4Hz)，7.33(1H，d，J＝5Hz)，7.42-7.55(6H，m)，8.55(1H，d，J＝5Hz).
MS(ESI
+)：m/z 448.
Embodiment 513
3-[4-(2-chloro-4-pyridyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl propionate
1H NMR(CDCl
3)δ1.09(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.98-2.08(2H，m)，2.75-2.85(2H，m)，3.03(2H，q，J＝7Hz)，3.92(2H，q，J＝7Hz)，6.00(1H，d，J＝4Hz)，6.67(1H，d，J＝4Hz)，7.32(1H，d，J＝5Hz)，7.42(1H，s)，7.43-7.57(5H，m)，8.55(1H，d，J＝5Hz).
MS(ESI
+)：m/z 434.
Embodiment 514
2-[4-(2-chloro-4-pyridyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] and oxyethyl group } methyl acetate
1H NMR(CDCl
3)δ1.36(3H，t，J＝7Hz)，2.73-2.85(2H，t，J＝7Hz)，3.03(2H，t，J＝7Hz)，3.15(2H，t，J＝7Hz)，3.74(2H，s)，4.09(3H，s)，6.02(1H，d，J＝4Hz)，6.67(1H，d，J＝4Hz)，7.39(1H，m)，7.42-7.60(6H，m)，8.53(1H，d，J＝5Hz).
MS(ESI
+)：m/z 450.
Embodiment 515
5-[4-(3-cyano-phenyl)-7-ethyl-2-(3-methyl-2-thienyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H-NMR(CDCl
3)δ1.09-1.26(7H，m)，1.36(3H，t，J＝7Hz)，1.93(2H，t，J＝7Hz)，2.23(3H，s)，2.39(2H，m)，3.03(2H，q，J＝7Hz)，4.03(2H，q，J＝7Hz)，5.93(1H，d，J＝5Hz)，6.64(1H，d，J＝7Hz)，6.96(1H，d，J＝5Hz)，7.33(1H，d，J＝5Hz)，7.60-7.67(2H，m)，7.72-7.79(2H，m).
Embodiment 516
5-[4-(3-cyano-phenyl)-7-ethyl-2-(2-thienyl) pyrrolo-[1,2-b] pyridazine-3-yl] methyl valerate
1H-NMR(CDCl
3)δ1.21-1.47(7H，m)，2.04(2H，t，J＝7Hz)，2.60(2H，m)，3.05(2H，q，J＝7Hz)，3.61(3H，s)，5.37(1H，d，J＝5Hz)，6.63(1H，d，J＝5Hz)，7.13(1H，m)，7.36(1H，m)，7.44(1H，m)，7.62-7.78(4H，m).
Embodiment 517
3-[4-(3-cyano-phenyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl propionate
1H-NMR(CDCl
3)δ1.08(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.98(2H，m)，2.75(2H，m)，3.02(2H，q，J＝7Hz)，3.89(2H，q，J＝7Hz)，5.93(1H，d，J＝5Hz)，6.63(1H，d，J＝5Hz)，7.41-7.55(5H，m)，7.57-7.78(4H，m).
MS(ESI
+)：m/z 424(M+H)
Embodiment 518
5-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
1H-NMR(CDCl
3)δ1.02-1.25(7H，m)，1.37(3H，t，J＝7Hz)，1.88(2H，t，J＝7Hz)，2.43(2H，m)，3.01(2H，q，J＝7Hz)，4.00(2H，q，J＝7Hz)，5.96(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.29(1H，m)，7.37-7.54(8H，m).
MS(ESI
+)：m/z 461
Embodiment 519
4-(5-bromo-3-pyridyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-nitrile also
1H NMR(CDCl
3)δ1.42(3H，t，J＝8Hz)，3.12(2H，t，J＝8Hz)，6.65(1H，d，J＝5Hz)，6.94(1H，d，J＝5Hz)，7.51-7.59(3H，m)，7.83-7.91(2H，m)，8.19(1H，m)，8.85-8.92(2H，m).
MS(ESI
+)：m/z 403，405(M+H).
Following compound is to obtain with embodiment 175 essentially identical modes.
Embodiment 520
5-{4-(3-cyano-phenyl)-7-ethyl-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.36-1.57(4H，m)，2.16(2H，t，J＝7Hz)，2.51-2.62(2H，m)，3.03(2H，q，J＝7Hz)，4.69(2H，s)，4.78(2H，s)，5.87(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.35(2H，d，J＝5Hz)，7.61(2H，d，J＝5Hz)，7.67(1H，s)，7.77(1H，m)，8.54(2H，d，J＝5Hz).
MS(ESI
-)：m/z 467，MS(ESI
+)：m/z 469.
Embodiment 521
5-{4-[3-(aminocarboxyl) phenyl]-7-ethyl-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.47-1.68(4H，m)，2.15-2.40(2H，m)，2.40-2.56(1H，m)，2.82-2.96(1H，m)，3.05(2H，q，J＝7Hz)，4.68(2H，s)，4.72(1H，d，J＝17Hz)，4.93(1H，d，J＝17Hz)，5.83(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.31(2H，d，J＝5Hz)，7.39(1H，br)，7.45(1H，d，J＝8Hz)，7.58(1H，t，J＝8Hz)，7.69(1H，br)，7.77(1H，br)，7.98(1H，d，J＝8Hz)，8.57(2H，d，J＝5Hz).
MS(ESI
-)：m/z 485，MS(ESI
+)：m/z 487.
Embodiment 522
5-{4-(3-cyano-phenyl)-7-ethyl-2-[(2-pyrazinyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.30-1.57(4H，m)，2.18(2H，m)，2.48-2.65(2H，m)，3.03(2H，q，J＝7Hz)，4.83(2H，s)，4.85(2H，s)，5.86(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.61(2H，d，J＝5Hz)，7.68(1H，s)，7.77(1H，m)，8.53(2H，d，J＝5Hz)，8.76(1H，s).
MS(ESI
-)：m/z 468，MS(ESI
+)：m/z 470.
Embodiment 523
5-{4-(3-cyano-phenyl)-7-ethyl-2-[(3-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.38-1.57(4H，m)，2.15(2H，t，J＝7Hz)，2.49-2.62(2H，m)，3.04(2H，q，J＝7Hz)，4.69(2H，s)，4.76(2H，s)，5.85(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.33(1H，m)，7.62(2H，m)，7.67(1H，s)，7.73-7.82(2H，m)，8.53(1H，d，J＝5Hz)，8.67(1H，s).
MS(ESI
-)：m/z 467，MS(ESI
+)：m/z 469.
Embodiment 524
5-[4-(3-cyano-phenyl)-7-ethyl-2-(5-methyl-3-different _ azoles base) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H-NMR(CDCl
3)δ1.34-1.52(7H，m)，2.17(2H，t，J＝7Hz)，2.53(3H，s)，2.77(2H，m)，3.03(2H，q，J＝7Hz)，5.89(1H，d，J＝5Hz)，6.54(1H，s)，6.67(1H，d，J＝5Hz)，7.63(2H，m)，7.68(1H，s)，7.78(1H，m).
Embodiment 525
5-[4-(3-cyano-phenyl)-7-ethyl-2-(2-thienyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H-NMR(CDCl
3)δ1.23-1.42(7H，m)，2.07(2H，t，J＝7Hz)，2.58(2H，m)，3.03(2H，q，J＝7Hz)，5.87(1H，d，J＝5hz)，6.56(1H，d，J＝5Hz)，7.13(1H，m)，7.36(1H，m)，7.43(1H，d，J＝5Hz)，7.62(2H，m)，7.70(1H，s)，7.76(1H，m).
Embodiment 526
3-[4-(3-cyano-phenyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] propionic acid
1H-NMR(CDCl
3)δ1.36(3H，t，J＝7Hz)，1.99(2H，m)，2.75(2H，m)，3.00(2H，q，J＝7Hz)，5.93(1H，d，J＝5Hz)，6.63(1H，d，J＝5Hz)，7.42-7.55(5H，m)，7.57-7.78(4H，m).
Embodiment 527
5-[4-(3-chloro-phenyl-)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
1H-NMR(CDCl
3)δ1.03-1.25(4H，m)，1.36(3H，t，J＝7Hz)，1.90(2H，t，J＝7Hz)，2.41(2H，m)，3.00(2H，q，J＝7Hz)，5.97(1H，d，J＝5Hz)，6.59(1H，d，J＝5Hz)，7.28(1H，m)，7.35-7.54(8H，m).
MS(ESI
+)：m/z 433(M+H)
Following compound is to obtain with embodiment 180 essentially identical modes.
Embodiment 528
5-[4-(3-cyano-phenyl)-7-ethyl-2-(5-methyl-3-different _ azoles base) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H-NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.32-1.46(5H，m)，1.72(2H，m)，2.10(2H，t，J＝7Hz)，2.54(3H，s)，2.78(2H，m)，3.03(2H，q，J＝7Hz)，4.06(2H，q，J＝7Hz)，5.89(1H，d，J＝5Hz)，6.54(1H，s)，6.66(1H，d，J＝5Hz)，7.62(2H，m)，7.67(1H，s)，7.77(1H，m).
Following compound is to obtain with preparation example 176 essentially identical modes.
Embodiment 529
4-[4-(aminocarboxyl)-3-bromophenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-ethyl formate also
1H-NMR(CDCl
3)δ1.03(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，2.60(3H，s)，3.03(2H，q，J＝7Hz)，4.07(2H，q，J＝7Hz)，5.83(1H，s，br)，6.19(1H，s，br)，6.28(1H，d，J＝5Hz)，6.67(1H，d，J＝5Hz)，7.46(1H，d，J＝8Hz)，7.72(1H，s)，7.77(1H，d，J＝8Hz).
Following compound is to obtain with embodiment 184 essentially identical modes.
Embodiment 530
3-[2-(cyclopentyl amino)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile
1H-NMR(CDCl
3)δ1.36(3H，t，J＝7Hz)，1.51-1.80(6H，m)，2.15(2H，m)，2.96(2H，q，J＝7Hz)，3.05(3H，s)，4.27(1H，m)，5.94(1H，d，J＝5Hz)，6.47-6.53(2H，m)，7.53-7.59(3H，m)，7.74(1H，m).
Embodiment 531
3-[7-ethyl-2-(methylamino)-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile
1H-NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，2.94-3.07(8H，m)，5.95(1H，d，J＝5Hz)，6.50(2H，m)，7.54-7.59(3H，m)，7.74(1H，m).
Following compound is to obtain with embodiment 225 essentially identical modes.
Embodiment 532
Three (2; the 2-neopentanoic acid) (2R; 3R; 4S, 5S, 6R)-2-({ 3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1; 2-b] pyridazine-3-yl] propionyl } amino)-6-{[(2; 2-dimethyl propylene acyl group) oxygen base] methyl } tetrahydrochysene-2H-pyrans-3,4,5-three basic esters
1H-NMR(CDCl
3)δ1.07(9H，s)，1.11(9H，s)，1.16(9H，s)，1.18(9H，s)，1.37(3H，t，J＝7Hz)，2.23(2H，m)，2.84(2H，m)，3.03(2H，q，J＝7Hz)，3.48(3H，s)，3.91-4.21(3H，m)，4.62-4.67(2H，m)，5.00-5.26(3H，m)，5.43(2H，m)，5.91(1H，d，J＝5Hz)，6.55(1H，m，br)，6.62(1H，d，J＝5Hz)，7.84(1H，m)，8.51(1H，m)，8.77(1H，m).
Following compound is to obtain with embodiment 226 essentially identical modes.
Embodiment 533
[4-(3-chloro-phenyl-)-7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-3-yl] methyl alcohol
1H-NMR(CDCl
3)δ1.40(3H，t，J＝7Hz)，2.53(1H，t，J＝7Hz)，3.07(2H，q，J＝7Hz)，4.48(2H，m)，6.23(1H，d，J＝5Hz)，6.62(1H，m)，6.71(1H，d，J＝5Hz)，7.10(1H，d，J＝5Hz)，7.46-7.52(3H，m)，7.61(1H，m)，7.64(1H，m).
Embodiment 534
[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] methyl alcohol
1H NMR(CDCl
3)δ1.38(3H，t，J＝8Hz)，3.05(2H，q，J＝8Hz)，3.45-3.55(4H，m)，4.40(2H，brd，J＝7Hz)，4.77(2H，br s)，6.22(1H，d，J＝5Hz)，6.70(1H，d，J＝5Hz)，8.11(1H，m)，8.74(1H，br s)，8.80(1H，d，J＝2Hz).
MS(ESI
+)：m/z 302(M+H).
Following compound is to obtain with embodiment 227 essentially identical modes.
Embodiment 535
Nitrilotriacetic (2R, 3S, 4S, 5R, 6R)-and the 2-[(acetoxyl group) methyl]-6-(5-[4-(3-cyano-phenyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-yl also] and amyl group } the oxygen base) tetrahydrochysene-2H-pyrans-3,4,5-three basic esters
1H-NMR(CDCl
3)δ0.82-1.18(6H，m)，1.37(3H，t，J＝7Hz)，1.92-2.17(14H，m)，2.35(2H，m)，3.01(2H，q，J＝7Hz)，3.16(1H，m)，3.62(1H，m)，3.85(1H，m)，4.11(2H，m)，4.10(2H，m)，4.30(1H，d，J＝8.1Hz)，4.96(1H，m)，5.11(1H，m)，5.35(1H，m)，5.90(1H，d，J＝5Hz)，6.62(1H，d，J＝5Hz)，7.44-7.53(5H，m)，7.60-7.80(4H，m).
Following compound is to obtain with embodiment 228 essentially identical modes.
Embodiment 536
3-[7-ethyl-2-(methylol)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(CDCl
3)δ1.19(3H，t，J＝7Hz)，1.39(3H，t，J＝7Hz)，2.33(2H，t，J＝7Hz)，2.43(3H，s)，2.70-2.82(2H，m)，3.04(2H，q，J＝7Hz)，3.71(1H，t，J＝5Hz)，4.05(2H，q，J＝7Hz)，4.89(2H，d，J＝5Hz)，5.98(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.52(1H，s)，8.42(1H，d，J＝2Hz)，8.56(1H，d，J＝2Hz).
MS(ESI
+)：m/z 368.
Embodiment 537
4-[7-ethyl-2-(methylol)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，1.39(3H，t，J＝7Hz)，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＝7Hz)，3.86(1H，t，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.90(2H，m)，5.96(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.53(1H，s)，8.44(1H，s)，8.56(1H，s).
MS(ESI
+)：m/z 382.
Embodiment 538
5-[4-(3-cyano-phenyl)-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.26(3H，t，J＝7Hz)，1.39(3H，t，J＝7Hz)，1.46-1.65(4H，m)，2.16(2H，t，J＝7Hz)，2.32-2.44(2H，m)，3.04(2H，q，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.86(2H，s)，5.91(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.58-7.68(3H，m)，7.75-7.82(1H，m).
MS(ESI
+)：m/z 406.
Embodiment 539
4-[4-(5-bromo-3-pyridyl]-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H NMR(CDCl
3)δ1.25(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.64-1.79(2H，m)，2.23(2H，t，J＝7Hz)，2.42-2.53(2H，m)，3.04(2H，q，J＝7Hz)，4.10(2H，q，J＝7Hz)，4.91(2H，s)，5.97(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.89(1H，m)，8.56(1H，d，J＝2Hz)，8.80(1H，d，J＝2Hz).
MS(ESI
+)：m/z 446 448.
Embodiment 540
3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(CDCl
3)δ1.20(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，2.32(2H，m)，2.68-2.90(2H，m)，3.03(2H，q，J＝7Hz)，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).
MS(ESI
+)：m/z 432 434.
Embodiment 541
4-[4-(5-chloro-3-pyridyl]-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H NMR(300MHz，CDCl
3)δ1.22(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.67(2H，tt，J＝7,7Hz)，2.20(2H，t，J＝7Hz)，2.37-2.79(2H，m)，3.04(2H，q，J＝7Hz)，3.77(1H，t，J＝4Hz)，4.07(2H，q，J＝7Hz)，4.91(2H，d，J＝4Hz)，5.96(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.73(1H，dd，J＝2,2Hz)，8.52(1H，d，J＝2Hz)，8.70(1H，d，J＝2Hz).
Embodiment 542
3-[4-(3-chloro-phenyl-)-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(300MHz，CDCl
3)δ1.20(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，2.31(2H，t，J＝8Hz)，2.85(2H，t，J＝8Hz)，3.04(2H，q，J＝7Hz)，3.69-3.75(1H，br s)，4.06(2H，q，J＝7Hz)，4.88(2H，s)，6.00(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，7.23-7.26(1H，m)，7.36(1H，s)，7.44-7.46(2H，m).
Embodiment 543
4-[4-(the 3-chloro-phenyl-]-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H NMR (CDCl
3) δ 1.21 (3H, t, J=8Hz), 1.38 (3H, t, J=8Hz), 1.57 (3H, s), 1.59-1.74 (2H, m), 2.20 (2H, t, J=8Hz), 2.37-2.47 (2H, m), 3.03 (2H, q, J=8Hz), 3.84 (1H, t, J=5Hz), 4.06 (2H, q, J=8Hz), 4.39 (2H, d, J=5Hz), 5.32 (2H, s), 5.96 (1H, d, J=5hz), 6.56 (J=5Hz), (1H is with CDCl for 7.21-7.29 for 1H, d
3Overlapping), 7.36 (1H, br s), 7.39-7.47 (2H, m).
Embodiment 544
9-(5-bromo-3-pyridyl)-6-ethyl-1H, 3H-furo [3,4-e] pyrrolo-[1,2-b] pyridazine-1-ketone
1H NMR(CDCl
3)δ1.42(3H，t，J＝8Hz)，3.11(2H，q，J＝8Hz)，5.32(2H，s)，6.87(1H，d，J＝5Hz)，6.99(1H，d，J＝5Hz)，8.20(1H，m)，8.83-8.87(2H，m).
MS(ESI
+)：m/z 358，360(M+H).
4-(5-bromo-3-pyridyl)-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-formic acid
1H NMR(CDCl
3-CD3OD)δ1.40(3H，t，J＝8Hz)，3.09(2H，q，J＝8Hz)，4.93(2H，s)，6.34(1H，d，J＝5Hz)，6.79(1H，d，J＝5Hz)，7.96(1H，m)，8.55(1H，br s)，8.73(1H，br s).
MS(ESI
+)：m/z 376，378(M+H).
