# Patent

## Title
Pyrrolopyridazine derivatives

## Abstract

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

## Background
TECHNICAL FIELD
This invention relates to new pyrrolopyridazine derivatives and pharmaceutically acceptable salts thereof which inhibit enzymatic activity of phosphodiesterase IV (PDE IV) and production of tumor necrosis factor-α (TNF-α).
BACKGROUND ART
Cyclic adenosine monophosphate (adenosine 3′,5′-cyclic monophosphate, “cAMP” or “cyclic AMP”) is known as an intracellular second messenger, which is intermediated by a first messenger (hormone, neurotransmitter or autacoid) and the cellar responses. The first messenger stimulates the enzyme responsible for synthesis of cAMP, and then the cAMP intervenes in many functions such as metabolic, contractile or secretory. The effect of cAMP end when it is degraded by cyclic nucleotide phosphodiesterases, in particular phosphosiesterase-4 (PDE4 or PDE-IV), which is specific for cAMP. PDE-IV have been identified in many tissues including the central nervous systems, the heart, vascular smooth muscle, airway smooth muscle, myeloid lines, lymphoid, and the like. Evaluation of cAMP level by using the PDE-IV inhibitor would produce beneficial effect on inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells.
A major concern with the use of PDE-IV inhibitors is the side effect of emesis which has been observed for several candidate compounds as described in C. Burnouf et al., (Ann. Rep. In Med. Chem., 33:91-109(1998)). Burnouf describe the wide variation of the severity of the undesirable side effects exhibited by various compounds.
Some condensed heterocyclic derivatives having the inhibitory activity of PDE-IV have been known, for example in WO03/016279, WO03/018579, WO0.3/000679 and the like. However, there remains a need for novel compounds that inhibit PDE-TV with minimal side effects. Although some pyrrolopyridazine derivatives having the inhibitory activity of hydroxymethylglutaryl (HMG) CoA reductase have been known, for example, in WO91/18903, pyrrolopyridazine derivatives having the inhibitory activity of PDE-IV have not been known.
DISCLOSURE OF INVENTION
This invention relates to new pyrrolopyridazine derivatives.
The compounds of this invention inhibit cAMP phosphodiesterase enzymes, in particular phosphodiesterase-4 enzyme, and also inhibit the production of tumor necrosis factor-α (TNF-α), a serum glycoprotein.
Accordingly, one object of this invention is to provide the new and useful pyrrolopyridazine derivatives and pharmaceutically acceptable salts thereof which possess a strong phosphodiesterase-4 (PDE IV)-inhibitory activity and a strong inhibitory activity on the production of tumor necrosis factor (TNF).
Another object of this invention is to provide processes for preparation of the pyrrolopyridazine derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising said pyrrolopyridazine derivatives or a pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a use of said pyrrolopyridazine derivatives or a pharmaceutically acceptable salt thereof as a medicament for prophylactic and therapeutic treatment of PDE-IV and TNF mediated diseases such as chronic inflammatory diseases, specific autoimmune diseases, sepsis-induced organ injury, and the like in human being and animals.
The object pyrrolopyridazine derivatives of the present invention are novel and can be represented by the following general formula (I):




in which

    R1 is (1) carboxy or protected carboxy,
    
        (2) —CONR5R6,
        (3) hydroxy or lower alkoxy,
        (4) amino, cyclo(lower)alkylamino or mono- or di(lower)alkylamino optionally substituted by lower alkoxy,
        (5) trihalo(lower)alkyl,
        (6) trihalo(lower)alkylsulfonyloxy or arylsulfonylamino,
        (7) substituted or unsubstituted lower alkyl,
        (8) substituted or unsubstituted aryl, or
        (9) substituted or unsubstituted heterocyclic group,
    
    
    R2 is R7 or -(A1)p-X-A2-R7,
    
        wherein
        p is integer of 0 or 1;
        A1 is (C1-C2)alkylene or —CH═CH—;
        A2 is —(C1-C2)n- or —(CH═CH)m- [wherein n is integer which may range from 1 to 6 and m is integer which may range from 1 to 3];
        X is single bond, —O—, —NR8—, —C(═O)—, —C(═NR9)— or hydroxy(C1-C2)alkylene [wherein R8 is hydrogen or lower alkyl, and R9 is substituted or unsubstituted N-containing heterocyclic group]; and
        R7 is
        (1) hydrogen,
        (2) substituted or unsubstituted aryl,
        (3) substituted or unsubstituted heterocyclic group,
        (4) carboxy, protected carboxy or CONR10R11,
        (5) acyl or halocarbonyl,
        (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 alkylsulfinyl or lower alkylsulfonyl, or
        (10) —O—R12,
        or
    
    
    R1 and R2 are combined together to form lower alkylene or lower alkenylen group, which is optionally interrupted by amino or sulfonyl and optionally fuse with benzene ring, and also is optionally substituted by the group consisting of lower alkyl, hydroxy, oxo and lower alkoxy,
    R3 is substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group,
    R4 is hydrogen, halogen, cyano, carbamoyl, acyl, thiocyanate, lower alkylthio, lower alkenyl, hydroxyl(lower)alkyl, trihalo(lower)alkyl or lower alkyl,
    R5, R6, R10 and R11 each independently represents hydrogen, lower alkylsulfonyl, heterocyclic group or lower alkyl optionally substituted by hydroxy, alkoxy, sulfo, carboxy, protected carboxy or —R17,
    
        or alternatively R5 and R6 or R10 and R11, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group, and
    
    
    R12 and R17 are each independently a group derived from protected or unprotected sugar by removal of the hydroxy group therefrom,

or a pharmaceutically acceptable salt thereof, or prodrug thereof.



Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.).
The “prodrug” means the derivatives of the object compound (I) having a chemically or metabolically degradable group, which became pharmaceutically active after chemo- or biotransformation.
Preferred embodiments of the object compound (I) are as follows.




in which

    R1 is (1) carboxy or esterified carboxy (more preferably, ethoxycarbonyl),
    
        (2) —CONR5R6 [wherein R5 and R6 each independently represents lower alkyl, or alternatively R5 and R6, together with nitrogen atom to which they are attached represents saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s).] (more preferably, dimethylcarbamoyl or 1-pyrrolidinylcarbonyl),
        (3) hydroxy or lower alkoxy,
        (4) amino, cyclo(lower)alkylamino, or mono- or di(lower)alkylamino optionally substituted by lower alkoxy,
        (5) trihalo(lower)alkyl,
        (6) trihalo(lower)alkylsulfonyloxy or arylsulfonylamino,
        (7) lower alkyl optionally substituted by (i) halogen; (ii) carboxy; (iii) protected carboxy; (iv) cyano; (v) carbamoyl; (vi) —OCONR15R16 [wherein R15 and R16 each independently represents hydrogen, aryl or lower alkyl optionally substituted by aryl, or R15 and R16, together with the nitrogen atom to which they are attached, represents saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom.] (more preferably, dimethylcarbamoyloxy, methyl-phenylcarbamoyloxy, morpholinylcarbonyloxy or pyrrolidinylcarbonyloxy); (vii) lower alkylthio; (viii) lower alkylsulfonyl; (ix) lower alkylsulfonyloxy; (x) lower alkylsulfonylamino; (xi) mono- or di(lower)alkylamino optionally substituted by hydroxy, lower alkoxy, aryloxy, or substituted or unsubstituted aryl; (xii) amino; (xiii) acylamino (more preferably, lower alkanoylamino such as acetylamino, aroylamino such as benzoylamino, or heterocycliccarbonylamino such as pyrazinylcarbonylamino); (xiv) protected amino such as phthalimide, benzylamino or lower alkoxycarbonylamino; (xv) hydroxy; (xvi) acyloxy (more preferably, lower alkanoyloxy such as acetyloxy); (xvii) cyclo(lower)alkyloxy; (xviii) aryloxy; (xix) substituted or unsubstituted aryl (more preferably, phenyl); (xx) saturated or unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 3 nitrogen atom(s) and also optionally containing oxygen atom or sulfur atom (more preferably, piperazinyl, morpholinyl, oxazolidinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or triazolyl) optionally substituted by lower alkyl, hydroxy(lower)alkyl, aryl or oxo; or (xxi) lower alkoxy optionally substituted by carboxy, protected carboxy, hydroxy, protected hydroxy, lower alkoxy, cyclo(lower)alkyl, substituted or unsubstituted aryl (more preferably, phenyl optionally substituted by cyano, carboxy, protected carboxy or carbamoyl), saturated or unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) (more preferably, pyridinyl, pyrazinyl or piperazinyl) optionally substituted by lower alkyl, or —CONR13R14 [wherein R13 and R14 each independently represents hydrogen or lower alkyl optionally substituted by aryl, or R13 and R14, together with the nitrogen atom to which they are attached, represents saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom.] (more preferably, carbamoyl, methylcarbamoyl, benzylcarbamoyl or morpholinylcarbonyl),
        (8) aryl (more preferably, phenyl) optionally substituted by the substituent(s) selected from the group consisting of halogen, or
        (9) saturated or unsaturated 5- or 6-membered heteromonocyclic group (more preferably, pyrrolidinyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, furanyl, thienyl, pyridinyl) optionally substituted by lower alkyl or halogen,
    
    
    R2 is R7 or -(A1)p-X-A2-R7 
    
        wherein
        p is 0 or 1,
        A1 is (C1-C2)alkylene or —CH═CH—;
        A2 is —(CH2)n- or —CH═CH)m- [wherein n is integer which may range from 1 to 6 and m is integer which may range from 1 to 3];
        X is single bond, —O—, —NR8—, —C(═O)—, —C(═NR9)— or hydroxy(C1-C2)alkylene;
        [wherein R8 is hydrogen or lower alkyl, and R9 is substituted or unsubstituted pyrrolyl such as 2-ethyl-5-(4-fluorobenzoyl)pyrrolyl]
        R7 is
        (1) hydrogen,
        (2) aryl (more preferably, phenyl) optionally substituted by lower alkoxy,
        (3) unsaturated heteromonocyclic group containing 1 to 2 nitrogen atom(s), (more preferably, pyridinyl),
        (4) carboxy, esterified carboxy (more preferably, lower alkoxycarbonyl) or —CONR10R11 [wherein R10 and R11 each independently represents hydrogen, lower alkylsulfonyl, unsaturated heteromonocyclic group containing 1 to 2 nitrogen atom(s) such as pyridinyl or lower alkyl optionally substituted by hydroxy, alkoxy, carboxy, protected carboxy, sulfo or —R17, or alternatively R10 and R11, together with the nitrogen atom to which they are attached, represents saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom such as morpholinyl.],
        (5) acyl (e.g. lower alkanoyl such as formyl or acetyl, and heterocycliccarbonyl such as pyridinylcarbonyl) or halocarbonyl,
        (6) cyano,
        (7) amino, protected amino such as lower alkoxycarbonylamino, or mono- or di(lower)alkylamino,
        (8) hydroxy, aryloxy, acyloxy or lower alkoxy optionally substituted by hydroxy or acyloxy (e.g. lower alkanoyloxy),
        (9) lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl, or
        (10) —O—R12,
        or
    
    
    R1 and R2 are combined together to form lower alkylene or lower alkenylen group which is optionally interrupted by amino or sulfonyl and also is optionally substituted by the group consisting of lower alkyl, hydroxy, oxo and lower alkoxy, which is represented by the following formula:






    
    
        that may include the following ones;
    
    






    R3 is (1) aryl (more preferably, phenyl or naphthyl) optionally substituted by at least one substituent(s) selected from the group consisting of (i) halogen, (ii) carboxy, (iii) protected carboxy, (iv) cyano, (v) —CONR15R16 [wherein R15 and R16 each independently represents hydrogen, lower alkyl optionally substituted by hydroxy], (vi) lower alkyl, (vii) cyclo(lower)alkyl, (viii) hydroxy(lower)alkyl, (ix) lower alkoxy, (x) trihalo(lower)alkyl, (xi) unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 2 nitrogen atom(s) such as oxazolyl, (xii) lower alkylsulfonyl, (xiii) nitro, (xiv) sulfamoyl, and (xv) protected sulfamoyl; or
    
        (2) heterocyclic group selected from the group consisting of pyridinyl, pyrazinyl, oxazolyl, isooxazolyl, furanyl, thienyl, quinolyl, benzofuranyl and benzothienyl, wherein said heterocyclic group is optionally substituted by at least one substituent(s) selected from the group consisting of (i) lower alkyl, (ii) cyclo(lower)alkyl, (iii) lower alkoxy, (iv) acyl such as lower alkanoyl, (v) amino, (vi) mono- or di(lower)alkylamino, (vii) protected amino such as lower alkoxycarbonylamino, (viii) cyano, (ix) carboxy, (x) protected carboxy such as ethoxycarbonyl or methoxycarbonyl, (xi) —CONR15R16 [wherein R15 and R16 each independently represents hydrogen, lower alkyl optionally substituted by hydroxy], (xii) lower alkenyl optionally substituted by lower alkoxy, (xiii) halogen, (xiv) lower alkylthio and (xv) hydroxy;
    
    
    R4 is hydrogen, halogen, cyano, carbamoyl, lower alkanoyl, thiocyanate, lower alkylthio, lower alkenyl, hydroxyl(lower)alkyl, trihalo(lower)alkyl or lower alkyl, and
    R12 and R17 are each independently a group derived from protected or unprotected sugar such as galactose by removal of the hydroxy group therefrom,

or a pharmaceutically acceptable salt thereof.



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

    R1 is (1) mono- or di(lower)alkylamino,
    
        (2) aryl such as phenyl,
        (3) saturated or unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 2 hetero atom(s) selected from nitrogen, oxygen or sulfur atom(s) (more preferably, pyrrolidinyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, furanyl, thienyl, pyridinyl, etc), or
        (4) lower alkyl optionally substituted by lower alkoxy or saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom (more preferably, piperazinyl or morpholinyl), wherein lower alkoxy is optionally substituted by cyclo(lower)alkyl or unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) (more preferably, pyridinyl),
    
    
    R2 is R7 or -A2-R7, wherein
    
        A2 is —(CH2)n- or —(CH═CH)m- [wherein n is integer which may range 2 to 6 and
        m is integer of 1 or 2, and
        R7 is hydrogen, lower alkylsulfonyl, carboxy, protected carboxy or unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) (more preferably, pyridinyl),
    
    
    R3 is (1) aryl optionally substituted by lower alkyl, cyclo(lower)alkyl, halogen, cyano or carbamoyl; or
    
        (2) unsaturated condensed heterocyclic group containing 1 to 2 nitrogen atom(s) (more preferably, quinolinyl); or unsaturated 5 to 6 membered heteromonocyclic group containing at least one nitrogen atom(s) (more preferably, 3-pyridinyl and 4-pyridinyl) substituted by lower alkyl, cyclo(lower)alkyl or halogen, and
    
    
    R4 is lower alkyl.


Most preferred compounds of formula (I) are those in which:

    R1 is phenyl, saturated or unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 2 hetero atom(s) selected from nitrogen, oxygen or sulfur atom(s) (more preferably, pyrrolyl, isooxazolyl, furanyl, thienyl, etc.) or lower alkyl optionally substituted by lower alkoxy or saturated or saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom (more preferably, piperazinyl or morpholinyl), wherein lower alkoxy is optionally substituted by cyclo(lower)alkyl or unsaturated 5 to 6 membered heteromonocyclic group containing at least one nitrogen atom(s) (more preferably, pyridinyl),
    R2 is —(CH2)n-R7, wherein n is integer which may range 2 to 5, and R7 is carboxy or protected carboxy,
    R3 is (1) phenyl optionally substituted by lower alkyl, cyclo(lower)alkyl, lower alkoxy, halogen, cyano or carbamoyl; or (2) unsaturated 5 to 6 membered heteromonocyclic group containing at least one nitrogen atom(s) (more preferably, 3-pyridinyl and 4-pyridinyl) substituted by lower alkyl, cyclo(lower)alkyl, lower alkoxy, carbamoyl or halogen, and
    R4 is lower alkyl.


Preferred concrete compound of formula (I) is:

    (1) 3-[7-Ethyl-2-methyl-3-(4-pyridinyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,
    (2) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,
    (3) 4-[7-Ethyl-2-methyl-3-(methylsulfonyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,
    (4) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide,
    (5) Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate,
    (6) 2-{[4-(3-Chlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methyl}-1,3-propanediol,
    (7) 3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,
    (8) 5-[7-Ethyl-2-methyl-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,
    (9) 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,
    (10) 5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,
    (11) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,
    (12) 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,
    (13) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,
    (14) Ethyl (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propenoate,
    (15) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-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]butanoic acid,
    (18) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,
    (19) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid.
    (20) 4-{4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoic acid,
    (21) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid,
    (22) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid,
    (23) 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid, or
    (24) 5-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid,

or a pharmaceutically acceptable salt thereof.



More preferred concrete compound of formula (I) is:

    (1) Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate,
    (2) 3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,
    (3) 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,
    (4) 5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,
    (5) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,
    (6) 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,
    (7) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,
    (8) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid
    (9) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,
    (10) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid,
    (11) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid, and
    (12) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid,
    (13) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid, or
    (14) 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,

or a pharmaceutically acceptable salt thereof.



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






















wherein R1, R2, R3 and R4 are each as defined above,

    
    
        R1a is the same as above R1 having protected carboxy moiety,
        R1b is the same as above R1 having carboxy moiety,
        R1c is —CONR5R6,
        R1d is carbamoyl(lower)alkyl,
        R1e is amino, mono- or di(lower)alkylamino-, lower alkoxy(lower)alkylamino, nitrogen-containing heterocyclic group, amino(lower)alkyl, mono- or di(lower)alkylamino(lower)alkyl, lower alkoxy(lower)alkylamino(lower)alkyl, nitrogen-containing heterocyclic(lower)alkyl,
        R1f is lower alkylthio(lower)alkyl,
        R1g is lower alkylsulfonyl(lower)alkyl,
        R1h is trifluoromethanesulfonyloxy or trifluoromethanesulfonyloxy(lower)alkyl,
        R1i is lower alkoxy or lower alkoxy(lower)alkyl,
        R1j is hydroxy or hydroxy(lower)alkyl,
        R1a is lower alkoxycarbonyl,
        R2b is the same as above R2 having protected carboxy moiety,
        R2c is the same as above R2 having carboxy moiety,
        R2d is the same as above R2 having carbamoyl moiety,
        R2e is the same as above R2 having protected hydroxy moiety,
        R2f is the same as above R2 having hydroxy moiety,
        R2g is the same as above R2 having hydroxymethyl moiety,
        R2h is —OR12,
        R2i is lower alkoxycarbonyl or lower alkylsulfonyl,
        R2j is substituted or unsubstituted lower alkenyl as mentioned in the above R2, wherein said lower alkenyl is lower 1-alken-1-yl,
        R2k is the same as above R2 having hydroxy(lower)alkyl moiety,
        R2l is the same as above R2 having oxo(lower)alkyl moiety,
        R2m is the same as above R2 having protected amino moiety,
        R2n is the same as above R2 having amino moiety,
        R2o is the same as above R2 having protected hydroxy moiety,
        R2p is the same as above R2 having hydroxy(lower)alkylamino(lower)alkyl moiety,
        R2q is the same as above R2 having lower alkoxycarbonyl(lower)alkyl moiety,
        R2r is the same as above R2 having lower alkoxycarbonylmethylcarbonyl moiety,
        R3a is the same as above R3 having cyano moiety,
        R3b is the same as above R3 having carbamoyl moiety,
        R3c is the same as above R3 having carboxy moiety,
        R3d is the same as above R3 having protected sulfamoyl moiety,
        R3e is the same as above R3 having sulfamoyl moiety,
        R3f is the same as above R3 having —CONR10R11 moiety,
        R3g is the same as above R3 having haloheterocyclic moiety,
        R3h is the same as above R3 having alkoxyheterocyclic, thioalkoxyheterocyclic or hydroxy moiety,
        R3i is the same as above R3 having 1-(lower)alkoxy(lower)alken-1-ylheterocyclic moiety,
        R3j is the same as above R3 having lower alkanoylheterocyclic moiety,
        R3k is the same as above R3 having aminomethylheterocyclic moiety,
        R3l is the same as above R3 having mono- or di(lower)alkylaminoheterocyclic moiety,
        R3m is the same as above R3 having (lower)alken-1-ylheterocyclic group or 1-(lower)alkoxy-1-(lower)alken-1-yl-heterocyclic moiety,
        R4a is halogen,
        R4b is formyl,
        R4c is lower 1-alken-1-yl,
        R4d is lower alkyl,
        R12 is lower alkyl or a group derived from protected or unprotected sugar by removal of the hydroxy group therefrom,
        X is a leaving group, and
        a group of the formula:
    
    






    
    
         is lower alkylene interrupted by imino moiety and substituted by oxo groups.
    
    


The starting compound (II) of the present invention can be prepared according to a conventional manner or in a similar manner as described in the following Preparations and/or Examples.
Another point to be noted is that the pyrrolopyridazine moiety of the compound (I) can also exist in the tautomeric form, and such tautomeric equilibrium can be represented, for example, by the following formula.




wherein R1 R2, R3 and R4 are each as defined above.

Both of the above tautomeric isomers are included within the scope of the present invention, and in the present specification and claims, however, the object compound (I) is represented for convenience' sake by one expression of the possible tautomeric forms of pyrrolopyridazine ring.
In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.
The term “lower” is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
Suitable “lower alkyl” and “lower alkyl moiety” may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like, and in which more preferable example may be C1-C4 alkyl.
Suitable “lower alkenyl” may include vinyl(ethenyl), 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)hexenyl, 1-methylvinyl, 1-ethylvinyl, 1-(or 2-)methyl-1-(or 2-)propenyl, 1-(or 2-)ethyl-1-(or 2-)propenyl, 1-(or 2- or 3-)methyl-1-(or 2- or 3-)butenyl, and the like, in which more preferable example may be C2-C4 alkenyl.
Suitable “lower alkynyl” may include ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, and the like.
Suitable “lower alkylene” may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene, propylene, and the like, in which more preferable example may be C1-C4 alkylene and the most preferable one may be methylene.
Example of hydroxy(C1-C2)alkylene is hydroxymethylene, (hydroxymethyl)methylene or 1-(or 2-)hydroxyethylene.
Suitable “lower alkoxy” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
Suitable “halogen” and “halogen moiety” may include fluorine, bromine, chlorine and iodine.
Suitable “trihalo(lower)alkyl” may include trichloromethyl, trifluoromethyl, trichloroethyl, tribromoethyl, and the like.
Suitable “mono- or di(lower)alkylamino” may include amino group substituted by one or two lower alkyl such as methylamino, ethylamino, dimethylamino, and the like.
Example of “mono- or di(lower)alkylamino substituted by lower alkoxy” may be methoxymetylamino, methoxyethylamino, methoxyethyl(methyl)amino, methoxyethyl(ethyl)amino, di(methoxyethyl)amino, ethoxymethylamino, ethoxyethylamino, and the like.
Suitable “lower alkylthio” may include conventional ones such as methylthio, ethylthio, propylthio, butylthio, and the like.
Suitable “lower alkylsulfinyl” may include conventional ones such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, and the like.
Suitable “lower alkylsulfonyl” may include conventional ones such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, bytylsulfonyl, and the like.
Suitable “trihalo(lower)alkylsulfonyloxy” may include sulfonyloxy group substituted by trihalo(lower)alkyl such as trifluoromethylsulfonyloxy, trifluoroethylsulfonyloxy, trichloromethylsulfonyloxy, and the like.
Suitable “protected carboxy” and “protected carboxy moiety” may include esterified carboxy and the like.
And suitable example of said ester may be the ones such as

    lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.);
    lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.);
    lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.);
    lower alkoxy(lower)alkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.);
    lower alkylthio(lower)alkyl ester (e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropoxythiomethyl ester, etc.);
    mono(or di or tri)halo(lower)alkyl ester (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.);
    lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.);
    lower alkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, 1-(or 2-)-[methoxycarbonyloxy]ethyl ester, 1-(or 2-)-[ethoxycarbonyloxy]ethyl ester, 1-(or 2-)-[propoxycarbonyloxy]ethyl ester, 1-(or 2-)-[isopropoxycarbonyloxy]ethyl ester, etc.);
    lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2-mesylethyl ester, etc.);
    lower alkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester, 1-(or 2-)-ethoxycarbonyloxyethyl ester, 1-(or 2-)-isopropoxycarbonyloxyethyl ester, etc.);
    phthalidylidene(lower)alkyl ester;
    (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g., (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.];
    mono(or di or tri)aryl(lower)alkyl ester, for example, mono(or di or tri)phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.);
    aryl ester which may have one or more suitable substituent(s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.);
    tri(lower)alkylsilyl ester (e.g. trimethylsilyl ester, triethylsilyl ester, etc.);
    tri(lower)alkylsilyl(lower)alkyl ester (e.g. 2-trimethylsilylethyl ester, etc.);

and the like, in which more preferable example may be lower alkyl ester, i.e., lower alkoxycarbonyl (e.g. ethoxycarbonyl, etc.).



The term “protected amino” means an amino group bonded to the amino-protecting group. Example of such amino-protecting group include lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.); lower alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.); optionally substituted aryl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.); phthalimide; and the like. Further example of amino-protecting group are well-known in organic synthesis and are described by T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” Second Edition, John Wiley and Sons, New York, N.Y., which is herein incorporated by reference.
The term “protected sulfamoyl” means sulfamoyl group having the amino-protecting group mentioned above on the nitrogen atom. A preferred amino-protecting group is aryl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.); and the like.
Suitable “acyl” and “acyl moiety” may include aliphatic acyl group, and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
Suitable example of said acyl may be illustrated as follows:

    Aliphatic acyl such as
    lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.); in which preferable “lower alkanoyl” may include straight or branched one such as formyl, acetyl, propionyl, butyryl, and the like.
    lower or higher alkenoyl (e.g., acryloyl, 2-(or 3-)-butenoyl, 2-(or 3- or 4-)pentenoyl, 2-(or 3- or 4- or 5-)-hexenoyl, etc.);
    lower alkadienoyl (e.g., heptadienoyl, hexadienoyl, etc.);
    cyclo(lower)alkylcarbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.);
    lower alkylglyoxyloyl (e.g., methylglyoxyloyl, ethylglyoxyloyl, propylglyoxyloyl, etc.);
    lower alkoxyglyoxyloyl (e.g., methoxyglyoxyloyl, ethoxyglyoxyloyl, propoxyglyoxyloyl, etc.);

or the like;

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

in which suitable “heterocyclic moiety” may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like, as mentioned below and preferable “heterocyclic-carbonyl” may include carbonyl group substituted by heterocyclic group as mentioned below such as pyrrolidinylcarbonyl, pyridinylcarbonyl, pyrazinylcarbonyl, and the like.



Suitable “halocarbonyl” may include chlorocarbonyl, bromocarbonyl, and the like.
Suitable “cyclo(lower)alkyl” and “cyclo(lower)alkyl moeity” may include one having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
Suitable “aryl” and “aryl moiety” may include C6-C10 aryl such as phenyl, naphthyl and the like.
Suitable “heterocyclic moiety” may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
Preferable heterocyclic group may be heterocyclic group such as

    (1) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridinyl, dihydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
    (2) saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;
    (3) unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, tetrahydroquinolyl (e.g., 1,2,3,4-tetrahydroquinolyl, etc.), isoquinolyl, indazolyl, benzotriazolyl, benzopyrimidinyl (e.g., benzo[b]pyrimidinyl, etc.), etc.;
    (4) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
    (5) saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;
    (6) unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
    (7) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
    (8) saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;
    (9) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;
    (10) unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.;
    (11) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, furanyl, etc.;
    (12) unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s), for example, benzodioxolyl (e.g. methylenedioxyphenyl, etc.), benzofuranyl, etc.;
    (13) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;
    (14) unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl (e.g., benzo[b]thienyl, etc.), benzodithiinyl, etc.;
    (15) unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like.


Suitable “heterocyclic group” and “heterocyclic moiety” in the terms “heterocycliccarbonyl” can be referred to the ones as mentioned above.
Suitable “N-containing heterocyclic group” and “N-containing heterocyclic moiety” can be referred to the ones as mentioned above, wherein the heterocyclic group is containing at least one nitrogen atom such as 1-pyrrolidinyl, morpholinyl and the like.
A group derived from a sugar may be the group derived from, for example, glyceraldehydes; an aldose such as erythrose, threose, arabinose, ribose, xylose, lyxose, glucose, mannose or galactose; a ketose such as fructose or sorbose; or a discccharide such as maltose, lactose or sucrose.
Protecting groups for the hydroxy group of the above-mentioned sugars are an aliphatic acyl group, such as formyl, or acetyl; a cyclic ether group such as tetrahydro-2-furanyl or tetrahydro-2-pyranyl; a 1-alkoxyethyl group such as 1-methoxyethyl or 1-ethoxyethyl; and a silyl group such as trimethylsilyl, triethylsilyl or t-butyldimethylsilyl.
Suitable “substituted or unsubstituted lower alkyl” for R1 may include straight or branched lower alkyl (e.g. methyl, isopropyl, neopentyl, etc.) optionally substituted by; (1) halogen (e.g. fluoro, bromo, etc.), (2) carboxy, (3) protected carboxy (e.g. esterified carboxy such as ethoxycarbonyl, etc.), (4) cyano, (5) carbamoyl, (6) —OCONR15R16 [wherein R15 and R16 each independently represents hydrogen, aryl or lower alkyl optionally substituted by aryl, or R13 and R14, together with the nitrogen atom to which they are attached, represents saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom.] (more preferably, dimethylcarbamoyloxy, methyl-phenylcarbamoyloxy, morpholinylcarbonyloxy, pyrrolidinylcarbonyloxy, etc); (7) lower alkylthio (e.g. methylthio, etc.), (8) lower alkylsulfonyl (e.g. methylsulfonyl, etc.), (9) lower alkylsulfonyloxy (e.g. methylsulfonyoxyl, etc.), (10) lower alkylsulfonylamino (e.g. methylsulfonylamino, etc.), (11) mono- or di(lower)alkylamino optionally substituted by hydroxy, lower alkoxy, acyloxy (e.g. phenoxy, etc.), or substituted or unsubstituted aryl (e.g. benzylamino, etc.), (12) amino; (13) acylamino (more preferably, lower alkanoylamino such as acetylamino, aroylamino such as benzoylamino, or heterocycliccarbonylamino such as pyrazinylcarbonylamino, or the like), (14) protected amino (e.g., methoxycarbonylamino, phthalimide, etc.), (15) hydroxy, (16) acyloxy (more preferably, lower alkanoyloxy such as acetyloxy, or the like), (17) cyclo(lower)alkyloxy, (18) aryloxy (e.g. phenoxy, etc.) (19) substituted or unsubstituted aryl (more preferably, phenyl), (20) saturated or unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 3 nitrogen atom(s) and also optionally containing oxygen atom or sulfur atom (more preferably, piperazinyl, morpholinyl, oxazolidinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or triazolyl) optionally substituted by lower alkyl, hydroxy(lower)alkyl, aryl or oxo, (21) lower alkoxy (e.g. methoxy, ethoxy, iso-propoxy, etc.) optionally substituted by carboxy, protected carboxy (e.g. tert-butoxycarbonyl, etc.), hydroxy, protected hydroxy (e.g. tetrahydro-2H-pyran-2-yloxy, etc.), cyclo(lower)alkyl (e.g. cyclopropyl, cyclohexyl, etc.), substituted or unsubstituted aryl (e.g. phenyl optionally substituted by cyano, carboxy, protected carboxy or carbamoyl, such as phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-carboxyphenyl, 2-, 3- or 4-(methoxycarbonyl)phenyl, 2-, 3- or 4-carbamoylphenyl, etc.), saturated or unsaturated 5- or 6-membered heterocyclic group containing 1 to 2 nitrogen atom(s) optionally substituted by lower (more preferably, 2-, 3- or 4-pyridinyl, pyrazinyl or 4-methylpiperazinyl)(e.g. 2-, 3- or 4-pyridinyl, pyrazinyl, etc.), or —CONR13R14 [wherein R13 and R14 each independently hydrogen or lower alkyl optionally substituted by aryl, or R13 and R14, together with the nitrogen atom to which they are attached, represents N-containing heterocyclic group] (e.g. morpholinocarbonyl, dimethylcarbamoyl, etc.), and the like.
Suitable “substituted or unsubstituted aryl” may include C6-C10 aryl (e.g. phenyl, naphthyl, etc.) optionally substituted by the substituent(s) selected from the group consisting of (1) halogen (e.g. fluoro, chloro, etc.), (2) carboxy, (3) protected carboxy, (4) cyano, (5) —CONR15R16 [wherein R15 and R16 are each independently represents hydrogen, lower alkyl optionally substituted by hydroxy] (e.g. carbamoyl, hydroxyethylcarbamoyl, etc.), (6) lower alkyl (e.g. methyl, etc.), (7) cyclo(lower)alkyl (e.g. cyclopropyl, etc) (8) lower alkoxy (e.g. methoxy, etc.), (9) trihalo(lower)alkyl (e.g. trifluoromethyl, etc.), (10) heterocyclic group such as oxazolyl, (11) lower alkylsulfonyl (e.g. methylsulfonyl, etc.), (12) nitro, (13) amino, (14) sulfamoyl, and (15) protected sulfamoyl such as ar(lower)alkoxycarbonylsulfamoyl, and the like.
In which,

    preferable example of “substituted or unsubstituted aryl” for R1 is aryl optionally substituted by the substituent(s) selected from the group consisting of halogen (e.g. phenyl, 4-fluorophenyl, etc.);
    preferable example of “substituted or unsubstituted aryl” for R3 is aryl optionally substituted by the substituent(s) selected from the group consisting of (1) halogen, (2) carboxy, (3) protected carboxy such as esterified carboxy (e.g. benzyloxycarbonyl, etc,), (4) cyano, (5) —CONR15R16 [wherein R15 and R16 are each independently represents hydrogen, lower alkyl optionally substituted by hydroxy], (6) lower alkyl, (7) cyclo(lower)alkyl, (8) lower alkoxy, (9) trihalo(lower)alkyl, (10) heterocyclic group, (11) lower alkylsulfonyl, (12) nitro, (13) amino, (14) sulfamoyl, and (15) protected sulfamoyl, and the like. (e.g. phenyl, 2-naphthyl, 2- or 3-chlorophenyl, 2,3-, 2,4-, 3,4- or 3,5-dichlorophenyl, 3- or 4-fluorophenyl, 3- or 4-cyanophenyl, 3- or 4-carbamoylphenyl, 4-sulfamoylphenyl, 4-(benzyloxycarbonylsulfamoyl)phenyl, 3-carboxyphenyl, 3-(N-(2-hydroxyethyl)carbamoyl)phenyl, 3-nitrophenyl, 3-trifluoromethylphenyl, 3-methylsulfonylphenyl, 3-(5-oxazolyl)phenyl, 3-methoxyphenyl, 3-methylphenyl, etc.); and
    preferable example of “substituted or unsubstituted aryl” for R7 is aryl optionally substituted by lower alkoxy (e.g. phenyl, 2-, 3- or 4-methoxyphenyl, etc.).


Suitable “substituted or unsubstituted heterocyclic group” may include heterocyclic group mentioned above (more preferably, pyridinyl, pyrazinyl, oxazolyl, isooxazolyl, furanyl, thienyl, quinolinyl, benzofuranyl and benzothienyl), which is optionally substituted by the substituent(s) selected from the group consisting of (1) lower alkyl (e.g. methyl, etc.), (2) cyclo(lower)alkyl (e.g. cyclopropyl, etc.) (3) lower alkoxy (e.g. methoxy, etc.), (4) acyl (e.g. lower alkanoyl such as acetyl, etc.), (5) amino, (6) mono- or di(lower)alkylamino (e.g. dimethylamino, etc.), (7) protected amino (e.g. lower alkoxycarbonylamino such as tert-butoxycarbonylamino, etc.), (8) cyano, (9) carboxy, (10) protected carboxy (e.g. benzyloxycarbonyl, etc.), (11) —CONR15R16 [wherein R15 and R16 are each independently represents hydrogen, lower alkyl optionally substituted by hydroxy] (e.g. carbamoyl, hydroxyethylcarbamoyl, etc.), (12) lower alkenyl optionally substituted by lower alkoxy (e.g. vinyl, 1-ethoxyvinyl, etc.), (13) halogen (e.g. chloro, bromo, etc.), (14) lower alkylthio, (15) hydroxy, and the like.
In which,

    preferable example of “substituted or unsubstituted heterocyclic group” for R1 is heterocyclic group optionally substituted by lower alkyl or halogen (e.g. 2-pyridinyl, 5-blomo-3-pyridinyl, 1-methyl-2-pyrrolyl, 1-pyrrolyl, 1-pyrrolidinyl, 3-methyl-2-thienyl, 2-thienyl, 2- or 3-furanyl, 2-thiazolyl, 5-oxazolyl, 5-methyl-isooxazolyl, 3,5-dimethyl-4-isoxazolyl, etc.); and
    preferable example of “substituted or unsubstituted heterocyclic group” for R3 is heterocyclic group optionally substituted by at least one substituent(s) selected from the group consisting of (1) lower alkyl, (2) cyclo(lower)alkyl, (3) lower alkoxy, (4) acyl such as lower alkanoyl, (5) amino, (6) mono- or di(lower)alkylamino, (7) protected amino such as lower alkoxycarbonylamino, (8) cyano, (9) carboxy, (10) protected carboxy such as esterified carboxy (e.g. benzyloxycarbonyl), (11) carbamoyl, (12) lower alkenyl optionally substituted by lower alkoxy, (13) halogen, (14) lower alkylthio, and (15) hydroxy (e.g. 3- or 4-pyridyl, 2-pyrazinyl, 6-methoxy-2-pyrazinyl, 4- or 5-oxazolyl, 2-benzofuranyl, 2-benzothienyl, 3- or 6-quinolinyl, 2-chloro-4-pyridyl, 5-bromo-3-pyridyl, 5-chloro-2-thienyl, 5,6-dichloro-2-pyridyl, 4-chloro-2-pyridyl, 5-cyano-3-pyridyl, 5-carboxy-3-pyridinyl, 5-carbamoyl-3-pyridyl, 5-(benzyloxycarbonyl)-3-pyridyl, 5-(tert-butoxycarbonylamino)-3-pyridinyl, 5-amino-3-pyridinyl, 2-methoxy-4-pyridyl, 3-methoxy-5-isoxazolyl, 2-methylthio-4-pyridinyl, 2-hydroxy-4-pyridyl, 5-methyl-3-pyridyl, 5-ethyl-3-pyridyl, 5-methyl-3-isoxazolyl, 5-vinyl-3-pyridyl, 2-vinyl-4-pyridyl, 5-acetyl-3-pyridyl, 2-dimethylamino-4-pyridyl, 5-(1-ethoxyvinyl)-3-pyridyl, 2-oxo-1,2-dihydro-4-pyridyl, or 2-methylthio-4-pyridyl, etc.).


R1 and R2 are combined together to form lower alkylene or lower alkenylen group which is optionally interrupted by amino or sulfonyl and also is optionally substituted by the group consisting of lower alkyl, hydroxy, oxo and lower alkoxy, which is represented by the following formula:




The above formula may include following ones;




Suitable “substituted or unsubstituted aryl(lower)alkenyl” may include C6-C10 aryl(lower)alkenyl which is optionally substituted by halogen (e.g. 2-phenylvinyl, 2-(2- or 3-chlorophenyl)vinyl, etc.).
Suitable “leaving group” may include acid residue, lower alkoxy as exemplified above, and the like.
The above Processes can be carried out according to a conventional manner such as the one described in Preparations and/or Examples, or in a similar manner thereto. Among the above Processes, fused heterocyclic ring forming processes (such as Process 1 and Process 12) are important for carrying out of this invention and are explained in more detail.
According to the Process 1, pyrrolopyridazine derivatives (I) can be prepared by reacting the 1-amino-2-acylpyrrole derivative (II) or a salt thereof and the compound (III) or a salt thereof in the presence of a catalytic amount of acid catalyst in an inert solvent, preferably with concomitant removal of the water being produced by physical (e.g. Dean-Stark trap) or chemical (e.g. molecular sieves) means. Suitable acid catalyst is, for example p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, trifluoroacetic acid and so on. Suitable inert solvent is, for example, benzene, toluene, tetrahydrofuran and the like.
Another ring forming process is described in Process 12, in this process pyrrolopyridazine derivatives (I) can be also prepared reacting 1-aminopyrole derivative (V) or a salt thereof and β-diketone derivative or a salt thereof under the similar condition before mentioned Process 1, and therefore the reaction conditions can be referred to those of the Process 1.
The compounds of the present invention can be purified by any conventional purification methods employed for purifying organic compounds, such as re-crystallization, column chromatography, thin-layer chromatography, high-performance liquid chromatography and the like. The compounds can be identified by conventional methods such as NMR spectrography, mass spectrography, IR spectrography, elemental analysis, and measurement of melting point.
Suitable salts of the object and the starting compounds in Processes 1 to 40 can be referred to the ones as exemplified for the compound (I).
The new pyrrolopyridazine derivatives (I) and pharmaceutically acceptable salts thereof hardly possess a strong inhibitory activity against phosphodiesterase III (PDE III), but possess a strong inhibitory activity against phosphodiesterase IV (PDE IV) and a strong inhibitory activity on the tumor necrosis factor (TNF).
That is, the pyrrolopyridazine derivatives (I) and pharmaceutically acceptable salts thereof are selective inhibitors of phosphodiesterase IV (PDE IV) and inhibitors on the production of tumor necrosis factor (TNF).
Accordingly, the new pyrrolopyridazine derivatives (I) and a pharmaceutically acceptable salt thereof can be used for prophylactic and therapeutic treatment of PDE-IV and TNF mediated diseases such as chronic inflammatory diseases (e.g., rheumatoid arthritis, osteoarthritis, emphysema, chronic bronchiolitis, allergic rhinitis, etc.), osteoporosis, rejection by transplantation, asthma, chronic obstructive pulmonary disease (COPD), eosinophilia, fibrotic disease (e.g., cystic fibrosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, etc.), (viral alcoholic, drug-induced) acute and fulminant hepatitis, hepatic steatosis (alcoholic and non-alcoholic steato-hepatitis), chronic (viral and non-viral) hepatitis, hepatic cirrhosis, autoimmune hepatitis, pancreatitis, nephritis, endotoxin shock, specific autoimmune diseases [e.g., ankylosing spondylitis, autoimmune encephalomyelitis, autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, etc.), systemic lupus erythematosus (SLE), polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis (Wilson's disease, etc.), myasthenia gravis, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease, etc.), endocrine ophthalmopathy, Grave's disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), Reiter's syndrome, non infection uveitis, autoimmune keratitis (e.g., keratoconjunctivitis sicca, vernal keratoconjunctivitis, etc.), interstitial lung fibrosis, psoriatic arthritis, etc.], dermatological disorders associated with PDE-IV enzyme (such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria), neurodegenerative disorders such as Parkinson disease, Alzheimer's disease, acute and chronic multiple sclerosis, cancer cachexia, viral infection, AIDS cachexia, thrombosis, and the like.
For therapeutic administration, the compound (I), or its prodrug, or a salt thereof can be administered alone or in the form of a mixture, preferably, with a pharmaceutical vehicle or carrier.
The active ingredient of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains a compound (I), as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external (topical), enteral, intravenous, intramuscular, parenteral or intra-mucous applications. The active ingredient can be formulated, for example, with the conventional non-toxic, pharmaceutically acceptable carriers for ointment, cream, plaster, tablets, pellets, capsules, suppositories, solution (saline, for example), emulsion, suspension (olive oil, for example), aerosols, pills, powders, syrups, injections, troches, cataplasms, aromatic waters, lotions, buccal tablets, sublingual tablets, nasal drops and any other form suitable for use. The carriers which can be used are water, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paster, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active compound is included in a pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the diseases.
The active ingredient can be formulated into, for example, preparations for oral application, preparations for injection, preparations for external application, preparations for inhalation, and preparations for application to mucous membranes.
Further, the compound of this invention can be used in combination with other therapeutic compounds. In particular, the combinations of the PDE4 inhibiting compound of this invention can be advantageously used in combination with i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii) COX-2 selective inhibitors, iv) statins, v) NSAIDs, vi) M2/M3 antagonists, vii) corticosteroids, viii) Hi (histamine) receptor antagonists, ix) beta 2 adrenoceptor agonist, x) interferon, xi) antiviral drugs for hepatitis C virus (HCV) such as protease inhibitor, helicase inhibitor, polymerase inhibitor, or the like, xii) antiviral drug for hepatitis B virus such as lamivudine, xiii) ursodesoxycholic acid, xiv) glycyrrhizin, xv) human grouth factor (HGF), xvi) aminosalicylic acid such as salazosulfapyridine, mesalazin, or the like, xvii) steroids such as prednisolone farnesylate, xviii) immunosuppressant such as azathioprine, 6-mercaptopurine, tacrolimus, and the like.
Mammals which may be treated by the present invention include livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and humans, preferably humans.
While the dosage of therapeutically effective amount of the compound (I) will vary depending upon the age and condition of each individual patient, an average single dose to a human patient of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, and 1000 mg of the compound (I) may be effective for treating the above-mentioned diseases. In general, amounts between 0.01 mg/body and about 1,000 mg/body may be administered per day.
In order to show the utilities of the pyrrolopyridazine derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention, pharmacological test data of the representative compound of the pyrrolopyridazine derivatives (I) are illustrated in the following.
(a) Inhibition of U937 Phosphodiesterase IV (PDE IV)
1. Test Method:
Cultured U937 cells were washed twice and harvested with phosphate-buffered saline (PBS) by cell-scraper. After centrifugation, the cell pellet was suspended in homogenizing buffer (0.5% deoxycholate [DOC], 5 mM 2-mercaptoethanol, 1 μM leupeptin, 100 μM PMSF, 20 μM p-tosyl-L-lysine-chloromethyl ketone [TLCK] in PBS). The cell suspension was then sonicated for a couple of minutes and homogenized by a glass-Teflon homogenizer with twenty strokes. The homogenate was centrifuged at 200 g for 30 minutes, and the supernatant was further ultra-centrifuged at 100,000×g for 90 minutes (4° C.). The final supernatant was dialyzed against dialysis buffer, which was the same component as homogenizing buffer without DOC. The dialysate of enzyme preparation was stored at −20° C. until assay.
PDE4, activity was estimated with a Phosphodiesterase [3H]cAMP SPA Enzyme Assay System (Amersham Pharmacia Biotech), using a 96 well Opti-plate. Reactions were initiated by addition of 0.025 μCi/well of [3H]cAMP to the enzyme mixture containing 50 mM Tris-HCl (pH 7.5), 8.3 mM MgCl2, 1.7 mM EGTA, and various concentrations of the test compound or vehicle. CI-930 (10 μM in final), a specific PDE3, inhibitor, was also added in the reaction mixture. After incubation at 30° C. for 15 minutes, 50 μL of SPA beads suspension was added to each well. The well-plate was then shaken for 20 minutes by a plate mixer. Radio-activity in each well was counted by a Top Counter.
Test compounds were dissolved in 100% dimethylsulfoxide (DMSO) and diluted into respective concentrations with the final solution containing 1% v/v of DMSO.
IC50 values of test compounds for the enzyme activity of PDE4 was determined from regression analysis for log-logit conversion values of percent inhibition in the compound-treated tubes compared to that of the control. Percent inhibition was calculated with the following equation: Inhibition (%)={1−(C−B)/(A−B)}×100; in which A, B and C means mean values of radio-activity counts (dpm) of control, blank and the compound-treated tubes, respectively.
2. Test Results
The following table illustrates the inhibitory activity on PDE-IV of the representative compound of formula (I):












Example
Compound name
IC50 (μM)







198
6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-
<1



methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid









(b) Inhibition on TNF-alpha Production in Human Mononuclear Cells

1. Test Method

(1) Human Peripheral Blood Mononuclear Cells (PBMCs) Preparation

Blood (30 ml for each person) was collected from the median cubital vein of healthy volunteer was divided 15 mL each in heparin containing conical tube and the same volume of RPMI1640 was added to each tube. Diluted blood was then piled up to 20 mL of Ficoll-Paque PLUS (Amersham Pharmacia Biotech) in polystyrene centrifuge tube. After centrifugation at 1,600 rpm for 30 minutes, cells gathering in the center area of the gradient were collected by capillary and washed with 40 mL of RPMI1640 in several times with centrifugation at 1,200 rpm for 10 minutes. PBMC finally precipitated were suspended in RPMI1640 containing 1% fetal bovine serum and antibiotics. After cell counting, final suspension at 3×106 cells/mL in culture medium was prepared.
(2) TNF-alpha Production from Stimulated PBMCs
Human PBMCs prepared by the density gradient method using Ficoll-Paque PLUS were suspended in the culture medium mentioned above with the concentration of 3×106 cells/mL and 0.5 mL of the suspension was sowed into each well of a 24-well culture plate. Cells were incubated in the CO2 incubator for 24 hours with 0.25 mL of LPS in addition of 0.25 mL of concentrations of drugs or vehicle at the start of the incubation. Final concentration of LPS in the incubation medium was 1 μg/mL. After 24 hours, the supernatant of each well by centrifugation at 1,700 rpm for 10 minutes was stored at −80° C. until assay. TNF-alpha levels in the medium were measured by ELISA.
The IC50 values of drugs on cytokine productions in LPS stimulated PBMC were estimated by the regression analysis for the relative values of cytokine level in the drug-treated wells compared to those of the vehicle-treated ones.
2. Test Results












Example
Compound name
IC50 (nM)







