Pyrrolopyrazine derivatives, pharmaceutical composition, method for prevention and treatment of diseases, application as phosphodiesterase iv and/or tumor necrosis factor production inhibitor

FIELD: chemistry.

SUBSTANCE: invention relates to the novel inhibitor of phosphodiesterase (PDE) IV and/or to the tumor necrosis factor (TNF) production inhibitor, which corresponds to the compound with formula (I), where R1 is: (1) mono- or di(inferior)alkylamino, (2) phenyl, (3) saturated or unsaturated 5-or 6-membered heteromonocyclic group, selected from a group which includes pyrrolidinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl and piridinyl, or (4) inferior alkyl not necessarily substituted with (i) inferior alkoxi or (ii) saturated 5- or 6-membered heteromonocyclic group, selected from the group, consisting of piperazinyl and morpholinyl, where the inferior alkoxi is not necessarily substituted with cyclo(inferior)alkyl or piridinyl, R2 corresponds to R7 or - A2R7 , where A2 is -(CH2)n- or -(CH=CH)m- [where n is an even number within 2 to 6, and m is an even number 1 or 2], and R7 is a hydrogen, inferior alkylsulfonyl, carboxy, etherificated carboxy or piridinyl; R3 is: (1) phenyl, not necessarily substituted with inferior alkyl, cyclo(inferior)alkyl, inferior alkoxi, halogen, cyano or carbamoyl; or (2) quinolinyl; or piridinyl, substituted with inferior alkyl, cyclo(inferior)alkyl, inferior alkoxi, carbamoyl or halogen, and R4 corresponds to the inferior alkyl, or its pharmaceutically acceptable salt. The application of the compound with formula is invented, for producing the therapeutic agent with the PDE IV and/or TNF production inhibiting activity and the pharmaceutical composition containing the effective amount of compounds with formula (I) mixed with the pharmaceutically acceptable carriers. The method for prevention and treatment of the diseases where the application of the PDE IV and/or TNF production inhibitor is considered to be reasonable, including the administration of the therapeutically effective amount of the compound with formula (I). The method for prevention and treatment of asthma, chronic obstructive pulmonary disease, fibrous disorders, acute and fulminant hepatitis, hepatic steatosis, chronic hepatitis, cirrhosis, autoimmune hepatitis, autoimmune inflammatory intestine disease, atopic dermatitis, Alzheimer's disease or viral infection, including the administration of the therapeutically or preventively effective amount of the compound with formula (I).

EFFECT: compound with the PDE IV and/or TNF production inhibiting activity.

11 cl, 2 tbl, 672 ex

 

The technical field to which the invention relates.

The present invention relates to new derivatives pyrrolopyridine and their pharmaceutically acceptable salts, which inhibit the enzymatic activity of phosphodiesterase IV (PDE IV) and the production of factor-α tumor necrosis (TNF-α).

Background of invention

Cyclic amp (adenosine 3',5'-cyclic monophosphate, cyclic amp (camp) or cyclic AMP") is known as an intracellular second messenger-mediated primary messenger (hormone, neurotransmitter or physiologically active substance) and responses of cells. Primary messenger stimulates the enzyme responsible for the synthesis of camp, and then camp interferes with many functions, such as metabolic, contractile or secretory function. The effect of camp is terminated after the destruction of its cyclic nucleotide-phosphodiesterase, in particular, a phosphodiesterase-4 (PDE4 or PDE-IV)specific to cyclic amp. PDE-IV were identified in many tissues, including the Central nervous system, heart, smooth muscles of blood vessels, smooth muscles of the respiratory tract, of the myeloid lineage, lymphoid tissue, and the like. Increased levels of camp through the use of an inhibitor of PDE-IV has a beneficial effect on the inappropriate activation of smooth muscle is s respiratory tract and a variety of inflammatory cells.

The main concern in the application of inhibitors PDE-IV is, as described by C. Burnouf et al., (Ann. Rep. in Med. Chem., 33:91-109(1998)), observed for some of the proposed connection side effect in the form of vomiting. Burnouf describes many different severe unwanted side effects, showing various connections.

Known for some of the condensed heterocyclic derivative having inhibitory activity against PDE-IV, which are described, for example, in WO 03/016279, WO 03/018579, WO 03/000679 and the like. However, there is still a need for new compounds inhibiting PDE-IV with minimal side effects. Some derivatives pyrrolopyridine possessing inhibitory activity against hydroxymethylglutaryl (HMG)-CoA-reductase, for example, described in WO 91/18903, but not known derivatives pyrrolopyridine possessing inhibitory activity against PDE-IV.

Disclosure of the invention

The present invention relates to new derivatives pyrrolopyridine.

Compounds of the present invention inhibit camp-phosphodiesterase enzymes, in particular, the enzyme phosphodiesterase-4 and inhibit the production of factor-α tumor necrosis (TNF-α), serum glycoprotein.

Thus, one purpose of the present invention is the creation of new is useful derivatives pyrrolopyridine and their pharmaceutically acceptable salts, which have a strong inhibitory activity against phosphodiesterase-4 (PDE-IV) and a strong inhibitory activity against the production of tumor necrosis factor (TNF).

Another objective of the present invention is to provide methods of obtaining derivatives pyrrolopyridine and their salts.

Another objective of the present invention is to provide pharmaceutical compositions containing these derivatives pyrrolopyridine or their pharmaceutically acceptable salts.

And another purpose of the present invention is the use of these derivatives pyrrolopyridine or their pharmaceutically acceptable salts as a drug for the prophylactic and therapeutic treatment of PDE-IV and TNF-mediated diseases, such as chronic inflammatory diseases, specific autoimmune disease caused by sepsis damage to the body, and similar in humans and animals.

The proposed derivatives pyrrolopyridine of the present invention are new and can be represented by the following General formula (I):

where

R1represents:

(1) carboxy or protected carboxy,

(2) -CONR5R6,

(3) hydroxy or lower alkoxy,

(4) amino, cyclo(lower)alkylamino is mono - or di(lower)alkylamino, optionally substituted lower alkoxy,

(5) trihalogen(lower)alkyl,

(6) trihalogen(lower)alkylsulfonate or arylsulfonate,

(7) substituted or unsubstituted lower alkyl,

(8) substituted or unsubstituted aryl or

(9) substituted or unsubstituted heterocyclic group,

R2is an R7or(A1)p-h-a2-R7,

where

p is an integer 0 or 1;

And1is a (C1-C2)alkylene or-CH=CH-;

And2represents -(CH2)n - or -(CH=CH)m- [where n is an integer, which may be in the range of from 1 to 6, and m is an integer, which may be in the range from 1 to 3];

X represents a single bond, -O-, -NR8-, -C(=O)-, -C(=NR9)or hydroxy(C1-C2)alkylen [where R8represents hydrogen or lower alkyl and R9represents a substituted or unsubstituted N-containing heterocyclic group]; and

R7represents:

(1) hydrogen,

(2) substituted or unsubstituted aryl,

(3) substituted or unsubstituted heterocyclic group,

(4) carboxy, protected carboxy or CONR10R11,

(5) acyl or halogencarbonic,

(6) cyano,

(7) amino, protected amino, or mono - or di(lower)alkylamino,

<> (8) hydroxy, aryloxy, acyloxy or lower alkoxy, optionally substituted by hydroxy or acyloxy,

(9) lower alkylthio, lower alkylsulfonyl or lower alkylsulfonyl, or

(10) -O-R12,

or

R1and R2combined with each other with the formation of the lower alkalinous or lower alkynylamino group, which is optionally interrupted by amino or sulfonyl and optionally condensed with a benzene ring, and optionally substituted group consisting of lower alkyl, hydroxy, oxo, and lower alkoxy,

R3represents a substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group,

R4represents hydrogen, halogen, cyano, carbarnoyl, acyl, thiocyanate, lower alkylthio, lower alkenyl, hydroxy(lower)alkyl, trihalogen(lower)alkyl or lower alkyl,

R5, R6, R10and R11each independently represents hydrogen, lower alkylsulfonyl, heterocyclic group, or lower alkyl, optionally substituted hydroxy, alkoxy, sulfo, carboxy, protected carboxy, or-R17,

or, alternatively, R5and R6or R10and R11together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group, and

R12and R17every illegal is isimo is a group, formed from a protected or unprotected sugar removing the hydroxy-group,

or its pharmaceutically acceptable salt or prodrug.

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

"Prodrug" means a derivative of the proposed compound (I)having the chemical is Ki or metabolically degradable group, which is becoming pharmaceutically active after chemo - or biotransformation.

Preferred variants of the proposed compounds of formula (I) are the following compounds:

where

R1represents:

(1) carboxy or esterified carboxy (more preferably etoxycarbonyl),

(2) -CONR5R6[where R5and R6each independently represents a lower alkyl or, alternatively, R5and R6together with the nitrogen atom to which they are attached, represent a saturated 5 - or 6-membered heterogenities group containing 1-2 nitrogen atom] (more preferably dimethylcarbamoyl or 1-pyrrolidinylcarbonyl),

(3) hydroxy or lower alkoxy,

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

(5) trihalogen(lower)alkyl,

(6) trihalogen(lower)alkylsulfonate or arylsulfonate,

(7) lower alkyl, optionally substituted (i) halogen; (ii) carboxy; (iii) protected carboxy; (iv) cyano; (v) carbamoyl; (vi) -OCONR15R16[where R15and R16each independently represents hydrogen, aryl or lower alkyl, optionally substituted aryl, or R15and R16together with the nitrogen atom to which they are attached represent a saturated 5 - or 6-membered heterogenities group, containing 1-2 nitrogen atom and optionally containing an oxygen atom] (more preferably, dimethylcarbamoyl, methylphenylcarbinol, morpholinylcarbonyl or pyrrolidinylcarbonyl); (vii) lower alkylthio; (viii) lower alkylsulfonyl; (ix) lower alkylsulfonate; (x) a lower alkylsulfonyl; (xi) a mono - or di(lower)alkylamino, optionally substituted by hydroxy, lower alkoxy, aryloxy or substituted or unsubstituted aryl; (xii) amino; (xiii) acylamino (more preferably lower alkanolamine, such as acetylamino, aroylamino, such as benzoylamine, or heterocyclic, carbylamine, such as pyrazinecarboxamide); (xiv) protected amino, such as phthalimide, benzylamino or lower alkoxycarbonyl; (xv) hydroxy; (xvi) acyloxy (more preferably lower alkanoyloxy, such as the atomic charges); (xvii) cyclo(lower)alkyloxy; (xviii) aryloxy; (xix) a substituted or unsubstituted aryl (more preferably phenyl); (xx) a saturated or unsaturated 5 - or 6-membered heterophilically group containing 1-3 nitrogen atom and optionally containing an oxygen atom or a sulfur atom (more preferably the piperazinil, morpholinium, oxazolidinyl, thiomorpholine, piperidinium, pyrrolidinium or triazolam), optionally substituted lower alkyl, hydroxy(lower)is Kilom, the aryl or oxo; or (xxi) lower alkoxy, optionally substituted carboxy, protected carboxy, hydroxy, protected hydroxy, lower alkoxy, cyclo(lower)alkyl, substituted or unsubstituted aryl (more preferably phenyl, optionally substituted by cyano, carboxy, protected carboxy or carbamoyl), a saturated or unsaturated 5 - or 6-membered heterophilically group containing 1-2 nitrogen atom (more preferably a pyridinyl, pyrazinium or piperazinil), optionally substituted lower alkyl, or-CONR13R14[where R13and R14each independently represents hydrogen or lower alkyl, optionally substituted aryl, or R13and R14together with the nitrogen atom to which they are attached, represent a saturated 5 - or 6-membered heterogenities group containing 1-2 nitrogen atom and optionally containing an oxygen atom] (more preferably carbamoyl, methylcarbamoyl, benzylcarbamoyl or morpholinylcarbonyl),

(8) aryl (more preferably phenyl), optionally substituted by substituent(s)selected(s) from the group consisting of halogen, or

(9) saturated or unsaturated 5 - or 6-membered heterogenities group (more preferably pyrrolidinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, Anil, pyridinyl), optionally substituted lower alkyl or halogen,

R2is an R7or(A1)p-h-a2-R7,

where

p is 0 or 1;

And1is a (C1-C2)alkylene or-CH=CH-;

And2represents -(CH2)n - or -(CH=CH)m- [where n is an integer, which may be in the range of from 1 to 6, and m is an integer, which may be in the range from 1 to 3];

X represents a single bond, -O-, -NR8-, -C(=O)-, -C(=NR9)or hydroxy(C1-C2)alkylen [where R8represents hydrogen or lower alkyl and R9represents a substituted or unsubstituted pyrrolyl, such as

2-ethyl-5-(4-perbenzoic)pyrrolyl];

R7represents:

(1) hydrogen,

(2) aryl (more preferably phenyl), optionally substituted lower alkoxy,

(3) unsaturated heterogenities group containing 1-2 nitrogen atom (more preferably pyridinyl),

(4) carboxy, esterified carboxy (more preferably lower alkoxycarbonyl) or-CONR10R11[where R10and R11each independently represents hydrogen, lower alkylsulfonyl, unsaturated heterogenities group containing 1-2 nitrogen atom, such as pyridinyl, or Nissi is alkyl, optionally substituted by hydroxy, alkoxy, carboxy, protected carboxy, sulfo or-R17or, alternatively, R10and R11together with the nitrogen atom to which they are attached, represent a saturated 5 - or 6-membered heterogenities group containing 1-2 nitrogen atom and optionally containing an oxygen atom, such as morpholinyl],

(5) acyl (e.g. lower alkanoyl, such as formyl or acetyl, and heterocyclic carbonyl, such as pyridylcarbonyl) or halogencarbonic,

(6) cyano,

(7) amino, protected amino, such as lower alkoxycarbonyl, or mono - or di(lower)alkylamino,

(8) hydroxy, aryloxy, acyloxy or lower alkoxy, optionally substituted by hydroxy or acyloxy (for example, lower alkanoyloxy),

(9) lower alkylthio, lower alkylsulfonyl or lower alkylsulfonyl, or

(10) -O-R12,

or

R1and R2combined with each other with the formation of the lower alkalinous or lower alkynylamino group, which is optionally interrupted by amino or sulfonyl, and optionally substituted group consisting of lower alkyl, hydroxy, oxo, and lower alkoxy, and which is represented by the following formula:

which may include the following formulas:

R3represents:

(1) aryl (more preferably phenyl or naphthyl), optionally substituted by at least one Deputy, selected from the group consisting of (i) halogen, (ii) carboxy, (iii) protected carboxy, (iv) cyano, (v) -CONR15R16[where R15and R16each independently represents hydrogen, lower alkyl, optionally substituted hydroxy-group], (vi) lower alkyl, (vii) cyclo(lower)alkyl, (viii) hydroxy(lower)alkyl, (ix) lower alkoxy, (x) trihalogen(lower)alkyl, (xi) an unsaturated 5 - or 6-membered heterophilically group containing 1-2 oxygen atoms and 1-2 nitrogen atom, such as oxazolyl, (xii) lower alkylsulfonyl, (xiii) nitro, (xiv) sulfamoyl and (xv) protected sulfamoyl; or

(2) a heterocyclic group selected from the group consisting of pyridinyl, pyrazinyl, oxazolyl, isoxazolyl, furanyl, teinila, chinoline, benzofuranyl and benzothiazyl where the specified heterocyclic group optionally substituted by at least one Deputy, selected from the group consisting of (i) lower alkyl, (ii) cyclo(lower)alkyl, (iii) lower alkoxy, (iv) acyl, such as lower alkanoyl, (v) amino, (vi) mono - or di(lower)alkylamino, (vii) protected amino, such as lower alkoxycarbonyl, (viii) cyano, (ix) carboxy, (x), protected carboxy, such as ATOC carbonyl or methoxycarbonyl, (xi) -CONR15R16[where R15and R16each independently represents hydrogen, lower alkyl, optionally substituted hydroxy-group], (xii) lower alkenyl, optionally substituted lower alkoxy, (xiii) halogen, (xiv) lower alkylthio and (xv) hydroxy;

R4represents hydrogen, halogen, cyano, carbarnoyl, acyl, thiocyanate, lower alkylthio, lower alkenyl, hydroxy(lower)alkyl, trihalogen(lower)alkyl or lower alkyl, and

R12and R17each independently represents a group formed from a protected or unprotected sugars, such as galactose, removing the hydroxy-group,

or their pharmaceutically acceptable salts or prodrugs.

More preferred compounds of formula (I) are compounds in which:

R1represents:

(1) mono - or di(lower)alkylamino,

(2) aryl, such as phenyl,

(3) saturated or unsaturated 5-6 membered heterogenities group containing 1-2 heteroatoms selected from atom(s), nitrogen, oxygen or sulfur (preferably pyrrolidinyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, furanyl, thienyl, pyridinyl, etc.), or

(4) lower alkyl, optionally substituted lower alkoxy, or a saturated 5 - or 6-membered heterophilically group containing 1-2 nitrogen atom, and neo is Astelin containing an oxygen atom (more preferably a piperazinil or morpholinyl), where lower alkoxy optionally substituted cyclo(lower)alkyl or unsaturated 5-6 membered heterophilically group containing 1-2 nitrogen atom (more preferably a pyridinyl),

R2is an R7or-And2-R7,

where

And2represents -(CH2)n - or -(CH=CH)m- [where n is an integer, which may be in the range of from 2 to 6, and m is an integer 1 or 2], and

R7represents hydrogen, lower alkylsulfonyl, carboxy, protected carboxy or unsaturated 5-6 membered heterogenities group containing 1-2 nitrogen atom (more preferably pyridinyl),

R3represents:

(1) aryl, optionally substituted lower alkyl, cyclo(lower)alkyl, halogen, cyano or carbamoyl; or

(2) unsaturated condensed heterocyclic group containing 1-2 nitrogen atom (more preferably chinoline), or unsaturated 5-6 membered heterogenities group containing at least one nitrogen atom (more preferably 3-pyridinyl and 4-pyridinyl)substituted lower alkyl, cyclo(lower)alkyl or halogen, and

R4represents lower alkyl.

The most preferred compounds of formula (I) are compounds in which:

R1represents phenyl, which sennou or unsaturated 5-6 membered heterogenities group, containing 1-2 heteroatoms selected from atom(s), nitrogen, oxygen or sulfur (preferably pyrrolyl, isooxazolyl, furanyl, thienyl etc), or lower alkyl, optionally substituted lower alkoxy, or a saturated 5 - or 6-membered heterophilically group containing 1-2 nitrogen atom and optionally containing an oxygen atom (more preferably a piperazinil or morpholinyl), where lower alkoxy optionally substituted cyclo(lower)alkyl or unsaturated 5-6 membered heterophilically group containing at least one nitrogen atom (more preferably a pyridinyl),

R2represents -(CH2)n-R7where n is an integer, which may be in the range of 2 to 5, and R7represents carboxy or protected carboxy,

R3represents (1) phenyl, optionally substituted lower alkyl, cyclo(lower)alkyl, lower alkoxy, halogen, cyano or carbamoyl; or (2) unsaturated 5-6 membered heterogenities group containing at least one nitrogen atom (more preferably 3-pyridinyl and 4-pyridinyl)substituted lower alkyl, cyclo(lower)alkyl, lower alkoxy, carbamoyl or halogen, and

R4represents lower alkyl.

Preferred specific compound of formula (I) t is aetsa:

(1) 3-[7-ethyl-2-methyl-3-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,

(2) 3-[7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,

(3) 4-[7-ethyl-2-methyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,

(4) 3-[7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide,

(5) ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate,

(6) 2-{[4-(3-chlorophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]methyl}-1,3-propandiol,

(7) 3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]propanoic acid,

(8) 5-[7-ethyl-2-methyl-4-(6-chinoline)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid,

(9) 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid,

(10) 5-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid,

(11) 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid,

(12) 3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,

(13) 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid,

(14) ethyl-(2E)-3-[7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]-2-propenoate,

(15) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}hexanoic acid,

(16) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin the-3-yl]propanoic acid,

(17) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid,

(18) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid,

(19) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid,

(20) 4-{4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butane acid,

(21) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid,

(22) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid,

(23) 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid or

(24) 5-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid,

or their pharmaceutically acceptable salt.

More preferred specific compound of formula (I) is:

(1) ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate,

(2) 3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]propanoic acid,

(3) 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid,

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

(5) 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(labels shall imethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid,

(6) 3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,

(7) 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid,

(8) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}hexanoic acid,

(9) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,

(10) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid,

(11) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid,

(12) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid,

(13) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid, or

(14) 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid,

or their pharmaceutically acceptable salt.

The proposed compound (I) of the present invention can be obtained in the following ways :

Method 1

/tr>
< / br>
or its salt
(II) or its salt(I) or its salt

Method 2

Hydrolysis

(I-a) or its salt(I-b) or its salt

Method 3

Remove carboxyamide group in R1a< / br>
(I-c) or its salt(I-d) or its salt

Method 4

The amidation

(I-d) or its salt

or a reactive derivative at carboxypropyl
(I-e) or its salt

Method 5

Cyclization of

(I-e) or its salt(I-g) or its salt

Method 6

Hydrolysis

(I-b) or its salt(I-h) or its salt

Method 7

Remove carboxyamide group in R2b< / br>
(I-i) or its salt(I-j) or its salt

Method 8

The amidation

(I-j) or its salt or reactive derivative at carboxypropyl(I-k) or its salt

Method 9

Remove hydroxyamino group in R2e< / br>
(I-l) or its salt(I-v) or its salt

Method 10

Recovery

(I-i) or its salt(I-n) or its salt

Method 11

X-R12< / br>
(IV)

(I-n) or its salt(I-o) or its salt

Way 12

< / br>
(VI) or its salt
(V) or its salt(I) or its salt

Way 13

Halogenoalkane

(I-p) or its salt(I-g) or its salt

Way 14

Remove aminosidine

group in R3d< / br>
(I-r) or its salt(I-s) or its salt

Way 15

Cyclization of

(VI)(I-t) or its salt

Way 16

Interaction with amines

(I-u) or its salt or reactive derivative at the hydroxy-group(I-v) or its salt

Method 17

Interaction with compounds containing activated methylene fragment

(I-w) or its salt(I-x) or its salt

Method 18

The amidation

(I-h) or its salt(I-y) or its salt

Method 19

Alcohol or dispert, or its salt

(I-z) or its salt(I-aa) or its salt

Method 20

The solvolysis

(I-ab) or its salt(I-ac) or its salt

Method 21

Oxidation

(I-ad) or its salt(I-ae) or its salt

Method 22

Oxidation

(I-af) or its salt(I-ag) or its salt

Method 23

At Olenye

(I-a) or its salt(I-ah) or its salt

Method 24

Remove aminosidine group

(I-ai) or its salt(I-aj) or its salt

Method 25

Amines

(I-z) or its salt(I-ak) or its salt

Method 26

Cyclization of

(I-al) or its salt(I-am) or its salt

Way 27

tr>
Recovery

(I-am) or its salt(I-an) or its salt

Method 28

Lowest alkylhalogenide

(I-an) or its salt(I-ao) or its salt

Method 29

Lowest alkylhalogenide

(I-an) or its salt(I-ap) or its salt

The method 30

Oxalicacid

(I-aq) or its salt (I-ar) or its salt

Method 31

Triftormetilfullerenov anhydride

(I-u) or its salt(I-as) or its salt

Fashion 32

Alkylation

(I-as) or its salt(I-at) or its salt

Method 33

Lowest alkyldiphenyl-phosphonylated

(I-au) or its salt(I-av) or its salt

Method 34

Recovery

(I-av) or its salt(I-aw) or its salt

Method 35

Introduction hydroxyamino group

(I-af) or its salt(I-ax) or its salt

Method 36

Interaction with amines

(I-ag) or its salt(I-ay) or its salt

Method 37

(I) or its salt

Method 38

(I-az) or its salt

Method 39

three(lower)alkyl(lower alkene-1-yl)tin or three(lower)alkyl(1-(lower)alkyl(lower alkene-1-yl)tin

(I-z) or its salt(I-ba) or its salt

The method 40

bis(3-(lower)alkoxy-3-oxopropanoic) magnesium

(I-r) or its salt(I-bb) or its salt

where R1, R2, R3and R4each is as defined above,

R1ais the same as indicated above for R1containing protected carboximide,

R1bis the same as indicated above for R1containing carboximide,

R1cis a-CONR5R6,

R1drepresents carbarnoyl(lower)alkyl,

R1erepresents amino, mono - or di(lower)alkylamino, lower alkoxy(lower)alkylamino, nitrogen-containing heterocycle is a mini-group, amino(lower)alkyl, mono - or di(lower)alkylamino(lower)alkyl, lower alkoxy(lower)alkylamino(lower)alkyl, a nitrogen-containing heterocycle(lower)alkyl,

R1frepresents a lower alkylthio(lower)alkyl,

R1grepresents a lower alkylsulfonyl(lower)alkyl,

R1hrepresents tripterocalyx or tripterocalyx(lower)alkyl,

R1irepresents a lower alkoxy or lower alkoxy(lower)alkyl,

R1jrepresents hydroxy or hydroxy(lower)alkyl,

R2arepresents the lowest alkoxycarbonyl,

R2bis the same as indicated above for R2containing protected carboximide,

R2cis the same as indicated above for R2containing carboximide,

R2dis the same as indicated above for R2containing carbamoyl fragment

R2eis the same as indicated above for R2containing protected hydroxyprimer,

R2fis the same as indicated above for R2containing hydroxyprimer,

R2gis the same as indicated above for R2containing hydroxym is tilen fragment

R2hrepresents-OR12,

R2irepresents the lowest alkoxycarbonyl or lower alkylsulfonyl,

R2jrepresents a substituted or unsubstituted lower alkenyl, such as described above for R2where the specified lower alkenyl is a lower 1-alkene-1-yl,

R2kis the same as indicated above for R2containing hydroxy(lower)alkyl fragment

R2lis the same as indicated above for R2containing oxo(lower)alkyl fragment

R2mis the same as indicated above for R2containing protected aminophen,

R2nis the same as indicated above for R2containing aminophen,

R2ois the same as indicated above for R2containing protected hydroxyprimer,

R2pis the same as indicated above for R2containing hydroxy(lower)alkylamino(lower)alkyl fragment

R2qis the same as indicated above for R2that contains the lowest alkoxycarbonyl(lower)alkyl fragment

R2ris the same as indicated above for R2containing lower alkoxycarbonylmethyl FR is gment,

R3ais the same as indicated above for R3containing Cineframe,

R3bis the same as indicated above for R3containing carbamoyl fragment

R3cis the same as indicated above for R3containing carboximide,

R3dis the same as indicated above for R3containing protected selfamily fragment

R3eis the same as indicated above for R3containing selfamily fragment

R3fis the same as indicated above for R3containing-CONR10R11fragment

R3gis the same as indicated above for R3containing gelegenheitstrinker fragment

R3his the same as indicated above for R3containing alkoxycarbonylmethyl, dialkoxybenzene or hydroxyprimer,

R3iis the same as indicated above for R3containing 1-(lower)alkoxy(lower)alken-1-retracycline fragment

R3jis the same as indicated above for R3containing lower albanerpetontidae fragment

R3kis the same as indicated above for R3containing aminomethyl teracycline fragment

R3lis the same as indicated above for R3containing mono - or di(lower)alkylamidoimidazoline fragment

R3mis the same as indicated above for R3containing (lower)alken-1-retrocyclin group or 1-(lower)alkoxy-1-(lower)alken-1-retracycline fragment

R4arepresents halogen,

R4brepresents formyl,

R4cis a lower 1-alkene-1-yl,

R4drepresents lower alkyl,

R12represents a lower alkyl or a group formed from a protected or unprotected sugars, by removal of the hydroxy-group,

X represents a leaving group, and a group of the formularepresents the lowest alkylen, interrupted by imioramine and replaced by exography.

The original compound (II) according to the present invention can be obtained in the usual way or in any manner similar to that described in the following "Get" and/or "Examples".

Another point that should be noted is that pyrrolopyridines fragment of the compound (I) may also exist in tautomeric form and such tautomeric equilibrium can be represented, for example, the following formula is mi.

where R1, R2, R3and R4each is the same as above.

Both of the above tautomeric isomers are included in the scope of the present invention, but in this description and the claims of the proposed compound (I) is represented for convenience, one of the possible tautomeric forms pyrrolopyridines rings.

Hereinafter in the description provides a detailed description of suitable examples and illustrations of the various definitions included in the scope of the present invention.

The term "lower" used to refer to groups containing 1-6, preferably 1-4, carbon atoms, unless otherwise specified.

Suitable "lower alkyl" and "lower alkyl fragment can include an unbranched or branched "lower alkyl" or "lower alkyl fragment containing 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl and the like, of which more preferred example may be C1-C4alkyl.

Suitable "lower alkenyl" may include vinyl(ethynyl),

1-(or 2-)propenyl, 1-(or 2 - or 3-)butenyl,

1-(or 2 - or 3 - or 4-)pentenyl,

1-(or 2 - or 3 - or 4 - or 5-)hexenyl,

1-methylvinyl, 1-ethyl vinyl, 1-(or 2-)methyl-1-(or 2-)propenyl, 1-(or 2-)ethyl-1-(or 2-)PDEC the Nile

1-(or 2 - or 3-)methyl-1-(or 2 - or 3-)butenyl and the like, of which more preferred example may be C2-C4alkenyl.

Suitable "lower quinil" may include ethinyl, 1-PROPYNYL, propargyl, 1-methylpropenyl, 1 or 2 or 3 butynyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl and the like.

Suitable "lower alkylene may include unbranched or branched "low alkylen", such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, METROTILE, ethylethylene, propylene and the like, of which more preferred example may be C1-C4alkylene and the most preferable example may be methylene.

Example hydroxy(C1-C2)alkylene is hydroxymethylene, (hydroxymethyl)methylene or 1-(or 2-)hydroxyethylene.

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

Suitable "halogen" and "halogen fragment" may include fluorine, bromine, chlorine and iodine.

Suitable "trihalogen(lower)alkyl" may include trichloromethyl, trifluoromethyl, trichloroethyl, tribromide and the like.

Suitable mono - or di(lower)alkylamino" may include amino group, substituted by one, and the two lowest alkilani, such as methylamino, ethylamino, dimethylamino and the like.

Example mono - or di(lower)alkylamino, substituted lower alkoxy" may be methoxyethylamine, methoxyethylamine, methoxyethyl(methyl)amino, methoxyethyl(ethyl)amino, di(methoxyethyl)amino, ethoxymethylene, ethoxyethylene and the like.

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

Suitable "lower alkylsulfonyl" may include a conventional "low alkylsulfonyl", such as methylsulfinyl, ethylsulfinyl, propylsulfonyl, butylsulfonyl and the like.

Suitable "lower alkylsulfonyl" may include the usual "lower alkylsulfonyl", such as methylsulphonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like.

Suitable "trihalogen(lower)alkylsulfonate" may include sulfonyloxy, substituted trihalogen(lower)alkyl, such as tripterocalyx, tripterocalyx, trichlorocarbanilide and the like.

Suitable "protected carboxy" and "protected carboximide" may include esterified carboxy and the like.

A suitable example of the specified complex ester may be an ester, such as a complex lower alkilany ether (for example, methyl is a new ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, tert-butyl methyl ether, pentalogy ether, tert-pentalogy ether, hexyl ether, etc.);

lower alkenilovyh ester (e.g. vinyl ester, allyl ether, etc.);

lower alkinilovymi ether (for example, atinlay ether, propenyloxy ether, etc.);

lower alkoxy(lower)alkilany ether (for example, methoxymethyl ether, ethoxymethyl ether, isopropoxyethanol ether, 1-methoxyethoxy ether, 1-ethoxyethyl ether, etc.);

lower alkylthio(lower)alkilany ether (for example, methylthiomethyl ether, ethyldimethylamine ether, ethylthioethyl ether, isopropoxytitanium ether, etc.);

mono(or di or three)halogen(lower)alkilany ether (for example, 2-itatiaia ether, 2,2,2-trichlorethylene ether, etc.);

lower alkanoyloxy(lower)alkilany ether (for example, acetoxymethyl ether, propionylacetate ether, butyrylacetate ether, veterinarinary ether, pivaloyloxymethyl ether, hexaniacinate ether, 1-ecotoxicology ether, 2-ecotoxicology ether, 2-propionylacetate ether, etc.);

lower alkoxycarbonyl(lower)alkilany ether (for example, methoxycarbonylmethyl ether, ethoxycarbonylmethylene ether, propoxycarbazone ether,

1-(or 2-)[methoxycarbonylamino]ethyl the air,

1-(or 2-)[ethoxycarbonyl]ethyl ester,

1-(or 2-)[propoxycarbonyl]ethyl ester,

1-(or 2-)[isopropoxycarbonyl]ethyl ester, etc.);

lower alkanesulfonyl(lower)alkilany ether (for example, methylotrophy ether, 2-mutilative ether, etc.);

lower alkoxycarbonyl(lower)alkilany ether (for example, methoxycarbonylmethyl ether, ethoxycarbonylmethylene ether, propoxycarbazone ether,

tert-butoxycarbonyloxyimino ether,

1-(or 2-)methoxycarbonylmethylene ether,

1-(or 2-)ethoxycarbonylmethylene ether,

1-(or 2-)isopropoxycarbonyloxymethyl ether, etc.);

thalidomide(lower)alkilany ether;

(5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkilany ester [for example, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,

(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,

(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester and so on];

mono(or di or three)aryl(lower)alkilany ether, for example, mono(or di or three)phenyl(lower)alkilany ester which may have one or more suitable substituents (e.g., benzyl ester, 4-methoxybenzyloxy ether, 4-nitrobenzyloxy ether, finitely ether, trailovic ether, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ether, 4-hydroxy-3,5-di-tert-butylbenzylamine ether, etc.);

p> arrowy ester which may have one or more suitable substituents such as substituted or unsubstituted phenyl ether (for example, phenyl ether, tallowy ether, tert-BUTYLPEROXY ether, Kilroy ether, mesityloxy ether, comenjoy ether, 4-hlorfenilovy ether, 4-methoxyphenacyl ether, etc.);

three(lower)alkylsilane ether (for example, trimethylsilyloxy ether, triethylsilyl ether, etc.);

three(lower)alkylsilane(lower)alkilany ether (for example, 2-trimethylsilylethynyl ether, etc. and the like, of which more preferred example may be lower alkilany ether, namely the lowest alkoxycarbonyl (for example, etoxycarbonyl etc).

The term "protected amino" means aminogroup associated with aminosidine group. Examples of such aminosidine groups include lower alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl etc); lower alkenylbenzenes (for example, vinyloxycarbonyl, allyloxycarbonyl etc.); optionally substituted aryl(lower)alkoxycarbonyl (for example, benzyloxycarbonyl etc.); phthalimide and the like. Other examples aminosidine groups are well known in organic chemistry and described in the publication by T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," Second Edition, John Wiley and Sons, New York, N.Y., which is incorporated in this description by reference is I.

The term "protected sulfamoyl" means sulfamoyl group containing aminosidine group specified above, at the nitrogen atom. Preferred aminosidine group represents aryl(lower)alkoxycarbonyl (for example, benzyloxycarbonyl etc) and the like.

Suitable "acyl" and "acyl fragment" may include aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.

A suitable example of the specified acyl can be illustrated as follows:

aliphatic acyl, such as:

the lowest or highest alkanoyl (for example, formyl, acetyl, propanol, butanol, 2-methylpropanol, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanol, deletion, pentadecanol, hexadecanol, heptadecanol, octadecanol, nonadecanoic, emosanal etc), of which preferred "lower alkanoyl may include unbranched or branched lower alkanoyl, such as formyl, acetyl, propionyl, butyryl and the like;

the lowest or highest alkanoyl (for example, acryloyl,

2-(or 3-)butenyl, 2-(or 3 - or 4-)pentenyl,

2-(or 3 - or 4 - or 5-)hexanoyl etc.);

lowest alkadienes (EmOC is emer, heptadienyl, hexadienyl etc.);

cyclo(lower)alkylaryl (for example, cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl etc.);

lowest alkylglycerol (for example, methylglyoxal, acylglycerol, papillionaceae etc.);

lowest alkoxyglycerols (for example, methoxylation, toxigenicity, propoxylation etc.);

or the like;

aromatic acyl such as:

aroyl (for example, benzoyl, toluoyl, Naftoli etc.);

ar(lower)alkanoyl [for example, phenyl(lower)alkanoyl (for example, phenylacetyl, phenylpropanol, phenylmethanol, phenylethanol, phenylmethanol, phenylhexanoic etc), naphthyl(lower)alkanoyl (for example, naphthylacetyl, afterrepair, afterburner etc) and so on];

ar(lower)alkanoyl [for example, phenyl(lower)alkanoyl (for example, phenylpropenoyl, phenylmethanol, phenylmethanol, phenylmethanol, phenylhexanoic etc), naphthyl(lower)alkanoyl (for example, afterproperties, afterburner etc) and so on];

aryloxy(lower)alkanoyl (for example, phenoxyacetyl, phenoxypropionyl etc.);

acilglycerol (for example, phenylglyoxylic, afterpotential etc.);

heterocyclic acyl, such as:

heterocyclicamines;

heterocycle(lower)alkanoyl (for example, heterocyclization, heterocyclization, heterocyclization, the heterocycle is pentanoyl, heterocyclisation etc.);

heterocycle(lower)alkanoyl (for example, heterocyclization, heterocyclization, heterocyclization, heterocyclisation etc.);

heterosynaptically; heterocyclisation or the like; in which suitable "heterocyclic fragment" may include saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one heteroatom such as oxygen atom, sulfur, nitrogen and the like, as shown and preferred "heterocyclicamines may include a carbonyl group, a substituted heterocyclic group, as defined below, such as pyrrolidinylcarbonyl, pyridylcarbonyl, PersonalCabinet and the like.

Suitable "halogencarbonic" may include chlorocarbonyl, bromocarbons and the like.

Suitable "cyclo(lower)alkyl" and "cyclo(lower)alkyl fragment can include cyclo(lower)alkyl or cyclo(lower)alkyl fragment containing 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

Suitable "aryl" and "aryl fragment can include With6-C10aryl, such as phenyl, naphthyl and the like.

Suitable "heterocyclic fragment" may include saturated or unsaturated monocyclic the th or polycyclic heterocyclic group, containing at least one heteroatom such as oxygen atom, sulfur, nitrogen and the like.

Preferable heterocyclic group may be heterocyclic group such as:

(1) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group containing 1-4 nitrogen atom, for example, pyrrolyl, pyrrolidyl, imidazolyl, pyrazolyl, pyridinyl, dihydropyridines, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (for example, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc), tetrazolyl (for example, 1H-tetrazolyl, 2H-tetrazolyl etc), etc.;

(2) saturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group containing 1-4 nitrogen atom, for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinil etc.;

(3) unsaturated condensed heterocyclic group containing 1-4 nitrogen atom, for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, hinely, tetrahydroquinolin (for example, 1,2,3,4-tetrahydroquinolin etc), ethanolic, indazoles, benzotriazolyl, benzoperylene (for example, benzo[b]pyrimidinyl etc), etc.;

(4) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group containing 1-2 oxygen atoms and 1-3 nitrogen atom, for example, oxazolyl, isoxazolyl, oxadiazolyl(for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl etc), etc.;

(5) saturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group containing 1-2 oxygen atoms and 1-3 nitrogen atom, for example, morpholinyl, Sydney etc.;

(6) unsaturated condensed heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atom, for example, benzoxazolyl, benzoxadiazole etc.;

(7) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group containing 1-2 sulfur atom and 1 to 3 nitrogen atom, for example, thiazolyl, isothiazolin, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl etc), dihydrothiazine etc.;

(8) saturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group containing 1-2 sulfur atom and 1 to 3 nitrogen atom, for example, diazolidinyl etc.;

(9) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group containing 1-2 sulfur atom, for example, thienyl, dehydrodidemnin, dehydrodidemnin etc.;

(10) unsaturated condensed heterocyclic group containing 1-2 sulfur atom and 1 to 3 nitrogen atom, for example, benzothiazolyl, benzothiadiazole etc.;

(11) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group, the content is based on the oxygen atom, for example, furanyl etc.;

(12) unsaturated condensed heterocyclic group containing 1-2 oxygen atom, for example, benzodioxolyl (e.g., methylenedioxyphenyl, etc.), benzofuranyl etc.;

(13) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group containing an oxygen atom and 1 to 2 sulfur atom, for example, dihydroartemisinin etc.;

(14) unsaturated condensed heterocyclic group containing 1-2 sulfur atom, for example, benzothiazyl (for example, benzo[b]thienyl etc), benzodithiol etc.;

(15) unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom, for example, benzoxanthenes etc; and the like.

Suitable "heterocyclic group" and "heterocyclic fragment" for "geterotsiklicheskikh can be above heterocyclic groups and fragments.

Suitable "N-containing heterocyclic group" and "N-containing heterocyclic fragment" may be the above groups and fragments, in which the heterocyclic group contains at least one nitrogen atom, such as 1-pyrrolidinyl, morpholinyl and the like.

The group, formed from sugar, there may be a group formed, for example, from glyceraldehyde; an aldose such as erythrose, threose, arabinose, ribose, who silosa, lyxose, glucose, mannose or galactose; ketosis, such as fructose or sorbose; or disaccharide, such as maltose, lactose or sucrose.

Protective groups for the hydroxy-group of the above sugars are aliphatic acyl group such as formyl or acetyl; a cyclic ether group such as tetrahydro-2-furanyl or tetrahydro-2-pyranyl; 1-alkoxyethyl group such as 1-methoxyethyl or 1-ethoxyethyl; and a silyl group such as trimethylsilyl, triethylsilyl or tert-butyldimethylsilyl.

Suitable "substituted or unsubstituted lower alkyl for R1may include unbranched or branched lower alkyl (e.g. methyl, isopropyl, neopentyl etc), optionally substituted: (1) halogen (e.g. fluorine, bromine, etc.), (2) carboxy, (3) protected carboxy (for example, esterified carboxy, such as etoxycarbonyl etc.), (4) cyano, (5) carbamoyl, (6) group-OCONR15R16[where R15and R16each independently represents hydrogen, aryl or lower alkyl, optionally substituted aryl, or R13and R14together with the nitrogen atom to which they are attached, represent a saturated 5 - or 6-membered heterogenities group containing 1-2 nitrogen atom and optionally containing an oxygen atom] (more preferably is dimethylcarbamoyl, methylphenylcarbinol, morpholinylcarbonyl, pyrrolidinylcarbonyl etc); (7) lower alkylthio (for example, methylthio, etc.), (8) lower alkylsulfonyl (for example, methylsulfonyl etc.), (9) lower alkylsulfonate (for example, methylsulfonylamino etc.), (10) lower alkylsulfonyl (for example, methylsulfonylamino etc.), (11) mono - or di(lower)alkylamino, optionally substituted by a hydroxy-group, the lower alkoxy, acyloxy (for example, phenoxy etc) or substituted or unsubstituted aryl (e.g., benzylamino etc), (12) amino; (13) acylamino (more preferably lower alkanolamine, such as acetylamino, aroylamino, such as benzoylamine, or getrollbackonly, such as pyrazinecarboxamide, or the like), (14) protected amino (for example, methoxycarbonylamino, phthalimido etc.), (15) hydroxy, (16) acyloxy (more preferably, lower alkanoyloxy, such as atomic charges, or the like), (17) cyclo(lower)alkyloxy, (18) aryloxy (for example, phenoxy etc.) (19) substituted or unsubstituted aryl (more preferably phenyl), (20) a saturated or unsaturated 5 - or 6-membered heterophilically group containing 1-3 nitrogen atom and optionally containing an oxygen atom or a sulfur atom (more preferably piperazinil, morpholinyl, oxazolidinyl, thiomorpholine, piperidine is l, pyrrolidinyl or triazolyl), optionally substituted lower alkyl, hydroxy(lower)alkyl, aryl or oxo, (21) lower alkoxy (e.g. methoxy, ethoxy, isopropoxy etc), optionally substituted by carboxypropyl, protected carboxy (e.g., tert-butoxycarbonyl etc), hydroxy, protected hydroxy (e.g., tetrahydro-2H-Piran-2-yloxy etc), cyclo(lower)alkyl (e.g., cyclopropyl, cyclohexyl, etc.), substituted or unsubstituted aryl (e.g. phenyl, optionally substituted by cyano, carboxy, protected carboxy or carbamoyl, such as phenyl, 2-, 3 - or 4-cyanophenyl, 2-, 3 - or 4-carboxyphenyl, 2-, 3 - or 4-(methoxycarbonyl)phenyl, 2-, 3 - or 4-carbamoylmethyl etc), a saturated or unsaturated 5 - or 6-membered heterocyclic group containing 1-2 nitrogen atom, optionally substituted lower alkyl (more preferably 2-, 3 - or 4-pyridinyl, pyrazinium or 4-methylpiperazine) (for example, 2-, 3 - or 4-pyridinyl, pyrazinium etc), or the group,- CONR13R14[where R13and R14each independently represents hydrogen or lower alkyl, optionally substituted aryl, or R13and R14together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group] (for example, morpholinomethyl, dimethylcarbamoyl etc), and the like.

Suitable "substituted or unsubstituted aryl" may include With6-C10alkyl group, alkyl group, aryl (e.g. phenyl, naphthyl, etc.), optionally substituted by substituent(s)selected(s) from the group consisting of (1) halogen (e.g. fluorine, chlorine, etc.), (2) carboxy, (3) protected carboxy, (4) cyano, (5) group,- CONR15R16[where R15and R16each independently represents hydrogen, lower alkyl, optionally substituted by hydroxy], for example, carbamoyl, hydroxyethylcellulose etc.), (6) lower alkyl (e.g. methyl etc), (7) cyclo(lower)alkyl (e.g., cyclopropyl etc.), (8) lower alkoxy (e.g. methoxy, etc.), (9) trihalogen(lower)alkyl (e.g., trifloromethyl etc.), (10) heterocyclic groups, such as oxazolyl, (11) lower alkylsulfonyl (for example, methylsulfonyl etc.), (12) nitro, (13) amino, (14) sulfamoyl and (15) protected sulfamoyl, such as ar(lower)alkoxycarbonylmethyl, and the like.

Moreover, preferred examples of the substituted or unsubstituted aryl" for R1is aryl, optionally substituted by substituent(s)selected(s) from the group consisting of halogen (e.g., phenyl, 4-forfinal etc.); preferred examples of substituted or unsubstituted aryl" for R3is aryl, the optional Sames the config substituent(s), selected(I) from the group consisting of (1) halogen, (2) carboxy, (3) protected carboxy, such as esterified carboxy (e.g., benzyloxycarbonyl etc.), (4) cyano, (5) group,- CONR15R16[where R15and R16each independently represents hydrogen, lower alkyl, optionally substituted by hydroxy], (6) lower alkyl, (7) cyclo(lower)alkyl, (8) lower alkoxy, (9) trihalogen(lower)alkyl, (10) heterocyclic group, (11) lower alkylsulfonyl, (12) nitro, (13) amino, (14) sulfamoyl and (15) protected sulfamoyl, and the like (for example, phenyl, 2-naphthyl, 2 - or 3-chlorophenyl,

2,3-, 2,4-, 3,4 - or 3,5-dichlorophenyl, 3 - or 4-forfinal,

3 - or 4-cyanophenyl, 3 - or 4-carbamoylethyl, 4-sulfamoylbenzoyl,

4-(benzyloxycarbonylamino)phenyl, 3-carboxyphenyl,

3-(N-(2-hydroxyethyl)carbarnoyl)phenyl, 3-nitrophenyl,

3-triptoreline, 3-methylsulfinylphenyl,

3-(5-oxazolyl)phenyl, 3-methoxyphenyl, 3-were and so on); and preferred examples of the substituted or unsubstituted aryl" for R7is aryl, optionally substituted lower alkoxy (for example, phenyl, 2-, 3 - or 4-methoxyphenyl, and so on).

Suitable "substituted or unsubstituted heterocyclic group" may include heterocyclic group, the above (more preferably pyridinyl, pyrazinyl, oxazolyl, isooxazolyl, f is wounded, thienyl, chinoline, benzofuranyl and benzothiazyl), which is optionally substituted by substituent(s)selected(s) from the group consisting of (1) lower alkyl (e.g. methyl etc), (2) cyclo(lower)alkyl (e.g., cyclopropyl etc.) (3) lower alkoxy (e.g. methoxy, etc.), (4) acyl (e.g. lower alkanoyl, such as acetyl, etc.), (5) amino, (6) mono - or di(lower)alkylamino (for example, dimethylamino, etc.), (7) protected amino (e.g., lower alkoxycarbonyl, such as tert-butoxycarbonylamino etc.), (8) cyano, (9) carboxy, (10) protected carboxy (for example, benzyloxycarbonyl etc.), (11) group,- CONR15R16[where R15and R16each independently represents hydrogen, lower alkyl, optionally substituted by hydroxy], for example, carbamoyl, hydroxyethylcellulose etc.), (12) lower alkenyl, optionally substituted lower alkoxy (for example, vinyl, 1-ethoxyphenyl etc.), (13) halogen (e.g. chlorine, bromine, etc.), (14) lower alkylthio, (15) hydroxy, and the like.

Moreover, preferred examples of the substituted or unsubstituted heterocyclic group" for R1is a heterocyclic group, optionally substituted by lower alkyl or halogen (for example, 2-pyridinyl,

5-bromo-3-pyridinyl, 1-methyl-2-pyrrolyl, 1-pyrrolyl,

1-pyrrolidinyl, 3-methyl-2-thienyl, 2-ti the Nile, 2 - or 3-furanyl,

2-thiazolyl, 5-oxazolyl, 5-methylisoxazole,

3,5-dimethyl-4-isoxazolyl etc); and preferred examples of the substituted or unsubstituted heterocyclic group" for R3is a heterocyclic group optionally substituted by at least one Deputy, selected from the group consisting of (1) lower alkyl, (2) cyclo(lower)alkyl, (3) lower alkoxy, (4) acyl, such as lower alkanoyl, (5) amino, (6) mono - or di(lower)alkylamino, (7) protected amino, such as lower alkoxycarbonyl, (8) cyano, (9) carboxy, (10) protected carboxy, such as esterified carboxy (e.g., benzyloxycarbonyl), (11) carbamoyl, (12) lower alkenyl, optionally substituted lower alkoxy, (13) halogen, (14) lower alkylthio and (15) hydroxy (for example,

3 - or 4-pyridyl, 2-pyrazinyl, 6-methoxy-2-pyrazinyl,

4 - or 5-oxazolyl, 2-benzofuranyl, 2-benzothiazyl,

3 - or 6-chinoline, 2-chloro-4-pyridyl, 5-bromo-3-pyridyl,

5-chloro-2-thienyl, 5,6-dichloro-2-pyridyl, 4-chloro-2-pyridyl,

5-cyano-3-pyridyl, 5-carboxy-3-pyridinyl,

5-carbarnoyl-3-pyridyl, 5-(benzyloxycarbonyl)-3-pyridyl,

5-(tert-butoxycarbonylamino)-3-pyridinyl, 5-amino-3-pyridinyl,

2-methoxy-4-pyridyl, 3-methoxy-5-isoxazolyl,

2-methylthio-4-pyridinyl, 2-hydroxy-4-pyridyl, 5-methyl-3-pyridyl,

5-ethyl-3-pyridyl, 5-methyl-3-isoxazol the sludge, 5-vinyl-3-pyridyl,

2-vinyl-4-pyridyl, 5-acetyl-3-pyridyl, 2-dimethylamino-4-pyridyl,

5-(1-ethoxyphenyl)-3-pyridyl, 2-oxo-1,2-dihydro-4-pyridyl or

2-methylthio-4-pyridyl, and so on).

R1and R2combined with each other, form the lower alkylenes or lower alkynylamino group, which is optionally interrupted by amino or sulfonyl, and optionally substituted group consisting of lower alkyl, hydroxy, oxo, and lower alkoxy, and which is represented by the following formula:

This formula may include the following formula:

Suitable "substituted or unsubstituted aryl(lower)alkenyl" can include With6-C10alkyl group, aryl(lower)alkenyl, optionally substituted with halogen (e.g., 2-phenylphenyl, 2-(2 - or 3-chlorophenyl)vinyl etc).

Suitable "leaving group" may include an acid residue, lower alkoxy, examples of which are given above, and the like.

The above methods of obtaining can be carried out in the usual way, as described in "Receiving" and/or "Examples", or similar. Among these methods are important for the implementation of the present invention are methods of formation of condensed heterocyclic rings (such as method 1 and method 12), caloriewise in more detail.

In accordance with method 1 derivatives (I) pyrrolopyridine can be obtained by the interaction of the derivative of 1-amino-2-acylpyrrole (II) or its salt and the compound (III) or its salt in the presence of catalytic amounts of an acid catalyst in an inert solvent, preferably with simultaneous removal of the water formed physical (for example, using traps Dean-stark) or chemical (for example, using molecular sieves). Suitable acid catalyst are, for example, p-toluensulfonate acid, methanesulfonate acid, hydrochloric acid, triperoxonane acid and so on. Suitable inert solvents are, for example, benzene, toluene, tetrahydrofuran and the like.

Another method of forming rings described in method 12, in which the derivatives (I) pyrrolopyridine can be obtained by the interaction of the derivative (V) 1-aminopyrrolo or its salt and a derivative β-diketone or its salts in the similar conditions described in method 1, and, consequently, with respect to the reaction conditions, you can refer to method 1.

Compounds of the present invention can be purified by conventional purification methods used for the purification of organic compounds, such as recrystallization, column chromatography, thin-layer, HRO is ecografia, high-performance liquid chromatography and the like. Compounds can be identified by traditional methods, such as NMR spectroscopy, mass spectroscopy, infrared spectroscopy, elemental analysis and melting point determination.

Suitable salts of the target and source connections in ways 1-40 can be called salts mentioned as an example for compound (I).

New derivatives of (I) pyrrolopyridine and their pharmaceutically acceptable salts hardly possess high inhibitory activity against phosphodiesterase III (PDE III), but have high inhibitory activity against phosphodiesterase IV (PDE IV) and a high inhibitory activity against tumor necrosis factor (TNF).

That is, the derivative (I) pyrrolopyridine are selective inhibitors of phosphodiesterase IV (PDE IV) inhibitors and the production of tumor necrosis factor (TNF).

Thus, the new derivatives (I) pyrrolopyridine and their pharmaceutically acceptable salts can be used for prophylactic and therapeutic treatment of PDE-IV - and TNF-mediated diseases, such as chronic inflammatory diseases (e.g. rheumatoid arthritis, osteoarthritis, emphysema, chronic bronchiolitis, allergic rhinitis, etc.), osteoporosis, rejection after transplantation, asthma, chronic obstruc the passive lung disease (COPD), eosinophilia, fibrotic diseases (e.g. cystic fibrosis, pulmonary fibrosis, liver fibrosis, kidney fibrosis, etc.), (viral, alcohol, drugs) acute and fulminant hepatitis, hepatic steatosis (alcoholic and non-alcoholic steatohepatitis), chronic (viral and non-viral) hepatitis, cirrhosis, autoimmune hepatitis, pancreatitis, nephritis, endotoxin shock, specific autoimmune diseases [for example, ankylosing spondylitis, autoimmune encephalomyelitis, autoimmune hematological disorders (e.g. hemolytic anaemia, aplastic anaemia, pure red cell anemia, idiopathic thrombocytopenia, and so on), systemic lupus erythematosus (SLE; SLE), polyhedric, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis (Wilson's disease etc), heavy psevdomatematicheskoe myasthenia gravis, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease etc), endocrine ophthalmopathy, graves disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), Reiter syndrome, non-infectious uveitis, autoimmune keratitis (e.g., dry keratoconjunctivitis, vernal keratoconjunctivitis, and so on), interstitial pulmonary fibrosis, psoriatic arthritis is so], dermatological disorders associated with enzyme PGE-IV (such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis and urticaria), neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, cancer cachexia, viral infection, cachexia in AIDS, thrombosis and the like.

With therapeutic use of the compound (I) or its prodrug, or their salt, you can enter individually or as a mixture, preferably with a pharmaceutical excipient or carrier.

The active ingredient of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which contains the compound (I)as an active ingredient, in a mixture with an organic or inorganic carrier or excipient, suitable for topical (local), enteral, intravenous, intramuscular, parenteral or intramucosal application. The active ingredient can be used, for example, with conventional non-toxic pharmaceutically acceptable carriers for the manufacture of ointments, creams, patches, pills, pellets, capsules, suppositories, solution (e.g. saline), emulsions, suspensions (e.g. the measures in olive oil), aerosols, pills, powders, syrups, injectable solutions, tablets, poultices, aromatic waters, lotions, transbukkalno tablets, sublingual tablets, nasal drops and other forms suitable for use. The media that can be used are water, wax, glucose, lactose, Arabian gum, gelatin, mannitol, starch plasticizer, magnesium trisilicate, talc, corn starch, keratin, waxes, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid or liquid form, and, in addition, you can use an auxiliary, stabilizing, thickening and coloring agents and perfumes. The active connection is included in the pharmaceutical composition in an effective amount, sufficient to provide the desired effect on the process or condition of diseases.

The active ingredient can be used for manufacturing, for example, preparations for oral administration, the preparations for injections, drugs for exterior use, preparations for inhalation and preparations for application to mucous membranes.

In addition, the compound of the present invention can be used in combination with other therapeutic compounds. In particular, ingibiruet the PDE4 compound of the present invention can be used in combination with i) leukotriene receptor antagonists, ii) inhibitors of leukotriene biosynthesis, (iii) selective inhibitors SOH-2, iv) statins, v) NSAID, vi) antagonists M2/M3, (vii) a corticosteroid, (viii) receptor antagonists Hi (histamine), (ix) an agonist of beta 2-adrenergic receptors, x) interferon, xi) antiviral drugs against hepatitis C virus (HCV), such as a protease inhibitor, an inhibitor of helicase, a polymerase inhibitor, or the like, (xii) antiviral drugs against hepatitis b virus, such as lamivudine, xiii) ursodeoxycholic acid, xiv) glycyrrhizin, xv) human growth factor (HGF), xvi) aminosalicylic acid, such as salazosulfapiridin, mesalazin or the like, xvii) steroids, such as prednisolone, farnesyl, xviii) immunosuppressants such as azathioprine, 6-mercaptopurine, tacrolimus, and the like.

Mammals that can be treated using the present invention include livestock, such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and people, preferably people.

While the dosage of therapeutically effective amount of compound (I) varies depending on the age and condition of each individual patient, but the average single dose for a patient man, which constitutes about 0.01 mg, 0.1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg joint is (I), may be effective for treating the above diseases. Usually you can enter a day number in the range from 0.01 mg/body weight to about 1000 mg/body weight.

To show the usefulness of derivatives (I) pyrrolopyridine of the present invention and their pharmaceutically acceptable salts, below is the information about the pharmacological testing of compounds, which is a typical representative of the derivatives (I) pyrrolopyridine.

(a) Inhibition of U937 phosphodiesterase IV (PDE IV)

1. Test method:

Cultured U937 cells were washed twice and collected using phosphate buffered solution (PBS), using a scraper to collect the cells. After centrifugation of the cell precipitate suspended in homogenizing buffer (0.5 % dezoksiholatom [DOC], 5 mm 2-mercaptoethanol, 1 μm leupeptin, 100 μm PMSF, 20 μm p-tosyl-L-disinheritance [TLCK] in PBS). The cell suspension was then destroyed by ultrasound within two minutes and homogenized glass-Teflon homogenizer with twenty blows. The homogenate was centrifuged at 200×g for 30 minutes and then the supernatant was subjected to ultracentrifugation at 100000×g for 90 minutes (4°C). The final supernatant dialyzed in buffer for dialysis, which had the same composition as homogenizing buffer without DOC. Dialysate drug fer the enta kept at -20° C until analysis.

The PDE4 activity was evaluated using a system of phosphodiesterase-[3H]cAMP SPA enzyme assay (Amersham Pharmacia Biotech), using 96-well Opti-tablet. The reaction was initiated by addition of 0.025 µci/well of [3H]cAMP to the enzyme mixture containing 50 mm Tris-HCl (pH 7.5), 8.3 mm MgCl2, 1.7 mm EGTA and various concentrations of the test compounds or media. To the reaction mixture were added CI-930 (10 µm final concentration), a specific inhibitor of PDE3. After incubation at 30°C for 15 minutes in each well was added 50 μl of the suspension of granules SPA. Then the tablet was shaken for 20 minutes using a mixer for tablets. Using the counter Top Counter, radioactivity was determined in each hole.

Compound was dissolved in 100% dimethyl sulfoxide (DMSO) and diluted to the appropriate concentration of the final solution containing 1% vol./about. DMSO.

In relation to the activity of the enzyme PDE4 determine the values of the IC50the tested compounds by regression analysis on the values of the log-log transformation of the percentage inhibition in the treated compounds tubes compared with the control. The percentage inhibition was calculated by the following equation: inhibition (%)={1-(C-B)/(A-B)}×100, where A, B and C represent the mean values of counts of radioactivity (dpm, the number of disintegrations per minute) to ntalnyh, raw and processed by the connection tubes, respectively.

2. The results of the test

The following table illustrates the inhibitory activity against PDE-IV typical compounds of formula (I):

ExampleConnection nameIC50(µm)
1986-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}hexanoic acid<1

(b) Inhibition of production of TNF-alpha in human mononuclear cells

1. Test method

(1) preparation of human mononuclear cells peripheral blood (PBMC)

From the ulnar medial vein of healthy volunteers took blood (30 ml each)were separated on a 15 ml conical tube containing heparin, and was added in each tube with the same volume of RPMI1640. The diluted blood was then placed in 20 ml of Ficoll-Paque PLUS (Amersham Pharmacia Biotech) in polystyrene centrifuge tube. After centrifugation at 1600 rpm for 30 minutes, cells gathered in the Central zone of the gradient were collected with capillary tube and washed with 40 ml of RPMI1640 several times with centrifugation at 1200 rpm for 10 minutes. Finally besieged PBMC suspended in RPMI1640 containing 1% fetal calf serum and antibiotics. The settlement of the e-counting of cells were prepared suspension in a nutrient medium with a final concentration of 3× 106cells/ml

(2) the Production of TNF-alpha-stimulated PBMC

Human PBMC, obtained by the method of density gradient using Ficoll-Paque PLUS, suspended in the above culture medium with a concentration of 3×106cells/ml, and 0.5 ml of the suspension were sown in each cell 24-cell Petri dishes. Cells were incubated in an incubator with CO2within 24 hours with 0.25 ml LPS in addition to concentrations of 0.25 ml of medicines or media at the beginning of incubation. The final concentration of LPS in the incubation medium was 1 µg/ml After 24 hours, the supernatant of each cell, after centrifugation at 1700 rpm for 10 minutes and stored at -80°C until analysis. The levels of TNF-alpha in the medium were measured using ELISA method.

Determine the values of the IC50drugs in relation to the production of cytokines in PBMC stimulated by LPS, regression analysis on the relative values of the levels of cytokines in cells treated with drugs, compared with the relative levels of cytokines in cells treated with media.

The results of the test

ExampleConnection nameIC50(nm)
1986-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}hexanoic acidThe best way of carrying out the invention

The following examples are given to further illustrate details of obtaining compounds of the present invention. Examples in no way meant to restrict the scope of the present invention and should not be construed as limiting. In addition, one should not assume that only compounds described in the following examples, form a class, regarded as the invention, for any combination of compounds or their fragments may itself form a class. Specialists in this field will easily understand that to obtain these compounds can be used known variants of conditions and the following methods to retrieve.

The initial substance and the intermediate receiving, using or adapting known methods, for example, the methods described in reference examples, or their obvious chemical equivalents.

Abbreviations, symbols and terms used in the making, examples and formulas have the following meanings:

DMFN,N-dimethylformamide
EtOAc or AcOEtThe ethyl acetate
THFTetrahydrofuran
Et3NThe triethylamine
MeonMethanol
EtOHEthanol
BuOHButanol
DHMDichloromethane
Pd/CPalladium on powdered carbon

Getting 1

To a suspension of 2-pyridinethiol (17 g) in tetrahydrofuran (200 ml) was added triethylamine (15.5 g) in a bath of ice-water in the atmosphere N2. To the mixture was added a solution of 4-cyanobenzaldehyde (25,3 g) in tetrahydrofuran (80 ml) at a temperature below 10°C for 30 minutes. After 15 minutes the bath was removed and the mixture was stirred over night at ambient temperature. The mixture was concentrated in vacuum. The residue was distributed between chloroform and water. The organic layer was washed with saturated sodium bicarbonate solution and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The remainder (38 g) is triturated in isopropyl ether to obtain S-(2-pyridinyl) 4-cyanobenzaldehyde (32,5 g) as a pale brown solid.

S-(2-Pyridinyl)-4-cyanobenzeneboronic

NMR (CDCl3that δ): 7,38 (1H, t, J=7 Hz), 7,72 (1H, d, J=8 Hz), 7,75-7,87 (3H, m), 8,11 (2H, d, J=8 Hz), 8,71 (1H, d, J=2 Hz).

MS (ESI+): m/z 241 (M+H).

The following compounds were obtained according to a similar method of obtaining 1.

Getting 2

S-(2-Pyridinyl)-2-chloro-4-pyridylcarbonyl

NMR (CDl 3that δ): 7,40 (1H, m), the 7.65 to 7.75 (2H, m), 7,75-of 7.90 (2H, m), to 8.62 (1H, d, J=5 Hz), to 8.70 (1H, m).

Getting 4

S-(2-Pyridinyl)-3-cyanobenzeneboronic

NMR (CDCl3that δ): 7,39 (1H, m), 7,66 (1H, t, J=8 Hz), 7,72 (1H, t, J=8 Hz), 7,83 (1H, m), to $ 7.91 (1H, d, J=8 Hz), 8,24 (1H, d, J=8 Hz), 8,29 (1H, s)8,71 (1H, m).

MS (ESI+): m/z 241 (M+H).

Getting 5

S-(2-Pyridinyl)-3-methoxybenzeneboronic

NMR (CDCl3that δ): a 3.87 (3H, s), 7,16 (1H, m), 7,32-7,44 (2H, m), 7,51 (1H, m), 7,63 (1H, d, J=8 Hz), 7,71-7,83 (2H, m), 8,69 (1H, m).

Getting 6

S-(2-Pyridinyl)-4-pyridylcarbonyl

NMR (CDCl3that δ): 7,35-the 7.43 (1H, m), 7,73 (1H, d, J=8 Hz), to 7.77-7,88 (3H, m), to 8.70 (1H, d, J=7 Hz), cent to 8.85 (2H, d, J=8 Hz).

MS (ESI+): m/z 217.

Getting 7

S-(2-Pyridinyl)-2-pyrazinecarboxamide

NMR (CDCl3that δ): 7,38 (1H, m), 7,71 (1H, d, J=8 Hz), 7,82 (1H, m), 8,73 (2H, m), 8,86 (1H, m), 9,17 (1H, s).

Getting 8

S-(2-Pyridinyl)-3-pyridylcarbonyl

NMR (CDCl3that δ): 7,37 (1H, m), 7,46 (1H, m), 7,73 (1H, m), 7,83 (1H, m), of 8.27 (1H, m), 8,68 (1H, m), 8,84 (1H, m), 9,23 (1H, m).

9

To a solution of 2-ethyl-1H-pyrrole in toluene (120 ml) was added dropwise 1M methylmagnesium in tetrahydrofuran (170 ml) in a bath of dry ice-acetone to -60°C for 30 minutes. Then the mixture was stirred in a bath of ice-water for 40 minutes. To the obtained reaction mixture was added S-(2-pyridinyl)4-cyanobenzeneboronic (15.2 g) in portions over 10 minutes in a bath of dry ice-acetone. After 1.5 hours stirring was added saturated ammonium chloride (00 ml) and the reaction mixture was allowed to warm to ambient temperature. The mixture was distributed between ethyl acetate and water. The organic layer was washed for 1H. sodium hydroxide (100 ml) two times water and a saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue is triturated in isopropyl ether to obtain 4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (12.7 g) as a pale yellow solid.

4-[(5-Ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile

NMR (CDCl3that δ): 1,32 (3H, t, J=8 Hz), a 2.75 (2H, square, J=8 Hz), 6,11 (1H, d, J=5 Hz), 6,76 (1H, d, J=5 Hz), to 7.77 (2H, d, J=8 Hz), 7,94 (2H, d, J=8 Hz), 9,49 (1H, users).

MS (ESI+): m/z 225 (M+H).

The following compound was obtained according to a similar method of obtaining 9.

Receive 10

(2E)-1-(5-Ethyl-1H-pyrrol-2-yl)-3-phenyl-2-propen-1-he

NMR (CDCl3that δ): 1,31 (3H, t, J=7 Hz), 2,73 (2H, square, J=7 Hz), 6,10 (1H, m), 7,02 (1H, m), 7,27 (1H, d, J=16 Hz), 7,35-the 7.43 (3H, m), 7,63 (2H, m), 7,79 (1H, d, J=16 Hz).

MS (ESI+): m/z 226 (M+H).

Receipt 11

To a solution of 4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (12.5 g) in N,N-dimethylformamide (63 ml) was added 60% sodium hydride in oil (2,68 g) in a bath of ice-water in the atmosphere N2. After 30 minutes, to the mixture was added 1-(aminooxy)-2,4-dinitrobenzene (13.3 g). After 2 hours the mixture was distributed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water (100 ml) 3 times, 1N. sodium hydroxide (100 ml) and saturated salt solution, dried over Sul is an atom of magnesium and evaporated in vacuum. The residue was purified flash chromatography on silica gel (silica gel, 500 ml), elwira a mixture of hexane-chloroform=1-2, 1-5, 1-10, and then triturated in isopropyl ether to obtain 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (8,1 g, 60,7%) as a yellow solid. Mixed fraction and uterine layer (7 g) was again purified flash chromatography on silica gel (silica gel, 200 ml), elwira a mixture of hexane-chloroform=2-1 and 1-1, then triturated in isopropyl ether to obtain 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (2.0 g, 15%) as a pale yellow solid.

4-[(1-Amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile

NMR (CDCl3that δ): of 1.29 (3H, t, J=8 Hz), 2,77 (2H, square, J=8 Hz), of 5.75 (2H, users), 5,94 (1H, d, J=5 Hz), 6,59 (1H, d, J=5 Hz), 7,76 (2H, d, J=8 Hz), a 7.85 (2H, d, J=8 Hz).

MS (ESI+): m/z 240 (M+H).

The following compounds were obtained according to a similar method of obtaining 11.

Getting 12

(1-Amino-5-ethyl-1H-pyrrol-2-yl)(2-chloro-4-pyridinyl)metano

NMR (CDCl3that δ): of 1.29 (3H, t, J=7 Hz), 2,77 (2H, square, J=7 Hz), 5,71 (2H, s), 5,96 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), to 7.50 (1H, d, J=4 Hz), to 7.61 (1H, s), charged 8.52 (1H, d, J=4 Hz).

MS: (m/z 250 (M+H).

13

3-[(1-Amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile

NMR (CDCl3that δ): of 1.29 (3H, t, J=7 Hz), 2,77 (2H, square, J=7 Hz), 5,74 (2H, s)5,94 (1H, d, J=5 Hz), 6,59 (1H, d, J=5 Hz), to 7.59 (1H, t, J=8 Hz), 7,82 (1H, d, J=8 Hz), 8,00 (1H, d, J=8 Hz), 8,06 (1H, s).

Getting 14

(2E)-1-(1-Amino-5-ethyl-1H-pyrrol-2-yl)-3-phenyl-2-propen-1-he

NMR (CDCl3that δ): of 1.28 (3H, t, J=7 Hz), 2,73 (2H, square, J=7 Hz), to 5.93 (1H, d, J=5 Hz), of 6.99 (1H, d, J=5 Hz), 7,30 (1H, d, J=16 Hz), 7,37-the 7.43 (3H, m), a 7.62 (2H, m), 7,74 (1H, d, J=16 Hz).

MS (ESI+): m/z 241 (M+H).

Receive 15

(1-Amino-5-ethyl-1H-pyrrol-2-yl)(3-methoxyphenyl)metano

NMR (CDCl3that δ): of 1.26 (3H, t, J=7 Hz), a 2.75 (2H, square, J=7 Hz), 3,86 (3H, s), 5,79 (2H, s), of 5.89 (1H, d, J=4 Hz), to 6.67 (1H, d, J=4 Hz), 7,07 (1H, m), 7,29-7,40 (3H, m).

MS (ESI+): m/z 245.

Getting 16

(1-Amino-5-ethyl-1H-pyrrol-2-yl)(4-pyridinyl)metano

NMR (CDCl3that δ): of 1.29 (3H, t, J=7 Hz), 2,77 (2H, square, J=7 Hz), USD 5.76 (2H, s)5,94 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,58 (2H, d, J=7 Hz), is 8.75 (2H, d, J=7 Hz).

MS (ESI+): m/z 216.

Getting 17

(1-Amino-5-ethyl-1H-pyrrol-2-yl)(2-pyrazinyl)metano

NMR (CDCl3that δ): of 1.29 (3H, t, J=7 Hz), 2,77 (2H, square, J=7 Hz), 5,79 (2H, s), 5,98 (1H, d, J=4 Hz), 7,27 (1H, d, J=4 Hz), 8,63 (1H, m), 8,71 (1H, m), 9,17 (1H, m).

Getting 18

(1-Amino-5-ethyl-1H-pyrrol-2-yl)(3-pyridinyl)metano

NMR (CDCl3that δ): of 1.29 (3H, t, J=7 Hz), 2,77 (2H, square, J=7 Hz), 5,78 (2H, s)5,94 (1H, d, J=4 Hz), of 6.65 (1H, d, J=4 Hz), 7,39 (1H, m), of 8.06 (1H, m), a total of 8.74 (1H, m), 8,99 (1H, m).

Getting 19

(1-Amino-5-ethyl-1H-pyrrol-2-yl)(5-bromo-3-pyridinyl)metano

NMR (CDCl3that δ): of 1.29 (3H, t, J=7 Hz), was 2.76 (2H, square, J=7 Hz), 5,72 (2H, s), 5,96 (1H, m), of 6.65 (1H, m), 8,19 (1H, m), to 8.70 (1H, m), 8,89 (1H, m).

20

To a solution of tert-butyl 3-oxobutanoate (20,0 g) in tetrahydrofuran (200 ml) was added 60% sodium hydride in oil (to 5.56 g) in portions over 20 minutes in a bath of ice-water in the atmosphere 2. After 40 minutes, to the mixture was added ethyl-5-iodopentane (35,6 g) at the same temperature. After 15 minutes, the mixture was stirred at ambient temperature. After 1 hour the reaction mixture was heated at 50°C within 24 hours. The cooled mixture was distributed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified flash chromatography on silica gel (silica gel, 1 l), elwira a mixture of hexane-ethyl acetate=50-1, 20-1, 10-1, 8-1, to obtain 1-tert-butyl-7-ethyl-2-acetylsalicylate (27,3 g, 75,4%) as a colourless oil.

1-tert-Butyl-7-ethyl-2-acetylmethadol

NMR (CDCl3that δ): 1,20-to 1.38 (5H, m)of 1.46 (9H, s), 1,54-1,71 (2H, m), a 1.75-to 1.87 (2H, m), 2,12 (3H, s), is 2.30 (2H, t, J=8 Hz), 3,30 (12H, t, J=8 Hz), 4,11 (2H, square, J=8 Hz).

The following compounds were obtained according to a similar method of obtaining 20.

Getting 21

1-tert-Butyl-9-ethyl-2-actinonaias

NMR (CDCl3that δ): of 1.23 and 1.33 (9H, m)of 1.46 (9H, s)of 1.55 (2H, m), 1.77 in (2H, m), of 2.21 (3H, s), 2,28 (2H, t, J=7 Hz), with 3.27 (1H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz).

MS (ESI+): m/z 315 (M+H).

Getting 22

tert-Butyl-2-aceticket

NMR (CDCl3that δ): of 0.90 (3H, t, J=8 Hz), 1,28-of 1.40 (4H, m)of 1.46 (9H, s), 1,73-1,89 (2H, m), 2,22 (3H, s), 3,30 (1H, t, J=8 Hz).

23

1-tert-Butyl-8-ethyl-2-acetylethyl

NMR (CDCl3that δ ): 1,21-1,33 (7H, m)of 1.46 (9H, s), 1,54 was 1.69 (2H, m), 1,74-of 1.85 (2H, m), of 2.21 (3H, s), 2,28 (2H, t, J=8 Hz), 3,29 (1H, t, J=8 Hz), of 4.12 (2H, square, J=8 Hz).

Getting 24

To a suspension of magnesium chloride (1,33 g) in dichloromethane (40 ml) was added 1-tert-butyl-7-ethyl-2-acetylmethadol (4.0 g) at ambient temperature in an atmosphere of N2. To the mixture was added dropwise pyridine (of 2.26 ml) in a bath of ice-water. Then the mixture was stirred at ambient temperature for 40 minutes. To the reaction mixture was added a solution of 3-cyanobenzaldehyde (3,01 g) in dichloromethane (6 ml) dropwise over 2 minutes. The reaction mixture was stirred at ambient temperature for 2 hours. To the mixture was added 1N. hydrogen chloride and ethyl acetate in a bath of ice-water. The organic layer was washed for 1H. chloride hydrogen, water, and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum to obtain a solid substance. The residue was purified flash chromatography on silica gel (silica gel, 300 ml), elwira a mixture of hexane-ethyl acetate=10-1, 8-1, 5-1 and 3-1, to obtain 1-tert-butyl-7-ethyl-2-acetyl-2-(3-cyanobenzoyl)heptanoate (to 4.23 g, 72,9%) as a colourless oil.

1-tert-Butyl-7-ethyl-2-acetyl-2-(3-cyanobenzoyl)heptanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=8 Hz), 1,28-1,40 (11H, m), 1,63 is 1.75 (2H, m), 2,19-of 2.28 (2H, m), 2,32 (2H, t, J=8 Hz), a 2.45 (3H, s), 4,11 (2H, square, J=8 Hz), 7,56 (1H, t, J=8 Hz), 7,80 (2H, DD, J=8, 1 Hz), 7,95 (2H, DD, J=8, 1 Hz), of 8.06 (1H, users

MS (ESI+): m/z 416 (M+H).

The following compounds were obtained according to a similar method of obtaining 24.

Receive 25

Ethyl-2-isobutyryl-4-methyl-3-oxopentanoate

NMR (300 MHz, CDCl3that δ): 1,10-of 1.23 (12H, m), 1.30 and USD 1.43 (3H, m), 2.91 in-3,10 (2H, m), 4,21 is 4.36 (2H, m).

Getting 26

Ethyl-2-(2-chlorobenzoyl)-4-methyl-3-oxopentanoate

NMR (300 MHz, CDCl3that δ): 0,79 (3H, t, J=7.5 Hz),to 1.22 (6H, d, J=7.5 Hz), 3,36-of 3.54 (1H, m), 3,88 (2H, square, J=7.5 Hz), 7,26-7,44 (4H, m).

Getting 27

Ethyl-4-methyl-2-(2-naphtol)-3-oxopentanoate

NMR (300 MHz, CDCl3that δ): from 0.76 to 1.03 (3H, m), 1,10-1,30 (6H, m), 2,56-2,71 (1/2H, m), 2,88 totaling 3.04 (1/6H, m), 3,20-3,35 (1/3H, m), 3.72 points-4,336 (3H, m), 7,50-7,68 (2+1/3H, m), 7,82-8,01 (3+2/3H, m), 8,09 (1/3H, ), 8,35 (1/2H, s), to 8.41 (1/6H, s).

MS (ES+): m/e 313,45.

Getting 28

1-tert-Butyl-7-ethyl-2-acetyl-2-[3-(trifluoromethyl)benzoyl]heptanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1,32 (9H, s), 1,36 is 1.75 (4H, m), 2,15-of 2.36 (4H, m), of 2.45 (3H, s), 4,11 (2H, square, J=7 Hz), 7,56 (1H, t, J=8 Hz), 7,79 (1H, d, J=8 Hz), to 7.93 (1H, d, J=8 Hz), 8,04 (1H, s).

Getting 29

1-tert-Butyl-7-ethyl-2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyl]heptanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1,27-of 1.42 (2H, m)of 1.34 (9H, s), 1,65-to 1.77 (2H, m), 2,16 to 2.35 (4H, m), 2,39 (3H, s), 2,43 (3H, s), 4,10 (2H, square, J=7 Hz), 7,87 (1H, s), 8,56 (1H, s), 8,73 (1H, s).

MS (ESI+): m/z 406 (M+H).

30

1-tert-Butyl-7-ethyl-2-(methoxyacetyl)-2-[(3-methoxy-5-isoxazolyl)carbonyl]heptanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.39 (9H, s), 1,35 of 1.50 (2H, m), 1,64 is 1.75 (2H, m), 2,15-of 2.23 (2H, m), 2,32 (2H, t, J=7 Hz) 3,40 (3H, C)to 4.01 (3H, s), of 4.12 (2H, square, J=7 Hz), of 4.57 (2H, s), is 6.54 (1H, s).

Getting 31

1-tert-Butyl-7-ethyl-2-acetyl-2-[3-(1,3-oxazol-5-yl)benzoyl]heptanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.33 (9H, s), 1.30 and USD 1.43 (2H, m), 1,62 to 1.76 (2H, m), 2,17 to 2.35 (4H, m), is 2.44 (3H, s), 4.09 to (2H, square, J=7 Hz), 7,42 (1H, s)of 7.48 (1H, t, J=8 Hz), 7,69 (1H, d, J=8 Hz), 7,82 (1H, d, J=8 Hz), 7,94 (1H, s), of 8.09 (1H, m).

Getting 32

1-tert-Butyl-7-ethyl-2-acetyl-2-(3,4-dichlorobenzoyl)heptanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), 1.30 and USD 1.43 (2H, m)of 1.35 (9H, s), 1,63-of 1.74 (2H, m), 2,15-of 2.34 (4H, m), is 2.41 (3H, s), 4,10 (2H, square, J=7 Hz), of 7.48 (1H, d, J=8 Hz), 7,56 (1H, DD, J=2, 8 Hz), 7,88 (1H, d, J=2 Hz).

Receive 33

1-tert-Butyl-7-ethyl-2-acetyl-2-[(4-chloro-2-pyridinyl)carbonyl]heptanoate

NMR (CDCl3that δ): 1,23-of 1.30 (3H, m), 1,25 (9H, s), 1,40 is 1.58 (2H, m), 1,65-to 1.77 (2H, m), 2,10-of 2.21 (2H, m)to 2.35 (2H, t, J=7 Hz), 2,61 (3H, s), of 4.12 (2H, square, J=7 Hz), 7,39 (1H, m), of 8.04 (1H, m), 8,43 (1H, d, J=5 Hz).

MS (ESI+): m/z 426 (M+H).

Getting 34

1-tert-Butyl-7-ethyl-2-[(5-chloro-2-thienyl)carbonyl]-2-(methoxyacetyl)heptanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), 1,25-1,40 (2H, m)of 1.41 (9H, s), 1,62-of 1.74 (2H, m), 2.26 and-is 2.37 (4H, m), 3,37 (3H, s), 4,11 (2H, square, J=7 Hz), 4,30 (1H, d, J=17 Hz), 4,42 (1H, d, J=17 Hz), 6,92 (1H, d, J=4 Hz), 7,39 (1H, d, J=4 Hz).

Receive 35

1-tert-Butyl-7-ethyl-2-acetyl-2-[(6-methoxy-2-pyrazinyl)carbonyl]heptanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1.26 in (9H, s), 1,38-1,49 (2H, m), 1,66 and 1.80 (2H, m), 2,14-of 2.26 (2H, m), of 2.33 (2H, t, J=7 Hz), to 2.57 (3H, s), 3,90 (3H, s), of 4.12 (2H, square, J=7 Hz), of 8.37 (1H, s), 8,83 (1H, s).

Getting 36

1-tert-Butyl-7-etil-acetyl-2-(1-benzofuran-2-ylcarbonyl)heptanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.33 (9H, s), 1,38-of 1.55 (2H, m), 1,64-to 1.77 (2H, m), 2,23-of 2.36 (4H, m), 2.49 USD (3H, s)4,08 (2H, square, J=7 Hz), 7,32 (1H, m), 7,46 (2H, m), 7,54 (1H, s), 7,71 (1H, d, J=8 Hz).

Getting 37

1-tert-Butyl-7-ethyl-2-acetyl-2-(1-benzothieno-2-ylcarbonyl)heptanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), 1,30-1,45 (2H, m)of 1.39 (9H, s), of 1.62 and 1.75 (2H, m), 2,25-of 2.38 (4H, m), is 2.40 (3H, s), 4,10 (2H, square, J=7 Hz), of 7.36-7,51 (2H, m), 7,76 (1H, s), 7,82-7,88 (2H, m).

Getting 38

1-tert-Butyl-7-ethyl-2-acetyl-2-(1,3-oxazol-5-ylcarbonyl)heptanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1,30-1,45 (2H, m)to 1.38 (9H, s), 1,63-to 1.77 (2H, m), 2,15-of 2.27 (2H, m), is 2.30 (2H, t, J=7 Hz), 2,43 (3H, s), 4,10 (2H, square, J=7 Hz), 7,80 (1H, s), to 7.93 (1H, s).

Getting 39

1-tert-Butyl-7-ethyl-2-acetyl-2-benzoylmethyl

NMR (CDCl3that δ): of 1.26 (3H, t, J=7 Hz), 1,20-1,40 (2H, m)of 1.32 (9H, s), 1.60-to of 1.73 (2H, m), 2.26 and-of 2.38 (4H, m), is 2.40 (3H, s), of 4.12 (2H, square, J=7 Hz), of 7.36 for 7.78 (5H, m).

Receive 40

1-tert-Butyl-7-ethyl-2-acetyl-2-(6-chinainternational)heptanoate

NMR (CDCl3that δ): to 1.21 (3H, t, J=7 Hz), of 1.30 (9H, s), 1.32 to about 1.47 (2H, m), 1,64-to 1.77 (2H, m), 2.26 and-of 2.38 (4H, m), the 2.46 (3H, s)4,08 (2H, square, J=7 Hz), of 7.48 (1H, m), of 8.04 (1H, DD, J=2 Hz, 8 Hz), 8,13 (1H, d, J=8 Hz), 8,23 (1H, d, J=8 Hz), of 8.28 (1H, d, J=2 Hz), 9,00 (1H, m).

MS (ESI+): m/z 442 (M+H).

Getting 41

1-tert-Butyl-9-ethyl-2-acetyl-2-[4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoyl]nonindian

NMR (CDCl3that δ): 1,23-1,37 (11H, m)to 1.60 (9H, s), 2,15-2,31 (4H, m), the 2.46 (3H, s), of 4.12 (2H, square, J=7 Hz), 5,10 (2H, s), 7,26-7,40 (5H, m), the 7.65 (1H, s, of usher.), to 7.84 (2H, d, J=9 Hz), of 8.06 (2H, d, J=9 Hz).

Recip is of 42

1-tert-Butyl-7-ethyl-2-acetyl-2-(2-horizonation)heptanoate

NMR (CDCl3that δ): 1,20-1,40 (14H, m), 1,61 is 1.75 (2H, m), 2,19-of 2.28 (2H, m), of 2.20 (2H, t, J=8 Hz), 2,31 (2H, t, J=8 Hz), 2,46 (3H, s), 4,11 (2H, square, J=8 Hz), 7,41 (1H, DD, J=7, 1 Hz), 7,55 (1H, d, J=1 Hz)and 8.50 (1H, d, J=7 Hz).

Getting 43

1-tert-Butyl-7-ethyl-2-acetyl-2-[3-(methylsulphonyl)benzoyl]heptanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=8 Hz), 1,27-1,40 (11H, m), 1,61 is 1.75 (2H, m), 2,19 to 2.35 (4H, m), the 2.46 (3H, s), of 3.07 (3H, s), 4,10 (2H, square, J=8 Hz), the 7.65 (1H, t, J=8 Hz), to 7.99 (1H, DD, J=8, 1 Hz), 8,09 (2H, userd, J=8 Hz), a 8.34 (1H, users).

Getting 44

1-tert-Butyl-7-ethyl-2-acetyl-2-(3-nitrobenzoyl)heptanoate

NMR (CDCl3that δ): 1,30-of 1.39 (12H, m), 1,61 is 1.75 (2H, m), 2,19 to 2.35 (4H, m), 2,47 (3H, s), 4,10 (2H, square, J=8 Hz), 7,63 (1H, t, J=8 Hz), of 8.09 (1H, userd, J=8 Hz), 8,39 (1H, userd, J=8 Hz), 7,60 (1H, users).

45

tert-Butyl 2-acetyl-2-(4-cyanobenzoyl)hexanoate

NMR (CDCl3that δ): of 0.90 (3H, t, J=8 Hz), 1,20-1,44 (13H, m), 2,15 was 2.25 (2H, m), of 2.45 (3H, s), of 7.70 (2H, d, J=8 Hz), 7,83 (2H, d, J=8 Hz).

Getting 46

1-tert-Butyl-7-ethyl-2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]heptanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.36 (9H, s), 1.32 to to 1.45 (2H, m), 1,65-to 1.77 (2H, m), 2,18-of 2.28 (2H, m), 2,32 (2H, t, J=7 Hz), a 2.45 (3H, s), 4,11 (2H, square, J=7 Hz), to 8.20 (1H, m), 8,80 (2H, m).

MS: (m/z) 470, 472 (M+H).

Getting 47

1-tert-Butyl-7-ethyl-2-(2-horizonation)-2-[(methylthio)acetyl]heptanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.37 (9H, s), 1,23-to 1.45 (2H, m), 1,63-to 1.77 (2H, m), is 2.05 (3H, s), 2,16-of 2.28 (2H, m), 2,32 (2H, t, J=7 Hz), and 3.16 (1H, d, J=17 Hz), 4,7 (1H, d, J=17 Hz), 4,11 (2H, square, J=7 Hz), to 7.68 (1H, d, J=5 Hz), 7,87 (1H, s), 8,49 (1H, d, J=5 Hz).

Getting 48

Ethyl-2-(4-perbenzoic)-3-oxobutanoate

NMR (CDCl3that δ): (mixture of tautomers) 0,97 and of 1.02 (3H, t, J=7 Hz), 2,07 and to 2.42 (3H, s), 4,01 and 4.13 (2H, square, J=7 Hz), 7,06-7,18, 7,56, and a 7.85 (4H, m).

MS (ESI+): m/z 275 (M+H).

Getting 49

1-tert-Butyl-8-ethyl-2-acetyl-2-(3-cyanobenzoyl)actantial

NMR (CDCl3that δ): 1,21-1,46 (16H, m), 1.56 to to 1.70 (2H, m), 2,15 was 2.25 (2H, m)to 2.29 (2H, t, J=8 Hz), a 2.45 (3H, s), of 4.12 (2H, square, J=8 Hz), 7,56 (1H, t, J=8 Hz), 7,80 (2H, DD, J=8, 1 Hz), 7,95 (2H, DD, J=8, 1 Hz), with 8.05 (1H, users).

Receive 50

1-tert-Butyl-7-ethyl-2-acetyl-2-[(6-chloro-2-pyridinyl)carbonyl]heptanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.27 (9H, s), 1,20-of 1.78 (4H, m), of 2.08 (2H, t, J=7 Hz), and 2.26-2.40 a (2H, m), 2,69 (3H, s), of 4.12 (2H, square, J=7 Hz), 7,43 (1H, d, J=8 Hz), 7,81 (1H, t, J=8 Hz), of 7.96 (1H, d, J=8 Hz).

MS (ESI+): m/z 426.

Getting 51

1-tert-Butyl-7-ethyl-2-acetyl-2-(3-methoxybenzoyl)heptanoate

NMR (CDCl3that δ): 1,25 (3H, m)of 1.34 (9H, s), 1,20-of 1.92 (4H, m), 2,10-of 2.38 (4H, m), is 2.41 (3H, s), of 3.84 (3H, s), 4.04 the-4,22 (2H, m), was 7.08 (1H, usher.), of 7.23-7,40 (3H, m).

Getting 52

1-tert-Butyl-7-ethyl-2-acetyl-2-(3,5-dichlorobenzoyl)heptanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1,26-of 1.40 (2H, m)of 1.36 (9H, s), and 1.63 to 1.76 (2H, m), 2,15-of 2.36 (4H, m), 2,43 (3H, s), 4,10 (2H, square, J=7 Hz), 7,51 (1H, m), 7,60 (2H, m).

Getting 53

1-tert-Butyl-7-ethyl-2-acetyl-2-[(5-chloro-2-thienyl)carbonyl]heptanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.40 (9H, s), 1.30 and 1,90 (4H, m), of 2.20 to 2.35 (4H, m), of 2.38 (3H, s), 4,11 (2H, sq J=7 Hz), 6,91 (1H, d, J=4 Hz), 7,32 (1H, d, J=4 Hz).

Getting 54

1-tert-Butyl-7-ethyl-2-acetyl-2-(3-perbenzoic)heptanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.35 (9H, s), 1,35-1,45 (2H, m), 1,64-of 1.74 (2H, m), 2,16 to 2.35 (4H, m), 2,42 (3H, s), 4.09 to (2H, square, J=7 Hz), 7,24 (1H, m), 7,35-the 7.43 (1H, m), 7,46-7,53 (2H, m).

Receive 55

1-tert-Butyl-7-ethyl-2-acetyl-2-(3-chinainternational)heptanoate

NMR (CDCl3that δ): 1,22 (3H, t, J=7 Hz), of 1.33 (9H, s), 1,33-of 1.53 (2H, m), 1,65-of 1.78 (2H, m), 2,25 is 2.43 (4H, m), 2,47 (3H, s)4,08 (2H, square, J=7 Hz), 7,63 (1H, t, J=8 Hz), 7,81-7,87 (1H, t, J=8 Hz), to $ 7.91 (1H, d, J=8 Hz), 8,56 (1H, m), 9,24 (1H, m).

MS (ESI+): m/z 442.

Getting 56

1-tert-Butyl-7-ethyl-2-acetyl-2-isonicotinohydrazide

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), is 1.31 (9H, s), 1,30-1,45 (2H, m)of 1.65 to 1.76 (2H, m), 2,18-of 2.28 (2H, m), 2,31 (2H, t, J=7 Hz), a 2.45 (3H, s), 4,10 (2H, square, J=7 Hz), 7,52 (2H, d, J=7 Hz), is 8.75 (2H, d, J=7 Hz).

Getting 57

1-tert-Butyl-7-ethyl-2-acetyl-2-[(3-methoxy-5-isoxazolyl)carbonyl]heptanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.39 (9H, s), 1,35 of 1.50 (2H, m), of 1.62 and 1.75 (2H, m), 2,11-of 2.23 (2H, m), of 2.33 (2H, t, J=7 Hz), 2.49 USD (3H, s)to 4.01 (3H, s), 4,11 (2H, square, J=7 Hz), 6,53 (1H, s).

Getting 58

1-tert-Butyl-7-ethyl-2-acetyl-2-[(5-methyl-3-isoxazolyl)carbonyl]heptanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), is 1.31 to 1.48 (2H, m)to 1.37 (9H, s), and 1.63 and 1.75 (2H, m), 2,18-of 2.26 (2H, m), 2,31 (2H, t, J=7 Hz), 2,47 (3H, s)of 2.50 (3H, s), 4,11 (2H, square, J=7 Hz), 6,38 (1H, s).

Getting 59

1-tert-Butyl-7-ethyl-2-(2-horizonation)-2-(methoxyacetyl)heptanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 132-1,45 (2H, m)of 1.36 (9H, s), 1,64-of 1.78 (2H, m), 2,16-of 2.28 (2H, m), 2,31 (2H, t, J=7 Hz), to 3.36 (3H, s), 4,11 (2H, square, J=7 Hz), 4,25 (1H, d, J=17 Hz), 4,39 (1H, d, J=17 Hz), 7,39 (1H, d, J=5 Hz), 7,54 (1H, ), and 8.50 (1H, d, J=5 Hz).