Embodiment 545
3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl]-N-[(2R, 3R, 4S, 5R, 6R)-3,4, and 5-trihydroxy-6-(methylol) tetrahydrochysene-2H-pyrans-2-yl] propionic acid amide
1H-NMR(DMSO-d
6)δ1.30(3H，t，J＝7Hz)，2.21(1H，m)，2.96(2H，q，J＝7Hz)，3.25-3.45(8H，m)，3.66(1H，m)，4.40(1H，m)，4.55-4.67(5H，m)，4.75(1H，m)，5.85(1H，d，J＝5Hz)，6.66(1H，d，J＝5Hz)，8.23(1H，m)，8.33(1H，d，br，J＝7Hz)，8.61(1H，m)，8.84(1H，m).
Embodiment 546
3-[7-ethyl-2-phenyl-3-(5-{[(2R, 3R, 4S, 5R, 6R)-3,4, and 5-trihydroxy-6-(methylol) tetrahydrochysene-2H-pyrans-2-yl] the oxygen base } amyl group) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile
1H-NMR(CDCl
3)δ0.85-1.38(6H，m)，1.46(3H，t，J＝7Hz)，2.13(2H，m)，2.38(2H，m)，2.65(1H，m)，2.73(1H，m)，3.02(2H，q，J＝7Hz)，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＝5Hz)，663(1H，d，J＝5Hz)，7.42-7.55(5H，m)，7.60-7.79(4H，m).
Following compound is to obtain with embodiment 235 essentially identical modes.
Embodiment 547
N-(2-amino-ethyl)-3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid amide
1H-NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，2.29(2H，m)，2.72-3.07(6H，m)，3.33(2H，q，J＝7Hz)，3.49(3H，s)，4.68(2H，s)，5.93(1H，d，J＝5Hz)，6.06(1H，m，br)，6.62(1H，d，J＝5Hz)，7.89(1H，m)，8.55(1H，m)，8.77(1H，m).
MS (ESI
+) m/z:460 and 462 (M+H)
Following compound is to obtain with embodiment 268 essentially identical modes.
Embodiment 548
3-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } ethyl propionate
1H NMR(CDCl
3)δ1.15(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，2.37(2H，t，J＝7Hz)，2.43(3H，s)，2.86-3.01(2H，m)，3.03(2H，q，J＝7Hz)，3.99(2H，q，J＝7Hz)，4.68(2H，s)，4.81(2H，s)，5.95(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.27(2H，d，J＝7Hz)，7.51(1H，s)，8.43(1H，s)，8.56(1H，s)，8.57(2H，d，J＝7Hz).
MS(ESI
+)：m/z 459.
Embodiment 549
3-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(2-pyrazinyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } ethyl propionate
1H NMR(CDCl
3)δ1.16(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，2.39(2H，t，J＝7Hz)，2.43(3H，s)，2.88-3.03(2H，m)，3.04(2H，q，J＝7Hz)，4.01(2H，q，J＝7Hz)，4.83(2H，s)，4.90(2H，s)，5.94(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.53(1H，s)，8.42(1H，m)，8.48-8.55(3H，m)，8.76(1H，s).
MS(ESI
+)：m/z 460.
Embodiment 550
3-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(2-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } ethyl propionate
1H NMR(CDCl
3)δ1.15(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，2.40(2H，t，J＝7Hz)，2.42(3H，s)，2.88-3.00(2H，m)，3.03(2H，q，J＝7Hz)，3.99(2H，q，J＝7Hz)，4.79(2H，s)，4.86(2H，s)，5.92(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，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.
Embodiment 551
4-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } ethyl butyrate
1H NMR(CDCl
3)δ1.18(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.60-1.80(2H，m)，2.13-2.25(2H，m)，2.43(3H，s)，2.53-2.76(2H，m)，3.03(2H，q，J＝7Hz)，4.03(2H，q，J＝7Hz)，4.68(2H，s)，4.83(2H，m)，5.92(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.27(2H，d，J＝5Hz)，7.53(1H，s)，8.42(1H，s)，8.53(1H，s)，8.55(2H，d，J＝5Hz).
MS(ESI
+)：m/z 473.
Embodiment 552
5-{4-(3-cyano-phenyl)-7-ethyl-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.35-1.57(4H，m)，2.11(2H，t，J＝7Hz)，2.53-2.65(2H，m)，3.03(2H，q，J＝7Hz)，4.03(2H，q，J＝7Hz)，4.67(2H，s)，4.78(2H，s)，5.87(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.28(2H，d，J＝5Hz)，7.61(2H，m)，7.66(1H，s)，7.78(1H，m)，8.58(2H，d，J＝5Hz).
MS(ESI
+)：m/z 497.
Embodiment 553
5-{4-(3-cyano-phenyl)-7-ethyl-2-[(2-pyrazinyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.35-1.58(4H，m)，2.11(2H，t，J＝7Hz)，2.55-2.65(2H，m)，3.03(2H，q，J＝7Hz)，4.10(2H，q，J＝7Hz)，4.82(2H，s)，4.86(2H，s)，5.86(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，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.
Embodiment 554
5-{4-(3-cyano-phenyl)-7-ethyl-2-[(3-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.39(3H，t，J＝7Hz)，1.32-1.66(4H，m)，2.10(2H，t，J＝7Hz)，2.48-2.60(2H，m)，3.03(2H，q，J＝7Hz)，4.08(2H，q，J＝7Hz)，4.66(2H，s)，4.75(2H，s)，5.86(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.28(1H，m)，7.58-7.63(2H，m)，7.66(1H，s)，7.66-7.80(2H，m)，8.54(1H，m)，8.62(1H，m).
MS(ESI
+)：m/z 497.
Embodiment 555
5-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.40-1.62(4H，m)，2.16(2H，t，J＝7Hz)，2.53-2.71(2H，m)，3.05(2H，q，J＝7Hz)，4.09(2H，q，J＝7Hz)，4.67(2H，s)，4.78(2H，s)，5.93(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.31(2H，d，J＝5Hz)，7.88(1H，m)，8.56(1H，d，J＝2Hz)，8.58(2H，d，J＝5Hz)，8.79(1H，d，J＝2Hz).
Embodiment 556
5-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(3-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.40(3H，t，J＝7Hz)，1.30-1.60(4H，m)，2.15(2H，t，J＝7Hz)，2.50-2.68(2H，m)，3.06(2H，q，J＝7Hz)，4.12(2H，q，J＝7Hz)，4.68(2H，s)，4.78(2H，s)，5.95(1H，m)，6.63(1H，m)，7.24-7.38(1H，m)，7.75(1H，m)，7.89(1H，m)，8.58(2H，s)，8.64(1H，s)，8.80(1H，s).
MS(ESI
+)：m/z 551 553.
Embodiment 557
5-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
1H NMR(CDCl
3)δ1.24(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.58(4H，m)，2.12(2H，t，J＝7Hz)，2.53-2.68(2H，m)，3.03(2H，q，J＝7Hz)，4.10(2H，q，J＝7Hz)，4.78(2H，s)，4.84(2H，s)，5.92(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.22(1H，m)，7.48(1H，d，J＝8Hz)，7.68-7.75(1H，m)，7.88(1H，m)，8.57(2H，m)，8.78(1H，d，J＝2Hz).
Embodiment 558
5-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-pyrazinyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.40-1.62(4H，m)，2.15(2H，t，J＝7Hz)，2.53-2.72(2H，m)，3.05(2H，q，J＝7Hz)，4.08(2H，q，J＝7Hz)，4.82(2H，s)，4.86(2H，s)，5.94(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.88(1H，m)，8.52(2H，m)，8.55(1H，d，J＝2Hz)，8.74(1H，m)，8.79(1H，d，J＝2Hz).
MS(ESI
+)：m/z 552 554.
Embodiment 559
4-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } ethyl butyrate
1H NMR(CDCl
3)δ1.19(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.60-1.80(2H，m)，2.22(2H，t，J＝7Hz)，2.55-2.74(2H，m)，3.05(2H，q，J＝7Hz)，4.06(2H，q，J＝7Hz)，4.69(2H，s)，4.83(2H，s)，5.96(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.30(2H，d，J＝6Hz)，7.88(1H，m)，8.56(2H，d，J＝6Hz)，8.57(1h，m)，8.80(1H，m).
MS(ESI
+)：m/z 537 539.
Embodiment 560
4-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(3-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } ethyl butyrate
1H NMR(CDCl
3)δ1.26(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.55-1.82(2H，m)，2.18(2H，t，J＝7Hz)，2.52-2.72(2H，m)，3.05(2H，q，J＝7Hz)，4.05(2H，q，J＝7Hz)，4.68(2H，s)，4.83(2H，s)，5.94(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.28(1H，m)，7.73(1H，d，J＝8Hz)，7，88(1H，m)，8.54(2H，m)，8.62(1H，s)，8.79(1H，s)
Embodiment 561
4-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } ethyl butyrate
1H NMR(CDCl
3)δ1.26(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.63-1.82(2H，m)，2.18(2H，t，J＝7Hz)，2.55-2.75(2H，m)，3.06(2H，q，J＝7Hz)，4.00(2H，q，J＝7Hz)，4.80(2H，s)，4.88(2H，s)，5.93(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.22(1H，m)，7.48(1H，d，J＝8Hz)，7.71(1H，t，J＝8Hz)，7.89(1H，m)，8.55(2H，m)，8.78(1H，d，J＝2Hz).
MS(ESI
+)：m/z 537 539.
Embodiment 562
4-{4-(5-bromo-3-pyridyl)-2-[(cyclo propyl methoxy) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } ethyl butyrate
1H NMR(CDCl
3)δ0.25(2H，m)，0.60(2H，m)，1.08-1.22(1H，m)，1.22(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.69-1.82(2H，m)，2.21(2H，t，J＝7Hz)，2.56-2.72(2H，m)，3.03(2H，q，J＝7Hz)，3.42(2H，d，J＝7Hz)，4.04(2H，q，J＝7Hz)，4.73(2H，s)，5.91(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，7.89(1H，m)，8.56(1H，d，J＝2Hz)，8.79(1H，d，J＝2Hz).
MS(ESI
+)：m/z 500 502.
Embodiment 563
4-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-pyrazinyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } ethyl butyrate
1H NMR(CDCl
3)δ1.19(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.70-1.82(2H，m)，2.23(2H，t，J＝7Hz)，2.56-2.76(2H，m)，3.06(2H，q，J＝7Hz)，4.04(2H，q，J＝7Hz)，4.84(2H，s)，4.95(2H，m)，5.94(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，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.
Embodiment 564
3-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } ethyl propionate
1H NMR(CDCl
3)δ1.16(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，2.41(2H，t，J＝7Hz)，2.85-3.07(2H，m)，3.06(2H，q，J＝7Hz)，4.02(2H，q，J＝7Hz)，4.68(2H，s)，4.81(2H，s)，5.95(1H，d，J＝4Hz)，6.65(1H，d，J＝4Hz)，7.31(2H，d，J＝6Hz)，7.87(1H，m)，8.55(1H，m)，8.56(2H，d，J＝6Hz)，8.79(1H，d，J＝2Hz).
MS(ESI
+)：m/z 523 525.
Embodiment 565
4-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) oxyethyl group] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) ethyl butyrate
1H NMR(CDCl
3)δ1.20(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.46-1.93(8H，m)，2.21(2H，t，J＝7Hz)，2.55-2.76(2H，m)，3.02(2H，q，J＝7Hz)，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＝7Hz)，4.63(1H，m)，4.77(2H，s)，5.91(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.89(1H，m)，8.56(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
Embodiment 566
4-{4-(5-chloro-3-pyridyl)-7-ethyl-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } ethyl butyrate
1H NMR(300MHz，CDCl
3)δ1.19(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.70(2H，t，J＝7Hz)，2.19(2H，t，J＝7Hz)，2.55-2.67(2H，m)，3.04(2H，q，J＝7Hz)，4.03(2H，q，J＝7Hz)，4.69(2H，s)，4.83(2H，s)，5.94(1H，d，J＝5Hz)，6.63(1H，d，J＝5Hz)，7.29(2H，d，J＝6Hz)，7.73(1H，dd，J＝2,2Hz)，8.52(1H，d，J＝2Hz)，8.58(2H，d，J＝6Hz)，8.69(1H，d，J＝2Hz).
Embodiment 567
3-[4-(3-chloro-phenyl-)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR (CDCl
3) δ 1.20 (3H, t, J=8Hz), 1.37 (3H, t, J=8Hz), and 2.33-2.44 (2H, m), 2.84-2.94 (2H, m), 3.03 (2H, q, J=8Hz), 3.45 (3H, s), 4.05 (2H, q, J=8Hz), 4.64 (2H, s), 5.94 (1H, d, J=5Hz), 6.58 (1H, d, J=5Hz), (1H is with CDCl for 7.21-7.29
3Overlapping), 7.36 (1H, br s), 7.38-7.46 (2H, m).
Embodiment 568
4-[4-(the 3-chloro-phenyl-]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H NMR (CDCl
3) δ 1.20 (3H, t, J=8Hz), 1.37 (3H, t, J=8Hz), and 1.62-1.78 (2H, m), 2.14-2.28 (2H, m), 2.53-2.66 (2H, m), 3.04 (2H, q, J=8Hz), 3.46 (3H, s), 4.04 (2H, q, J=8Hz), 4.65 (2H, s), 5.93 (1H, d, J=5Hz), 6.58 (J=5Hz), (1H is with CDCl for 7.21-7.29 for 1H, d
3Overlapping), 7.36 (1H, br s), 7.39-7.46 (2H, m).
Following compound is to obtain with embodiment 272 essentially identical modes.
Embodiment 569
5-{4-(5-bromo-3-pyridyl)-2-[(1,1-dioxo-4-thio-morpholinyl) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } Valeric acid ethylester
1H NMR(300MHz，CDCl
3)δ1.23(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.39-1.53(4H，m)，2.19(2H，t，J＝7Hz)，2.50-2.61(2H，m)，3.00(2H，q，J＝7Hz)，3.10(4H，t，J＝6Hz)，3.21(4H，t，J＝6Hz)，3.85(2H，s)，4.10(2H，q，J＝7Hz)，5.92(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.88(1H，dd，J＝2，2Hz)，8.55(1H，d，J＝2Hz)，8.80(1H，d，J＝2Hz).
Embodiment 570
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(4-thiomorpholine ylmethyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(300MHz，CDCl
3)δ1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.41-1.54(4H，m)，2.19(2H，t，J＝7Hz)，2.50-2.61(2H，m)，2.66(4H，t，J＝4Hz)，2.85(4H，t，J＝4Hz)，3.01(2H，q，J＝7Hz)，3.67(2H，s)，4.10(2H，q，J＝7H)，5.88(1H，d，J＝5Hz)，6.57(1H，d，J＝5Hz)，7.88(1H，dd，J＝2，2Hz)，8.55(1H，d，J＝2Hz)，8.79(1H，d，J＝2Hz).
Embodiment 571
5-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[4-(2-hydroxyethyl)-1-piperazinyl] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) Valeric acid ethylester
1H NMR(300MHz，CDCl
3)δ1.23(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.40-1.55(4H，m)，2.18(2H，t，J＝7Hz)，2.48-2.66(12H，m)，3.02(2H，q，J＝7Hz)，3.61(2H，t，J＝5Hz)，3.66(2H，s)，4.10(2H，q，J＝7Hz)，5.88(1H，d，J＝4Hz)，6.57(1H，d，J＝4Hz)，7.88(1H，dd，J＝2,2Hz)，855(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
Embodiment 572
4-[4-(5-chloro-3-pyridyl]-7-ethyl-2-(4-thiomorpholine ylmethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H NMR(300MHz，CDCl
3)δ1.21(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.70(2H，tt，J＝7,7Hz)，2.19(2H，t，J＝7Hz)，2.50-2.67(6H，m)，2.86(4H，t，J＝5Hz)，3.02(2H，q，J＝7Hz)，3.70(2H，s)，4.05(2H，q，J＝5Hz)，5.89(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.74(1H，dd，J＝2,2Hz)，8.52(1H，d，J＝2Hz)，8.68(1H，d，J＝2Hz).
Embodiment 573
4-[4-(5-chloro-3-pyridyl]-7-ethyl-2-(4-morpholinyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H NMR(300MHz，CDCl
3)δ1.21(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.72(2H，tt，J＝7,7Hz)，2.20(2H，t，J＝7Hz)，2.56-2.69(6H，m)，3.02(2H，q，J＝7Hz)，3.68-3.71(6H，m)，4.05(2H，q，J＝7Hz)5.89(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.74(1H，dd，J＝2,2Hz)，8.53(1H，d，J＝2Hz)，8.69(1H，d，J＝2Hz).
Embodiment 574
3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(4-morpholinyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(300MHz，CDCl
3)δ1.21(3H，t，J＝7Hz)，1.34(3H，t，J＝7Hz)，2.47-2.54(2H，m)，2.59(4H，t，J＝5Hz)，2.81-2.95(2H，m)，3.02(2H，q，J＝7Hz)，3.67(4H，t，J＝5Hz)，3.69(2H，s)，4.07(2H，q，J＝7Hz)，5.90(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，7.88(1H，dd，J＝2，2Hz)，8.55(1H，d，J＝2Hz)，8.79(1H，d，J＝2Hz).
Embodiment 575
4-[4-(5-bromo-3-pyridyl]-7-ethyl-2-(4-morpholinyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H NMR(300MHz，CDCl
3)δ1.21(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.73(2H，tt，J＝7，7Hz)，2.20(2H，t，J＝7Hz)，2.55-2.69(6H，m)，3.02(2H，q，J＝7Hz)，3.69(4H，t，J＝5Hz)，4.05(2H，q，J＝7Hz)，5.89(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.89(1H，dd，J＝2,2Hz)，8.57(1H，d，J＝2Hz)，8.79(1H，d，J＝2Hz).
Embodiment 576
4-{4-(5-chloro-3-pyridyl)-2-[(cyclopropyl amino) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } ethyl butyrate
1H NMR(300MHz，CDCl
3)δ0.46-0.52(4H，m)，1.21(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.71(2H，tt，J＝8，8Hz)，2.21(2H，t，J＝8Hz)，2.32-2.39(1H，m)，2.45-2.54(2H，m)，3.04(2H，q，J＝7Hz)，4.06(2H，q，J＝7Hz)，4.07(2H，s)，5.89(1H，d，J＝4Hz)，6.57(1H，d，J＝4Hz)，7.72(1H，dd，J＝2,2Hz)，8.50(1H，d，J＝2Hz)，8.68(1H，d，J＝2Hz).