198
6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-
<100



methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid











BEST MODE FOR CARRYING OUT THE INVENTION
The following examples are provided to further illustrate details for the preparation of the compounds of the present invention. The examples are not intended to be limitations on the scope of the instant invention in any way, and they should not be so construed. Furthermore, the compounds described in the following examples are not to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
The starting materials and intermediates are prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
The abbreviations, symbols and terms used in the Preparations, Examples and Formulae have the following meanings.
DMF N,N-dimethylformamide
EtOAc or AcOEt Ethyl acetate
THF Tetrahydrofuran
Et3N Triethylamine
MeOH Methanol
EtOH Ethanol
BuOH Butanol
DCM Dichloromethane
Pd/C Palladium on carbon powder
Preparation 1
To a suspension of 2-pyridinethiol (17 g) in tetrahydrofuran (200 mL) was added triethylamine (15.5 g) in an ice-water bath under N2. To this was added a solution of 4-cyanobenzoyl chloride (25.3 g) in tetrahydrofuran (80 mL) below 10° C. over 30 minutes. After 15 minutes, the bath was removed and the mixture was stirred overnight at ambient temperature. The mixture was concentrated in vacuo. The residue was partitioned between chloroform and water. The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue (38 g) was triturated with isopropyl ether to give S-(2-pyridinyl) 4-cyanobenzenecarbothioate (325 g) as a pale brown solid.
S-(2-Pyridinyl) 4-cyanobenzenecarbothioate
NMR (CDCl3, 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 compound(s) was (were) obtained in substantially the same manner as that of Preparation 1.
Preparation 2
S-(2-Pyridinyl) 2-chloro-4-pyridinecarbothioate
NMR (CDCl3, δ): 7.40 (1H, m), 7.65-7.75 (2H, m), 7.75-7.90 (2H, m), 8.62 (1H, d, J=5 Hz), 8.70 (1H, m)
Preparation 4
S-(2-Pyridinyl) 3-cyanobenzenecarbothioate
NMR (CDCl3, δ): 7.39 (1H, m), 7.66 (1H, t, J=8 Hz), 7.72 (1H, t, J=8 Hz), 7.83 (1H, m), 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)
Preparation 5
S-(2-Pyridinyl) 3-methoxybenzenecarbothioate
NMR (CDCl3, δ): 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)
Preparation 6
S-(2-Pyridinyl) 4-pyridinecarbothioate
NMR (CDCl3, δ): 7.35-7.43 (1H, m), 7.73 (1H, d, J=8 Hz), 7.77-7.88 (3H, m), 8.70 (1H, d, J=7 Hz), 8.85 (2H, d, J=8 Hz) MS (ESI+): m/z 217
Preparation 7
S-(2-Pyridinyl) 2-pyrazinecarbothioate
NMR (CDCl3, 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)
Preparation 8
S-(2-Pyridinyl) 3-pyridinecarbothioate
NMR (CDCl3, δ): 7.37 (1H, m), 7.46 (1H, m), 7.73 (1H, m), 7.83 (1H, m), 8.27 (1H, m), 8.68 (1H, m), 8.84 (1H, m), 9.23 (1H, m)
Preparation 9
To a solution of 2-ethyl-1H-pyrrole in toluene (120 mL) was added dropwise 1M methylmagnesium bromide in tetrahydrofuran (170 mL) in a dry ice-acetone bath below −60° C. over 30 minutes. Then the mixture was stirred in an ice-water bath for 40 minutes. To this reaction mixture was added S-(2-pyridinyl) 4-cyanobenzenecarbothioate (15.2 g) portionwise over 10 minutes in a dryice-acetone bath. After 1.5 hours stirring, saturated ammonium chloride (100 mL) was added therein and the reaction mixture was allowed to ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1N sodium hydroxide (100 mL) twice, water, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with isopropyl ether to give 4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (12.7 g) as a pale yellow solid.
4-[(5-Ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile
NMR (CDCl3, δ): 1.32 (3H, t, J=8 Hz), 2.75 (2H, q, J=8 Hz), 6.11 (1H, d, J=5 Hz), 6.76 (1H, d, J=5 Hz), 7.77 (2H, d, J=8 Hz), 7.94 (2H, d, J=8 Hz), 9.49 (1H, br s) MS (ESI+): m/z 225 (M+H)
The following compound was obtained in substantially the same manner as that of Preparation 9.
Preparation 10
(2E)-1-(5-Ethyl-1H-pyrrol-2-yl)-3-phenyl-2-propen-1-one
NMR (CDCl3, δ): 1.31 (3H, t, J=7 Hz), 2.73 (2H, q, J=7 Hz), 6.10 (1H, m), 7.02 (1H, m), 7.27 (1H, d, J=16 Hz), 7.35-7.43 (3H, m), 7.63 (2H, m), 7.79 (1H, d, J=16 Hz) MS (ESI+): m/z 226 (M+H)
Preparation 11
To a solution of 4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]-benzonitrile (12.5 g) in N,N-dimethylformamide (63 mL) was added 60% sodium hydride in oil (2.68 g) in an ice-water bath under N2. After 30 minutes, to the mixture was added 1-(aminooxy)-2,4-dinitrobenzene (13.3 g). After 2 hours, the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water (100 mL) 3 times, 1N sodium hydroxide (100 mL), and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 500 mL) eluted with hexane-chloroform=1-2, 1-5, and 1-10 followed by triturated with isopropyl ether to give 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (8.1 g, 60.7%) as an yellow solid. The mixed fraction and the mother layer (7 g) were repurified by flash silica gel chromatography (silica gel, 200 mL) eluted with hexane-chloroform=2-1 and 1-1 followed by triturated with isopropyl ether to give 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (2.0 g, 15%) as a pale yellow solid.
4-[(1-Amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-benzonitrile
NMR (CDCl3, δ): 1.29 (3H, t, J=8 Hz), 2.77 (2H, q, J=8 Hz), 5.75 (2H, br s), 5.94 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.76 (2H, d, J=8 Hz), 7.85 (2H, d, J=8 Hz) MS (ESI+): m/z 240 (M+H)
The following compounds were obtained in substantially the same manner as that of Preparation 11.
Preparation 12
(1-Amino-5-ethyl-1H-pyrrol-2-yl)(2-chloro-4-pyridinyl)methanone
NMR (CDCl3, δ): 1.29 (3H, t, J=7 Hz), 2.77 (2H, q, J=7 Hz), 5.71 (2H, s), 5.96 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.50 (1H, d, J=4 Hz), 7.61 (1H, s), 8.52 (1H, d, J=4 Hz) MS: (m/z) 250 (M+H)
Preparation 13
3-[(1-Amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-benzonitrile
NMR (CDCl3, δ): 1.29 (3H, t, J=7 Hz), 2.77 (2H, q, J=7 Hz), 5.74 (2H, s), 5.94 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 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)
Preparation 14
(2E)-1-(1-Amino-5-ethyl-1H-pyrrol-2-yl)-3-phenyl-2-propen-1-one
NMR (CDCl3, δ): 1.28 (3H, t, J=7 Hz), 2.73 (2H, q, J=7 Hz), 5.93 (1H, d, J=5 Hz), 6.99 (1H, d, J=5 Hz), 7.30 (1H, d, J=16 Hz), 7.37-7.43 (3H, m), 7.62 (2H, m), 7.74 (1H, d, J=16 Hz) MS (ESI+): m/z 241 (M+H)
Preparation 15
(1-Amino-5-ethyl-1H-pyrrol-2-yl)(3-methoxyphenyl)-methanone
NMR (CDCl3, δ): 1.26 (3H, t, J=7 Hz), 2.75 (2H, q, J=7 Hz), 3.86 (3H, s), 5.79 (2H, s), 5.89 (1H, d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 7.07 (1H, m), 7.29-7.40 (3H, m) MS (ESI+): m/z 245
Preparation 16
(1-Amino-5-ethyl-1H-pyrrol-2-yl)(4-pyridinyl)methanone
NMR (CDCl3, δ): 1.29 (3H, t, J=7 Hz), 2.77 (2H, q, J=7 Hz), 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), 8.75 (2H, d, J=7 Hz) MS (ESI+): m/z 216
Preparation 17
(1-Amino-5-ethyl-1H-pyrrol-2-yl)(2-pyrazinyl)methanone
NMR (CDCl3, δ): 1.29 (3H, t, J=7 Hz), 2.77 (2H, q, 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)
Preparation 18
(1-Amino-5-ethyl-1H-pyrrol-2-yl)(3-pyridinyl)methanone
NMR (CDCl3, δ): 1.29 (3H, t, J=7 Hz), 2.77 (2H, q, J=7 Hz), 5.78 (2H, s), 5.94 (1H, d, J=4 Hz), 6.65 (1H, d, J=4 Hz), 7.39 (1H, m), 8.06 (1H, m), 8.74 (1H, m), 8.99 (1H, m)
Preparation 19
(1-Amino-5-ethyl-1H-pyrrol-2-yl)(5-bromo-3-pyridinyl)-methanone
NMR (CDCl3, δ): 1.29 (3H, t, J=7 Hz), 2.76 (2H, q, J=7 Hz), 5.72 (2H, s), 5.96 (1H, m), 6.65 (1H, m), 8.19 (1H, m), 8.70 (1H, m), 8.89 (1H, m)
Preparation 20
To a solution of tert-butyl 3-oxobutanoate (20.0 g) in tetrahydrofuran (200 mL) was added 60% sodium hydride in oil (556 g) portionwise over 20 minutes in an ice-water bath under N2. After 40 minutes, to the mixture was added ethyl 5-iodopentanoate (35.6 g) at the temperature. After 15 minutes, the mixture was stirred at ambient temperature. After 1 hour, the reaction mixture was heated at 50° C. for 24 hours. The cooled mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 1 L) eluting with hexane-ethyl acetate=50-1, 20-1, 10-1, and 8-1 to give 1-tert-butyl 7-ethyl 2-acetylheptanedioate (27.3 g, 75.4%) as colorless oil.
1-tert-Butyl 7-ethyl 2-acetylheptanedioate
NMR (CDCl3, δ): 1.20-1.38 (5H, m), 1.46 (9H, s), 1.54-1.71 (2H, m), 1.75-1.87 (2H, m), 2.12 (3H, s), 2.30 (2H, t, J=8 Hz), 3.30 (12H, t, J=8 Hz), 4.11 (2H, q, J=8 Hz)
The following compounds were obtained in substantially the same manner as that of Preparation 20.
Preparation 21
1-tert-Butyl 9-ethyl 2-acetylnonanedioate
NMR (CDCl3, δ): 1.23-1.33 (9H, m), 1.46 (9H, s), 1.55 (2H, m), 1.77 (2H, m), 2.21 (3H, s), 2.28 (2H, t, J=7 Hz), 3.27 (1H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz) MS (ESI+): m/z 315 (M+H)
Preparation 22
tert-Butyl 2-acetylhexanoate
NMR (CDCl3, δ): 0.90 (3H, t, J=8 Hz), 1.28-1.40 (4H, m), 1.46 (9H, s), 1.73-1.89 (2H, m), 2.22 (3H, s), 3.30 (1H, t, J=8 Hz)
Preparation 23
1-tert-Butyl 8-ethyl 2-acetyloctanedioate
NMR (CDCl3, δ): 1.21-1.33 (7H, m), 1.46 (9H, s), 1.54-1.69 (2H, m), 1.74-1.85 (2H, m), 2.21 (3H, s), 2.28 (2H, t, J=8 Hz), 3.29 (1H, t, J=8 Hz), 4.12 (2H, q, J=8 Hz)
Preparation 24
To a suspension of magnesium chloride (1.33 g) in dichloromethane (40 mL) was added 1-tert-butyl 7-ethyl 2-acetylheptanedioate (4.0 g) at ambient temperature under N2.
To this mixture was added dropwise pyridine (2.26 mL) in an ice-water bath. Then the mixture was stirred at ambient temperature for 40 minutes. To the reaction mixture was added a solution of 3-cyanobenzoyl chloride (3.01 g) in dichloromethane (6 mL) dropwise over 2 minutes. The reaction mixture was stirred at ambient temperature for 2 hours. To the mixture was added 1N hydrogen chloride and ethyl acetate in an ice-water bath. The organic layer was washed with 1N hydrogen chloride, water, and brine, dried over magnesium sulfate, and evaporated in vacuo to give a solid. The residue was purified by flash silica gel chromatography (silica gel, 300 mL) eluting with hexane-ethyl acetate=10-1, 8-1, 5-1, and 3-1 to give 1-tert-butyl 7-ethyl 2-acetyl-2-(3-cyanobenzoyl)heptanedioate (4.23 g, 72.9%) as colorless oil.
1-tert-Butyl 7-ethyl 2-acetyl-2-(3-cyanobenzoyl)-heptanedioate
NMR (CDCl3, δ): 1.25 (3H, t, J=8 Hz), 1.28-1.40 (11H, m), 1.63-1.75 (2H, m), 2.19-2.28 (2H, m), 2.32 (2H, t, J=8 Hz), 2.45 (3H, s), 4.11 (2H, q, 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), 8.06 (1H, br s) MS (ESI+): m/z 416 (M+H)
The following compounds were obtained in substantially the same manner as that of Preparation 24.
Preparation 25
Ethyl 2-isobutyryl-4-methyl-3-oxopentanoate
NMR (300 MHz, CDCl3, δ): 1.10-1.23 (12H, m), 1.30-1.43 (3H, m), 2.91-3.10 (2H, m), 4.21-4.36 (2H, m)
Preparation 26
Ethyl 2-(2-chlorobenzoyl)-4-methyl-3-oxopentanoate
NMR (300 MHz, CDCl3, δ): 0.79 (3H, t, J=75 Hz), 1.22 (6H, d, J=75 Hz), 3.36-3.54 (1H, m), 3.88 (2H, q, J=75 Hz), 7.26-7.44 (4H, m)
Preparation 27
Ethyl 4-methyl-2-(2-naphthoyl)-3-oxopentanoate
NMR (300 MHz, CDCl3, δ): 0.76-1.03 (3H, m), 1.10-1.30 (6H, m), 2.56-2.71 (1⁄2H, m), 2.88-3.04 (1⁄6H, m), 3.20-3.35 (1⁄3H, m), 3.72-4.336 (3H, m), 7.50-7.68 (2+1⁄3H, m), 7.82-8.01 (3+2⁄3H, m), 8.09 (1⁄3H, s), 8.35 (1⁄2H, s), 8.41 (1⁄6H, s) MS (ES+): m/e 313.45
Preparation 28
1-tert-Butyl 7-ethyl 2-acetyl-2-[3-(trifluoromethyl)benzoyl]heptanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.32 (9H, s), 1.36-1.75 (4H, m), 2.15-2.36 (4H, m), 2.45 (3H, s), 4.11 (2H, q, J=7 Hz), 7.56 (1H, t, J=8 Hz), 7.79 (1H, d, J=8 Hz), 7.93 (1H, d, J=8 Hz), 8.04 (1H, s)
Preparation 29
1-tert-Butyl 7-ethyl 2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyl]heptanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.27-1.42 (2H, m), 1.34 (9H, s), 1.65-1.77 (2H, m), 2.16-2.35 (4H, m), 2.39 (3H, s), 2.43 (3H, s), 4.10 (2H, q, J=7 Hz), 7.87 (1H, s), 8.56 (1H, s), 8.73 (1H, s) MS (ESI+): m/z 406 (M+H)
Preparation 30
1-tert-Butyl 7-ethyl 2-(methoxyacetyl)-2-[(3-methoxy-5isoxazolyl)carbonyl]heptanedioate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.39 (9H, s), 1.35-1.50 (2H, m), 1.64-1.75 (2H, m), 2.15-2.23 (2H, m), 2.32 (2H, t, J=7 Hz), 3.40 (3H, s), 4.01 (3H, s), 4.12 (2H, q, J=7 Hz), 4.57 (2H, s), 6.54 (1H, s)
Preparation 31
1-tert-Butyl 7-ethyl 2-acetyl-2-[3-(1,3-oxazol-5-yl)benzoyl]heptanedioate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.33 (9H, s), 1.30-1.43 (2H, m), 1.62-1.76 (2H, m), 2.17-2.35 (4H, m), 2.44 (3H, s), 4.09 (2H, q, J=7 Hz), 7.42 (1H, s), 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), 8.09 (1H, m)
Preparation 32
1-tert-Butyl 7-ethyl 2-acetyl-2-(3,4-dichlorobenzoyl)heptanedioate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.35 (9H, s), 1.63-1.74 (2H, m), 2.15-2.34 (4H, m), 2.41 (3H, s), 4.10 (2H, q, J=7 Hz), 7.48 (1H, d, J=8 Hz), 7.56 (1H, dd, J=2, 8 Hz), 7.88 (1H, d, J=2 Hz)
Preparation 33
1-tert-Butyl 7-ethyl 2-acetyl-2-[(4-chloro-2-pyridinyl)carbonyl]heptanedioate
NMR (CDCl3, δ): 1.23-1.30 (3H, m), 1.25 (9H, s), 1.40-1.58 (2H, m), 1.65-1.77 (2H, m), 2.10-2.21 (2H, m), 2.35 (2H, t, J=7 Hz), 2.61 (3H, s), 4.12 (2H, q, J=7 Hz), 7.39 (1H, m), 8.04 (1H, m), 8.43 (1H, d, J=5 Hz) MS (ESI+): m/z 426 (M+H)
Preparation 34
1-tert-Butyl 7-ethyl 2-[(5-chloro-2-thienyl)carbonyl]-2-(methoxyacetyl)heptanedioate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.25-1.40 (2H, m), 1.41 (9H, s), 1.62-1.74 (2H, m), 2.26-2.37 (4H, m), 3.37 (3H, s), 4.11 (2H, q, J=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)
Preparation 35
1-tert-Butyl 7-ethyl 2-acetyl-2-[(6-methoxy-2-pyrazinyl)carbonyl]heptanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.26 (9H, s), 1.38-1.49 (2H, m), 1.66-1.80 (2H, m), 2.14-2.26 (2H, m), 2.33 (2H, t, J=7 Hz), 2.57 (3H, s), 3.90 (3H, s), 4.12 (2H, q, J=7 Hz), 8.37 (1H, s), 8.83 (1H, s)
Preparation 36
1-tert-Butyl 7-ethyl 2-acetyl-2-(1-benzofuran-2-ylcarbonyl)heptanedioate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.33 (9H, s), 1.38-1.55 (2H, m), 1.64-1.77 (2H, m), 2.23-2.36 (4H, m), 2.49 (3H, s), 4.08 (2H, q, J=7 Hz), 7.32 (1H, m), 7.46 (2H, m), 7.54 (1H, s), 7.71 (1H, d, J=8 Hz)
Preparation 37
1-tert-Butyl 7-ethyl 2-acetyl-2-(1-benzothien-2-ylcarbonyl)heptanedioate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.30-1.45 (2H, m), 1.39 (9H, s), 1.62-1.75 (2H, m), 2.25-2.38 (4H, m), 2.40 (3H, s), 4.10 (2H, q, J=7 Hz), 7.36-7.51 (2H, m), 7.76 (1H, s), 7.82-7.88 (2H, m)
Preparation 38
1-tert-Butyl 7-ethyl 2-acetyl-2-(1,3-oxazol-5-ylcarbonyl)heptanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.30-1.45 (2H, m), 1.38 (9H, s), 1.63-1.77 (2H, m), 2.15-2.27 (2H, m), 2.30 (2H, t, J=7 Hz), 2.43 (3H, s), 4.10 (2H, q, J=7 Hz), 7.80 (1H, s), 7.93 (1H, s)
Preparation 39
1-tert-Butyl 7-ethyl 2-acetyl-2-benzoylheptanedioate
NMR (CDCl3, δ): 1.26 (3H, t, J=7 Hz), 1.20-1.40 (2H, m), 1.32 (9H, s), 1.60-1.73 (2H, m), 2.26-2.38 (4H, m), 2.40 (3H, s), 4.12 (2H, q, J=7 Hz), 7.36-7.78 (5H, m)
Preparation 40
1-tert-Butyl 7-ethyl 2-acetyl-2-(6-quinolinylcarbonyl)heptanedioate
NMR (CDCl3, δ): 1.21 (3H, t, J=7 Hz), 1.30 (9H, s), 1.32-1.47 (2H, m), 1.64-1.77 (2H, m), 2.26-2.38 (4H, m), 2.46 (3H, s), 4.08 (2H, q, J=7 Hz), 7.48 (1H, m), 8.04 (1H, dd, J=2 Hz, 8 Hz), 8.13 (1H, d, J=8 Hz), 8.23 (1H, d, J=8 Hz), 8.28 (1H, d, J=2 Hz), 9.00 (1H, m) MS (ESI+): m/z 442 (M+H)
Preparation 41
1-tert-Butyl 9-ethyl 2-acetyl-2-[4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoyl]-nonanedioate
NMR (CDCl3, δ): 1.23-1.37 (11H, m), 1.60 (9H, s), 2.15-2.31 (4H, m), 2.46 (3H, s), 4.12 (2H, q, J=7 Hz), 5.10 (2H, s), 7.26-7.40 (5H, m), 7.65 (1H, s, br), 7.84 (2H, d, J=9 Hz), 8.06 (2H, d, J=9 Hz)
Preparation 42
1-tert-Butyl 7-ethyl 2-acetyl-2-(2-chloroisonicotinoyl)heptanedioate
NMR (CDCl3, δ): 1.20-1.40 (14H, m), 1.61-1.75 (2H, m), 2.19-2.28 (2H, m), 2.20 (2H, t, J=8 Hz), 2.31 (2H, t, J=8 Hz), 2.46 (3H, s), 4.11 (2H, q, J=8 Hz), 7.41 (1H, dd, J=7, 1 Hz), 7.55 (1H, d, J=1 Hz), 8.50 (1H, d, J=7 Hz)
Preparation 43
1-tert-Butyl 7-ethyl 2-acetyl-2-[3-(methylsulfonyl)benzoyl]heptanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=8 Hz), 1.27-1.40 (11H, m), 1.61-1.75 (2H, m), 2.19-2.35 (4H, m), 2.46 (3H, s), 3.07 (3H, s), 4.10 (2H, q, J=8 Hz), 7.65 (1H, t, J=8 Hz), 7.99 (1H, dd, J=8, 1 Hz), 8.09 (2H, br d, J=8 Hz), 8.34 (1H, br s)
Preparation 44
1-tert-Butyl 7-ethyl 2-acetyl-2-(3-nitrobenzoyl)heptanedioate
NMR (CDCl3, δ): 1.30-1.39 (12H, m), 1.61-1.75 (2H, m), 2.19-2.35 (4H, m), 2.47(3H, s), 4.10 (2H, q, J=8 Hz), 7.63 (1H, t, J=8 Hz), 8.09 (1H, br d, J=8 Hz), 8.39 (1H, br d, J=8 Hz), 8.60 (1H, br s)
Preparation 45
tert-Butyl 2-acetyl-2-(4-cyanobenzoyl)hexanoate
NMR (CDCl3, δ): 0.90 (3H, t, J=8 Hz), 1.20-1.44 (13H, m), 2.15-2.25 (2H, m), 2.45 (3H, s), 7.70 (2H, d, J=8 Hz), 7.83 (2H, d, J=8 Hz)
Preparation 46
1-tert-Butyl 7-ethyl 2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]heptanedioate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.36 (9H, s), 1.32-1.45 (2H, m), 1.65-1.77 (2H, m), 2.18-2.28 (2H, m), 2.32 (2H, t, J=7 Hz), 2.45 (3H, s), 4.11 (2H, q, J=7 Hz), 8.20 (1H, m), 8.80 (2H, m) MS: (m/z) 470, 472 (M+H)
Preparation 47
1-tert-Butyl 7-ethyl 2-(2-chloroisonicotinoyl)-2-[(methylthio)acetyl]heptanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.37 (9H, s), 1.23-1.45 (2H, m), 1.63-1.77 (2H, m), 2.05 (3H, s), 2.16-2.28 (2H, m), 2.32 (2H, t, J=7 Hz), 3.16 (1H, d, J=17 Hz), 4.07 (1H, d, J=17 Hz), 4.11 (2H, q, J=7 Hz), 7.68 (1H, d, J=5 Hz), 7.87 (1H, s), 8.49 (1H, d, J=5 Hz)
Preparation 48
Ethyl 2-(4-fluorobenzoyl)-3-oxobutanoate
NMR (CDCl3, δ): (mixture of tautomers) 0.97 and 1.02 (3H, t, J=7 Hz), 2.07 and 2.42 (3H, s), 4.01 and 4.13 (2H, q, J=7 Hz), 7.06-7.18, 7.56, and 7.85 (4H, m) MS (ESI+): m/z 275 (M+H)
Preparation 49
1-tert-Butyl 8-ethyl 2-acetyl-2-(3-cyanobenzoyl)octanedioate
NMR (CDCl3, δ): 1.21-1.46 (16H, m), 1.56-1.70 (2H, m), 2.15-2.25 (2H, m), 2.29 (2H, t, J=8 Hz), 2.45 (3H, s), 4.12 (2H, q, 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), 8.05 (1H, br s)
Preparation 50
1-tert-Butyl 7-ethyl 2-acetyl-2-[(6-chloro-2-pyridinyl)carbonyl]heptanedioate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.27 (9H, s), 1.20-1.78 (4H, m), 2.08 (2H, t, J=7 Hz), 2.26-2.40 (2H, m), 2.69 (3H, s), 4.12 (2H, q, J=7 Hz), 7.43 (1H, d, J=8 Hz), 7.81 (1H, t, J=8 Hz), 7.96 (1H, d, J=8 Hz) MS (ESI+): m/z 426
Preparation 51
1-tert-Butyl 7-ethyl 2-acetyl-2-(3-methoxybenzoyl)heptanedioate
NMR (CDCl3, δ): 1.25 (3H, m), 1.34 (9H, s), 1.20-1.92 (4H, m), 2.10-2.38 (4H, m), 2.41 (3H, s), 3.84 (3H, s), 4.04-4.22 (2H, m), 7.08 (1H, br), 7.23-7.40 (3H, m)
Preparation 52
1-tert-Butyl 7-ethyl 2-acetyl-2-(3,5-dichlorobenzoyl)heptanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.26-1.40 (2H, m), 1.36 (9H, s), 1.63-1.76 (2H, m), 2.15-2.36 (4H, m), 2.43 (3H, s), 4.10 (2H, q, J=7 Hz), 7.51 (1H, m), 7.60 (2H, m)
Preparation 53
1-tert-Butyl 7-ethyl 2-acetyl-2-[(5-chloro-2-thienyl)carbonyl]heptanedioate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.40 (9H, s), 1.30-1.90 (4H, m), 2.20-2.35 (4H, m), 2.38 (3H, s), 4.11 (2H, q, J=7 Hz), 6.91 (1H, d, J=4 Hz), 7.32 (1H, d, J=4 Hz)
Preparation 54
1-tert-Butyl 7-ethyl 2-acetyl-2-(3-fluorobenzoyl)heptanedioate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.35 (9H, s), 1.35-1.45 (2H, m), 1.64-1.74 (2H, m), 2.16-2.35 (4H, m), 2.42 (3H, s), 4.09 (2H, q, J=7 Hz), 7.24 (1H, m), 7.35-7.43 (1H, m), 7.46-7.53 (2H, m)
Preparation 55
1-tert-Butyl 7-ethyl 2-acetyl-2-(3-quinolinylcarbonyl)heptanedioate
NMR (CDCl3, δ): 1.22 (3H, t, J=7 Hz), 1.33 (9H, s), 1.33-1.53 (2H, m), 1.65-1.78 (2H, m), 2.25-2.43 (4H, m), 2.47 (3H, s), 4.08 (2H, q, J=7 Hz), 7.63 (1H, t, J=8 Hz), 7.81-7.87 (1H, t, J=8 Hz), 7.91 (1H, d, J=8 Hz), 8.56 (1H, m), 9.24 (1H, m) MS (ESI+): m/z 442
Preparation 56
1-tert-Butyl 7-ethyl 2-acetyl-2-isonicotinoylheptanedioate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.31 (9H, s), 1.30-1.45 (2H, m), 1.65-1.76 (2H, m), 2.18-2.28 (2H, m), 2.31 (2H, t, J=7 Hz), 2.45 (3H, s), 4.10 (2H, q, J=7 Hz), 7.52 (2H, d, J=7 Hz), 8.75 (2H, d, J=7 Hz)
Preparation 57
1-tert-Butyl 7-ethyl 2-acetyl-2-[(3-methoxy-5-isoxazolyl)carbonyl]heptanedioate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.39 (9H, s), 1.35-1.50 (2H, m), 1.62-1.75 (2H, m), 2.11-2.23 (2H, m), 2.33 (2H, t, J=7 Hz), 2.49 (3H, s), 4.01 (3H, s), 4.11 (2H, q, J=7 Hz), 6.53 (1H, s)
Preparation 58
1-tert-Butyl 7-ethyl 2-acetyl-2-[(5-methyl-3-isoxazolyl)carbonyl]heptanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.31-1.48 (2H, m), 1.37 (9H, s), 1.63-1.75 (2H, m), 2.18-2.26 (2H, m), 2.31 (2H, t, J=7 Hz), 2.47 (3H, s), 2.50 (3H, s), 4.11 (2H, q, J=7 Hz), 6.38 (1H, s)
Preparation 59
1-tert-Butyl 7-ethyl 2-(2-chloroisonicotinoyl)-2-(methoxyacetyl)heptanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.32-1.45 (2H, m), 1.36 (9H, s), 1.64-1.78 (2H, m), 2.16-2.28 (2H, m), 2.31 (2H, t, J=7 Hz), 3.36 (3H, s), 4.11 (2H, q, 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, s), 8.50 (1H, d, J=5 Hz) MS (ESI+): m/z 456
Preparation 60
1-tert-Butyl 7-ethyl 2-(methoxyacetyl)-2-(3-methoxybenzoyl)heptanedioate
NMR (CDCl3, δ): 1.22 (3H, t, J=7 Hz), 1.25-1.33 (2H, m), 1.34 (9H, s), 1.60-1.75 (2H, m), 2.15-2.40 (4H, m), 3.38 (3H, s), 3.83 (3H, s), 4.08 (2H, q, J=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
Preparation 61
1-tert-Butyl 7-ethyl 2-(methoxyacetyl)-2-(6-quinolinylcarbonyl)heptanedioate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.32 (9H, s), 1.30-1.50 (2H, m), 1.65-1.78 (2H, m), 2.26-2.44 (4H, m), 3.38 (3H, s), 4.11 (2H, q, J=7 Hz), 4.38 (1H, d, J=17 Hz), 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), 8.28 (1H, d, J=8 Hz), 8.27 (1H, s), 9.01 (1H, m) MS (ESI+): m/z 472
Preparation 62
1-tert-Butyl 7-ethyl 2-(methoxyacetyl)-2-(3-pyridinylcarbonyl)heptanedioate
NMR (CDCl3, δ): 1.23 (3H, 1, J=7 Hz), 1.30-1.47 (2H, m), 1.35 (9H, s), 1.63-1.78 (2H, m), 2.22-2.38 (4H, m), 3.37 (3H, s), 4.10 (2H, q, J=7 Hz), 4.32 (1H, d, J=17 Hz), 4.45 (1H, d, J=17 Hz), 7.37 (1H, m), 8.03 (1H, m), 8.73 (1H, m), 8.92 (1H, m)
Preparation 63
1-tert-Butyl 7-ethyl 2-(3-chlorobenzoyl)-2-(methoxyacetyl)heptanedioate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.35 (9H, s), 1.20-1.50 (2H, m), 1.60-1.73 (2H, m), 2.25-2.35 (4H, m), 3.37 (3H, s), 4.12 (2H, q, J=7 Hz), 4.35 (1H, d, J=17 Hz), 4.50 (1H, d, J=17 Hz), 7.34 (1H, m), 7.48 (1H, d, J=8 Hz), 7.59 (1H, d, J=8 Hz), 7.73 (1H, m)
Preparation 64
1-tert-Butyl 7-ethyl 2-acetyl-2-(3-methylbenzoyl)heptanedioate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.30-1.40 (2H, m), 1.33 (9H, s), 1.60-1.72 (2H, m), 2.10-2.38 (4H, m), 2.21 (3H, s), 2.39 (3H, s), 4.10 (2H, q, J=7 Hz), 7.26-7.36 (2H, m), 7.48-7.62 (2H, m) MS (ESI+): m/z 405
Preparation 67
1-tert-Butyl 7-ethyl 2-(methoxyacetyl)-2-[(5-methyl-3-pyridinyl)carbonyl]heptanedioate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.36 (9H, s), 1.30-1.45 (2H, m), 1.62-1.76 (2H, m), 2.20-2.36 (4H, m), 2.40 (3H, s), 3.38 (3H, s), 4.10 (2H, q, J=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
Preparation 68
1-tert-Butyl 7-ethyl 2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]heptanedioate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.36 (9H, s), 1.32-1.45 (2H, m), 1.65-1.77 (2H, m), 2.18-2.28 (2H, m), 2.32 (2H, t, J=7 Hz), 2.45 (3H, s), 4.11 (2H, q, J=7 Hz), 8.20 (1H, m), 8.80 (2H, m) MS (ESI+): m/z 470, 472
Preparation 69
1-tert-Butyl 7-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2-(methoxyacetyl)heptanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.30-1.44 (2H, m), 1.37 (9H, s), 1.65-1.77 (2H, m), 2.18-2.36 (4H, m), 3.36 (3H, s), 4.10 (2H, q, J=7 Hz), 4.28 (1H, d, J=17 Hz), 4.40 (1H, d, J=17 Hz), 8.18 (1H, m), 8.80 (2H, m) MS (ESI+): m/z 500, 502
Preparation 70
1-tert-Butyl 7-ethyl 2-acetyl-2-[(5,6-dichloro-3-pyridinyl)carbonyl]heptanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.25-1.40 (2H, m), 1.38 (9H, s), 1.65-1.75 (2H, m), 2.18-2.27 (2H, m), 2.28-2.37 (2H, m), 2.44 (3H, s), 4.12 (2H, q, J=7 Hz), 8.13 (1H, d, J=2 Hz), 8.57 (1H, d, J=2 Hz)
Preparation 71
1-tert-Butyl 6-ethyl 2-(methoxyacetyl)-2-[(5-methyl-3-pyridinyl)carbonyl]hexanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.36 (9H, s), 1.60-1.80 (2H, m), 2.20-2.45 (4H, m), 2.39 (3H, s), 3.38 (3H, s), 4.12 (2H, q, J=7 Hz), 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
Preparation 72
1-tert-Butyl 5-ethyl 2-(methoxyacetyl)-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.37 (9H, s), 2.23-2.70 (4H, m), 2.39 (3H, s), 3.37 (3H, s), 4.12 (2H, q, J=7 Hz), 4.32 (1H, d, J=18 Hz), 4.43 (1H, d, J=18 Hz), 7.84 (1H, s), 8.55 (1H, s), 8.73 (1H, s) MS (ESI+): m/z 408
Preparation 73
1-tert-Butyl 6-ethyl 2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyl]hexanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.34 (9H, s), 1.60-1.75 (2H, m), 2.20-2.39 (4H, m), 2.39 (3H, s), 2.46 (3H, s), 4.11 (2H, q, J=7 Hz), 7.87 (1H, s), 8.56 (1H, s), 8.73 (1H, s) MS (ESI+): m/z 392
Preparation 74
1-tert-Butyl 5-ethyl 2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.36 (9H, s), 2.39 (3H, s), 2.44 (3H, s), 2.35-2.47 (2H, m), 2.56-2.70 (2H, m), 4.11 (2H, q, J=7 Hz), 7.88 (1H, s), 8.56 (1H, s), 8.74 (1H, s) MS (ESI+): m/z 378
Preparation 75
1-tert-Butyl 5-ethyl 2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]pentanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.37 (9H, s), 2.40 (2H, t, J=7 Hz), 2.59 (2H, t, J=7 Hz), 2.46 (3H, s), 4.13 (2H, q, J=7 Hz), 8.20 (1H, t, J=3 Hz), 8.81 (2H, dd, J=7, 3 Hz)
Preparation 76
1-tert-Butyl 7-ethyl 2-(3-cyanobenzoyl)-2-(methoxyacetyl)heptanedioate
NMR (CDCl3, δ): 1.20-1.41 (14H, m), 1.60-1.74 (2H, m), 2.27-2.34 (4H, m), 3.37 (83H, s), 4.10 (2H, q, J=8 Hz), 4.29 (1H, d, J=16 Hz), 4.46 (1H, d, J=16 Hz), 7.55 (1H, t, J=8 Hz), 7.80 (1H, dd, J=8, 1 Hz), 7.93 (1H, dd, J=8, 1 Hz), 8.04 (1H, br s)
Preparation 77
1-tert-Butyl 7-ethyl 2-[(acetyloxy)acetyl]-2-[(5-bromo-3-pyridinyl)carbonyl]heptanedioate
NMR (CDCl3, δ): 1.22-1.28 (5H, m), 1.36 (9H, s), 1.68 (2H, m), 2.14 (3H, s), 2.32 (2H, m), 4.11 (2H, q, J=7 Hz), 5.07 (1H, d, J=18 Hz), 5.34 (1H, d, J=18 Hz), 8.21 (1H, m), 8.81 (2H, m)
Preparation 78
To 1-tert-butyl 7-ethyl 2-acetyl-2-(3-cyanobenzoyl)-heptanedioate (4.2 g) was added trifluoroacetic acid (20 mL) in an ice-water bath. After 30 minutes, the bath was removed and the reaction mixture was stirred at ambient temperature. After 1 hour, the mixture was concentrated. The residue was dissolved in toluene and was evaporated in vacuo to give ethyl 6-(3-cyanobenzoyl)-7-oxooctanoate (3.20 g, 100.4%) as colorless oil.
Ethyl 6-(3-cyanobenzoyl)-7-oxooctanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=8 Hz), 1.28-1.40 (2H, m), 1.60-1.74 (2H, m), 1.91-2.14 (2H, m), 2.17 (3H, s), 2.31 (2H, t, J=8 Hz), 4.11 (2H, q, J=8 Hz), 4.39 (1H, t, J=8 Hz), 7.64 (1H, t, J=8 Hz), 7.87 (2H, dd, J=8, 1 Hz), 8.20 (2H, dd, J=8, 1 Hz), 8.26 (1H, br s) MS (ESI−): m/z 314 (M−H)
The following compounds were obtained in substantially the same manner as that of Preparation 78.
Preparation 79
Ethyl 7-oxo-6-[3-(trifluoromethyl)benzoyl]octanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.32-1.43 (2H, m), 1.62-1.77 (2H, m), 1.96-2.17 (2H, m), 2.17 (3H, s), 2.30 (2H, t, J=7 Hz), 4.11 (2H, q, J=7 Hz), 4.44 (1H, t, J=7 Hz), 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)
Preparation 80
Ethyl 6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate
NMR (CDCl3, δ): 1.26 (3H, t, J=7 Hz), 1.27-1.44 (2H, m), 1.65-1.75 (2H, m), 1.90-2.12 (2H, m), 2.17 (3H, s), 2.25-2.34 (2H, m), 2.43 (3H, s), 4.10 (2H, q, J=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)
Preparation 81
Ethyl 8-methoxy-6-[(3-methoxy-5-isoxazolyl)carbonyl]-7-oxooctanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.34-1.47 (2H, m), 1.65-1.74 (2H, m), 1.83-2.03 (2H, m), 2.29 (2H, t, J=7 Hz), 3.31 (3H, s), 4.05 (5H, s), 4.11 (2H, q, J=7 Hz), 4.51 (1H, t, J=7 Hz), 6.56 (1H, s) MS (ESI+): m/z 342 (M+H)
Preparation 82
Ethyl 6-[3-(1,3-oxazol-5-yl)benzoyl]-7-oxooctanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.33-1.46 (2H, m), 1.63-1.77 (2H, m), 1.95-2.17 (2H, m), 2.17 (3H, s), 2.30 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.46 (1H, t, J=7 Hz), 7.47 (1H, s), 7.56 (1H, t, J=8 Hz), 7.85-7.96 (2H, m), 7.98 (1H, s), 8.27 (1H, m)
Preparation 83
Ethyl 6-(3,4-dichlorobenzoyl)-7-oxooctanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.60-1.74 (2H, m), 1.91-2.14 (2H, m), 2.14 (3H, s), 2.30 (2H, t, J=7 Hz), 4.11 (2H, q, J=7 Hz), 4.34 (1H, t, J=7 Hz), 7.57 (1H, d, J=8 Hz), 7.78 (1H, dd, J=2, 8 Hz), 8.06 (1H, d, J=2 Hz)
Preparation 84
Ethyl 6-[(4-chloro-2-pyridinyl)carbonyl]-7-oxooctanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.34-1.48 (2H, m), 1.62-1.77 (2H, m), 1.80-2.10 (2H, m), 2.31 (2H, t, J=7 Hz), 2.34 (3H, s), 4.12 (2H, q, J=7 Hz), 4.83-4.92 (1H, m), 7.49 (1H, dd, J=2 Hz, 5 Hz), 8.04 (1H, d, J=2 Hz), 8.57 (1H, d, J=5 Hz) MS (ESI+): m/z 326 (M+H)
Preparation 85
Ethyl 6-[(5-chloro-2-thienyl)carbonyl]-8-methoxy-7-oxooctanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.32-1.42 (2H, m), 1.60-1.73 (2H, m), 1.84-2.06 (2H, m), 2.28 (2H, t, J=7 Hz), 3.30 (3H, s), 3.97 (1H, d, J=17 Hz), 4.06 (1H, d, J=17 Hz), 4.11 (2H, q, J=7 Hz), 4.40 (1H, t, J=7 Hz), 6.99 (1H, d, J=4 Hz), 7.56 (1H, d, J=4 Hz)
Preparation 86
Ethyl 6-[(6-methoxy-2-pyrazinyl)carbonyl]-7-oxooctanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.34-1.48 (2H, m), 1.60-1.78 (2H, m), 1.88-2.08 (2H, m), 2.31 (3H, s), 2.32 (2H, t, J=7 Hz), 4.01 (3H, s), 4.11 (2H, q, J=7 Hz), 4.62 (1H, t, J=7 Hz), 8.44 (1H, s), 8.81 (1H, s) MS (ESI+): m/z 323 (M+H)
Preparation 87
Ethyl 6-(1-benzofuran-2-ylcarbonyl)-7-oxooctanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.34-1.48 (2H, m), 1.62-1.76 (2H, m), 1.93-2.19 (2H, m), 2.24 (3H, s), 2.30 (2H, t, J=7 Hz), 4.10 (2H, q, J=7 Hz), 4.37 (1H, t, J=7 Hz), 7.34 (1H, t, J=8 Hz), 7.51 (1H, t, J=8 Hz), 7.56-7.65 (2H, m), 7.73 (1H, d, J=8 Hz) MS (ESI+): m/z 895 (M+H)
Preparation 88
Ethyl 6-(1-benzothien-2-ylcarbonyl)-7-oxooctanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.35-1.48 (2H, m), 1.60-1.80 (2H, m), 1.95-2.17 (2H, m), 2.19 (3H, s), 2.30 (2H, t, J=7 Hz), 4.10 (2H, q, J=7 Hz), 4.36 (1H, t, J=7 Hz), 7.38-7.53 (2H, m), 7.82-7.93 (2H, m), 8.05 (1H, s)
Preparation 89
Ethyl 6-(1,3-oxazol-5-ylcarbonyl)-7-oxooctanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.65-1.78 (2H, m), 1.92-2.10 (2H, m), 2.21 (3H, s), 2.32 (2H, t, J=7 Hz), 4.11 (3H, m), 7.88 (1H, s), 8.05 (1H, s)
Preparation 90
Ethyl 6-benzoyl-7-oxooctanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.29-1.42 (2H, m), 1.60-1.75 (2H, m), 1.92-2.12 (2H, m), 2.14 (3H, s), 2.29 (2H, t, J=7 Hz), 4.10 (2H, q, J=7 Hz), 4.43 (1H, t, J=7 Hz), 7.42-7.53 (2H, m), 7.55-7.64 (1H, m), 7.98 (2H, d, J=8 Hz)
Preparation 91
Ethyl 7-oxo-6-(6-quinolinylcarbonyl)octanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.36-1.48 (2H, m), 1.65-1.78 (2H, m), 2.00-2.18 (2H, m), 2.18 (3H, s), 2.30 (2H, t, J=7 Hz), 4.10 (2H, q, J=7 Hz), 4.58 (1H, t, J=8 Hz), 7.54 (1H, m), 8.18 (1H, d, J=8 Hz), 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)
Preparation 92
Ethyl 8-[4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoyl]-9-oxodecanoate
NMR (CDCl3, δ): 1.23-1.37 (9H, m), 1.55-1.68 (1H, s), 2.01 (2H, m), 2.18 (3H, s), 2.29 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.39 (1H, t, J=7 Hz), 5.11 (2H, s), 7.30-7.49 (5H, m), 7.74 (1H, s, br), 8.04-8.13 (4H, m) MS (ESI−): m/z 530 (M−H)
Preparation 93
Ethyl 7-(1,3-oxazol-5-yl)-7-oxoheptanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.41 (2H, m), 1.76 (2H, m), 2.03 (2H, m), 2.31 (2H, m), 3.20 (2H, m), 4.10 (2H, q, J=7 Hz), 7.94 (1H, s), 8.10 (1H, s)
Preparation 94
Ethyl 6-[3-(methylsulfonyl)benzoyl]-7-oxooctanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=8 Hz), 1.59-1.64 (2H, m), 1.91-2.15 (2H, m), 2.18 (3H, s), 2.30 (2H, t, J=8 Hz), 3.11 (3H, s), 4.10 (2H, q, J=8 Hz), 4.45 (1H, t, J=8 Hz), 7.23 (1H, t, J=8 Hz), 8.17 (1H, dd, J=8, 1 Hz), 8.25 (2H, br d, J=8 Hz), 8.53 (1H, br s) MS (ESI+): m/z 369 (M+H)
Preparation 95
Ethyl 6-(2-chloroisonicotinoyl)-7-oxooctanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=8 Hz), 1.30-1.40 (2H, m), 1.60-1.71 (2H, m), 1.90-2.14 (2H, m), 2.27 (3H, s), 2.25-2.74 (2H, m), 4.11 (2H, q, J=8 Hz), 4.32 (1H, t, J=8 Hz), 7.15 (1H, dd, J=7, 1 Hz), 7.76 (1H, d, J=1 Hz), 8.09 (1H, d, J=7 Hz) MS (ESI+): m/z 326 (M+H)
Preparation 96
Ethyl 6-(3-nitrobenzoyl)-7-oxooctanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=8 Hz), 1.29-1.41 (2H, m), 1.60-1.74 (2H, m), 1.91-2.16 (2H, m), 2.19 (3H, s), 2.30 (2H, t, J=8 Hz), 4.11 (2H, q, J=8 Hz), 4.46 (1H, t, J=8 Hz), 7.71 (1H, t, J=8 Hz), 8.30 (1H, br d, J=8 Hz), 8.45 (4H, br d, J=8 Hz), 8.80 (1H, br s) MS (ESI+): m/z 337 (M+H)
Preparation 97
4-(2-Acetylhexanoyl)benzonitrile
NMR (CDCl3, δ): 0.90 (3H, t, J=8 Hz), 1.18-1.44 (4H, m), 1.90-2.12 (2H, m), 2.17 (3H, s), 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)
Preparation 98
Ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-7-oxooctanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.32-1.43 (2H, m), 1.60-1.76 (2H, m), 1.96-2.15 (2H, m), 2.19 (3H, s), 2.30 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.36 (1H, t, J=7 Hz), 8.37 (1H, s), 8.87 (1H, br), 9.07 (1H, br) MS: (m/z) 370, 372 (M+H)
Preparation 99
Ethyl 6-(2-chloroisonicotinoyl)-8-(methylthio)-7-oxooctanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.34-1.47 (2H, m), 1.60-1.77 (2H, m), 1.92 (3H, s), 1.93-2.05 (2H, m), 2.30 (2H, t, J=7 Hz), 3.19 (1H, d, J=17 Hz), 3.26 (1H, d, J=17 Hz), 4.11 (2H, q, J=7 Hz), 4.68 (1H, t, J=7 Hz), 7.72 (1H, d, J=5 Hz), 7.86 (1H, s), 8.57 (1H, d, J=5 Hz) MS: (m/z) 370 (M−H), 372 (M+H)
Preparation 100
Ethyl 7-(3-cyanobenzoyl)-8-oxononanoate
NMR (CDCl3, δ): 1.21-1.44 (7H, m), 1.55-1.69 (2H, m), 1.89-2.15 (2H, m), 2.17 (3H, s), 2.29 (2H, t, J=8 Hz), 4.12 (2H, q, J=8 Hz), 4.39 (1H, t, J=8 Hz), 7.64 (1H, t, J=8 Hz), 7.87 (1H, dd, J=8, 1 Hz), 8.20 (1H, dd, J=8, 1 Hz), 8.27 (1H, br s) MS (ESI+): m/z 330 (M+H)
Preparation 101
Ethyl 6-[(6-chloro-2-pyridinyl)carbonyl]-7-oxooctanoate
NMR (CDCl3, δ): 1.26 (3H, t, J=7 Hz), 1.36-1.52 (2H, m), 1.63-1.75 (2H, m), 1.77-2.06 (2H, m), 2.29 (2H, t, J=7 Hz), 2.45 (3H, s), 4.12 (2H, q, J=7 Hz), 4.82 (1H, t, J=7 Hz), 7.51 (1H, d, J=8 Hz), 7.82 (1H, t, J=8 Hz), 7.97 (1H, d, J=8 Hz) MS (ESI+): m/z 326
Preparation 102
Ethyl 6-(3-methoxybenzoyl)-7-oxooctanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.60-1.77 (2H, m), 1.92-2.12 (2H, m), 2.15 (3H, s), 2.31 (2H, t, J=7 Hz), 3.88 (3H, s), 4.12 (2H, q, 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
Preparation 103
Ethyl 6-(3,5-dichlorobenzoyl)-7-oxooctanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.32-1.42 (2H, m), 1.63-1.75 (2H, m), 1.90-2.12 (2H, m), 2.16 (3H, s), 2.30 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.32 (1H, t, J=7 Hz), 7.58 (1H, m), 7.82 (2H, m)
Preparation 104
Ethyl 6-[(5-chloro-2-thienyl)carbonyl]-7-oxooctanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.30-1.40 (2H, m), 1.62-1.74 (2H, m), 1.90-2.12 (2H, m), 2.16 (3H, s), 2.29 (2H, t, J=7 Hz), 4.13 (2H, q, J=7 Hz), 4.14 (1H, m), 6.98 (1H, d, J=4 Hz), 7.58 (1H, d, J=4 Hz)
Preparation 105
Ethyl 6-(3-fluorobenzoyl)-7-oxooctanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.28-1.42 (2H, m), 1.60-1.75 (2H, m), 1.90-2.13 (2H, m), 2.14 (3H, s), 2.29 (2H, t, J=7 Hz), 4.11 (2H, q, J=7 Hz), 4.37 (1H, t, J=7 Hz), 7.26-7.33 (1H, m), 7.43-7.52 (1H, m), 7.63-7.68 (1H, m), 7.76 (1H, d, J=8 Hz) MS (ESI+): m/z 309
Preparation 106
Ethyl 7-oxo-6-(3-quinolinylcarbonyl)octanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.35-1.47 (2H, m), 1.63-1.77 (2H, m), 1.98-2.18 (2H, m), 2.20 (3H, s), 2.31 (2H, t, J=7 Hz), 4.10 (2H, q, J=7 Hz), 4.55 (1H, t, J=7 Hz), 7.66 (1H, t, J=8 Hz), 7.87 (1H, t, J=8 Hz), 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
Preparation 107
Ethyl 6-isonicotinoyl-7-oxooctanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.26-1.45 (2H, m), 1.60-1.75 (2H, m), 1.94-2.07 (2H, m), 2.17 (3H, s), 2.27-2.35 (2H, m), 4.11 (2H, q, J=7 Hz), 4.38 (1H, t, J=7 Hz), 7.74 (2H, m), 8.83 (2H, m)
Preparation 108
Ethyl 6-[(3-methoxy-5-isoxazolyl)carbonyl]-7-oxooctanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.33-1.45 (2H, m), 1.60-1.80 (2H, m), 1.88-2.05 (2H, m), 2.28 (3H, s), 2.30-2.45 (2H, m), 4.03 (3H, s), 4.11 (2H, q, J=7 Hz), 4.33 (1H, t, J=7 Hz), 6.56 (1H, s) MS (ESI+): m/z 312
Preparation 109
Ethyl 6-[(5-methyl-3-isoxazolyl)carbonyl]-7-oxooctanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.32-1.44 (2H, m), 1.61-1.74 (2H, m), 1.85-2.07 (2H, m), 2.26-2.38 (2H, m), 2.29 (3H, s), 2.49 (3H, s), 4.11 (2H, q, J=7 Hz), 4.64 (1H, m), 6.39 (1H, s) MS (ESI+): m/z 296
Preparation 110
Ethyl 6-(2-chloroisonicotinoyl)-8-methoxy-7-oxooctanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.28-1.43 (2H, m), 1.66 (2H, t, J=7 Hz), 1.73-1.86 (1H, m), 1.93-2.07 (1H, m), 2.73 (2H, t, J=7 Hz), 3.23 (3H, s), 3.89 (1H, d, J=17 Hz), 4.00 (1H, d, J=17 Hz), 4.10 (2H, q, J=7 Hz), 4.58 (1H, t, J=7 Hz), 7.66 (1H, d, J=5 Hz), 7.78 (1H, s), 8.60 (1H, d, J=5 Hz) MS (ESI+): m/z 356, MS (ESI−): m/z 354
Preparation 111
Ethyl 8-methoxy-6-(3-methoxybenzoyl)-7-oxooctanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.60-1.73 (2H, m), 1.79-2.04 (2H, m), 2.28 (2H, t, J=7 Hz), 3.27 (3H, s), 3.87 (3H, s), 4.00 (2H, m), 4.12 (2H, q, J=7 Hz), 4.66 (1H, t, J=7 Hz), 7.13 (1H, m), 7.39 (1H, m), 7.45-7.55 (2H, m)
Preparation 112
Ethyl 8-methoxy-7-oxo-6-(6-quinolinylcarbonyl)octanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.34-1.47 (2H, m), 1.60-1.75 (2H, m), 1.86-2.10 (2H, m), 2.27 (2H, t, J=7 Hz), 3.24 (3H, s), 4.02-4.10 (2H, m), 4.12 (2H, q, J=7 Hz), 4.83 (1H, t, J=7 Hz), 7.48-7.55 (1H, m), 8.16-8.33 (3H, m), 8.49 (1H, m), 9.02 (1H, m) MS (ESI+): m/z 372
Preparation 113
Ethyl 8-methoxy-7-oxo-6-(3-pyridinylcarbonyl)octanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.31-1.45 (2H, m), 1.60-1.73 (2H, m), 1.75-2.08 (2H, m), 2.28 (2H, t, J=7 Hz), 3.24 (3H, s), 3.94 (1H, d, J=17 Hz), 4.00 (1H, d, J=17 Hz), 4.10 (2H, q, J=7 Hz), 4.67 (1H, t, J=7 Hz), 7.44 (1H, m), 8.22 (1H, m), 8.81 (1H, d, J=5 Hz), 9.18 (1H, m) MS (ESI+): m/z 322
Preparation 114
Ethyl 6-(3-chlorobenzoyl)-8-methoxy-7-oxooctanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.30-1.44 (2H, m), 1.60-1.74 (2H, m), 1.75-1.92 (1H, m), 1.94-2.10 (1H, m), 2.28 (2H, t, J=7 Hz), 3.25 (3H, s), 3.93 (1H, d, J=17 Hz), 4.02 (1H, d, J=17 Hz), 4.12 (2H, q, J=7 Hz), 4.63 (1H, t, J=7 Hz), 7.43 (1H, t, J=8 Hz), 7.57 (1H, d, J=8 Hz), 7.83 (1H, d, J=8 Hz), 7.94 (1H, s)
Preparation 115
Ethyl 6-(3-methylbenzoyl)-7-oxooctanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.29-1.42 (2H, m), 1.60-1.73 (2H, m), 1.90-2.06 (2H, m), 2.13 (3H, s), 2.28 (2H, t, J=7 Hz), 2.42 (3H, s), 4.10 (2H, q, J=7 Hz), 4.42 (1H, t, J=7 Hz), 7.31-7.43 (2H, m), 7.73-7.78 (2H, m)
Preparation 118
Ethyl 8-methoxy-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.30-1.47 (2H, m), 1.60-1.74 (2H, m), 1.75-1.93 (1H, m), 1.93-2.08 (1H, m), 2.26 (2H, t, J=7 Hz), 2.43 (3H, s), 3.25 (3H, s), 3.95 (1H, d, J=17 Hz), 4.03 (1H, d, J=17 Hz), 4.12 (2H, q, J=7 Hz), 4.67 (1H, t, J=7 Hz), 8.03 (1H, s), 8.63 (1H, s), 8.98 (1H, s) MS (ESI+): m/z 336
Preparation 119
Ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-7-oxooctanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.32-1.43 (2H, m), 1.60-1.76 (2H, m), 1.96-2.15 (2H, m), 2.19 (3H, s), 2.30 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.36 (1H, t, J=7 Hz), 8.37 (1H, s), 8.87 (1H, br), 9.07 (1H, br) MS (ESI+): m/z 370, 372
Preparation 120
Ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-8-methoxy-7-oxooctanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.30-1.47 (2H, m), 1.60-1.72 (2H, m), 1.75-1.93 (1H, m), 1.95-2.08 (1H, m), 2.27 (2H, t, J=7 Hz), 3.25 (3H, s), 3.93 (1H, d, J=17 Hz), 4.02 (1H, d, J=17 Hz), 4.10 (2H, q, J=7 Hz), 4.63 (1H, t, J=7 Hz), 8.38 (1H, m), 8.88 (1H, m), 9.07 (1H, m) MS (ESI+): m/z 400, 402
Preparation 121
Ethyl 6-[(5,6-dichloro-3-pyridinyl)carbonyl]-7-oxooctanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.60-1.77 (2H, m), 1.95-2.17 (2H, m), 2.19 (3H, s), 2.30 (2H, t, J=7 Hz), 4.11 (2H, q, J=7 Hz), 4.32 (1H, t, J=7 Hz), 8.31 (1H, d, J=2 Hz), 8.82 (1H, d, J=2 Hz)
Preparation 122
Ethyl 7-methoxy-5-[(5-methyl-3-pyridinyl)carbonyl]-6-oxoheptanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.60-1.75 (2H, m), 1.78-1.95 (1H, m), 1.95-2.12 (1H, m), 2.32 (2H, t, J=7 Hz), 2.44 (3H, s), 3.25 (3H, s), 3.94 (1H, d, J=18 Hz), 4.02 (1H, d, J=18 Hz), 4.12 (2H, q, J=7 Hz), 4.69 (1H, t, J=7 Hz), 8.04 (1H, s), 8.63 (1H, s), 9.00 (1H, s) MS (ESI+): m/z 322
Preparation 123
Ethyl 6-methoxy-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 2.08-2.55 (4H, m), 2.44 (3H, s), 3.23 (3H, s), 3.94 (1H, d, J=18 Hz), 4.01 (1H, d, J=18 Hz), 4.12 (2H, q, J=7 Hz), 4.88 (1H, m), 8.12 (1H, s), 8.64 (1H, s), 9.04 (1H, s) MS (ESI+): m/z 308
Preparation 124
Ethyl 5-[(5-methyl-3-pyridinyl)carbonyl]-6-oxoheptanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.60-1.75 (2H, m), 1.96-2.13 (2H, m), 2.18 (3H, s), 2.36 (2H, t, J=7 Hz), 2.43 (3H, s), 4.12 (2H, q, J=7 Hz), 4.43 (1H, t, J=7 Hz), 8.04 (1H, s), 8.63 (1H, s), 8.97 (1H, s) MS (ESI+): m/z 292
Preparation 125
Ethyl 4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 2.20 (3H, s), 2.26-2.48 (4H, m), 2.43 (3H, s), 4.13 (2H, q, J=7 Hz), 4.62 (1H, t, J=7 Hz), 8.08 (1H, s), 8.64 (1H, s), 9.02 (1H, s) MS (ESI+): m/z 278
Preparation 126
Ethyl 4-[(5-bromo-3-pyridinyl)carbonyl]-5-oxohexanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 2.26 (3H, s), 2.30 (2H, t, J=7 Hz), 2.43 (2H, t, J=7 Hz), 4.15 (2H, q, J=7 Hz), 8.65(1H, s), 8.94 (1H, s), 9.22(1H, s)
Preparation 127
Ethyl 6-(3-cyanobenzoyl)-8-methoxy-7-oxooctanoate
NMR (CDCl3, δ): 1.19-1.43 (12H, m), 1.57-1.70 (2H, m), 1.80 (1H, m), 1.99 (1H, m), 2.28 (2H, t, J=8 Hz), 3.24 (3H, s), 3.91 (1H, d, J=16 Hz), 4.01 (1H, d, J=16 Hz), 4.09 (2H, q, J=8 Hz), 4.65 (1H, t, J=8 Hz), 7.64 (1H, t, J=8 Hz), 7.87 (1H, dd, J=8, 1 Hz), 8.18 (1H, dd, J=8, 1 Hz), 8.25 (1H, br s)
Preparation 128
Ethyl 8-(acetyloxy)-6-[(5-bromo-3-pyridinyl)carbonyl]-7-oxooctanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.37 (2H, m), 1.67 (2H, m), 1.98-2.06 (5H, m), 2.30 (2H, t, J=7 Hz), 4.11 (2H, q, J=7 Hz), 4.47 (1H, t, J=7 Hz), 4.66 (d, J=17 Hz), 4.74 (d, J=17 Hz), 8.37 (1H, m), 8.88 (1H, m), 9.06 (1H, m)
Preparation 129
To a solution of Meldrum's acid (30 g, 0.208 mol) in dichloromethane (420 mL) was added pyridine (33.7 mL, 0.416 mol) over 3 minutes in an ice-methanol bath under nitrogen atmosphere (−9° C.). To this mixture was added dropwise a solution of methoxyacetyl chloride (24.8 g) in dichloromethane (180 mL) over 1 hour period at the temperature. After addition, the reaction mixture was stirred at the temperature for 1 hour and at ambient temperature for 2 hours. The mixture was quenched with 1N hydrochoric acid (600 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give 5-(methoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione as dark orange oil (38.1 g, 84.7%).
5-(Methoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
NMR (CDCl3, δ): 1.75 (6H, s), 3.53 (3H, s), 4.87 (2H, s)
Preparation 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 refluxed for 2 hours under nitrogen atmosphere. The mixture was evaporated in vacuo to give brown oil (325 g). The residue was dissolved in hexane-ethyl acetate=2-1 (200 mL) and was added silica gel (65 g) therein. After stirring for 30 minutes at ambient temperature, the mixture was filtered and washed with hexane-ethyl acetate=2-1 (200 mL). The filtrate was concentrated in vacuo to give tert-butyl 4-methoxy-3-oxobutanoate as pale yellow oil (30.1 g, 91.0%).
tert-Butyl 4-methoxy-3-oxobutanoate
NMR (CDCl3, δ): 150 (9H, s), 3.41 (2H, s), 3.43 (3H, s), 4.08 (2H, s)
Preparation 131
To a mixture of 3-formylbenzoic acid (500 mg) and p-toluenesulfonylmethyl isocyanide (715 mg) in methanol (20 mL) was added potassium carbonate (1.38 g) and the mixture was heated under reflux for 2 hours. After evaporation of solvent, the residue was partitioned between ethyl acetate and water. The aqueous layer was separated and acidified with 1N hydrochloric acid. The resulting precipitates were collected and washed with water, methanol and ether to give 3-(1,3-oxazol-5-yl)benzoic acid as a colorless amorphous powder (484 mg).