MS (ESI+): m/z 456

Getting 60

1-tert-Butyl-7-ethyl-2-(methoxyacetyl)-2-(3-methoxybenzoyl)heptanoate

NMR (CDCl3that δ): 1,22 (3H, t, J=7 Hz), 1,25-of 1.33 (2H, m)of 1.34 (9H, s), 1,60-1,75 (2H, m), 2,15-to 2.40 (4H, m)to 3.38 (3H, s), 3,83 (3H, s)4,08 (2H, square, J=7 Hz), 4,39 (1H, d, J=17 Hz), 4,55 (1H, d, J=17 Hz), 7,07 (1H, m), 7,26-7,34 (3H, m).

MS (ESI+): m/z 451.

Getting 61

1-tert-Butyl-7-ethyl-2-(methoxyacetyl)-2-(6-chinainternational)heptanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), 1,32 (9H, s), 1,30-1,50 (2H, m), 1,65-of 1.78 (2H, m), 2.26 and is 2.44 (4H, m)to 3.38 (3H, s), 4,11 (2H, square, J=7 Hz), to 4.38 (1H, d, J=17 Hz), of 4.57 (1H, d, J=17 Hz), 7,47 (1H, m), 8,03 (1H, d, J=8 Hz), 8,13 (1H, d, J=8 Hz), of 8.28 (1H, d, J=8 Hz), of 8.27 (1H, s), 9,01 (1H, m).

MS (ESI+): m/z 472.

Getting 62

1-tert-Butyl-7-ethyl-2-(methoxyacetyl)-2-(3-pyridylcarbonyl)heptanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.30 to 1.47 (2H, m)of 1.35 (9H, s), 1,63-of 1.78 (2H, m), 2,22-of 2.38 (4H, m), 3,37 (3H, s), 4,10 (2H, square, J=7 Hz), 4,32 (1H, d, J=17 Hz), of 4.45 (1H, d, J=17 Hz), 7,37 (1H, m), 8,03 (1H, m), 8,73 (1H, m), of 8.92 (1H, m).

Getting 63

1-tert-Butyl-7-ethyl-2-(3-chlorobenzoyl)-2-(methoxyacetyl)heptanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.35 (9H, s), 1,20-1,50 (2H, m), 1.60-to of 1.73 (2H, m), of 2.25 to 2.35 (4H, m), 3,37 (3H, s), of 4.12 (2H, square, J=7 Hz), 4,35 (1H, d, J=17 Hz), 4,50 (1H, d, J=17 Hz), 7,34 (1H, m)of 7.48 (1H, d, J=8 Hz), to 7.59 (1H, d, J=8 Hz), 7,73 (1H, m).

Getting 64

1-tert-Butyl-7-ethyl-2-acetyl-2-(3-methylb soil)heptanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), 1,30-1,40 (2H, m)of 1.33 (9H, s), 1.60-to 1,72 (2H, m), 2,10-of 2.38 (4H, m), of 2.21 (3H, s), 2,39 (3H, s), 4,10 (2H, square, J=7 Hz), 7,26 and 7.36 (2H, m), of 7.48 to 7.62 (2H, m).

MS (ESI+): m/z 405.

Getting 67

1-tert-Butyl-7-ethyl-2-(methoxyacetyl)-2-[(5-methyl-3-pyridinyl)carbonyl]heptanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.36 (9H, s), 1,30-1,45 (2H, m), 1,62 to 1.76 (2H, m), 2,20-of 2.36 (4H, m), is 2.40 (3H, s)to 3.38 (3H, s), 4,10 (2H, square, J=7 Hz), 4,34 (1H, d, J=17 Hz), 4,49 (1H, d, J=17 Hz), 7,86 (1H, s), 8,56 (1H, s), 8,73 (1H, s).

MS (ESI+): m/z 436.

Getting 68

1-tert-Butyl-7-ethyl-2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]heptanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.36 (9H, s), 1.32 to to 1.45 (2H, m), 1,65-to 1.77 (2H, m), 2,18-of 2.28 (2H, m), 2,32 (2H, t, J=7 Hz), a 2.45 (3H, s), 4,11 (2H, square, J=7 Hz), to 8.20 (1H, m), 8,80 (2H, m).

MS (ESI+): m/z 470, 472.

Getting 69

1-tert-Butyl-7-ethyl-2-[(5-bromo-3-pyridinyl)carbonyl]-2-(methoxyacetyl)heptanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1.30 and the 1.44 (2H, m)to 1.37 (9H, s), 1,65-to 1.77 (2H, m), 2,18-of 2.36 (4H, m)to 3.36 (3H, s), 4,10 (2H, square, J=7 Hz), 4,28 (1H, d, J=17 Hz), and 4.40 (1H, d, J=17 Hz), 8,18 (1H, m), 8,80 (2H, m).

MS (ESI+): m/z 500, 502.

Getting 70

1-tert-Butyl-7-ethyl-2-acetyl-2-[(5,6-dichloro-3-pyridinyl)carbonyl]heptanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1,25-1,40 (2H, m)to 1.38 (9H, s)of 1.65 and 1.75 (2H, m), 2,18-of 2.27 (2H, m), 2,28-is 2.37 (2H, m), is 2.44 (3H, s), of 4.12 (2H, square, J=7 Hz), 8,13 (1H, d, J=2 Hz), to 8.57 (1H, d, J=2 Hz).

Getting 71

1-tert-Butyl-6-ethyl-2-(methoxyacetyl)-2-[(5-methyl-3-pyridinyl)carbonyl]hexanedioic

NMR (CDCl that δ): 1,24 (3H, t, J=7 Hz), of 1.36 (9H, s), 1,60-1,80 (2H, m), 2,20-of 2.45 (4H, m), 2,39 (3H, s)to 3.38 (3H, s), of 4.12 (2H, square, J=7 Hz), to 4.38 (1H, d, J=18 Hz), 4,50 (1H, d, J=18 Hz), 7,87 (1H, s), 8,55 (1H, s), 8,73 (1H, s).

MS (ESI+): m/z 422.

Getting 72

1-tert-Butyl-5-ethyl-2-(methoxyacetyl)-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioic

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.37 (9H, s), 2,23-2,70 (4H, m), 2,39 (3H, s), 3,37 (3H, s), of 4.12 (2H, square, J=7 Hz), 4,32 (1H, d, J=18 Hz), 4,43 (1H, d, J=18 Hz), to 7.84 (1H, s), 8,55 (1H, s), 8,73 (1H, s).

MS (ESI+): m/z 408.

Getting 73

1-tert-Butyl-6-ethyl-2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyl]hexanedioic

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.34 (9H, s), 1,60-1,75 (2H, m), 2,20-2,39 (4H, m), 2,39 (3H, s)to 2.46 (3H, s), 4,11 (2H, square, J=7 Hz), 7,87 (1H, s), 8,56 (1H, s), 8,73 (1H, s).

MS (ESI+): m/z 392.

Getting 74

1-tert-Butyl-5-ethyl-2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioic

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.36 (9H, s), 2,39 (3H, s), is 2.44 (3H, s), 2,35-2,47 (2H, m), 2,56-2,70 (2H, m), 4,11 (2H, square, J=7 Hz), 7,88 (1H, s), 8,56 (1H, s), a total of 8.74 (1H, s).

MS (ESI+): m/z 378.

Getting 75

1-tert-Butyl-5-ethyl-2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]pentanedioic

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.37 (9H, s), is 2.40 (2H, t, J=7 Hz), at 2.59 (2H, t, J=7 Hz), 2,46 (3H, s), of 4.13 (2H, square, J=7 Hz), to 8.20 (1H, t, J=3 Hz), 8,81 (2H, DD, J=7, 3 Hz).

Getting 76

1-tert-Butyl-7-ethyl-2-(3-cyanobenzoyl)-2-(methoxyacetyl)heptanoate

NMR (CDCl3that δ): 1,20-1,41 (14H, m), 1.60-to around 1.74 (2H, m), 2,27-of 2.34 (4H, m), 3,37 (83H, C), 4,10 (2H, square, J=8 Hz), 4,29 (1H, d, J=16 Hz), 4,46 (1H, q, j =16 Hz), at 7.55 (1H, t, J=8 Hz), 7,80 (1H, DD, J=8, 1 Hz), to 7.93 (1H, DD, J=8, 1 Hz), of 8.04 (1H, users).

Getting 77

1-tert-Butyl-7-ethyl-2-[(atomic charges)acetyl]-2-[(5-bromo-3-pyridinyl)carbonyl]heptanoate

NMR (CDCl3that δ): 1,22 of 1.28 (5H, m)of 1.36 (9H, s), by 1.68 (2H, m), and 2.14 (3H, s), 2,32 (2H, m), 4,11 (2H, square, J=7 Hz), 5,07 (1H, d, J=18 Hz), of 5.34 (1H, d, J=18 Hz), 8,21 (1H, m), 8,81 (2H, m).

Getting 78

To 1-tert-butyl-7-ethyl-2-acetyl-2-(3-cyanobenzoyl)heptanedionato of 4.2 g) was added triperoxonane acid (20 ml) in a bath of ice-water. After 30 minutes the bath was removed and the reaction mixture was stirred at ambient temperature. After 1 hour the mixture was concentrated. The residue was dissolved in toluene and evaporated in vacuo to obtain ethyl-6-(3-cyanobenzoyl)-7-oxooctanoate (3,20 g, 100,4%) as a colourless oil.

Ethyl-6-(3-cyanobenzoyl)-7-oxooctanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=8 Hz), 1,28-of 1.40 (2H, m), 1.60-to around 1.74 (2H, m), 1,91 with 2.14 (2H, m), 2,17 (3H, s), 2,31 (2H, t, J=8 Hz), 4,11 (2H, square, J=8 Hz), 4,39 (1H, t, J=8 Hz), to 7.64 (1H, t, J=8 Hz), 7,87 (2H, DD, J=8, 1 Hz), to 8.20 (2H, DD, J=8, 1 Hz), compared to 8.26 (1H, users).

MS (ESI-): m/z 314 (M-H).

The following compounds were obtained according to a similar technique to obtain 78.

Getting 79

Ethyl-7-oxo-6-[3-(trifluoromethyl)benzoyl]octanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1,32 was 1.43 (2H, m), 1,62-to 1.77 (2H, m), 1,96-2,17 (2H, m), 2,17 (3H, s), is 2.30 (2H, t, J=7 Hz), 4,11 (2H, square, J=7 Hz), of 4.44 (1H, t, J=7 Hz), to 7.64 (1H, t, J=8 Hz), 7,86 (1H, d, J=8 Hz), 8,15 (1H, d, J=8 Hz), 8,24 (1H, s).

80

Ethyl-6-[(5-methyl-3-pyridinyl)ka is bonyl]-7-oxooctanoate

NMR (CDCl3that δ): of 1.26 (3H, t, J=7 Hz), 1,27-of 1.44 (2H, m)of 1.65 and 1.75 (2H, m), 1,90-2,12 (2H, m), 2,17 (3H, s), 2,25-of 2.34 (2H, m), 2,43 (3H, s), 4,10 (2H, square, J=7 Hz), 4,42 (1H, t, J=7 Hz), 8,03 (1H, s), 8,63 (1H, s), 8,98 (1H, s).

MS (ESI+): m/z 306 (M+H).

Getting 81

Ethyl-8-methoxy-6-[(3-methoxy-5-isoxazolyl)carbonyl]-7-oxooctanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.34 to 1.47 (2H, m), 1,65-of 1.74 (2H, m), 1,83-2,03 (2H, m)to 2.29 (2H, t, J=7 Hz), and 3.31 (3H, s), of 4.05 (5H, s), 4,11 (2H, square, J=7 Hz), 4,51 (1H, t, J=7 Hz), 6,56 (1H, C).

MS (ESI+): m/z 342 (M+H).

Getting 82

Ethyl-6-[3-(1,3-oxazol-5-yl)benzoyl]-7-oxooctanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), 1,33 of 1.46 (2H, m), 1,63-to 1.77 (2H, m), 1,95-2,17 (2H, m), 2,17 (3H, s), is 2.30 (2H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,46 (1H, t, J=7 Hz), 7,47 (1H, s), 7,56 (1H, t, J=8 Hz), a 7.85-of 7.96 (2H, m), 7,98 (1H, s), of 8.27 (1H, m).

Getting 83

Ethyl-6-(3,4-dichlorobenzoyl)-7-oxooctanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1.30 and USD 1.43 (2H, m), 1.60-to around 1.74 (2H, m), 1,91 with 2.14 (2H, m), and 2.14 (3H, s), is 2.30 (2H, t, J=7 Hz), 4,11 (2H, square, J=7 Hz), 4,34 (1H, t, J=7 Hz), EUR 7.57 (1H, d, J=8 Hz), 7,78 (1H, DD, J=2, 8 Hz), of 8.06 (1H, d, J=2 Hz).

Getting 84

Ethyl-6-[(4-chloro-2-pyridinyl)carbonyl]-7-oxooctanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.34 to 1.48 (2H, m), 1,62-to 1.77 (2H, m), 1,80-2,10 (2H, m), 2,31 (2H, t, J=7 Hz), was 2.34 (3H, s), of 4.12 (2H, square, J=7 Hz), a 4.83 to 4.92 (1H, m), 7,49 (1H, DD, J=2 Hz, 5 Hz), of 8.04 (1H, d, J=2 Hz), to 8.57 (1H, d, J=5 Hz).

MS (ESI+): m/z 326 (M+H).

Getting 85

Ethyl-6-[(5-chloro-2-thienyl)carbonyl]-8-methoxy-7-oxooctanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1.32 to to 1.42 (2H, m), 1.60-to of 1.73 (2H, m), 1,84 e 2.06 (2H, m), 2,28 2H, t, J=7 Hz), 3,30 (3H, s), of 3.97 (1H, d, J=17 Hz), 4,06 (1H, d, J=17 Hz), 4,11 (2H, square, J=7 Hz), and 4.40 (1H, t, J=7 Hz), of 6.99 (1H, d, J=4 Hz), 7,56 (1H, d, J=4 Hz).

Getting 86

Ethyl-6-[(6-methoxy-2-pyrazinyl)carbonyl]-7-oxooctanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.34 to 1.48 (2H, m), 1.60-to of 1.78 (2H, m), 1,88-of 2.08 (2H, m), 2,31 (3H, s), 2,32 (2H, t, J=7 Hz), to 4.01 (3H, s), 4,11 (2H, square, J=7 Hz), to 4.62 (1H, t, J=7 Hz), 8,44 (1H, C)8,81 (1H, s).

MS (ESI+): m/z 323 (M+H).

Getting 87

Ethyl-6-(1-benzofuran-2-ylcarbonyl)-7-oxooctanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.34 to 1.48 (2H, m), 1,62 to 1.76 (2H, m), 1.93 and-2,19 (2H, m), 2,24 (3H, s), is 2.30 (2H, t, J=7 Hz), 4,10 (2H, square, J=7 Hz), 4,37 (1H, t, J=7 Hz), 7,34 (1H, t, J=8 Hz), 7,51 (1H, t, J=8 Hz), 7,56-the 7.65 (2H, m), 7,73 (1H, d, J=8 Hz).

MS (ESI+): m/z 895 (M+H).

Getting 88

Ethyl-6-(1-benzothieno-2-ylcarbonyl)-7-oxooctanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.35 to 1.48 (2H, m), 1,60-1,80 (2H, m), 1,95-2,17 (2H, m), are 2.19 (3H, s), is 2.30 (2H, t, J=7 Hz), 4,10 (2H, square, J=7 Hz), 4,36 (1H, t, J=7 Hz), 7,38-7,53 (2H, m), 7,82-to 7.93 (2H, m), with 8.05 (1H, s).

Getting 89

Ethyl-6-(1,3-oxazol-5-ylcarbonyl)-7-oxooctanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), 1.30 and USD 1.43 (2H, m), 1,65-of 1.78 (2H, m), 1,92 is 2.10 (2H, m), of 2.21 (3H, s), 2,32 (2H, t, J=7 Hz), 4,11 (3H, m), 7,88 (1H, s), with 8.05 (1H, s).

Getting 90

Ethyl-6-benzoyl-7-oxooctanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1,29-of 1.42 (2H, m), 1,60-1,75 (2H, m), 1,92-2,12 (2H, m), and 2.14 (3H, s)to 2.29 (2H, t, J=7 Hz), 4,10 (2H, square, J=7 Hz), 4,43 (1H, t, J=7 Hz), 7,42-7,53 (2H, m), 7,55-to 7.64 (1H, m), 7,98 (2H, d, J=8 Hz).

Getting 91

Ethyl-7-oxo-6-(6-chinainternational)octanoate

NMR (CDCl3 that δ): of 1.23 (3H, t, J=7 Hz), 1,36 is 1.48 (2H, m), 1,65-of 1.78 (2H, m), 2.00 in to 2.18 (2H, m)to 2.18 (3H, s), is 2.30 (2H, t, J=7 Hz), 4,10 (2H, square, J=7 Hz), 4,58 (1H, t, J=8 Hz), 7,54 (1H, m), 8,18 (1H, d, J=8 Hz), of 8.28 (1H, DD, J=2 Hz, 8 Hz), 8,32 (1H, d, J=8 Hz), 8,51 (1H, d, J=2 Hz), 9,05 (1H, m).

MS (ESI+): m/z 342 (M+H).

Getting 92

Ethyl-8-[4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoyl]-9-octadecanoate

NMR (CDCl3that δ): of 1.23 to 1.37 (9H, m), 1,55-1,68 (11H, s), a 2.01 (2H, m)to 2.18 (3H, s)to 2.29 (2H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,39 (1H, t, J=7 Hz), 5,11 (2H, s), 7,30-7,49 (5H, m), 7,74 (1H, s, of user.), 8,04-8,13 (4H, m).

MS (ESI-): m/z 530 (M-H).

Getting 93

Ethyl-7-(1,3-oxazol-5-yl)-7-oxogedunin

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.41 (2H, m)of 1.76 (2H, m), 2,03 (2H, m), 2,31 (2H, m), 3,20 (2H, m), 4,10 (2H, square, J=7 Hz), 7,94 (1H, s), 8,10 (1H, s).

Getting 94

Ethyl-6-[3-(methylsulphonyl)benzoyl]-7-oxooctanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=8 Hz), 1,59-of 1.64 (2H, m), 1,91-of 2.15 (2H, m)to 2.18 (3H, s), is 2.30 (2H, t, J=8 Hz), 3,11 (3H, s), 4,10 (2H, square, J=8 Hz), of 4.45 (1H, t, J=8 Hz), 7.23 percent (1H, t, J=8 Hz), 8.17 and (1H, DD, J=8, 1 Hz), of 8.25 (2H, userd, J=8 Hz), 8,53 (1H, users).

MS (ESI+): m/z 369 (M+H).

Getting 95

Ethyl-6-(2-horizonation)-7-oxooctanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=8 Hz), 1,30-1,40 (2H, m), 1.60-to 1,71 (2H, m), 1,90 with 2.14 (2H, m), and 2.27 (3H, s), 2,25-to 2.74 (2H, m), 4,11 (2H, square, J=8 Hz), 4,32 (1H, t, J=8 Hz), to 7.15 (1H, DD, J=7, 1 Hz), 7,76 (1H, d, J=1 Hz), of 8.09 (1H, d, J=7 Hz).

MS (ESI+): m/z 326 (M+H).

Getting 96

Ethyl-6-(3-nitrobenzoyl)-7-oxooctanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=8 Hz), 1,29-of 1.41 (2H, m), 1.60-to around 1.74 (2H, m), 1,91-of 2.16 (2H, m), 2,9 (3H, C)of 2.30 (2H, t, J=8 Hz), 4,11 (2H, square, J=8 Hz), 4,46 (1H, t, J=8 Hz), 7,71 (1H, t, J=8 Hz), 8,30 (1H, userd, J=8 Hz), to 8.45 (4H, userd, J=8 Hz), 8,80 (1H, users).

MS (ESI+): m/z 337 (M+H).

Getting 97

4-(2-Acetylamino)benzonitrile

NMR (CDCl3that δ): of 0.90 (3H, t, J=8 Hz), 1.18 to the 1.44 (4H, m), 1,90-2,12 (2H, m), 2,17 (3H, s), and 4.40 (1H, t, J=8 Hz), 7,80 (2H, d, J=8 Hz), 8,08 (2H, d, J=8 Hz).

MS (ESI-): m/z 242 (M-H).

Getting 98

Ethyl-6-[(5-bromo-3-pyridinyl)carbonyl]-7-oxooctanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), 1,32 was 1.43 (2H, m), 1,60 to 1.76 (2H, m), 1,96-of 2.15 (2H, m), are 2.19 (3H, s), is 2.30 (2H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,36 (1H, t, J=7 Hz), of 8.37 (1H, s), 8,87 (1H, user.), 9,07 (1H, usher.).

MS: (m/z) 370, 372 (M+H).

Getting 99

Ethyl-6-(2-horizonation)-8-(methylthio)-7-oxooctanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.34 to 1.47 (2H, m), 1.60-to or 1.77 (2H, m), with 1.92 (3H, s), 1.93 and-2,05 (2H, m), is 2.30 (2H, t, J=7 Hz), 3,19 (1H, d, J=17 Hz), 3,26 (1H, d, J=17 Hz), 4,11 (2H, square, J=7 Hz), and 4.68 (1H, t, J=7 Hz), 7,72 (1H, d, J=5 Hz), 7,86 (1H, s), to 8.57 (1H, d, J=5 Hz).

MS: (m/z 370 (M-H), 372 (M+H).

100

Ethyl-7-(3-cyanobenzoyl)-8-exonerat

NMR (CDCl3that δ): 1,21-1,44 (7H, m), 1,55 was 1.69 (2H, m), 1,89-of 2.15 (2H, m), 2,17 (3H, s)to 2.29 (2H, t, J=8 Hz), of 4.12 (2H, square, J=8 Hz), 4,39 (1H, t, J=8 Hz), to 7.64 (1H, t, J=8 Hz), 7,87 (1H, DD, J=8, 1 Hz), to 8.20 (1H, DD, J=8, 1 Hz), of 8.27 (1H, users).

MS (ESI+): m/z 330 (M+H).

Getting 101

Ethyl-6-[(6-chloro-2-pyridinyl)carbonyl]-7-oxooctanoate

NMR (CDCl3that δ): of 1.26 (3H, t, J=7 Hz), 1,36-of 1.52 (2H, m), 1,63 is 1.75 (2H, m), 1.77 in e 2.06 (2H, m)to 2.29 (2H, t, J=7 Hz), a 2.45 (3H, s), of 4.12 (2H, square, J=7 Hz), 4,82 (1H, t, J=7 Hz), 7,51 (1H, d, J=8 Hz), of 7.82 (1H, t, J=8 Hz), of 7.97 (1H, d, J=8 Hz).

MS (ESI+): m/z 326.

Getting 102

Ethyl-6-(3-methoxybenzoyl)-7-oxooctanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), 1.30 and USD 1.43 (2H, m), 1.60-to or 1.77 (2H,m), 1,92-2,12 (2H, m), of 2.15 (3H, s), 2,31 (2H, t, J=7 Hz), 3,88 (3H, s), of 4.12 (2H, square, J=7 Hz), 4,42 (1H, t, J=7 Hz), 7,14 (1H, DD, J=2 Hz, 8 Hz), 7,40 (1H, t, J=8 Hz), 7,46-7,58 (2H, m).

MS (ESI+): m/z 321.

Getting 103

Ethyl-6-(3,5-dichlorobenzoyl)-7-oxooctanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), 1.32 to to 1.42 (2H, m), 1,63 is 1.75 (2H, m), 1,90-2,12 (2H, m)of 2.16 (3H, s), is 2.30 (2H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,32 (1H, t, J=7 Hz), 7,58 (1H, m), 7,82 (2H, m).

Getting 104

Ethyl-6-[(5-chloro-2-thienyl)carbonyl]-7-oxooctanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1,30-1,40 (2H, m), 1,62-of 1.74 (2H, m), 1,90-2,12 (2H, m)of 2.16 (3H, s)to 2.29 (2H, t, J=7 Hz), 4,13 (2H, square, J=7 Hz), 4,14 (1H, m), 6,98 (1H, d, J=4 Hz), 7,58 (1H, d, J=4 Hz).

Getting 105

Ethyl-6-(3-perbenzoic)-7-oxooctanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1,28-of 1.42 (2H, m), 1,60-1,75 (2H, m), 1,90 and 2.13 (2H, m), and 2.14 (3H, s)to 2.29 (2H, t, J=7 Hz), 4,11 (2H, square, J=7 Hz), 4,37 (1H, t, J=7 Hz), 7,26-7,33 (1H, m), 7,43-7,52 (1H, m), 7,63-to 7.68 (1H, m), 7,76 (1H, d, J=8 Hz).

MS (ESI+): m/z 309.

Getting 106

Ethyl-7-oxo-6-(3-chinainternational)octanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.35 to 1.47 (2H, m), 1,63-to 1.77 (2H, m), 1,98-to 2.18 (2H, m), of 2.20 (3H, s), 2,31 (2H, t, J=7 Hz), 4,10 (2H, square, J=7 Hz), 4,55 (1H, t, J=7 Hz), 7,66 (1H, t, J=8 Hz), 7,87 (1H, t, J=8 Hz), of 7.97 (1H, d, J=8 Hz), 8,18 (1H, d, J=8 Hz), 8,78 (1H, d, J=2 Hz), 9,43 (1H, d, J=2 Hz).

MS (ESI+): m/z 342.

Getting 107

Ethyl-6-isonicotinoyl-7-ox is octanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1.26 in-a 1.45 (2H, m), 1,60-1,75 (2H, m), 1,94-2,07 (2H, m), 2,17 (3H, s), and 2.27 to 2.35 (2H, m), 4,11 (2H, square, J=7 Hz), to 4.38 (1H, t, J=7 Hz), 7,74 (2H, m), 8,83 (2H, m).

Getting 108

Ethyl-6-[(3-methoxy-5-isoxazolyl)carbonyl]-7-oxooctanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), 1,33-to 1.45 (2H, m), 1,60-1,80 (2H, m), 1,88-of 2.05 (2H, m), of 2.28 (3H, s), 2,30 at 2.45 (2H, m), a 4.03 (3H, s), 4,11 (2H, square, J=7 Hz), 4,33 (1H, t, J=7 Hz), 6,56 (1H, s).

MS (ESI+): m/z 312.

Getting 109

Ethyl-6-[(5-methyl-3-isoxazolyl)carbonyl]-7-oxooctanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1.32 to the 1.44 (2H, m), 1,61-of 1.74 (2H, m), 1.85 to 2,07 (2H, m), 2.26 and-of 2.38 (2H, m)to 2.29 (3H, s), 2.49 USD (3H, s), 4,11 (2H, square, J=7 Hz), with 4.64 (1H, m), to 6.39 (1H, s).

MS (ESI+): m/z 296.

Getting 110

Ethyl-6-(2-horizonation)-8-methoxy-7-oxooctanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1,28 was 1.43 (2H, m)of 1.66 (2H, t, J=7 Hz), 1,73 is 1.86 (1H, m), 1.93 and-2,07 (1H, m), by 2.73 (2H, t, J=7 Hz), 3,23 (3H, s)to 3.89 (1H, d, J=17 Hz), 4,00 (1H, d, J=17 Hz), 4,10 (2H, square, J=7 Hz), 4,58 (1H, t, J=7 Hz), 7,66 (1H, d, J=5 Hz), 7,78 (1H, s), at 8.60 (1H, d, J=5 Hz).

MS (ESI+): m/z 356, MS (ESI-): m/z 354.

Getting 111

Ethyl-8-methoxy-6-(3-methoxybenzoyl)-7-oxooctanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1.30 and USD 1.43 (2H, m), 1.60-to of 1.73 (2H, m), 1,79-2,04 (2H, m), 2,28 (2H, t, J=7 Hz), with 3.27 (3H, s), a 3.87 (3H, s), of 4.00 (2H, m), of 4.12 (2H, square, J=7 Hz), of 4.66 (1H, t, J=7 Hz), 7,13 (1H, m), 7,39 (1H, m), 7,45-of 7.55 (2H, m).

Getting 112

Ethyl-8-methoxy-7-oxo-6-(6-chinainternational)octanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.34 to 1.47 (2H, m), 1,60-1,75 (2H, m), 1,86 is 2.10 (2H, m), and 2.27 (2H, t, J=7 Hz, 3,24 (3H, s), as 4.02-4,10 (2H, m), of 4.12 (2H, square, J=7 Hz), a 4.83 (1H, t, J=7 Hz), of 7.48-of 7.55 (1H, m), 8,16-8,33 (3H, m), 8,49 (1H, m), of 9.02 (1H, m).

MS (ESI+): m/z 372.

Getting 113

Ethyl-8-methoxy-7-oxo-6-(3-pyridylcarbonyl)octanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), 1,31-to 1.45 (2H, m), 1.60-to of 1.73 (2H, m), 1,75-of 2.08 (2H, m), 2,28 (2H, t, J=7 Hz), 3,24 (3H, s), of 3.94 (1H, d, J=17 Hz), 4,00 (1H, d, J=17 Hz), 4,10 (2H, square, J=7 Hz), of 4.67 (1H, t, J=7 Hz), 7,44 (1H, m), by 8.22 (1H, m), 8,81 (1H, d, J=5 Hz), 9,18 (1H, m).

MS (ESI+): m/z 322.

Getting 114

Ethyl-6-(3-chlorobenzoyl)-8-methoxy-7-oxooctanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), 1.30 and the 1.44 (2H, m), 1.60-to around 1.74 (2H, m), 1,75-of 1.92 (1H, m), 1,94-2,10 (1H, m), 2,28 (2H, t, J=7 Hz)at 3.25 (3H, s), 3,93 (1H, d, J=17 Hz), was 4.02 (1H, d, J=17 Hz), 4,12 (2H, square, J=7 Hz), 4,63 (1H, t, J=7 Hz), 7,43 (1H, t, J=8 Hz), EUR 7.57 (1H, d, J=8 Hz), 7,83 (1H, d, J=8 Hz), 7,94 (1H, s).

Getting 115

Ethyl-6-(3-methylbenzoyl)-7-oxooctanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1,29-of 1.42 (2H, m), 1.60-to of 1.73 (2H, m), 1,90 e 2.06 (2H, m)to 2.13 (3H, s), 2,28 (2H, t, J=7 Hz), 2,42 (3H, s), 4,10 (2H, square, J=7 Hz), 4,42 (1H, t, J=7 Hz), 7,31-7,43 (2H, m), 7,73 for 7.78 (2H, m).

Getting 118

Ethyl-8-methoxy-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.30 to 1.47 (2H, m), 1.60-to around 1.74 (2H, m), 1,75-of 1.93 (1H, m), 1.93 and-of 2.08 (1H, m), and 2.26 (2H, t, J=7 Hz), 2,43 (3H, s)of 3.25 (3H, s), 3,95 (1H, d, J=17 Hz), a 4.03 (1H, d, J=17 Hz), of 4.12 (2H, square, J=7 Hz), of 4.67 (1H, t, J=7 Hz), 8,03 (1H, s), 8,63 (1H, s), 8,98 (1H, s).

MS (ESI+): m/z 336.

Getting 119

Ethyl-6-[(5-bromo-3-pyridinyl)carbonyl]-7-oxooctanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), 1,32 was 1.43 (2H, m), 1.60-to 1,7 (2H, m), 1,96-of 2.15 (2H, m), are 2.19 (3H, s), is 2.30 (2H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,36 (1H, t, J=7 Hz), of 8.37 (1H, s), 8,87 (1H, usher.), 9,07 (1H, usher.).

MS (ESI+): m/z 370, 372.

Getting 120

Ethyl-6-[(5-bromo-3-pyridinyl)carbonyl]-8-methoxy-7-oxooctanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.30 to 1.47 (2H, m), 1.60-to 1,72 (2H, m), 1,75-of 1.93 (1H, m), 1,95-of 2.08 (1H, m), and 2.27 (2H, t, J=7 Hz)at 3.25 (3H, s), 3,93 (1H, d, J=17 Hz), was 4.02 (1H, d, J=17 Hz), 4,10 (2H, square, J=7 Hz), 4,63 (1H, t, J=7 Hz), scored 8.38 (1H, m), 8,88 (1H, m), 9,07 (1H, m).

MS (ESI+): m/z 400, 402.

Getting 121

Ethyl-6-[(5,6-dichloro-3-pyridinyl)carbonyl]-7-oxooctanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1.30 and USD 1.43 (2H, m), 1.60-to or 1.77 (2H, m), 1,95-2,17 (2H, m), are 2.19 (3H, s), is 2.30 (2H, t, J=7 Hz), 4,11 (2H, square, J=7 Hz), 4,32 (1H, t, J=7 Hz), 8,31 (1H, d, J=2 Hz), 8,82 (1H, d, J=2 Hz).

Getting 122

Ethyl-7-methoxy-5-[(5-methyl-3-pyridinyl)carbonyl]-6-oxogedunin

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), 1,60-1,75 (2H, m), 1,78-of 1.95 (1H, m), 1,95-2,12 (1H, m), 2,32 (2H, t, J=7 Hz), 2,44 (3H, s)of 3.25 (3H, s), of 3.94 (1H, d, J=18 Hz), was 4.02 (1H, d, J=18 Hz), of 4.12 (2H, square, J=7 Hz), 4,69 (1H, t, J=7 Hz), of 8.04 (1H, s), 8,63 (1H, s), of 9.00 (1H, s).

MS (ESI+): m/z 322.

Getting 123

Ethyl-6-methoxy-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 2,08 is 2.55 (4H, m), is 2.44 (3H, s), 3,23 (3H, s), of 3.94 (1H, d, J=18 Hz), 4,01 (1H, d, J=18 Hz), of 4.12 (2H, square, J=7 Hz), 4,88 (1H, m)to 8.12 (1H, s)8,64 (1H, s), 9,04 (1H, s).

MS (ESI+): m/z 308.

Getting 124

Ethyl-5-[(5-methyl-3-pyridinyl)carbonyl]-6-oxogedunin

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), 1,60-1,75 (2H, m), 1,96 and 2.13 (2H,m), to 2.18 (3H, s), a 2.36 (2H, t, J=7 Hz), 2,43 (3H, s), of 4.12 (2H, square, J=7 Hz), 4,43 (1H, t, J=7 Hz), of 8.04 (1H, s), 8,63 (1H, s), 8,97 (1H, s).

MS (ESI+): m/z 292.

Getting 125

Ethyl-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), measuring 2.20 (3H, s), 2.26 and-2,48 (4H, m), 2,43 (3H, s), of 4.13 (2H, square, J=7 Hz), to 4.62 (1H, t, J=7 Hz), 8,08 (1H, s)8,64 (1H, s), of 9.02 (1H, s).

MS (ESI+): m/z 278.

Getting 126

Ethyl-4-[(5-bromo-3-pyridinyl)carbonyl]-5-oxohexanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), and 2.26 (3H, s), is 2.30 (2H, t, J=7 Hz), 2,43 (2H, t, J=7 Hz), is 4.15 (2H, square, J=7 Hz), 8,65 (1H, s), to 8.94 (1H, s), which 9.22 (1H, s).

Getting 127

Ethyl-6-(3-cyanobenzoyl)-8-methoxy-7-oxooctanoate

NMR (CDCl3that δ): 1,19 was 1.43 (12H, m), 1,57 is 1.70 (2H, m), of 1.80 (1H, m), 1,99 (1H, m), 2,28 (2H, t, J=8 Hz), 3,24 (3H, s), 3,91 (1H, d, J=16 Hz), 4,01 (1H, d, J=16 Hz), 4.09 to (2H, square, J=8 Hz)and 4.65 (1H, t, J=8 Hz), to 7.64 (1H, t, J=8 Hz), 7,87 (1H, DD, J=8, 1 Hz), 8,18 (1H, DD, J=8, 1 Hz), of 8.25 (1H, users).

Getting 128

Ethyl-8-(atomic charges)-6-[(5-bromo-3-pyridinyl)carbonyl]-7-oxooctanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.37 (2H, m)to 1.67 (2H, m), 1,98 e 2.06 (5H, m), is 2.30 (2H, t, J=7 Hz), 4,11 (2H, square, J=7 Hz), 4,47 (1H, t, J=7 Hz), of 4.66 (d, J=17 Hz), 4,74 (d, J=17 Hz), of 8.37 (1H, m), 8,88 (1H, m), 9,06 (1H, m).

Getting 129

To a solution of acid Meldrum (30 g, 0,208 mol) in dichloromethane (420 ml) was added pyridine (33,7 ml, 0,416 mol) for 3 minutes in a bath of ice-methanol in nitrogen atmosphere (-9°C). To the mixture was added dropwise a solution of methoxyacetanilide (24.8 g) in dichloromethane (180 ml) during the 1 hour at the same temperature. After the addition the reaction mixture was stirred at the same temperature for 1 hour and at ambient temperature for 2 hours. The mixture was suppressed 1H. hydrochloric acid (600 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated in vacuo to obtain 5-(methoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione in the form of a dark orange oil (38,1 g, 84.7 per cent).

5-(Methoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

NMR (CDCl3that δ)of 1.75 (6H, s), 3,53 (3H, s), to 4.87 (2H, s).

Getting 130

A solution of 5-(methoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (38 g) in tert-butanol (120 ml) and toluene (120 ml) was boiled under reflux for 2 hours in nitrogen atmosphere. The mixture was evaporated in vacuum to obtain a brown oil (32,5 g). The residue was dissolved in a mixture of hexane-ethyl acetate=2:1 (200 ml) was added silica gel (65 g). After stirring for 30 minutes at ambient temperature the mixture was filtered and washed with a mixture of hexane-ethyl acetate=2-1 (200 ml). The filtrate was concentrated in vacuum to obtain tert-butyl-4-methoxy-3-oxobutanoate in the form of a pale yellow oil (30.1 g, 91,0%).

tert-Butyl-4-methoxy-3-oxobutanoate

NMR (CDCl3that δ): 1,50 (9H, s)to 3.41 (2H, s), 3.43 points (3H, s)4,08 (2H, s).

Getting 131

To a mixture of 3-f is reventlow acid (500 mg) and p-toluensulfonate (715 mg) in methanol (20 ml) was added potassium carbonate (1,38 g) and the mixture is boiled under reflux for 2 hours. After evaporation of the solvent the residue was distributed between ethyl acetate and water. The aqueous layer was separated and acidified 1H. hydrochloric acid. The obtained precipitation was collected and washed with water, methanol and ether to obtain 3-(1,3-oxazol-5-yl)benzoic acid as an amorphous powder (484 mg).

3-(1,3-Oxazol-5-yl)benzoic acid

NMR (DMSO-d6, δ): 7,63 (1H, t, J=8 Hz), to 7.84 (1H, s), 7,89-8,02 (2H, m), of 8.25 (1H, m), and 8.50 (1H, s), 13,22 (1H, usher.).

MS (ESI+): m/z 188 (M-H).

Getting 132

A mixture of 1-(3-chlorophenyl)-1,3-butanedione (500 mg), 5-(iodomethyl)-2,2-dimethyl-1,3-dioxane (716 mg) and potassium carbonate (351 mg) in dimethyl sulfoxide (2.5 ml) was stirred for 14 hours at room temperature and 7 hours at 40°C. the Mixture was distributed between ethyl acetate (20 ml) and water (10 ml). The organic layer was washed with water (10×2 ml) and saturated salt solution, dried over magnesium sulfate and evaporated to obtain a brown oil. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1:10-2:5 gave 1-(3-chlorophenyl)-2-[(2,2-dimethyl-1,3-dioxane-5-yl)methyl]-1,3-butandiol in the form of a yellow oil (614 mg).

1-(3-Chlorophenyl)-2-[(2,2-dimethyl-1,3-dioxane-5-yl)methyl]-1,3-butandiol

NMR (CDCl3that δ): of 1.39 (6H, s)to 1.70 (1H, m), 1,91-of 2.15 (2H, m)of 2.16 (3H, s), 3,61 (2H, m), 3,88 (2H, m), 4,46 (1H, t, J=7 Hz), 7,44 (1H, t, J=9 Hz), EUR 7.57 (1H, m), 7,86 (1H, d, J=9 Hz), of 7.96 (1H, m).

The following compounds were obtained by analogion the th technique to obtain 132.

Getting 133

1-tert-Butyl-7-ethyl-2-(1,3-oxazol-5-ylcarbonyl)heptanoate

NMR (CDCl3that δ): of 1.26 (3H, t, J=7 Hz), 1.32 to 1,38 (11H, m)to 1.67 (2H, m)of 1.97 (2H, m), is 2.30 (2H, m), 3,86 (1H, t, J=7 Hz), 4,11 (2H, square, J=7 Hz), 7,86 (1H, s), 8,03 (1H, s).

Getting 134

1-tert-Butyl-7-ethyl-2-[(3,5-dimethyl-4-isoxazolyl)carbonyl]heptanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), 1,33-1,41 (11H, m)of 1.64 (2H, m)of 1.93 (2H, m), is 2.30 (2H, m), 2,47 (3H, s), 2,69 (2H, s), with 3.79 (1H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz).

Getting 135

To a suspension of magnesium chloride (1,46 g) in tetrahydrofuran (10 ml) was added a solution of ethyl-3-oxo-4-phenylbutanoate (2.0 g) in tetrahydrofuran (10 ml) and the mixture was cooled to 0°C, then added pyridine (2.5 ml). The mixture was stirred at 20°C for 30 minutes, then was added a solution of 4-tormentilla (2,44 g) in tetrahydrofuran (10 ml) at 0°C. After stirring at 20°C within 2 hours the mixture was distributed between 0,5h. hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated. The residue was chromatographically on silica gel, elwira a mixture of ethyl acetate and hexane (1:5), to obtain ethyl-2-(4-perbenzoic)-3-oxo-4-phenylbutanoate (2.15 g) as oil.

Ethyl-2-(4-perbenzoic)-3-oxo-4-phenylbutanoate

(mixture of tautomers, too difficult to identify).

Getting 136

A mixture of 1-(4-forfinal)butane-1,3-di is at (1.0 g), potassium carbonate (3.42 g) and tetrabutylammonium (20 mg) in toluene (10 ml) was boiled under reflux for 3 hours. After cooling to 20°C to the mixture was added ethylbromoacetate (0,74 ml). After maturation of the mixture at 20°C overnight the mixture was distributed between ethyl acetate and 0,5h. hydrochloric acid. The organic layer was separated, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated. The residue was chromatographically on silica gel, elwira a mixture of ethyl acetate and hexane (1:5), to obtain ethyl-3-(4-perbenzoic)-4-oxopentanoate (964 mg) as oil.

Ethyl-3-(4-perbenzoic)-4-oxopentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), to 2.18 (3H, s), 3,01 (2H, d, J=7 Hz), of 4.12 (2H, square, J=7 Hz), of 4.95 (1H, d, J=7 Hz), 7,18 (2H, dt, J=2, 7 Hz), 8,07 (2H, DDD, J=2, 5, 7 Hz).

Getting 137

A mixture of 1-(4-forfinal)butane-1,3-dione (1.0 g), potassium carbonate (3,84 g) and tetrabutylammonium (90 mg) in toluene (20 ml) was boiled under reflux for 3 hours, then was added ethyl-6-Bromhexine (1,18 ml). After stirring at 100°C for 3 hours the mixture was distributed between ethyl acetate and 0,5h. hydrochloric acid. The organic layer was separated, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated. The residue was chromatographically on silica gel, elwira a mixture of ethyl acetate and hexane (1:5), with the floor is the group of ethyl-7-(4-perbenzoic)-8-exonerat (983 mg) as oil.

Ethyl-7-(4-perbenzoic)-8-exonerat

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1,25-1,45 (4H, m), 1,55-1,70 (2H, m), 1,90-2,10 (2H, m)to 2.13 (3H, s), and 2.27 (2H, t, J=7 Hz), 4,11 (2H, square, J=7 Hz), 4,37 (1H, t, J=7 Hz), 7,16 (2H, t, J=9 Hz), 8,02 (2H, DD, J=5, 9 Hz).

Getting 138

A mixture of pentane-2,4-dione (5.0 g), ethyl-7-bromoheptanoate (11.1 g), potassium carbonate (13.8 g) and cesium carbonate (1.63 g) in a mixture of acetonitrile (150 ml) and dimethyl sulfoxide (30 ml) was stirred at 20°C overnight, then was added pentane-2,4-dione (5 g). After stirring at 20°C overnight the mixture was distributed between ethyl acetate and 0,5h. hydrochloric acid. The organic layer was separated, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated. The residue was chromatographically on silica gel, elwira a mixture of ethyl acetate and hexane (1:5), to obtain ethyl-8-acetyl-9-octadecanoate (5.5 g) in the form of oil.

Ethyl-7-acetyl-8-exonerat

(mixture of tautomers, too difficult to identify).

Getting 139

To a mixture of ethyl-7-acetyl-8-exonerat (4.0 g) and magnesium chloride (1.27 g) in dichloromethane (70 ml) was added pyridine (2,15 ml) at 0°C. the Mixture was stirred at 20°C for 1 hour, then was added a solution of 4-cyanobenzaldehyde (2,87 g) in dichloromethane (10 ml). After stirring for 3 hours at 20°C the mixture was distributed between ether and 1N. hydrochloric acid. Organic saitgali, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated. The residue was chromatographically on silica gel, elwira a mixture of ethyl acetate and hexane (1:5), to obtain ethyl-7-acetyl-7-(4-cyanobenzoyl)-8-exonerat (3,52 g) in the form of oil.

1-tert-Butyl-8-ethyl-2-acetyl-2-(4-cyanobenzoyl)actantial

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1,25-1,45 (4H, m)of 1.30 (9H, s), 1,55-1,70 (2H, m), of 2.20 (2H, t, J=7 Hz), 2,28 (2H, t, J=7 Hz), 2,44 (3H, s), of 4.12 (2H, square, J=7 Hz), 7,72 (2H, t, J=9 Hz), 7,83 (2H, d, J=9 Hz).

Getting 140

Ethyl-7-acetyl-7-(4-cyanobenzoyl)-8-exonerat (3.5 g) was dissolved in triperoxonane acid (12,6 ml) and the mixture was stirred at 20°C for 15 minutes. The mixture was distributed between ethyl acetate and water. The organic layer was separated, washed with water, aqueous sodium bicarbonate solution and saturated salt solution, dried over MgSO4(magnesium sulfate) and was evaporated to obtain ethyl-7-(4-cyanobenzoyl)-8-exonerat (2.25 g) as oil.

Ethyl-7-(4-cyanobenzoyl)-8-exonerat

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), 1,25-1,45 (4H, m), 1,55-1,70 (2H, m), 1,80-2,10 (2H, m)of 2.16 (3H, s), 2,28 (2H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), and 4.40 (1H, t, J=7 Hz), 7,80 (2H, t, J=9 Hz), 8,07 (2H, d, J=9 Hz).

Getting 141

A mixture of methyl-4-(aminosulfonyl)benzoate (5.10 g) and potassium carbonate (6,55 g) dimethoxyethane (50 ml) was boiled under reflux for 5 minutes. After cooling, the mixture solution was added to benzylchloride is arbonate (the 5.25 g) in dimethoxyethane (30 ml) and the resulting mixture was boiled under reflux for 1 hour. The reaction was suppressed by the addition of 1N. hydrochloric acid (100 ml). The mixture was extracted with ethyl acetate (200 ml) and the organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated to obtain a pale yellow oil which hardened on standing. The solid is triturated in diisopropyl ether (30 ml) to obtain methyl

4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoate as a white powder (3,38 g).

Methyl-4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoate

NMR (CDCl3that δ): 3,98 (3H, s), 5,10 (2H, s), 7,22 (2H, m), 7,34 (3H, m), of 7.64 (1H, s, of usher.), 8,08 (2H, d, J=9 Hz), 8,16 (2H, d, J=9 Hz).

Getting 142

A suspension of methyl 4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoate (to 3.38 g) and 85% potassium hydroxide (1.28 g) in methanol (40 ml) was stirred for 35 minutes. The methanol is evaporated and to the mixture was added 1N. hydrochloric acid (20 ml). The resulting crystals were collected by filtration, washed with water and diisopropyl ether and dried in vacuum. The result was obtained 4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoic acid as white crystals (2,92 g).

4-({[(Benzyloxy)carbonyl]amino}sulfonyl)benzoic acid

NMR (DMSO-d6, δ): is 5.06 (2H, s), 7,25 (2H, m), 7,33 (3H, m), of 8.00 (2H, d, J=9 Hz), 8,15 (2H, d, J=9 Hz).

MS (ESI-): m/z 334 (M-H).

Getting 143

To a suspension of S-(2-pyridinyl) 3-cyanobenzaldehyde (2,40 g) in tolua the e (10 ml) was added titanium chloride (1,99 g) in a bath of ice-methanol for 5 minutes (-7 to -2° C). After stirring for 10 minutes a solution of 2-ethyl-1H-pyrrole (1,00 g) in toluene (10 ml) was added within 5 minutes (-4 to 0°C). The obtained heterogeneous mixture was stirred for 1.5 hours at room temperature. Added ethyl acetate (20 ml) and water (20 ml) and the mixture was filtered through celite. The filtrate was diluted with ethyl acetate (80 ml) and water (30 ml) and the organic extract was washed with water (30 ml), 1N. sodium hydroxide (50 ml) and saturated salt solution (50 ml), dried over magnesium sulfate and evaporated to obtain a dark-colored crystals (2,46 g). The crystals are triturated in diisopropyl ether (10 ml) to give 3-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile in the form of brown crystals (1,57 g, 70.1 percent).

3-[(5-Ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile

NMR (CDCl3that δ): of 1.33 (3H, t, J=7 Hz), a 2.75 (2H, square, J=7 Hz), 6,12 (1H, m), 6,78 (1H, m), 7,60 (1H, t, J=8 Hz), 7,82 (1H, d, J=8 Hz), 8,07 (1H, d, J=8 Hz), 8,14 (1H, s), 9,50 (1H, s, of usher.).

Getting 144

To a suspension of magnesium chloride (3,01 g) in tetrahydrofuran (30 ml) was added tert-butyl 3-oxobutanoate (5,00 g). The mixture was cooled in a bath with ice. Then was added pyridine (5,00 g) for 15 minutes. After stirring for 1 hour at room temperature the mixture was cooled in a bath with ice. Was added over 15 minutes a solution of 2-chlorobenzylchloride (to 4.98 g) in tetrahydrofuran (30 ml). The mixture was stirred for 1 hour at to the room temperature. The reaction was suppressed by the addition of 1N. hydrochloric acid (65 ml). The mixture was filtered and the solvent evaporated. The residue was extracted with ethyl acetate (150 ml). The extract was washed with water (100 ml), saturated sodium bicarbonate solution (100 ml) and saturated salt solution, dried over magnesium sulfate and evaporated to obtain tert-butyl 2-(3-chlorobenzoyl)-3-oxobutanoate as a yellow oil (8,82 g).

tert-Butyl 2-(3-chlorobenzoyl)-3-oxobutanoate

NMR (CDCl3that δ): mixture of tautomers: 1,20 and of 1.27 (9H, s), 2.16 and is 2.44 (3H, s), 7,33-7,71 (4H, m), 13,66 (1H, s).

Getting 145

A solution of tert-butyl 2-(3-chlorobenzoyl)-3-oxobutanoate (8,82 g) in triperoxonane acid (40 ml) was stirred for 1 hour in a bath with ice. Volatiles were removed in vacuum and the residue was distributed between ethyl acetate (150 ml) and saturated sodium bicarbonate solution. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated to obtain 1-(3-chlorophenyl)-1,3-butanedione as pale orange crystals (5,33 g).

1-(3-Chlorophenyl)-1,3-butandiol

NMR (CDCl3that δ): of 2.21 (3H, s), 6,14 (1H, s), 7,38 (1H, t, J=9 Hz), of 7.48 (1H, d, J=9 Hz), of 7.75 (1H, d, J=9 Hz), the 7.85 (1H, s).

Getting 146

To a mixture of 2-(trimethylsilyl)ethanol (20.5 g) and pyridine (18.7 g) in dichloromethane (40 ml) solution was added ethiopiaid (10.0 g) in dichloromethane (20 ml) for 30 minutes in a bath with ice (6-20° (C) Bath was removed and the mixture was stirred for 0.5 hour. The mixture was filtered and the filtrate was distributed between ethyl acetate (200 ml) and 1N. hydrochloric acid (200 ml). The organic layer was washed with saturated sodium bicarbonate solution and saturated salt solution, dried over magnesium sulfate and evaporated to obtain bis[2-(trimethylsilyl)ethyl]oxalate in the form of a pale yellow oil (25.1 g).

bis[2-(Trimethylsilyl)ethyl]oxalate

NMR (CDCl3that δ): 0,08 (18H, s)of 1.12 (4H, m), to 4.38 (4H, m).

Getting 147

To a suspension of dimethyl sulfone (7,00 g) in diethyl ether (50 ml) was added tert-piperonyl potassium (8,76 g). To the mixture was added bis[2-(trimethylsilyl)ethyl]oxalate (23,8 g). The resulting mixture was stirred for 36 hours at room temperature. The mixture was distributed between ethyl acetate (100 ml) and 1N. hydrochloric acid (50 ml). The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated to obtain a dark orange oil. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1:25-8:5 gave 2-(trimethylsilyl)ethyl-3-(methylsulphonyl)-2-oxopropanoic in the form of a pale brown oil (of 8.37 g).

2-(Trimethylsilyl)ethyl-3-(methylsulphonyl)-2-oxopropanoic

NMR (CDCl3that δ): 0,08 (9H, s)to 1.14 (2H, m), 3,11 (3H, s), 4,43 (4H, m), 4,56 (2H, s).

MS (ESI-): m/z 265 (M-H).

Getting 148

A mixture of 4-oxo-4-phenylbutanoate acid (5,00 g), is canola (2,59 g), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (6,46 g) and 4-(dimethylamino)pyridine (171 mg) in N,N-dimethylformamide (25 ml) was stirred for 1.5 hours at room temperature. The mixture was distributed between ethyl acetate (100 ml) and 1N. hydrochloric acid (75 ml) and the organic layer was washed with water (75×3 ml), saturated sodium bicarbonate solution (75 ml) and saturated salt solution (75 ml), dried over magnesium sulfate and evaporated to obtain ethyl-4-oxo-4-phenylbutanoate in the form of a colorless oil (4,19 g).

Ethyl-4-oxo-4-phenylbutanoate

NMR (CDCl3that δ): of 1.27 (3H, t, J=7 Hz), was 2.76 (2H, t, J=7 Hz), 3,32 (2H, t, J=7 Hz), 4,16 (2H, square, J=7 Hz), 7,47 (2H, t, J=9 Hz), 7,55 (1H, d, J=9 Hz), 7,98 (2H, d, J=9 Hz).

MS (ESI+): m/z 207 (M+H).

The following compound was obtained according to a similar method of obtaining 148.

Getting 149

Ethyl-5-oxo-5-phenylpentane

NMR (CDCl3that δ): of 1.26 (3H, t, J=7 Hz), of 2.08 (2H, m)2,44 (2H, t, J=7 Hz), 3,06 (2H, t, J=7 Hz), 4,14 (2H, square, J=7 Hz), 7,46 (2H, t, J=9 Hz), 7,56 (1H, d, J=9 Hz), of 7.97 (2H, d, J=9 Hz).

MS (ESI+): m/z 221 (M+H).

Getting 150

A mixture of 2-benzoylecognine (1,00 g), ethoxide sodium (404 mg) in ethanol (5 ml) was stirred for 3.5 hours at room temperature. The reaction was suppressed by the addition of 1N. hydrochloric acid (1 ml). The solvent evaporated and the residue was distributed between ethyl acetate and water. The organic layer was washed with saturated of rest the rum salt, was dried over magnesium sulfate and evaporated to obtain ethyl-7-oxo-7-phenylheptanoic in the form of a brown oil (1,33 g).

Ethyl-7-oxo-7-phenylheptanoic

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.42 (2H, m), 1,63-of 1.81 (4H, m), 2,32 (2H, t, J=7 Hz), 2,98 (2H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 7,47 (2H, t, J=9 Hz), 7,54 (1H, d, J=7 Hz), 7,95 (2H, d, J=9 Hz).

Getting 151

To a solution of ethyl-7-chloro-7-exagerate (1.31 g) in dichloromethane (25 ml) was added a solution of 2-(trimethylsilyl)-1,3-thiazole (500 mg) in dichloromethane (5 ml) under nitrogen atmosphere. After stirring for 3 hours the reaction was suppressed by the addition of saturated sodium bicarbonate solution (5 ml). The mixture was distributed between ethyl acetate (30 ml) and saturated sodium bicarbonate solution (30 ml) and the organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated to obtain a colorless oil. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1:10-2:5 gave ethyl-7-oxo-7-(1,3-thiazol-2-yl)heptanoate in the form of a colorless oil (778 mg).

Ethyl-7-oxo-7-(1,3-thiazol-2-yl)heptanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.44 (2H, m), 1,64-of 1.85 (4H, m), 2,32 (2H, t, J=7 Hz), 3,17 (2H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 7,66 (1H, d, J=3 Hz), 8,00 (1H, d, J=3 Hz).

MS (ESI+): m/z 256 (M+H).

Getting 152

To a solution of 7-methoxy-7-exogamous acid (1,00 g) in dichloromethane (10 ml) solution was added triperoxonane anhydride (1,33 g) in chlormethine (2 ml). After stirring for 0.5 hours the solution was added 1-methyl-1H-pyrrole (1,49 g) in dichloromethane (2 ml). The mixture was stirred for 2 hours and 40 minutes at room temperature and 2 hours at 35°C. the Mixture was distributed between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated to obtain a brown oil. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1:20-4:5 gave methyl-7-(1-methyl-1H-pyrrol-2-yl)-7-oxogedunin in the form of a colorless oil (615 mg).

Methyl-7-(1-methyl-1H-pyrrol-2-yl)-7-oxogedunin

NMR (CDCl3that δ): 1,34 (2H, m), 1,61-to 1.77 (4H, m), 2,32 (2H, t, J=7 Hz), 2,77 (2H, t, J=7 Hz), 3,66 (3H, s), of 3.94 (3H, s), 6,13 (1H, m), 6,79 (1H, m), 6,93 (1H, m).

MS (ESI+): m/z 238 (M+H).

Getting 153

To a suspension of 4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoic acid (2,90 g) in dichloromethane (30 ml) was added N,N-dimethylformamide (19,0 mg) and then oxalicacid (1,15 g) in a bath with ice. The mixture was stirred for 0.5 hour at room temperature and boiled under reflux for 1 hour. After adding oxalicacid (439 mg) the mixture was boiled under reflux for another 5 minutes. Evaporated volatiles to obtain white solids. The solid is triturated in diisopropyl ether with the floor is the group of benzyl[4-(chlorocarbonyl)phenyl]sulfonylamino in the form of a white powder (2,40 g), which was used in the next reaction without further purification.

Benzyl[4-(chlorocarbonyl)phenyl]sulfonylurea

Getting 154

To a solution of tert-butyl 4-(methylthio)-3-oxobutanoate (5,00 g) and potassium carbonate (and 3.72 g) in dimethylformamide (25 ml) was added ethyl-5-iodopentane (6,89 g) and the mixture was stirred at ambient temperature for 15 hours. The mixture was distributed between ethyl acetate and water. The organic layer was separated, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (20:1-10:1), to obtain 1-tert-butyl-7-ethyl-2-[(methylthio)acetyl]heptanoate in the form of a colorless oil (5,88 g).

1-tert-butyl-7-ethyl-2-[(methylthio)acetyl]heptanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), 1.30 and of 1.42 (2H, m)of 1.45 (9H, s), 1,63-of 1.74 (2H, m), 1,81-of 1.93 (2H, m), is 2.05 (3H, s), is 2.30 (2H, t, J=7 Hz), 3,23 (1H, d, J=17 Hz), 3,38 (1H, d, J=17 Hz), 3,74 (1H, t, J=7 Hz), 4,11 (2H, square, J=7 Hz).

Getting 155

To a suspension of hydroxylamine hydrochloride (29,4 g) in dichloromethane (200 ml) was added diisopropylethylamine (54.6 g) for 3 minutes in a bath of ice-methanol in a nitrogen atmosphere. After adding a white precipitate appeared. After stirring for 1 hour at bath were added within 60 minutes, the solution diphenylphosphinite (20,0 g) in dichloromethane (20 ml). After dopaminereleasing white crystals. The mixture was heated to 0°C for 1 hour under stirring. The reaction was suppressed by addition of water (200 ml) for 3 minutes. After stirring the mixture for 0.5 hours, the crystals were collected by filtration. The crystals were washed with water (50×3 ml) and then with diisopropyl ether (50×3 ml). The collected crystals were dried overnight in air and 3 hours under reduced pressure with a small pool (4°C), resulting in the crude product. The crude product is triturated in EtOH (ethanol) to obtain the oxide (aminooxy)(diphenyl)phosphine in the form of white crystals (15.3 g).

Oxide (aminooxy)(diphenyl)phosphine

NMR (CDCl3that δ): 7,54-7,58 (6H, m), 7,74-7,83 (4H, m), 8,20-of 8.33 (2H, m).

Getting 156

To a solution of 1-(1H-pyrrol-2-yl)ethanone (of 5.00 g) in tetrahydrofuran (100 ml) was added tert-piperonyl potassium (6,17 g) in a water bath under nitrogen atmosphere. After stirring for 1 hour was added within 2 hours of the oxide (aminooxy)(diphenyl)phosphine (12.8 g). After stirring for 2 hours at room temperature was added for 3 minutes, water (4 ml) to obtain a transparent solution. The solvent evaporated and the residue was distributed between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (25×5 ml) and the combined organic extracts were washed with saturated salt solution, dried over anhydrous magnesium sulfate and perivale to obtain a brown oil (6,01 g). The oil was dissolved in diisopropyl ether (30 ml) and to the solution was added hexane (15 ml) to give pale yellow crystals. After stirring for 1 hour the crystals were removed by filtration. The filtrate was evaporated to obtain a brown oil (5,69 g). The oil was dissolved in ethyl acetate (45,5 ml), the solution was cooled in a bath with ice. To the cooled solution was added 4n. hydrogen chloride in ethyl acetate (11.5 ml) for 15 minutes to obtain a pale brown solid. After stirring the mixture for 0.5 hours at bath the precipitate was collected by filtration and washed with ethyl acetate (5×3 ml) to give pale brown powder (5,33 g). The powder is suspended in ethyl acetate (37 ml) and was heated to 3°C. the Suspension was stirred for 1 hour at room temperature. The powder was collected by filtration and washed with ethyl acetate (5×3 ml) to give the hydrochloride of 1-(1-amino-1H-pyrrol-2-yl)ethanone in the form of a pale brown powder (5,25 g).

Hydrochloride of 1-(1-Amino-1H-pyrrol-2-yl)ethanone

NMR (CDCl3that δ): is 2.37 (3H, s), with 5.22 (2H, s, of usher.), 6,07 (1H, m), of 6.99 (1H, m), to 7.15 (1H, m).

Getting 157

In the atmosphere of nitrogen hydrazine monohydrate (530 g) was added to ethanol (1.7 l) for 55 minutes. To the mixture was added the hydrochloride of 1-(1-amino-1H-pyrrol-2-yl)ethanone (170 g) for 20 minutes. The mixture was stirred for 10 minutes at room temperature and heated is about the boiling point under reflux for 55 minutes and boiled under reflux for 15 minutes. After cooling in a water bath to a mixture of (30-31° (C) was added water (1.7 l). Evaporated ethanol and the resulting mixture was extracted with chloroform (0,85×4 ml). The combined organic extracts were washed with saturated salt solution (1.3 l). A saturated salt solution was extracted with chloroform (0,85 l). The combined organic extracts were dried over anhydrous magnesium sulfate and was evaporated to obtain (1E)-1-(1-amino-1H-pyrrol-2-yl)economicrate in the form of brown crystals (112 g).

(1E)-1-(1-Amino-1H-pyrrol-2-yl)economicrate

NMR (CDCl3that δ): 2,10 (3H, s), 5,11 (2H, s, of usher.), of 5.83 (2H, s, of usher.), 5,98 (1H, m), and 6.25 (1H, m), 6,79 (1H, m).

MS (ESI+): m/z 139 (M+H).

Getting 158

To a suspension of (1E)-1-(1-amino-1H-pyrrol-2-yl)economicrate (110 g) in toluene (1.1 l) was added tert-piperonyl potassium (93,8 g) for 5 minutes in a nitrogen atmosphere and the mixture was heated to boiling point under reflux for 45 minutes. After boiling under reflux for 15 minutes, the mixture was cooled to room temperature and distributed between ethyl acetate (1.1 l) and water (1.1 l). The aqueous layer was again extracted with ethyl acetate (1.1 l). The combined organic extracts were washed with saturated salt solution (1.1 l) and saturated salt solution was extracted with ethyl acetate (0.5 l). All organic layers were combined, dried over anhydrous magnesium sulfate and evaporated with what rucenim 2-ethyl-1H-pyrrol-1-amine as a brown oil (94,4 g).

2-Ethyl-1H-pyrrol-1-amine

NMR (CDCl3that δ): of 1.26 (3H, t, J=7 Hz), 21,62 (2H, square, J=7 Hz), a 4.53 (2H, s, of usher.), 5,80 (1H, m), of 5.99 (1H, m), to 6.67 (1H, m).

Getting 159

To a suspension of tert-butyl-4-methoxy-3-oxobutanoate (3,09 g) and potassium carbonate (2.50 g) in dimethylformamide (20 ml) was added ethyl-5-iodopentane (4,62 g) and the mixture was stirred at ambient temperature for 15 hours. The mixture was distributed between ethyl acetate and water. The organic layer was separated, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (20:1-5:1), to obtain 1-tert-butyl-7-ethyl-2-(methoxyacetyl)heptanoate in the form of a colorless oil (4,33 g).

1-tert-Butyl-7-ethyl-2-(methoxyacetyl)heptanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), 1.30 and the 1.44 (2H, m)of 1.45 (9H, s), 1.60-to of 1.73 (2H, m), 1,80-of 1.93 (2H, m)to 2.29 (2H, t, J=7 Hz), to 3.41 (3H, s), 3,47 (1H, t, J=7 Hz), was 4.02 (4H, m).

MS: (m/z 317 (M+H).

The following compounds were obtained according to a similar method of obtaining 159.

Getting 160

1-tert-Butyl-6-ethyl-2-(methoxyacetyl)hexanedioic

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.46 (9H, s), 1,52-of 1.73 (2H, m), 1,82-of 1.94 (2H, m), of 2.33 (2H, t, J=7 Hz), 3,42 (3H, s), 3,50 (1H, t, J=7 Hz), 4,10 (2H, s), of 4.12 (2H, square, J=7 Hz).

Getting 161

1-tert-Butyl-5-ethyl-2-(methoxyacetyl)pentanedioic

NMR (CDCl3that δ): of 1.26 (3H, t, J=7 Hz), of 1.47 (9H, s), 2,10-of 2.25 (2H, m), 2,37 (H, t, J=7 Hz), 3,42 (3H, s), 3,62 (1H, t, J=7 Hz), of 4.12 (2H, s), of 4.13 (2H, square, J=7 Hz).

Getting 162

1-tert-Butyl-6-ethyl-2-acetylenediolate

NMR (CDCl3that δ): of 1.26 (3H, t, J=7 Hz), of 1.47 (9H, s), 1,57 is 1.75 (2H, m), 1,79-of 1.93 (2H, m), of 2.23 (3H, s), of 2.33 (2H, t, J=7 Hz), to 3.33 (1H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz).

MS (ESI+): m/z 273.

Getting 163

1-tert-Butyl-5-ethyl-2-acetylethyl

NMR (CDCl3that δ): of 1.26 (3H, t, J=7 Hz), of 1.47 (9H, s), 2,08-2,22 (2H, m), 2,24 (3H, s), 2,33-to 2.42 (2H, m), of 3.45 (1H, t, J=7 Hz), 4,13 (2H, square, J=7 Hz).

Getting 164

To a solution of 2-ethyl-1H-pyrrole (7,00 g) in tetrahydrofuran (14 ml) was added 0,93 M ethylmagnesium (198 ml) in a bath with ice. The mixture was stirred for 1 hour at room temperature. Then the resulting solution was added to a suspension of 5-bromonicotinate (22,3 g) in tetrahydrofuran (110 ml) over 50 minutes in a bath with ice. After stirring for 15 minutes on the specified bath the reaction was suppressed by the addition of saturated ammonium chloride (30 ml). The mixture was distributed between ethyl acetate (350 ml) and water (350 ml). The organic layer was washed with saturated sodium bicarbonate solution and saturated salt solution, dried over magnesium sulfate and evaporated to obtain resin dark color (33,9 g). The resin was dispersively in a mixture of ethyl acetate-hexane (1:3, 150 ml) in the presence of silica gel (150 ml). The mixture was filtered and the filtrate was concentrated to obtain yellow crystals (20.6 g). Flash chromatography n is a column of silica gel with elution with a mixture of ethyl acetate : hexane=1:20-4:5 gave (5-bromo-3-pyridinyl)(5-ethyl-1H-pyrrol-2-yl)methanon in the form of a pale yellow solid (7,11 g).

(5-Bromo-3-pyridinyl)(5-ethyl-1H-pyrrol-2-yl)methanon

NMR (CDCl3that δ): of 1.33 (3H, t, J=7 Hz), a 2.75 (2H, square, J=7 Hz), 6,14 (1H, m), 6,83 (1H, m), of 8.27 (1H, m), 8,82 (1H, m), 8,98 (1H, m).

MS (ESI+): m/z 279 (M+H).

Getting 165

To a solution of tert-butyl 4-(atomic charges)-3-oxobutanoate (30.0 g) and ethyl-5-iodopentane (35.5 g) in N,N-dimethylformamide (150 ml) was added potassium carbonate (19.2 g) at room temperature. After stirring for 4 hours the mixture was suppressed by the addition of 1N. hydrochloric acid (140 ml) in a bath with ice. The mixture was distributed between ethyl acetate (450 ml) and water (300 ml). The organic extract was washed with water (500 ml, three times) and saturated salt solution, dried over magnesium sulfate and evaporated to obtain a brown oil containing 1-tert-butyl-7-ethyl-2-[(atomic charges)acetyl]heptanoate (and 63.4 g, 43 wt.% purity).

1-tert-Butyl-7-ethyl-2-[(atomic charges)acetyl]heptanoate

NMR (CDCl3that δ): of 1.20 to 1.37 (5H, m)of 1.46 (9H, s), and 1.63 (2H, m), of 1.85 (2H, m), 2,17 (3H, s), is 2.30 (2H, t, J=7 Hz), 3,39 (1H, t, J=7 Hz), 4,11 82H, square, J=7 Hz), to 4.73 (1H, d, J=17 Hz), 4,82 (1H, d, J=17 Hz).

Getting 166

To a solution of ethylthiophene (2.00 g) and ethyl-7-chloro-7-exagerate (5,39 g) in dichloromethane (20 ml) was added 1M solution of tin chloride in dichloromethane (38,9 ml) for 0.5 hour in a bath with ice (5-8°C). After stirring for 0.5 hour the mixture was stirred for 0.5 hour at room temperature. The mixture was poured into water with l is ω (100 ml) and was extracted with ethyl acetate (100 ml). The organic extract was washed with water (100 ml) and saturated salt solution, dried over magnesium sulfate and evaporated to obtain a brown oil. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1:10-3:10 gave ethyl-7-oxo-7-(2-thienyl)heptanoate in the form of a brown oil (5,79 g).

Ethyl-7-oxo-7-(2-thienyl)heptanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.42 (2H, m), 1,63-1,72 (4H, m), 2,31 (2H, t, J=7 Hz), only 2.91 (2H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 7,13 (1H, m)7,612 (1H, m), of 7.70 (1H, m).

The following compounds were obtained according to similar methods of obtaining 129 and 130.

Getting 167

tert-Butyl 3-(3,5-dimethyl-4-isoxazolyl)-3-oxopropanoic

NMR (CDCl3that δ): of 1.47 (9H, s)to 2.46 (3H, s), 2,68 (3H, s), 3,68 (2H, s).

Getting 168

Ethyl-4-methyl-3-oxopentanoate

NMR (CDCl3that δ): to 1.14 (6H, d, J=7 Hz), of 1.28 (3H, t, J=7 Hz), 2,71 (1H, quintet, J=7 Hz), 3,50 (s, 2H), 4,19 (2H, square, J=7 Hz), 7,06-7,18, 7,56, and a 7.85 (4H, m).

Getting 169

tert-Butyl 4-(methylthio)-3-oxobutanoate

NMR (CDCl3that δ): of 1.47 (9H, s)2,07 (3H, s), and 3.31 (2H, s)to 3.58 (2H, s).

Getting 170

tert-Butyl 3-(1,3-oxazol-5-yl)-3-oxopropanoic

NMR (CDCl3that δ): (mixture of ketoform and enol forms); ketoform: a 1.45 (9H, s), of 3.77 (2H, s), a 7.85 (1H, s), of 8.04 (1H, s); enol form: δ a 1.45 (9H, s)5,54 (1H, s), 7,53 (1H, s), to $ 7.91 (1H, s).

The following compounds were obtained according to a similar method of obtaining 143.

Getting 171

(2-Chloro-4-pyridinyl)(5-ethyl-1H-p is rol-2-yl)methanon

NMR (CDCl3that δ): 1,32 (3H, t, J=7 Hz), is 2.74 (2H, square, J=7 Hz), 6,13 (1H, m), 6,79 (1H, m), 7,56 (1H, d, J=5 Hz), 7,69 (1H, s), 8,54 (1H, d, J=5 Hz), 9,40 (1H, usher.).

Getting 172

(5-Ethyl-1H-pyrrol-2-yl)(3-methoxyphenyl)metano

NMR (CDCl3that δ): 1,32 (3H, t, J=7 Hz), is 2.74 (2H, square, J=7 Hz), a 3.87 (3H, s), between 6.08 (1H, m), 6,83 (1H, m), was 7.08 (1H, DD, J=2 Hz, 8 Hz), 7,33-7,42 (2H, m), 7,47 (1H, d, J=8 Hz), 9,58 (1H, usher.).

MS (ESI+): m/z 230.

Getting 173

(5-Ethyl-1H-pyrrol-2-yl)(4-pyridinyl)metano

NMR (CDCl3that δ): 1,32 (3H, t, J=7 Hz), of 2.72 (2H, square, J=7 Hz), 6,13 (1H, m), for 6.81 (1H, m), the 7.65 (2H, d, J=7 Hz), 8,77 (2H, d, J=7 Hz), 9,39 (1H, usher.).

Getting 174

(5-Ethyl-1H-pyrrol-2-yl)(2-pyrazinyl)metano

NMR (CDCl3that δ): of 1.33 (3H, t, J=7 Hz), 2,77 (2H, square, J=7 Hz), 6,14 (1H, m), 7,51 (1H, m), 8,65 (1H, m), a total of 8.74 (1H, m), 9,36 (1H, usher.).

Getting 175

(5-Ethyl-1H-pyrrol-2-yl)(3-pyridinyl)metano

NMR (CDCl3that δ): of 1.33 (3H, t, J=7 Hz), was 2.76 (2H, square, J=7 Hz), 6,12 (1H, m), for 6.81 (1H, m), 7,42 (1H, m), 8,13 (1H, m), 8,76 (1H, m), the remaining 9.08 (1H, m), 9,36 (1H, usher.).

Getting 176

A mixture of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (300 mg), methansulfonate acid (208 mg), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (361 mg) and 1-hydroxybenzotriazole (254 mg) in N,N-dimethylformamide (1 ml) was stirred for 1.5 hours. The mixture was distributed between ethyl acetate and water. The organic layer was washed with water two times, saturated sodium bicarbonate solution and saturated salt solution, dried over sulfate is Agnes and evaporated to obtain a pale brown solid. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1/2-1/0 gave N-[2-(3-cyanobenzoyl)-5-ethyl-1H-pyrrol-1-yl]-2-(methylsulphonyl)ndimethylacetamide in the form of a pale brown foam, which hardened on standing (505 mg).

N-[2-(3-Cyanobenzoyl)-5-ethyl-1H-pyrrol-1-yl]-2-(methylsulphonyl)ndimethylacetamide

NMR (CDCl3that δ): of 1.29 (3H, t, J=7 Hz), 2,62 (2H, square, J=7 Hz), or 3.28 (3H, s)to 4.15 (2H, s), 6,12 (1H, d, J=5 Hz), to 6.75 (1H, d, J=5 Hz), 7,58 (1H, t, J=9 Hz), 7,82 (1H, d, J=9 Hz), 8,01 (1H, d, J=9 Hz), of 8.06 (1H, s).

The following compound was obtained according to a similar method of obtaining 176.

Getting 177

Ethyl-3-{[2-(4-cyanobenzoyl)-5-ethyl-1H-pyrrol-1-yl]amino}-3-oxopropanoic

NMR (CDCl3that δ): of 1.20 to 1.37 (6H, m), of 2.56 (2H, square, J=7 Hz), of 3.57 (2H, s), 4,30 (2H, square, J=7 Hz), the 6.06 (1H, d, J=5 Hz), of 6.68 (1H, d, J=5 Hz), 7,54 (2H, d, J=9 Hz), to 7.84 (2H, d, J=9 Hz).

Example 1

To a solution of 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (100 mg) in toluene (1 ml) was added 1-(4-methoxyphenyl)acetone (103 mg) and monohydrate p-toluensulfonate acid (16 mg) at ambient temperature. The reaction mixture was heated at 80°C for 3 hours. The mixture was evaporated in vacuum. The residue was purified flash chromatography on a column of silica gel with elution by the mixture hexane-ethyl acetate=20:1 and 15:1 to obtain 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrole[1,2-b]pyridazin-4-yl]benzonitrile (31 mg, 20,2%) as a yellow solid.

4-[7-Ethyl-3-(4-netoxygen the l)-2-methylpyrrole[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl3that δ): 1,40 (3H, t, J=8 Hz), 2,31 (3H, s), and 3.16 (2H, square, J=8 Hz), of 3.77 (3H, s), 6,10 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), to 6.75 (2H, d, J=8 Hz), 6,93 (2H, d, J=8 Hz), 7,33 (2H, d, J=8 Hz), 7,53 (2H, d, J=8 Hz).

MS (ESI+): m/z 368 (M+H).

The following compounds were obtained according to a similar method of example 1.

Example 2

Ethyl-4-(4-cyanophenyl)-2-(2-ethoxy-2-oxoethyl)-7-acylpyrrole[1,2-b]pyridazin-3-carboxylate

NMR (CDCl3that δ): 0,84 (3H, t, J=7 Hz), of 1.28 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 3.04 from (2H, square, J=7 Hz), 3,93 (2H, square, J=7 Hz), 4,13 (3H, s), 4,19 (2H, square, J=7 Hz), 6,24 (1H, d, J=5 Hz), 6,62 (1H, d, J=5 Hz), 7,13 (2H, d, J=9 Hz), 7,76 (2H, d, J=9 Hz).

Example 3

Ethyl-4-(4-cyanophenyl)-7-ethyl-2-(trifluoromethyl)pyrrolo[1,2-b]pyridazin-3-carboxylate

NMR (CDCl3that δ): 1,08 (3H, t, J=7 Hz), of 1.41 (3H, t, J=7 Hz), 3,11 (2H, square, J=7 Hz), 4,11 (2H, square, J=7 Hz), to 6.43 (1H, d, J=5 Hz), 6,93 (1H, d, J=5 Hz), a 7.62 (2H, d, J=9 Hz), 7,80 (2H, d, J=9 Hz).

Example 4

4-[7-Ethyl-2-methyl-3-(3-pyridylcarbonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl3that δ): USD 1.43 (t, J=7 Hz, 3H), 2,47 (s, 3H), 3,09 (sq, J=7 Hz, 2 H), 6.35mm (d, J=5 Hz, 1H), 6,74 (d, J=5 Hz, 1H), 7.23 percent (1H, m), of 7.48 (2H, d, J=9 Hz), 7,55 (2H, d, J=9 Hz), to 7.93 (1H, m), to 8.62 (1H, m), a total of 8.74 (1H, m).

Example 5

3-[7-Ethyl-2-methyl-3-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl3that δ): of 1.42 (3H, t, J=7 Hz), 2,32 (3H, s), is 3.08 (2H, square, J=7 Hz), x 6.15 (1H, d, J=5 Hz), to 6.67 (1H, d, J=5 Hz), 7,00 (2H, d, J=9 Hz), 7,37 (2H, m), EUR 7.57 (2H, m), and 8.50 (2H, d, J=9 Hz).

Example 6

4-(3-Benzyl-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-4-yl)benzonitrile

NMR (CDCl3, δ): 1,40 (3H, t, J=8 Hz), to 2.35 (3H, s), 3.04 from (2H, square, J=8 Hz), 3,83 (3H, s)5,94 (1H, d, J=5 Hz), to 6.57 (1H, d, J=5 Hz), 6,98 (2H, d, J=8 Hz), 7,14-7,30 (3H, m), 7,46 (2H, d, J=8 Hz), to 7.68 (2H, d, J=8 Hz).

MS (ESI+): m/z 352 (M+H).

Example 7

4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-carbonitril

NMR (CDCl3that δ): of 1.41 (3H, t, J=8 Hz), 3,10 (2H, square, J=8 Hz), of 6.65 (1H, d, J=5 Hz), to 6.88 (1H, d, J=5 Hz), 7,47-to 7.64 (6H, m), of 7.70 (1H, users), 7,81-of 7.90 (2H, m).

Example 8

3-(3-Ethyl-7,7,9,9-tetramethyl-6,7,8,9-tetrahydropyrrolo[1,2-b]cinnolin-10-yl)benzonitrile

NMR (CDCl3that δ): 1,00-of 1.15 (12H, m)to 1.37 (3H, t, J=8 Hz), of 2.81 (3H, s)of 3.00 (2H, square, J=8 Hz), 3,82 (2H, t, J=5 Hz), 5,46 (1H, d, J=5 Hz), 6,46 (1H, d, J=5 Hz), 7,50-the 7.65 (3H, m), 7,72 (1H, m).

Example 9

3-(3-Ethyl-9-oxo-6,7,8,9-tetrahydropyrrolo[1,2-b]cinnolin-10-yl)benzonitrile

NMR (CDCl3that δ): 1,40 (3H, t, J=8 Hz), 2,08-2,22 (2H, m)2,60 (2H, t, J=7 Hz), 3.00 and-3,15 (4H, m), of 6.26 (1H, d, J=5 Hz), 6,74 (1H, d, J=5 Hz), 7,49-to 7.61 (3H, m), 7,74 (1H, m).

MS (ESI+): m/z 316 (M+H).

Example 10

3-(6-Ethyl-1-oxo-2,3-dihydro-1H-cyclopent[e]pyrrolo[1,2-b]pyridazin-9-yl)benzonitrile

NMR (CDCl3that δ): USD 1.43 (3H, t, J=8 Hz), a 2.75 (2H, t, J=7 Hz), 3,10 (2H, square, J=8 Hz), 3,24 (2H, t, J=7 Hz), to 6.67 (1H, d, J=5 Hz), 6.87 in (1H, d, J=5 Hz), 7,60 (1H, t, J=8 Hz), 7,75-of 7.90 (3H, m).

MS (ESI+): m/z 324 (M+Na).

Example 11

3-(7-Ethyl-2-neopentylene[1,2-b]pyridazin-4-yl)benzonitrile

NMR (CDCl3that δ): of 1.05 (9H, s)of 1.39 (3H, t, J=8 Hz), 2,68 (2H, s), 3.04 from (2H, square, J=8 Hz), 6,36 (1H, s), 6.48 in (1H, d, J=5 Hz), to 6.67 (1H, d, J=5 Hz), 7,51 (1H, t, J=8 Hz), of 7.75 (1H, userd, J=8 Hz), 7,92 shed 8.01 (2H, m).

MS (ESI+): m/z 318 (M+H).

Example 12

3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl3that δ): the 1.44 (3H, t, J=8 Hz), 3,11 (2H, square, J=8 Hz), 6,52-6,60 (2H, m), 6,74 (1H, d, J=5 Hz), 6,98 (1H, s), to 7.09 (1H, d, J=5 Hz), 7,56-to 7.68 (2H, m), 7,78 (1H, DD, J=8, 1 Hz), of 7.96-8,08 (2H, m).

MS (ESI+): m/z 314 (M+H).

Example 13

4-[7-Ethyl-2-methyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl3that δ): to 1.38 (3H, t, J=8 Hz), 2,89 (3H, s), 3.00 and-3,11 (5H, m)6,09 (1H, d, J=5 Hz), was 6.73 (1H, d, J=5 Hz), was 7.45 (2H, d, J=8 Hz), 7,76 (2H, d, J=8 Hz).

MS (ESI+): m/z 340 (M+H).

Example 13-2

4-{7-Ethyl-2-[(methylsulphonyl)methyl]pyrrolo[1,2-b]pyridazin-4-yl}benzonitrile

NMR (CDCl3that δ): of 1.39 (3H, t, J=8 Hz), 2,96-3,09 (5H, m), of 4.44 (2H, s), 6,63 (1H, d, J=5 Hz), of 6.71 (1H, s), for 6.81 (1H, d, J=5 Hz), 7,79 (2H, d, J=8 Hz), a 7.85 (2H, d, J=8 Hz).

MS (ESI+): m/z 340 (M+H).

Example 15

3-[7-Ethyl-2-methyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl3that δ): of 1.39 (3H, t, J=8 Hz), 2,89 (3H, s), 3.00 and-3,11 (5H, m)6,09 (1H, d, J=5 Hz), was 6.73 (1H, d, J=5 Hz), 7,54-7,63 (3H, m), to 7.77 (1H, m).

Example 16

To a solution of 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrole[1,2-b]pyridazin-4-yl]benzonitrile (22 mg) in N,N-dimethylformamide (1 ml) was added 1N. sodium hydroxide (0,12 ml) and 30% hydrogen peroxide (0,07 ml) at ambient temperature. After 1 hour stirring, the reaction mixture was distributed between ethyl acetate and water. The organic layer was washed with water three times and with saturated salt solution, dried over sulfate mA the of and evaporated in vacuum. The residue was purified flash chromatography on a column of silica gel (silica gel, 30 ml), elwira a mixture of hexane-ethyl acetate=5:1 and 0:1, to obtain 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrole[1,2-b]pyridazin-4-yl]benzamide (18 mg, 78,0%) as a yellow solid.

4-[7-Ethyl-3-(4-methoxyphenyl)-2-methylpyrrole[1,2-b]pyridazin-4-yl]benzamide

NMR (CDCl3that δ): of 1.41 (3H, t, J=8 Hz), 2,31 (3H, s), 3,17 (2H, square, J=8 Hz), of 3.77 (3H, s), 5,61 (0,2H, users), 6,02 (0,4H, users), 6,13 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), to 6.75 (2H, d, J=8 Hz), 6,95 (2H, d, J=8 Hz), 7,31 (2H, d, J=8 Hz), to 7.68 (2H, d, J=8 Hz).

MS (ESI+): m/z 386 (M+H).

The following compound was obtained according to a similar method of example 16.

Example 17

3-[2-(Dimethylamino)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide

NMR (CDCl3that δ): 1,32 (3H, t, J=7 Hz), 2,90 (6H, s), 2,95 (2H, square, J=7 Hz), to 3.36 (3H, s), 6,21 (1H, d, J=5 Hz), 6,79 (1H, d, J=5 Hz), 7,44 (1H, s, of usher.), 7,52-7,56 (2H, m), of 7.90 (1H, s), 7,94-of 8.06 (2H, m).

MS (ESI+): m/z 387 (M+H).

Example 18

3-(7-Ethyl-2-neopentylene[1,2-b]pyridazin-4-yl)benzamid

NMR (CDCl3that δ): of 1.05 (9H, s)of 1.39 (3H, t, J=8 Hz), 2,68 (2H, s), 3.04 from (2H, square, J=8 Hz), 5,70 (1H, users), 6,11 (1H, users), 6,41 (1H, s), of 6.52 (1H, d, J=5 Hz), of 6.65 (1H, d, J=5 Hz), to 7.59 (1H, t, J=8 Hz,), a 7.85-to 7.93 (2H, m), 8,15 (1H, users).

MS (ESI+): m/z 336 (M+H).

Example 19

3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide

NMR (CDCl3that δ): USD 1.43 (3H, t, J=8 Hz), 3,10 (2H, square, J=8 Hz), 5,70 (1H, users), 6,13 (1H, users), 6,53-6,60 (2H, m), of 6.71 (1H, d, J=5 Hz), 7,02 (1H, s), 7,06(1H, d, J=5 Hz), 7,55-the 7.65 (2H, m), 7,79-7,98 (2H, m), 8,02 (1H, users).

MS (ESI+): m/z 332 (M+H).

Example 20

5-[2-({[4-(Aminocarbonyl)benzyl]oxy}methyl)-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (DMSO-d6that δ): 1,27-1,45 (7H, m)to 1.99 (2H, m), 2,96 (2H, m), 3,40 (2H, m), of 4.67 (2H, s), 4.72 in (2H, s), 5,88 (1H, d, J=5 Hz), to 6.67 (1H, d, J=5 Hz), 7,35 (1H, s, of usher.), 7,44 (2H, d, J=8 Hz), 7,86 (2H, d, J=8 Hz), of 7.96 (1H, s, of usher.), 8,21 (1H, m), at 8.60 (1H, m), 8,86 (1H, m).

Example 21

To a solution of ethyl-6-(3-cyanobenzoyl)-7-oxooctanoate (3,18 g) in toluene (30 ml) was added 2-ethyl-1H-pyrrol-1-amine (1,17 g) and monohydrate p-toluensulfonate acid (96 mg) at ambient temperature. The reaction mixture is boiled under reflux for 1 hour. The mixture was evaporated in vacuum. The residue was purified flash chromatography on silica gel (silica gel, 200 ml), elwira a mixture of hexane-ethyl acetate=20:1, 15:1 and 10:1, to obtain ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate (3,29 g, 83,8%) as a yellow oil.

Ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=8 Hz), 1,32 is 1.58 (7H, m)to 2.18 (2H, t, J=8 Hz), 2,35 at 2.45 (2H, m), 3,01 (2H, square, J=8 Hz), 4,10 (2H, square, J=8 Hz), 5,79 (1H, d, J=5 Hz), 6,51 (1H, d, J=5 Hz), EUR 7.57-to 7.67 (3H, m), of 7.75 (1H, m).

The following compounds were obtained according to a similar method of example 21.

Example 22

Ethyl-2,4-diisopropylphenol[1,2-b]pyridazin-3-carboxylate

NMR (300 M Hz, CDCl3 that δ): 1,32 (6H, d, J=7.5 Hz), of 1.39 (3H, t, J=7.5 Hz), of 1.46 (6H, d, J=7.5 Hz), 2.91 in was 3.05 (1H, m), 3,05-3,20 (1H, m), to 4.38 (2H, square, J=7.5 Hz), 6,64 of 6.68 (1H, m), 6,76-to 6.80 (1H, m), 7,65-to 7.68 (1H, m).

MS (ES+) m/e 275,33.

Example 23

Ethyl-4-(2-chlorophenyl)-2-isopropylindole[1,2-b]pyridazin-3-carboxylate

NMR (300 MHz, CDCl3that δ): 0,89 (3H, t, J=7.5 Hz), 1,30-1,40 (6H, m), 3,36-3,51 (1H, m)4,00 (2H, square, J=7.5 Hz), 6,10-6,18 (1H, m), 6.75 in-6,84 (1H, m), 7,28 was 7.45 (3H, m), 7,45-of 7.55 (1H, m), 7,75-7,81 (1H, m).

Example 24

Ethyl-2-isopropyl-4-(2-naphthyl)pyrrolo[1,2-b]pyridazin-3-carboxylate

NMR (300 MHz, CDCl3that δ): 0,78 (3H, t, J=7.5 Hz), to 1.38 (6H, d, J=7.5 Hz), 3,24-to 3.35 (1H, m), of 3.95 (2H, square, J=7.5 Hz), 6,36-6,40 (1H, m), 6,80-6,85 (1H, m), 7,50-rate of 7.54 (3H, m), 7,78-of 7.82 (1H, m), 7,82-of 8.00 (4H, m).

MS (ES+) m/e 359,56.

Example 25

Ethyl-5-{7-ethyl-2-methyl-4-[3-(trifluoromethyl)phenyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

NMR (CDCl3that δ): 1,22 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-to 1.59 (4H, m), and 2.14 (2H, t, J=7 Hz), 2,38 is 2.46 (2H, m)to 2.55 (3H, s), 3,01 (2H, square, J=7 Hz), 4,10 (2H, square, J=7 Hz), of 5.83 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz), 7,53-to 7.64 (3H, m), 7,71 (1H, d, J=8 Hz).

MS (ESI+): m/z 433 (M+H).

Example 26

Ethyl-5-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,38 is 1.60 (4H, m)to 2.18 (2H, t, J=7 Hz), 2,42 (3H, s), 2,38-of 2.50 (2H, m)to 2.55 (3H, s)of 3.00 (2H, square, J=7 Hz), 4.09 to (2H, square, J=7 Hz), by 5.87 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz), to 7.50 (1H, s), 8,39 (1H, s), 8,53 (1H, s).

MS (ESI+): m/z 380 (M+H).

Example 27

Ethyl-5-[7-ethyl-4-(3-methoxy-5-isoxazolyl)-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]n tanout

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,55-of 1.64 (2H, m), 1,64 and 1.80 (2H, m), of 2.33 (2H, t, J=7 Hz), 2,74-to 2.85 (2H, m), 3,03 (2H, square, J=7 Hz), 3.43 points (3H, s)4,08 (3H, s), of 4.12 (2H, square, J=7 Hz), to 4.62 (2H, s), 6,28 (1H, s)6,38 (1H, d, J=4 Hz), of 6.65 (1H, d, J=4 Hz).

MS (ESI+): m/z 416 (M+H).

Example 28

Ethyl-5-{7-ethyl-2-methyl-4-[3-(1,3-oxazol-5-yl)phenyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

NMR (CDCl3that δ): of 1.20 (3H, t, J=7 Hz), of 1.35 (3H, t, J=7 Hz), 1,40-to 1.63 (4H, m), 2,17 (2H, t, J=7 Hz), 2,44-to 2.57 (2H, m), of 2.56 (3H, s), to 3.02 (2H, square, J=7 Hz), of 4.05 (2H, square, J=7 Hz), of 5.89 (1H, d, J=4 Hz), 6,50 (1H, d, J=4 Hz), 7,33 (1H, d, J=8 Hz), 7,39 (1H, s), 7,53 (1H, t, J=8 Hz), 7,66 (1H, m), 7,74 (1H, d, J=8 Hz), to 7.93 (1H, s).

Example 29

Ethyl-5-[4-(3,4-dichlorophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), to 1.38 to 1.48 (2H, m), 1,50-of 1.65 (2H, m), of 2.20 (2H, t, J=7 Hz), 2,38-2,47 (2H, m), of 2.54 (3H, s)of 3.00 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), by 5.87 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz), 7,19 (1H, DD, J=2 Hz, 8 Hz), 7,46 (1H, d, J=2 Hz), 7,56 (1H, d, J=8 Hz).

MS (ESI+): m/z 433 (M+H).

Example 30

Ethyl-5-[4-(4-chloro-2-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,44-to 1.67 (4H, m), 2,15-of 2.26 (2H, m), 2,42-of 2.56 (2H, m), of 2.56 (3H, s), 3,01 (2H, square, J=7 Hz), 4,10 (2H, square, J=7 Hz), 5,95 (1H, d, J=3 Hz)that is 6.54 (1H, d, J=3 Hz), 7,40 (1H, DD, J=2 Hz, 4 Hz), 7,54 (1H, d, J=2 Hz), 8,67 (1H, d, J=4 Hz).

MS (ESI+): m/z 400 (M+H).

Example 31

Ethyl-5-[4-(5-chloro-2-thienyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): a 1.25 (3H, t,J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,48-of 1.74 (4H, m), 2,28 (2H, t, J=7 Hz), 2,68-2,77 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,44 (3H, s), of 4.12 (2H, square, J=7 Hz), 4,60 (2H, s), and 6.25 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 6,97 (2H, m).

MS (ESI+): m/z 435 (M+H).

Example 32

Ethyl-5-[7-ethyl-4-(6-methoxy-2-pyrazinyl)-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,52 by 1.68 (4H, m), of 2.23 (2H, t, J=7 Hz), 2,48 is 2.55 (2H, m), of 2.56 (3H, s), to 3.02 (2H, square, J=7 Hz), 3,98 (3H, s), 4.09 to (2H, square, J=7 Hz), 6,03 (1H, d, J=4 Hz), 6,55 (1H, d, J=4 Hz), 8,30 (1H, s), with 8.33 (1H, s).