Embodiment 577
5-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[(2-phenoxy group ethyl) amino] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) Valeric acid ethylester
1H NMR(300MHz，CDCl
3)δ1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.56(4H，m)，2.18(2H，t，J＝8Hz)，2.41-2.52(2H，m)，3.04(2H，q，J＝7Hz)，3.19(2H，t，J＝5Hz)，4.07(2H，s)，4.09(2H，q，J＝7Hz)，4.17(2H，t，J＝5Hz)，5.90(1H，d，J＝4Hz)，6.57(1H，d，J＝4Hz)，6.92-6.98(3H，m)，7.29-7.32(2H，m)，7.86(1H，dd，J＝2,2Hz)，8.54(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
Embodiment 578
5-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[(2-hydroxyethyl) (methyl) amino] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) Valeric acid ethylester
1H NMR(300MHz，CDCl
3)δ1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.42-1.63(4H，m)，2.20(2H，t，J＝8Hz)，2.38(3H，s)，2.53-2.64(2H，m)，2.75(2H，t，J＝5Hz)，3.02(2H，q，J＝7Hz)，3.66(2H，t，J＝5Hz)，3.77(2H，s)，4.10(2H，q，J＝7Hz)，5.90(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，7.88(1H，dd，J＝2,2Hz)，8.55(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
Embodiment 579
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(piperidino methyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(300MHz，CDCl
3)δ1.23(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.42-1.58(6H，m)，1.69(4H，tt，J＝5，5Hz)，2.18(2H，t，J＝8Hz)，2.53-2.64(2H，m)，3.02(2H，q，J＝7Hz)，3.19(4H，t，J＝5Hz)，3.60(2H，s)，4.07(2H，q，J＝7Hz)，5.86(1H，d，J＝5Hz)，6.54(1H，d，J＝5Hz)，7.89(1H，dd，J＝2,2Hz)，8.56(1H，d，J＝2Hz)，8.75(1H，d，J＝2Hz).
Embodiment 580
3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(4-thiomorpholine ylmethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H NMR(300MHz，CDCl
3)δ1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，2.46(2H，t，J＝8Hz)，2.64(4H，t，J＝5Hz)，2.86(6H，m)，3.02(2H，q，J＝7Hz)，3.69(2H，s)，4.06(2H，q，J＝7Hz)，5.91(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.88(1H，dd，J＝2,2Hz)，8.56(1H，d，J＝2Hz)，8.80(1H，d，J＝2Hz).
Embodiment 581
3-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[4-(2-hydroxyethyl)-1-piperazinyl] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) ethyl propionate
1H NMR(300MHz，CDCl
3)δ1.21(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，2.46-2.63(12H，m)，2.80-2.94(2H，m)，3.03(2H，q，J＝7Hz)，3.61(2H，t，J＝5Hz)，3.70(2H，s)，4.08(2H，q，J＝7Hz)，5.90(1H，d，J＝5Hz)，6.59(1H，d，J＝5Hz)，7.88(1H，dd，J＝2,2Hz)，8.56(1H，d，J＝2Hz)，8.79(1H，d，J＝2Hz).
Embodiment 582
5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(1-pyrrolidyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(300MHz，CDCl
3)δ1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.55(4H，m)，1.75-1.80(4H，m)，2.19(2H，t，J＝7Hz)，2.54-2.66(6H，m)，3.02(2H，q，J＝7Hz)，3.76-3.81(2H，m)，4.10(2H，q，J＝7Hz)，5.87(1H，d，J＝5Hz)，6.55(1H，d，J＝5Hz)，7.89(1H，dd，J＝2,2Hz)，8.56(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
Embodiment 583
5-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(4-phenyl-peiperazinyl) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
1H NMR(300MHz，CDCl
3)δ1.21(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，1.41-1.54(4H，m)，2.17(2H，t，J＝7Hz)，2.53-2.68(2H，m)，2.75(4H，t，J＝5Hz)，3.03(2H，q，J＝7Hz)，3.19(4H，t，J＝5Hz)，3.73(2H，s)，4.07(2H，q，J＝7Hz)，5.89(1H，d，J＝5Hz)，6.58(1H，d，J＝5Hz)，6.85(1H，dd，J＝8，8Hz)，6.93(2H，J＝8Hz)，7.25(2H，J＝8Hz)，7.89(1H，dd，J＝2,2Hz)，8.56(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
Embodiment 584
5-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[(2-methoxy ethyl) amino] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) Valeric acid ethylester
1H NMR(300MHz，CDCl
3)δ1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.41-1.60(4H，m)，2.19(2H，t，J＝7Hz)，2.43-2.52(2H，m)，2.96(2H，t，J＝5Hz)，3.03(2H，q，J＝7Hz)，3.40(3H，s)，3.58(2H，t，J＝5Hz)，3.99(2H，s)，4.10(2H，q，J＝7Hz)，5.89(1H，d，J＝5Hz)，6.56(1H，d，J＝5Hz)，7.87(1H，dd，J＝2,2Hz)，8.54(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
Following compound is to obtain with embodiment 385 essentially identical modes.
Embodiment 585
3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl]-N-[2-hydroxyl-1,1-two (methylol) ethyl] propionic acid amide
1H-NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，2.25-3.10(6H，m)，3.49(3H，s)，3.58(4H，m)，3.81(2H，m)，4.55(2H，s)，5.97(1H，d，J＝5Hz)，6.54(1H，s)，6.64(1H，d，J＝5Hz)，7.93(1H，m)，8.52(1H，m)，8.78(1H，m).
Embodiment 586
[2-(3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] and propionyl } amino) ethyl] t-butyl carbamate
1H-NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.43(9H，s)，2.26(2H，m)，2.88(2H，m)，3.04(2H，q，J＝7Hz)，3.20(2H，m)，3.28(2H，m)，3.48(3H，s)，4.67(2H，s)，4.85(1H，s，br)，5.93(1H，d，J＝5Hz)，6.20(1H，s，br)，6.63(1H，d，J＝5Hz)，7.88(1H，m)，8.53(1H，m)，8.79(1H，m).
Following compound is to obtain with embodiment 330 essentially identical modes.
Embodiment 587
5-[2-{[2-(benzylamino)-2-oxo oxyethyl group] methyl }-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.34(3H，t，J＝7Hz)，1.33-1.55(4H，m)，2.12(2H，t，J＝7Hz)，2.43(3H，s)，2.40-2.56(2H，m)，2.96(2H，q，J＝7Hz)，4.07(2H，q，J＝7Hz)，4.19(2H，s)，4.52(2H，d，J＝7Hz)，4.76(2H，s)，5.93(1H，d，J＝4Hz)，6.59(1H，d，J＝4Hz)，7.06(1H，br)，7.23-7.38(5H，m)，7.49(1H，s)，8.40(1H，s)，8.54(1H，s).
MS(ESI
+)：m/z 543.
Following compound is to obtain with embodiment 333 essentially identical modes.
Embodiment 588
4-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(4H-1,2,4-triazole-4-ylmethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H-NMR(CDCl
3)δ1.22-1.34(6H，m)，1.67(2H，m)，2.23(2H，m)，2.51(2H，m)，2.98(2H，q，J＝7Hz)，4.21(2H，q，J＝7Hz)，5.67(2H，m)，5.97(1H，d，J＝5Hz)，6.63(1H，d，J＝5Hz)，7.85(1H，m)，7.96(1H，s)，8.34(1H，s)，8.53(1H，m)，8.79(1H，m).
Following compound is to obtain with embodiment 336 essentially identical modes.
Embodiment 589
5-(7-ethyl-4-(5-methyl-3-pyridyl)-2-{[(benzenesulfonyl) amino] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.26-1.57(4H，m)，2.16(2H，t，J＝7Hz)，2.33-2.46(2H，m)，2.42(3H，s)，2.98(2H，q，J＝7Hz)，4.11(2H，q，J＝7Hz)，4.38(2H，m)，5.91(1H，br)，5.92(1H，d，J＝4Hz)，6.58(1H，d，J＝4Hz)，7.43-755(4H，m)，7.93(2H，d，J＝8Hz)，8.33(1H，d，J＝2Hz)，8.54(1H，d，J＝2Hz).
MS(ESI
+)：m/z 535.
Following compound is to obtain with embodiment 340 essentially identical modes.
Embodiment 590
4-{4-(5-bromo-3-pyridyl)-2-[(cyclopropyl amino) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } ethyl butyrate
1H-NMR(CDCl
3)δ0.48(4H，m)，1.19(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.70(2H，t，J＝7Hz)，2.22(2H，m)，2.50(2H，m)，2.95-3.07(3H，m)，3.96-4.12(4H，m)，5.90(1H，d，J＝5Hz)，6.57(1H，d，J＝5Hz)，7.88(1H，m)，8.54(1H，m)，8.77(1H，m).
Embodiment 591
Under ice-water cooling to LiAlH
4(113mg) add [4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl acetate (600mg) and under 0 ℃, stirring the mixture 2 hours in the suspension in THF (10mL).In mixture, add sodium tartrate potassium solution and elimination insolubles.After the evaporating solvent, resistates is distributed between AcOEt and water.Separate organic layer, use the salt water washing, pass through MgSO
4Drying, and evaporation in a vacuum.By with hexane and AcOEt (5: 1-1: 1) the silica gel column chromatography purification resistates of mixture drip washing obtains also [1,2-b] pyridazine-3-yl of yellow oil 2-[4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole] ethanol (246mg).
2-[4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethanol
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，2.60(3H，s)，2.72-2.84(2H，m)，3.03(2H，q，J＝7Hz)，3.65(2H，t，J＝7Hz)，5.89(1H，d，J＝4Hz)，6.55(1H，d，J＝4Hz)，7.91(1H，t，J＝2Hz)，8.56(1H，d，J＝2Hz)，8.76(1H，d，J＝2Hz).
MS(ESI
+)：m/z 360 362.
Embodiment 592
With 3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] heating 2 hours under refluxing of propionic acid (1.07g), diphenyl phosphoryl azide (1.14g) and the mixture of Et3N (0.576mL) in BuOH (30mL).After the evaporating solvent, resistates is distributed between AcOEt and water.Separate organic layer, use NaHCO
3MgSO is passed through in the aqueous solution and salt water washing
4Drying, and evaporation in a vacuum.By using hexane and AcOEt (20: 1-3: 1) the silica gel column chromatography purification resistates of mixture drip washing, obtain yellow oil { 2-[4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl } t-butyl carbamate (450mg).
2-[4-(5-bromo-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] and ethyl } t-butyl carbamate
1H NMR(CDCl
3)δ1.37(9H，s)，1.37(3H，t，J＝7Hz)，2.64(3H，s)，2.62-2.75(2H，m)，3.03(2H，q，J＝7Hz)，3.10-3.27(2H，m)，4.40-4.52(1H，m)，5.89(1H，d，J＝4Hz)，6.55(1H，d，J＝4Hz)，7.89(1H，m)，8.53(1H，m)，8.77(1H，m).
Embodiment 593
Under ice-water cooling, in the suspension of 60%NaH (74mg) in DMF (3mL), add 3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate (200mg), and under 0 ℃, stirred the mixture 0.5 hour.Under ice-water cooling, to wherein adding 3-(brooethyl) pyridine hydrobromide (234mg), and at room temperature stirred the mixture 2 hours.Mixture is distributed between AcOEt and water.Water layer is separated, be acidified to pH 3-4 and extract with AcOEt with HCl.Water and salt water washing organic layer pass through MgSO
4Drying, and evaporation in a vacuum.By using CHCl
3And methyl alcohol (100: 1-20: 1) the silica gel column chromatography purification resistates of mixture drip washing obtains yellow powder 3-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(3-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } propionic acid (110mg).
3-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(3-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } propionic acid
1H NMR(CDCl
3)δ1.39(3H，t，J＝7Hz)，2.41(2H，t，J＝7Hz)，2.80-2.98(2H，m)，3.04(2H，q，J＝7Hz)，4.70(2H，s)，4.83(2H，s)，5.93(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.32-7.38(1H，m)，7.81(1H，d，J＝8Hz)，7.87(1H，m)，8.52(1H，d，J＝8Hz)，8.53(1H，d，J＝2Hz)，8.63(1H，s)，8.77(1H，d，J＝2Hz).
Following compound is to obtain with embodiment 593 essentially identical modes.
Embodiment 594
4-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-methoxy ethoxy) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } butyric acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.72-1.83(2H，m)，2.28(2H，t，J＝7Hz)，2.60-2.77(2H，m)，3.03(2H，q，J＝7Hz)，3.39(3H，s)，3.62(2H，m)，3.77(2H，m)，4.75(2H，s)，5.93(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.92(1H，m)，8.56(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
MS(ESI
-)：m/z 474 476，MS(ESI
+)：m/z 476 478.
Embodiment 595
3-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } propionic acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，2.48-2.62(2H，m)，2.98-3.10(2H，m)，3.05(2H，q，J＝7Hz)，4.82(2H，s)，4.88(2H，s)，5.94(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.27(1H，m)，7.48(1H，d，J＝8Hz)，7.77(1H，t，J＝8Hz)，7.90(1H，m)，8.56(2H，m)，8.80(1H，m).
MS(ESI
+)：m/z 495 497.
Embodiment 596
3-{4-(5-bromo-3-pyridyl)-2-[(cyclo propyl methoxy) methyl]-7-N-ethyl pyrrole N-[1,2-b] pyridazine-3-yl also } propionic acid
1H NMR(CDCl
3)δ0.25(2H，m)，0.58(2H，m)，1.12(1H，m)，1.37(3H，t，J＝7Hz)，2.40-2.63(2H，m)，2.85-3.05(2H，m)，3.02(2H，q，J＝7Hz)，3.42(2H，d，J＝7Hz)，4.73(2H，s)，5.93(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.89(1H，m)，8.55(1H，d，J＝2Hz)，8.77(1H，d，J＝2Hz).
MS(ESI
-)：m/z 456 458，MS(ESI
+)：m/z 458 460.
Embodiment 597
3-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-pyrazinyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } propionic acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，2.48(2H，t，J＝7Hz)，2.85-3.09(2H，m)，3.06(2H，q，J＝7Hz)，4.84(2H，s)，4.92(2H，s)，5.96(1H，d，J＝4Hz)，6.65(1H，d，J＝4Hz)，7.90(1H，m)，8.48-8.62(3H，m)，8.77(2H，m).
Embodiment 598
With 4-(4-(5-bromo-3-pyridyl)-7-ethyl-2-{[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) oxyethyl group] methyl } pyrrolo-[1,2-b] pyridazine-3-yl) ethyl butyrate (89mg) with the tosic acid pyridine _ (0.8mg) mixture in MeOH (5mL) heated 2 hours under refluxing.After the evaporating solvent, by using hexane and AcOEt (10: 1-1: 1) the silica gel column chromatography purification resistates of drip washing, obtain yellow oil 4-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-hydroxyl-oxethyl) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } ethyl butyrate (69mg).
4-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-hydroxyl-oxethyl) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } ethyl butyrate
1H NMR(CDCl
3)δ1.22(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.69-1.84(2H，m)，2.22(2H，t，J＝7Hz)，2.53-2.72(2H，m)，3.03(2H，q，J＝7Hz)，3.76(2H，m)，3.83(2H，m)，4.07(2H，q，J＝7Hz)，4.79(2H，s)，5.93(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.89(1H，m)，8.56(1H，d，J＝2Hz)，8.79(1H，d，J＝2Hz).
MS(ESI
+)：m/z 490 492.
Embodiment 599
Under ice-water cooling, in the suspension of 60%NaH (69.5mg) in DMF (3mL), add 5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester (200mg), and under 0 ℃, stirred the mixture 0.5 hour.To wherein adding 4-morpholine acyl chlorides (659mg) and at room temperature stirring the mixture 15 hours.Mixture is distributed between AcOEt and water.Separate organic layer, MgSO is passed through in water and salt water washing
4Drying, and evaporation in a vacuum.By using hexane and AcOEt (20: 1-1: 1) the silica gel column chromatography purification resistates of mixture drip washing, obtain yellow oil 4-morpholine formic acid [4-(5-bromo-3-pyridyl)-3-(5-oxyethyl group-5-oxo amyl group)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-2-yl also] methyl esters (75mg).
4-morpholine formic acid [4-(5-bromo-3-pyridyl)-3-(5-oxyethyl group-5-oxo amyl group)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-2-yl also] methyl esters
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.40-1.60(4H，m)，2.18(2H，t，J＝7Hz)，2.42-2.54(2H，m)，3.03(2H，q，J＝7Hz)，3.53-3.57(4H，m)，3.63-3.78(4H，m)，4.09(2H，q，J＝7Hz)，5.33(2H，s)，5.93(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.87(1H，m)，8.54(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
MS(ESI
+)：m/z 573 575.
Following compound is to obtain with embodiment 599 essentially identical modes.
Embodiment 600
5-[4-(5-bromo-3-pyridyl)-2-({ [(dimethylamino) carbonyl] oxygen base } methyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] Valeric acid ethylester
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.35-1.60(4H，m)，2.17(2H，t，J＝7Hz)，2.44-2.57(2H，m)，2.98(6H，s)，3.03(2H，q，J＝7Hz)，4.09(2H，q，J＝7Hz)，5.30(2H，s)，5.93(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.87(1H，m)，8.54(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
MS(ESI
+)：m/z 531 533.
Embodiment 601
1-pyrrolidinecarboxylic acid [4-(5-bromo-3-pyridyl)-3-(5-oxyethyl group-5-oxo amyl group)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-2-yl also] methyl esters
1H NMR(CDCl
3)δ1.23(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.38-1.60(4H，m)，1.86-1.98(4H，m)，2.17(2H，t，J＝7Hz)，2.44-2.57(2H，m)，3.03(2H，q，J＝7Hz)，3.36-3.52(4H，m)，4.11(2H，q，J＝7Hz)，5.32(2H，s)，5.92(1H，d，J＝4Hz)，6.61(1H，d，J＝4Hz)，7.87(1H，m)，8.55(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
Embodiment 602
5-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[({[methyl (phenyl) amino] carbonyl } the oxygen base) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } Valeric acid ethylester
1H NMR(CDCl
3)δ1.20(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.32-1.57(4H，m)，2.13(2H，t，J＝7Hz)，2.33-2.48(2H，m)，3.03(2H，q，J＝7Hz)，3.38(3H，s)，4.08(2H，q，J＝7Hz)，5.34(2H，s)，5.92(1H，d，J＝4Hz)，6.60(1H，d，J＝4Hz)，7.20-7.38(5H，m)，7.83(1H，s)，8.49(1H，s)，8.77(1H，s).