3-(1,3-Oxazol-5-yl)benzoic acid
NMR (DMSO-d6, δ): 7.63 (1H, t, J=8 Hz), 7.84 (1H, s), 7.89-8.02 (2H, m), 8.25 (1H, m), 8.50 (1H, s), 13.22 (1H, br) MS (ESI+): m/z 188 (M−H)
Preparation 132
A mixture of 1-(3-chlorophenyl)-1,3-butanedione (500 mg), 5-(iodomethyl)-2,2-dimethyl-1,3-dioxane (716 mg), and potassium carbonate (351 mg) in dimethylsulfoxide (2.5 mL) was stirred for 14 hours at room temperature and 7 hours at 40° C. The mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with water (10×2 mL) and brine, dried over magnesium sulfate, and evaporated to give a brown oil. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-10 to 2-5 afforded 1-(3-chlorophenyl)-2-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-1,3-butanedione as an yellow oil (614 mg).
1-(3-Chlorophenyl)-2-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-1,3-butanedione
NMR (CDCl3, δ): 1.39 (6H, s), 1.70 (1H, m), 1.91-2.15 (2H, m), 2.16 (3H, s), 3.61 (2H, m), 3.88 (2H, m), 4.46 (1H, t, J=7 Hz), 7.44 (1H, t, J=9 Hz), 7.57 (1H, m), 7.86 (1H, d, J=9 Hz), 7.96 (1H, m)
The following compounds were obtained in substantially the same manner as that of Preparation 132.
Preparation 133
1-tert-Butyl 7-ethyl 2-(1,3-oxazol-5-ylcarbonyl)heptanedioate
NMR (CDCl3, δ): 1.26 (3H, t, J=7 Hz), 1.32-1.38 (11H, m), 1.67 (2H, m), 1.97 (2H, m), 2.30 (2H, m), 3.86 (1H, t, 3=7 Hz), 4.11 (2H, q, J=7 Hz), 7.86 (1H, s), 8.03 (1H, s)
Preparation 134
1-tert-Butyl 7-ethyl 2-[(3,5-dimethyl-4-isoxazolyl)carbonyl]heptanedioate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.33-1.41 (11H, m), 1.64 (2H, m), 1.93 (2H, m), 2.30 (2H, m), 2.47 (3H, s), 2.69 (2H, s), 3.79 (1H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz)
Preparation 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 pyridine (25 ml) was added. The mixture was stirred at 20° C. for 30 minutes, then a solution of 4-fluorobenzoyl chloride (2.44 g) in tetrahydrofuran (10 ml) was added at 0° C. After stirring at 20° C. for 2 hours, the mixture was partitioned between 0.5N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 2-(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate (2.15 g) as an oil.
Ethyl 2-(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate
(mixture of tautomers, too complicated to be assigned)
Preparation 136
A mixture of 1-(4-fluorophenyl)butane-1,3-dione (1.0 g), potassium carbonate (3.42 g), and tetrabutylammonium bromide (20 mg) in toluene (10 ml) was refluxed for 3 hours. After cooling to 20° C., ethyl bromoacetate (0.74 ml) was added to the mixture. After being allowed to stand at 20° C. overnight, the mixture was partitioned between ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 3-(4-fluorobenzoyl)-4-oxopentanoate (964 mg) as an oil.
Ethyl 3-(4-fluorobenzoyl)-4-oxopentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 2.18 (3H, s), 3.01 (2H, d, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.95 (1H, d, J=7 Hz), 7.18 (2H, dt, J=2, 7 Hz), 8.07 (2H, ddd, J=2, 5, 7 Hz)
Preparation 137
A mixture of 1-(4-fluorophenyl)butane-1,3-dione (1.0 g), potassium carbonate (3.84 g), and tetrabutylammonium bromide (90 mg) in toluene (20 ml) was refluxed for 3 hours, then ethyl 6-bromohexanoate (1.18 ml) was added. After stirring at 100° C. for 3 hours, the mixture was partitioned between ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 7-(4-fluorobenzoyl)-8-oxononanoate (983 mg) as an oil.
Ethyl 7-(4-fluorobenzoyl)-8-oxononanoate
NMR (CDCl3, 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), 2.13 (3H, s), 2.27 (2H, t, J=7 Hz), 4.11 (2H, q, 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)
Preparation 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 dimethylsulfoxide (30 ml) was stirred at 20° C. overnight, then pentane-2,4-dione (5 g) was added. After stirring at 20° C. overnight, the mixture was partitioned between ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 8-acetyl-9-oxodecanoate (55 g) as an oil.
Ethyl 7-acetyl-8-oxononanoate
(mixture of tautomers, too complicated to be assigned)
Preparation 139
To a mixture of ethyl 7-acetyl-8-oxononanoate (4.0 g) and magnesium chloride (1.27 g) in dichloromethane (70 ml) was added pyridine (2.15 ml) at 0° C. The mixture was stirred at 20° C. for 1 hour, then a solution of 4-cyanobenzoyl chloride (2.87 g) in dichloromethane (10 ml) was added. After stirring for 3 hours at 20° C., the mixture was partitioned between ether and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 7-acetyl-7-(4-cyanobenzoyl)-8-oxononanoate (352 g) as an oil.
1-tert-Butyl 8-ethyl 2-acetyl-2-(4-cyanobenzoyl)octanedioate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.25-1.45 (4H, m), 1.30 (9H, s), 1.55-1.70 (2H, m), 2.20 (2H, t, J=7 Hz), 2.28 (2H, t, J=7 Hz), 2.44 (3H, s), 4.12 (2H, q, J=7 Hz), 7.72 (2H, t, J=9 Hz), 7.83 (2H, d, J=9 Hz)
Preparation 140
Ethyl 7-acetyl-7-(4-cyanobenzoyl)-8-oxononanoate (3.5 g) was dissolved in trifluoroacetic acid (12.6 ml) and the mixture was stirred at 20° C. for 15 minutes. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, aqueous sodium bicarbonate and brine, dried over MgSO4 (magnesium sulfate), and evaporated to give ethyl 7-(4-cyanobenzoyl)-8-oxononanoate (2.25 g) as an oil.
Ethyl 7-(4-cyanobenzoyl)-8-oxononanoate
NMR (CDCl3, δ): 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), 2.16 (3H, s), 2.28 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.40 (1H, t, J=7 Hz), 7.80 (2H, t, J=9 Hz), 8.07 (2H, d, J=9 Hz)
Preparation 141
A mixture of methyl 4-(aminosulfonyl)benzoate (5.10 g) and potassium carbonate (655 g) in dimethoxyethane (50 mL) was refluxed for 5 minutes. After cooling the mixture, a solution of benzyl chloridocarbonate (5.25 g) in dimethoxyethane (30 mL), and the resulting mixture was refluxed for 1 hour. The reaction was quenched by adding 1N hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (200 mL), and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give a pale yellow oil, which was solidified upon standing. The solid was triturated in diisopropyl ether (30 mL) to give methyl 4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoate as a white powder (3.38 g).
Methyl 4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoate
NMR (CDCl3, δ): 3.98 (3H, s), 5.10 (2H, s), 7.22 (2H, m), 7.34 (3H, m), 7.64 (1H, s, br), 8.08 (2H, d, J=9 Hz), 8.16 (2H, d, J=9 Hz)
Preparation 142
A suspension of methyl 4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoate (3.38 g) and 85% pottasium hydroxide (1.28 g) in methanol (40 mL) was stirred for 35 minutes. Methanol was evaporated off, and to the mixture was added 1N hydrochloric acid (20 mL). A white crystal was formed, which was collected by filtration and washed with water and diisopropyl ether, and dried under vacuum. 4-({[(Benzyloxy)carbonyl]amino}sulfonyl)benzoic acid was obtained as a white crystal (2.92 g).
4-({[(Benzyloxy)carbonyl]amino}sulfonyl)benzoic acid
NMR (DMSO-d6, δ): 5.06 (2H, s), 7.25 (2H, m), 7.33 (3H, m), 8.00 (2H, d, J=9 Hz), 8.15 (2H, d, J=9 Hz) MS (ESI−): m/z 334 (M−H)
Preparation 143
To a suspension of S-(2-pyridinyl) 3-cyanobenzenecarbothioate (2.40 g) in toluene (10 mL) was added titanium chloride (1.99 g) under an ice-methanol bath over 5 minutes (−7 to −2° C.). After stirring for 10 minutes, a solution of 2-ethyl-1H-pyrrole (1.00 g) in toluene (10 mL) was added over 5 minutes (−4 to 0° C.). The resulting heterogeneous mixture was stirred for 15 hours at room temperature. Ethyl acetate (20 mL) and water (20 mL) were added, and the mixture was filtered through celite. The filtrate was diluted with ethyl acetate (80 mL) and water (30 mL), and organic extract was washed with water (30 mL), 1N sodium hydroxide (50 mL), and brine (50 mL), dried over magnesium sulfate, and evaporated to give a dark colored crystal (2.46 g). The crystal was triturated in diisopropyl ether (10 mL) to give 3-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile as a brown crystal (157 g, 70.1%).
3-[(5-Ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile
NMR (CDCl3, δ): 1.33 (3H, t, J=7 Hz), 2.75 (2H, q, 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, br)
Preparation 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 under an ice-bath. Then, pyridine (5.00 g) was added over 15 minutes. After stirring for 1 hour at room temperature, the resulting mixture was cooled under the ice-bath. A solution of 2-chlorobenzoyl chloride (4.98 g) in tetrahydrofuran (30 mL) was added over 15 minutes. The mixture was stirred for 1 hour at room temperature. The reaction was quenched by adding 1N hydrochloric acid (65 mL). The mixture was filtered, and the solvent was evaporated off. The residue was extracted with ethyl acetate (150 mL). The extract was washed with water (100 mL), saturated sodium bicarbonate (100 mL), and brine, dried over magnesium sulfate, and evaporated to give tert-butyl 2-(3-chlorobenzoyl)-3-oxobutanoate as an yellow oil (8.82 g).
tert-Butyl 2-(3-chlorobenzoyl)-3-oxobutanoate
NMR (CDCl3, δ): mixture of tautomers: 1.20 and 1.27 (9H, s), 2.16 and 2.44 (3H, s), 7.33-7.71 (4H, m), 13.66 (1H, s)
Preparation 145
A solution of tert-butyl 2-(3-chlorobenzoyl)-3-oxobutanoate (8.82 g) in trifluoroacetic acid (40 mL) was stirred for 1 hour under an ice-bath. The volatile was removed in vacuo, and the residue was partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give 1-(3-chlorophenyl)-1,3-butanedione as a pale orange crystal (533 g).
1-(3-Chlorophenyl)-1,3-butanedione
NMR (CDCl3, δ): 2.21 (3H, s), 6.14 (1H, s), 7.38 (1H, t, J=9 Hz), 7.48 (1H, d, J=9 Hz), 7.75 (1H, d, J=9 Hz), 7.85 (1H, s)
Preparation 146
To a mixture of 2-(trimethylsilyl)ethanol (20.5 g) and pyridine (18.7 g) in dichloromethane (40 mL) was added a solution of ethanedioyl dichloride (10.0 g) in dichloromethane (20 mL) over 30 minutes under an ice-bath (6 to 20° C.). The bath was removed, and the mixture was stirred for 0.5 hour. The mixture was filtered, and the filtrate was partitioned between ethyl acetate (200 mL) and 1N hydrochloric acid (200 mL). The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated to give bis[2-(trimethylsilyl)ethyl]oxalate as a pale yellow oil (25.1 g).
bis[2-(Trimethylsilyl)ethyl]oxalate
NMR (CDCl3, δ): 0.08 (18H, s), 1.12 (4H, m), 4.38 (4H, m)
Preparation 147
To a suspension of dimethyl sulfone (7.00 g) in diethyl ether (50 mL) was added potassium tert-butoxide (8.76 g). To the resulting mixture was added bis[2-(trimethylsilyl)ethyl]oxalate (23.8 g). The resulting mixture was stirred for 36 hours at room temperature. The mixture was partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL). The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give a dark orange oil. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-25 to 8-5 afforded 2-(trimethylsilyl)ethyl 3-(methylsulfonyl)-2-oxopropanoate as a pale brown oil (8.37 g).
2-(Trimethylsilyl)ethyl 3-(methylsulfonyl)-2-oxopropanoate
NMR (CDCl3, δ): 0.08 (9H, s), 1.14 (2H, m), 3.11 (3H, s), 4.43 (4H, m), 4.56 (2H, s) MS (ESI−): m/z 265 (M−H)
Preparation 148
A mixture of 4-oxo-4-phenylbutanoic acid (5.00 g), ethanol (2.59 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.46 g), and 4-(dimethylamino)pyridine (171 mg) in N,N-dimethylformamide (25 mL) was stirred for 1.5 hours at room temperature. The mixture was partitioned 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 (75 mL), and brine (75 mL), dried over magnesium sulfate, and evaporated to give ethyl 4-oxo-4-phenylbutanoate as a colorless oil (4.19 g).
Ethyl 4-oxo-4-phenylbutanoate
NMR (CDCl3, δ): 1.27 (3H, t, J=7 Hz), 2.76 (2H, t, J=7 Hz), 3.32 (2H, t, J=7 Hz), 4.16 (2H, q, 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 in substantially the same manner as that of Preparation 148.
Preparation 149
Ethyl 5-oxo-5-phenylpentanoate
NMR (CDCl3, δ): 1.26 (3H, t, J=7 Hz), 2.08 (2H, m), 2.44 (2H, t, J=7 Hz), 3.06 (2H, t, J=7 Hz), 4.14 (2H, q, J=7 Hz), 7.46 (2H, t, J=9 Hz), 7.56 (1H, d, J=9 Hz), 7.97 (2H, d, J=9 Hz) MS (ESI+): m/z 221 (M+H)
Preparation 150
A mixture of 2-benzoylcyclohexanone (1.00 g), sodium ethoxide (404 mg) in ethanol (5 mL) was stirred for 3.5 hours at room temperature. The reaction was quenched by adding 1N hydrochloric acid (1 mL). The solvent was evaporated off, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give ethyl 7-oxo-7-phenylheptanoate as a brown oil (1.33 g).
Ethyl 7-oxo-7-phenylheptanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.42 (2H, m), 1.63-1.81 (4H, m), 2.32 (2H, t, J=7 Hz), 2.98 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 7.47 (2H, t, J=9 Hz), 7.54 (1H, d, J=7 Hz), 7.95 (2H, d, J=9 Hz)
Preparation 151
To a solution of ethyl 7-chloro-7-oxoheptanoate (1.31 g) in dichloromethane (25 mL) was added a solution of 2-(trimethylsilyl)-1,3-thiazole (500 mg) in dichloromethane (5 mL) under nitrogen. After stirring for 3 hours, the reaction was quenched by adding saturated sodium bicarbonate (5 mL). The mixture was partitioned between ethyl acetate (30 mL) and saturated sodium bicarbonate (30 mL), and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give a colorless oil. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-10 to 2-5 afforded ethyl 7-oxo-7-(1,3-thiazol-2-yl)heptanoate as a colorless oil (778 mg).
Ethyl 7-oxo-7-(1,3-thiazol-2-yl)heptanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.44 (2H, m), 1.64-1.85 (4H, m), 2.32 (2H, t, J=7 Hz), 3.17 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 7.66 (1H, d, J=3 Hz), 8.00 (1H, d, J=3 Hz) MS (ESI+): m/z 256 (M+H)
Preparation 152
To a solution of 7-methoxy-7-oxoheptanoic acid (1.00 g) in dichloromethane (10 mL) was added a solution of trifluoroacetic anhydride (1.33 g) in dichloromethane (2 mL). After stirring for 0.5 hour, a solution of 1-methyl-1H-pyrrole (1.49 g) in dichloromethane (2 mL) was added. The mixture was stirred for 2 hours 40 minutes at room temperature and 2 hours at 35° C. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give a brown oil. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-20 to 4-5 afforded methyl 7-(1-methyl-1H-pyrrol-2-yl)-7-oxoheptanoate as a colorless oil (615 mg).
Methyl 7-(1-methyl-1H-pyrrol-2-yl)-7-oxoheptanoate
NMR (CDCl3, δ): 1.34 (2H, m), 1.61-1.77 (4H, m), 2.32 (2H, t, J=7 Hz), 2.77 (2H, t, J=7 Hz), 3.66 (3H, s), 3.94 (3H, s), 6.13 (1H, m), 6.79 (1H, m), 6.93 (1H, m) MS (ESI+): m/z 238 (M+H)
Preparation 153
To a suspension of 4-({[(benzyloxy)carbonyl]amino}-sulfonyl)benzoic acid (2.90 g) in dichloromethane (30 mL) was added N,N-dimethylformamide (19.0 mg) and followed by oxalyl chloride (1.15 g) under an ice-bath. The mixture was stirred for 0.5 hour at room temperature and refluxed for 1 hour. The resulting mixture was refluxed further for 5 minutes after adding oxalyl chloride (439 mg). The volatile was evaporated off to give a white solid. The solid was triturated in diisopropyl ether to give benzyl [4-(chlorocarbonyl)phenyl]sulfonylcarbamate as a white powder (2.40 g), which was used for the next reaction without further purification.
Benzyl [4-(chlorocarbonyl)phenyl]sulfonylcarbamate
Preparation 154
To a solution of tert-butyl 4-(methylthio)-3-oxobutanoate (5.00 g) and potassium carbonate (3.72 g) in dimethylformamide (25 mL) was added ethyl 5-iodopentanoate (6.89 g) and the mixture was stirred at ambient temperature for 15 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-10:1) to give 1-tert-butyl 7-ethyl 2-[(methylthio)acetyl]heptanedioate as colorless oil (5.88 g).
1-tert-butyl 7-ethyl 2-[(methylthio)acetyl]heptanedioate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.30-1.42 (2H, m), 1.45 (9H, s), 1.63-1.74 (2H, m), 1.81-1.93 (2H, m), 2.05 (3H, s), 2.30 (2H, t, J=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, q, J=7 Hz)
Preparation 155
To a suspension of hydroxylamine hydrochloride (29.4 g) in dichloromethane (200 mL) was added diisopropylethylamine (54.6 g) over 3 minutes in a methanol-ice bath under a nitrogen atmosphere. A white precipitate was formed upon the addition. After stirring for 1 hour under the bath, a solution of diphenylphosphinic chloride (20.0 g) in dichloromethane (20 mL) was added over 60 minutes. A white crystal was formed upon the addition. The mixture was warmed to 0° C. over 1 hour with stirring. The reaction was quenched by adding water (200 mL) over 3 minutes. After stirring the mixture for 0.5 hour, the crystal was collected by filtration. The crystal was washed with water (50×3 mL) followed by diisopropyl ether (50×3 mL). The collected crystal was dried overnight in the air and 3 hours under a reduced pressure with slight warming (4° C.) to give a crude product. The crude product was triturated in EtOH (ethanol) to give (aminooxy)(diphenyl)phosphine oxide as a white crystal (15.3 g).
(Aminooxy)(diphenyl)phosphine oxide
NMR (CDCl3, δ): 7.54-7.58 (6H, m), 7.74-7.83 (4H, m), 8.20-8.33 (2H, m)
Preparation 156
To a solution of 1-(1H-pyrrol-2-yl)ethanone (5.00 g) in tetrahydrofuran (100 mL) was added potassium tert-butoxide (6.17 g) in a water bath under a nitrogen atmosphere. After stirring for 1 hour, (aminooxy)(diphenyl)phosphine oxide (12.8 g) was added over 2 hours. After stirring for 2 hours at room temperature, water (4 mL) was added over 3 minutes to give a clear solution. The solvent was evaporated off, and the residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (25×5 mL), and the combined organic extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give a brown oil (6.01 g). The oil was dissolved in diisopropyl ether (30 mL), and to the solution was added hexane (15 mL) to afford a pale yellow crystal. After stirring for 1 hour, the crystal was removed by filtration. The filtrate was evaporated to give a brown oil (5.69 g). The oil was dissolved in ethyl acetate (45.5 mL), the solution was cooled under an ice-bath. To the cooled solution was added 4N hydrogen chloride in ethyl acetate (115 mL) over 15 minutes to afford a pale brown precipitate. After stirring the mixture for 0.5 hour under the bath, the precipitate was collected by filtration and washed with ethyl acetate (5×3 mL) to give a pale brown powder (5.33 g). The powder was suspended in ethyl acetate (37 mL) and warmed 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 1-(1-amino-1H-pyrrol-2-yl)ethanone hydrochloride as a pale brown powder (5.25 g).
1-(1-Amino-1H-pyrrol-2-yl)ethanone hydrochloride
NMR (CDCl3, δ): 2.37 (3H, s), 5.22 (2H, s, br), 6.07 (1H, m), 6.99 (1H, m), 7.15 (1H, m)
Preparation 157
Under a nitrogen atmosphere, hydrazine monohydrate (530 g) was added to ethanol (1.7 L) over 55 minutes. To the mixture was added 1-(1-amino-1H-pyrrol-2-yl)ethanone hydrochloride (170 g) over 20 minutes. The mixture was stirred for 10 minutes at room temperature and heated to refluxing temperature over 55 minutes, and refluxed for 15 minutes. After cooling the mixture under a water bath, water (1.7 L) was added to the mixture (30 to 31° C.). Ethanol was evaporated off, and the resulting mixture was extracted with chloroform (0.85×4 mL). The combined organic extract was washed with brine (1.3 L). The brine was extracted with chloroform (0.85 L). The combined organic extract was dried over anhydrous magnesium sulfate, and evaporated to give (1E)-1-(1-amino-1H-pyrrol-2-yl)ethanone hydrazone as a brown crystal (112 g).
(1E)-1-(1-Amino-1H-pyrrol-2-yl)ethanone hydrazone
NMR (CDCl3, δ): 2.10 (3H, s), 5.11 (2H, s, br), 5.83 (2H, s, br), 5.98 (1H, m), 6.25 (1H, m), 6.79 (1H, m) MS (ESI+): m/z 139 (M+H)
Preparation 158
To a suspension of (1E)-1-(1-amino-1H-pyrrol-2-yl)ethanone hydrazone (110 g) in toluene (1.1 L) was added potassium tert-butoxide (93.8 g) over 5 minutes under a nitrogen atmosphere, and the mixture was heated to refluxing temperature over 45 minutes. After refluxing for 15 minutes, the mixture was cooled to room temperature and partitioned between ethyl acetate (1.1 L) and water (1.1 L). The aqueous layer was extracted with ethyl acetate (1.1 L) again. The combined organic extract was was washed with brine (1.1 L), and the brine was extracted with ethyl acetate (0.5 L). All the organic layer was combined, dried over anhydrous magnesium sulfate, and evaporated to give 2-ethyl-1H-pyrrol-1-amine as a brown oil (94.4 g).
2-Ethyl-1H-pyrrol-1-amine
NMR (CDCl3, δ): 1.26 (3H, t, J=7 Hz), 21.62 (2H, q, J=7 Hz), 4.53 (2H, s, br), 5.80 (1H, m), 5.99 (1H, m), 6.67 (1H, m)
Preparation 159
To a suspension of tert-butyl 4-methoxy-3-oxobutanoate (3.09 g) and potassium carbonate (2.50 g) in dimethylformamide (20 mL) was added ethyl 5-iodopentanoate (4.62 g) and the mixture was stirred at ambient temperature for 15 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-5:1) to give 1-tert-butyl 7-ethyl 2-(methoxyacetyl)heptanedioate as colorless oil (4.33 g).
1-tert-Butyl 7-ethyl 2-(methoxyacetyl)heptanedioate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.30-1.44 (2H, m), 1.45 (9H, s), 1.60-1.73 (2H, m), 1.80-1.93 (2H, m), 2.29 (2H, t, J=7 Hz), 3.41 (3H, s), 3.47 (1H, t, J=7 Hz), 4.02 (4H, m) MS: (m/z) 317 (M+H)
The following compounds were obtained in substantially the same manner as that of Preparation 159.
Preparation 160
1-tert-Butyl 6-ethyl 2-(methoxyacetyl)hexanedioate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.46 (9H, s), 1.52-1.73 (2H, m), 1.82-1.94 (2H, m), 2.33 (2H, t, J=7 Hz), 3.42 (3H, s), 3.50 (1H, t, J=7 Hz), 4.10 (2H, s), 4.12 (2H, q, J=7 Hz)
Preparation 161
1-tert-Butyl 5-ethyl 2-(methoxyacetyl)pentanedioate
NMR (CDCl3, δ): 1.26 (3H, t, J=7 Hz), 1.47 (9H, s), 2.10-2.25 (2H, m), 2.37 (2H, t, J=7 Hz), 3.42 (3H, s), 3.62 (1H, t, J=7 Hz), 4.12 (2H, s), 4.13 (2H, q, J=7 Hz)
Preparation 162
1-tert-Butyl 6-ethyl 2-acetylhexanedioate
NMR (CDCl3, δ): 1.26 (3H, t, J=7 Hz), 1.47 (9H, s), 1.57-1.75 (2H, m), 1.79-1.93 (2H, m), 2.23 (3H, s), 2.33 (2H, t, J=7 Hz), 3.33 (1H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz) MS (ESI+): m/z 273
Preparation 163
1-tert-Butyl 5-ethyl 2-acetylpentanedioate
NMR (CDCl3, δ): 1.26 (3H, t, J=7 Hz), 1.47 (9H, s), 2.08-2.22 (2H, m), 2.24 (3H, s), 2.33-2.42 (2H, m), 3.45 (1H, t, J=7 Hz), 4.13 (2H, q, J=7 Hz)
Preparation 164
To a solution of 2-ethyl-1H-pyrrole (7.00 g) in tetrahydrofuran (14 mL) was added 0.93 M ethyl magnesium bromide (198 mL) under an ice-bath. The mixture was stirred for 1 hour at room temperature. Then the resulting solution was added to a suspension of 5-bromonicotinoyl chloride (22.3 g) in tetrahydrofuran (110 mL) over 50 minutes under an ice-bath. After stirring for 15 minutes under the bath, the reaction was quenched by adding saturated ammonium chloride (30 mL). The mixture was partitioned between ethyl acetate (350 mL) and water (350 mL). The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated to give a dark colored gum (33.9 g). The gum was dispersed in ethyl acetate/hexane (1:3, 150 mL) in the presence of silica gel (150 mL). The mixture was filtered, and the filtrate was concentrated to give an yellow crystal (20.6 g). Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-20 to 4-5 afforded (5-bromo-3-pyridinyl)(5-ethyl-1H-pyrrol-2-yl)methanone as a pale yellow solid (7.11 g).
(5-Bromo-3-pyridinyl)(5-ethyl-1H-pyrrol-2-yl)methanone
NMR (CDCl3, δ): 1.33 (3H, t, J=7 Hz), 2.75 (2H, q, J=7 Hz), 6.14 (1H, m), 6.83 (1H, m), 8.27 (1H, m), 8.82 (1H, m), 8.98 (1H, m) MS (ESI+): m/z 279 (M+H)
Preparation 165
To a solution of tert-butyl 4-(acetyloxy)-3-oxobutanoate (30.0 g) and ethyl 5-iodopentanoate (35.5 g) in N,N-dimethylformamide (150 mL) was added potassium carbonate (19.2 g) at room temperature. After stirring for 4 hours, the mixture was quenched by adding 1N hydrochloric acid (140 mL) under an ice-bath. The mixture was partitioned between ethyl acetate (450 mL) and water (300 mL). The organic extract was washed with water (500 mL, three times) and brine, dried over magnesium sulfate, and evaporated to give a brown oil containing 1-tert-butyl 7-ethyl 2-[(acetyloxy)acetyl]heptanedioate (63.4 g, 43% wt purity).
1-tert-Butyl 7-ethyl 2-[(acetyloxy)acetyl]heptanedioate
NMR (CDCl3, δ): 1.20-1.37 (5H, m), 1.46 (9H, s), 1.63 (2H, m), 1.85 (2H, m), 2.17 (3H, s), 2.30 (2H, t, J=7 Hz), 3.39 (1H, t, J=7 Hz), 4.11 82H, q, J=7 Hz), 4.73 (1H, d, J=17 Hz), 4.82 (1H, d, J=17 Hz)
Preparation 166
To a solution of ethyl thiophene (2.00 g) and ethyl 7-chloro-7-oxoheptanoate (5.39 g) in dichloromethane (20 mL) was added 1 M tin chloride in dichloromethane (38.9 mL) over 0.5 hour under an ice-bath (5 to 8° C.). After stirring for 0.5 hour, the mixture was stirred for 0.5 hour at room temperature. The mixture was poured into ice-water (100 mL), and extracted with ethyl acetate (100 mL). The organic extract was washed with water (100 mL) and brine, dried over magnesium sulfate, and evaporated to give a brown oil. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-10 to 3-10 afforded ethyl 7-oxo-7-(2-thienyl)heptanoate as a brown oil (5.79 g).
Ethyl 7-oxo-7-(2-thienyl)heptanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.42 (2H, m), 1.63-1.72 (4H, m), 2.31 (2H, t, J=7 Hz), 2.91 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 7.13 (1H, m), 7.612 (1H, m), 7.70 (1H, m)
The following compounds were obtained in substantially the same manner as those of Preparations 129 and 130.
Preparation 167
tert-Butyl 3-(3,5-dimethyl-4-isoxazolyl)-3-oxopropanoate
NMR (CDCl3, δ): 1.47 (9H, s), 2.46 (3H, s), 2.68 (3H, s), 3.68 (2H, s)
Preparation 168
Ethyl 4-methyl-3-oxopentanoate
NMR (CDCl3, δ): 1.14 (6H, d, J=7 Hz), 1.28 (3H, t, J=7 Hz), 2.71 (1H, quintet, J=7 Hz), 3.50 (s, 2H), 4.19 (2H, q, J=7 Hz), 7.06-7.18, 7.56, and 7.85 (4H, m)
Preparation 169
tert-Butyl 4-(methylthio)-3-oxobutanoate
NMR (CDCl3, δ): 1.47 (9H, s), 2.07 (3H, s), 3.31 (2H, s), 3.58 (2H, s)
Preparation 170
tert-Butyl 3-(1,3-oxazol-5-yl)-3-oxopropanoate
NMR (CDCl3, δ): (a mixture of keto- and enol-form); keto-form: 1.45 (9H, s), 3.77 (2H, s), 7.85 (1H, s), 8.04 (1H, s); enol-form: d 1.45 (9H, s), 5.54 (1H, s), 7.53 (1H, s), 7.91 (1H, s)
The following compounds were obtained in substantially the same manner as that of Preparation 143.
Preparation 171
(2-Chloro-4-pyridinyl)(5-ethyl-1H-pyrrol-2-yl)methanone
NMR (CDCl3, δ): 1.32 (3H, t, J=7 Hz), 2.74 (2H, q, 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, br)
Preparation 172
(5-Ethyl-1H-pyrrol-2-yl)(3-methoxyphenyl)methanone
NMR (CDCl3, δ): 1.32 (3H, t, J=7 Hz), 2.74 (2H, q, J=7 Hz), 3.87 (3H, s), 6.08 (1H, m), 6.83 (1H, m), 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, br) MS (ESI+): m/z 230
Preparation 173
(5-Ethyl-1H-pyrrol-2-yl)(4-pyridinyl)methanone
NMR (CDCl3, δ): 1.32 (3H, t, J=7 Hz), 2.72 (2H, q, J=7 Hz), 6.13 (1H, m), 6.81 (1H, m), 7.65 (2H, d, J=7 Hz), 8.77 (2H, d, J=7 Hz), 9.39 (1H, br)
Preparation 174
(5-Ethyl-1H-pyrrol-2-yl)(2-pyrazinyl)methanone
NMR (CDCl3, δ): 1.33 (3H, t, J=7 Hz), 2.77 (2H, q, J=7 Hz), 6.14 (1H, m), 7.51 (1H, m), 8.65 (1H, m), 8.74 (1H, m), 9.36 (1H, br)
Preparation 175
(5-Ethyl-1H-pyrrol-2-yl)(3-pyridinyl)methanone
NMR (CDCl3, δ): 1.33 (3H, t, J=7 Hz), 2.76 (2H, q, J=7 Hz), 6.12 (1H, m), 6.81 (1H, m), 7.42 (1H, m), 8.13 (1H, m), 8.76 (1H, m), 9.08 (1H, m), 9.36 (1H, br)
Preparation 176
A mixture of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (300 mg), methanesulfonylacetic acid (208 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (361 mg), and 1-hydroxybenzotriazole (254 mg) in N,N-dimethylformamide (1 mL) was stirred for 1.5 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water two times, saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and evaporated to give a pale brown solid. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1⁄2 to 1/0 afforded N-[2-(3-cyanobenzoyl)-5-ethyl-1H-pyrrol-1-yl]-2-(methylsulfonyl)acetamide as a pale brown foam, which was solidified upon standing (505 mg).
N-[2-(3-Cyanobenzoyl)-5-ethyl-1H-pyrrol-1-yl]-2-(methylsulfonyl)acetamide
NMR (CDCl3, δ): 1.29 (3H, t, J=7 Hz), 2.62 (2H, q, J=7 Hz), 3.28 (3H, s), 4.15 (2H, s), 6.12 (1H, d, J=5 Hz), 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), 8.06 (1H, s)
The following compound was obtained in substantially the same manner as that of Preparation 176.
Preparation 177
Ethyl 3-{[2-(4-cyanobenzoyl)-5-ethyl-1H-pyrrol-1-yl]amino}-3-oxopropanoate
NMR (CDCl3, δ): 1.20-1.37 (6H, m), 2.56 (2H, q, J=7 Hz), 3.57 (2H, s), 4.30 (2H, q, J=7 Hz), 6.06 (1H, d, J=5 Hz), 6.68 (1H, d, J=5 Hz), 7.54 (2H, d, J=9 Hz), 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) were added 1-(4-methoxyphenyl)acetone (103 mg) and p-toluene-sulfonic acid monohydrate (16 mg) at ambient temperature. The reaction mixture was heated at 80° C. for 3 hours. The mixture was evaporated in vacuo. The residue was purified by flash silica gel column chromatography eluting with hexane-ethyl acetate 20-1 and 15-1 to give 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile (31 mg, 20.2%) as an yellow solid.
4-[7-Ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
NMR (CDCl3, δ): 1.40 (3H, t, J=8 Hz), 2.31 (3H, s), 3.16 (2H, q, J=8 Hz), 3.77 (3H, s), 6.10 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 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 in substantially the same manner as that of Example 1.
EXAMPLE 2
Ethyl 4-(4-cyanophenyl)-2-(2-ethoxy-2-oxoethyl)-7-ethylpyrrolo[1,2-b]pyridazine-3-carboxylate
NMR (CDCl3, δ): 0.84 (3H, t, J=7 Hz), 1.28 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 3.04 (2H, q, J=7 Hz), 3.93 (2H, q, J=7 Hz), 4.13 (3H, s), 4.19 (2H, q, 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]pyridazine-3-carboxylate
NMR (CDCl3, δ): 1.08 (3H, t, J=7 Hz), 1.41 (3H, t, J=7 Hz), 3.11 (2H, q, J=7 Hz), 4.11 (2H, q, J=7 Hz), 6.43 (1H, d, J=5 Hz), 6.93 (1H, d, J=5 Hz), 7.62 (2H, d, J=9 Hz), 7.80 (2H, d, J=9 Hz)
EXAMPLE 4
4-[7-Ethyl-2-methyl-3-(3-pyridinylcarbonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
NMR (CDCl3, δ): 1.43 (t, J=7 Hz, 3H), 2.47 (s, 3H), 3.09 (q, J=7 Hz, 2H), 6.35 (d, J=5 Hz, 1H), 6.74 (d, J=5 Hz, 1H), 7.23 (1H, m), 7.48 (2H, d, J=9 Hz), 7.55 (2H, d, J=9 Hz), 7.93 (1H, m), 8.62 (1H, m), 8.74 (1H, m)
EXAMPLE 5
3-[7-Ethyl-2-methyl-3-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
NMR (CDCl3, δ): 1.42 (3H, t, J=7 Hz), 2.32 (3H, s), 3.08 (2H, q, J=7 Hz), 6.15 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.00 (2H, d, J=9 Hz), 7.37 (2H, m), 7.57 (2H, m), 8.50 (2H, d, J=9 Hz)
EXAMPLE 6
4-(3-Benzyl-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile
NMR (CDCl3, δ): 1.40 (3H, t, J=8 Hz), 2.35 (3H, s), 3.04 (2H, q, J=8 Hz), 3.83 (3H, s), 5.94 (1H, d, J=5 Hz), 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), 7.68 (2H, d, J=8 Hz) MS (ESI+): m/z 352 (M+H)
EXAMPLE 7
4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazine-3-carbonitrile
mp: 172-173° C. NMR (CDCl3, δ): 1.41 (3H, t, J=8 Hz), 3.10 (2H, q, J=8 Hz), 6.65 (1H, d, J=5 Hz), 6.88 (1H, d, J=5 Hz), 7.47-7.64 (6H, m), 7.70 (1H, br s), 7.81-7.90 (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 (CDCl3, δ): 1.00-1.15 (12H, m), 1.37 (3H, t, J=8 Hz), 2.81 (3H, s), 3.00 (2H, q, J=8 Hz), 3.82 (2H, t, J=5 Hz), 5.46 (1H, d, J=5 Hz), 6.46 (1H, d, J=5 Hz), 7.50-7.65 (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 (CDCl3, δ): 1.40 (3H, t, J=8 Hz), 2.08-2.22 (2H, m), 2.60 (2H, t, J=7 Hz), 3.00-3.15 (4H, m), 6.26 (1H, d, J=5 Hz), 6.74 (1H, d, J=5 Hz), 7.49-7.61 (3H, m), 7.74 (1H, m) MS (ESI+): m/z 316 (M+H)
EXAMPLE 10
3-(6-Ethyl-1-oxo-2,3-dihydro-1H-cyclopenta[e]pyrrolo[1,2-b]pyridazin-9-yl)benzonitrile
mp: 150-154° C. NMR (CDCl3, δ): 1.43 (3H, t, J=8 Hz), 2.75 (2H, t, J=7 Hz), 3.10 (2H, q, J=8 Hz), 3.24 (2H, t, J=7 Hz), 6.67 (1H, d, J=5 Hz), 6.87 (1H, d, J=5 Hz), 7.60 (1H, t, J=8 Hz), 7.75-7.90 (3H, m) MS (ESI+): m/z 324 (M+Na)
EXAMPLE 11
3-(7-Ethyl-2-neopentylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile
NMR (CDCl3, δ): 1.05 (9H, s), 1.39 (3H, t, J=8 Hz), 2.68 (2H, s), 3.04 (2H, q, J=8 Hz), 6.36 (1H, s), 6.48 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.51 (1H, t, J=8 Hz), 7.75 (1H, br d, J=8 Hz), 7.92-8.01 (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 (CDCl3, δ): 1.44 (3H, t, J=8 Hz), 3.11 (2H, q, J=8 Hz), 6.52-6.60 (2H, m), 6.74 (1H, d, J=5 Hz), 6.98 (1H, s), 7.09 (1H, d, J=5 Hz), 7.56-7.68 (2H, m), 7.78 (1H, dd, J=8, 1 Hz), 7.96-8.08 (2H, m) MS (ESI+): m/z 314 (M+H)
EXAMPLE 13
4-[7-Ethyl-2-methyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
NMR (CDCl3, δ): 1.38 (3H, t, J=8 Hz), 2.89 (3H, s), 3.00-3.11 (5H, m), 6.09 (1H, d, J=5 Hz), 6.73 (1H, d, J=5 Hz), 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-[(methylsulfonyl)methyl]pyrrolo[1,2-b]pyridazin-4-yl}benzonitrile
NMR (CDCl3, δ): 1.39 (3H, t, J=8 Hz), 2.96-3.09 (5H, m), 4.44 (2H, s), 6.63 (1H, d, J=5 Hz), 6.71 (1H, s), 6.81 (1H, d, J=5 Hz), 7.79 (2H, d, J=8 Hz), 7.85 (2H, d, J=8 Hz) MS (ESI+): m/z 340 (M+H)
EXAMPLE 15
3-[7-Ethyl-2-methyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
NMR (CDCl3, δ): 1.39 (3H, t, J=8 Hz), 2.89 (3H, s), 3.00-3.11 (5H, m), 6.09 (1H, d, J=5 Hz), 6.73 (1H, d, J=5 Hz), 7.54-7.63 (3H, m), 7.77 (1H, m)
EXAMPLE 16
To a solution of 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile (22 mg) in N,N-dimethylformamide (1 mL) were added 1N sodium hydroxide (0.12 mL) and 30% hydrogen peroxide (0.07 mL) at ambient temperature. After 1 hour stirring, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel column chromatography (silica gel, 30 mL) eluting with hexane-ethyl acetate=5-1 and 0-1 to give 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzamide (18 mg, 78.0%) as an yellow solid.
4-[7-Ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzamide
NMR (CDCl3, δ): 1.41 (3H, t, J=8 Hz), 2.31 (3H, s), 3.17 (2H, q, J=8 Hz), 3.77 (3H, s), 5.61 (0.2H, br s), 6.02 (0.4H, br s), 6.13 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 6.75 (2H, d, J=8 Hz), 6.95 (2H, d, J=8 Hz), 7.31 (2H, d, J=8 Hz), 7.68 (2H, d, J=8 Hz) MS (ESI+): m/z 386 (M+H)
The following compound was obtained in substantially the same manner as that of Example 16.
EXAMPLE 17
[2-(Dimethylamino)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide
NMR (CDCl3, δ): 1.32 (3H, t, J=7 Hz), 2.90 (6H, s), 2.95 (2H, q, J=7 Hz), 3.36 (3H, s), 6.21 (1H, d, J=5 Hz), 6.79 (1H, d, J=5 Hz), 7.44 (1H, s, br), 7.52-7.56 (2H, m), 7.90 (1H, s), 7.94-8.06 (2H, m) MS (ESI+): m/z 387 (M+H)
EXAMPLE 18
3-(7-Ethyl-2-neopentylpyrrolo[1,2-b]pyridazin-4-yl)benzamide
NMR (CDCl3, δ): 1.05 (9H, s), 1.39 (3H, t, J=8 Hz), 2.68 (2H, s), 3.04 (2H, q, J=8 Hz), 5.70 (1H, br s), 6.11 (1H, br s), 6.41 (1H, s), 6.52 (1H, d, J=5 Hz), 6.65 (1H, d, J=5 Hz), 7.59 (1H, t, J=8 Hz), 7.85-7.93 (2H, m), 8.15 (1H, br s) MS (ESI+): m/z 336 (M+H)
EXAMPLE 19
3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide
NMR (CDCl3, δ): 1.43 (3H, t, J=8 Hz), 3.10 (2H, q, J=8 Hz), 5.70 (1H, br s), 6.13 (1H, br s), 6.53-6.60 (2H, m), 6.71 (1H, d, J=5 Hz), 7.02 (1H, s), 7.06 (1H, d, J=5 Hz), 7.55-7.65 (2H, m), 7.79-7.98 (2H, m), 8.02 (1H, br s) MS (ESI+): m/z 332 (M+H)
EXAMPLE 20
5-[2-({[4-(Aminocarbonyl)benzyl,]oxy}methyl)-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (DMSO-d6, δ): 1.27-1.45 (7H, m), 1.99 (2H, m), 2.96 (2H, m), 3.40 (2H, m), 4.67 (2H, s), 4.72 (2H, s), 5.88 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.35 (1H, s, br), 7.44 (2H, d, J=8 Hz), 7.86 (2H, d, J=8 Hz), 7.96 (1H, s, br), 8.21 (1H, m), 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 p-toluenesulfonic acid monohydrate (96 mg) at ambient temperature. The reaction mixture was refluxed for 1 hour. The mixture was evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 200 mL) eluting with hexane-ethyl acetate=20-1, 15-1, and 10-1 to give ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (3.29 g, 83.8%) as an yellow oil.
Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=8 Hz), 1.32-1.58 (7H, m), 2.18 (2H, t, J=8 Hz), 2.35-2.45 (2H, m), 3.01 (2H, q, J=8 Hz), 4.10 (2H, q, J=8 Hz), 5.79 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.57-7.67 (3H, m), 7.75 (1H, m)
The following compounds were obtained in substantially the same manner as that of Example 21.
EXAMPLE 22
Ethyl 2,4-diisopropylpyrrolo[1,2-b]pyridazine-3-carboxylate
NMR (300 MHz, CDCl3, δ): 1.32 (6H, d, J=7.5 Hz), 1.39 (3H, t, J=75 Hz), 1.46 (6H, d, J=75 Hz), 2.91-3.05 (1H, m), 3.05-3.20 (1H, m), 4.38 (2H, q, J=75 Hz), 6.64-6.68 (1H, m), 6.76-6.80 (1H, m), 7.65-7.68 (1H, m) MS (ES+) m/e 275.33
EXAMPLE 23
Ethyl 4-(2-chlorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate
NMR (300 MHz, CDCl3, δ): 0.89 (3H, t, J=7.5 Hz), 1.30-1.40 (6H, m), 3.36-3.51 (1H, m), 4.00 (2H, q, J=7.5 Hz), 6.10-6.18 (1H, m), 6.75-6.84 (1H, m), 7.28-7.45 (3H, m), 7.45-7.55 (1H, m), 7.75-7.81 (1H, m)
EXAMPLE 24
Ethyl 2-isopropyl-4-(2-naphthyl)pyrrolo[1,2-b]pyridazine-3-carboxylate
NMR (300 MHz, CDCl3, δ): 0.78 (3H, t, J=7.5 Hz), 1.38 (6H, d, J=75 Hz), 3.24-3.35 (1H, m), 3.95 (2H, q, J=7.5 Hz), 6.36-6.40 (1H, m), 6.80-6.85 (1H, m), 7.50-7.54 (3H, m), 7.78-7.82 (1H, m), 7.82-8.00 (4H, m) MS (ES+) m/e 359.56
EXAMPLE 25
Ethyl 5-{7-ethyl-2-methyl-4-[3-(trifluoromethyl)phenyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
NMR (CDCl3, δ): 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.59 (4H, m), 2.14 (2H, t, J=7 Hz), 2.38-2.46 (2H, m), 2.55 (3H, s), 3.01 (2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 5.83 (1H, d, J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.53-7.64 (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 (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.38-1.60 (4H, m), 2.18 (2H, t, J=7 Hz), 2.42 (3H, s), 2.38-2.50 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.51 (1H, d, J=4 Hz), 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]pentanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.55-1.64 (2H, m), 1.64-1.80 (2H, m), 2.33 (2H, t, J=7 Hz), 2.74-2.85 (2H, m), 3.03 (2H, q, J=7 Hz), 3.43 (3H, s), 4.08 (3H, s), 4.12 (2H, q, J=7 Hz), 4.62 (2H, s), 6.28 (1H, s), 6.38 (1H, d, J=4 Hz), 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 (CDCl3, δ): 1.20 (3H, t, J=7 Hz), 1.35 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 2.17 (2H, t, J=7 Hz), 2.44-2.57 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 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), 7.93 (1H, s)
EXAMPLE 29
Ethyl 5-[4-(3,4-dichlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.38-1.48 (2H, m), 1.50-1.65 (2H, m), 2.20 (2H, t, J=7 Hz), 2.38-2.47 (2H, m), 2.54 (3H, s), 3.00 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.44-1.67 (4H, m), 2.15-2.26 (2H, m), 2.42-2.56 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 5.95 (1H, d, J=3 Hz), 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 (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.48-1.74 (4H, m), 2.28 (2H, t, J=7 Hz), 2.68-2.77 (2H, m), 3.02 (2H, q, J=7 Hz), 3.44 (3H, s), 4.12 (2H, q, J=7 Hz), 4.60 (2H, s), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.52-1.68 (4H, m), 2.23 (2H, t, J=7 Hz), 2.48-2.55 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 3.98 (3H, s), 4.09 (2H, q, J=7 Hz), 6.03 (1H, d, J=4 Hz), 6.55 (1H, d, J=4 Hz), 8.30 (1H, s), 8.33 (1H, s) MS (ESI+): m/z 397 (M+H)
EXAMPLE 33
Ethyl 5-[4-(1-benzofuran-2-yl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.62-1.83 (4H, m), 2.33 (2H, t, J=7 Hz), 2.57 (3H, s), 2.69-2.78 (2H, m), 3.03 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 6.48 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.15 (1H, s), 7.26-7.42 (2H, m), 7.57 (1H, d, J=8 Hz), 7.68 (1H, d, J=8 Hz) MS (ESI+): m/z 405 (M+H)
EXAMPLE 34
Ethyl 5-[4-(1-benzothien-2-yl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.21 (3H, t, J=7 Hz), 1.35 (3H, t, J=7 Hz), 1.52-1.69 (4H, m), 2.23 (2H, t, J=7 Hz), 2.56 (3H, s), 2.61-2.70 (2H, m), 3.02 (2H, q, J=7 Hz), 4.07(2H, q, J=7 Hz), 6.21 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.35-7.43 (3H, m), 7.81-7.92 (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 (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.53-1.66 (2H, m), 1.66-1.83 (2H, m), 2.34 (2H, t, J=7 Hz), 2.56 (3H, s), 2.62-2.73 (2H, m), 3.02 (2H, q, J=7 Hz), 4.13 (2H, q, J=7 Hz), 6.42 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.50 (1H, s), 8.10 (1H, s) MS (ESI+): m/z 356 (M+H)
EXAMPLE 36
Ethyl 5-(7-ethyl-2-methyl-4-phenylpyrrolo[1,2-b]pyridazin-3-yl)pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.60 (4H, m), 2.15 (2H, t, J=7 Hz), 2.41-2.48 (2H, m), 2.55 (3H, s), 3.02 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 5.88 (1H, d, J=4 Hz), 6.48 (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-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.18 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.39-1.55 (4H, m), 2.14 (2H, d, J=7 Hz), 2.44-2.55 (2H, m), 2.58 (3H, s), 3.03 (2H, q, J=7 Hz), 4.03 (2H, q, J=7 Hz), 5.86 (1H, d, J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.45-7.52 (1H, m), 7.69 (1H, dd, J=2 Hz, 8 Hz), 7.84 (1H, d, J=2 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl}heptanoate
NMR (CDCl3, δ): 1.12-1.23 (7H, m), 1.33-1.51 (7H, s), 2.17 (2H, t, J=7 Hz), 2.35 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 4.11 (2H, q, J=7 Hz), 5.17 (2H, s), 5.78 (1H, d, J=5 Hz), 6.52 (1H, d, J=5 Hz), 7.29-7.38 (5H, m), 7.49 (2H, d, J=9 Hz), 7.87 (1H, s, br), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]methyl}-1,3-propanediol
NMR (CDCl3, δ): 1.26 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.64-1.82 (3H, m), 2.59 (3H, s), 3.02 (2H, q, J=7 Hz), 3.45 (2H, m), 3.63 (2H, m), 4.12 (2H, q, J=7 Hz), 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-(methylsulfonyl)phenyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
NMR (CDCl3, δ): 1.22 (3H, t, J=8 Hz), 1.33-1.57 (7H, m), 2.18 (2H, t, J=8 Hz), 2.35-2.45 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 3.12 (3H, s), 4.08 (2H, q, J=8 Hz), 5.80 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.64-7.74 (2H, m), 7.96 (1H, br s), 8.04 (1H, m) MS (ESI+): m/z 443 (M+H)
EXAMPLE 41
Ethyl 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=8 Hz), 1.30-1.62 (7H, m), 2.21 (2H, t, J=8 Hz), 2.35-2.45 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=8 Hz), 4.10 (2H, q, J=8 Hz), 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, br s), 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 (CDCl3, δ): 1.21 (3H, t, J=8 Hz), 1.34-1.59 (7H, m), 2.17 (2H, t, J=8 Hz), 2.37-2.47 (2H, m), 2.57 (3H, s), 3.01 (2H, q, J=8 Hz), 4.08 (2H, q, J=8 Hz), 5.81 (1H, d, J=5 Hz), 6.52 (1H, d, J=5 Hz), 7.64-7.74 (2H, m), 8.25 (1H, br s), 8.33 (1H, m) MS (ESI+): m/z 410 (M+H)
EXAMPLE 43
Ethyl 4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate
NMR (CDCl3, δ): 0.98 (3H, t, J=8 Hz), 2.55 (3H, s), 4.05 (2H, q, J=8 Hz), 6.35 (1H, m), 6.81 (1H, m), 7.12-7.22 (2H, m), 7.41-7.50 (2H, m), 7.76 (1H, m) MS (ESI+): m/z 359 (M+H)
EXAMPLE 44
4-(3-Butyl-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile
NMR (CDCl3, δ): 0.78 (3H, t, J=8 Hz), 1.12-1.43 (7H, m), 2.31-2.40 (2H, m), 2.56 (3H, s), 3.00 (2H, q, J=8 Hz), 5.79 (1H, d, J=5 Hz), 6.50 (1H, d, J=5 Hz), 7.47 (2H, d, J=8 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.65 (4H, m), 2.21 (2H, t, J=7 Hz), 2.37-2.49 (2H, m), 2.56 (3H, s), 3.00 (2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 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 (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 2.18 (3H, s), 2.20 (2H, t, J=7 Hz), 2.48-2.58 (2H, m), 3.02 (2H, q, J=7 Hz), 3.81 (2H, s), 4.10 (2H, q, J=7 Hz), 5.89 (1H, d, J=4 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate
NMR (CDCl3, δ): 1.15-1.29 (5H, m), 1.32-1.61 (7H, m), 2.20 (2H, t, J=8 Hz), 2.33-2.43 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 4.10 (2H, q, J=8 Hz), 5.79 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.57-7.67 (3H, m), 7.75 (1H, m) MS (ESI+): m/z 404 (M+H)
EXAMPLE 48