MS (ESI+): m/z 397 (M+H).

Example 33

Ethyl-5-[4-(1-benzofuran-2-yl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,62 of-1.83 (4H, m), of 2.33 (2H, t, J=7 Hz), to 2.57 (3H, s), 2,69-2,78 (2H, m), 3,03 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 6.48 in (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), to 7.15 (1H, s), 7,26-7,42 (2H, m), EUR 7.57 (1H, d, J=8 Hz), to 7.68 (1H, d, J=8 Hz).

MS (ESI+): m/z 405 (M+H).

Example 34

Ethyl-5-[4-(1-benzothieno-2-yl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): to 1.21 (3H, t, J=7 Hz), of 1.35 (3H, t, J=7 Hz), 1,52 was 1.69 (4H, m), of 2.23 (2H, t, J=7 Hz), of 2.56 (3H, s), 2,61-2,70 (2H, m), to 3.02 (2H, square, J=7 Hz), 4,07 (2H, square, J=7 Hz), 6,21 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,35-the 7.43 (3H, m), 7,81-a 7.92 (2H, m).

Example 35

Ethyl-5-[7-ethyl-2-methyl-4-(1,3-oxazol-5-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,53-of 1.66 (2H, m), 1,66 of-1.83 (2H, m), of 2.34 (2H, t, J=7 Hz), of 2.56 (3H, s), 2,62-by 2.73 (2H, m), to 3.02 (2H, square, J=7 Hz), 4,13 (2H, square, J=7 Hz), 6.42 per (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), to 7.50 (1H, s), 810 (1H, C).

MS (ESI+): m/z 356 (M+H).

Example 36

Ethyl-5-(7-ethyl-2-methyl-4-phenylpyrrole[1,2-b]pyridazin-3-yl)pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-1,60 (4H, m), of 2.15 (2H, t, J=7 Hz), 2,41-2,48 (2H, m)to 2.55 (3H, s), to 3.02 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), 5,88 (1H, d, J=4 Hz), 6.48 in (1H, d, J=4 Hz), 7,31-7,34 (2H, m), 7,40-7,49 (3H, m).

MS (ESI+): m/z 365 (M+H).

Example 37

Ethyl-5-[7-ethyl-2-methyl-4-(6-chinoline)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.18 (3H, t, J=7 Hz), of 1.39 (3H, t, J=7 Hz), 1,39-of 1.55 (4H, m), and 2.14 (2H, d, J=7 Hz), 2,44 is 2.55 (2H, m), 2,58 (3H, s), 3,03 (2H, square, J=7 Hz), a 4.03 (2H, square, J=7 Hz), 5,86 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz), 7,45-7,52 (1H, m), of 7.69 (1H, DD, J=2 Hz, 8 Hz), to 7.84 (1H, d, J=2 Hz), to 8.20 (2H, d, J=8 Hz), 9,00 (1H, m).

Example 38

Ethyl-7-{4-[4-({[(benzyloxy)carbonyl]amino}sulfonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}heptanoate

NMR (CDCl3that δ): 1,12-1,23 (7H, m), 1,33-1,51 (7H, s), 2,17 (2H, t, J=7 Hz), 2,35 (2H, m), of 2.56 (3H, s), to 3.02 (2H, square, J=7 Hz), 4,11 (2H, square, J=7 Hz), to 5.17 (2H, s), 5,78 (1H, d, J=5 Hz), of 6.52 (1H, d, J=5 Hz), 7,29-7,38 (5H, m), 7,49 (2H, d, J=9 Hz), 7,87 (1H, s, of usher.), 8,11 (2H, d, J=9 Hz).

MS (ESI+): m/z 606 (M+H).

MS (ESI-): m/z 604 (M-H).

Example 39

2-{[4-(3-Chlorophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]methyl}-1,3-propandiol

NMR (CDCl3that δ): of 1.26 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,64-to 1.82 (3H, m), 2,59 (3H, s), to 3.02 (2H, square, J=7 Hz), of 3.45 (2H, m), 3,63 (2H, m), of 4.12 (2H, square, J=7 Hz), to 5.93 (1H, d), J=5 Hz), 6,53 (1H, d, J=5 Hz), 7,28 (1H, m), 7,42-7,44 (3H, m).

Example 40

Ethyl-5-{7-ethyl-2-methyl-4-[3-(methylsulphonyl)FeNi is]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

NMR (CDCl3that δ): 1,22 (3H, t, J=8 Hz), 1,33-1,57 (7H, m)to 2.18 (2H, t, J=8 Hz), 2,35 at 2.45 (2H, m), of 2.56 (3H, s), 3,01 (2H, square, J=8 Hz), of 3.12 (3H, s)4,08 (2H, square, J=8 Hz), 5,80 (1H, d, J=5 Hz), 6,51 (1H, d, J=5 Hz), of 7.64-7,74 (2H, m), of 7.96 (1H, users), of 8.04 (1H, m).

MS (ESI+): m/z 443 (M+H).

Example 41

Ethyl-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=8 Hz), 1.30 and 1,62 (7H, m), of 2.21 (2H, t, J=8 Hz), 2,35 at 2.45 (2H, m)to 2.55 (3H, s)of 3.00 (2H, square, J=8 Hz), 4,10 (2H, square, J=8 Hz), to 5.85 (1H, d, J=5 Hz), 6,53 (1H, d, J=5 Hz), 7,24 (1H, DD, J=7, 1 Hz), 7,35 (1H, users), 8,53 (1H, d, J=7 Hz).

MS (ESI+): m/z 400 (M+H).

Example 42

Ethyl-5-[7-ethyl-2-methyl-4-(3-nitrophenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): to 1.21 (3H, t, J=8 Hz), 1,34-to 1.59 (7H, m), 2,17 (2H, t, J=8 Hz), 2,37-2,47 (2H, m), to 2.57 (3H, s), 3,01 (2H, square, J=8 Hz), 4,08 (2H, square, J=8 Hz), of 5.81 (1H, d, J=5 Hz), of 6.52 (1H, d, J=5 Hz), of 7.64-7,74 (2H, m), of 8.25 (1H, users), with 8.33 (1H, m).

MS (ESI+): m/z 410 (M+H).

Example 43

Ethyl-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-carboxylate

NMR (CDCl3that δ): 0,98 (3H, t, J=8 Hz), to 2.55 (3H, s), of 4.05 (2H, square, J=8 Hz), 6.35mm (1H, m), for 6.81 (1H, m), 7,12-7,22 (2H, m), 7,41-to 7.50 (2H, m), 7,76 (1H, m).

MS (ESI+): m/z 359 (M+H).

Example 44

4-(3-Butyl-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-4-yl)benzonitrile

NMR (CDCl3that δ): 0,78 (3H, t, J=8 Hz), 1,12-1,43 (7H, m), 2,31-to 2.40 (2H, m), of 2.56 (3H, s)of 3.00 (2H, square, J=8 Hz), 5,79 (1H, d, J=5 Hz), 6,50 (1H, d, J=5 Hz), 7,47 (2H, d, J=8 Hz), to 7.77 (2H, d, J=8 Hz).

MS (ESI+): m/z 318 (M+H).

Example 45

Ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-meth is pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-of 1.65 (4H, m), of 2.21 (2H, t, J=7 Hz), 2,37-2,49 (2H, m), of 2.56 (3H, s)of 3.00 (2H, square, J=7 Hz), 4,10 (2H, square, J=7 Hz), by 5.87 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), a 7.85 (1H, m), 8,53 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS: (m/z) 444, 446 (M+H).

Example 46

Ethyl-5-{4-(2-chloro-4-pyridinyl)-7-ethyl-2-[(methylthio)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,40-to 1.63 (4H, m)to 2.18 (3H, s), measuring 2.20 (2H, t, J=7 Hz), 2,48-of 2.58 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,81 (2H, s), 4,10 (2H, square, J=7 Hz), of 5.89 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), 7,27 (1H, m), 7,38 (1H, s), 8,53 (1H, d, J=4 Hz).

MS: (m/z 446 (M+H).

Example 47

Ethyl-6-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]hexanoate

NMR (CDCl3that δ): 1,15-of 1.29 (5H, m), 1.32 to 1,61 (7H, m), of 2.20 (2H, t, J=8 Hz), 2,33 is 2.43 (2H, m), of 2.56 (3H, s), 3,01 (2H, square, J=8 Hz), 4,10 (2H, square, J=8 Hz), 5,79 (1H, d, J=5 Hz), 6,51 (1H, d, J=5 Hz), EUR 7.57-to 7.67 (3H, m), of 7.75 (1H, m).

MS (ESI+): m/z 404 (M+H).

Example 48

Ethyl-5-[4-(6-chloro-2-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,46-of 1.65 (4H, m), 2,22 (2H, t, J=7 Hz), 2,46-to 2.57 (2H, m), of 2.54 (3H, s)of 3.00 (2H, square, J=7 Hz), 4.09 to (2H, square, J=7 Hz), 5,95 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz), 7,38-7,47 (2H, m), 7,80 (1H, t, J=8 Hz).

MS (ESI+): m/z 400.

Example 49

Ethyl-5-[7-ethyl-4-(3-methoxyphenyl)-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,40-of 1.62 (4H, m), 2,17 (2H, t, J=7 Hz), 2,43-2,52 (2H, m), of 2.54 (3H, s)of 3.00 (2H, square, J=7 Hz), 3,83 (3H, s)4,08 (2H, square, J=Hz), 5,91 (1H, d, J=4 Hz), of 6.49 (1H, d, J=4 Hz), 6.87 in-6,99 (3H, m), 7,37 (1H, t, J=8 Hz).

MS (ESI+): m/z 395.

Example 50

Ethyl-5-[4-(3,5-dichlorophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,39-of 1.52 (2H, m), 1,52-of 1.64 (2H, m), 2,22 (2H, t, J=7 Hz), 2,38-2,48 (2H, m), of 2.54 (3H, s)of 3.00 (2H, square, J=7 Hz), 4,10 (2H, square, J=7 Hz), 5,88 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz), 7,25 (2H, m), 7,45 (1H, m).

MS (ESI+): m/z 433.

Example 51

Ethyl-5-[4-(5-chloro-2-thienyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,46 is 1.58 (2H, m), 1.60-to around 1.74 (2H, m), 2,28 (2H, t, J=7 Hz), 2,53 (3H, s), 2,56-of 2.66 (2H, m), 2,98 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), of 6.20 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 6,94 (1H, d, J=4 Hz), 6,98 (1H, d, J=4 Hz).

MS (ESI+): m/z 405.

Example 52

Ethyl-5-[7-ethyl-4-(3-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.39 (3H, t, J=7 Hz), 1,38 of 1.50 (2H, m), 1,50-to 1.63 (2H, m), 2,17 (2H, t, J=7 Hz), 2,39-2,48 (2H, m), of 2.54 (3H, s), 3,03 (2H, square, J=7 Hz), 4.09 to (2H, square, J=7 Hz), 5,88 (1H, d, J=4 Hz), 6,50 (1H, d, J=4 Hz), 7.03 is-7,16 (3H, m), 7,38-7,47 (1H, m).

MS (ESI+): m/z 383.

Example 53

Ethyl-5-[7-ethyl-2-methyl-4-(3-chinoline)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.18 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,40-1,60 (4H, m)of 2.16 (2H, t, J=7 Hz), 2,44-of 2.56 (2H, m), 2,59 (3H, s), 3.04 from (2H, square, J=7 Hz), a 4.03 (2H, square, J=7 Hz), of 5.89 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), a 7.62 (1H, t, J=8 Hz), 7,80 (1H, t, J=8 Hz), of 7.90 (1H, d, J=8 Hz), 8,21 (2H, m), of 8.90 (1H, d, J=2 Hz).

MS (ESI+): m/z 416

Note the p 54

Ethyl-5-[7-ethyl-2-methyl-4-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,40-of 1.64 (4H, m), 2,19 (2H, t, J=7 Hz), 2,38-2,52 (2H, m)to 2.55 (3H, s), to 3.02 (2H, square, J=7 Hz), 4.09 to (2H, square, J=7 Hz), of 5.83 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz), 7,29 (2H, m), 8,72 (2H, m).

MS (ESI+): m/z 366.

Example 55

Ethyl-5-[7-ethyl-4-(3-methoxy-5-isoxazolyl)-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,55-to 1.82 (4H, m), of 2.33 (2H, t, J=7 Hz), to 2.55 (3H, s), 2,62-of 2.72 (2H, m), 2,99 (2H, square, J=7 Hz), 4,08 (3H, s), of 4.12 (2H, square, J=7 Hz), 6,26 (1H, s)6,34 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz).

Example 56

Ethyl-5-[7-ethyl-2-methyl-4-(5-methyl-3-isoxazolyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,50-1,75 (4H, m)to 2.29 (2H, t, J=7 Hz), to 2.55 (6H, s), 2,56-to 2.65 (2H, m), 2,99 (2H, square, J=7 Hz), 4,11 (2H, square, J=7 Hz), 6,16 (1H, d, J=4 Hz), to 6.22 (1H, s), is 6.54 (1H, d, J=4 Hz).

MS (ESI+): m/z 370.

Example 57

Ethyl-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,36-to 1.63 (4H, m), of 2.20 (2H, t, J=7 Hz), 2,48-2,63 (2H, m), 3,03 (2H, square, J=7 Hz), of 3.45 (3H, s), 4.09 to (2H, square, J=7 Hz), to 4.62 (2H, s), of 5.89 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,26 (1H, m), 7,37 (1H, s), 8,53 (1H, d, J=5 Hz).

MS (ESI+): m/z 430.

Example 58

Ethyl-5-[7-ethyl-2-(methoxymethyl)-4-(3-methoxyphenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,22 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-to 1.63 (4H, m)of 2.16 (2H, t, J=7 Hz, 2,54-to 2.65 (2H, m), 3.04 from (2H, square, J=7 Hz), of 3.45 (3H, s), 3,83 (3H, s)4,08 (2H, square, J=7 Hz), to 4.62 (2H, s), 5,96 (1H, d, J=4 Hz), 6,56 (1H, d, J=4 Hz), 6.87 in-to 7.00 (3H, m), 7,38 (1H, t, J=8 Hz).

MS (ESI+): m/z 425.

Example 59

Ethyl-5-[7-ethyl-2-(methoxymethyl)-4-(6-chinoline)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,17 (3H, t, J=7 Hz), USD 1.43 (3H, t, J=7 Hz), 1,36 is 1.58 (4H, m), 2,10 (2H, m), 2,56 of 2.68 (2H, m), of 3.07 (2H, square, J=7 Hz), 3,48 (3H, s), was 4.02 (2H, square, J=7 Hz), of 4.66 (2H, s), 5,90 (1H, d, J=4 Hz), 6,56 (1H, d, J=4 Hz), 7,45 is 7.50 (1H, m), 7,72 (1H, DD, J=2 Hz, 8 Hz), 7,86 (1H, d, J=2 Hz), 8,16-8,24 (2H, m), 8,98 (1H, m).

Example 60

Ethyl-5-[7-ethyl-2-(methoxymethyl)-4-(3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,22 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,40-1,60 (4H, m), 2,17 (2H, t, J=7 Hz), 2,52-of 2.64 (2H, m), 3.04 from (2H, square, J=7 Hz), of 3.46 (3H, s), 4,10 (2H, square, J=7 Hz), 4,63 (2H, s), of 5.89 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,42 (1H, m), 7,71 (1H, m), to 8.62 (1H, m), to 8.70 (1H, m).

MS (ESI+): m/z 396.

Example 61

Ethyl-5-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40 is 1.58 (4H, m), 2,17 (2H, t, J=7 Hz), of 2.51-2,62 (2H, m), 3,03 (2H, square, J=7 Hz), of 3.45 (3H, s)4,08 (2H, square, J=7 Hz), br4.61 (2H, s), of 5.92 (1H, d, J=4 Hz), 6,56 (1H, d, J=4 Hz), 7,25 (1H, m), 7,37 (1H, s), 7,42 (2H, m).

Example 62

Ethyl-5-[7-ethyl-2-methyl-4-(3-were)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-1,60 (4H, m)of 2.16 (2H, t, J=7 Hz), 2.40 a (3H, s), 2.40 a-2,50 (2H, m), of 2.54 (3H, s), 3,03 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), 5,90 (1H, d, J=4 Hz), of 6.49 (1H, d, J=4 Hz), 7,10-7,15 2H, m), from 7.24 (1H, m), 7,33 (1H, m).

MS: (m/z 379 (M+H).

Example 65

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

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-1,60 (4H, m)to 2.18 (2H, t, J=7 Hz), 2,42 (3H, s), 2,48-2,63 (2H, m), 3,05 (2H, square, J=7 Hz), of 3.46 (3H, s)4,08 (2H, square, J=7 Hz), 4,62 (2H, s), 5,90 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), 7,51 (1H, s), to 8.41 (1H, s), 8,53 (1H, s).

MS (ESI+): m/z 410.

Example 66

Ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-of 1.65 (4H, m), of 2.21 (2H, t, J=7 Hz), 2,37-2,49 (2H, m), of 2.56 (3H, s)of 3.00 (2H, square, J=7 Hz), 4,10 (2H, square, J=7 Hz), by 5.87 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), a 7.85 (1H, m), 8,53 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (ESI+): m/z 444, 446.

Example 67

Ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-to 1.63 (4H, m), 2,19 (2H, t, J=7 Hz), 2,50-of 2.66 (2H, m), 3,03 (2H, square, J=7 Hz), of 3.46 (3H, s), 4,10 (2H, square, J=7 Hz), to 4.62 (2H, s), 5,91 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,88 (1H, m), 8,55 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (ESI+): m/z 474, 476.

Example 68

Ethyl-5-[4-(5,6-dichloro-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,36 is 1.60 (4H, m), of 2.23 (2H, t, J=7 Hz), 2,37-of 2.50 (2H, m)to 2.55 (3H, s), to 3.02 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), by 5.87 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,81 (1H, d, J=2 Hz), 8,30 (1H, d, J=2 Hz).

MS (ESI+): m/z 434.

Example 69

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,65-of 1.78 (2H, m), 2,16 was 2.25 (2H, m), 2,42 (3H, s), 2,53-to 2.65 (2H, m), 3.04 from (2H, square, J=7 Hz), of 3.46 (3H, s), of 4.12 (2H, square, J=7 Hz), of 4.67 (2H, m), 5,91 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,53 (1H, s), 8,43 (1H, s), 8,54 (1H, s).

MS (ESI+): m/z 396.

Example 70

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

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 2,35 is 2.55 (2H, m), 2,42 (3H, s), 2,84-2,96 (2H, m), 3.04 from (2H, square, J=7 Hz), of 3.46 (3H, s)4,08 (2H, square, J=7 Hz)and 4.65 (2H, s), 5,91 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,51 (1H, s), to 8.41 (1H, s), charged 8.52 (1H, s).

Example 71

Ethyl-4-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

NMR (CDCl3that δ): of 1.20 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,66-to 1.82 (2H, m), 2,16-of 2.28 (2H, m), 2,42 (3H, s), 2,44 of $ 2.53 (2H, m), 2,59 (3H, s), to 3.02 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), by 5.87 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,51 (1H, s), to 8.41 (1H, d, J=2 Hz), 8,53 (1H, d, J=2 Hz).

MS (ESI+): m/z 366.

Example 72

Ethyl-3-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 2,30 is 2.43 (2H, m), 2,42 (3H, s), 2,58 (3H, s), was 2.76-of 2.86 (2H, m), to 3.02 (2H, square, J=7 Hz), 4,10 (2H, square, J=7 Hz), by 5.87 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), of 7.48 (1H, s), 8,40 (1H, d, J=2 Hz), 8,53 (1H, d, J=2 Hz).

MS (ESI+): m/z 352.

Example 73

Ethyl-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]propanoate

NMR (CDCl3that δ): to 1.21 (3H, t, J=7 Hz), of 1.39 (2H, t, J=7 Hz), 2,35 (2H, t, J=7 Hz), 2,58 (3H, s), 2,74-and 2.83 (2H, m), 3,01 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), and 5.8 (1H, d, J=4 Hz), 6,55 (1H, d, J=4 Hz), 7,87 (1H, s), 8,53 (1H, s), 8,79 (1H, s).

MS: (m/z 416 (M+), 418 (M+-2), 85(dB).

Example 74

Ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=8 Hz), 1.32 to 1.55V (5H, m)of 2.16 (2H, t, J=8 Hz), 2,46-to 2.57 (2H, m), 3,03 (2H, square, J=8 Hz), of 3.46 (3H, s), 4.09 to (1H, square, J=8 Hz), to 4.62 (2H, s), of 5.34 (1H, d, J=5 Hz), 6,57 (1H, d, J=5 Hz), to 7.59-to 7.64 (2H, m), 7,68 (1H, users), of 7.75 (1H, m).

MS (ESI+): 420 (M+H).

Example 75

Ethyl-5-[2-[(atomic charges)methyl]-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), 1,34-of 1.55 (7H, m), 2,11-2,22 (5H, m), 2,47 (2H, m), to 3.02 (2H, square, J=7 Hz), 4.09 to (2H, square, J=7 Hz), from 5.29 (2H, s)5,94 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), 7,88 (1H, m), 8,56 (1H, m), 8,79 (1H, m).

Example 76

To a solution of ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate (1.20 g) in ethanol (12 ml) was added 1N. sodium hydroxide (4,62 ml) and stirred at ambient temperature for 2 hours. The reaction mixture was acidified using 1N. chloride hydrogen and distributed between ethyl acetate and water. The organic layer was washed with water and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified flash chromatography on silica gel (silica gel, 100 ml), elwira a mixture of hexane-ethyl acetate=3:1, 2:1 and 1:1, to obtain yellow solid (846 mg). The solid is recrystallized from a mixture of hexane-utilized the t (5-1) to obtain 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanol acid as pale yellow crystals (795 mg, 71,4%).

5-[4-(3-Cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,33-to 1.60 (7H, m), 2,42 (2H, t, J=8 Hz), 2,34-2,48 (2H, m), of 2.56 (3H, s), 3,01 (2H, square, J=8 Hz), 5,80 (1H, d, J=5 Hz), of 6.52 (1H, d, J=5 Hz), 7,56-to 7.64 (2H, m), 7,66 (1H, users), 7,76 (1H, m).

MS (ESI+): m/z 362 (M-H).

The following compounds were obtained according to a similar method of example 76.

Example 77

3-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]propanoic acid

NMR (CDCl3that δ): of 1.36 (3H, t, J=7 H), and 1.56 (2H, m), 2,03 (2H, m), and 2.79 (2H, m), 3,01 (2H, square, J=7 Hz), 6,01 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), 7,27 (1H, m), 7,40-7,53 (8H, m).

Example 78

5-{7-Ethyl-2-methyl-4-[3-(trifluoromethyl)phenyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,40-of 1.62 (4H, m), 2,22 (2H, t, J=7 Hz), 2,38 is 2.46 (2H, m), of 2.56 (3H, s), to 3.02 (2H, square, J=7 Hz), of 5.84 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz), 7,53-to 7.64 (3H, m), 7,72 (1H, d, J=8 Hz).

MS (ESI+): m/z 403 (M-H), 405 (M+H).

Example 79

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

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,45-to 1.67 (4H, m), 2,22 (2H, t, J=7 Hz), 2,42 (3H, s), 2,35-2,48 (2H, m), of 2.56 (3H, s), to 3.02 (2H, square, J=7 Hz), of 5.83 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz), 7,53 (1H, s), 8,39 (1H, s), 8,53 (1H, s).

MS (ESI+): m/z 352 (M+H).

Example 80

5-[7-Ethyl-4-(3-methoxy-5-isoxazolyl)-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): of 1.36 (3H, t, J=7 Hz), 1,58 of-1.83 (4H, m), of 2.38 (2H, t, J=7 Hz), 2,74-to 2.85 (2H, m), 3,03 (2H, square, J=7 Hz), 3,4 (3H, C)4,08 (3H, s), to 4.62 (2H, s), 6,28 (1H, s)6,41 (1H, d, J=4 Hz), to 6.67 (1H, d, J=4 Hz).

MS (ESI+): m/z 386 (M-H), 388 (M+H).

Example 81

5-{7-Ethyl-2-methyl-4-[3-(1,3-oxazol-5-yl)phenyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

NMR (CDCl3that δ): to 1.38 (3H, t, J=7 Hz), 1,45-of 1.65 (4H, m), of 2.21 (2H, t, J=7 Hz), 2,43 of $ 2.53 (2H, m), of 2.56 (3H, s), 3,03 (2H, square, J=7 Hz), of 5.89 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz), 7,32 (1H, d, J=8 Hz), 7,39 (1H, s), 7,53 (1H, t, J=8 Hz), the 7.65 (1H, s), 7,73 (1H, d, J=8 Hz), to 7.93 (1H, s).

MS (ESI+): m/z 402 (M-H), 404 (M+H).

Example 82

5-[4-(3,4-Dichlorophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,42-of 1.65 (4H, m), and 2.27 (2H, t, J=7 Hz), 2,38-2,48 (2H, m), of 2.54 (3H, s), to 3.02 (2H, square, J=7 Hz), by 5.87 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz), 7,19 (1H, DD, J=2 Hz, 8 Hz), was 7.45 (1H, d, J=2 Hz), 7,56 (1H, d, J=8 Hz).

MS (ESI+): m/z 403 (M-H), 405 (M+H).

Example 83

5-[4-(4-Chloro-2-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): of 1.36 (3H, t, J=7 Hz), 1,47-of 1.66 (4H, m), 2,24 (2H, t, J=7 Hz), 1,45-of 2.56 (2H, m)to 2.55 (3H, s)of 3.00 (2H, square, J=7 Hz), 5,94 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,39 (1H, DD, J=2 Hz, 7 Hz), 7,53 (1H, d, J=2 Hz), 8,67 (1H, d, J=7 Hz).

MS (ESI+): m/z 372 (M+H).

Example 84

5-[4-(5-Chloro-2-thienyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): of 1.36 (3H, t, J=7 Hz), 1,52-of 1.74 (4H, m), of 2.33 (2H, t, J=7 Hz), 2,69-2,78 (2H, m), 3,01 (2H, square, J=7 Hz), 3,44 (3H, s), 4,60 (2H, s), and 6.25 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 6,97 (2H, m).

MS (ESI+): m/z 405 (M-H), 407 (M+H).

Example 85

5-[7-Ethyl--(6-methoxy-2-pyrazinyl)-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,55 was 1.69 (4H, m), 2,28 (2H, m), 2,52 (2H, m), of 2.56 (3H, s), 3,03 (2H, square, J=7 Hz), of 3.97 (3H, s), 6,03 (1H, d, J=4 Hz), is 6.54 (1H, d, J=4 Hz), 8,30 (1H, s), 8,32 (1H, s).

MS (ESI+): m/z 369 (M+H).

Example 86

5-[4-(1-Benzofuran-2-yl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): of 1.39 (3H, t, J=7 Hz), 1,66 is 1.86 (4H, m), 2,34-2,47 (2H, m), 2,58 (3H, s), 2,69-to 2.85 (2H, m), 3,03 (2H, square, J=7 Hz), 6,47 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,16 (1H, s), 7,26-7,43 (2H, m), EUR 7.57 (1H, d, J=8 Hz), to 7.68 (1H, d, J=8 Hz).

Example 87

5-[4-(1-Benzothieno-2-yl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,53-of 1.73 (4H, m), is 2.30 (2H, t, J=7 Hz), of 2.56 (3H, s), 2,62-by 2.73 (2H, m), to 3.02 (2H, square, J=7 Hz), to 6.19 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,34 was 7.45 (3H, m), 7,79-to 7.93 (2H, m).

Example 88

5-[7-Ethyl-2-methyl-4-(1,3-oxazol-5-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,57 is 1.70 (2H, m), 1.70 to a 1.88 (2H, m), 2,43 (2H, t, J=7 Hz), of 2.56 (3H, s), 2,66 is 2.75 (2H, m), to 3.02 (2H, square, J=7 Hz), 6,41 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,52 (1H, s), 8,13 (1H, s).

MS (ESI+): m/z 328 (M+H).

Example 89

5-(7-Ethyl-2-methyl-4-phenylpyrrole[1,2-b]pyridazin-3-yl)pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,40-of 1.62 (4H, m), of 2.20 (2H, t, J=7 Hz), 2,43-2,52 (2H, m), of 2.54 (3H, s), 3,01 (2H, square, J=7 Hz), of 5.89 (1H, d, J=4 Hz), 6.48 in (1H, d, J=4 Hz), 7,33 (2H, m), 7,38-7,52 (3H, m).

MS (ESI+): m/z 337 (M+H).

Example 90

5-[7-Ethyl-2-methyl-4-(6-chinoline)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3/sub> that δ): of 1.39 (3H, t, J=7 Hz), 1,47-to 1.61 (4H, m), 2,14-of 2.23 (2H, m), 2,44 is 2.55 (2H, m), 2,59 (3H, s), 3,05 (2H, square, J=7 Hz), 5,86 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz), 7,49 (1H, m), 7,73 (1H, DD, J=2 Hz, 8 Hz), a 7.85 (1H, d, J=2 Hz), 8,23 (2H, m), 8,97 (1H, m).

MS (ESI+): m/z 386 (M-H), 388 (M+H).

Example 91

7-{4-[4-(Aminosulfonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}heptane acid

NMR (CDCl3that δ): 0,98 (2H, m), 1,17 is 1.48 (9H, m), and 2.27 (2H, t, J=7 Hz), a 2.36 (2H, m), of 2.56 (3H, s), to 3.02 (2H, square, J=7 Hz), is 5.06 (2H, s, of usher.), of 5.84 (1H, d, J=5 Hz), of 6.52 (1H, d, J=5 Hz), 7,52 (2H, d, J=9 Hz), of 8.04 (2H, d, J=9 Hz).

MS (ESI+): m/z 444 (M+H).

Example 92

({[4-(3-Chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-3-yl]carbonyl}amino)acetic acid

NMR (CDCl3that δ): of 1.41 (3H, t, J=7 Hz), of 3.07 (2H, square, J=7 Hz), 3,95 (2H, d, J=5 Hz), of 6.02 (1H, t, user, 5 Hz), 6,37 (1H, d, J=5 Hz), 6,50 (1H, m), of 6.75 (1H, d, J=5 Hz), 7,01 (1H, d, J=7 Hz), 7,37-was 7.45 (3H, m), 7,51 (1H, m), 7,55 (1H, m).

Example 93

5-{7-Ethyl-2-methyl-4-[3-(methylsulphonyl)phenyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

NMR (CDCl3that δ): 1,30-to 1.59 (7H, m), 2,22 (2H, t, J=8 Hz), 2,33-2,49 (2H, m), of 2.56 (3H, s), 3,01 (2H, square, J=8 Hz), of 3.12 (3H, s)5,80 (1H, d, J=5 Hz), 6,50 (1H, d, J=5 Hz), 7,63-7,74 (2H, m), 7,95 (1H, users), 8,03 (1H, userd, J=8 Hz).

MS (ESI+): m/z 415 (M+H).

Example 94

5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,32-1,64 (7H, m), 2,28 (2H, t, J=8 Hz), 2,36 is 2.46 (2H, m)to 2.55 (3H, s)of 3.00 (2H, square, J=8 Hz), to 5.85 (1H, d, J=5 Hz), of 6.52 (1H, d, J=5 Hz), 7,24 (1H, userd, J=7 Hz), was 7.36 (1H, users), 8,53 (1H, d, J=7 Hz).

MS (ESI +): m/z 372 (M+H).

Example 95

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

NMR (CDCl3that δ): of 1.36 (3H, t, J=8 Hz), 1,40-of 1.62 (4H, m), of 2.25 (2H, t, J=8 Hz), 2,35-2,47 (2H, m), of 2.56 (3H, s)of 3.00 (2H, square, J=8 Hz), 5,54 (1H, d, J=10 Hz), 5,86 (1H, d, J=5 Hz), 6,23 (1H, d, J=16 Hz), 6,51 (1H, d, J=5 Hz), to 6.88 (1H, DD, J=16, 10 Hz), 7,20 (1H, DD, J=6, 1 Hz), 7,38 (1H, users), to 8.70 (1H, d, J=6 Hz).

Example 96

5-[7-Ethyl-2-methyl-4-(3-nitrophenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=8 Hz), 1.41 to to 1.59 (4H, m), of 2.23 (2H, t, J=8 Hz), 2,37-2,47 (2H, m), to 2.57 (3H, s), to 3.02 (2H, square, J=8 Hz), of 5.81 (1H, d, J=5 Hz), 6,51 (1H, d, J=5 Hz), 7,63-7,74 (2H, m), to 8.25 (1H, users), 8,32 (1H, m).

Example 97

{[7-Ethyl-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]methoxy}acetic acid

NMR (CDCl3that δ): 1,33-of 1.45 (9 H, m), 3.04 from (2H, square, J=8 Hz), 3,43 (1H, m)to 4.01 (2H, s), of 4.45 (2H, s)6,09 (1H, d, J=5 Hz), to 6.58 (1H, d, J=5 Hz), 7,13-7,22 (2H, m), 7,40-7,49 (2H, m).

Example 98

5-[4-(5-Acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,43-to 1.63 (4H, m), of 2.23 (2H, t, J=7 Hz), 2,35-2,48 (2H, m), to 2.57 (3H, s), 2,69 (3H, s), 3,03 (2H, square, J=7 Hz), 5,80 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), compared to 8.26 (1H, m), 8,78 (1H, d, J=2 Hz), 9,23 (1H, d, J=2 Hz).

MS: (m/z 378 (M-H), 380 (M+H).

Example 99

5-{4-(2-Chloro-4-pyridinyl)-7-ethyl-2-[(methylthio)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

NMR (CDCl3that δ): of 1.36 (3H, t, J=7 Hz), 1,42-of 1.65 (4H, m)to 2.18 (3H, s), 2,28 (2H, t, J=7 Hz), 2,48-2,60 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,81 (2H, s), 89 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), 7,27 (1H, m), 7,38 (1H, s), 8,53 (1H, d, J=5 Hz).

MS: (m/z 416 (M-H), 418 (M+H).

Example 100

5-{4-(2-Chloro-4-pyridinyl)-7-ethyl-2-[(methylsulphonyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,45-of 1.65 (4H, m)to 2.29 (2H, t, J=7 Hz), 2,56-to 2.67 (2H, m), 2,98 (2H, square, J=7 Hz), 3,13 (3H, s), of 4.54 (2H, s), 5,98 (1H, d, J=4 Hz), 6,69 (1H, d, J=4 Hz), 7,27 (1H, m), 7,38 (1H, s), 8,56 (1H, d, J=5 Hz).

MS: (m/z 448 (M-H), 450 (M+H).

Example 101

5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,03-of 1.45 (4H, m)of 1.36 (3H, t, J=7 Hz), of 1.97 (2H, t, J=7 Hz), a 2.36-2,48 (2H, m), to 3.02 (2H, square, J=7 Hz), 5,96 (1H, d, J=4 Hz), only 6.64 (1H, d, J=4 Hz), 7,31 (1H, d, J=5 Hz), 7,39-7,53 (6H, m), 8,55 (1H, d, J=5 Hz).

Example 102

5-[4-(6-Chloro-2-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): of 1.36 (3H, t, J=7 Hz), 1.56 to at 1.73 (4H, m)to 2.29 (2H, t, J=7 Hz), 2,46-of 2.56 (2H, m), of 2.56 (3H, s), to 3.02 (2H, square, J=7 Hz), 5,96 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,38-of 7.48 (2H, m), 7,78 (1H, t, J=8 Hz).

MS (ESI+): m/z 372 (M+H), MS (ESI-): m/z 370.

Example 103

5-[7-Ethyl-4-(3-methoxyphenyl)-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,46-to 1.63 (4H, m), 2,22 (2H, t, J=7 Hz), 2,44 of $ 2.53 (2H, m), of 2.54 (3H, s), 3,01 (2H, square, J=7 Hz), 3,82 (3H, s), of 5.92 (1H, d, J=4 Hz), of 6.49 (1H, d, J=4 Hz), 6.87 in-7,01 (3H, m), 7,37 (1H, t, J=8 Hz).

MS (ESI+): m/z 367, MS (ESI-): m/z 365.

Example 104

5-[4-(3,5-Dichlorophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid is the

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,42-of 1.53 (2H, m), 1,53-of 1.66 (2H, m), and 2.27 (2H, t, J=7 Hz), 2,41-2,49 (2H, m), of 2.54 (3H, s), 3,01 (2H, square, J=7 Hz), 5,88 (1H, d, J=4 Hz), of 6.52 (1H, d, J=4 Hz), 7,26 (2H, m), 7,45 (1H, m).

MS (ESI+): m/z 405, MS (ESI-): m/z 403.

Example 105

5-[4-(5-Chloro-2-thienyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): of 1.36 (3H, t, J=7 Hz), 1,48-of 1.62 (2H, m), 1,62-of 1.73 (2H, m), of 2.34 (2H, t, J=7 Hz), 2,53 (3H, s), 2,58-to 2.67 (2H, m), 2,99 (2H, square, J=7 Hz), of 6.20 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 6,94 (1H, d, J=4 Hz), 6,98 (1H, d, J=4 Hz).

MS (ESI+): m/z 377, MS (ESI-): m/z 375.

Example 106

5-[7-Ethyl-4-(3-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,40-of 1.64 (4H, m), of 2.23 (2H, t, J=7 Hz), 2,41-2,49 (2H, m)to 2.55 (3H, s)of 3.00 (2H, square, J=7 Hz), 5,88 (1H, d, J=4 Hz), 6,50 (1H, d, J=4 Hz), 7.03 is-7,16 (3H, m), 7,38-7,47 (1H, m).

MS (ESI+): m/z 355, MS (ESI-): m/z 353

Example 107

5-[7-Ethyl-2-methyl-4-(3-chinoline)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): of 1.39 (3H, t, J=7 Hz), 1,47-of 1.65 (4H, m), 2,20-of 2.30 (2H, m), 2,45 of $ 2.53 (2H, m), 2,59 (3H, s), 3,05 (2H, square, J=7 Hz), by 5.87 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), a 7.62 (1H, t, J=8 Hz), 7,79 (1H, t, J=8 Hz), 7,87 (1H, d, J=8 Hz), 8,21 (2H, m), 8,88 (1H, d, J=2 Hz).

MS (ESI+): m/z 388, MS (ESI-): m/z 386.

Example 108

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

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,40-1,70 (4H, m), 2,20-of 2.30 (2H, m), 2,37 of $ 2.53 (2H, m), of 2.56 (3H, s), 3,01 (2H, square, J=7 Hz), of 5.84 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz),7,39 (2H, d, J=7 Hz), a total of 8.74 (2H, d, J=7 Hz).

Example 109

5-[7-Ethyl-4-(3-methoxy-5-isoxazolyl)-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): of 1.36 (3H, t, J=7 Hz), 1,57-of 1.84 (4H, m), is 2.41 (2H, t, J=7 Hz), to 2.55 (3H, s), 2,63-of 2.72 (2H, m), to 3.02 (2H, square, J=7 Hz), 4,08 (3H, s), 6,27 (1H, s)6,34 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz).

Example 110

5-[7-Ethyl-4-(3-methoxyphenyl)-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,06-of 1.33 (4H, m)of 1.36 (3H, t, J=7 Hz), at 1.91 (2H, t, J=7 Hz), 2,42 of $ 2.53 (2H, m), 3,01 (2H, square, J=7 Hz), 3,83 (3H, s), 6,03 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 6,93-7,02 (3H, m)that was 7.36-rate of 7.54 (6H, m).

MS (ESI+): m/z 429

Example 111

5-[7-Ethyl-2-methyl-4-(5-methyl-3-isoxazolyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): of 1.36 (3H, t, J=7 Hz), of 1.52-1.77 in (4H, m)to 2.35 (2H, t, J=7 Hz), to 2.55 (6H, s), 2,56-to 2.67 (2H, m), 3,01 (2H, square, J=7 Hz), 6,16 (1H, d, J=4 Hz), 6,23 (1H, s), is 6.54 (1H, d, J=4 Hz).

MS (ESI+): m/z 342, MS (ESI-): m/z 340.

Example 112

5-[7-Ethyl-2-phenyl-4-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,11-of 1.33 (4H, m)of 1.36 (3H, t, J=7 Hz), 1,99 (2H, t, J=7 Hz), 2,38-of 2.50 (2H, m), 3,03 (2H, square, J=7 Hz), 5,94 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,38-7,56 (7H, m), a total of 8.74 (2H, d, J=6 Hz).

Example 113

5-[7-Ethyl-2-phenyl-4-(2-pyrazinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,10-of 1.33 (4H, m)of 1.36 (3H, t, J=7 Hz), 1,95 (2H, t, J=7 Hz), 2,45-to 2.57 (2H, m), to 3.02 (2H, square, J=7 Hz), equal to 6.05 (1H, d, J=4 Hz), of 6.66 (1H, d, J=4 Hz), 7,40-of 7.55 (5H, m), 8,67 (1H, d, J=3 Hz), 8,77 (1H, s), cent to 8.85 (1H, s).

MS (ESI+: m/z 401, MS (ESI-): m/z 399.

Example 114

5-[7-Ethyl-2-phenyl-4-(3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,05-1,30 (4H, m)of 1.36 (3H, t, J=7 Hz), 1,95 (2H, t, J=7 Hz), 2,35-2,48 (2H, m), to 3.02 (2H, square, J=7 Hz), 5,94 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,40-of 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.

Example 115

5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,42-of 1.64 (4H, m), and 2.27 (2H, t, J=7 Hz), 2,48-2,62 (2H, m), 3.04 from (2H, square, J=7 Hz), of 3.45 (3H, s), to 4.62 (2H, s), 5,90 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,27 (1H, m), 7,38 (1H, s), 8,53 (1H, d, J=5 Hz).

MS (ESI+): m/z 402.

Example 116

5-[7-Ethyl-2-(methoxymethyl)-4-(3-methoxyphenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,40-of 1.62 (4H, m), 2,19 (2H, t, J=7 Hz), 2,55-of 2.66 (2H, m), 3,03 (2H, square, J=7 Hz), of 3.45 (3H, s), 3,82 (3H, s), to 4.62 (2H, s), 5,96 (1H, d, J=4 Hz), 6,56 (1H, d, J=4 Hz), 6.87 in-to 7.00 (3H, m), 7,37 (1H, t, J=8 Hz).

MS (ESI+): m/z 397, MS (ESI-): m/z 395.

Example 117

5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,20-1,50 (4H, m)to 1.38 (3H, t, J=7 Hz), of 2.15 (2H, t, J=7 Hz), 2,55 of 2.68 (2H, m), 3.04 from (2H, square, J=7 Hz), to 5.93 (1H, d, J=4 Hz), only 6.64 (1H, d, J=4 Hz), 7,13 (1H, t, J=5 Hz), 7,28 (1H, d, J=5 Hz), 7,35-7,47 (3H, m), 8,54 (1H, d, J=5 Hz).

MS (ESI+): m/z 440.

Example 118

5-[7-Ethyl-2-(methoxymethyl)-4-(6-chinoline)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

YAM is (CDCl 3that δ): of 1.39 (3H, t, J=7 Hz), 1,45-to 1.60 (4H, m)of 2.16 (2H, m), 2,55 is 2.75 (2H, m), of 3.07 (2H, square, J=7 Hz), 3,47 (3H, s), of 4.66 (2H, s), of 5.89 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), 7,45-7,53 (1H, m), 7,72 (1H, d, J=8 Hz), 7,86 (1H, s), by 8.22 (2H, m), to 8.94 (1H, m).

MS (ESI+): m/z 418, MS (ESI-): m/z 416.

Example 119

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

NMR (CDCl3that δ): to 1.38 (3H, t, J=7 Hz), 1,45-of 1.64 (4H, m), 2,22 (2H, t, J=7 Hz), 2,48 of 2.68 (2H, m), 3,06 (2H, square, J=7 Hz), of 3.46 (3H, s), 4,63 (2H, s), of 5.89 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), of 7.48 (1H, m), 7,78 (1H, m), to 8.62 (1H, m), 8,69 (1H, m).

MS (ESI+): m/z 368.

Example 120

5-[4-(3-Chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,45-to 1.63 (4H, m), of 2.23 (2H, t, J=7 Hz), 2,53-2,63 (2H, m), 3.04 from (2H, square, J=7 Hz), of 3.45 (3H, s), 4,63 (2H, s), to 5.93 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,25 (1H, m), of 7.36 (1H, s), 7,42 (2H, m).

Example 121

5-[7-Ethyl-2-methyl-4-(3-were)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,23-to 1.63 (4H, m)to 1.37 (3H, t, J=7 Hz), 2,22 (2H, t, J=7 Hz), 2.40 a (3H, s), 2.40 a-2,49 (2H, m), of 2.54 (3H, s), to 3.02 (2H, square, J=7 Hz), of 5.89 (1H, d, J=4 Hz), 6.48 in (1H, d, J=4 Hz), 7,10-7,14 (2H, m), 7.23 percent-7,27 (1H, m), 7,32-7,38 (1H, m).

MS (ESI+): m/z 351.

Example 124

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

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,44-of 1.65 (4H, m), 2,16-of 2.26 (2H, m), 2,43 (3H, s), 2,47-2,69 (2H, m), 3,03 (2H, square, J=7 Hz), of 3.45 (3H, s), 4,63 (2H, m), 5,88 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), 7,56 (1H, s), 8,42 (1H, s), 8,53 (1H, s).

MS (ESI+): m/z 382, MS (ESI-): m/z 380.

Example 125

5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,45-to 1.67 (4H, m), and 2.27 (2H, t, J=7 Hz), 2,38-2,52 (2H, m), of 2.56 (3H, s), to 3.02 (2H, square, J=7 Hz), by 5.87 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,88 (1H, m), 8,53 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (ESI+): m/z 416, 418.

Example 126

5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,45-of 1.65 (4H, m), of 2.25 (2H, t, J=7 Hz), 2,49 of 2.68 (2H, m), 3,03 (2H, square, J=7 Hz), of 3.45 (3H, s), 4,63 (2H, s), 5,91 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,89 (1H, m), 8,51 (1H, s), 8,79 (1H, m).

MS (ESI+): m/z 446, 448.

Example 127

5-[4-(5,6-Dichloro-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,43 by 1.68 (4H, m)to 2.29 (2H, t, J=7 Hz), 2,38-2,52 (2H, m), to 2.57 (3H, s), to 3.02 (2H, square, J=7 Hz), by 5.87 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,81 (1H, d, J=2 Hz), 8,31 (1H, d, J=2 Hz).

MS (ESI+): m/z 406, MS (ESI-): m/z 404.

Example 128

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

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,45 by 1.68 (4H, m), of 2.23 (2H, t, J=7 Hz), 2,38 of $ 2.53 (2H, m), of 2.56 (3H, s), to 3.02 (2H, square, J=7 Hz), 5,46 (1H, d, J=11 Hz), 5,86 (1H, d, J=4 Hz), of 5.89 (1H, d, J=17 Hz), of 6.52 (1H, d, J=4 Hz), 6,72-6,83 (1H, DD, J=11 Hz, 17 Hz), to 7.77 (1H, m), of 8.47 (1H, d, J=2 Hz), 8,68 (1H, d, J=2 Hz).

MS (ESI+): m/z 364.

Example 129

5-[7-Ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)p is Rolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,45-of 1.65 (4H, m), 2,22 (2H, t, J=7 Hz), 2,45-by 2.73 (2H, m), 3.04 from (2H, square, J=7 Hz), of 3.46 (3H, s), 4,63 (2H, m), 5,44 (1H, d, J=11 Hz), by 5.87 (1H, d, J=18 Hz), of 5.92 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), 6,72-6,83 (1H, DD, J=11 Hz and 18 Hz), 7,78 (1H, s), 8,48 (1H, s), 8,68 (1H, s).

MS (ESI+): m/z 394 (M+H), MS (ESI-): m/z 392.

Example 130

5-[4-(5-Acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.38 (3H, t, J=7 Hz), 1,44 is 1.60 (4H, m), 2,22 (2H, t, J=7 Hz), 2,50-2,63 (2H, m), 2,69 (3H, s), to 3.02 (2H, square, J=7 Hz), of 3.46 (3H, s), with 4.64 (2H, s), 5,86 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 8,29 (1H, m), 8,79 (1H, d, J=2 Hz), 9,23 (1H, d, J=2 Hz).

MS (ESI+): m/z 410, MS (ESI-): m/z 408.

Example 131

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

NMR (CDCl3that δ): to 1.38 (3H, t, J=7 Hz), 1.70 to to 1.87 (2H, m), and 2.26 (2H, t, J=7 Hz), a 2.45 (3H, s), 2,53-of 2.81 (2H, m), 3,06 (2H, square, J=7 Hz), of 3.46 (3H, s), of 4.66 (2H, m), 5,90 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), to 7.61 (1H, s), 8,43 (1H, s), 8,46 (1H, s).

MS (ESI+): m/z 368.

Example 132

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

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 2,30-2,60 (2H, m), 2,42 (3H, s), 2.77-to of 3.13 (2H, m), 3,05 (2H, square, J=7 Hz), 3,47 (3H, s), of 4.66 (2H, s), 5,91 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,58 (1H, s), 8,42 (1H, s), 8,54 (1H, s).

MS (ESI+): m/z 354.

Example 133

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

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1.70 to a 1.88 (2H, m) 2,22 of-2.32 (2H, m), of 2.45 (3H, s), 2,50-2,62 (2H, m), 2,59 (3H, s), to 3.02 (2H, square, J=7 Hz), 5,86 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,60 (1H, s), 8,42 (2H, m).

MS (ESI+): m/z 338, MS (ESI-): m/z 336.

Example 134

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

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 2,42 (3H, s), 2,40 of $ 2.53 (2H, m), 2,59 (3H, s), 2,82 (2H, t, J=7 Hz), 3,03 (2H, square, J=7 Hz), 5,86 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), EUR 7.57 (1H, s), scored 8.38 (1H with), charged 8.52 (1H, s).

MS (ESI+): m/z 324, MS (ESI-): m/z 322.

Example 135

3-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]propanoic acid

TPL: 181-182°C

NMR (CDCl3that δ): 1,38 (2H, t, J=7 Hz), 2,4 (2H, t, J=7 Hz), 2,58 (3H, s), 2,74-to 2.85 (2H, m), 3,01 (2H, square, J=7 Hz), of 5.89 (1H, d, J=4 Hz), 6,55 (1H, d, J=4 Hz), 7,87 (1H, s), 8,54 (1H, s), 8,77 (1H with).

MS: (m/z) 388 (M+), 390(M++2), 114(dB).

Example 136

5-[4-(3-Cyanophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1.30 and 1.57 in (5H, m), of 2.21 (2H, t, J=8 Hz), 2,47-to 2.57 (2H, m), 3,03 (2H, square, J=8 Hz), of 3.45 (3H, s), to 4.62 (2H, s), of 5.84 (1H, d, J=5 Hz), to 6.57 (1H, d, J=5 Hz), to 7.59-to 7.64 (2H, m), 7,68 (1H, users), of 7.75 (1H, m).

MS (ESI+): 392 (M+H).

Example 136-2

5-[4-[3-(Aminocarbonyl)phenyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,30-1,70 (5H, covered with H2O), 2,20-of 2.50 (4H, m), 2,80-of 2.93 (2H, m), 3,03 (2H, square, J=8 Hz), of 3.46 (3H, s), of 4.54 (1H, d, J=10 Hz), of 4.77 (1H, d, J=10 Hz), 5,80 (1H, d, J=5 Hz), 6,55 (1H, d, J=5 Hz), 7,43-to 7.50 (2H, m), 7,58 (1H, t, J=8 Hz), to 7.77 (1H, users), 7,88 (1H, users), ,99 (1H, userd, J=8 Hz).

MS (ESI+): 410 (M+H).

Example 137

5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,06-of 1.26 (4H, m)of 1.36 (3H, t, J=7 Hz), was 1.94 (2H, t, J=7 Hz), 2.40 a (2H, m), 2,99 (2H, square, J=7 Hz), 5,96 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), 7,40-7,52 (5H, m), to 7.93 (1H, s), 8,59 (1H, s), 8,77 (1H, s).

Example 138

5-[7-Ethyl-4-(5-ethyl-3-pyridinyl)-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,05-1,42 (10H, m), with 1.92 (2H, m), is 2.41 (2H, m)of 2.75 (2H, square, J=7 Hz), 3,01 (2H, square, J=7 Hz), to 5.93 (1H, d, J=5 Hz), 6,55 (1H, d, J=5 Hz), 7,37-rate of 7.54 (5H, m), a 7.62 (1H, m), to 8.45 (1H, m), charged 8.52 (1H, m).

Example 139

5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,25-1,48 (7H, m), 2,12 (2H, t, J=7 Hz), 2,62 (2H, m), 3,03 (2H, square, J=7 Hz), to 5.93 (1H, d, J=5 Hz), only 6.64 (1H, d, J=5 Hz), 7,14 (1H, m), 7,37 (1H, d, J=5 Hz), the 7.43 (1H, d, J=5 Hz), a 7.92 (1H, s) 8,58 (1H, m), 8,79 (1H, m).

MS (ESI+): m/z 484 (M+H).

Example 140

5-[2-[(Benzyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.34 to 1.48 (5H, m), is 2.09 (2H, m), 2,53 (2H, m), 3.04 from (2H, square, J=7 Hz), 4,07 (2H, J=7 Hz)and 4.65 (2H, s), 4.72 in (2H, s), 5,90 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,29-7,38 (5H, m), 7,86 (1H, s), 8,54 (1H, m), 8,77 (1H, m).

Example 141

5-(4-(5-Bromo-3-pyridinyl)-2-{[(4-cyanobenzyl)oxy]methyl}-7-acylpyrrole[1,2-b]pyridazin-3-yl)pentane acid

NMR (CDCl3that δ): 1,35-1,56 (7H, m)to 2.18 (2H, m), 2.57 m (2H, m), 3,03 (2H, square, J=7 Hz), 4,69 (2H, s), 4,74 (2H, s), of 5.92 (1H, is, J=5 Hz), 6,62 (1H, d, J=5 Hz), 7,47 (2H, d, J=8 Hz), to 7.64 (2H, d, J=8 Hz), 7,88 (1H, s), 8,54 (1H, m), 8,79 (1H, m).

Example 142

5-[2-[(Benzylamino)methyl]-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,20-1,49 (7H, m), 2,17 (2H, m), 2,32 (2H, m), 3.04 from (2H, square, J=7 Hz), 4,29 (4H, s)5,94 (1H, d, J=5 Hz), 6,51 (1H, s, of usher.), 6,12 (1H, d, J=5 Hz), 7,27 was 7.36 (3H, m), of 7.48 (2H, m), to 7.84 (1H, m), 8,49 (1H, m), is 8.75 (1H, m).

Example 143

5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,20-to 1.38 (5H, m), for 1.49 (4H, m), 2,24 (2H, square, J=7 Hz), 2,59 (4H, m), 3,01 (2H, square, J=7 Hz), 3,70 (4H, m), 5,88 (1H, d, J=5 Hz), 6,55 (1H, d, J=5 Hz), of 7.90 (1H, m), 8,55 81H, m), 8,78 (1H, m).

Example 144

5-{4-[5-(Aminocarbonyl)-3-pyridinyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}pentane acid from ethyl-5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,10-1,70 (4H, m)to 1.37 (3H, t, J=7 Hz), 2,24-2,77 (4H, m), 2,59 (3H, s), to 3.02 (2H, square, J=7 Hz), 5,77 (1H, d, J=4 Hz), of 6.52 (1H, d, J=4 Hz), EUR 7.57 (1H, usher.), of 7.97 (1H, usher.), 8,07 (1H, s), 8,68 (1H, s), 9,18 (1H, s).

MS (ESI+): m/z 381.

Example 145

5-[4-[5-(Aminocarbonyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,16-1,72 (4H, m)to 1.37 (3H, t, J=7 Hz), 2,25-2,50 (3H, m), 2,83-of 2.97 (1H, m), 3.04 from (2H, square, J=7 Hz), 3,47 (3H, s), 4,56 (1H, d, J=17 Hz), of 4.77 (1H, d, J=17 Hz), of 5.81 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,52 (1H, usher.), of 7.82 (1H, usher.), 8,11 (1H, m), to 8.70 (1H, d, J=2 Hz), 9,18 (1H, d, J=2 Hz).

MS (ESI +): m/z 411.

Example 146

To a solution of triethyl-4-phosphonocrotonate (2,13 g) in tetrahydrofuran (20 ml) was added dropwise bis(trimethylsilyl)amide lithium (1.1 mol/l solution in hexano, 15 ml) at 2°C in nitrogen atmosphere and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of 4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carbaldehyde (1.2 g) in tetrahydrofuran (20 ml). After stirring for 3 hours at 2°C the mixture was poured into a saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel (eluent; 3% ethyl acetate in n-hexane) to obtain the specified title compound (1.06 g) as yellow crystals.

Ethyl-(2E,4E)-5-[4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]-2,4-pentadienoic

NMR (300 MHz, CDCl3that δ): of 1.28 (3H, t, J=7 Hz), of 1.35(6H, d, J=7 Hz), 3,30 (1H, quintet, J=7 Hz), 4,19 (2H, Quartet, J=7 Hz), 5,63 (1H, d, J=16 Hz), 5,94 (1H, DD, J=16,11 Hz), 6,16 (1H, DD, J=4,4,1,5 Hz), 6,76 (1H, DD, J=4,4,2,6 Hz), 6,78 (1H, d, J=16 Hz), 7,11-of 7.23 (3H, m), 7,33-7,40 (2H, m), 7,72 (1H, DD, J=2,6,1,5 Hz).

MS (ESI+): m/z 379 (M+H).

The following compounds were obtained according to a similar method of example 146.

Example 147

Ethyl-(2E)-3-[7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]feast is dazin-3-yl]-2-propenoate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 1.40 (6H, d, J=7 Hz), to 3.38 (1H, m)to 4.16 (2H, square, J=7 Hz), to 5.57 (1H, d, J=15 Hz), and 6.25 (1H, d, J=5 Hz), 6,74 (1H, d, J=5 Hz), to 7.15 (1H, d, J=8.5 Hz), 7,29 (1H, d, J=8.5 Hz), 7,33 (1H, d, J=8.5 Hz), 7,35 (1H, d, J=8.5 Hz), 7,63 (1H, d, J=15 Hz).

MS (ESI-): m/z 385 (M-H).

Example 148

(2E)-3-[7-Chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]-2-propenenitrile

NMR (CDCl3that δ): of 1.41 (6H, d, J=7 Hz), or 3.28 (1H, m), 4,99 (1H, d, J=15 Hz), 6,24 (1H, d, J=5 Hz), 6,76 (1H, d, J=15 Hz), 7,17-7,27 (2H, m), 7,30-7,40 (3H, m).

MS (ESI-): m/z 340 (M+H).

Example 149

To a solution of ethyl-(2E,4E)-5-[4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]-2,4-pentadienoic (300 mg) in tetrahydrofuran (3 ml) and acetic acid (1 ml) was added dropwise N-chlorosuccinimide (106 mg). The mixture was stirred at ambient temperature for 24 hours. The mixture was concentrated and distributed between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel (eluent; 1% ethyl acetate in n-hexane) to obtain the specified title compound (110 mg) as oil.

Ethyl-(2E,4E)-5-[7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]-2,4-pentadienoic

NMR (300 MHz, CDCl3that δ): of 1.28 (3H, t, J=7 Hz), of 1.40 (6H, d, J=7 Hz), to 3.33 (1H, quintet, J=7 Hz), 4,19 (2H, Quartet, J=7 Hz),5,64 (1H, d, J=16 Hz), 5,94 (1H, DD, J=16,11 Hz), 6,18 (1H, d, J=4.4 Hz), of 6.71 (1H, d, J=4.4 Hz), 6,79 (1H, d, J=16 Hz), 7,13-of 7.23 (3H, m), 7,32-7,37 (2H, m).

The following compounds were obtained according to a similar method of example 149.

Example 151

Ethyl-7-chloro-4-(2-chlorophenyl)-2-isopropylindole[1,2-b]pyridazin-3-carboxylate

NMR (300 MHz, CDCl3that δ): 0,89 (3H, t, J=7.5 Hz), of 1.41 (6H, d, J=7.5 Hz), 3,41 of 3.56 (1H, m)4,00 (2H, square, J=7.5 Hz), 6,16 (1H, d, J=5 Hz), 6,76 (1H, d, J=5 Hz), 7,25-7,53 (4H, m).

MS (ES+): m/e 377,44.

Example 152

Ethyl-7-chloro-2-isopropyl-4-(2-naphthyl)pyrrolo[1,2-b]pyridazin-3-carboxylate

NMR (300 MHz, CDCl3that δ): 0,78 (3H, t, J=7.5 Hz), USD 1.43 (6H, d, J=7.5 Hz), 3,29-to 3.41 (1H, m), of 3.95 (2H, square, J=7.5 Hz), 6,40 (1H, d, J=5 Hz), 6,79 (1H, d, J=5 Hz), 7,50-of 7.60 (3H, m), 7,81-of 8.00 (4H, m).

Example 153

To a solution of ethyl-(2E,4E)-5-[7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]-2,4-pentadienoic (82 mg) in ethanol (2 ml) was added 1N. the sodium hydroxide solution (0.5 ml) and the mixture was stirred at ambient temperature for 12 hours. The resulting mixture was concentrated in vacuo, the residue was dissolved in water, acidified 1H. hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with water, saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel (eluent; 50% ethyl acetate in n-hexane) to obtain the specified title compound (14 mg) as a brown Amor the aqueous solids, which is recrystallized from aqueous ethanol.

(2E,4E)-5-[7-Chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]-2,4-pentadienoic acid

NMR (300 MHz, CDCl3that δ): 1,40 (6H, d, J=7 Hz), 1.30 and 1,90 (1H, usher.), to 3.34 (1H, quintet, J=7 Hz), 5,64 (1H, d, J=16 Hz), 5,98 (1H, DD, J=16,11 Hz), to 6.19 (1H, d, J=4.4 Hz), 6,72 (1H, d, J=4.4 Hz), at 6.84 (1H, d, J=16 Hz), 7,14-7,37 (5H, m).

MS (ESI-): m/z 383 (M-H).

Example 154

To a mixture of ethyl-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (130 mg) in toluene (5 ml) was added a 28% methanolic solution of sodium methylate (536 mg) and the mixture is boiled under reflux for 2 hours. The solution was acidified to pH 4 1H. hydrochloric acid and was extracted with chloroform. The organic layer was separated, dried over magnesium sulfate and evaporated in vacuum. To the residue in ethanol (5 ml) was added 1N. the sodium hydroxide solution (1 ml) and the mixture was heated at 60°C for 1 hour. The solution was acidified to pH 4 1H. hydrochloric acid and was extracted with chloroform. The organic layer was separated, washed with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (1:1), to obtain 5-[7-ethyl-4-(2-methoxy-4-pyridinyl)-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanol acid as a yellow powder (50.0 mg).

5-[7-Ethyl-4-(2-m is toxi-4-pyridinyl)-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): of 1.30 to 1.48 (4H, m)to 1.38 (3H, t, J=7 Hz), 2,13 (2H, t, J=7 Hz), 2,58-2,69 (2H, m), to 3.02 (2H, square, J=7 Hz), was 4.02 (3H, s), 5,96 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 6,78 (1H, s), 6.90 to (1H, d, J=5 Hz), 7,12 (1H, m), 7,34 (1H, m), 7,42 (1H, d, J=5 Hz), 8,29 (1H, d, J=5 Hz).

The following compounds were obtained according to the similar procedure of example 154.

Example 155

5-[7-Ethyl-4-(2-methoxy-4-pyridinyl)-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,31-1,64 (7H, m), of 2.25 (2H, t, J=8 Hz), 2,43 (2H, ushort, J=8 Hz), of 2.54 (3H, s)of 3.00 (2H, square, J=8 Hz), Android 4.04 (3H, s), ceiling of 5.60 (1H, users), 5,90 (1H, d, J=5 Hz), 6,51 (1H, d, J=5 Hz), for 6.81 (1H, users), 6,93 (1H, userd, J=7 Hz), 8,30 (1H, d, J=7 Hz).

MS (ESI+): m/z 368 (M+H).

Example 155-2

5-[7-Ethyl-2-methyl-4-(2-oxo-1,2-dihydro-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,29-1,67 (7H, m)to 2.29 (2H, t, J=8 Hz), 2,35-2,60 (5H, m)of 3.00 (2H, square, J=8 Hz), 5,94 (1H, d, J=5 Hz), is 6.54 (1H, d, J=5 Hz), only 6.64 (1H, userd, J=7 Hz), at 6.84 (1H, users), of 7.70 (1H, userd, J=7 Hz).

MS (ESI+): m/z 354 (M+H).

The following compounds were obtained according to the similar procedure of example 154.

Example 156

5-[7-Ethyl-4-(2-methoxy-4-pyridinyl)-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,08-of 1.30 (4H, m)of 1.36 (3H, t, J=7 Hz), 1,95 (2H, t, J=7 Hz), 2,48 of $ 2.53 (2H, m), 3,03 (2H, square, J=7 Hz), to 4.01 (3H, s), of 6.02 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), PC 6.82 (1H, s), 6,94 (1H, d, J=5 Hz), 7,42-rate of 7.54 (5H, m), 8,29 (1H, d, J=5 Hz).

MS (ESI+): m/z 430.

Example 157

5-[7-Ethyl-2-(methoxymethyl)-4-(2-methoxy-4-pyridinyl)pyrrolo[1,2-b]PI is idaten-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,40-of 1.64 (4H, m), 2,24 (2H, t, J=7 Hz), 2,53-of 2.64 (2H, m), 3,03 (2H, square, J=7 Hz), of 3.45 (3H, s)to 4.01 (3H, s), br4.61 (2H, s)5,94 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 6,77 (1H, s), 6.89 in (1H, d, J=5 Hz), of 8.28 (1H, d, J=5 Hz).

MS (ESI+): m/z 398, MS (ESI-): m/z 396.

Example 158

To a solution of ethyl-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentanoate (120 mg) in toluene (5 ml) and tetrahydrofuran (10 ml) was added thiamethoxam sodium (91,0 mg) and the mixture is boiled under reflux for 4 hours. The solution was acidified using 1N. hydrochloric acid and was extracted with chloroform. The organic layer was separated, washed with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (10:1-3:1), to obtain 5-{7-ethyl-4-[2-(methylthio)-4-pyridinyl]-2-phenylpyrrole[1,2-b]pyridazin-3-yl}pentanol acid as a yellow powder (85,0 mg).

5-{7-Ethyl-4-[2-(methylthio)-4-pyridinyl]-2-phenylpyrrole[1,2-b]pyridazin-3-yl}pentane acid

NMR (CDCl3that δ): 1,07-1,17 (2H, m), 1,17-of 1.30 (2H, m)of 1.36 (3H, t, J=7 Hz), of 1.97 (2H, t, J=7 Hz), 2,38-2,48 (2H, m), 2,61 (3H, s), to 3.02 (2H, square, J=7 Hz), 5,98 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,03 (1H, DD, J=1 Hz, 5 Hz), 7,25 (1H, m), 7,43-of 7.55 (5H, m), to 8.57 (1H, d, J=5 Hz).

MS (ESI+): m/z 446 (M+H).

Example 159

A mixture of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (3.00 g), ethyl-6-benzoylecgonine (5,07 is) and triftormetilfullerenov acid (376 mg) in toluene (60 ml) was boiled under reflux for 1 hour and 20 minutes, using the nozzle Dean-stark. The mixture was distributed between ethyl acetate (60 ml) and water (60 ml) and the organic layer was washed with a saturated solution of sodium bicarbonate (60 ml) and saturated salt solution (60 ml), dried over magnesium sulfate and evaporated to obtain a dark colorless oil. Flash chromatography on a column of silica gel with elution with acetone=1:100-7:100 gave ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentanoate as an orange oil (4,45 g, 78.6 per cent).

Ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,01-1.27mm (7H, m)of 1.36 (3H, t, J=7 Hz), to 1.86 (2H, t, J=7 Hz), 2.40 a (2H, m), to 3.02 (2H, square, J=7 Hz), was 4.02 (2H, square, J=7 Hz), 5,90 (1H, d, J=5 Hz), is 6.61 (1H, d, J=5 Hz), 7,44-7,53 (5H with), 7,60-of 7.69 (2H, m), 7,74-7,79 (2H, m).

The following compounds were obtained according to the similar procedure of example 159.

Example 160

Ethyl-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): to 1.21 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), of 1.25 to 1.48 (4H, m)2,07 (2H, t, J=7 Hz), 2.57 m) of 2.68 (2H, m), 3.04 from (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), to 5.93 (1H, d, J=4 Hz), only 6.64 (1H, d, J=4 Hz), 7,12 (1H, m), 7,28 (1H, DD, J=1 Hz, 5 Hz), 7,37 (1H, m), 7,41 (1H, s), 7,45 (1H, d, J=5 Hz), 8,55 (1H, d, J=5 Hz).

MS: (m/z 468 (M+H).

Example 161

Ethyl-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,05-1,17 (2H, m), 1,19-of 1.30 (2H, m)of 1.28 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), at 1.91 (2H, t, J=7 Hz), 2,38-2,48 (2H, m), to 3.02 (2H, square,J=7 Hz), of 4.12 (2H, square, J=7 Hz), 5,96 (1H, d, J=4 Hz), only 6.64 (1H, d, J=4 Hz), 7,31 (1H, DD, J=2 Hz, 5 Hz), 7,41-rate of 7.54 (6H, m), 8,56 (1H, d, J=5 Hz).

MS (ESI+): m/z 462 (M+H).

Example 162

Ethyl[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]acetate

NMR (CDCl3that δ): 1,08 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 3,03 (2H, square, J=7 Hz), to 3.36 (2H, s), 3,93 (2H, square, J=7 Hz), 6,09 (1H, d, J=5 Hz), of 6.66 (1H, d, J=5 Hz), 7,33 (1H, m), 7,41-to 7.50 (8H, m).

MS (ESI+): m/z 419 (M+H).

Example 163

Ethyl-4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-3-carboxylate

NMR (CDCl3that δ): of 1.06 (3H, t, J=7 Hz), of 1.41 (3H, t, J=7 Hz), is 3.08 (2H, square, J=7 Hz), 4.09 to (2H, square, J=7 Hz), 6,34 (1H, d, J=5 Hz), 6,53 (1H, m), 6,74 (1H, d, J=5 Hz), 6,97 (1H, m), 7,39-7,46 (3H, m), 752 (2H, m).

MS (ESI+): m/z 395 (M+H).

Example 164

Ethyl-4-(3-chlorophenyl)-7-ethyl-2-(2-pyridinyl)pyrrolo[1,2-b]pyridazin-3-carboxylate

NMR (CDCl3that δ): 0,94 (3H, m)of 1.41 (3H, m), is 3.08 (2H, square, J=7 Hz), 3,11 (2H, m)4,00 (2H, m), 6,36 (1H, m), 6,76 (1H, m), 7,26-of 7.55 (4H, m), to 7.84 (1H, m), 8,15 (1H, m), to 8.57 (1H, m).

MS (ESI+): m/z 406 (M+H).

Example 165

Ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-(1,3-thiazol-2-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): to 1.21 (3H, t, J=7 Hz), 1,33 of 1.50 (7H, m), and 2.14 (2H, t, J=7 Hz), 2,46 (2H, m), of 2.97 (2H, square, J=7 Hz), 3,06 (2H, square, J=7 Hz), of 4.05 (2H, square, J=7 Hz), 5,88 (1H, d, J=5 Hz), to 6.67 (1H, d, J=5 Hz), the 7.43 (1H, d, J=3 Hz), of 7.64-to 7.67 (2H, m), of 7.70 (1H, m), 7,78 (1H, m), to 7.93 (1H, d, J=3 Hz).

Example 166

Methyl-5-[4-(3-cyanophenyl)-7-ethyl-2-(1-methyl-1H-pyrrol-2-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,04 (2H, m), 1,21-of 1.41 (5H, m), 199 (2H, t, J=7 Hz), 2,46 (2H, m), to 3.02 (2H, square, J=7 Hz), of 3.60 (3H, s), 3,68 (3H, s), of 5.89 (1H, d, J=5 Hz), 6,23 (1H, m), 6.35mm (1H, m), 6,62 (1H, d, J=5 Hz), 6,76 (1H, m), 7,62-7,79 (4H, m).

Example 167

Ethyl-3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]propanoate

NMR (CDCl3that δ): 1,08 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 2,02 (2H, m), 2,80 (2H, m), to 3.02 (2H, square, J=7 Hz), with 3.89 (2H, square, J=7 Hz), 6,01 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), 7,31 (1H, m), 7,41-rate of 7.54 (8H, m).

Example 168

Ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-(1,3-oxazol-5-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,17-1,49 (10H, m), of 2.08 (2H, t, J=7 Hz), to 2.57 (2H, m), 3,03 (2H, square, J=7 Hz), 4,06 (2H, square, J=7 Hz), 5,91 (1H, d, J=5 Hz), of 6.66 (1H, d, J=5 Hz), 7,55 (1H, s), 7,62-to 7.68 (3H, m), 7,78 (1H, m), of 8.04 (1H, s).

Example 169

Ethyl-5-[7-ethyl-4-(3-methoxyphenyl)-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,05-of 1.29 (4H, m)of 1.18 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), to 1.86 (2H, t, J=7 Hz), 2,42-2,52 (2H, m), to 3.02 (2H, square, J=7 Hz), of 3.84 (3H, s), was 4.02 (2H, square, J=7 Hz), of 6.02 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 6,95-7,02 (3H, m), of 7.36-7,56 (6H, m).

Example 170

Ethyl-5-[7-ethyl-2-phenyl-4-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,04-of 1.29 (4H, m)to 1.19 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), a 1.88 (2H, t, J=7 Hz), 2,38-2,48 (2H, m), to 3.02 (2H, square, J=7 Hz), Android 4.04 (2H, square, J=7 Hz), 5,95 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), was 7.36 (2H, m), 7,42-rate of 7.54 (5H, m), 8,76 (2H, m).

Example 171

Ethyl-5-[7-ethyl-2-phenyl-4-(2-pyrazinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,10-of 1.32 (4H, m)of 1.18 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,90 (2H, t, J=7 Hz), 2,45 is 2.55 (2H, m), to 3.02 (2H, square, J=7 G is), as 4.02 (2H, square, J=7 Hz), equal to 6.05 (1H, d, J=4 Hz), of 6.66 (1H, d, J=4 Hz), 7,43-7,56 (5H, m), 8,66 (1H, m), 8,77 (1H, m), 8,86 (1H, m).

Example 172

Ethyl-5-[7-ethyl-2-phenyl-4-(3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,04-of 1.30 (4H, m)of 1.18 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), to 1.87 (2H, t, J=7 Hz), 2,38-of 2.50 (2H, m), to 3.02 (2H, square, J=7 Hz), 4,01 (2H, square, J=7 Hz), 5,96 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,42-of 7.55 (6H, m), to 7.77 (1H, m), 8,66-8,73 (2H, m).

Example 173

Ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,12-1,28 (7H, m)of 1.36 (3H, t, J=7 Hz), 1,89 (2H, t, J=7 Hz), 2,43 (2H, m), 3,01 (2H, m), was 4.02 (2H, square, J=7 Hz), 5,97 (1H, d, J=5 Hz), of 6.65 (1H, d, J=5 Hz), 7,43-of 7.55 (5H, m), 7,93 (1H, m), 8,61 (1H, m), 8,79 (1H, m).

Example 174

Ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,16-1,46 (10H, m)of 1.57 (2H, t, J=7 Hz), 2,62 (2H, m), is 2.30 (2H, m), 3,03 (2H, square, J=7 Hz), of 4.05 (2H, square, J=7 Hz), to 5.93 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), was 7.36 (1H, m), 7,44 (1H, m), to $ 7.91 (1H, m).

Example 175

To a solution of ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentanoate (1,00 g) in dimethyl sulfoxide (20 ml) was added 1N. sodium hydroxide (5,31 ml) for 1.5 hours. The reaction was suppressed by the addition of 1N. hydrochloric acid (6 ml) in a bath with ice. The mixture was distributed between ethyl acetate (50 ml) and water (50 ml). The organic layer was washed with water (50×2 ml) and saturated salt solution, dried over magnesium sulfate and evaporated. Flash chromatography on Colo is ke silica gel with elution with a mixture of ethyl acetate : hexane=1/3-1/1 gave 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentane acid as a yellow solid (668 mg).

5-[4-(3-Cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,03-1,25 (4H, m)of 1.36 (3H, t, J=7 Hz), of 1.93 (2H, t, J=7 Hz), 2,39 (2H, m), to 3.02 (2H, square, J=7 Hz), 5,91 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), 7,26-7,53 (5H, s), 7,56-of 7.69 (2H, m), 7,72-7,79 (2H, m).

MS (ESI+): m/z 424 (M+H).

The following compounds were obtained according to a similar method of example 175.

Example 176

5-[4-(3-Cyanophenyl)-7-ethyl-2-(1,3-thiazol-2-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,20-1,52 (7H, m), 2,19 (2H, m), 2,98 (2H, m), 3.04 from (2H, square, J=7 Hz), of 4.05 (2H, square, J=7 Hz), 5,38 (1H, d, J=5 Hz), to 6.67 (1H, d, J=5 Hz), the 7.43 (1H, d, J=3 Hz), 7,60-to 7.64 (2H, m), to 7.67 (1H, m), 7,76 (1H, m), 7,92 (1H, d, J=3 Hz).

MS (ESI+): m/z 431 (M+H).

Example 177

5-[4-(3-Cyanophenyl)-7-ethyl-2-(1-methyl-1H-pyrrol-2-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,12 (2H, m), 1,23-of 1.41 (5H, m), 2,04 (2H, t, J=7 Hz), 2,48 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,68 (3H, s), 5,90 (1H, d, J=5 Hz), to 6.22 (1H, m), 6.35mm (1H, m), 6,62 (1H, d, J=5 Hz), 6.75 in (1H, m), EUR 7.57-7,789 (4H, m).

MS (ESI+): m/z 427 (M+H).

Example 178

5-[4-(3-Cyanophenyl)-7-ethyl-2-(1,3-oxazol-5-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,31-1,49 (7H, m), 2,17 (2H, t, J=7 Hz), to 2.57 (2H, m), 3.04 from (2H, square, J=7 Hz), 5,42 (1H, d, J=5 Hz), to 6.67 (1H, d, J=5 Hz), 7,56 (1H, s), to 7.64 (2H, m), to 7.67 (1H, s), 7,78 (1H, m), 8,07 (1H, s).

Example 179

5-[4-(3-Cyanophenyl)-2-(3,5-dimethyl-4-isoxazolyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,04-1,30 (7H, m)of 1.97 (2H, t, J=7 Hz), 226-2,35 (5H, m)to 2.41 (3H, s)of 3.00 (2H, square, J=7 Hz), 4,06 (2H, square, J=7 Hz), 5,97 (1H, d, J=5 Hz), of 6.68 (1H, d, J=5 Hz), to 7.61-to 7.68 (2H, m), 7,73 (1H, s), 7,79 (1H, m).

Example 180

A solution of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (120 mg), 1-tert-butyl-7-ethyl-2-[(3,5-dimethyl-4-isoxazolyl)carbonyl]heptanoate (203 mg) and monohydrate toluensulfonate acid(3,76 mg) in toluene (1 ml) was boiled under reflux for 1 hour. Added additional monohydrate p-toluensulfonate acid (14,5 mg) and the mixture is boiled under reflux for 1 hour. The mixture was stirred for another 0.5 hour after addition of triftormetilfullerenov acid (3,76 mg). The mixture was distributed between ethyl acetate (20 ml) and saturated sodium bicarbonate solution (10 ml). The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1/40-2/5 gave ethyl-5-[4-(3-cyanophenyl)-2-(3,5-dimethyl-4-isoxazolyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate in the form of a yellow resin (75,7 mg, 19.1 percent).

Ethyl-5-[4-(3-cyanophenyl)-2-(3,5-dimethyl-4-isoxazolyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,04-1,30 (7H, m)of 1.97 (2H, t, J=7 Hz), 2.26 and to 2.35 (5H, m)to 2.41 (3H, s)of 3.00 (2H, square, J=7 Hz), 4,06 (2H, square, J=7 Hz), 5,97 (1H, d, J=5 Hz), of 6.68 (1H, d, J=5 Hz), to 7.61-to 7.68 (2H, m), 7,73 (1H, s), 7,79 (1H, m).

Example 181

To a solution of N-[2-(3-cyanobenzoyl)-5-ethyl-1H-shall Errol-1-yl]-2-(methylsulphonyl)ndimethylacetamide (2.70 g) in tetrahydrofuran (30 ml) was added sodium hydride (601 mg, 60% in oil) in a bath with ice. After stirring for 40 minutes, the reaction was suppressed by the addition of 1N. hydrochloric acid (15 ml). The mixture was extracted with ethyl acetate (50 ml) and the extract was washed with water (50×2 ml) and saturated salt solution (50 ml), dried over magnesium sulfate and evaporated to obtain a brown-yellow solid (3,36 g). The solid is triturated in diisopropyl ether (20 ml) to give 3-[7-ethyl-3-(methylsulphonyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4-yl]benzonitrile in the form of a yellow powder (2,31 g, 90.1%of).

3-[7-Ethyl-3-(methylsulphonyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 2,46-of 3.07 (5H, m), for 6.81 (1H, d, J=5 Hz), 6,70 (1H, d, J=5 Hz), 7,60-of 7.69 (3H, m), 7,83 (1H, d, J=9 Hz).

The following compound was obtained according to a similar method of example 181.

Example 182

Ethyl-4-(4-cyanophenyl)-7-ethyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-3-carboxylate

NMR (CDCl3that δ): 0,78 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), to 3.02 (2H, square, J=7 Hz), was 4.02 (2H, square, J=7 Hz), x 6.15 (1H, d, J=5 Hz), only 6.64 (1H, d, J=5 Hz), 7,42 (2H, d, J=9 Hz), to 7.77 (2H, d, J=9 Hz), 11,74 (1H, s, of usher.).

MS (ESI+): m/z 336 (M+H).

Example 183

To a solution of 3-[7-ethyl-3-(methylsulphonyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4-yl]benzonitrile (1,30 g) and triethylamine (578 mg) in dichloromethane (18 ml) was added triftormetilfullerenov anhydride (1,61 g) in a bath with ice for 30 minutes (3-7° (C) After stirring for 0.5 hour the reaction was suppressed by addition of water (100 ml). The mixture was distributed between ethyl acetate (200 ml)containing chloroform (200 ml), and 1N. hydrochloric acid (50 ml). The insoluble yellow solid was collected by filtration (0,542 g). The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated to obtain a dark yellow solid (1.27 g). Both solids were combined and triturated in diisopropyl ether (30 ml) to obtain 4-(3-cyanophenyl)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-2-intraformational in the form of a brownish-yellow powder (1,67 g, 92.6 per cent).

4-(3-Cyanophenyl)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-2-intraformational

NMR (CDCl3that δ): of 1.39 (3H, t, J=7 Hz), to 3.02 (2H, square, J=7 Hz), up 3.22 (3H, s)6,40 (1H, d, J=5 Hz), 6,93 (1H, d, J=5 Hz), 7,63 (3H, m), 7,82 (1H, m).

Example 184

A mixture of 4-(3-cyanophenyl)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-2-intraformational (150 mg) and pyrrolidine (45,6 mg) in tetrahydrofuran (1 ml) was boiled under reflux for 1.5 hours. The mixture was distributed between ethyl acetate (20 ml) and 1N. hydrochloric acid (10 ml). The organic extract was washed with saturated salt solution, dried over magnesium sulfate and evaporated to obtain solid dark color. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1:4-1:2 gave 3-[7-ethyl-3-(IU is ylsulphonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile in the form of a yellow oil, which crystallized upon standing (112 mg, 89.6 per cent).

3-[7-Ethyl-3-(methylsulphonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl3that δ): to 1.38 (3H, t, J=7 Hz), 1,99 (4H, m)to 3.99 (2H, square, J=7 Hz), up 3.22 (3H, s), 3,42-3,70 (4H, m), 6,28 (1H, d, J=5 Hz), of 6.68 (1H, d, J=5 Hz), EUR 7.57 (1H, t, J=9 Hz), 7,69 for 7.78 (3H, m).

MS (ESI+): m/z 395 (M+H).

The following compounds were obtained according to a similar method of example 184.

Example 185

3-[2-(Dimethylamino)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl3that δ): of 1.39 (3H, t, J=7 Hz), of 2.97 (6H, s), to 3.02 (2H, square, J=7 Hz), 3,26 (3H, s), 6,28 (1H, d, J=5 Hz), 6,69 (1H, d, J=5 Hz), EUR 7.57 (1H, t, J=9 Hz), 7,66 - 7,79 (3H, m).

MS (ESI+): m/z 369 (M+H).

Example 186

3-[7-Ethyl-2-[(2-methoxyethyl)amino]-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl3that δ): up to 1.35 (3H, t, J=7 Hz), 2,96 (2H, square, J=7 Hz), of 3.07 (3H, s), 3.43 points (3H, s), 3,61-to 3.73 (4H, m), 5,96 (1H, d, J=5 Hz), 6,51 (1H, d, J=5 Hz), 6.75 in (1H, m, usher.), 7,51 - of 7.60 (3H, m), 7,74 (1H, m).

MS (ESI+): m/z 399 (M+H).

Example 187

A mixture of ethyl-2-(4-perbenzoic)-3-oxo-4-phenylbutanoate (1.4 g), 1H-pyrrol-1-amine (350 mg) and monohydrate p-toluensulfonate acid (41 mg) in ethanol (10 ml) was boiled under reflux for 5 hours. The mixture was distributed between ethyl acetate and water. The organic layer was separated, washed with saturated salt solution, dried over magnesium sulfate and evaporated. The residue was chromatographically on silica gel, elwira mixture is Yu ethyl acetate and hexane (1:4), to obtain ethyl-2-benzyl-4-(4-forfinal)pyrrolo[1,2-b]pyridazin-3-carboxylate (828 mg) as oil.

Ethyl-2-benzyl-4-(4-forfinal)pyrrolo[1,2-b]pyridazin-3-carboxylate

NMR (CDCl3that δ): 0,70 (3H, t, J=7 Hz), 3,71 (2H, square, J=7 Hz), the 4.29 (2H, s), 6,37 (1H, DD, J=1, 4 Hz), 6,85 (1H, DD, J=2, 4 Hz), 7,10-7,30 (7H, m), 7,38-7,46 (2H, m), 7,83 (1H, DD, 1, 2 Hz).

Example 188

To a solution of ethyl-2-benzyl-4-(4-forfinal)pyrrolo[1,2-b]pyridazin-3-carboxylate (730 mg) in tetrahydrofuran (10 ml) was added N-chlorosuccinimide (260 mg) and the mixture was stirred at 20°C for 2 hours. The mixture was distributed between ethyl acetate and water. The organic layer was separated, washed with aqueous sodium thiosulfate solution, water and saturated salt solution, dried over magnesium sulfate and evaporated. The residue was purified column chromatography on silica gel, elwira mixture of toluene and ethyl acetate (10:1), to obtain ethyl-2-benzyl-7-chloro-4-(4-forfinal)pyrrolo[1,2-b]pyridazin-3-carboxylate (285 mg) as a yellow oil.

Ethyl-2-benzyl-7-chloro-4-(4-forfinal)pyrrolo[1,2-b]pyridazin-3-carboxylate

NMR (CDCl3that δ): 0,69 (3H, t, J=7 Hz), 3,70 (2H, square, J=7 Hz), 4,37 (2H, s), to 6.39 (1H, d, J=4 Hz), PC 6.82 (1H, d, J=4 Hz), 7,10-7,30 (7H, m), 7,35-7,45 (2H, m).

Example 189

A mixture of ethyl-3-(4-perbenzoic)-4-oxopentanoate (800 mg), 1H-pyrrol-1-amine (265 mg) and monohydrate p-toluensulfonate acid (31 mg) in ethanol (5 ml) was boiled under reflux for 5 hours. The mixture is dissolved, and delali between ethyl acetate and water. The organic layer was separated, washed with saturated salt solution, dried over magnesium sulfate and evaporated. The residue was chromatographically on silica gel, elwira a mixture of ethyl acetate and hexane (1:4), to obtain ethyl[4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]acetate (1,09 g) in the form of oil.

Ethyl[4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]acetate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), a 2.45 (3H, s), of 3.45 (2H, s)to 4.16 (2H, square, J=7 Hz), 6,03 (1H, DD, J=1, 4 Hz), 6,72 (1H, DD, J=2, 4 Hz), 7,17 (2H, dt, J=2, 7 Hz), 7,40 (2H, DDD, J=2, 5, 7 Hz), to 7.68 (1H, DD, J=1, 2 Hz).

Example 190

To a solution of ethyl[4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]acetate (100 mg) in tetrahydrofuran (2 ml) was added N-chlorosuccinimide (43 mg) and the mixture was stirred at 20°C for 2 hours. The mixture was distributed between ethyl acetate and water. The organic layer was separated, washed with water ethyl acetate, water and saturated salt solution, dried over magnesium sulfate and evaporated. The residue was purified column chromatography on silica gel, elwira mixture of toluene and ethyl acetate (10:1), to obtain ethyl[7-chloro-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]acetate (34 mg) as a yellow oil.

Ethyl[7-chloro-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]acetate

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), of 2.54 (3H, s), 3,47 (2H, s)to 4.16 (2H, square, J=7 Hz), equal to 6.05 (1H, d, J=4 Hz), of 6.68 (1H, d, J=4 Hz), 7,18 (2H, dt, J=2, 7 Hz), 7,38 (2H, DDD, J=2, 5, 7 Hz).

Example 191

To a solution of ethyl[7-chloro-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]acetate (300 mg) in tetrahydrofuran (4 ml) was added 1N. sodium hydroxide (1.7 ml) and then methanol (2 ml). After maturation at 20°C overnight the mixture was distributed between 1N. hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated. The residue is triturated in ether to obtain [7-chloro-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]acetic acid (250 mg) as a yellow powder.

[7-Chloro-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]acetic acid

NMR (CDCl3that δ): to 2.57 (3H, s), of 3.54 (2H, s), the 6.06 (1H, d, J=4 Hz), 6,69 (1H, d, J=4 Hz), 7,19 (2H, t, J=7 Hz), 7,38 (2H, DD, J=5, 7 Hz).

Example 192

To a solution of [7-chloro-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]acetic acid (220 mg) in tetrahydrofuran (10 ml) was added 1,1'-carbonyldiimidazole (18 mg), the mixture was stirred at 20°C for 1 hour and then was added bis(3-ethoxy-3-oxopropanoic) magnesium (109 mg). After stirring the mixture overnight at 20°C was added bis(3-ethoxy-3-oxopropanoic) magnesium (109 mg). After stirring for 3 hours the mixture was distributed between 1N. hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated. The residue was chromatographically on silica gel, elwira a mixture of ethyl acetate and hexane (1:5), to obtain the product (237 mg) is the form of oil, which is triturated in ethyl acetate and washed with isopropyl ether to obtain ethyl-4-[7-chloro-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]-3-oxobutanoate (212 mg) as a yellow powder.

Ethyl-4-[7-chloro-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]-3-oxobutanoate

TPL 116-118°C

NMR (CDCl3that δ): a 1.25 (3H, t, J=7 Hz), 2,46 (3H, s), 3,40 (2H, in), 3.75 (2H, s)to 4.16 (2H, square, J=7 Hz), 6,04 (1H, d, J=4 Hz), of 6.68 (1H, d, J=4 Hz), 7,20 (2H, t, J=7 Hz), 7,28 (2H, DD, J=5, 7 Hz).

Example 193

To a solution of ethyl-4-[7-chloro-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]-3-oxobutanoate (160 mg) in methanol (5 ml) was added borohydride sodium (23,4 mg) at 0°C and the mixture was stirred at the same temperature for 1 hour. The mixture was distributed between 1N. hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated. The residue was purified preparative thin-layer chromatography, elwira a mixture of ethyl acetate and hexane (1:3), and triturated in ethyl acetate to obtain ethyl-4-[7-chloro-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]-3-hydroxybutanoic (95 mg) as a yellow powder.

Ethyl-4-[7-chloro-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]-3-hydroxybutanoic

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), 2,18-of 2.38 (2H, m)to 2.67 (3H, s), 2,70-to 2.85 (2H, m), a 4.03 (1H, m), 4.09 to (2H, square, J=7 Hz), 5,96 (1H, d, J=4 Hz), of 6.65 (1H, d, J=4 Hz), 7,19 (2H, t, J=7 Hz), 7,30 was 7.45(2H, m).

Example 194

To a solution of ethyl-4-[7-chloro-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]-3-hydroxybutanoic (52 mg) in tetrahydrofuran (1 ml) was added 1N. sodium hydroxide (0,27 ml) and then methanol (1 ml). After maturation at 20°C overnight the mixture was distributed between 1N. hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated to obtain 4-[7-chloro-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]-3-hydroxybutanoic acid (45 mg) as a yellow oil.

4-[7-Chloro-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]-3-hydroxybutanoic acid

NMR (CDCl3that δ): 2,125-of 2.45 (2H, m)to 2.66 (3H, s), 2,70-is 2.88 (2H, m), was 4.02 (1H, m), 5,97 (1H, d, J=4 Hz), of 6.65 (1H, d, J=4 Hz), 7,20 (2H, t, J=7 Hz), 7,30 was 7.45 (2H, m).

Example 195

A mixture of ethyl-7-(4-perbenzoic)-8-exonerat (300 mg), (1-amino-5-ethyl-1H-pyrrol-2-yl)(4-forfinal)methanone (216 mg) and monohydrate p-toluensulfonate acid (35.4 mg) in ethanol (6 ml) was boiled under reflux for 5 hours. The mixture was distributed between ethyl acetate and water. The organic layer was separated, washed with saturated salt solution, dried over magnesium sulfate and evaporated. The residue was chromatographically on silica gel, elwira a mixture of ethyl acetate and hexane (1:4), to obtain ethyl-6-[7-ethyl-2,4-bis(4-forfinal)pyrrolo[1,2-b]pyridazin-3-yl]hexane the one (83 mg) and ethyl-6-[7-ethyl-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]hexanoate (40 mg) in the form of oil.

Ethyl-6-[7-ethyl-2,4-bis(4-forfinal)pyrrolo[1,2-b]pyridazin-3-yl]hexanoate

NMR (CDCl3that δ): of 0.85 to 1.00 (2H, m), 1,00-1,10 (2H, m), 1,16-of 1.30 (2H, m)to 1.21 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 2,00 (2H, t, J=7 Hz), 2.40 a (2H, t, J=7 Hz), 3,01 (2H, square, J=7 Hz), 4,06 (2H, square, J=7 Hz), 5,97 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,12-7,24 (4H, m), 7,38 (2H, DD, J=5, 9 Hz), to 7.50 (2H, DD, J=5, 9 Hz).

Ethyl-6-[7-ethyl-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]hexanoate

NMR (CDCl3that δ): 1,15-1,30 (2H, m)of 1.23 (3H, t, J=7 Hz), 1,35-1,45 (2H, m)to 1.37 (3H, t, J=7 Hz), 1,45-1,55 (2H, m)to 2.18 (2H, t, J=7 Hz), 2.40 a (2H, t, J=7 Hz), of 2.54 (3H, s), 3,01 (2H, square, J=7 Hz), 4,10 (2H, square, J=7 Hz), to 5.85 (1H, d, J=4 Hz), of 6.49 (1H, d, J=4 Hz), 7,16 (2H, t, J=9 Hz), 7,32 (2H, DD, J=5, 9 Hz).

Example 196

A mixture of (1-amino-5-ethyl-1H-pyrrol-2-yl)(4-forfinal)methanone (500 mg), ethyl 8-acetyl-9-octadecanoate (678 mg) and monohydrate p-toluensulfonate acid (82 mg) in ethanol (5 ml) was boiled under reflux for 2 hours. The mixture was distributed between ethyl acetate and 1N. hydrochloric acid. The organic layer was separated, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated. The residue was chromatographically on silica gel, elwira toluene, to obtain ethyl-6-[7-ethyl-4-(4-forfinal)-2-methylpyrrole[1,2-eb]pyridazin-3-yl]hexanoate (130 mg) in the form of oil and [5-ethyl-1-({(1E)-1-[7-ethyl-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]ethylidene}amino)-1H-pyrrole-2-yl](4-forfinal)methanone (70 mg) as yellow crystals.