Embodiment 603
4-morpholine formic acid [4-(5-bromo-3-pyridyl)-3-(4-oxyethyl group-4-oxo butyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-2-yl also] methyl esters
1H NMR(CDCl
3)δ1.20(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.63-1.80(2H，m)，2.22(2H，t，J＝7Hz)，2.44-2.65(2H，m)，3.03(2H，q，J＝7Hz)，3.54(4H，m)，3.68(4H，m)，4.05(2H，q，J＝7Hz)，5.37(2H，s)，5.94(1H，d，J＝4Hz)，6.62(1H，d，J＝4Hz)，7.87(1H，m)，8.55(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
MS(ESI
+)：m/z 559 561.
Embodiment 604
4-[4-(5-bromo-3-pyridyl)-2-({ [(dimethylamino) carbonyl] oxygen base } methyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] ethyl butyrate
1H NMR(CDCl
3)δ1.20(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，1.66-1.79(2H，m)，2.20(2H，t，J＝7Hz)，2.46-2.62(2H，m)，2.97(6H，s)，3.03(2H，q，J＝7Hz)，4.04(2H，q，J＝7Hz)，5.34(2H，s)，5.93(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.89(1H，m)，8.56(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
MS(ESI
+)：m/z 517 519.
Embodiment 605
3-[4-(5-bromo-3-pyridyl)-2-({ [(dimethylamino) carbonyl] oxygen base } methyl)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-yl also] ethyl propionate
1H NMR(CDCl
3)δ1.20(3H，t，J＝7Hz)，1.36(3H，t，J＝7Hz)，2.37(2H，t，J＝7Hz)，2.82-2.93(2H，m)，2.97(6H，s)，3.03(2H，q，J＝7Hz)，4.05(2H，q，J＝7Hz)，5.32(2H，s)，5.96(1H，d，J＝4Hz)，6.63(1H，d，J＝4Hz)，7.88(1H，m)，8.54(1H，d，J＝2Hz)，8.78(1H，d，J＝2Hz).
Embodiment 606
Under frozen water cooling, in the solution of sodium hydride (93.1mg) in DMF (4mL), add 3-[4-(3-chloro-phenyl-)-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate (150mg) and under this temperature, stirring the mixture 1 hour.To wherein adding 4-(brooethyl) pyridine hydrobromide (196mg), and at room temperature stirred the mixture 1 hour.Make the reaction quenching by adding water.Use CHCl
3The extraction mixture.Water and salt water washing organic layer pass through MgSO
4Drying, and evaporation in a vacuum.By using CHCl
3The silica gel column chromatography purification resistates of the mixture drip washing of-MeOH=30-1 obtains yellow solid 3-{4-(3-chloro-phenyl-)-7-ethyl-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } propionic acid (18mg).
3-{4-(3-chloro-phenyl-)-7-ethyl-2-[(4-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } propionic acid
1H NMR(300MHz，CDCl
3)δ1.39(3H，t，J＝7Hz)，2.33(2H，t，J＝7Hz)，2.84-2.91(2H，m)，3.04(2H，q，J＝7Hz)，4.73(2H，s)，4.82(2H，s)，5.96(1H，d，J＝5Hz)，6.62(1H，d，J＝5Hz)，7.23-7.26(1H，m)，7.36-7.38(3H，m)，7.42-7.44(2H，m)，8.41(2H，d，J＝5Hz).
MS(m/z)450(M+H).
Following compound is to obtain with embodiment 606 essentially identical modes.
Embodiment 607
3-{4-(3-chloro-phenyl-)-7-ethyl-2-[(3-pyridyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } propionic acid
1H NMR(300MHz，CDCl
3)δ1.39(3H，t，J＝7Hz)，2.32-2.38(2H，m)，2.84-2.92(2H，m)，3.04(2H，q，J＝7Hz)，4.70(2H，s)，4.82(2H，s)，5.94(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.21-7.24(1H，m)，7.31-7.36(2H，m)，7.40-7.42(2H，m)，7.80(2H，d，J＝8Hz)，8.51(1H，d，J＝5Hz)，8.64(1H，s).
Embodiment 608
3-{4-(3-chloro-phenyl-)-7-ethyl-2-[(2-pyrazinyl methoxyl group) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } propionic acid
1H NMR(300MHz，CDCl
3)δ1.38(3H，t，J＝7Hz)，2.42(2H，t，J＝7Hz)，2.91-2.97(2H，m)，3.03(2H，q，J＝7Hz)，4.83(2H，s)，4.90(2H，s)，5.96(2H，d，J＝5Hz)，6.62(2H，d，J＝5Hz)，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).
Embodiment 609
To 5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] add 10%Pd/C (2mg) in the solution of valeric acid (15mg) in MeOH.Under hydrogen atmosphere (1 normal atmosphere), stirred the mixture 6 hours.By celite filter reaction mixture and concentrated filtrate in a vacuum.Resistates and hexane are ground, obtain also [1,2-b] pyridazine-3-yl of yellow solid 5-[7-ethyl-4-(2-ethyl-4-pyridyl)-2-methylpyrrole] valeric acid (14mg).
5-[7-ethyl-4-(2-ethyl-4-pyridyl)-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] valeric acid
1H NMR(CDCl
3)δ1.29-1.64(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＝5Hz)，6.53(1H，d，J＝16Hz)，6.51(1H，d，J＝5Hz)，7.25-7.32(2H，m)，8.69(1H，br s).
Embodiment 610
In ice bath to 4-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methylol) pyrrolo-[1,2-b] pyridazine-3-yl] add tributylphosphine (0.098mL), 1 successively, 3-_ azoles alkane-2-ketone (34.1mg) in the solution of ethyl butyrate (70.0mg) in toluene (1mL).After stirring 5 minutes, in mixture, add 1,1 '-(azo dicarbapentaborane) two piperidines (98.9mg).Mixture was stirred in ice bath 10 minutes and at room temperature stirred 8 hours.Add hexane (5mL), and filtering mixt.Evaporated filtrate.Preparation thin-layer chromatography (ethyl acetate-hexane=1-1) obtain yellow glue 4-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-oxo-1,3-_ azoles alkane-3-yl) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } ethyl butyrate (25.0mg).
4-{4-(5-bromo-3-pyridyl)-7-ethyl-2-[(2-oxo-1,3-_ azoles alkane-3-yl) methyl] pyrrolo-[1,2-b] pyridazine-3-yl } ethyl butyrate
1H-NMR(CDCl
3)δ1.20(3H，t，J＝7Hz)，1.369(3H，t，J＝7Hz)，1.65(3H，t，J＝7Hz)，2.25(2H，t，J＝7Hz)，2.51(2H，m)，2.99(2H，q，J＝7Hz)，3.79(2H，t，J＝7Hz)，4.04(2H，q，J＝7Hz)，4.43(2H，t，J＝7Hz)，4.69(2H，m)，5.95(1H，d，J＝5Hz)，6.61(1H，d，J＝5Hz)，7.87(1H，m)，8.55(1H，m)，8.80(1H，m).
Embodiment 611
In ice bath to 2-bromo-4-[3-(ethoxy carbonyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-4-yl also] add 1M borine-tetrahydrofuran complex solution (0.348mL) in the solution of phenylformic acid (50.0mg) in tetrahydrofuran (THF) (1mL).After at room temperature stirring 2 hours, add borine-tetrahydrofuran complex solution (0.348mL) in addition.At room temperature stirred the mixture 15 hours.Mixture is distributed between ethyl acetate and 1N hydrochloric acid.Water, saturated sodium bicarbonate and salt water washing organic layer, by dried over mgso, and evaporation obtains yellow oil 4-[3-bromo-4-(methylol) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-ethyl formate (54.2mg) also.
4-[3-bromo-4-(methylol) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-ethyl formate also
1H-NMR(CDCl
3)δ0.99(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，2.59(3H，s)，3.03(2H，q，J＝7Hz)，4.07(2H，q，J＝7Hz)，4.82(2H，s)，6.33(1H，d，J＝5Hz)，6.66(1H，d，J＝5Hz)，7.44(1H，d，J＝8Hz)，7.58(1H，d，J＝8Hz)，7.67(1H，s).
Embodiment 612
In acetate 2-(2-{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] oxyethyl group } oxyethyl group) solution of ethyl ester (62.0mg) in methyl alcohol (1mL), add salt of wormwood (22.2mg).After stirring 1.5 hours, solvent evaporated.Preparation thin-layer chromatography (CHCl
3-MeOH=20-1) obtain desired product (54.1mg) into yellow glue.With this peptization in 1N HCl (1mL), and with the solution lyophilize, the dark green coloring agent of crystalline when obtaining placing.In diisopropyl ether, grind crystal, obtain yellow powder 2-(2-{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] oxyethyl group } oxyethyl group) ethanol hydrochloride (40.3mg).
2-(2-{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] oxyethyl group } oxyethyl group) the ethanol hydrochloride
1H-NMR(DMSO-d
6)：1.29(3H，t，J＝7Hz)，2.51(3H，s)，2.56(3H，s)，2.62(2H，m)，2.94(2H，q，J＝7Hz)，3.30-3.47(10H，m)，5.84(1H，d，J＝5Hz)，6.59(1H，d，J＝5Hz)，8.26(1H，m)，8.77(1H，m)，8.85(1H，m).
Embodiment 613
At room temperature with 5-[2-(brooethyl)-4-(3-cyano-phenyl)-7-N-ethyl pyrrole N-also [1,2-b] pyridazine-3-yl] Valeric acid ethylester (70.0mg), phenol (21.1mg) and salt of wormwood (31.0mg) are at N, and the mixture in the dinethylformamide stirred 2.5 hours.Mixture is distributed between ethyl acetate and 1N hydrochloric acid.Water, saturated sodium bicarbonate and salt water washing organic layer, by dried over mgso, and evaporation obtains yellow glue 5-[4-(3-cyano-phenyl)-7-ethyl-2-(phenoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester (77.5mg, 108%).
5-[4-(3-cyano-phenyl)-7-ethyl-2-(phenoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H-NMR(CDCl
3)δ1.21(3H，t，J＝7Hz)，1.35-1.53(7H，m)，2.07(2H，m)，2.54(2H，m)，3.03(2H，q，J＝7Hz)，4.05(2H，q，J＝7Hz)，5.24(2H，s)，5.86(1H，d，J＝5Hz)，6.65(1H，d，J＝5Hz)，6.80-7.01(3H，m)，7.03(2H，d，J＝9Hz)，7.32(2H，t，J＝9Hz)，7.55-7.63(2H，m)，7.67(1H，s)，7.76(1H，m).
MS(ESI
+)：m/z 482(M+H)
Embodiment 614
Under 85 ℃, trifluoromethanesulfonic acid 4-(3-cyano-phenyl)-7-ethyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-2-base ester (50.0mg), 3-furyl boric acid (23.6mg), dichloro two (triphenylphosphine) palladium (3.71mg) and the mixture of 2N yellow soda ash (44.8mg in the 0.2mL water) in two _ alkane were stirred 20 minutes.Mixture is distributed between EtOAc and water, with salt water washing organic layer, dry and evaporation.The preparation thin-layer chromatography (EtOAc-hexane=1-1) obtains orange/yellow solid 3-[7-ethyl-2-(2-furyl)-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile (11.5mg).
3-[7-ethyl-2-(2-furyl)-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile
1H-NMR(CDCl
3)δ1.40(3H，t，J＝7Hz)，3.10(2H，q，J＝7Hz)，3.20(3H，s)，6.30(1H，d，J＝5Hz)，6.63(1H，m)，6.87(1H，d，J＝5Hz)，6.95(1H，m)，7.60-7.73(4H，m)，8.79(1H，m).
Embodiment 615
Under nitrogen atmosphere in the ice bath to 5-[4-(3-cyano-phenyl)-7-ethyl-2-phenylpyrrole [1,2-b] pyridazine-3-yl also] add 1M borine-tetrahydrofuran complex (0.708mL) in the solution of valeric acid (100mg) in tetrahydrofuran (THF) (1mL).Mixture was stirred in ice bath 4 hours and at room temperature stirred 1 hour.Make the reaction quenching by adding 1N hydrochloric acid (1mL).Mixture is distributed between EtOAc (10mL) and 1N hydrochloric acid (5mL).Water and salt water washing organic layer, by dried over mgso, and evaporation.Preparation thin-layer chromatography with acetone-hexane=1-2 drip washing obtains also [1,2-b] pyridazine-4-yl of yellow glue 3-[7-ethyl-3-(5-hydroxyl amyl group)-2-phenylpyrrole] benzonitrile (104mg).
3-[7-ethyl-3-(5-hydroxyl amyl group)-2-phenylpyrrole is [1,2-b] pyridazine-4-yl also] benzonitrile
1H-NMR(CDCl
3)δ0.98-1.17(6H，m)，1.36(3H，t，J＝7Hz)，2.38(2H，m)，2.58(2H，m)，3.34(2H，m)，5.89(1H，d，J＝5Hz)，6.62(1H，d，J＝5Hz)，7.45-7.53(5H，m)，7.55-7.67(4H，m).
MS(ESI+)：m/z 410(M+H)
Following compound is to obtain with preparation example 24 essentially identical modes.
Preparation example 343
2-[(5-bromo-3-pyridyl) carbonyl]-4-methoxyl group-ethyl 3-oxobutanoate
1H NMR(CDCl
3)δ0.96-1.10(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(0.5H，br s)，8.60-8.91(2H，m).
Preparation example 344
2-ethanoyl-2-[(6-cyano group-3-pyridyl) carbonyl] suberic acid 1-tertiary butyl 8-ethyl ester
1H NMR(CDCl
3)δ1.22-1.46(16H，m)，1.55-1.70(2H，m)，2.17-2.34(4H，m)，2.48(3H，s)，4.14(2H，q，J＝8Hz)，7.77(1H，br d，J＝8Hz)，8.17(1H，dd，J＝8，2Hz)，8.97(1H，d，J＝2Hz).
Following compound is to obtain with preparation example 78 essentially identical modes.
Preparation example 345
7-[(6-cyano group-3-pyridyl) carbonyl]-8-oxo ethyl pelargonate
1H NMR(CDCl
3)δ1.20-1.45(7H，m)，1.52-1.70(2H，m)，1.92-2.14(2H，m)，2.17-2.39(5H，m)，4.11(2H，q，J＝8Hz)，4.40(1H，t，J＝8Hz)，7.84(1H，br d，J＝8Hz)，8.39(1H，m)，9.23(1H，br s).
Following compound is to obtain with preparation example 130 essentially identical modes.
Preparation example 346
4-methoxyl group-ethyl 3-oxobutanoate
1H NMR(CDCl
3)δ1.28(3H，t，J＝8Hz)，3.42(3H，s)，3.51(2H，s)，4.09(2H，s)，4.20(2H，q，J＝8Hz).
Following compound is to obtain with preparation example 338 essentially identical modes.
Preparation example 347
3-[(1-amino-5-ethyl-1H-pyrroles-2-yl) carbonyl]-5-bromo-benzoic acid benzyl ester
1H-NMR(CDCl
3)δ1.28(3H，t，J＝7Hz)，2.75(2H，q，J＝7Hz)，5.37(2H，s)，5.73(2H，s)，5.94(1H，d，J＝5Hz)，6.66(1H，d，J＝5Hz)，7.35-7.48(5H，m)，7.99(1H，s)，8.33(1H，s)，8.38(1H，s).
Following compound is to obtain with preparation example 321 essentially identical modes.
Preparation example 348
3-bromo-5-[(5-ethyl-1H-pyrroles-2-yl) carbonyl] phenylformic acid benzyl ester
1H-NMR(CDCl
3)δ1.29(3H，t，J＝7Hz)，2.72(2H，q，J＝7Hz)，5.37(2H，s)，6.09(1H，m)，6.78(1H，m)，7.33-7.45(5H，m)，8.15(1H，s)，8.33(1H，s)，8.45(1H，s).
Following compound is to obtain with preparation example 310 essentially identical modes.
Preparation example 349
3-bromo-5-(chloroformyl) phenylformic acid benzyl ester
Preparation example 350
Under nitrogen atmosphere, in the ice bath, in the solution of 3-bromo-5-iodo-benzoic acid benzyl ester (1.00g) in THF (10mL), add 0.76M bromination isopropyl-magnesium (3.16mL).After stirring 0.5 hour, mixture is poured on the dry ice.Through 1 hour mixture heating up is arrived room temperature.Mixture is distributed between EtOAc and 1N HCl.With salt water washing organic layer, pass through MgS0
4Drying, and evaporation.Flash distillation silica gel column chromatography (chloroform-methanol=50-0 is to 50-2) obtains white solid 3-benzyloxycarbonyl-5-bromo-benzoic acid (273mg).
The 3-[(benzyloxy) carbonyl]-the 5-bromo-benzoic acid
1H-NMR(DMSO-d
6)δ5.39(2H，s)，7.30-7.52(5H，m)，8.29(2H，s)，8.43(1H，s).
Preparation example 351
Under nitrogen atmosphere, in the ice bath,, add oxalyl chloride (1.47mL) in the mixture of dinethylformamide (0.059mL) in methylene dichloride (50mL) to 3-bromo-5-iodobenzoic acid (5.00g) and N.After stirring 1 hour, evaporate volatile matter.Resistates is dissolved in methylene dichloride (50mL), and in ice bath, in solution, adds benzylalcohol (1.82g), add triethylamine (3.2mL) subsequently.At room temperature stirred the mixture 2 hours.Mixture is distributed between EtOAc and water.Wash organic layer (twice) with water, use saturated NaHCO
3With salt water washing organic layer, pass through MgSO
4Drying, and evaporation.Flash distillation silica gel column chromatography (EtOAc-hexane=1/200 is to 20/200) obtains white crystal 3-bromo-5-iodo-benzoic acid benzyl ester (5.95g).
3-bromo-5-iodo-benzoic acid benzyl ester
1H-NMR(CDCl
3)δ5.35(3H，s)，7.35-7.68(5H，m)，8.04(1H，s)，8.16(1H，m)，8.30(1H，s).
Following compound is to obtain in mode substantially the same manner as Example 1.
Embodiment 615
3-bromo-5-[7-ethyl-2-methyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-4-yl] phenylformic acid benzyl ester
1H-NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，2.88(3H，s)，3.05(3H，s)，3.06(2H，q，J＝7Hz)，5.35(2H，s)，6.15(1H，d，J＝5Hz)，6.72(1H，d，J＝5Hz)，7.33-7.45(5H，m)，7.68(1H，m)，7.94(1H，m)，8.28(1H，m).