Ethyl 5-[4-(6-chloro-2-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.46-1.65 (4H, m), 2.22 (2H, t, J=7 Hz), 2.46-2.57 (2H, m), 2.54 (3H, s), 3.00 (2H, q, J=7 Hz), 4.09 (2H, q, 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.40-1.62 (4H, m), 2.17 (2H, t, J=7 Hz), 2.43-2.52 (2H, m), 2.54 (3H, s), 3.00 (2H, q, J=7 Hz), 3.83 (3H, s), 4.08 (2H, q, J=7 Hz), 5.91 (1H, d, J=4 Hz), 6.49 (1H, d, J=4 Hz), 6.87-6.99 (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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.39-1.52 (2H, m), 1.52-1.64 (2H, m), 2.22 (2H, t, J=7 Hz), 2.38-2.48 (2H, m), 2.54 (3H, s), 3.00 (2H, q, J=7 Hz), 4.10 (2H, q, 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.46-1.58 (2H, m), 1.60-1.74 (2H, m), 2.28 (2H, t, J=7 Hz), 2.53 (3H, s), 2.56-2.66 (2H, m), 2.98 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 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-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.38-1.50 (2H, m), 150-1.63 (2H, m), 2.17 (2H, t, J=7 Hz), 2.39-2.48 (2H, m), 2.54 (3H, s), 3.03 (2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 5.88 (1H, d, J=4 Hz), 6.50 (1H, d, J=4 Hz), 7.03-7.16 (3H, m), 7.38-7.47 (1H, m) MS (ESI+): m/z 383
EXAMPLE 53
Ethyl 5-[7-ethyl-2-methyl-4-(3-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.18 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.60 (4H, m), 2.16 (2H, t, J=7 Hz), 2.44-2.56 (2H, m), 2.59 (3H, s), 3.04 (2H, q, J=7 Hz), 4.03 (2H, q, J=7 Hz), 5.89 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.62 (1H, t, J=8 Hz), 7.80 (1H, t, J=8 Hz), 7.90 (1H, d, J=8 Hz), 8.21 (2H, m), 8.90 (1H, d, J=2 Hz) MS (ESI+): m/z 416
EXAMPLE 54
Ethyl 5-[7-ethyl-2-methyl-4-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.64 (4H, m), 2.19 (2H, t, J=7 Hz), 2.38-2.52 (2H, m), 2.55 (3H, s), 3.02 (2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.55-1.82 (4H, m), 2.33 (2H, t, J=7 Hz), 2.55 (3H, s), 2.62-2.72 (2H, m), 2.99 (2H, q, J=7 Hz), 4.08 (3H, s), 4.12 (2H, q, J=7 Hz), 6.26 (1H, s), 6.34 (1H, d, J=4 Hz), 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 (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.50-1.75 (4H, m), 2.29 (2H, t, J=7 Hz), 2.55 (6H, s), 2.56-2.65 (2H, m), 2.99 (2H, q, J=7 Hz), 4.11 (2H, q, J=7 Hz), 6.16 (1H, d, J=4 Hz), 6.22 (1H, s), 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 (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.36-1.63 (4H, m), 2.20 (2H, t, J=7 Hz), 2.48-2.63 (2H, m), 3.03 (2H, q, J=7 Hz), 3.45 (3H, s), 4.09 (2H, q, J=7 Hz), 4.62 (2H, s), 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 (CDCl3, δ): 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 2.16 (2H, t, J=7 Hz), 2.54-2.65 (2H, m), 3.04 (2H, q, J=7 Hz), 3.45 (3H, s), 3.83 (3H, s), 4.08 (2H, q, J=7 Hz), 4.62 (2H, s), 5.96 (1H, d, J=4 Hz), 6.56 (1H, d, J=4 Hz), 6.87-7.00 (3H, m), 7.38 (1H, t, J=8 Hz) MS (ESI+): m/z 425
EXAMPLE 59
Ethyl 5-[7-ethyl-2-(methoxymethyl)-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.17 (3H, t, J=7 Hz), 1.43 (3H, t, J=7 Hz), 1.36-1.58 (4H, m), 2.10 (2H, m), 2.56-2.68 (2H, m), 3.07 (2H, q, J=7 Hz), 3.48 (3H, s), 4.02 (2H, q, J=7 Hz), 4.66 (2H, s), 5.90 (1H, d, J=4 Hz), 6.56 (1H, d, J=4 Hz), 7.45-7.50 (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 (CDCl3, δ): 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.60 (4H, m), 2.17 (2H, t, J=7 Hz), 2.52-2.64 (2H, m), 3.04 (2H, q, J=7 Hz), 3.46 (3H, s), 4.10 (2H, q, J=7 Hz), 4.63 (2H, s), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.42 (1H, m), 7.71 (1H, m), 8.62 (1H, m), 8.70 (1H, m) MS (ESI+): m/z 396
EXAMPLE 61
Ethyl 5-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.58 (4H, m), 2.17 (2H, t, J=7 Hz), 2.51-2.62 (2H, m), 3.03 (2H, q, J=7 Hz), 3.45 (3H, s), 4.08 (2H, q, J=7 Hz), 4.61 (2H, s), 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-methylphenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.60 (4H, m), 2.16 (2H, t, J=7 Hz), 2.40 (3H, s), 2.40-2.50 (2H, m), 2.54 (3H, s), 3.03 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 5.90 (1H, d, J=4 Hz), 6.49 (1H, d, J=4 Hz), 7.10-7.15 (2H, m), 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 (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.60 (4H, m), 2.18 (2H, t, J=7 Hz), 2.42 (3H, s), 2.48-2.63 (2H, m), 3.05 (2H, q, J=7 Hz), 3.46 (3H, s), 4.08 (2H, q, J=7 Hz), 4.62 (2H, s), 5.90 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.51 (1H, s), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.65 (4H, m), 2.21 (2H, t, J=7 Hz), 2.37-2.49 (2H, m), 2.56 (3H, s), 3.00 (2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 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 (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 2.19 (2H, t, J=7 Hz), 2.50-2.66 (2H, m), 3.03 (2H, q, J=7 Hz), 3.46 (3H, s), 4.10 (2H, q, J=7 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.36-1.60 (4H, m), 2.23 (2H, t, J=7 Hz), 2.37-2.50 (2H, m), 2.55 (3H, s), 3.02 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 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
Ethyl 4-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.65-1.78 (2H, m), 2.16-2.25 (2H, m), 2.42 (3H, s), 2.53-2.65 (2H, m), 3.04 (2H, q, J=7 Hz), 3.46 (3H, s), 4.12 (2H, q, J=7 Hz), 4.67 (2H, m), 5.91 (1H, d, J=4 Hz), 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 (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.35-2.55 (2H, m), 2.42 (3H, s), 2.84-2.96 (2H, m), 3.04 (2H, q, J=7 Hz), 3.46 (3H, s), 4.08 (2H, q, J=7 Hz), 4.65 (2H, s), 5.91 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.51 (1H, s), 8.41 (1H, s), 8.52 (1H, s)
EXAMPLE 71
Ethyl 4-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate
NMR (CDCl3, δ): 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.66-1.82 (2H, m), 2.16-2.28 (2H, m), 2.42 (3H, s), 2.44-2.53 (2H, m), 2.59 (3H, s), 3.02 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.51 (1H, s), 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 (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.30-2.43 (2H, m), 2.42 (3H, s), 2.58 (3H, s), 2.76-2.86 (2H, m), 3.02 (2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoate
NMR (CDCl3, δ): 1.21 (3H, t, J=7 Hz), 1.39 (2H, t, J=7 Hz), 2.35 (2H, t, J=7 Hz), 2.58 (3H, s), 2.74-2.83 (2H, m), 3.01 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 5.89 (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(bp)
EXAMPLE 74
Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=8 Hz), 1.32-1.55 (5H, m), 2.16 (2H, t, J=8 Hz), 2.46-2.57 (2H, m), 3.03 (2H, q, J=8 Hz), 3.46 (3H, s), 4.09 (1H, q, J=8 Hz), 4.62 (2H, s), 5.34 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.59-7.64 (2H, m), 7.68 (1H, br s), 7.75 (1H, m) MS (ESI+): 420 (M+H)
EXAMPLE 75
Ethyl 5-[2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.34-1.55 (7H, m), 2.11-2.22 (5H, m), 2.47 (2H, m), 3.02 (2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (1.20 g) in ethanol (12 mL) was added 1N sodium hydroxide (4.62 mL) and was stirred at ambient temperature for 2 hours. The reaction mixture was acidified with 1N hydrogen chloride and was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 100 mL) eluted with hexane-ethyl acetate=3-1, 2-1, and 1-1 to give an yellow solid (846 mg). The solid was recrystallized from hexane-ethyl acetate (5-1) to give 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid as a pale yellow crystals (795 mg, 71.4%).
5-[4-(3-Cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
mp: 109-110° C. NMR (CDCl3, δ): 1.33-1.60 (7H, m), 2.42 (2H, t, J=8 Hz), 2.34-2.48 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 5.80 (1H, d, J=5 Hz), 6.52 (1H, d, J=5 Hz), 7.56-7.64 (2H, m), 7.66 (1H, br s), 7.76 (1H, m) MS (ESI+): m/z 362 (M−H)
The following compounds were obtained in substantially the same manner as that of Example 76.
EXAMPLE 77
3-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoic acid
NMR (CDCl3, δ): 1.36 (3H, t, J=7H), 1.56 (2H, m), 2.03 (2H, m), 2.79 (2H, m), 3.01 (2H, q, 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}pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.40-1.62 (4H, m), 2.22 (2H, t, J=7 Hz), 2.38-2.46 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 5.84 (1H, d, J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.53-7.64 (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]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.45-1.67 (4H, m), 2.22 (2H, t, J=7 Hz), 2.42 (3H, s), 2.35-2.48 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 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]pentanoic acid
NMR (CDCl3, δ): 1.36 (3H, t, J=7 Hz), 1.58-1.83 (4H, m), 2.38 (2H, t, J=7 Hz), 2.74-2.85 (2H, m), 3.03 (2H, q, J=7 Hz), 3.43 (3H, s), 4.08 (3H, s), 4.62 (2H, s), 6.28 (1H, s), 6.41 (1H, d, J=4 Hz), 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}pentanoic acid
NMR (CDCl3, δ): 1.38 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.21 (2H, t, J=7 Hz), 2.43-2.53 (2H, m), 2.56 (3H, s), 3.03 (2H, q, J=7 Hz), 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), 7.65 (1H, s), 7.73 (1H, d, J=8 Hz), 7.93 (1H, s) MS (ESI+): m/z 402 (M−H), 404 (M+H)
EXAMPLE 82
5-[4-(3,4-Dichlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.42-1.65 (4H, m), 2.27 (2H, t, J=7 Hz), 2.38-2.48 (2H, m), 2.54 (3H, s), 3.02 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.19 (1H, dd, J=2 Hz, 8 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.36 (3H, t, J=7 Hz), 1.47-1.66 (4H, m), 2.24 (2H, t, J=7 Hz), 1.45-2.56 (2H, m), 2.55 (3H, s), 3.00 (2H, q, 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]pentanoic acid
NMR (CDCl3, δ): 1.36 (3H, t, J=7 Hz), 1.52-1.74 (4H, m), 2.33 (2H, t, J=7 Hz), 2.69-2.78 (2H, m), 3.01 (2H, q, J=7 Hz), 3.44 (3H, s), 4.60 (2H, s), 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-4-(6-methoxy-2-pyrazinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.55-1.69 (4H, m), 2.28 (2H, m), 2.52 (2H, m), 2.56 (3H, s), 3.03 (2H, q, J=7 Hz), 3.97 (3H, s), 6.03 (1H, d, J=4 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.39 (3H, t, J=7 Hz), 1.66-1.86 (4H, m), 2.34-2.47 (2H, m), 2.58 (3H, s), 2.69-2.85 (2H, m), 3.03 (2H, q, J=7 Hz), 6.47 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.16 (1H, s), 7.26-7.43 (2H, m), 7.57 (1H, d, J=8 Hz), 7.68 (1H, d, J=8 Hz)
EXAMPLE 87
5-[4-(1-Benzothien-2-yl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.53-1.73 (4H, m), 2.30 (2H, t, J=7 Hz), 2.56 (3H, s), 2.62-2.73 (2H, m), 3.02 (2H, q, J=7 Hz), 6.19 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.34-7.45 (3H, m), 7.79-7.93 (2H, m)
EXAMPLE 88
5-[7-Ethyl-2-methyl-4-(1,3-oxazol-5-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.57-1.70 (2H, m), 1.70-1.88 (2H, m), 2.43 (2H, t, J=7 Hz), 2.56 (3H, s), 2.66-2.75 (2H, m), 3.02 (2H, q, 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-phenylpyrrolo[1,2-b]pyridazin-3-yl)pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.40-1.62 (4H, m), 2.20 (2H, t, J=7 Hz), 2.43-2.52 (2H, m), 2.54 (3H, s), 3.01 (2H, q, J=7 Hz), 5.89 (1H, d, J=4 Hz), 6.48 (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-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.39 (3H, t, J=7 Hz), 1.47-1.61 (4H, m), 2.14-2.23 (2H, m), 2.44-2.55 (2H, m), 2.59 (3H, s), 3.05 (2H, q, J=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), 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-methylpyrrolo[1,2-b]pyridazin-3-yl}heptanoic acid
NMR (CDCl3, δ): 0.98 (2H, m), 1.17-1.48 (9H, m), 2.27 (2H, t, J=7 Hz), 2.36 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 5.06 (2H, s, br), 5.84 (1H, d, J=5 Hz), 6.52 (1H, d, J=5 Hz), 7.52 (2H, d, J=9 Hz), 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 (CDCl3, δ): 1.41 (3H, t, J=7 Hz), 3.07 (2H, q, J=7 Hz), 3.95 (2H, d, J=5 Hz), 6.02 (1H, t, br, 5 Hz), 6.37 (1H, d, J=5 Hz), 6.50 (1H, m), 6.75 (1H, d, J=5 Hz), 7.01 (1H, d, J=7 Hz), 7.37-7.45 (3H, m), 7.51 (1H, m), 7.55 (1H, m)
EXAMPLE 93
5-{7-Ethyl-2-methyl-4-[3-(methylsulfonyl)phenyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
NMR (CDCl3, δ): 1.30-1.59 (7H, m), 2.22 (2H, t, J=8 Hz), 2.33-2.49 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 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, br s), 8.03 (1H, br d, J=8 Hz) MS (ESI+): m/z 415 (M+H)
EXAMPLE 94
5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
mp: 139-140° C. NMR (CDCl3, δ): 1.32-1.64 (7H, m), 2.28 (2H, t, J=8 Hz), 2.36-2.46 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=8 Hz), 5.85 (1H, d, J=5 Hz), 6.52 (1H, d, J=5 Hz), 7.24 (1H, br d, J=7 Hz), 7.36 (1H, br s), 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]pentanoic acid
NMR (CDCl3, δ): 1.36 (3H, t, J=8 Hz), 1.40-1.62 (4H, m), 2.25 (2H, t, J=8 Hz), 2.35-2.47 (2H, m), 2.56 (3H, s), 3.00 (2H, q, 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), 6.88 (1H, dd, J=16, 10 Hz), 7.20 (1H, dd, J=6, 1 Hz), 7.38 (1H, br s), 8.70 (1H, d, J=6 Hz)
EXAMPLE 96
5-[7-Ethyl-2-methyl-4-(3-nitrophenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=8 Hz), 1.41-1.59 (4H, m), 2.23 (2H, t, J=8 Hz), 2.37-2.47 (2H, m), 2.57 (3H, s), 3.02 (2H, q, J=8 Hz), 5.81 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.63-7.74 (2H, m), 8.25 (1H, br s), 8.32 (1H, m)
EXAMPLE 97
{[7-Ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methoxy}acetic acid
NMR (CDCl3, δ): 1.33-1.45 (9H, m), 3.04 (2H, q, J=8 Hz), 3.43 (1H, m), 4.01 (2H, s), 4.45 (2H, s), 6.09 (1H, d, J=5 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.43-1.63 (4H, m), 2.23 (2H, t, J=7 Hz), 2.35-2.48 (2H, m), 2.57 (3H, s), 2.69 (3H, s), 3.03 (2H, q, J=7 Hz), 5.80 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 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}pentanoic acid
NMR (CDCl3, δ): 1.36 (3H, t, J=7 Hz), 1.42-1.65 (4H, m), 2.18 (3H, s), 2.28 (2H, t, J=7 Hz), 2.48-2.60 (2H, m), 3.02 (2H, q, J=7 Hz), 3.81 (2H, s), 5.89 (1H, d, J=4 Hz), 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-[(methylsulfonyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.29 (2H, t, J=7 Hz), 2.56-2.67 (2H, m), 2.98 (2H, q, J=7 Hz), 3.13 (3H, s), 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-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.03-1.45 (4H, m), 1.36 (3H, t, J=7 Hz), 1.97 (2H, t, J=7 Hz), 2.36-2.48 (2H, m), 3.02 (2H, q, J=7 Hz), 5.96 (1H, d, J=4 Hz), 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-methylpyrrolo-[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.36 (3H, t, J=7 Hz), 1.56-1.73 (4H, m), 2.29 (2H, t, J=7 Hz), 2.46-2.56 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 5.96 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.38-7.48 (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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.46-1.63 (4H, m), 2.22 (2H, t, J=7 Hz), 2.44-2.53 (2H, m), 2.54 (3H, s), 3.01 (2H, q, J=7 Hz), 3.82 (3H, s), 5.92 (1H, d, J=4 Hz), 6.49 (1H, d, J=4 Hz), 6.87-7.01 (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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.42-1.53 (2H, m), 1.53-1.66 (2H, m), 2.27 (2H, t, J=7 Hz), 2.41-2.49 (2H, m), 2.54 (3H, s), 3.01 (2H, q, J=7 Hz), 5.88 (1H, d, J=4 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.36 (3H, t, J=7 Hz), 1.48-1.62 (2H, m), 1.62-1.73 (2H, m), 2.34 (2H, t, J=7 Hz), 2.53 (3H, s), 2.58-2.67 (2H, m), 2.99 (2H, q, J=7 Hz), 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-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.40-1.64 (4H, m), 2.23 (2H, t, J=7 Hz), 2.41-2.49 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=7 Hz), 5.88 (1H, d, J=4 Hz), 6.50 (1H, d, J=4 Hz), 7.03-7.16 (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-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.39 (3H, t, J=7 Hz), 1.47-1.65 (4H, m), 2.20-2.30 (2H, m), 2.45-2.53 (2H, m), 2.59 (3H, s), 3.05 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 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]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.40-1.70 (4H, m), 2.20-2.30 (2H, m), 2.37-2.53 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=7 Hz), 5.84 (1H, d, J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.39 (2H, d, J=7 Hz), 8.74 (2H, d, J=7 Hz)
EXAMPLE 109
5-[7-Ethyl-4-(3-methoxy-5-isoxazolyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.36 (3H, t, J=7 Hz), 1.57-1.84 (4H, m), 2.41 (2H, t, J=7 Hz), 2.55 (3H, s), 2.63-2.72 (2H, m), 3.02 (2H, q, J=7 Hz), 4.08 (3H, s), 6.27 (1H, s), 6.34 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz)
EXAMPLE 110
5-[7-Ethyl-4-(3-methoxyphenyl)-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.06-1.33 (4H, m), 1.36 (3H, t, J=7 Hz), 1.91 (2H, t, J=7 Hz), 2.42-2.53 (2H, m), 3.01 (2H, q, 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), 7.36-7.54 (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]pentanoic acid
NMR (CDCl3, δ): 1.36 (3H, t, J=7 Hz), 1.52-1.77 (4H, m), 2.35 (2H, t, J=7 Hz), 2.55 (6H, s), 2.56-2.67 (2H, m), 3.01 (2H, q, J=7 Hz), 6.16 (1H, d, J=4 Hz), 6.23 (1H, s), 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]pentanoic acid
NMR (CDCl3, δ): 1.11-1.33 (4H, m), 1.36 (3H, t, J=7 Hz), 1.99 (2H, t, J=7 Hz), 2.38-2.50 (2H, m), 3.03 (2H, q, J=7 Hz), 5.94 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.38-7.56 (7H, m), 8.74 (2H, d, J=6 Hz)
EXAMPLE 113
5-[7-Ethyl-2-phenyl-4-(2-pyrazinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.10-1.33 (4H, m), 1.36 (3H, t, J=7 Hz), 1.95 (2H, t, J=7 Hz), 2.45-2.57 (2H, m), 3.02 (2H, q, J=7 Hz), 6.05 (1H, d, J=4 Hz), 6.66 (1H, d, J=4 Hz), 7.40-7.55 (5H, m), 8.67 (1H, d, J=3 Hz), 8.77 (1H, s), 8.85 (1H, s) MS (ESI+): m/z 401, MS (ESI−): m/z 399
EXAMPLE 114
5-[7-Ethyl-2-phenyl-4-(3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.05-1.30 (4H, m), 1.36 (3H, t, J=7 Hz), 1.95 (2H, t, J=7 Hz), 2.35-2.48 (2H, m), 3.02 (2H, q, J=7 Hz), 5.94 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.40-7.55 (6H, m), 7.76-7.83 (1H, m), 8.65-8.72 (2H, m) MS (ESI+): m/z 400, MS (ESI−): m/z 398
EXAMPLE 115
5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.42-1.64 (4H, m), 2.27 (2H, t, J=7 Hz), 2.48-2.62 (2H, m), 3.04 (2H, q, J=7 Hz), 3.45 (3H, s), 4.62 (2H, s), 5.90 (1H, d, J=4 Hz), 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]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.40-1.62 (4H, m), 2.19 (2H, t, J=7 Hz), 2.55-2.66 (2H, m), 3.03 (2H, q, J=7 Hz), 3.45 (3H, s), 3.82 (3H, s), 4.62 (2H, s), 5.96 (1H, d, J=4 Hz), 6.56 (1H, d, J=4 Hz), 6.87-7.00 (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]pentanoic acid
NMR (CDCl3, δ): 1.20-1.50 (4H, m), 1.38 (3H, t, J=7 Hz), 2.15 (2H, t, J=7 Hz), 2.55-2.68 (2H, m), 3.04 (2H, q, J=7 Hz), 5.93 (1H, d, J=4 Hz), 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-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.39 (3H, t, J=7 Hz), 1.45-1.60 (4H, m), 2.16 (2H, m), 2.55-2.75 (2H, m), 3.07 (2H, q, J=7 Hz), 3.47 (3H, s), 4.66 (2H, s), 5.89 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.45-7.53 (1H, m), 7.72 (1H, d, J=8 Hz), 7.86 (1H, s), 8.22 (2H, m), 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]pentanoic acid
NMR (CDCl3, δ): 1.38 (3H, t, J=7 Hz), 1.45-1.64 (4H, m), 2.22 (2H, t, J=7 Hz), 2.48-2.68 (2H, m), 3.06 (2H, q, J=7 Hz), 3.46 (3H, s), 4.63 (2H, s), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.48 (1H, m), 7.78 (1H, m), 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]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.45-1.63 (4H, m), 2.23 (2H, t, J=7 Hz), 2.53-2.63 (2H, m), 3.04 (2H, q, J=7 Hz), 3.45 (3H, s), 4.63 (2H, s), 5.93 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.25 (1H, m), 7.36 (1H, s), 7.42 (2H, m)
EXAMPLE 121
5-[7-Ethyl-2-methyl-4-(3-methylphenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.23-1.63 (4H, m), 1.37 (3H, t, J=7 Hz), 2.22 (2H, t, J=7 Hz), 2.40 (3H, s), 2.40-2.49 (2H, m), 2.54 (3H, s), 3.02 (2H, q, J=7 Hz), 5.89 (1H, d, J=4 Hz), 6.48 (1H, d, J=4 Hz), 7.10-7.14 (2H, m), 7.23-7.27 (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]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.44-1.65 (4H, m), 2.16-2.26 (2H, m), 2.43 (3H, s), 2.47-2.69 (2H, m), 3.03 (2H, q, J=7 Hz), 3.45 (3H, s), 4.63 (2H, m), 5.88 (1H, d, J=4 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.45-1.67 (4H, m), 2.27 (2H, t, J=7 Hz), 2.38-2.52 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 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]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.25 (2H, t, J=7 Hz), 2.49-2.68 (2H, m), 3.03 (2H, q, J=7 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.43-1.68 (4H, m), 2.29 (2H, t, J=7 Hz), 2.38-2.52 (2H, m), 2.57 (3H, s), 3.02 (2H, q, J=7 Hz), 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]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.45-1.68 (4H, m), 2.23 (2H, t, J=7 Hz), 2.38-2.53 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 5.46 (1H, d, J=1 Hz), 5.86 (1H, d, J=4 Hz), 5.89 (1H, d, J=17 Hz), 6.52 (1H, d, J=4 Hz), 6.72-6.83 (1H, dd, J=11 Hz, 17 Hz), 7.77 (1H, m), 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)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.22 (2H, t, J=7 Hz), 2.45-2.73 (2H, m), 3.04 (2H, q, J=7 Hz), 3.46 (3H, s), 4.63 (2H, m), 5.44 (1H, d, J=11 Hz), 5.87 (1H, d, J=18 Hz), 5.92 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 6.72-6.83 (1H, dd, J=11 Hz, 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]pentanoic acid
NMR (CDCl3, δ): 1.38 (3H, t, J=7 Hz), 1.44-1.60 (4H, m), 2.22 (2H, t, J=7 Hz), 2.50-2.63 (2H, m), 2.69 (3H, s), 3.02 (2H, q, J=7 Hz), 3.46 (3H, s), 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]butanoic acid
NMR (CDCl3, δ): 1.38 (3H, t, J=7 Hz), 1.70-1.87 (2H, m), 2.26 (2H, t, J=7 Hz), 2.45 (3H, s), 2.53-2.81 (2H, m), 3.06 (2H, q, J=7 Hz), 3.46 (3H, s), 4.66 (2H, m), 5.90 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 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 (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 2.30-2.60 (2H, m), 2.42 (3H, s), 2.77-3.13 (2H, m), 3.05 (2H, q, J=7 Hz), 3.47 (3H, s), 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]butanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.70-1.88 (2H, m), 2.22-2.32 (2H, m), 2.45 (3H, s), 2.50-2.62 (2H, m), 2.59 (3H, s), 3.02 (2H, q, J=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 (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 2.42 (3H, s), 2.40-2.53 (2H, m), 2.59 (3H, s), 2.82 (2H, t, J=7 Hz), 3.03 (2H, q, J=7 Hz), 5.86 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.57 (1H, s), 8.38 (1H, s), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoic acid
mp: 181-182° C. NMR (CDCl3, δ): 1.38(2H, t, J=7 Hz), 2.4(2H, t, J=7 Hz), 2.58(3H, s), 2.74-2.85(2H, m), 3.01(2H, q, J=7 Hz), 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, s) MS: (m/z) 388 (M+), 390(M++2), 114(bp)
EXAMPLE 136
5-[4-(3-Cyanophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NNMR (CDCl3, δ): 1.30-1.57 (5H, m), 2.21 (2H, t, J=8 Hz), 2.47-2.57 (2H, m), 3.03 (2H, q, J=8 Hz), 3.45 (3H, s), 4.62 (2H, s), 5.84 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.59-7.64 (2H, m), 7.68 (1H, br s), 7.75 (1H, m) MS (ESI+): 392 (M+H)
EXAMPLE 136-2
5-[4-[3-(Aminocarbonyl)phenyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.30-1.70 (5H, overlapped with H2O), 2.20-2.50 (4H, m), 2.80-2.93 (2H, m), 3.03 (2H, q, J=8 Hz), 3.46 (3H, s), 4.54 (1H, d, J=10 Hz), 4.77 (1H, d, J=10 Hz), 5.80 (1H, d, J=5 Hz), 6.55 (1H, d, J=5 Hz), 7.43-7.50 (2H, m), 7.58 (1H, t, J=8 Hz), 7.77 (1H, br s), 7.88 (1H, br s), 7.99 (1H, br d, J=8 Hz) MS (ESI+): 410 (M+H)
EXAMPLE 137
5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.06-1.26 (4H, m), 1.36 (3H, t, J=7 Hz), 1.94 (2H, t, J=7 Hz), 2.40 (2H, m), 2.99 (2H, q, J=7 Hz), 5.96 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.40-7.52 (5H, m), 7.93 (1H, s), 8.59 (1H, s), 8.77 (1H, s)
EXAMPLE 138
5-[7-Ethyl-4-(5-ethyl-3-pyridinyl)-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.05-1.42 (10H, m), 1.92 (2H, m), 2.41 (2H, m), 2.75 (2H, q, J=7 Hz), 3.01 (2H, q, J=7 Hz), 5.93 (1H, d, J=5 Hz), 6.55 (1H, d, J=5 Hz), 7.37-7.54 (5H, m), 7.62 (1H, m), 8.45 (1H, m), 8.52 (1H, m)
EXAMPLE 139
5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.25-1.48 (7H, m), 2.12 (2H, t, J=7 Hz), 2.62 (2H, m), 3.03 (2H, q, J=7 Hz), 5.93 (1H, d, J=5 Hz), 6.64 (1H, d, J=5 Hz), 7.14 (1H, m), 7.37 (1H, d, J=5 Hz), 7.43 (1H, d, J=5 Hz), 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-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.34-1.48 (5H, m), 2.09 (2H, m), 2.53 (2H, m), 3.04 (2H, q, J=7 Hz), 4.07 (2H, J=7 Hz), 4.65 (2H, s), 4.72 (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-ethylpyrrolo[1,2-b]pyridazin-3-yl)pentanoic acid
NMR (CDCl3, δ): 1.35-1.56 (7H, m), 2.18 (2H, m), 2.57 (2H, m), 3.03 (2H, q, J=7 Hz), 4.69 (2H, s), 4.74 (2H, s), 5.92 (1H, d, J=5 Hz), 6.62 (1H, d, J=5 Hz), 7.47 (2H, d, J=8 Hz), 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-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.20-1.49 (7H, m), 2.17 (2H, m), 2.32 (2H, m), 3.04 (2H, q, J=7 Hz), 4.29 (4H, s), 5.94 (1H, d, J=5 Hz), 6.51 (1H, s, br), 6.12 (1H, d, J=5 Hz), 7.27-7.36 (3H, m), 7.48 (2H, m), 7.84 (1H, m), 8.49 (1H, m), 8.75 (1H, m)
EXAMPLE 143
5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.20-1.38 (5H, m), 1.49 (4H, m), 2.24 (2H, q, J=7 Hz), 2.59 (4H, m), 3.01 (2H, q, J=7 Hz), 3.70 (4H, m), 5.88 (1H, d, J=5 Hz), 6.55 (1H, d, J=5 Hz), 7.90 (1H, m), 8.55 81H, m), 8.78 (1H, m)
EXAMPLE 144
5-{4-[5-(Aminocarbonyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid from ethyl 5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]-pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.10-1.70 (4H, m), 1.37 (3H, t, J=7 Hz), 2.24-2.77 (4H, m), 2.59 (3H, s), 3.02 (2H, q, J=7 Hz), 5.77 (1H, d, J=4 Hz), 6.52 (1H, d, J=4 Hz), 7.57 (1H, br), 7.97 (1H, br), 8.07 (1H, s), 8.68 (1H, s), 9.18 (1H, s) MS (ESI+): m/z 381
EXAMPLE 145
5-[4-[5-(Aminocarbonyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.16-1.72 (4H, m), 1.37 (3H, t, J=7 Hz), 2.25-2.50 (3H, m), 2.83-2.97 (1H, m), 3.04 (2H, q, J=7 Hz), 3.47 (3H, s), 4.56 (1H, d, J=17 Hz), 4.77 (1H, d, J=17 Hz), 5.81 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.52 (1H, br), 7.82 (1H, br), 8.11 (1H, m), 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 lithium bis(trimethylsilyl)amide (1.1 mol/L solution in hexanes, 15 mL) at 2° C. under nitrogen, and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of 4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carbaldehyde (1.2 g) in tetrahydrofuran (20 mL). After being stirred for 3 hours at 2° C., the mixture was poured into saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent; 3% ethyl acetate in n-hexane) to give the title compound (1.06 g) as an yellow crystals.
Ethyl (2E,4E)-5-[4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2,4-pentadienoate
NMR (300 MHz, CDCl3, δ): 1.28(3H, t, J=7 Hz), 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), 7.11-7.23(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 in substantially the same manner as that of Example 146.
EXAMPLE 147
Ethyl (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propenoate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 1.40 (6H, d, J=7 Hz), 3.38 (1H, m), 4.16 (2H, q, J=7 Hz), 5.57 (1H, d, J=15 Hz), 6.25 (1H, d, J=5 Hz), 6.74 (1H, d, J=5 Hz), 7.15 (1H, d, J=8.5 Hz), 7.29 (1H, d, J=85 Hz), 7.33 (1H, d, J=8.5 Hz), 7.35 (1H, d, J=85 Hz), 7.63 (1H, d, J=15 Hz) MS (ESI−): m/z 385 (M−H)
EXAMPLE 148
(2E)-3-[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propenenitrile
NMR (CDCl3, δ): 1.41 (6H, d, J=7 Hz), 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-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2,4-pentadienoate (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 resulting mixture was concentrated and partitioned between saturated aqueous sodium hydrogencarbonate and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent; 1% ethyl acetate in n-hexane) to give the title compound (110 mg) as an oil.
Ethyl (2E,4E)-5-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2,4-pentadienoate
NMR (300 MHz, CDCl3, δ): 1.28(3H, t, J=7 Hz), 1.40(6H, d, J=7 Hz), 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), 6.71(1H, d, J=4.4 Hz), 6.79(1H, d, J=16 Hz), 7.13-7.23(3H, m), 7.32-7.37(2H, m)
The following compounds were obtained in substantially the same manner as that of Example 149.
EXAMPLE 151
Ethyl 7-chloro-4-(2-chlorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate
NMR (300 MHz, CDCl3, δ): 0.89 (3H, t, J=75 Hz), 1.41 (6H, d, J=75 Hz), 3.41-3.56 (1H, m), 4.00 (2H, q, 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]pyridazine-3-carboxylate
NMR (300 MHz, CDCl3, δ): 0.78 (3H, t, J=75 Hz), 1.43 (6H, d, J=75 Hz), 3.29-3.41 (1H, m), 3.95 (2H, q, J=75 Hz), 6.40 (1H, d, J=5 Hz), 6.79 (1H, d, J=5 Hz), 7.50-7.60 (3H, m), 7.81-8.00 (4H, m)
EXAMPLE 153
To a solution of ethyl (2E,4E)-5-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2,4-pentadienoate (82 mg) in ethanol (2 mL) was added 1N sodium hydroxide solution (0.5 mL), and the mixture was stirred at ambient temperature for 12 hours. The resulting mixture was concentrated in vacuo, and the residue was dissolved in water, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent; 50% ethyl acetate in n-hexane) to give the title compound (14 mg) as a brown amorphous solid, which was recrystallized from aqueous ethanol.
(2E,4E)-5-[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2,4-pentadienoic acid
NMR (300 MHz, CDCl3, δ): 1.40 (6H, d, J=7 Hz), 1.30-1.90 (1H, br), 3.34 (1H, quintet, J=7 Hz), 5.64 (1H, d, J=16 Hz), 5.98 (1H, dd, J=16,11 Hz), 6.19 (1H, d, J=4.4 Hz), 6.72 (1H, d, J=4.4 Hz), 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 28% sodium methylate methanol solution (536 mg) and the mixture was heated under reflux for 2 hours. The solution was acidified to pH 4 with 1N hydrochloric acid and extracted with chloroform. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. To the residue in ethanol (5 mL) was added 1N sodium hydroxide solution (1 mL) and the mixture was heated at 60° C. for 1 hour. The solution was acidified to pH 4 with 1N hydrochloric acid and extracted with chloroform. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (1:1) to give 5-[7-ethyl-4-(2-methoxy-4-pyridinyl)-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid as an yellow powder (50.0 mg).
5-[7-Ethyl-4-(2-methoxy-4-pyridinyl)-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.30-1.48 (4H, m), 1.38 (3H, t, J=7 Hz), 2.13 (2H, t, J=7 Hz), 2.58-2.69 (2H, m), 3.02 (2H, q, J=7 Hz), 4.02 (3H, s), 5.96 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 6.78 (1H, s), 6.90 (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 in substantially the same manner as that of Example 154.
EXAMPLE 155
5-[7-Ethyl-4-(2-methoxy-4-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.31-1.64 (7H, m), 2.25 (2H, t, J=8 Hz), 2.43 (2H, br t, J=8 Hz), 2.54 (3H, s), 3.00 (2H, q, J=8 Hz), 4.04 (3H, s), 5.60 (1H, br s), 5.90 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 6.81 (1H, br s), 6.93 (1H, br d, 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]pentanoic acid
NMR (CDCl3, δ): 1.29-1.67 (7H, m), 2.29 (2H, t, J=8 Hz), 2.35-2.60 (5H, m), 3.00 (2H, q, J=8 Hz), 5.94 (1H, d, J=5 Hz), 6.54 (1H, d, J=5 Hz), 6.64 (1H, br d, J=7 Hz), 6.84 (1H, br s), 7.70 (1H, br d, J=7 Hz) MS (ESI+): m/z 354 (M+H)
The following compounds were obtained in substantially the same manner as that of Example 154.
EXAMPLE 156
5-[7-Ethyl-4-(2-methoxy-4-pyridinyl)-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.08-1.30 (4H, m), 1.36 (3H, t, J=7 Hz), 1.95 (2H, t, J=7 Hz), 2.48-2.53 (2H, m), 3.03 (2H, q, J=7 Hz), 4.01 (3H, s), 6.02 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 6.82 (1H, s), 6.94 (1H, d, J=5 Hz), 7.42-7.54 (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]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.40-1.64 (4H, m), 2.24 (2H, t, J=7 Hz), 2.53-2.64 (2H, m), 3.03 (2H, q, J=7 Hz), 3.45 (3H, s), 4.01 (3H, s), 4.61 (2H, s), 5.94 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 6.77 (1H, s), 6.89 (1H, d, J=5 Hz), 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-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (120 mg) in toluene (5 mL) and tetrahydrofuran (10 mL) was added sodium thiomethoxide (91.0 mg) and the mixture was heated under reflux for 4 hours. The solution was acidfied with 1N hydrochloric acid and extracted with chloroform. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1-3:1) to give 5-{7-ethyl-4-[2-(methylthio)-4-pyridinyl]-2-phenylpyrrolo-[1,2-b]pyridazin-3-yl}pentanoic acid as an yellow powder (85.0 mg).
5-{7-Ethyl-4-[2-(methylthio)-4-pyridinyl]-2-phenylpyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
NMR (CDCl3, δ): 1.07-1.17 (2H, m), 1.17-1.30 (2H, m), 1.36 (3H, t, J=7 Hz), 1.97 (2H, t, J=7 Hz), 2.38-2.48 (2H, m), 2.61 (3H, s), 3.02 (2H, q, 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), 7.43-7.55 (5H, m), 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-benzoylhexanoate (5.07 g), and trifluoromethanesulfonic acid (376 mg) in toluene (60 mL) was refluxed for 1 hour and 20 minutes with Dean-Stark equipment. The mixture was partitioned between ethyl acetate (60 mL) and water (60 mL), and the organic layer was washed with saturated sodium bicarbonate (60 mL) and brine (60 mL), dried over magnesium sulfate, and evaporated to give a dark colored oil. Flash silica gel column chromatography eluting with acetone=1-100 to 7-100 afforded ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo-[1,2-b]pyridazin-3-yl]pentanoate as an orange oil (4.45 g, 78.6%).
Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.01-1.27 (7H, m), 1.36 (3H, t, J=7 Hz), 1.86 (2H, t, J=7 Hz), 2.40 (2H, m), 3.02 (2H, q, J=7 Hz), 4.02 (2H, q, J=7 Hz), 5.90 (1H, d, J=5 Hz), 6.61 (1H, d, J=5 Hz), 7.44-7.53 (5H, s), 7.60-7.69 (2H, m), 7.74-7.79 (2H, m)
The following compound was obtained in substantially the same manner as that of 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 (CDCl3, δ): 1.21 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.25-1.48 (4H, m), 2.07 (2H, t, J=7 Hz), 2.57-2.68 (2H, m), 3.04 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.93 (1H, d, J=4 Hz), 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-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.05-1.17 (2H, m), 1.19-1.30 (2H, m), 1.28 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.91 (2H, t, J=7 Hz), 2.38-2.48 (2H, m), 3.02 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.96 (1H, d, J=4 Hz), 6.64 (1H, d, J=4 Hz), 7.31 (1H, dd, J=2 Hz, 5 Hz), 7.41-7.54 (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-phenylpyrrolo[1,2-b]pyridazin-3-yl]acetate
NMR (CDCl3, δ): 1.08 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 3.03 (2H, q, J=7 Hz), 3.36 (2H, s), 3.93 (2H, q, J=7 Hz), 6.09 (1H, d, J=5 Hz), 6.66 (1H, d, J=5 Hz), 7.33 (1H, m), 7.41-7.50 (8H, m) MS (ESI+): m/z 419 (M+H)
EXAMPLE 163
Ethyl 4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carboxylate
NMR (CDCl3, δ): 1.06 (3H, t, J=7 Hz), 1.41 (3H, t, J=7 Hz), 3.08 (2H, q, J=7 Hz), 4.09 (2H, q, 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), 7.52 (2H, m) MS (ESI+): m/z 395 (M+H)
EXAMPLE 164
Ethyl 4-(3-chlorophenyl)-7-ethyl-2-(2-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylate
NMR (CDCl3, δ): 0.94 (3H, m), 1.41 (3H, m), 3.08 (2H, q, J=7 Hz), 3.11 (2H, m), 4.00 (2H, m), 6.36 (1H, m), 6.76 (1H, m), 7.26-7.55 (4H, m), 7.84 (1H, m), 8.15 (1H, m), 8.57 (1H, m) MS (ESI+): m/z 406 (M+H)
EXAMPLE 165
Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-(1,3-thiazol-2-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.21 (3H, t, J=7 Hz), 1.33-1.50 (7H, m), 2.14 (2H, t, J=7 Hz), 2.46 (2H, m), 2.97 (2H, q, J=7 Hz), 3.06 (2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.88 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.43 (1H, d, J=3 Hz), 7.64-7.67 (2H, m), 7.70 (1H, m), 7.78 (1H, m), 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 (CDCl3, δ): 1.04 (2H, m), 1.21-1.41 (5H, m), 1.99 (2H, t, J=7 Hz), 2.46 (2H, m), 3.02 (2H, q, J=7 Hz), 3.60 (3H, s), 3.68 (3H, s), 5.89 (1H, d, J=5 Hz), 6.23 (1H, m), 6.35 (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-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoate
NMR (CDCl3, δ): 1.08 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.02 (2H, m), 2.80 (2H, m), 3.02 (2H, q, J=7 Hz), 3.89 (2H, q, J=7 Hz), 6.01 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.31 (1H, m), 7.41-7.54 (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 (CDCl3, δ): 1.17-1.49 (10H, m), 2.08 (2H, t, J=7 Hz), 2.57 (2H, m), 3.03 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 5.91 (1H, d, J=5 Hz), 6.66 (1H, d J=5 Hz), 7.55 (1H, s), 7.62-7.68 (3H, m), 7.78 (1H, m), 8.04 (1H, s)
EXAMPLE 169
Ethyl 5-[7-ethyl-4-(3-methoxyphenyl)-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.05-1.29 (4H, m), 1.18 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.86 (2H, t, J=7 Hz), 2.42-2.52 (2H, m), 3.02 (2H, q, J=7 Hz), 3.84 (3H, s), 4.02 (2H, q, J=7 Hz), 6.02 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 6.95-7.02 (3H, m), 7.36-7.56 (6H, m)
EXAMPLE 170
Ethyl 5-[7-ethyl-2-phenyl-4-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.04-1.29 (4H, m), 1.19 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.88 (2H, t, J=7 Hz), 2.38-2.48 (2H, m), 3.02 (2H, q, J=7 Hz), 4.04 (2H, q, J=7 Hz), 5.95 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.36 (2H, m), 7.42-7.54 (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 (CDCl3, δ): 1.10-1.32 (4H, m), 1.18 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.90 (2H, t, J=7 Hz), 2.45-2.55 (2H, m), 3.02 (2H, q, J=7 Hz), 4.02 (2H, q, J=7 Hz), 6.05 (1H, d, J=4 Hz), 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 (CDCl3, δ): 1.04-1.30 (4H, m), 1.18 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.87 (2H, t, J=7 Hz), 2.38-2.50 (2H, m), 3.02 (2H, q, J=7 Hz), 4.01 (2H, q, J=7 Hz), 5.96 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.42-7.55 (6H, m), 7.77 (1H, m), 8.66-8.73 (2H, m)
EXAMPLE 173
Ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.12-1.28 (7H, m), 1.36 (3H, t, J=7 Hz), 1.89 (2H, t, J=7 Hz), 2.43 (2H, m), 3.01 (2H, m), 4.02 (2H, q, J=7 Hz), 5.97 (1H, d, J=5 Hz), 6.65 (1H, d, J=5 Hz), 7.43-7.55 (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 (CDCl3, δ): 1.16-1.46 (10H, m), 1.57 (2H, t, J=7 Hz), 2.62 (2H, m), 2.30 (2H, m), 3.03 (2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.93 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.36 (1H, m), 7.44 (1H, m), 7.91 (1 H, m)
EXAMPLE 175
To a solution of ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (1.00 g) in dimethylsulfoxide (20 mL) was added 1N sodium hydroxide (5.31 mL) over 1.5 hours. The reaction was quenched by adding 1N hydrochloric acid (6 mL) under an ice-bath. The mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with water (50×2 mL) and brine, dried over magnesium sulfate, and evaporated. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1/3 to 1/1 afforded 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid as an yellow solid (668 mg).
5-[4-(3-Cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.03-1.25 (4H, m), 1.36 (3H, t, J=7 Hz), 1.93 (2H, t, J=7 Hz), 2.39 (2H, m), 3.02 (2H, q, J=7 Hz), 5.91(1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.26-7.53 (5H, s), 7.56-7.69 (2H, m), 7.72-7.79 (2H, m) MS (ESI+): m/z 424 (M+H)
The following compounds were obtained in substantially the same manner as that of Example 175.
EXAMPLE 176
5-[4-(3-Cyanophenyl)-7-ethyl-2-(1,3-thiazol-2-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.20-1.52 (7H, m), 2.19 (2H, m), 2.98 (2H, m), 3.04 (2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.38 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.43 (1H, d, J=3 Hz), 7.60-7.64 (2H, m), 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]pentanoic acid
NMR (CDCl3, δ): 1.12 (2H, m), 1.23-1.41 (5H, m), 2.04 (2H, t, J=7 Hz), 2.48 (2H, m), 3.02 (2H, q, J=7 Hz), 3.68(3H, s), 5.90 (1H, d, J=5 Hz), 6.22 (1H, m), 6.35 (1H, m), 6.62 (1H, d, J=5 Hz), 6.75 (1H, m), 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]pentanoic acid
NMR (CDCl3, δ): 1.31-1.49 (7H, m), 2.17 (2H, t, J=7 Hz), 2.57 (2H, m), 3.04 (2H, q, J=7 Hz), 5.42 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.56 (1H, s), 7.64 (2H, m), 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-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.04-1.30 (7H, m), 1.97 (2H, t, J=7 Hz), 2.26-2.35 (5H, m), 2.41 (3H, s), 3.00 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 5.97 (1H, d, J=5 Hz), 6.68 (1H, d, J=5 Hz), 7.61-7.68 (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]heptanedioate (203 mg), and toluenesulfonic acid monohydrate (3.76 mg) in toluene (1 mL) was refluxed for 1 hour.
Additional p-toluenesulfonic acid monohydrate (14.5 mg) was added, and the mixture was refluxed for 1 hour. The mixture was stirred further for 0.5 hour after adding trifluoromethanesulfonic acid (3.76 mg). The mixture was partitioned between ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL). The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1/40 to 2/5 afforded ethyl 5-[4-(3-cyanophenyl)-2-(3,5-dimethyl-4-isoxazolyl)-7-ethylpyrrolo-[1,2-b]pyridazin-3-yl]pentanoate as an yellow gum (75.7 mg, 19.1%).
Ethyl 5-[4-(3-cyanophenyl)-2-(3,5-dimethyl-4-isoxazolyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.04-1.30 (7H, m), 1.97 (2H, t, J=7 Hz), 2.26-2.35 (5H, m), 2.41 (3H, s), 3.00 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 5.97 (1H, d, J=5 Hz), 6.68 (1H, d, J=5 Hz), 7.61-7.68 (2H, m), 7.73 (1H, s), 7.79 (1H, m)
EXAMPLE 181
To a solution of N-[2-(3-cyanobenzoyl)-5-ethyl-1H-pyrrol-1-yl]-2-(methylsulfonyl)acetamide (2.70 g) in tetrahydrofuran (30 mL) was added sodium hydride (601 mg, 60% in oil) under an ice-bath. After stirring for 40 minutes, the reaction was quenched by adding 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 brine (50 mL), dried over magnesium sulfate, and evaporated to give a brownish yellow solid (3.36 g). The solid was triturated in diisopropyl ether (20 mL) to give 3-[7-ethyl-3-(methylsulfonyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4-yl]benzonitrile as an yellow powder (2.31 g, 90.1%).
3-[7-Ethyl-3-(methylsulfonyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 2.46-3.07 (5H, m), 6.81 (1H, d, J=5 Hz), 6.70 (1H, d, J=5 Hz), 7.60-7.69 (3H, m), 7.83 (1H, d, J=9 Hz)
The following compound was obtained in substantially the same manner as that of Example 181.
EXAMPLE 182
Ethyl 4-(4-cyanophenyl)-7-ethyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3-carboxylate
NMR (CDCl3, δ): 0.78 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 3.02 (2H, q, J=7 Hz), 4.02 (2H, q, J=7 Hz), 6.15 (1H, d, J=5 Hz), 6.64 (1H, d, J=5 Hz), 7.42 (2H, d, J=9 Hz), 7.77 (2H, d, J=9 Hz), 11.74 (1H, s, br) MS (ESI+): m/z 336 (M+H)
EXAMPLE 183
To a solution of 3-[7-ethyl-3-(methylsulfonyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4-yl]benzonitrile (1.30 g) and triethylamine (578 mg) in dichloromethane (18 mL) was added trifluoromethanesulfonic anhydride (1.61 g) under an ice-bath over 30 minutes (3 to 7° C.). After stirring for 0.5 hour, the reaction was quenched by adding water (100 mL). The mixture was partitioned between ethyl acetate (200 mL) containing chloroform (200 mL) and 1N hydrochloric acid (50 mL). An insoluble yellow solid was collected by filtration (0.542 g). The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give a dark yellow solid (1.27 g). Both the solid was combined, and triturated in diisopropyl ether (30 mL) to give 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-2-yl trifluoromethanesulfonate as a brownish yellow powder (1.67 g, 92.6%).
4-(3-Cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-2-yl trifluoromethanesulfonate
NMR (CDCl3, δ): 139 (3H, t, J=7 Hz), 3.02 (2H, q, J=7 Hz), 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-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-2-yl trifluoromethanesulfonate (150 mg) and pyrrolidine (45.6 mg) in tetrahydrofuran (1 mL) was refluxed for 1.5 hours. The mixture was partitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (10 mL). The organic extract was washed with brine, dried over magnesium sulfate, and evaporated to give a dark colored solid. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-4 to 1-2 afforded 3-[7-ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile as an yellow oil, which was crystalyzed upon standing (112 mg, 89.6%).