[5-Ethyl-1-({(1E)--[7-ethyl-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]ethylidene}amino)-1H-pyrrol-2-yl](4-forfinal)metano

NMR (CDCl3that δ): of 1.13 (3H, t, J=7 Hz), of 1.39 (3H, t, J=7 Hz), 1,80-2,00 (2H, m), at 1.91 (3H, s), of 2.86 (3H, s), 3,06 (2H, square, J=7 Hz), 5,97 (1H, d, J=4 Hz), 6,11 (1H, d, J=4 Hz), 6,62 (2H, t, J=4 Hz), 7,11 (4H, t, J=9 Hz), of 7.48 (2H, DD, J=5, 9 Hz), 7,82 (2H, DD, J=5, 9 Hz).

Ethyl-6-[7-ethyl-4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]hexanoate

NMR (CDCl3that δ): 1,15-1,30 (2H, m)of 1.23 (3H, t, J=7 Hz), 1,35-1,45 (2H, m)to 1.37 (3H, t, J=7 Hz), 1,45-1,55 (2H, m)to 2.18 (2H, t, J=7 Hz), 2.40 a (2H, t, J=7 Hz), of 2.54 (3H, s), 3,01 (2H, square, J=7 Hz), 4,10 (2H, square, J=7 Hz), to 5.85 (1H, d, J=4 Hz), of 6.49 (1H, d, J=4 Hz), 7,16 (2H, t, J=9 Hz), 7,32 (2H, DD, J=5, 9 Hz).

Example 197

A mixture of ethyl-7-(4-cyanobenzoyl)-8-exonerat (2.2 g), 2-ethyl-1H-pyrrol-1-amine (809 mg) and monohydrate p-toluensulfonate acid (64 mg) in toluene (40 ml) was boiled under reflux for 20 minutes. The mixture was distributed between ethyl acetate and 1N. hydrochloric acid. The organic layer was separated, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated. The residue was chromatographically on silica gel, elwira a mixture of ethyl acetate and hexane (1:5), to obtain the product, which is triturated in hexane to obtain ethyl-6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]hexanoate (of 2.21 g) as yellow crystals.

Ethyl-6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]hexanoate

NMR (CDCl3that δ): 1,15-1,25 (2H, m), 1,25 (3H, t, J=7 Hz), 1,30-1,45 (2H, m)to 1.38 (3H, t, J=7 Hz), 1,45-of 1.65 (2H, m), 2,19 (2H, t, J=7 Hz), of 2.38 (2H, t, J=7 Hz), of 2.56 (3H, s, to 3.02 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 5,80 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz), of 7.48 (2H, t, J=9 Hz), 7,78 (2H, d, J=9 Hz).

Example 198

To a solution of ethyl-6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]hexanoate (1.5 g) in tetrahydrofuran (15 ml) was added 2n. potassium hydroxide (7,4 ml) and then methanol (7.4 ml). After stirring at 50°C within 2 hours and 60°C for 3 hours the mixture was distributed between 1N. hydrochloric acid and ethyl acetate. Precipitation was filtered and washed with ethyl acetate. The organic layer and wash water were combined, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated. The residue is triturated in ethyl acetate and precipitation was filtered. The filtrate was purified column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (1:1), and triturated in isopropyl ether to obtain 6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]hexanoic acid (650 mg) as yellow crystals. Two sediment were combined and recrystallized from ethyl acetate to obtain 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}hexanoic acid (550 mg, 37,6%) as yellow crystals.

6-[4-(4-Cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]hexanoic acid

NMR (CDCl3that δ): 1,15-1,30 (2H, m), 1,35-1,45 (2H, m)to 1.38 (3H, t, J=7 Hz), 1,45-to 1.60 (2H, m), and 2.26 (2H, t, J=7 Hz), of 2.38 (2H, t, J=7 Hz), of 2.56 (3H, s), to 3.02 (2H, square, J=Hz), 5,80 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz), of 7.48 (2H, t, J=9 Hz), 7,79 (2H, d, J=9 Hz).

6-{4-[4-(Aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}hexanoic acid

NMR (CDCl3that δ): 1,1-1,20 (2H, m)of 1.29 (3H, t, J=7 Hz), 1,30-1,45 (4H, m), 2,10 (2H, t, J=7 Hz), is 2.37 (2H, t, J=7 Hz), of 2.51 (3H, s), of 2.92 (2H, square, J=7 Hz), 5,73 (1H, d, J=4 Hz), 6,51 (1H, d, J=4 Hz), 7,45 (2H, t, J=9 Hz), 7,47 (1H, s), 7,80 (2H, d, J=9 Hz), of 8.09 (1H, s).

Example 199

To a solution of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (200 mg) in toluene (6 ml) was added 2,4-pentanedione (837 mg) and monohydrate p-toluensulfonate acid (32 mg) at ambient temperature. The reaction mixture is boiled under reflux for 1 hour. The residue was purified flash chromatography on silica gel (silica gel, 80 ml), elwira a mixture of hexane-ethyl acetate=10:1, with 3-(3-acetyl-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-4-yl)benzonitrile (63 mg, 24,8%) as a yellow solid.

3-(3-Acetyl-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-4-yl)benzonitrile

NMR (CDCl3that δ): of 1.39 (3H, t, J=8 Hz), 1,95 (3H, s)of 2.50 (3H, s), 3.04 from (2H, square, J=8 Hz), 6,27 (1H, d, J=5 Hz), 6,69 (1H, d, J=5 Hz), to 7.59-7,72 (2H, m), 7,76-to 7.84 (2H, m).

MS (ESI+): m/z 304 (M+H).

Example 200

To a solution of ethyl-(2E)-3-[7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]-2-propenoate (50 mg) in toluene was added dropwise 1,5M diisobutylaluminium (0,277 ml) in toluene (24 ml) in a bath of dry ice-acetone. After the addition the mixture is stirred during the course is 2 hours (-10° C). The reaction mixture was extinguished by tartrate sodium potassium and filtered through celite. The organic layer was separated, dried over magnesium sulfate and evaporated in vacuum. The residue was purified flash chromatography on silica gel (silica gel, 40 ml), elwira a mixture of hexane-ethyl acetate=10:1, 5:1 and 3:1, to obtain (2E)-3-[7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]-2-propen-1-ol as a yellow solid (30 mg).

(2E)-3-[7-Chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]-2-propen-1-ol

NMR (CDCl3that δ): to 1.38 (6H, d, J=7 Hz), and 3.31 (1H, m), 4,05-4,11 (2H, m), of 5.48 (1H, dt, J=15, 6 Hz), 6,11 (1H, d, J=5 Hz), of 6.45 (1H, d, J=15 Hz), of 6.68 (1H, d, J=5 Hz), 7,08-to 7.18 (2H, m), 7,29-7,40 (2H, m).

MS (ESI-): m/z 345 (M+H).

The following compounds were obtained according to a similar method of example 200.

Example 201

[4-(4-Forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]methanol

NMR (CDCl3that δ): 1,45 (1H, t, J=5 Hz), 2,65 (3H, s), 4,47 (2H, d, J=5 Hz), 6,13 (1H, m), 6.73 x (1H, m), 7,14-7,28 (2H, m), 7,43-7,51 (2H, m), of 7.70 (1H, m).

MS (ESI+): m/z 257 (M+H).

Example 202

[7-Ethyl-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]methanol

NMR (CDCl3that δ): 1,31-1,46 (10 H, m), 3.04 from (2H, square, J=8 Hz), of 3.46 (1H, m), of 4.49 (2H, d, J=5 Hz), equal to 6.05 (1H, d, J=5 Hz), 6,56 (1H, d, J=5 Hz), 7,12-7,22 (2H, m), 7,41-to 7.50 (2H, m).

MS (ESI+): m/z 313 (M+H).

Example 203

2-{[7-Ethyl-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]methoxy}ethanol

NMR (CDCl3that δ): 1,30-1,45 (9 H, m), 3.04 from (2H, square, J=8 Hz), at 3.35 (1H, m), of 3.46 (2H, t, J=6 Hz), of 3.69 (2H, ushort, J=8 Hz), 4,30 (2H, s), 6,07 (1H, d, J=5 Hz), 6,55 (1H, d, J=5 Hz), 7,11-7,22 (2H, m), 7,41-7,51 (2H, m).

MS (ESI+): m/z 357 (M+H).

Example 204

To a solution of (2E)-3-[7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]-2-propen-1-ol (30 mg) in N,N-dimethylformamide (1 ml) was added 60% sodium hydride in oil (3.8 mg) in a bath of ice-water in a nitrogen atmosphere. After 20 minutes, to the mixture was added methyliodide (18.5 mg) at the same temperature. After 15 minutes the reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was distributed between ethyl acetate and water. The organic layer was washed with water three times and with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified p-TLC (hexane-ethyl acetate=10:1) to obtain 7-chloro-4-(4-forfinal)-2-isopropyl-3-[(1E)-3-methoxy-1-propenyl]pyrrolo[1,2-b]pyridazine in the form of a brown oil (3.5 mg, 10.2 per cent).

7-Chloro-4-(4-forfinal)-2-isopropyl-3-[(1E)-3-methoxy-1-propenyl]pyrrolo[1,2-b]pyridazin

NMR (CDCl3that δ): to 1.38 (3H, t, J=7 Hz), and 3.31 (1H, m), 4,05-4,11 (2H, m), of 5.48 (1H, dt, J=15, 6 Hz), 6,11 (1H, d, J=5 Hz), of 6.45 (1H, d, J=15 Hz), of 6.68 (1H, d, J=5 Hz), 7,08-to 7.18 (2H, m), 7,29-7,40 (2H, m).

MS (ESI-): m/z 345 (M+H).

Example 205

To dimethylsulfoxide (0.5 ml) was added 60% sodium hydride in oil (27 mg) and heated at 60°C for 40 minutes. To the mixture was added

(3-carboxypropyl)(triphenyl)phospholipase (124 mg) at t is mperature environment and was stirred for 40 minutes. Added 7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carbaldehyde (40 mg) at ambient temperature. After 4 hours the reaction mixture was acidified using 1N. chloride hydrogen and distributed between ethyl acetate and water. The organic layer was washed with water three times and with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified p-TLC (hexane-ethyl acetate=1:1) to give (4E)-5-[7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]-4-pentenol acid as a yellow oil (21 mg, E:Z=16:1, 56,3%).

(4E)-5-[7-Chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]-4-pontenova acid

NMR (CDCl3that δ): 1,40 (6H, d, J=7 Hz), 2,20-is 2.37 (4H, m)of 3.25 (1H, m), and 5.30 (0,94H, dt, J=15, 7 Hz), 5,01 (0,06H, m)6,09 (1H, d, J=5 Hz), 6,24 (0,94H, d, J=15 Hz), 6,84 (0,06H, d, J=10 Hz), 6,67 (0,94H, d, J=5 Hz), 6,70 (0,06H, d, J=5 Hz), 7,07-7,17 (2H, m), 7,26-to 7.35 (2H, m).

MS (ESI-): m/z 385 (M-H).

Example 206

To a solution of 7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carbaldehyde (40 mg) was added 1N. sodium hydroxide (19.3 mg) and acetone (0,425 ml) at ambient temperature. After 8 hours the reaction mixture was distributed between ethyl acetate and water. The organic layer was washed with water and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified p-TLC (hexane-ethyl acetate=5:1) to give (3E)-4-[7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyrido the Jn-3-yl]-3-butene-2-it is in the form of a yellow solid (33 mg).

(3E)-4-[7-Chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]-3-butene-2-he

NMR (CDCl3that δ): 1,40 (6H, d, J=7 Hz), to 2.13 (3H, s)to 3.38 (1H, m), of 5.89 (1H, d, J=15 Hz), 6,23 (1H, d, J=5 Hz), to 6.75 (1H, d, J=5 Hz), 7,13-of 7.23 (2H, m), 7,30-7,39 (2H, m), 7,49 (1H, d, J=15 Hz).

Example 207

A solution of ethyl-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carboxylate (100 mg) in tetrahydrofuran (1 ml) was purged with gaseous nitrogen in a bath of dry ice-acetone. To the mixture was added 2,2'-azobisisobutyronitrile (0.5 mg). After 5 minutes was added 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (43,8 mg). The resulting mixture was stirred for 3 hours (from -78 to -30°C). Was added water (5 ml) and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and was evaporated to obtain a yellow resin. Flash chromatography on a column of silica gel with elution with a mixture of toluene-hexane=1:5-2:3 gave ethyl-7-bromo-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carboxylate as a yellow resin (a 90.0 mg, 72,5%).

Ethyl-7-bromo-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carboxylate

NMR (CDCl3that δ): 0,98 (3H, t, J=7 Hz), of 1.40 (6H, d, J=7 Hz), and 3.31 (1H, septet, J=7 Hz), of 4.05 (2H, square, J=7 Hz), to 6.39 (1H, d, J=5 Hz), 6.87 in (1H, d, J=5 Hz), 7,16 (2H, t, J=9 Hz), was 7.45 (2H, DD, J=4 and 9 Hz).

MS (ESI+): m/z 405 (M+H).

Example 208

A suspension of sodium hydride (74,4 mg) in dimethyl sulfoxide (1,4 ml) was stirred during the s 1 hour at 60° C. the Mixture was added to a solution of methyltriphenylphosphonium (1,11 g) in dimethyl sulfoxide (1.0 ml) at room temperature. After stirring for 0.5 hour, to the mixture was added ethyl-4-(4-forfinal)-7-formyl-2-isopropylindole[1,2-b]pyridazin-3-carboxylate (500 mg). After stirring for 15 hours, the mixture was distributed between ethyl acetate (20 ml) and water (5 ml). The organic layer was washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated to obtain an orange resin. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1:7-3:1 gave ethyl-4-(4-forfinal)-2-isopropyl-7-vinylpyrrole[1,2-b]pyridazin-3-carboxylate as a yellow resin, which is hardened when standing (361 mg, 72.6 per cent).

Ethyl-4-(4-forfinal)-2-isopropyl-7-vinylpyrrole[1,2-b]pyridazin-3-carboxylate

NMR (CDCl3that δ): 0,97 (3H, t, J=7 Hz), to 1.38 (6H, d, J=7 Hz), 3,32 (1H, septet, J=7 Hz), a 4.03 (2H, square, J=7 Hz), to 5.35 (1H, DD, J=2 and 12 Hz), 6,11 (1H, DD, J=2 and 18 Hz), 6,34 (1H, d, J=5 Hz), of 6.99 (1H, d, J=5 Hz), 7,16 (1H, t, J=9 Hz), 7,25 (1H, DD, J=12 and 18 Hz), was 7.45 (2H, d, J=4 and 9 Hz).

Example 209

To a solution of ethyl-7-{4-[4-({[(benzyloxy)carbonyl]amino}sulfonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}heptanoate (169 mg) in ethanol (2 ml) was added 10% palladium on charcoal (1.6 mg) and the mixture was stirred under hydrogen pressure (3 kg/cm2within 2 hours. The resulting mixture Phi is trevali through celite and the filtrate was concentrated to obtain a yellow resin. Preparative thin layer chromatography on silica gel with elution with a mixture of ethyl acetate : hexane=1:1 gave ethyl-7-{4-[4-(aminosulfonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}heptanoate in the form of a yellow resin (76,8 mg, 58.4 percent).

Ethyl-7-{4-[4-(aminosulfonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}heptanoate

NMR (CDCl3that δ): 1,07-1,25 (7H, m), 1.30 and 1,46 (7H, m)to 2.18 (2H, t, J=7 Hz), a 2.36 (2H, m)to 2.55 (3H, s)of 3.00 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), to 5.21 (2H, s), of 5.82 (1H, d, J=5 Hz), 6,50 (1H, d, J=5 Hz), 7,52 (2H, d, J=9 Hz), with 8.05 (2H, d, J=9 Hz).

MS (ESI+): m/z 472 (M+H).

Example 210

To a solution of ethyl-4-(4-cyanophenyl)-2-(2-ethoxy-2-oxoethyl)-7-acylpyrrole[1,2-b]pyridazin-3-carboxylate (77.9 mg) in ethanol (0.5 ml) and tetrahydrofuran (0.5 ml) was added 1N. the potassium hydroxide. The resulting solution was stirred for 2.5 hours at room temperature. After adding 1N. potassium hydroxide (0.04 ml) and the mixture was stirred for another 1 hour. The reaction was suppressed by the addition of 1N. hydrochloric acid (0,23 ml). Evaporated volatile substances and the resulting residue was distributed between ethyl acetate (10 ml) and 1N. hydrochloric acid (6 ml). The organic layer was washed with saturated salt solution, dried and evaporated to obtain [4-(4-cyanophenyl)-3-(etoxycarbonyl)-7-acylpyrrole[1,2-b]pyridazin-2-yl]acetic acid as a yellow solid (67,7 mg, 93,4%).

[4-(4-Cyanophenyl)-3-(etoxycarbonyl)-7-e is almirola[1,2-b]pyridazin-2-yl]acetic acid

NMR (CDCl3that δ): 0,84 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 3,05 (2H, square, J=7 Hz), 3,93 (2H, square, J=7 Hz), 4,18 (3H, s), 6,27 (1H, d, J=5 Hz), 6,74 (1H, d, J=5 Hz), 7,52 (2H, d, J=9 Hz), 7,76 (2H, d, J=9 Hz).

MS (ESI+): m/z 378 (M+H).

Example 211

To a solution of ethyl-2-(2-amino-2-oxoethyl)-4-(4-cyanophenyl)-7-acylpyrrole[1,2-b]pyridazin-3-carboxylate (35,0 mg) in tetrahydrofuran (1 ml) was added 60% sodium hydride (4,50 mg) in a bath with ice. The resulting mixture was stirred for 1 hour. The reaction was suppressed by the addition of 1N. HCl (4 ml). The mixture was extracted with ethyl acetate (10 ml) and the organic layer was washed with water and saturated salt solution, dried over magnesium sulfate and evaporated. Preparative thin layer chromatography on silica gel with elution by the mixture of achillobator-methanol=10:1 gave 4-(7-ethyl-1,3-dioxo-1,2,3,4-tetrahydropyrido[3,4-e]pyrrolo[1,2-b]pyridazin-10-yl)benzonitrile in the form of a yellow solid (3,86 mg, 12.6 per cent).

4-(7-Ethyl-1,3-dioxo-1,2,3,4-tetrahydropyrido[3,4-e]pyrrolo[1,2-b]pyridazin-10-yl)benzonitrile

NMR (CDCl3that δ): 1,40 (3H, t, J=7 Hz), is 3.08 (2H, square, J=7 Hz), 4,16 (3H, s)6,38 (1H, d, J=5 Hz), 6,85 (1H, d, J=5 Hz), 7,46 (2H, d, J=9 Hz), 7,78 (2H, d, J=9 Hz), 7,92 (1H, s, of usher.).

Example 212

To a methanol (1 ml) was added 60% sodium hydride (6,51 mg) at room temperature. Then to the mixture was added 4-(3-cyanophenyl)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-2-intraformational (70.0 mg). The resulting mixture was stirred for 2 cha is s at room temperature and 1 hour at 50° C. the Mixture was distributed between ethyl acetate and water. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated. Preparative thin layer chromatography on silica gel with elution with a mixture of ethyl acetate : hexane=1:1 gave 3-[7-ethyl-2-methoxy-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile in the form of a yellow solid (1,92 mg, 3.7 per cent).

3-[7-Ethyl-2-methoxy-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl3that δ): to 1.38 (3H, t, J=7 Hz), 3,01 (2H, square, J=7 Hz), 3,24 (3H, s), 4,18 (3H, s), 6,12 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), 7,53-to 7.64 (3H, m), 7,76 (1H, m).

Example 213

To a solution of ethyl-4-(3-cyanophenyl)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-2-carboxylate (92,6 mg) in tetrahydrofuran (1 ml) and ethanol (0.5 ml) was added 1N. sodium hydroxide (0,349 ml). The resulting mixture was stirred for 3 hours at room temperature. After adding 1N. sodium hydroxide (0.1 ml) the resulting mixture was stirred for another 40 minutes. After adding 1N. sodium hydroxide (0.1 ml) and the mixture was stirred for further 1.5 hours. The reaction was suppressed by the addition of 1N. hydrochloric acid (1 ml) and the mixture was distributed between ethyl acetate (20 ml) and water (10 ml). The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated to obtain a red oil. Flash chromatography on a column of silica gel when e is funding a mixture of ethyl acetate-hexane=1:1 gave 3-(6-ethyl-1,1-dioxido-3-oxo-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridin-9-yl)benzonitrile as a red foam (to 52.4 mg, 64,0%).

3-(6-Ethyl-1,1-dioxido-3-oxo-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridin-9-yl)benzonitrile

NMR (CDCl3that δ): 1,45 (3H, t, J=7 Hz), 3,21, (3H, s), 4,28 (2H, s)6,91 (1H, d, J=5 Hz), 7,26 (1H, d, J=5 Hz), of 7.75 (1H, t, J=9 Hz), to $ 7.91 (1H, d, J=9 Hz), 8,08-8,16 (2H, m).

MS (ESI+): m/z 352 (M+H).

Example 214

To a solution of 3-(6-ethyl-1,1-dioxido-3-oxo-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridin-9-yl)benzonitrile (60,0 mg) in tetrahydrofuran (0.2 ml) was added 1M solution of borane-tertrahydrofuran ring complex in tetrahydrofuran (0,487 ml) in a bath with ice. After stirring for 1 hour the reaction was suppressed by the addition of 1N. hydrochloric acid (1 ml). The mixture was distributed between ethyl acetate (20 ml) and water (10 ml) and the organic layer was washed with saturated salt solution, dried and evaporated to obtain 3-(6-ethyl-3-hydroxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridin-9-yl)benzonitrile as a yellow foam (576 mg, 99.8 per cent).

3-(6-Ethyl-3-hydroxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridin-9-yl)benzonitrile

NMR (CDCl3that δ): 1,45 (3H, t, J=7 Hz), 3,21, (3H, s), 4,28 (2H, s)6,91 (1H, d, J=5 Hz), 7,26 (1H, d, J=5 Hz), of 7.75 (1H, t, J=9 Hz), to $ 7.91 (1H, d, J=9 Hz), 8,08-8,16 (2H, m).

Example 215

To a solution of 3-(6-ethyl-3-hydroxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridin-9-yl)benzonitrile (54,0 mg) in tetrahydrofuran (1 ml) was added 60% sodium hydride (6,69 mg) in a bath with ice. After stirring for 0.5 hours we use the and methyliodide (25,9 mg) and the mixture was stirred for 3 hours and 20 minutes at room temperature. The mixture was stirred for another 6 hours after adding under the conditions (25,9 mg). The mixture was stirred for another 1 hour after addition of 60% sodium hydride (3.0 mg) and under the conditions (25,9 mg). The mixture was distributed between ethyl acetate and 1N. hydrochloric acid and the organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated to obtain a yellow oil. Preparative thin layer chromatography on silica gel with elution with a mixture of ethyl acetate : hexane=1:2 gave 3-(6-ethyl-1,1-deoxidation[1,2-b]thieno[2,3-e]pyridin-9-yl)benzonitrile (5.9 mg, 10,5%, yellow solid) and 3-(6-ethyl-3-methoxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridin-9-yl)benzonitrile (16,8 mg, and 30.0%, orange resin).

3-(6-Ethyl-1,1-deoxidation[1,2-b]thieno[2,3-e]pyridin-9-yl)benzonitrile

NMR (CDCl3that δ): 1,40 (3H, t, J=7 Hz), of 3.07 (2H, square, J=7 Hz), of 6.68 (1H, d, J=5 Hz), PC 6.82 (1H, d, J=5 Hz), 7,02 (1H, d, J=7 Hz), 7,37 (1H, d, J=7 Hz), 7,72 (1H, t, J=9 Hz), 7,87 (1H, d, J=9 Hz), 8,11-8,16 (2H, m).

3-(6-Ethyl-3-methoxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridin-9-yl)benzonitrile

NMR (CDCl3that δ): of 1.42 (3H, t, J=7 Hz), 3,12 (2H, square, J=7 Hz), to 3.67 (3H, s), of 3.73 (2H, m), 5,02 (1H, m), 6,74 (1H, d, J=5 Hz), 6,97 (1H, d, J=5 Hz), of 7.70 (1H, t, J=9 Hz), the 7.85 (1H, d, J=9 Hz), 8,04-8,13 (2H, m).

MS (ESI+): m/z 368 (M+H).

Example 216

A mixture of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (1,00 g), ethyl-3-(methylsulphonyl)-2-oxopropanoic (1,34 g) and monohydro is a p-toluensulfonate acid (79,5 mg) in toluene (20 ml) was boiled under reflux for 1 hour, using a condenser, Dean-stark. Was removed in vacuo volatile substances. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1:10-9:15 gave intermediate Imin (1,38 g, 67,7%) as an orange foam. The foam was dissolved in N-methylmorpholine (10 ml) and the solution was stirred for 1 hour at 130°C. the Mixture was distributed between ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with water (30×2 ml) and saturated salt solution, dried over magnesium sulfate and evaporated to obtain a dark orange solid. The solid is triturated in diisopropyl ether (10 ml) to give 2-(trimethylsilyl)ethyl-4-(3-cyanophenyl)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-2-carboxylate as a yellow powder (1,11 g, 67.7 percent).

2-(Trimethylsilyl)ethyl-4-(3-cyanophenyl)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-2-carboxylate

NMR (CDCl3that δ): 0,12 (9H, s), 1,22 (2H, m)of 1.39 (3H, t, J=7 Hz), to 3.09 (2H, square, J=7 Hz), 3,23 (3H, s), a 4.53 (2H, m), 6,30 (1H, d, J=5 Hz), 6.89 in (1H, d, J=5 Hz), 7,50-to 7.67 (3H, m), 7,82 (1H, m).

MS (ESI+): m/z 470 (M+H).

The following compound was obtained according to a similar method of example 216.

Example 217

Ethyl-4-(3-cyanophenyl)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-2-carboxylate

NMR (CDCl3that δ): of 1.39 (3H, t, J=7 Hz), of 1.47 (3H, t, J=7 Hz), 3,10 (2H, square, J=7 Hz), 3,21, (3H, s), 4,51 (2H, square, J=7 Hz), 6,30 (1H, d, J=5 Hz), make 6.90 (1H, d, J=5 Hz), to 7.61-to 7.67 (3H, m), 7,72 (1H, m).

P the emer 218

A solution of 2-(trimethylsilyl)ethyl-4-(3-cyanophenyl)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-2-carboxylate (1,09 mg) in triperoxonane acid (5 ml) was stirred for 1.5 hours in a bath with ice. The reaction was suppressed by addition of water (20 ml). Adding formed yellow crystals, which were collected by filtration. The crystals were washed with water (5 ml) and hexane (3 ml) to obtain 4-(3-cyanophenyl)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-2-carboxylic acid as yellow crystals (756 mg, 88,2%).

4-(3-Cyanophenyl)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-2-carboxylic acid

NMR (CDCl3that δ): 1,41 (2H, m), 3,10 (2H, square, J=7 Hz), 3,30 (3H, s), 6,36 (1H, d, J=5 Hz), 6,94 (1H, d, J=5 Hz), 7,53-to 7.67 (3H, m), 7,82 (1H, m).

MS (ESI+): m/z 370 (M+H).

Example 219

A mixture of 4-(3-cyanophenyl)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-2-carboxylic acid (40,0 mg), dimethylamine hydrochloride (12,4 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide of 25.2 mg) and 1-hydroxybenzotriazole (to 21.9 mg) in N,N-dimethylformamide (1 ml) was stirred for 3 hours at room temperature. The mixture was distributed between ethyl acetate (20 ml) and 1N. hydrochloric acid (10 ml). The organic layer was washed with water (10×3 ml), saturated sodium bicarbonate solution(10 ml) and saturated salt solution, dried over magnesium sulfate and evaporated to obtain 4-(3-cyanophenyl)-7-ethyl-N,N-dimethy the-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-2-carboxamide as a yellow solid (43,4 mg, 101%).

4-(3-Cyanophenyl)-7-ethyl-N,N-dimethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-2-carboxamide

NMR (CDCl3that δ): to 1.38 (2H, m), of 3.07 (2H, square, J=7 Hz), of 3.12 (3H, s)3,18 (3H, s), with 3.27 (3H, s), 6,27 (1H, d, J=5 Hz), 6,85 (1H, d, J=5 Hz), EUR 7.57-to 7.67 (3H, m), 7,81 (1H, m).

MS (ESI+): m/z 397 (M+H).

Example 220

A mixture of ethyl-4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-3-carboxylate (450 mg) and 85% potassium hydroxide (3,01 g) in ethanol (3 ml) and water (2 ml) was boiled under reflux for 2.5 hours. The reaction mixture was cooled in a bath with ice and was suppressed by the addition of concentrated hydrochloric acid (5 ml). The mixture was distributed between ethyl acetate (20 ml) and water (10 ml) and the organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated to obtain yellow solid (388 mg). The solid is triturated in hexane to obtain 4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-3-carboxylic acid as a yellow powder (361 mg, 86.4 per cent).

4-(3-Chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-3-carboxylic acid

NMR (CDCl3that δ): of 1.41 (3H, t, J=7 Hz), is 3.08 (2H, square, J=7 Hz), 6,37 (1H, d, J=5 Hz), 6,55 (1H, m), 6,76 (1H, d, J=5 Hz), 7,02 (1H, d, J=3 Hz), 7,40-of 7.55 (5H, m).

MS (ESI+): m/z 367 (M+H).

Example 221

To a solution of 4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-3-carboxylic acid (358 mg) and N,N-dimethylformamide (1,39 mg) in dichloromethane (3 ml) was added to oxalicacid (157 mg) at room temperature. After stirring for 30 minutes was removed in vacuum volatiles and the residue was subjected to azeotropic distillation with toluene three times to obtain 4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-3-carbonylchloride in the form of a yellow resin (396 mg, 106%).

4-(3-Chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-3-carbonylchloride

NMR (CDCl3that δ): of 1.42 (3H, t, J=7 Hz), 3,10 (2H, square, J=7 Hz), of 6.45 (1H, d, J=5 Hz), 6,59 (1H, m), PC 6.82 (1H, d, J=5 Hz), 7,06 (1H, d, J=7 Hz), 7,38-of 7.55 (4H, m), 7,63 (1H, m).

Example 222

To a solution of hydrochloride methyliminodiacetic (26.1 mg) and triethylamine (42,0 mg) in dichloromethane (0.5 ml) was added a solution of 4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-3-carbonylchloride (40,0 mg) in dichloromethane (0.5 ml) in a bath with ice. The mixture was distributed between ethyl acetate (20 ml) and 1N. hydrochloric acid (10 ml) and the organic layer was washed with saturated salt solution (10 ml), dried over magnesium sulfate and evaporated to obtain methyl({[4-(3-chlorophenyl)-7-ethyl-2-(3-furyl)pyrrolo[1,2-b]pyridazin-3-yl]carbonyl}amino)acetate as a yellow resin (50,6 mg, 111%).

Methyl({[4-(3-chlorophenyl)-7-ethyl-2-(3-furyl)pyrrolo[1,2-b]pyridazin-3-yl]carbonyl}amino)acetate

NMR (CDCl3that δ): of 1.41 (3H, t, J=7 Hz), 3,10 (2H, square, J=7 Hz), of 3.69 (3H, s), 3,95 (2H, d, J=5 Hz), 6,01 (1H, t, user., 5 Hz), 6.35mm (1H, d, J=5 Hz), 6,51 (1H, m), of 6.75 (1H, d, J=5 Hz), 7,01 (1H, d, J=7 Hz), 7,37-of 7.48 (3H, m), 7,53 (1H, m), 7,58 (1H, m).

MS (ESI+): m/z 438 (M+H).

Next connect the tion was obtained by the similar procedure of example 222.

Example 223

4-(3-Chlorophenyl)-7-ethyl-2-(2-furyl)-N,N-bis(2-hydroxyethyl)pyrrolo[1,2-b]pyridazin-3-carboxamide

NMR (CDCl3that δ): of 1.42 (3H, t, J=7 Hz), 2,35-of 2.72 (4H, m), is 3.08 (2H, d, J=5 Hz), 3,20-3,63 (4H, m), 3,82 (2H, m), 6,40 (1H, t, user., 5 Hz), is 6.54 (1H, m), of 6.75 (1H, d, J=5 Hz),? 7.04 baby mortality (1H, d, J=3 Hz), 7,40-of 7.48 (2H, m), 7,53-of 7.60 (2H, m), 7,71 (1H, m).

MS (ESI+): m/z 454 (M+H).

Example 224

To a solution of 3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]propanoic acid (100 mg) in dioxane (0.5 ml) was added triethylamine (25,2 mg) and then a solution of pivaloate (30.1 mg) in dioxane (0.5 ml). Formed a white precipitate. After stirring for 40 minutes at room temperature, the precipitate was removed by filtration and washed with dioxane (2 ml). To the United proryvnym water solution was added 2-aminoethanesulfonic acid (38,6 mg) in 1H. the sodium hydroxide (0,247 ml). The resulting mixture was stirred for 1 hour at room temperature. The mixture was distributed between ethyl acetate (15 ml) and water (5 ml). The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated. Preparative thin layer chromatography on silica gel with elution with a mixture of chloroform-methanol=5:1 gave 2-({3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]propanol}amino)econsultancy acid as a yellow solid (104 mg, 82,0%).

2-({3-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]peridas the n-3-yl]propanol}amino)econsultancy acid

NMR (CDCl3that δ): 1,27 (5H, m), 2,59 (4H, m), 2,90-3,14 (4H, m), 5,96 (1H, m), the 6.06 (1H, m), 7,06-7,40 (9H, m).

Example 225

A solution of 3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]propanoic acid (100 mg), (2R,3R,4S,5S,6R)-2-amino-3,5-bis[(2,2-dimethylpropanoyl)oxy]-6-{[(2,2-dimethylpropanoyl)oxy]methyl}tetrahydro-2H-Piran-4-revelate (255 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0,494 mmol) and 1-hydroxybenzotriazole (66,7 mg) in N,N-dimethylformamide (1 ml) was stirred for 1 hour at room temperature. The mixture was distributed between ethyl acetate (20 ml) and 1N. hydrochloric acid (10 ml). The organic layer was washed with water (10×3 ml), saturated sodium bicarbonate solution (10 ml) and saturated salt solution, dried over magnesium sulfate and evaporated to obtain a yellow foam (339 mg). Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1:10-2:5 gave (2R,3R,4S,5S,6R)-2-({3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]propanol}amino)for 3,5-bis[(2,2-dimethylpropanoyl)oxy]-6-{[(2,2-dimethylpropanoyl)oxy]methyl}tetrahydro-2H-Piran-4-revelat as a yellow foam (240 mg, 108%).

(2R,3R,4S,5S,6R)-2-({3-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]propanol}amino)for 3,5-bis[(2,2-dimethylpropanoyl)oxy]-6-{[(2,2-dimethylpropanoyl)oxy]methyl}tetrahydro-2H-Piran-4-revelat

NMR (CDCl3that δ): 0,97-1,26 (36H, m)of 1.35 (3H, t, J=7 Hz)and 1.83 (2H, m), of 2.81 (2H, m), 01 (2H, square, J=7 Hz), a 3.87-4,16 (3H, m), 4,90 at 5.27 (3H, m), are 5.36-the 5.51 (2H, m), 6,01 (1H, d, J=5 Hz), of 6.52 (1H, d, J=5 Hz), 7,29 (1H, m), 7,40-to 7.59 (8H, m).

Example 226

To a solution of ethyl[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]acetate (114 mg) in tetrahydrofuran (2 ml) was added 1M diisobutylaluminium in toluene (0,816 ml) in a bath with ice. After stirring for 1 hour at room temperature was added 1M diisobutylaluminium (0,41 ml). After 1 hour the reaction was suppressed by the addition of 1N. hydrochloric acid (1 ml). The mixture was distributed between ethyl acetate (20 ml) and 1N. hydrochloric acid (10 ml) and filtered through celite. The organic layer was washed with water (10 ml) and saturated salt solution, dried over magnesium sulfate and evaporated to obtain a yellow resin. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1:20-2:50 gave 2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]ethanol as a yellow oil, which crystallized upon standing (107 mg, 104%).

2-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]ethanol

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 2,77 (2H, t, J=7 Hz), 3,01 (2H, square, J=7 Hz), 3,26 (2H, m), 3,26 (2H, m)6,00 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), 7,34 (1H, m), 7,41-of 7.55 (8H, m).

Example 227

To a mixture of 2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]ethanol (105 mg), 2,3,4,6-Tetra-O-acetyl-beta-D-galactosylceramide (299 mg), silver carbonate 154 mg) in toluene (2 ml) was added triflate silver (to 3.58 mg) in a bath with ice. After 40 minutes was added 2,3,4,6-Tetra-O-acetyl-beta-D-galactosidase (114 mg), silver carbonate (229 mg) and the mixture was stirred for 50 minutes. The mixture was stirred for another 50 minutes after the addition of 2,3,4,6-Tetra-O-acetyl-beta-D-galactosylceramide (114 mg) and silver carbonate (154 mg). The mixture was filtered through celite and the filtrate was distributed between ethyl acetate and water. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated to obtain a yellow resin. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1:10-7:10 gave (2R,3R,4S,5S,6R)-4,5-bis(atomic charges)-6-[(atomic charges)methyl]-2-{2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]ethoxy}tetrahydro-2H-Piran-3-ylacetic in the form of a yellow resin (115 mg, 58.4%of).

(2R,3R,4S,5S,6R)-4,5-bis(atomic charges)-6-[(atomic charges)methyl]-2-{2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]ethoxy}tetrahydro-2H-Piran-3-ylacetic

NMR (CDCl3that δ): up to 1.35 (3H, t, J=7 Hz), to 1.70 (3H, m), of 1.94 (3H, s)2,04 (3H, s), 2,11 (3H, s), 2,78 (2H, m), 3,01 (2H, square, J=7 Hz), 3,10 (1H, m), of 3.46 (1H, m), 3,62 (1H, t, J=6 Hz), with 3.79 (1H, d, J=8 Hz), 3,98 (2H, m), a 4.83 (1H, DD, J=3 and 10 Hz), equal to 4.97 (1H, DD, J=8 and 10 Hz), 5,28 (1H, d, J=3 Hz), of 6.02 (1H, d, J=5 Hz), only 6.64 (1H, d, J=5 Hz), 7,31 (1H, m), 7,41-7,56 (8H, m).

Example 228

To a solution of (2R,3R,4S,5S,6R)-4,5-bis(atomic charges)-6-[(atomic charges)methyl]-2-{2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]ethoxy}tetrahydro-2H-Piran-3-ilaclama (113 mg) in methanol ( ml) was added sodium methoxide (0,86 mg) at room temperature. After stirring for 2 hours, the solvent evaporated and the mixture was distributed between ethyl acetate (20 ml) and water (10 ml). The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated to obtain a yellow foam (77,3 mg). Foam triturated in hexane to obtain (2R,3R,4S,5R,6R)-2-{2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]ethoxy}-6-(hydroxymethyl)tetrahydro-2H-Piran-3,4,5-triol as a yellow powder (to 48.3 mg, 89,7%).

(2R,3R,4S,5R,6R)-2-{2-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]ethoxy}-6-(hydroxymethyl)tetrahydro-2H-Piran-3,4,5-triol

NMR (CDCl3that δ): of 1.36 (3H, t, J=7 Hz), with 1.92 (1H, m)to 2.06 (1H, m), of 2.56 (1H, s, of usher.), was 2.76 of 2.92 (3H, m), to 3.02 (2H, square, J=7 Hz), 3,24 (2H, m), 3,38-3,50 (3H, m), 3,63-a-3.84 (3H, m), 2,41 (1H, s, of usher.), 6,01 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), 7,32 (1H, m), 7,41-EUR 7.57 (8H, m).

The following compounds were obtained according to a similar method of example 228.

Example 229

3-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]-N-[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-Piran-2-yl]propanamide

NMR (CDCl3that δ): to 1.38 (3H, t, J=7 Hz), of 1.97 (2H, m), and 2.83 (2H, m), 3,01 (2H, square, J=7 Hz), 3,31-to 3.52 (3H, m), 3,61 is 3.76 (2H, m), 3,88 (1H, m), 4,63 (1H, d, J=9 Hz), 6,01 (1H, d, J=5 Hz), only 6.64 (1H, d, J=5 Hz), 7,34 (1H, m), 7,42-to 7.59 (8H, m).

Example 230

Ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate of ethyl-5-[2-[(atomic charges)methyl]-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin the-3-yl]pentanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), 1,34 of 1.50 (5H, m), and 1.54 (2H, m), 2,19 (2H, t, J=7 Hz), is 2.37 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,71 (1H, t, J=5 Hz), 4,10 (2H, square, J=7 Hz), a 4.86 (2H, d, J=5 Hz), 5,97 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,88 (1H, m), 8,55 (1H, m), 8,79 (1H, m).

Example 231

To a solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanol acid (50 mg) in N,N-dimethylformamide (1 ml) was added 1,1'-carbonyldiimidazole (33.6 mg) at ambient temperature. After 1 hour of stirring to the mixture was added methanesulfonamide (19.7 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (of 31.6 mg). The mixture was heated at 50°C for 2 hours. The reaction mixture was distributed between ethyl acetate and water. The aqueous layer was acidified using 1N. chloride and hydrogen were extracted with ethyl acetate. The organic layer was washed with water 3 times and saturated salt solution, dried over magnesium sulfate and evaporated in vacuo to obtain a yellow solid. The residue was led from IPE to obtain yellow solid (45 mg). The solid is recrystallized from ethanol to obtain N-{5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoyl}methanesulfonamide (25 mg) as a yellow solid.

N-{5-[4-(3-Cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoyl}methanesulfonamide

NMR (CDCl3that δ): 1,33-1,61 (7H, m), of 2.21 (2H, t, J=8 Hz), 2.40 a (2H, t, J=8 Hz), to 2.55 (3H, s)of 3.00 (2H, square, J=8 Hz), 3,29 (3H, s)5,80 (1H, d, J=5 is C), of 6.52 (1H, d, J=5 Hz), 7,58-to 7.67 (3H, m), 7,76 (1H, m), 7,86 (1H, users).

MS (ESI+): m/z 439 (M+H).

Example 232

To a solution of ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate (45 mg) in tetrahydrofuran (1 ml) was added borohydride lithium (5 mg) in a bath of ice-water. Then the reaction mixture was stirred at ambient temperature. After 2 hours, added borohydride lithium (5 mg) and the mixture was stirred over night. The reaction mixture was distributed between ethyl acetate and water. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified p-TLC (hexane-ethyl acetate=1:1) to obtain 3-[7-ethyl-3-(6-hydroxyhexyl)-2-methylpyrrole[1,2-b]pyridazin-4-yl]benzonitrile (26 mg, 64,5%) as a yellow oil, and 6-{4-[3-(aminomethyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}-1-hexanol (13 mg, 31.9%of the) as a yellow solid.

3-[7-Ethyl-3-(6-hydroxyhexyl)-2-methylpyrrole[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl3that δ): 1,15-1,53 (11H, m), 2,32-to 2.41 (2H, m), of 2.56 (3H, s), 3,01 (2H, square, J=8 Hz), to 3.58 (2H, ushort, J=8 Hz), to 5.58 (1H, ushort, J=8 Hz), 5,79 (1H, d, J=5 Hz), 6,51 (1H, d, J=5 Hz), EUR 7.57-7,63 (2H, m), the 7.65 (1H, users), of 7.75 (1H, m).

MS (ESI+): m/z 362 (M+H).

6-{4-[3-(Aminomethyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}-1-hexanol

NMR (CDCl3that δ): 1,03-1,43 (11H, m)to 2.41 (2H, t, J=8 Hz), to 2.55 (3H, s), 3,01 (2H, square, J=8 Hz), 3,39-3,61 (2H, m), 3,88-Android 4.04 (2H, m), 4,25 (2H, users, 5,31 (1H, d, J=5 Hz), of 6.49 (1H, d, J=5 Hz), 7,28-7,40 (3H, m), 7,51 (1H, t, J=8 Hz).

MS (ESI+): m/z 366 (M+H).

Example 233

To a suspension of 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}hexanoic acid (590 mg) in water (3 ml) was added 1N. sodium hydroxide (1.5 ml) at ambient temperature. After 5 hours the mixture became a transparent solution. The solution was filtered through a membrane filter, washed with water (0.4 ml×3) and was dried by freezing for 15 hours to obtain sodium salt of 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}hexanoic acid (612 mg, of 98.2%) as a pale yellow powder.

Sodium salt of 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}hexanoic acid

NMR (DMSO-d6that δ): 1,10-1,15 (2H, m), 1,20-1,40 (7H, m), 1,74 (2H, t, J=8 Hz), 2,25-of 2.38 (2H, m)of 2.50 (3H, s), 2.91 in (2H, square, J=8 Hz), 5,72 (1H, d, J=5 Hz), 6,50 (1H, d, J=5 Hz), 7,39-7,46 (3H, m), 7,97 (2H, d, J=8 Hz), compared to 8.26 (1H, users).

Example 234

A solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanol acid (100 mg), triethylamine (29,4 mg) and diphenylphosphinite (79,9 mg) in tert-butanol (2 ml) was heated at 80°C for 8 hours. The cooled reaction mixture was distributed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated salt solution, dried over magnesium sulfate and UPrev is whether in vacuum. The residue was purified p-TLC (hexane-ethyl acetate=3:1) to obtain tert-butyl 4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]BUTYLCARBAMATE (28 mg, 23,4%) as a yellow oil.

tert-Butyl 4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]BUTYLCARBAMATE

NMR (CDCl3that δ): of 1.27 to 1.47 (14H, m), 2,34 at 2.45 (2H, m)to 2.55 (3H, s), 2.91 in-to 3.02 (4H, m), 4,39 (1H, users), 5,79 (1H, d, J=5 Hz), 6,51 (1H, d, J=5 Hz), 7,56-to 7.67 (3H, m), of 7.75 (1H, m).

MS (ESI+): m/z 433 (M+H).

Example 235

To tert-butyl 4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]BUTYLCARBAMATE (25 mg) was added 4n. hydrogen chloride in ethyl acetate (1 ml) at ambient temperature. After 1 hour the mixture was evaporated in vacuum. The residue is triturated in isopropyl ether to obtain the hydrochloride of 3-[3-(4-aminobutyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-4-yl]benzonitrile in the form of a dark green amorphous material (18 mg).

Hydrochloride 3-[3-(4-aminobutyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl3that δ): of 1.27 to 1.47 (14H, m), 2,34 at 2.45 (2H, m)to 2.55 (3H, s), 2.91 in-to 3.02 (4H, m), 4,39 (1H, users), 5,79 (1H, d, J=5 Hz), 6,51 (1H, d, J=5 Hz), 7,56-to 7.67 (3H, m), of 7.75 (1H, m).

MS (ESI+): m/z 333 (M+H).

Example 236

For the lithium chloride (16.5 mg) was added to a solution of ethyl-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate (65 mg) and tributyl(vinyl)stannane (56,7 mg) in dioxane (1 ml) and tetrakis(triphenylphosphine)palladium(0) (1.9 mg). The mixture was boiled with about the military refrigerator. After 4 hours was added tributyl(vinyl)stannane (50 mg) and tetrakis(triphenylphosphine)palladium(0) (1.9 mg). After boiling under reflux overnight, the reaction mixture was suppressed by potassium fluoride (1.8 mmol) in H2O. the Mixture was filtered through celite and washed with ethyl acetate. The organic layer was separated, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified flash chromatography on silica gel (silica gel, 50 ml), elwira a mixture of hexane-ethyl acetate=5:1 and 3:1, to obtain ethyl 5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (18 mg, 28,3%) as a yellow oil.

Ethyl-5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,15 is 1.70 (10H, m)to 2.18 (2H, t, J=8 Hz), 2,36 is 2.46 (2H, m)to 2.55 (3H, s)of 3.00 (2H, square, J=8 Hz), 4,08 (2H, square, J=8 Hz), 5,54 (1H, d, J=10 Hz), 5,86 (1H, d, J=5 Hz), and 6.25 (1H, d, J=16 Hz), 6,51 (1H, d, J=5 Hz), 6.87 in (1H, DD, J=16, 10 Hz), 7,16 (1H, DD, J=6, 1 Hz), 7,33 (1H, users), to 8.70 (1H, d, J=6 Hz).

MS (ESI+): m/z 392 (M+H).

The following compounds were obtained according to a similar method of example 236.

Example 237

Ethyl-5-{4-[5-(1-ethoxyphenyl)-3-pyridinyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), of 1.42 (3H, t, J=7 Hz), 1,40-1,60 (4H, m), of 2.20 (2H, t, J=7 Hz), 2,38-2,52 (2H, m), of 2.56 (3H, s), 3,03 (2H, square, J=7 Hz), 3.96 points (2H, square, J=7 Hz), 4.09 to (2H, square, J=7 Hz), 4,34 (1H, d, J=2 Hz), was 4.76 (1H, d, J=2 Hz), by 5.87 1H, d, J=4 Hz), of 6.52 (1H, d, J=4 Hz), 7,89 (1H, m), 8,53 (1H, d, J=2 Hz), 8,93 (1H, d, J=2 Hz).

MS: (m/z 436 (M+H).

Example 238

Ethyl-5-[7-ethyl-2-methyl-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,22 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-of 1.65 (4H, m)to 2.18 (2H, t, J=7 Hz), 2.40 a of $ 2.53 (2H, m), of 2.56 (3H, s), to 3.02 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), 5,43 (1H, d, J=11 Hz), 5,88 (1H, d, J=4 Hz), of 5.89 (1H, d, J=18 Hz), of 6.52 (1H, d, J=4 Hz), of 6.71-6,83 (1H, DD, J=11 Hz and 18 Hz), 7,73 (1H, m), of 8.47 (1H, d, J=2 Hz), 8,68 (1H, d, J=2 Hz).

Example 239

Ethyl-5-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,22 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,40-1,60 (4H, m), 2,17 (2H, t, J=7 Hz), 2,52-to 2.65 (2H, m), 3.04 from (2H, square, J=7 Hz), of 3.46 (3H, s)4,08 (2H, square, J=7 Hz), 4,63 (2H, s), 5,43 (1H, d, J=11 Hz), 5,88 (1H, d, J=18 Hz), 5,91 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), of 6.71-6,83 (1H, DD, J=11 Hz and 18 Hz), of 7.75 (1H, m), 8,49 (1H, d, J=2 Hz), 8,71 (1H, d, J=2 Hz).

Example 240

Ethyl-5-[4-[5-(1-ethoxyphenyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,22 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), of 1.42 (3H, t, J=7 Hz), 1,40-to 1.63 (4H, m)to 2.18 (2H, t, J=7 Hz), of 2.51 2.63 in (2H, m), 3,03 (2H, square, J=7 Hz), 3,47 (3H, s), 3,93 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,35 (1H, d, J=3 Hz), 4,63 (2H, s), of 4.77 (1H, d, J=3 Hz), of 5.92 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,92 (1H, m), 8,53 (1H, d, J=2 Hz), 8,93 (1H, d, J=2 Hz).

MS (ESI+): m/z 466.

Example 241

Ethyl-5-[7-ethyl-2-phenyl-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,15-1,31 (7H, m)to 1.37 (3H, t, J=7 Hz), to 1.87 (2H, t, J=7 Hz),2,43 (2H, m)a 3.01 (2H, square, J=7 Hz), 3,98 (2H, square, J=7 Hz), of 5.45 (1H, d, J=11 Hz), 5,88 (1H, d, J=18 Hz), 5,98 (1H, d, J=5 Hz), 6,62 (1H, d, J=5 Hz), 6,78 (1H, DD, J=11 and 18 Hz), 7,44-of 7.55 (5H, m), 7,81 (1H, m), 8,55 (1H, m), 8,72 (1H, m).

Example 242

To a solution of 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanol acid (50 mg) in dioxane (1.5 ml) in a hermetically sealed tube was added 50% dimethylamine in water (1.5 ml). The mixture was heated at 175°C during the night. The cooled reaction mixture was concentrated in vacuum. The residue was dissolved in water (1 ml) and the pH was brought to 7-8. The mixture was extracted with chloroform three times. The organic layer was dried over magnesium sulfate and evaporated in vacuum. The residue was purified flash chromatography on silica gel (silica gel, 50 ml), elwira a mixture of chloroform-ethyl acetate=1:1 and chloroform-methanol=20:1, to obtain a yellow oil (43 mg). The oil was led from isopropyl ether to obtain 5-{4-[2-(dimethylamino)-4-pyridinyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}pentanol acid as a yellow solid (27 mg, 52.8 per cent).

5-{4-[2-(Dimethylamino)-4-pyridinyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}pentane acid

NMR (CDCl3that δ): of 1.36 (3H, t, J=8 Hz), 1,40-of 1.65 (4H, m), of 2.25 (2H, t, J=8 Hz), 1,86 is 1.96 (2H, m)to 2.55 (3H, s)of 3.00 (2H, square, J=8 Hz), 4,08 (2H, square, J=8 Hz), 5,54 (1H, d, J=10 Hz), 5,86 (1H, d, J=5 Hz), and 6.25 (1H, d, J=16 Hz), 6,51 (1H, d, J=5 Hz), 6.87 in (1H, DD, J=16, 10 Hz), 7,16 (1H, DD, J=6, 1 Hz), 7,33 (1H, users), to 8.70 (1H, d, J=6 Hz).

Example 243

the suspension of 7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carbaldehyde (40 mg) in ethanol (1 ml) was added 2-aminoethanol (11.8 mg), cyanoborohydride sodium (12.1 mg) and acetic acid (1 drop) in a bath of ice-water. After 10 minutes, the mixture was stirred at ambient temperature. After 2 hours was added cyanoborohydride sodium (11.8 mg) and the reaction mixture was acidified to pH 4 with acetic acid (5 drops). After stirring over night the reaction mixture was distributed between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate solution, water and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified p-TLC (chloroform-methanol=10:1) to obtain 2-({[7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]methyl}amino)ethanol as a pale yellow oil (21 mg).

2-({[7-Chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]methyl}amino)ethanol

NMR (CDCl3that δ): USD 1.43 (6H, d, J=7 Hz), to 2.65 (2H, t, J=7 Hz), 3,42 (1H, m), 3,53 (2H, t, J=7 Hz)and 3.59 (2H, s), 6,01 (1H, d, J=5 Hz), 6,77 (1H, d, J=5 Hz), 7,14-7,24 (2H, m), 7,35-7,44 (2H, m).

MS (ESI+): m/z 362 (M+H).

Example 244

To a solution of [4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-yl]methanol (505 mg) and triethylamine (997 mg) in dichloromethane (4 ml) and dimethylsulfoxide (2 ml) was added to the complex of sulfur trioxide and pyridine (941 mg) in a bath of ice-water in a nitrogen atmosphere. After 30 minutes, the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated to about 1/3 of the volume of the and. The mixture was distributed between ethyl acetate and water. The organic layer was washed with water three times and with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified flash chromatography on silica gel (silica gel, 30 ml), elwira a mixture of hexane-chloroform=3:1 and 2:1, to obtain 4-(4-forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-carbaldehyde as a yellow solid (340 mg, 67.9 percent).

4-(4-Forfinal)-2-methylpyrrole[1,2-b]pyridazin-3-carbaldehyde

NMR (CDCl3that δ): 2,77 (3H, s), 6,50 (1H, m)6,86 (1H, m), 7,20-7,30 (2H, m), 7,44-rate of 7.54 (2H, m), 8,89 (1H, users), 9,79 (1H, s).

Example 245

A mixture of ethyl-4-(4-forfinal)-2-isopropyl-7-vinylpyrrole[1,2-b]pyridazin-3-carboxylate (8,9 g) and 10% palladium on carbon (900 mg) in ethanol (180 ml) was stirred in hydrogen atmosphere (3.5 ATM) at ambient temperature. After 10 hours the mixture was stood overnight. To the mixture was added 10% palladium on carbon (900 mg) and was stirred in hydrogen atmosphere (3.5 ATM) at ambient temperature. After 12 hours the mixture was stood overnight. To the mixture was added 10% palladium on carbon (900 mg) and was stirred in hydrogen atmosphere (3.5 ATM) at ambient temperature for 8 hours. The mixture was filtered through celite. The filtrate was concentrated in vacuo to obtain ethyl-7-ethyl-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carboxylate as a yellow oil (9 g, 100,5%).

Ethyl-7-ethyl-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carboxylate

NMR (CDCl3that δ)as 0.96 (3H, t, J=8 Hz), to 1.38 (3H, t, J=8 Hz), 3,05 (2H, square, J=8 Hz), 4,01 (2H, square, J=8 Hz), 6,27 (1H, d, J=5 Hz), only 6.64 (1H, d, J=5 Hz), 7,10-7,19 (2H, m), 7,41-7,49 (2H, m).

MS (ESI+): m/z 362 (M +H).

The following compounds were obtained according to a similar method of example 245.

Example 246

5-[7-Ethyl-4-(5-ethyl-3-pyridinyl)-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid from 5-[7-ethyl-2-methyl-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanol acid

NMR (CDCl3that δ): of 1.30 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,45-of 1.65 (4H, m), 2,22 (2H, m), 2,35-of 2.50 (2H, m), of 2.56 (3H, s)of 2.75 (2H, square, J=7 Hz), of 3.00 (2H, square, J=7 Hz), of 5.84 (1H, d, J=4 Hz), 6,52 (1H, d, J=4 Hz), EUR 7.57 (1H, s), 8,42 (1H, d, J=2 Hz), 8,53 (1H, d, J=2 Hz).

MS (ESI+): m/z 366 (M+H), MS (ESI-): m/z 364.

Example 247

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

NMR (CDCl3that δ): of 1.30 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,45-of 1.64 (4H, m), 2,17 (2H, m), 2,45-to 2.67 (2H, m), 2,73 (2H, square, J=7 Hz), 3.04 from (2H, square, J=7 Hz), of 3.45 (3H, s), to 4.62 (2H, m), of 5.89 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), to 7.59 (1H, s), 8,44 (1H, s), 8,54 (1H, s).

MS (ESI+): m/z 396.

Example 248

Ethyl-5-[7-ethyl-4-(5-ethyl-3-pyridinyl)-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,04-1,23 (7H, m)of 1.32 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), to 1.86 (2H, t, J=7 Hz), 2,42 (2H, m), is 2.74 (2H, square, J=7 Hz), 3,01 (2H, square, J=7 Hz), 3,99 (2H, square, J=7 Hz), 5,97 (1H, d, J=5 Hz), 6,62 (1H, d, J=5 Hz), 7,45-7,53 (5H, m), 7,60 (1H, m), and 8.50 (1H, m), 8,56 (1H, m).

Example 249

To a solution of 3-(7-ethyl-2-neopentylene[1,2-b]pyridazin-4-yl)benzamide (35 mg) in ethanol (1 ml) was added water (0.2 ml) and potassium hydroxide (68,9 mg) at ambient temperature. The reaction mixture was heated at 60°C. After 2 hours, was added potassium hydroxide (100 mg). After 5 hours was added potassium hydroxide (100 mg). After 12 hours the mixture was acidified using 1N. chloride hydrogen. The precipitate was filtered, washed with water and ethyl acetate to obtain 3-(7-ethyl-2-neopentylene[1,2-b]pyridazin-4-yl)benzoic acid as a yellow solid (19 mg, 54.1 per cent).

3-(7-Ethyl-2-neopentylene[1,2-b]pyridazin-4-yl)benzoic acid

NMR (CDCl3that δ): of 1.05 (9H, s)of 1.39 (3H, t, J=8 Hz), 2,69 (2H, s), 3.04 from (2H, square, J=8 Hz), 6.42 per (1H, s), is 6.54 (1H, d, J=5 Hz), of 6.65 (1H, d, J=5 Hz), a 7.62 (1H, t, J=8 Hz), of 7.97 (1H, d, J=8 Hz), 8,21 (1H, d, J=8 Hz), 8,46 (1H, users).

MS (ESI+): m/z 337 (M+H).

The following compound was obtained according to a similar method of example 249.

Example 250

3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid

NMR (CDCl3that δ): the 1.44 (3H, t, J=8 Hz), 3,11 (2H, square, J=8 Hz), 6,56 (1H, m), is 6.61 (1H, d, J=5 Hz), 6,72 (1H, d, J=5 Hz), 7,03 (1H, users), 7,07 (1H, d, J=5 Hz), 7,55-of 7.69 (2H, m), 8,03 (1H, userd, J=8 Hz,), 8,23 (1H, userd, J=8 Hz), charged 8.52 (1H, users).

Example 251

A solution of ethyl-5-{4-[5-(1-ethoxyphenyl)-3-pyridinyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}pentanoate (190 mg) in methanol (5 ml) and 1N. hydrochloric acid (5 ml) var is stirred at ambient temperature for 2 hours. The solution was diluted with saturated salt solution and was extracted with chloroform. The organic layer was separated, dried over magnesium sulfate and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (10:1-2:1), to obtain ethyl-5-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate in the form of a yellow oil (160 mg).

Ethyl-5-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,40-1,60 (4H, m), 2,19 (2H, t, J=7 Hz), a 2.36-2,47 (2H, m), to 2.57 (3H, s), 2,70 (3H, s), to 3.02 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), 5,81 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 8,23 (1H, m), 8,78 (1H, d, J=2 Hz), 9,23 (1H, d, J=2 Hz).

MS: (m/z 408 (M+H).

The following compound was obtained according to a similar method of example 251.

Example 252

Ethyl-5-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,40-to 1.59 (4H, m), 2,17 (2H, t, J=7 Hz), 2,50-2,63 (2H, m), 2,70 (3H, s), 3,03 (2H, square, J=7 Hz), of 3.46 (3H, s), of 4.12 (2H, square, J=7 Hz), 4,63 (2H, s), 5,86 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), compared to 8.26 (1H, m), 8,79 (1H, d, J=2 Hz), 9,24 (1H, d, J=2 Hz).

MS (ESI+): m/z 438.

Example 253

To a solution of ethyl-5-{4-(2-chloro-4-pyridinyl)-7-ethyl-2-[(methylthio)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate (139 mg) in tetrahydrofuran (4 ml) and water (1 ml) was added Oxon (287 mg) and the mixture was stirred at ambient temperature with the food within 4 hours. The solution was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with a saturated solution of sodium bicarbonate, sodium thiosulfate solution and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (10:1-1:1), to obtain ethyl-5-{4-(2-chloro-4-pyridinyl)-7-ethyl-2-[(methylsulphonyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate in the form of a yellow oil (124 mg).

Ethyl-5-{4-(2-chloro-4-pyridinyl)-7-ethyl-2-[(methylsulphonyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-to 1.63 (4H, m), of 2.21 (2H, t, J=7 Hz), 2.57 m) of 2.68 (2H, m), to 3.02 (2H, square, J=7 Hz), of 3.12 (3H, s), 4,10 (2H, square, J=7 Hz), a 4.53 (2H, s), 5,98 (1H, d, J=4 Hz), of 6.68 (1H, d, J=4 Hz), 7,27 (1H, m), 7,38 (1H, s), 8,56 (1H, d, J=5 Hz).

Example 254

A mixture of ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate (167 mg) and copper cyanide(I) (37 mg) in 1-methyl-2-pyrrolidinone (3 ml) was stirred at 170°C for 4 hours. The mixture was distributed between ethyl acetate and water. The organic layer was separated, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (20:1-5:1), to obtain ethyl-5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrole[12-b]pyridazin-3-yl]pentanoate in the form of a yellow oil (88 mg).

Ethyl-5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): 1,24 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-of 1.62 (4H, m), of 2.21 (2H, t, J=7 Hz), 2,35-2,47 (2H, m), to 2.57 (3H, s), to 3.02 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 5,79 (1H, d, J=4 Hz), is 6.54 (1H, d, J=4 Hz), 7,98 (1H, m), 8,80 (1H, d, J=2 Hz), 8,97 (1H, d, J=2 Hz).

MS (ESI+): m/z 391.

The following compounds were obtained according to a similar method of example 254.

Example 255

5-[4-(5-Cyano-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,40-to 1.67 (4H, m), 2,28 (2H, m), 2,37-2,47 (2H, m), to 2.57 (3H, s), 3,01 (2H, square, J=7 Hz), 5,80 (1H, d, J=4 Hz), 6,55 (1H, d, J=4 Hz), 8,01 (1H, s), 8,81 (1H, user.), 8,98 (1H, usher.).

Example 256

Ethyl-5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-1,60 (4H, m), 2,19 (2H, t, J=7 Hz), 2,49-2,60 (2H, m), 3.04 from (2H, square, J=7 Hz), of 3.46 (3H, s), of 4.12 (2H, square, J=7 Hz), 4,63 (2H, s), of 5.84 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 8,02 (1H, m), 8,83 (1H, d, J=2 Hz), 8,98 (1H, d, J=2 Hz).

Example 257

5-[4-(5-Cyano-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): to 1.38 (3H, t, J=7 Hz), 1,40-of 1.65 (4H, m), and 2.27 (2H, t, J=7 Hz), 2,48-of 2.64 (2H, m), 3,03 (2H, square, J=7 Hz), of 3.46 (3H, s), with 4.64 (2H, s), of 5.84 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 8,03 (1H, s), 8,82 (1H, s), 8,97 (1H, s).

Example 258

5-[4-(5-Cyano-3-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

NMR (CDCl3that δ): 1,06-1,4 (4H, m)of 1.36 (3H, t, J=7 Hz), was 1.94 (2H, t, J=7 Hz), of 2.38 (2H, m), 2,99 (2H, square, J=7 Hz), 5,88 (1H, d, J=5 Hz), only 6.64 (1H, d, J=5 Hz), 7,44-7,52 (5H, m), of 8.06 (1H, s), 8,87 (1H, s), 8,98 (1H, s).

MS (ESI+): m/z 425 (M+H).

Example 259

To a suspension of sociallyengaged (98,8 mg) in tetrahydrofuran (10 ml) was added ethyl-5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentanoate (600 mg) in tetrahydrofuran (10 ml) while cooling the mixture in ice-water and the mixture was stirred at 0°C for 2 hours. The reaction was suppressed with a saturated solution of potassium tartrate of sodium and insoluble substances were filtered off and washed with ethyl acetate. The filtrate was washed with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (10:1-2:1), to obtain 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]-1-pentanol in the form of a yellow oil (478 mg).

5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]-1-pentanol

NMR (CDCl3that δ): 0,90-1,22 (6H, m), 1.27mm (1H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 2,37-2,47 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,29-to 3.41 (2H, m), 5,97 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,32 (1H, m), 7,40-of 7.55 (8H, m).

Example 260

To a solution of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]-1-pentanol (63,0 mg) and triethylamine (of 22.8 mg) in dichloromethane (3 ml) was added methanesulfonamide (18,9 mg) while cooling the mixture in ice-water and the mixture was stirred at 0�B0; C for 1 hour. The solution was washed with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was added sodium cyanide (14,7 mg) in dimethylformamide (2 ml) and the mixture was stirred at 60°C for 5 hours. The mixture was distributed between ethyl acetate and water. The organic layer was separated, washed with water and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (20:1-5:1), to obtain 6-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]hexanenitrile in the form of a yellow oil (58.5 mg).

6-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]hexanenitrile

NMR (CDCl3that δ): 1,00-of 1.15 (4H, m), 1,17 of 1.28 (2H, m)of 1.36 (3H, t, J=7 Hz), to 1.98 (2H, t, J=7 Hz), 2,38-2,47 (2H, m), 3,03 (2H, square, J=7 Hz), of 5.99 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,32 (1H, m), 7,38-7,56 (8H, m).

MS (ESI+): m/z 428.

Example 261

A mixture of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]-1-pentanol (65 mg), tetrafluoroborate trimethylhexane (27.5 mg) and 2,6-di-tert-butyl-4-methylpyridine (47,8 mg) in 1,2-dichloroethane (3 ml) was stirred at ambient temperature for 4 hours. The solution was washed with water, 1N. hydrochloric acid, water, saturated sodium bicarbonate solution and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The mod is to purified column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (20:1-5:1), to obtain 4-(3-chlorophenyl)-7-ethyl-3-(5-methoxyphenyl)-2-phenylpyrrole[1,2-b]pyridazine in the form of a yellow oil (60 mg).

4-(3-chlorophenyl)-7-ethyl-3-(5-methoxyphenyl)-2-phenylpyrrole[1,2-b]pyridazin

NMR (CDCl3that δ): 00,90-of 1.32 (6H, m)of 1.36 (3H, t, J=7 Hz), 2,37-2,47 (2H, m), 3,03 (2H, square, J=7 Hz), is 3.08 (2H, t, J=7 Hz), and 3.31 (3H, s), 5,97 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,27-7,33 (1H, m), 7,38-7,53 (8H, m).

MS (ESI+): m/z 433.

Example 262

To a solution of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]-1-pentanol (55 mg) and triethylamine (19.9 mg) in dichloromethane (3 ml) was added methanesulfonamide (16.5 mg) while cooling the mixture in ice-water and the mixture was stirred at 0°C for 1 hour. The solution was washed with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. To the residue in 1,2-dichloroethane (3 ml) was added 2M dimethylamine in tetrahydrofuran (3 ml) and the mixture was stirred at 60°C for 120 hours. The solution was diluted with chloroform, washed with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (20:1-5:1), to obtain 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]-N,N-dimethyl-1-pentamine in the form of a yellow oil (38 mg).

N-{5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentyl}-N,N-dimethylamine

The Mr (CDCl 3that δ): 0,86 to 0.97 (2H, m), 1,02-of 1.15 (4H, m)of 1.36 (3H, t, J=7 Hz), 1,97-2,04 (2H, m), 2,11 (6H, s), 2,37-2,47 (2H, m), to 3.02 (2H, square, J=7 Hz), 5,97 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,31 (1H, m), 7,39-rate of 7.54 (8H, m).

MS (ESI+): m/z 446.

Example 263

To a stirred solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentanol acid (60 mg) in dichloromethane (2 ml) was added the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (35,3 mg) and 2-aminopyridine (20 mg) and the reaction mixture was stirred for 10 minutes. Added 4-dimethylaminopyridine (2 mg) and the reaction mixture was stirred at room temperature for 15 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, saturated salt solution, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was purified column flash chromatography on silica gel, elwira a mixture of ethyl acetate and n-hexane (1:2), to obtain 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]-N-(2-pyridinyl)pentanolide (55.7 mg) as a yellow amorphous substance.

5-[4-(3-Cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]-N-(2-pyridinyl)pentanone

TPL: 67°

NMR (CDCl3that δ): 1,12 (2H, quintet, J=7 Hz), of 1.30 (2H, quintet, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,95 (2H, t, J=7 Hz), 2,43 (2H, square, J=7 Hz), to 3.02 (2H, square, J=7 Hz), 5,90 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,00-7,05 (1H, m), 7,43-rate of 7.54 (5H, m), to 7.59-to 7.77 (6H, m), 8,11 (1H, d, J=7.5 Hz), 8,24 (1H, d, J=4 G is).

MS: (m/z 499 (M+), 45 (dB).

The following compounds were obtained according to a similar method of example 263.

Example 264

5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]-N-(2-pyridinyl)pentanone

NMR (CDCl3that δ): 1,15 (2H, quintet, J=7 Hz), 1,24 (2H, quintet, J=7 Hz), of 1.36 (3H, t, J=7 Hz), at 1.91 (2H, t, J=7 Hz), a 2.45 (2H, t, J=7 Hz), of 3.00 (2H, square, J=7 Hz), 5,97 (1H, d, J=5 Hz), 6,60 (1H, d, J=4 Hz), 7,00 (1H, t, J=7 Hz), 7,30 (1H, s), 7,38-7,53(7H, m), 7,65-7,73 (2H, m), 8,11 (1H, d, J=7 Hz), of 8.25 (1H, d, J=5 Hz).

MS: (m/z 509 (M++H), 74 (dB).

Example 265

N-{5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentanoyl}methanesulfonamide

NMR (CDCl3that δ): 1,08 (2H, quintet, J=7 Hz), 1,23 (2H, quintet, J=7 Hz), of 1.36 (3H, t, J=7 Hz), of 1.85 (2H, t, J=7 Hz), 2,44 (2H, t, J=7 Hz), to 3.02 (2H, square, J=7 Hz), 3,21 (3H, s), of 5.99 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,30-7,33 (1H, m), 7,43-of 7.55 (8H, m).

Example 266

5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]-N-(2-pyridinyl)pentanone

NMR (CDCl3that δ): 1,12 (2H, quintet, J=7 Hz), 1.27mm (2H, quintet, J=7 Hz), of 1.36 (3H, t, J=7 Hz), of 1.97 (2H, t, J=7 Hz), a 2.45 (2H, t, J=7 Hz), 3,01 (2H, square, J=7 Hz), 5,95 (1H, d, J=5 Hz), 6,63 (1H, d, J=4 Hz), 7,01 (1H, t, J=7 Hz), 7,31 (1H, d, J=7 Hz), 7,41-7,53 (6H, m), 7,68 (1H, DDD, J=7,7,1 Hz), to 7.77 (1H, s)to 8.12 (1H, d, J=7.5 Hz), 8,24 (1H, d, J=5 Hz), 8,53 (1H, d, J=6 Hz).

MS: (m/z 510 (M++H), 80 (dB).

Example 267

N-{5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoyl}methanesulfonamide

TPL: 124-125°C

NMR (CDCl3that δ): to 1.37 (3H, t, J=7 Hz), 1,43-1,49 (2H, m), 1,55-1,65 (2H, m), of 2.23 (2H, t, J=7 is C), 2,34-2,48 (2H, m)to 2.55 (3H, s), 3,01 (2H, square, J=7 Hz), or 3.28 (3H, s), by 5.87 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), to 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 (dB).

Example 268

To a solution of ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (100.0 mg) and (methyl bromide)benzene (111 mg) in N,N-dimethylformamide (1 ml) was added 60% sodium hydride (17,4 mg) in a bath with ice. After stirring for 2.5 hours the reaction was suppressed by the addition of 1N. hydrochloric acid (1 ml) and the mixture was distributed between ethyl acetate (10 ml) and water (5 ml). The organic layer was washed for 1H. hydrochloric acid (5 ml), water (5 ml, three times) and saturated salt solution, dried over magnesium sulfate and evaporated. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1/40-20/40 gave ethyl-5-[2-[(benzyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate in the form of a yellow resin (47,7 mg, 39.9 per cent).

Ethyl-5-[2-[(benzyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), of 1.34 to 1.48 (5H, m), is 2.09 (2H, m), 2,53 (2H, m), 3.04 from (2H, square, J=7 Hz), 4,07 (2H, J=7 Hz)and 4.65 (2H, s), 4.72 in (2H, s), 5,90 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,29-7,38 (5H, m), 7,86 (1H, s), 8,54 (1H, m), 8,77 (1H, m).

The following compound was obtained according to a similar method of example 268.

Example 269

Ethyl-5-(4-(5-bromo-3-pyridinyl)-2-{[(4-cyanobenzyl)oxy]methyl}-7-milperra[1,2-b]pyridazin-3-yl)pentanoate

NMR (CDCl3that δ): 1,23 (3H, J=7 Hz), 1,35-of 1.55 (7H, m), 2,12 (2H, t, J=7 Hz), to 2.57 (2H, m), to 3.02 (2H, square, J=7 Hz), 4,07 (2H, square, J=7 Hz), of 4.49 (2H, s), was 4.76 (2H, s), to 5.93 (1H, d, J=7 Hz), 6,62 (1H, d, J=7 Hz), of 7.48 (2H, d, J=8 Hz), the 7.65 (2H, d, J=8 Hz), 7,86 (1H, m), 8,54 (1H, m), 8,78 (1H, m).

Example 270

To a solution of ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (200 mg) and triethylamine (65.9 mg) in dichloromethane (2 ml) was added methanesulfonamide (54,7 mg) in a bath with ice. After stirring for 1 hour the reaction was suppressed by the addition of 1N. hydrochloric acid (1 ml). The mixture was distributed between ethyl acetate (20 ml) and 1N. hydrochloric acid (5 ml). The organic layer was washed with saturated sodium bicarbonate solution and saturated salt solution, dried over magnesium sulfate and evaporated to obtain ethyl-5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(methylsulphonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate in the form of a yellow resin (247 mg).

Ethyl-5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(methylsulphonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

NMR (CDCl3that δ): 1,22 (3H, t, J=7 Hz), 1,34-of 1.65 (7H, m), of 2.20 (2H, t, J=7 Hz), to 2.55 (2H, m), to 3.02 (2H, square, J=7 Hz)and 3.15 (3H, s)4,07 (2H, square, J=7 Hz), 5,42 (2H, s), of 5.99 (1H, d, J=5 Hz), of 6.68 (1H, d, J=5 Hz), 7,87 (1H, m), 8,54 (1H, m), 8,81 (1H, m).

Example 271

A mixture of ethyl-5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(methylsulphonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate (50.0 mg), benzylamine (29,8 mg) in dichloro the Ana (1 ml) was stirred for 20 hours at room temperature. The mixture was distributed between ethyl acetate and water. The organic layer was washed with saturated salt solution, dried and evaporated. Preparative thin layer chromatography with elution with a mixture of ethyl acetate : hexane=1:2 gave ethyl-5-[2-[(benzylamino)methyl]-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate in the form of a yellow resin (19.1 mg).

Ethyl-5-[2-[(benzylamino)methyl]-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), 1,30-1,50 (7H, m), 2,13 (2H, t, J=7 Hz), 2,42 (2H, m), 3,03 (2H, square, J=7 Hz), 3.96 points (4H, m), 4.09 to (2H, square, J=7 Hz), of 5.89 (1H, d, J=5 Hz), to 6.57 (1H, d, J=5 Hz), 7.23 percent-7,42 (5H, m), 7,86 (1H, m), 8,53 (1H, m), 8,77 (1H, m).

The following compound was obtained according to a similar method of example 271.

Example 272

Ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl3that δ): of 1.23 (3H, t, J=7 Hz), 1,31-1,56 (7H, m), 2,19 (2H, t, J=7 Hz), 2,45-to 2.65 (6H, m), to 3.02 (2H, square, J=7 Hz), 3,60 of 3.75 (6H, m), 4.09 to (2H, square, J=7 Hz), 5,88 (1H, d, J=5 Hz), to 6.57 (1H, d, J=5 Hz), 7,89 (1H, m), 8,55 (1H, m), 8,78 (1H, m).

Example 273

To a solution of (7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl)methanol (40 mg) in N,N-dimethylformamide (1 ml) was added 40% sodium hydride in oil (5.5 mg) in a bath of ice-water. After 20 minutes, to the mixture was added 2-Bromeliaceae (31 mg) at the same temperature. After 15 minutes the reaction mixture was stirred at ambient temperature for 5 hours. actionnow the mixture was distributed between ethyl acetate and water. The organic layer was washed with water three times and with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified p-TLC (hexane-ethyl acetate=10-1) to give [7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]acetate as a pale yellow solid (42 mg).

[7-Chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]acetate

NMR (CDCl3that δ): of 1.41 (6H, d, J=8 Hz), to 2.06 (3H, s), 3,21 (1H, m)to 4.92 (2H, s), 6,14 (1H, d, J=5 Hz), 6,72 (1H, d, J=5 Hz), 7,13-7,24 (2H, m), 7,34-the 7.43 (2H, m).

MS (ESI+): m/z 361 (M+H).

The following compound was obtained according to a similar method of obtaining 20.

Example 274

Ethyl{[7-ethyl-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]methoxy}acetate

NMR (CDCl3that δ): a 1.25 (3H, t, J=8 Hz), 1,30-1,45 (9 H, m), 3.04 from (2H, square, J=8 Hz), 3,51 (1H, m), of 3.97 (2H, s), is 4.15 (2H, square, J=8 Hz), and 4.40 (2H, s), the 6.06 (1H, d, J=5 Hz), 6,56 (1H, d, J=5 Hz), 7,11-7,22 (2H, m), 7,41-7,51 (2H, m).

MS (ESI+): m/z 399 (M+H).

The following compound was obtained according to a similar method of obtaining 276.

Example 275

Ethyl-2-(2-amino-2-oxoethyl)-4-(4-cyanophenyl)-7-acylpyrrole[1,2-b]pyridazin-3-carboxylate

NMR (CDCl3that δ): 0,84 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 3,06 (2H, square, J=7 Hz), 3.96 points (2H, square, J=7 Hz), was 4.02 (3H, s)5,41 (1H, s, of usher.), 6,09 (1H, s, of usher.), 6,28 (1H, d, J=5 Hz), to 6.75 (1H, d, J=5 Hz), 7,53 (2H, d, J=9 Hz), to 7.77 (2H, d, J=9 Hz).

MS (ESI+): m/z 753 (2M+H).

Example 276

A mixture of 4-(3-cyanophenyl)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]p is ridazin-2-carboxylic acid (40,0 mg), pyrrolidine (10,8 mg), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (31,1 mg) and 1-hydroxybenzotriazole (to 21.9 mg) in N,N-dimethylformamide (1 ml) was stirred for 6 hours at room temperature. The mixture was distributed between ethyl acetate (20 ml) and 1N. hydrochloric acid (10 ml). The organic layer was washed with water (10 ml) three times, saturated sodium bicarbonate solution (10 ml) and saturated salt solution, dried and evaporated to obtain 3-[7-ethyl-3-(methylsulphonyl)-2-(1-pyrrolidinylcarbonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile in the form of a yellow solid (35.6 mg).

3-[7-Ethyl-3-(methylsulphonyl)-2-(1-pyrrolidinylcarbonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl3that δ): to 1.38 (2H, m)to 1.99 (4H, m), of 3.07 (2H, square, J=7 Hz), 3,23 (3H, s)and 3.59 (2H, t, J=7 Hz), 3,68 (2H, t, J=7 Hz), 6,27 (1H, d, J=5 Hz), 6,83 (1H, d, J=5 Hz), EUR 7.57-7,66 (3H, m), 7,79 (1H, m).

MS (ESI+): m/z 423 (M+H).

Example 277

To a solution of 3-[7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid (40 mg) in N,N-dimethylformamide (4 ml) were added hydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (30 mg), 1-hydroxybenzotriazole (24 mg) and 2-aminoethanol (15 mg) at ambient temperature. After stirring over night the reaction mixture was distributed between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with water 3 times and saturated salt solution,dried over magnesium sulfate and evaporated in vacuum. The residue was purified flash chromatography on a column of silica gel (silica gel, 40 ml), elwira a mixture of chloroform-methanol=50:1 and 20:1, to obtain yellow solid (42 mg). The solid is triturated in isopropyl ether to obtain 3-[7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]-N-(2-hydroxyethyl)benzamide as a yellow solid (35 mg).

3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]-N-(2-hydroxyethyl)benzamide

NMR (CDCl3that δ): USD 1.43 (3H, t, J=8 Hz), 2,39-2,49 (2H, m), 3,10 (2H, square, J=8 Hz), 3,60-3,74 (2H, m), 3,80-of 3.94 (2H, m), 6,53-6,86 (4H, m), 7,00 (1H, s), is 6.61 (1H, d, J=5 Hz), 6,72 (1H, d, J=5 Hz), 7,03 (1H, users), 7,07 (1H, d, J=5 Hz), 7,55-the 7.65 (2H, m), 7,86-of 7.97 (2H, m), 8,17 (1H, users).

MS (ESI+): m/z 376 (M+H).

The following compounds were obtained according to a similar method of example 283.

Example 278

5-[4-(3-Cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]-N-methylpentanoic

TPL: 60°C

NMR (CDCl3that δ): 1,02-1,12 (2H, m), 1,17-1,25 (2H, m)of 1.36 (3H, t, J=7 Hz), at 1.73 (2H, t, J=7 Hz), 2.40 a( 2H, t, J=7 Hz), 2,71 (3H, d, J=7 Hz), 3,03 (2H, square, J=7 Hz), 5,09 (1H, users), 5,90 (1H, d, J=4 Hz), 6,63 1H, d, J=4 Hz), 7,45-of 7.55 (5H, m), 7,60 for 7.78 (4H, m).

MS: (m/z 437 (M++H), 115 (dB).

Example 279

4-(3-Chlorophenyl)-7-ethyl-3-[5-(4-morpholinyl)-5-oxobutyl]-2-phenylpyrrole[1,2-b]pyridazin

TPL: 55-58°C

NMR (CDCl3that δ): of 1.05 to 1.14 (2H, m), 1,17-of 1.23 (2H, m)of 1.35 (3H, t, J=7 Hz), of 1.84 (2H, t, J=7 Hz), a 2.45 (2H, t, J=7 Hz), to 3.02 (2H, square, J=7 Hz), 3,24 (2H, t, J=6 Hz), 3,50 (2H, t, J=6 Hz), 3,55-3,62 (4H, m), of 5.99 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz),7,30-to 7.35 (1H, m), 7,40-of 7.55 (8H, m).

MS: (m/z 502 (M++H), 115 (dB).

Example 280

5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]-N-methylpentanoic

TPL: 70-72°C

NMR (CDCl3that δ): 1,06 (2H, quintet, J=7 Hz), 1,22 (2H, quintet, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,72 (2H, t, J=7 Hz), 2,43 (2H, t, J=7 Hz), 2,70 (3H, d, J=7 Hz), 3,03 (2H, square, J=7 Hz), to 5.08 (1H, users), 5,99 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,29-7,33 (1H, m), 7,41-of 7.55 (8H, m).

MS: (m/z 446 (M++H), 115 (dB).

Example 281

5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]-N-methylpentanoic

NMR (CDCl3that δ)with 1.07 (2H, quintet, J=7 Hz), 1,23 (2H, quintet, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,74 (2H, t, J=7 Hz), is 2.41 (2H, t, J=7 Hz), 2,71 (3H, d, J=7 Hz), to 3.02 (2H, square, J=7 Hz), 5,10 (1H, users), 5,95 (1H, d, J=4 Hz), only 6.64 (1H, d, J=4 Hz), 7,31 (1H, d, J=7 Hz), 7,42 (1H, s), 7,46-7,52 (1H, m), 7,41-of 7.55 (1H, d, J=7 Hz).

MS: (m/z 447 (M++H), 115 (dB).

Example 282

3-{7-Ethyl-3-[5-(4-morpholinyl)-5-oxobutyl]-2-phenylpyrrole[1,2-b]pyridazin-4-yl}benzonitrile of 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentanol acid

TPL: 66-69°C

NMR (CDCl3that δ): 1,04-1,12 (2H, m), 1,17-of 1.23 (2H, m)of 1.36 (3H, t, J=7 Hz), of 1.84 (2H, t, J=7 Hz), 2,42 (2H, t, J=7 Hz), 3,03 (2H, square, J=7 Hz), 3,23 (2H, t, J=6 Hz), 3,50 (2H, t, J=6 Hz), 3,55-3,63 (4H, m), 5,90 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,43-of 7.55 (5H, m), 7,60 for 7.78 (4H, m).

MS: (m/z 493 (M++H), 126 (dB).

Example 283

To a solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanol acid (50 mg) in N,N-dimethylformamide (1 ml) was added hydrochlor the d 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (35 mg) and 1-hydroxybenzotriazole (28 mg) at ambient temperature. After 30 minutes, to the mixture was added morpholine (24 mg). After 5 hours the reaction mixture was distributed between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with water three times and with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified flash chromatography on a column of silica gel (silica gel, 40 ml), elwira a mixture of hexane-ethyl acetate=3:1, 2:1, 1:1, 1:3 and 0:1, with 3-{7-ethyl-2-methyl-3-[5-(4-morpholinyl)-5-oxopent]pyrrolo[1,2-b]pyridazin-4-yl}benzonitrile in the form of a yellow resin (53 mg).

3-{7-Ethyl-2-methyl-3-[5-(4-morpholinyl)-5-oxopent]pyrrolo[1,2-b]pyridazin-4-yl}benzonitrile

NMR (CDCl3that δ): 1,15-1,61 (7H, m)to 2.18 (2H, t, J=8 Hz), is 2.41 (2H, t, J=8 Hz), of 2.56 (3H, s)of 3.00 (2H, square, J=8 Hz), 3,82 (2H, t, J=5 Hz), 3,51-3,68 (6H, m), 5,78 (1H, d, J=5 Hz), 6,50 (1H, d, J=5 Hz), 7,56-to 7.67 (3H, m), 7,74 (1H, m).

MS (ESI+): m/z 431 (M+H).

The following compound was obtained according to a similar method of example 283.

Example 284

5-[4-(3-Cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanone

NMR (CDCl3that δ): 1,31-1,61 (7H, m), 2,11 (2H, t, J=8 Hz), 2.40 a (2H, t, J=8 Hz), of 2.56 (3H, s)of 3.00 (2H, square, J=8 Hz), are 5.36 (2H, users), 5,79 (1H, d, J=5 Hz), 6,50 (1H, d, J=5 Hz), 7,56-to 7.67 (3H, m), 7,75 (1H, m).

MS (ESI+): m/z 361 (M+H).

Getting 178

To a suspension of 60% sodium hydride (8,79 g) in tetrahydrofuran (500 ml) was added cyclohexanol (10 g) and the mixture was stirred at 0°C for 0.5 hour. To the mixture was added Romexpo acid (13,9 g) under cooling with a mixture of ice-water and the mixture boiled under reflux for 2 hours. Then to the mixture was added water and the organic solvent evaporated in vacuum. The aqueous solution was diluted with water, washed with ether, acidified 1H. hydrochloric acid and was extracted with ether. The organic layer was separated, dried over magnesium sulfate and evaporated in vacuum to obtain (cyclohexyloxy)acetic acid as a colourless oil (13.3 g).

(Cyclohexyloxy)acetic acid

1H NMR (CDCl3) δ of 1.18 to 1.47 (5H, m), 1,52-to 1.63 (1H, m), 1,72-of 1.85 (2H, m), 1,90-2,03 (2H, m), 3,36-3,47 (1H, m), of 4.13 (2H, s).

The following compound was obtained according to a similar method of producing 178.

Getting 179

Isopropoxyphenyl acid

1H NMR (CDCl3) δ to 1.24 (6H, d, J=7 Hz), 3,68-3,82 (1H, m), 4,11 (2H, s).

The following compounds were obtained according to a similar method of obtaining 129 and receive 130.

Getting 180

tert-Butyl 4-(benzyloxy)-3-oxobutanoate

1H NMR (CDCl3) δ the 1.44 (9H, s), of 3.45 (2H, s), 4,14 (2H, s), 4,60 (2H, s), 7,28-7,40 (5H, m).

Getting 181

tert-Butyl 4-(cyclohexyloxy)-3-oxobutanoate

1H NMR (CDCl3) δ 1,18-1,43 (5H, m)of 1.47 (9H, s), 1,53-to 1.63 (1H, m), 1,69-of 1.85 (2H, m), 1,87-of 1.97 (2H, m), 3,24-to 3.38 (1H, m), of 3.46 (2H, s), 4,11 (2H, s).

Getting 182

tert-Butyl-4-isopropoxy-3-oxobutanoate

1H NMR (CDCl3) δ of 1.20 (6H, d, J=7 Hz), of 1.47 (9H, s), of 3.45 (2H, s), 3,60-3,70 (1H, m), 4,08 (2H, s).

The following compounds were obtained according to a similar method of obtaining 159.

aluchemie 183

1-tert-butyl-4-ethyl-2-acetylcystine

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), of 1.47 (9H, s)to 2.35 (3H, s), is 3.08 (2H, m), 3,93 (1H, m), of 4.12 (2H, square, J=7 Hz).

Getting 184

1-tert-butyl-7-ethyl-2-[(benzyloxy)acetyl]heptanoate

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), 1,30-1,50 (2H, m)of 1.40 (9H, s), 1.56 to 1,72 (2H, m), 1,75-of 1.95 (2H, m), 2,28 (2H, t, J=7 Hz), 3,52 (1H, t, J=7 Hz), 4,11 (2H, square, J=7 Hz), 4,16 (2H, s), 4,59 (2H, s), 7,27-7,40 (5H, m).

Getting 185

1-tert-butyl-5-ethyl-2-[(benzyloxy)acetyl]pentanedioic

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), of 1.41 (9H, s), 2,10-of 2.23 (2H, m), a 2.36 (2H, t, J=7 Hz), 3,66 (1H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,18 (2H, s), 4,60 (2H, s), 7,26-7,38 (5H, m).

Getting 186

1-tert-butyl-7-ethyl-2-[(cyclohexyloxy)acetyl]heptanoate

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), of 1.44 (9H, s), 1,15-1,92 (16H, m)to 2.29 (2H, t, J=7 Hz), 3,24-to 3.38 (1H, m), of 3.56 (1H, t, J=7 Hz), 4,12 (4H, m).

Getting 187

1-tert-butyl-7-ethyl-2-(isopropoxyphenyl)heptanoate

1H NMR (CDCl3) δ of 1.20 (6H, d, J=7 Hz), 1,25 (3H, t, J=7 Hz), 1,25-1,45 (2H, m)of 1.45 (9H, s), 1.60-to 1,72 (2H, m), 1,75-of 1.95 (2H, m)to 2.29 (2H, t, J=7 Hz), of 3.54 (1H, t, J=7 Hz), 3,60-3,68 (1H, m), 4,11 (2H, C)of 4.12 (2H, square, J=7 Hz).

MS (ESI+): m/z 345.

The following compound was obtained according to a similar method of obtaining 20.

Getting 188

1-tert-butyl-5-ethyl-2-[(cyclohexyloxy)acetyl]pentanedioic

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), a 1.45 (9H, s), 1,18-of 1.62 (6H, m), 1,66-of 1.78 (2H, m), 1,84-to 1.98 (2H, m), 2,10-of 2.23 (2H, m), of 2.38 (2H, t, J=7 Hz), 3.25 to to 3.38 (1H, m), of 3.69 (1H, t, J=7 G is), of 4.12 (2H, square, J=7 Hz), is 4.15 (2H, s).

MS (ESI+): m/z 357.

Getting 189

To a suspension of 60% sodium hydride (527 mg) in dimethylformamide (20 ml) was added 3,5-pyridylcarbonyl acid (2.00 g) under cooling with a mixture of ice-water and the mixture was stirred at 0°C for 1 hour. To the mixture was added methyl bromide)benzene (2,05 g) and the mixture was stirred at 60°C for 2 hours. The mixture was distributed between ethyl acetate and water. The organic layer was washed with water and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue is triturated in ethyl acetate to obtain 5-[(benzyloxy)carbonyl]nicotinic acid as pale yellow powder (722 mg).

5-[(benzyloxy)carbonyl]nicotinic acid

1H NMR (DMSO-d6) δ 5,42 (2H, s), 7,34-rate of 7.54 (5H, m), 8,63 (1H, m), 9,23-9,34 (2H, m).

The following compounds were obtained according to a similar method of obtaining 24.

Getting 190

1-tert-butyl-4-ethyl-2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyl]succinate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.40 (9H, s), of 2.38 (3H, s), a 2.45 (3H, s), 3,20 (2H, m), 4,13 (2H, square, J=7 Hz), 7,88 (1H, s), to 8.57 (1H, s), a total of 8.74 (1H, s).

MS (ESI+): m/z 363.

Getting 191

Ethyl-2-[(5-methyl-3-pyridinyl)carbonyl]-3-oxobutanoate

1H NMR (CDCl3) δ to 0.96 (3H, t, J=7 Hz), of 2.15 (3H, s), a 2.45 (3H, s), a 4.03 (2H, square, J=7 Hz), of 4.12 (1H, t, J=7 Hz), 7,89 (1H, s), 8,54 (1H, s), 8,72 (1H, s).

MS (ESI+): m/z 250.

Getting 192

1-tert-butyl-6-e of the Il-2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]hexanedioic

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), of 1.36 (9H, s), 1.60-to of 1.73 (2H, m), 2,23 to 2.35 (2H, m), of 2.38 (2H, t, J=7 Hz), 2,48 (3H, s), of 4.12 (2H, square, J=7 Hz), to 8.20 (1H, m), 8,78 (1H, m), 8,81 (1H, m).