Embodiment 616
4-(3-cyano-phenyl)-7-ethyl-2-phenylpyrrole is [1,2-b] pyridazine-3-nitrile also
1H NMR(CDCl
3)δ1.42(3H，t，J＝8Hz)，3.12(2H，q，J＝8Hz)，6.60(1H，d，J＝5Hz)，6.92(1H，d，J＝5Hz)，7.50-7.58(3H，m)，7.73(1H，t，J＝8Hz)，7.82-7.91(3H，m)，7.93-8.01(2H，m).
Embodiment 617
The 2-tertiary butyl-4-(3-chloro-phenyl-)-7-N-ethyl pyrrole N-is [1,2-b] pyridazine-3-nitrile also
1H NMR(CDCl
3)δ1.38(3H，t，J＝8Hz)，1.60(9H，s)，3.05(2H，q，J＝8Hz)，6.48(1H，d，J＝5Hz)，6.77(1H，d，J＝5Hz)，7.45-7.54(3H，m)，7.60(1H，br s).
Following compound is to obtain with preparation example 78 essentially identical modes.
Embodiment 618
6-[4-(6-cyano group-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] ethyl hexanoate
1H NMR(CDCl
3)δ1.15-1.64(12H，m)，2.21(1H，t，J＝8Hz)，2.32-2.44(2H，m)，2.56(3H，s)，3.01(2H，q，J＝8Hz)，4.10(2H，q，J＝8Hz)，5.79(1H，d，J＝5Hz)，6.54(1H，d，J＝5Hz)，7.85(1H，br s)，8.30(1H，br d，J＝8Hz)，8.72(1H，br s).
MS(ESI
+)：m/z 405(M+H).
Following compound is to obtain in mode substantially the same manner as Example 21.
Embodiment 619
4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-ethyl formate
1H NMR(CDCl
3)δ1.04(3H，t，J＝8Hz)，1.38(3H，t，J＝8Hz)，3.06(2H，q，J＝8Hz)，339(3H，s)，4.10(2H，q，J＝8Hz)，4.76(2H，s)，6.33(1H，d，J＝5Hz)，6.74(1H，d，J＝5Hz)，7.96(1H，br s)，8.61(1H，br s)，8.78(1H，d，J＝2Hz).
MS(ESI
+)：m/z 418，420(M+H).
Following compound is to obtain with embodiment 76 essentially identical modes.
Embodiment 620
3-bromo-5-[7-ethyl-2-methyl-3-(methyl sulphonyl) pyrrolo-[1,2-b] pyridazine-4-yl] phenylformic acid
1H-NMR(CDCl
3+CD3OD)δ1.38(3H，t，J＝7Hz)，2.86(3H，s)，3.05(3H，s)，3.06(2H，q，J＝7Hz)，6.19(1H，d，J＝5Hz)，6.71(1H，d，J＝5Hz)，7.53(1H，s)，7.90(1H，s)，8.23(1H，s).
Embodiment 621
(2E)-and 3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] vinylformic acid
1H NMR(CDCl
3)δ1.39(3H，t，J＝8Hz)，3.07(2H，q，J＝8Hz)，3.51(3H，s)，4.65(2H，s)，5.96(1H，d，J＝15Hz)，6.27(1H，d，J＝5Hz)，6.74(1H，d，J＝5Hz)，7.68(1H，d，J＝15Hz)，7.93(1H，m)，8.57(1H，d，J＝1Hz)，8.70(1H，d，J＝2Hz).
MS(ESI
+)：m/z 416，418(M+H).
Embodiment 622
6-[4-(6-cyano group-3-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also] caproic acid
1H NMR(CDCl
3)δ1.15-1.69(9H，m)，1.90-2.50(4H，m)，2.56(3H，s)，3.01(2H，q，J＝8Hz)，5.80(1H，d，J＝5Hz)，6.51(1H，d，J＝5Hz)，7.84(1H，dd，J＝8，2Hz)，8.28(1H，d，J＝8Hz)，8.51(1H，d，J＝2Hz).
MS(ESI
+)：m/z 377(M+H).
Embodiment 622-2
6-{4-[6-(aminocarboxyl)-3-pyridyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } caproic acid
1H NMR(CDCl
3)δ1.16-1.51(9H，m)，2.10-2.24(2H，m)，2.35-2.47(2H，m)，2.58(3H，s)，3.01(2H，q，J＝8Hz)，5.85(1H，d，J＝5Hz)，6.54(1H，d，J＝5Hz)，7.22(1H，br s)，7.90(1H，dd，J＝8，1Hz)，8.01(1H，br s)，8.34(1H，d，J＝8Hz)，8.61(1H，d，J＝1Hz).
MS(ESI
+)：m/z 395(M+H).
Following compound is to obtain with embodiment 147 essentially identical modes.
Embodiment 623
(2E)-and 3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propenoate
1H NMR(CDCl
3)δ1.27(3H，t，J＝8Hz)，1.39(3H，t，J＝8Hz)，3.06(2H，q，J＝8Hz)，3.51(3H，s)，4.17(2H，q，J＝8Hz)，4.64(2H，s)，5.97(1H，d，J＝15Hz)，6.24(1H，d，J＝5Hz)，6.73(1H，d，J＝5Hz)，7.51(1H，d，J＝15Hz)，7.91(1H，br s)，8.57(1H，br s)，8.70(1H，br s).
MS(ESI
+)：m/z 444，446(M+H).
Following compound is to obtain with embodiment 200 essentially identical modes.
Embodiment 624
[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] methyl alcohol
1H NMR(CDCl
3)δ1.38(3H，t，J＝8Hz)，3.05(2H，q，J＝8Hz)，3.45-3.55(4H，m)，4.40(2H，br d，J＝7Hz)，4.77(2H，br s)，6.22(1H，d，J＝5Hz)，6.70(1H，d，J＝5Hz)，8.11(1H，m)，8.74(1H，br s)，8.80(1H，d，J＝2Hz).
MS(ESI
+)：m/z 376，378(M+H).
Following compound is to obtain with embodiment 205 essentially identical modes.
Embodiment 625
(4E)-5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also]-the 4-pentenoic acid
1H NMR(CDCl
3)δ1.37(3H，t，J＝8Hz)，2.26-2.43(4H，m)，2.50(3H，s)，3.01(2H，q，J＝8Hz)，5.40(1H，dt，J＝15，7Hz)，6.05(1H，d，J＝5Hz)，6.20(1H，d，J＝15Hz)，6.56(1H，d，J＝5Hz)，7.28(1H，br d，J＝5Hz)，7.39(1H，br s)，8.47(1H，br d，J＝5Hz).
MS(ESI
+)：m/z 370(M+H).
Embodiment 625-2
(4Z)-5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also]-the 4-pentenoic acid
1H NMR(CDCl
3)δ1.39(3H，t，J＝8Hz)，1.87-2.00(2H，m)，2.12(2H，t，J＝8Hz)，2.42(3H，s)，3.03(2H，q，J＝8Hz)，5.58(1H，dt，J＝10，8Hz)，6.17(1H，d，J＝5Hz)，6.26(1H，br d，J＝10Hz)，6.60(1H，d，J＝5Hz)，7.35(1H，br d，J＝5Hz)，7.44(1H，br s)，8.48(1H，br d，J＝5Hz).
MS(ESI
+)：m/z 370(M+H).
Following compound is to obtain with embodiment 220 essentially identical modes.
Embodiment 626
4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-formic acid
1H NMR(CDCl
3)δ1.39(3H，t，J＝8Hz)，3.06(2H，q，J＝8Hz)，3.44(3H，s)，4.82(2H，s)，6.36(1H，d，J＝5Hz)，6.77(1H，d，J＝5Hz)，8.09(1H，br s)，8.65(1H，br s)，8.72(1H，br s).
MS(ESI
+)：m/z 390，392(M+H).
Embodiment 627
4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-formic acid also
1H NMR(CDCl
3)δ1.38(3H，t，J＝8Hz)，2.70(3H，s)，3.06(2H，q，J＝8Hz)，6.26(1H，d，J＝5Hz)，6.72(1H，d，J＝5Hz)，7.32(1H，dd，J＝5，1Hz)，7.43(1H，brs)，8.50(1H，d，J＝5Hz).
MS(ESI
+)：m/z 316(M+H).
Following compound is to obtain with embodiment 244 essentially identical modes.
Embodiment 628
4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-formaldehyde also
1H NMR(CDCl
3)δ1.39(3H，t，J＝8Hz)，2.81(3H，s)，3.09(2H，q，J＝8Hz)，6.43(1H，d，J＝5Hz)，6.78(1H，d，J＝5Hz)，7.34(1H，br d，J＝5Hz)，7.46(1H，br s)，8.56(1H，d，J＝5Hz)，9.76(1H，s).
MS(ESI
+)：m/z 300(M+H).
Embodiment 629
4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-formaldehyde
1H NMR(CDCl
3)δ1.41(3H，t，J＝8Hz)，3.14(2H，q，J＝8Hz)，3.55(3H，s)，4.94(2H，s)，6.50(1H，d，J＝5Hz)，6.84(1H，d，J＝5Hz)，7.95(1H，br s)，8.12(1H，br s)，8.84(1H，br s)，9.85(1H，s).
MS(ESI
+)：m/z 374，376(M+H).
Embodiment 630
At room temperature with phosphoryl chloride (241mg, 1.57mmol) at N, the solution stirring in the dinethylformamide (4mL) 10 minutes.The mixture that obtains is cooled to 0 ℃, and interpolation 4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate (428mg, 1.31mmol) at N, the solution in the dinethylformamide (0.7mL).With the mixture heating up to 50 that obtains ℃, and stirred 45 minutes.Keep parent material, the interpolation phosphoryl chloride (621mg, 0.67mmol) at N, the solution in the dinethylformamide (0.2mL), and stirred the mixture 15 minutes.Pour the mixture that obtains in the ice-cooled water (10mL), and extract with ethyl acetate (30mL).Water and saturated sodium bicarbonate washing organic layer.With all water layers of ethyl acetate extraction.With salt water washing blended organic extract liquid, by anhydrous magnesium sulfate drying, and evaporation obtains blue oil.With ethyl acetate-hexane=1-20 crystalline yellow oil 4-(4-fluorophenyl)-7-formyl radical-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate (360mg, 77.5%) when the flash distillation silica gel column chromatography of 1-10 drip washing obtains placing.
1H-NMR (CDCl
3) δ 1.02 (3H, t, J=7Hz), 1.41 (6H, d, J=7Hz), 3.29 (1H, septet, J=7Hz), 4.10 (2H, q, J=7Hz), 6.42 (1H, d, J=5Hz), 7.20 (2H, t, J=9Hz), 7.45-7.51 (3H, m), 10.56 (1H, s).
MS(ESI
+)：m/z 355(M+H)
Embodiment 631
Under 0 ℃, to N,N-dimethylacetamide (80.1mg, 0.919mmol) add in the solution in ethylene dichloride (1mL) phosphoryl chloride in the ethylene dichloride (0.5mL) (141mg, 0.919mmol).After stirring 0.5 hour, add 4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate (200mg, 0.613mmol) solution in ethylene dichloride (0.5mL).The mixture that stirring at room temperature obtains 3 days.Mixture is distributed between ethyl acetate (30mL) and water (5mL), and with saturated sodium bicarbonate, salt water washing organic layer, by anhydrous magnesium sulfate drying, and evaporation obtains orange coloring agent.Obtain yellow glue 7-ethanoyl-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate (144mg, 63.8%) with ethyl acetate-hexane=1-20 to the flash distillation silica gel column chromatography of 1-10 drip washing.
1H-NMR (CDCl
3) δ 1.00 (3H, t, J=7Hz), 1.41 (6H, d, J=7Hz), 2.88 (3H, s), 3.09 (1H, septet, J=7Hz), 4.09 (2H, q, J=7Hz), 6.40 (1H, d, J=5Hz), 7.19 (2H, t, J=9Hz), 7.46 (2H, dd, J=3 and 9Hz), 7.57 (2H, d, J=7Hz).
MS(ESI
+)：m/z 369(M+H)
Embodiment 632
Under ice bath with 4-(4-fluorophenyl)-7-formyl radical 2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate (100mg, 0.282mmol) and sodium borohydride (10.7mg, 0.282mmol) solution stirring in ethanol (1mL) is 0.5 hour.Mixture is distributed between ethyl acetate (10mL) and water (5mL), and with salt water washing organic layer, by anhydrous magnesium sulfate drying, and evaporation obtains yellow glue 4-(4-fluorophenyl)-7-methylol-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate (89.1mg, 89.1%).
1H-NMR (CDCl
3) δ 0.97 (3H, t, J=7Hz), 1.37 (6H,, J=7Hz), 3.25-3.37 (2H, m), 4.04 (2H, q, J=7Hz), 5.06 (1H, d, J=7Hz), 6.32 (1H, d, J=5Hz), 6.78 (1H, d, J=5Hz), 7.19 (2H, t, J=9Hz), 7.46 (2H, d, J=4 and 9Hz).
Embodiment 633
Under-20 ℃, to 4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate (80.0mg, 0.245mmol) and N, (29.9mg is 0.245mmol) at N for the N-Dimethylamino pyridine, add trifluoromethanesulfonic acid 3 in the solution in the dinethylformamide (0.5mL), 7-dinitrobenzene-5-(trifluoromethyl) dibenzo [b, d] thiophene _ salt (120mg, 0.245mmol).The mixture that obtains was stirred 45 minutes down and at room temperature stirred 12 hours at 0 ℃.Add water (5mL) and ethyl acetate (10mL), and filter the mixture that obtains.With salt water washing organic layer, by anhydrous magnesium sulfate drying, and evaporation obtains brown glue.Obtain also [1,2-b] pyridazine-3-ethyl formate product (46.7mg, 48.3%) of yellow glue 4-(4-fluorophenyl)-2-sec.-propyl-7-trifluoromethyl pyrpole with toluene-hexane=1-5 to the flash distillation silica gel column chromatography of 4-5 drip washing.
1H-NMR (CDCl
3) δ 1.00 (3H, t, J=7Hz), 1.38 (6H, d, J=7Hz), 3.26 (1H, septets, J=7Hz), 4.08 (2H, q, J=7Hz), 6.33 (1H, d, J=5Hz), 7.12 (1H, d, J=5Hz), 7.19 (2H, t, J=9Hz), 7.47 (2H, d, J=4 and 9Hz).
MS(ESI
+)：m/z 395(M+H)
Embodiment 634
With 4-(4-fluorophenyl)-7-formyl radical 2-sec.-propyl pyrrolo-[1; 2-b] pyridazine-3-ethyl formate (200mg; 0.564mmol), oxammonium hydrochloride (51.0mg, 0.734mmol) and sodium formiate (69.1mg, 1.02mmol) solution in formic acid (2mL) refluxed 2 hours.Evaporating mixture obtains green glue.Glue is distributed between ethyl acetate (10mL) and saturated sodium bicarbonate (5mL).With salt water washing organic layer, by anhydrous magnesium sulfate drying, and evaporation obtains green glue.Obtain yellow crystals 7-cyano group-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate (144mg, 72.6%) with ethyl acetate-hexane=1-10 to the flash distillation silicon crystal column chromatography of 1-8 drip washing.
1H-NMR (CDCl
3) δ 1.01 (3H, t, J=7Hz), 1.41 (6H, d, J=7Hz), 3.26 (1H, septets, J=7Hz), 4.09 (2H, q, J=7Hz), 6.36 (1H, d, J=5Hz), 7.20 (2H, t, J=9Hz), 7.28 (1H, d, J=5Hz), 7.47 (2H, d, J=4 and 9Hz).
MS(ESI
+)：m/z 398(M+HCOOH+H)
Embodiment 635
(70.4mg, 0.200mmol) solution stirring in sulfuric acid (1mL) is 50 minutes with 7-cyano group-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate under 70 ℃.Solution is distributed between ethyl acetate and water.With salt water washing organic layer, by anhydrous magnesium sulfate drying, and evaporation obtains brown glue.Preparation silica gel thin-layer chromatography with ethyl acetate-hexane=1-1 drip washing obtains orange solids 7-aminocarboxyl-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate (5.2mg, 7.0%).
1H-NMR (CDCl
3) δ 0.99 (3H, t, J=7Hz), 1.41 (6H, d, J=7Hz), 3.41 (1H, septet, J=7Hz), 4.08 (2H, q, J=7Hz), 5.93 (1H, br s), 6.46 (1H, d, J=5Hz), 7.45 (2H, t, J=9Hz), 7.28 (1H, d, J=5Hz), 8.90 (1H, br s).
Embodiment 636
In ice bath to 4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-ethyl formate (100mg, 0.306mmol) and ammonium thiocyanate (28.0mg, 0.368mmol) add in the mixture in methyl alcohol (100mL) ceric ammonium nitrate (386mg, 0.705mmol).Stirred the mixture 30 minutes.(8.2mg 0.107mmol) stirred the mixture 10 minutes afterwards in addition to add ammonium thiocyanate.Add water (5mL), and extract mixture with ethyl acetate (20mL).With salt water washing organic extract liquid, by anhydrous magnesium sulfate drying, and evaporation obtains dark green coloring agent.Obtain yellow glue 4-(4-fluorophenyl)-2-sec.-propyl-7-thiocyano pyrrolo-[1,2-b] pyridazine-3-ethyl formate (89.6mg, 82.3%) with ethyl acetate-hexane=1-10 to the flash distillation silica gel column chromatography of 3-20 drip washing.
1H-NMR (CDCl
3) δ 1.01 (3H, t, J=7Hz), 1.46 (6H, d, J=7Hz), 3.36 (1H, septets, J=7Hz), 4.08 (2H, q, J=7Hz), 6.23 (1H, d, J=5Hz), 7.14-7.22 (3H, m), 7.16 (2H, t, J=9Hz), 7.46 (2H, dd, J=4 and 9Hz).
Embodiment 637
At room temperature to 4-(4-fluorophenyl)-2-sec.-propyl-7-thiocyano pyrrolo-[1,2-b] pyridazine-3-ethyl formate (77.7mg, 0.219mmol) add in the solution in methyl alcohol (0.7mL) 85% potassium hydroxide (0.3mg, 0.004mmol).After stirring 5 minutes, mixture is distributed between ethyl acetate (20mL) and water (5mL).With salt water washing organic layer, by anhydrous magnesium sulfate drying, and evaporation obtains yellow glue.Preparation silica gel thin-layer chromatography with ethyl acetate-hexane=1-7 drip washing obtains yellow glue 4-(4-fluorophenyl)-2-sec.-propyl-7-(methylthio group) pyrrolo-[1,2-b] pyridazine-3-ethyl formate (35.9mg, 44.1%).