3-[7-Ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
NMR (CDCl3, δ): 1.38 (3H, t, J=7 Hz), 1.99 (4H, m), 3.99 (2H, q, J=7 Hz), 3.22 (3H, s), 3.42-3.70 (4H, m), 6.28 (1H, d, J=5 Hz), 6.68 (1H, d, J=5 Hz), 7.57 (1H, t, J=9 Hz), 7.69-7.78 (3H, m) MS (ESI+): m/z 395 (M+H)
The following compounds were obtained in substantially the same manner as that of Example 184.
EXAMPLE 185
3-[2-(Dimethylamino)-7-ethyl-3-(methyl sulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
NMR (CDCl3, δ): 1.39 (3H, t, J=7 Hz), 2.97 (6H, s), 3.02 (2H, q, J=7 Hz), 3.26 (3H, s), 6.28 (1H, d, J=5 Hz), 6.69 (1H, d, J=5 Hz), 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-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
NMR (CDCl3, δ): 1.35 (3H, t, J=7 Hz), 2.96 (2H, q, J=7 Hz), 3.07 (3H, s), 3.43 (3H, s), 3.61-3.73 (4H, m), 5.96 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 6.75 (1H, m, br), 7.51-7.60 (3H, m), 7.74 (1H, m) MS (ESI+): m/z 399 (M+H)
EXAMPLE 187
A mixture of ethyl 2-(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate (1.4 g), 1H-pyrrol-1-amine (350 mg), and p-toluenesulfonic acid monohydrate (41 mg) in ethanol (10 ml) was refluxed for 5 hours. The mixture was partioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 2-benzyl-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (828 mg) as an oil.
Ethyl 2-benzyl-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate
NMR (CDCl3, δ): 0.70 (3H, t, J=7 Hz), 3.71 (2H, q, J=7 Hz), 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-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (730 mg) in tetrahydrofuran (10 ml) was added N-chlorosuccinimide (260 mg) and the mixture was stirred at 20° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with aqueous sodium thiosulfate, water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography eluting with a mixture of toluene and ethyl acetate (10:1) to give ethyl 2-benzyl-7-chloro-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (285 mg) as an yellow oil.
Ethyl 2-benzyl-7-chloro-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate
NMR (CDCl3, δ): 0.69 (3H, t, J=7 Hz), 3.70 (2H, q, J=7 Hz), 4.37 (2H, s), 6.39 (1H, d, J=4 Hz), 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-fluorobenzoyl)-4-oxopentanoate (800 mg), 1H-pyrrol-1-amine (265 mg), and p-toluenesulfonic acid monohydrate (31 mg) in ethanol (5 ml) was refluxed for 5 hours. The mixture was partioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl[4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate (1.09 g) as an oil.
Ethyl [4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 2.45 (3H, s), 3.45 (2H, s), 4.16 (2H, q, 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), 7.68 (1H, dd, J=1, 2 Hz)
EXAMPLE 190
To a solution of ethyl[4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate (100 mg) in tetrahydrofuran (2 ml) was added N-chlorosuccinimide (43 mg) and the mixture was stirred at 20° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with aqueous ethyl acetate, water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography eluting with a mixture of toluene and ethyl acetate (10:1) to give ethyl[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate (34 mg) as an yellow oil.
Ethyl [7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate
NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 2.54 (3H, s), 3.47 (2H, s), 4.16 (2H, q, J=7 Hz), 6.05 (1H, d, J=4 Hz), 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-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate (300 mg) in tetrahydrofuran (4 ml) was added 1N sodium hydroxide (1.7 ml), followed by methanol (2 ml). After standing at 20° C. overnight, the mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was triturated with ether to give [7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetic acid (250 mg) as an yellow powder.
[7-Chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetic acid
NMR (CDCl3, δ): 2.57 (3H, s), 3.54 (2H, s), 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-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetic acid (220 mg) in tetrahydrofuran (10 ml) was added 1,1′-carbonyldiimidazole (18 mg) and the mixture was stirred at 20° C. for 1 hour, then magnesium bis(3-ethoxy-3-oxo-propanoate) (109 mg) was added. After the mixture was stirred overnight at 20° C., magnesium bis(3-ethoxy-3-oxo-propanoate) (109 mg) was added. After stirring for 3 hours, the mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give the product (237 mg) as an oil, which was triturated with ethyl acetate and washed with isopropyl ether to give ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-oxobutanoate (212 mg) as an yellow powder.
Ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-oxobutanoate
mp 116-118° C. NMR (CDCl3, δ): 1.25 (3H, t, J=7 Hz), 2.46 (3H, s), 3.40 (2H, s), 3.75 (2H, s), 4.16 (2H, q, J=7 Hz), 6.04 (1H, d, J=4 Hz), 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-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-oxo-butanoate (160 mg) in methanol (5 ml) was added sodium borohydride (23.4 mg) at 0° C. and the mixture was stirred at the same temperature for 1 hour. The mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by preparative thin-layer chromatography eluting with a mixture of ethyl acetate and hexane (1:3) and triturated with ethyl acetate to give ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoate (95 mg) as an yellow powder.
Ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 2.18-2.38 (2H, m), 2.67 (3H, s), 2.70-2.85 (2H, m), 4.03 (1H, m), 4.09 (2H, q, J=7 Hz), 5.96 (1H, d, J=4 Hz), 6.65 (1H, d, J=4 Hz), 7.19 (2H, t, J=7 Hz), 7.30-7.45 (2H, m)
EXAMPLE 194
To a solution of ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoate (52 mg) in tetrahydrofuran (1 ml) was added 1N sodium hydroxide (0.27 ml), followed by methanol (1 ml). After standing at 20° C. overnight, the mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated to give 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoic acid (45 mg) as an yellow oil.
4-[7-Chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoic acid
NMR (CDCl3, δ): 2.125-2.45 (2H, m), 2.66 (3H, s), 2.70-2.88 (2H, m), 4.02 (1H, m), 5.97 (1H, d, J=4 Hz), 6.65 (1H, d, J=4 Hz), 7.20 (2H, t, J=7 Hz), 7.30-7.45 (2H, m)
EXAMPLE 195
A mixture of ethyl 7-(4-fluorobenzoyl)-8-oxononanoate (300 mg), (1-amino-5-ethyl-1H-pyrrol-2-yl)(4-fluorophenyl)methanone (216 mg), and p-toluenesulfonic acid monohydrate (35.4 mg) in ethanol (6 ml) was refluxed for 5 hours. The mixture was partioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 6-[7-ethyl-2,4-bis(4-fluorophenyl)pyrrolo[1,2-b]pyridazin-3-yl]hexanoate (83 mg) and ethyl 6-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate (40 mg) as an oil.
Ethyl 6-[7-ethyl-2,4-bis(4-fluorophenyl)pyrrolo[1,2-b]pyridazin-3-yl]hexanoate
NMR (CDCl3, δ): 0.85-1.00 (2H, m), 1.00-1.10 (2H, m), 1.16-1.30 (2H, m), 1.21 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 2.00 (2H, t, J=7 Hz), 2.40 (2H, t, J=7 Hz), 3.01 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 5.97 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.12-7.24 (4H, m), 7.38 (2H, dd, J=5, 9 Hz), 7.50 (2H, dd, J=5, 9 Hz)
Ethyl 6-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate
NMR (CDCl3, δ): 1.15-1.30 (2H, m), 1.23 (3H, t, J=7 Hz), 1.35-1.45 (2H, m), 1.37 (3H, t, J=7 Hz), 1.45-1.55 (2H, m), 2.18 (2H, t, J=7 Hz), 2.40 (2H, t, J=7 Hz), 2.54 (3H, s), 3.01 (2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 5.85 (1H, d, J=4 Hz), 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-fluorophenyl)methanone (500 mg), ethyl 8-acetyl-9-oxodecanoate (678 mg), and p-toluenesulfonic acid monohydrate (82 mg) in ethanol (5 ml) was refluxed for 2 hours. The mixture was partioned between ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with toluene to give ethyl 6-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-eb]pyridazin-3-yl]hexanoate (130 mg) as an oil and [5-ethyl-1-({(1E)-1-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]ethylidene}amino)-1H-pyrrol-2-yl](4-fluorophenyl)methanone (70 mg) as an yellow crystal.
[5-Ethyl-1-({(1E)-1-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]ethylidene}amino)-1H-pyrrol-2-yl](4-fluorophenyl)methanone
NMR (CDCl3, δ): 1.13 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.80-2.00 (2H, m), 1.91 (3H, s), 2.86 (3H, s), 3.06 (2H, q, 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), 7.48 (2H, dd, J=5, 9 Hz), 7.82 (2H, dd, J=5, 9 Hz)
Ethyl 6-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate
NMR (CDCl3, δ): 1.15-1.30 (2H, m), 1.23 (3H, t, J=7 Hz), 1.35-1.45 (2H, m), 1.37 (3H, t, J=7 Hz), 1.45-1.55 (2H, m), 2.18 (2H, t, J=7 Hz), 2.40 (2H, t, J=7 Hz), 2.54 (3H, s), 3.01 (2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 5.85 (1H, d, J=4 Hz), 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-oxononanoate (2.2 g), 2-ethyl-1H-pyrrol-1-amine (809 mg), and p-toluenesulfonic acid monohydrate (64 mg) in toluene (40 ml) was refluxed for 20 minutes. The mixture was partioned between ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give the product, which was triturated with hexane to give ethyl 6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo-[1,2-b]pyridazin-3-yl]hexanoate (2.21 g) as an yellow crystals.
Ethyl 6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate
NMR (CDCl3, δ): 1.15-1.25 (2H, m), 1.25 (3H, t, J=7 Hz), 1.30-1.45 (2H, m), 1.38 (3H, t, J=7 Hz), 1.45-1.65 (2H, m), 2.19 (2H, t, J=7 Hz), 2.38 (2H, t, J=7 Hz), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.80 (1H, d, J=4 Hz), 6.51 (1H, d, J=4 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate (15 g) in tetrahydrofuran (15 ml) was added 2N potassium hydroxide (7.4 ml), followed by methanol (7.4 ml). After stirring at 50° C. for 2 hours and 60° C. for 3 hours, the mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The precipitates were filtered and washed with ethyl acetate. The organic layer and the washings were combined, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was triturated with ethyl acetate and the precipitates were filtered. The filtrate was purified by silica gel column chromatography eluting with a mixture of ethyl acetate and hexane (1:1) and triturated with isopropyl ether to give 6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoic acid (650 mg) as an yellow crystals. The two precipitates were combined and recrystallized from ethyl acetate to give 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid (550 mg, 37.6%) as an yellow crystals.
6-[4-(4-Cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoic acid
NMR (CDCl3, δ): 1.15-1.30 (2H, m), 1.35-1.45 (2H, m), 1.38 (3H, t, J=7 Hz), 1.45-1.60 (2H, m), 2.26 (2H, t, J=7 Hz), 2.38 (2H, t, J=7 Hz), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 5.80 (1H, d, J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.48 (2H, t, J=9 Hz), 7.79 (2H, d, J=9 Hz)
6-{4-[4-(Aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid
NMR (CDCl3, δ): 1.1-1.20 (2H, m), 1.29 (3H, t, J=7 Hz), 1.30-1.45 (4H, m), 2.10 (2H, t, J=7 Hz), 2.37 (2H, t, J=7 Hz), 2.51 (3H, s), 2.92 (2H, q, 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), 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 p-toluenesulfonic acid monohydrate (32 mg) at ambient temperature. The reaction mixture was refluxed for 1 hour. The residue was purified by flash silica gel chromatography (silica gel, 80 mL) eluted with hexane-ethyl acetate=10-1 to give 3-(3-acetyl-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile (63 mg, 24.8%) as an yellow solid.
3-(3-Acetyl-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile
NMR (CDCl3, δ): 1.39 (3H, t, J=8 Hz), 1.95 (3H, s), 2.50 (3H, s), 3.04 (2H, q, J=8 Hz), 6.27 (1H, d, J=5 Hz), 6.69 (1H, d, J=5 Hz), 7.59-7.72 (2H, m), 7.76-7.84 (2H, m) MS (ESI+): m/z 304 (M+H)
EXAMPLE 200
To a solution of ethyl (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propenoate (50 mg) in toluene was added dropwise 1.5 M diisobutylaluminum hydride (0.277 mL) in toluene (24 mL) in a dryice-acetone bath. After addition, the mixture was stirred for 2 hours (−10° C.). The reaction mixture was quenched with sodium, potassium-tartarate and was filtered through Celite. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 40 mL) eluted with hexane-ethyl acetate=10-1, 5-1, and 3-1 to give (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propen-1-ol as an yellow solid (30 mg).
(2E)-3-[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propen-1-ol
NMR (CDCl3, δ): 1.38 (6H, d, J=7 Hz), 3.31 (1H, m), 4.05-4.11 (2H, m), 5.48 (1H, dt, J=15, 6 Hz), 6.11 (1H, d, J=5 Hz), 6.45 (1H, d, J=15 Hz), 6.68 (1H, d, J=5 Hz), 7.08-7.18 (2H, m), 7.29-7.40 (2H, m) MS (ESI−): m/z 345 (M+H)
The following compounds were obtained in substantially the same manner as that of Example 200.
EXAMPLE 201
[4-(4-Fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methanol
NMR (CDCl3, 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 (1H, m), 7.14-7.28 (2H, m), 7.43-7.51 (2H, m), 7.70 (1H, m) MS (ESI+): m/z 257 (M+H)
EXAMPLE 202
[7-Ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methanol
NMR (CDCl3, δ): 1.31-1.46 (10H, m), 3.04 (2H, q, J=8 Hz), 3.46 (1H, m), 4.49 (2H, d, J=5 Hz), 6.05 (1H, d, J=5 Hz), 6.56 (1H, d, J=5 Hz), 7.12-7.22 (2H, m), 7.41-7.50 (2H, m) MS (ESI+): m/z 313 (M+H)
EXAMPLE 203
2-{[7-Ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methoxy}ethanol
NMR (CDCl3, δ): 1.30-1.45 (9H, m), 3.04 (2H, q, J=8 Hz), 3.35 (1H, m), 3.46 (2H, t, J=6 Hz), 3.69 (2H, br t, 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-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propen-1-ol (30 mg) in N,N-dimethylformamide (1 mL) was added 60% sodium hydride in oil (3.8 mg) in an ice-water bath under nitrogen atmosphere. After 20 minutes, to the mixture was added methyl iodide (18.5 mg) at the temperature. After 15 minutes, the reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate=10-1) to give 7-chloro-4-(4-fluorophenyl)-2-isopropyl-3-[(1E)-3-methoxy-1-propenyl]pyrrolo[1,2-b]pyridazine as a brown oil (35 mg, 10.2%).
7-Chloro-4-(4-fluorophenyl)-2-isopropyl-3-[(1E)-3-methoxy-1-propenyl]pyrrolo[1,2-b]pyridazine
NMR (CDCl3, δ): 1.38 (3H, t, J=7 Hz), 3.31 (1H, m), 4.05-4.11 (2H, m), 5.48 (1H, dt, J=15, 6 Hz), 6.11 (1H, d, J=5 Hz), 6.45 (1H, d, J=15 Hz), 6.68 (1H, d, J=5 Hz), 7.08-7.18 (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 was heated at 60° C. for 40 minutes. To this mixture was added (3-carboxypropyl)(triphenyl)phosphonium bromide (124 mg) at ambient temperature and was stirred for 40 minutes. 7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carbaldehyde (40 mg) was added therein at ambient temperature. After 4 hours, the reaction mixture was acidified with 1N hydrogen chloride and was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate=1-1) to give (4E)-5-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-4-pentenoic acid as an yellow oil (21 mg, E:Z=16:1, 56.3%).
(4E)-5-[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-4-pentenoic acid
NMR (CDCl3, δ): 1.40 (6H, d, J=7 Hz), 2.20-2.37 (4H, m), 3.25 (1H, m), 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), 7.26-7.35 (2H, m). MS (ESI−): m/z 385 (M−H)
EXAMPLE 206
To a solution of 7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carbaldehyde (40 mg) was added 1N sodium hydroxide (19.3 mg) and acetone (0.425 mL) at ambient temperature. After 8 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate=5-1) to give (3E)-4-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-3-buten-2-one as an yellow solid (33 mg).
(3E)-4-[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-3-buten-2-one
NMR (CDCl3, δ): 1.40 (6H, d, J=7 Hz), 2.13 (3H, s), 3.38 (1H, m), 5.89(1H, d, J=15 Hz), 6.23 (1H, d, J=5 Hz), 6.75 (1H, d, J=5 Hz), 7.13-7.23 (2H, m), 7.30-7.39 (2H, m), 7.49 (1H, d, J=15 Hz)
EXAMPLE 207
A solution of ethyl 4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (100 mg) in tetrahydrofuran (1 mL) was purged with nitrogen gas under a dryice-acetone bath. To the mixture was added 2,2′-azobisisobutyronitrile (0.5 mg) was added to the mixture. After 5 minutes, was added 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (43.8 mg). The resulting mixture was stirred for 3 hours (−78 to −30° C.). Water (5 mL) was added, and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give an yellow gum. Flash silica gel column chromatography eluting with toluene-hexane=1-5 to 2-3 afforded ethyl 7-bromo-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate product as an yellow gum (90.0 mg, 72.5%).
Ethyl 7-bromo-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate
NMR (CDCl3, δ): 0.98 (3H, t, J=7 Hz), 1.40 (6H, d, J=7 Hz), 3.31 (1H, septet, J=7 Hz), 4.05 (2H, q, J=7 Hz), 6.39 (1H, d, J=5 Hz), 6.87 (1H, d, J=5 Hz), 7.16 (2H, t, J=9 Hz), 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 dimethylsulfoxide (1.4 mL) was stirred for 1 hour at 60° C. The mixture was added to a solution of methyl triphenylphosphonium bromide (1.11 g) in dimethylsulfoxide (1.0 mL) at room temperature. After stirring for 0.5 hour, the mixture was added ethyl 4-(4-fluorophenyl)-7-formyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (500 mg). After stirring for 15 hours, the mixture was partitioned between ethyl acetate (20 mL) and water (5 mL). The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated to give an orange gum. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-7 to 3-1 afforded ethyl 4-(4-fluorophenyl)-2-isopropyl-7-vinylpyrrolo[1,2-b]pyridazine-3-carboxylate an yellow gum, which was solidified upon standing (36.1 mg, 72.6%).
Ethyl 4-(4-fluorophenyl)-2-isopropyl-7-vinylpyrrolo[1,2-b]pyridazine-3-carboxylate
NMR (CDCl3, δ): 0.97 (3H, t, J=7 Hz), 1.38 (6H, d, J=7 Hz), 3.32 (1H, septet, J=7 Hz), 4.03 (2H, q, J=7 Hz), 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), 6.99 (1H, d, J=5 Hz), 7.16 (1H, t, J=9 Hz), 7.25 (1H, dd, J=12 and 18 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl}heptanoate (169 mg) in ethanol (2 mL) was added 10% palladium on activated carbon (1.6 mg), and the mixture was stirred under hydrogen pressure (3 kg/cm2) for 2 hours. The resulting mixture was filtered through celite, and the filtrate was concentrated to give an yellow gum. Preparative silica gel thin layer chromatography eluting with ethyl acetate-hexane=1-1 afforded ethyl 7-{4-[4-(aminosulfonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}heptanoate as an yellow gum (76.8 mg, 58.4%).
Ethyl 7-{4-[4-(aminosulfonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}heptanoate
NMR (CDCl3, δ): 1.07-1.25 (7H, m), 1.30-1.46 (7H, m), 2.18 (2H, t, J=7 Hz), 2.36 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.21 (2H, s), 5.82 (1H, d, J=5 Hz), 6.50 (1H, d, J=5 Hz), 7.52 (2H, d, J=9 Hz), 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-ethylpyrrolo[1,2-b]pyridazine-3-carboxylate (77.9 mg) in ethanol (0.5 mL)-tetrahydrofuran (0.5 mL) was added 1N potassium hydroxide. The resulting solution was stirred for 2.5 hours at room temperature. The mixture was stirred for further 1 hour after adding 1N potassium hydroxide (0.04 mL). The reaction was quenched by adding 1N hydrochloric acid (0.23 mL). The volatile was evaporated off, and the resulting residue was partitioned between ethyl acetate (10 mL) and 1N hydrochloric acid (6 mL). The organic layer was washed with brine, dried, and evaporated to give [4-(4-cyanophenyl)-3-(ethoxycarbonyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]acetic acid as an yellow solid (67.7 mg, 93.4%).
[4-(4-Cyanophenyl)-3-(ethoxycarbonyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]acetic acid
NMR (CDCl3, δ): 0.84 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 3.05 (2H, q, J=7 Hz), 3.93 (2H, q, 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-ethylpyrrolo[1,2-b]pyridazine-3-carboxylate (35.0 mg) in tetrahydrofuran (1 mL) was added 60% sodium hydride (4.50 mg) under an ice-bath. The resulting mixture was stirred for 1 hour. The reaction was quenched by adding 1N HCl (4 mL). The mixture was extracted with ethyl acetate (10 mL), and the organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated. Preparative silica gel thin layer chromatography eluting with ethyl chloroform-methanol=10-1 afforded 4-(7-ethyl-1,3-dioxo-1,2,3,4-tetrahydropyrido[3,4-e]pyrrolo[1,2-b]-pyridazin-10-yl)benzonitrile as an yellow solid (3.86 mg, 12.6%).
4-(7-Ethyl-1,3-dioxo-1,2,3,4-tetrahydropyrido[3,4-e]pyrrolo[1,2-b]pyridazin-10-yl)benzonitrile
NMR (CDCl3, δ): 1.40 (3H, t, J=7 Hz), 3.08 (2H, q, 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, br)
EXAMPLE 212
To methanol (1 mL) was added 60% sodium hydride (651 mg) at room temperature. Then, 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-2-yl trifluoromethanesulfonate (70.0 mg) was added to the mixture. The resulting mixture was stirred for 2 hours at room temperature and 1 hour at 50° C. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. Preparative silica gel thin layer chromatography eluting with ethyl acetate-hexane=1-1 afforded 3-[7-ethyl-2-methoxy-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile as an yellow solid (1.92 mg, 3.7%).
3-[7-Ethyl-2-methoxy-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
NMR (CDCl3, δ): 1.38 (3H, t, J=7 Hz), 3.01 (2H, q, 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), 7.53-7.64 (3H, m), 7.76 (1H, m)
EXAMPLE 213
To a solution of ethyl 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-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. The resulting mixture was stirred further for 40 minutes after adding 1N sodium hydroxide (0.1 mL). The mixture was stirred further for 1.5 hours after adding 1N sodium hydroxide (0.1 mL). The reaction was quenched by adding 1N hydrochloric acid (1 mL), and the mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give a red oil. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-1 afforded 3-(6-ethyl-1,1-dioxido-3-oxo-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile as a red foam (52.4 mg, 64.0%).
3-(6-Ethyl-1,1-dioxido-3-oxo-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile
NMR (CDCl3, 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), 7.75 (1H, t, J=9 Hz), 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]pyridazin-9-yl)benzonitrile (60.0 mg) in tetrahydrofuran (0.2 mL) was added 1 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (0.487 mL) under an ice-bath. After stirring for 1 hour, the reaction was quenched by adding 1N hydrochloric acid (1 mL). The mixture was partitioned between ethyl acetate (20 mL) and water (10 mL), and the organic layer was washed with brine, dried, and evaporated to give 3-(6-ethyl-3-hydroxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)-benzonitrile as an yellow foam (576 mg, 99.8%).
3-(6-Ethyl-3-hydroxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile
NMR (CDCl3, 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), 7.75 (1H, t, J=9 Hz), 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]pyridazin-9-yl)benzonitrile (54.0 mg) in tetrahydrofuran (1 mL) was added 60% sodium hydride (6.69 mg) under an ice-bath. After stirring for 0.5 hour, methyl iodide (25.9 mg) was added, and the mixture was stirred for 3 hours 20 minutes at room temperature. The mixture was stirred for another 6 hours after adding methyl iodide (25.9 mg). The mixture was further stirred for 1 hour after adding 60% sodium hydride (3.0 mg) and methyl iodide (25.9 mg). The mixture was partitioned between ethyl acetate and 1N hydrochloric acid, and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give an yellow oil. Preparative silica gel thin layer chromatography eluting with ethyl acetate-hexane=1-2 afforded 3-(6-ethyl-1,1-dioxidopyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile (5.9 mg, 10.5%, an yellow solid) and 3-(6-ethyl-3-methoxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile (16.8 mg, 30.0%, an orange gum).
3-(6-Ethyl-1,1-dioxidopyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile
NMR (CDCl3, δ): 1.40 (3H, t, J=7 Hz), 3.07 (2H, q, J=7 Hz), 6.68 (1H, d, J=5 Hz), 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]pyridazin-9-yl)benzonitrile
NMR (CDCl3, δ): 1.42 (3H, t, J=7 Hz), 3.12 (2H, q, J=7 Hz), 3.67 (3H, s), 3.73 (2H, m), 5.02 (1H, m), 6.74 (1H, d, J=5 Hz), 6.97 (1H, d, J=5 Hz), 7.70 (1H, t, J=9 Hz), 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-(methylsulfonyl)-2-oxopropanoate (1.34 g), and p-toluenesulfonic acid monohydrate (79.5 mg) in toluene (20 mL) was refluxed for 1 hour with Dean-Stark condenser. The volatile was removed in vacuo. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-10 to 9-15 afforded the intermediate imine (1.38 g, 67.7%) as an orange foam. The foam was dissolved in N-methylmorpholine (10 mL), and the solution was stirred for 1 hour at 130° C. The mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with water (30×2 mL) and brine, dried over magnesium sulfate, and evaporated to give a dark orange solid. The solid was triturated in diisopropyl ether (10 mL) to give 2-(trimethylsilyl)ethyl 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylate as an yellow powder (1.11 g, 67.7%).
2-(Trimethylsilyl)ethyl 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylate
NMR (CDCl3, δ): 0.12 (9H, s), 1.22 (2H, m), 1.39 (3H, t, J=7 Hz), 3.09 (2H, q, J=7 Hz), 3.23 (3H, s), 4.53 (2H, m), 6.30 (1H, d, J=5 Hz), 6.89 (1H, d, J=5 Hz), 7.50-7.67 (3H, m), 7.82 (1H, m) MS (ESI+): m/z 470 (M+H)
The following compound was obtained in substantially the same manner as that of Example 216.
EXAMPLE 217
Ethyl 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylate
NMR (CDCl3, δ): 1.39 (3H, t, J=7 Hz), 1.47 (3H, t, J=7 Hz), 3.10 (2H, q, J=7 Hz), 3.21, (3H, s), 4.51 (2H, q, J=7 Hz), 6.30 (1H, d, J=5 Hz), 6.90 (1H, d, J=5 Hz), 7.61-7.67 (3H, m), 7.72 (1H, m)
EXAMPLE 218
A solution of 2-(trimethylsilyl)ethyl 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylate (1.09) in trifluoroacetic acid (5 mL) was stirred for 1.5 hours under an ice-bath. The reaction was quenched by adding water (20 mL). An yellow crystal was formed upon the addition, which was collected by filtration. The crystal was washed with water (5 mL) and hexane (3 mL) to give 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylic acid as an yellow crystal (756 mg, 88.2%).
4-(3-Cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylic acid
NMR (CDCl3, δ): 1.41 (2H, m), 3.10 (2H, q, J=7 Hz), 3.30 (3H, s), 6.36 (1H, d, J=5 Hz), 6.94 (1H, d, J=5 Hz), 7.53-7.67 (3H, m), 7.82 (1H, m) MS (ESI+): m/z 370 (M+H)
EXAMPLE 219
A mixture of 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylic acid (40.0 mg), diemthylamine hydrochloride (12.4 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (25.2 mg), and 1-hydroxybenzotriazole (21.9 mg) in N,N-dimethylformamide (1 mL) was stirred for 3 hours at room temperature. The mixture was partitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (10 mL). The organic layer was washed with water (10×3 mL), saturated sodium bicarbonate (10 mL), and brine, dried over magnesium sulfate, and evaporated to give 4-(3-cyanophenyl)-7-ethyl-N,N-dimethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxamide as an yellow solid (43.4 mg, 101%).
4-(3-Cyanophenyl)-7-ethyl-N,N-dimethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxamide
NMR (CDCl3, δ): 1.38 (2H, m), 3.07 (2H, q, J=7 Hz), 3.12 (3H, s), 3.18 (3H, s), 3.27 (3H, s), 6.27 (1H, d, J=5 Hz), 6.85 (1H, d, J=5 Hz), 7.57-7.67 (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]pyridazine-3-carboxylate (450 mg) and 85% potassium hydroxide (3.01 g) in a mixture of ethanol (3 mL) and water (2 mL) was refluxed for 25 hours. The reaction mixture was cooled under an ice-bath, and quenched by adding concentrated hydrochloric (5 mL). The mixture was partitioned between ethyl acetate (20 mL) and water (10 mL), and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give an yellow solid (388 mg). The solid was triturated in hexane to give 4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid as an yellow powder (361 mg, 86.4%).
4-(3-Chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid
NMR (CDCl3, δ): 1.41 (3H, t, J=7 Hz), 3.08 (2H, q, 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), 7.40-7.55 (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]pyridazine-3-carboxylic acid (358 mg) and N,N-dimethylformamide (1.39 mg) in dichloromethane (3 mL) was added oxalyl chloride (157 mg) at room temperature. After stirring for 30 minutes, the volatile was removed in vacuo, and the residue was azeotroped with toluene three times to afford 4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carbonyl chloride as an yellow gum (396 mg, 106%).
4-(3-Chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carbonyl chloride
NMR (CDCl3, δ): 1.42 (3H, t, J=7 Hz), 3.10 (2H, q, J=7 Hz), 6.45 (1H, d, J=5 Hz), 6.59 (1H, m), 6.82 (1H, d, J=5 Hz), 7.06 (1H, d, J=7 Hz), 7.38-7.55 (4H, m), 7.63 (1H, m)
EXAMPLE 222
To a solution of methyl aminoacetate hydrochloride (26.1 mg) and triethylamine (42.0 mg) in dichloromethane (0.5 mL) was added a solution of 4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carbonyl chloride (40.0 mg) in dichloromethane (0.5 mL) under an ice-bath. The mixture was partitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (10 mL), and the organic layer was washed with brine (10 mL), dried over magnesium sulfate, and evaporated to give methyl ({[4-(3-chlorophenyl)-7-ethyl-2-(3-furyl)pyrrolo[1,2-b]pyridazin-3-yl]carbonyl}amino)acetate as an yellow gum (50.6 mg, 111%).
Methyl ({[4-(3-chlorophenyl)-7-ethyl-2-(3-furyl)pyrrolo[1,2-b]pyridazin-3-yl]carbonyl}amino)acetate
NMR (CDCl3, δ): 1.41 (3H, t, J=7 Hz), 3.10 (2H, q, J=7 Hz), 3.69 (3H, s), 3.95 (2H, d, J=5 Hz), 6.01 (1H, t, br, 5 Hz), 6.35 (1H, d, J=5 Hz), 6.51 (1H, m), 6.75 (1H, d, J=5 Hz), 7.01 (1H, d, J=7 Hz), 7.37-7.48 (3H, m), 7.53 (1H, m), 7.58 (1H, m) MS (ESI+): m/z 438 (M+H)
The following compound was obtained in substantially the same manner as that of Example 222.
EXAMPLE 223
4-(3-Chlorophenyl)-7-ethyl-2-(2-furyl)-N,N-bis(2-hydroxyethyl)pyrrolo[1,2-b]pyridazine-3-carboxamide
NMR (CDCl3, δ): 1.42 (3H, t, J=7 Hz), 2.35-2.72 (4H, m), 3.08 (2H, d, J=5 Hz), 3.20-3.63 (4H, m), 3.82 (2H, m), 6.40 (1H, t, br, 5 Hz), 6.54 (1H, m), 6.75 (1H, d, J=5 Hz), 7.04 (1H, d, J=3 Hz), 7.40-7.48 (2H, m), 7.53-7.60 (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-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoic acid (100 mg) in dioxane (0.5 mL) was added triethylamine (25.2 mg) followed by a solution of pivaloyl chloride (30.1 mg) in dioxane (0.5 mL). A white precipitate was formed. After stirring for 40 minutes at room temperature, the precipitate was removed by filtration, and washed with dioxane (2 mL). To the combined washing was added a solution of 2-aminoethanesulfonic acid (38.6 mg) in 1N sodium hydroxide (0.247 mL). The resulting mixture was stirred for 1 hour at room temperature. The mixture was partitioned between ethyl acetate (15 mL) and water (5 mL). The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. Preparative silica gel thin layer chromatography eluting with chloroform-methanol=5-1 afforded 2-({3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo-[1,2-b]pyridazin-3-yl]propanoyl}amino)ethanesulfonic acid as an yellow solid (104 mg, 82.0%).
2-({3-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoyl}amino)ethanesulfonic acid
NMR (CDCl3, δ): 1.27 (5H, m), 2.59 (4H, m), 2.90-3.14 (4H, m), 5.96 (1H, m), 6.06 (1H, m), 7.06-7.40 (9H, m)
EXAMPLE 225
A solution of 3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[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-pyran-4-yl pivalate (255 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.494 mmol), and 1-hydroxybenzotriazole (66.7 mg) in N,N-dimethylformamide (1 mL) was stirred for 1 hour at room temperature. The mixture was partitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (10 mL). The organic layer was washed with water (10×3 mL), saturated sodium bicarbonate (10 mL), and brine, dried over magnesium sulfate, and evaporated to give an yellow foam (339 mg). Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-10 to 2-5 afforded (2R,3R,4S,5S,6R)-2-({3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoyl}amino)-3,5-bis[(2,2-dimethylpropanoyl)oxy]-6-{[(2,2-dimethylpropanoyl)oxy]methyl}tetrahydro-2H-pyran-4-yl pivalate an yellow foam (240 mg, 108%).
(2R,3R,4S,5S,6R)-2-({3-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoyl}amino)-3,5-bis[(2,2-dimethylpropanoyl)oxy]-6-{[(2,2-dimethylpropanoyl)oxy]methyl}tetrahydro-2H-pyran-4-yl pivalate
NMR (CDCl3, δ): 0.97-1.26 (3H, m), 1.35 (3H, t, J=7 Hz), 1.83 (2H, m), 2.81 (2H, m), 3.01 (2H, q, J=7 Hz), 3.87-4.16 (3H, m), 4.90-5.27 (3H, m), 5.36-5.51 (2H, m), 6.01 (1H, d, J=5 Hz), 6.52 (1H, d, J=5 Hz), 7.29 (1H, m), 7.40-7.59 (8H, m)
EXAMPLE 226
To a solution of ethyl[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]acetate (114 mg) in tetrahydrofuran (2 mL) was added 1 M diisobutylaluminum hydride in toluene (0.816 mL) under an ice-bath. After stirring for 1 hour at room temperature, additional 1 M diisobutylaluminum hydride (0.41 mL) was added. The reaction was quenched by adding 1N hydrochloric acid (1 mL) after 1 hour. The mixture was partitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (10 mL), and filtered through celite. The organic layer was washed with water (10 mL) and brine, dried over magnesium sulfate, and evaporated to give an yellow gum. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-20 to 2-50 afforded 2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethanol as an yellow oil, which was crystalyzed upon standing (107 mg, 104%).
2-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethanol
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 2.77 (2H, t, J=7 Hz), 3.01 (2H, q, 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), 7.41-7.55 (8H, m)
EXAMPLE 227
To a mixture of 2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethanol (105 mg), 2,3,4,6-tetra-O-acetyl-beta-D-galactosyl bromide (299 mg), silver carbonate (154 mg) in toluene (2 mL) was added silver triflate (3.58 mg) under an ice bath. After 40 minutes, 2,3,4,6-tetra-O-acetyl-beta-D-galactosyl bromide (114 mg), silver carbonate (229 mg) was added, and the mixture was stirred for 50 minutes. The mixture was further stirred for 50 minutes after adding 2,3,4,6-tetra-O-acetyl-beta-D-galactosyl bromide (114 mg), silver carbonate (154 mg). The mixture was filtered through celite, and the filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give an yellow gum. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-10 to 7/10 afforded (2R,3R,4S,5S,6R)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]-2-{2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}tetrahydro-2H-pyran-3-yl acetate as an yellow gum (115 mg, 58.4%).
(2R,3R,4S,5S,6R)-4,5-bis(Acetyloxy)-6-[(acetyloxy)methyl]-2-{2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}tetrahydro-2H-pyran-3-yl acetate
NMR (CDCl3, δ): 1.35 (3H, t, J=7 Hz), 1.70 (3H, m), 1.94 (3H, s), 2.04 (3H, s), 2.11 (3H, s), 2.78 (2H, m), 3.01 (2H, q, J=7 Hz), 3.10 (1H, m), 3.46 (1H, m), 3.62 (1H, t, J=6 Hz), 3.79 (1H, d, J=8 Hz), 3.98 (2H, m), 4.83 (1H, dd, J=3 and 10 Hz), 4.97 (1H, dd, J=8 and 10 Hz), 5.28 (1H, d, J=3 Hz), 6.02 (1H, d, J=5 Hz), 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(acetyloxy)-6-[(acetyloxy)methyl]-2-{2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}tetrahydro-2H-pyran-3-yl acetate (113 mg) in methanol (2 mL) was added sodium methoxide (0.86 mg) at room temperature. After stirring for 2 hours, the solvent was evaporated off, and the mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give an yellow foam (77.3 mg). The foam was triturated in hexane to give (2R,3R,4S,5R,6R)-2-{2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol as an yellow powder (48.3 mg, 89.7%).
(2R,3R,4S,5R,6R)-2-{2-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
NMR (CDCl3, δ): 1.36 (3H, t, J=7 Hz), 1.92 (1H, m), 2.06 (1H, m), 2.56 (1H, s, br), 2.76-2.92 (3H, m), 3.02 (2H, q, J=7 Hz), 3.24 (2H, m), 3.38-3.50 (3H, m), 3.63-3.84 (3H, m), 2.41 (1H, s, br), 6.01 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.32 (1H, m), 7.41-7.57 (8H, m)
The following compounds were obtained in substantially the same manner as that of Example 228.
EXAMPLE 229
3-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]propanamide
NMR (CDCl3, δ): 1.38 (3H, t, J=7 Hz), 1.97 (2H, m), 2.83 (2H, m), 3.01 (2H, q, J=7 Hz), 3.31-3.52 (3H, m), 3.61-3.76 (2H, m), 3.88 (1H, m), 4.63 (1H, d, J=9 Hz), 6.01 (1H, d, J=5 Hz), 6.64 (1H, d, J=5 Hz), 7.34 (1H, m), 7.42-7.59 (8H, m)
EXAMPLE 230
Ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate from ethyl 5-[2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.34-1.50 (5H, m), 154 (2H, m), 2.19 (2H, t, J=7 Hz), 2.37 (2H, m), 3.02 (2H, q, J=7 Hz), 3.71 (1H, t, J=5 Hz), 4.10 (2H, q, J=7 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (50 mg) in N,N-dimethylformamide (1 mL) was added 1,1′-carbonyldiimidazole (33.6 mg) at ambient temperature. After 1 hour stirring, to the mixture was added methanesulfonamide (19.7 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (31.6 mg). The mixture was heated at 50° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 1N hydrogen chloride and was extracted with ethyl acetate. The organic layer was washed with water 3 times and brine, dried over magnesium sulfate, and evaporated in vacuo to give an yellow solid. The residue was crystallized from IPE to give yellow solid (45 mg). The solid was recrystallized from ethanol to give N-{5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoyl}methanesulfonamide (25 mg) as an yellow solid.
N-{5-[4-(3-Cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoyl}methanesulfonamide
NMR (CDCl3, δ): 1.33-1.61 (7H, m), 2.21 (2H, t, J=8 Hz), 2.40 (2H, t, J=8 Hz), 2.55 (3H, s), 3.00 (2H, q, J=8 Hz), 3.29 (3H, s), 5.80 (1H, d, J=5 Hz), 6.52 (1H, d, J=5 Hz), 7.58-7.67 (3H, m), 7.76 (1H, m), 7.86 (1H, br s) MS (ESI+): m/z 439 (M+H)
EXAMPLE 232
To a solution of ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (45 mg) in tetrahydrofuran (1 mL) was added lithium borohydride (5 mg) in an ice-water bath. Then the reaction mixture was stirred at ambient temperature. After 2 hours, another lithium borohydride (5 mg) was added therein and was stirred overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and was evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate=1-1) to give 3-[7-ethyl-3-(6-hydroxyhexyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile (26 mg, 64.5%) as an yellow oil and 6-{4-[3-(aminomethyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}-1-hexanol (13 mg, 31.9%) as a yellow solid.
3-[7-Ethyl-3-(6-hydroxyhexyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
NMR (CDCl3, δ): 1.15-1.53 (11H, m), 2.32-2.41 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 3.58 (2H, br t, J=8 Hz), 5.58 (1H, br t, J=8 Hz), 5.79 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.57-7.63 (2H, m), 7.65 (1H, br s), 7.75 (1H, m) MS (ESI+): m/z 362 (M+H)
6-{4-[3-(Aminomethyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}-1-hexanol
NMR (CDCl3, δ): 1.03-1.43 (11H, m), 2.41 (2H, t, J=8 Hz), 2.55 (3H, s), 3.01 (2H, q, J=8 Hz), 3.39-3.61 (2H, m), 3.88-4.04 (2H, m), 4.25 (2H, br s), 5.31 (1H, d, J=5 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid (590 mg) in water (3 mL) was added 1N sodium hydroxide (15 mL) at ambient temperature. After 5 hours, the mixture became clear solution. The solution was filtered through membrane filter, washed with water (0.4 mL×3), and was freeze dried for 15 hours to give 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid sodium salt (612 mg, 98.2%) as a pale yellow powder.
6-{4-[4-(Aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid sodium salt
NMR (DMSO-d6, δ): 1.10-1.15 (2H, m), 1.20-1.40 (7H, m), 1.74 (2H, t, J=8 Hz), 2.25-2.38 (2H, m), 2.50 (3H, s), 2.91 (2H, q, 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), 8.26 (1H, br s)
EXAMPLE 234
A solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (100 mg), triethylamine (29.4 mg), and diphenylphosphoryl azide (79.9 mg) in tert-butanol (2 mL) was heated at 80° C. for 8 hours. The cooled reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate=3-1) to give tert-butyl 4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butylcarbamate (28 mg, 23.4%) as an yellow oil.
tert-Butyl 4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butylcarbamate
NMR (CDCl3, δ): 1.27-1.47 (14H, m), 2.34-2.45 (2H, m), 2.55 (3H, s), 2.91-3.02 (4H, m), 4.39 (1H, br s), 5.79 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.56-7.67 (3H, m), 7.75 (1H, m) MS (ESI+): m/z 433 (M+H)
EXAMPLE 235
To tert-butyl 4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butylcarbamate (25 mg) was added 4N hydrogen chloride in ethyl acetate (1 mL) at ambient temperature. After 1 hour, the mixture was evaporated in vacuo. The residue was triturated with isopropyl ether to give 3-[3-(4-aminobutyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile hydrochloride as dark green amorphous (18 mg).
3-[3-(4-Aminobutyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile hydrochloride
NMR (CDCl3, δ): 1.27-1.47 (14H, m), 2.34-2.45 (2H, m), 2.55 (3H, s), 2.91-3.02 (4H, m), 4.39 (1H, br s), 5.79 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.56-7.67 (3H, m), 7.75 (1H, m) MS (ESI+): m/z 333 (M+H)
EXAMPLE 236
To lithium chloride (16.5 mg) was added a solution of ethyl 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (65 mg) and tributyl(vinyl)stannane (56.7 mg) in dioxane (1 mL) and tetrakis(triphenylphosphine)palladium(0) (1.9 mg). The mixture was refluxed. After 4 hours, tributyl(vinyl)stannane (50 mg) and tetrakis(triphenylphosphine)palladium(0) (1.9 mg) was added. After refluxed over night, the reaction mixture was quenched with potassium fluoride (1.8 mmol) in H2O. The mixture was filtered through Celite and was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 50 mL) eluted with hexane-ethyl acetate=5-1 and 3-1 to give ethyl 5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (18 mg, 28.3%) as an yellow oil.
Ethyl 5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.15-1.70 (10H, m), 2.18 (2H, t, J=8 Hz), 2.36-2.46 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=8 Hz), 4.08 (2H, q, J=8 Hz), 5.54 (1H, d, J=10 Hz), 5.86 (1H, d, J=5 Hz), 6.25 (1H, d, J=16 Hz), 6.51 (1H, d, J=5 Hz), 6.87 (1H, dd, J=16, 10 Hz), 7.16 (1H, dd, J=6, 1 Hz), 7.33 (1H, br s), 8.70 (1H, d, J=6 Hz) MS (ESI+): m/z 392 (M+H)
The following compounds were obtained in substantially the same manner as that of Example 236.
EXAMPLE 237
Ethyl 5-{4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.42 (3H, t, J=7 Hz), 1.40-1.60 (4H, m), 2.20 (2H, t, J=7 Hz), 2.38-2.52 (2H, m), 2.56 (3H, s), 3.03 (2H, q, J=7 Hz), 3.96 (2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 4.34 (1H, d, J=2 Hz), 4.76 (1H, d, J=2 Hz), 5.87 (1H, d, J=4 Hz), 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 (CDCl3, δ): 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.65 (4H, m), 2.18 (2H, t, J=7 Hz), 2.40-2.53 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 5.43 (1H, d, J=11 Hz), 5.88 (1H, d, J=4 Hz), 5.89 (1H, d, J=18 Hz), 6.52 (1H, d, J=4 Hz), 6.71-6.83 (1H, dd, J=11 Hz, 18 Hz), 7.73 (1H, m), 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 (CDCl3, δ): 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.60 (4H, m), 2.17 (2H, t, J=7 Hz), 2.52-2.65 (2H, m), 3.04 (2H, q, J=7 Hz), 3.46 (3H, s), 4.08 (2H, q, 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), 6.58 (1H, d, J=4 Hz), 6.71-6.83 (1H, dd, J=11 Hz, 18 Hz), 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-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.42 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 2.18 (2H, t, J=7 Hz), 2.51-2.63 (2H, m), 3.03 (2H, q, J=7 Hz), 3.47 (3H, s), 3.93 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.35 (1H, d, J=3 Hz), 4.63 (2H, s), 4.77 (1H, d, J=3 Hz), 5.92 (1H, d, J=4 Hz), 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 (CDCl3, δ): 1.15-1.31 (7H, m), 1.37 (3H, t, J=7 Hz), 1.87 (2H, t, J=7 Hz), 2.43 (2H, m), 3.01 (2H, q, J=7 Hz), 3.98 (2H, q, J=7 Hz), 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), 7.44-7.55 (5H, m), 7.81 (1H, m), 8.55 (1H, m), 8.72 (1H, m)