Getting 193

1-tert-butyl-5-ethyl-2-[(5-bromo-3-pyridinyl)carbonyl]-2-(methoxyacetyl)pentanedioic

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), of 1.39 (9H, s), 2.40 a-2,47 (2H, m), 2,55-to 2.67 (2H, m)to 3.36 (3H, s), of 4.12 (2H, square, J=7 Hz), 4,27 (1H, d, J=17 Hz), and 4.40 (1H, d, J=17 Hz), 8,21 (1H, m), 8,79 (1H, d, J=2 Hz), 8,82 (1H, d, J=2 Hz).

MS (ESI+): m/z 472, 474.

Getting 194

1-tert-butyl-7-ethyl-2-acetyl-2-({5-[(benzyloxy)carbonyl]-3-pyridinyl}carbonyl)heptanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), 1,20-1,40 (2H, m)of 1.32 (9H, s)of 1.65 to 1.76 (2H, m), 2,19-of 2.26 (2H, m), 2,32 (2H, t, J=7 Hz), 2,44 (3H, s), of 4.12 (2H, square, J=7 Hz), 5,41 (2H, s), 7,35-of 7.48 (5H, m), 8,62 (1H, m), 9,07 (1H, d, J=2 Hz), was 9.33 (1H, d, J=2 Hz).

MS (ESI+): m/z 526.

Getting 195

1-tert-butyl-7-ethyl-2-[(benzyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]heptanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), 1,20-of 1.46 (2H, m)of 1.32 (9H, s), 1.60-to around 1.74 (2H, m), 2,10-of 2.36 (4H, m)to 2.35 (3H, s), 4,10 (2H, square, J=7 Hz), to 4.38 (1H, d, J=18 Hz), a 4.53 (1H, d, J=18 Hz), of 4.54 (2H, m), 7,27-7,40 (5H, m), 7,79 (1H, m), 8,54 (1H, d, J=2 Hz), 8,72 (1H, d, J=2 Hz),

MS (ESI+): m/z 512.

Getting 196

1-tert-butyl-5-ethyl-2-[(benzyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioic

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), of 1.34 (9H, s)to 2.35 (3H, s), 2.40 a-2,72 (4H, m), of 4.12 (2H, square, J=7 Hz), to 4.38 (1H, d, J=17 Hz), 4,50 (1H, d, J=17 Hz), 4,53 (2H, m), 7,25-7,38 (5H, m), 7,81 (1H, s), 8,54 (H, C)8,73 (1H, s),

MS (ESI+): m/z 484.

Getting 197

1-tert-butyl-7-ethyl-2-[(cyclohexyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]heptanoate

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), 1,16-of 1.55 (10H, m)to 1.37 (9H, s), 1,60 to 1.76 (2H, m), of 1.78-1.90 (2H, m), 2,15-of 2.28 (2H, m), 2,31 (2H, t, J=7 Hz), 2,39 (3H, s), 3,17-3,29 (1H, m), of 4.12 (2H, square, J=7 Hz), 4,34 (1H, d, J=18 Hz), of 4.44 (1H, d, J=18 Hz), 7,86 (1H, s), 8,56 (1H, s), 8,76 (1H, s),

MS (ESI+): m/z 504.

Getting 198

1-tert-butyl-7-ethyl-2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(cyclohexyloxy)acetyl]heptanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.39 (9H, s), 1,16-1,88 (14H, m), 2,15-to 2.40 (4H, m), 3,16 of 3.28 (1H, m), 4,10 (2H, square, J=7 Hz), 4,28 (1H, d, J=18 Hz), to 4.38 (1H, d, J=18 Hz), to 8.20 (1H, m), 8,78 (1H, d, J=2 Hz), 8,84 (1H, d, J=2 Hz),

MS (ESI+): m/z 568, 570.

Getting 199

1-tert-butyl-5-ethyl-2-[(cyclohexyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioic

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), 1,15-to 1.38 (4H, m)of 1.39 (9H, s)of 1.45 and 1.75 (4H, m), 1,76-of 1.93 (2H, m), 2,39 (3H, s), 2,45 is 2.75 (4H, m), 3,17-3,30 (1H, m), of 4.12 (2H, square, J=7 Hz), 4,32 (1H, d, J=17 Hz), to 4.41 (1H, d, J=17 Hz), 7,88 (1H, s), 8,55 (1H, s), 8,77 (1H, s).

MS (ESI+): m/z 476.

Getting 200

1-tert-butyl-5-ethyl-2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(cyclohexyloxy)acetyl]pentanedioic

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), 1,15-1,35 (4H, m)of 1.40 (9H, s), 1,40-of 1.65 (2H, m)of 1.65 and 1.75 (2H, m), 1,75-of 1.92 (2H, m), 2,35-to 2.85 (4H, m), 3,16-of 3.32 (1H, m), of 4.12 (2H, square, J=7 Hz), 4,28 (1H, d, J=17 Hz), 4,35 (1H, d, J=17 Hz), by 8.22 (1H, t, J=2 Hz), 8,78 (1H, d, J=2 Hz), 8,87 (1H, d, J=2 Hz),

MS (ES +): m/z 540, 542.

Getting 201

1-tert-butyl-7-ethyl-2-(isopropoxyphenyl)-2-[(5-methyl-3-pyridinyl)carbonyl]heptanoate

1H NMR (CDCl3) δ of 1.12 (6H, d, J=7 Hz), of 1.23 (3H, t, J=7 Hz), 1.30 and of 1.55 (2H, m)to 1.37 (9H, s), 1,63-to 1.77 (2H, m), 2,19-of 2.28 (2H, m), 2,28 (2H, t, J=7 Hz), 2,39 (3H, s), 3,53-of 3.64 (1H, m), 4,10 (2H, square, J=7 Hz), or 4.31 (1H, d, J=18 Hz), 4,42 (1H, d, J=18 Hz), 7,86 (1H, s), 8,55 (1H, s), a total of 8.74 (1H, s),

MS (ESI+): m/z 464.

Getting 202

1-tert-butyl-7-ethyl-2-[(5-bromo-3-pyridinyl)carbonyl]-2-(isopropoxyphenyl)heptanoate

1H NMR (CDCl3) δ of 1.10 (6H, d, J=7 Hz), 1,24 (3H, t, J=7 Hz), of 1.39 (9H, s), of 1.18 to 1.48 (2H, m), 1,64-to 1.77 (2H, m), 2,18-is 2.37 (4H, m), 3,52-of 3.64 (1H, m), of 4.12 (2H, square, J=7 Hz), 4,25 (1H, d, J=17 Hz), 4,36 (1H, d, J=17 Hz), 8,19 (1H, t, J=2 Hz), 8,77 (1H, d, J=2 Hz), 8,83 (1H, d, J=2 Hz),

MS (ESI+): m/z 528, 530.

Getting 203

1-tert-butyl-7-ethyl-2-[(atomic charges)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]heptanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.33 (9H, s), 1,20-of 1.42 (2H, m), 1,63-of 1.74 (2H, m), and 2.14 (3H, s), 2,27-of 2.38 (4H, m), is 2.40 (3H, s), 4,10 (2H, square, J=7 Hz), to 5.08 (1H, d, J=18 Hz), are 5.36 (1H, d, J=18 Hz), to 7.84 (1H, s), 8,56 (1H, s), is 8.75 (1H, s).

MS (ESI+): m/z 464.

The following compounds were obtained according to a similar technique to obtain 78.

Getting 204

Ethyl-3-[(5-methyl-3-pyridinyl)carbonyl]-4-oxopentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 2.21 (3H, s), is 2.44 (3H, s), 3,03 (2H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,96 (1H, t, J=7 Hz), 8,08 (1H, s), 8,66 (1H, s), 9,03 (1H, s).

MS (ESI+): m/z 264.

Getting 205

Ethyl-5-[(5-bromo-3-pyrid the Nile)carbonyl]-6-oxogedunin

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), 1.60-to of 1.78 (2H, m), 1,98-2,12 (2H, m), of 2.20 (3H, s), a 2.36 (2H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,39 (1H, t, J=7 Hz), scored 8.38 (1H, m), 8,87 (1H, d, J=2 Hz), the remaining 9.08 (1H, d, J=2 Hz).

Getting 206

Ethyl-4-[(5-bromo-3-pyridinyl)carbonyl]-6-methoxy-5-oxohexanoate

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), 2,04-of 2.16 (1H, m), 2,20-of 2.34 (1H, m), 2.40 a-2,48 (2H, m), up 3.22 (3H, s), 3,93 (1H, d, J=17 Hz), 4,00 (1H, d, J=17 Hz), of 4.12 (2H, square, J=7 Hz), is 4.85 (1H, m), of 8.47 (1H, m), 8,88 (1H, s), 9,16 (1H, s).

MS (ESI+): m/z 372, 374.

Getting 207

Benzyl-5-(2-acetyl-7-ethoxy-7-oxoethyl)nicotinate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), 1.30 and USD 1.43 (2H, m)of 1.65 and 1.75 (2H, m), 1.93 and-of 2.15 (2H, m), are 2.19 (3H, s)to 2.29 (2H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), of 4.44 (1H, t, J=7 Hz), 5,43 (2H, s), 7,35 is 7.50 (5H, m), 8,81 (1H, m), 9.28 are (1H, d, J=2 Hz), 9,39 (1H, d, J=2 Hz).

MS (ESI+): m/z 426.

Getting 208

Ethyl-8-(benzyloxy)-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), 1.30 and USD 1.43 (2H, m), 1,60 was 1.69 (2H, m), 1,73 is 1.86 (1H, m), 1,95-of 2.08 (1H, m), of 2.25 (2H, t, J=7 Hz), was 2.34 (3H, s), of 4.05 (2H, s)4,07 (2H, square, J=7 Hz), 4,35 is 4.45 (2H, m), 4,69 (1H, t, J=7 Hz), to 7.09 (2H, m), 7,17-of 7.25 (3H, m), to 7.93 (1H, s), 8,58 (1H, d, J=2 Hz), to 8.94 (1H, d, J=2 Hz).

MS (ESI+): m/z 412.

Getting 209

Ethyl-6-(benzyloxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), 2,07 to 2.35 (2H, m), of 2.34 (3H, s), 2,38-2,48 (2H, m), of 4.05 (2H, s), of 4.12 (2H, square, J=7 Hz), 4,34 (1H, d, J=17 Hz), to 4.41 (1H, d, J=17 Hz), the 4.90 (1H, m), 7,03 (2H, m), 7,15-to 7.25 (3H, m), of 8.00 (1H, s), to 8.57 (1H, s), of 9.02 (1H, s).

MS (ESI +): m/z 384.

Getting 210

Ethyl-8-(cyclohexyloxy)-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate

1H NMR (CDCl3) δ 0,91 is 1.70 (12H, m)of 1.23 (3H, t, J=7 Hz), 1.70 to of 1.85 (2H, m), 1,96-2,04 (2H, m), and 2.27 (2H, t, J=7 Hz), 2,43 (3H, s), 3,14 of 3.28 (1H, m)4,00 (2H, s), of 4.12 (2H, square, J=7 Hz), was 4.76 (1H, t, J=7 Hz), of 8.04 (1H, s), to 8.62 (1H, s), of 9.00 (1H, s).

MS (ESI+): m/z 404.

Getting 211

Ethyl-6-[(5-bromo-3-pyridinyl)carbonyl]-8-(cyclohexyloxy)-7-oxooctanoate

1H NMR (CDCl3) δ 0,95-1,87 (14H, m)of 1.23 (3H, t, J=7 Hz), 1,96-2,07 (2H, m), 2,28 (2H, t, J=7 Hz), 3,16-of 3.27 (1H, m), 3.96 points-4,07 (2H, m), of 4.12 (2H, square, J=7 Hz), 4.72 in (1H, t, J=7 Hz), scored 8.38 (1H, m), 8,87 (1H, d, J=2 Hz), the remaining 9.08 (1H, d, J=2 Hz).

MS (ESI+): m/z 468, 470.

Getting 212

Ethyl-6-(cyclohexyloxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate

1H NMR (CDCl3) δ from 0.88 to 1.25 (5H, m)of 1.24 (3H, t, J=7 Hz), 1,40 of-1.83 (5H, m), 2,04 with 2.14 (1H, m), 2,18-of 2.34 (1H, m), 2,42 (2H, m), is 2.44 (3H, s), 3,13-of 3.27 (1H, m)4,00 (2H, s), of 4.12 (2H, square, J=7 Hz), is 4.93 (1H, m,), 8,13 (1H, s), 8,63 (1H, d, J=2 Hz), 9,07 (1H, d, J=2 Hz).

MS (ESI+): m/z 376.

Getting 213

Ethyl-4-[(5-bromo-3-pyridinyl)carbonyl]-6-(cyclohexyloxy)-5-oxohexanoate

1H NMR (CDCl3) δ 0,88-of 1.85 (10H, m), 1,25 (3H, t, J=7 Hz), 2,02 with 2.14 (1H, m), 2,18-of 2.34 (1H, m), 2.40 a-2,50 (2H, m), 3,15-of 3.27 (1H, m), of 3.97 (1H, d, J=17 Hz), was 4.02 (1H, d, J=17 Hz), 4,13 (2H, square, J=7 Hz), 4,87-of 4.95 (1H, m), 8,48 (1H, t, J=2 Hz), 8,88 (1H, d, J=2 Hz), 9,19 (1H, d, J=2 Hz).

MS (ESI+): m/z 440, 442.

Getting 214

Ethyl-8-isopropoxy-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate

1H NMR (CDCl3/sub> ) δ 0,86 (3H, d, J=7 Hz), of 1.02 (3H, d, J=7 Hz), of 1.23 (3H, t, J=7 Hz), of 1.30 to 1.48 (2H, m), 1.60-to 1,72 (2H, m), 1,72-of 1.88 (1H, m), 1,95-2,07 (1H, m), and 2.27 (2H, t, J=7 Hz), 2,43 (3H, s), 3,44-3,54 (1H, m), 3,95 (1H, d, J=18 Hz), a 4.03 (1H, d, J=18 Hz), 4,08 (2H, square, J=7 Hz), to 4.73 (1H, t, J=7 Hz), of 8.06 (1H, s), 8,63 (1H, s), of 9.02 (1H, s).

MS (ESI+): m/z 364.

Getting 215

Ethyl-6-[(5-bromo-3-pyridinyl)carbonyl]-8-isopropoxy-7-oxooctanoate

1H NMR (CDCl3) δ to 0.88 (3H, d, J=7 Hz), of 1.03 (3H, t, J=7 Hz), of 1.23 (3H, t, J=7 Hz), 1,20-of 1.46 (2H, m), 1,58-1,72 (2H, m), 1,73-to 1.87 (1H, m), 1,95-2,07 (1H, m), and 2.27 (2H, t, J=7 Hz), 3.46 in-to 3.58 (1H, m), 3,94 (1H, d, J=17 Hz), a 4.03 (1H, d, J=17 Hz), 4,10 (2H, square, J=7 Hz), and 4.68 (1H, t, J=7 Hz), 8,40 (1H, t, J=2 Hz), 8,86 (1H, d, J=2 Hz), the remaining 9.08 (1H, d, J=2 Hz).

MS (ESI+): m/z 428, 430.

Getting 216

Ethyl-8-(atomic charges)-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.37 to 1.47 (2H, m), 1.60-to or 1.77 (2H, m), a 2.01 (3H, s), 1,97-of 2.08 (2H, m)to 2.29 (2H, t, J=7 Hz), 2,44 (3H, s), 4,10 (2H, square, J=7 Hz), to 4.52 (1H, t, J=7 Hz), and 4.68 (1H, d, J=18 Hz), was 4.76 (1H, d, J=18 Hz), of 8.04 (1H, s), 8,66 (1H, s), 8,98 (1H, s).

MS (ESI+): m/z 364.

The following compounds were obtained according to a similar method of example 21.

Example 285

Ethyl[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]acetate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 2.40 a (3H, s)of 2.50 (3H, s), to 3.02 (2H, square, J=7 Hz), 3,44 (2H, s), 4,14 (2H, square, J=7 Hz), 5,98 (1H, d, J=4 Hz), 6,56 (1H, d, J=4 Hz), 7,55 (1H, s), to 8.45 (1H, s), 8,54 (1H, s).

MS (ESI+): m/z 338.

Example 286

Ethyl-7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-carboxylate

1H NMR (CDCl3) δ to 0.96 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), is 2.41 (3H, s), 2,61 (3H, s), 3.04 from (2H, square, J=7 Hz), of 4.05 (2H, square, J=7 Hz), 6,30 (1H, d, J=4 Hz), to 6.67 (1H, d, J=4 Hz), 7,58 (1H, s), 8,48 (1H, d, J=2 Hz), 8,51 (1H, d, J=2 Hz).

MS (ESI+): m/z 324.

Example 287

Ethyl-4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ to 1.21 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,67-of 1.78 (2H, m), 2,22 (2H, t, J=7 Hz), 2,42-of 2.54 (2H, m), 2,59 (3H, s), 3,01 (2H, square, J=7 Hz), 4,06 (2H, square, J=7 Hz), by 5.87 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,87 (1H, m), 8,54 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (ESI+): m/z 430, 432.

Example 288

Ethyl-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ of 1.20 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 2,42 (2H, t, J=7 Hz), 2,85-of 2.97 (2H, m), 3,06 (2H, square, J=7 Hz), of 3.46 (3H, s)4,08 (2H, square, J=7 Hz)and 4.65 (2H, s)5,94 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,87 (1H, m), 8,54 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

MS (ESI+): m/z 446, 448.

Example 289

Ethyl-4-[2-[(atomic charges)methyl]-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ of 1.20 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,60-1,75 (2H, m), 2,17 (3H, s), 2,10-of 2.28 (2H, m), 2,45-2,60 (2H, m), to 3.02 (2H, square, J=7 Hz), of 4.05 (2H, square, J=7 Hz), 5,32 (2H, s), 5,95 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,88 (1H, m), 8,55 (1H, m), 8,78 (1H, m).

MS (ESI+): m/z 488, 490.

Example 290

Benzyl-5-[3-(5-ethoxy-5-oxobutyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-4-yl]nicotinate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.37 (3H, t, J= Hz), 1,33-to 1.60 (4H, m)to 2.18 (2H, t, J=7 Hz), 2,35-2,47 (2H, m), of 2.56 (3H, s), 3,03 (2H, square, J=7 Hz), 4,10 (2H, square, J=7 Hz), 5,42 (2H, s), of 5.82 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), of 7.36-7,47 (5H, m), with 8.33 (1H, m), 8,77 (1H, d, J=2 Hz), was 9.33 (1H, d, J=2 Hz).

MS (ESI+): m/z 500.

Example 291

Ethyl-5-[2-[(benzyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,20-1,50 (4H, m)to 2.06 (2H, t, J=7 Hz), 2,42 (3H, s), 2,47-2,63 (2H, m), 3,05 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), with 4.64 (2H, s), to 4.73 (2H,with), 5,90 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,27-7,39 (5H, m), 7,51 (1H, s), to 8.41 (1H, d, J=2 Hz), 8,53 (1H, d, J=2 Hz).

Example 292

Ethyl-3-[2-[(benzyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ to 1.16 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), a 2.36 (2H, t, J=7 Hz), 2,42 (3H, s), 2,80-3,00 (2H, m), 3,06 (2H, square, J=7 Hz), a 4.03 (2H, square, J=7 Hz)and 4.65 (2H, s), and 4.75 (2H, s), of 5.92 (1H, d, J=2 Hz), 6,59 (1H, d, J=2 Hz), 7,26-7,38 (5H, m), of 7.48 (1H, s), 8,40 (1H, d, J=2 Hz), 8,53 (1H, d, J=2 Hz).

MS (ESI+): m/z 458.

Example 293

Ethyl-5-[2-[(cyclohexyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ 1,20-1,60 (10H, m), 1,25 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1.70 to to 1.83 (2H, m), 1,96-2,07 (2H, m), of 2.15 (2H, t, J=7 Hz), 2,43 (3H, s), 2,53 of 2.68 (2H, m), 3.04 from (2H, square, J=7 Hz), 3,42-3,53 (1H, m), 4,08 (2H, square, J=7 Hz), 4,69 (2H, s), 5,88 (1H, d, J=4 Hz), 6,55 (1H, d, J=4 Hz), 7,53 (1H, s), 8,42 (1H, d, J=2 Hz), 8,53 (1H, d, J=2 Hz).

Example 294

Ethyl-5-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}entanet

1H NMR (CDCl3) δ 1,22-1,62 (10H, m)of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,73 is 1.86 (2H, m), 1,98-2,07 (2H, m)to 2.18 (2H, t, J=7 Hz), 2,53-2,70 (2H, m), 3,03 (2H, square, J=7 Hz), 3.42 points of 3.56 (1H, m), 4,12 (2H, square, J=7 Hz), 4,69 (2H, s), 5,88 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,88 (1H, m), 8,54 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

Example 295

Ethyl-3-[2-[(cyclohexyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ to 1.19 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,16-of 1.45 (4H, m), 1,52-of 1.65 (2H, m), 1,73 of-1.83 (2H, m), 1,98-2,07 (2H, m), 2,35-2,47 (2H, m), 2,42 (3H, s), 2,84 are 2.98 (2H, m), 3,03 (2H, square, J=7 Hz), 3,45 of 3.56 (1H, m)4,06 (2H, square, J=7 Hz), 4,71 (2H, s), of 5.89 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), to 7.50 (1H, s), 8,42 (1H, s), 8,53 (1H, s).

MS (ESI+): m/z 450.

Example 296

Ethyl-3-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}propanoate

1H NMR (CDCl3) δ of 1.20 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,15-to 1.60 (6H, m), 1,73-of 1.85 (2H, m), 1,97-of 2.08 (2H, m), of 2.45 (2H, t, J=7 Hz), 2,83-of 2.97 (2H, m), 3,05 (2H, square, J=7 Hz), 3.42 points of 3.56 (1H, m), 4,08 (2H, square, J=7 Hz), 4,71 (2H, s), 5,90 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,86 (1H, t, J=2 Hz), 8,53 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (ESI+): m/z 514, 516.

Example 297

Ethyl-5-[7-ethyl-2-(isopropoxyphenyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.26 (6H, d, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,38-of 1.62 (4H, m), 2,17 (2H, t, J=7 Hz), 2,43 (3H, s), 2,53 of 2.68 (2H, m), 3,03 (2H, square, J=7 Hz), 3,76-3,88 (1H, m), 4,08 (2H, square, J=7 Hz), of 4.66 (2H, s), 5,88 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), 7,52 (1H, s), 8,42 (1H, s), 8,53 (1H, s).

MS ESI +): m/z 438.

Example 298

Ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isopropoxyphenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), 1,25 (6H, d, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,37-of 1.64 (4H, m), of 2.15 (2H, t, J=7 Hz), 2,54-of 2.72 (2H, m), to 3.02 (2H, square, J=7 Hz), 3.75 to a 3.87 (1H, m), 4.09 to (2H, square, J=7 Hz), of 4.66 (2H, s), of 5.89 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,88 (1H, m), 8,55 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

MS (ESI+): m/z 502, 504.

Example 299

Ethyl-5-[2-[(atomic charges)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1.30 and was 1.58 (4H, m), 2,13 (2H, t, J=7 Hz), to 2.18 (3H, s), is 2.44 (3H, s), 2.40 a is 2.55 (2H, m), to 3.02 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), from 5.29 (2H,with), to 5.93 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,52 (1H, s), 8,42 (1H, s), 8,53 (1H, s).

MS (ESI+): m/z 438.

The following compounds were obtained according to a similar method of example 236.

Example 300

Ethyl-4-{4-[5-(1-ethoxyphenyl)-3-pyridinyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}butanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), of 1.41 (3H, t, J=7 Hz), 1,68 and 1.80 (2H, m), 2,22 (2H, t, J=7 Hz), 2,44-of 2.54 (2H, m), 2,59 (3H, s), 3,03 (2H, square, J=7 Hz), 3,95 (2H, square, J=7 Hz), 4,10 (2H, square, J=7 Hz), 4,36 (1H, d, J=3 Hz), of 4.77 (1H, d, J=3 Hz), 5,88 (1H, d, J=4 Hz), of 6.52 (1H, d, J=4 Hz), 7,92 (1H, m), 8,53 (1H, d, J=2 Hz), 8,93 (1H, d, J=2 Hz).

MS (ESI+): m/z 422.

Example 301

Ethyl-3-[4-[5-(1-ethoxyphenyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ to 1.19 (3H, t, J=7 Hz), and 1.6 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 2,42 (2H, t, J=7 Hz), 2,84-of 2.97 (2H, m), of 3.07 (2H, square, J=7 Hz), 3,47 (3H, s), of 3.97 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), 4,36 (1H, d, J=3 Hz), of 4.66 (2H, C)of 4.77 (1H, d, J=3 Hz), 5,95 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,92 (1H, m), 8,54 (1H, d, J=2 Hz), of 8.95 (1H, d, J=2 Hz).

MS (ESI+): m/z 438.

Example 302

Ethyl-3-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ of 1.18 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 2.40 a (2H, t, J=7 Hz), 2,84 are 2.98 (2H, m), 3,03 (2H, square, J=7 Hz), 3,47 (3H, s), Android 4.04 (2H, square, J=7 Hz)and 4.65 (2H, s), 5,46 (1H, d, J=11 Hz), by 5.87 (1H, d, J=18 Hz), 5,94 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 6,72-6,83 (1H, DD, J=11 Hz and 18 Hz), 7,74 (1H, m), 8,49 (1H, d, J=2 Hz), 8,72 (1H, d, J=2 Hz).

MS (ESI+): m/z 394.

Example 303

Methyl-4-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,65-of 1.78 (2H, m), of 2.23 (2H, t, J=7 Hz), 2,54-2,70 (2H, m), 3,05 (2H, square, J=7 Hz), 3,47 (3H, s)to 3.58 (3H, s), of 4.67 (2H, s), 5,46 (1H, d, J=11 Hz), 5,88 (1H, d, J=18 Hz), to 5.93 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 6.73 x-6,83 (1H, DD, J=11 Hz and 18 Hz), to 7.77 (1H, m), 8,51 (1H, d, J=2 Hz), 8,71 (1H, d, J=2 Hz).

MS (ESI+): m/z 394.

Example 304

Methyl-4-[4-[5-(1-ethoxyphenyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,67-to 1.82 (2H, m), 2,22 (2H, t, J=7 Hz), 2,53-to 2.67 (2H, m), 3.04 from (2H, square, J=7 Hz), 3,47 (3H, s)to 3.58 (3H, s), of 3.95 (2H, square, J=7 Hz), 4,34 (1H, d, J=2 Hz), of 4.67 (2H, s), of 4.77 (1H, d, J=2 Hz), to 5.93 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 7,92 (1H, m), 8,54 (1H, d, J=2 Hz), of 8.95 (1H, d, J=2 Hz)

MS (ESI+): m/z 438.

Example 305

Ethyl-3-{4-[5-(1-ethoxyphenyl)-3-pyridinyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}propanoate

1H NMR (CDCl3) δ to 1.19 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), of 1.44 (3H, t, J=7 Hz), 2,33 is 2.43 (2H, m), 2,58 (3H, s), was 2.76-2,87 (2H, m), 3,03 (2H, square, J=7 Hz), 3.96 points (2H, square, J=7 Hz), 4,06 (2H, square, J=7 Hz), 4,36 (1H, d, J=2 Hz), of 4.77 (1H, d, J=2 Hz), 5,91 (1H, d, J=4 Hz), is 6.54 (1H, d, J=4 Hz), to $ 7.91 (1H, m), 8,53 (1H, d, J=2 Hz), 8,96 (1H, d, J=2 Hz).

MS (ESI+): m/z 408.

The following compounds were obtained according to the similar procedure of example 251.

Example 306

Ethyl-4-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ to 1.19 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,66-to 1.82 (2H, m), of 2.21 (2H, t, J=7 Hz), 2,41 is 2.51 (2H, m)2,60 (3H, s), 2,69 (3H, s), 3,03 (2H, square, J=7 Hz), a 4.03 (2H, square, J=7 Hz), of 5.83 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), of 8.25 (1H, m), 8,79 (1H, d, J=2 Hz), the 9.25 (1H, d, J=2 Hz).

MS (ESI+): m/z 394.

Example 307

Ethyl-3-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ of 1.18 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), is 2.41 (2H, t, J=7 Hz), 2,70 (3H, s), 2,83-2,96 (2H, m), 3,06 (2H, square, J=7 Hz), 3,47 (3H, s), a 4.03 (2H, square, J=7 Hz), of 4.66 (2H, s), 5,88 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), compared to 8.26 (1H, m), 8,79 (1H, d, J=2 Hz), the 9.25 (1H, d, J=2 Hz).

Example 308

Methyl-4-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,64 and 1.80 (2H, m), of 2.20 (2H, t, J=7 Hz), 2,53-to 2.65 (2H, m), 2,70 (3H, s), 3,05 (2H, square, J=7 Hz), 3,47 (3H, s), and 3.7 (3H, C)of 4.67 (2H, s), by 5.87 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), of 8.27 (1H, s), 8,81 (1H, d, J=2 Hz), 9,26 (1H, d, J=2 Hz).

MS (ESI+): m/z 410.

Example 309

Ethyl-3-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ to 1.19 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 2,33-to 2.42 (2H, m), 2,59 (3H, s), 2,69 (3H, s), 2,75-and 2.83 (2H, m), to 3.02 (2H, square, J=7 Hz), of 4.05 (2H, square, J=7 Hz), of 5.83 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), of 8.25 (1H, m), 8,78 (1H, d, J=2 Hz), 9,26 (1H, d, J=2 Hz).

MS (ESI+): m/z 380.

Example 310

A mixture of benzyl-5-[3-(5-ethoxy-5-oxobutyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-4-yl]nicotinate (330 mg) and 10% palladium on carbon (33 mg) in methanol (10 ml) was stirred in hydrogen atmosphere (4 ATM) at ambient temperature for 2 hours. The catalyst was filtered and washed with chloroform. The filtrate was evaporated in vacuo to obtain 5-[3-(5-ethoxy-5-oxobutyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-4-yl]nicotinic acid as a yellow oil (272 mg).

5-[3-(5-ethoxy-5-oxobutyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-4-yl]nicotinic acid

1H NMR (CDCl3) δ to 1.21 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,35-to 1.63 (4H, m), 2,19 (2H, t, J=7 Hz), 2,38-2,49 (2H, m), to 2.57 (3H, s), 3,03 (2H, square, J=7 Hz), 4,11 (2H, square, J=7 Hz), to 5.85 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 8,40 (1H, m), 8,83 (1H, d, J=2 Hz), 9,37 (1H, d, J=2 Hz).

MS (ESI-): m/z 408, MS (ESI+): m/z 410.

Example 311

To a solution of 5-[3-(5-ethoxy-5-oxobutyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-4-yl]nicotinic acid (25 mg) and triethylamine (87,1 mg) in tert-butanol (10 ml) was added diphenylphosphoryl (237 mg) and the mixture is boiled under reflux for 2 hours. After evaporation of the solvent the residue was distributed between ethyl acetate and water. The organic layer was separated, washed with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (20:1-2:1), to obtain ethyl-5-(4-{5-[(tert-butoxycarbonyl)amino]-3-pyridinyl}-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl)pentanoate in the form of a yellow oil (190 mg).

Ethyl-5-(4-{5-[(tert-butoxycarbonyl)amino]-3-pyridinyl}-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl)pentanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,42-to 1.67 (4H, m), of 1.52 (9H, s), 2,19-of 2.28 (2H, m), 2,38-of 2.50 (2H, m)to 2.55 (3H, s), 3,03 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), of 5.92 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 6,93 (1H, usher.), 7,87 (1H, s), 8,30 (1H, d, J=2 Hz), to 8.70 (1H, d, J=2 Hz).

MS (ESI+): m/z 481.

Example 312

A solution of ethyl-5-(4-{5-[(tert-butoxycarbonyl)amino]-3-pyridinyl}-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl)pentanoate (190 mg) in 2n. an ethyl acetate solution of hydrogen chloride (4 ml) was stirred at ambient temperature for 2 hours. After evaporation of the solvent the residue was distributed between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, washed with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified column of chromatogra what s on silica gel, elwira with a mixture of chloroform and methanol (100:1-20:1), to obtain ethyl-5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate in the form of a yellow oil (140 mg).

Ethyl-5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-of 1.65 (4H, m), of 2.23 (2H, t, J=7 Hz), a 2.45 (2H, t, J=7 Hz), of 2.54 (3H, s), 3,03 (2H, square, J=7 Hz), of 3.97 (2H, usher.), of 4.12 (2H, square, J=7 Hz), 5,94 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,02 (1H, m), 8,02 (1H, d, J=2 Hz), 8,17 (1H, d, J=2 Hz).

MS (ESI+): m/z 381 (M+H).

Example 313

To a solution of ethyl-5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate (55 mg), 37% solution of formaldehyde (277 mg) and cyanoborohydride sodium (27.3 mg) in acetonitrile (1 ml) and methanol (1 ml) was added acetic acid (2 drops) and the mixture was stirred at ambient temperature for 2 hours. The solution was diluted with saturated sodium bicarbonate solution and was extracted with chloroform. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified preparative column chromatography on silica gel, elwira with a mixture of chloroform and methanol (20:1), to obtain ethyl-5-{4-[5-(dimethylamino)-3-pyridinyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}pentanoate in the form of a yellow oil (to 36.5 mg).

Ethyl-5-{4-[5-(dimethylamino)-3-pyridinyl]-7-ethyl-2-methylpyrrole[1,2-b]is ridazin-3-yl}pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-to 1.63 (4H, m), 2,19 (2H, t, J=7 Hz), 2.40 a of $ 2.53 (2H, m)to 2.55 (3H, s), to 3.02 (6H, s), 3,03 (2H, square, J=7 Hz), 4.09 to (2H, square, J=7 Hz), to 5.93 (1H, d, J=4 Hz), 6,50 (1H, d, J=4 Hz), of 6.96 (1H, m), 7,95 (1H, d, J=2 Hz), to 8.20 (1H, d, J=2 Hz).

MS (ESI+): m/z 409.

The following compounds were obtained according to a similar method of example 245.

Example 314

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

1H NMR (CDCl3) δ of 1.29 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 2,45-of 2.58 (2H, m), 2,73 (2H, square, J=7 Hz), 2,82-to 3.02 (2H, m), 3,03 (2H, square, J=7 Hz), 3,47 (3H, s), of 4.67 (2H, s), 5,91 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 7,58 (1H, m), 8,43 (1H, d, J=2 Hz), 8,53 (1H, d, J=2 Hz).

MS (ESI-): m/z 366, MS (ESI+): m/z 368.

Example 315

4-[7-ethyl-4-(5-ethyl-3-pyridinyl)-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid

1H NMR (CDCl3) δ to 1.31 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,69-of 1.85 (2H, m), 2,20-2,31 (2H, m), 2,52 is 2.75 (2H, m), 2,77 (2H, square, J=7 Hz), 3,06 (2H, square, J=7 Hz), of 3.46 (3H, s), 4,60-4,80 (2H, m), 5,91 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), to 7.61 (1H, s), 8,44 are 8.53 (2H, m).

MS (ESI+): m/z 382.

The following compounds were obtained according to a similar method of example 228.

Example 316

Methyl-4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,65-to 1.79 (2H, m), of 2.25 (2H, t, J=7 Hz), 2,39 of $ 2.53 (2H, m), 3,06 (2H, square, J=7 Hz), 3,61 (3H, s), the 4.90 (2H, s), 5,96 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,88 (1H, m), 8,55 (1H, d, J=2 Hz), 8,79 (1H, d, J=2 Hz).

MS (ESI+): m/z 432, 434.

Example 317

Ethyl-5-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,35-to 1.60 (4H, m), 2,17 (2H, t, J=7 Hz), 2,35 at 2.45 (2H, m), 2,43 (3H, s), 3.04 from (2H, square, J=7 Hz), 3,83 (1H, t, J=7 Hz), 4,10 (2H, square, J=7 Hz), is 4.85 (2H, d, J=7 Hz), 5,96 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), to 7.50 (1H, s), 8,42 (1H, s), 8,54 (1H, s).

MS (ESI+): m/z 396.

The following compounds were obtained according to a similar method of example 268.

Example 318

Methyl-4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,65-to 1.79 (2H, m), 2,24 (2H, t, J=7 Hz), 2,52-2,70 (2H, m), 3.04 from (2H, square, J=7 Hz), of 3.46 (3H, s), of 3.60 (3H, s), was 4.76 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,88 (1H, m), 8,56 (1H, d, J=2 Hz), 8,79 (1H, d, J=2 Hz).

MS (ESI+): m/z 446, 448.

Example 319

Ethyl-5-[2-[(2-tert-butoxy-2-oksidoksi)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,30-1,60 (4H, m)of 1.47 (9H, s), 2,17 (2H, t, J=7 Hz), 2,43 (3H, s), 2,58-of 2.72 (2H, m), 3,03 (2H, square, J=7 Hz), 4,08 (2H, s), of 4.12 (2H, square, J=7 Hz), to 4.81 (2H, s), 5,91 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,53 (1H, s), 8,43 (1H, s), 8,53 (1H, s).

MS (ESI+): m/z 510.

Example 320

Ethyl-5-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ 0,20-0,32 (2H, m), of 0.53 to 0.63 (2H, m), 1,07 is 1.20 (1H, m)to 1.22 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-1,60 (4H, m), of 2.15 (2H, t, J=7 Hz), 2,43 (3H, s), 2,53 of 2.68 (2H, m), to 3.02 (2H, square, J=7 Hz), to 3.41 (2H, d, J=7 Hz), 4,08 (2H, square, J=7 Hz), 4,70 (2H, s), of 5.89 (1H, d, J=4 Hz), 6,56 (1H, d, J=4 Hz), 7,52 (1H, s), 8,43 (1H, s), 8,53 (1H, s).

MS (ESI+): m/z 450.

Example 321

Ethyl-5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ from 0.88 to 1.05 (2H, m), of 1.16 and 1.35 (4H, m), 1,25 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,38-to 1.59 (4H, m), 1.60-to of 1.87 (5H, m)of 2.16 (2H, t, J=7 Hz), 2,43 (3H, s), 2,54-to 2.67 (2H, m), 3,03 (2H, square, J=7 Hz), 3,35 (2H, d, J=7 Hz), 4,10 (2H, square, J=7 Hz), with 4.64 (2H, s), of 5.89 (1H, d, J=4 Hz), 6,56 (1H, d, J=4 Hz), 7,52 (1H, s), 8,43 (1H, d, J=2 Hz), 8,53 (1H, d, J=2 Hz).

MS (ESI+): m/z 492.

Example 322

Ethyl-5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(3-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), of 1.39 (3H, t, J=7 Hz), 1,35-and 1.54 (4H, m), 2,12 (2H, t, J=7 Hz), 2,43 (3H, s), 2,50-2,63 (2H, m), 3,03 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), of 4.66 (2H, s), was 4.76 (2H,, (C), of 5.92 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,28 (1H, m), 7,52 (1H, s), 7,72 (1H, d, J=8 Hz), 8,42 (1H, d, J=2 Hz), 8,54 (2H, m), to 8.62 (1H,d, J=2 Hz).

MS (ESI+): m/z 487.

Example 323

Ethyl-5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (CDCl3) δ to 1.21 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,36-and 1.54 (4H, m), 2,12 (2H, t, J=7 Hz), 2,42 (3H, s), 2,56 of 2.68 (2H, m), 3,03 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), of 4.77 (2H, s), is 4.85 (2H,, (C), of 5.92 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,22 (1H, m), 7,43-rate of 7.54 (2H, m), 7,66-7,74 (1H, m), 8,42 (1H, d, J=2 Hz), 8,54 (1H, d, J=2 Hz), to 8.57 (1H, d, J=5 Hz).

MS (ESI+): m/z 487.

Example 324

Ethyl-5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), of 1.39 (3H, t, J=7 Hz), 1,38-of 1.57 (4H, m), 2,12 (2H, t, J=7 Hz), 2,43 (3H, s), 2,52 of 2.68 (2H, m), 3,05 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), of 4.66 (2H, s), of 4.77 (2H,with), to 5.93 (1H, d, J=4 Hz), 6,60 (1H, d, J=2 Hz), 7,28 (2H, d, J=7 Hz), 7,52 (1H, s), 8,42 (1H, d, J=2 Hz), 8,53 (1H, d, J=2 Hz), 8,58 (2H, d, J=7 Hz).

MS (ESI+): m/z 487.

Example 325

Ethyl-5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-personalitate)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,38-of 1.57 (4H, m), 2,13 (2H, t, J=7 Hz), 2,43 (3H, s), 2,52 of 2.68 (2H, m), 3,03 (2H, square, J=7 Hz), 4,07 (2H, square, J=7 Hz), 4,82 (2H, s), 4,88 (2H,, m)of 5.92 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,52 (1H, s), 8,43 (1H, d, J=2 Hz), 8,48-to 8.57 (3H, m), is 8.75 (1H, m).

MS (ESI+): m/z 488.

Example 326

Ethyl-5-[4-(3-cyanophenyl)-2-(ethoxymethyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ 1,18-of 1.29 (6H, m), 1,34-1,53 (7H, m), and 2.14 (2H, t, J=7 Hz), 2,52 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,53 (2H, square, J=7 Hz), 4,07 (2H, square, J=7 Hz), of 4.66 (1H, s), 5,73 (1J, d, J=5 Hz), 6,56 (1H, d, J=5 Hz), 7,60 (2H, m), to 7.67 (1H, s), of 7.75 (1H, m).

Example 327

Ethyl-5-[2-[(benzyloxy)methyl]-4-(3-cyanophenyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), 1.30 and 1,46 (7H, m)to 2.06 (2H, t, J=7 Hz), of 2.51 (2H, m), to 3.02 (2H, square, J=7 Hz), 4,07 (2H, square, J=7 Hz), with 4.64 (3H, s), 4.72 in (3H, s), of 5.83 (1H, d, J=5 Hz), to 6.57 (1H, d, J=5 Hz), 7,25-7,38 (5H, m), EUR 7.57 (2H, the, J=9 Hz), the 7.65 (1H, s), 7,74 (1H, m).

Example 328

Methyl-4-({[4-(3-cyanophenyl)-3-(5-ethoxy-5-oxobutyl)-7-acylpyrrole[1,2-b]pyridazin-2-yl]methoxy}methyl)benzoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), 1.32 to-1,49 (7H, m), a 2.01 (2H, t, J=7 Hz), 2,52 (2H, m), to 3.02 (2H, t, J=7 Hz), to 3.92 (3H, s)4,07 (2H, t, J=7 Hz), 4,69 (2H, s), and 4.75 (2H, s), at 6.84 (1H, d, J=5 Hz), 6,59 (1H, d, J=5 Hz), the 7.43 (2H, d, J=9 Hz), 7,60 (2H, m), the 7.65 (1H, s), of 7.75 (1H, m), 8,02 (2H, d, J=9 Hz),

Example 329

A solution of ethyl-5-[2-[(2-tert-butoxy-2-oksidoksi)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (60 mg) in triperoxonane acid (2 ml) was stirred at ambient temperature for 2 hours and evaporated in vacuum to obtain {[3-(5-ethoxy-5-oxobutyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-2-yl]methoxy}acetic acid as a brown oil (55 mg).

{[3-(5-ethoxy-5-oxobutyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-2-yl]methoxy}acetic acid

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,35-to 1.60 (4H, m), of 2.23 (2H, t, J=7 Hz), 2,50-of 2.58 (2H, m)to 2.67 (3H, s), 3,03 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), 4,30 (2H, s), to 4.87 (2H,with), 5,86 (1H, d, J=4 Hz), to 6.67 (1H, d, J=4 Hz), 8,15 (1H, s), 8,69 (1H, s), cent to 8.85 (1H, s).

MS (ESI-): m/z 452, MS (ESI+): m/z 454.

Example 330

To a solution of {[3-(5-ethoxy-5-oxobutyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-2-yl]methoxy}acetic acid (55 mg), hydrochloride of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (34,9 mg) and 1-guide is oxibendazole (24.6 mg) in dimethylformamide (2 ml) was added morpholine (12.7mm mg) and the mixture was stirred at ambient temperature in for 1 hour. The mixture was distributed between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira a mixture of ethyl acetate and methanol (50:1-20:1), to obtain ethyl-5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[2-(4-morpholinyl)-2-oksidoksi]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate in the form of a yellow oil (50 mg).

Ethyl-5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[2-(4-morpholinyl)-2-oksidoksi]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-to 1.63 (4H, m), of 2.15 (2H, t, J=7 Hz), 2,43 (3H, s), 2,54 of 2.68 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,48 is 3.57 (2H, m), 3,63-of 3.78 (6H, m), 4,08 (2H, square, J=7 Hz), 4,30 (2H, s), 4,78 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,52 (1H, s), 8,43 (1H, d, J=2 Hz), 8,54 (1H, d, J=2 Hz).

MS (ESI+): m/z 523.

The following compound was obtained according to a similar method of example 330.

Example 331

Ethyl-5-[7-ethyl-2-{[2-(methylamino)-2-oksidoksi]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,38-of 1.62 (4H, m)to 2.18 (2H, t, J=7 Hz), 2,44 (3H, s), 2,48-2,62 (2H, m), is 2.88 (3H, d, J=7 Hz), 3,03 (2H, square, J=7 Hz), 4,11 (2H, square, J=7 Hz), of 4.13 (2H, s), of 4.77 (2H, s)5,94 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 6,79 (1H, usher.), 7,53 (1H, s), 8,44 (1H, s), 8,56 (1H, s).

MS (ESI+): m/z 467.

The following connection recip is whether a similar method of example 271.

Example 332

Ethyl-5-[2-[(benzylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,30-1,50 (2H, m), 1.60-to of 1.85 (2H, m), 2,12 (2H, t, J=7 Hz), 2,30 at 2.45 (2H, m), 2,42 (3H, s), 3,03 (2H, square, J=7 Hz), of 3.96 (2H, s), 3,98 (2H, s), 4,08 (2H, square, J=7 Hz), by 5.87 (1H, d, J=4 Hz), is 6.54 (1H, d, J=4 Hz), 7,27-the 7.43 (5H, m), of 7.48 (1H, s), scored 8.38 (1H, d, J=2 Hz), 8,53 (1H, d, J=2 Hz).

MS (ESI+): m/z 485.

Example 333

A mixture of ethyl-5-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (100 mg), 1H-isoindole-1,3(2H)-dione (44,6 mg), diisopropylcarbodiimide (76,7 mg) and triphenylphosphine (99,5 mg) in tetrahydrofuran (2 ml) was stirred at ambient temperature for 1 hour. After evaporation of the solvent the residue was purified column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (20:1-1:1), to obtain ethyl-5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate in the form of a yellow oil (107 mg).

Ethyl-5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ to 0.89 (3H, t, J=7 Hz), of 1.26 (3H, t, J=7 Hz), 1,20-1,40 (2H, m), 1,53 is 1.75 (2H, m), 2,24 (2H, t, J=7 Hz), 2,44 (3H, s), 2,47 (2H, square, J=7 Hz), 2,50-of 2.64 (2H, m), of 4.12 (2H, square, J=7 Hz), 5,10 (2H, s), to 5.85 (1H, d, J=4 Hz), to 6.43 (1H, d, J=4 Hz), 7,51 (1H, s), 7,78 (2H, m), of 7.96 (2H, m), 8,43 (1H, s), 8,55 (1H, s).

MS (ESI+): m/ 525.

Example 334

A mixture of ethyl-5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (107 mg) and hydrazine monohydrate (51,1 mg) in ethanol (2 ml) was boiled under reflux for 2 hours. After evaporation of the solvent the residue was distributed between chloroform and saturated sodium bicarbonate solution. The organic layer was separated, washed with saturated salt solution, dried over magnesium sulfate and evaporated in vacuo to obtain ethyl-5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate in the form of a yellow oil (67,6 mg).

Ethyl-5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,38-of 1.62 (4H, m), and 2.14 (2H, t, J=7 Hz), 2,42 (3H, s), 2,38-of 2.56 (2H, m), 3.04 from (2H, square, J=7 Hz), 4,06 (2H, s)4,08 (2H, square, J=7 Hz), 5,90 (1H, d, J=4 Hz), 6,55 (1H, d, J=4 Hz), 7,51 (1H, s), to 8.41 (1H, s), 8,53 (1H, s).

MS (ESI+): m/z 395.

Example 335

A mixture of ethyl-5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (67,6 mg) and acetic anhydride (19.2 mg) in dichloromethane (3 ml) was stirred at ambient temperature for 1 hour. The solution was diluted with chloroform, washed with saturated sodium bicarbonate solution and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified is reparative column chromatography on silica gel, elwira with a mixture of chloroform and methanol (20:1), to obtain ethyl-5-[2-[(acetylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate in the form of a yellow oil (70 mg).

Ethyl-5-[2-[(acetylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), of 1.40 (3H, t, J=7 Hz), 1,40-to 1.63 (4H, m), 2,12 (2H, m), of 2.15 (3H, s), 2,43 (3H, s), 2,40 of $ 2.53 (2H, m), 3,03 (2H, square, J=7 Hz), 4,10 (2H, square, J=7 Hz), of 4.66 (2H, m), 5,94 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 6,85 (1H, usher.), to 7.50 (1H, s), 8,40 (1H, d, J=2 Hz), 8,54 (1H, d, J=2 Hz).

MS (ESI+): m/z 437.

Example 336

To a solution of ethyl-5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (80 mg) and pyridine (1 ml) in dichloromethane (2 ml) was added methanesulfonamide (34.8 mg) while cooling the mixture in ice-water and the mixture was stirred at ambient temperature for 1 hour. The solution was diluted with chloroform, washed with saturated sodium bicarbonate solution and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified preparative column chromatography on silica gel, elwira with a mixture of chloroform and methanol (20:1), to obtain ethyl-5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(methylsulphonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate in the form of a yellow oil (of 62.8 mg).

Ethyl-5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(methylsulphonyl)amino]methyl}pyrrolo[1,2-b]p is ridazin-3-yl)pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.39 (3H, t, J=7 Hz), 1,40-of 1.62 (4H, m), 2,19 (2H, t, J=7 Hz), 2,44 (3H, s), 2,38 is 2.51 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,06 (3H, s)4,08 (2H, square, J=7 Hz), 4,58 (2H,with), 5,63 (1H, usher.), 5,97 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), to 7.50 (1H, s), to 8.41 (1H, d, J=2 Hz), 8,54 (1H, d, J=2 Hz).

MS (ESI+): m/z 473.

Example 337

A mixture of ethyl-5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (75 mg), benzoic acid (27.9 mg), hydrochloride of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (54,7 mg) and 1-hydroxybenzotriazole (a 38.5 mg) in dimethylformamide (2 ml) was stirred at ambient temperature for 2 hours. The mixture was distributed between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified preparative column chromatography on silica gel, elwira with a mixture of chloroform and methanol (20:1), to obtain ethyl-5-[2-[(benzoylamine)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate in the form of a yellow oil (60 mg).

Ethyl-5-[2-[(benzoylamine)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.42 (3H, t, J=7 Hz), 1,42-of 1.65 (4H, m), 2,17 (2H, t, J=7 Hz), 2,44 (3H, s), 2,44-of 2.58 (2H, m), 3,06 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), a 4.86 (2H, m), 5,96 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,46-to 7.59 (4H, m, for 7.78 (1H, usher.), to $ 7.91-of 7.97 (2H, m), 8,44 (1H, d, J=2 Hz), 8,56 (1H, d, J=2 Hz).

MS (ESI+): m/z 499.

The following compound was obtained according to a similar method of example 337.

Example 338

Ethyl-5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(2-pyrazinecarboxamide)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.41 (3H, t, J=7 Hz), 1,42-of 1.64 (4H, m)to 2.18 (2H, t, J=7 Hz), 2,44 (3H, s), 2,47 at 2.59 (2H, m), is 3.08 (2H, square, J=7 Hz), 4.09 to (2H, square, J=7 Hz), 4,89 (2H, d, J=7 Hz), 5,96 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,53 (1H, s), 8,43 (1H, d, J=2 Hz), 8,55 (1H, d, J=2 Hz), to 8.62 (1H, m), 8,79 (1H, m)to 9.15 (1H, usher.), 9,46 (1H, m).

MS (ESI+): m/z 501.

Example 339

To a solution of ethyl-5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (80 mg) and pyridine (1 ml) in dichloromethane (2 ml) was added methylchlorosilanes (34.8 mg) while cooling the mixture in ice-water and the mixture was stirred at ambient temperature for 2 hours. After evaporation of the solvent the residue was distributed between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified preparative column chromatography on silica gel, elwira with a mixture of chloroform and methanol (20:1), to obtain ethyl 5-[7-ethyl-2-{[(methoxycarbonyl)amino]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate in the IDA yellow oil (70 mg).

Ethyl-5-[7-ethyl-2-{[(methoxycarbonyl)amino]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.39 (3H, t, J=7 Hz), 1,40-to 1.63 (4H, m), 2,19 (2H, t, J=7 Hz), 2,44 (3H, s), 2.40 a is 2.55 (2H, m), 3,03 (2H, square, J=7 Hz), of 3.07 (3H, s), of 4.12 (2H, square, J=7 Hz), of 4.57 (2H,, m)5,72 (1H, usher.), 5,97 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,51 (1H, s), to 8.41 (1H, s), 8,56 (1H, s).

Example 340

To a solution of ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (70.0 mg) and triethylamine (18.5 mg) in dichloromethane (1 ml) was added methanesulfonamide (20,9 mg) in a bath with ice. After stirring for 1 hour to the mixture was added 1-methylpiperazine (27.0 mg). The mixture was stirred for 0.5 hour in a bath with ice and overnight at room temperature. The mixture was distributed between ethyl acetate and water. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated. Preparative thin layer chromatography on silica gel (chloroform-methanol=20:1) gave ethyl-5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-methyl-1-piperazinil)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate in the form of a yellow resin (a 52.4 mg, 63.5 per cent).

Ethyl-5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-methyl-1-piperazinil)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (CDCl3): of 1.23 (3H, t, J=7 Hz), 1,33-1,60 (7 H, m)of 2.16 (2H, t, J=7 Hz), to 2.29 (3H, s), 2,34-to 2.65 (6H, m)of 3.00 (2H, square, J=7 Hz), of 3.54 (2H, s)4,08 (2H, square, J=7 Hz), 5,86 (1H, d, J=5 Hz), and 6.5 (1H, d, J=5 Hz), 7,87 (1H, m), 8,54 (1H, m), 8,77 (1H, m).

Example 341

To a solution of ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (300 mg, 0,652 mmol) and tetrabromomethane (432 mg, of 1.30 mmol) in tetrahydrofuran (3 ml) was added triphenylphosphine (308 mg, 1,17 mmol) for 40 minutes. The mixture was concentrated and the residue was subjected to flash chromatography on a column of silica gel (ethyl acetate-hexane=1:8-1:5) to give ethyl-5-[2-(methyl bromide)-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate in the form of a yellow resin (229 mg, 50.4 percent).

Ethyl-5-[2-(methyl bromide)-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1.41 to 1.50 in (4H, m), 2,19 (2H, t, J=7 Hz), 2,58 (2H, m), 3,01 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), of 4.66 (2H, s)5,94 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), 7,88 (1H, m), 8,55 (1H, m), 8,79 (1H, m).

Example 342

A mixture of ethyl-5-[2-(methyl bromide)-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate (70.0 mg) and potassium cyanide (13.1 mg) in N,N-dimethylformamide (1 ml) was stirred for 28 hours at room temperature. The mixture was distributed between ethyl acetate and water. The organic layer was washed with water (twice), saturated salt solution, dried over magnesium sulfate and evaporated to obtain ethyl-5-[4-(5-bromo-3-pyridinyl)-2-(cyanomethyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate in the form of a yellow resin (28.8 mg, 45.9 per cent).

Ethyl-5-[4-(5-bromo-3-p is riginal)-2-(cyanomethyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ to 1.24 (3H,t, J=7 Hz), 1,46-of 1.65 (7H, m), 2,22 (2H, t, J=7 Hz), 2,48 (2H, m), 3.04 from (2H, square, J=7 Hz), 3,98 (2H, s), 4,10 (2H, square, J=7 Hz), 5,98 (1H, d, J=5 Hz), of 6.65 (1H, d, J=5 Hz), 7,88 (1H, m), 8,55 (1H, m), 8,81 (1H, m).

The following compounds were obtained according to a similar method of example 76.

Example 343

[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]acetic acid

1H NMR (CDCl3) δ of 1.36 (3H, t, J=7 Hz), a 2.45 (3H, s), of 2.56 (3H, s), to 3.02 (2H, square, J=7 Hz), or 3.28 (1H, d, J=17 Hz), 3,53 (1H, d, J=17 Hz), 5,91 (1H, d, J=4 Hz), of 6.52 (1H, d, J=4 Hz), 7,71 (1H, s), of 8.47 (1H, s), 8,59 (1H, s).

MS (ESI-): m/z 308, MS (ESI+): m/z 310.

Example 344

4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]butane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,65-of 1.85 (2H, m), 2,31 (2H, t, J=7 Hz), a 2.45-2.63 in (2H, m), 2,59 (3H, s), 3,03 (2H, square, J=7 Hz), 5,88 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), of 7.90 (1H, s), 8,53 (1H with), is 8.75 (1H, s).

MS (ESI-): m/z 400, 402, MS (ESI+): m/z 402, 404.

Example 345

4-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]butane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,68-to 1.82 (2H, m), and 2.26 (2H, t, J=7 Hz), 2,45-of 2.58 (2H, m)2,60 (3H, s), 2,70 (3H, s), 3,03 (2H, square, J=7 Hz), of 5.83 (1H, d, J=4 Hz), is 6.54 (1H, d, J=4 Hz), of 8.28 (1H, m), 8,77 (1H, d, J=2 Hz), 9,19 (1H, d, J=2 Hz).

Example 346

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

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 2.49 USD (2H, t, J=7 Hz), 2,80-3,00 (2H, m), 3,05 (2H, square, J=7 Hz), 3.46 in (H, C)of 4.66 (2H, s)5,94 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,88 (1H, s), 8,55 (1H, s), 8,77 (1H, s).

MS (ESI-): m/z 416, 418, MS (ESI+): m/z 418, 420.

Example 347

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

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 2,48 (2H, t, J=7 Hz), 2,68 (3H, s), 2,85-of 2.97 (2H, m), 3,05 (2H, square, J=7 Hz), 3,47 (3H, s), of 4.67 (2H, s), 5,88 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), of 8.27 (1H, m,), 8,78 (1H, d, J=2 Hz), 9,23 (1H, d, J=2 Hz).

MS (ESI-): m/z 380, MS (ESI+): m/z 382.

Example 348

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

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 2,46-of 2.58 (2H, m), 2,83-3,03 (2H, m), 3,05 (2H, square, J=7 Hz), 3,47 (3H, s), and 4.68 (2H, s), 5,46 (1H, d, J=11 Hz), 5,88 (1H, d, J=18 Hz), to 5.93 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 6,68-PC 6.82 (1H, DD, J=11 Hz and 18 Hz), 7,78 (1H, m), of 8.47 (1H, d, J=2 Hz), 8,68 (1H, d, J=2 Hz).

MS (ESI-): m/z 364, MS (ESI+): m/z 366.

Example 349

4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,68-to 1.82 (2H, m)to 2.29 (2H, t, J=7 Hz), 2,55 is 2.75 (2H, m), 3.04 from (2H, square, J=7 Hz), of 3.45 (3H, s), with 4.64 (2H, s), to 5.93 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), to $ 7.91 (1H, m), 8,56 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (ESI-): m/z 430, 432, MS (ESI+): m/z 432, 434.

Example 350

4-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,72-to 1.87 (2H, m), and 2.26 (2H, t, J=7 Hz), 2,3-2,80 (2H, m)a 3.06 (2H, square, J=7 Hz), of 3.46 (3H, s), and 4.68 (2H, m), vs. 5.47 (1H, d, J=11 Hz), 5,88 (1H, d, J=18 Hz), to 5.93 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 6,72-6,83 (1H, DD, J=11 Hz and 18 Hz), 7,81 (1H, m), and 8.50 (1H, d, J=2 Hz), 8,63 (1H, d, J=2 Hz).

MS (ESI-): m/z 378, MS (ESI+): m/z 380.

Example 351

4-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,66 of-1.83 (2H, m), and 2.26 (2H, t, J=7 Hz), 2,55-2,70 (2H, m), 2,70 (3H, s), 3,05 (2H, square, J=7 Hz), of 3.46 (3H, s), of 4.67 (2H, s), 5,88 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz),8,29 (1H, m), 8,80 (1H, d, J=2 Hz), which 9.22 (1H, d, J=2 Hz).

MS (ESI-): m/z 394, MS (ESI+): m/z 396.

Example 352

5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ of 1.34 (3H, t, J=7 Hz), 1,44-of 1.65 (4H, m), 2,16 of-2.32 (2H, m), 2,34 is 2.46 (2H, m), of 2.53 (3H, s), to 3.02 (2H, square, J=7 Hz), is 5.06 (2H, usher.), 5,86 (1H, d, J=4 Hz), 5,98 (1H, d, J=4 Hz), 7,45 (1H, s), to 7.84 (1H, s), 8,58 (1H, s).

MS (ESI-): m/z 351, MS (ESI+): m/z 353.

Example 353

5-{4-[5-(dimethylamino)-3-pyridinyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,40-1,70 (4H, m), of 2.23 (2H, m), a 2.36-of 2.50 (2H, m), of 2.56 (3H, s), 3,03 (2H, square, J=7 Hz), 3,06 (6H, s), 5,88 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,13 (1H, s), of 7.90 (1H, s)to 8.14 (1H, m).

MS (ESI+): m/z 381.

Example 354

3-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]propanoic acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 2.40 a of $ 2.53 (2H, m)2,60 (3H, s), 2,68 (3H, s), and 2.83 (2H, t, J=7 is C), 3,03 (2H, square, J=7 Hz), of 5.83 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), of 8.27 (1H, m), 8,78 (1H, d, J=2 Hz), which 9.22 (1H, d, J=2 Hz).

MS (ESI-): m/z 350, MS (ESI+): m/z 352.

Example 355

5-[2-[(benzyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,35-of 1.55 (4H, m), 2.05 is-of 2.20 (2H, m), 2,42 (3H, s), 2.40 a-2,70 (2H, m), 3,03 (2H, square, J=7 Hz), 4,63 (2H, s), 4,74 (2H, m), 5,88 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,27-7,42 (5H, m), 7,53 (1H, s), 8,40 (1H, s), 8,53 (1H, s).

MS (ESI+): m/z 458.

Example 356

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

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 2.40 a (3H, s), 2,40-of 2.54 (2H, m), 2,80-is 3.08 (2H, m), 3,06 (2H, square, J=7 Hz)and 4.65 (2H, s), of 4.77 (2H, m), of 5.89 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,26-7,42 (5H, m), 7,54 (1H, s), 8,39 (1H, d, J=2 Hz), 8,48 (1H, d, J=2 Hz).

MS (ESI-): m/z 428, MS (ESI+): m/z 430.

Example 357

5-[2-[(cyclohexyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ 1,20-of 1.45 (6H, m)of 1.36 (3H, t, J=7 Hz), 1,45-to 1.63 (4H, m), 1.70 to to 1.83 (2H, m), 1,95-of 2.08 (2H, m), 2,14-of 2.28 (2H, m), 2,42 (3H, s), 2,46-2,60 (1H, m), 2,60-of 2.75 (1H, m), 3,03 (2H, square, J=7 Hz), 3,42-of 3.54 (1H, m), 4.72 in (2H, m), by 5.87 (1H, d, J=4 Hz), is 6.54 (1H, d, J=4 Hz), 7,55 (1H, s), to 8.41 (1H, s), 8,53 (1H, s).

MS (ESI-): m/z 448, MS (ESI+): m/z 450.

Example 358

5-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ 1,18-to 1.60 (10H, m), of 1.36 (3H, t, J=7 Hz), 1,70-1,80 (2H, m), 1,95-of 2.05 (2H, m), 2,22 (2H, t, J=7 Hz), 2,50-2,70 (2H, m), 3,03 (2H, square, J=7 Hz), 3,42-of 3.53 (1H, m), and 4.68 (2H, s), of 5.89 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,88 (1H, s), 8,54 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (ESI+): m/z 514, 516.

Example 359

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

1H NMR (CDCl3) δ 1,20-of 1.45 (5H, m)to 1.37 (3H, t, J=7 Hz), 1,50-1,60 (1H, m), 1,72-of 1.84 (2H, m), 1,96-of 2.08 (2H, m), 2,42 (3H, s), 2,48-2,62 (2H, m), 2,80-3,10 (2H, m), 3,03 (2H, square, J=7 Hz), 3,44-3,66 (1H, m), 4,73 (2H, s), 5,88 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), 7,55 (1H, s), 8,40 (1H, s), 8,51 (1H, s).

MS (ESI+): m/z 422.

Example 360

3-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}propanoic acid

1H NMR (CDCl3) δ of 1.18 to 1.47 (5H, m)to 1.37 (3H, t, J=7 Hz), 1,52-to 1.63 (1H, m), 1,72-of 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, square, J=7 Hz), 3,44 is 3.57 (1H, m), to 4.73 (2H, s), 5,91 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,88 (1H, t, J=2 Hz), 8,55 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (ESI-): m/z 484, 486, MS (ESI+): m/z 486, 488.

Example 361

5-[7-ethyl-2-(isopropoxyphenyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ 1,25 (6H, d, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,44-to 1.63 (4H, m), 2,15-of 2.27 (2H, m), 2,43 (3H, s), 2,47-2,60 (1H, m), 2,60-by 2.73 (1H, m), 3,03 (2H, square, J=7 Hz), 3.75 to a 3.87 (1H, m), of 4.67 (2H, s), by 5.87 (1H, d, J=4 Hz), 6,56 (1H, d, J=4 Hz), 7,55 (1H, s), to 8.41 (1H, s), 8,53 (1H, s).

MS (ESI-): m/z 408, MS (ESI+): m/z 410.

Example 362

5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-isopropoxyphenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ 1,25 (6H, d, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,45-of 1.65 (4H, m), of 2.23 (2H, t, J=7 Hz), 2,50-2,60 (2H, m), 3,03 (2H, square, J=7 Hz), 3.75 to of 3.85 (1H, m), of 4.66 (2H, s), of 5.89 (1H, d, J=4 Hz), 6,58 (1H, d, J=4 Hz), 7,89 (1H, m), 8,54 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (ESI+): m/z 474, 476.

Example 363

5-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,40-of 1.65 (4H, m), 2,22 (2H, t, J=7 Hz), 2,33 at 2.45 (2H, m), 2,43 (3H, s), 3,03 (2H, square, J=7 Hz), to 4.87 (2H, s)5,94 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), 7,56 (1H with), 8,43 (1H, s), 8,54 (1H, s).

MS (ESI-): m/z 366, MS (ESI+): m/z 368.

Example 364

5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[2-(4-morpholinyl)-2-oksidoksi]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentane acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,40-to 1.63 (4H, m), 2,22 (2H, t, J=7 Hz), 2,43 (3H, s), 2,50-of 2.72 (2H, m), 3,03 (2H, square, J=7 Hz), 3,51 (2H, m), 3,57 of 3.75 (6H, m), 4,32 (2H, s), 4,70-a 4.86 (2H, m), 5,90 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 7,53 (1H, s), 8,42 (1H, s), 8,53 (1H, s).

MS (ESI-): m/z 493, MS (ESI+): m/z 495.

Example 365

5-[7-ethyl-2-{[2-(methylamino)-2-oksidoksi]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,40-of 1.65 (4H, m), 2,22 (2H, t, J=7 Hz), 2,44 (3H, s), 2,45-of 2.64 (2H, m), 2,87 (3H, m), 3,03 (2H, square, J=7 Hz), 4,13 (2H, s), 4,74 (2H, m), to 5.93 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 6,83 (1H, usher.), EUR 7.57 (1H, s), 8,42 (1H, s), 8,53 (1H, s).

MS (ESI-): m/z 437, MS (ESI+): m/z 439.

Example 366

5-[2-[(cyclopropylmethoxy)IU is Il]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ 0,23 is 0.33 (2H, m), 0.55 to 0.64 in (2H, m), 1,07-1,22 (1H, m)of 1.36 (3H, t, J=7 Hz), 1,45 by 1.68 (4H, m), 2,19 (2H, t, J=7 Hz), 2,43 (3H, s), 2,50-2,75 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,40 (2H, d, J=7 Hz), 4,70 (2H, m), by 5.87 (1H, d, J=4 Hz), 6,56 (1H, d, J=4 Hz), EUR 7.57 (1H, s), 8,40 (1H, s), 8,54 (1H, s).

MS (ESI+): m/z 422.

Example 367

5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ 0,87 of-1.04 (2H, m), 1,10-1,82 (13H, m)to 1.37 (3H, t, J=7 Hz), to 2.18 (2H, t, J=7 Hz), 2,43 (3H, s), 2,47-of 2.72 (2H, m), 3,03 (2H, square, J=7 Hz), to 3.33 (2H, d, J=7 Hz), 4,63 (2H, m), by 5.87 (1H, d, J=4 Hz), 6,56 (1H, d, J=4 Hz), 7,56 (1H, s), 8,42 (1H, s), 8,53 (1H, s).

MS (ESI-): m/z 462, MS (ESI+): m/z 464.

Example 368

5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(3-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,35-of 1.57 (4H, m), 2,13 (2H, t, J=7 Hz), 2,42 (3H, s), 2,47-of 2.66 (2H, m), 3,03 (2H, square, J=7 Hz), and 4.68 (2H, s), of 4.77 (2H, m), 5,90 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 7,28 and 7.36 (1H, m), 7,53 (1H, s), 7,73 (1H, d, J=8 Hz), to 8.41 (1H, d, J=2 Hz), 8,53 (2H, m), 8,63 (1H, s).

MS (ESI-): m/z 457, MS (ESI+): m/z 459.

Example 369

5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,45-of 1.65 (4H, m), of 2.23 (2H, t, J=7 Hz), is 2.41 (3H, s), 2,48-to 2.74 (2H, m), 3,03 (2H, square, J=7 Hz), 4,80 (2H, s), 4,82 (2H, m), 5,88 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), 7,26 (1H, m), 7,47-7,53 (2H, m), 7,69-to 7.77 (1H, m), 8,42 (1H, d, J=2 Hz)and 8.50 (1H, d, J=2 Hz), 8,58 (1H, d, J=7 Hz).

MS(ESI -): m/z 457, MS (ESI+): m/z 459.

Example 370

5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,40-of 1.62 (4H, m)of 2.16 (2H, t, J=7 Hz), 2,43 (3H, s), 2,48-a 2.71 (2H, m), to 3.02 (2H, square, J=7 Hz), and 4.68 (2H, s), 4,79 (2H, m), 5,91 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,32 (2H, d, J=7 Hz), 7,54 (1H, s), 8,42 (1H, d, J=2 Hz), 8,54 (1H, d, J=2 Hz), 8,55 (2H, d, J=7 Hz).

MS (ESI-): m/z 457, MS (ESI+): m/z 459.

Example 371

5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-personalitate)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,45-of 1.62 (4H, m)to 2.18 (2H, t, J=7 Hz), 2,43 (3H, s), 2,48-by 2.73 (2H, m), 3,03 (2H, square, J=7 Hz), a 4.83 (2H, s), 4,88 (2H, m), 5,90 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 7,54 (1H, s), 8,42 (1H, s), 8,48-8,56 (3H, m), 8,76 (1H, s).

MS (ESI-): m/z 458, MS (ESI+): m/z 460.

Example 372

5-[2-[(benzylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (DMSO-d6) δ of 1.33 (3H, t, J=7 Hz), of 1.28 to 1.48 (4H, m), 2,03 and 2.13 (2H, m), 2,30 at 2.45 (2H, m), is 2.40 (3H, s), 3,06 (2H, square, J=7 Hz), 4,37 (2H, s), to 4.46 (2H, s), of 5.92 (1H, d, J=4 Hz), of 6.68 (1H, d, J=4 Hz), 7,40-7,52 (3H, m), 7,56-to 7.67 (3H, m), at 8.36 (1H, d, J=2 Hz), to 8.57 (1H, d, J=2 Hz).

MS (ESI+): m/z 457.

Example 373

5-[2-[(acetylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ of 1.40 (3H, t, J=7 Hz), 1,40-of 1.64 (4H, m)of 2.16 (3H, s), of 2.23 (2H, t, J=7 Hz), 2,35-of 2.50 (2H, m), 2,43 (3H, s), 3,03 (2H, square, J=Hz), 4,63-4,72 (2H, m), of 5.92 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), 6,88-6,97 (1H, usher.), 7,53 (1H, s), to 8.41 (1H, s), 8,53 (1H, s).

MS (ESI-): m/z 407, MS (ESI+): m/z 409.

Example 374

5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(methylsulphonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,46-of 1.66 (4H, m), of 2.23 (2H, t, J=7 Hz), 2,44 (3H, s), 2,39 of $ 2.53 (2H, m), 3,03 (2H, square, J=7 Hz), 3,05 (3H, s), of 4.57 (2H, s)5,72 (1H, usher.), 5,96 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,54 (1H, s), to 8.41 (1H, d, J=2 Hz), 8,55 (1H, d, J=2 Hz).

MS (ESI-): m/z 443, MS (ESI+): m/z 445.

Example 375

5-[2-[(benzoylamine)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ of 1.42 (3H, t, J=7 Hz), 1.50 is by 1.68 (4H, m), of 2.25 (2H, t, J=7 Hz), 2,44 (3H, s), 2,40-2,60 (2H, m), of 3.07 (2H, square, J=7 Hz), 4,89 (2H, m), 5,95 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,46-7,60 (4H, m), 7,83 (1H, usher.), to 7.93 (2H, d, J=8 Hz), 8,44 (1H, d, J=2 Hz), 8,56 (1H, d, J=2 Hz).

MS (ESI-): m/z 469, MS (ESI+): m/z 471.

Example 376

5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(2-pyrazinecarboxamide)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentane acid

1H NMR (CDCl3) δ of 1.41 (3H, t, J=7 Hz), 1,51-1,72 (4H, m), 2,24 (2H, t, J=7 Hz), 2,44 (3H, s), 2,45-of 2.58 (2H, m), 3,10 (2H, square, J=7 Hz), of 4.90 (2H, m)5,94 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 7,55 (1H with), 8,43 (1H, s), 8,53 (1H, s), to 8.62 (1H, m), 8,79 (1H, d, J=2 Hz), 9,20 (1H, usher.), to 9.45 (1H, d, J=2 Hz).

MS (ESI-): m/z 471, MS (ESI+): m/z 473.

Example 377

5-[7-ethyl-2-{[(methoxycarbonyl)amino]methyl}-4-(5-methyl-3-pyridinyl)Pyrrhus is lo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,45-of 1.65 (4H, m), of 2.23 (2H, t, J=7 Hz), 2.40 a of $ 2.53 (2H, m), is 2.44 (3H, s), to 3.02 (2H, square, J=7 Hz), 3,05 (3H, s), 4,58 (2H, s)5,69 (1H, usher.), 5,96 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,53 (1H, s), to 8.41 (1H, d, J=2 Hz), 8,54 (1H, d, J=2 Hz).

Example 378

To a solution of ethyl-7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-carboxylate (682 mg) in ethanol (20 ml) was added a solution (10 ml) of potassium hydroxide (5 g) and the mixture is boiled under reflux for 1 hour. The solution was acidified using 1N. hydrochloric acid to pH 3-4 and was diluted with saturated salt solution and was extracted with chloroform twice. The organic layer was separated, dried over magnesium sulfate and evaporated in vacuum. The crude product is triturated in ethyl acetate to obtain 7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-carboxylic acid as a yellow powder (590 mg).

7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-carboxylic acid

1H NMR (CDCl3) δ of 1.39 (3H, t, J=7 Hz), 2,44 (3H, s), 2,69 (3H, s), 3,05 (2H, square, J=7 Hz), of 6.29 (1H, d, J=4 Hz), to 6.67 (1H, d, J=4 Hz), of 7.97 (1H, s), to 8.41 (1H, s), 8,58 (1H, s).

MS (ESI-): m/z 294, MS (ESI+): m/z 296.

The following compounds were obtained according to a similar method of example 175.

Example 379

5-[4-(3-cyanophenyl)-2-(ethoxymethyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), 1,34-1,53 (7H, m), of 2.20 (2H, t, J=7 Hz), 2,53 (2H, m),3,03 (2H, square, J=7 Hz), 3,62 (2H, square, J=7 Hz), of 4.66 (2H, s), 5,33 (1H, d, J=5 Hz), to 6.57 (1H, d, J=5 Hz), 7,60 (2H, m), 7,66 (1H, s), 7,74 (1H, m).

Example 380

5-[2-[(benzyloxy)methyl]-4-(3-cyanophenyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ 1,30-1,46 (7H, m), 2,11 (2H, t, J=7 Hz), 2,50 (2H, m), to 3.02 (2H, square, J=7 Hz), with 4.64 (3H, s), 4,71 (3H, s), of 5.83 (1H, d, J=5 Hz), 6,56 (1H, d, J=5 Hz), 7,25-7,34 (5H, m), EUR 7.57 (2H, d, J=9 Hz), the 7.65 (1H, s), 7,74 (1H, m)

MS (ESI+): m/z 468 (M+H).

Example 381

4-({[3-(4-carboxybutyl)-4-(3-cyanophenyl)-7-acylpyrrole[1,2-b]pyridazin-2-yl]methoxy}methyl)benzoic acid

1H-NMR (CDCl3) δ 1,05 was 1.43 (7H, m), with 1.92 (2H, m), 2,31 (2H, m), 3.04 from (2H, m)and 4.65 (2H, s), 4.72 in (2H, s), of 5.82 (1H, m), to 6.58 (1H, m), 7,46-to 7.77 (6H, m), of 8.09 (2H, d, J=8 Hz).

MS (ESI+): m/z 510 (M-H).

Example 381-2

4-({[4-[3-(carbarnoyl)phenyl]-3-(4-carboxybutyl)-7-acylpyrrole[1,2-b]pyridazin-2-yl]methoxy}methyl)benzoic acid

1H-NMR (CDCl3) δ 1,20-1,45 (7H, m), 2,03 (2H, m), 2,52 (2H, m), 3,03 (2H, square, J=7 Hz), 4,69 (2H, s), to 4.73 (2H, s), are 5.36 (1H, d, J=5 Hz), to 6.57 (1H, d, J=5 Hz), 7,39-of 7.60 (4H, m), to 7.77 (1H, s), to 7.93 (1H, d, J=8 Hz), 7,98 (2H, d, J=8 Hz).

MS (ESI+): m/z 528 (M-H).

The following compounds were obtained according to a similar method of example 77.

Example 382

5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-methyl-1-piperazinil)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ of 1.34 (3H, t, J=7 Hz), 1,38-to 1.59 (4H, m), 2,22 (2H, m), 2,43-2,60 (5H, m), 2,83 totaling 3.04 (8H, m), 3,74 (3H, s), 5,88 (1H, d, J=5 Hz), 6,56 (1H, d, J=5 Hz), 7,87 (1H, m), 8,54 (1H, m), 8,76 (1H, m).

Example 383

5-[4-(5-bromo-3-pyridinyl)-2-(cyanomethyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ 1,35-to 1.60 (7H, m), and 2.27 (2H, m), 2,46 (2H, m), 3,03 (2H, square, J=7 Hz), 3,98 (2H, s), of 3.97 (1H, d, J=5 Hz), of 6.65 (1H, d, J=5 Hz), of 7.90 (1H, m), 8,54 (1H, s, of usher.), 8,79 (1H, s, of usher.).

Example 384

5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ 1,35-to 1.60 (7H, m), 2,22 (2H, t, J=7 Hz), of 2.38 (2H, m), to 3.02 (2H, square, J=7 Hz), a 4.86 (2H, s), 5,95 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,88 (1H, m), 8,54 (1H, s, of usher.), 8,79 (1H, s, of usher.).

Example 385

To a solution of 7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-carboxylic acid (70 mg), hydrochloride of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (68,2 mg) and 1-hydroxybenzotriazole (48 mg) in dimethylformamide (2 ml) was added 2-aminoethanol (17,4 mg) and the mixture was stirred at ambient temperature for 1 hour. The mixture was distributed between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of chloroform and methanol (50:1-10:1). The crude product is triturated in isopropyl ether to obtain 7-ethyl-N-(2-hydroxyethyl)-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-carboxym is Yes in the form of a yellow powder (47 mg).

7-ethyl-N-(2-hydroxyethyl)-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-carboxamide

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 2,39 (3H, s), to 2.57 (3H, s), to 3.02 (2H, square, J=7 Hz), to 3.33 (2H, m), of 3.45 (2H, m), 6,03 (1H, usher.), of 6.31 (1H, d, J=4 Hz), of 6.66 (1H, d, J=4 Hz), 7,71 (1H, s), of 8.47 (1H, s), 8,58 (1H, s).

MS (ESI-): m/z 337, MS (ESI+): m/z 339.

The following compounds were obtained according to a similar method of example 385.

Example 386

N-butyl-7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-carboxamide

1H NMR (CDCl3) δ to 0.80 (3H, t, J=7 Hz), 0,96-1,08 (2H, m), 1,08-1,25 (2H, m)to 1.38 (3H, t, J=7 Hz), 2.40 a (3H, s), of 2.56 (3H, s), 3,03 (2H, square, J=7 Hz), and 3.16 (2H, m), are 5.36 (1H, usher.), of 6.31 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,69 (1H, s), 8,53 (1H, s), to 8.62 (1H, s).

MS (ESI+): m/z 351.

Example 387

Ethyl-3-({[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]carbonyl}amino)propanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), of 2.21 (2H, t, J=7 Hz), 2.40 a (3H, s)to 2.55 (3H, s), 3,03 (2H, square, J=7 Hz), 3.43 points (2H, square, J=7 Hz), Android 4.04 (2H, square, J=7 Hz), between 6.08 (1H, usher.), 6,30 (1H, d, J=4 Hz), of 6.65 (1H, d, J=4 Hz), to 7.67 (1H, s), and 8.50 (1H, d, J=1 Hz), at 8.60 (1H, d, J=1 Hz).

MS (ESI+): m/z 395.

The following compounds were obtained according to a similar method of obtaining 176.

Example 388

4-(5-bromo-3-pyridinyl)-7-ethyl-2-methyl-3-[3-(4-morpholinyl)-3-oxopropyl]pyrrolo[1,2-b]pyridazin

1H NMR(CDCl3) δ to 1.37 (3H, t, J=7 Hz), is 2.41 (2H, t, J=7 Hz), 2,60 (3H, s), 2,72-2,82 (2H, m), 3,01 (2H, square, J=7 Hz), 3,19 (2H, t, J=5 Hz), 3,55 (4H, t, J=5 Hz), 3,63(2H, t, J=5 Hz), of 5.89 (1H, d, J=4 Hz), 6,55 (1H, d, J=4 Hz), 7,87 (1H, t, J=1 Hz), 8,54 (1H, d, J=1 Hz), 8,77 (1H, d, J=1 Hz).

MS (m/z 457(M+), 459(M++2), 115(dB).

TPL 178-180°C.

Example 389

3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]-N-methylpropanamide

1H NMR(CDCl3) δ to 1.38 (3H, t, J=7 Hz), measuring 2.20 (2H, t, J=7 Hz), 2,60 (3H, s)of 2.75 (3H, d, J=6 Hz), 2,78-2,89 (2H, m), 3,01 (2H, square, J=7 Hz), to 5.21 at 5.27 (1H, m), 5,88 (1H, d, J=4 Hz), is 6.54 (1H, d, J=4 Hz), 7,86 (1H, t, J=1 Hz), 8,53 (1H, d, J=1 Hz), 8,78 (1H, d, J=1 Hz).

MS (m/z 401(M++1), 403(M++1), 115(dB).

TPL 172-174°C.

The following compound was obtained according to a similar method of example 263.

Example 390

N-{3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]propanol}methanesulfonamide

1H NMR(CDCl3) δ of 1.36 (3H, t, J=7 Hz), 2,33 at 2.45 (2H, m), 2,58 (3H, s), 2,84-2,95 (2H, m), 3,01 (2H, square, J=7 Hz), 3,26 (3H,s), of 5.89 (1H, d, J=4 Hz), 6,56 (1H, d, J=4 Hz), of 7.90 (1H, s), and 8.50 (1H, s), 8,77 (1H, s).

MS (m/z 465(M+, dB), 467(M+-2, dB).

TPL 196,5-197,5°C.

The following compound was obtained according to a similar method of example 224.

Example 391

2-[{3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]propanol}(methyl)amino]econsultancy acid

1H NMR (CDCl3) δ to 1.32 (3H, t, J=7 Hz), 1,90 2H, m), and 2.26 (3H, s), 2.57 m-2,2,78 (4H, m), 2,98 (2H, square, J=7 Hz), and 3.31 (2H, m)6,00 (1H, d, J=5 Hz), is 6.61 (1H, d, J=5 Hz), 7,20-7,52 (5H, m).

The following compounds were obtained according to a similar method of obtaining 20.

Getting 217

1-tert-butyl-7-e is Il-2-(isobutoxy)heptanoate

1H NMR (300 MHz, CDCl3) δ of 0.95 (6H, d, J=7 Hz), of 1.27 (3H, t, J=7 Hz), 1,31-of 1.41 (2H, m)of 1.46 (9H, s)of 1.66 (2H, TT, J=7, 7 Hz), a 1.75-to 1.98 (3H, m), 2,31 (2H, t, J=8 Hz), 3,26 (2H, d, J=7 Hz), of 3.56 (1H, t, J=7 Hz), 4,06-4,17 (4H, m).

Getting 218

1-tert-butyl-6-ethyl-2-(isobutoxy)hexanedioic

1H NMR (300 MHz, CDCl3) δ of 0.93 (6H, d, J=7 Hz), 1,25 (3H, t, J=7 Hz), a 1.45 (9H, s), 1,59 was 1.69 (2H, m), 1,80-of 1.95 (3H, m), 2,32 (2H, t, J=7 Hz), of 2.25 (2H, d, J=7 Hz), 3,57 (1H, t, J=7 Hz), 4,10 (2H, s), of 4.12 (2H,, square, J=7 Hz).

The following compounds were obtained according to a similar method of obtaining 24.

Getting 219

1-tert-butyl-6-ethyl-2-acetyl-2-(2-horizonation)hexanedioic

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), of 1.34 (9H, s), 1.60-to of 1.73 (2H, m), 2,22 of-2.32 (2H, m), 2,39 (2H, t, J=7 Hz), 2.49 USD (3H, s), of 4.12 (2H, square, J=7 Hz), 7,43 (1H, d, J=5 Hz), EUR 7.57 (1H, s), and 8.50 (1H, d, J=5 Hz).

MS (ESI+): m/z 412.

Getting 220

1-tert-butyl-5-ethyl-2-acetyl-2-(2-horizonation)pentanedioic

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,72-of 1.84 (2H, m), of 2.33 (2H, t, J=7 Hz), 2,47-to 2.57 (2H, m), 2,58 (3H, s), 3,03 (2H, square, J=7 Hz), 5,88 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,27 (1H, m), 7,38 (1H with), 8,53 (1H, d, J=5 Hz).

MS (ESI-): m/z 356, MS (ESI+): m/z 358.

Getting 221

1-tert-butyl-7-ethyl-2-(2-horizonation)-2-(phenylacetyl)heptanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.35 (9H, s), and 1.63 to 1.76 (2H, m), 2,22-is 2.37 (4H, m), 3,93 (1H, d, J=17 Hz), of 4.12 (2H, square, J=7 Hz), 4,29 (1H, d, J=17 Hz), 7,22 (2H, d, J=8 Hz), 7,26 and 7.36 (4H, m), 7,50 (1H, s), 8,42 (1H, d, J=5 Hz),

MS (ESI+): m/z 502.

Getting 222/p>

tert-Butyl 2-[2-(2-methoxy-2-oksidoksi)ethyl]-2-[(5-methyl-3-pyridinyl)carbonyl]-3-oxobutanoate

1H NMR (CDCl3) δ of 1.33 (9H, s), 2,39 (3H, s), 2,47 (3H, s), 2,62 (2H, t, J=7 Hz), 3,66 (2H, m), 3,70 (3H, s), 3,90 (2H, s), 7,87 (1H, s), 8,56 (1H, s), is 8.75 (1H, s).

MS (ESI+): m/z 394.

Getting 223

1-tert-butyl-4-ethyl-2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]succinate

1H NMR (CDCl3) δ of 1.27 (3H, t, J=7 Hz), of 1.41 (9H, s), a 2.45 (3H, s), up 3.22 (2H, m), of 4.12 (2H, square, J=7 Hz), by 8.22 (1H, m), 8,80 (1H, m), 8,82 (1H, m).

MS (ESI+): m/z 428, 430.

Getting 224

1-tert-butyl-5-ethyl-2-[(atomic charges)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioic

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.35 (9H, s), and 2.14 (3H, s), is 2.40 (3H, s), 2.40 a-2,48 (2H, m), 2,62-2,70 (2H, m), of 4.12 (2H, square, J=7 Hz), 5,12 (1H, d, J=18 Hz), of 5.34 (1H, d, J=18 Hz), the 7.85 (1H, s), 8,58 (1H, s), 8,78 (1H, s),

MS (ESI+): m/z 436.

Getting 225

1-tert-butyl-6-ethyl-2-[(atomic charges)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]hexanedioic

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.34 (9H, s), 1,60-1,75 (2H, m), and 2.14 (3H, s), 2.26 and-2,39 (4H, m), is 2.40 (3H, s), of 4.12 (2H, square, J=7 Hz), 5,13 (1H, d, J=18 Hz), of 5.40 (1H, d, J=18 Hz), 7,86 (1H, s), to 8.57 (1H, s), 8,78 (1H, s).

MS (ESI+): m/z 450.

Getting 226

1-tert-butyl-7-ethyl-2-[(atomic charges)acetyl]-2-(3-cyanobenzoyl)heptanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), 1,32 (9H, s), 1,26 of 1.46 (2H, m), of 1.66-1.77 in (2H, m), and 2.14 (3H, s), 2.26 and-of 2.38 (4H, m), of 4.12 (2H, square, J=7 Hz), is 5.06 (1H, d, J=18 Hz), 5,42 (1H, d, J=18 Hz), EUR 7.57 (1H, t, J=8 Hz), 7,81 (1H, d, J=8 Hz), 7,92 (1H, d, J=8 Hz), of 8.09 (1H, s).

Getting 227

1-tert-butyl-6-ethyl-2-[(atomic charges)acetyl]-2-[(5-bromo-3-pyridinyl)carbonyl]hexanedioic

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), of 1.36 (9H, s), 1.60-to around 1.74 (2H, m), 1.85 to a 1.96 (2H, m), and 2.14 (3H, s), 2,28-to 2.42 (2H, m), of 4.12 (2H, square, J=7 Hz), 5,12 (1H, d, J=17 Hz), 5,42 (1H, d, J=17 Hz), 8,23 (1H, m), 8,81 (1H, m), 8,83 (1H, m).

Getting 228

1-tert-butyl-5-ethyl-2-[(atomic charges)acetyl]-2-[(5-bromo-3-pyridinyl)carbonyl]pentanedioic

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), of 1.37 (9H, s), and 2.14 (3H, s), 2,41 is 2.51 (2H, m)to 2.66 (2H, t, J=7 Hz), 4,13 (2H, square, J=7 Hz), 5,11 (1H, d, J=18 Hz), 5,33 (1H, d, J=18 Hz), by 8.22 (1H, m), 8,82 (2H, m,).

MS (ESI+): m/z 500, 502.

Getting 229

1-tert-butyl-5-ethyl-2-[(cyclohexylmethoxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioic

1H NMR (CDCl3) δ 0,80-0,98 (2H, m), and 1.00-to 1.32 (3H, m)of 1.23 (3H, t, J=7 Hz), to 1.38 (9H, s), 1,46-of 1.62 (6H, m), 2,39 (3H, s), 2.40 a-2,72 (4H, m), 3,19 (2H, d, J=7 Hz), of 4.12 (2H, square, J=7 Hz), or 4.31 (1H, d, J=17 Hz), 4,39 (1H, d, J=17 Hz), 7,88 (1H, s), 8,56 (1H, s), 8,77 (1H, s).

MS (ESI+): m/z 490.

Getting 230

1-tert-butyl-5-ethyl-2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(cyclohexylmethoxy)acetyl]pentanedioic

1H NMR (CDCl3) δ 0,78-0,98 (2H, m), 1,10-of 1.33 (3H, m), 1,25 (3H, t, J=7 Hz), of 1.40 (9H, s), 1,38 of-1.83 (6H, m), 2,35 is 2.75 (4H, m), up 3.22 (2H, d, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,25 (1H, d, J=17 Hz), 4,37 (1H, d, J=17 Hz), by 8.22 (1H, s), 8,78 (1H, s), 8,86 (1H, s).

MS (ESI+): m/z 554, 556.

Getting 231

1-tert-butyl-6-ethyl-2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(cyclohexylmethoxy)acetyl]hexanedioic

1H I Is R (CDCl 3) δ the 0.80 to 0.97 (2H, m), 1,12-of 1.35 (3H, m), 1,25 (3H, t, J=7 Hz), of 1.39 (9H, s), 1,46 and 1.80 (10H, m), 2,22 at 2.45 (2H, m), 3,20 (2H, d, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,30 (1H, d, J=17 Hz), to 4.38 (1H, d, J=17 Hz), by 8.22 (1H, s), 8,78 (1H, s), cent to 8.85 (1H, s).

MS (ESI+): m/z 568, 570.

Getting 232

1-tert-butyl-6-ethyl-2-[(cyclopropylmethoxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]hexanedioic

1H NMR (CDCl3) δ of 0.16 to 0.28 (2H, m), 0,48 is 0.59 (2H, m), 0,98-1,12 (1H, m)of 1.24 (3H, t, J=7 Hz), of 1.37 (9H, s), 1.55V and 1.80 (4H, m), 2,18-to 2.40 (2H, m), 2,39 (3H, s), and 3.31 (2H, m), of 4.12 (2H, square, J=7 Hz), to 4.38 (1H, d, J=17 Hz), a 4.53 (1H, d, J=17 Hz), 7,88 (1H, s), 8,55 (1H, d, J=2 Hz), the rate of 8.75 (1H, d, J=2 Hz),

MS (ESI+): m/z 462.

Getting 233

1-tert-butyl-5-ethyl-2-[(cyclopropylmethoxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioic

1H NMR (CDCl3) δ 0,15-0,23 (2H, m), 0,48-of 0.56 (2H, m), 0,95-1,10 (1H, m)of 1.24 (3H, t, J=7 Hz), of 1.39 (9H, s), 2,39 (3H, s), 2,40 of 2.68 (4H, m), or 3.28 (2H, m), of 4.12 (2H, square, J=7 Hz), 4,36 (1H, d, J=17 Hz), 4,48 (1H, d, J=17 Hz), 7,88 (1H, s), 8,55 (1H, s), is 8.75 (1H, s).

MS (ESI+): m/z 448.

Getting 234

1-tert-butyl-5-ethyl-2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(2-methoxyethoxy)acetyl]pentanedioic

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), of 1.46 (9H, s), 2,15 was 2.25 (2H, m), 2,42-of 2.72 (2H, m)to 3.38 (3H, s), 3,48-and 3.72 (4H, m), of 4.12 (2H, square, J=7 Hz), 4,43 (1H, d, J=17 Hz), 4,58 (1H, d, J=17 Hz), by 8.22 (1H, s), 8,78 (1H, s), 8,82 (1H, s).

MS (ESI+): m/z 516, 518.

Getting 235

tert-Butyl 2-[(5-bromo-3-pyridinyl)carbonyl]-3-oxobutanoate

1H NMR (CDCl3) δ 1,22, of 1.30 (9H, s), 2,22, of 2.45 (3H, s), of 7.96, 8,13 (1H, s), 8,66, 8,76-8,80 (2H, m).