1H-NMR (CDCl
3) δ 0.98 (3H, t, J=7Hz), 1.41 (6H, d, J=7Hz), 2.52 (3H, s), 3.32 (1H, septet, J=7Hz), 4.05 (2H, q, J=7Hz), 6.35 (1H, d, J=5Hz), 6.89 (1H, d, J=5Hz), 7.16 (2H, t, J=9Hz), 7.44 (2H, d, J=4 and 9Hz).
MS(ESI
+)：m/z 373(M+H)
Following compound is to obtain in mode substantially the same manner as Example 1.
Embodiment 638
3-(9-ethyl-3-methoxyl group-5,6-dihydrobenzo [f] pyrrolo-[1,2-b] cinnolines-12-yl) benzonitrile
1H NMR(CDCl
3)δ1.41(3H，t，J＝8Hz)，2.91-3.11(6H，m)，3.78(3H，s)，6.09(1H，d，J＝5Hz)，6.38(1H，dd，J＝8,3Hz)，6.52(1H，d，J＝8Hz)，6.59(1H，d，J＝5Hz)，6.77(1H，br s)，7.56(1H，t，J＝8Hz)，7.67(1H，br d，J＝8Hz)，7.70-7.77(2H，m).
Embodiment 639
4-(3-ethyl-6H-indeno [1,2-e] pyrrolo-[1,2-b] pyridazine-11-yl) benzonitrile
1H NMR (CDCl
3) (J=8Hz), 3.09 (J=8Hz), 4.11 (3H, s), 6.14 (J=5Hz), 6.64 (J=5Hz), 6.71 (J=8Hz), 7.07 (J=8Hz), (1H is with CDCl for 7.20-7.30 for 1H, t for 1H, d for 1H, d for 1H, d for 2H, q for 3H, t for δ 1.43
3Overlapping), 7.49 (1H, d, J=8Hz), 7.69 (2H, d, J=8Hz), 7.88 (2H, d, J=8Hz).
MS(ESI
+)：m/z 336(M+H).
Following compound is to obtain with preparation example 24 essentially identical modes.
Preparation example 352
4-methoxyl group-2-[(5-methyl-3-pyridyl) carbonyl]-ethyl 3-oxobutanoate
1H NMR(CDCl
3)δ0.97，1.26(3H，t，J＝7Hz)，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).
Preparation example 353
2-[(5-chloro-3-pyridyl) carbonyl]-4-methoxyl group-ethyl 3-oxobutanoate
1H NMR(CDCl
3)δ1.00，1.06，1.28，1.35(3H，t，J＝7Hz)，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(3H，m).
Following compound is to obtain with preparation example 176 essentially identical modes.
Preparation example 354
3-bromo-5-(1-[(cyano group ethanoyl) amino]-5-ethyl-1H-pyrroles-2-yl } carbonyl) t-butyl perbenzoate
1H-NMR(CDCl
3)δ1.29(34H，t，J＝7Hz)，1.60(9H，s)，2.61(2H，q，J＝7Hz)，3.64(2H，s)，6.00(1H，m)，6.80(1H，m)，8.03(1H，m)，8.26(1H，m)，8.28(1H，m).
Preparation example 355
3-bromo-5-[(5-ethyl-1-{[(methyl sulphonyl) ethanoyl] amino }-1H-pyrroles-2-yl) carbonyl] t-butyl perbenzoate
1H-NMR(CDCl
3)δ1.29(3H，t，J＝7Hz)，1.60(9H，s)，2.60(2H，q，J＝7Hz)，2.92(3H，s)，4.04(2H，s)，6.11(1H，m)，6.78(1H，m)，8.03(1H，m)，8.25(1H，m)，8.27(1H，m).
Following compound is to obtain with preparation example 153 essentially identical modes.
Preparation example 356
3-bromo-5-(chloroformyl) t-butyl perbenzoate
Following compound is to obtain with preparation example 164 essentially identical modes.
Preparation example 357
3-bromo-5-[(5-ethyl-1H-pyrroles-2-yl) carbonyl] t-butyl perbenzoate
1H-NMR(CDCl
3)δ1.32(3H，t，J＝7Hz)，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).
Following compound is to obtain with preparation example 338 essentially identical modes.
Preparation example 358
3-[(1-amino-5-ethyl-1H-pyrroles-2-yl) carbonyl]-the 5-bromo-benzoic acid tert-butyl ester
1H-NMR(CDCl
3)δ1.29(3H，t，J＝7Hz)，1.61(9H，s)，2.76(2H，q，J＝7Hz)，5.74(2H，s，br)，5.93(1H，d，J＝5Hz)，6.63(1H，d，J＝5Hz)，8.05(1H，m)，8.25(1H，m)，8.29(1H，m).
Preparation example 359
Under nitrogen atmosphere, in the ice-methanol bath, in the solution of the 3-bromo-5-iodo-benzoic acid tert-butyl ester (4.00g) in tetrahydrofuran (THF) (30mL), add 0.76M bromination isopropyl-magnesium (13.7mL).After stirring 0.5 hour, mixture is poured on the dry ice.Through 1 hour mixture heating up is arrived room temperature.Mixture is distributed between EtOAc and 1N hydrochloric acid.With organic layer 1N sodium hydroxide reextraction (twice).Make the extraction liquid acidifying by adding concentrated hydrochloric acid, and with chloroform extraction (twice).With salt water washing organic extract liquid, pass through MgSO
4Drying, and evaporation obtains light brown solid 3-bromo-5-(tert-butoxycarbonyl) phenylformic acid (529mg).
3-bromo-5-(tert-butoxycarbonyl) phenylformic acid
1H-NMR(DMSO-d6)δ1.57(9H，s)，8.21(1H，s)，8.25(1H，s)，8.37(1H，s).
Preparation example 360
The powder MgSO that to vigorous stirring at room temperature
4(7.36g) add sulfuric acid (0.758mL) in the suspension in methylene dichloride (50mL).After stirring 15 minutes, in mixture, add 3-bromo-5-iodo-benzoic acid (5.00g), add the trimethyl carbinol (7.31mL) subsequently.At room temperature stirred the mixture 3 days.Mixture is distributed between EtOAc and water.Use saturated NaHCO
3With salt water washing organic layer, pass through MgSO
4Drying, and evaporation obtains lavender crystal 3-bromo-5-iodo-benzoic acid tert-butyl ester (4.44g).
The 3-bromo-5-iodo-benzoic acid tert-butyl ester
1H-NMR(CDCl
3)δ1.58(9H，s)，8.00(1H，m)，8.06(1H，m)，8.22(1H，m).
Preparation example 361
Under nitrogen atmosphere, in methyl alcohol-ice bath, in the suspension of 20 fens clockwise lithiums (316mg) in ether (10mL), add the Cyclopropyl Bromide (2.50g) in the ether (10mL).In ice bath, stirred the mixture 0.5 hour.In dry ice-propanone is bathed, mixture is cooled off.Added the solution of three isopropoxy borines (5.05g) in tetrahydrofuran (THF) (5mL) through 15 minutes in the clockwise mixture.Through 2 hours mixture heating up is arrived room temperature.Make the reaction quenching by adding hydrochloric acid.Evaporate organic solvent, and extract residual solution (30mL, five times) with ether.Pass through MgSO
4The dry extraction liquid that merges, and evaporation obtains white solid (968mg).Solid grinds in cold hexane and obtains white powder cyclopropylboronic acid (789mg).
Cyclopropylboronic acid
1H-NMR(DMSO-d
6)δ-0.40(1H，m)，0.32(2H，m)，0.39(2H，m)，7.28(2H，s).
Following compound is to obtain in mode substantially the same manner as Example 21.
Embodiment 640
7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-ethyl formate
1H NMR(CDCl
3)δ0.99(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，2.41(3H，s)，3.06(2H，q，J＝7Hz)，3.38(3H，s)，4.06(2H，q，J＝7Hz)，4.75(2H，s)，6.33(1H，d，J＝4Hz)，6.71(1H，d，J＝4Hz)，7.61(1H，s)，8.52(1H，d，J＝2Hz)，8.54(1H，d，J＝2Hz).
MS(ESI
+)：m/z 354.
Embodiment 641
4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-ethyl formate
1H NMR(300MHz，CDCl
3)δ1.04(3H，t，J＝7Hz)，1.38(3H，t，J＝7Hz)，3.06(2H，q，J＝7Hz)，3.39(3H，s)，4.09(2H，q，J＝7Hz)，4.76(2H，s)，6.33(1H，d，J＝4Hz)，6.75(1H，d，J＝4Hz)，7.81(1H，dd，J＝2，2Hz)，8.57(1H，d，J＝2Hz)，8.68(1H，d，J＝2Hz).
MS(m/z)374(M+1).
Following compound is to obtain with embodiment 076 essentially identical mode.
Embodiment 642
(2E)-and 3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] vinylformic acid
1H NMR(CDCl
3)δ1.39(3H，t，J＝7Hz)，2.43(3H，s)，3.07(2H，q，J＝7Hz)，3.51(3H，s)，4.65(2H，s)，5.97(1H，d，J＝16Hz)，6.27(1H，d，J＝4Hz)，6.71(1H，d，J＝4Hz)，7.61(1H，s)，7.72(1H，d，J＝16Hz)，8.46(1H，d，J＝2Hz)，8.57(1H，d，J＝2Hz).
MS(ESI
+)：m/z 352.
Embodiment 643
(2E)-and 3-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] vinylformic acid
1H NMR(300MHz，CDCl
3)δ1.39(3H，t，J＝7Hz)，3.07(2H，q，J＝7Hz)，3.51(3H，s)，4.65(2H，s)，5.97(1H，d，J＝16Hz)，6.27(1H，d，J＝4Hz)，6.75(1H，d，J＝4Hz)，7.69(1H，d，J＝16Hz)，7.78(1H，dd，J＝2,2Hz)，8.54(1H，d，J＝2Hz)，8.71(1H，d，J＝2Hz).
MS(m/z)400(M+1).
Embodiment 644
4-[4-(5-cyclopropyl-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid
1H-NMR(CDCl
3)δ0.78(2H，m)，1.10(2H，m)，1.37(3H，t，J＝7Hz)，1.73(2H，m)，1.98(1H，m)，2.23(2H，m)，2.62(2H，m)，3.02(2H，q，J＝7Hz9，3.46(3H，s)，4.65(2H，q，J＝7Hz)，5.88(1H，d，J＝5Hz)，6.57(1H，d，J＝5Hz)，7.36(1H，m)，8.41(1H，m)，8.47(1H，m).
Embodiment 645
5-[4-(5-cyclopropyl-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid
1H-NMR(CDCl
3)δ0.75(2H，m)，1.08(2H，m)，1.37(3H，t，J＝7Hz)，1.40-1.57(4H，m)，1.96(1H，m)，2.18(2H，m)，2.51(2H，m)，3.02(2H，q，J＝7Hz)，3.45(3H，s)，4.61(2H，m)，5.87(1H，d，J＝5Hz)，6.56(1H，d，J＝5Hz)，7.34(1H，m)，8.39(1H，m)，8.50(1H，m).
Embodiment 646
3-[4-(5-cyclopropyl-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
1H-NMR(DMSO-d6)δ0.76(2H，m)，1.08(2H，m)，1.37(3H，t，J＝7Hz)，1.95(1H，m)，2.48(2H，m)，2.87(2H，m)，3.02(2H，q，J＝7Hz)，3.47(3H，s)，4.66(2H，m)，5.90(1H，d，J＝5Hz)，6.59(1H，d，J＝5Hz)，7.35(1H，m)，8.40(1H，m)，8.48(1H，m).
Embodiment 647
5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also]-the 5-oxopentanoic acid
1H NMR(CDCl
3)δ1.38(3H，t，J＝8Hz)，1.73-1.85(2H，m)，2.26(2H，t，J＝8Hz)，2.36(2H，t，J＝8Hz)，2.46(3H，s)，3.04(2H，q，J＝8Hz)，6.33(1H，d，J＝5Hz)，6.70(1H，d，J＝5Hz)，7.34(1H，br d)，7.45(1H，br s)，8.53(1H，d，J＝6Hz).
Embodiment 648
(2E)-and 3-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] vinylformic acid
1H NMR (CDCl
3) (J=8Hz), 2.67 (3H, s), 3.05 (J=8Hz), 5.79 (J=15Hz), 6.19 (J=5Hz), 6.67 (J=5Hz), (1H is with CDCl for 7.24-7.29 for 1H, d for 1H, d for 1H, d for 2H, q for 3H, t for δ 1.38
3Overlapping), 7.40 (1H, br s), 7.51 (1H, d, J=15Hz), 8.55 (1H, d, J=5Hz).
Following compound is to obtain with embodiment 146 essentially identical modes.
Embodiment 649
(2E)-and 3-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] ethyl propenoate
1H NMR (CDCl
3) δ 1.27 (3H, t, J=8Hz), 1.38 (3H, t, J=8Hz), 2.65 (3H, s), 3.04 (2H, q, J=8Hz), 4.17 (2H, q, J=8Hz), 5.76 (1H, d, J=15Hz), 6.16 (J=5Hz), 6.65 (J=5Hz), (1H is with CDCl for 7.24-7.29 for 1H, d for 1H, d
3Overlapping), 7.40 (1H, br s), 7.53 (1H, d, J=15Hz), 8.53 (1H, d, J=5Hz).
MS(ESI
+)：m/z 370(M+H).
Following compound is to obtain with embodiment 181 essentially identical modes.
Embodiment 650
3-bromo-5-(3-cyano group-7-ethyl-2-oxo-1,2-pyrrolin is [1,2-b] pyridazine-4-yl also) t-butyl perbenzoate
1H-NMR(CDCl
3)δ1.36(3H，t，J＝7Hz)，2.94(2H，q，J＝7Hz)，6.57(1H，d，J＝5Hz)，6.72(1H，d，J＝5Hz)，7.94(1H，m)，8.20(1H，m)，8.38(1H，m).
Embodiment 651
3-bromo-5-[7-ethyl-3-(methyl sulphonyl)-2-oxo-1,2-pyrrolin be [1,2-b] pyridazine-4-yl also] t-butyl perbenzoate
1H-NMR(CDCl
3)δ1.35(3H，t，J＝7Hz)，3.02(2H，q，J＝7Hz)，3.06(3H，s)，6.24(1H，d，J＝5Hz)，6.70(1H，d，J＝5Hz)，7.23(1H，m)，7.94(1H，m)，8.25(1H，m).
Following compound is to obtain with embodiment 183 essentially identical modes.
Embodiment 652
3-bromo-5-(3-cyano group-7-ethyl-2-{[(trifluoromethyl) alkylsulfonyl] the oxygen base } pyrrolo-[1,2-b] pyridazine-4-yl) t-butyl perbenzoate
1H-NMR(CDCl
3)δ1.39(3H，t，J＝7Hz)，1.61(9H，s)，3.02(2H，q，J＝7Hz)，6.81(1H，d，J＝5Hz)，700(1H，d，J＝5Hz)，7.96(1H，m)，8.21(1H，m)，8.33(1H，m).
Embodiment 653
3-bromo-5-(7-ethyl-3-(methyl sulphonyl)-2-{[(trifluoromethyl) alkylsulfonyl] the oxygen base } pyrrolo-[1,2-b] pyridazine-4-yl) t-butyl perbenzoate
1H-NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，1.59(9H，s)，3.01(2H，q，J＝7Hz)，3.22(3H，s)，6.46(1H，d，J＝5Hz)，7.12(1H，d，J＝5Hz)，7.67(1H，m)，7.90(1H，m)，8.23(1H，m).
Following compound is to obtain with embodiment 184 essentially identical modes.
Embodiment 654
3-bromo-5-[3-cyano group-7-ethyl-2-(1-pyrrolidyl) pyrrolo-[1,2-b] pyridazine-4-yl] t-butyl perbenzoate
1H-NMR(CDCl
3)δ1.35(3H，t，J＝7Hz)，1.60(9H，s)，2.01(4H，m)，2.93(2H，q，J＝7Hz)，3.73(4H，m)，6.32(1H，d，J＝5Hz)，6.58(1H，d，J＝7Hz)，7.86(1H，m)，8.12(1H，m)，8.24(1H，m).
Embodiment 655
3-bromo-5-[7-ethyl-3-(methyl sulphonyl)-2-(1-pyrrolidyl) pyrrolo-[1,2-b] pyridazine-4-yl] t-butyl perbenzoate
1H-NMR(CDCl
3)δ1.37(3H，t，J＝7Hz)，1.58(9H，s)，1.99(4H，m)，2.98(2H，q，J＝7Hz)，3.21(3H，s)，3.52(4H，m)，6.30(1H，d，J＝5Hz)，6.66(1H，d，J＝5Hz)，7.76(1H，m)，8.00(1H，m)，8.19(1H，m).
Following compound is to obtain with embodiment 147 essentially identical modes.
Embodiment 656
(2E)-and 3-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propenoate
1H NMR(300MHz，CDCl
3)δ1.27(3H，t，J＝7Hz)，1.39(3H，t，J＝7Hz)，3.07(2H，q，J＝7Hz)，3.51(3H，s)，4.18(2H，q，J＝7Hz)，4.64(2H，s)，5.97(1H，d，J＝16Hz)，6.24(1H，d，J＝4Hz)，6.72(1H，d，J＝4Hz)，7.61(1H，d，J＝16Hz)，7.76(1H，dd，J＝2，2Hz)，8.54(1H，d，J＝2Hz)，8.68(1H，d，J＝2Hz).
Following compound is to obtain with embodiment 205 essentially identical modes.
Embodiment 657
(4E)-5-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl]-the 4-pentenoic acid
1H NMR(300MHz，CDCl
3)δ1.38(3H，t，J＝7Hz)，2.25-2.41(4H，m)，3.05(2H，q，J＝7Hz)，3.50(3H，s)，4.57(2H，s)，5.53(1H，dd，J＝16，7Hz)，6.13(1H，d，J＝4Hz)，6.36(1H，d，J＝16Hz)，6.65(1H，d，J＝4Hz)，7.80(1H，s)，8.54(1H，br s)，8.62(1H，br s).
MS(m/z)400(M+1).
Following compound is to obtain with preparation example 153 essentially identical modes.
Embodiment 658
4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-formyl chloride also
Following compound is to obtain with embodiment 244 essentially identical modes.