EXAMPLE 242
A solution of 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (50 mg) in dioxane (15 mL) in a sealed tube was added 50% dimethylamine in water (15 mL). The mixture was heated at 175° C. overnight. The cooled reaction mixture was concentrated in vacuo. The residue was dissolved in water (1 mL) and the pH was adjusted to 7-8. The mixture was extracted with chloroform three times. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 50 mL) eluted with chloroform-ethyl acetate=1-1 and chloroform-methanol=20-1 to give yellow oil (43 mg). The oil was crystallized from isopropyl ether to give 5-{4-[2-(dimethylamino)-4-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid as an yellow solid (27 mg, 52.8%).
5-{4-[2-(Dimethylamino)-4-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
NMR (CDCl3, δ): 1.36 (3H, t, J=8 Hz), 1.40-1.65 (4H, m), 2.25 (2H, t, J=8 Hz), 1.86-1.96 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=8 Hz), 4.08 (2H, q, J=8 Hz), 5.54 (1H, d, J=10 Hz), 5.86 (1H, d, J=5 Hz), 6.25 (1H, d, J=16 Hz), 6.51 (1H, d, J=5 Hz), 6.87 (1H, dd, J=16, 10 Hz), 7.16 (1H, dd, J=6, 1 Hz), 7.33 (1H, br s), 8.70 (1H, d, J=6 Hz)
EXAMPLE 243
To a suspension of 7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carbaldehyde (40 mg) in ethanol (1 mL) was added 2-aminoethanol (11.8 mg), sodium cyanoborohydride (12.1 mg), and acetic acid (1 drop) in an ice-water bath. After 10 minutes, the mixture was stirred at ambient temperature. After 2 hours, sodium cyanoborohydride (11.8 mg) was added and the reaction mixture was acidified to pH4 with acetic acid (5 drops). After stirring overnight, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, water, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (chloroform-methanol=10-1) to give 2-({[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methyl}amino)ethanol as pale yellow oil (21 mg).
2-({[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methyl}amino)ethanol
NMR (CDCl3, δ): 1.43 (6H, d, J=7 Hz), 2.65 (2H, t, J=7 Hz), 3.42 (1H, m), 353 (2H, t, J=7 Hz), 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-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methanol (505 mg) and triethylamine (997 mg) in dichloromethane (4 mL) and dimethyl sulfoxide (2 mL) was added sulfur trioxide pyridine complex (941 mg) in an ice-water bath under nitrogen. After 30 minutes, the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated to about 1⁄3 volume. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 30 mL) eluted with hexane-chloroform=3-1 and 2-1 to give 4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazine-3-carbaldehyde as an yellow solid (340 mg, 67.9%).
4-(4-Fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazine-3-carbaldehyde
NMR (CDCl3, δ): 2.77 (3H, s), 6.50 (1H, m), 6.86 (1H, m), 7.20-7.30 (2H, m), 7.44-7.54 (2H, m), 8.89 (1H, br s), 9.79 (1H, s)
EXAMPLE 245
A mixture of ethyl 4-(4-fluorophenyl)-2-isopropyl-7-vinylpyrrolo[1,2-b]pyridazine-3-carboxylate (8.9 g) and 10% palladium on carbon (900 mg) in ethanol (180 mL) was stirred under hydrogen atomosphere (3.5 atm) at ambient temperature. After 10 hours, the mixture was stood overnight. To the mixture was added 10% palladium on carbon (900 mg) and was stirred under hydrogen atomosphere (35 atm) at ambient temperature. After 12 hours, the mixture was stood overnight. To the mixture was added 10% palladium on carbon (900 mg) and was stirred under hydrogen atomosphere (35 atm) at ambient temperature for 8 hours. The mixture was filtered through Celite. The filtrate was concentrated in vacuo to give ethyl 7-ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow oil (9.0 g, 100.5%).
Ethyl 7-ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate
NMR (CDCl3, δ): 0.96 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 3.05 (2H, q, J=8 Hz), 4.01 (2H, q, J=8 Hz), 6.27 (1H, d, J=5 Hz), 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 in substantially the same manner as that of Example 245.
EXAMPLE 246
5-[7-Ethyl-4-(5-ethyl-3-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid from 5-[7-ethyl-2-methyl-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.30 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.22 (2H, m), 2.35-2.50 (2H, m), 2.56 (3H, s), 2.75 (2H, q, J=7 Hz), 3.00 (2H, q, J=7 Hz), 5.84 (1H, d, J=4 Hz), 6.52 (1H, d, J=4 Hz), 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]pentanoic acid
NMR (CDCl3, δ): 130 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.45-1.64 (4H, m), 2.17 (2H, m), 2.45-2.67 (2H, m), 2.73 (2H, q, J=7 Hz), 3.04 (2H, q, J=7 Hz), 3.45 (3H, s), 4.62 (2H, m), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 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-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.04-1.23 (7H, m), 1.32 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.86 (2H, t, J=7 Hz), 2.42 (2H, m), 2.74 (2H, q, J=7 Hz), 3.01 (2H, q, J=7 Hz), 3.99 (2H, q, 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), 8.50 (1H, m), 8.56 (1H, m)
EXAMPLE 249
To a solution of 3-(7-ethyl-2-neopentylpyrrolo[1,2-b]pyridazin-4-yl)benzamide (35 mg) in ethanol (1 mL) was added water (0.2 mL) and potassium hydroxide (68.9 mg) at ambient temperature. The reaction mixture was heated at 60° C. After 2 hours, potassium hydroxide (100 mg) was added. After 5 hours, potassium hydroxide (100 mg) was added. After 12 hours, the mixture was acidified with 1N hydrogen chloride. The precipitate was filtered, washed with water and ethyl acetate to give 3-(7-ethyl-2-neopentylpyrrolo-[1,2-b]pyridazin-4-yl)benzoic acid as an yellow solid (19 mg, 54.1%).
3-(7-Ethyl-2-neopentylpyrrolo[1,2-b]pyridazin-4-yl)benzoic acid
NMR (CDCl3, δ): 1.05 (9H, s), 1.39 (3H, t, J=8 Hz), 2.69 (2H, s), 3.04 (2H, q, J=8 Hz), 6.42 (1H, s), 6.54 (1H, d, J=5 Hz), 6.65 (1H, d, J=5 Hz), 7.62 (1H, t, J=8 Hz), 7.97 (1H, d, J=8 Hz), 8.21 (1H, d, J=8 Hz), 8.46 (1H, br s) MS (ESI+): m/z 337 (M+H)
The following compound was obtained in substantially the same manner as that of Example 249.
EXAMPLE 250
3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid
NMR (CDCl3, δ): 1.44 (3H, t, J=8 Hz), 3.11 (2H, q, J=8 Hz), 6.56 (1H, m), 6.61 (1H, d, J=5 Hz), 6.72 (1H, d, J=5 Hz), 7.03 (1H, br s), 7.07 (1H, d, J=5 Hz), 7.55-7.69 (2H, m), 8.03 (1H, br d, J=8 Hz), 8.23 (1H, br d, J=8 Hz), 8.52 (1H, br s)
EXAMPLE 251
A solution of ethyl 5-{4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate (190 mg) in methanol (5 mL) and 1N hydrochloric acid (5 mL) was stirred at ambient temperature for 2 hours. The solution was diluted with brine and extracted with chloroform. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1-2:1) to give ethyl 5-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow oil (160 mg).
Ethyl 5-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.60 (4H, m), 2.19 (2H, t, J=7 Hz), 2.36-2.47 (2H, m), 2.57 (3H, s), 2.70 (3H, s), 3.02 (2H, q, J=7 Hz), 4.08 (2H, q, 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 in substantially the same manner as that of Example 251.
EXAMPLE 252
Ethyl 5-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.59 (4H, m), 2.17 (2H, t, J=7 Hz), 2.50-2.63 (2H, m), 2.70 (3H, s), 3.03 (2H, q, J=7 Hz), 3.46 (3H, s), 4.12 (2H, q, J=7 Hz), 4.63 (2H, s), 5.86 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 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 oxone (287 mg) and the mixture was stirred at ambient temperature for 4 hours. The solution was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with saturated sodium bicarbonate solution, sodium thiosulfate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1-1:1) to give ethyl 5-{4-(2-chloro-4-pyridinyl)-7-ethyl-2-[(methylsulfonyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate as an yellow oil (124 mg).
Ethyl 5-{4-(2-chloro-4-pyridinyl)-7-ethyl-2-[(methylsulfonyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 2.21 (2H, t, J=7 Hz), 2.57-2.68 (2H, m), 3.02 (2H, q, J=7 Hz), 3.12 (3H, s), 4.10 (2H, q, J=7 Hz), 4.53 (2H, s), 5.98 (1H, d, J=4 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (167 mg) and copper(I) cyanide (37 mg) in 1-methyl-2-pyrrolidinone (3 mL) was stirred at 170° C. for 4 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-5:1) to give ethyl 5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow oil (88 mg).
Ethyl 5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 124 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.62 (4H, m), 2.21 (2H, t, J=7 Hz), 2.35-2.47 (2H, m), 2.57 (3H, s), 3.02 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.79 (1H, d, J=4 Hz), 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 in substantially the same manner as that of Example 254.
EXAMPLE 255
5-[4-(5-Cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.40-1.67 (4H, m), 2.28 (2H, m), 2.37-2.47 (2H, m), 2.57 (3H, s), 3.01 (2H, q, J=7 Hz), 5.80 (1H, d, J=4 Hz), 6.55 (1H, d, J=4 Hz), 8.01 (1H, s), 8.81 (1H, br), 8.98 (1H, br)
EXAMPLE 256
Ethyl 5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 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 (2H, q, J=7 Hz), 3.46 (3H, s), 4.12 (2H, q, J=7 Hz), 4.63 (2H, s), 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]pentanoic acid
NMR (CDCl3, δ): 1.38 (3H, t, J=7 Hz), 1.40-1.65 (4H, m), 2.27 (2H, t, J=7 Hz), 2.48-2.64 (2H, m), 3.03 (2H, q, J=7 Hz), 3.46 (3H, s), 4.64 (2H, s), 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-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
NMR (CDCl3, δ): 1.06-1.24 (4H, m), 1.36 (3H, t, J=7 Hz), 1.94 (2H, t, J=7 Hz), 2.38 (2H, m), 2.99 (2H, q, J=7 Hz), 5.88 (1H, d, J=5 Hz), 6.64 (1H, d, J=5 Hz), 7.44-7.52 (5H, m), 8.06 (1H, s), 8.87 (1H, s), 8.98 (1H, s) MS (ESI+): m/z 425 (M+H)
EXAMPLE 259
To a suspension of lithium aluminum hydride (98.8 mg) in tetrahydrofuran (10 mL) was added ethyl 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (600 mg) in tetrahydrofuran (10 mL) under ice-water cooling and the mixture was stirred at 0° C. for 2 hours. The reaction was quenched with saturated potassium sodium tartrate solution and the insolubles were filtered off and washed with ethyl acetate. The filtrates were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1-2:1) to give 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol as an yellow oil (478 mg).
5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol
NMR (CDCl3, δ): 0.90-1.22 (6H, m), 1.27 (1H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 2.37-2.47 (2H, m), 3.02 (2H, q, J=7 Hz), 3.29-3.41 (2H, m), 5.97 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.32 (1H, m), 7.40-7.55 (8H, m)
EXAMPLE 260
To a solution of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol (63.0 mg) and triethylamine (22.8 mg) in dichloromethane (3 mL) was added methanesulfonyl chloride (18.9 mg) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. The solution was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was added to sodium cyanide (14.7 mg) in dimethylformamide (2 mL) and the mixture was stirred at 60° C. for 5 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-5:1) to give 6-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]hexanenitrile as an yellow oil (58.5 mg).
6-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]hexanenitrile
NMR (CDCl3, δ): 1.00-1.15 (4H, m), 1.17-1.28 (2H, m), 1.36 (3H, t, J=7 Hz), 1.98 (2H, t, J=7 Hz), 2.38-2.47 (2H, m), 3.03 (2H, q, J=7 Hz), 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-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol (65 mg), trimethyloxonium tetrafluoroborate (27.5 mg) and 2,6-di-t-butyl-4-methylpyridine (47.8 mg) in 1,2-dichloroethane (3 mL) was stirred at ambient temperature for 4 hours. The solution was washed with water, 1N hydrochloric acid, water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-5:1) to give 4-(3-chlorophenyl)-7-ethyl-3-(5-methoxypentyl)-2-phenylpyrrolo[1,2-b]pyridazine as an yellow oil (60 mg).
4-(3-chlorophenyl)-7-ethyl-3-(5-methoxypentyl)-2-phenylpyrrolo[1,2-b]pyridazine
NMR (CDCl3, δ): 0.90-1.32 (6H, m), 1.36 (3H, t, J=7 Hz), 2.37-2.47 (2H, m), 3.03 (2H, q, J=7 Hz), 3.08 (2H, t, J=7 Hz), 3.31 (3H, s), 5.97 (1H, d, J=4 Hz), 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-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol (55 mg) and triethylamine (19.9 mg) in dichloromethane (3 mL) was added methanesulfonyl chloride (165 mg) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. The solution was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. To the residue in 1,2-dichloroethane (3 mL) was added 2 M dimethylamine in tetrahydrofuran (3 mL) and the mixture was stirred at 60° C. for 120 hours. The solution was diluted with chloroform, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-5:1) to give 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N,N-dimethyl-1-pentanamine as an yellow oil (38 mg).
N-{5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentyl}-N,N-dimethylamine
NMR (CDCl3, δ): 0.86-0.97 (2H, m), 1.02-1.15 (4H, m), 1.36 (3H, t, J=7 Hz), 1.97-2.04 (2H, m), 2.11 (6H, s), 2.37-2.47 (2H, m), 3.02 (2H, q, J=7 Hz), 5.97 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.31 (1H, m), 7.39-7.54 (8H, m) MS (ESI+): m/z 446
EXAMPLE 263
To a stirred solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (60 mg) in dichloromethane (2 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35.3 mg) and 2-aminopyridine (20 mg) and the reaction mixture was stirred for 10 minutes. 4-Dimethylaminopyridine (2 mg) was added and the reaction mixture was stirred at room temperature for 15 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of ethyl acetate and n-hexane (1:2) to give 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-(2-pyridinyl)pentanamide (55.7 mg) as an yellow amorphous.
5-[4-(3-Cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-(2-pyridinyl)pentanamide
mp: 67-70° C. NMR (CDCl3, δ): 1.12 (2H, quintet, J=7 Hz), 1.30 (2H, quintet, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.95 (2H, t, J=7 Hz), 2.43 (2H, q, J=7 Hz), 3.02 (2H, q, J=7 Hz), 5.90 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.00-7.05 (1H, m), 7.43-7.54 (5H, m), 7.59-7.77 (6H, m), 8.11 (1H, d, J=7.5 Hz), 8.24 (1H, d, J=4 Hz) MS: (m/z) 499 (M+), 45 (bp)
The following compounds were obtained in substantially the same manner as that of Example 263.
EXAMPLE 264
5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-(2-pyridinyl)pentanamide
NMR (CDCl3, δ): 1.15 (2H, quintet, J=7 Hz), 1.24(2H, quintet, J=7 Hz), 1.36(3H, t, J=7 Hz), 1.91(2H, t, J=7 Hz), 2.45(2H, t, J=7 Hz), 3.00(2H, q, 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), 8.25(1H, d, J=5 Hz) MS: (m/z) 509 (M++H), 74 (bp)
EXAMPLE 265
N-{5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoyl}methanesulfonamide
NMR (CDCl3, δ): 1.08 (2H, quintet, J=7 Hz), 1.23 (2H, quintet, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.85 (2H, t, J=7 Hz), 2.44 (2H, t, J=7 Hz), 3.02 (2H, q, J=7 Hz), 3.21 (3H, s), 5.99 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.30-7.33 (1H, m), 7.43-7.55 (8H, m)
EXAMPLE 266
5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-(2-pyridinyl)pentanamide
NMR (CDCl3, δ): 1.12 (2H, quintet, J=7 Hz), 1.27 (2H, quintet, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.97 (2H, t, J=7 Hz), 2.45 (2H, t, J=7 Hz), 3.01 (2H, q, 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), 7.77 (1H, s), 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 (bp)
EXAMPLE 267
N-{5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoyl}methanesulfonamide
mp: 124-125° C. NMR (CDCl3, δ): 1.37 (3H, t, J=7 Hz), 1.43-1.49 (2H, m), 1.55-1.65 (2H, m), 2.23 (2H, t, J=7 Hz), 2.34-2.48 (2H, m), 2.55 (3H, s), 3.01 (2H, q, J=7 Hz), 3.28 (3H, s), 5.87 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.09 (1H, s), 7.40 (1H, s), 8.53 (1H, s), 8.77 (1H, s) MS: (m/z) 493(M+), 491 (M+−2), 137 (bp)
EXAMPLE 268
To a solution of ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (100.0 mg) and (bromomethyl)benzene (111 mg) in N,N-dimethylformamide (1 mL) was added 60% sodium hydride (17.4 mg) under an ice-bath. After stirring for 2.5 hour, the reaction was quenched by adding 1N hydrochloric acid (1 mL), and the mixture was partitioned between ethyl acetate (10 mL) and water (5 mL). The organic layer was washed with 1N hydrochloric acid (5 mL), water (5 mL, three times), and brine, dried over magnesium sulfate, and evaporated. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1/40 to 20/40 afforded ethyl 5-[2-[(benzyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow gum (47.7 mg, 39.9%).
Ethyl 5-[2-[(benzyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.34-1.48 (5H, m), 2.09 (2H, m), 2.53 (2H, m), 3.04 (2H, q, J=7 Hz), 4.07 (2H, J=7 Hz), 4.65 (2H, s), 4.72 (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 in substantially the same manner as that of Example 268.
EXAMPLE 269
Ethyl 5-(4-(5-bromo-3-pyridinyl)-2-{[(4-cyanobenzyl)oxy]methyl}-7-ethylpyrrolo[1,2-b]pyridazin-3-yl)pentanoate
NMR (CDCl3, δ): 1.23 (3H, J=7 Hz), 1.35-1.55 (7H, m), 2.12 (2H, t, J=7 Hz), 2.57 (2H, m), 3.02 (2H, q, J=7 Hz), 4.07 (2H, q, J=7 Hz), 4.49 (2H, s), 4.76 (2H, s), 5.93 (1H, d, J=7 Hz), 6.62 (1H, d, J=7 Hz), 7.48 (2H, d, J=8 Hz), 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 methanesulfonyl chloride (54.7 mg) under an ice-bath. After stirring for 1 hour, the reaction was quenched by adding 1N hydrochloric acid (1 mL). The mixture was partitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (5 mL). The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated to give ethyl 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(methylsulfonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate as an yellow gum (247 mg).
Ethyl 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(methylsulfonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate
NMR (CDCl3, δ): 1.22 (3H, t, J=7 Hz), 1.34-1.65 (7H, m), 2.20 (2H, t, J=7 Hz), 2.55 (2H, m), 3.02 (2H, q, J=7 Hz), 3.15 (3H, s), 4.07 (2H, q, J=7 Hz), 5.42 (2H, s), 5.99 (1H, d, J=5 Hz), 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-{[(methylsulfonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate (50.0 mg), benzylamine (29.8 mg) in dichloromethane (1 mL) was stirred for 20 hour at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, and evaporated. Preparative thin layer chromatography eluting with ethyl acetate-hexane=1:2 afforded ethyl 5-[2-[(benzylamino)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow gum (19.1 mg).
Ethyl 5-[2-[(benzylamino)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 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, q, J=7 Hz), 3.96 (4H, m), 4.09 (2H, q, J=7 Hz), 5.89 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.23-7.42 (5H, m), 7.86 (1H, m), 8.53 (1H, m), 8.77 (1H, m)
The following compound was obtained in substantially the same manner as that of Example 271.
EXAMPLE 272
Ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.31-1.56 (7H, m), 2.19 (2H, t, J=7 Hz), 2.45-2.65 (6H, m), 3.02 (2H, q, J=7 Hz), 3.60-3.75 (6H, m), 4.09 (2H, q, J=7 Hz), 5.88 (1H, d, J=5 Hz), 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-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl)methanol (40 mg) in N,N-dimethylformamide (1 mL) was added 40% sodium hydride in oil (55 mg) in an ice-water bath. After 20 minutes, to the mixture was added 2-bromoethyl acetate (31 mg) at the temperature. After 15 minutes, the reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate=10-1) to give [7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methyl acetate as a pale yellow solid (42 mg).
[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methyl acetate
NMR (CDCl3, δ): 1.41 (6H, d, J=8 Hz), 2.06 (3H, s), 3.21 (1H, m), 4.92 (2H, s), 6.14 (1H, d, J=5 Hz), 6.72 (1H, d, J=5 Hz), 7.13-7.24 (2H, m), 7.34-7.43 (2H, m) MS (ESI+): m/z 361 (M+H)
The following compound was obtained in substantially the same manner as that of Preparation 20.
EXAMPLE 274
Ethyl{[7-ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methoxy}acetate
NMR (CDCl3, δ): 1.25 (3H, t, J=8 Hz), 1.30-1.45 (9H, m), 3.04 (2H, q, J=8 Hz), 3.51 (1H, m), 3.97 (2H, s), 4.15 (2H, q, J=8 Hz), 4.40 (2H, s), 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 in substantially the same manner as that of Preparation 276.
EXAMPLE 275
Ethyl 2-(2-amino-2-oxoethyl)-4-(4-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazine-3-carboxylate
NMR (CDCl3, δ): 0.84 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 3.06 (2H, q, J=7 Hz), 3.96 (2H, q, J=7 Hz), 4.02 (3H, s), 5.41 (1H, s, br), 6.09 (1H, s, br), 6.28 (1H, d, J=5 Hz), 6.75 (1H, d, J=5 Hz), 7.53 (2H, d, J=9 Hz), 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-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylic acid (40.0 mg), pyrrolidine (10.8 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.1 mg), and 1-hydroxybenzotriazole (21.9 mg) in N,N-dimethylformamide (1 mL) was stirred for 6 hour at room temperature. The mixture was partitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (10 mL). The organic layer was washed with water (10 mL) three times, saturated sodium bicarbonate (10 mL), and brine, dried, and evaporated to give 3-[7-ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinylcarbonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile as an yellow solid (35.6 mg).
3-[7-Ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinylcarbonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
NMR (CDCl3, δ): 1.38 (2H, m), 1.99 (4H, m), 3.07 (2H, q, J=7 Hz), 3.23 (3H, s), 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), 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) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30 mg), 1-hydroxybenzotriazole (24 mg), and 2-aminoethanol (15 mg) at ambient temperature. After stirring overnight, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with water 3 times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel column chromatography (silica gel, 40 mL) eluted with chloroform-methanol=50-1 and 20-1 to give an yellow solid (42 mg). The solid was triturated with isopropyl ether to give 3-[7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]-N-(2-hydroxyethyl)benzamide as an yellow solid (35 mg).
3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]-N-(2-hydroxyethyl)benzamide
NMR (CDCl3, δ): 1.43 (3H, t, J=8 Hz), 2.39-2.49 (2H, m), 3.10 (2H, q, J=8 Hz), 3.60-3.74 (2H, m), 3.80-3.94 (2H, m), 6.53-6.86 (4H, m), 7.00 (1H, s), 6.61 (1H, d, J=5 Hz), 6.72 (1H, d, J=5 Hz), 7.03 (1H, br s), 7.07 (1H, d, J=5 Hz), 7.55-7.65 (2H, m), 7.86-7.97 (2H, m), 8.17 (1H, br s) MS (ESI+): m/z 376 (M+H)
The following compounds were obtained in substantially the same manner as that of Example 283.
EXAMPLE 278
5-[4-(3-Cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-methylpentanamide
mp: 60° C. NMR (CDCl3, δ): 1.02-1.12 (2H, m), 1.17-1.25 (2H, m), 1.36 (3H, t, J=7 Hz), 1.73 (2H, t, J=7 Hz), 2.40(2H, t, J=7 Hz), 2.71 (3H, d, J=7 Hz), 3.03 (2H, q, J=7 Hz), 5.09 (1H, broad s), 5.90 (1H, d, J=4 Hz), 6.63 1H, d, J=4 Hz), 7.45-7.55 (5H, m), 7.60-7.78 (4H, m) MS: (m/z) 437 (M++H), 115 (bp)
EXAMPLE 279
4-(3-Chlorophenyl)-7-ethyl-3-[5-(4-morpholinyl)-5-oxopentyl]-2-phenylpyrrolo[1,2-b]pyridazine
mp: 55-58° C. NMR (CDCl3, δ): 1.05-1.14 (2H, m), 1.17-1.23 (2H, m), 1.35 (3H, t, J=7 Hz), 1.84 (2H, t, J=7 Hz), 2.45 (2H, t, J=7 Hz), 3.02 (2H, q, J=7 Hz), 3.24 (2H, t, J=6 Hz), 3.50 (2H, t, J=6 Hz), 3.55-3.62 (4H, m), 5.99 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.30-7.35 (1H, m), 7.40-7.55 (8H, m) MS: (m/z) 502 (M++H), 115 (bp)
EXAMPLE 280
5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-methylpentanamide
mp: 70-72° C. NMR (CDCl3, δ): 1.06 (2H, quintet, J=7 Hz), 1.22 (2H, quintet, J=7 Hz), 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, q, J=7 Hz), 5.08 (1H, broad s), 5.99 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.29-7.33 (1H, m), 7.41-7.55 (8H, m) MS: (m/z) 446 (M++H), 115 (bp)
EXAMPLE 281
5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-methylpentanamide
NMR (CDCl3, δ): 1.07 (2H, quintet, J=7 Hz), 1.23 (2H, quintet, J=7 Hz), 1.36(3H, t, J=7 Hz), 1.74 (2H, t, J=7 Hz), 2.41 (2H, t, J=7 Hz), 2.71 (3H, d, J=7 Hz), 3.02 (2H, q, J=7 Hz), 5.10 (1H, broad s), 5.95 (1H, d, J=4 Hz), 6.64 (1H, d, J=4 Hz), 7.31 (1H, d, J=7 Hz), 7.42 (1H, s), 7.46-7.52 (1H, m), 7.41-7.55 (1H, d, J=7 Hz) MS: (m/z) 447 (M++H), 115 (bp)
EXAMPLE 282
3-{7-Ethyl-3-[5-(4-morpholinyl)-5-oxopentyl]-2-phenylpyrrolo[1,2-b]pyridazin-4-yl}benzonitrile from 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
mp: 66-69° C. NMR (CDCl3, δ): 1.04-1.12 (2H, m), 1.17-1.23 (2H, m), 1.36 (3H, t, J=7 Hz), 1.84 (2H, t, J=7 Hz), 2.42 (2H, t, J=7 Hz), 3.03 (2H, q, 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), 7.43-7.55 (5H, m), 7.60-7.78 (4H, m) MS: (m/z) 493 (M++H), 126 (bp)
EXAMPLE 283
To a solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (50 mg) in N,N-dimethylformamide (1 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35 mg) and 1-hydroxybenzotriazole (28 mg) at ambient temperature. After 30 minutes, to the mixture was added morpholine (24 mg). After 5 hours, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel column chromatography (silica gel, 40 mL) eluted with hexane-ethyl acetate=3-1, 2-1, 1-1, 1-3, and 0-1 to give 3-{7-ethyl-2-methyl-3-[5-(4-morpholinyl)-5-oxopentyl]pyrrolo[1,2-b]pyridazin-4-yl}benzonitrile as an yellow gum (53 mg).
3-{7-Ethyl-2-methyl-3-[5-(4-morpholinyl)-5-oxopentyl]pyrrolo[1,2-b]pyridazin-4-yl}benzonitrile
NMR (CDCl3, δ): 1.15-1.61 (7H, m), 2.18 (2H, t, J=8 Hz), 2.41 (2H, t, J=8 Hz), 2.56 (3H, s), 3.00 (2H, q, 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), 7.56-7.67 (3H, m), 7.74 (1H, m) MS (ESI+): m/z 431 (M+H)
The following compound was obtained in substantially the same manner as that of Example 283.
EXAMPLE 284
5-[4-(3-Cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanamide
NMR (CDCl3, δ): 1.31-1.61 (7H, m), 2.11 (2H, t, J=8 Hz), 2.40 (2H, t, J=8 Hz), 2.56 (3H, s), 3.00 (2H, q, J=8 Hz), 5.36 (2H, br s), 5.79 (1H, d, J=5 Hz), 6.50 (1H, d, J=5 Hz), 7.56-7.67 (3H, m), 7.75 (1H, m) MS (ESI+): m/z 361 (M+H)
Preparation 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 bromoacetic acid (13.9 g) under ice-water cooling and the mixture was heated under reflux for 2 hours. After adding water to the mixture and organic solvent was evaporated in vacuo. The aqueous solution was diluted with water, washed with ether, acidified with 1 N hydrochloric acid, and extracted with ether. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo to give (cyclohexyloxy)acetic acid as colorless oil (133 g).
(cyclohexyloxy)acetic acid
1H NMR (CDCl3) δ 1.18-1.47 (5H, m), 1.52-1.63 (1H, m), 1.72-1.85 (2H, m), 1.90-2.03 (2H, m), 3.36-3.47 (1H, m), 4.13 (2H, s).
The following compound(s) was (were) obtained in substantially the same manner as that of Preparation 178.
Preparation 179
isopropoxyacetic acid
1H NMR (CDCl3) δ 1.24 (6H, d, J=7 Hz), 3.68-3.82 (1H, m), 4.11 (2H, s).
The following compound(s) was (were) obtained in substantially the same manner as that of Preparation 129 and Preparation 130.
Preparation 180
tert-butyl 4-(benzyloxy)-3-oxobutanoate
1H NMR (CDCl3) δ 1.44 (9H, s), 3.45 (2H, s), 4.14 (2H, s), 4.60 (2H, s), 7.28-7.40 (5H, m).
Preparation 181
tert-butyl 4-(cyclohexyloxy)-3-oxobutanoate
1H NMR (CDCl3) δ 1.18-1.43 (5H, m), 1.47 (9H, s), 1.53-1.63 (1H, m), 1.69-1.85 (2H, m), 1.87-1.97 (2H, m), 3.24-3.38 (1H, m), 3.46 (2H, s), 4.11 (2H, s).
Preparation 182
tert-butyl 4-isopropoxy-3-oxobutanoate
1H NMR (CDCl3) δ 1.20 (6H, d, J=7 Hz), 1.47 (9H, s), 3.45 (2H, s), 3.60-3.70 (1H, m), 4.08 (2H, s).
The following compound(s) was (were) obtained in substantially the same manner as that of Preparation 159.
Preparation 183
1-tert-butyl 4-ethyl 2-acetylsuccinate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.47 (9H, s), 2.35 (3H, s), 3.08 (2H, m), 3.93 (1H, m), 4.12 (2H, q, J=7 Hz).
Preparation 184
1-tert-butyl 7-ethyl 2-[(benzyloxy)acetyl]heptanedioate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.30-1.50 (2H, m), 1.40 (9H, s), 1.56-1.72 (2H, m), 1.75-1.95 (2H, m), 2.28 (2H, t, J=7 Hz), 3.52 (1H, t, J=7 Hz), 4.11 (2H, q, J=7 Hz), 4.16 (2H, s), 4.59 (2H, s), 7.27-7.40 (5H, m).
Preparation 185
1-tert-butyl 5-ethyl 2-[(benzyloxy)acetyl]pentanedioate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.41 (9H, s), 2.10-2.23 (2H, m), 2.36 (2H, t, J=7 Hz), 3.66 (1H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.18 (2H, s), 4.60 (2H, s), 7.26-7.38 (5H, m).
Preparation 186
1-tert-butyl 7-ethyl 2-[(cyclohexyloxy)acetyl]heptanedioate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.44 (9H, s), 1.15-1.92 (16H, m), 2.29 (2H, t, J=7 Hz), 3.24-3.38 (1H, m), 3.56 (1H, t, J=7 Hz), 4.12 (4H, m),
Preparation 187
1-tert-butyl 7-ethyl 2-(isopropoxyacetyl)heptanedioate
1H NMR (CDCl3) δ 1.20 (6H, d, J=7 Hz), 1.25 (3H, t, J=7 Hz), 1.25-1.45 (2H, m), 1.45 (9H, s), 1.60-1.72 (2H, m), 1.75-1.95 (2H, m), 2.29 (2H, t, J=7 Hz), 3.54 (1H, t, J=7 Hz), 3.60-3.68 (1H, m), 4.11 (2H, s), 4.12 (2H, q, J=7 Hz). MS (ESI+): m/z 345.
The following compound(s) was (were) obtained in substantially the same manner as that of Preparation 20.
Preparation 188
1-tert-butyl 5-ethyl 2-[(cyclohexyloxy)acetyl]pentanedioate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7 Hz), 1.45 (9H, s), 1.18-1.62 (6H, m), 1.66-1.78 (2H, m), 1.84-1.98 (2H, m), 2.10-2.23 (2H, m), 2.38 (2H, t, J=7 Hz), 3.25-3.38 (1H, m), 3.69 (1H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.15 (2H, s). MS (ESI+): m/z 357.
Preparation 189
To a suspension of 60% sodium hydride (527 mg) in dimethylformamide (20 mL) was added 3,5-pyridinedicarboxylic acid (2.00 g) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. To the mixture was added (bromomethyl)benzene (2.05 g) and the mixture was stirred at 60° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with ethyl acetate to give 5-[(benzyloxy)carbonyl]nicotinic acid as a pale yellow powder (722 mg).
5-[(benzyloxy)carbonyl]nicotinic acid
1H NMR (DMSO-d6) δ 5.42 (2H, s), 7.34-7.54 (5H, m), 8.63 (1H, m), 9.23-9.34 (2H, m).
The following compound(s) was (were) obtained in substantially the same manner as that of Preparation 24.
Preparation 190
1-tert-butyl 4-ethyl 2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyl]succinate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.40 (9H, s), 2.38 (3H, s), 2.45 (3H, s), 3.20 (2H, m), 4.13 (2H, q, J=7 Hz), 7.88 (1H, s), 8.57 (1H, s), 8.74 (1H, s). MS (ESI+): m/z 363.
Preparation 191
ethyl 2-[(5-methyl-3-pyridinyl)carbonyl]-3-oxobutanoate
1H NMR (CDCl3) δ 0.96 (3H, t, J=7 Hz), 2.15 (3H, s), 2.45 (3H, s), 4.03 (2H, q, J=7 Hz), 4.12 (1H, t, J=7 Hz), 7.89 (1H, s), 8.54 (1H, s), 8.72 (1H, s). MS (ESI+): m/z 250.
Preparation 192
1-tert-butyl 6-ethyl 2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]hexanedioate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.36 (9H, s), 1.60-1.73(2H, m), 2.23-2.35 (2H, m), 2.38 (2H, t, J=7 Hz), 2.48 (3H, s), 4.12 (2H, q, J=7 Hz), 8.20 (1H, m), 8.78 (1H, m), 8.81 (1H, m).
Preparation 193
1-tert-butyl 5-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2-(methoxyacetyl)pentanedioate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.39 (9H, s), 2.40-2.47 (2H, m), 2.55-2.67 (2H, m), 3.36 (3H, s), 4.12 (2H, q, J=7 Hz), 4.27 (1H, d, J=17 Hz), 4.40 (1H, d, J=17 Hz), 8.21 (1H, m), 8.79 (1H, d, J=2 Hz), 8.82 (1H, d, J=2 Hz). MS (ESI+): m/z 472 474.
Preparation 194
1-tert-butyl 7-ethyl 2-acetyl-2-({5-[(benzyloxy)carbonyl]-3-pyridinyl}carbonyl)heptanedioate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.20-1.40 (2H, m), 1.32 (9H, s), 1.65-1.76 (2H, m), 2.19-2.26 (2H, m), 2.32 (2H, t, J=7 Hz), 2.44 (3H, s), 4.12 (2H, q, J=7 Hz), 5.41 (2H, s), 7.35-7.48 (5H, m), 8.62 (1H, m), 9.07 (1H, d, J=2 Hz), 933 (1H, d, J=2 Hz). MS (ESI+): m/z 526.
Preparation 195
1-tert-butyl 7-ethyl 2-[(benzyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]heptanedioate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.20-1.46 (2H, m), 1.32 (9H, s), 1.60-1.74 (2H, m), 2.10-2.36 (4H, m), 2.35 (3H, s), 4.10 (2H, q, J=7 Hz), 4.38 (1H, d, J=18 Hz), 4.53 (1H, d, J=18 Hz), 4.54 (2H, m), 7.27-7.40 (5H, m), 7.79 (1H, m), 8.54 (1H, d, J=2 Hz), 8.72 (1H, d, J=2 Hz). MS (ESI+): m/z 512.
Preparation 196
1-tert-butyl 5-ethyl 2-[(benzyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7 Hz), 1.34 (9H, s), 2.35 (3H, s), 2.40-2.72 (4H, m), 4.12 (2H, q, J=7 Hz), 4.38 (1H, d, J=17 Hz), 4.50 (1H, d, J=17 Hz), 4.53 (2H, m), 7.25-7.38 (5H, m), 7.81 (1H, s), 8.54 (1H, s), 8.73 (1H, s). MS (ESI+): m/z 484.
Preparation 197
1-tert-butyl 7-ethyl 2-[(cyclohexyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]heptanedioate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.16-1.55 (10H, m), 1.37 (9H, s), 1.60-1.76 (2H, m), 1.78-1.90 (2H, m), 2.15-2.28 (2H, m), 2.31 (2H, t, J=7 Hz), 2.39 (3H, s), 3.17-3.29 (1H, m), 4.12 (2H, q, J=7 Hz), 4.34 (1H, d, J=18 Hz), 4.44 (1H, d, J=18 Hz), 7.86 (1H, s), 8.56 (1H, s), 8.76 (1H, s). MS (ESI+): m/z 504.
Preparation 198
1-tert-butyl 7-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(cyclohexyloxy)acetyl]heptanedioate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.39 (9H, s), 1.16-1.88 (14H, m), 2.15-2.40 (4H, m), 3.16-3.28 (1H, m), 4.10 (2H, q, J=7 Hz), 4.28 (1H, d, J=18 Hz), 4.38 (1H, d, J=18 Hz), 8.20 (1H, m), 8.78 (1H, d, J=2 Hz), 8.84 (1H, d, J=2 Hz). MS (ESI+): m/z 568 570.
Preparation 199
1-tert-butyl 5-ethyl 2-[(cyclohexyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.15-1.38 (4H, m), 1.39 (9H, s), 1.45-1.75 (4H, m), 1.76-1.93 (2H, m), 2.39 (3H, s), 2.45-2.75 (4H, m), 3.17-3.30 (1H, m), 4.12 (2H, q, J=7 Hz), 4.32 (1H, d, J=17 Hz), 4.41 (1H, d, J=17 Hz), 7.88 (1H, s), 8.55 (1H, s), 8.77 (1H, s). MS (ESI+): m/z 476.
Preparation 200
1-tert-butyl 5-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(cyclohexyloxy)acetyl]pentanedioate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7 Hz), 1.15-1.35 (4H, m), 1.40 (9H, s), 1.40-1.65 (2H, m), 1.65-1.75 (2H, m), 1.75-1.92 (2H, m), 2.35-2.85 (4H, m), 3.16-3.32 (1H, m), 4.12 (2H, q, J=7 Hz), 4.28 (1H, d, J=17 Hz), 4.35 (1H, d, J=17 Hz), 8.22 (1H, t, J=2 Hz), 8.78 (1H, d, J=2 Hz), 8.87 (1H, d, J=2 Hz). MS (ESI+): m/z 540 542.
Preparation 201
1-tert-butyl 7-ethyl 2-(isopropoxyacetyl)-2-[(5-methyl-3-pyridinyl)carbonyl]heptanedioate
1H NMR (CDCl3) δ 1.12 (6H, d, J=7 Hz), 1.23 (3H, t, J=7 Hz), 1.30-1.55 (2H, m), 1.37 (9H, s), 1.63-1.77 (2H, m), 2.19-2.28 (2H, m), 2.28 (2H, t, J=7 Hz), 2.39 (3H, s), 3.53-3.64 (1H, m), 4.10 (2H, q, J=7 Hz), 4.31 (1H, d, J=18 Hz), 4.42 (1H, d, J=18 Hz), 7.86 (1H, s), 8.55 (1H, s), 8.74 (1H, s). MS (ESI+): m/z 464.
Preparation 202
1-tert-butyl 7-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2-(isopropoxyacetyl)heptanedioate
1H NMR (CDCl3) δ 1.10 (6H, d, J=7 Hz), 1.24 (3H, t, J=7 Hz), 1.39 (9H, s), 1.18-1.48 (2H, m), 1.64-1.77 (2H, m), 2.18-2.37 (4H, m), 3.52-3.64 (1H, m), 4.12 (2H, q, J=7 Hz), 4.25 (1H, d, J=17 Hz), 4.36 (1H, d, J=17 Hz), 8.19 (1H, t, J=2 Hz), 8.77 (1H, d, J=2 Hz), 8.83 (1H, d, J=2 Hz). MS (ESI+): m/z 528 530.
Preparation 203
1-tert-butyl 7-ethyl 2-[(acetyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]heptanedioate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.33 (9H, s), 1.20-1.42 (2H, m), 1.63-1.74 (2H, m), 2.14 (3H, s), 2.27-2.38 (4H, m), 2.40 (3H, s), 4.10 (2H, q, J=7 Hz), 5.08 (1H, d, J=18 Hz), 5.36 (1H, d, J=18 Hz), 7.84 (1H, s), 8.56 (1H, s), 8.75 (1H, s). MS (ESI+): m/z 464.
The following compound(s) was (were) obtained in substantially the same manner as that of Preparation 78.
Preparation 204
ethyl 3-[(5-methyl-3-pyridinyl)carbonyl]-4-oxopentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 2.21 (3H, s), 2.44 (3H, s), 3.03 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.96 (1H, t, J=7 Hz), 8.08 (1H, s), 8.66 (1H, s), 9.03 (1H, s). MS (ESI+): m/z 264.
Preparation 205
ethyl 5-[(5-bromo-3-pyridinyl)carbonyl]-6-oxoheptanoate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.60-1.78 (2H, m), 1.98-2.12 (2H, m), 2.20 (3H, s), 2.36 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.39 (1H, t, J=7 Hz), 8.38 (1H, m), 8.87 (1H, d, J=2 Hz), 9.08 (1H, d, J=2 Hz).
Preparation 206
ethyl 4-[(5-bromo-3-pyridinyl)carbonyl]-6-methoxy-5-oxohexanoate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 2.04-2.16 (1H, m), 2.20-2.34 (1H, m), 2.40-2.48 (2H, m), 3.22 (3H, s), 3.93 (1H, d, J=17 Hz), 4.00 (1H, d, J=17 Hz), 4.12 (2H, q, J=7 Hz), 4.85 (1H, m), 8.47 (1H, m), 8.88 (1H, s), 9.16 (1H, s). MS (ESI+): m/z 372 374.
Preparation 207
benzyl 5-(2-acetyl-7-ethoxy-7-oxoheptanoyl)nicotinate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.65-1.75 (2H, m), 1.93-2.15 (2H, m), 2.19 (3H, s), 2.29 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.44 (1H, t, J=7 Hz), 5.43 (2H, s), 7.35-7.50 (5H, m), 8.81 (1H, m), 9.28 (1H, d, J=2 Hz), 939 (1H, d, J=2 Hz). MS (ESI+): m/z 426.
Preparation 208
ethyl 8-(benzyloxy)-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate
1H NMR (CDCl3) δ 1.22 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.60-1.69 (2H, m), 1.73-1.86 (1H, m), 1.95-2.08 (1H, m), 2.25 (2H, t, J=7 Hz), 2.34 (3H, s), 4.05 (2H, s), 4.07 (2H, q, J=7 Hz), 4.35-4.45 (2H, m), 4.69 (1H, t, J=7 Hz), 7.09 (2H, m), 7.17-7.25 (3H, m), 7.93 (1H, s), 8.58 (1H, d, J=2 Hz), 8.94 (1H, d, J=2 Hz). MS (ESI+): m/z 412.
Preparation 209
ethyl 6-(benzyloxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 2.07-2.35 (2H, m), 2.34 (3H, s), 2.38-2.48 (2H, m), 4.05 (2H, s), 4.12 (2H, q, J=7 Hz), 4.34 (1H, d, J=17 Hz), 4.41 (1H, d, J=17 Hz), 4.90 (1H, m), 7.03 (2H, m), 7.15-7.25 (3H, m), 8.00 (1H, s), 8.57 (1H, s), 9.02 (1H, s). MS (ESI+): m/z 384.
Preparation 210
ethyl 8-(cyclohexyloxy)-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate
1H NMR (CDCl3) δ 0.91-1.70 (12H, m), 1.23 (3H, t, J=7 Hz), 1.70-1.85 (2H, m), 1.96-2.04 (2H, m), 2.27 (2H, t, J=7 Hz), 2.43 (3H, s), 3.14-3.28 (1H, m), 4.00 (2H, s), 4.12 (2H, q, J=7 Hz), 4.76 (1H, t, J=7 Hz), 8.04 (1H, s), 8.62 (1H, s), 9.00 (1H, s). MS (ESI+): m/z 404.
Preparation 211
ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-8-(cyclohexyloxy)-7-oxooctanoate
1H NMR (CDCl3) δ 0.95-1.87 (14H, m), 1.23 (3H, t, J=7 Hz), 1.96-2.07 (2H, m), 2.28 (2H, t, J=7 Hz), 3.16-3.27 (1H, m), 3.96-4.07 (2H, m), 4.12 (2H, q, J=7 Hz), 4.72 (1H, t, J=7 Hz), 8.38 (1H, m), 8.87 (1H, d, J=2 Hz), 9.08 (1H, d, J=2 Hz). MS (ESI+): m/z 468 470.
Preparation 212
ethyl 6-(cyclohexyloxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate
1H NMR (CDCl3) δ 0.88-1.25 (5H, m), 1.24 (3H, t, J=7 Hz), 1.40-1.83 (5H, m), 2.04-2.14 (1H, m), 2.18-2.34 (1H, m), 2.42 (2H, m), 2.44 (3H, s), 3.13-3.27 (1H, m), 4.00 (2H, s), 4.12 (2H, q, J=7 Hz), 4.93 (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.
Preparation 213
ethyl 4-[(5-bromo-3-pyridinyl)carbonyl]-6-(cyclohexyloxy)-5-oxohexanoate
1H NMR (CDCl3) δ 0.88-1.85 (10H, m), 1.25 (3H, t, J=7 Hz), 2.02-2.14 (1H, m), 2.18-2.34 (1H, m), 2.40-2.50 (2H, m), 3.15-3.27 (1H, m), 3.97 (1H, d, J=17 Hz), 4.02 (1H, d, J=17 Hz), 4.13 (2H, q, J=7 Hz), 4.87-4.95 (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.
Preparation 214
ethyl 8-isopropoxy-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate
1H NMR (CDCl3) δ 0.86 (3H, d, J=7 Hz), 1.02 (3H, d, J=7 Hz), 1.23 (3H, t, J=7 Hz), 1.30-1.48 (2H, m), 1.60-1.72 (2H, m), 1.72-1.88 (1H, m), 1.95-2.07 (1H, m), 2.27 (2H, t, J=7 Hz), 2.43 (3H, s), 3.44-3.54 (1H, m), 3.95 (1H, d, J=18 Hz), 4.03 (1H, d, J=18 Hz), 4.08 (2H, q, J=7 Hz), 4.73 (1H, t, J=7 Hz), 8.06 (1H, s), 8.63 (1H, s), 9.02 (1H, s). MS (ESI+): m/z 364.
Preparation 215
ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-8-isopropoxy-7-oxooctanoate
1H NMR (CDCl3) δ 0.88 (3H, d, J=7 Hz), 1.03 (3H, t, J=7 Hz), 1.23 (3H, t, J=7 Hz), 1.20-1.46 (2H, m), 1.58-1.72 (2H, m), 1.73-1.87 (1H, m), 1.95-2.07 (1H, m), 2.27 (2H, 1, J=7 Hz), 3.46-3.58 (1H, m), 3.94 (1H, d, J=17 Hz), 4.03 (1H, d, J=17 Hz), 4.10 (2H, q, J=7 Hz), 4.68 (1H, t, J=7 Hz), 8.40 (1H, t, J=2 Hz), 8.86 (1H, d, J=2 Hz), 9.08 (1H, d, J=2 Hz). MS (ESI+): m/z 428 430.
Preparation 216
ethyl 8-(acetyloxy)-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.37-1.47 (2H, m), 1.60-1.77 (2H, m), 2.01 (3H, s), 1.97-2.08 (2H, m), 2.29 (2H, t, J=7 Hz), 2.44 (3H, s), 4.10 (2H, q, J=7 Hz), 4.52 (1H, t, J=7 Hz), 4.68 (1H, d, J=18 Hz), 4.76 (1H, d, J=18 Hz), 8.04 (1H, s), 8.66 (1H, s), 8.98 (1H, s). MS (ESI+): m/z 364.
The following compound(s) was (were) obtained in substantially the same manner as that 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 1.24 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.40 (3H, s), 2.50 (3H, s), 3.02 (2H, q, J=7 Hz), 3.44 (2H, s), 4.14 (2H, q, J=7 Hz), 5.98 (1H, d, J=4 Hz), 6.56 (1H, d, J=4 Hz), 7.55 (1H, s), 8.45 (1H, s), 8.54 (1H, s). MS (ESI+): m/z 338.
EXAMPLE 286
ethyl 7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylate
1H NMR (CDCl3) δ 0.96 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.41 (3H, s), 2.61 (3H, s), 3.04 (2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 6.30 (1H, d, J=4 Hz), 6.67 (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-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (CDCl3) δ 10.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.67-1.78 (2H, m), 2.22 (2H, t, J=7 Hz), 2.42-2.54 (2H, m), 2.59 (3H, s), 3.01 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.87 (1H, m), 8.54 (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 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.42 (2H, t, J=7 Hz), 2.85-2.97 (2H, m), 3.06 (2H, q, J=7 Hz), 3.46 (3H, s), 4.08 (2H, q, J=7 Hz), 4.65 (2H, s), 5.94 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.87 (1H, m), 8.54 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz). MS (ESI+): m/z 446 448.
EXAMPLE 289
ethyl 4-[2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (CDCl3) δ 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.60-1.75 (2H, m), 2.17 (3H, s), 2.10-2.28 (2H, m), 2.45-2.60 (2H, m), 3.02 (2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.32 (2H, s), 5.95 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.88 (1H, m), 8.55 (1H, m), 8.78 (1H, m). MS (ESI+): m/z 488 490.
EXAMPLE 290
benzyl 5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]nicotinate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.33-1.60 (4H, m), 2.18 (2H, t, J=7 Hz), 2.35-2.47 (2H, m), 2.56 (3H, s), 3.03 (2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 5.42 (2H, s), 5.82 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.36-7.47 (5H, m), 8.33 (1H, m), 8.77 (1H, d, J=2 Hz), 933 (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 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.20-1.50 (4H, m), 2.06 (2H, t, J=7 Hz), 2.42 (3H, s), 2.47-2.63 (2H, m), 3.05 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.64 (2H, s), 4.73 (2H, s), 5.90 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.27-7.39 (5H, m), 7.51 (1H, s), 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 1.16 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.36 (2H, t, J=7 Hz), 2.42 (3H, s), 2.80-3.00 (2H, m), 3.06 (2H, q, J=7 Hz), 4.03 (2H, q, J=7 Hz), 4.65 (2H, s), 4.75 (2H, s), 5.92 (1H, d, J=2 Hz), 6.59 (1H, d, J=2 Hz), 7.26-7.38 (5H, m), 7.48 (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), 1.37 (3H, t, J=7 Hz), 1.70-1.83 (2H, m), 1.96-2.07 (2H, m), 2.15 (2H, t, J=7 Hz), 2.43 (3H, s), 2.53-2.68 (2H, m), 3.04 (2H, q, J=7 Hz), 3.42-3.53 (1H, m), 4.08 (2H, q, J=7 Hz), 4.69 (2H, s), 5.88 (1H, d, J=4 Hz), 6.55 (1H, d, J=4 Hz), 7.53 (1H, s), 8.42 (1H, d, J=2 Hz), 8.53 (1H, d, J=2 Hz).