Paul is an increase of 236

1-tert-butyl-6-ethyl-2-[(atomic charges)acetyl]-2-[(5-chloro-3-pyridinyl)carbonyl]hexanedioic

1H NMR (300 MHz, CDCl3) δ 1,25 (3H, t, J=7 Hz), of 1.36 (9H, s), 1,63-1,71 (2H, m), and 2.14 (3H, s), 2,27-to 2.40 (4H, m), 4,13 (2H, square, J=7 Hz), 5,11 (1H, d, J=18 Hz), 5,38 (1H, d, J=18 Hz), 8,07 (1H, DD, J=2 Hz), 8,71 (1H, d, J=2 Hz), 8,80 (1H, d, J=2 Hz).

Getting 237

1-tert-butyl-7-ethyl-2-[(5-chloro-3-pyridinyl)carbonyl]-2-[(cyclopropylmethoxy)acetyl]heptanoate

1H NMR (300 MHz, CDCl3) δ 0,15-0,20 (2H, m), 0,49 is 0.58 (2H, m), 0,95 was 1.04 (1H, m)of 1.24 (3H, t, J=7 Hz), to 1.38 (9H, s), 1,68 (2H, TT, J=7, 7 Hz), 2,14 is 2.33 (4H, m), 3,26-3,29 (2H, m), 4,07-4,19 (4H, m), or 4.31 (1H, d, J=17 Hz), of 4.45 (1H, d, J=17 Hz), with 8.05 (1H, DD, J=2 Hz), 8,68 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

Getting 238

1-tert-butyl-6-ethyl-2-[(5-chloro-3-pyridinyl)carbonyl]-2-[(cyclopropylmethoxy)acetyl]hexanedioic

1H NMR (300 MHz, CDCl3) δ of 0.14-0.21 (2H, m), 0,49 is 0.55 (2H, m), 0,92 of-1.04 (1H, m), 1,25 (3H, t, J=7 Hz), of 1.39 (9H, s), 1,62-of 1.74 (2H, m), 1,82-1,90 (2H, m), 2.21 are of 2.33 (2H, m), 3.27 to and 3.31 (2H, m), of 4.12 (2H, square, J=7 Hz), 4,34 (1H, d, J=18 Hz), 4,46 (1H, d, J=18 Hz), 8,07 (1H, DD, J=2, 2 Hz), 8,68 (1H, d, J=2 Hz), 8,80 (1H, d, J=2 Hz).

Getting 239

1-tert-butyl-7-ethyl-2-[(5-bromo-3-pyridinyl)carbonyl]-2-(isobutoxy)heptanoate

1H NMR (300 MHz, CDCl3) δ of 0.85 (6H, d, J=7 Hz), 1,24 (3H, t, J=7 Hz), to 1.38 (9H, s)to 1.67 (2H, t, J=7 Hz), 1,75-of 1.93 (3H, m), 2,24 is 2.33 (4H, m), 3,17 (2H, d, J=7 Hz), 4,11 (2H, square, J=7 Hz), 4,28 (1H, d, J=17 Hz), to 4.38 (1H, d, J=17 Hz), to 8.20 (1H, DD, J=2, 2 Hz), 8,79 (1H, d, J=2 Hz), 8,84 (1H, d, J=2 Hz).

Getting 240

1-tert-butyl-5-ethyl-2-[(5-chloro-3-pyridinyl)carbonyl]-2-(from butoxyethyl)pentanedioic

1H NMR (300 MHz, CDCl3) δ 0,84 (6H, d, J=7 Hz), 1,24 (3H, t, J=7 Hz), of 1.39 (9H, s), of 1.80 (1H, cut, J=7 Hz), 2,34-a 2.71 (4H, m), 3,17 (2H, d, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,28 (1H, d, J=18 Hz), 4,36 (1H, d, J=18 Hz), 8,07 (1H, s), 8,69 (1H, s), 8,83 (1H, s).

Getting 241

1-tert-butyl-5-ethyl-2-[(atomic charges)acetyl]-2-(3-chlorobenzoyl)pentanedioic

1H NMR (300 MHz, CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.34 (9H, s), and 2.14 (3H, s), 2,35 is 2.44 (2H, m), 2,60 of 2.68 (2H, m), 4,11 (2H, square, J=7 Hz), 5,11 (1H, d, J=18 Hz), to 5.35 (1H, d, J=18 Hz), 7,38 (1H, DD, J=8, 8 Hz), 7,53 (1H, d, J=8 Hz), 7,60 (1H, d, J=8 Hz), 7,79 (1H, s).

Getting 242

1-tert-butyl-6-ethyl-2-[(5-bromo-3-pyridinyl)carbonyl]-2-(isobutoxy)hexanedioic

1H NMR (300 MHz, CDCl3) δ of 0.85 (6H, d, J=7 Hz), 1,25 (3H, t, J=7 Hz), of 1.39 (9H, s), 1,59-1,72 (2H, m), of 1.80 (1H, cut, J=7, 7 Hz), 2,19-2,39 (4H, m), 3,18 (2H, d, J=7 Hz), of 4.12 (2H, square, J=7 Hz), or 4.31 (1H, d, J=17 Hz), and 4.40 (1H, d, J=17 Hz), by 8.22 (1H, DD, J=2, 2 Hz), 8,79 (1H, d, J=2 Hz), cent to 8.85 (1H, d, J=2 Hz).

Getting 243

tert-Butyl 3-(5-bromo-3-pyridinyl)-2-[(5-bromo-3-pyridinyl)carbonyl]-3-oxopropanoic

1H NMR (CDCl3) δ of 1.05 (9H, s), 7,86 (2H, s), 8,46 (2H, s), 8,61 (2H, s).

MS (ESI-): m/z 481, 483, 485.

Getting 244

1-tert-butyl-6-ethyl-2-[(atomic charges)acetyl]-2-(3-chlorobenzoyl)hexanedioic

1H NMR (CDCl3) δ to 1.24 (3H, t, J=8 Hz), of 1.33 (9H, s), 1.56 to 1,72 (2H, m), of 2.15 (3H, s), 2,20-to 2.41 (4H, m), 4,11 (2H, square, J=8 Hz), 5,13 (1H, d, J=18 Hz), of 5.40 (1H, d, J=18 Hz), 7,38 (1H, t, J=8 Hz), 7,52 (1H, userd, J=8 Hz), 7,60 (1H, userd, J=8 Hz), 7,79 (1H, users).

Getting 245

1-tert-butyl-7-ethyl-2-(methoxyacetyl)-2-[(-methoxy-3-pyridinyl)carbonyl]heptanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=8 Hz), 1,27-1,43 (11H, m), 1.60-to around 1.74 (2H, m), 2,15-of 2.34 (4H, m), 3,37 (3H, s), 3,90 (3H, s), 4,10 (2H, square, J=8 Hz), 4,35 (1H, d, J=18 Hz), 4,48 (1H, d, J=18 Hz), 7,58 (1H, m), 8,43 (1H, d, J=3 Hz)and 8.50 (1H, d, J=1 Hz).

MS (ESI+): m/z 452 (M+H).

Getting 246

1-tert-butyl-7-ethyl-2-acetyl-2-[(5-methoxy-3-pyridinyl)carbonyl]heptanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=8 Hz), 1,27-1,40 (11H, m), 1.60-to around 1.74 (2H, m), 2,15-of 2.34 (4H, m), is 2.44 (3H, s)to 3.89 (3H, s), 4,10 (2H, square, J=8 Hz), to 7.61 (1H, m), 8,43 (1H, d, J=3 Hz), 8,49 (1H, d, J=1 Hz).

MS (ESI+): m/z 422 (M+H).

Getting 247

1-tert-butyl-5-ethyl-2-(methoxyacetyl)-2-[(5-methoxy-3-pyridinyl)carbonyl]pentanedioic

1H NMR (CDCl3) δ to 1.24 (3H, t, J=8 Hz), to 1.38 (9H, s), a 2.36-2,48 (2H, m), 2,53-to 2.67 (2H, m), 3,37 (3H, s), 3,90 (3H, s), 4,11 (2H, square, J=8 Hz), 4,33 (1H, d, J=18 Hz), of 4.45 (1H, d, J=18 Hz), to 7.59 (1H, m), 8,43 (1H, d, J=3 Hz), 8,51 (1H, d, J=1 Hz).

MS (ESI+): m/z 446 (M++Na).

Getting 248

1-tert-butyl-6-ethyl-2-(methoxyacetyl)-2-[(5-methoxy-3-pyridinyl)carbonyl]hexanedioic

1H NMR (CDCl3) δ to 1.24 (3H, t, J=8 Hz), of 1.37 (9H, s), 1,52 is 1.75 (2H, m), 2,18-2,39 (4H, m)to 3.38 (3H, s), 3,90 (3H, s), 4,11 (2H, square, J=8 Hz), 4,37 (1H, d, J=18 Hz), 4,51 (1H, d, J=18 Hz), 7,60 (1H, m), 8,43 (1H, d, J=3 Hz)and 8.50 (1H, d, J=1 Hz).

MS (ESI+): m/z 438 (M+H).

Getting 249

1-tert-butyl-7-ethyl-2-(methoxyacetyl)-2-(5-pyrimidinecarbonitrile)heptanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=8 Hz), 1.30 and 1.44MB (11H, m), of 1.62 and 1.75 (2H, m), 2,16 to 2.35 (4H, m)to 3.35 (3H, s), 4,11 (2H, square, J=8 Hz), 4,20 (1H, d, J=18 Hz), 4,33 (1H, d, J=18 Hz), 9,01 (2H, s), 9,31 (1H, Jerusalem.).

MS (ESI+): m/z 423 (M+H).

Getting 250

1-tert-butyl-6-ethyl-2-[(5-chloro-3-pyridinyl)carbonyl]-2-(methoxyacetyl)hexanedioic

1H NMR (CDCl3) δ of 1.26 (3H, t, J=8 Hz), of 1.39 (9H, s), 1,57-of 1.74 (2H, m), of 1.78 (2H, ushort, J=8 Hz), 2,23-to 2.41 (2H, m)to 3.38 (3H, s), 4,14 (2H, square, J=8 Hz), 4,33 (1H, d, J=18 Hz), of 4.45 (1H, d, J=18 Hz), 8,07 (1H, m)8,71 (1H, users), 8,80 (1H, users).

MS (ESI+): m/z 442 (M+H).

Getting 251

1-tert-butyl-5-ethyl-2-[(5-chloro-3-pyridinyl)carbonyl]-2-(methoxyacetyl)pentanedioic

1H NMR (CDCl3) δ 1,25 (3H, t, J=8 Hz), of 1.39 (9H, s), 2,37-2,48 (2H, m), 2,53-to 2.65 (2H, m)to 3.36 (3H, s), of 4.13 (2H, square, J=8 Hz), 4.26 deaths (1H, d, J=18 Hz), and 4.40 (1H, d, J=18 Hz), of 8.06 (1H, users), to 8.70 (1H, users), 8,80 (1H, users).

MS (ESI+): m/z 428 (M+H).

Getting 252

1-tert-butyl-7-ethyl-2-[(5-chloro-3-pyridinyl)carbonyl]-2-(methoxyacetyl)heptanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=8 Hz), is 1.31 to 1.48 (11H, m), 1,55-1,75 (2H, m), of 2.15 to 2.35 (4H, m)to 3.36 (3H, s), 4,10 (2H, square, J=8 Hz), 4,27 (1H, d, J=18 Hz), 4,43 (1H, d, J=18 Hz), 8,03 (1H, t, J=2 Hz), 8,69 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (ESI+): m/z 456 (M+H).

Getting 253

Methyl-4-(atomic charges)-2-[(5-bromo-3-pyridinyl)carbonyl]-3-oxobutanoate

1H NMR (CDCl3) δ of 2.21 (3H, s)to 3.58 (3H, users), to 4.87 (1H, users), 5,19 (2H, users), 7,98 (1H, users), 8,58 (1H, users), 8,79 (1H, users).

MS (ESI+): m/z 358, 360 (M+H).

Getting 254

tert-Butyl 2-(2-{2-[2-(atomic charges)ethoxy]ethoxy}ethyl)-2-[(5-methyl-3-pyridinyl)carbonyl]-3-oxobutanoate

1H-NMR (CDCl3) δ 1,32 9H, C)2,07 (3H, s), of 2.38 (3H, s), a 2.45 (3H, s), to 2.57 (2H, t, J=7 Hz), 3.43 points (4H, m), of 3.57 (4H, m)to 4.16 (2H, m), to 7.84 (1H, m), 8,53 (1H, m), is 8.75 (1H, m).

Getting 255

1-tert-butyl-6-ethyl-2-[(5-bromo-3-pyridinyl)carbonyl]-2-(methoxyacetyl)hexanedioic

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), of 1.39 (9H, s), 1,55-1,75 (2H, m), 2,23 at 2.45 (4H, m)to 3.38 (3H, s), of 4.12 (2H, square, J=7 Hz), 4,34 (1H, d, J=18 Hz), 4,47 (1H, d, J=18 Hz), by 8.22 (1H, m), 8,81 (1H, d, J=2 Hz), 8,83 (1H, d, J=2 Hz).

MS (ESI+): m/z 486, 488.

Getting 256

Ethyl-2-(2-horizonation)-3-oxobutanoate

1H NMR (CDCl3) δ of 0.91 to 1.00 (3H, m), 2,24 (1,2H, C), 2,48 (1,8H, C), was 4.02 (1,2H, square, J=8 Hz), 4,10 (0,8H, q, J=8 Hz), 7.24 to (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).

The following compounds were obtained according to a similar technique to obtain 78.

Getting 257

Ethyl-5-(2-horizonation)-6-oxogedunin

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), 1.60-to of 1.73 (2H, m), 1,98 is 2.10 (2H, m), of 2.20 (3H, s)to 2.35 (2H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,37 (1H, t, J=7 Hz), to 7.67 (1H, d, J=5 Hz), to 7.77 (1H, s), 8,59 (1H, d, J=5 Hz).

MS (ESI+): m/z 312.

Getting 258

Ethyl-4-(2-horizonation)-5-oxohexanoate

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), of 2.21 (3H, s), 2,22 to 2.35 (2H, m), a 2.36-2,47 (2H, m), of 4.12 (2H, square, J=7 Hz), of 4.57 (1H, t, J=7 Hz), 7,76 (1H, DD, J=2 Hz, 5 Hz), 7,83 (1H, d, J=2 Hz), 8,61 (1H, d, J=5 Hz).

MS (ESI+): m/z 298.

Getting 259

Ethyl-6-(2-horizonation)-7-oxo-8-phenyloctanoic

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), 1,20-to 1.38 (2H, m), 1.60-to 1,72 (2H, m), 1,95 e 2.06 (2H, m), of 2.28 (2H, t, J=7 Hz), 3,71 (1H, d, J=17 Hz), 3,80 (1H, d, J=17 Hz), of 4.12 (2H, square, J=7 Hz), to 4.41 (1H, t, J=7 Hz), 7,10 (2H, m), 7,20-7,33 (4H, m), 7,39 (1H, s), 8,42 (1H, d, J=5 Hz).

Getting 260

Methyl({3-[(5-methyl-3-pyridinyl)carbonyl]-4-oxobutyl}oxy)acetate

1H NMR (CDCl3) δ of 2.23 (3H, s), 2,23-to 2.40 (2H, m), is 2.44 (3H, s)to 3.58 (2H, m), 3,71 (3H, s), was 4.02 (2H, s), 4,89 (1H, t, J=7 Hz), to 8.12 (1H, s)8,64 (1H, s), 9,07 (1H, s).

MS (ESI+): m/z 294.

Getting 261

Methyl(4-oxo-4-phenylbutane)acetate

1H NMR (CDCl3) δ 2,04-of 2.16 (2H, m)and 3.15 (2H, t, J=7 Hz), to 3.64 (2H, t, J=7 Hz), to 3.73 (3H, s), 4.09 to (2H, s), 7,46 (2H, t, J=8 Hz), 7,56 (1H, t, J=8 Hz), to 7.99 (2H, d, J=8 Hz).

MS (ESI+): m/z 237.

The following compounds were obtained according to a similar technique to obtain 78.

Getting 262

Ethyl-3-[(5-bromo-3-pyridinyl)carbonyl]-4-oxopentanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), 2,22 (3H, s), 2,97-3,17 (2H, m), of 4.12 (2H, square, J=7 Hz), 4,91 (1H, m), to 8.41 (1H, m), 8,88 (1H, m), 9,12 (1H, m).

MS (ESI+): m/z 328, 330.

Getting 263

Ethyl-6-(atomic charges)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), to 1.98 (3H, s), 2,23-of 2.34 (2H, m), 2.40 a-2,50 (2H, m), of 2.45 (3H, s), of 4.12 (2H, square, J=7 Hz), 4,69 (2H, m), 4,82 (1H, t, J=7 Hz), 8,14 (1H, s), 8,67 (1H, s), 9,07 (1H, s).

MS (ESI+): m/z 336.

Getting 264

Ethyl-7-(atomic charges)-5-[(5-methyl-3-pyridinyl)carbonyl]-6-oxogedunin

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), 1,60-1,80 (2H, m), 2,02 (3H, s), 1,97 and 2.13 (2H, m)to 2.35 (2H, t, J=7 Hz), a 2.45 (3H, s), of 4.12 (2H, square, J=7 Hz), 4,56 (1H, t, J=7 Hz), 4,69 (H, d, J=17 Hz), 4,78 (1H, d, J=17 Hz), of 8.06 (1H, s), 8,66 (1H, s), of 9.00 (1H, s).

MS (ESI+): m/z 350.

Getting 265

Ethyl-8-(atomic charges)-6-(3-cyanobenzoyl)-7-oxooctanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), 1,35 of 1.50 (2H, m), 1.60-to of 1.78 (2H, m), 2,04 (3H, s), 2.00 in a 2.12 (2H, m)to 2.29 (2H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,49 (1H, t, J=7 Hz), and 4.68 (1H, d, J=17 Hz), 4.75 in (1H, d, J=17 Hz), 7,66 (1H, t, J=8 Hz), 7,88 (1H, d, J=8 Hz), 8,16 (1H, d, J=8 Hz), compared to 8.26 (1H, s).

MS (ESI-): m/z 372.

Getting 266

Ethyl-7-(atomic charges)-5-[(5-bromo-3-pyridinyl)carbonyl]-6-oxogedunin

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), 1.60-to is 1.82 (2H, m), 2,04 (3H, s), 2,03-of 2.15 (2H, m)to 2.35 (2H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,51 (1H, t, J=7 Hz), 4,70 (1H, d, J=17 Hz), and 4.75 (1H, d, J=17 Hz), 8,39 (1H, m), 8,88 (1H, s), 9,07 (1H, s).

MS (ESI-): m/z 414, 416, MS (ESI+): m/z 414, 416.

Getting 267

Ethyl-6-(atomic charges)-4-[(5-bromo-3-pyridinyl)carbonyl]-5-oxohexanoate

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), from 2.00 (3H, s), 2,22-of 2.36 (2H, m), 2,43 of $ 2.53 (2H, m), 4,13 (2H, square, J=7 Hz), 4,70 (2H, m), 4,80 (1H, t, J=7 Hz), 8,48 (1H, s), of 8.90 (1H, s), 9,19 (1H, s).

MS (ESI+): m/z 400, 402.

Getting 268

Ethyl-6-(cyclohexylmethoxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate

1H NMR (CDCl3) δ 0,60-of 0.82 (2H, m), 0,93-1,10 (3H, m), 1,12-of 1.65 (6H, m), 1,25 (3H, t, J=7 Hz), 2,07-2,17 (1H, m), 2,22 to 2.35 (1H, m), 2,42 (2H, m), is 2.44 (3H, s), 3,05 is 3.23 (2H, m), of 3.96 (2H, s), of 4.12 (2H, square, J=7 Hz), to 4.92 (1H, m), 8,16 (1H, s), 8,66 (1H, s), the remaining 9.08 (1H, s).

MS (ESI+): m/z 390.

Getting 269

Ethyl-4-[(5-bromo-3-pyridinyl)carbonyl]-6-(cyclohexylmethoxy and)-5-oxohexanoate

1H NMR (CDCl3) δ 0,63-0,84 (2H, m), 0,93-of 1.88 (3H, m), 1,25 (3H, t, J=7 Hz), 1,35-1,90 (6H, m), 2,02 with 2.14 (1H, m), 2,20-of 2.36 (1H, m)2,44 (2H, t, J=7 Hz), 3.04 from-3,20 (2H, m), of 3.95 (2H, s), of 4.13 (2H, square, J=7 Hz), 4,85-is 4.93 (1H, m), and 8.50 (1H, m), 8,88 (1H, d, J=2 Hz), 9,20 (1H, d, J=2 Hz).

MS (ESI+): m/z 454, 456.

Getting 270

Ethyl-5-[(5-bromo-3-pyridinyl)carbonyl]-7-(cyclohexylmethoxy)-6-oxogedunin

1H NMR (300 MHz, CDCl3) δ 0,75 is 0.86 (2H, m), 0,95-of 1.15 (3H, m)of 1.24 (3H, t, J=7 Hz), 1,40-1,90 (10H, m), a 2.36 (2H, t, J=7 Hz), 3,12 (2H, square, J=7 Hz), of 3.97 (2H, s), of 4.12 (2H, square, J=7 Hz), 4,71 (1H, t, J=7 Hz), to 8.41 (1H, s), 8,88 (1H, s), 9,12 (1H, s).

MS (ESI+): m/z 468, 470.

Getting 271

Ethyl-7-(cyclopropylmethoxy)-5-[(5-methyl-3-pyridinyl)carbonyl]-6-oxogedunin

1H NMR (CDCl3) δ -0,08-0,00 (1H, m)0,00-0,15 (1H, m), 0,28-0,49 (2H, m), 0,72-of 0.87 (1H, m)of 1.23 (3H, t, J=7 Hz), 1,58 and 2.13 (4H, m), 2,32 (2H, t, J=7 Hz), 2,44 (3H, s), 3,10-3,26 (2H, m), was 4.02 (2H, m), of 4.12 (2H,, square, J=7 Hz), of 4.77 (1H, t, J=7 Hz), 8,07 (1H, s), 8,63 (1H, s), 9,03 (1H, s).

MS (ESI+): m/z 362.

Getting 272

Ethyl-6-(cyclopropylmethoxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate

1H NMR (CDCl3) δ -0,08-0,00 (1H, m)0,00-0,13 (1H, m), 0,23 of 0.47 (2H, m), 0,68-0,84 (1H, m)of 1.24 (3H, t, J=7 Hz), 2,03-2,17 (1H, m), 2,22-of 2.36 (1H, m), 2.40 a (2H, m), is 2.44 (3H, s), of 3.12 (2H, m), 3,98 (1H, d, J=17 Hz), 4,06 (1H, d, J=17 Hz), of 4.12 (2H, square, J=7 Hz), is 4.93 (1H, m)to 8.12 (1H, s), 8,65 (1H, s), the remaining 9.08 (1H, s).

MS (ESI+): m/z 348.

Getting 273

Ethyl-4-[(5-bromo-3-pyridinyl)carbonyl]-6-(2-methoxyethoxy)-5-oxohexanoate

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), 1,90-2,37 2H, m), 2,43 (2H, t, J=7 Hz), 3,18 (3H, s), 3,16-to 3.73 (4H, m)4,06 (2H, square, J=7 Hz), 4,10-4,24 (2H, m), 4,86-is 4.93 (1H, m), 8,51 (1H, m), 8,87 (1H, d, J=2 Hz), 9,20 (1H, d, J=2 Hz).

MS (ESI-): m/z 414, 416, MS (ESI+): m/z 416, 418.

Getting 274

1-(5-bromo-3-pyridinyl)-1,3-butandiol

1H NMR (CDCl3) δ of 2.25 (3H, s), 6,18 (1H, s), 8,31 (1H, s), 8,78 (1H, s), 8,96 (1H, s).

MS (ESI+): m/z 242, 244.

Getting 275

Ethyl-7-(atomic charges)-5-[(5-chloro-3-pyridinyl)carbonyl]-6-oxogedunin

1H NMR (300 MHz, CDCl3) δ 1,25 (3H, t, J=7 Hz), 1,60-1,70 (4H, m), 2,04 (3H, s)to 2.35 (2H, t, J=6 Hz), of 4.12 (2H, square, J=7 Hz), to 4.52 (1H, t, J=7 Hz), 4,69 (1H, d, J=18 Hz), 4,78 (1H, d, J=18 Hz), 8,24 (1H, s), 8,78 (1H, s), 9,05 (1H, s).

Getting 276

Ethyl-6-[(5-chloro-3-pyridinyl)carbonyl]-8-(cyclopropylmethoxy)-7-oxooctanoate

1H NMR (300 MHz, CDCl3) δ -0,09-0,11 (2H, m), 0,25-0,35 (1H, m), from 0.37 and 0.46 (1H, m), 0.70 to 0.79, which (1H, m)of 1.24 (3H, t, J=7 Hz), 1,29-of 1.41 (2H, m)of 1.64 (2H, t, J=7 Hz), 1,72-of 1.84 (1H, m), 1,96-of 2.08 (1H, m), 2,28 (2H, t, J=7 Hz), of 3.12 (1H, DD, J=10, 7 Hz), 3,21 (1H, DD, J=10, 7 Hz), of 3.97 (1H, d, J=12 Hz), of 4.05 (1H, d, J=12 Hz), 4,11 (2H, square, J=7 Hz), 4,70 (1H, t, J=7 Hz), compared to 8.26 (1H, DD, J=2, 2 Hz), 8,77 (1H, DD, J=2 Hz), which is 9.09 (1H, DD, J=2 Hz).

Getting 277

Ethyl-5-[(5-chloro-3-pyridinyl)carbonyl]-7-(cyclopropylmethoxy)-6-oxogedunin

1H NMR (300 MHz, CDCl3) δ -0,07-0,09 (2H, m), 0.24 to 0,46 (2H, m), 0,68-of 0.79 (1H, m)of 1.23 (3H, t, J=7 Hz), 1,47-of 1.84 (3H, m), 1,98-2,10 (1H, m), of 2.33 (2H, t, J=7 Hz), of 3.12 (1H, DD, J=10, 7 Hz), 3,21 (1H, DD, J=10, 7 Hz), of 3.97 (1H, d, J=17 Hz), 4,06 (1H, d, J=17 Hz), 4,10 (2H, square, J=7 Hz), to 4.73 (1H, t, J=6 Hz), of 8.27 (1H, DD, J=2, 2 Hz), 8,77 (1H, d, J=2 Hz), 9,10 (1H, d, J=2 Hz).

P is torching 278

Ethyl-6-[(5-bromo-3-pyridinyl)carbonyl]-8-isobutoxy-7-oxooctanoate

1H NMR (300 MHz, CDCl3) δ to 0.72 (3H, d, J=7 Hz), of 0.77 (3H, d, J=7 Hz), 1,24 (3H, t, J=7 Hz), 1.30 and of 1.42 (2H, m), 1,54 is 1.70 (3H, m), a 1.75-to 1.87 (1H, m), 1,95-of 2.08 (1H, m), 2,28 (2H, t, J=8 Hz), 3,10 (1H, DD, J=9, 7 Hz), 3,14 (1H, DD, J=9, 7 Hz), 3,98 (2H, s), 4,11 (2H, square, J=7 Hz), 4,70 (1H, t, J=6 Hz), 8,39 (1H, DD, J=2 Hz), 8,87 (1H, d, J=2 Hz), the remaining 9.08 (1H, d, J=2 Hz).

Getting 279

Ethyl-4-[(5-chloro-3-pyridinyl)carbonyl]-6-isobutoxy-5-oxohexanoate

1H NMR (300 MHz, CDCl3) δ of 0.68 (3H, d, J=7 Hz), to 0.72 (3H, d, J=7 Hz), 1,25 (3H, t, J=7 Hz), of 1.52 (1H, cut, J=7, 7 Hz), 2,02 and 2.13 (1H, m), 2,20 of-2.32 (1H, m)2,44 (2H, t, J=7 Hz), of 3.07 (1H, DD, J=9, 7 Hz), 3,12 (1H, DD, J=9, 7 Hz), 3,98 (2H, s), 4,14 (2H, square, J=7 Hz), of 4.90 (1H, d, J=9 Hz), to 4.92 (1H, d, J=9 Hz), a 8.34 (1H, DD, J=2 Hz), 8,78 (1H, d, J=2 Hz)to 9.15 (1H, d, J=2 Hz).

Getting 280

Ethyl-6-(atomic charges)-4-(3-chlorobenzoyl)-5-oxohexanoate

1H NMR (300 MHz, CDCl3) δ of 1.26 (3H, t, J=7 Hz), 1,95 (3H, s), 2,20-to 2.29 (2H, m), 2,41-2,47 (2H, m), is 4.15 (2H, square, J=7 Hz), with 4.64 (1H, d, J=17 Hz), 4,71 (1H, d, J=17 Hz), 4,78 (1H, t, J=6 Hz), of 7.48 (1H, DD, J=8, 8 Hz), 7,60 (1H, d, J=8 Hz), of 7.96 (1H, d, J=8 Hz), of 8.04 (1H, s).

Getting 281

Ethyl-5-[(5-bromo-3-pyridinyl)carbonyl]-7-isobutoxy-6-oxogedunin

1H NMR (300 MHz, CDCl3) δ to 0.72 (3H, d, J=7 Hz), of 0.77 (3H, d, J=7 Hz), of 1.23 (3H, t, J=7 Hz), 1,61-of 1.73 (3H, m), 1.77 in-a 1.88 (1H, m), 1,98-2,10 (1H, m), of 2.33 (2H, t, J=7 Hz), 3,10 (1H, DD, J=9, 7 Hz)and 3.15 (1H, DD, J=9, 7 Hz), 3,99 (2H, s), 4,11 (2H, square, J=7 Hz), to 4.73 (1H, t, J=7 Hz), 8,40 (1H, DD, J=2, 2 Hz), 8,87 (1H, d, J=2 Hz), 9,10 (1H, d, J=2 Hz).

Getting 282

1,3-bis(5-bromo-3-pyridinyl)-1,3-propandiol

1H NMR (DMSO-d6) δ of 7.60 (1H, s), 8,78 (2H, s), 8,88 (2H, s), of 9.30 (2H, s).

Getting 283

Ethyl-7-(atomic charges)-5-(3-chlorobenzoyl)-6-oxogedunin

1H NMR (CDCl3) δ to 1.24 (3H, t, J=8 Hz), 1,57 is 1.75 (2H, m), 1,90-2,12 (5H, m), of 2.34 (2H, t, J=8 Hz), 4,11 (2H, square, J=8 Hz), to 4.52 (1H, t, J=8 Hz), 4,71 (2H, square, J=8 Hz)and 4.65 (1H, d, J=16 Hz), and 4.75 (1H, d, J=16 Hz), the 7.43 (1H, t, J=8 Hz), 7,60 (1H, userd, J=8 Hz), to 7.84 (1H, userd, J=8 Hz), of 7.96 (1H, users).

Getting 284

Ethyl-8-methoxy-6-[(5-methoxy-3-pyridinyl)carbonyl]-7-oxooctanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=8 Hz), 1,27 was 1.43 (2H, m), 1,55-1,70 (2H, m)of 1.84 (1H, m), from 2.00 (1H, m), and 2.27 (2H, d, J=8 Hz), 3,26 (3H, s)to 3.92 (3H, s), 3,98 (2H, d, J=5 Hz), 4,10 (2H, square, J=8 Hz), 4,67 (1H, t, J=8 Hz), 7,71 (1H, m), and 8.50 (1H, d, J=3 Hz), 8,78 (1H, users).

MS (ESI+): m/z 352 (M+H).

Getting 285

Ethyl-6-[(5-methoxy-3-pyridinyl)carbonyl]-7-oxooctanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=8 Hz), 1,27-of 1.41 (2H, m), 1.60-to of 1.73 (2H, m), 1,90 with 2.14 (2H, m)to 2.18 (3H, s), 2,24-2,84 (2H, m), 3,26 (3H, s)to 3.92 (3H, s), 4,10 (2H, square, J=8 Hz), and 4.40 (1H, t, J=8 Hz), 7,71 (1H, m), 8,51 (1H, d, J=3 Hz), 8,78 (1H, users).

Getting 286

Ethyl-6-methoxy-4-[(5-methoxy-3-pyridinyl)carbonyl]-5-oxohexanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=8 Hz), 2,10 (1H, m), of 2.25 (1H, m), 2,38-2,47 (2H, m), 3,24 (3H, s), of 3.94 (3H, s), 3,95 (1H, d, J=16 Hz), 4,00 (1H, d, J=16 Hz), of 4.12 (2H, square, J=8 Hz), to 4.38 (1H, m), 7,83 (1H, m), charged 8.52 (1H, d, J=3 Hz), 8,87 (1H, d, J=1 Hz).

MS (ESI+): m/z 346 (M++Na).

Getting 287

Ethyl-7-methoxy-5-[(5-methoxy-3-pyridinyl)carbonyl]-6-oxogedunin

1H YAM who (CDCl 3) δ of 1.23 (3H, t, J=8 Hz), 1,54-of 1.74 (2H, m)of 1.84 (1H, m), 2,02 (1H, m), 2,32 (2H, d, J=8 Hz), 3,26 (3H, s)to 3.92 (3H, s)to 3.99 (2H, d, J=5 Hz), 4,10 (2H, square, J=8 Hz), 4,70 (1H, t, J=8 Hz,), 7,71 (1H, m), 8,51 (1H, d, J=3 Hz), 8,79 (1H, users).

MS (ESI+): m/z 338 (M+H).

Getting 288

Ethyl-8-methoxy-7-oxo-6-(5-pyrimidinecarbonitrile)octanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=8 Hz), 1,25-1,45 (2H, m), 1,55-1,70 (2H, m), is 1.81 (1H, m), 2,03 (1H, m), 2,28 (2H, t, J=8 Hz), 3,24 (3H, s)to 3.92 (1H, d, J=18 Hz), 4,01 (1H, d, J=18 Hz), 4,10 (2H, square, J=8 Hz), 9,26 (2H, s), 9,40 (1H, s).

MS (ESI+): m/z 323 (M+H).

Getting 289

Ethyl-5-[(5-chloro-3-pyridinyl)carbonyl]-7-methoxy-6-oxogedunin

1H NMR (CDCl3) δ to 1.24 (3H, t, J=8 Hz), 1,52-of 1.74 (2H, m)and 1.83 (1H, m), 2,02 (1H, m), 2,34-to 2.40 (2H, m)of 3.25 (3H, s)to 3.92 (1H, d, J=16 Hz), 4,01 (1H, d, J=16 Hz), 4,11 (2H, square, J=8 Hz), and 4.68 (1H, t, J=8 Hz), 8,23 (1H, users), 8,78 (1H, users), 9,05 (1H, users).

MS (ESI+): m/z 342 (M+H).

Getting 290

Ethyl-4-[(5-chloro-3-pyridinyl)carbonyl]-6-methoxy-5-oxohexanoate

1H NMR (CDCl3) δ 1,25 (3H, t, J=8 Hz), is 2.09 (1H, m), of 2.25 (1H, m), of 2.38-2.49 USD (2H, m), up 3.22 (3H, s), 3,91 (1H, d, J=18 Hz), 4.00 points (1H, d, J=18 Hz), 4,14 (2H, square, J=8 Hz), is 4.85 (1H, m), with 8.33 (1H, users), 8,78 (1H, users), 9,14 (1H, users).

MS (ESI+): m/z 328 (M+H).

Getting 291

Ethyl-6-[(5-chloro-3-pyridinyl)carbonyl]-8-methoxy-7-oxooctanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=8 Hz), 1,27 was 1.43 (2H, m), 1,50-1,71 (2H, m), equal to 1.82 (1H, m), from 2.00 (1H, m), and 2.27 (2H, d, J=8 Hz), of 3.25 (3H, s)to 3.92 (1H, d, J=16 Hz), was 4.02 (1H, d, J=16 Hz), 4,10 (2H, square, J=8 Hz), 4,63 (1H, t, J=8 Hz), 8,23 (1H, users), 8,78 (1H, users), 9,03 (1H users).

MS (ESI+): m/z 356 (M+H).

Getting 292

Triptorelin 2-[2-({3-[(5-methyl-3-pyridinyl)carbonyl]-4-oxobutyl}oxy)ethoxy]acetic acid ethyl ester

1H-NMR (CDCl3) δ to 2.06 (3H, s), of 2.28 (3H, s), 2,33 (2H, m), 2,65 (3H, s), 3,47-to 3.67 (8H, m), 4,17 (2H, m), 4,71 (1H, t, J=7 Hz), 8,66 (1H, m), 8,88 (1H, m), 9,31 (1H, m).

Getting 293

Ethyl-5-[(5-bromo-3-pyridinyl)carbonyl]-7-methoxy-6-oxogedunin

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), 1.56 to at 1.73 (2H, m), 1.77 in-1,92 (1H, m), 1,96-2,10 (1H, m), 2,32 (2H, t, J=7 Hz)at 3.25 (3H, s)to 3.92 (1H, d, J=17 Hz), was 4.02 (1H, d, J=17 Hz), of 4.12 (2H, square, J=7 Hz), 4,67 (1H, t, J=7 Hz), 8,39 (1H, m), 8,87 (1H, d, J=2 Hz), which is 9.09 (1H, d, J=2 Hz).

MS (ESI+): m/z 386, 388.

The following compounds were obtained according to similar methods of obtaining 129 and 130.

Getting 294

tert-Butyl 3-oxo-4-phenylbutanoate

1H NMR (CDCl3) δ of 1.46 (9H, s), 3,37 (2H, s), 3,82 (2H, s), 7,21 (2H, d, J=8 Hz), 7,25-7,37 (3H, m).

Getting 295

tert-Butyl 3-oxo-3-phenylpropanoate

1H NMR (CDCl3) δ of 1.43 (9H, s), 3,81 (2H, s), 7,40-7,52 (2H, m), 7,56-7,63 (1H, m), 7,94 (2H, d, J=8 Hz).

Getting 296

tert-Butyl 4-(cyclohexylmethoxy)-3-oxobutanoate

1H NMR (CDCl3) δ 0,89-of 1.07 (2H, m), 1,13-of 1.40 (3H, m)of 1.47 (9H, s), 1.60-to to 1.83 (6H, m), or 3.28 (2H, d, J=7 Hz), of 3.45 (2H, s)4,06 (2H, s).

Getting 297

tert-Butyl 4-(cyclopropylmethoxy)-3-oxobutanoate

1H NMR (CDCl3) δ of 0.20 to 0.28 (2H, m), 0.55 to 0.64 in (2H, m), 1,03-1,17 (1H, m)of 1.47 (9H, s)to 3.36 (2H, d, J=7 Hz), of 3.45 (2H, s), is 4.15 (2H, s).

Getting 298

tert-Butyl 4-(2-Metacritic and)-3-oxobutanoate

1H NMR (CDCl3) δ to 1.47 (9H, s)to 3.38 (3H, s), 3,44 (2H, s), of 3.57 (2H, m), 3,70 (2H, m), 4,20 (2H, s).

Getting 299

tert-Butyl-4-isobutoxy-3-oxobutanoate

1H NMR (300 MHz, CDCl3) δ of 0.93 (6H, d, J=7 Hz), a 1.45 (9H, s), at 1.91 (1H, cut, J=7, 7 Hz), 3,26 (2H, d, J=7 Hz), of 3.45 (2H, s)4,07 (2H, s).

Getting 300

tert-Butyl 3-(3-methyl-2-thienyl)-3-oxopropanoic

1H-NMR (CDCl3) δ to 1.47 (9H, s), to 2.57 (3H, s), with 3.79 (2H, s), of 6.96 (1H, d, J=5 Hz), 7,44 (1H, d, J=5 Hz).

Getting 301

tert-Butyl 3-(5-methyl-3-isoxazolyl)-3-oxopropanoic

1H-NMR (CDCl3) δ 1,475-of 1.57 (9H, m), 2.49 USD (3H, m), of 3.95 (2H, s)6,40 (1H, s).

The following compounds were obtained according to a similar technique to obtain 132.

Getting 302

Ethyl-(2E)-5-(3-cyanobenzoyl)-6-oxo-2-heptenoic

1H-NMR (CDCl3) δ of 1.28 (3H, t, J=7 Hz), measuring 2.20 (3H, s), is 2.88 (2H, m)to 4.16 (2H, square, J=7 Hz), of 4.54 (1H, t, J=7 Hz), 5,88 (1H, d, J=16 Hz), PC 6.82 (1H, dt, J=7 and 16 Hz), the 7.65 (1H, t, J=8 Hz), 7,89 (1H, d, J=8 Hz), to 8.20 (1H, d, J=8 Hz), of 8.27 (1H, s).

MS (ESI+): m/z 300,14 (M+H).

Getting 303

1-tert-butyl-7-ethyl-2-[(3-methyl-2-thienyl)carbonyl]heptanoate

1H-NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), 1,35-1,51 (11H, m), of 1.65 (2H, m), a 1.96 (2H, m), is 2.30 (2H, t, J=7 Hz), 2,58 (3H, s), of 3.94 (1H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz),6,97 (1H, d, J=5 Hz), 7,44 (1H, d, J=5 Hz).

Getting 304

1-tert-butyl-7-ethyl-2-[(5-methyl-3-isoxazolyl)carbonyl]heptanoate

1H-NMR (CDCl3) δ 11,24 (3H, t, J=7 Hz), of 1.39 (9H, s)to 1.67 (2H, m)to 1.98 (2H, m), 2.49 USD (3H, s), 4,10 (2H, square, J=7 Hz), 4.26 deaths (1H, t, J=7 Hz), 6,37 1H, C).

The following compound was obtained according to a similar method of obtaining 152.

Getting 305

Methyl-7-oxo-7-(2-thienyl)heptanoate

1H-NMR (CDCl3) δ of 1.41 (2H, m), 1,63-to 1.82 (4H, m), of 2.33 (2H, t, J=7 Hz), only 2.91 (2H, t, J=7 Hz), to 3.67 (3H, s)of 1.73 (1H, m), a 7.62 (1H, m), of 7.70 (1H, m).

The following compounds were obtained according to a similar method of obtaining 153.

Getting 306

hydrochloride 5-methoxynicotinate

Getting 307

hydrochloride 5-pyrimidinecarbonitrile

Getting 308

hydrochloride 5-chloronicotinamide

Getting 309

Methyl 2-bromo-4-(chlorocarbonyl)benzoate

The following compounds were obtained according to a similar method of obtaining 159.

Getting 310

1-tert-butyl-7-ethyl-2-(phenylacetyl)heptanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), 1.18 to a 1.50 (2H, m)of 1.46 (9H, s), 1,50-1,75 (2H, m), 1,75-of 1.88 (2H, m), 2,24 (2H, t, J=7 Hz), 3,47 (1H, t, J=7 Hz), 3,81 (2H, s), 4,10 (2H, square, J=7 Hz), 7,20 (2H, d, J=8 Hz), 7,25-7,37 (3H, m).

Getting 311

tert-Butyl 2-[2-(2-methoxy-2-oksidoksi)ethyl]-3-oxobutanoate

1H NMR (CDCl3) δ of 1.46 (9H, s), 2,04-of 2.23 (2H, m)to 2.29 (3H, s), of 3.54 (2H, t, J=7 Hz), of 3.69 (1H, t, J=7 Hz), 3,74 (3H, s), Android 4.04 (2H, s).

Getting 312

tert-Butyl-2-benzoyl-4-(2-methoxy-2-oksidoksi)butanoate

1H NMR (CDCl3) δ of 1.34 (9H, s), and 2.26-2.40 a (2H, m), 3,55-to 3.67 (2H, m), 3,70 (3H, s), Android 4.04 (2H, s), of 4.57 (1H, t, J=7 Hz), 7,47 (2H, t, J=8 Hz), 7,56 (1H, m), 8,01 (2H, d, J=8 Hz).

Getting 313

1-tert-butyl-6-ethyl-2-[(atomic charges)acetyl]hexane is John,

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), to 1.48 (9H, s), 1.60-to of 1.73 (2H, m), 1,82-of 1.95 (2H, m), 2,17 (3H, s), 2,32 (2H, t, J=7 Hz), 3,43 (1H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4.72 in (1H, d, J=17 Hz), a 4.83 (1H, d, J=17 Hz).

Getting 314

1-tert-butyl-5-ethyl-2-[(cyclohexylmethoxy)acetyl]pentanedioic

1H NMR (CDCl3) δ 0,85 was 1.06 (2H, m), of 1.13 to 1.34 (3H, m)of 1.26 (3H, t, J=7 Hz), a 1.45 (9H, s), 1.60-to of 1.85 (6H, m), 2,08-of 2.23 (2H, m), a 2.36 (2H, t, J=7 Hz), with 3.27 (2H, d, J=7 Hz), to 3.67 (1H, t, J=7 Hz), 4,10 (2H, C)of 4.12 (2H, square, J=7 Hz).

Getting 315

1-tert-butyl-6-ethyl-2-[(cyclohexylmethoxy)acetyl]hexanedioic

1H NMR (CDCl3) δ 0,88 was 1.06 (2H, m), 1,12-of 1.34 (3H, m), 1,25 (3H, t, J=7 Hz), a 1.45 (9H, s), 1,54-of 1.94 (10H, m), 2,32 (2H, t, J=7 Hz), with 3.27 (2H, d, J=7 Hz), of 3.56 (1H, t, J=7 Hz), 4.09 to (2H, s), 4,11 (2H, square, J=7 Hz).

MS (ESI+): m/z 385.

Getting 316

1-tert-butyl-6-ethyl-2-[(cyclopropylmethoxy)acetyl]hexanedioic

1H NMR (CDCl3) δ 0,22 is 0.33 (2H, m), 0,54-of 0.64 (2H, m), 1.04 million-of 1.18 (1H, m), 1,25 (3H, t, J=7 Hz), a 1.45 (9H, s), 1.60-to of 1.73 (2H, m), 1,83-of 1.95 (2H, m), of 2.33 (2H, t, J=7 Hz), to 3.33 (2H, d, J=7 Hz), 3,53 (1H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,18 (2H, m).

MS (ESI+): m/z 343.

Getting 317

1-tert-butyl-5-ethyl-2-[(cyclopropylmethoxy)acetyl]pentanedioic

1H NMR (CDCl3) δ 0,20-0,35 (2H, m), 0.56 to 0.64 in (2H, m), 1.04 million-to 1.16 (1H, m)of 1.26 (3H, t, J=7 Hz), a 1.45 (9H, s), 2,12-of 2.24 (2H, m), of 2.38 (2H, t, J=7 Hz), to 3.36 (2H, m), the 3.65 (1H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,19 (2H, s).

Getting 318

1-tert-butyl-5-ethyl-2-[(2-methoxyethoxy)acetyl]pentanedioic

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), of 1.46 (9H, s), 10-2,23 (2H, m)of 2.38 (2H, t, J=7 Hz), 3,37 (3H, s), of 3.60 (2H, m), 3,62 (1H, t, J=7 Hz), 3,70 (2H, m), of 4.12 (2H, square, J=7 Hz), 4,23 (1H, d, J=17 Hz), 4,30 (1H, d, J=17 Hz).

MS (ESI+): m/z 333.

Getting 319

1-tert-butyl-5-ethyl-2-(isobutoxy)pentanedioic

1H NMR (300 MHz, CDCl3) δ of 0.93 (6H, d, J=7 Hz), of 1.26 (3H, t, J=7 Hz), a 1.45 (9H, s), at 1.91 (1H, cut, J=7, 7 Hz), 2,13 (2H, m), is 2.37 (2H, t, J=7 Hz)at 3.25 (2H, d, J=7 Hz), to 3.67 (1H, t, J=7 Hz), of 4.12 (2H, s), of 4.13 (2H, square, J=7 Hz).

The following compound was obtained according to a similar method of obtaining 164.

Getting 320

Methyl 2-bromo-4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate

1H-NMR (CDCl3) δ to 1.32 (3H, t, J=7 Hz), of 2.72 (2H, square, J=7 Hz), of 3.97 (3H, s), 6,10 (1H, m), 6,77 (1H, m), 7,81 (1H, d, J=8 Hz), a 7.85 (1H, d, J=8 Hz), 8,11 (1H, s), to 9.32 (1H, s, of usher.).

The following compounds were obtained according to a similar method of obtaining 165.

Getting 321

tert-Butyl 2-(2-{2-[2-(atomic charges)ethoxy]ethoxy}ethyl)-3-oxobutanoate

1H-NMR (CDCl3) δ of 1.46 (9H, s), 2,00-2,17 (5H, m), of 2.25 (3H, s), 3,45-3,70 (10H, m), 4,22 (2H, m).

The following compound was obtained according to a similar method of producing 178.

Getting 322

isobutoxide acid

1H NMR (300 MHz, CDCl3) δ to 0.94 (6H, d, J=7 Hz), of 1.93 (1H, cut, J=7, 7 Hz), 3,34 (2H, d, J=7 Hz), of 4.12 (2H, s).

Getting 323

To a suspension of 60% NaH (2.66 g) in DMF (20 ml) was added methylhydroxylamine (5,00 g) under cooling with a mixture of ice-water and the mixture was stirred at 0°C for 0.5 hour. To the mixture was added 2-(2-bromato the si)tetrahydro-2H-Piran (12.8 g) under cooling with a mixture of ice-water and the mixture was stirred at ambient temperature for 2 hours. The mixture was distributed between AcOEt and water. The organic layer was separated, washed with water and saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and AcOEt (10:1-3:1), with methyl[2-(tetrahydro-2H-Piran-2-yloxy)ethoxy]acetate as a pale yellow oil (4,45 g).

Methyl[2-(tetrahydro-2H-Piran-2-yloxy)ethoxy]acetate

1H NMR (CDCl3) δ 1,48-of 1.95 (6H, m), 3.46 in is 3.57 (2H, m), 3,64 of 3.75 (2H, m), 3,76 (3H, s), 3,82-of 3.97 (2H, m), 4,20 (2H, s), of 4.66 (1H, m).

Getting 324

A mixture of methyl[2-(tetrahydro-2H-Piran-2-yloxy)ethoxy]acetate (1.07 g) and p-toluensulfonate pyridinium (24.6 mg) in MeOH (10 ml) was boiled under reflux for 2 hours. After evaporation of the solvent the residue was purified column chromatography on silica gel, elwira with a mixture of hexane and AcOEt (10:1-1:3), with methyl(2-hydroxyethoxy)acetate as a colorless oil (555 mg).

Methyl(2-hydroxyethoxy)acetate

1H NMR (CDCl3) δ of 3.69 (2H, m), 3,76 (2H, m), of 3.78 (3H, s)to 4.16 (2H, s).

Getting 325

To a solution of methyl(2-hydroxyethoxy)acetate (540 mg), imidazole (411 mg) and triphenylphosphine (1,37 g) in ether (2 ml) and CH3CN (1 ml) was added iodine (1,43 g) under cooling with a mixture of ice-water and the mixture was stirred at 0°C for 2 hours. After filtering off insoluble matters, the filtrate was diluted with AcOEt, washed the one solution of Na 2SO3and saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and AcOEt (20:1-5:1), to obtain methyl(2-iodoxy)acetate as a colorless oil (898 mg).

Methyl(2-iodoxy)acetate

1H NMR (CDCl3) δ 3,30 (2H, t, J=7 Hz), of 3.77 (3H, s), a-3.84 (2H, t, J=7 Hz), 4,17 (2H, s).

Getting 326

To a suspension of 60% NaH (1,02 g) in THF (50 ml) was added tert-butyl 4-(atomic charges)-3-oxobutanoate (5,00 g) under cooling with a mixture of ice-water and the mixture was stirred at 0°C for 0.5 hour. To the mixture was added ethyl-3-iodopropane (5,54 g) and the mixture was stirred at 50°C for 8 hours. The mixture was distributed between AcOEt and water. The organic layer was separated, washed with saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and AcOEt (20:1-3:1), to obtain 1-tert-butyl-5-ethyl-2-[(atomic charges)acetyl]pentanoate in the form of a yellow oil (4,27 g).

1-tert-butyl-5-ethyl-2-[(atomic charges)acetyl]pentanedioic

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), of 1.46 (9H, s), 2,14-of 2.24 (2H, m), 2,17 (3H, s), a 2.36 (2H, t, J=7 Hz), 3,60 (1H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), to 4.73 (1H, d, J=18 Hz), a 4.83 (1H, d, J=18 Hz).

Getting 327

To a solution of benzyl-4-timehelicobacter (4.8 g) in methanol (30 ml) and H2O (20 ml) was added Oxon (16.2 g)under cooling with a mixture of ice-water and the mixture was stirred at ambient temperature for 2 hours. The solution was evaporated in vacuum and was distributed between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and EtOAc, to obtain 1,1-dioxide benzyl-4-timehelicobacter in the form of a colorless solid (3.8 g).

1,1-dioxide benzyl-4-timehelicobacter

1H NMR (300 MHz, CDCl3) δ to 3.02 (4H, users), to 4.01 (4H, t, J=5 Hz), 5,16 (2H, s), 7,33-7,40 (5H, m).

Getting 328

To a solution of thiomorpholine (2 g) in 1H. NaOH (to 11.6 ml) was added benzylaminocarbonyl (1,66 ml) while cooling the mixture in ice-water and the mixture was stirred at ambient temperature for 2 hours. The solution was neutralized 1H. HCl and was extracted with EtOAc twice. The combined organic layer was washed with water and saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue was purified column chromatography on silica gel to obtain benzyl-4-timehelicobacter in the form of a colorless solid (4.8 g).

Benzyl-4-timehelicobacter

1H NMR (300 MHz, CDCl3) δ at 2.59 (4H, users), of 3.77 (4H, t, J=5 Hz), 5,14 (2H, s), 7,30-7,41 (5H, m).

Getting 329

To a solution of 1,1-dioxide benzyl-4-timehelicobacter (3.8 g) in methanol (32 ml) and 1,4-dioxane (8 is l) was added palladium (10 wt.%) activated carbon (380 mg) at ambient temperature. The mixture was stirred at ambient temperature for 4 hours in an atmosphere of H2(3.4 ATM). The mixture was filtered and evaporated in vacuum to obtain 1,1-dioxide thiomorpholine in the form of a colorless solid (2,22 g).

1,1-dioxide thiomorpholine

1H NMR (300 MHz, CDCl3) δ 3,03 (4H, t, J=5 Hz)to 3.33 (4H, t, J=5 Hz).

MS (m/z 136 (M+H).

Getting 330

To a suspension of [(5-chloro-4-mercapto-6-methyl-3-pyridinyl)oxy]acetic acid (10 g) in dichloromethane (100 ml) was added Et3N (14 ml) in a bath of ice-MeOH. To the mixture was added dropwise triftormetilfullerenov anhydride (14,3 ml) at a temperature below 10°within 30 minutes After 2 hours the mixture was distributed between CHCl3and water. The aqueous layer was extracted with CHCl3twice. The combined organic layer was dried over MgSO4and evaporated in vacuo to obtain a brown oil. The residue was purified column chromatography on silica gel (silica gel, 100 ml), elwira a mixture of hexane-EtOAc=15:1 and 10:1, to obtain 5-chloro-3-pyridinedicarboxylate (15,8 g) as pale brown oil.

5-chloro-3-pyridineacetonitrile

1H NMR (300 MHz, CDCl3) δ of 7.69 (1H, DD, J=4, 4 Hz), charged 8.52 (1H, d, J=4 Hz), 8,65 (1H, d, J=4 Hz).

Getting 331

To ethanol (66 ml) and DMF (66 ml) was added Et3N (29,4 ml), 1,3-propanediylbis(diphenylphosphine) (3,48 g) and palladium acetate (1.9 g) at ice bath in the A. To the mixture was added 5-chloro-3-pyridineacetonitrile (22.1 g) at the same temperature. The mixture was stirred at 50°C for 4 hours in an atmosphere of CO (1 ATM). The mixture was distributed between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water three times, dried over MgSO4and evaporated in vacuum. The residue was purified column chromatography on silica gel (silica gel, 200 ml), elwira a mixture of hexane-EtOAc=15:1 and 10:1, to obtain ethyl-5-chloronicotinate (10.5 g) as a pale brown oil.

Ethyl-5-chloronicotinate

1H NMR (300 MHz, CDCl3) δ of 1.42 (3H, t, J=7 Hz), 4,43 (2H, square, J=7 Hz), of 8.28 (1H, DD, J=3, 3 Hz), a total of 8.74 (1H, d, J=3 Hz), which is 9.09 (1H, d, J=3 Hz).

Getting 332

To 5-chloronicotinate (10.5 g) was added 1H. NaOH (84,9 ml) at ambient temperature. The mixture was heated at 60°C for 1 hour. The reaction mixture is brought to pH 4-5 by addition of HCl. The precipitate was filtered to obtain 5-chloronicotinic acid (6.9 g) as a colourless solid.

5-chloronicotinic acid

1H NMR (300 MHz, DMSO-d6) δ 8,30 (1H, DD, J=3, 3 Hz), 8,88 (1H, d, J=3 Hz), 9,01 (1H, d, J=3 Hz), 13,8 (1H, users).

The following compounds were obtained according to a similar method of obtaining 332.

Getting 333

5-methoxynicotinic acid

1H NMR (DMSO-d6) δ a 3.87 (3H, s), 7,73 (1H, m), 8,48 (1H, d, J=3 Hz), 8,65 (1H, d, J=1 Hz).

MS (ESI+/sup> ): m/z 154 (M+H).

Getting 334

5-pyrimidinecarbonitrile acid

1H NMR (DMSO-d6) δ 9,20 (2H, s), 9,37 (1H, s).

MS (ESI+): m/z 148 (M++Na).

Getting 335

To a solution of Diisopropylamine (5,41 g) in THF (30 ml) was added 1.5 m hexane solution of n-utility (35 ml) under cooling with a mixture of dry ice-acetone and the mixture was stirred at -78°C for 10 minutes. To the mixture was added tert-butyl acetate (by 5.87 g) under cooling with a mixture of dry ice-acetone, and the mixture was stirred at -78°C for 10 minutes and added dropwise to a solution of 5-bromonicotinic acid (3.00 g) and N,N-carbonyldiimidazole (2.65 g) in THF (30 ml) under cooling with a mixture of dry ice-acetone. The mixture was stirred at -78°C for 0.5 hour. The mixture was distributed between ethyl acetate and aqueous solution of NH4Cl. The organic layer was separated, washed with aqueous solution of NaHCO3and saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue is triturated in isopropyl ether to obtain tert-butyl 3-(5-bromo-3-pyridinyl)-3-oxopropanoic in the form of a colourless powder (3,71 g).

tert-Butyl 3-(5-bromo-3-pyridinyl)-3-oxopropanoic

Enol form:1H NMR (CDCl3) δ and 1.54 (9H, s), 5,62 (1H, s), 8,19 (1H, m), 8,72 (1H, d, J=2 Hz), 8,86 (1H, d, J=2 Hz),

Ketoform:1H NMR (CDCl3) δ the 1.44 (9H, s), 3,90 (2H, s)of 8.37 (1H, m), 8,86 (1H, d, J=2 Hz), 9,03 (1H, d, J=2 Hz),

MS (ESI+): m/z 300,302.

Getting 336

To a suspension of NaH in DMF (50 ml)which was washed with hexane 3 times, added portions methyl-5-hydroxynicotinate (10.2 g) at a temperature below 10°in a bath of ice-water in a nitrogen atmosphere. After 30 min, to the mixture was added dropwise methyliodide (4,56 ml). Appeared residue, and the mixture becomes difficult to stir. Was added DMF (30 ml). After 20 min the mixture was stirred at ambient temperature for 3 hours, the Reaction mixture was suppressed by addition of MeOH and concentrated in vacuum. To the residue was added CHCl3saturated NaHCO3and a saturated solution of salt. The organic layer was separated and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over MgSO4and evaporated in vacuum. The residue was purified flash chromatography on silica gel (silica gel, 200 ml), elwira a mixture of hexane-AcOEt=5:1 and 3:1, to obtain methyl-5-methoxynicotinate (3,47 g) as a pale brown solid.

Methyl-5-methoxynicotinic

1H NMR (CDCl3) δ 3,91 (3H, s), of 3.96 (3H, s), 7,76 (1H, m), of 8.47 (1H, d, J=3 Hz), 8,83 (1H, d, J=1 Hz).

MS (ESI+): m/z 168 (M+H).

Getting 337

To a solution of methyl 2-bromo-4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate (330 mg) in N,N-dimethylformamide (5 ml) was added 60% sodium hydride in oil (58,4 mg) in a bath with ice for 5 minutes. After stirring for 1 hour was added in portions oxide (aminooxy)(diphenyl)FOS is in (340 mg) for 40 minutes. The resulting mixture was stirred for 1 hour at the specified bath. The reaction mixture was suppressed by addition of water (10 ml). The mixture was distributed between ethyl acetate and water. The organic layer was washed with water (twice) and saturated salt solution, dried over magnesium sulfate and evaporated. The residue was dissolved in a mixture of ethyl acetate-hexane (1:5) and to the solution was added silica gel. The mixture was filtered and the filtrate was evaporated to obtain methyl 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-2-bromobenzoate as an orange solid (310 mg).

Methyl-4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-2-bromobenzoate

1H-NMR (CDCl3) δ of 1.29 (3H, t, J=7 Hz), was 2.76 (2H, square, J=7 Hz), of 3.97 (3H, s), 5,73 (2H, s, of usher.), to 5.93 (1H, d, J=5 Hz), 6,62 (1H, d, J=5 Hz), 7,73 (1H, d, J=8 Hz), to 7.84 (1H, d, J=8 Hz), 8,02 (1H, s).

Getting 338

To a solution of dimethyl-2-bromoterephthalic (1.04 g) in methanol (10 ml) was added 1N. a solution of sodium hydroxide (5,71 ml) at room temperature. After stirring for 1.5 hours the reaction mixture was suppressed by the addition of 1N. hydrochloric acid (7 ml). Formed white crystals. To promote crystallization, was added water (10 ml). The crystals were collected by filtration, washed with water and dried in the air. The result was obtained 3-bromo-4-(methoxycarbonyl)benzoic acid as white crystals (532 mg).

3-bromo-4-(methoxycarbonyl)benzoic acid

1 H-NMR (DMSO-d6) δ the 3.89 (3H, s), 7,87 (1H, d, J=8 Hz), 8,01 (1H, d, J=8 Hz), 8,17 (1H, s).

Getting 339

A mixture of 2-[2-(2-chloroethoxy)ethoxy]ethyl acetate (6,23 g) and sodium iodide (22,2 g) in acetone (60 ml) was boiled under reflux for 4 hours. The mixture is still boiled under reflux for 4 hours after addition of sodium iodide (11,0 g). The solvent evaporated and the residue was distributed between EtOAc (50 ml) and water (50 ml). The aqueous layer was washed with 10% sodium thiosulfate solution and saturated salt solution, dried over MgSO4and was evaporated to obtain 2-[2-(2-iodoxy)ethoxy]acetic acid ethyl ester as a pale yellow oil (9,74 g).

2-[2-(2-iodoxy)ethoxy]acetate

1H-NMR (CDCl3) δ of 2.09 (3H, s), with 3.27 (2H, t, J=7 Hz), 3,65-of 3.78 (8H, m), 4,24 (2H, m).

Getting 340

A solution of 1-tert-butyl-7-ethyl-2-[(5-methyl-3-isoxazolyl)carbonyl]heptanoate (126 mg) in triperoxonane acid (1 ml) was stirred for 1.5 hours at room temperature. Evaporated volatile substances and subjected to azeotropic distillation with toluene to obtain 7-ethoxy-2-[(5-methyl-3-isoxazolyl)carbonyl]-7-exogamous acid as a pale orange oil (106 mg).

7 ethoxy-2-[(5-methyl-3-isoxazolyl)carbonyl]-7-oxyptera acid

1H-NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.41 (2H, m), of 1.65 (2H, m), 2,02 (2H, m), is 2.30 (2H, m)of 2.50 (3H, s)to 2.55 (1H, s, of usher.), 4,10 (2H, square, J=7 Hz), 4,47 (1H, t, J=7 Hz), 6,40 (1H, s).

M is (ESI +): m/z 296,22 (M-H) and 593,52 (2M-H).

Getting 341

To a suspension of dimethyl sulfone (5,43 g) in tetrahydrofuran (10 ml) was added 1,59M n-utility (36,3 ml) in a bath of dry ice-acetone in nitrogen atmosphere. After stirring for 0.5 hours the solution was added methylmetacrylate (2.00 g) in tetrahydrofuran (5 ml). The resulting mixture was stirred for 2 hours at the specified bath and allowed to warm to room temperature for 2 hours. The mixture was distributed between EtOAc and 4h. hydrochloric acid. The reaction was suppressed by the addition of 4n. hydrochloric acid in EtOAc (15 ml). The mixture was distributed between EtOAc (100 ml) and saturated salt solution (100 ml). The aqueous layer was washed with EtOAc (100 ml, five times). The organic layer was combined and the combined extracts were dried over MgSO4and was evaporated. Column flash chromatography on silica gel (EtOAc-hexane=50:200-300:100) gave 2-(methylsulphonyl)-1-methoxyethanol in the form of a colorless oil (2.24 g).

1-methoxy-3-(methylsulphonyl)acetone

1H-NMR (CDCl3) δ 2,99 (3H, s), is 3.08 (2H, s), 3,47 (3H, s), 4,19 (2H, s).

The following compounds were obtained according to a similar method of example 1.

Example 392

Ethyl-4-[3-bromo-4-(methoxycarbonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-carboxylate

1H-NMR (CDCl3) δ and 0.98 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 2,61 (3H, s), 3.04 from (2H, square, J=7 Hz), 3,98 (3H, s), of 4.05 (2H, square, J=7 Hz), of 6.29 (1H, d, J=5 Hz), to 6.67 (1H, d, J=7 Hz), 7,44 (1H,d, J=8 Hz), 7,76 (1H, s), 7,89 (1H, d, J=8 Hz).

Example 393

3-[7-ethyl-2-(methoxymethyl)-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

1H-NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 2,98 (2H, square, J=7 Hz), 3,18 (3H, s), of 3.45 (3H, s), 4,59 (2H, s), and 6.25 (1H, d, J=5 Hz), of 6.71 (1H, d, J=5 Hz), the 7.65 (1H, t, J=8 Hz), 7,78 (1H, d, J=8 Hz), 7,94 (1H, d, J=8 Hz), to 7.99 (1H, s).

MS (ESI+): m/z 370 (M+H).

The following compound was obtained according to a similar method of example 16.

Example 394

5-{4-[3-(aminocarbonyl)phenyl]-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl}pentane acid

1H-NMR (CDCl3) δ of 1.02 (4H, m)of 1.28 (3H, t, J=7 Hz), to 1.70 (2H, m), is 2.37 (2H, m), of 2.92 (2H, square, J=7 Hz), by 5.87 (1H, d, J=5 Hz), of 6.66 (1H, d, J=5 Hz), 7,46-to 7.67 (5H, m), of 7.96-8,08 (3H, m).

The following compounds were obtained according to a similar method of example 21.

Example 395

Ethyl-4-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ to 1.21 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,65-of 1.78 (2H, m), 2,22 (2H, t, J=7 Hz), 2.40 a-2,52 (2H, m), 2,58 (3H, s), 3,03 (2H, square, J=7 Hz), of 4.05 (2H, square, J=7 Hz), 5,86 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,25 (1H, d, J=5 Hz), was 7.36 (1H, s), 8,53 (1H, d, J=5 Hz).

MS (ESI+): m/z 386.

Example 396

Ethyl-3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 2,30-2,39 (2H, m), to 2.57 (3H, s), 2,74-and 2.83 (2H, m), 3,03 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 5,88 (1H, d, J=4 Hz), 6,55 (1H, d, J=4 Hz), from 7.24 (1H, d, J=5 Hz), 7,35 (1H, s), 8,53 (1H, d, J=5 Hz).

MS (ESI+): m/z 372.

Example 397

Ethyl-5-[2-benzyl-4-(2-chloro-4-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,30-1,50 (4H, m), 2,10 (2H, t, J=7 Hz), 2,23 to 2.35 (2H, m), 3.04 from (2H, square, J=7 Hz), 4.09 to (2H, square, J=7 Hz), is 4.21 (2H, s), 5,88 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,14-to 7.32 (7H, m), and 8.50 (1H, d, J=5 Hz).

Example 398

Methyl{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy}acetate

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 2,42 (3H, s), 2,61 (3H, s), 2,78-is 2.88 (2H, m), 3,03 (2H, square, J=7 Hz), 3.46 in is 3.57 (2H, m), 3,71 (3H, s), of 3.95 (2H, s), by 5.87 (1H, d, J=4 Hz), of 6.52 (1H, d, J=4 Hz), 7,54 (1H, s), 8,43 (1H, d, J=2 Hz), 8,53 (1H, d, J=2 Hz).

MS (ESI+): m/z 368.

Example 399

Ethyl[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]acetate

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), of 2.51 (3H, s), 3,03 (2H, square, J=7 Hz), 3.43 points (2H, s), of 4.12 (2H, square, J=7 Hz), of 5.99 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,94 (1H, m), 8,58 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

MS (ESI+): m/z 402, 404.

Example 400

Ethyl-3-[2-[(atomic charges)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), of 2.16 (3H, s), 2,32-to 2.42 (2H, m), is 2.44 (3H, s), 2.77-to 2,90 (2H, m), 3,03 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 5,31 (2H, s), 5,96 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,53 (1H, s), 8,42 (1H, d, J=2 Hz), 8,55 (1H, d, J=2 Hz).

MS (ESI+): m/z 410.

Example 401

Ethyl-4-[2-[(atomic charges)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1/sup> H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,64-of 1.78 (2H, m), 2,10-of 2.23 (2H, m), 2,17 (3H, s), 2,43 (3H, s), 2,43-of 2.58 (2H, m), to 3.02 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 5,33 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,53 (1H, s), 8,43 (1H, s), 8,55 (1H, s).

MS (ESI+): m/z 424.

Example 402

Ethyl-5-[2-[(atomic charges)methyl]-4-(3-cyanophenyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-1,60 (4H, m)of 2.16 (2H, t, J=7 Hz), 2,17 (3H, s), 2.40 a-2,52 (2H, m), 3,03 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), from 5.29 (2H, s), 5,88 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,60-to 7.68 (3H, m), 7,75-7,83 (1H, m).

MS (ESI+): m/z 448.

Example 403

Ethyl-4-[2-[(atomic charges)methyl]-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,65-to 1.82 (2H, m), 2,17 (3H, s), of 2.21 (2H, t, J=7 Hz), a 2.45-2.63 in (2H, m), to 3.02 (2H, square, J=7 Hz), of 4.05 (2H, square, J=7 Hz), 5,33 (2H, s), 5,95 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), of 7.90 (1H, m), to 8.57 (1H, d, J=2 Hz), 8,80 (1H, d, J=2 Hz).

MS (ESI+): m/z 488, 490.

Example 404

Ethyl-3-[2-[(atomic charges)methyl]-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), of 2.16 (3H, s), a 2.36 (2H, t, J=7 Hz), 2.77-to 2,95 (2H, m), to 3.02 (2H, square, J=7 Hz), 4,06 (2H, square, J=7 Hz), 5,31 (2H, s), 5,96 (1H, d, J=4 Hz), only 6.64 (1H, d, J=4 Hz), 7,88 (1H, s), 8,56 (1H, m), 8,80 (1H, m).

MS (ESI+): m/z 474, 476.

Example 405

Ethyl-3-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1 3) δ 0,88 was 1.06 (2H, m)to 1.19 (3H, t, J=7 Hz), 1,15-of 1.36 (3H, m)to 1.37 (3H, t, J=7 Hz), 1,58-of 1.85 (6H, m), 2,42 (2H, m), 2,43 (3H, s), 2,83-of 2.97 (2H, m), 3,05 (2H, square, J=7 Hz), to 3.38 (2H, d, J=7 Hz), 4,06 (2H, square, J=7 Hz), of 4.66 (2H, s), 5,91 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,52 (1H, s), 8,42 (1H, d, J=2 Hz), 8,54 (1H, d, J=2 Hz).

Example 406

Ethyl-3-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexylmethoxy)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}propanoate

1H NMR (CDCl3) δ 0,85 was 1.06 (2H, m)of 1.20 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,16-of 1.46 (3H, m), 1,55-of 1.84 (6H, m), 2,43 (2H, t, J=7 Hz), 2,82-of 3.00 (2H, m), 3,06 (2H, square, J=7 Hz), 3,37 (2H, d, J=7 Hz), 4,06 (2H, square, J=7 Hz), of 4.66 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,87 (1H, m), 8,55 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

MS (ESI+): m/z 528, 530.

Example 407

Ethyl-4-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexylmethoxy)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}butanoate

1H NMR (CDCl3) δ 0,87 was 1.06 (2H, m)to 1.21 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,16-of 1.46 (3H, m), 1,50-of 1.85 (8H, m), of 2.23 (2H, t, J=7 Hz), 2,55 is 2.75 (2H, m), 3.04 from (2H, square, J=7 Hz), to 3.38 (2H, d, J=7 Hz), 4,08 (2H, square, J=7 Hz), of 4.67 (2H, s), of 5.92 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,89 (1H, m), 8,56 (1H, d, J=2 Hz), 8,79 (1H, d, J=2 Hz).

MS (ESI+): m/z 542, 544.

Example 408

Ethyl-4-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ 0,22-0,32 (2H, m), 0,53 is 0.65 (2H, m), of 1.10-1.20 (1H, m)to 1.19 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), of 1.65 and 1.80 (2H, m), 2,14-of 2.30 (2H, m), 2,43 (3H, s), 2.57 m-to 2.74 (2H, m), 3,05 (2H, square, J=7 Hz), of 3.43 (2H, d, J=7 Hz), a 4.03 (2H, square, J=7 Hz), 4,74 (2H, s), 5,90 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), 7,53 (1H, s), 8,43 (1H, s), 8,54 (H, C).

MS (ESI+): m/z 436.

Example 409

Ethyl-3-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ 0,22-0,32 (2H, m), of 0.54 to 0.63 (2H, m), of 1.10-1.20 (1H, m)to 1.21 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 2.40 a-2,50 (2H, m), 2,43 (3H, s), 2,86 are 2.98 (2H, m), 3,05 (2H, square, J=7 Hz), 3,42 (2H, d, J=7 Hz), 4,06 (2H, square, J=7 Hz), 4,71 (2H, s), of 5.92 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,52 (1H, s), 8,42 (1H, s), 8,54 (1H, s).

MS (ESI+): m/z 422.

Example 410

Ethyl-3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-methoxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoate

1H NMR (CDCl3) δ of 1.20 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 2,44 (2H, t, J=7 Hz), 2,82 are 2.98 (2H, m), 3,05 (2H, square, J=7 Hz), to 3.38 (3H, s)to 3.58 (2H, m), 3,76 (2H, m), of 4.05 (2H, square, J=7 Hz), was 4.76 (2H, ), to 5.93 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,87 (1H, m), 8,54 (1H, s), 8,79 (1H, s).

MS (ESI+): m/z 490, 492.

Example 411

4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin

1H NMR (CDCl3) δ of 1.39 (3H, t, J=7 Hz), of 2.54 (3H, s), 3.04 from (2H, square, J=7 Hz), to 6.39 (1H, s), 6,51 (1H, d, J=4 Hz), to 6.67 (1H, d, J=4 Hz), 8,17 (1H, m), 8,76 (1H, d, J=2 Hz), 8,86 (1H, d, J=2 Hz).

MS (ESI+): m/z 316, 318.

Example 412

Ethyl-4-[2-[(atomic charges)methyl]-4-(5-chloro-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]butanoate

1H NMR (300 MHz, CDCl3) δ of 1.20 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), to 1.70 (2H, TT, J=7, 7 Hz), 2,17 (3H, s), measuring 2.20 (2H, t, J=7 Hz), 2,45-of 2.54 (2H, m), to 3.02 (2H, square, J=7 Hz), Android 4.04 (2H, square, J=7 Hz), 5,33 (2H, ), 5,94 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,74 (1H, DD, J=2, 2 Hz), 8,53 (1H, d, J=2 Hz), to 8.70 (1H, d, J=2 Hz).

When the EP 413

Ethyl-5-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (300 MHz, CDCl3) δ 0,23-0,26 (2H, m), 0,54 is 0.59 (2H, m), 1,07 is 1.16 (1H, m)of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1.41 to and 1.56 (4H, m), 2,17 (2H, t, J=7 Hz), 2,53-of 2.64 (2H, m), 3,03 (2H, square, J=7 Hz), 3,41 (2H, d, J=7 Hz), 4.09 to (2H, square, J=7 Hz), 4,70 (2H, s), 5,90 (1H, d, J=5 Hz), to 6.58 (1H, d, J=5 Hz), 7,72 (1H, s), 8,51 (1H, s), 8,68 (1H, s).

Example 414

Ethyl-4-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}butanoate

1H NMR (300 MHz, CDCl3) δ 0,24 (2H, dt, J=7, 7 Hz), of 0.56 (2H, dt, J=7, 7 Hz), 1,07-of 1.15 (1H, m)of 1.20 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,72 (2H, TT, J=7, 7 Hz), of 2.21 (2H, t, J=7 Hz), 2,55-of 2.66 (2H, m), to 3.02 (2H, square, J=7 Hz), 3.43 points (2H, d, J=7 Hz), Android 4.04 (2H, square, J=7 Hz), to 4.73 (2H, s), 5,91 (1H, d, J=5 Hz), 6,59 (1H, d, J=5 Hz), 7,74 (1H, DD, J=2, 2 Hz), charged 8.52 (1H, d, J=2 Hz), 8,68 (1H, d, J=2 Hz).

Example 415

Ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isobutoxide)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (300 MHz, CDCl3) δ to 0.92 (6 H, d, J=7 Hz), of 1.26 (3H, t, J=7 Hz), of 1.34 (3H, t, J=7 Hz), 1,38-of 1.56 (4H, m), with 1.92 (1H, cut, J=7, 7 Hz), of 2.15 (2H, t, J=7 Hz), of 2.51 2.63 in (2H, m), 3,03 (2H, square, J=7 Hz), 3.33 and (2H, d, J=7 Hz), 4.09 to (2H, square, J=7 Hz)and 4.65 (2H, s), 5,90 (1H, d, J=7 Hz), 6,59 (1H, d, J=7 Hz), 7,88 (1H, DD, J=2, 2 Hz), 8,55 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

Example 416

Ethyl-3-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(isobutoxide)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (300 MHz, CDCl3) δ to 0.92 (6H, d, J=7 Hz), 1,19 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), at 1.91 (1H, cut, J=7, 7 Hz), is 2.41 (2H, t, J=8 Hz), 84-2,94 (2H, m), 3,03 (2H, square, J=7 Hz), 3,35 (2H, d, J=7 H), of 4.05 (2H, square, J=7 Hz), and 4.68 (2H, s), of 5.92 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,72 (1H, DD, J=2, 2 Hz), 8,51 (1H, d, J=2 Hz), 8,69 (1H, d, J=2 Hz).

Example 417

Ethyl-3-[2-[(atomic charges)methyl]-4-(3-chlorophenyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]propanoate

1H NMR (300 MHz, CDCl3) δ to 1.19 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), of 2.15 (3H, s), of 2.33 (2H, t, J=8 Hz), 2,82 (2H, t, J=8 Hz), to 3.02 (2H, square, J=7 Hz), 4,06 (2H, square, J=7 Hz), 5,31 (2H, s), 5,97 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7.23 percent-7,26 (1H, m), 7,37 (1H, s), 7,44-7,46 (2H, m).

Example 418

Ethyl-4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isobutoxide)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (300 MHz, CDCl3) δ to 0.92 (6H, d, J=7 Hz), of 1.20 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,71 (2H, TT, J=8, 8 Hz), at 1.91 (1H, cut, J=7, 7 Hz), measuring 2.20 (2H, t, J=8 Hz), 2,56-of 2.66 (2H, m), 3,03 (2H, square, J=7 Hz), to 3.34 (2H, d, J=7 Hz), of 4.05 (2H, square, J=7 Hz), 4,69 (2H, s), 5,91 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,89 (1H, s), 8,56 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

Example 419

2,4-bis(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin

1H NMR (CDCl3) δ a 1.45 (3H, t, J=7 Hz), 3,14 (2H, square, J=7 Hz), of 6.66 (1H, d, J=4 Hz), 6,86 (1H, d, J=4 Hz), 6,91 (1H, s)8,23 (1H, m), 8,48 (1H, m), 8,77 (1H, m), 8,83 (1H, m), to 8.94 (1H, d, J=2 Hz), 9,18 (1H, d, J=2 Hz).

Example 420

Ethyl-4-[2-[(atomic charges)methyl]-4-(3-chlorophenyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ to 1.19 (3H, t, J=8 Hz), of 1.34 (3H, t, J=8 Hz), and 1.63 to 1.76 (2H, m), 2,10-2,22 (5H, m), 2,45 is 2.55 (2H, m), 3,01 (2H, square, J=8 Hz), Android 4.04 (2H, square, J=8 Hz), 5,32 (2H, s), 5,95 (1H, d, J=5 Hz), 6,59 (1H, d, J=5 Hz), 7,21-7,29 (1H, overlapping CDCl3), was 7.36 (1H,users), 7,38-7,46 (2H, m).

MS (ESI+): m/z 443 (M+H).

Example 421

Ethyl-5-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=8 Hz), 1,33-to 1.60 (7H, m), 1,55-1,70 (2H, m), 2,17 (2H, t, J=8 Hz), 2,46-of 2.64 (2H, m), 3.04 from (2H, d, J=8 Hz), of 3.46 (3H, s), 3,90 (3H, s), 4.09 to (2H, square, J=8 Hz), to 4.62 (2H, s), to 5.93 (1H, d, J=5 Hz), 6,59 (1H, d, J=5 Hz), 7.23 percent (1H, m), by 8.22 (1H, d, J=1 Hz), 8,40 (1H, d, J=3 Hz).

MS (ESI+): m/z 426 (M+H).

Example 422

Ethyl-5-[7-ethyl-4-(5-methoxy-3-pyridinyl)-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=8 Hz), 1,33-1,62 (7H, m)to 2.18 (2H, t, J=8 Hz), 2,38-2,49 (2H, m), of 2.56 (3H, s), 3,01 (2H, square, J=8 Hz), 3,90 (3H, s)4,08 (2H, square, J=8 Hz), of 5.89 (1H, d, J=5 Hz), 6,51 (1H, d, J=5 Hz), 7,21 (1H, m), 8,21 (1H, d, J=1 Hz), 8,40 (1H, d, J=3 Hz).

MS (ESI+): m/z 396 (M+H).

Example 423

Ethyl-3-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ of 1.20 (3H, t, J=8 Hz), to 1.38 (3H, t, J=8 Hz), 2.40 a (2H, t, J=8 Hz), 2,81-2,96 (2H, m), 3.04 from (2H, d, J=8 Hz), 3,47 (3H, s), 3,90 (3H, s), of 4.05 (2H, square, J=8 Hz)and 4.65 (2H, s), 5,96 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,21 (1H, m), 8,23 (1H, users), 8,40 (1H, d, J=3 Hz).

MS (ESI+): m/z 398 (M+H).

Example 424

Ethyl-4-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ of 1.20 (3H, t, J=8 Hz), to 1.38 (3H, t, J=8 Hz), 1,64-to 1.79 (2H, m), 2,14-of 2.24 (2H, m), 2,53-of 2.66 (2H, m), 3.04 from (2H, d, J=8 Hz), 3,47 (3H, s), 3,90 (3H, s), Android 4.04 (2H, square, J=8 Hz), of 4.67 (2H, users), 5,94 (1H, d, J=5 Hz), 6,59 (1H, d, J=5 Hz) of 7.23 (1H, m), by 8.22 (1H, d, J=1 Hz), 8,40 (1H, d, J=3 Hz).

MS (ESI+): m/z 412 (M+H).

Example 425

Ethyl-5-[7-ethyl-2-(methoxymethyl)-4-(5-pyrimidinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=8 Hz), 1.30 and 1,62 (7H, m), 2,19 (2H, t, J=8 Hz), 2,46-2,60 (2H, m), 3.04 from (2H, d, J=8 Hz), 3,47 (3H, s), 3,90 (3H, s), 4.09 to (2H, square, J=8 Hz), 4,63 (2H, s), 5,90 (1H, d, J=5 Hz), is 6.61 (1H, d, J=5 Hz), 8,80 (2H, s), 9,34 (1H, s).

MS (ESI+): m/z 397 (M+H).

Example 426

Ethyl-4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ to 1.21 (3H, t, J=8 Hz), of 1.37 (3H, t, J=8 Hz), 1,62 to 1.76 (2H, m), of 2.21 (2H, t, J=8 Hz), 2,49-to 2.67 (2H, m), 3.04 from (2H, d, J=8 Hz), of 3.46 (3H, s)4,06 (2H, square, J=8 Hz), of 4.67 (2H, users), of 5.92 (1H, d, J=5 Hz), is 6.61 (1H, d, J=5 Hz), 7,74 (1H, m), 8,53 (1H, d, J=1 Hz), 8,69 (1H, d, J=2 Hz).

MS (ESI+): m/z 414 (M-H).

Example 427

Ethyl-3-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ of 1.20 (3H, t, J=8 Hz), to 1.38 (3H, t, J=8 Hz), 2.40 a (2H, t, J=8 Hz), 2,82-to 2.94 (2H, m), 3.04 from (2H, d, J=8 Hz), 3,47 (3H, s)4,06 (2H, square, J=8 Hz)and 4.65 (2H, s), to 5.93 (1H, d, J=5 Hz), to 6.67 (1H, d, J=5 Hz), 7,73 (1H, users), 8,51 (1H, users), to 8.70 (1H, users).

MS (ESI+): m/z 402 (M+H).

Example 428

Ethyl-5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=8 Hz), 1,34 is 1.60 (7H, m), 2,19 (2H, t, J=8 Hz), 2,47-of 2.64 (2H, m), 3.04 from (2H, d, J=8 Hz), of 3.46 (3H, s), 4,10 (2H, square, J=8 Hz), to 4.62 (2H, s), 5,90 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,73 (1H, m), 8,51 (1H, users), 8,68 (1H, ush the D.C).

MS (ESI+): m/z 426 (M+H).

Example 429

Methyl-2-[(atomic charges)methyl]-4-(5-bromo-3-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-carboxylate

TPL 122-123°C.

1H-NMR (CDCl3) δ to 1.38 (3H, t, J=8 Hz), 2,12 (3H, s), 3,06 (2H, t, J=8 Hz), 3,61 (3H, s), 5,43 (2H, s), 6,37 (1H, d, J=5 Hz), 6,78 (1H, d, J=5 Hz), to 7.93 (1H, t, J=1 Hz), to 8.57 (1H, d, J=1 Hz), 8,78 (1H, d, J=1 Hz).

MS (ESI+): m/z 432, 434 (M+H).

Example 430

2-(2-{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy}ethoxy)acetate

1H-NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), was 2.05 (3H, s), 2,42 (3H, s)at 2.59 (3H, s)of 2.75 (2H, m)of 3.00 (2H, square, J=7 Hz), 3,39-of 3.48 (4H, m), of 3.54 (2H, m), 3,63 (2H, m)to 4.16 (2H, m), 5,86 (1H, d, J=5 Hz), 6,52 (1H, d, J=5 Hz), 7,50 (1H, m), 8,43 (1H, m), charged 8.52 (1H, m).

Example 431

Ethyl-(2E)-4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]-2-butenoate

1H-NMR (CDCl3) δ of 1.27 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 2.49 USD (3H, s), to 3.02 (2H, square, J=7 Hz), 3,30 (2H, m)to 4.16 (2H, square, J=7 Hz), to 5.58 (1H, d, J=16 Hz), 5,90 (1H, d, J=5 Hz), 6,56 (1H, d, J=5 Hz), 6,97 (1H, dt, J=7 and 16 Hz), 7,58 (2H, m), the 7.65 (1H, s), of 7.75 (1H, m).

Example 432

Ethyl-4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (300 MHz, CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,65-of 1.78 (2H, m), of 2.23 (2H, t, J=7 Hz), 2,54-of 2.72 (2H, m), 3.04 from (2H, square, J=7 Hz), of 3.46 (3H, s)4,06 (2H, square, J=7 Hz), of 4.66 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,89 (1H, m), 8,55 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (ESI+): m/z 460, 462.

Example 433

Ethyl-4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[,2-b]pyridazin-3-carboxylate

1H NMR (CDCl3) δ 0,99 (3H, t, J=8 Hz), to 1.38 (3H, t, J=8 Hz), 2.63 in (3H, s), 3,05 (2H, square, J=8 Hz), 4,07 (2H, square, J=8 Hz), 6,27 (1H, d, J=5 Hz), 6,70 (1H, d, J=5 Hz), 7,30 (1H, DD, J=5, 1 Hz), 7,41 (1H, users), 8,49 (1H, d, J=5 Hz).

MS (ESI+): m/z 344 (M+H).

The following compounds were obtained according to a similar method of example 76.

Example 434

4-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]butane acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,72-of 1.84 (2H, m), of 2.33 (2H, t, J=7 Hz), 2,47-to 2.57 (2H, m), 2,58 (3H, s), 3,03 (2H, square, J=7 Hz), 5,88 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,27 (1H, m), 7,38 (1H with), 8,53 (1H, d, J=5 Hz).

MS (ESI-): m/z 356, MS (ESI+): m/z 358.

Example 435

3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]propanoic acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), a 2.36-2,47 (2H, m), 2,58 (3H, s), was 2.76-is 2.88 (2H, m), 3,03 (2H, square, J=7 Hz), of 5.89 (1H, d, J=4 Hz), 6,55 (1H, d, J=4 Hz), 7,25 (1H, d, J=5 Hz), 7,35 (1H, s), 8,53 (1H, d, J=5 Hz).

Example 436

4-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]butane acid

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), 1.30 and of 1.42 (2H, m)of 1.35 (9H, s), and 1.63 to 1.76 (2H, m), 2,22-is 2.37 (4H, m), 3,93 (1H, d, J=17 Hz), of 4.12 (2H, square, J=7 Hz), 4,29 (1H, d, J=17 Hz), 7,22 (2H, d, J=8 Hz), 7,26 and 7.36 (4H, m)to 7.50 (1H, s), 8,42 (1H, d, J=5 Hz),

MS (ESI-): m/z 418, MS (ESI+): m/z 420,

Example 437

3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]propanoic acid

1H NMR (CDCl3) δ of 1.36 (3H, t, J=7 Hz), to 2.06 (2H, t, J=7 Hz), 2,78 (2H, t, J=7 Hz), 04 (2H, square, J=7 Hz), of 5.99 (1H, d, J=4 Hz), to 6.67 (1H, d, J=4 Hz), 7,28 (1H, d, J=5 Hz), 7,41 (1H, s), 7,45-of 7.55 (5H, m), 8,53 (1H, d, J=5 Hz).

MS (ESI-): m/z 404, MS (ESI+): m/z 406.

Example 438

5-[2-benzyl-4-(2-chloro-4-pyridinyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ 1,16-1,32 (2H, m)of 1.39 (3H, t, J=7 Hz), 1,38-of 1.53 (2H, m), of 2.15 (2H, t, J=7 Hz), 2,30-to 2.40 (2H, m), 3,06 (2H, square, J=7 Hz), is 4.21 (2H, s), 5,88 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7.18 in-to 7.35 (7H, m), 8,49 (1H, d, J=5 Hz).

MS (ESI-): m/z 446, MS (ESI+): m/z 448.

Example 439

{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy}acetic acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 2,44 (3H, s)at 2.59 (3H, s), 2,74 of 2.92 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,54-3,66 (2H, m), 3,93 (2H, m), of 5.82 (1H, d, J=4 Hz), 6,53 (1H, d, J=4 Hz), 7,63 (1H, s), charged 8.52 (1H, s), 8,56 (1H, s).

Example 440

{2-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]ethoxy}acetic acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 2,80 (2H, t, J=7 Hz), 3,03 (2H, square, J=7 Hz), 3,20 (2H, t, J=7 Hz), and 3.72 (3H, s), 6,01 (1H, d, J=4 Hz), to 6.67 (1H, d, J=4 Hz), 7,42 (1H, d, J=5 Hz), 7,45-7,60 (6H, m), to 8.57 (1H, d, J=5 Hz).

Example 441

[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]acetic acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), to 2.55 (3H, s), 2,97-3,10 (2H, m), 3,30-3,62 (2H, m), 5,97 (1H, m), to 6.57 (1H, m), 8,03 (1H, s), 8,69 (1H, s), 8,77 (1H, s).

MS (ESI+): m/z 374, 376.

Example 442

3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}prop the new acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 2,33-of 2.50 (2H, m), 2,42 (3H, s), 2,80-3,00 (2H, m), 3,06 (2H, square, J=7 Hz), 4.72 in (2H, s), a 4.83 (2H, s), of 5.92 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), was 7.36 (2H, d, J=7 Hz), 7,55 (1H, s), to 8.41 (1H, s), 8,44 (2H, d, J=7 Hz), 8,53 (1H, s).

MS (ESI+): m/z 429, 431.

Example 443

3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-personalitate)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 2,42 (3H, s), 2.40 a is 2.55 (2H, m), 2,83-of 3.12 (2H, m), 3,03 (2H, square, J=7 Hz), 4,84 (2H, s), 4,91 (2H, m), of 5.92 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), EUR 7.57 (1H, s), 8,42 (1H, s), 8,48-8,55 (3H, m), 8,76 (1H, s).

MS (ESI+): m/z 432.

Example 444

3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 2,43 (3H, s), 2,50-2,60 (2H, m), 2,88 was 3.05 (2H, m), 3,03 (2H, square, J=7 Hz), to 4.81 (2H, s), to 4.87 (2H, s), of 5.82 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,27 (1H, m), of 7.48 (1H, d, J=8 Hz), 7,56 (1H, s), to 7.77 (1H, t, J=8 Hz), 8,43 (1H, s), 8,54 (2H, m).

Example 445

4-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butane acid

1H NMR (CDCl3) δ of 1.40 (3H, t, J=7 Hz), 1.70 to of 1.85 (2H, m), 2,16-2,31 (2H, m), is 2.44 (3H, s), 2,53-and 2.83 (2H, m), 3,05 (2H, square, J=7 Hz), 4.72 in (2H, s), a 4.83-to 4.98 (2H, m), of 5.92 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,30 (2H, d, J=7 Hz), EUR 7.57 (1H, s), scored 8.38-8,55 (4H, m).

MS (ESI-): m/z 443, MS (ESI+): m/z 445.

Example 446

5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,40-to 1.63 (4H, m), of 2.20 (2H, t, J=7 Hz), 2,52 of 2.68 (2H, m), 3.04 from (2H, square, J=7 Hz), 4,69 (2H, s), 4,78 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,35 (2H,, d, J=6 Hz), 7,88 (1H, m), 8,54 (2H, d, J=6 Hz), 8,55 (1H, m), 8,79 (1H, m).

Example 447

5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,40-of 1.62 (4H, m), 2,17 (2H, t, J=7 Hz), 2,50-to 2.67 (2H, m), 3.04 from (2H, square, J=7 Hz), 4,69 (2H, s), was 4.76 (2H, s), of 5.92 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,32-7,38 (1H, m), to 7.77 (1H, d, J=8 Hz), 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.

Example 448

5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,48-to 1.67 (4H, m), and 2.26 (2H, t, J=7 Hz), 2,53 is 2.75 (2H, m), 3,03 (2H, square, J=7 Hz), 4,82 (2H, s), a 4.83 (2H, s), 5,90 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,26-7,34 (1H, m), 7,53 (1H, d, J=8 Hz), 7,75-7,83 (1H, m), 7,87 (1H, m), 8,55 (1H, d, J=2 Hz), to 8.62 (1H, m), 8,77 (1H, d, J=2 Hz).

MS (ESI+): m/z 523, 525.

Example 449

5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-personalitate)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,45-of 1.64 (4H, m), of 2.23 (2H, t, J=7 Hz), 2,53-of 2.72 (2H, m), 3,03 (2H, square, J=7 Hz), a 4.83 (2H, s), to 4.87 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,88 (1H, m), 8,53 (3H, m), 8,77 (2H, m).

MS (ESI-): m/z 522, 524, MS (ESI+): m/z 524, 526.

Example 450

4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinyl is hydroxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butane acid

1H NMR (CDCl3) δ of 1.39 (3H, t, J=7 Hz), 1,69-of 1.84 (2H, m), and 2.27 (2H, t, J=7 Hz), 2,56 is 2.80 (2H, m), to 3.02 (2H, square, J=7 Hz), to 4.73 (2H, s)to 4.92 (2H, m)5,94 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,31 (2H,, d, J=6 Hz), of 7.90 (1H, m), 8,46 (2H, d, J=6 Hz), to 8.57 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

MS (ESI-): m/z 507, 509, MS (ESI+): m/z 509, 511.