Embodiment 659
7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-formaldehyde
1H NMR(CDCl
3)δ1.40(3H，t，J＝7Hz)，2.45(3H，s)，3.12(2h，q，J＝7Hz)，3.56(3H，s)，4.96(2H，s)，6.51(1H，d，J＝4Hz)，6.80(1H，d，J＝4Hz)，7.62(1H，s)，8.54(1H，s)，8.61(1H，s)，9.79(1H，s).
MS(ESI
+)：m/z 310.
Embodiment 660
4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-formaldehyde
1H NMR(300MHz，CDCl
3)δ1.41(3H，t，J＝7Hz)，3.12(2H，q，J＝7Hz)，3.54(3H，s)，4.94(2H，s)，6.50(1H，d，J＝4Hz)，6.84(1H，d，J＝4Hz)，7.81(1H，dd，J＝2，2Hz)，8.59(1H，d，J＝2Hz)，8.74(1H，d，J＝2Hz)，9.85(1H，s).
Following compound is to obtain with embodiment 533 essentially identical modes.
Embodiment 661
[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] methyl alcohol
1H NMR(CDCl
3)δ1.38(3H，t，J＝7Hz)，2.43(3H，s)，3.05(2H，q，J＝7Hz)，3.52(3H，s)，4.37-4.51(2H，br)，4.66-4.78(2H，br)，6.20(1H，d，J＝4Hz)，6.67(1H，d，J＝4Hz)，7.75(1H，s)，8.54(1H，s)，8.60(1H，s).
MS(ESI
+)：m/z 312.
Embodiment 662
[4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] methyl alcohol
1H NMR(300MHz，CDCl
3)δ1.38(3H，t，J＝7Hz)，3.05(2H，q，J＝7Hz)，3.53(3H，s)，4.41(2H，d，J＝6Hz)，4.77(2H，s)，6.22(1H，d，J＝4Hz)，6.70(1H，d，J＝4Hz)，7.97(1H，dd，J＝2，2Hz)，8.69-8.71(2H，m).
MS(m/z)332(M+1).
Embodiment 663
At room temperature 7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-formaldehyde (48mg) and (the inferior phosphoranyl of triphenyl) ethyl acetate (56.8mg) mixture in THF (3mL) were stirred 2 hours.After the evaporating solvent, by using hexane and AcOEt (5: 1-2: 1) the silica gel column chromatography purification resistates of mixture drip washing, obtain yellow powder (2E)-3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propenoate (30mg).
(2E)-and 3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propenoate
1H NMR(CDCl
3)δ1.26(3H，t，J＝7Hz)，1.39(3H，t，J＝7Hz)，2.42(3H，s)，3.07(2H，q，J＝7Hz)，3.51(3H，s)，4.12(2H，q，J＝7Hz)，4.64(2H，s)，5.97(1H，d，J＝16Hz)，6.24(1H，d，J＝4Hz)，6.70(1H，d，J＝4Hz)，7.55(1H，s)，7.63(1H，d，J＝16Hz)，8.47(1H，d，J＝2Hz)，8.55(1H，d，J＝2Hz).
MS(ESI
+)：m/z 380.
Embodiment 664
To 4-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] add acid chloride (1.83mg) in ethyl butyrate (75.0mg), cyclopropylboronic acid (18.2mg), tricyclohexyl phosphine (4.57mg) and the mixture of potassiumphosphate (104mg) in toluene-water (1mL-0.2mL).Under 100 ℃, stirred the mixture 2 hours.Mixture is distributed between EtOAc and water.With salt water washing organic layer, pass through MgSO
4Drying, and evaporation.The preparation silica gel thin-layer chromatography (EtOAc-hexane=1-3) obtains yellow glue 4-[4-(5-cyclopropyl-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate (60.9mg).
4-[4-(5-cyclopropyl-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl butyrate
1H-NMR(CDCl
3)δ0.76(2H，m)，1.07(2H，m)，1.20(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.68(2H，m)，1.96(1H，m)，2.17(2H，m)，2.56(2H，m)，3.02(2H，q，J＝7Hz)，3.46(3H，s)，4.03(2H，q，J＝7Hz)，4.65(2H，m)，5.90(1H，d，J＝5Hz)，6.57(1H，d，J＝5Hz)，7.30(1H，m)，8.40(1H，m)，8.51(1H，m).
Following compound is to obtain with embodiment 664 essentially identical modes.
Embodiment 665
5-[4-(5-cyclopropyl-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] Valeric acid ethylester
1H-NMR(CDCl
3)δ0.76(2H，m)，1.08(2H，m)，1.23(3H，t，J＝7Hz)，1.35-1.57(7H，m)，1.96(1H，m)，2.16(2H，t，J＝7Hz)，2.53(2H，m)，3.03(2H，q，J＝7Hz)，3.46(3H，s)，4.08(2H，q，J＝7Hz)，4.62(2H，s)，5.89(1H，d，J＝5Hz)，6.56(1H，d，J＝5Hz)，7.29(1H，m)，8.40(1H，m)，8.52(1H，m).
Embodiment 666
3-[4-(5-cyclopropyl-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] ethyl propionate
1H-NMR(CDCl
3)δ0.76(2H，m)，1.08(2H，m)，1.19(3H，t，J＝7Hz)，1.37(3H，t，J＝7Hz)，1.97(1H，m)，2.38(2H，m)，2.85(2H，m)，3.02(2H，q，J＝7Hz)，3.46(3H，s)，4.04(2H，q，J＝7Hz)，4.64(2H，s)，5.92(1H，d，J＝5Hz)，6.59(1H，d，J＝5Hz)，7.29(1H，m)，8.40(1H，m)，8.53(1H，m).
Embodiment 667
3-[3-cyano group-7-ethyl-2-(1-pyrrolidyl) pyrrolo-[1,2-b] pyridazine-4-yl]-5-cyclopropyl-phenyl t-butyl formate
1H-NMR(CDCl
3)δ0.81(2H，m)，1.03(2H，m)，1.35(3H，t，J＝7Hz)，1.59(9H，s)，1.94-2.08(5H，m)，2.94(2H，q，J＝7Hz)，3.68-3.77(4H，m)，6.35(1H，j，J＝5Hz)，6.55(1H，d，J＝5Hz)，7.43(1H，s)，7.84(1H，s)，7.97(1H，s).
Embodiment 668
At room temperature with 3-bromo-5-[3-cyano group-7-ethyl-2-(1-pyrrolidyl) pyrrolo-[1,2-b] pyridazine-4-yl] solution stirring of t-butyl perbenzoate (16.0mg) in trifluoroacetic acid (0.5mL) 0.5 hour.Make the reaction quenching by adding water.By adding NaOH with mixture neutralization (pH=3).Extract mixture with EtOAc.With salt water washing extraction liquid, pass through MgSO
4Drying, and evaporation obtains the green-yellow solid.At hexane-CHCl
3Abrasive solid (2-1) obtains yellow powder 3-bromo-5-[3-cyano group-7-ethyl-2-(1-pyrrolidyl) pyrrolo-[1,2-b] pyridazine-4-yl] phenylformic acid (10.8mg).
3-bromo-5-[3-cyano group-7-ethyl-2-(1-pyrrolidyl) pyrrolo-[1,2-b] pyridazine-4-yl] phenylformic acid
1H-NMR(CDCl
3+CD
3OD)δ1.36(3H，t，J＝7Hz)，2.01(4H，m)，2.94(2H，q，J＝7Hz)，3.72(4H，m)，6.36(1H，d，J＝5Hz)，6.60(1H，d，J＝5Hz)，7.92(1H，m)，8.23(1H，m)，8.35(1H，m).
Following compound is to obtain with embodiment 668 essentially identical modes.
Embodiment 669
3-[3-cyano group-7-ethyl-2-(1-pyrrolidyl) pyrrolo-[1,2-b] pyridazine-4-yl]-5-cyclopropyl-phenyl formic acid
1H-NMR(CDCl
3+CD3OD)δ0.81(2H，m)，1.05(2H，m)，1.35(3H，t，J＝7Hz)，2.01(5H，m)，2.94(2H，q，J＝7Hz)，7.73(4H，m)，6.37(1H，d，J＝5Hz)，6.57(1H，d，J＝5Hz)，6.98(1H，s)，7.90(1H，s)，8.08(1H，s).
Embodiment 670
3-bromo-5-[7-ethyl-3-(methyl sulphonyl)-2-(1-pyrrolidyl) pyrrolo-[1,2-b] pyridazine-4-yl] phenylformic acid
1H-NMR(CDCl
3+CD3OD)δ1.37(3H，t，J＝7Hz)，1.98(4H，m)，2.99(2H，q，J＝7Hz)，320(3H，s)，3.56(4H，m)，6.32(1H，d，J＝5Hz)，6.67(1H，d，J＝5Hz)，7.80(1H，m)，8.08(1H，m)，8.30(1H，m).
Embodiment 671
At N
2In room temperature, in the 3 neck flasks that contain the Zn-Cu coupling agent, add the solution of 4-iodine ethyl butyrate (369mg) in toluene (3mL) and N,N-dimethylacetamide (0.2mL) down.Mixture was stirred 1 hour under this temperature, stirred 3 hours down at 60 ℃ then.Add tetrakis triphenylphosphine palladium (44mg) in toluene (0.5mL) suspension and stirred 5 minutes.Remove after the oil bath, mixture cools off in ice-water-bath.In this mixture, drip also [1, the 2-b] pyridazine-solution of 3-formyl chloride (212mg) in DCM (1mL) of 4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole.After 10 minutes, at room temperature stirred reaction mixture is 2 hours.With reaction mixture at AcOEt and H
2Distribute between the O.Use saturated NaHCO
3With salt water washing organic layer, pass through MgSO
4Drying, and evaporation in a vacuum.By flash distillation silica gel chromatography (silica gel with hexane-AcOEt=10-1 and 5-1 drip washing, 80mL) purification resistates, obtain also [1,2-b] pyridazine-3-yl of yellow amorphous substance 5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole]-5-oxopentanoic acid ethyl ester (143mg).
5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also]-5-oxopentanoic acid ethyl ester
1H NMR(CDCl
3)δ1.23(3H，t，J＝8Hz)，1.38(3H，t，J＝8Hz)，1.71-1.84(2H，m)，2.17(3H，t，J＝8Hz)，2.32(3H，t，J＝8Hz)，2.46(3H，s)，3.04(2H，q，J＝8Hz)，4.06(2H，q，J＝8Hz)，6.32(1H，d，J＝5Hz)，6.70(1H，d，J＝5Hz)，7.32(1H，dd，J＝5,1)，7.46(1H，br s)，8.53(1H，d，J＝5Hz).
Embodiment 672
At N
2In the following ice-water-bath to 5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also]-add sodium borohydride (5mg) in the solution of 5-oxopentanoic acid (47mg) in EtOH (1mg).After 10 minutes, at room temperature stir the mixture.After 1 hour, add sodium borohydride (5mg) again.After 2 hours, with reaction mixture at CHCl
3And H
2Distribute between the O.Use CHCl
3Twice of aqueous layer extracted.The organic layer that merges is passed through MgSO
4Drying, and evaporation in a vacuum.By p-TLC (CHCl
3The purification resistates of-methyl alcohol=10-1) obtains also [1,2-b] pyridazine-3-yl of yellow amorphous substance 5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole]-5-hydroxypentanoic acid (28mg).
5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole is [1,2-b] pyridazine-3-yl also]-the 5-hydroxypentanoic acid
1H NMR (CDCl
3) δ 1.36 (3H, t, J=8Hz), 1.46-1.83 (3H, m), 1.95 (1H, m), 2.70 (3H, br s), 3.01 (J=8Hz), 4.63 (1H, m), 5.85 (1H, m), 6.55 (J=5Hz), (1H is with CDCl for 7.18-7.29 for 1H, d for 2H, q
3Overlapping), 7.34 (1H, d, J=2Hz), 8.49 (1H, d, J=5Hz).
Claims (15)
1. the compound of a following formula:
Wherein
R
1Be (1) carboxyl or esterifying carboxyl group,
(2)-CONR
5R
6，
(3) hydroxyl or C
1-C
6Alkoxyl group,
(4) amino, optional by C
1-C
6Ring (the C that alkoxyl group replaces
3-C
6) alkylamino or
Single-or two (C
1-C
6) alkylamino,
(5) three halogen (C
1-C
6) alkyl,
(6) three halogen (C
1-C
6) alkyl sulphonyl oxygen base or arlysulfonylamino,
(7) C
1-C
6Alkyl, it is chosen wantonly and is replaced by following group: (i) halogen; (ii) carboxyl; (iii) esterifying carboxyl group; (iv) cyano group; (v) formamyl; (vi)-OCONR
15R
16, R wherein
15And R
16Represent hydrogen, aryl or the optional C that replaces by aryl independently of one another
1-C
6Alkyl, or R
15And R
16Represent to contain 1 to 2 nitrogen-atoms and also optional saturated 5 yuan or 6 yuan of heteromonocyclic group groups that contain Sauerstoffatom with the nitrogen-atoms that they were keyed to; (vii) C
1-C
6Alkylthio; (viii) C
1-C
6Alkyl sulphonyl; (ix) C
1-C
6Alkyl sulphonyl oxygen base; (x) C
1-C
6Alkyl sulfonyl-amino; (xi) singly-or two (C
1-C
6) alkylamino, optional by hydroxyl, C
1-C
6Alkoxyl group, aryloxy or replacement or unsubstituting aromatic yl replace; (xii) amino; (xiii) amide group; (xiv) protection is amino; (xv) hydroxyl; (xvi) acyloxy; (xvii) ring (C
3-C
6) alkoxyl group; (xviii) aryloxy; (xix) aryl; (xx) contain 1 to 3 nitrogen-atoms and also optional saturated or unsaturated 5 yuan or 6 yuan of heteromonocyclic group groups that contain Sauerstoffatom or sulphur atom, optional by C
1-C
6Alkyl, hydroxyl (C
1-C
6) alkyl, aryl or oxo replace; Or (xxi) C
1-C
6Alkoxyl group, optional by following group replacement: carboxyl, esterifying carboxyl group, hydroxyl, protection hydroxyl, C
1-C
6Alkoxyl group, ring (C
3-C
6) alkyl, replacement or unsubstituting aromatic yl, optional by C
1-C
6Saturated or unsaturated 5 yuan or 6 yuan of heteromonocyclic group groups of containing 1 to 2 nitrogen-atoms that alkyl replaces, or-CONR
13R
14, R wherein
13And R
14Represent hydrogen or the optional C that replaces by aryl independently of one another
1-C
6Alkyl, or R
13And R
14Represent to contain 1 to 2 nitrogen-atoms and also optional saturated 5 yuan or 6 yuan of heteromonocyclic group groups that contain Sauerstoffatom with the nitrogen-atoms that they were keyed to;
(8) the optional aryl that is selected from the substituting group replacement of halogen, or
(9) the optional C that is selected from
1-C
6The heterocyclic group that the substituting group of alkyl or halogen replaces,
R
2Be R
7Or-(A
1) p-X-A
2-R
7,
Wherein
P is 0 or 1 integer;
A
1Be (C
1-C
2) alkylidene group or-CH=CH-;
A
2Be-(CH
2) n-or-(CH=CH) m-, wherein n can arrive for 1
6 integer and m can be 1 to 3 integer;
X be singly-bound ,-O-,-NR
8,-C (=O)-,-C (=NR
9)-or hydroxyl (C
1-C
2) alkylidene group, wherein R
8Be hydrogen or C
1-C
6Alkyl, and R
9Be optional (the i) (C that is selected from
1-C
6) alkyl and (ii) acyl substituted contain the N heterocyclic group and
R
7Be
(1) hydrogen,
(2) optional by (C
1-C
6) aryl that replaces of alkoxyl group,
(3) heterocyclic group, it is chosen wantonly and is replaced by following group: (i) C
1-C
6Alkyl; (ii) encircle (C
3-C
6) alkyl; (iii) C
1-C
6Alkoxyl group; (iv) acyl group; (v) amino; (vi) single-or two (C
1-C
6) alkylamino; (vii) protection is amino; (viii) cyano group; (ix) carboxyl; (x) esterifying carboxyl group; (xi)-CONR
15R
16, R wherein
15And R
16Represent hydrogen, the optional C that is replaced by hydroxyl independently of one another
1-C
6Alkyl; (xii) optional by C
1-C
6The C that alkoxyl group replaces
2-C
6Thiazolinyl; (xiii) halogen; (xiv) C
1-C
6Alkylthio and (xv) hydroxyl;
(4) carboxyl, esterifying carboxyl group or CONR
10R
11,
(5) acyl group or halo carbonyl,
(6) cyano group,
(7) amino, protection is amino or single-or two (C
1-C
6) alkylamino,
(8) hydroxyl, aryloxy, acyloxy or the optional C that replaces by hydroxyl or acyloxy
1-C
6Alkyl,
(9) C
1-C
6Alkylthio, C
1-C
6Alkyl sulfinyl or C
1-C
6Alkyl sulphonyl,
Or
(10)-O-R
12，
Or
R
1And R
2Be combined together to form C
1-C
6Alkylidene group or C
1-C
6Alkylene group optional interrupted and is optionally condensed with phenyl ring by amino or alkylsulfonyl, and also chooses wantonly by C
1-C
6Alkyl, hydroxyl, oxo and C
1-C
6Alkoxyl group replaces,
R
3The aryl that is replaced by following group: (i) halogen; (ii) carboxyl; (iii) esterifying carboxyl group; (iv) cyano group; (v)-CONR
15R
16, R wherein
15And R
16Represent hydrogen, the optional C that replaces by hydroxyl independently of one another
1-C
6Alkyl; (vi) C
1-C
6Alkyl; (vii) encircle (C
3-C
6) alkyl; (viii) hydroxyl (C
1-C
6) alkyl; (ix) C
1-C
6Alkoxyl group; (x) three halogen (C
1-C
6) alkyl; (xi) contain 1 to 2 nitrogen-atoms and also optional unsaturated 5 yuan or 6 yuan of heteromonocyclic group groups that contain 1 to 2 Sauerstoffatom; (xii) C
1-C
6Alkyl sulphonyl; (xiii) nitro; (xiv) sulfamyl; (xv) protection sulfamyl;
Or heterocyclic radical, it is chosen wantonly and is replaced by following group: (i) C
1-C
6Alkyl; (ii) encircle (C
3-C
6) alkyl; (iii) C
1-C
6Alkoxyl group; (iv) acyl group; (v) amino; (vi) single-or two (C
1-C
6) alkylamino; (vii) protection is amino; (viii) cyano group; (ix) carboxyl; (x) esterifying carboxyl group; (xi)-CONR
15R
16, R wherein
15And R
16Represent hydrogen, the optional C that is replaced by hydroxyl independently of one another
1-C
6Alkyl; (xii) optional by C
1-C
6The C that alkoxyl group replaces
2-C
6Thiazolinyl; (xiii) halogen; (xiv) C
1-C
6Alkylthio and (xv) hydroxyl;
R
4Be hydrogen, halogen, cyano group, formamyl, acyl group, thiocyanate ion, C
1-C
6Alkylthio, C
2-C
6Alkenyl, hydroxyl (C
1-C
6) alkyl, three halogen (C
1-C
6) alkyl or C
1-C
6Alkyl,
R
5, R
6, R
10And R
11Represent hydrogen, C independently of one another
1-C
6Alkyl sulphonyl, heterocyclic group or optional by hydroxyl, alkoxyl group, sulfo group, carboxyl, esterifying carboxyl group or-R
17The C that replaces
1-C
6Alkyl,
Or selectively, R
5With R
6Or R
10With R
11Represent to contain the N heterocyclic group with the nitrogen-atoms that they were keyed to, and
R
12And R
17Independently of one another derived from the protection of therefrom removing hydroxyl or the group of protection sugar,
Or its pharmacologically acceptable salt.