EXAMPLE 294
ethyl 5-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (CDCl3) δ 1.22-1.62 (10H, m), 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.73-1.86 (2H, m), 1.98-2.07 (2H, m), 2.18 (2H, t, J=7 Hz), 2.53-2.70 (2H, m), 3.03 (2H, q, J=7 Hz), 3.42-3.56 (1H, m), 4.12 (2H, q, J=7 Hz), 4.69 (2H, s), 5.88 (1H, d, J=4 Hz), 6.58 (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 1.19 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.16-1.45 (4H, m), 1.52-1.65 (2H, m), 1.73-1.83 (2H, m), 1.98-2.07 (2H, m), 2.35-2.47 (2H, m), 2.42 (3H, s), 2.84-2.98 (2H, m), 3.03 (2H, q, J=7 Hz), 3.45-3.56 (1H, m), 4.06 (2H, q, J=7 Hz), 4.71 (2H, s), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.50 (1H, s), 8.42 (1H, s), 8.53 (1H, s). MS (ESI+): m/z 450.
EXAMPLE 296
ethyl 3-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}propanoate
1H NMR (CDCl3) δ 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.15-1.60 (6H, m), 1.73-1.85 (2H, m), 1.97-2.08 (2H, m), 2.45 (2H, t, J=7 Hz), 2.83-2.97 (2H, m), 3.05 (2H, q, J=7 Hz), 3.42-3.56 (1H, m), 4.08 (2H, q, J=7 Hz), 4.71 (2H, s), 5.90 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.86 (1H, t, J=2 Hz), 8.53 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz). MS (ESI+): m/z 514 516.
EXAMPLE 297
ethyl 5-[7-ethyl-2-(isopropoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.26 (6H, d, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.38-1.62 (4H, m), 2.17 (2H, t, J=7 Hz), 2.43 (3H, s), 2.53-2.68 (2H, m), 3.03 (2H, q, J=7 Hz), 3.76-3.88 (1H, m), 4.08 (2H, q, J=7 Hz), 4.66 (2H, s), 5.88 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.52 (1H, s), 8.42 (1H, s), 8.53 (1H, s). MS (ESI+): m/z 438.
EXAMPLE 298
ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isopropoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.25 (6H, d, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.37-1.64 (4H, m), 2.15 (2H, t, J=7 Hz), 2.54-2.72 (2H, m), 3.02 (2H, q, J=7 Hz), 3.75-3.87 (1H, m), 4.09 (2H, q, J=7 Hz), 4.66 (2H, s), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.88 (1H, m), 8.55 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz). MS (ESI+): m/z 502 504.
EXAMPLE 299
ethyl 5-[2-[(acetyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.30-158 (4H, m), 2.13 (2H, t, J=7 Hz), 2.18 (3H, s), 2.44 (3H, s), 2.40-2.55 (2H, m), 3.02 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 5.29 (2H, s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.52 (1H, s), 8.42 (1H, s), 8.53 (1H, s). MS (ESI+): m/z 438.
The following compound(s) was (were) obtained in substantially the same manner as that of Example 236.
EXAMPLE 300
ethyl 4-{4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}butanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.41 (3H, t, J=7 Hz), 1.68-1.80 (2H, m), 2.22 (2H, t, J=7 Hz), 2.44-2.54 (2H, m), 2.59 (3H, s), 3.03 (2H, q, J=7 Hz), 3.95 (2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 4.36 (1H, d, J=3 Hz), 4.77 (1H, d, J=3 Hz), 5.88 (1H, d, J=4 Hz), 6.52 (1H, d, J=4 Hz), 7.92 (1H, m), 8.53 (1H, d, J=2 Hz), 8.93 (1H, d, J=2 Hz). MS (ESI+): m/z 422.
EXAMPLE 301
ethyl 3-[4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate
1H NMR (CDCl3) δ 1.19 (3H, 1, J=7 Hz), 1.26 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.42 (2H, t, J=7 Hz), 2.84-2.97 (2H, m), 3.07 (2H, q, J=7 Hz), 3.47 (3H, s), 3.97 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.36 (1H, d, J=3 Hz), 4.66 (2H, s), 4.77 (1H, d, J=3 Hz), 5.95 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.92 (1H, m), 8.54 (1H, d, J=2 Hz), 8.95 (1H, d, J=2 Hz). MS (ESI+): m/z 438.
EXAMPLE 302
ethyl 3-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate
1H NMR (CDCl3) δ 1.18 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.40 (2H, t, J=7 Hz), 2.84-2.98 (2H, m), 3.03 (2H, q, J=7 Hz), 3.47 (3H, s), 4.04 (2H, q, J=7 Hz), 4.65 (2H, s), 5.46 (1H, d, J=11 Hz), 5.87 (1H, d, J=18 Hz), 5.94 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 6.72-6.83 (1H, dd, J=11 Hz, 18 Hz), 7.74 (1H, m), 8.49 (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 1.38 (3H, t, J=7 Hz), 1.65-1.78 (2H, m), 2.23 (2H, t, J=7 Hz), 2.54-2.70 (2H, m), 3.05 (2H, q, J=7 Hz), 3.47 (3H, s), 3.58 (3H, s), 4.67 (2H, s), 5.46 (1H, d, J=11 Hz), 5.88 (1H, d, J=18 Hz), 5.93 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 6.73-6.83 (1H, dd, J=11 Hz, 18 Hz), 7.77 (1H, m), 8.51 (1H, d, J=2 Hz), 8.71 (1H, d, J=2 Hz). MS (ESI+): m/z 394.
EXAMPLE 304
methyl 4-[4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.67-1.82 (2H, m), 2.22 (2H, t, J=7 Hz), 2.53-2.67 (2H, m), 3.04 (2H, q, J=7 Hz), 3.47 (3H, s), 3.58 (3H, s), 3.95 (2H, q, J=7 Hz), 4.34 (1H, d, J=2 Hz), 4.67 (2H, s), 4.77 (1H, d, J=2 Hz), 5.93 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.92 (1H, m), 8.54 (1H, d, J=2 Hz), 8.95 (1H, d, J=2 Hz). MS (ESI+): m/z 438.
EXAMPLE 305
ethyl 3-{4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}propanoate
1H NMR (CDCl3) δ 1.19 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.44 (3H, t, J=7 Hz), 2.33-2.43 (2H, m), 2.58 (3H, s), 2.76-2.87 (2H, m), 3.03 (2H, q, J=7 Hz), 3.96 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 4.36 (1H, d; J=2 Hz), 4.77 (1H, d, J=2 Hz), 5.91 (1H, d, J=4 Hz), 6.54 (1H, d, J=4 Hz), 7.91 (1H, m), 8.53 (1H, d, J=2 Hz), 8.96 (1H, d, J=2 Hz). MS (ESI+): m/z 408.
The following compound(s) was (were) obtained in substantially the same manner as that of Example 251.
EXAMPLE 306
ethyl 4-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (CDCl3) δ 1.19 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.66-1.82 (2H, m), 2.21 (2H, t, J=7 Hz), 2.41-2.51 (2H, m), 2.60 (3H, s), 2.69 (3H, s), 3.03 (2H, q, J=7 Hz), 4.03 (2H, q, J=7 Hz), 5.83 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 8.25 (1H, m), 8.79 (1H, d, J=2 Hz), 9.25 (1H, d, J=2 Hz). MS (ESI+): m/z 394.
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 1.18 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.41 (2H, t, J=7 Hz), 2.70 (3H, s), 2.83-2.96 (2H, m), 3.06 (2H, q, J=7 Hz), 3.47 (3H, s), 4.03 (2H, q, J=7 Hz), 4.66 (2H, s), 5.88 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 8.26 (1H, m), 8.79 (1H, d, J=2 Hz), 9.25 (1H, d, J=2 Hz).
EXAMPLE 308
methyl 4-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.64-1.80 (2H, m), 2.20 (2H, t, J=7 Hz), 2.53-2.65 (2H, m), 2.70 (3H, s), 3.05 (2H, q, J=7 Hz), 3.47 (3H, s), 3.57 (3H, s), 4.67 (2H, s), 5.87 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoate
1H NMR (CDCl3) δ 1.19 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.33-2.42 (2H, m), 2.59 (3H, s), 2.69 (3H, s), 2.75-2.83 (2H, m), 3.02 (2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.83 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 8.25 (1H, m), 8.78 (1H, d, J=2 Hz), 9.26(1H, d, J=2 Hz). MS (ESI+): m/z 380.
EXAMPLE 310
A mixture of benzyl 5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]nicotinate (330 mg) and 10% palladium on carbon (33 mg) in methanol (10 mL) was stirred under 4 atm hydrogen atmosphere at ambient temperature for 2 hours. The catalysts were filtered off and washed with chloroform. The filtrates were evaporated in vacuo to give 5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]nicotinic acid as yellow oil (272 mg).
5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]nicotinic acid
1H NMR (CDCl3) δ 1.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.35-1.63 (4H, m), 2.19 (2H, t, J=7 Hz), 2.38-2.49 (2H, m), 2.57 (3H, s), 3.03 (2H, q, J=7 Hz), 4.11 (2H, q, J=7 Hz), 5.85 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 8.40 (1H, m), 8.83 (1H, d, J=2 Hz), 937 (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-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]nicotinic acid (235 mg) and triethylamine (87.1 mg) in t-butanol (10 mL) was added diphenylphosphoryl azide (237 mg) and the mixture was heated under reflux for 2 hours. After evaporation of solvent, the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-2:1) to give ethyl 5-(4-{5-[(tert-butoxycarbonyl)amino]-3-pyridinyl}-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl)pentanoate as yellow oil (190 mg).
ethyl 5-(4-{5-[(tert-butoxycarbonyl)amino]-3-pyridinyl}-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl)pentanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.42-1.67 (4H, m), 1.52 (9H, s), 2.19-2.28 (2H, m), 2.38-2.50 (2H, m), 2.55 (3H, s), 3.03 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.92 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 6.93 (1H, br), 7.87 (1H, s), 8.30 (1H, d, J=2 Hz), 8.70 (1H, d, J=2 Hz). MS (ESI+): m/z 481.
EXAMPLE 312
A solution of ethyl 5-(4-{5-[(tert-butoxycarbonyl)amino]-3-pyridinyl}-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl)pentanoate (190 mg) in 2 N hydrogen chloride ethyl acetate solution (4 mL) was stirred at ambient temperature for 2 hours. After evaporation of solvent, the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (100:1-20:1) to give ethyl 5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (140 mg).
ethyl 5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.65 (4H, m), 2.23 (2H, t, J=7 Hz), 2.45 (2H, t, J=7 Hz), 2.54 (3H, s), 3.03 (2H, q, J=7 Hz), 3.97 (2H, br), 4.12 (2H, q, J=7 Hz), 5.94 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (55 mg), 37% formaldehyde solution (277 mg) and sodium cyanoborohydride (273 mg) in acetnitrile (1 mL) and methanol (1 mL) was added acetic acid (2 drops) and the mixture was stirred at ambient temperature for 2 hours. The solution was diluted with saturated sodium bicarbonate solution and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-{4-[5-(dimethylamino)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate as yellow oil (365 mg).
ethyl 5-{4-[5-(dimethylamino)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 2.19 (2H, t, J=7 Hz), 2.40-2.53 (2H, m), 2.55 (3H, s), 3.02 (6H, s), 3.03 (2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 5.93 (1H, d, J=4 Hz), 6.50 (1H, d, J=4 Hz), 6.96 (1H, m), 7.95 (1H, d, J=2 Hz), 8.20 (1H, d, J=2 Hz). MS (ESI+): m/z 409.
The following compound(s) was (were) obtained in substantially the same manner as that of Example 245.
EXAMPLE 314
3-[7-ethyl-4-(5-ethyl-3-pyridinyl)-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid
1H NMR (CDCl3) δ 1.29 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.45-2.58 (2H, m), 2.73 (2H, q, J=7 Hz), 2.82-3.02 (2H, m), 3.03 (2H, q, J=7 Hz), 3.47 (3H, s), 4.67 (2H, s), 5.91 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.58 (1H, m), 8.43 (1H, d, J=2 Hz), 8.53 (1H, d, J=2 Hz). MS (ESI−): m/z 366, MS (ESI+): m/z 368.
EXAMPLE 315
4-[7-ethyl-4-(5-ethyl-3-pyridinyl)-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H NMR (CDCl3) δ 1.31 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.69-1.85 (2H, m), 2.20-2.31 (2H, m), 2.52-2.75 (2H, m), 2.77 (2H, q, J=7 Hz), 3.06 (2H, q, J=7 Hz), 3.46 (3H, s), 4.60-4.80 (2H, m), 5.91 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.61 (1H, s), 8.44-8.53 (2H, m). MS (ESI+): m/z 382.
The following compound(s) was (were) obtained in substantially the same manner as that of Example 228.
EXAMPLE 316
methyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.65-1.79 (2H, m), 2.25 (2H, t, J=7 Hz), 2.39-2.53 (2H, m), 3.06 (2H, q, J=7 Hz), 3.61 (3H, s), 4.90 (2H, s), 5.96 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.88 (1H, m), 8.55 (1H, d, J=2 Hz), 8.79 (1H, d, J=2 Hz). 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 1.23 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.35-1.60 (4H, m), 2.17 (2H, t, J=7 Hz), 2.35-2.45 (2H, m), 2.43 (3H, s), 3.04 (2H, q, J=7 Hz), 3.83 (1H, t, J=7 Hz), 4.10 (2H, q, J=7 Hz), 4.85 (2H, d, J=7 Hz), 5.96 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.50 (1H, s), 8.42 (1H, s), 8.54 (1H, s). MS (ESI+): m/z 396.
The following compound(s) was (were) obtained in substantially the same manner as that 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 1.37 (3H, t, J=7 Hz), 1.65-1.79 (2H, m), 2.24 (2H, t, J=7 Hz), 2.52-2.70 (2H, m), 3.04 (2H, q, J=7 Hz), 3.46 (3H, s), 3.60 (3H, s), 4.76 (2H, s), 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-oxoethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.30-1.60 (4H, m), 1.47 (9H, s), 2.17 (2H, t, J=7 Hz), 2.43 (3H, s), 2.58-2.72 (2H, m), 3.03 (2H, q, J=7 Hz), 4.08 (2H, s), 4.12 (2H, q, J=7 Hz), 4.81 (2H, s), 5.91 (1H, d, J=4 Hz), 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), 0.53-0.63 (2H, m), 1.07-1.20 (1H, m), 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.60 (4H, m), 2.15 (2H, t, J=7 Hz), 2.43 (3H, s), 2.53-2.68 (2H, m), 3.02 (2H, q, J=7 Hz), 3.41 (2H, d, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.70 (2H, s), 5.89 (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 0.88-1.05 (2H, m), 1.16-1.35 (4H, m), 1.25 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.38-1.59 (4H, m), 1.60-1.87 (5H, m), 2.16 (2H, t, J=7 Hz), 2.43 (3H, s), 2.54-2.67 (2H, m), 3.03 (2H, q, J=7 Hz), 3.35 (2H, d, J=7 Hz), 4.10 (2H, q, J=7 Hz), 4.64 (2H, s), 5.89 (1H, d, J=4 Hz), 6.56 (1H, d, J=4 Hz), 7.52 (1H, s), 8.43 (1H, d, J=2 Hz), 8.53 (1H, d, J=2 Hz). MS (ESI+): m/z 492.
EXAMPLE 322
ethyl 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (CDCl3) δ 1.22 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.35-1.54 (4H, m), 2.12 (2H, t, J=7 Hz), 2.43 (3H, s), 2.50-2.63 (2H, m), 3.03 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.66 (2H, s), 4.76 (2H, s), 5.92 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.28 (1H, m), 7.52 (1H, s), 7.72 (1H, d, J=8 Hz), 8.42 (1H, d, J=2 Hz), 8.54 (2H, m), 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-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (CDCl3) δ 1.21 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.36-1.54 (4H, m), 2.12 (2H, t, J=7 Hz), 2.42 (3H, s), 2.56-2.68 (2H, m), 3.03 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.77 (2H, s), 4.85 (2H, s), 5.92 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.22 (1H, m), 7.43-7.54 (2H, m), 7.66-7.74 (1H, m), 8.42 (1H, d, J=2 Hz), 8.54 (1H, d, J=2 Hz), 8.57 (1H, d, J=5 Hz). MS (ESI+): m/z 487.
EXAMPLE 324
ethyl 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (CDCl3) δ 1.22 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.38-1.57 (4H, m), 2.12 (2H, t, J=7 Hz), 2.43 (3H, s), 2.52-2.68 (2H, m), 3.05 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.66 (2H, s), 4.77 (2H, s), 5.93 (1H, d, J=4 Hz), 6.60 (1H, d, J=2 Hz), 7.28 (2H, d, J=7 Hz), 7.52 (1H, s), 8.42 (1H, d, J=2 Hz), 8.53 (1H, d, J=2 Hz), 858 (2H, d, J=7 Hz). MS (ESI+): m/z 487.
EXAMPLE 325
ethyl 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (CDCl3) δ 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.38-1.57 (4H, m), 2.13 (2H, t, J=7 Hz), 2.43 (3H, s), 2.52-2.68 (2H, m), 3.03 (2H, q, J=7 Hz), 4.07 (2H, q, J=7 Hz), 4.82 (2H, s), 4.88 (2H, m), 5.92 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.52 (1H, s), 8.43 (1H, d, J=2 Hz), 8.48-8.57 (3H, m), 8.75 (1H, m). MS (ESI+): m/z 488.
EXAMPLE 326
ethyl 5-[4-(3-cyanophenyl)-2-(ethoxymethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.18-1.29 (6H, m), 1.34-1.53 (7H, m), 2.14 (2H, t, J=7 Hz), 2.52 (2H, m), 3.02 (2H, q, J=7 Hz), 3.53 (2H, q, J=7 Hz), 4.07 (2H, q, J=7 Hz), 4.66 (1H, s), 5.73 (1 J, d, J=5 Hz), 6.56 (1H, d, J=5 Hz), 7.60 (2H, m), 7.67 (1H, s), 7.75 (1H, m)
EXAMPLE 327
ethyl 5-[2-[(benzyloxy)methyl]-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.22 (3H, t, J=7 Hz), 1.30-1.46 (7H, m), 2.06 (2H, t, J=7 Hz), 2.51 (2H, m), 3.02 (2H, q, J=7 Hz), 4.07 (2H, q, J=7 Hz), 4.64 (3H, s), 4.72 (3H, s), 5.83 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.25-7.38 (5H, m), 7.57 (2H, d, J=9 Hz), 7.65 (1H, s), 7.74 (1H, m).
EXAMPLE 328
methyl 4-({[4-(3-cyanophenyl)-3-(5-ethoxy-5-oxopentyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methoxy}methyl)benzoate
1H NMR (CDCl3) δ 1.22 (3H, t, J=7 Hz), 1.32-1.49 (7H, m), 2.01 (2H, t, J=7 Hz), 2.52 (2H, m), 3.02 (2H, t, J=7 Hz), 3.92 (3H, s), 4.07 (2H, t, J=7 Hz), 4.69 (2H, s), 4.75 (2H, s), 6.84 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.43 (2H, d, J=9 Hz), 7.60 (2H, m), 7.65 (1H, s), 7.75 (1H, m), 8.02 (2H, d, J=9 Hz).
EXAMPLE 329
A solution of ethyl 5-[2-[(2-tert-butoxy-2-oxoethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (60 mg) in trifluoroacetic acid (2 mL) was stirred at ambient temperature for 2 hours, and evaporated in vacuo to give {[3-(5-ethoxy-5-oxopentyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-2-yl]methoxy}acetic acid as brown oil (55 mg).
{[3-(5-ethoxy-5-oxopentyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-2-yl]methoxy}acetic acid
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.35-1.60 (4H, m), 2.23 (2H, t, J=7 Hz), 2.50-2.58 (2H, m), 2.67 (3H, s), 3.03 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.30 (2H, s), 4.87 (2H, s), 5.86 (1H, d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 8.15 (1H, s), 8.69 (1H, s), 8.85 (1H, s). MS (ESI−): m/z 452, MS (ESI+): m/z 454.
EXAMPLE 330
To a solution of {[3-(5-ethoxy-5-oxopentyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-2-yl]methoxy}acetic acid (55 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (34.9 mg) and 1-hydroxybenotriazole (24.6 mg) in dimethylformamide (2 mL) was added morpholine (12.7 mg) and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of ethyl acetate and methanol (50:1-20:1) to give ethyl 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[2-(4-morpholinyl)-2-oxoethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate as yellow oil (50 mg).
ethyl 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[2-(4-morpholinyl)-2-oxoethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate
1H NMR (CDCl3) δ 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 2.15 (2H, t, J=7 Hz), 2.43 (3H, s), 2.54-2.68 (2H, m), 3.02 (2H, q, J=7 Hz), 3.48-357 (2H, m), 3.63-3.78 (6H, m), 4.08 (2H, q, J=7 Hz), 4.30 (2H, s), 4.78 (2H, s), 5.93 (H, 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(s) was (were) obtained in substantially the same manner as that of Example 330.
EXAMPLE 331
ethyl 5-[7-ethyl-2-{[2-(methylamino)-2-oxoethoxy]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.38-1.62 (4H, m), 2.18 (2H, t, J=7 Hz), 2.44 (3H, s), 2.48-2.62 (2H, m), 2.88 (3H, d, J=7 Hz), 3.03 (2H, q, J=7 Hz), 4.11 (2H, q, J=7 Hz), 4.13 (2H, s), 4.77 (2H, s), 5.94 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 6.79 (1H, br), 753 (1H, s), 8.44 (1H, s), 8.56 (1H, s). MS (ESI+): m/z 467.
The following compound(s) was (were) obtained in substantially the same manner as that 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 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.30-1.50 (2H, m), 1.60-1.85 (2H, m), 2.12 (2H, t, J=7 Hz), 2.30-2.45 (2H, m), 2.42 (3H, s), 3.03 (2H, q, J=7 Hz), 3.96 (2H, s), 3.98 (2H, s), 4.08 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.54 (1H, d, J=4 Hz), 7.27-7.43 (5H, m), 7.48 (1H, s), 8.38 (1H, d, J=2 Hz), 853 (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) diisopropyl azodicarboxylate (76.7 mg) and triphenylphosphine (99.5 mg) in tetrahydrofuran (2 mL) was stirred at ambient temperature for 1 hour. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-1:1) to give ethyl 5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (107 mg).
ethyl 5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 0.89 (3H, t, J=7 Hz), 1.26 (3H, t, J=7 Hz), 1.20-1.40 (2H, m), 1.53-1.75 (2H, m), 2.24 (2H, t, J=7 Hz), 2.44 (3H, s), 2.47 (2H, q, J=7 Hz), 2.50-2.64 (2H, m), 4.12 (2H, q, J=7 Hz), 5.10 (2H, s), 5.85 (1H, d, J=4 Hz), 6.43 (1H, d, J=4 Hz), 7.51 (1H, s), 7.78 (2H, m), 7.96 (2H, m), 8.43 (1H, s), 8.55 (1H, s). MS (ESI+): m/z 525.
EXAMPLE 334
A mixture of ethyl 5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (107 mg) and hydrazine monohydrate (51.1 mg) in ethanol (2 mL) was heated under reflux for 2 hours. After evaporation of solvent, the residue was partitioned between chloroform and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (67.6 mg).
ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.38-1.62 (4H, m), 2.14 (2H, t, J=7 Hz), 2.42 (3H, s), 2.38-2.56 (2H, m), 3.04 (2H, q, J=7 Hz), 4.06 (2H, s), 4.08 (2H, q, J=7 Hz), 5.90 (1H, d, J=4 Hz), 6.55 (1H, d, J=4 Hz), 7.51 (1H, s), 8.41 (1H, s), 8.53 (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 brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-[2-[(acetylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as 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 1.22 (3H, t, J=7 Hz), 1.40 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 2.12 (2H, m), 2.15 (3H, s), 2.43 (3H, s), 2.40-2.53 (2H, m), 3.03 (2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 4.66 (2H, m), 5.94 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 6.85 (1H, br), 750 (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 methanesulfonyl chloride (34.8 mg) under ice-water cooling and the mixture was stirred at ambient temperature for 1 hour. The solution was diluted with chloroform, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(methylsulfonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate as yellow oil (62.8 mg)
ethyl 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(methylsulfonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.40-1.62 (4H, m), 2.19 (2H, t, J=7 Hz), 2.44 (3H, s), 2.38-2.51 (2H, m), 3.02 (2H, q, J=7 Hz), 3.06 (3H, s), 4.08 (2H, q, J=7 Hz), 4.58 (2H, s), 5.63 (1H, br), 5.97 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.50 (1H, s), 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), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (54.7 mg) and 1-hydroxybenotriazole (385 mg) in dimethylformamide (2 mL) was stirred at ambient temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-[2-[(benzoylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (60 mg).
ethyl 5-[2-[(benzoylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.42 (3H, t, J=7 Hz), 1.42-1.65 (4H, m), 2.17 (2H, t, J=7 Hz), 2.44 (3H, s), 2.44-2.58 (2H, m), 3.06 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.86 (2H, m), 5.96 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.46-7.59 (4H, m), 7.78 (1H, br), 7.91-7.97 (2H, m), 8.44 (1H, d, J=2 Hz), 8.56 (1H, d, J=2 Hz). MS (ESI+): m/z 499.
The following compound(s) was (were) obtained in substantially the same manner as that of Example 337.
EXAMPLE 338
ethyl 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(2-pyrazinylcarbonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.41 (3H, t, J=7 Hz), 1.42-1.64 (4H, m), 2.18 (2H, t, J=7 Hz), 2.44 (3H, s), 2.47-2.59 (2H, m), 3.08 (2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 4.89 (2H, d, J=7 Hz), 5.96 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.53 (1H, s), 8.43 (1H, d, J=2 Hz), 8.55 (1H, d, J=2 Hz), 8.62 (1H, m), 8.79 (1H, m), 9.15 (1H, br), 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 methyl chloridocarbonate (34.8 mg) under ice-water cooling and the mixture was stirred at ambient temperature for 2 hours.
After evaporation of solvent, the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-[7-ethyl-2-{[(methoxycarbonyl)amino]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (70 mg).
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 1.23 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 2.19 (2H, t, J=7 Hz), 2.44 (3H, s), 2.40-2.55 (2H, m), 3.03 (2H, q, J=7 Hz), 3.07 (3H, s), 4.12 (2H, q, J=7 Hz), 4.57 (2H, m), 5.72 (1H, br), 5.97 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.51 (1H, s), 8.41 (1H, s), 8.56 (1H, s).
EXAMPLE 340
To a solution of ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (70.0 mg) and triethyl amine (185 mg) in dichloromethane (1 mL) was added methanesulfonyl chloride (20.9 mg) under an ice bath. After stirring for 1 hour, to the mixture was added 1-methylpiperazine (27.0 mg). The mixture was stirred for 0.5 hour under an ice bath and overnight at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. Preparative silica gel thin layer chromatography (chloroform-methanol=20-1) afforded ethyl 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-methyl-1-piperazinyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate as an yellow gum (52.4 mg, 63.5%).
ethyl 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-methyl-1-piperazinyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (CDCl3): 1.23 (3H, t, J=7 Hz), 1.33-1.60 (7H, m), 2.16 (2H, t, J=7 Hz), 2.29 (3H, s), 2.34-2.65 (6H, m), 3.00 (2H, q, J=7 Hz), 3.54 (2H, s), 4.08 (2H, q, J=7 Hz), 5.86 (1H, d, J=5 Hz), 6.55 (1H, d, J=5 Hz 9, 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, 1.30 mmol) in tetrahydrofuran (3 mL) was added triphenylphosphine (308 mg, 1.17 mmol) over 40 minutes. The mixture was concentrated, and the residue was chromatographed on a flash silica gel column chromatography (ethyl acetate-hexane=1-8 to 1-5) to afford ethyl 5-[2-(bromomethyl)-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow gum (229 mg, 50.4%).
ethyl 5-[2-(bromomethyl)-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.41-1.50 (4H, m), 2.19 (2H, t, J=7 Hz), 2.58 (2H, m), 3.01 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.66 (2H, s), 5.94 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.88 (1H, m), 8.55 (1H, m), 8.79 (1H, m).
EXAMPLE 342
A mixture of ethyl 5-[2-(bromomethyl)-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (70.0 mg) and potassium cyanide (13.1 mg) in N,N-dimethylformamide (1 mL) was stirred for 28 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (two times), brine, dried over magnesium sulfate, and evaporated to give ethyl 5-[4-(5-bromo-3-pyridinyl)-2-(cyanomethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow gum (28.8 mg, 45.9%).
ethyl 5-[4-(5-bromo-3-pyridinyl)-2-(cyanomethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.46-1.65 (7H, m), 2.22 (2H, t, J=7 Hz), 2.48 (2H, m), 3.04 (2H, q, J=7 Hz), 3.98 (2H, s), 4.10 (2H, q, J=7 Hz), 5.98 (1H, d, J=5 Hz), 6.65 (1H, d, J=5 Hz), 7.88 (1H, m), 8.55 (1H, m), 8.81 (1H, m).
The following compound(s) was (were) obtained in substantially the same manner as that of Example 76.
EXAMPLE 343
[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]acetic acid
1H NMR (CDCl3) δ 1.36 (3H, t, J=7 Hz), 2.45 (3H, s), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 3.28 (1H, d, J=17 Hz), 3.53 (1H, d, J=17 Hz), 5.91 (1H, d, J=4 Hz), 6.52 (1H, d, J=4 Hz), 7.71 (1H, s), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.65-1.85 (2H, m), 2.31 (2H, t, J=7 Hz), 2.45-2.63 (2H, m), 2.59 (3H, s), 3.03 (2H, q, J=7 Hz), 5.88 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.90 (1H, s), 8.53 (1H, s), 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-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.68-1.82 (2H, m), 2.26 (2H, t, J=7 Hz), 2.45-2.58 (2H, m), 2.60 (3H, s), 2.70 (3H, s), 3.03 (2H, q, J=7 Hz), 5.83 (1H, d, J=4 Hz), 6.54 (1H, d, J=4 Hz), 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 1.37 (3H, t, J=7 Hz), 2.49 (2H, t, J=7 Hz), 2.80-3.00 (2H, m), 3.05 (2H, q, J=7 Hz), 3.46 (3H, s), 4.66 (2H, s), 5.94 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.88 (1H, s), 8.55 (1H, s), 8.77 (1H, s). 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 1.38 (3H, t, J=7 Hz), 2.48 (2H, t, J=7 Hz), 2.68 (3H, s), 2.85-2.97 (2H, m), 3.05 (2H, q, J=7 Hz), 3.47 (3H, s), 4.67 (2H, s), 5.88 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 8.27 (1H, m), 8.78 (1H, d, J=2 Hz), 9.23 (1H, d, J=2 Hz). MS (ESI−): m/z 380, MS (ESI+): m/z 382.
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 1.38 (3H, t, J=7 Hz), 2.46-2.58 (2H, m), 2.83-3.03 (2H, m), 3.05 (2H, q, J=7 Hz), 3.47 (3H, s), 4.68 (2H, s), 5.46 (1H, d, J=11 Hz), 5.88 (1H, d, J=18 Hz), 5.93 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 6.68-6.82 (1H, dd, J=11 Hz, 18 Hz), 7.78 (1H, m), 8.47 (1H, d, J=2 Hz), 8.68 (1H, d, J=2 Hz). MS (ESI−): m/z 364, MS (ESI+): m/z 366.
EXAMPLE 349
4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.68-1.82 (2H, m), 2.29 (2H, t, J=7 Hz), 2.55-2.75 (2H, m), 3.04 (2H, q, J=7 Hz), 3.45 (3H, s), 4.64 (2H, s), 5.93 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.91 (1H, m), 8.56 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz). MS (ESI−): m/z 430 432, MS (ESI+): m/z 432 434.
EXAMPLE 350
4-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.72-1.87 (2H, m), 2.26 (2H, t, J=7 Hz), 2.53-2.80 (2H, m), 3.06 (2H, q, J=7 Hz), 3.46 (3H, s), 4.68 (2H, m), 5.47 (1H, d, J=11 Hz), 5.88 (1H, d, J=18 Hz), 5.93 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 6.72-6.83 (1H, dd, J=11 Hz, 18 Hz), 7.81 (1H, m), 8.50 (1H, d, J=2 Hz), 8.63 (1H, d, J=2 Hz). MS (ESI−): m/z 378, MS (ESI+): m/z 380.
EXAMPLE 351
4-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.66-1.83 (2H, m), 2.26 (2H, t, J=7 Hz), 2.55-2.70 (2H, m), 2.70 (3H, s), 3.05 (2H, q, J=7 Hz), 3.46 (3H, s), 4.67 (2H, s), 5.88 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 8.29 (1H, m), 8.80 (1H, d, J=2 Hz), 9.22 (1H, d, J=2 Hz). MS (ESI−): m/z 394, MS (ESI+): m/z 396.
EXAMPLE 352
5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.34 (3H, t, J=7 Hz), 1.44-1.65 (4H, m), 2.16-2.32 (2H, m), 2.34-2.46 (2H, m), 2.53 (3H, s), 3.02 (2H, q, J=7 Hz), 5.06 (2H, br), 5.86 (1H, d, J=4 Hz), 5.98 (1H, d, J=4 Hz), 7.45 (1H, s), 7.84 (1H, s), 8.58 (1H, s). MS (ESI−): m/z 351, MS (ESI+): m/z 353.
EXAMPLE 353
5-{4-[5-(dimethylamino)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.40-1.70 (4H, m), 2.23 (2H, m), 2.36-2.50 (2H, m), 2.56 (3H, s), 3.03 (2H, q, J=7 Hz), 3.06 (6H, s), 5.88 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.13 (1H, s), 7.90 (1H, s), 8.14 (1H, m). MS (ESI+): m/z 381.
EXAMPLE 354
3-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 2.40-2.53 (2H, m), 2.60 (3H, s), 2.68 (3H, s), 2.83 (2H, t, J=7 Hz), 3.03 (2H, q, J=7 Hz), 5.83 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 8.27 (1H, m), 8.78 (1H, d, J=2 Hz), 9.22 (1H, d, J=2 Hz). MS (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]pentanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.35-1.55 (4H, m), 2.05-2.20 (2H, m), 2.42 (3H, s), 2.40-2.70 (2H, m), 3.03 (2H, q, J=7 Hz), 4.63 (2H, s), 4.74 (2H, m), 5.88 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.27-7.42 (5H, m), 7.53 (1H, s), 8.40 (1H, 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 1.38 (3H, t, J=7 Hz), 2.40 (3H, s), 2.40-2.54 (2H, m), 2.80-3.08 (2H, m), 3.06 (2H, q, J=7 Hz), 4.65 (2H, s), 4.77 (2H, m), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.26-7.42 (5H, m), 7.54 (1H, s), 8.39 (1H, d, J=2 Hz), 8.48 (1H, d, J=2 Hz). 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]pentanoic acid
1H NMR (CDCl3) δ 1.20-1.45 (6H, m), 1.36 (3H, t, J=7 Hz), 1.45-1.63 (4H, m), 1.70-1.83 (2H, m), 1.95-2.08 (2H, m), 2.14-2.28 (2H, m), 2.42 (3H, s), 2.46-2.60 (1H, m), 2.60-2.75 (1H, m), 3.03 (2H, q, J=7 Hz), 3.42-3.54 (1H, m), 4.72 (2H, m), 5.87 (1H, d, J=4 Hz), 6.54 (1H, d, J=4 Hz), 7.55 (1H, s), 8.41 (1H, s), 8.53 (1H, s). MS (ESI−): m/z 448, MS (ESI+): m/z 450.
EXAMPLE 358
5-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (CDCl3) δ 1.18-1.60 (10H, m), 1.36 (3H, t, J=7 Hz), 1.70-1.80 (2H, m), 1.95-2.05 (2H, m), 2.22 (2H, t, J=7 Hz), 2.50-2.70 (2H, m), 3.03 (2H, q, J=7 Hz), 3.42-3.53 (1H, m), 4.68 (2H, s), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.88 (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 1.20-1.45 (5H, m), 1.37 (3H, t, J=7 Hz), 1.50-1.60 (1H, m), 1.72-1.84 (2H, m), 1.96-2.08 (2H, m), 2.42 (3H, s), 2.48-2.62 (2H, m), 2.80-3.10 (2H, m), 3.03 (2H, q, J=7 Hz), 3.44-3.66 (1H, m), 4.73 (2H, s), 5.88 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.55 (1H, s), 8.40 (1H, s), 8.51 (1H, s). MS (ESI+): m/z 422.
EXAMPLE 360
3-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}propanoic acid
1H NMR (CDCl3) δ 1.18-1.47 (5H, m), 1.37 (3H, t, J=7 Hz), 1.52-1.63 (1H, m), 1.72-1.85 (2H, m), 1.97-2.07 (2H, m), 2.48-2.62 (2H, m), 2.80-3.10 (2H, m), 3.03 (2H, q, J=7 Hz), 3.44-3.57 (1H, m), 4.73 (2H, s), 5.91 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.88 (1H, t, J=2 Hz), 8.55 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz). MS (ESI−): m/z 484 486, MS (ESI+): m/z 486 488.
EXAMPLE 361
5-[7-ethyl-2-(isopropoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.25 (6H, d, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.44-1.63 (4H, m), 2.15-2.27 (2H, m), 2.43 (3H, s), 2.47-2.60 (1H, m), 2.60-2.73 (1H, m), 3.03 (2H, q, J=7 Hz), 3.75-3.87 (1H, m), 4.67 (2H, s), 5.87 (1H, d, J=4 Hz), 6.56 (1H, d, J=4 Hz), 7.55 (1H, s), 8.41 (1H, s), 8.53 (1H, s). MS (ESI−): m/z 408, MS (ESI+): m/z 410.
EXAMPLE 362
5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isopropoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.25 (6H, d, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.23 (2H, t, J=7 Hz), 2.50-2.60 (2H, m), 3.03 (2H, q, J=7 Hz), 3.75-3.85 (1H, m), 4.66 (2H, s), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.89 (1H, m), 8.54 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz). MS (ESI+): m/z 474 476.
EXAMPLE 363
5-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.40-1.65 (4H, m), 2.22 (2H, t, J=7 Hz), 2.33-2.45 (2H, m), 2.43 (3H, s), 3.03 (2H, q, J=7 Hz), 4.87 (2H, s), 5.94 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.56 (1H, s), 8.43 (1H, s), 8.54 (1H, s). MS (ESI−): m/z 366, MS (ESI+): m/z 368.
EXAMPLE 364
5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[2-(4-morpholinyl)-2-oxoethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 2.22 (2H, t, J=7 Hz), 2.43 (3H, s), 2.50-2.72 (2H, m), 3.03 (2H, q, J=7 Hz), 3.51 (2H, m), 3.57-3.75 (6H, m), 4.32 (2H, s), 4.70-4.86 (2H, m), 5.90 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 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-oxoethoxy]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.40-1.65 (4H, m), 2.22 (2H, t, J=7 Hz), 2.44 (3H, s), 2.45-2.64 (2H, m), 2.87 (3H, m), 3.03 (2H, q, J=7 Hz), 4.13 (2H, s), 4.74 (2H, m), 5.93 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 6.83 (1H, br), 7.57 (1H, s), 8.42 (1H, s), 8.53 (1H, s). MS (ESI−): m/z 437, MS (ESI+): m/z 439.
EXAMPLE 366
5-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 0.23-0.33 (2H, m), 0.55-0.64 (2H, m), 1.07-1.22 (1H, m), 1.36 (3H, t, J=7 Hz), 1.45-1.68 (4H, m), 2.19 (2H, t, J=7 Hz), 2.43 (3H, s), 2.50-2.75 (2H, m), 3.02 (2H, q, J=7 Hz), 3.40 (2H, d, J=7 Hz), 4.70 (2H, m), 5.87 (1H, d, J=4 Hz), 6.56 (1H, d, J=4 Hz), 7.57 (1H, s), 8.40 (1H, s), 8.54 (1H, s). MS (ESI+): m/z 422.
EXAMPLE 367
5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 0.87-1.04 (2H, m), 1.10-1.82 (13H, m), 1.37 (3H, t, J=7 Hz), 2.18 (2H, t, J=7 Hz), 2.43 (3H, s), 2.47-2.72 (2H, m), 3.03 (2H, q, J=7 Hz), 3.33 (2H, d, J=7 Hz), 4.63 (2H, m), 5.87 (1H, d, J=4 Hz), 6.56 (1H, d, J=4 Hz), 7.56 (1H, s), 8.42 (1H, s), 8.53 (1H, s). MS (ESI−): m/z 462, MS (ESI+): m/z 464.
EXAMPLE 368
5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.35-1.57 (4H, m), 2.13 (2H, t, J=7 Hz), 2.42 (3H, s), 2.47-2.66 (2H, m), 3.03 (2H, q, J=7 Hz), 4.68 (2H, s), 4.77 (2H, m), 5.90 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.28-7.36 (1H, m), 7.53 (1H, s), 7.73 (1H, d, J=8 Hz), 8.41 (1H, d, J=2 Hz), 8.53 (2H, m), 8.63 (1H, s). MS (ESI−): m/z 457, MS (ESI+): m/z 459.
EXAMPLE 369
5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.23 (2H, t, J=7 Hz), 2.41 (3H, s), 2.48-2.74 (2H, m), 3.03 (2H, q, J=7 Hz), 4.80 (2H, s), 4.82 (2H, m), 5.88 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.26 (1H, m), 7.47-7.53 (2H, m), 7.69-7.77 (1H, m), 8.42 (1H, d, J=2 Hz), 8.50 (1H, d, J=2 Hz), 8.58 (1H, d, J=7 Hz). MS (ESI−): m/z 457, MS (ESI+): m/z 459.
EXAMPLE 370
5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-]pyridazin-3-yl}pentanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.40-1.62 (4H, m), 2.16 (2H, t, J=7 Hz), 2.43 (3H, s), 2.48-2.71 (2H, m), 3.02 (2H, q, J=7 Hz), 4.68 (2H, s), 4.79 (2H, m), 5.91 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.32 (2H, d, J=7 Hz), 7.54 (1H, s), 8.42 (1H, d, J=2 Hz), 8.54 (1H, d, J=2 Hz), 8.55 (2H, d, J=7 Hz). MS (ESI−): m/z 457, MS (ESI+): m/z 459.
EXAMPLE 371
5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.45-1.62 (4H, m), 2.18 (2H, t, J=7 Hz), 2.43 (3H, s), 2.48-2.73 (2H, m), 3.03 (2H, q, J=7 Hz), 4.83 (2H, s), 4.88 (2H, m), 5.90 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.54 (1H, s), 8.42 (1H, s), 8.48-8.56 (3H, m), 8.76 (1H, s). MS (ESI−): m/z 458, MS (ESI+): m/z 460.
EXAMPLE 372
5-[2-[(benzylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (DMSO-d6) δ 1.33 (3H, t, J=7 Hz), 1.28-1.48 (4H, m), 2.03-2.13 (2H, m), 2.30-2.45 (2H, m), 2.40 (3H, s), 3.06 (2H, q, J=7 Hz), 4.37 (2H, s), 4.46 (2H, s), 5.92 (1H, d, J=4 Hz), 6.68 (1H, d, J=4 Hz), 7.40-7.52 (3H, m), 7.56-7.67 (3H, m), 8.36 (1H, d, J=2 Hz), 8.57 (1H, d, J=2 Hz). MS (ESI+): m/z 457.
EXAMPLE 373
5-[2-[(acetylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.40 (3H, t, J=7 Hz), 1.40-1.64 (4H, m), 2.16 (3H, s), 2.23 (2H, t, J=7 Hz), 2.35-2.50 (2H, m), 2.43 (3H, s), 3.03 (2H, q, J=7 Hz), 4.63-4.72 (2H, m), 5.92 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 6.88-6.97 (1H, br), 7.53 (1H, s), 8.41 (1H, s), 8.53 (1H, s). MS (ESI−): m/z 407, MS (ESI+): m/z 409.
EXAMPLE 374
5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(methylsulfonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.46-1.66 (4H, m), 2.23 (2H, t, J=7 Hz), 2.44 (3H, s), 2.39-2.53 (2H, m), 3.03 (2H, q, J=7 Hz), 3.05 (3H, s), 4.57 (2H, s), 5.72 (1H, br), 5.96 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.54 (1H, s), 8.41 (1H, d, J=2 Hz), 8.55 (1H, d, J=2 Hz). MS (ESI−): m/z 443, MS (ESI+): m/z 445.
EXAMPLE 375
5-[2-[(benzoylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.42 (3H, t, J=7 Hz), 1.50-1.68 (4H, m), 2.25 (2H, t, J=7 Hz), 2.44 (3H, s), 2.40-2.60 (2H, m), 3.07 (2H, q, J=7 Hz), 4.89 (2H, m), 5.95 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.46-7.60 (4H, m), 7.83 (1H, br), 7.93 (2H, d, J=8 Hz), 8.44 (1H, d, J=2 Hz), 8.56 (1H, d, J=2 Hz). MS (ESI−): m/z 469, MS (ESI+): m/z 471.
EXAMPLE 376
5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(2-pyrazinylcarbonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoic acid
1H NMR (CDCl3) δ 1.41 (3H, t, J=7 Hz), 1.51-1.72 (4H, m), 2.24 (2H, t, J=7 Hz), 2.44 (3H, s), 2.45-2.58 (2H, m), 3.10 (2H, q, J=7 Hz), 4.90 (2H, m), 5.94 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.55 (1H, s), 8.43 (1H, s), 8.53 (1H, s), 8.62 (1H, m), 8.79 (1H, d, J=2 Hz), 9.20 (1H, br), 9.45 (1H, d, J=2 Hz). MS (ESI−): m/z 471, MS (ESI+): m/z 473.
EXAMPLE 377
5-[7-ethyl-2-{[(methoxycarbonyl)amino]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.23 (2H, t, J=7 Hz), 2.40-2.53 (2H, m), 2.44 (3H, s), 3.02 (2H, q, J=7 Hz), 3.05 (3H, s), 4.58 (2H, s), 5.69 (1H, br), 5.96 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.53 (1H, s), 8.41 (1H, d, J=2 Hz), 8.54 (1H, d, J=2 Hz).
EXAMPLE 378
To a solution of ethyl 7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (682 mg) in ethanol (20 mL) was added potassium hydroxide (5 g) solution (10 mL) and the mixture was heated under reflux for 1 hour. The solution was acidified with 1 N hydrochloric acid to pH 3-4 and diluted with brine, and extracted with chloroform twice. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The crude product was triturated with ethyl acetate to give 7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid as a yellow powder (590 mg)
7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid
1H NMR (CDCl3) δ 1.39 (3H, t, J=7 Hz), 2.44 (3H, s), 2.69 (3H, s), 3.05 (2H, q, J=7 Hz), 6.29 (1H, d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 7.97 (1H, s), 8.41 (1H, s), 8.58 (1H, s). MS (ESI−): m/z 294, MS (ESI+): m/z 296.
The following compound(s) was (were) obtained in substantially the same manner as that of Example 175.
EXAMPLE 379
5-[4-(3-cyanophenyl)-2-(ethoxymethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.34-1.53 (7H, m), 2.20 (2H, t, J=7 Hz), 2.53 (2H, m), 3.03 (2H, q, J=7 Hz), 3.62 (2H, q, J=7 Hz), 4.66 (2H, s), 5.33 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.60 (2H, m), 7.66 (1H, s), 7.74 (1H, m)
EXAMPLE 380
5-[2-[(benzyloxy)methyl]-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.30-1.46 (7H, m), 2.11 (2H, t, J=7 Hz), 2.50 (2H, m), 3.02 (2H, q, J=7 Hz), 4.64 (3H, s), 4.71 (3H, s), 5.83 (1H, d, J=5 Hz), 6.56 (1H, d, J=5 Hz), 7.25-7.34 (5H, m), 7.57 (2H, d, J=9 Hz), 7.65 (1H, s), 7.74 (1H, m). MS (ESI+): m/z 468 (M+H)
EXAMPLE 381
4-({[3-(4-carboxybutyl)-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methoxy}methyl)benzoic acid
1H-NMR (CDCl3) δ 1.05-1.43 (7H, m), 1.92 (2H, m), 2.31 (2H, m), 3.04 (2H, m), 4.65 (2H, s), 4.72 (2H, s), 5.82 (1H, m), 6.58 (1H, m), 7.46-7.77 (6H, m), 8.09 (2H, d, J=8 Hz). MS (ESI+): m/z 510 (M−H)
EXAMPLE 381-2
4-({[4-[3-(carbamoyl)phenyl]-3-(4-carboxybutyl)-7-ethylpyrrolo[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, q, J=7 Hz), 4.69 (2H, s), 4.73 (2H, s), 5.36 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.39-7.60 (4H, m), 7.77 (1H, s), 7.93 (1H, d, J=8 Hz), 7.98 (2H, d, J=8 Hz). MS (ESI+): m/z 528 (M−H)
The following compound(s) was (were) obtained in substantially the same manner as that of Example 77.
EXAMPLE 382
5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-methyl-1-piperazinyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (CDCl3) δ 1.34 (3H, t, J=7 Hz), 1.38-1.59 (4H, m), 2.22 (2H, m), 2.43-2.60 (5H, m), 2.83-3.04 (8H, m), 3.74 (3H, s), 5.88 (1H, d, J=5 Hz), 6.56 (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-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.35-1.60 (7H, m), 2.27 (2H, m), 2.46 (2H, m), 3.03 (2H, q, J=7 Hz), 3.98 (2H, s), 3.97 (1H, d, J=5 Hz), 6.65 (1H, d, J=5 Hz), 7.90 (1H, m), 8.54 (1H, s, br), 8.79 (1H, s, br).
EXAMPLE 384
5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.35-1.60 (7H, m), 2.22 (2H, t, J=7 Hz), 2.38 (2H, m), 3.02 (2H, q, J=7 Hz), 4.86 (2H, s), 5.95 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.88 (1H, m), 8.54 (1H, s, br), 8.79 (1H, s, br).
EXAMPLE 385
To a solution of 7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid (70 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (68.2 mg) and 1-hydroxybenotriazole (48 mg) in dimethylformamide (2 mL) was added 2-aminoethanol (17.4 mg) and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (50:1-10:1). The crude product was triturated with isopropylether to give 7-ethyl-N-(2-hydroxyethyl)-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxamide as a yellow powder (47 mg).
7-ethyl-N-(2-hydroxyethyl)-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxamide
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 2.39 (3H, s), 2.57 (3H, s), 3.02 (2H, q, J=7 Hz), 3.33 (2H, m), 3.45 (2H, m), 6.03 (1H, br), 6.31 (1H, d, J=4 Hz), 6.66 (1H, d, J=4 Hz), 7.71 (1H, s), 8.47 (1H, s), 8.58 (1H, s). MS (ESI−): m/z 337, MS (ESI+): m/z 339.
The following compound(s) was (were) obtained in substantially the same manner as that of Example 385.
EXAMPLE 386
N-butyl-7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxamide
1H NMR (CDCl3) δ 0.80 (3H, t, J=7 Hz), 0.96-1.08 (2H, m), 1.08-1.25 (2H, m), 1.38 (3H, t, J=7 Hz), 2.40 (3H, s), 2.56 (3H, s), 3.03 (2H, q, J=7 Hz), 3.16 (2H, m), 5.36 (1H, br), 6.31 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.69 (1H, s), 8.53 (1H, s), 8.62 (1H, s). MS (ESI+): m/z 351.
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 1.24 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.21 (2H, t, J=7 Hz), 2.40 (3H, s), 2.55 (3H, s), 3.03 (2H, q, J=7 Hz), 3.43 (2H, q, J=7 Hz), 4.04 (2H, q, J=7 Hz), 6.08 (1H, br), 6.30 (1H, d, J=4 Hz), 6.65 (1H, d, J=4 Hz), 7.67 (1H, s), 8.50 (1H, d, J=1 Hz), 8.60 (1H, d, J=1 Hz). MS (ESI+): m/z 395.
The following compound(s) was (were) obtained in substantially the same manner as that of Preparation 176.
EXAMPLE 388
4-(5-bromo-3-pyridinyl)-7-ethyl-2-methyl-3-[3-(4-morpholinyl)-3-oxopropyl]pyrrolo[1,2-b]pyridazine