Example 451

4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,66 of-1.83 (2H, m), and 2.26 (2H, t, J=7 Hz), 2,53-2,77 (2H, m), 3.04 from (2H, square, J=7 Hz), 4,71 (2H, s), a 4.86 (2H, m), of 5.92 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,33 (1H, m), 7,78 (1H, d, J=8 Hz), of 7.90 (1H, m), and 8.50 (1H, m), 8,56 (1H, d, J=2 Hz), at 8.60 (1H, s), 8,78 (1H, d, J=2 Hz).

MS (ESI+): m/z 509, 511.

Example 452

4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butane acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1.70 to of 1.85 (2H, m), 2,23-of 2.34 (2H, m), 2.57 m) was 2.76 (2H, m), 3,03 (2H, square, J=7 Hz), to 4.81 (2H, s), the 4.90 (2H, m), 5,91 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,28 (1H, m), 7,49 (1H, d, J=7 Hz), to 7.77 (1H, t, J=8 Hz), 7,88 (1H, m), 8,55 (1H, d, J=2 Hz), to 8.57 (1H, m), a total of 8.74 (1H, d, J=2 Hz).

MS (ESI+): m/z 509, 511.

Example 453

4-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}butane acid

1H NMR (CDCl3) δ 0,22 (2H, m), or 0.57 (2H, m), 1,07-1,22 (1H, m)to 1.37 (3H, t, J=7 Hz), 1,72-to 1.87 (2H, m), 2,28 (2H, t, J=7 Hz), 2,58-2,77 (2H, m), 3,03 (2H, square, J=7 Hz), to 3.41 (2H, d, J=7 Hz), 4.72 in (2H, s), of 5.92 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), to 7.93 (1H, m), 8,56 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (ESI -): m/z 470, 472, MS (ESI+): m/z 472, 474.

Example 454

4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-personalitate)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,68 of-1.83 (2H, m), and 2.27 (2H, t, J=7 Hz), 2,56-2,78 (2H, m), 3,03 (2H, square, J=7 Hz), 4,84 (2H, s)to 4.92 (2H, m)5,94 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), to $ 7.91 (1H, m), 8,51 (2H, m), 8,56 (1H, d, J=2 Hz), 8,76 (2H, m).

MS (ESI-): m/z 508, 510, MS (ESI+): m/z 510, 512.

Example 455

3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid

1H NMR (CDCl3) δ of 1.39 (3H, t, J=7 Hz), of 2.38 (2H, t, J=7 Hz), 2,83 are 2.98 (2H, m), of 3.07 (2H, square, J=7 Hz), 4,74 (2H, s), a 4.83 (2H, s), 5,95 (1H, d, J=4 Hz), of 6.65 (1H, d, J=4 Hz), 7,38 (2H, d, J=6 Hz), 7,88 (1H, s), 8,43 (2H, d, J=6 Hz), 8,55 (1H, s), 8,78 (1H, s).

MS (ESI-): m/z 493, 495, MS (ESI+): m/z 495, 497.

Example 456

4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-hydroxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butane acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,68 of-1.83 (2H, m), 2,28 (2H, t, J=7 Hz), 2,53 was 2.76 (2H, m), to 3.02 (2H, square, J=7 Hz), of 3.75 (2H, m), with 3.79 (2H, m), 4,78 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), of 7.90 (1H, s), 8,56 (1H, s), 8,78 (1H, s).

MS (ESI-): m/z 460, 462, MS (ESI+): m/z 462, 464.

Example 457

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

1H NMR (CDCl3) δ 0,88 was 1.06 (2H, m), 1,10-of 1.36 (3H, m)to 1.37 (3H, t, J=7 Hz), 1,58-of 1.85 (6H, m), 2,42 (3H, s), 2,48-2,60 (2H, m), 2,80-to 3.02 (2H, m), 3.04 from (2H, square, J=7 G is), 3,39 (2H, d, J=7 Hz), of 4.67 (2H, m), of 5.89 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), EUR 7.57 (1H, s), 8,42 (1H, s), 8,53 (1H, s).

MS (ESI-): m/z 434, MS (ESI+): m/z 436.

Example 458

3-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexylmethoxy)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}propanoic acid

1H NMR (CDCl3) δ from 0.88 to 1.05 (2H, m), 1,10-of 1.36 (3H, m)to 1.37 (3H, t, J=7 Hz), 1.56 to to 1.83 (6H, m), of 2.51 (2H, t, J=7 Hz), 2,80-of 3.07 (2H, m), 3,06 (2H, square, J=7 Hz), 3,37 (2H, d, J=7 Hz), of 4.67 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,89 (1H, m), 8,55 (1H, s), 8,79 (1H, s).

MS (ESI-): m/z 498, 500, MS (ESI+): m/z 500, 502.

Example 459

4-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexylmethoxy)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}butane acid

1H NMR (CDCl3) δ 0,86-of 1.03 (2H, m), 1,10-of 1.35 (3H, m)to 1.37 (3H, t, J=7 Hz), 1.60-to is 1.82 (8H, m), 2,28 (2H, t, J=7 Hz), 2,55 was 2.76 (2H, m), 3,05 (2H, square, J=7 Hz), to 3.36 (2H, d, J=7 Hz), of 4.67 (2H, s), of 5.92 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), to $ 7.91 (1H, m), 8,55 (1H, d, J=2 Hz), 8,76 (1H, d, J=2 Hz).

MS (ESI-): m/z 512, 514, MS (ESI+): m/z 514, 516.

Example 460

4-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid

1H NMR (CDCl3) δ 0,22-0,32 (2H, m), of 0.55 to 0.63 (2H, m), 1,10-1,22 (1H, m)to 1.37 (3H, t, J=7 Hz), 1,73 is 1.86 (2H, m), of 2.20 to 2.35 (2H, m), the 2.46 (3H, s), 2,55-of 2.86 (2H, m), 3.04 from (2H, square, J=7 Hz), 3.43 points (2H, d, J=7 Hz), 4,70-4,85 (2H, m), 5,88 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), a 7.62 (1H, s), 8,42 (1H, s), 8,46 (1H, s).

MS (ESI+): m/z 408.

Example 461

3-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propane is the first acid

1H NMR (CDCl3) δ to 0.23 and 0.35 (2H, m), 0,54 is 0.65 (2H, m), 1,08-1,24 (1H, m)to 1.37 (3H, t, J=7 Hz), 2,43 (3H, s), 2,50-to 2.65 (2H, m), 2,70 was 3.05 (2H, m), 3.04 from (2H, square, J=7 Hz), 3,44 (2H, d, J=7 Hz), 4,74 (2H, s), of 5.89 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,56 (1H, s), 8,42 (1H, s), 8,53 (1H, s).

MS (ESI-): m/z 392, MS (ESI+): m/z 394.

Example 462

3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-methoxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 2,48-2,62 (2H, m), 2,83-to 3.02 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,37 (3H, s), of 3.60 (2H, m), of 3.73 (2H, m), and 4.75 (2H, s), of 5.92 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,89 (1H, m), 8,55 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

MS (ESI-): m/z 460, 462, MS (ESI+): m/z 462, 464.

Example 463

5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(4-morpholinylcarbonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentane acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,35-of 1.65 (4H, m), of 2.23 (2H, t, J=7 Hz), 2,40-of 2.56 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,48 is 3.57 (4H, m), 3,60-of 3.78 (4H, m), 5,33 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,89 (1H, m), 8,56 (1H, d, J=2 Hz), 8,79 (1H, d, J=2 Hz).

Example 464

5-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ of 1.36 (3H, t, J=7 Hz), 1,45-of 1.65 (4H, m), 2,22 (2H, t, J=7 Hz), 2,42-to 2.57 (2H, m), of 2.97 (6H, s), 3,03 (2H, square, J=7 Hz), and 5.30 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,89 (1H with), 8,54 (1H, s), 8,78 (1H, s).

MS (ESI+): m/z 503, 505.

Example 465

5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(1-pyrrolidinylcarbonyl)oxy]methyl}pyrrolo,2-b]pyridazin-3-yl)pentane acid

1H NMR (CDCl3) δ of 1.36 (3H, t, J=7 Hz), 1,40-to 1.63 (4H, m), 1,82-of 1.97 (4H, m), of 2.23 (2H, t, J=7 Hz), 2,43-of 2.58 (2H, m), 3,03 (2H, square, J=7 Hz), 3,37-to 3.52 (4H, m), 5,31 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,88 (1H, m), 8,54 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

MS (ESI-): m/z 527, 529, MS (ESI+): m/z 529, 531.

Example 466

5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[({[methyl(phenyl)amino]carbonyl}oxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,40 is 1.58 (4H, m)to 2.18 (2H, t, J=7 Hz), 2,32 of $ 2.53 (2H, m), 3.04 from (2H, square, J=7 Hz), 3,37 (3H, s), are 5.36 (2H, s), of 5.92 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,16-7,40 (5H, m), 7,87 (1H, s), charged 8.52 (1H, s), 8,79 (1H, s).

Example 467

4-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(4-morpholinylcarbonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)butane acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,65-of 1.84 (2H, m), and 2.27 (2H, t, J=7 Hz), 2,45 of 2.68 (2H, m), 3.04 from (2H, square, J=7 Hz), 3,53 (4H, m), of 3.69 (4H, m), are 5.36 (2H, s), 5,95 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), to $ 7.91 (1H, m), 8,55 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

Example 468

4-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]butane acid

1H NMR (CDCl3) δ of 1.36 (3H, t, J=7 Hz), 1,66-to 1.82 (2H, m), and 2.27 (2H, t, J=7 Hz), 2,46 of 2.68 (2H, m), of 2.97 (6H, s), 3.04 from (2H, square, J=7 Hz), 5,33 (2H, s)5,94 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,92 (1H, m), 8,56 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

Example 469

3-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]propanoic acid

1H NMR (CDCl 3) δ of 1.36 (3H, t, J=7 Hz), a 2.45 (2H, t, J=7 Hz), 2,82-2,96 (2H, m), of 2.97 (6H, s), 3,03 (2H, square, J=7 Hz), 5,33 (2H, s), 5,96 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,89 (1H, m), 8,55 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

MS (ESI-): m/z 473, 475, MS (ESI+): m/z 475, 477.

Example 470

5-{4-(5-bromo-3-pyridinyl)-2-[(1,1-dioxido-4-thiomorpholine)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (300 MHz, CDCl3) δ of 1.36 (3H, t, J=7 Hz), 1,42-of 1.56 (4H, m), and 2.26 (2H, t, J=7 Hz), 2,48-2,61 (2H, m), 3,01 (2H, square, J=7 Hz), 3,10 (4H, t, J=6 Hz), 3,19 (4H, t, J=6 Hz), 3,85 (2H, s), of 5.92 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,89 (1H, DD, J=2, 2 Hz), 8,56 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

MS (m/z 550 (M+H).

Example 471

5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomorpholine)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (300 MHz, CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,43 is 1.58 (4H, m), 2,24 (2H, t, J=7 Hz), 2,49-2,61 (2H, m)to 2.66 (4H, t, J=4 Hz), of 2.86 (4H, t, J=4 Hz), to 3.02 (2H, square, J=7 Hz), 3,68 (2H, s), of 5.89 (1H, d, J=5 Hz), to 6.58 (1H, d, J=5 Hz), of 7.90 (1H, s), 8,56 (1H, s), 8,79 (1H, s).

MS (m/z 518 (M+H).

Example 472

5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[4-(2-hydroxyethyl)-1-piperazinil]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentane acid

1H NMR (300 MHz, CDCl3) δ of 1.34 (3H, t, J=7 Hz), 1.41 to of 1.57 (4H, m), of 2.21 (2H, t, J=6 Hz), 2,43-to 2.57 (2H, m), 2,80-2,84 (4H, m), 2.91 in is 3.00 (6H, m), the 3.65 (2H, s), 3,83 (2H, m), 5,88 (1H, d, J=5 Hz), to 6.57 (1H, d, J=5 Hz), 7,88 (1H, s), 8,55 (1H, s), 8,77 (1H, s).

MS (m/z 545 (M+H).

Example 473

4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-thiomorpholine)pyrrolo[1,2-b]pyridazin-3-yl]butane acid

1H NMR (300 MHz, CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,72 (2H, TT, J=7, 7 Hz), and 2.26 (2H, t, J=7 Hz), 2,53 of 2.68 (6H, m), 2,87-2,90 (4H, m), to 3.02 (2H, square, J=7 Hz), and 3.72 (2H, s), 5,91 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 7,78 (1H, DD, J=2, 2 Hz), charged 8.52 (1H, d, J=2 Hz), 8,68 (1H, d, J=2 Hz).

MS (m/z 460 (M+H).

Example 474

4-{4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butane acid

1H NMR (300 MHz, CDCl3) δ to 1.38 (3H, t, J=7 Hz), at 1.73 (2H, TT, J=7, 7 Hz), of 2.25 (2H, t, J=7 Hz), 2.57 m)-by 2.73 (2H, m), 3.04 from (2H, square, J=7 Hz), 4.72 in (2H, s), 4,89 (2H, s), to 5.93 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), 7,31 (2H, d, J=6 Hz), 7,76 (1H, DD, J=2, 2 Hz), 8,46 (2H, d, J=6 Hz), 8,53 (1H, d, J=2 Hz), 8,67 (1H, d, J=2 Hz).

MS (m/z 465 (M+H).

Example 475

4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid

1H NMR (300 MHz, CDCl3) δ to 1.37 (3H, t, J=7 Hz), at 1.73 (2H, TT, J=7, 7 Hz), and 2.26 (2H, t, J=7 Hz), 2,54-of 2.72 (6H, m), 3,03 (2H, square, J=7 Hz), 3,66-to 3.73 (6H, m), 5,90 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 7,79 (1H with), 8,53 (1H, s), 8,67 (1H, s).

MS (m/z 443 (M+H).

Example 476

5-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (300 MHz, CDCl3) δ 0,24 (2H, dt, J=7, 7 Hz), or 0.57 (2H, dt, J=7, 7 Hz), 1,07-1,17 (1H, m)to 1.38 (3H, t, J=7 Hz), 1,45-to 1.61 (4H, m), of 2.23 (2H, t, J=7 Hz), 2,52-of 2.66 (2H, m), to 3.02 (2H, square, J=7 Hz), to 3.41 (2H, d, J=7 Hz), 4,70 (2H, s), 5,90 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 7,74 (1H, DD, J=2, 2 Hz), charged 8.52 (1H, d, J=2 Hz), 8,68 (1H, d, J=2 Hz).

MS (m/z 442 (M+H).

Example 477

4-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]7-acylpyrrole[1,2-b]pyridazin-3-yl}butane acid

1H NMR (300 MHz, CDCl3) δ 0,23 (2H, dt, J=6, 6 Hz), of 0.56 (2H, dt, J=6, 6 Hz), 1,05-1,17 (1H, m)to 1.37 (3H, t, J=7 Hz), a 1.75 (2H, TT, J=7, 7 Hz), 2,28 (2H, t, J=7 Hz), 2.57 m)-2,70 (2H, m), 3,03 (2H, square, J=7 Hz), 3,42 (2H, d, J=7 Hz), to 4.73 (2H, s), 5,91 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), to 7.77 (1H, DD, J=2, 2 Hz), charged 8.52 (1H, d, J=2 Hz), 8,66 (1H, d, J=2 Hz).

MS (m/z 428 (M+H).

Example 478

5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isobutoxide)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (300 MHz, CDCl3) δ of 0.93 (6H, d, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,42-to 1.59 (4H, m), with 1.92 (1H, cut, J=7, 7 Hz), 2,24 (2H, t, J=7 Hz), 2,48-2,69 (2H, m), 3,03 (2H, square, J=7 Hz), to 3.33 (2H, d, J=7 Hz), of 4.66 (2H,with), 5,91 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), of 7.90 (1H, DD, J=2, 2 Hz), 8,56 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (m/z 489 (M+H).

Example 479

3-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(isobutoxide)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid

1H NMR (300 MHz, CDCl3) δ to 0.92 (6H, d, J=7 Hz), of 1.37 (3H, t, J=7 Hz), at 1.91 (1H, cut, J=7, 7 Hz), 2.49 USD (2H, t, J=8 Hz), 2,82 are 2.98 (2H, m), 3,03 (2H, square, J=7 Hz), 3,35 (2H, d, J=7 Hz), 4,69 (2H, s), of 5.92 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,72 (1H, DD, J=2, 2 Hz), 8,51 (1H, d, J=2 Hz), 8,69 (1H, d, J=2 Hz).

MS (m/z 416 (M+H).

Example 480

3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid

1H NMR (300 MHz, CDCl3) δ of 1.36 (3H, t, J=7 Hz), to 2.55 (2H, t, J=8 Hz), 2,66 (4H, users), 2,79-of 2.97 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,70-3,74 (6H, m), of 5.92 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), of 7.90 (1H, DD, J=2, 2 Hz), 8,55 (1H, d, J=2 Hz), 8,79 (1H, d, J=2 Hz).

MS (m/z 474 (M+H).

Example 481

4-[4-(5-bromo-3-pyrid the Nile)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid

1H NMR (300 MHz, CDCl3) δ of 1.36 (3H, t, J=7 Hz), at 1.73 (2H, TT, J=7, 7 Hz), and 2.26 (2H, t, J=7 Hz), 2.57 m)-2,70 (6H, m), to 3.02 (2H, square, J=7 Hz), of 3.69 (6H, m), 5,90 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), to 7.93 (1H, DD, J=2, 2 Hz), to 8.57 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (m/z 488 (M+H).

Example 482

4-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylamino)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}butane acid

1H NMR (300 MHz, CDCl3) δ of 0.54 to 0.60 (2H, m), 0.74 and-of 0.79 (2H, m)to 1.38 (3H, t, J=7 Hz), of 1.65 (2H, TT, J=6, 6 Hz), of 2.21 (2H, t, J=6 Hz), 2,45 is 2.55 (2H, m), 3,03 (2H, square, J=7 Hz), 4,30 (2H, s), 5,04 (1H, users), to 5.93 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,73 (1H, DD, J=2, 2 Hz), charged 8.52 (1H, d, J=2 Hz), 8,69 (1H, d, J=2 Hz).

MS (m/z 413 (M+H).

Example 483

5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(2-phenoxyethyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentane acid

1H NMR (300 MHz, CDCl3) δ of 1.36 (3H, t, J=7 Hz), 1,42-of 1.56 (4H, m), 2,22 (2H, users), 2,34-2,48 (2H, m), 3,03 (2H, square, J=7 Hz), 3,38-of 3.43 (2H, users), 4,23-4,50 (4H, m), to 5.93 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 6.89 in-6,97 (3H, m), 7.23 percent-7,30 (2H, m), a 7.85 (1H, s), charged 8.52 (1H, s), 8,78 (1H, s).

MS (m/z 552 (M+H).

Example 484

5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(2-hydroxyethyl)(methyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentane acid

1H NMR (300 MHz, CDCl3) δ of 1.36 (3H, t, J=7 Hz), 1,34-and 1.54 (4H, m), 2,15-of 2.26 (2H, m), 2,33-2,52 (2H, m), 2,98 (2H, square, J=7 Hz), and 3.16 (3H, s), 3,59-and 3.72 (2H, m), 3,99-4,10 (2H, m), 4,70 (2H, s)5,94 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), a 7.85 (1H, s), 8,51 (1H, s), 8,73 (1H, s).

MS (m/z 490 (M+H).

Example 485

5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(1-piperidinylmethyl)pyrrolo[,2-b]pyridazin-3-yl]pentane acid

1H NMR (300 MHz, CDCl3) δ of 1.36 (3H, t, J=7 Hz), 1,39-is 1.51 (6H, m), 1,62-1,71 (4H, m), 2,19 (2H, t, J=6 Hz), 2,52-to 2.65 (2H, m), 2,78-only 2.91 (4H, m), 3,10 (2H, square, J=7 Hz), the 3.65 (2H, s), of 5.89 (1H, d, J=5 Hz), to 6.58 (1H, d, J=5 Hz), 7,88 (1H, s), 8,55 (1H, s), 8,76 (1H, s).

MS (m/z 500 (M+H).

Example 486

3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomorpholine)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid

1H NMR (300 MHz, CDCl3) δ to 1.37 (3H, t, J=7 Hz), 2,52 (2H, t, J=8 Hz), 2,68 (4H, t, J=5 Hz), 2,81-2,95 (6H, m), to 3.02 (2H, square, J=7 Hz), 3,74 (2H, s), of 5.92 (1H, d, J=5 Hz), is 6.61 (1H, d, J=5 Hz), 7,89 (1H, DD, J=2, 2 Hz), 8,55 (1H, d, J=2 Hz), 8,79 (1H, d, J=2 Hz).

MS (m/z 490 (M+H).

Example 487

3-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[4-(2-hydroxyethyl)-1-piperazinil]methyl}pyrrolo[1,2-b]pyridazin-3-yl)propanoic acid

1H NMR (300 MHz, DMSO-d6) δ to 1.32 (3H, t, J=7 Hz), 2.40 a-2,56 (12H, m), 2,58-to 2.65 (2H, m)to 2.94 (2H, square, J=7 Hz), 3,52 (2H, t, J=5 Hz)to 3.67 (2H, s), of 5.83 (1H, d, J=5 Hz), 6,62 (1H, d, J=5 Hz), of 8.25 (1H, DD, J=2, 2 Hz), 8,63 (1H, d, J=2 Hz), 8,86 (1H, d, J=2 Hz).

MS (m/z 517 (M+H).

Example 488

4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isobutoxide)pyrrolo[1,2-b]pyridazin-3-yl]butane acid

1H NMR (300 MHz, CDCl3) δ of 0.91 (6H, d, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,74 (2H, TT, J=8, 8 Hz), at 1.91 (1H, cut, J=7, 7 Hz), and 2.27 (2H, t, J=8 Hz), 2,56-by 2.73 (2H, m), 3,03 (2H, square, J=7 Hz), to 3.33 (2H, d, J=7 Hz), and 4.68 (2H, s), of 5.92 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,92 (1H, DD, J=7, 7 Hz), 8,56 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (m/z 475 (M+H).

Example 489

5-[2-{[2-(benzylamino)-2-oksidoksi]methyl}-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyrid the Zin-3-yl]pentane acid

1H NMR (CDCl3) δ of 1.33 (3H, t, J=7 Hz), 1,39 is 1.60 (4H, m), of 2.15 (2H, t, J=7 Hz), 2,42 (3H, s), 2,40-of 2.58 (2H, m), 2,95 (2H, square, J=7 Hz), 4,19 (2H, s), 4,50 (2H, d, J=7 Hz), and 4.75 (2H, m), 5,91 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 7,07 (1H, usher.), 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.

Example 490

5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(phenylsulfonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentane acid

1H NMR (CDCl3) δ of 1.36 (3H, t, J=7 Hz), 1,23-to 1.60 (4H, m), 2,19 (2H, t, J=7 Hz), 2,28 is 2.46 (2H, m), 2,42 (3H, s), of 2.97 (2H, square, J=7 Hz), 4,37 (2H, m), of 5.89 (1H, d, J=4 Hz), 5,90 (1H, m), to 6.57 (1H, d, J=4 Hz), 7,42-7,53 (4H, m), of 7.90 (2H, d, J=8 Hz), a 8.34 (1H, s), 8,53 (1H, s).

MS (ESI-): m/z 505, MS (ESI+): m/z 507.

Example 491

5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (300 MHz, CDCl3) δ to 1.35 (3H, t, J=7 Hz), 1,39-of 1.57 (4H, m), 1,79-of 1.88 (4H, m)to 2.18 (2H, t, J=7 Hz), 2,84-2,89 (6H, m)of 3.00 (2H, square, J=7 Hz), 3,89-was 4.02 (2H, m), 5,88 (1H, d, J=5 Hz), 6,56 (1H, d, J=5 Hz), 7,87 (1H, s), 8,55 (1H, s), is 8.75 (1H, s).

MS (m/z 486 (M+H).

Example 492

3-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=8 Hz), 2,39-2,48 (2H, m), 2,83-to 2.94 (2H, m), 3,03 (2H, square, J=8 Hz), of 3.45 (3H, s)and 4.65 (2H, s), 5,95 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,24 (1H, m), 7,35 (1H, users), 7,40-7,46 (2H, m).

MS (ESI+): m/z 373 (M+H).

Example 493

4-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid

1 H NMR (CDCl3) δ to 1.37 (3H, t, J=8 Hz), 1,64-of 1.78 (2H, m), 2,24 (2H, t, J=8 Hz), 2,56-of 2.66 (2H, m), 3.04 from (2H, square, J=8 Hz), of 3.45 (3H, s)and 4.65 (2H, s)5,94 (1H, d, J=5 Hz), 6,59 (1H, d, J=5 Hz), 7,21-7,29 (1H, overlapping CDCl3), was 7.36 (1H, users), 7,39-7,46 (2H, m).

MS (ESI+): m/z 387 (M+H).

Example 494

5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-phenyl-1-piperazinil)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (300 MHz, CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1.41 to to 1.61 (4H, m), 2,22 (2H, t, J=7 Hz), 2,49-to 2.67 (2H, m), was 2.76 (4H, t, J=5 Hz), 3,03 (2H, square, J=7 Hz), 3,20 (4H, t, J=5 Hz), to 3.73 (2H, s), of 5.89 (1H, d, J=5 Hz), to 6.58 (1H, d, J=5 Hz), 6,85 (1H, DD, J=8, 8 Hz), 6,93 (2H, J=8 Hz), 7,25 (2H, J=8 Hz), of 7.90 (1H, DD, J=2, 2 Hz), 8,56 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

Example 495

5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(2-methoxyethyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentane acid

1H NMR (300 MHz, CDCl3) δ of 1.28 (3H, t, J=7 Hz), 1,32 was 1.43 (4H, m), 2,03-2,17 (2H, m), 2,23-to 2.41 (2H, m), 2,49-is 2.88 (2H, m), 2,98 (2H, square, J=7 Hz), 3,37 (3H, s), 3,89-3,99 (2H, m), 4,51 (2H, s), 5,91 (1H, d, J=5 Hz), to 6.57 (1H, d, J=5 Hz), 7,82 (1H, s), of 8.47 (1H, s), 8,72 (1H, s).

Example 496

5-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

TPL 111-112°

1H NMR (CDCl3) δ to 1.37 (3H, t, J=8 Hz), 1.41 to to 1.60 (4H, m), of 2.21 (2H, ushort, J=8 Hz), 2,30-2,70 (2H, m), 3.04 from (2H, d, J=8 Hz), of 3.46 (3H, s), 3,90 (3H, s), 4,63 (2H, userd, J=5 Hz), of 5.92 (1H, d, J=5 Hz), to 6.58 (2H,, d, J=8 Hz), 7,25 (1H, m), by 8.22 (1H, d, J=1 Hz), 8,40 (1H, d, J=3 Hz).

MS (ESI+): m/z 398 (M+H).

Example 497

5-[7-ethyl-4-(5-methoxy-3-pyridinyl)-2-metile is Rolo[1,2-b]pyridazin-3-yl]pentane acid

TPL 133-134°

1H NMR (CDCl3) δ to 1.37 (3H, t, J=8 Hz), 1,40-1,62 (7H, m), 2,24 (2H, t, J=8 Hz), 2,35-2,49 (2H, m), of 2.56 (3H, s), 3,01 (2H, square, J=8 Hz), with 3.89 (3H, s), by 5.87 (1H, d, J=5 Hz), 6,51 (1H, d, J=5 Hz), 7.23 percent (1H, m), to 8.20 (1H, d, J=1 Hz), 8,39 (1H, d, J=3 Hz).

MS (ESI+): m/z 369 (M+H).

Example 498

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

TPL 164-165°

1H NMR (CDCl3) δ to 1.37 (3H, t, J=8 Hz), 2,44-of 2.54 (2H, m), 2,80-3,00 (2H, m), 3.04 from (2H, d, J=8 Hz), 3,47 (3H, s)to 3.89 (3H, s), of 4.66 (2H, users), 5,95 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,25 (1H, m), by 8.22 (1H, d, J=1 Hz), scored 8.38 (1H, d, J=3 Hz).

MS (ESI+): m/z 370 (M+H).

Example 499

4-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid

TPL 140-141°

1H NMR (CDCl3) δ to 1.38 (3H, t, J=8 Hz), 1,68-to 1.82 (2H, m), of 2.25 (2H, t, J=8 Hz), 2,52 is 2.75 (2H, m), 3.04 from (2H, d, J=8 Hz), of 3.46 (3H, s)to 3.92 (3H, s)and 4.65 (2H, userd, J=7 Hz), 5,94 (1H, d, J=5 Hz), 6,59 (1H, d, J=5 Hz), 7,29 (1H, m), 8,23 (1H, d, J=1 Hz), of 8.37 (1H, d, J=3 Hz).

MS (ESI+): m/z 384 (M+H).

Example 500

5-[7-ethyl-2-(methoxymethyl)-4-(5-pyrimidinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=8 Hz), 1,40-of 1.64 (4H, m), of 2.25 (2H, t, J=8 Hz), 2,49-2,61 (2H, m), 3.04 from (2H, d, J=8 Hz), 3,47 (3H, s)and 4.65 (2H, s), 5,91 (1H, d, J=5 Hz), 6,62 (1H, d, J=5 Hz), 8,82 (2H,with), to 9.32 (1H, s).

MS (ESI+): m/z 369 (M+H).

Example 501

4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid

TPL 112-113°the

1H NMR (CDCl3) δ to 1.38 (3H, t, J=8 Hz), 1,66-to 1.79 (2H, m), 2,28 (2H, t, J=8 Hz), 2,52-a 2.71 (2H, m), 3,05 (2H, d, J=8 Hz), of 3.46 (3H, s), of 4.66 (2H, users), of 5.92 (1H, d, J=5 Hz), is 6.61 (1H, d, J=5 Hz), to 7.77 (1H, m), 8,53 (1H, d, J=1 Hz), 8,67 (1H, d, J=2 Hz).

MS (ESI+): m/z 388 (M+H).

Example 502

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

TPL 159-160°

1H NMR (CDCl3) δ to 1.38 (3H, t, J=8 Hz), 2,47 (2H, ushort, J=8 Hz), 2,79 are 2.98 (2H, m), 3.04 from (2H, d, J=8 Hz), 3,47 (3H, s), of 4.66 (2H, s), to 5.93 (1H, d, J=5 Hz), to 6.67 (1H, d, J=5 Hz), 7,74 (1H, m), 8,51 (1H, d, J=1 Hz), 8,68 (1H, d, J=3 Hz).

MS (ESI+): m/z 374, 376 (M+H).

Example 503

5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

TPL 118-119°

1H NMR (CDCl3) δ to 1.37 (3H, t, J=8 Hz), 1,40-1,62 (7H, m), 2,24 (2H, t, J=8 Hz), 2,45-of 2.64 (2H, m), 3.04 from (2H, d, J=8 Hz), of 3.45 (3H, s), 4,63 (2H, s), 5,91 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,74 (1H, m), 8,51 (1H, d, J=1 Hz), 8,67 (1H, d, J=2 Hz).

MS (ESI+): m/z 402, 404 (M+H).

Example 504

4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4H-1,2,4-triazole-4-ylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid

1H-NMR (CDCl3) δ of 1.36 (3H, t, J=7 Hz), 1,60 (2H, m), 2,32 (2H, m), 2,46 (2H, m), 3,01 (2H, square, J=7 Hz), of 5.75 (2H, m), 5,97 (1H, d, J=5 Hz), of 6.66 (1H, d, J=5 Hz), 7,87 (1H, m), of 7.97 (1H, s), 8,53 (1H, ), 8,65 (1H, s), 8,69 (1H, s).

Example 505

4-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylamino)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}butane acid

1H-NMR (CDCl3) δ of 0.56 (2H, m), is 0.75 (2H, m)to 1.38 (3H, the, J=7 Hz), of 1.65 (2H, m), of 2.21 (2H, m)of 2.50 (2H, m), 3,01 (2H,square, J=7 Hz), with 3.27 (3H, usher.), the 4.29 (2H, s), to 5.93 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,98 (1H, m), 8,55 (1H, m), 8,78 (1H, m)

MS (ESI+) m/z: 457 and 459 (M+H).

Example 506

4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-oxo-1,3-oxazolidin-3-yl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butane acid

1H-NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,68 (2H, m), 2,31 (2H, m), 2,53 (2H, m), 2,98 (2H, square, J=7 Hz), of 3.77 (2H, m), 4,42 (2H, t, J=7 Hz), of 4.67 (2H, m)5,94 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), 7,89 (1H, m), 8,55 (1H, m), 8,78 (1H, m).

Example 507

2-bromo-4-[3-(etoxycarbonyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-4-yl]benzoic acid

1H-NMR (CDCl3) δ and 1.00 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 2,62 (3H, s), 3.04 from (2H, square, J=7 Hz), 4,06 (2H, square, J=7 Hz), of 6.29 (1H, d, J=5 Hz), of 6.68 (1H, d, J=5 Hz), 7,49 (2H, DD, J=2 and 8 Hz), 7,82 (1H, d, J=2 Hz), 8,07 (1H, d, J=8 Hz).

MS (ESI+) m/z: 431 and 433 (M+H).

Example 508

5-[4-(3-cyanophenyl)-7-ethyl-2-(phenoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H-NMR (CDCl3) δ 1,25-1,49 (7H, m), of 2.15 (2H, m), of 2.54 (2H, m), to 3.02 (2H, square, J=7 Hz), 5,23 (2H, s), 5,86 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 6,98 (1H, t, J=8 Hz), 7,06 (2H, d, J=8 Hz), 7,28 (2H, t, J=8 Hz), 7,60 (2H, m), to 7.67 (1H, s), to 7.77 (1H, m).

Example 509

5-[4-(3-cyanophenyl)-7-ethyl-2-(3-methyl-2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H-NMR (CDCl3) δ 1,14 of 1.28 (4H, m)to 1.37 (3H, t, J=7 Hz), a 2.01 (2H, t, J=7 Hz), of 2.23 (3H, s), is 2.40 (2H, m), to 3.02 (2H, square, J=7 Hz), of 5.92 (1J, d, J=5 Hz)(, only 6.64 (1H, d, J=5 Hz), 6,94 (1J, d, J=5 Hz), 7,33 (1H, d, J=5 Hz), EUR 7.57-7,66 (2H, m), 7,73-7,76 (2H, m).

P the emer 510

(2E)-4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]-2-butenova acid

1H-NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), to 2.55 (3H, s), 3,03 (2H, square, J=7 Hz), to 3.09 (2H, d, J=7 Hz), of 5.45 (1H, dt, J=7 and 16 Hz), equal to 6.05 (1H, d, J=5 Hz), and 6.25 (1H, d, J=16 Hz), to 6.57 (1H, d, J=5 Hz), 7,55 (1H, t, J=8 Hz), 7,66+-7,72 (3H, m).

MS (ESI+): m/z 345 (M+H).

Example 511

4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,68-of 1.84 (2H, m), 2,28 (2H, t, J=7 Hz), 2,56-to 2.74 (2H, m), 3,03 (2H, square, J=7 Hz), of 3.46 (3H, s), of 4.66 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,92 (1H, m), to 8.57 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

MS (ESI-): m/z 430, 432, MS (ESI+): m/z 432, 434.

The following compounds were obtained according to the similar procedure of example 159.

Example 512

Ethyl-4-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,35-1,45 (2H, m), a 1.88 (2H, t, J=7 Hz), 2,43 is 2.55 (2H, m), 3,03 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 5,98 (1H, d, J=4 Hz), of 6.65 (1H, d, J=4 Hz), 7,33 (1H, d, J=5 Hz), 7,42-of 7.55 (6H, m), 8,55 (1H, d, J=5 Hz).

MS (ESI+): m/z 448.

Example 513

Ethyl-3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ of 1.09 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,98-of 2.08 (2H, m), of 2,75 2,85 (2H, m), 3,03 (2H, square, J=7 Hz), 3,92 (2H, square, J=7 Hz), 6,00 (1H, d, J=4 Hz), to 6.67 (1H, d, J=4 Hz), 7,32 (1H, d, J=5 Hz), 7,42 (1H, s), 7,43-EUR 7.57 (5H, m), 8,55 (1H, d, J=5 Hz).

MS (ESI+): m/z 434.

Example 514

Meth is l{2-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]ethoxy}acetate

1H NMR (CDCl3) δ of 1.36 (3H, t, J=7 Hz), 2,73-to 2.85 (2H, t, J=7 Hz), 3,03 (2H, t, J=7 Hz)and 3.15 (2H, t, J=7 Hz), 3,74 (2H, s), 4.09 to (3H, s), of 6.02 (1H, d, J=4 Hz), to 6.67 (1H, d, J=4 Hz), 7,39 (1H, m), 7,42-of 7.60 (6H, m), 8,53 (1H, d, J=5 Hz).

MS (ESI+): m/z 450.

Example 515

Ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-(3-methyl-2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H-NMR (CDCl3) δ 1,09-1,26 (7H, m)of 1.36 (3H, t, J=7 Hz), of 1.93 (2H, t, J=7 Hz), of 2.23 (3H, s), 2,39 (2H, m), 3,03 (2H, square, J=7 Hz), a 4.03 (2H, square, J=7 Hz), to 5.93 (1H, d, J=5 Hz), only 6.64 (1H, d, J=7 Hz), of 6.96 (1H, d, J=5 Hz), 7,33 (1H, d, J=5 Hz), 7,60-to 7.67 (2H, m), 7,72-7,79 (2H, m).

Example 516

Methyl-5-[4-(3-cyanophenyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H-NMR (CDCl3) δ to 1.21 to 1.47 (7H, m), 2,04 (2H, t, J=7 Hz), 2,60 (2H, m), 3,05 (2H, square, J=7 Hz), 3,61 (3H, s), lower than the 5.37 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), 7,13 (1H, m), of 7.36 (1H, m), 7,44 (1H, m), 7,62-7,78 (4H, m).

Example 517

Ethyl-3-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]propanoate

1H-NMR (CDCl3) δ a 1.08 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), to 1.98 (2H, m)of 2.75 (2H, m), to 3.02 (2H, square, J=7 Hz), with 3.89 (2H, square, J=7 Hz), to 5.93 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), 7,41-of 7.55 (5H, m), EUR 7.57 for 7.78 (4H, m).

MS (ESI+): m/z 424 (M+H).

Example 518

Ethyl-5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

1H-NMR (CDCl3) δ 1,02-1,25 (7H, m)to 1.37 (3H, t, J=7 Hz), a 1.88 (2H, t, J=7 Hz), 2,43 (2H, m), 3,01 (2H, square, J=7 Hz), 4.00 points (2H, square, J=7 Hz), 5,96 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,29 (1H, m), 7,37-rate of 7.54 (8H, m).

MS (ESI+): m/z 461.

Example 519

4-(5-bromo-3-pyridinyl)-7-these is-2-phenylpyrrole[1,2-b]pyridazin-3-carbonitril

1H NMR (CDCl3) δ of 1.42 (3H, t, J=8 Hz), of 3.12 (2H, t, J=8 Hz), of 6.65 (1H, d, J=5 Hz), 6,94 (1H, d, J=5 Hz), 7,51-to 7.59 (3H, m), 7,83-to $ 7.91 (2H, m), 8,19 (1H, m), cent to 8.85-of 8.92 (2H, m).

MS (ESI+): m/z 403, 405 (M+H).

The following compounds were obtained according to a similar method of example 175.

Example 520

5-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,36-of 1.57 (4H, m)of 2.16 (2H, t, J=7 Hz), of 2.51-2,62 (2H, m), 3,03 (2H, square, J=7 Hz), 4,69 (2H, s), 4,78 (2H, s), by 5.87 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,35 (2H,, d, J=5 Hz), to 7.61 (2H, d, J=5 Hz), to 7.67 (1H, s), to 7.77 (1H, m), 8,54 (2H, d, J=5 Hz).

MS (ESI-): m/z 467, MS (ESI+): m/z 469.

Example 521

5-{4-[3-(aminocarbonyl)phenyl]-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,47 by 1.68 (4H, m), 2,15-to 2.40 (2H, m), 2,40-of 2.56 (1H, m), 2,82-2,96 (1H, m), 3,05 (2H, square, J=7 Hz), and 4.68 (2H, s), 4.72 in (1H, d, J=17 Hz), is 4.93 (1H, d, J=17 Hz), of 5.83 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,31 (2H, d, J=5 Hz), 7,39 (1H, usher.), was 7.45 (1H, d, J=8 Hz), 7,58 (1H, t, J=8 Hz), 7,69 (1H, usher.), to 7.77 (1H, usher.), 7,98 (1H, d, J=8 Hz), to 8.57 (2H, d, J=5 Hz).

MS (ESI-): m/z 485, MS (ESI+): m/z 487.

Example 522

5-{4-(3-cyanophenyl)-7-ethyl-2-[(2-personalitate)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1.30 and 1.57 in (4H, m)to 2.18 (2H, m), 2,48-to 2.65 (2H, m), 3,03 (2H, square, J=7 Hz), a 4.83 (2H, s), is 4.85 (2H, s), 5,86 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), to 7.61 (2H, d, J=5 Hz), 7,68 (1H, s), to 7.77 (1H, m), 8,53 (2H, q, j =5 Hz), 8,76 (1H, s).

MS (ESI-): m/z 468, MS (ESI+): m/z 470.

Example 523

5-{4-(3-cyanophenyl)-7-ethyl-2-[(3-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 1,38-of 1.57 (4H, m), of 2.15 (2H, t, J=7 Hz), 2,49-2,62 (2H, m), 3.04 from (2H, square, J=7 Hz), 4,69 (2H, s), was 4.76 (2H, s), to 5.85 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,33 (1H, m), a 7.62 (2H, m), to 7.67 (1H, s), 7,73-of 7.82 (2H, m), 8,53 (1H, d, J=5 Hz), 8,67 (1H, s).

MS (ESI-): m/z 467, MS (ESI+): m/z 469.

Example 524

5-[4-(3-cyanophenyl)-7-ethyl-2-(5-methyl-3-isoxazolyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H-NMR (CDCl3) δ 1,34-1,52 (7H, m), 2,17 (2H, t, J=7 Hz), 2,53 (3H, s), 2,77 (2H, m), 3,03 (2H, square, J=7 Hz), of 5.89 (1H, d, J=5 Hz), is 6.54 (1H, s), to 6.67 (1H, d, J=5 Hz), 7,63 (2H, m), 7,68 (1H, s), 7,78 (1H, m).

Example 525

5-[4-(3-cyanophenyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H-NMR (CDCl3) δ 1,23-of 1.42 (7H, m)2,07 (2H, t, J=7 Hz), 2,58 (2H, m), 3,03 (2H, square, J=7 Hz), by 5.87 (1H, d, J=5 Hz), 6,56 (1H, d, J=5 Hz), 7,13 (1H, m), of 7.36 (1H, m), the 7.43 (1H, d, J=5 Hz), a 7.62 (2H, m,), of 7.70 (1H, s), 7,76 (1H, m).

Example 526

3-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]propanoic acid

1H-NMR (CDCl3) δ of 1.36 (3H, t, J=7 Hz), 1,99 (2H, m)of 2.75 (2H, m)of 3.00 (2H, square, J=7 Hz), to 5.93 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), 7,42-of 7.55 (5H, m), EUR 7.57 for 7.78 (4H, m).

Example 527

5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

1H-NMR (CDCl3) δ 1,03-1,25 (4H, m)of 1.36 (3H, t, J=7 Hz), 1,90 (2H, t, J=7 Hz), 2,41 (H, m)of 3.00 (2H, square, J=7 Hz), 5,97 (1H, d, J=5 Hz), 6,59 (1H, d, J=5 Hz), 7,28 (1H, m), 7,35-rate of 7.54 (8H, m).

MS (ESI+): m/z 433 (M+H).

The following compound was obtained according to a similar method of example 180.

Example 528

Ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-(5-methyl-3-isoxazolyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H-NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), 1,32 of 1.46 (5H, m), 1,72 (2H, m), 2,10 (2H, t, J=7 Hz), of 2.54 (3H, s), 2,78 (2H, m), 3,03 (2H, square, J=7 Hz), 4,06 (2H, square, J=7 Hz), of 5.89 (1H, d, J=5 Hz), is 6.54 (1H, ), of 6.66 (1H, d, J=5 Hz), a 7.62 (2H, m), to 7.67 (1H, s), to 7.77 (1H, m).

The following compound was obtained according to a similar method of obtaining 176.

Example 529

Ethyl-4-[4-(aminocarbonyl)-3-bromophenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-carboxylate

1H-NMR (CDCl3) δ of 1.03 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 2,60 (3H, s), 3,03 (2H, square, J=7 Hz), 4,07 (2H, square, J=7 Hz), of 5.83 (1H, s, of usher.), to 6.19 (1H, s, of usher.), 6,28 (1H, d, J=5 Hz), to 6.67 (1H, d, J=5 Hz), 7,46 (1H, d, J=8 Hz), 7,72 (1H, s), to 7.77 (1H, d, J=8 Hz),

The following compounds were obtained according to a similar method of example 184.

Example 530

3-[2-(cyclopentylamine)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

1H-NMR (CDCl3) δ of 1.36 (3H, t, J=7 Hz), 1,51 and 1.80 (6H, m), of 2.15 (2H, m), 2,96 (2H, square, J=7 Hz), 3,05 (3H, s), 4,27 (1H, m)5,94 (1H, d, J=5 Hz), 6,47-6,53 (2H, m), 7,53-to 7.59 (3H, m), 7,74 (1H, m).

Example 531

3-[7-ethyl-2-(methylamino)-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

1H-NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 2,94-3,07 (8H, m), 5,95 (1H, d, J=5 Hz), 6,50 (2H, m), 7.5 to to 7.59 (3H, m), 7,74 (1H, m).

The following compound was obtained according to a similar method of example 225.

Example 532

(2R,3R,4S,5S,6R)-2-({3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanol}amino)-6-{[(2,2-dimethylpropanoyl)oxy]methyl}tetrahydro-2H-Piran-3,4,5-Treillis(2,2-dimethylpropanoate).

1H-NMR (CDCl3) δ of 1.07 (9H, s), is 1.11 (9H, s)of 1.16 (9H, s)of 1.18 (9H, s)to 1.37 (3H, t, J=7 Hz), of 2.23 (2H, m), 2,84 (2H, m), 3,03 (2H, square, J=7 Hz), 3,48 (3H, s), 3,91-is 4.21 (3H, m), 4,62-of 4.67 (2H, m), 5,00-5,26 (3H, m), 5,43 (2H, m), 5,91 (1H, d, J=5 Hz), 6,55 (1H, m, usher.), 6,62 (1H, d, J=5 Hz), to 7.84 (1H, m), 8,51 (1H, m), 8,77 (1H, m).

The following compounds were obtained according to a similar method of example 226.

Example 533

[4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-3-yl]methanol

1H-NMR (CDCl3) δ of 1.40 (3H, t, J=7 Hz), 2,53 (1H, t, J=7 Hz), of 3.07 (2H, square, J=7 Hz), 4,48 (2H, m), 6,23 (1H, d, J=5 Hz), 6,62 (1H, m), of 6.71 (1H, d, J=5 Hz), 7,10 (1H, d, J=5 Hz), 7,46-7,52 (3H, m), to 7.61 (1H, m), of 7.64 (1H, m).

Example 534

[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]methanol

1H NMR (CDCl3) δ to 1.38 (3H, t, J=8 Hz), 3,05 (2H, square, J=8 Hz), 3,45-3,55 (4H, m), and 4.40 (2H, userd, J=7 Hz), of 4.77 (2H, users), to 6.22 (1H, d, J=5 Hz), 6,70 (1H, d, J=5 Hz), 8,11 (1H, m), a total of 8.74 (1H, users), 8,80 (1H, d, J=2 Hz).

MS (ESI+): m/z 302 (M+H).

The following compound was obtained according to a similar method of example 227.

Example 535

(2R,3S,4S,5R,6R)-2-[(atomic charges)methyl]-6-({5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentyl}oxy)tetrahydro-2H-Piran-34,5-trialreset

1H-NMR (CDCl3) δ 0,82-of 1.18 (6H, m)to 1.37 (3H, t, J=7 Hz), 1,92-2,17 (14H, m)to 2.35 (2H, m), 3,01 (2H, square, J=7 Hz), and 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=8,1 Hz), 4,96 (1H, m), 5,11 (1H, m), to 5.35 (1H, m), 5,90 (1H, d, J=5 Hz), 6,62 (1H, d, J=5 Hz), 7,44-7,53 (5H, m), 7,60-7,80 (4H, m).

The following compounds were obtained according to a similar method of example 228.

Example 536

Ethyl-3-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ to 1.19 (3H, t, J=7 Hz), of 1.39 (3H, t, J=7 Hz), 2,33 (2H, t, J=7 Hz), 2,43 (3H, s), 2,70-2,82 (2H, m), 3.04 from (2H, square, J=7 Hz), 3,71 (1H, t, J=5 Hz), of 4.05 (2H, square, J=7 Hz), 4,89 (2H, d, J=5 Hz), 5,98 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,52 (1H, s), 8,42 (1H, d, J=2 Hz), 8,56 (1H, d, J=2 Hz).

MS (ESI+): m/z 368.

Example 537

Ethyl-4-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.39 (3H, t, J=7 Hz), 1,62-of 1.78 (2H, m), 2,16-of 2.28 (2H, m), 2,36 of $ 2.53 (2H, m), is 2.44 (3H, s), 3,06 (2H, square, J=7 Hz), 3,86 (1H, t, J=7 Hz), of 4.12 (2H, square, J=7 Hz), 4,90 (2H, m), 5,96 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,53 (1H, s), 8,44 (1H, s), 8,56 (1H, s).

MS (ESI+): m/z 382.

Example 538

Ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), of 1.39 (3H, t, J=7 Hz), 1,46-of 1.65 (4H, m)of 2.16 (2H, t, J=7 Hz), 2,32 is 2.44 (2H, m), 3.04 from (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), a 4.86 (2H, s), 5,91 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,58-to 7.68 (3H, m), 7,75-of 7.82 (1H, m).

MS (ESI+): m/z 406.

Example 539

Ethyl-4-[4-(5-bromo-3-Piri is inyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ 1,25 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,64-to 1.79 (2H, m), of 2.23 (2H, t, J=7 Hz), 2,42 of $ 2.53 (2H, m), 3.04 from (2H, square, J=7 Hz), 4,10 (2H, square, J=7 Hz), 4,91 (2H, s), 5,97 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,89 (1H, m), 8,56 (1H, d, J=2 Hz), 8,80 (1H, d, J=2 Hz).

MS (ESI+): m/z 446, 448.

Example 540

Ethyl-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ of 1.20 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 2,32 (2H, m), 2,68-2,90 (2H, m), 3,03 (2H, square, J=7 Hz), 4,10 (2H, m), 4,89 (2H, s), 6,03 (1H, m), of 6.65 (1H, m), of 7.90 (1H, m), 8,58 (1H, m), 8,83 (1H, m).

MS (ESI+): m/z 432, 434.

Example 541

Ethyl-4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (300 MHz, CDCl3) δ to 1.22 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,67 (2H, TT, J=7, 7 Hz), measuring 2.20 (2H, t, J=7 Hz), 2,37-and 2.79 (2H, m), 3.04 from (2H, square, J=7 Hz), of 3.77 (1H, t, J=4 Hz), 4,07 (2H, square, J=7 Hz), 4,91 (2H, d, J=4 Hz), 5,96 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,73 (1H, DD, J=2, 2 Hz), charged 8.52 (1H, d, J=2 Hz), to 8.70 (1H, d, J=2 Hz).

Example 542

Ethyl-3-[4-(3-chlorophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (300 MHz, CDCl3) δ of 1.20 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 2,31 (2H, t, J=8 Hz), 2,85 (2H, t, J=8 Hz), 3.04 from (2H, square, J=7 Hz), 3,69 of 3.75 (1H, users), 4,06 (2H, square, J=7 Hz), 4,88 (2H, s), 6,00 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 7.23 percent-7,26 (1H, m), of 7.36 (1H, s), 7,44-7,46 (2H, m).

Example 543

Ethyl-4-[4-(3-chlorophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ to 1.21 (3H, t, J=8 Hz), to 1.38 (3H, t, J=8 Hz), of 1.57 (3H, s, 1,59-of 1.74 (2H, m), of 2.20 (2H, t, J=8 Hz), 2,37-2,47 (2H, m), 3,03 (2H, square, J=8 Hz), a-3.84 (1H, t, J=5 Hz), 4,06 (2H, square, J=8 Hz), 4,39 (2H, d, J=5 Hz), 5,32 (2H, s), 5,96 (1H, d, J=5 Hz), 6,56 (1H, d, J=5 Hz), 7,21-7,29 (1H, overlapping CDCl3), was 7.36 (1H, users), 7,39-7,47 (2H, m).

Example 544

9-(5-bromo-3-pyridinyl)-6-ethyl-1H,3H-furo[3,4-e]pyrrolo[1,2-b]pyridazin-1-he

1H NMR (CDCl3) δ of 1.42 (3H, t, J=8 Hz), 3,11 (2H, square, J=8 Hz), 5,32 (2H, s), 6.87 in (1H, d, J=5 Hz), of 6.99 (1H, d, J=5 Hz), to 8.20 (1H, m), 8,83-8,87 (2H, m).

MS (ESI+): m/z 358, 360 (M+H).

4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-carboxylic acid

1H NMR (CDCl3CD3OD) δ of 1.40 (3H, t, J=8 Hz), to 3.09 (2H, square, J=8 Hz), is 4.93 (2H, s), 6,34 (1H, d, J=5 Hz), 6,79 (1H, d, J=5 Hz), of 7.96 (1H, m), 8,55 (1H, users), 8,73 (1H, users).

MS (ESI+): m/z 376, 378 (M+H).

Example 545

3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]-N-[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-Piran-2-yl]propanamide

1H-NMR (DMSO-d6) δ of 1.30 (3H, t, J=7 Hz), of 2.21 (1H, m), 2,96 (2H, square, J=7 Hz), of 3.25 to 3.45 (8H, m), 3,66 (1H, m), and 4.40 (1H, m), 4,55-4,67 (5H, m), and 4.75 (1H, m), of 5.85 (1H, d, J=5 Hz), of 6.66 (1H, d, J=5 Hz), 8,23 (1H, m), with 8.33 (1H, d, user., J=7 Hz), 8,61 (1H, m), 8,84 (1H, m).

Example 546

3-[7-ethyl-2-phenyl-3-(5-{[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-Piran-2-yl]oxy}of pentyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

1H-NMR (CDCl3) δ 0,85-to 1.38 (6H, m)of 1.46 (3H, t, J=7 Hz), 2,13 (2H, m), of 2.38 (2H, m), 2,65 (1H, m), 2,73 (1H, m), to 3.02 (2H, square, J=7 Hz), 3,23 (1H, m), 3,48-3,70 (4H, m) of 3.80-4,01 (3H, m), of 4.13 (1H, m), 5,90 (1H, d, J=5 Hz), 663 (1H, d, J=5 Hz), 7,42-of 7.55 (5H, m), 7,60-7,79 (4H, m).

The following compound was obtained according to a similar method of example 235.

Example 547

N-(2-amino-ethyl)-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanamide

1H-NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), to 2.29 (2H, m), 2,72-of 3.07 (6H, m)to 3.33 (2H, square, J=7 Hz), 3,49 (3H, s), and 4.68 (2H, s), to 5.93 (1H, d, J=5 Hz), the 6.06 (1H, m, usher.), 6,62 (1H, d, J=5 Hz), 7,89 (1H, m), 8,55 (1H, m), 8,77 (1H, m)

MS (ESI+) m/z: 460 and 462 (M+H).

The following compounds were obtained according to a similar method of example 268.

Example 548

Ethyl-3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoate

1H NMR (CDCl3) δ to 1.15 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), is 2.37 (2H, t, J=7 Hz), 2,43 (3H, s), 2,86-a 3.01 (2H, m), 3,03 (2H, square, J=7 Hz), 3,99 (2H, square, J=7 Hz), and 4.68 (2H, s), to 4.81 (2H, s), 5,95 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,27 (2H, d, J=7 Hz), 7,51 (1H, s), 8,43 (1H, s), 8,56 (1H, s), to 8.57 (2H, d, J=7 Hz).

MS (ESI+): m/z 459.

Example 549

Ethyl-3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-personalitate)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoate

1H NMR (CDCl3) δ to 1.16 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 2,39 (2H, t, J=7 Hz), 2,43 (3H, s), 2,88-3,03 (2H, m), 3.04 from (2H, square, J=7 Hz), 4,01 (2H, square, J=7 Hz), a 4.83 (2H, s), the 4.90 (2H, s)5,94 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,53 (1H, s), 8,42 (1H, m), 8,48-8,55 (3H, m), 8,76 (1H, s).

MS (ESI+): m/z 460.

Example 550

Ethyl-3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-and the}propanoate

1H NMR (CDCl3) δ to 1.15 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 2.40 a (2H, t, J=7 Hz), 2,42 (3H, s), 2,88-of 3.00 (2H, m), 3,03 (2H, square, J=7 Hz), 3,99 (2H, square, J=7 Hz), 4,79 (2H, s), a 4.86 (2H, s), of 5.92 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,16-of 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.

Example 551

Ethyl-4-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

1H NMR (CDCl3) δ of 1.18 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,60-1,80 (2H, m), 2.13 and was 2.25 (2H, m), 2,43 (3H, s), 2,53 was 2.76 (2H, m), 3,03 (2H, square, J=7 Hz), a 4.03 (2H, square, J=7 Hz), and 4.68 (2H, s), a 4.83 (2H, m), of 5.92 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,27 (2H, d, J=5 Hz), 7,53 (1H, s), 8,42 (1H, s), 8,53 (1H, s), 8,55 (2H, d, J=5 Hz).

MS (ESI+): m/z 473.

Example 552

Ethyl-5-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,35-of 1.57 (4H, m), 2,11 (2H, t, J=7 Hz), 2,53-to 2.65 (2H, m), 3,03 (2H, square, J=7 Hz), a 4.03 (2H, square, J=7 Hz), of 4.67 (2H, s), 4,78 (2H, s), by 5.87 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,28 (2H, d, J=5 Hz), to 7.61 (2H, m), 7,66 (1H, s), 7,78 (1H, m), 8,58 (2H, d, J=5 Hz).

MS (ESI+): m/z 497.

Example 553

Ethyl-5-{4-(3-cyanophenyl)-7-ethyl-2-[(2-personalitate)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,35 is 1.58 (4H, m), 2,11 (2H, t, J=7 Hz), 2,55-to 2.65 (2H, m), 3,03 (2H, square, J=7 Hz), 4,10 (2H, square, J=7 Hz), 4,82 (2H, s), a 4.86 (2H, s), 5,86 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), a 7.62 (2H, m), to 7.67 (1H, s), 7,78 (1H, m), 8,51 (2H, m), a total of 8.74 (1H, s).

MS (ESI+): m/z 498.

The use of the 554

Ethyl-5-{4-(3-cyanophenyl)-7-ethyl-2-[(3-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), of 1.39 (3H, t, J=7 Hz), 1.32 to of 1.66 (4H, m), 2,10 (2H, t, J=7 Hz), 2,48-2,60 (2H, m), 3,03 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), of 4.66 (2H, s), and 4.75 (2H, s), 5,86 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,28 (1H, m), 7,58-7,63 (2H, m), 7,66 (1H, s), 7,66-7,80 (2H, m), 8,54 (1H, m), to 8.62 (1H, m).

MS (ESI+): m/z 497.

Example 555

Ethyl-5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,40-of 1.62 (4H, m)of 2.16 (2H, t, J=7 Hz), 2,53-a 2.71 (2H, m), 3,05 (2H, square, J=7 Hz), 4.09 to (2H, square, J=7 Hz), of 4.67 (2H, s), 4,78 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,31 (2H, d, J=5 Hz), 7,88 (1H, m), 8,56 (1H, d, J=2 Hz), 8,58 (2H, d, J=5 Hz), 8,79 (1H, d, J=2 Hz).

Example 556

Ethyl-5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.40 (3H, t, J=7 Hz), 1,30-1,60 (4H, m), of 2.15 (2H, t, J=7 Hz), 2,50 of 2.68 (2H, m), 3,06 (2H, square, J=7 Hz), of 4.12 (2H, square, J=7 Hz), and 4.68 (2H, s), 4,78 (2H, s), 5,95 (1H, m), 6,63 (1H, m), 7.24 to 7,38 (1H, m), of 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.

Example 557

Ethyl-5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (CDCl3) δ to 1.24 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40 is 1.58 (4H, m), 2,12 (2H, t, J=7 Hz), 2,53 of 2.68 (2H, m), 3,03 (2H, square, J=7 Hz), 4,10 (2H, square, J=7 Hz), 4,78 (2H, s), 4,84 (2H, s), of 5.92 (1H, d, J=4 Hz, 6,62 (1H, d, J=4 Hz), 7,22 (1H, m), of 7.48 (1H, d, J=8 Hz), 7.68 per to 7.75 (1H, m), 7,88 (1H, m), to 8.57 (2H, m), 8,78 (1H, d, J=2 Hz).

Example 558

Ethyl-5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-personalitate)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,40-of 1.62 (4H, m), of 2.15 (2H, t, J=7 Hz), 2,53-of 2.72 (2H, m), 3,05 (2H, square, J=7 Hz), 4,08 (2H, square, J=7 Hz), 4,82 (2H, s), a 4.86 (2H, s)5,94 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,88 (1H, m), charged 8.52 (2H, m), 8,55 (1H, d, J=2 Hz), a total of 8.74 (1H, m), 8,79 (1H, d, J=2 Hz).

MS (ESI+): m/z 552, 554.

Example 559

Ethyl-4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

1H NMR (CDCl3) δ to 1.19 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,60-1,80 (2H, m), 2,22 (2H, t, J=7 Hz), 2,55-to 2.74 (2H, m), 3,05 (2H, square, J=7 Hz), 4,06 (2H, square, J=7 Hz), 4,69 (2H, s), a 4.83 (2H, s), 5,96 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,30 (2H, d, J=6 Hz), 7,88 (1H, m), 8,56 (2H, d, J=6 Hz), to 8.57 (1H, m), 8,80 (1H, m).

MS (ESI+): m/z 537, 539.

Example 560

Ethyl-4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,55-to 1.82 (2H, m)to 2.18 (2H, t, J=7 Hz), 2,52-of 2.72 (2H, m), 3,05 (2H, square, J=7 Hz), of 4.05 (2H, square, J=7 Hz), and 4.68 (2H, s), a 4.83 (2H, s)5,94 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,28 (1H, m), 7,73 (1H, d, J=8 Hz), 7,88 (1H, m), 8,54 (2H, m), to 8.62 (1H, s), 8,79 (1H, s).

Example 561

Ethyl-4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz, 1,63-to 1.82 (2H, m)to 2.18 (2H, t, J=7 Hz), 2,55 is 2.75 (2H, m), 3,06 (2H, square, J=7 Hz), 4.00 points (2H, square, J=7 Hz), 4,80 (2H, s), 4,88 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,22 (1H, m), of 7.48 (1H, d, J=8 Hz), 7,71 (1H, t, J=8 Hz), 7,89 (1H, m), 8,55 (2H, m), 8,78 (1H, d, J=2 Hz).

MS (ESI+): m/z 537, 539.

Example 562

Ethyl-4-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}butanoate

1H NMR (CDCl3) δ 0,25 (2H, m)0,60 (2H, m), 1,08-1,22 (1H, m)to 1.22 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,69-to 1.82 (2H, m), of 2.21 (2H, t, J=7 Hz), 2,56-of 2.72 (2H, m), 3,03 (2H, square, J=7 Hz), 3,42 (2H, d, J=7 Hz), Android 4.04 (2H, square, J=7 Hz), to 4.73 (2H, s), 5,91 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 7,89 (1H, m), 8,56 (1H, d, J=2 Hz), 8,79 (1H, d, J=2 Hz).

MS (ESI+): m/z 500, 502.

Example 563

Ethyl-4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-personalitate)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

1H NMR (CDCl3) δ to 1.19 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1.70 to to 1.82 (2H, m), of 2.23 (2H, t, J=7 Hz), 2,56 was 2.76 (2H, m), 3,06 (2H, square, J=7 Hz), Android 4.04 (2H, square, J=7 Hz), 4,84 (2H, s), of 4.95 (2H, m)5,94 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,89 (1H, m), and 8.50 (2H, m), 8,56 (1H, s), a total of 8.74 (1H, s), 8,79 (1H, m).

MS (ESI+): m/z 538, 540.

Example 564

Ethyl-3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoate

1H NMR (CDCl3) δ to 1.16 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), is 2.41 (2H, t, J=7 Hz), 2,85-of 3.07 (2H, m), 3,06 (2H, square, J=7 Hz), was 4.02 (2H, square, J=7 Hz), and 4.68 (2H, s), to 4.81 (2H, s), 5,95 (1H, d, J=4 Hz), of 6.65 (1H, d, J=4 Hz), 7,31 (2H, d, J=6 Hz), 7,87 (1H, m), 8,55 (1H, m), 8,56 (2H, d, J=6 Hz), 8,79 (1H, d, J=2 Hz).

MS (ESI+): m/z 523, 525.

Example 565

Etil-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[2-(tetrahydro-2H-Piran-2-yloxy)ethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)butanoate

1H NMR (CDCl3) δ of 1.20 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,46-of 1.93 (8H, m), of 2.21 (2H, t, J=7 Hz), 2,55 was 2.76 (2H, m), to 3.02 (2H, square, J=7 Hz), 3.46 in of 3.56 (1H, m), 3,60-3,68 (1H, m), 3,74-3,82 (2H, m), 3,83-of 3.96 (2H, m), a 4.03 (2H, square, J=7 Hz), 4,63 (1H, m), of 4.77 (2H, s), 5,91 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,89 (1H, m), 8,56 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

Example 566

Ethyl-4-{4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

1H NMR (300 MHz, CDCl3) δ to 1.19 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), to 1.70 (2H, t, J=7 Hz), 2,19 (2H, t, J=7 Hz), 2,55-to 2.67 (2H, m), 3.04 from (2H, square, J=7 Hz), a 4.03 (2H, square, J=7 Hz), 4,69 (2H, s), a 4.83 (2H, s), 5,94 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), 7,29 (2H, d, J=6 Hz), 7,73 (1H, DD, J=2, 2 Hz), charged 8.52 (1H, d, J=2 Hz), 8,58 (2H, d, J=6 Hz), 8,69 (1H, d, J=2 Hz).

Example 567

Ethyl-3-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ of 1.20 (3H, t, J=8 Hz), of 1.37 (3H, t, J=8 Hz), 2,33 is 2.44 (2H, m), 2,84-to 2.94 (2H, m), 3,03 (2H, square, J=8 Hz), of 3.45 (3H, s), of 4.05 (2H, square, J=8 Hz), with 4.64 (2H, s)5,94 (1H, d, J=5 Hz), to 6.58 (1H, d, J=5 Hz), 7,21-7,29 (1H, overlapping CDCl3), was 7.36 (1H, users), 7,38-7,46 (2H, m).

Example 568

Ethyl-4-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ of 1.20 (3H, t, J=8 Hz), of 1.37 (3H, t, J=8 Hz), 1,62-of 1.78 (2H, m), 2,14-of 2.28 (2H, m), 2,53-of 2.66 (2H, m), 3.04 from (2H, square, J=8 Hz), of 3.46 (3H, s), Android 4.04 (2H, square, J=8 Hz)and 4.65 (2H, s), to 5.93 (1H, d, J=5 Hz), to 6.58 (1H, d, J=5 Hz), 7,21-7,29 (1H, overlapping CDCl3), was 7.36 (1H, users), 7,39-7,46 (2H, m).

The following compounds were obtained according to a similar method PR is a measure of 272.

Example 569

Ethyl-5-{4-(5-bromo-3-pyridinyl)-2-[(1,1-dioxido-4-thiomorpholine)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (300 MHz, CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,39-of 1.53 (4H, m), 2,19 (2H, t, J=7 Hz), 2,50-2,61 (2H, m)of 3.00 (2H, square, J=7 Hz), 3,10 (4H, t, J=6 Hz), 3,21 (4H, t, J=6 Hz), 3,85 (2H, ), 4,10 (2H, square, J=7 Hz), of 5.92 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,88 (1H, DD, J=2, 2 Hz), 8,55 (1H, d, J=2 Hz), 8,80 (1H, d, J=2 Hz).

Example 570

Ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomorpholine)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (300 MHz, CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1.41 to and 1.54 (4H, m), 2,19 (2H, t, J=7 Hz), 2,50-2,61 (2H, m)to 2.66 (4H, t, J=4 Hz), 2,85 (4H, t, J=4 Hz), 3,01 (2H, square, J=7 Hz), to 3.67 (2H, ), 4,10 (2H, square, J=7 H), 5,88 (1H, d, J=5 Hz), to 6.57 (1H, d, J=5 Hz), 7,88 (1H, DD, J=2, 2 Hz), 8,55 (1H, d, J=2 Hz), 8,79 (1H, d, J=2 Hz).

Example 571

Ethyl-5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[4-(2-hydroxyethyl)-1-piperazinil]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

1H NMR (300 MHz, CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,40-of 1.55 (4H, m)to 2.18 (2H, t, J=7 Hz), 2,48-2,66 (12H, m), to 3.02 (2H, square, J=7 Hz), 3,61 (2H, t, J=5 Hz), 3,66 (2H, s), 4,10 (2H, square, J=7 Hz), 5,88 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), 7,88 (1H, DD, J=2, 2 Hz), 8,55 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

Example 572

Ethyl-4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-thiomorpholine)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (300 MHz, CDCl3) δ to 1.21 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), to 1.70 (2H, TT, J=7, 7 Hz), 2,19 (2H, t, J=7 Hz), 2,50-to 2.67 (6H, m), of 2.86 (4H, t, J=5 Hz), to 3.02 (2H, square, J=7 Hz), 3,70 (2H, s), of 4.05 (2H, square, J=5 Hz), of 5.89 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,74 (1H, DD, J=2, 2 Hz), charged 8.52 (1H, d, J=2 Hz), 8,68 (1H, d, J=2 Hz).

Example 573

Ethyl-4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (300 MHz, CDCl3) δ to 1.21 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,72 (2H, TT, J=7, 7 Hz), measuring 2.20 (2H, t, J=7 Hz), 2,56-2,69 (6H, m), to 3.02 (2H, square, J=7 Hz), 3,68-3,71 (6H, m), of 4.05 (2H, square, J=7 Hz) of 5.89 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,74 (1H, DD, J=2, 2 Hz), 8,53 (1H, d, J=2 Hz), 8,69 (1H, d, J=2 Hz).

Example 574

Ethyl-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H NMR (300 MHz, CDCl3) δ to 1.21 (3H, t, J=7 Hz), of 1.34 (3H, t, J=7 Hz), 2,47-of 2.54 (2H, m), 2,59 (4H, t, J=5 Hz), 2,81-2,95 (2H, m), to 3.02 (2H, square, J=7 Hz), to 3.67 (4H, t, J=5 Hz), of 3.69 (2H, s)4,07 (2H, square, J=7 Hz), 5,90 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 7,88 (1H, DD, J=2, 2 Hz), 8,55 (1H, d, J=2 Hz), 8,79 (1H, d, J=2 Hz).

Example 575

Ethyl-4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H NMR (300 MHz, CDCl3) δ to 1.21 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), at 1.73 (2H, TT, J=7, 7 Hz), measuring 2.20 (2H, t, J=7 Hz), 2,55-2,69 (6H, m), to 3.02 (2H, square, J=7 Hz), of 3.69 (4H, t, J=5 Hz), of 4.05 (2H, square, J=7 Hz), of 5.89 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,89 (1H, DD, J=2, 2 Hz), to 8.57 (1H, d, J=2 Hz), 8,79 (1H, d, J=2 Hz).

Example 576

Ethyl-4-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylamino)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}butanoate

1H NMR (300 MHz, CDCl3) δ 0,46-0,52 (4H, m)to 1.21 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1,71 (2H, TT, J=8, 8 Hz), of 2.21 (2H, t, J=8 Hz), 2,32-2,39 (1H, m), 2,45-2,54 (2, m), totaling 3.04 (2H, square, J=7 Hz), 4,06 (2H, square, J=7 Hz), 4,07 (2H, s), of 5.89 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), 7,72 (1H, DD, J=2, 2 Hz)and 8.50 (1H, d, J=2 Hz), 8,68 (1H, d, J=2 Hz).

Example 577

Ethyl-5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(2-phenoxyethyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

1H NMR (300 MHz, CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-of 1.56 (4H, m)to 2.18 (2H, t, J=8 Hz), 2,41-2,52 (2H, m), 3.04 from (2H, square, J=7 Hz), 3,19 (2H, t, J=5 Hz), 4,07 (2H, s), 4.09 to (2H, square, J=7 Hz), to 4.17 (2H, t, J=5 Hz), 5,90 (1H, d, J=4 Hz), to 6.57 (1H, d, J=4 Hz), 6,92-6,98 (3H, m), 7,29-to 7.32 (2H, m), 7,86 (1H, DD, J=2, 2 Hz), 8,54 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

Example 578

Ethyl-5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(2-hydroxyethyl)(methyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

1H NMR (300 MHz, CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,42-to 1.63 (4H, m), of 2.20 (2H, t, J=8 Hz), of 2.38 (3H, s), 2,53-of 2.64 (2H, m)of 2.75 (2H, t, J=5 Hz), to 3.02 (2H, square, J=7 Hz), 3,66 (2H, t, J=5 Hz), of 3.77 (2H, s), 4,10 (2H, square, J=7 Hz), 5,90 (1H, d, J=4 Hz), 6,59 (1H, d, J=4 Hz), 7,88 (1H, DD, J=2, 2 Hz), 8,55 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

Example 579

Ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(1-piperidinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (300 MHz, CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,42 is 1.58 (6H, m), 1.69 in (4H, TT, J=5, 5 Hz)to 2.18 (2H, t, J=8 Hz), 2,53-of 2.64 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,19 (4H, t, J=5 Hz), 3,60 (2H,, C)4,07 (2H, square, J=7 Hz), 5,86 (1H, d, J=5 Hz), is 6.54 (1H, d, J=5 Hz), 7,89 (1H, DD, J=2, 2 Hz), 8,56 (1H, d, J=2 Hz), the rate of 8.75 (1H, d, J=2 Hz).

Example 580

Ethyl-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomorpholine)pyrrolo[1,2-b]pyridazin-3-yl]n openout

1H NMR (300 MHz, CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 2,46 (2H, t, J=8 Hz), of 2.64 (4H, t, J=5 Hz), 2,86 (6H, m), to 3.02 (2H, square, J=7 Hz), of 3.69 (2H, s)4,06 (2H, square, J=7 Hz), 5,91 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,88 (1H, DD, J=2, 2 Hz), 8,56 (1H, d, J=2 Hz), 8,80 (1H, d, J=2 Hz).

Example 581

Ethyl-3-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[4-(2-hydroxyethyl)-1-piperazinil]methyl}pyrrolo[1,2-b]pyridazin-3-yl)propanoate

1H NMR (300 MHz, CDCl3) δ to 1.21 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 2,46-2,63 (12H, m), 2,80-to 2.94 (2H, m), 3,03 (2H, square, J=7 Hz), 3,61 (2H, t, J=5 Hz), 3,70 (2H, s)4,08 (2H, square, J=7 Hz), 5,90 (1H, d, J=5 Hz), 6,59 (1H, d, J=5 Hz), 7,88 (1H, DD, J=2, 2 Hz), 8,56 (1H, d, J=2 Hz), 8,79 (1H, d, J=2 Hz).

Example 582

Ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (300 MHz, CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-of 1.55 (4H, m), 1,75-1,80 (4H, m), 2,19 (2H, t, J=7 Hz), 2,54-of 2.66 (6H, m), to 3.02 (2H, square, J=7 Hz), 3,76-3,81 (2H, m), 4,10 (2H, square, J=7 Hz), by 5.87 (1H, d, J=5 Hz), 6,55 (1H, d, J=5 Hz), 7,89 (1H, DD, J=2, 2 Hz), 8,56 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

Example 583

Ethyl-5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-phenyl-1-piperazinil)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (300 MHz, CDCl3) δ to 1.21 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 1.41 to and 1.54 (4H, m), 2,17 (2H, t, J=7 Hz), 2,53 of 2.68 (2H, m)of 2.75 (4H, t, J=5 Hz), 3,03 (2H, square, J=7 Hz), 3,19 (4H, t, J=5 Hz), to 3.73 (2H, ), 4,07 (2H, square, J=7 Hz), of 5.89 (1H, d, J=5 Hz), to 6.58 (1H, d, J=5 Hz), 6,85 (1H, DD, J=8, 8 Hz), 6,93 (2H, J=8 Hz), 7,25 (2H, J=8 Hz), 7,89 (1H, DD, J=2, 2 Hz), 8,56 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

Example 584

Ethyl-5-(4-(5-bro is-3-pyridinyl)-7-ethyl-2-{[(2-methoxyethyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

1H NMR (300 MHz, CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1.41 to to 1.60 (4H, m), 2,19 (2H, t, J=7 Hz), 2,43-2,52 (2H, m), 2,96 (2H, t, J=5 Hz), 3,03 (2H, square, J=7 Hz), 3,40 (3H, s)to 3.58 (2H, t, J=5 Hz), to 3.99 (2H, s), 4,10 (2H, square, J=7 Hz), of 5.89 (1H, d, J=5 Hz), 6,56 (1H, d, J=5 Hz), 7,87 (1H, DD, J=2, 2 Hz), 8,54 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

The following compounds were obtained according to a similar method of example 385.

Example 585

3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]-N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]propanamide

1H-NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 2,25-3,10 (6H, m), 3,49 (3H, s)to 3.58 (4H, m), 3,81 (2H, m), 4,55 (2H, s), 5,97 (1H, d, J=5 Hz), is 6.54 (1H, s), only 6.64 (1H, d, J=5 Hz), to 7.93 (1H, m), charged 8.52 (1H, m), 8,78 (1H, m).

Example 586

tert-Butyl[2-({3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanol}amino)ethyl]carbamate

1H-NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), USD 1.43 (9H, s), and 2.26 (2H, m), is 2.88 (2H, m), 3.04 from (2H, square, J=7 Hz), 3,20 (2H, m), or 3.28 (2H, m), of 3.48 (3H, s), of 4.67 (2H, s), is 4.85 (1H, s, of usher.), to 5.93 (1H, d, J=5 Hz), of 6.20 (1H, s, of usher.), 6,63 (1H, d, J=5 Hz), 7,88 (1H, m), 8,53 (1H, m), 8,79 (1H, m)

The following compound was obtained according to a similar method of example 330.

Example 587

Ethyl-5-[2-{[2-(benzylamino)-2-oksidoksi]methyl}-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), of 1.34 (3H, t, J=7 Hz), 1,33-of 1.55 (4H, m), 2,12 (2H, t, J=7 Hz), 2,43 (3H, s), 2,40-of 2.56 (2H, m), 2,96 (2H, square, J=7 Hz), 4,07 (2H, square, J=7 Hz), 4,19 (2H, s)to 4.52 (2H,, d, J=7 Hz), was 4.76 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,59(1H, d, J=4 Hz), 7,06 (1H, usher.), of 7.23-7,38 (5H, m), 7,49 (1H, s), 8,40 (1H, s), 8,54 (1H, s).

MS (ESI+): m/z 543.

The following compound was obtained according to a similar method of example 333.

Example 588

Ethyl-4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4H-1,2,4-triazole-4-ylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H-NMR (CDCl3) δ to 1.22 to 1.34 (6H, m)to 1.67 (2H, m), of 2.23 (2H, m), of 2.51 (2H, m), 2,98 (2H, square, J=7 Hz), is 4.21 (2H, square, J=7 Hz), 5,67 (2H, m), 5,97 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), the 7.85 (1H, m), of 7.96 (1H with), to 8.34 (1H, s), 8,53 (1H, m), 8,79 (1H, m).

The following compound was obtained according to a similar method of example 336.

Example 589

Ethyl-5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(phenylsulfonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,26-of 1.57 (4H, m)of 2.16 (2H, t, J=7 Hz), 2,33 is 2.46 (2H, m), 2,42 (3H, s), 2,98 (2H, square, J=7 Hz), 4,11 (2H, square, J=7 Hz), to 4.38 (2H, m), 5,91 (1H user.), of 5.92 (1H, d, J=4 Hz), to 6.58 (1H, d, J=4 Hz), 7,43-of 7.55 (4H, m), to 7.93 (2H, d, J=8 Hz), with 8.33 (1H, d, J=2 Hz), 8,54 (1H, d, J=2 Hz).

MS (ESI+): m/z 535.

The following compound was obtained according to a similar method of example 340.

Example 590

Ethyl-4-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylamino)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}butanoate

1H-NMR (CDCl3) δ 0,48 (4H, m)to 1.19 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), to 1.70 (2H, t, J=7 Hz), 2,22 (2H, m)of 2.50 (2H, m), 2.95 and-of 3.07 (3H, m), 3.96 points-of 4.12 (4H, m), 5,90 (1H, d, J=5 Hz), to 6.57 (1H, d, J=5 Hz), 7,88 (1H, m), 8,54 (1H, m), 8,77 (1H, m).

Example 591

To a suspension of LiAlH4(113 mg) in THF (10 ml) was added to these is[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]acetate (600 mg) while cooling the mixture in ice-water and the mixture was stirred at 0° C for 2 hours. To the mixture was added a solution of tartrate of potassium-sodium was filtered and the insoluble substances. After evaporation of the solvent the residue was distributed between AcOEt and water. The organic layer was separated, washed with saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and AcOEt (5:1-1:1), to obtain 2-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]ethanol as a yellow oil (246 mg).

2-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]ethanol

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 2,60 (3H, s), 2,72-2,84 (2H, m), 3,03 (2H, square, J=7 Hz), the 3.65 (2H, t, J=7 Hz), of 5.89 (1H, d, J=4 Hz), 6,55 (1H, d, J=4 Hz), to $ 7.91 (1H, t, J=2 Hz), 8,56 (1H, d, J=2 Hz), 8,76 (1H, d, J=2 Hz).

MS (ESI+): m/z 360, 362.

Example 592

A mixture of 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]propanoic acid (1.07 g), diphenylphosphinite (1,14 g) and Et3N (0,576 ml) in BuOH (30 ml) was boiled under reflux for 2 hours. After evaporation of the solvent the residue was distributed between AcOEt and water. The organic layer was separated, washed with aqueous solution of NaHCO3and saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and AcOEt (20:1-3:1), to obtain tert-butyl{2-[4-(5-bromo-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]ethyl}carbamate as a yellow oil (450 mg).

tert-Butyl{2-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]ethyl}carbamate

1H NMR (CDCl3) δ to 1.37 (9H, s)to 1.37 (3H, t, J=7 Hz), of 2.64 (3H, s), 2,62 is 2.75 (2H, m), 3,03 (2H, square, J=7 Hz), 3,10-of 3.27 (2H, m), 4,40-to 4.52 (1H, m), of 5.89 (1H, d, J=4 Hz), 6,55 (1H, d, J=4 Hz), 7,89 (1H, m), 8,53 (1H, m), 8,77 (1H, m).

Example 593

To a suspension of 60% NaH (74 mg) in DMF (3 ml) was added ethyl-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate (200 mg) under cooling with a mixture of ice-water and the mixture was stirred at 0°C for 0.5 hour. To the mixture was added hydrogen bromide 3-(methyl bromide)pyridine (234 mg) while cooling the mixture in ice-water and the mixture was stirred at ambient temperature for 2 hours. The mixture was distributed between AcOEt and water. The aqueous layer was separated, acidified to pH 3-4 by addition of HCl and was extracted with AcOEt. The organic layer was washed with water and saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira a mixture of CHCl3and MeOH (100:1-20:1), to obtain 3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid as a yellow powder (110 mg).

3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid

1H NMR (CDCl3) δ of 1.39 (3H, t, J=7 Hz), is 2.41 (2H, t, J=7 Hz), 2,80 are 2.98 (2H, m), 3.04 from (2H, square, J=7 Hz), 4,70(2H, C)a 4.83 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,32-7,38 (1H, m), 7,81 (1H, d, J=8 Hz), 7,87 (1H, m), charged 8.52 (1H, d, J=8 Hz), 8,53 (1H, d, J=2 Hz), 8,63 (1H, s), 8,77 (1H, d, J=2 Hz).

The following compounds were obtained according to a similar method of example 593.

Example 594

4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-methoxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butane acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), 1,72 of-1.83 (2H, m), 2,28 (2H, t, J=7 Hz), 2,60-2,77 (2H, m), 3,03 (2H, square, J=7 Hz), 3,39 (3H, s), 3,62 (2H, m), of 3.77 (2H, m), and 4.75 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,92 (1H, m), 8,56 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (ESI-): m/z 474, 476, MS (ESI+): m/z 476, 478.

Example 595

3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 2,48-2,62 (2H, m), 2,98-3,10 (2H, m), 3,05 (2H, square, J=7 Hz), 4,82 (2H, s), 4,88 (2H, s)5,94 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,27 (1H, m), of 7.48 (1H, d, J=8 Hz), to 7.77 (1H, t, J=8 Hz), of 7.90 (1H, m), 8,56 (2H, m), 8,80 (1H, m).

MS (ESI+): m/z 495, 497.

Example 596

3-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-acylpyrrole[1,2-b]pyridazin-3-yl}propanoic acid

1H NMR (CDCl3) δ 0,25 (2H, m)of 0.58 (2H, m), 1,12 (1H, m)to 1.37 (3H, t, J=7 Hz), 2.40 a-2,63 (2H, m), 2,85 was 3.05 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,42 (2H, d, J=7 Hz), to 4.73 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,89 (1H, m), 8,55 (1H, d, J=2 Hz), 8,77 (1H, d, J=2 Hz).

MS (ESI-): m/z 456, 458, MS (ESI+): m/z 458, 460.

Example 597

3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-personalitate)met the l]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 2,48 (2H, t, J=7 Hz), 2,85-to 3.09 (2H, m), 3,06 (2H, square, J=7 Hz), 4,84 (2H, s)to 4.92 (2H, s), 5,96 (1H, d, J=4 Hz), of 6.65 (1H, d, J=4 Hz), of 7.90 (1H, m), 8,48-to 8.62 (3H, m), 8,77 (2H, m).

Example 598

A mixture of ethyl-4-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[2-(tetrahydro-2H-Piran-2-yloxy)ethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)butanoate (89 mg) and p-toluensulfonate pyridinium (0.8 mg) in MeOH (5 ml) was boiled under reflux for 2 hours. After evaporation of the solvent the residue was purified column chromatography on silica gel, elwira with a mixture of hexane and AcOEt (10:1-1:1), to obtain ethyl-4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-hydroxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate in the form of a yellow oil (69 mg).

Ethyl-4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-hydroxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

1H NMR (CDCl3) δ to 1.22 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,69-of 1.84 (2H, m), 2,22 (2H, t, J=7 Hz), 2,53-of 2.72 (2H, m), 3,03 (2H, square, J=7 Hz), 3,76 (2H, m), 3,83 (2H, m), 4,07 (2H, square, J=7 Hz), 4,79 (2H,with), to 5.93 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,89 (1H, m), 8,56 (1H, d, J=2 Hz), 8,79 (1H, d, J=2 Hz).

MS (ESI+): m/z 490, 492.

Example 599

To a suspension of 60% NaH (69,5 mg) in DMF (3 ml) was added ethyl-5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (200 mg) under cooling with a mixture of ice-water and the mixture was stirred at 0°C for 0.5 hour. To the mixture was added 4-morpholinylcarbonyl (659 mg) and the mixture peremeshivaniya ambient temperature for 15 hours. The mixture was distributed between AcOEt and water. The organic layer was separated, washed with water and saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira with a mixture of hexane and AcOEt (20:1-1:1), to obtain [4-(5-bromo-3-pyridinyl)-3-(5-ethoxy-5-oxobutyl)-7-acylpyrrole[1,2-b]pyridazin-2-yl]methyl-4-morpholinylcarbonyl in the form of a yellow oil (75 mg).

[4-(5-bromo-3-pyridinyl)-3-(5-ethoxy-5-oxobutyl)-7-acylpyrrole[1,2-b]pyridazin-2-yl]methyl-4-morpholinylcarbonyl

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,40-1,60 (4H, m)to 2.18 (2H, t, J=7 Hz), 2,42-of 2.54 (2H, m), 3,03 (2H, square, J=7 Hz), 3,53 is 3.57 (4H, m), 3,63-of 3.78 (4H, m), 4.09 to (2H, square, J=7 Hz), 5,33 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,87 (1H, m), 8,54 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

MS (ESI+): m/z 573, 575.

The following compounds were obtained according to a similar method of example 599.

Example 600

Ethyl-5-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,35-to 1.60 (4H, m), 2,17 (2H, t, J=7 Hz), 2,44-to 2.57 (2H, m), 2,98 (6H, s), 3,03 (2H, square, J=7 Hz), 4.09 to (2H, square, J=7 Hz), and 5.30 (2H, s), to 5.93 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,87 (1H, m), 8,54 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

MS (ESI+): m/z 531, 533.

Example 601

[4-(5-bromo-3-pyridinyl)-3-(5-ethoxy-5-oxobutyl)-7-acylpyrrole[1,2-b]pyridazin-2-yl]methyl-1-pyrrolidinecarboxylic

1H YAM who (CDCl 3) δ of 1.23 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,38 is 1.60 (4H, m), 1,86-to 1.98 (4H, m), 2,17 (2H, t, J=7 Hz), 2,44-to 2.57 (2H, m), 3,03 (2H, square, J=7 Hz), 3,36-to 3.52 (4H, m), 4,11 (2H, square, J=7 Hz), 5,32 (2H, s), of 5.92 (1H, d, J=4 Hz), is 6.61 (1H, d, J=4 Hz), 7,87 (1H, m), 8,55 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

Example 602

Ethyl-5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[({[methyl(phenyl)amino]carbonyl}oxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

1H NMR (CDCl3) δ of 1.20 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1.32 to of 1.57 (4H, m), 2,13 (2H, t, J=7 Hz), 2,33-2,48 (2H, m), 3,03 (2H, square, J=7 Hz), to 3.38 (3H, s)4,08 (2H, square, J=7 Hz), of 5.34 (2H, s), of 5.92 (1H, d, J=4 Hz), 6,60 (1H, d, J=4 Hz), 7,20-7,38 (5H, m), 7,83 (1H, s), 8,49 (1H, s), 8,77 (1H, s).

Example 603

[4-(5-bromo-3-pyridinyl)-3-(4-ethoxy-4-oxobutyl)-7-acylpyrrole[1,2-b]pyridazin-2-yl]methyl-4-morpholinylcarbonyl

1H NMR (CDCl3) δ of 1.20 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,63 and 1.80 (2H, m), 2,22 (2H, t, J=7 Hz), 2,44-to 2.65 (2H, m), 3,03 (2H, square, J=7 Hz), of 3.54 (4H, m), 3,68 (4H, m), of 4.05 (2H, square, J=7 Hz), lower than the 5.37 (2H,, C)5,94 (1H, d, J=4 Hz), 6,62 (1H, d, J=4 Hz), 7,87 (1H, m), 8,55 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

MS (ESI+): m/z 559, 561.

Example 604

Ethyl-4-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]butanoate

1H NMR (CDCl3) δ of 1.20 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), 1,66-to 1.79 (2H, m), of 2.20 (2H, t, J=7 Hz), 2,46-2,62 (2H, m), of 2.97 (6H, s), 3,03 (2H, square, J=7 Hz), Android 4.04 (2H, square, J=7 Hz), of 5.34 (2H, s), to 5.93 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,89 (1H, m), 8,56 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

MS (ESI+): m/z 517, 519.

Example 605

Ethyl-3-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)ka is bonyl]oxy}methyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]propanoate

1H NMR (CDCl3) δ of 1.20 (3H, t, J=7 Hz), of 1.36 (3H, t, J=7 Hz), is 2.37 (2H, t, J=7 Hz), 2,82-of 2.93 (2H, m), of 2.97 (6H, s), 3,03 (2H, square, J=7 Hz), of 4.05 (2H, square, J=7 Hz), 5,32 (2H, s), 5,96 (1H, d, J=4 Hz), 6,63 (1H, d, J=4 Hz), 7,88 (1H, m), 8,54 (1H, d, J=2 Hz), 8,78 (1H, d, J=2 Hz).

Example 606

To a solution of sodium hydride (br93.1 mg) in DMF (4 ml) was added ethyl-3-[4-(3-chlorophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate (150 mg) under cooling with a mixture of ice-water and the mixture was stirred at the same temperature for 1 hour. To the mixture was added hydrogen bromide 4-(methyl bromide)pyridine (196 mg) and the mixture was stirred for 1 hour at ambient temperature. The reaction was suppressed by the addition of water. The mixture was extracted with CHCl3. The organic layer was washed with water and saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue was purified column chromatography on silica gel, elwira a mixture of CHCl3-MeOH=30:1, with 3-{4-(3-chlorophenyl)-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid (18 mg) as a yellow solid.

3-{4-(3-chlorophenyl)-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid

1H NMR (300 MHz, CDCl3) δ of 1.39 (3H, t, J=7 Hz), 2,33 (2H, t, J=7 Hz), 2,84-only 2.91 (2H, m), 3.04 from (2H, square, J=7 Hz), to 4.73 (2H, s), 4,82 (2H, s), 5,96 (1H, d, J=5 Hz), 6,62 (1H, d, J=5 Hz), 7.23 percent-7,26 (1H, m), of 7.36-7,38 (3H, m), 7,42-7,44 (2H, m), to 8.41 (2H, d, J=5 Hz).

MS (m/z 450 (M+H).

Sleduyusheye was obtained by the similar procedure of example 606.

Example 607

3-{4-(3-chlorophenyl)-7-ethyl-2-[(3-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid

1H NMR (300 MHz, CDCl3) δ of 1.39 (3H, t, J=7 Hz), 2,32-of 2.38 (2H, m), 2,84 of 2.92 (2H, m), 3.04 from (2H, square, J=7 Hz), 4,70 (2H, s), 4,82 (2H, s)5,94 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,21-7,24 (1H, m), 7,31 and 7.36 (2H, m), 7,40-7,42 (2H, m), 7,80 (2H, d, J=8 Hz), 8,51 (1H, d, J=5 Hz), 8,64 (1H, s).

Example 608

3-{4-(3-chlorophenyl)-7-ethyl-2-[(2-personalitate)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid

1H NMR (300 MHz, CDCl3) δ to 1.38 (3H, t, J=7 Hz), 2,42 (2H, t, J=7 Hz), 2.91 in-of 2.97 (2H, m), 3,03 (2H, square, J=7 Hz), a 4.83 (2H, s), the 4.90 (2H, s), 5,96 (2H, d, J=5 Hz), 6,62 (2H, d, J=5 Hz), 7.23 percent-7,26 (1H, m), of 7.36 (1H with), 7,43-7,44 (2H, m), 8,51 are 8.53 (2H, m), is 8.75 (1H, s).

Example 609

To a solution of 5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanol acid (15 mg) in MeOH was added 10% Pd/C (2 mg). The mixture was stirred in hydrogen atmosphere (1 ATM) for 6 hours, the Reaction mixture was filtered through celite and the filtrate was concentrated in vacuum. The residue is triturated in hexane to obtain 5-[7-ethyl-4-(2-ethyl-4-pyridinyl)-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanol acid (14 mg) as a yellow solid.

5-[7-ethyl-4-(2-ethyl-4-pyridinyl)-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid

1H NMR (CDCl3) δ 1,29-1,64 (10H, m), 2,18-of 2.30 (2H, m), 2,45-2,48 (2H, m), of 2.56 (3H, s), 2.91 in-a 3.06 (4H, m), of 5.84 (1H, d, J=5 Hz), 6,53 (1H, d, J=16 Hz), 6,51 (1H, d, J=5 Hz), 7,25-to 7.32 (2H, m), 8,69 (1H, users).