2. the compound of claim 1, wherein
R
1Be (1) carboxyl or esterifying carboxyl group,
(2)-CONR
5R
6, R wherein
5And R
6Represent C independently of one another
1-C
6Alkyl, or selectively, R
5And R
6Represent to contain saturated 5 yuan or 6 yuan of heteromonocyclic group groups of 1 to 2 nitrogen-atoms with the nitrogen-atoms that they were keyed to,
(3) hydroxyl or C
1-C
6Alkoxyl group,
(4) amino, optional by C
1-C
6Ring (the C that alkoxyl group replaces
3-C
6) alkylamino or single-or two (C
1-C
6) alkylamino,
(5) three halogen (C
1-C
6) alkyl,
(6) three halogen (C
1-C
6) alkyl sulphonyl oxygen base or arlysulfonylamino,
(7) the optional C that replaces by following group
1-C
6Alkyl: (i) halogen; (ii) carboxyl; (iii) esterifying carboxyl group; (iv) cyano group; (v) formamyl; (vi)-OCONR
15R
16, R wherein
15And R
16Represent hydrogen, aryl or the optional C that replaces by aryl independently of one another
1-C
6Alkyl, or R
15And R
16Represent to contain 1 to 2 nitrogen-atoms and also optional saturated 5 yuan or 6 yuan of heteromonocyclic group groups that contain Sauerstoffatom with the nitrogen-atoms that they were keyed to; (vii) C
1-C
6Alkylthio; (viii) C
1-C
6Alkyl sulphonyl; (ix) C
1-C
6Alkyl sulphonyl oxygen base; (x) C
1-C
6Alkyl sulfonyl-amino; (xi) optional by hydroxyl, C
1-C
6The list that alkoxyl group, aryloxy or replacement or unsubstituting aromatic yl replace-or two (C
1-C
6) alkylamino; (xii) amino; (xiii) amide group; (xiv) protection is amino; (xv) hydroxyl; (xvi) acyloxy; (xvii) ring (C
3-C
6) alkoxyl group; (xviii) aryloxy; (xix) aryl; (xx) contain 1 to 3 nitrogen-atoms and also optional saturated or unsaturated 5 yuan or 6 yuan of heteromonocyclic group groups that contain Sauerstoffatom or sulphur atom, optional by C
1-C
6Alkyl, hydroxyl (C
1-C
6) alkyl, aryl or oxo replace; Or (xxi) C
1-C
6Alkoxyl group, optional by following group replacement: carboxyl, esterifying carboxyl group, hydroxyl, protection hydroxyl, C
1-C
6Alkoxyl group, ring (C
3-C
6) alkyl, replacement or unsubstituting aromatic yl, optional by C
1-C
6Alkyl replaces contain 1 to 2 nitrogen-atoms saturated or unsaturated 5 yuan or 6 yuan of heteromonocyclic group groups or-CONR
13R
14, R wherein
13And R
14Represent the C that hydrogen or optional aryl replace independently of one another
1-C
6Alkyl, or R
13And R
14Represent to contain 1 to 2 nitrogen-atoms and also optional saturated 5 yuan or 6 yuan of heteromonocyclic group groups that contain Sauerstoffatom with the nitrogen-atoms that they were keyed to,
(8) aryl, optional by the substituting group replacement that is selected from halogen, or
(9) saturated or unsaturated 5 yuan or 6 yuan of heteromonocyclic group groups, optional by C
1-C
6Alkyl or halogen replace,
R
2Be R
7Or-(A
1) p-X-A
2-R
7
Wherein
Wherein p is 0 or 1;
A
1Be (C
1-C
2) alkylidene group or-CH=CH-;
A
2Be-(CH
2) n-or-(CH=CH) m-, wherein n can be 1 to 3 integer for 1 to 6 integer and m;
X be singly-bound ,-O-,-NR
8,-C (=O)-,-C (=NR
9)-or hydroxyl (C
1-C
2) alkylidene group; R wherein
8Be hydrogen or C
1-C
6Alkyl, and R
9Be optional being selected from
(i) (C
1-C
6) alkyl and the (ii) pyrryl that replaces of the substituting group of acyl group
R
7Be
(1) hydrogen,
(2) aryl, optional by C
1-C
6Alkoxyl group replaces,
(3) contain the unsaturated heteromonocyclic group group of 1 to 2 nitrogen-atoms,
(4) carboxyl of carboxyl, esterification or-CONR
10R
11, R wherein
10And R
11Represent hydrogen, C independently of one another
1-C
6Alkyl sulphonyl, contain 1 to 2 nitrogen-atoms unsaturated heteromonocyclic group group or optional by hydroxyl, alkoxyl group, carboxyl, esterifying carboxyl group, sulfo group or-R
17The C that replaces
1-C
6Alkyl, or R selectively
10And R
11Represent to contain 1 to 2 nitrogen-atoms and also optional saturated 5 yuan or 6 yuan of heteromonocyclic group groups that contain Sauerstoffatom with the nitrogen-atoms that they were keyed to,
(5) acyl group or halo carbonyl,
(6) cyano group,
(7) amino, protection is amino or single-or two (C
1-C
6) alkylamino,
(8) hydroxyl, aryloxy, acyloxy or the optional C that replaces by hydroxyl or acyloxy
1-C
6Alkoxyl group,
(9) C
1-C
6Alkylthio, C
1-C
6Alkyl sulfinyl or C
1-C
6Alkyl sulphonyl, or
(10)-O-R
12，
Or
R
3The aryl that to be (1) replaced by at least a substituting group that is selected from following group: (i) halogen, (ii) carboxyl, (iii) esterifying carboxyl group, (iv) cyano group, (v)-CONR
15R
16, R wherein
15And R
16Represent hydrogen, the optional C that replaces by hydroxyl independently of one another
1-C
6Alkyl, (vi) C
1-C
6Alkyl (vii) encircles (C
3-C
6) alkyl, (viii) hydroxyl (C
1-C
6) alkyl, (ix) C
1-C
6Alkoxyl group, (x) three halogen (C
1-C
6) alkyl, (xi) contain unsaturated 5 yuan or 6 yuan of heteromonocyclic group groups, (xii) C of 1 to 2 Sauerstoffatom and 1 to 2 nitrogen-atoms
1-C
6Alkyl sulphonyl, (xiii) nitro, (xiv) sulphonamide and (xv) protection sulphonamide; Or
(2) be selected from pyridyl, pyrazinyl, _ heterocyclic group of azoles base, different _ the azoles base, furyl, thienyl, quinolyl, benzofuryl and benzothienyl, wherein said heterocyclic group is optional to be replaced by at least a substituting group that is selected from following group: (i) C
1-C
6Alkyl, (ii) ring (C
3-C
6) alkyl, (iii) C
1-C
6Alkoxyl group, (iv) acyl group, (it is v) amino, (vi) single-or two (C
1-C
6) alkylamino, (vii) protection is amino, (and viii) cyano group, (ix) carboxyl, (x) esterifying carboxyl group, (xi)-CONR
15R
16, R wherein
15And R
16Represent hydrogen, the optional C that replaces by hydroxyl independently of one another
1-C
6Alkyl, (xii) C
2-C
6Alkenyl, optional by C
1-C
6Alkoxyl group replaces, (xiii) halogen, (xiv) C
1-C
6Alkylthio and (xv) hydroxyl;
R
4Be hydrogen, halogen, cyano group, formamyl, acyl group, thiocyanate ion, C
1-C
6Alkylthio, C
2-C
6Alkenyl, hydroxyl (C
1-C
6) alkyl, three halogen (C
1-C
6) alkyl or C
1-C
6Alkyl,
R
12And R
17Be derived from the protection of therefrom removing hydroxyl or the group of protection sugar independently of one another.
3. the compound of claim 2, wherein
R
4Be C
1-C
6Alkyl.
4. the compound of claim 3, wherein
R
1Be (1) single-or two (C
1-C
6) alkylamino,
(2) phenyl,
(3) be selected from pyrrolidyl, pyrryl, _ saturated or unsaturated 5 yuan or 6 yuan of heteromonocyclic group groups of azoles base, different _ the azoles base, thiazolyl, furyl, thienyl and pyridyl, or
(4) the optional C that replaces by following group
1-C
6Alkyl: (i) C
1-C
6Alkoxyl group or (ii) be selected from saturated 5 yuan or 6 yuan of heteromonocyclic group groups, wherein C of piperazinyl and morpholinyl
1-C
6Alkoxyl group is optional by ring (C
3-C
6) alkyl or pyridyl replacement.
5. the compound of claim 4, wherein
R
2Be R
7Or-A
2-R
7, wherein
A
2Be-(CH2) n-or-(CH=CH) m-, wherein n be can for 2 to 6 integer and m be 1 or 2 integer and
R
7Be hydrogen, C
1-C
6The carboxyl of alkyl sulphonyl, carboxyl, esterification or pyridyl,
R
3Be (1) phenyl, optional by C
1-C
6Alkyl, ring (C
3-C
6) alkyl, C
1-C
6Alkoxyl group, halogen, cyano group or formamyl replace; Or
(2) quinolyl; Or by C
1-C
6Alkyl, ring (C
3-C
6) alkyl, C
1-C
6The pyridyl that alkoxyl group, formamyl or halogen replace.
6. the compound of claim 5, wherein
R
1Be phenyl, pyrryl, different _ the azoles base, furyl, thienyl, optional by C
1-C
6The C that alkoxyl group replaces
1-C
6Alkyl, piperazinyl or morpholinyl, wherein C
1-C
6Alkoxyl group is optional by ring (C
3-C
6) alkyl or pyridyl replacement,
R
2Be-(CH2) n-R
7, wherein n can be 2 to 5 integer, and R
7Be the carboxyl of carboxyl or esterification, and
R
3Be (1) phenyl, optional by C
1-C
6Alkyl, ring (C
3-C
6) alkyl, C
1-C
6Alkoxyl group, halogen, cyano group or formamyl replace; Or (2) are by C
1-C
6Alkyl, ring (C
3-C
6) alkyl, C
1-C
6The pyridyl that alkoxyl group, formamyl or halogen replace.
7. the compound of claim 5, it is
(1) 3-[7-ethyl-2-methyl-3-(4-pyridyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile,
(2) 3-[7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile,
(3) 4-[7-ethyl-2-methyl-3-(methyl sulphonyl)-pyrrolo-[1,2-b] pyridazine-4-yl] benzonitrile,
(4) 3-[7-ethyl-2-(2-furyl) pyrrolo-[1,2-b] pyridazine-4-yl] benzamide,
(5) 5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] Valeric acid ethylester,
(6) 2-{[4-(3-chloro-phenyl-)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] methyl }-1, ammediol,
(7) 3-[4-(3-chloro-phenyl-)-7-ethyl-2-phenyl-pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid,
(8) 5-[7-ethyl-2-methyl-4-(6-quinolyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(9) 5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] valeric acid,
(10) 5-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(11) 5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(12) 3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid,
(13) 5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(4-morpholinyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(14) (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-sec.-propyl pyrrolo-[1,2-b] pyridazine-3-yl]-the 2-ethyl propenoate,
(15) 6-{4-[4-(aminocarboxyl) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } caproic acid,
(16) 3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid,
(17) 4-[4-(5-bromo-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid,
(18) methyl 5-[2-[(cyclohexyl methoxyl group)]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(19) methyl 5-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(4-pyridyl methoxyl group)] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid,
(20) methyl 4-{4-(5-chloro-3-pyridyl)-7-ethyl-2-[(4-pyridyl methoxyl group)] pyrrolo-[1,2-b] pyridazine-3-yl } butyric acid,
(21) 4-[4-(5-chloro-3-pyridyl]-7-ethyl-2-(4-morpholinyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid,
(22) 4-[4-(5-chloro-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid,
(23) 5-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid, or
(24) methyl 5-{4-(3-cyano-phenyl)-7-ethyl-2-[(4-pyridyl methoxyl group)] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid,
Or its pharmacologically acceptable salt.
8. the compound of claim 6, it is
(1) 5-[4-(3-cyano-phenyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] Valeric acid ethylester,
(2) 3-[4-(3-chloro-phenyl-)-7-ethyl-2-phenyl-pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid
(3) 5-[4-(2-chloro-4-pyridyl)-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also] valeric acid,
(4) 5-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(5) 5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(6) 3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid,
(7) 5-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(4-morpholinyl methyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(8) 6-{4-[4-(aminocarboxyl) phenyl]-7-ethyl-2-methylpyrrole [1,2-b] pyridazine-3-yl also } caproic acid,
(9) 3-[4-(5-bromo-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] propionic acid,
(10) 4-[4-(5-bromo-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid,
(11) methyl 5-[2-[(cyclohexyl methoxyl group)]-7-ethyl-4-(5-methyl-3-pyridyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
(12) methyl 5-{7-ethyl-4-(5-methyl-3-pyridyl)-2-[(4-pyridyl methoxyl group)] pyrrolo-[1,2-b] pyridazine-3-yl } valeric acid,
(13) 4-[4-(5-chloro-3-pyridyl]-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] butyric acid, or
(14) 5-[4-(5-chloro-3-pyridyl)-7-ethyl-2-(methoxymethyl) pyrrolo-[1,2-b] pyridazine-3-yl] valeric acid,
Or its pharmacologically acceptable salt.
9. a method that is used to prepare the compound of claim 1 comprises
(1) compound of following general formula (II)
R wherein
3And R
4As claim 1 definition, or its salt
Compound (III) with following general formula
R wherein
1And R
2As claim 1 definition, or its reactant salt,
Obtain the compound (I) of following general formula
R wherein
1, R
2, R
3And R
4As claim 1 definition, or its salt, or
(2) compound of following general formula (V)
R wherein
4As claim 1 definition, or the compound of its salt and following general formula (VI)
R wherein
1, R
2And R
3As claim 1 definition, or its reactant salt,
Obtain the compound (I) of following general formula
R wherein
1, R
2, R
3And R
4As claim 1 definition, or its salt.
10. pharmaceutical composition, it comprises and the compound of pharmaceutically acceptable carrier blended as the claim 1 of activeconstituents.
11. the pharmaceutical composition of claim 10 is characterized in that the generation that it is used to suppress the phosphodiesterase IN enzymic activity and/or suppresses tumour necrosis factor.
12. the pharmaceutical composition of claim 10 is characterized in that it is used to prevent or treat about the disease with phosphodiesterase IV inhibitors or tumour necrosis factor generation inhibitor for treating.
13. the pharmaceutical composition of claim 10 is used for prevention or treatment asthma, chronic obstructive pulmonary disease, fibrotic disease, acute and fulminant hepatitis, alcohols or non-monohydric aliphatic liver, virus or non-viral chronic hepatitis, liver cirrhosis, autoimmune hepatitis, autoimmunization inflammatory bowel, atopic dermatitis, senile dementia and virus infection.
14. the purposes of the compound of claim 1 in preparation prevention or treatment asthma, chronic obstructive pulmonary disease, fibrotic disease, acute and fulminant hepatitis, alcohols or non-monohydric aliphatic liver, virus or non-viral chronic hepatitis, liver cirrhosis, autoimmune hepatitis, autoimmunization inflammatory bowel, atopic dermatitis, senile dementia or medicine for treating viral infections.
15. the compound of claim 1 is used for preventing or treats the purposes of the medicine of relevant disease with phosphodiesterase IV inhibitors or the treatment of tumour necrosis factor synthetic inhibitor in preparation.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003900189A AU2003900189A0 (en) | 2003-01-09 | 2003-01-09 | Heterocyclic derivatives |
| AU2003900189 | 2003-01-09 | ||
| AU2003903628 | 2003-07-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1759117A CN1759117A (en) | 2006-04-12 |
| CN100349895C true CN100349895C (en) | 2007-11-21 |
Family
ID=30004896
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2003801101353A Expired - Fee Related CN100349895C (en) | 2003-01-09 | 2003-12-26 | Pyrrolopyridazine derivatives |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN100349895C (en) |
| AU (1) | AU2003900189A0 (en) |
| ZA (1) | ZA200505459B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232575B (en) * | 2017-07-10 | 2022-01-25 | 中国科学院上海药物研究所 | Pyrrole [1,2-b ] pyridazine compound or pharmaceutically acceptable salt thereof and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991018903A1 (en) * | 1990-05-25 | 1991-12-12 | Fujisawa Pharmaceutical Co., Ltd. | Pyrrolopyridazine compounds |
-
2003
- 2003-01-09 AU AU2003900189A patent/AU2003900189A0/en not_active Abandoned
- 2003-12-26 CN CNB2003801101353A patent/CN100349895C/en not_active Expired - Fee Related
-
2006
- 2006-01-17 ZA ZA200505459A patent/ZA200505459B/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991018903A1 (en) * | 1990-05-25 | 1991-12-12 | Fujisawa Pharmaceutical Co., Ltd. | Pyrrolopyridazine compounds |
Non-Patent Citations (1)
| Title |
|---|
| Tetrahedron Letters. W Flitsch,1479.1484,synthesis and reaction. 1968 * |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200505459B (en) | 2006-03-29 |
| AU2003900189A0 (en) | 2003-01-30 |
| CN1759117A (en) | 2006-04-12 |
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