Example 610

RA is Toru ethyl-4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate (70.0 mg) in toluene (1 ml) was added tributylphosphine (0,098 ml), 1,3-oxazolidin-2-he (to 34.1 mg) in that order in a bath with ice. After stirring for 5 minutes, to the mixture was added 1,1'-(azodicarbon)piperidin accounted for 98.9 mg). The mixture was stirred for 10 minutes at the specified bath and 8 hours at room temperature. Added hexane (5 ml) and the mixture was filtered. The filtrate was evaporated. Preparative thin layer chromatography (ethyl acetate : hexane=1:1) gave ethyl-4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-oxo-1,3-oxazolidin-3-yl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate in the form of a yellow resin (25.0 mg).

Ethyl-4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-oxo-1,3-oxazolidin-3-yl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

1H-NMR (CDCl3) δ of 1.20 (3H, t, J=7 Hz), 1,369 (3H, t, J=7 Hz), of 1.65 (3H, t, J=7 Hz), of 2.25 (2H, t, J=7 Hz), of 2.51 (2H, m), 2,99 (2H, square, J=7 Hz), with 3.79 (2H, t, J=7 Hz), Android 4.04 (2H, square, J=7 Hz), 4,43 (2H, t, J=7 Hz), 4,69 (2H, m), 5,95 (1H, d, J=5 Hz), is 6.61 (1H, d, J=5 Hz), 7,87 (1H, m), 8,55 (1H, m), 8,80 (1H, m).

Example 611

To a solution of 2-bromo-4-[3-(etoxycarbonyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-4-yl]benzoic acid (50.0 mg) in tetrahydrofuran (1 ml) was added a solution of 1M borane-tertrahydrofuran ring complex (0,348 ml) in a bath with ice. After stirring for 2 hours at room temperature was added a solution of the complex of borane and tetrahydrofuran (0,348 ml). The mixture was stirred for 15 hours at room temperature. The mixture was distributed between ethyl acetate and 1N. chlorine is stevedorage acid. The organic layer was washed with water, saturated sodium bicarbonate solution and saturated salt solution, dried over magnesium sulfate and evaporated to obtain ethyl-4-[3-bromo-4-(hydroxymethyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-carboxylate as a yellow oil (54,2 mg).

Ethyl-4-[3-bromo-4-(hydroxymethyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-carboxylate

1H-NMR (CDCl3) δ 0,99 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), at 2.59 (3H, s), 3,03 (2H, square, J=7 Hz), 4,07 (2H, square, J=7 Hz),4,82 (2H, s), 6,33 (1H, d, J=5 Hz), of 6.66 (1H, d, J=5 Hz), 7,44 (1H, d, J=8 Hz), 7,58 (1H, d, J=8 Hz), to 7.67 (1H, s).

Example 612

To a solution of 2-(2-{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy}ethoxy)ethyl acetate (62,0 mg) in methanol (1 ml) was added potassium carbonate (22,2 mg). After stirring for 1.5 hours the solvent evaporated. Preparative thin layer chromatography (CHCl3-MeOH=20:1) gave the desired product as a yellow resin (54,1 mg). The resin was dissolved in 1N. HCl (1 ml) and the solution was liofilizovane obtaining dark green resin, which crystallized upon standing. The crystals are triturated in diisopropyl ether to obtain the hydrochloride of 2-(2-{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy}ethoxy)ethanol as a yellow powder (of 40.3 mg).

Hydrochloride of 2-(2-{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy}ethoxy)ethanol

1 H-NMR (DMSO-d6): of 1.29 (3H, t, J=7 Hz), of 2.51 (3H, s), of 2.56 (3H, s), 2,62 (2H, m)to 2.94 (2H, square, J=7 Hz), 3,30-3,47 (10H, m), of 5.84 (1H, d, J=5 Hz), 6,59 (1H, d, J=5 Hz), compared to 8.26 (1H, m), 8,77 (1H, m), cent to 8.85 (1H, m).

Example 613

A mixture of ethyl-5-[2-(methyl bromide)-4-(3-cyanophenyl)-7-acylpyrrole[1,2-b]pyridazin-3-yl]pentanoate (70.0 mg), phenol (21.1 mg) and potassium carbonate (31,0 mg) in N,N-dimethylformamide was stirred for 2.5 hours at room temperature. The mixture was distributed between ethyl acetate and 1N. hydrochloric acid. The organic layer was washed with water, saturated sodium bicarbonate solution and saturated salt solution, dried over magnesium sulfate and evaporated to obtain ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-(phenoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate in the form of a yellow resin (77,5 mg, 108%).

Ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-(phenoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H-NMR (CDCl3) δ to 1.21 (3H, t, J=7 Hz), 1,35-1,53 (7H, m)2,07 (2H, m), of 2.54 (2H, m), 3,03 (2H, square, J=7 Hz), of 4.05 (2H, square, J=7 Hz), of 5.24 (2H, s), 5,86 (1H, d, J=5 Hz), of 6.65 (1H, d, J=5 Hz), 6,80-7,01 (3H, m), 7,03 (2H, d, J=9 Hz), 7,32 (2H, t, J=9 Hz), 7,55-7,63 (2H, m), to 7.67 (1H, s), 7,76 (1H, m).

MS (ESI+): m/z 482 (M+H).

Example 614

A mixture of 4-(3-cyanophenyl)-7-ethyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-2-intraformational (50.0 mg),

3-Puilboreau acid (23,6 mg),

dichlorobis(triphenylphosphine)palladium (3,71 mg) and 2n. sodium carbonate (44,8 mg in 0.2 ml of water) in dioxane was stirred for 20 minutes at 5° C. the Mixture was distributed between EtOAc and water and the organic layer was washed with saturated salt solution, dried and evaporated. Preparative thin layer chromatography (EtOAc-hexane=1:1) gave 3-[7-ethyl-2-(2-furyl)-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile as an orange solid (11.5 mg).

3-[7-ethyl-2-(2-furyl)-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

1H-NMR (CDCl3) δ of 1.40 (3H, t, J=7 Hz), 3,10 (2H, square, J=7 Hz), 3,20 (3H, s), 6,30 (1H, d, J=5 Hz), 6,63 (1H, m), 6.87 in (1H, d, J=5 Hz), to 6.95 (1H, m), 7,60-7,73 (4H, m), 8,79 (1H, m).

Example 615

To a solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentanol acid (100 mg) in tetrahydrofuran (1 ml) was added 1M borane-tertrahydrofuran ring complex (0,708 ml) in a bath with ice in a nitrogen atmosphere. The mixture was stirred for 4 hours at the specified bath and 1 hour at room temperature. The reaction was suppressed by the addition of 1N. hydrochloric acid (1 ml). The mixture was distributed between EtOAc (10 ml) and 1N. hydrochloric acid (5 ml). The organic layer was washed with water and saturated salt solution, dried over magnesium sulfate and evaporated. Preparative thin layer chromatography with elution with a mixture of acetone-hexane=1:2 gave 3-[7-ethyl-3-(5-hydroxyphenyl)-2-phenylpyrrole[1,2-b]pyridazin-4-yl]benzonitrile in the form of a yellow resin (104 mg).

3-[7-ethyl-3-(5-hydroxyphenyl)-2-phenylpyrrole[1,2-b]pyridazin the-4-yl]benzonitrile

1H-NMR (CDCl3) δ 0,98-1,17 (6H, m)of 1.36 (3H, t, J=7 Hz), of 2.38 (2H, m), 2,58 (2H, m)to 3.34 (2H, m), of 5.89 (1H, d, J=5 Hz), 6,62 (1H, d, J=5 Hz), 7,45-7,53 (5H, m), 7,55-to 7.67 (4H, m).

MS (ESI+): m/z 410 (M+H).

The following compounds were obtained according to a similar method of obtaining 24.

Getting 343

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

1H NMR (CDCl3) δ 0,96-1,10 (3H, m), 3,23 (1,5H, s), 3,49 (1,5H, s), 4,00-4,34 (4H, m), of 4.57 (1H, s), 8,00 (0,5H, users), 8,23 (0,5H, users), 8,60-8,91 (2H, m).

Getting 344

1-tert-butyl-8-ethyl-2-acetyl-2-[(6-cyano-3-pyridinyl)carbonyl]octanoate

1H NMR (CDCl3) δ 1,22-1,46 (16H, m), 1,55-1,70 (2H, m), 2,17-of 2.34 (4H, m), 2,48 (3H, s), 4,14 (2H, square, J=8 Hz), to 7.77 (1H, userd, J=8 Hz), 8,17 (1H, DD, J=8, 2 Hz), 8,97 (1H, d, J=2 Hz).

The following compound was obtained according to a similar technique to obtain 78.

Getting 345

Ethyl-7-[(6-cyano-3-pyridinyl)carbonyl]-8-exonerat

1H NMR (CDCl3) δ 1,20-1,45 (7H, m), 1,52 is 1.70 (2H, m), 1,92 with 2.14 (2H, m), 2,17-2,39 (5H, m), 4,11 (2H, square, J=8 Hz), and 4.40 (1H, t, J=8 Hz), to 7.84 (1H, userd, J=8 Hz), 8,39 (1H, m), 9,23 (1H, users).

The following compound was obtained according to a similar technique to obtain 130.

Getting 346

Ethyl-4-methoxy-3-oxobutanoate

1H NMR (CDCl3) δ of 1.28 (3H, t, J=8 Hz), 3,42 (3H, s), 3,51 (2H, s), 4.09 to (2H, s), 4,20 (2H, square, J=8 Hz).

The following compound was obtained according to a similar method of obtaining 338.

Getting 347

Benzyl-3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-5-bromobenzoate

1H-NMR (CDCl3) δ of 1.28 (3H, t, J=7 Hz), a 2.75 (2H, square, J=7 Hz), lower than the 5.37 (2H, s), 5,73 (2H, s)5,94 (1H, d, J=5 Hz), of 6.66 (1H, d, J=5 Hz), 7,35-of 7.48 (5H, m), to 7.99 (1H, s), with 8.33 (1H, s), scored 8.38 (1H, s).

The following compound was obtained according to a similar method of obtaining 321.

Getting 348

Benzyl-3-bromo-5-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate

1H-NMR (CDCl3) δ of 1.29 (3H, t, J=7 Hz), of 2.72 (2H, square, J=7 Hz), lower than the 5.37 (2H, s)6,09 (1H, m), 6,78 (1H, m), 7,33 was 7.45 (5H, m), 8,15 (1H, s), with 8.33 (1H, s), to 8.45 (1H, s).

The following compounds were obtained according to a similar method of obtaining 310.

Getting 349

Benzyl-3-bromo-5-(chlorocarbonyl)benzoate

Getting 350

To a solution of benzyl-3-bromo-5-iodobenzoate (1,00 g) in THF (10 ml) was added 0,76M isopropylacrylamide (3,16 ml) in a bath with ice in a nitrogen atmosphere. After stirring for 0.5 hours the mixture was poured onto dry ice. The mixture was heated to room temperature within 1 hour. The mixture was distributed between EtOAc and 1N. HCl. The organic layer was washed with saturated salt solution, dried over MgSO4and was evaporated. Column flash chromatography on silica gel (chloroform-methanol=50:0-50:2) gave

3-benzyloxycarbonyl-5-bromobenzoyl acid as a white solid (273 mg).

3-[(benzyloxy)carbonyl]-5-brabantia acid

1H-NMR (DMSO-d6) δ of 5.39 (2H, s), 7,30-7,52 (5H, m), 8,29 (2H, s), 8,43 (1H, s).

Getting 351

To a mixture of 3-bromo-5-iodobenzoyl acid (5,00 g) and N,N-dimethylfuran the IDA (0,059 ml) in dichloromethane (50 ml) was added oxalicacid (1,47 ml) in a bath with ice in a nitrogen atmosphere. After stirring for 1 hour, evaporated volatile substances. The residue was dissolved in dichloromethane (50 ml) and to the solution was added benzyl alcohol (1,82 g) and then triethylamine (3.2 ml) in a bath with ice. The mixture was stirred for 2 hours at room temperature. The mixture was distributed between EtOAc and water. The organic layer was washed with water (twice), saturated NaHCO3and saturated salt solution, dried over MgSO4and was evaporated. Column flash chromatography on silica gel (EtOAc-hexane=1/200-20/200) gave benzyl-3-bromo-5-iodobenzoate in the form of white crystals (5,95 g).

Benzyl-3-bromo-5-iodobenzoate

1H-NMR (CDCl3) δ to 5.35 (3H, s), 7,35-to 7.68 (5H, m), of 8.04 (1H, s), 8,16 (1H, m), 8,30 (1H, s).

The following compounds were obtained according to a similar method of example 1.

Example 615

Benzyl-3-bromo-5-[7-ethyl-2-methyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoate

1H-NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), is 2.88 (3H, s), 3,05 (3H, s), 3,06 (2H, square, J=7 Hz), to 5.35 (2H, s), x 6.15 (1H, d, J=5 Hz), 6,72 (1H, d, J=5 Hz), 7,33 was 7.45 (5H, m), 7,68 (1H, m), 7,94 (1H, m), of 8.28 (1H, m).

Example 616

4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-carbonitril

1H NMR (CDCl3) δ of 1.42 (3H, t, J=8 Hz), 3,12 (2H, square, J=8 Hz), 6,60 (1H, d, J=5 Hz), 6,92 (1H, d, J=5 Hz), 7,50-7,58 (3H, m), 7,73 (1H, t, J=8 Hz), 7,82-to $ 7.91 (3H, m), 7,93 shed 8.01 (2H, m).

Example 617

2-tert-butyl-4-(3-chlorophenyl)-7-acylpyrrole[1,2-b]pyridazin-3-carbonitril

1H NMR (CDCl3) &x003B4; to 1.38 (3H, t, J=8 Hz), to 1.60 (9H, s), 3,05 (2H, square, J=8 Hz), 6.48 in (1H, d, J=5 Hz), 6,77 (1H, d, J=5 Hz), 7,45-rate of 7.54 (3H, m), 7,60 (1H, users).

The following compound was obtained according to a similar technique to obtain 78.

Example 618

Ethyl-6-[4-(6-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]hexanoate

1H NMR (CDCl3) δ 1,15-of 1.64 (12H, m), of 2.21 (1H, t, J=8 Hz), 2,32 is 2.44 (2H, m), of 2.56 (3H, s), 3,01 (2H, square, J=8 Hz), 4,10 (2H, square, J=8 Hz), 5,79 (1H, d, J=5 Hz), is 6.54 (1H, d, J=5 Hz), the 7.85 (1H, users), 8,30 (1H, userd, J=8 Hz), 8,72 (1H, users).

MS (ESI+): m/z 405 (M+H).

The following compound was obtained according to a similar method of example 21.

Example 619

Ethyl-4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-carboxylate

1H NMR (CDCl3) δ was 1.04 (3H, t, J=8 Hz), to 1.38 (3H, t, J=8 Hz), 3,06 (2H, square, J=8 Hz), 3,39 (3H, s), 4,10 (2H, square, J=8 Hz), was 4.76 (2H, s), 6,33 (1H, d, J=5 Hz), 6,74 (1H, d, J=5 Hz), of 7.96 (1H, users), 8,61 (1H, users), 8,78 (1H, d, J=2 Hz).

MS (ESI+): m/z 418, 420 (M+H).

The following compounds were obtained according to a similar method of example 76.

Example 620

3-bromo-5-[7-ethyl-2-methyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid

1H-NMR (CDCl3+CD3OD) δ to 1.38 (3H, t, J=7 Hz), of 2.86 (3H, s), 3,05 (3H, s), 3,06 (2H, square, J=7 Hz), to 6.19 (1H, d, J=5 Hz), of 6.71 (1H, d, J=5 Hz), 7,53 (1H, s), of 7.90 (1H, s)8,23 (1H, s).

Example 621

(2E)-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylic acid

1H NMR (CDCl3) δ of 1.39 (3H, t, J=8 Hz), of 3.07 (2H, the century, J=8 Hz), 3,51 (3H, s)and 4.65 (2H, s), 5,96 (1H, d, J=15 Hz), 6,27 (1H, d, J=5 Hz), 6,74 (1H, d, J=5 Hz), to 7.68 (1H, d, J=15 Hz), to 7.93 (1H, m), to 8.57 (1H, d, J=1 Hz), to 8.70 (1H, d, J=2 Hz).

MS (ESI+): m/z 416, 418 (M+H).

Example 622

6-[4-(6-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]hexanoic acid

1H NMR (CDCl3) δ 1,15 was 1.69 (9H, m),1,90-of 2.50 (4H, m), of 2.56 (3H, s), 3,01 (2H, square, J=8 Hz), 5,80 (1H, d, J=5 Hz), 6,51 (1H, d, J=5 Hz), to 7.84 (1H, DD, J=8, 2 Hz), of 8.28 (1H, d, J=8 Hz), 8,51 (1H, d, J=2 Hz).

MS (ESI+): m/z 377 (M+H).

Example 622-2

6-{4-[6-(aminocarbonyl)-3-pyridinyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}hexanoic acid

1H NMR (CDCl3) δ 1,16-is 1.51 (9H, m), 2,10-of 2.24 (2H, m), 2,35-2,47 (2H, m), 2,58 (3H, s), 3,01 (2H, square, J=8 Hz), to 5.85 (1H, d, J=5 Hz), is 6.54 (1H, d, J=5 Hz), 7,22 (1H, users), of 7.90 (1H, DD, J=8, 1 Hz), 8,01 (1H, users), to 8.34 (1H, d, J=8 Hz), 8,61 (1H, d, J=1 Hz).

MS (ESI+): m/z 395 (M+H).

The following compound was obtained according to a similar method of example 147.

Example 623

Ethyl-(2E)-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylate

1H NMR (CDCl3) δ of 1.27 (3H, t, J=8 Hz), of 1.39 (3H, t, J=8 Hz), 3,06 (2H, square, J=8 Hz), 3,51 (3H, s), 4,17 (2H, square, J=8 Hz), with 4.64 (2H, s), 5,97 (1H, d, J=15 Hz), 6,24 (1H, d, J=5 Hz), was 6.73 (1H, d, J=5 Hz), 7,51 (1H, d, J=15 Hz), to $ 7.91 (1H, users), to 8.57 (1H, users), to 8.70 (1H, users).

MS (ESI+): m/z 444, 446 (M+H).

The following compound was obtained according to a similar method of example 200.

Example 624

[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]methanol/p>

1H NMR (CDCl3) δ to 1.38 (3H, t, J=8 Hz), 3,05 (2H, square, J=8 Hz), 3,45-3,55 (4H, m), and 4.40 (2H, userd, J=7 Hz), of 4.77 (2H, users), to 6.22 (1H, d, J=5 Hz), 6,70 (1H, d, J=5 Hz), 8,11 (1H, m), a total of 8.74 (1H, users), 8,80 (1H, d, J=2 Hz).

MS (ESI+): m/z 376, 378 (M+H).

The following compounds were obtained according to a similar method of example 205.

Example 625

(4E)-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]-4-pontenova acid

1H NMR (CDCl3) δ to 1.37 (3H, t, J=8 Hz), 2.26 and is 2.43 (4H, m)of 2.50 (3H, s), 3,01 (2H, square, J=8 Hz), of 5.40 (1H, dt, J=15, 7 Hz), equal to 6.05 (1H, d, J=5 Hz), of 6.20 (1H, d, J=15 Hz), 6,56 (1H, d, J=5 Hz), 7,28 (1H, userd, J=5 Hz), 7,39 (1H, users), of 8.47 (1H, userd, J=5 Hz).

MS (ESI+): m/z 370 (M+H).

Example 625-2

(4Z)-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]-4-pontenova acid

1H NMR (CDCl3) δ of 1.39 (3H, t, J=8 Hz), 1,87 is 2.00 (2H, m), 2,12 (2H, t, J=8 Hz), 2,42 (3H, s), 3,03 (2H, square, J=8 Hz), to 5.58 (1H, dt, J=10, 8 Hz), 6,17 (1H, d, J=5 Hz), of 6.26 (1H, userd, J=10 Hz), 6,60 (1H, d, J=5 Hz), 7,35 (1H, userd, J=5 Hz), 7,44 (1H, users), 8,48 (1H, userd, J=5 Hz).

MS (ESI+): m/z 370 (M+H).

The following compounds were obtained according to a similar method of example 220.

Example 626

4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-carboxylic acid

1H NMR (CDCl3) δ of 1.39 (3H, t, J=8 Hz), 3,06 (2H, square, J=8 Hz), 3,44 (3H, s), 4,82 (2H, s), 6,36 (1H, d, J=5 Hz), 6,77 (1H, d, J=5 Hz), of 8.09 (1H, users), 8,65 (1H, users), 8,72 (1H, users).

MS (ESI+): m/z 390, 392 (M+H).

Example 627

4-(2-chloro-4-pyridinyl)-7-the Teal-2-methylpyrrole[1,2-b]pyridazin-3-carboxylic acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=8 Hz), 2,70 (3H, s), 3,06 (2H, square, J=8 Hz), of 6.26 (1H, d, J=5 Hz), 6,72 (1H, d, J=5 Hz), 7,32 (1H, DD, J=5, 1 Hz), the 7.43 (1H, users), and 8.50 (1H, d, J=5 Hz).

MS (ESI+): m/z 316 (M+H).

The following compounds were obtained according to a similar method of example 244.

Example 628

4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-carbaldehyde

1H NMR (CDCl3) δ of 1.39 (3H, t, J=8 Hz), of 2.81 (3H, s)to 3.09 (2H, square, J=8 Hz), to 6.43 (1H, d, J=5 Hz), 6,78 (1H, d, J=5 Hz), 7,34 (1H, userd, J=5 Hz), 7,46 (1H, users), 8,56 (1H, d, J=5 Hz), 9,76 (1H, s).

MS (ESI+): m/z 300 (M+H).

Example 629

4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-carbaldehyde

1H NMR (CDCl3) δ of 1.41 (3H, t, J=8 Hz), 3,14 (2H, square, J=8 Hz), 3,55 (3H, s), 4,94 (2H, s), of 6.50 (1H, d, J=5 Hz), at 6.84 (1H, d, J=5 Hz), 7,95 (1H, users), to 8.12 (1H, users), 8,84 (1H, users), 9,85 (1H, s).

MS (ESI+): m/z 374, 376 (M+H).

Example 630

A solution of phosphorus oxychloride (241 mg, 1.57 mmol) in N,N-dimethylformamide (4 ml) was stirred for 10 min at room temperature. The resulting mixture was cooled to 0°and the solution was added ethyl-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carboxylate (428 mg, 1,31 mmol) in N,N-dimethylformamide (0.7 ml). The resulting mixture was heated to 50°and was stirred for 45 minutes Because the original substance remained, the solution was added phosphorus oxychloride (621 mg, 0.67 mmol) in N,N-dimethylformamide (0.2 ml) and the mixture was stirred is within 15 minutes The resulting mixture was poured into cooled with ice water (10 ml) and was extracted with ethyl acetate (30 ml). The organic layer was washed with water and saturated sodium bicarbonate solution. The entire water layer was extracted with ethyl acetate. The combined organic extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and was evaporated to obtain a blue oil. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1:20-1:10 gave ethyl-4-(4-forfinal)-7-formyl-2-isopropylindole[1,2-b]pyridazin-3-carboxylate as a yellow oil, which crystallized upon standing (360 mg, 77.5%of).

1H-NMR (CDCl3) δ of 1.02 (3H, t, J=7 Hz), of 1.41 (6H, d, J=7 Hz), 3,29 (1H, septet, J=7 Hz), 4,10 (2H, square, J=7 Hz), 6.42 per (1H, d, J=5 Hz), 7,20 (2H, t, J=9 Hz), 7,45-7,51 (3H, m), 10,56 (1H, s).

MS (ESI+): m/z 355 (M+H).

Example 631

To a solution of N,N-dimethylacetamide (80,1 mg, 0,919 mmol) in dichloroethane (1 ml) was added phosphorus oxychloride (141 mg, 0,919 mmol) in dichloroethane (0.5 ml) at 0°C. After stirring for 0.5 h the solution was added ethyl-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carboxylate (200 mg, 0,613 mmol) in dichloroethane (0.5 ml). The resulting mixture was stirred for 3 days at room temperature. The mixture was distributed between ethyl acetate (30 ml) and water (5 ml) and the organic layer was washed with saturated sodium bicarbonate solution, we settled on a solution of salt, was dried over anhydrous magnesium sulfate and evaporated to obtain an orange resin. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1:20-1:10 gave ethyl-7-acetyl-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carboxylate as a yellow resin (144 mg, 63.8 per cent).

1H-NMR (CDCl3) δ and 1.00 (3H, t, J=7 Hz), of 1.41 (6H, d, J=7 Hz), is 2.88 (3H, s)to 3.09 (1H, septet, J=7 Hz), 4.09 to (2H, square, J=7 Hz), 6,40 (1H, d, J=5 Hz), 7,19 (2H, t, J=9 Hz), 7,46 (2H, DD, J=3 and 9 Hz), EUR 7.57 (2H, d, J=7 Hz).

MS (ESI+): m/z 369 (M+H)

Example 632

A solution of ethyl-4-(4-forfinal)-7-formyl-2-isopropylindole[1,2-b]pyridazin-3-carboxylate (100 mg, 0,282 mmol) and sodium borohydride (10,7 mg, 0,282 mmol) in ethanol (1 ml) was stirred for 0.5 h in a bath with ice. The mixture was distributed between ethyl acetate (10 ml) and water (5 ml) and the organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated to obtain ethyl-4-(4-forfinal)-7-hydroxymethyl-2-isopropylindole[1,2-b]pyridazin-3-carboxylate as a yellow resin (89,1 mg, 89,1%).

1H-NMR (CDCl3) δ to 0.97 (3H, t, J=7 Hz), of 1.37 (6H, J=7 Hz), 3.25 to 3,37 (2H, m), Android 4.04 (2H, square, J=7 Hz), is 5.06 (1H, d, J=7 Hz), 6,32 (1H, d, J=5 Hz), 6,78 (1H, d, J=5 Hz), 7,19 (2H, t, J=9 Hz), 7,46 (2H, d, J=4 and 9 Hz).

Example 633

To a solution of ethyl-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carboxylate (80.0 mg, 0,245 mmol) and N,N-dimethylaminopyridine (29,9 mg, 0,245 mmol) in N,N-dimethylformamide (0,5ml) was added 3,7-dinitro-5-(trifluoromethyl)dibenzo[b,d]thiophenecarbonitrile (120 mg, 0,245 mmol) at -20°C. the resulting mixture was stirred for 45 min at 0°C and 12 h at room temperature. Was added water (5 ml) and ethyl acetate (10 ml) and the resulting mixture was filtered. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and was evaporated to obtain a brown resin. Flash chromatography on a column of silica gel with elution with a mixture of toluene-hexane=1:5-4:5 gave ethyl-4-(4-forfinal)-2-isopropyl-7-cryptomaterial[1,2-b]pyridazin-3-carboxylate as a yellow resin (46,7 mg, 48,3%).

1H-NMR (CDCl3) δ and 1.00 (3H, t, J=7 Hz), to 1.38 (6H, d, J=7 Hz), 3,26 (1H, septet, J=7 Hz), 4,08 (2H, square, J=7 Hz), 6,33 (1H, d, J=5 Hz), 7,12 (1H, d, J=5 Hz), 7,19 (2H, t, J=9 Hz), 7,47 (2H, d, J=4 and 9 Hz).

MS (ESI+): m/z 395 (M+H).

Example 634

A solution of ethyl-4-(4-forfinal)-7-formyl-2-isopropylindole[1,2-b]pyridazin-3-carboxylate (200 mg, 0,564 mmol), hydroxylamine hydrochloride (51,0 mg, 0,734 mmol) and sodium formate (69,1 mg of 1.02 mmol) in formic acid (2 ml) was boiled under reflux for 2 hours the Mixture was evaporated to obtain a green resin. The resin was distributed between ethyl acetate (10 ml) and saturated sodium bicarbonate solution (5 ml). The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and was evaporated to obtain a green resin. Flash chromatography on a column of silica gel with elution with whom ESU ethyl acetate : hexane=1:10-1:8 gave ethyl-7-cyano-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carboxylate as yellow crystals (144 mg, 72,6%).

1H-NMR (CDCl3) δ a 1.01 (3H, t, J=7 Hz), of 1.41 (6H, d, J=7 Hz), 3,26 (1H, septet, J=7 Hz), 4.09 to (2H, square, J=7 Hz), 6,36 (1H, d, J=5 Hz), 7,20 (2H, t, J=9 Hz), 7,28 (1H, d, J=5 Hz), 7,47 (2H, d, J=4 and 9 Hz).

Example 635

A solution of ethyl-7-cyano-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carboxylate (70,4 mg, 0,200 mmol) in sulfuric acid (1 ml) was stirred for 50 min at 70°C. the Solution was distributed between ethyl acetate and water. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and was evaporated to obtain a brown resin. Preparative thin layer chromatography on silica gel with elution with a mixture of ethyl acetate : hexane=1:1 gave ethyl-7-aminocarbonyl-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carboxylate as an orange solid (5.2 mg, 7.0 percent).

1H-NMR (CDCl3) δ 0,99 (3H, t, J=7 Hz), of 1.41 (6H, d, J=7 Hz), to 3.41 (1H, septet, J=7 Hz), 4,08 (2H, square, J=7 Hz), to 5.93 (1H, users), 6,46 (1H, d, J=5 Hz), 7,45 (2H, t, J=9 Hz), 7,28 (1H, d, J=5 Hz), of 8.90 (1H, users).

Example 636

To a mixture of ethyl-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-carboxylate (100 mg, 0,306 mmol) and ammonium thiocyanate (28,0 mg, 0,368 mmol) in methanol (100 ml) was added suryamaninagar (386 mg, 0,705 mmol) in a bath with ice. The mixture was stirred for 30 minutes and the Mixture was stirred for another 10 min after the addition of ammonium thiocyanate (8.2 mg, 0,107 mmol). Was added water (5 ml) and the mixture extra is Aravali with ethyl acetate (20 ml). The organic extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and was evaporated to obtain a dark green resin. Flash chromatography on a column of silica gel with elution with a mixture of ethyl acetate : hexane=1:10-3:20 gave ethyl-4-(4-forfinal)-2-isopropyl-7-thiocyanation[1,2-b]pyridazin-3-carboxylate as a yellow resin (89,6 mg, 82.3 per cent).

1H-NMR (CDCl3) δ a 1.01 (3H, t, J=7 Hz), of 1.46 (6H, d, J=7 Hz), to 3.36 (1H, septet, J=7 Hz), 4,08 (2H, square, J=7 Hz), 6,23 (1H, d, J=5 Hz), 7,14-7,22 (3H, m), 7,16 (2H, t, J=9 Hz), 7,46 (2H, DD, J=4 and 9 Hz).

Example 637

To a solution of ethyl-4-(4-forfinal)-2-isopropyl-7-thiocyanation[1,2-b]pyridazin-3-carboxylate (77,7 mg, 0,219 mmol) in methanol (0.7 ml) was added 85% potassium hydroxide (0.3 mg, of 0.004 mmol) at room temperature. After stirring for 5 min the mixture was distributed between ethyl acetate (20 ml) and water (5 ml). The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and was evaporated to obtain a yellow resin. Preparative thin layer chromatography on silica gel with elution with a mixture of ethyl acetate : hexane=1:7 gave ethyl-4-(4-forfinal)-2-isopropyl-7-(methylthio)pyrrolo[1,2-b]pyridazin-3-carboxylate as a yellow resin (35,9 mg, 44.1 per cent).

1H-NMR (CDCl3) δ and 0.98 (3H, t, J=7 Hz), of 1.41 (6H, d, J=7 Hz), 2,52 (3H, s), 3,32 (1H, septet, J=7 Hz), of 4.05 (2H, square, J=7 Hz), 6.35mm (1H, d, J=5 Hz), 6.89 in (1H, d, J=5 Hz), 7,16 (2H, t, J=9 Hz), 7,44 (2H, d, J4 and 9 Hz).

MS (ESI+): m/z 373 (M+H).

The following compounds were obtained according to a similar method of example 1.

Example 638

3-(9-ethyl-3-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-b]cinnolin-12-yl)benzonitrile

1H NMR (CDCl3) δ of 1.41 (3H, t, J=8 Hz), 2.91 in-3,11 (6H, m), of 3.78 (3H, s)6,09 (1H, d, J=5 Hz), 6,38 (1H, DD, J=8, 3 Hz), of 6.52 (1H, d, J=8 Hz), 6,59 (1H, d, J=5 Hz), 6,77 (1H, users), 7,56 (1H, t, J=8 Hz,), to 7.67 (1H, userd, J=8 Hz), 7,70-to 7.77 (2H, m).

Example 639

4-(3-ethyl-6H-indeno[1,2-e]pyrrolo[1,2-b]pyridazin-11-yl)benzonitrile

1H NMR (CDCl3) δ of 1.43 (3H, t, J=8 Hz), to 3.09 (2H, square, J=8 Hz), 4,11 (3H, s), 6,14 (1H, d, J=5 Hz), only 6.64 (1H, d, J=5 Hz), of 6.71 (1H, d, J=8 Hz), 7,07 (1H, t, J=8 Hz), 7,20-7,30 (1H, overlapping CDCl3), 7,49 (1H, d, J=8 Hz), 7,69 (2H, d, J=8 Hz), 7,88 (2H, d, J=8 Hz).

MS (ESI+): m/z 336 (M+H).

The following compounds were obtained according to a similar method of obtaining 24.

Getting 352

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

1H NMR (CDCl3) δ 0,97, of 1.26 (3H, t, J=7 Hz), 2.40 a (3H, s), 3,24, 3,35, to 3.49 (3H, s), 3,98-4,20 (2H, m), 4,11, 4,20, of 4.54 (2H, s)5,70 (1H, ), 7,67, 7,92, 8,02, 8,50-8,66, 8,77, 8,89 (3H, m).

Getting 353

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

1H NMR (CDCl3) δ 1,00, 1,06, 1,28, of 1.35 (3H, t, J=7 Hz), 3,23, 3,43, to 3.49 (3H, s), 4,05-to 4.33 (2H, m), 4,56 (2H, ), 7,85, 8,05, 8,22, 8,29, 8,58-8,82, 8,85, 9,01, 9,10 (3H, m).

The following compounds were obtained according to a similar method of obtaining 176.

Getting 354

tert-Butyl 3-bromo-5-({1-[(cyanoacetyl)amino]-5-ethyl-1H-Pierre is l-2-yl}carbonyl)benzoate

1H-NMR (CDCl3) δ 1,29 (34H, t, J=7 Hz), to 1.60 (9H, s), 2,61 (2H, square, J=7 Hz), to 3.64 (2H, s), 6,00 (1H, m), to 6.80 (1H, m), 8,03 (1H, m), compared to 8.26 (1H, m), of 8.28 (1H, m).

Getting 355

tert-Butyl 3-bromo-5-[(5-ethyl-1-{[(methylsulphonyl)acetyl]amino}-1H-pyrrol-2-yl)carbonyl]benzoate

1H-NMR (CDCl3) δ of 1.29 (3H, t, J=7 Hz), to 1.60 (9H, s), 2,60 (2H, square, J=7 Hz), of 2.92 (3H, s), Android 4.04 (2H, s), 6,11 (1H, m), 6,78 (1H, m), 8,03 (1H, m), of 8.25 (1H, m), of 8.27 (1H, m).

The following compound was obtained according to a similar method of obtaining 153.

Getting 356

tert-Butyl 3-bromo-5-(chlorocarbonyl)benzoate

The following compound was obtained according to a similar method of obtaining 164.

Getting 357

tert-Butyl 3-bromo-5-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate

1H-NMR (CDCl3) δ to 1.32 (3H, t, J=7 Hz), to 1.61 (9H, s), is 2.74 (2H, square, J=7 Hz), 6,10 (1H, m), to 6.80 (1H, m), 8,13 (1H, m), compared to 8.26 (1H, m), 8,39 (1H, m), 9,34 (1H, s, of usher.).

The following compound was obtained according to a similar method of obtaining 338.

Getting 358

tert-Butyl 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-5-bromobenzoate

1H-NMR (CDCl3) δ of 1.29 (3H, t, J=7 Hz), to 1.61 (9H, s), was 2.76 (2H, square, J=7 Hz), 5,74 (2H, s, of usher.), to 5.93 (1H, d, J=5 Hz), 6,63 (1H, d, J=5 Hz), with 8.05 (1H, m), of 8.25 (1H, m), 8,29 (1H, m).

Getting 359

To a solution of tert-butyl 3-bromo-5-iodobenzoate (of 4.00 g) in tetrahydrofuran (30 ml) was added 0,76M isopropylacrylamide (13,7 ml) in a bath of ice-methanol in a nitrogen atmosphere. After stirring for 0.5 hours the mixture was poured onto dry ice. The mixture on revali to room temperature for 1 hour. The mixture was distributed between EtOAc and 1N. hydrochloric acid. The organic layer was subjected to back extraction 1H. a solution of sodium hydroxide (twice). The extract was acidified by adding concentrated hydrochloric acid and was extracted with chloroform (twice). The organic extract was washed with saturated salt solution, dried over MgSO4and evaporated to obtain 3-bromo-5-(tert-butoxycarbonyl)benzoic acid as a pale brown solid (529 mg).

3-bromo-5-(tert-butoxycarbonyl)benzoic acid

1H-NMR (DMSO-d6) δ of 1.57 (9H, s), 8,21 (1H, s), of 8.25 (1H, s)of 8.37 (1H, s).

Getting 360

To intensively stirred suspension of powdered MgSO4(of 7.36 g) in dichloromethane (50 ml) was added sulfuric acid (0,758 ml) at room temperature. After stirring for 15 minutes, to the mixture was added 3-bromo-5-iodobenzoyl acid (5,00 g) and then tert-butanol (7,31 ml). The mixture was stirred for 3 days at room temperature. The mixture was distributed between EtOAc and water. The organic layer was washed with saturated NaHCO3and saturated salt solution, dried over MgSO4and was evaporated to obtain tert-butyl 3-bromo-5-iodobenzoate as pale purple crystals (4.44 g).

tert-Butyl 3-bromo-5-iodobenzoate

1H-NMR (CDCl3) δ was 1.58 (9H, s), 8,00 (1H, m), of 8.06 (1H, m), by 8.22 (1H, m).

Recip is of 361

To a suspension of lithium (316 mg) in ether (10 ml) was added cyclopropylboronic (2.50 g) in ether (10 ml) for 20 min in a bath of ice-methanol in a nitrogen atmosphere. The mixture was stirred for 0.5 hour in a bath with ice. The mixture was cooled in a bath of dry ice-acetone. To the mixture was added a solution of triisopropoxide (of 5.05 g) in tetrahydrofuran (5 ml) for 15 minutes. The mixture was allowed to warm to room temperature for 2 hours. The reaction was suppressed by the addition of hydrochloric acid. The organic solvent is evaporated and the residual solution was extracted with ether (30 ml, five times). The combined extract was dried over MgSO4and was evaporated to obtain white solids (968 mg). The solid is triturated in cold hexano with getting cyclopropylboronic acid as a white powder (789 mg).

Cyclopropylboronic acid

1H-NMR (DMSO-d6) δ -0,40 (1H, m), 0,32 (2H, m)to 0.39 (2H, m), 7,28 (2H, s).

The following compounds were obtained according to a similar method of example 21.

Example 640

Ethyl-7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-carboxylate

1H NMR (CDCl3) δ 0,99 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), is 2.41 (3H, s), 3,06 (2H, square, J=7 Hz), to 3.38 (3H, s)4,06 (2H, square, J=7 Hz), and 4.75 (2H, s), 6,33 (1H, d, J=4 Hz), of 6.71 (1H, d, J=4 Hz), to 7.61 (1H, s), charged 8.52 (1H, d, J=2 Hz), 8,54 (1H, d, J=2 Hz).

MS (ESI+): m/z 354.

Example 641

Ethyl-4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methods is simetal)pyrrolo[1,2-b]pyridazin-3-carboxylate

1H NMR (300 MHz, CDCl3) δ was 1.04 (3H, t, J=7 Hz), to 1.38 (3H, t, J=7 Hz), 3,06 (2H, square, J=7 Hz), 3,39 (3H, s), 4.09 to (2H, square, J=7 Hz), was 4.76 (2H, s), 6,33 (1H, d, J=4 Hz), to 6.75 (1H, d, J=4 Hz), 7,81 (1H, DD, J=2, 2 Hz), to 8.57 (1H, d, J=2 Hz), 8,68 (1H, d, J=2 Hz).

MS (m/z 374 (M+1).

The following compounds were obtained according to a similar method of example 076.

Example 642

(2E)-3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylic acid

1H NMR (CDCl3) δ of 1.39 (3H, t, J=7 Hz), 2,43 (3H, s), of 3.07 (2H, square, J=7 Hz), 3,51 (3H, s)and 4.65 (2H, s), 5,97 (1H, d, J=16 Hz), 6,27 (1H, d, J=4 Hz), of 6.71 (1H, d, J=4 Hz), to 7.61 (1H, s), 7,72 (1H, d, J=16 Hz), 8,46 (1H, d, J=2 Hz), to 8.57 (1H, d, J=2 Hz).

MS (ESI+): m/z 352.

Example 643

(2E)-3-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylic acid

1H NMR (300 MHz, CDCl3) δ of 1.39 (3H, t, J=7 Hz), of 3.07 (2H, square, J=7 Hz), 3,51 (3H, s)and 4.65 (2H, s), 5,97 (1H, d, J=16 Hz), 6,27 (1H, d, J=4 Hz), to 6.75 (1H, d, J=4 Hz), 7,69 (1H, d, J=16 Hz), 7,78 (1H, DD, J=2, 2 Hz), 8,54 (1H, d, J=2 Hz), 8,71 (1H, d, J=2 Hz).

MS (m/z 400 (M+1).

Example 644

4-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid

1H-NMR (CDCl3) δ 0,78 (2H, m), 1,10 (2H, m)to 1.37 (3H, t, J=7 Hz), at 1.73 (2H, m)to 1.98 (1H, m), of 2.23 (2H, m), 2,62 (2H, m), to 3.02 (2H, square, J=7 Hz), of 3.46 (3H, s)and 4.65 (2H, square, J=7 Hz), 5,88 (1H, d, J=5 Hz), to 6.57 (1H, d, J=5 Hz), was 7.36 (1H, m), to 8.41 (1H, m), of 8.47 (1H, m).

Example 645

5-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid

1H is the Mr (CDCl 3) δ 0,75 (2H, m)a 1.08 (2H, m)to 1.37 (3H, t, J=7 Hz), 1,40-of 1.57 (4H, m), a 1.96 (1H, m)to 2.18 (2H, m), of 2.51 (2H, m), to 3.02 (2H, square, J=7 Hz), of 3.45 (3H, s), br4.61 (2H, m), by 5.87 (1H, d, J=5 Hz), 6,56 (1H, d, J=5 Hz), 7,34 (1H, m), 8,39 (1H, m), and 8.50 (1H, m).

Example 646

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

1H-NMR (DMSO-d6) δ 0,76 (2H, m)a 1.08 (2H, m)to 1.37 (3H, t, J=7 Hz), of 1.95 (1H, m), 2,48 (2H, m), 2,87 (2H, m), to 3.02 (2H, square, J=7 Hz), 3,47 (3H, s), of 4.66 (2H, m), 5,90 (1H, d, J=5 Hz), 6,59 (1H, d, J=5 Hz), 7,35 (1H, m), 8,40 (1H, m), 8,48 (1H, m).

Example 647

5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]-5-oxopentanoic acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=8 Hz), 1,73-of 1.85 (2H, m), and 2.26 (2H, t, J=8 Hz), a 2.36 (2H, t, J=8 Hz), 2,46 (3H, s), 3.04 from (2H, square, J=8 Hz), 6,33 (1H, d, J=5 Hz), 6,70 (1H, d, J=5 Hz), 7,34 (1H, userd), was 7.45 (1H, users), 8,53 (1H, d, J=6 Hz).

Example 648

(2E)-3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]acrylic acid

1H NMR (CDCl3) δ to 1.38 (3H, t, J=8 Hz), to 2.67 (3H, s), 3,05 (2H, square, J=8 Hz), 5,79 (1H, d, J=15 Hz), to 6.19 (1H, d, J=5 Hz), to 6.67 (1H, d, J=5 Hz), 7.24 to 7,29 (1H, overlapped CDCl3), 7,40 (1H, users), 7,51 (1H, d, J=15 Hz), 8,55 (1H, d, J=5 Hz).

The following compound was obtained according to a similar method of example 146.

Example 649

Ethyl-(2E)-3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]acrylate

1H NMR (CDCl3) δ of 1.27 (3H, t, J=8 Hz), to 1.38 (3H, t, J=8 Hz), 2,65 (3H, s), 3.04 from (2H, square, J=8 Hz), 4,17 (2H, square, J=8 Hz), USD 5.76 (1H, d, J=15 Hz), 6,16 (1H, d, J=5 Hz), of 6.65 (1H, d, J=5 is C), 7,24-7,29 (1H, overlapping CDCl3), 7,40 (1H, users), 7,53 (1H, d, J=15 Hz), 8,53 (1H, d, J=5 Hz).

MS (ESI+): m/z 370 (M+H).

The following compounds were obtained according to a similar method of example 181.

Example 650

tert-Butyl 3-bromo-5-(3-cyano-7-ethyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4-yl)benzoate

1H-NMR (CDCl3) δ of 1.36 (3H, t, J=7 Hz), to 2.94 (2H, square, J=7 Hz), to 6.57 (1H, d, J=5 Hz), 6,72 (1H, d, J=5 Hz), 7,94 (1H, m), to 8.20 (1H, m), scored 8.38 (1H, m).

Example 651

tert-Butyl 3-bromo-5-[7-ethyl-3-(methylsulphonyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4-yl]benzoate

1H-NMR (CDCl3) δ to 1.35 (3H, t, J=7 Hz), to 3.02 (2H, square, J=7 Hz), 3,06 (3H, s), 6,24 (1H, d, J=5 Hz), 6,70 (1H, d, J=5 Hz), 7.23 percent (1H, m), 7,94 (1H, m), of 8.25 (1H, m).

The following compounds were obtained according to a similar method of example 183.

Example 652

tert-Butyl 3-bromo-5-(3-cyano-7-ethyl-2-{[(trifluoromethyl)sulfonyl]oxy}pyrrolo[1,2-b]pyridazin-4-yl)benzoate

1H-NMR (CDCl3) δ of 1.39 (3H, t, J=7 Hz), to 1.61 (9H, s), to 3.02 (2H, square, J=7 Hz), for 6.81 (1H, d, J=5 Hz), 700 (1H, d, J=5 Hz), of 7.96 (1H, m), 8,21 (1H, m), with 8.33 (1H, m).

Example 653

tert-Butyl 3-bromo-5-(7-ethyl-3-(methylsulphonyl)-2-{[(trifluoromethyl)sulfonyl]oxy}pyrrolo[1,2-b]pyridazin-4-yl)benzoate

1H-NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), to 1.59 (9H, s), 3,01 (2H, square, J=7 Hz), up 3.22 (3H, s), 6,46 (1H, d, J=5 Hz), 7,12 (1H, d, J=5 Hz), to 7.67 (1H, m), of 7.90 (1H, m), 8,23 (1H, m).

The following compounds were obtained according to a similar method of example 184.

Example 654

tert-Butyl 3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrole is[1,2-b]pyridazin-4-yl]benzoate

1H-NMR (CDCl3) δ to 1.35 (3H, t, J=7 Hz), to 1.60 (9H, s), a 2.01 (4H, m), with 2.93 (2H, square, J=7 Hz), to 3.73 (4H, m), 6,32 (1H, d, J=5 Hz), to 6.58 (1H, d, J=7 Hz), 7,86 (1H, m)to 8.12 (1H, m), 8,24 (1H, m).

Example 655

tert-Butyl 3-bromo-5-[7-ethyl-3-(methylsulphonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoate

1H-NMR (CDCl3) δ to 1.37 (3H, t, J=7 Hz), was 1.58 (9H, s)to 1.99 (4H, m), 2,98 (2H, square, J=7 Hz), 3,21 (3H, s), 3,52 (4H, m), 6,30 (1H, d, J=5 Hz), of 6.66 (1H, d, J=5 Hz), 7,76 (1H, m), 8,00 (1H, m), 8,19 (1H, m,).

The following compound was obtained according to a similar method of example 147.

Example 656

Ethyl-(2E)-3-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylate

1H NMR (300 MHz, CDCl3) δ of 1.27 (3H, t, J=7 Hz), of 1.39 (3H, t, J=7 Hz), of 3.07 (2H, square, J=7 Hz), 3,51 (3H, s), 4,18 (2H, square, J=7 Hz), with 4.64 (2H, s), 5,97 (1H, d, J=16 Hz), 6,24 (1H, d, J=4 Hz), 6,72 (1H, d, J=4 Hz), to 7.61 (1H, d, J=16 Hz), 7,76 (1H, DD, J=2, 2 Hz), 8,54 (1H, d, J=2 Hz), 8,68 (1H, d, J=2 Hz).

The following compound was obtained according to a similar method of example 205.

Example 657

(4E)-5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]-4-pontenova acid

1H NMR (300 MHz, CDCl3) δ to 1.38 (3H, t, J=7 Hz), 2,25-to 2.41 (4H, m), 3,05 (2H, square, J=7 Hz), 3,50 (3H, s), of 4.57 (2H, s), of 5.53 (1H, DD, J=16, 7 Hz), 6,13 (1H, d, J=4 Hz), 6,36 (1H, d, J=16 Hz), of 6.65 (1H, d, J=4 Hz), 7,80 (1H, s), 8,54 (1H, users), to 8.62 (1H, users).

MS (m/z 400 (M+1).

The following compound was obtained according to a similar method of obtaining 153.

Example 658

4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyrid the zine-3-carbonylchloride

The following compounds were obtained according to a similar method of example 244.

Example 659

7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-carbaldehyde

1H NMR (CDCl3) δ of 1.40 (3H, t, J=7 Hz), a 2.45 (3H, s), of 3.12 (2H, square, J=7 Hz), of 3.56 (3H, s), 4,96 (2H, s), 6,51 (1H, d, J=4 Hz), to 6.80 (1H, d, J=4 Hz), a 7.62 (1H, s), 8,54 (1H, s), 8,61 (1H, s), 9,79 (1H, ).

MS (ESI+): m/z 310.

Example 660

4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-carbaldehyde

1H NMR (300 MHz, CDCl3) δ of 1.41 (3H, t, J=7 Hz), 3,12 (2H, square, J=7 Hz), of 3.54 (3H, s), 4,94 (2H, s), of 6.50 (1H, d, J=4 Hz), at 6.84 (1H, d, J=4 Hz), 7,81 (1H, DD, J=2, 2 Hz), 8,59 (1H, d, J=2 Hz), a total of 8.74 (1H, d, J=2 Hz), 9,85 (1H, s).

The following compounds were obtained according to a similar method of example 533.

Example 661

[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]methanol

1H NMR (CDCl3) δ to 1.38 (3H, t, J=7 Hz), 2,43 (3H, s), 3,05 (2H, square, J=7 Hz), 3,52 (3H, s), 4,37-4,51 (2H, usher.), 4,66-4,78 (2H, usher.), of 6.20 (1H, d, J=4 Hz), to 6.67 (1H, d, J=4 Hz), of 7.75 (1H, s), 8,54 (1H, s), at 8.60 (1H, s).

MS (ESI+): m/z 312.

Example 662

[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]methanol

1H NMR (300 MHz, CDCl3) δ to 1.38 (3H, t, J=7 Hz), 3,05 (2H, square, J=7 Hz), 3,53 (3H, s)to 4.41 (2H, d, J=6 Hz), of 4.77 (2H, s), from 6.22 (1H, d, J=4 Hz), 6,70 (1H, d, J=4 Hz), of 7.97 (1H, DD, J=2, 2 Hz), 8,69-8,71 (2H, m,).

MS (m/z 332 (M+1).

Example 663

A mixture of 7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-carbamide is Yes (48 mg) and ethyl(triphenylphosphonium)acetate (56,8 mg) in THF (3 ml) was stirred at ambient temperature for 2 hours. After evaporation of the solvent the residue was purified column chromatography on silica gel, elwira with a mixture of hexane and AcOEt (5:1-2:1), to obtain ethyl(2E)-3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylate as a yellow powder (30 mg).

Ethyl-(2E)-3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylate

1H NMR (CDCl3) δ of 1.26 (3H, t, J=7 Hz), of 1.39 (3H, t, J=7 Hz), 2,42 (3H, s), of 3.07 (2H, square, J=7 Hz), 3,51 (3H, s), of 4.12 (2H, square, J=7 Hz), with 4.64 (2H, s), 5,97 (1H, d, J=16 Hz), 6,24 (1H, d, J=4 Hz), 6,70 (1H, d, J=4 Hz), 7,55 (1H, s), 7,63 (1H, d, J=16 Hz), of 8.47 (1H, d, J=2 Hz), 8,55 (1H, d, J=2 Hz).

MS (ESI+): m/z 380.

Example 664

To a mixture of ethyl-4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate (75,0 mg), cyclopropylboronic acid (18.2 mg), tricyclohexylphosphine (4,57 mg) and potassium phosphate (104 mg) in a mixture of toluene-water (1 ml 0.2 ml) was added palladium acetate (1,83 mg). The mixture was stirred for 2 hours at 100°C. the Mixture was distributed between EtOAc and water. The organic layer was washed with saturated salt solution, dried over MgSO4and was evaporated. Preparative thin layer chromatography on silica gel (EtOAc-hexane=1:3) gave ethyl-4-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate in the form of a yellow resin (60,9 mg).

Ethyl-4-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

1H-NMR (CDCl3) δ 0,76 (2H, m)of 1.07 (2H, m)of 1.20 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), 1,68 (2H, m), a 1.96 (1H, m), 2,17 (2H, m), of 2.56 (2H, m), to 3.02 (2H, square, J=7 Hz), of 3.46 (3H, s), a 4.03 (2H, square, J=7 Hz)and 4.65 (2H, m), 5,90 (1H, d, J=5 Hz), to 6.57 (1H, d, J=5 Hz), 7,30 (1H, m), 8,40 (1H, m), 8,51 (1H, m).

The following compounds were obtained according to a similar method of example 664.

Example 665

Ethyl-5-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

1H-NMR (CDCl3) δ 0,76 (2H, m)a 1.08 (2H, m)of 1.23 (3H, t, J=7 Hz), 1,35-1,57 (7H, m)a 1.96 (1H, m)of 2.16 (2H, t, J=7 Hz), 2,53 (2H, m), 3,03 (2H, square, J=7 Hz), of 3.46 (3H, s)4,08 (2H, square, J=7 Hz), to 4.62 (2H,, (C), of 5.89 (1H, d, J=5 Hz), 6,56 (1H, d, J=5 Hz), 7,29 (1H, m), 8,40 (1H, m), charged 8.52 (1H, m).

Example 666

Ethyl-3-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

1H-NMR (CDCl3) δ 0,76 (2H, m)a 1.08 (2H, m)to 1.19 (3H, t, J=7 Hz), of 1.37 (3H, t, J=7 Hz), of 1.97 (1H, m), of 2.38 (2H, m), 2,85 (2H, m), to 3.02 (2H, square, J=7 Hz), of 3.46 (3H, s), Android 4.04 (2H, square, J=7 Hz), with 4.64 (2H, ), of 5.92 (1H, d, J=5 Hz), 6,59 (1H, d, J=5 Hz), 7,29 (1H, m), 8,40 (1H, m), 8,53 (1H, m).

Example 667

tert-Butyl-3-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]-5-cyclopropylbenzene

1H-NMR (CDCl3) δ 0,81 (2H, m)of 1.03 (2H, m)of 1.35 (3H, t, J=7 Hz), to 1.59 (9H, s), 1,94-of 2.08 (5H, m)to 2.94 (2H, square, J=7 Hz), 3,68-of 3.77 (4H, m), 6.35mm (1H, j, J=5 Hz), 6,55 (1H, d, J=5 Hz), the 7.43 (1H, s), 7,84 (1H, s), of 7.97 (1H, s).

Example 668

A solution of tert-butyl 3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoate (16.0 mg) in triperoxonane acid is (0.5 ml) was stirred for 0.5 hour at room temperature. The reaction was suppressed by the addition of water. The mixture was neutralized by adding NaOH (pH=3). The mixture was extracted with EtOAc. The extract was washed with saturated salt solution, dried over MgSO4and was evaporated to obtain a greenish-yellow solid. The solid is triturated in a mixture of hexane-CHCl3(2:1) to obtain 3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid as a yellow powder (10,8 mg).

3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid

1H-NMR (CDCl3+CD3OD) δ of 1.36 (3H, t, J=7 Hz), a 2.01 (4H, m)to 2.94 (2H, square, J=7 Hz), and 3.72 (4H, m), 6,36 (1H, d, J=5 Hz), 6,60 (1H, d, J=5 Hz), 7,92 (1H, m), 8,23 (1H, m), 8,35 (1H, m).

The following compounds were obtained according to a similar method of example 668.

Example 669

3-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]-5-cyclopropylbenzene acid

1H-NMR (CDCl3+CD3OD) δ 0,81 (2H, m)of 1.05 (2H, m)of 1.35 (3H, t, J=7 Hz), a 2.01 (5H, m)to 2.94 (2H, square, J=7 Hz), 7,73 (4H, m), 6,37 (1H, d, J=5 Hz), to 6.57 (1H, d, J=5 Hz), 6,98 (1H, s), of 7.90 (1H, s), 8,08 (1H,C).

Example 670

3-bromo-5-[7-ethyl-3-(methylsulphonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid

1H-NMR (CDCl3+CD3OD) δ to 1.37 (3H, t, J=7 Hz), to 1.98 (4H, m), 2,99 (2H, square, J=7 Hz), 320 (3H, s), of 3.56 (4H, m), 6,32 (1H, d, J=5 Hz), to 6.67 (1H, d, J=5 Hz), 7,80 (1H, m), 8,08 (1H, m), 8,30 (1H, m).

Example 671

3-necked flask containing a pair Zn-Cu, was added a solution of e is Il-4-izbutinta (369 mg) in toluene (3 ml) and N,N-dimethylacetamide (0.2 ml) at ambient temperature in an atmosphere of N 2. The mixture was stirred at the same temperature for 1 h and then at 60°C for 3 hours was Added to a suspension of tetrakis(triphenylphosphine)palladium (44 mg) in toluene (0.5 ml) and was stirred for 5 minutes After removing the oil bath and the mixture was cooled in a bath of ice-water. To the mixture was added a solution of 4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-carbonylchloride (212 mg) in DHM (DCM) (1 ml) dropwise. After 10 min the reaction mixture was stirred at ambient temperature for 2 hours the Reaction mixture was distributed between AcOEt and H2O. the Organic layer was washed with saturated solution of NaHCO3and saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue was purified flash chromatography on silica gel (silica gel, 80 ml), elwira a mixture of hexane-AcOEt=10:1 and 5:1, to obtain ethyl-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]-5-oxopentanoate as a yellow amorphous substance (143 mg).

Ethyl-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]-5-oxopentanoate

1H NMR (CDCl3) δ of 1.23 (3H, t, J=8 Hz), to 1.38 (3H, t, J=8 Hz), 1,71-of 1.84 (2H, m), 2,17 (3H, t, J=8 Hz), 2,32 (3H, t, J=8 Hz), 2,46 (3H, s), 3.04 from (2H, square, J=8 Hz), 4,06 (2H, square, J=8 Hz), 6,32 (1H, d, J=5 Hz), 6,70 (1H, d, J=5 Hz), 7,32 (1H, DD, J=5, 1), 7,46 (1H, users), 8,53 (1H, d, J=5 Hz).

Example 672

To a solution of 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]-5-oxota Lanovoy acid (47 mg) in EtOH (1 ml) was added borohydride sodium (5 mg) in a bath of ice-water in the atmosphere N 2. After 10 min the mixture was stirred at ambient temperature. After 1 h another added borohydride sodium (5 mg). After 2 hours the reaction mixture was distributed between CHCl3and H2O. the Aqueous layer was extracted with CHCl3twice. The combined organic layer was dried over MgSO4and evaporated in vacuum. The residue was purified p-TLC (CHCl3-MeOH=10:1) to obtain 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]-5-hydroxypentanal acid as a yellow amorphous substance (28 mg).

5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]-5-hydroxypentanal acid

1H NMR (CDCl3) δ of 1.36 (3H, t, J=8 Hz), 1,46 of-1.83 (3H, m), of 1.95 (1H, m), 2,70 (3H, users), a 3.01 (2H, square, J=8 Hz), 4,63 (1H, m), of 5.85 (1H, m), 6,55 (1H, d, J=5 Hz), 7.18 in-7,29 (1H, overlapping CDCl3), 7,34 (1H, d, J=2 Hz), 8,49 (1H, d, J=5 Hz).

Table 1 presents the test results on the inhibition of U937 phosphodiesterase IV (PDE IV), a technique which is disclosed in this description, for some representative compounds of formula (I) of the present invention.

Table 1
ExampleConnection nameIC50(µm)
123-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile<1
15-[7-Ethyl-2-methyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile <1
765-[4-(3-Cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid<1
945-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid<1
1323-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid<1
1365-[4-(3-Cyanophenyl])-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid<1
1375-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentane acid<1
1545-[7-Ethyl-4-(2-methoxy-4-pyridinyl)-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid<1
1755-[4-(3-Cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-

yl]pentane acid
<1
1843-[7-Ethyl-3-(methylsulphonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile<1
3463-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid<1
3494-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo,2-b]pyridazin-3-yl]butane acid <1
4613-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid<1
501-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid<1

Table 2 presents the test results on the inhibition of production of TNF-alpha in human mononuclear cells, the method which is disclosed in this description, for some representative compounds of formula (I) of the present invention. Table 2

ExampleConnection nameIC50(nm)
123-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile<100
153-[7-Ethyl-2-methyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile<100
765-[4-(3-Cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid<100
945-[4-(2-Chloro-4-pyridinyl)-7-ethyl-

2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid
<100
1323-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-and the]propanoic acid <100
1365-[4-(3-Cyanophenyl])-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid<100
1375-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentane acid<100
1545-[7-Ethyl-4-(2-methoxy-4-pyridinyl)-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid<100
1755-[4-(3-Cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentane acid<100
1843-[7-Ethyl-3-(methylsulphonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile<100
3463-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid<100
3494-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid<100
4613-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid<100
501-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid<100

Test, in vivo

Engibarov the e liver enzymes in acute hepatitis, induced in D-Galactosamine/LPS in rats.

Materials

D-galactosamine (DGaIN; hydrochloride D(+)-galactosamine, Sigma) was dissolved in saline and brought the pH to 7.0 using 6M NaOH. Lipopolysaccharide (LPS; Sigma) was dissolved and diluted in saline. In the experiment with hepatitis 5 ml/kg of a solution DGalN/LPS (300 mg/kg DGaIN and 0.1 µg/kg LPS in General) was administered intravenously. Compounds at a dose of 3.2 mg/kg) suspended in 0.5% solution of methylcellulose (0.5% of MS) and was administered orally.

Method

Rats male Wistar aged 8 weeks were not fed. within 24 hours before drug administration and were divided into the following 3 groups:

The normal group was treated with 0.5% MC and saline;

the control group was treated with MS and DGalN/LPS, and the experimental group was treated with 3.2 mg/kg of the test compounds and DGalN/LPS. 24 hours after treatment DGalN/LPS rat was analizirovali simple ether and collected blood from the abdominal artery in heparin-containing disposable syringe and transferred into a plastic tube. Plasma samples were separated by centrifugation and levels of ALT and AST were determined using an auto-analyzer (TBA-120FR, Toshiba Medical Inc., Japan).

Test results

Table 3
ExampleConnection name% inhibition at 3.2 mg/kg, Perera is Ino ALT AST
945-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid68,768,9
1245-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid63,861,9
1265-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid72,771,4
1323-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid57,959,2
1365-[4-(3-Cyanophenyl])-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid50,155,4
1755-[4-(3-Cyanophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]pentane acid52,454,1
3463-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid54,261,4
3494-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid74,870,7
3675-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridine is l)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid 71,864,1
5014-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid66,667,8
5023-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid70,168,3
5035-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid64,663,5

Example 1 obtaining oral pharmaceutical composition

0.5 g portion of the compound of the present invention are weighed and mixed with a part (about 30 g) of the mixture of 66.1 g of lactose and 28.6 g of corn starch, and carefully mixed. This mixture was added to the remaining part of the mixture of lactose and corn starch, followed by additional mixing to obtain a homogeneous mixture. The resulting mixture granularit with 20 g of a 10% aqueous solution of hydroxypropylcellulose (for example, a product called HPC-SL, manufactured by Shin-Etsu Chemical Co., Ltd.), using the machine for granulation in the fluidized bed, followed by drying. The dried product is mixed with 2 g nitrosamines hydroxypropylcellulose (for example, a product called L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) and then mixed with 0.2 g of stearate m is fester to obtain a mixed powder for tableting. The mixed powder is subjected to pelletizing using a rotary machine for tabletting (e.g., produced by Kikusui Inc.) with mortar 7 mm diameter and pestle to obtain 100 mg-tablets, each containing 0.5 mg of the compound of the present invention.

Example 2 obtaining oral pharmaceutical composition

a 5 g portion of the compound of the present invention are weighed and mixed with the 63.6 g of lactose and 27.2 g of corn starch. Using the machine for granulation in the fluidized bed, the mixture granuliruth with 20 g of a 10% aqueous solution of hydroxypropylcellulose (for example, a product called HPC-SL, manufactured by Shin-Etsu Chemical Co., Ltd.), followed by drying. The dried product is mixed with 2 g nitrosamines hydroxypropylcellulose (for example, a product called L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) and then mixed with 0.2 g of magnesium stearate to obtain a mixed powder for tableting. The mixed powder is subjected to pelletizing using a rotary machine for tabletting (e.g., produced by Kikusui Inc.) with mortar 7 mm diameter and pestle to obtain 100 mg-tablets, each containing 5 mg of the compound of the present invention.

1. The compound of the formula

where R1represents a

(1) mono - or di(lower)al is ylamino,

(2) phenyl,

(3) saturated or unsaturated 5 - or 6-membered heterogenities group selected from the group comprising pyrrolidinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl and pyridinyl, or

(4) lower alkyl, optionally substituted (i) lower alkoxy or (ii) a saturated 5 - or 6-membered heterophilically group selected from the group consisting of piperazinil and morpholinyl, where lower alkoxy optionally substituted cyclo(lower)alkyl or pyridinyl,

R2is an R7or-And2R7where

And2represents -(CH2)n- or -(CH=CH)m-where n is an integer, which may be in the range of from 2 to 6, and m is an integer 1 or 2, and

R7represents hydrogen, lower alkylsulfonyl, carboxy, esterified carboxy or pyridinyl;

R3represents a

(1) phenyl, optionally substituted lower alkyl, cyclo(lower)alkyl, lower alkoxy, halogen, cyano or carbamoyl; or

(2) chinoline; or pyridinyl, substituted lower alkyl, cyclo(lower)alkyl, lower alkoxy, carbamoyl or halogen, and R4represents lower alkyl, or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where the

R1represents phenyl, pyrrolyl, isoxazolyl, furanyl, thienyl, lower alkyl, optionally substituted lower alkoxy, piperazinil or morpholinyl, where lower alkoxy optionally substituted cyclo(lower)alkyl or pyridinyl,

R2represents -(CH2)n-R7where n is an integer, which may be in the range of 2 to 5, and R7represents carboxy or esterified carboxy, and

R3represents (1) phenyl, optionally substituted lower alkyl, cyclo(lower)alkyl, lower alkoxy, halogen, cyano or carbamoyl; or (2) pyridinyl, substituted lower alkyl, cyclo(lower)alkyl, lower alkoxy, carbamoyl or halogen.

3. The compound according to claim 1, which is:

(1) 3-[7-ethyl-2-methyl-3-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,

(2) 3-[7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,

(3) 4-[7-ethyl-2-methyl-3-(methylsulphonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,

(4) 3-[7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide,

(5) ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate,

(6) 2-{[4-(3-chlorophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]methyl}-1,3-propandiol,

(7) 3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyrido the Jn-3-yl]propanoic acid,

(8) 5-[7-ethyl-2-methyl-4-(6-chinoline)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid,

(9) 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid,

(10) 5-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid,

(11) 5-[4-(5-bromo-3-pyridinyl)-7-Ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid,

(12) 3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,

(13) 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid,

(14) ethyl-(2E)-3-[7-chloro-4-(4-forfinal)-2-isopropylindole[1,2-b]pyridazin-3-yl]-2-propenoate,

(15) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}hexanoic acid,

(16) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,

(17) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid,

(18) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid, or

(19) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid,

or its pharmaceutically acceptable salt.

4. The compound according to claim 1, which is

p num="4545"> (1) ethyl-5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentanoate,

(2) 3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrole[1,2-b]pyridazin-3-yl]propanoic acid,

(3) 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl]pentane acid,

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

(5) 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid,

(6) 3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,

(7) 5-[4-(5-bromo-3-pyridinyl)-7-Ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid,

(8) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrole[1,2-b]pyridazin-3-yl}hexanoic acid,

(9) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,

(10) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid,

(11) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid, or

(12) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid,

or its pharmaceutically acceptable salt.

5. The compound according to claim 1, which is

(1) 4-{4-(5-chloro-3-original)-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butane acid,

(2) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid,

(3) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butane acid,

(4) 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentane acid, or

(5) 4-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylamino)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentane acid,

or its pharmaceutically acceptable salt.

6. Pharmaceutical composition having inhibitory activity against phosphodiesterase IV (PDE IV) and/or inhibiting the production of tumor necrosis factor (TNF) activity, which contains as an active ingredient an effective amount of a compound according to claim 1 in a mixture with pharmaceutically acceptable carriers.

7. The pharmaceutical composition according to claim 6 for the prevention or treatment of diseases for which treatment with an inhibitor of the enzyme PDE IV inhibitor of TNF production is appropriate.

8. The pharmaceutical composition according to claim 6 for the prevention or treatment of asthma, chronic obstructive pulmonary disease (COPD), fibrotic diseases, acute and fulminant hepatitis, hepatic steatosis (alcoholic and non-alcoholic steatohepatitis), chronic (viral and non-viral) hepatitis, liver cirrhosis, autoimmune hepati is a, autoimmune inflammatory bowel disease, atopic dermatitis, Alzheimer's disease and viral infections.

9. The method of prevention or treatment of diseases for which treatment with an inhibitor of the enzyme PDE IV inhibitor of the synthesis of TNF is appropriate, including the stage of introducing an effective amount of a compound according to claim 1.

10. The method of prevention or treatment of asthma, chronic obstructive pulmonary disease (COPD), fibrotic diseases, acute and fulminant hepatitis, hepatic steatosis (alcoholic and non-alcoholic steatohepatitis), chronic (viral and non-viral) hepatitis, liver cirrhosis, autoimmune hepatitis, autoimmune inflammatory bowel disease, atopic dermatitis, Alzheimer's disease or a viral infection, comprising the stage of introducing a therapeutically effective amount or prophylactically effective amount of a compound according to claim 1.

11. The use of compounds according to claim 1 for the manufacture of drugs having inhibitory activity against the enzyme PDE IV and/or inhibiting the production of TNF activity.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to producing the novel compounds with dipeptidyl peptidase IV (DPP-IV) inhibiting activity and particularly, it relates to the compounds with the condensed 1,3-dihydroimidazole cycle. The invention relates to the compounds represented by the common formula (II), or their pharmaceutically acceptable salts, where, Z3a means nitrogen atom or the group with formula -CR2a=; X3a means oxygen atom or sulfur atom; T1a means piperazine-1-yl group, 3-amino-piperidine-1-yl group, 3-methylamino-piperidine-1-yl group; X1a means oxygen atom hydrogen, C2-6-alkenyl group, C2-6-alkynyl group or benzyl group; each of R1a and R2a independently means hydrogen atom, halogenatom, C1-6-alkyl group, cyanogroup or group, represented with formula-A0a-A1a; A0a means oxygen atom, sulfur atom or group, represented with formula-NA2a-; Ala means hydrogen atom, C1-6-alkyl group, C1-6-alkenyl group, C2-6-alkynyl group, phenyl group, cyanophenyl group, carbamoylphenyl group, benzyl group; A2a means hydrogen atom or C1-6-alkyl group; X2a means hydrogen atom, C2-6-alkenyl group, C2-6-alkynyl group, 1H-piridine-2-onyl group, 1-methyl-1H-piridine-2-onyl group, C1-6-alkyl group, which can have a group, selected from the substitutes group specified below B, phenyl group, which can have a group, selected from the substitutes group specified below B, 5- or 6-membered heteroarylgroup, containing one or two nitrogen atoms, oxygen or sulfur, which can have a group, selected from the substitutes group specified below B, phenylC1-6-alkyl group, which can have a group, selected from the substitutes group specified below B: <Substitutes group B> substitutes group B is group, including chlorine atom, bromine atom; cyanogroup, C1-b-alkyl group, C2-b-alkenyl group, C2-6-alkynyl group, C3-8-cycloalkyl group, C1-6alcoxigroup, carbamoyl groupcarboxyl group and C1-6-alcoxicarbonyl group.

EFFECT: research and revealing compounds with DPP-IV inhibiting activity, useful as pharmaceutical agents which can be used as therapeutic and preventing medicines in such diseases as diabetes, obesity and hyperlipidemia.

12 cl, 84 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with formula I or their pharmaceutically acceptable salts and based on them pharmaceutics with the CRF (corticotrophin releasing factor) related activity. In the common formula I , X1 means (CH2)n, where n equal to 0-2, R1 means (1)C1-C10alkyl or C1-C10alkenyl, not necesserily substituted with substitute, selected from the group, including hydroxy, cyano, (C1-C3alkyl)arylamino and phenyl, and said phenyl not necesserily substituted with one-three substitutes, independently selected from the group including C1-C6alkyl, C1-C6alkoxi, halogen, (2) C3-C7cycloalkyl, not necesserily substituted with hydroxy,(3) C3-C7cycloalkyl(C1-C3)alkyl or C3-C7cycloalkenyl(C1-C3)alkyl,(4) C4-C12tricyclic alkyl,(5)C3-C7heterocycloalkyl or C3-C7heterocycloalkyl(C1-C3)alkyl, where each of the heterocyclic rings contains in the ring 1-2 heteroatoms, selected from nitrogen, oxygen or sulfur, and not necesserily can be substituted with the group C1-C3alkyl, phenyl or phenyl(C1-C6)alkyl, or the CH2 group in the heterocycloalkyl residue is substituted with C=O,(6) benzo-condensed (C5-C7)cycloalkyl,(7) phenyl, and said phenyl is not necesserily substituted with one-three substitutes, independently selected from the group including C1-C6alkyl, C1-C6alkoxi, methylendioxy, halogen, (8) naftyl, (9) heteroaryl(C1-C6)alkyl, and said heteroaryl(C1-C6)alkyl has 5-6 atoms in the ring and contains 1-2 heteroatoms, selected from nitrogen, oxygen or sulfur, can be condensed with the benzene ring and not necesserily substituted with one-three substitutes, selected from the group, including C1-C6alkyl, (10) 1,2-diphenylethyl,(12) C1-C3alkoxi(C1-C6)alkyl or (13) aryloxy(C1-C6)alkyl, R2 means C1-C6alkyl, R3 means (1) hydrogen,(2) C1-C6alkyl, not necesserily substituted with the group C1-C3acyloxy,(3) C3-C6alkenyl,(8) benzene, and R4 means phenyl, not necesserily substituted with one-three substitutes, independently selected from the group including C1-C6alkyl, halogen.

EFFECT: compounds can be used in treatment of phobias, stress dependent disorders, mental disorders, gastro-intestine disfunctions, neurodegenerative and other psychoneurologic disease.

19 cl, 2 dwg, 2 tbl, 8 ex

FIELD: medicine; pharmacology.

SUBSTANCE: new discovered pyrimidine compounds of formula where R1-R9 are those as specified are selective inhibitors of group Src of nonreceptor tyrosine kinases. These compounds and their pharmaceutically acceptable salts are antiproliferative agents applied for treatment and fight against solid tumours, specifically breast tumours, rectum tumours, liver and pancreatic tumours.

EFFECT: applicable for cancer treatment.

17 cl, 5 dwg, 16 ex, 1 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new condensed derivatives of azolpyrimidine of formula (I), their tautomeric or stereoisomeric form and their physiologically accepted salts. Compounds of this invention have improved activity of phosphatidyl inositol-3-kinase (P13K) inhibiting, specifically of P13K-γ inhibiting, and can be applied for production of medicinal agents for prevention and treatment of P13K- and P13K-γ activity based diseases. Those diseases are inflammatory and immunoregulatory diseases such as asthma and others. In compounds of formula (I) . X means CR5R6 or NH; Y1 means CR3 or N; chemical bond between means single bond or double bond, as long as means double bond, then Y2 and Y3 mean CH, and as long as mean single bond, then Y2 and Y3 mean regardless CR3R4; Z1, Z2, Z3 and Z4 mean redardless CH , CR2 or N; R1 means phenyl, optionally containing 1 to 3 substitutes selected from group including R11, C3-8cycloalkyl, optionally containing 1 to 3 substitutes selected from group including R11, C1-6alkyl, optionally containing as substitutes one or more halogen atoms, or 3-15-component mono- or bicyclic heterocyclic ring being saturated or non-saturated, optionally containing 1 to 3 substitutes selected from group including R11, and containing 1 to 3 heteroatoms selected from group including N, O and S, where R11 means halogen, nitro-, hydroxyl-, cyano-, carboxy-, amino-, N-(C1-6alkyl)amino-, K-(hydroxyC1-6alkyl)amino-, N,N-di(C1-6alkyl)amino-, N(C1-6acyl)amino-, N-(formyl)-N-(C1-6 alkyl) amino-, N-(C1-6alkansulphonyl)amino-, N-(carboxy C1-6 alkyl)-N-(C1-6 alkyl) amino-, N-(C1-6 alkansulphonyl)amino-, N-[N,N-di(C1.6 alkyl)aminomethylene] amino-, N-[N,N-di(C1-6 alkyl)amino(C1-6 alkyl)methylene]amino-, N-[N,N-di(C1-6 alkyl)aminoC1-6alkenyl]amides, aminocarbonyl, N-(C1-6 alkyl)aminocarbonyl, N,N-di(C1-6 alkyl)aminocarbonyl, C3-8 cycloalkyl, C1-6alkylthio, C1-6 alkansulphonyl, sulphamoyl, C1-6alkoxycarbonyl, phenylC1-6alkoxycarbonyl, where specified phenylic fragment optionally contains 1 to 3 substitutes selected from group including R101, C1-6alkyl, optionally containing as substitutes 1, 2 or 3 halogen atoms, C1-6alkoxy, optionally containing as substitutes 1, 2 or 3 halogen atoms, or 5- 7-component saturated or non-saturated ring containing 1 to 3 heteroatoms selected from group containing N, and optionally containing 1 to 3 substitutes selected from group including and R101, where R101 means halogen, carboxy, amino-, N-(C1-6alkyl)amino-, N,N-di(C1-6alkyl)amino-, aminocarbonyl, N-(C1-6alkyl)aminocarbonyl, N,N-di(C1-6alkyl)aminocarbonyl, C1-6alkyl, and C1-6alkoxy; R2 mean hydroxy, halogen, nitro-, cyano-, amino-, N-(C1-6alkyl)amino-, N,N-di(C1-6alkyl)amino-, N-(hydroxyC1-6alkyl)amino-, N-(hydroxyC1-6alkyl)-N-(C1-6alkyl)amino-, C1-6 acoxy, aminoC1-6 acoxy, C2-6alkenyl, phenyl, 5-7-compound saturated or non-saturated heterocyclic ring containing 1 to 2 heteroatoms selected from group including O and N, and optionally containing as substitutes: hydrohy, d-balkyl, N-(C1-6acyl)amino-, phenyl, phenylC1-6alkyl, C1-6alkyl, optionally containing as substitutes R21, or C1-6alkoxy, optionally containing as substitutes R21, where R21 means cyano group, 1, 2 or3 halogen atoms, hydroxy, amino-, N-(C1-6alkyl)amino-, N,N-di(C1-6alkyl)amino-, C1-6alkoxy, hydroxyC1-6alkoxy, -C(O)-R201, -NHC(O)-R201, C3-8 cycloalkyl, phthalymidil, 2-oxo-1,3-oxazolidinyl, phenyl or 5- or 6-compound saturated or non-saturated heterocyclic ring containing 1 to 4 heteroatoms selected from group including O and N, and optionally containing as substitutes hydroxy, C1-6alkyl, N-(C1-6acyl)amides or benzyl, where R201 means hydroxyl, amino-, N-(C1-6alkyl)amino-, N,N-di(C1-6alkyl)amino-, N-(halogenphenylC1-6 alkyl)amides, C1-6alkyl, aminoC1-6alkyl, C1-6alkoxy, 5- or 6-compound saturated or non-saturated heterocyclic ring containing 1 to 2 heteroatoms selected from group including O and N; R3 means hydrogen, halogen, aminocarbonyl or C1-6alkyl, optionally containing as substitutes phenylC1-6alkoxy or 1, 2 or 3 halogen atoms; R4 means hydrogen or C1-6alkyl; R5 means hydrogen or C1-6alkyl; and R means halogen, hydrogen or C1-6alkyl. Invention also refers to medicinal agent, inhibition method and compound application.

EFFECT: compounds under this invention have improved activity.

16 cl, 2 tbl, 18 ex

Asaindoles // 2326880

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to pharmaceutical formulation inhibiting protein kinase, containing inhibiting selective kinase compound amount of general formula (I): , where: R means aryl or indolyl, and the latter is optionally substituted with one or more groups selected from R4, -C(=O)-R, -C(=O)-OR5, -C(=O)-NY1Y2 and -Z2R; R2 means H; R3 means H; R4 means C1-C6 alkyl, optionally substituted with one substitute -C(=O)-NY1Y2; R5 means H; R7 means C1-C6 alkyl; R means C1-C6 alkyl; X1 means C-aryl, C-heteroaryl, such as pyridile or isoxasolyl, and the latter is optionally substituted with one or two C1-C6 alkyls, C-heterocycloalkyl, such as morpholinile or peperidynil, C-halogen, C-CN, C-OH, C-Z2R, C-C(=O)-OR5, C-NYlY2, C-C(=O)-NY1Y2; Y1 and Y2 means redardless H, aryl, C3-C6 cycloaryl, C1-C6 alkyl, optionally substituted with one group selected from phenyl, halogen, heterocyclil, such as morpholinile, phurile, hydroxyl, -C(=O)-OR5, OR7; or group-NY1Y2 can form morpholinile, peperidynil, optionally substituted with one or two substitutes selected from OH, C1-C6 alkyl; Z means O; where aryl as group or part of group means optionally substituted with one or two substitutes monocyclic aromatic C6carbocyclic fragment, where substitute is selected from halogen or C1-C6 alkoxy, C(=O)-OR5; except compounds: 4-chlorine-2-(4-tert-butylphenyl)-1H-pyrrole[2,3-b]pyridine, 2-(5-methoxy-1 -methyl-1 H-indole-3-il)-4-phenyl-1H- pyrrole[2,3-b]pyridine, 2-(5- methoxy-1 -methyl-1 H-indole-3-il)-1H- pyrrole[2,3-b] pyridine-4-carbonitrile, 4-chlorine-2-(5- methoxy-1 -methyl-1H-indole-3-il)-1H- pyrrole[2,3-b]pyridine, or 2-(5- methoxy-1H-indole-3-il)-1H- pyrrole[2,3-b]pyridine -4- carbonitrile.

EFFECT: application of compound for production of medicinal agent for inflammatory disease.

51 cl, 9 tbl, 148 ex

FIELD: chemistry.

SUBSTANCE: described is the compound of the general formula , where R1, R2, R3, R4, R5, R6, R7, R8 can be identical or different represent independently hydrogen, halogen, percahalogenalkyl, (C1-C3)alkyl or (C1-C3)alkoxy; R9, R10, R11, R12 R13 and R14 can be identical or different and represent independently hydrogen or (C1-C3)alkyl; "n" is equal to 1 or 2, it is preferable that n be equal to 1; not obligatorily R13 and R14 together with nitrogen atom cab form a 6- term heterocyclic ring, where heterocycle can also be substituted by (C1-C3)alkyl that can have "additional heretoatoms", selected from N and O. Described also are intermediate compounds, the method of their production, pharmaceutical composition and the use of pharmaceuticals intended for treatment of the cases when modulation of the 5-HT receptor activity.

EFFECT: compounds as per this invention are applicable in treatment of disturbances of nervous system.

16 cl, 34 ex

FIELD: medicine; pharmacology.

SUBSTANCE: this invention describes new crystal forms of tryazol[4,5-d]pyrimidine formula I , composition methods and based pharmaceutical formulations. Compounds develop high efficiency as antagonist P2T, can be applied for medical prevention and treatment of arterial thrombotic complication, as well as tumour growth and extension.

EFFECT: compounds show high metabolic stability and bioavailability.

22 cl, 5 ex, 6 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to organic substances production and can be applied for production of herbicides and other bioactive compounds. Production of 2-sulphanilamine-1,2,4-triazolo[1,5-a]pyrimidine of general formula , where R1 is metal, phenylic, 4-methyl phenylic, 4-chlorophenylic group, R is phenylic, 4-methyl phenylic, 4-chlorophenylic, methoxyphenylic group, R is metal, phenylic, 4-methyl phenylic, 4-chlorophenylic group is sulphurization of 2-amino-4,7-dihydro-1,2,4-triazolo [1,5-a]pyrimidines (II) by sulphochlorides (III) in pyrimidine and oxidation of produced 2-sulphanilamine-4,7-dihydro-1,2,4-triazolo[1,5-a] pyrimidines (IV) by bromine in acetic acid with sodium acetate occurrence.

EFFECT: method allows to produce compounds using low-price and reasonable raw materials without any complicated processing steps applied.

1 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of heterocyclic compounds, which contain pyrrolo[1,2-а][1,4]diazepine fragment, annelated to aromatic and heteroaromatic ring. Method for preparation of derivatives of pyrrolo[1,2-а][1,4]diazepine of general formula I, where А =

, is described. The said derivatives may be of use as substances with potential CNS activity, or with analgesic, antimicrobial and antifungal effect. Method implies recyclization of furan ring of 5-methyl-furfurylamides of general formula 2, , where А stands for above shown groups, by exposure to temperature of 60-70°С in the mixture of glacial acetic acid and strong hydrochloric acid in volumetric ratio 1:0.15 for 10-15 minutes.

EFFECT: provides for simultaneous formation of pyrrole and diazepine rings and improves yield of end products due to less number of process steps.

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 represents (C1-C4)-alkyl with branched or linear chain; R2 represents hydrogen atom (H); R3 represents (C1-C4)-alkyl with branched or linear chain; R4 represents (C1-C4)-alkyl with branched or linear chain, (C2-C4)-alkenyl; R5 represents -SO2NR10R11; R8 represents (C1-C4)-alkyl with branched or linear chain; each R10 and R11 represents independently H or (C1-C12)-alkyl with branched or linear chain; or R10 and R11 in common with nitrogen atom to which they are bound form pyrrolinone group, piperidyl, morpholinyl, 4-N(R13)-piperazinyl that are substituted optionally with (C1-C4)-alkyl with branched or linear chain, -NR14R15, phenyl group substituted optionally with -OH or phenyl group bound in common with other substituted phenyl group by carbonyl group; R13 represents (C1-C4)-alkyl with branched or linear chain, (C2-C6)-alkyl with branched or linear chain and substituted with hydroxyl; (C2-C6)-alkyl with branched or linear chain substituted with phenyl; (C2-C6)-hydrocarbon with branched or linear chain substituted with -CO2R8; wherein each radical among R14 and R15 represents independently H; (C1-C4)-alkyl with branched or linear chain, or its pharmaceutically acceptable salt. The claimed compounds possess inhibitory effect on activity of phosphodiesterase-5 and can be used for production of drug for treatment or prophylaxis of diseases associated with phospholipase and its function. Also, invention relates to pharmaceutical composition, medicinal composition for veterinary science, and intermediate compounds IA-IG used for synthesis of compound of the formula (I).

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

8 cl, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention describes application of 9-oxoacridine-10-acetic acid, it pharmaceutically acceptable salts and its ethers as additional means for treatment of conditions implying androgen action decrease is considered to be favourable, and method of condition treatment implying that androgen action decrease is considered to be favourable, and needy patient in introduced with effective amount of 9-oxoacridine-10-acetic acid it pharmaceutically acceptable salts and its ethers combined with hormonotherapy directed on androgen action decrease. Besides, method implies androgen-dependent tissue sensibility intensifying to antiandrogen hormonotherapy directed on androgen action decrease.

EFFECT: increased efficiency of antiandrogen hormonotherapy.

30 cl, 5 tbl, 9 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention pertains to nucleoside derivatives with general formula (I) , where R1 represents hydrogen; COR5, where R5 is chosen from C1-18 alkyl, phenyl, CH2OPh and CH2Ph; C(=O)OR5, where R5 represents C1-18 alkyl; or COCH(R6)NHR7, where R6 represents C1-5 alkyl, and R7 represents R5OCO, where R5 is C1-18 alkyl, R2 represents hydrogen; COR5 , where R5 is chosen from C1-18 alkyl, C1-18 alkenyl, phenyl or CH2OPh; C(=O)OR5, where R5 is chosen from C1-18 alkyl, C1-18 alkenyl, substituted with low alkyl; C(=O)NHR5, where R5 represents C1-18 alkenyl; or COCH(R6)NHR7, where R6 is chosen from side-chains of natural amino acid and C1-5alkyl, and R7 is chosen from hydrogen and R5OCO, where R5 is C1-18 alkyl; R3 and R4 are the same and are chosen from hydrogen; COR5, where R5 is chosen from C1-18 alkyl, or phenyl; C(=O)OR5, where R5 is C1-18 alkyl, or R3 and R4 together represent C(CH3)2; or their pharmaceutical acidic additive salts; under the condition that, at least one of R1, R2, R3 or R4 is not hydrogen. The invention also relates to pharmaceutical compositions, which have antiviral activity to HCV.

EFFECT: obtaining of a range of new biologically active substances.

15 cl, 2 tbl, 9 ex

FIELD: medicine; carcinology.

SUBSTANCE: method includes 2-4 presurgical chemotherapy courses within 14 days implying intravenous injections of adriamycin of daily dose 30 mg/m in 1st and 8th day and intramuscular injections of cyclophosphan of daily dose 100 mg/m2 during 14 days. Intervals between courses are 28 days. In addition course implies oral introduction of xeloda of daily dose 2000 mg/m2 twice a day. Method ensures reduction of total chemotherapy toxicity owing to selective activation of medicines directly inside of tumour tissue, and makes possible to perform organ preserving surgical treatment.

EFFECT: reduction of total chemotherapy toxicity; organ preserving surgical treatment.

3 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to using 4'-substituted nucleosides of the formula (I): wherein R means hydrogen atom; R1 means alkyl possibly substituted with hydroxyl, and alkenyl, alkynyl, alkoxy, cyano or azido group; R2 means hydrogen atom or hydroxyl; R3 and R4 mean hydrogen atom, hydroxyl, alkoxy or halogen atom under condition that at least one radical among R3 and R4 means hydrogen atom; B means 9-purinyl residue of the formula (B1): wherein R5 means hydrogen atom; R6 means hydroxyl or -NHR8; R7 means hydrogen atom; R8 means hydrogen atom or phenylcarbonyl; or B means 1-pyrimidinyl residue of the formula (B2): wherein Z means oxygen atom (O); R10 means hydroxyl or -NHR8; R11 means hydrogen atom; R8 means a value given above. Also, invention relates to pharmaceutically acceptable salts of the compounds used for preparing a drug for treatment of diseases mediated by hepatitis C virus (HCV). Also, invention relates to a pharmaceutical composition for preparing a drug used in treatment of diseases mediated by hepatitis C virus (HCV), and to using this pharmaceutical composition for preparing a drug for treatment of diseases mediated by hepatitis C virus (HCV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 9 sch, 3 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention proposes antitumor agents compositions and their using fro production of antitumor drugs. Compositions comprise a combination of at least chemotherapeutic agent chosen from capecitabine, cetuximab (C225 antibodies), bevacizumab and herceptin with compound of the formula (I): . Proposed combinations and compositions provide achievement of the synergistic anti-tumor effect.

EFFECT: valuable medicinal property of compositions.

7 cl, 9 tbl, 13 dwg, 12 ex

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for chemotherapy of acute leucosis. Method involves isolation of blast cells and interphase cells from marrow puncture sample leukocyte fraction of blood of a patient subjected for chemotherapy. Then cells are deposited by centrifugation in medium 199 and their concentration is brought about to the level (2-3) x 106 cells/ml. Then isolated cells are incubated with each chemotherapeutic drug chosen from the following group: dexamethasone, cyclophosphanum, vincristine, teniposide, etoposide, citarabinum that are diluted preliminary with isotonic solution to the concentration 1:1000. Then cells treated with chemotherapeutic drugs are centrifuged repeatedly in medium 199 followed by carrying out the annexin test. In the schedule treatment drugs that showed the maximal percent of cells apoptosis are used. Method provides maximal decreasing adverse and toxic effects of chemotherapeutic drugs and to enhance apoptosis of tumor cells based on individual selection of chemotherapeutic drugs for a patient, to prolong remission period and to exclude using additional curative effects.

EFFECT: improved and enhanced method of chemotherapy.

2 ex

FIELD: medicine.

SUBSTANCE: method involves introducing chemotherapeutic preparation taken in standard dose. Photosensitizer is introduced at standard dose at the second day. Laser radiation is applied on photosensitizer accumulation peak condition in corresponding illumination dose. Melanoma destruction being incomplete, the treatment is repeated every 3 weeks in 3 courses. Residual melanoma being available, its excision is to be done.

EFFECT: enhanced effectiveness in destroying primary and metastatic foci; prolonged remission period.

3 cl, 1 tbl

FIELD: medicine, oncology.

SUBSTANCE: in pre-surgical period in the 1st, 3d, 5th d of a 5-d-long irradiation course it is necessary to carry out a seance of distance gamma-therapy at single focal dosage (SFD) being 5 Gy at the background of a double intake of capecytabin at its daily dosage of 1.5 g/sq. m body surface. In the 2nd and 4th d at the background of a double intake of capecytabin at the same dosage, one should intrarectally introduce metronidasol at the rate of 10 g/sq. m body surface and after a 6-h-long exposure one should carry out a seance of distance gamma-therapy at SFD being 5 Gy. Moreover, metronidasol should be introduced as a composite mixture at the following ratios of the ingredients, weight%: metronidasol 12-22; sodium alginate 4-6; dimethyl sulfoxide 2; distilled water - up to 100. The innovation provides taking antilogarithms of the effect of radiomodifiers of different direction at the background of radiation therapy and, thus, the absence of locoregional relapses for the period of 2 yr, the decrease in the onset of distant metastases and the increased frequency in achieving radial pathomorphosis of degree III in the tumor.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine.

SUBSTANCE: method involves introducing Capecitabin on the background of preoperational irradiation as radio modifier at a dose of 1650 mg/m2 divided into 2 portions given 2 h before exposure and 12 h after the exposure.

EFFECT: prevented local relapse occurrence; prolonged survival period.

2 dwg, 9 tbl

FIELD: medicine, pharmacology, bioorganic chemistry, pharmacy.

SUBSTANCE: invention relates to the effective using amount of β-L-2'-deoxynucleoside of the formula (I) or (II) used in manufacturing a medicinal agent used in treatment of hepatitis B, pharmaceutical compositions containing thereof, and methods for treatment of hepatitis B. Proposed agent shows the enhanced effectiveness in treatment of hepatitis B.

EFFECT: enhanced and valuable medicinal properties of agent.

83 cl, 6 tbl, 11 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention pertains to derivatives of 7-phenylpyrazolopyridine with formula (I) ,where R1, R5, R6, R40, R41 and R42 represent different hydrocarbon substitutes or functional groups, its salts or hydrates, and especially to salts of N-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyradin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine. The compound with formula (I), especially salts of N-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyradin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine, act as antagonists of the receptor of corticotrophin release factor and can be used in medicine for treating various diseases of the nervous system and the gastrointestinal tract.

EFFECT: obtaining of new biologically active substances.

162 ex, 5 tbl

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