1H NMR(CDCl3) δ: 1H NMR(CDCl3) δ: 1.37(3H, t, J=7 Hz), 2.41(2H, t, J=7 Hz), 2.60(3H, s), 2.72-2.82(2H, m), 3.01(2H, q, J=7 Hz), 3.19(2H, t, J=5 Hz), 3.55(4H, t, J=5 Hz), 3.63(2H, t, J=5 Hz), 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(bp) mp. 178-180° C.
EXAMPLE 389
3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-N-methylpropanamide
1H NMR(CDCl3) δ: 1H NMR(CDCl3) δ: 1.38(3H, t, J=7 Hz), 2.20(2H, t, J=7 Hz), 2.60(3H, s), 2.75(3H, d, J=6 Hz), 2.78-2.89(2H, m), 3.01(2H, q, J=7 Hz), 5.21-5.27(1H, m), 5.88(1H, d, J=4 Hz), 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(bp) mp. 172-174° C.
The following compound(s) was (were) obtained in substantially the same manner as that of Example 263.
EXAMPLE 390
N-{3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoyl}methanesulfonamide
1H NMR(CDCl3) δ: 1.36(3H, t, J=7 Hz), 2.33-2.45(2H, m), 2.58(3H, s), 2.84-2.95(2H, m), 3.01(2H, q, J=7 Hz), 3.26(3H, s), 5.89(1H, d, J=4 Hz), 6.56(1H, d, J=4 Hz), 7.90(1H, s), 8.50(1H, s), 8.77(1H, s) MS (m/z) 465(M+, bp), 467(M+−2, bp) mp. 196.5-197.5° C.
The following compound(s) was (were) obtained in substantially the same manner as that of Example 224.
EXAMPLE 391
2-[{3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoyl}(methyl)amino]ethanesulfonic acid
1H NMR (CDCl3) δ 1.32 (3H, t, J=7 Hz), 1.90 2H, m), 2.26 (3H, s), 2.57-2.2.78 (4H, m), 2.98 (2H, q, J=7 Hz), 3.31 (2H, m), 6.00 (1H, d, J=5 Hz), 6.61 (1H, d, J=5 Hz), 7.20-7.52 (5H, m).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 20.
Preparation 217
1-tert-butyl 7-ethyl 2-(isobutoxyacetyl)heptanedioate
1H NMR (300 MHz, CDCl3) δ 0.95 (6H, d, J=7 Hz), 1.27 (3H, t, J=7 Hz), 1.31-1.41 (2H, m), 1.46 (9H, s), 1.66 (2H, tt, J=7, 7 Hz), 1.75-1.98 (3H, m), 2.31 (2H, t, J=8 Hz), 3.26 (2H, d, J=7 Hz), 3.56 (1H, t, J=7 Hz), 4.06-4.17 (4H, m).
Preparation 218
1-tert-butyl 6-ethyl 2-(isobutoxyacetyl)hexanedioate
1H NMR (300 MHz, CDCl3) δ 0.93 (6H, d, J=7 Hz), 1.25 (3H, t, J=7 Hz), 1.45 (9H, s), 1.59-1.69 (2H, m), 1.80-1.95 (3H, m), 2.32 (2H, t, J=7 Hz), 2.25 (2H, d, J=7 Hz), 3.57 (1H, t, J=7 Hz), 4.10 (2H, s), 4.12 (2H, q, J=7 Hz).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 24.
Preparation 219
1-tert-butyl 6-ethyl 2-acetyl-2-(2-chloroisonicotinoyl)hexanedioate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7 Hz), 1.34 (9H, s), 1.60-1.73 (2H, m), 2.22-2.32 (2H, m), 2.39 (2H, t, J=7 Hz), 2.49 (3H, s), 4.12 (2H, q, J=7 Hz), 7.43 (1H, d, J=5 Hz), 7.57 (1H, s), 8.50 (1H, d, J=5 Hz). MS (ESI+): m/z 412.
Preparation 220
1-tert-butyl 5-ethyl 2-acetyl-2-(2-chloroisonicotinoyl)pentanedioate
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.72-1.84 (2H, m), 2.33 (2H, t, J=7 Hz), 2.47-2.57 (2H, m), 2.58 (3H, s), 3.03 (2H, q, J=7 Hz), 5.88 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.27 (1H, m), 7.38 (1H, s), 8.53 (1H, d, J=5 Hz). MS (ESI−): m/z 356, MS (ESI+): m/z 358.
Preparation 221
1-tert-butyl 7-ethyl 2-(2-chloroisonicotinoyl)-2-(phenylacetyl)heptanedioate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.35 (9H, s), 1.63-1.76 (2H, m), 2.22-2.37 (4H, m), 3.93 (1H, d, J=17 Hz), 4.12 (2H, q, J=7 Hz), 4.29 (1H, d, J=17 Hz), 7.22 (2H, d, J=8 Hz), 7.26-7.36 (4H, m), 7.50 (1H, s), 8.42 (1H, d, J=5 Hz). MS (ESI+): m/z 502.
Preparation 222
tert-butyl 2-[2-(2-methoxy-2-oxoethoxy)ethyl]-2-[(5-methyl-3-pyridinyl)carbonyl]-3-oxobutanoate
1H NMR (CDCl3) δ 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), 8.75 (1H, s). MS (ESI+): m/z 394.
Preparation 223
1-tert-butyl 4-ethyl 2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]succinate
1H NMR (CDCl3) δ 1.27 (3H, t, J=7 Hz), 1.41 (9H, s), 2.45 (3H, s), 3.22 (2H, m), 4.12 (2H, q, J=7 Hz), 8.22 (1H, m), 8.80 (1H, m), 8.82 (1H, m). MS (ESI+): m/z 428 430.
Preparation 224
1-tert-butyl 5-ethyl 2-[(acetyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.35 (9H, s), 2.14 (3H, s), 2.40 (3H, s), 2.40-2.48 (2H, m), 2.62-2.70 (2H, m), 4.12 (2H, q, J=7 Hz), 5.12 (1H, d, J=18 Hz), 5.34 (1H, d, J=18 Hz), 7.85 (1H, s), 8.58 (1H, s), 8.78 (1H, s). MS (ESI+): m/z 436.
Preparation 225
1-tert-butyl 6-ethyl 2-[(acetyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]hexanedioate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.34 (9H, s), 1.60-1.75 (2H, m), 2.14 (3H, s), 2.26-2.39 (4H, m), 2.40 (3H, s), 4.12 (2H, q, J=7 Hz), 5.13 (1H, d, J=18 Hz), 5.40 (1H, d, J=18 Hz), 7.86 (1H, s), 8.57 (1H, s), 8.78 (1H, s). MS (ESI+): m/z 450.
Preparation 226
1-tert-butyl 7-ethyl 2-[(acetyloxy)acetyl]-2-(3-cyanobenzoyl)heptanedioate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.32 (9H, s), 1.26-1.46 (2H, m), 1.66-1.77 (2H, m), 2.14 (3H, s), 2.26-2.38 (4H, m), 4.12 (2H, q, J=7 Hz), 5.06 (1H, d, J=18 Hz), 5.42 (1H, d, J=18 Hz), 7.57 (1H, t, J=8 Hz), 7.81 (1H, d, J=8 Hz), 7.92 (1H, d, J=8 Hz), 8.09 (1H, s).
Preparation 227
1-tert-butyl 6-ethyl 2-[(acetyloxy)acetyl]-2-[(5-bromo-3-pyridinyl)carbonyl]hexanedioate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.36 (9H, s), 1.60-1.74 (2H, m), 1.85-1.96 (2H, m), 2.14 (3H, s), 2.28-2.42 (2H, m), 4.12 (2H, q, J=7 Hz), 5.12 (1H, d, J=17 Hz), 5.42 (1H, d, J=17 Hz), 8.23 (1H, m), 8.81 (1H, m), 8.83 (1H, m).
Preparation 228
1-tert-butyl 5-ethyl 2-[(acetyloxy)acetyl]-2-[(5-bromo-3-pyridinyl)carbonyl]pentanedioate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.37 (9H, s), 2.14 (3H, s), 2.41-2.51 (2H, m), 2.66 (2H, t, J=7 Hz), 4.13 (2H, q, J=7 Hz), 5.11 (1H, d, J=18 Hz), 5.33 (1H, d, J=18 Hz), 8.22 (1H, m), 8.82 (2H, m). MS (ESI+): m/z 500 502.
Preparation 229
1-tert-butyl 5-ethyl 2-[(cyclohexylmethoxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate
1H NMR (CDCl3) δ 0.80-0.98 (2H, m), 1.00-1.32 (3H, m), 1.23 (3H, t, J=7 Hz), 1.38 (9H, s), 1.46-1.62 (6H, m), 2.39 (3H, s), 2.40-2.72 (4H, m), 3.19 (2H, d, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.31 (1H, d, J=17 Hz), 4.39 (1H, d, J=17 Hz), 7.88 (1H, s), 8.56 (1H, s), 8.77 (1H, s). MS (ESI+): m/z 490.
Preparation 230
1-tert-butyl 5-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(cyclohexylmethoxy)acetyl]pentanedioate
1H NMR (CDCl3) δ 0.78-0.98 (2H, m), 1.10-1.33 (3H, m), 1.25 (3H, t, J=7 Hz), 1.40 (9H, s), 1.38-1.83 (6H, m), 2.35-2.75 (4H, m), 3.22 (2H, d, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.25 (1H, d, J=17 Hz), 4.37 (1H, d, J=17 Hz), 8.22 (1H, s), 8.78 (1H, s), 8.86 (1H, s). MS (ESI+): m/z 554 556.
Preparation 231
1-tert-butyl 6-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(cyclohexylmethoxy)acetyl]hexanedioate
1H NMR (CDCl3) δ 0.80-0.97 (2H, m), 1.12-1.35 (3H, m), 1.25 (3H, t, J=7 Hz), 1.39 (9H, s), 1.46-1.80 (10H, m), 2.22-2.45 (2H, m), 3.20 (2H, d, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.30 (1H, d, J=17 Hz), 4.38 (1H, d, J=17 Hz), 8.22 (1H, s), 8.78 (1H, s), 8.85 (1H, s). MS (ESI+): m/z 568 570.
Preparation 232
1-tert-butyl 6-ethyl 2-[(cyclopropylmethoxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]hexanedioate
1H NMR (CDCl3) δ 0.16-0.28 (2H, m), 0.48-0.59 (2H, m), 0.98-1.12 (1H, m), 1.24 (3H, t, J=7 Hz), 1.37 (9H, s), 1.55-1.80 (4H, m), 2.18-2.40 (2H, m), 2.39 (3H, s), 3.31 (2H, m), 4.12 (2H, q, J=7 Hz), 4.38 (1H, d, J=17 Hz), 4.53 (1H, d, J=17 Hz), 7.88 (1H, s), 8.55 (1H, d, J=2 Hz), 8.75 (1H, d, J=2 Hz). MS (ESI+): m/z 462.
Preparation 233
1-tert-butyl 5-ethyl 2-[(cyclopropylmethoxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate
1H NMR (CDCl3) δ 0.15-0.23 (2H, m), 0.48-0.56 (2H, m), 0.95-1.10 (1H, m), 1.24 (3H, t, J=7 Hz), 1.39 (9H, s), 2.39 (3H, s), 2.40-2.68 (4H, m), 3.28 (2H, m), 4.12 (2H, q, 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), 8.75 (1H, s). MS (ESI+): m/z 448.
Preparation 234
1-tert-butyl 5-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(2-methoxyethoxy)acetyl]pentanedioate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7 Hz), 1.46 (9H, s), 2.15-2.25 (2H, m), 2.42-2.72 (2H, m), 3.38 (3H, s), 3.48-3.72 (4H, m), 4.12 (2H, q, J=7 Hz), 4.43 (1H, d, J=17 Hz), 4.58 (1H, d, J=17 Hz), 8.22 (1H, s), 8.78 (1H, s), 8.82 (1H, s). MS (ESI+): m/z 516 518.
Preparation 235
tert-butyl 2-[(5-bromo-3-pyridinyl)carbonyl]-3-oxobutanoate
1H NMR (CDCl3) δ 1.22, 1.30 (9H, s), 2.22, 2.45 (3H, s), 7.96, 8.13 (1H, s), 8.66, 8.76-8.80 (2H, m).
Preparation 236
1-tert-butyl 6-ethyl 2-[(acetyloxy)acetyl]-2-[(5-chloro-3-pyridinyl)carbonyl]hexanedioate
1H NMR (300 MHz, CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.36 (9H, s), 1.63-1.71 (2H, m), 2.14 (3H, s), 2.27-2.40 (4H, m), 4.13 (2H, q, J=7 Hz), 5.11 (1H, d, J=18 Hz), 5.38 (1H, d, J=18 Hz), 8.07 (1H, dd, J=2 Hz), 8.71 (1H, d, J=2 Hz), 8.80 (1H, d, J=2 Hz).
Preparation 237
1-tert-butyl 7-ethyl 2-[(5-chloro-3-pyridinyl)carbonyl]-2-[(cyclopropylmethoxy)acetyl]heptanedioate
1H NMR (300 MHz, CDCl3) δ 0.15-0.20 (2H, m), 0.49-0.58 (2H, m), 0.95-1.04 (1H, m), 1.24 (3H, t, J=7 Hz), 1.38 (9H, s), 1.68 (2H, tt, J=7, 7 Hz), 2.14-2.33 (4H, m), 3.26-3.29 (2H, m), 4.07-4.19 (4H, m), 4.31 (1H, d, J=17 Hz), 4.45 (1H, d, J=17 Hz), 8.05 (1H, dd, J=2 Hz), 8.68 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).
Preparation 238
1-tert-butyl 6-ethyl 2-[(5-chloro-3-pyridinyl)carbonyl]-2-[(cyclopropylmethoxy)acetyl]hexanedioate
1H NMR (300 MHz, CDCl3) δ 0.14-0.21 (2H, m), 0.49-0.55 (2H, m), 0.92-1.04 (1H, m), 1.25 (3H, t, J=7 Hz), 1.39 (9H, s), 1.62-1.74 (2H, m), 1.82-1.90 (2H, m), 2.21-2.33 (2H, m), 3.27-3.31 (2H, m), 4.12 (2H, q, 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).
Preparation 239
1-tert-butyl 7-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2-(isobutoxyacetyl)heptanedioate
1H NMR (300 MHz, CDCl3) δ 0.85 (6H, d, J=7 Hz), 1.24 (3H, t, J=7 Hz), 1.38 (9H, s), 1.67 (2H, t, J=7 Hz), 1.75-1.93 (3H, m), 2.24-2.33 (4H, m), 3.17 (2H, d, J=7 Hz), 4.11 (2H, q, J=7 Hz), 4.28 (1H, d, J=17 Hz), 4.38 (1H, d, J=17 Hz), 8.20 (1H, dd, J=2, 2 Hz), 8.79 (1H, d, J=2 Hz), 8.84 (1H, d, J=2 Hz).
Preparation 240
1-tert-butyl 5-ethyl 2-[(5-chloro-3-pyridinyl)carbonyl]-2-(isobutoxyacetyl)pentanedioate
1H NMR (300 MHz, CDCl3) δ 0.84 (6H, d, J=7 Hz), 1.24 (3H, t, J=7 Hz), 1.39 (9H, s), 1.80 (1H, qt, J=7 Hz), 2.34-2.71 (4H, m), 3.17 (2H, d, J=7 Hz), 4.12 (2H, q, 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).
Preparation 241
1-tert-butyl 5-ethyl 2-[(acetyloxy)acetyl]-2-(3-chlorobenzoyl)pentanedioate
1H NMR (300 MHz, CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.34 (9H, s), 2.14 (3H, s), 2.35-2.44 (2H, m), 2.60-2.68 (2H, m), 4.11 (2H, q, J=7 Hz), 5.11 (1H, d, J=18 Hz), 5.35 (1H, d, J=18 Hz), 7.38 (1H, dd, J=8, 8 Hz), 7.53 (1H, d, J=8 Hz), 7.60 (1H, d, J=8 Hz), 7.79 (1H, s).
Preparation 242
1-tert-butyl 6-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2-(isobutoxyacetyl)hexanedioate
1H NMR (300 MHz, CDCl3) δ 0.85 (6H, d, J=7 Hz), 1.25 (3H, t, J=7 Hz), 1.39 (9H, s), 1.59-1.72 (2H, m), 1.80 (1H, qt, J=7, 7 Hz), 2.19-2.39 (4H, m), 3.18 (2H, d, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.31 (1H, d, J=17 Hz), 4.40 (1H, d, J=17 Hz), 8.22(1H, dd, J=2, 2 Hz), 8.79(1H, d, J=2 Hz), 8.85(1H, d, J=2 Hz).
Preparation 243
tert-butyl 3-(5-bromo-3-pyridinyl)-2-[(5-bromo-3-pyridinyl)carbonyl]-3-oxopropanoate
1H NMR (CDCl3) δ 1.05 (9H, s), 7.86 (2H, s), 8.46 (2H, s), 8.61 (2H, s). MS (ESI−): m/z 481 483 485.
Preparation 244
1-tert-butyl 6-ethyl 2-[(acetyloxy)acetyl]-2-(3-chlorobenzoyl)hexanedioate
1H NMR (CDCl3) δ 1.24 (3H, t, J=8 Hz), 1.33 (9H, s), 1.56-1.72 (2H, m), 2.15 (3H, s), 2.20-2.41 (4H, m), 4.11 (2H, q, J=8 Hz), 5.13 (1H, d, J=18 Hz), 5.40 (1H, d, J=18 Hz), 738(1H, t, J=8 Hz), 752(1H, br d, J=8 Hz), 7.60 (1H, br d, J=8 Hz), 7.79 (1H, br s).
Preparation 245
b 1-tert-butyl 7-ethyl 2-(methoxyacetyl)-2-[(5-methoxy-3-pyridinyl)carbonyl]heptanedioate
1H NMR (CDCl3) δ 1.23 (3H, t, J=8 Hz), 1.27-1.43 (11H, m), 1.60-1.74 (2H, m), 2.15-2.34 (4H, m), 3.37 (3H, s), 3.90 (3H, s), 4.10 (2H, q, J=8 Hz), 4.35 (1H, d, J=18 Hz), 4.48 (1H, d, J=18 Hz), 7.58 (1H, m), 8.43 (1H, d, J=3 Hz), 8.50 (1H, d, J=1 Hz). MS (ESI+): m/z 452 (M+H).
Preparation 246
1-tert-butyl 7-ethyl 2-acetyl-2-[(5-methoxy-3-pyridinyl)carbonyl]heptanedioate
1H NMR (CDCl3) δ 1.24 (3H, t, J=8 Hz), 1.27-1.40 (11H, m), 1.60-1.74 (2H, m), 2.15-2.34 (4H, m), 2.44 (3H, s), 3.89 (3H, s), 4.10 (2H, q, J=8 Hz), 7.61 (1H, m), 8.43 (1H, d, J=3 Hz), 8.49 (1H, d, J=1 Hz). MS (ESI+): m/z 422 (M+H).
Preparation 247
1-tert-butyl 5-ethyl 2-(methoxyacetyl)-2-[(5-methoxy-3-pyridinyl)carbonyl]pentanedioate
1H NMR (CDCl3) δ 1.24 (3H, t, J=8 Hz), 1.38 (9H, s), 2.36-2.48 (2H, m), 2.53-2.67 (2H, m), 3.37 (3H, s), 3.90 (3H, s), 4.11 (2H, q, J=8 Hz), 4.33 (1H, d, J=18 Hz), 4.45 (1H, d, J=18 Hz), 7.59 (1H, m), 8.43 (1H, d, J=3 Hz), 8.51 (1H, d, J=1 Hz). MS (ESI+): m/z 446 (M++Na).
Preparation 248
1-tert-butyl 6-ethyl 2-(methoxyacetyl)-2-[(5-methoxy-3-pyridinyl)carbonyl]hexanedioate
1H NMR (CDCl3) δ 1.24 (3H, t, J=8 Hz), 1.37 (9H, s), 1.52-1.75 (2H, m), 2.18-2.39 (4H, m), 3.38 (3H, s), 3.90 (3H, s), 4.11 (2H, q, J=8 Hz), 4.37 (1H, d, J=18 Hz), 4.51 (1H, d, J=18 Hz), 7.60 (1H, m), 8.43 (1H, d, J=3 Hz), 8.50 (1H, d, J=1 Hz). MS (ESI+): m/z 438 (M+H).
Preparation 249
1-tert-butyl 7-ethyl 2-(methoxyacetyl)-2-(5-pyrimidinylcarbonyl)heptanedioate
1H NMR (CDCl3) δ 1.24 (3H, t, J=8 Hz), 1.30-1.44 (11H, m), 1.62-1.75 (2H, m), 2.16-2.35 (4H, m), 3.35 (3H, s), 4.11 (2H, q, J=8 Hz), 4.20 (1H, d, J=18 Hz), 4.33 (1H, d, J=18 Hz), 9.01 (2H, s), 9.31 (1H, s). MS (ESI+): m/z 423 (M+H).
Preparation 250
1-tert-butyl 6-ethyl 2-[(5-chloro-3-pyridinyl)carbonyl]-2-(methoxyacetyl)hexanedioate
1H NMR (CDCl3) δ 1.26 (3H, t, J=8 Hz), 1.39 (9H, s), 1.57-1.74 (2H, m), 1.78 (2H, br t, J=8 Hz), 2.23-2.41 (2H, m), 3.38 (3H, s), 4.14 (2H, q, J=8 Hz), 4.33 (1H, d, J=18 Hz), 4.45 (1H, d, J=18 Hz), 8.07 (1H, m), 8.71 (1H, br s), 8.80 (1H, br s). MS (ESI+): m/z 442 (M+H).
Preparation 251
1-tert-butyl 5-ethyl 2-[(5-chloro-3-pyridinyl)carbonyl]-2-(methoxyacetyl)pentanedioate
1H NMR (CDCl3) δ 1.25 (3H, t, J=8 Hz), 1.39 (9H, s), 2.37-2.48 (2H, m), 2.53-2.65 (2H, m), 3.36 (3H, s), 4.13 (2H, q, J=8 Hz), 4.26 (1H, d, J=18 Hz), 4.40 (1H, d, J=18 Hz), 8.06 (1H, br s), 8.70 (1H, br s), 8.80 (1H, br s). MS (ESI+): m/z 428 (M+H).
Preparation 252
1-tert-butyl 7-ethyl 2-[(5-chloro-3-pyridinyl)carbonyl]-2-(methoxyacetyl)heptanedioate
1H NMR (CDCl3) δ 1.24 (3H, t, J=8 Hz), 1.31-1.48 (11H, m), 1.55-1.75 (2H, m), 2.15-2.35 (4H, m), 3.36 (3H, s), 4.10 (2H, q, J=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).
Preparation 253
methyl 4-(acetyloxy)-2-[(5-bromo-3-pyridinyl)carbonyl]-3-oxobutanoate
1H NMR (CDCl3) δ 2.21 (3H, s), 3.58 (3H, br s), 4.87 (1H, br s), 5.19 (2H, br s), 7.98 (1H, br s), 8.58 (1H, br s), 8.79 (1H, br s). MS (ESI+): m/z 358, 360 (M+H).
Preparation 254
tert-butyl 2-(2-{2-[2-(acetyloxy)ethoxy]ethoxy}ethyl)-2-[(5-methyl-3-pyridinyl)carbonyl]-3-oxobutanoate
1H-NMR (CDCl3) δ 1.32 (9H, s), 2.07 (3H, s), 2.38 (3H, s), 2.45 (3H, s), 2.57 (2H, t, J=7 Hz), 3.43 (4H, m), 3.57 (4H, m), 4.16 (2H, m), 7.84 (1H, m), 8.53 (1H, m), 8.75 (1H, m).
Preparation 255
1-tert-butyl 6-ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-2-(methoxyacetyl)hexanedioate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7 Hz), 1.39 (9H, s), 1.55-1.75 (2H, m), 2.23-2.45 (4H, m), 3.38 (3H, s), 4.12 (2H, q, J=7 Hz), 4.34 (1H, d, J=18 Hz), 4.47 (1H, d, J=18 Hz), 8.22 (1H, m), 8.81 (1H, d, J=2 Hz), 8.83 (1H, d, J=2 Hz). MS (ESI+): m/z 486 488.
Preparation 256
ethyl 2-(2-chloroisonicotinoyl)-3-oxobutanoate
1H NMR (CDCl3) δ 0.91-1.00 (3H, m), 2.24 (1.2H, s), 2.48 (1.8H, s), 4.02 (1.2H, q, J=8 Hz), 4.10 (0.8H, q J=8 Hz), 7.24 (0.6H, m), 7.39 (0.6H, s), 7.45 (0.4H, m), 7.54 (1H, s), 8.49 (1H, m). MS (ESI+): m/z 298 (M+H).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 78.
Preparation 257
ethyl 5-(2-chloroisonicotinoyl)-6-oxoheptanoate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.60-1.73 (2H, m), 1.98-2.10 (2H, m), 2.20 (3H, s), 2.35 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.37 (1H, t, J=7 Hz), 7.67 (1H, d, J=5 Hz), 7.77 (1H, s), 8.59 (1H, d, J=5 Hz). MS (ESI+): m/z 312.
Preparation 258
ethyl 4-(2-chloroisonicotinoyl)-5-oxohexanoate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7 Hz), 2.21 (3H, s), 2.22-2.35 (2H, m), 2.36-2.47 (2H, m), 4.12 (2H, q, J=7 Hz), 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.
Preparation 259
ethyl 6-(2-chloroisonicotinoyl)-7-oxo-8-phenyloctanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.20-1.38 (2H, m), 1.60-1.72 (2H, m), 1.95-2.06 (2H, m), 2.28 (2H, t, J=7 Hz), 3.71 (1H, d, J=17 Hz), 3.80 (1H, d, J=17 Hz), 4.12 (2H, q, J=7 Hz), 4.41 (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).
Preparation 260
methyl ({3-[(5-methyl-3-pyridinyl)carbonyl]-4-oxopentyl}oxy)acetate
1H NMR (CDCl3) δ 2.23 (3H, s), 2.23-2.40 (2H, m), 2.44 (3H, s), 3.58 (2H, m), 3.71 (3H, s), 4.02 (2H, s), 4.89 (1H, t, J=7 Hz), 8.12 (1H, s), 8.64 (1H, s), 9.07 (1H, s). MS (ESI+): m/z 294.
Preparation 261
methyl(4-oxo-4-phenylbutoxy)acetate
1H NMR (CDCl3) δ 2.04-2.16 (2H, m), 3.15 (2H, t, J=7 Hz), 3.64 (2H, t, J=7 Hz), 3.73 (3H, s), 4.09 (2H, s), 7.46 (2H, t, J=8 Hz), 7.56 (1H, t, J=8 Hz), 7.99 (2H, d, J=8 Hz). MS (ESI+): m/z 237.
The following compound(s) was (were) obtained in a similar manner to that of Preparation 78.
Preparation 262
ethyl 3-[(5-bromo-3-pyridinyl)carbonyl]-4-oxopentanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 2.22 (3H, s), 2.97-3.17 (2H, m), 4.12 (2H, q, J=7 Hz), 4.91 (1H, m), 8.41 (1H, m), 8.88 (1H, m), 9.12 (1H, m). MS (ESI+): m/z 328 330.
Preparation 263
ethyl 6-(acetyloxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.98 (3H, s), 2.23-2.34 (2H, m), 2.40-2.50 (2H, m), 2.45 (3H, s), 4.12 (2H, q, J=7 Hz), 4.69 (2H, m), 4.82 (1H, t, J=7 Hz), 8.14 (1H, s), 8.67 (1H, s), 9.07 (1H, s). MS (ESI+): m/z 336.
Preparation 264
ethyl 7-(acetyloxy)-5-[(5-methyl-3-pyridinyl)carbonyl]-6-oxoheptanoate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.60-1.80 (2H, m), 2.02 (3H, s), 1.97-2.13 (2H, m), 2.35 (2H, t, J=7 Hz), 2.45 (3H, s), 4.12 (2H, q, J=7 Hz), 4.56 (1H, t, J=7 Hz), 4.69 (1H, d, J=17 Hz), 4.78 (1H, d, J=17 Hz), 8.06 (1H, s), 8.66 (1H, s), 9.00 (1H, s). MS (ESI+): m/z 350.
Preparation 265
ethyl 8-(acetyloxy)-6-(3-cyanobenzoyl)-7-oxooctanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.35-1.50 (2H, m), 1.60-1.78 (2H, m), 2.04 (3H, s), 2.00-2.12 (2H, m), 2.29 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.49 (1H, t, J=7 Hz), 4.68 (1H, d, J=17 Hz), 4.75 (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), 8.26 (1H, s). MS (ESI−): m/z 372.
Preparation 266
ethyl 7-(acetyloxy)-5-[(5-bromo-3-pyridinyl)carbonyl]-6-oxoheptanoate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.60-1.82 (2H, m), 2.04 (3H, s), 2.03-2.15 (2H, m), 2.35 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.51 (1H, t, J=7 Hz), 4.70 (1H, d, J=17 Hz), 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.
Preparation 267
ethyl 6-(acetyloxy)-4-[(5-bromo-3-pyridinyl)carbonyl]-5-oxohexanoate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7 Hz), 2.00 (3H, s), 2.22-2.36 (2H, m), 2.43-2.53 (2H, m), 4.13 (2H, q, J=7 Hz), 4.70 (2H, m), 4.80 (1H, t, J=7 Hz), 8.48 (1H, s), 8.90 (1H, s), 9.19 (1H, s). MS (ESI+): m/z 400 402.
Preparation 268
ethyl 6-(cyclohexylmethoxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate
1H NMR (CDCl3) δ 0.60-0.82 (2H, m), 0.93-1.10 (3H, m), 1.12-1.65 (6H, m), 1.25 (3H, t, J=7 Hz), 2.07-2.17 (1H, m), 2.22-2.35 (1H, m), 2.42 (2H, m), 2.44 (3H, s), 3.05-3.23 (2H, m), 3.96 (2H, s), 4.12 (2H, q, J=7 Hz), 4.92 (1H, m), 8.16 (1H, s), 8.66 (1H, s), 9.08 (1H, s). MS (ESI+): m/z 390.
Preparation 269
ethyl 4-[(5-bromo-3-pyridinyl)carbonyl]-6-(cyclohexylmethoxy)-5-oxohexanoate
1H NMR (CDCl3) δ 0.63-0.84 (2H, m), 0.93-1.88 (3H, m), 1.25 (3H, t, J=7 Hz), 1.35-1.90 (6H, m), 2.02-2.14 (1H, m), 2.20-2.36 (1H, m), 2.44 (2H, t, J=7 Hz), 3.04-3.20 (2H, m), 3.95 (2H, s), 4.13 (2H, q, J=7 Hz), 4.854.93 (1H, m), 8.50 (1H, m), 8.88 (1H, d, J=2 Hz), 9.20 (1H, d, J=2 Hz). MS (ESI+): m/z 454 456.
Preparation 270
ethyl 5-[(5-bromo-3-pyridinyl)carbonyl]-7-(cyclohexylmethoxy)-6-oxoheptanoate
1H NMR (300 MHz, CDCl3) δ 0.75-0.86 (2H, m), 0.95-1.15 (3H, m), 1.24 (3H, t, J=7 Hz), 1.40-1.90 (10H, m), 2.36 (2H, t, J=7 Hz), 3.12 (2H, q, J=7 Hz), 3.97 (2H, s), 4.12 (2H, q, J=7 Hz), 4.71 (1H, t, J=7 Hz), 8.41 (1H, s), 8.88 (1H, s), 9.12 (1H, s). MS (ESI+): m/z 468 470.
Preparation 271
ethyl 7-(cyclopropylmethoxy)-5-[(5-methyl-3-pyridinyl)carbonyl]-6-oxoheptanoate
1H NMR (CDCl3) δ −0.08-0.00 (1H, m), 0.00-0.15 (1H, m), 0.28-0.49 (2H, m), 0.72-0.87 (1H, m), 1.23 (3H, t, J=7 Hz), 1.58-2.13 (4H, m), 2.32 (2H, t, J=7 Hz), 2.44 (3H, s), 3.10-3.26 (2H, m), 4.02 (2H, m), 4.12 (2H, q, J=7 Hz), 4.77 (1H, t, J=7 Hz), 8.07 (1H, s), 8.63 (1H, s), 9.03 (1H, s). MS (ESI+): m/z 362.
Preparation 272
ethyl 6-(cyclopropylmethoxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate
1H NMR (CDCl3) δ −0.08-0.00 (1H, m), 0.00-0.13 (1H, m), 0.23-0.47 (2H, m), 0.68-0.84 (1H, m), 1.24 (3H, t, J=7 Hz), 2.03-2.17 (1H, m), 2.22-2.36 (1H, m), 2.40 (2H, m), 2.44 (3H, s), 3.12 (2H, m), 3.98 (1H, d, J=17 Hz), 4.06 (1H, d, J=17 Hz), 4.12 (2H, q, J=7 Hz), 4.93 (1H, m), 8.12 (1H, s), 8.65 (1H, s), 9.08 (1H, s). MS (ESI+): m/z 348.
Preparation 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), 3.16-3.73 (4H, m), 4.06 (2H, q, J=7 Hz), 4.10-4.24 (2H, m), 4.86-4.93 (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.
Preparation 274
1-(5-bromo-3-pyridinyl)-1,3-butanedione
1H NMR (CDCl3) δ 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.
Preparation 275
ethyl 7-(acetyloxy)-5-[(5-chloro-3-pyridinyl)carbonyl]-6-oxoheptanoate
1H NMR (300 MHz, CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.60-1.70 (4H, m), 2.04 (3H, s), 2.35 (2H, t, J=6 Hz), 4.12 (2H, q, J=7 Hz), 4.52 (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).
Preparation 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), 0.37-0.46 (1H, m), 0.70-0.79 (1H, m), 1.24 (3H, t, J=7 Hz), 1.29-1.41 (2H, m), 1.64 (2H, t, J=7 Hz), 1.72-1.84 (1H, m), 1.96-2.08 (1H, m), 2.28 (2H, t, J=7 Hz), 3.12 (1H, dd, J=10, 7 Hz), 3.21 (1H, dd, J=10, 7 Hz), 3.97 (1H, d, J=12 Hz), 4.05 (1H, d, J=12 Hz), 4.11 (2H, q, J=7 Hz), 4.70 (1H, t, J=7 Hz), 8.26 (1H, dd, J=2, 2 Hz), 8.77 (1H, dd, J=2 Hz), 9.09 (1H, dd, J=2 Hz).
Preparation 277
ethyl 5-[(5-chloro-3-pyridinyl)carbonyl]-7-(cyclopropylmethoxy)-6-oxoheptanoate
1H NMR (300 MHz, CDCl3) δ −0.07-0.09 (2H, m), 0.24-0.46 (2H, m), 0.68-0.79 (1H, m), 1.23 (3H, t, J=7 Hz), 1.47-1.84 (3H, m), 1.98-2.10 (1H, m), 2.33 (2H, t, J=7 Hz), 3.12 (1H, dd, J=10, 7 Hz), 3.21 (1H, dd, J=10, 7 Hz), 3.97 (1H, d, J=17 Hz), 4.06 (1H, d, J=17 Hz), 4.10 (2H, q, J=7 Hz), 4.73 (1H, t, J=6 Hz), 8.27 (1H, dd, J=2, 2 Hz), 8.77 (1H, d, J=2 Hz), 9.10 (1H, d, J=2 Hz).
Preparation 278
ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-8-isobutoxy-7-oxooctanoate
1H NMR (300 MHz, CDCl3) δ 0.72 (3H, d, J=7 Hz), 0.77 (3H, d, J=7 Hz), 1.24 (3H, t, J=7 Hz), 1.30-1.42 (2H, m), 1.54-1.70 (3H, m), 1.75-1.87 (1H, m), 1.95-2.08 (1H, m), 2.28 (2H, t, J=8 Hz), 3.10 (1H, dd, J=9, 7 Hz), 3.14 (1H, dd, J=9, 7 Hz), 3.98 (2H, s), 4.11 (2H, q, J=7 Hz), 4.70 (1H, t, J=6 Hz), 8.39 (1H, dd, J=2 Hz), 8.87 (1H, d, J=2 Hz), 9.08 (1H, d, J=2 Hz).
Preparation 279
ethyl 4-[(5-chloro-3-pyridinyl)carbonyl]-6-isobutoxy-5-oxohexanoate
1H NMR (300 MHz, CDCl3) δ 0.68 (3H, d, J=7 Hz), 0.72 (3H, d, J=7 Hz), 1.25 (3H, t, J=7 Hz), 1.52 (1H, qt, J=7, 7 Hz), 2.02-2.13 (1H, m), 2.20-2.32 (1H, m), 2.44 (2H, t, J=7 Hz), 3.07 (1H, dd, J=9, 7 Hz), 3.12 (1H, dd, J=9, 7 Hz), 3.98 (2H, s), 4.14 (2H, q, J=7 Hz), 4.90 (1H, d, J=9 Hz), 4.92 (1H, d, J=9 Hz), 8.34 (1H, dd, J=2 Hz), 8.78 (1H, d, J=2 Hz), 9.15 (1H, d, J=2 Hz).
Preparation 280
ethyl 6-(acetyloxy)-4-(3-chlorobenzoyl)-5-oxohexanoate
1H NMR (300 MHz, CDCl3) δ 1.26 (3H, t, J=7 Hz), 1.95 (3H, s), 2.20-2.29 (2H, m), 2.41-2.47 (2H, m), 4.15 (2H, q, J=7 Hz), 4.64 (1H, d, J=17 Hz), 4.71 (1H, d, J=17 Hz), 4.78 (1H, t, J=6 Hz), 7.48 (1H, dd, J=8, 8 Hz), 7.60 (1H, d, J=8 Hz), 7.96 (1H, d, J=8 Hz), 8.04 (1H, s).
Preparation 281
ethyl 5-[(5-bromo-3-pyridinyl)carbonyl]-7-isobutoxy-6-oxoheptanoate
1H NMR (300 MHz, CDCl3) δ 0.72 (3H, d, J=7 Hz), 0.77 (3H, d, J=7 Hz), 1.23 (3H, t, J=7 Hz), 1.61-1.73 (3H, m), 1.77-1.88 (1H, m), 1.98-2.10 (1H, m), 2.33 (2H, t, J=7 Hz), 3.10 (1H, dd, J=9, 7 Hz), 3.15 (1H, dd, J=9, 7 Hz), 3.99 (2H, s), 4.11 (2H, q, J=7 Hz), 4.73 (1H, t, J=7 Hz), 8.40 (1H, dd, J=2, 2 Hz), 8.87 (1H, d, J=2 Hz), 9.10 (1H, d, J=2 Hz).
Preparation 282
1,3-bis(5-bromo-3-pyridinyl)-1,3-propanedione
1H NMR (DMSO-d6) δ 7.60 (1H, s), 8.78 (2H, s), 8.88 (2H, s), 9.30 (2H, s).
Preparation 283
ethyl 7-(acetyloxy)-5-(3-chlorobenzoyl)-6-oxoheptanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=8 Hz), 1.57-1.75 (2H, m), 1.90-2.12 (5H, m), 2.34 (2H, t, J=8 Hz), 4.11 (2H, q, J=8 Hz), 4.52 (1H, t, J=8 Hz), 4.71 (2H, q, J=8 Hz), 4.65 (1H, d, J=16 Hz), 4.75 (1H, d, J=16 Hz), 7.43 (1H, t, J=8 Hz), 7.60 (1H, br d, J=8 Hz), 7.84 (1H, br d, J=8 Hz), 7.96 (1H, br s).
Preparation 284
ethyl 8-methoxy-6-[(5-methoxy-3-pyridinyl)carbonyl]-7-oxooctanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=8 Hz), 1.27-1.43 (2H, m), 1.55-1.70 (2H, m), 1.84 (1H, m), 2.00 (1H, m), 2.27 (2H, d, J=8 Hz), 3.26 (3H, s), 3.92 (3H, s), 3.98 (2H, d, J=5 Hz), 4.10 (2H, q, J=8 Hz), 4.67 (1H, t, J=8 Hz), 7.71 (1H, m), 8.50 (1H, d, J=3 Hz), 8.78 (1H, br s). MS (ESI+): m/z 352 (M+H).
Preparation 285
ethyl 6-[(5-methoxy-3-pyridinyl)carbonyl]-7-oxooctanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=8 Hz), 1.27-1.41 (2H, m), 1.60-1.73 (2H, m), 1.90-2.14 (2H, m), 2.18 (3H, s), 2.24-2.84 (2H, m), 3.26 (3H, s), 3.92 (3H, s), 4.10 (2H, q, J=8 Hz), 4.40 (1H, t, J=8 Hz), 7.71 (1H, m), 8.51 (1H, d, J=3 Hz), 8.78 (1H, br s).
Preparation 286
ethyl 6-methoxy-4-[(5-methoxy-3-pyridinyl)carbonyl]-5-oxohexanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=8 Hz), 2.10 (1H, m), 2.25 (1H, m), 2.38-2.47 (2H, m), 3.24 (3H, s), 3.94 (3H, s), 3.95 (1H, d, J=16 Hz), 4.00 (1H, d, J=16 Hz), 4.12 (2H, q, J=8 Hz), 4.38 (1H, m), 7.83 (1H, m), 8.52 (1H, d, J=3 Hz), 8.87 (1H, d, J=1 Hz). MS (ESI+): m/z 346 (M++Na).
Preparation 287
ethyl 7-methoxy-5-[(5-methoxy-3-pyridinyl)carbonyl]-6-oxoheptanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=8 Hz), 1.54-1.74 (2H, m), 1.84 (1H, m), 2.02 (1H, m), 2.32 (2H, d, J=8 Hz), 3.26 (3H, s), 3.92 (3H, s), 3.99 (2H, d, J=5 Hz), 4.10 (2H, q, J=8 Hz), 4.70 (1H, t, J=8 Hz), 7.71 (1H, m), 8.51 (1H, d, J=3 Hz), 8.79 (1H, br s). MS (ESI+): m/z 338 (M+H).
Preparation 288
ethyl 8-methoxy-7-oxo-6-(5-pyrimidinylcarbonyl)octanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=8 Hz), 1.25-1.45 (2H, m), 1.55-1.70 (2H, m), 1.81 (1H, m), 2.03 (1H, m), 2.28 (2H, t, J=8 Hz), 3.24 (3H, s), 3.92 (1H, d, J=18 Hz), 4.01 (1H, d, J=18 Hz), 4.10 (2H, q, J=8 Hz), 9.26 (2H, s), 9.40 (1H, s). MS (ESI+): m/z 323 (M+H).
Preparation 289
ethyl 5-[(5-chloro-3-pyridinyl)carbonyl]-7-methoxy-6-oxoheptanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=8 Hz), 1.52-1.74 (2H, m), 1.83 (1H, m), 2.02 (1H, m), 2.34-2.40 (2H, m), 3.25 (3H, s), 3.92 (1H, d, J=16 Hz), 4.01 (1H, d, J=16 Hz), 4.11 (2H, q, J=8 Hz), 4.68 (1H, t, J=8 Hz), 8.23 (1H, br s), 8.78 (1H, br s), 9.05 (1H, br s). MS (ESI+): m/z 342 (M+H).
Preparation 290
ethyl 4-[(5-chloro-3-pyridinyl)carbonyl]-6-methoxy-5-oxohexanoate
1H NMR (CDCl3) δ 1.25 (3H, t, J=8 Hz), 2.09 (1H, m), 2.25 (1H, m), 2.38-2.49 (2H, m), 3.22 (3H, s), 3.91 (1H, d, J=18 Hz), 4.00 (1H, d, J=18 Hz), 4.14 (2H, q, J=8 Hz), 4.85 (1H, m), 8.33 (1H, br s), 8.78 (1H, br s), 9.14 (1H, br s). MS (ESI+): m/z 328 (M+H).
Preparation 291
ethyl 6-[(5-chloro-3-pyridinyl)carbonyl]-8-methoxy-7-oxooctanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=8 Hz), 1.27-1.43 (2H, m), 1.50-1.71 (2H, m), 1.82 (1H, m), 2.00 (1H, m), 2.27 (2H, d, J=8 Hz), 3.25 (3H, s), 3.92 (1H, d, J=16 Hz), 4.02 (1H, d, J=16 Hz), 4.10 (2H, q, J=8 Hz), 4.63 (1H, t, J=8 Hz), 8.23 (1H, br s), 8.78 (1H, br s), 9.03 (1H, br s). MS (ESI+): m/z 356 (M+H).
Preparation 292
2-[2-({3-[(5-methyl-3-pyridinyl)carbonyl]-4-oxopentyl}oxy)ethoxy]ethyl acetate trifluoroacetate
1H-NMR (CDCl3) δ 2.06 (3H, s), 2.28 (3H, s), 2.33 (2H, m), 2.65 (3H, s), 3.47-3.67 (8H, m), 4.17 (2H, m), 4.71 (1H, t, J=7 Hz), 8.66 (1H, m), 8.88 (11H, m), 9.31 (11H, m).
Preparation 293
ethyl 5-[(5-bromo-3-pyridinyl)carbonyl]-7-methoxy-6-oxoheptanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.56-1.73 (2H, m), 1.77-1.92 (1H, m), 1.96-2.10 (1H, m), 2.32 (2H, t, J=7 Hz), 3.25 (3H, s), 3.92 (1H, d, J=17 Hz), 4.02 (1H, d, J=17 Hz), 4.12 (2H, q, J=7 Hz), 4.67 (1H, t, J=7 Hz), 8.39 (1H, m), 8.87 (1H, d, J=2 Hz), 9.09 (1H, d, J=2 Hz). MS (ESI+): m/z 386 388.
The following compound(s) was (were) obtained in a similar manner to that of Preparation 129 and 130.
Preparation 294
tert-butyl 3-oxo-4-phenylbutanoate
1H NMR (CDCl3) δ 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).
Preparation 295
tert-butyl 3-oxo-3-phenylpropanoate
1H NMR (CDCl3) δ 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).
Preparation 296
tert-butyl 4-(cyclohexylmethoxy)-3-oxobutanoate
1H NMR (CDCl3) δ 0.89-1.07 (2H, m), 1.13-1.40 (3H, m), 1.47 (9H, s), 1.60-1.83 (6H, m), 3.28 (2H, d, J=7 Hz), 3.45 (2H, s), 4.06 (2H, s).
Preparation 297
tert-butyl 4-(cyclopropylmethoxy)-3-oxobutanoate
1H NMR (CDCl3) δ 0.20-0.28 (2H, m), 0.55-0.64 (2H, m), 1.03-1.17 (1H, m), 1.47 (9H, s), 3.36 (2H, d, J=7 Hz), 3.45 (2H, s), 4.15 (2H, s).
Preparation 298
tert-butyl 4-(2-methoxyethoxy)-3-oxobutanoate
1H NMR (CDCl3) δ 1.47 (9H, s), 3.38 (3H, s), 3.44 (2H, s), 3.57 (2H, m), 3.70 (2H, m), 4.20 (2H, s).
Preparation 299
tert-butyl 4-isobutoxy-3-oxobutanoate
1H NMR (300 MHz, CDCl3) δ 0.93 (6H, d, J=7 Hz), 1.45 (9H, s), 1.91 (1H, qt, J=7, 7 Hz), 3.26 (2H, d, J=7 Hz), 3.45 (2H, s), 4.07 (2H, s).
Preparation 300
tert-butyl 3-(3-methyl-2-thienyl)-3-oxopropanoate
1H-NMR (CDCl3) δ 1.47 (9H, s), 2.57 (3H, s), 3.79 (2H, s), 6.96 (1H, d, J=5 Hz), 7.44 (1H, d, J=5 Hz).
Preparation 301
tert-butyl 3-(5-methyl-3-isoxazolyl)-3-oxopropanoate
1H-NMR (CDCl3) δ 1.475-1.57 (9H, m), 2.49 (3H, m), 3.95 (2H, s), 6.40 (1H, s).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 132.
Preparation 302
ethyl (2E)-5-(3-cyanobenzoyl)-6-oxo-2-heptenoate
1H-NMR (CDCl3) δ 1.28 (3H, t, J=7 Hz), 2.20 (3H, s), 2.88 (2H, m), 4.16 (2H, q, J=7 Hz), 4.54 (1H, t, J=7 Hz), 5.88 (1H, d, J=16 Hz), 6.82 (1H, dt, J=7 and 16 Hz), 7.65 (1H, t, J=8 Hz), 7.89 (1H, d, J=8 Hz), 8.20 (1H, d, J=8 Hz), 8.27 (1H, s). MS (ESI+): m/z 300.14 (M+H)
Preparation 303
1-tert-butyl 7-ethyl 2-[(3-methyl-2-thienyl)carbonyl]heptanedioate
1H-NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.35-1.51 (11H, m), 1.65 (2H, m), 1.96 (2H, m), 2.30 (2H, t, J=7 Hz), 2.58 (3H, s), 3.94 (1H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz),6.97 (1H, d, J=5 Hz), 7.44 (1H, d, J=5 Hz).
Preparation 304
1-tert-butyl 7-ethyl 2-[(5-methyl-3-isoxazolyl)carbonyl]heptanedioate
1H-NMR (CDCl3) δ 11.24 (3H, t, J=7 Hz), 1.39 (9H, s), 1.67 (2H, m), 1.98 (2H, m), 2.49 (3H, s), 4.10 (2H, q, J=7 Hz), 4.26 (1H, t, J=7 Hz), 6.37 (1H, s).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 152.
Preparation 305
methyl 7-oxo-7-(2-thienyl)heptanoate
1H-NMR (CDCl3) δ 1.41 (2H, m), 1.63-1.82 (4H, m), 2.33 (2H, t, J=7 Hz), 2.91 (2H, t, J=7 Hz), 3.67 (3H, s), 1.73 (1H, m), 7.62 (1H, m), 7.70 (1H, m).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 153.
Preparation 306
5-methoxynicotinoyl chloride hydrochloride
Preparation 307
5-pyrimidinecarbonyl chloride hydrochloride
Preparation 308
5-chloronicotinoyl chloride hydrochloride
Preparation 309
methyl 2-bromo-4-(chlorocarbonyl)benzoate
The following compound(s) was (were) obtained in a similar manner to that of Preparation 159.
Preparation 310
1-tert-butyl 7-ethyl 2-(phenylacetyl)heptanedioate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.18-1.50 (2H, m), 1.46 (9H, s), 1.50-1.75 (2H, m), 1.75-1.88 (2H, m), 2.24 (2H, t, J=7 Hz), 3.47 (1H, t, J=7 Hz), 3.81 (2H, s), 4.10 (2H, q, J=7 Hz), 7.20 (2H, d, J=8 Hz), 7.25-7.37 (3H, m).
Preparation 311
tert-butyl 2-[2-(2-methoxy-2-oxoethoxy)ethyl]-3-oxobutanoate
1H NMR (CDCl3) δ 1.46 (9H, s), 2.04-2.23 (2H, m), 2.29 (3H, s), 3.54 (2H, t, J=7 Hz), 3.69 (1H, t, J=7 Hz), 3.74 (3H, s), 4.04 (2H, s).
Preparation 312
tert-butyl 2-benzoyl-4-(2-methoxy-2-oxoethoxy)butanoate
1H NMR (CDCl3) δ 1.34 (9H, s), 2.26-2.40 (2H, m), 3.55-3.67 (2H, m), 3.70 (3H, s), 4.04 (2H, s), 4.57 (1H, t, J=7 Hz), 7.47 (2H, t, J=8 Hz), 7.56 (1H, m), 8.01 (2H, d, J=8 Hz).
Preparation 313
1-tert-butyl 6-ethyl 2-[(acetyloxy)acetyl]hexanedioate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.48 (9H, s), 1.60-1.73 (2H, m), 1.82-1.95 (2H, m), 2.17 (3H, s), 2.32 (2H, t, J=7 Hz), 3.43 (1H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.72 (1H, d, J=17 Hz), 4.83 (1H, d, J=17 Hz).
Preparation 314
1-tert-butyl 5-ethyl 2-[(cyclohexylmethoxy)acetyl]pentanedioate
1H NMR (CDCl3) δ 0.85-1.06 (2H, m), 1.13-1.34 (3H, m), 1.26 (3H, t, J=7 Hz), 1.45 (9H, s), 1.60-1.85 (6H, m), 2.08-2.23 (2H, m), 2.36 (2H, t, J=7 Hz), 3.27 (2H, d, J=7 Hz), 3.67 (1H, t, J=7 Hz), 4.10 (2H, s), 4.12 (2H, q, J=7 Hz).
Preparation 315
1-tert-butyl 6-ethyl 2-[(cyclohexylmethoxy)acetyl]hexanedioate
1H NMR (CDCl3) δ 0.88-1.06 (2H, m), 1.12-1.34 (3H, m), 1.25 (3H, t, J=7 Hz), 1.45 (9H, s), 1.54-1.94 (10H, m), 2.32 (2H, t, J=7 Hz), 3.27 (2H, d, J=7 Hz), 3.56 (1H, t, J=7 Hz), 4.09 (2H, s), 4.11 (2H, q, J=7 Hz). MS (ESI+): m/z 385.
Preparation 316
1-tert-butyl 6-ethyl 2-[(cyclopropylmethoxy)acetyl]hexanedioate
1H NMR (CDCl3) δ 0.22-0.33 (2H, m), 0.54-0.64 (2H, m), 1.04-1.18 (1H, m), 1.25 (3H, t, J=7 Hz), 1.45 (9H, s), 1.60-1.73 (2H, m), 1.83-1.95 (2H, m), 2.33 (2H, t, J=7 Hz), 3.33 (2H, d, J=7 Hz), 3.53 (1H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.18 (2H, m). MS (ESI+): m/z 343.
Preparation 317
1-tert-butyl 5-ethyl 2-[(cyclopropylmethoxy)acetyl]pentanedioate
1H NMR (CDCl3) δ 0.20-0.35 (2H, m), 0.56-0.64 (2H, m), 1.04-1.16 (1H, m), 1.26 (3H, t, J=7 Hz), 1.45 (9H, s), 2.12-2.24 (2H, m), 2.38 (2H, t, J=7 Hz), 3.36 (2H, m), 3.65 (1H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.19 (2H, s).
Preparation 318
1-tert-butyl 5-ethyl 2-[(2-methoxyethoxy)acetyl]pentanedioate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.46 (9H, s), 2.10-2.23 (2H, m), 2.38 (2H, t, J=7 Hz), 3.37 (3H, s), 3.60 (2H, m), 3.62 (1H, t, J=7 Hz), 3.70 (2H, m), 4.12 (2H, q, J=7 Hz), 4.23 (1H, d, J=17 Hz), 4.30 (1H, d, J=17 Hz). MS (ESI+): m/z 333.
Preparation 319
1-tert-butyl 5-ethyl 2-(isobutoxyacetyl)pentanedioate
1H NMR (300 MHz, CDCl3) δ 0.93 (6H, d, J=7 Hz), 1.26 (3H, t, J=7 Hz), 1.45 (9H, s), 1.91 (1H, qt, J=7, 7 Hz), 2.13 (2H, m), 2.37 (2H, t, J=7 Hz), 3.25 (2H, d, J=7 Hz), 3.67 (1H, t, J=7 Hz), 4.12 (2H, s), 4.13 (2H, q, J=7 Hz).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 164.
Preparation 320
methyl 2-bromo-4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate
1H-NMR (CDCl3) δ 1.32 (3H, t, J=7 Hz), 2.72 (2H, q, J=7 Hz), 3.97 (3H, s), 6.10 (1H, m), 6.77 (1H, m), 7.81 (1H, d, J=8 Hz), 7.85 (1H, d, J=8 Hz), 8.11 (1H, s), 9.32 (1H, s, br).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 165.
Preparation 321
tert-butyl 2-(2-{2-[2-(acetyloxy)ethoxy]ethoxy}ethyl)-3-oxobutanoate
1H-NMR (CDCl3) δ 1.46 (9H, s), 2.00-2.17 (5H, m), 2.25 (3H, s), 3.45-3.70 (10H, m), 4.22 (2H, m).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 178.
Preparation 322
Isobutoxyacetic Acid
1H NMR (300 MHz, CDCl3) δ 0.94 (6H, d, J=7 Hz), 1.93 (1H, qt, J=7, 7 Hz), 3.34 (2H, d, J=7 Hz), 4.12 (2H, s).
Preparation 323
To a suspension of 60% NaH (2.66 g) in DMF (20 mL) was added methyl hydroxyacetate (5.00 g) under ice-water cooling, and the mixture was stirred at 0° C. for 0.5 hour. To this was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (12.8 g) under ice-water cooling, and the mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (10:1-3:1) to give methyl [2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]acetate pale yellow oil (445 g).
methyl[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]acetate
1H NMR (CDCl3) δ 1.48-1.95 (6H, m), 3.46-3.57 (2H, m), 3.64-3.75 (2H, m), 3.76 (3H, s), 3.82-3.97 (2H, m), 4.20 (2H, s), 4.66 (1H, m).
Preparation 324
A mixture of methyl [2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]acetate (1.07 g) and pyridinium p-toluenesulfonate (24.6 mg) in MeOH (10 mL) was heated under reflux for 2 hours. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (10:1-1:3) to give methyl (2-hydroxyethoxy)acetate as colorless oil (555 mg).
methyl(2-hydroxyethoxy)acetate
1H NMR (CDCl3) δ 3.69 (2H, m), 3.76 (2H, m), 3.78 (3H, s), 4.16 (2H, s).
Preparation 325
To 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 ice-water cooling and the mixture was stirred at 0° C. for 2 hours. After insolubles were filtered off, the filtrates were diluted with AcOEt, washed with aq Na2SO3 solution and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-5:1) to give methyl(2-iodoethoxy)acetate as colorless oil (898 mg).
methyl(2-iodoethoxy)acetate
1H NMR (CDCl3) δ 3.30 (2H, t, J=7 Hz), 3.77 (3H, s), 3.84 (2H, t, J=7 Hz), 4.17 (2H, s).
Preparation 326
To a suspension of 60% NaH (1.02 g) in THF (50 mL) was added tert-butyl 4-(acetyloxy)-3-oxobutanoate (5.00 g) under ice-water cooling and the mixture was stirred at 0° C. for 0.5 hour. To this added ethyl 3-iodopropanoate (5.54 g) and the mixture was stirred at 50° C. for 8 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-3:1) to give 1-tert-butyl 5-ethyl 2-[(acetyloxy)acetyl]pentanedioate as yellow oil (4.27 g).
1-tert-butyl 5-ethyl 2-[(acetyloxy)acetyl]pentanedioate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7 Hz), 1.46 (9H, s), 2.14-2.24 (2H, m), 2.17 (3H, s), 2.36 (2H, t, J=7 Hz), 3.60 (1H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.73 (1H, d, J=18 Hz), 4.83 (1H, d, J=18 Hz).
Preparation 327
To a solution of benzyl 4-thiomorpholinecarboxylate (4.8 g) in methanol (30 mL) and H2O (20 mL) was added oxone (16.2 g) under ice water cooling and the mixture was stirred at ambient temperature for 2 hours. The solution was evaporated in vacuo and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and EtOAc to give benzyl 4-thiomorpholinecarboxylate 1,1-dioxide as a colorless solid (3.8 g).
benzyl 4-thiomorpholinecarboxylate 1,1-dioxide
1H NMR (300 MHz, CDCl3) δ 3.02 (4H, br s), 4.01 (4H, t, J=5 Hz), 5.16 (2H, s), 7.33-7.40 (5H, m).
Preparation 328
To a solution of thiomorpholine (2 g) in 1N NaOH (11.6 mL) was added benzyl chloridocarbonate (1.66 mL) under ice water cooling and the mixture was stirred at ambient temperature for 2 hours. The solution was neutralized with 1N HCl and extracted with EtOAc twice. The combined organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography to give benzyl 4-thiomorpholinecarboxylate as a colorless solid (4.8 g).
benzyl 4-thiomorpholinecarboxylate
1H NMR (300 MHz, CDCl3) δ 2.59 (4H, br s), 3.77 (4H, t, J=5 Hz), 5.14 (2H, s), 7.30-7.41 (5H, m).
Preparation 329
To a solution of benzyl 4-thiomorpholinecarboxylate 1,1-dioxide (3.8 g) in methanol (32 mL) and 1,4-dioxane (8 mL) was added Palladium, 10 wt. % on activated carbon (380 mg) at ambient temperature. The mixture was stirred at ambient temperature for 4 hours under H2 (3.4 atom). The mixture was filtered and evaporated in vacuo to give thiomorpholine 1,1-dioxide as a colorless solid (2.22 g).
thiomorpholine 1,1-dioxide
1H NMR (300 MHz, CDCl3) δ 3.03 (4H, t, J=5 Hz), 3.33 (4H, t, J=5 Hz). MS (m/z) 1.36 (M+H).
Preparation 330
To a suspension of [(5-chloro-4-mercapto-6-methyl-3-pyridinyl)oxy]acetic acid (10 g) in dichloromethane (100 mL) was added Et3N (14 mL) in ice-MeOH bath. To this was added trifluoromethanesulfonic anhydride (14.3 mL) dropwise below 10° C. over 30 min. After 2 hours the mixture was partitioned between CHCl3 and water. The aqueous layer was extracted with CHCl3 twice. The combined organic layer was dried over MgSO4 and evaporated in vacuo to give brown oil. The residue was purified by silica gel column chromatography (silica gel, 100 mL) eluted with hexane-EtOAc=15-1 and 10-1 to give 5-chloro-3-pyridinyl trifluoromethanesulfonate (15.8 g) as a pale brown oil.
5-chloro-3-pyridinyl trifluoromethanesulfonate
1H NMR (300 MHz, CDCl3) δ 7.69 (1H, dd, J=4, 4 Hz), 8.52 (1H, d, J=4 Hz), 8.65 (1H, d, J=4 Hz).
Preparation 331
To ethanol (66 mL) and DMF (66 mL) was added Et3N (29.4 mL), 1,3-propanediylbis(diphenylphosphine) (3.48 g) and palladium acetate (1.9 g) in ice-water bath. To this was added 5-chloro-3-pyridinyl trifluoromethanesulfonate (22.1 g) at the temperature. The mixture was stirred at 50° C. for 4 hours under CO (1 atom). The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water three times, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography (silica gel, 200 mL) eluted with hexane-EtOAc=15-1 and 10-1 to give ethyl 5-chloronicotinate (105 g) as a pale brown oil.
ethyl 5-chloronicotinate
1H NMR (300 MHz, CDCl3) δ 1.42 (3H, t, J=7 Hz), 4.43 (2H, q, J=7 Hz), 8.28 (1H, dd, J=3, 3 Hz), 8.74 (1H, d, J=3 Hz), 9.09 (1H, d, J=3 Hz).
Preparation 332
To 5-chloronicotinate (105 g) was added 1N NaOH (84.9 mL) at ambient temperature. The mixture was heated at 60° C. for 1 hour. The reaction mixture was adjusted to pH 4-5 with HCl. The precipitate was filtered to give 5-chloronicotinic acid (6.9 g) a colorless solid.
1H NMR (300 MHz, DMSO-d6) δ 8.30 (1H, dd, J=3 Hz), 8.88 (1H, d, J=3 Hz), 9.01 (1H, d, J=3 Hz), 1.38 (1H, br s).
5-chloronicotinic acid
H 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), 1.38 (1H, br s).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 332.
Preparation 333
5-methoxynicotinic acid
1H NMR (DMSO-d6) δ 3.87 (3H, s), 7.73 (1H, m), 8.48 (1H, d, J=3 Hz), 8.65 (1H, d, J=1 Hz). MS (ESI+): m/z 154 (M+H).
Preparation 334
5-pyrimidinecarboxylic acid
1H NMR (DMSO-d6) δ 9.20 (2H, s), 9.37 (1H, s). MS (ESI+): m/z 148 (M++Na).
Preparation 335
To a solution of diisopropylamine (5.41 g) in THF (30 mL) was added 1.5 M n-butyllithium hexane solution (35 mL) under dryice acetone cooling and the mixture was stirred at −78° C. for 10 minutes. To this was added tert-butyl acetate (5.87 g) under dryice acetone cooling and the mixture was stirred at −78° 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 dryice acetone cooling. The mixture was stirred at −78° C. for 0.5 hour. The mixture was partitioned between ethyl acetate and aq NH4Cl solution. The organic layer was separated, washed with aq NaHCO3 solution and brine, dried over MgSO4, and evaporated in vacuo. The residue was triturated with isopropyl ether to give tert-butyl 3-(5-bromo-3-pyridinyl)-3-oxopropanoate as a colorless powder (3.71 g).
tert-butyl 3-(5-bromo-3-pyridinyl)-3-oxopropanoate
Enol form: 1H NMR (CDCl3) δ 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). Keto form: 1H NMR (CDCl3) δ 1.44 (9H, s), 3.90 (2H, s), 8.37 (1H, m), 8.86 (1H, d, J=2 Hz), 9.03 (1H, d, J=2 Hz). MS (ESI+): m/z 300 302.
Preparation 336
To a suspension of NaH in DMF (50 mL) which was washed with hexane 3 times was added methyl 5-hydroxynicotinate (10.2 g) portionwise below 10° C. in an ice-water bath under nitrogen atmosphere. After 30 min, methyl iodide (4.56 mL) was added dropwise therein. The precipitate appeared and the mixture was hard to be stirred. DMF (30 mL) was added. After 20 min, the mixture was stirred at ambient temperature for 3 h. The reaction mixture was quenched with MeOH and was concentrated in vacuo. To the residue was added CHCl3, sat. NaHCO3, and brine. The organic layer was separated and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over MgSO4 and was evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 200 mL) eluted with hexane-AcOEt=5-1 and 3-1 to give methyl 5-methoxynicotinate (3.47 g) as a pale brown solid.
methyl 5-methoxynicotinate
1H NMR (CDCl3) δ 3.91 (3H, s), 3.96 (3H, s), 7.76 (1H, m), 8.47 (1H, d, J=3 Hz), 8.83 (1H, d, J=1 Hz). MS (ESI+): m/z 168 (M+H).
Preparation 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 an ice-bath over 5 minutes. After stirring for 1 hour, (aminooxy)(diphenyl)phosphine oxide (340 mg) was added portionwise over 40 minutes. The resulting mixture was stirred for 1 hour in the bath. The reaction was quenched by adding water (10 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (two times) and brine, dried over magnesium sulfate, and evaporated. The residue was dissolved in ethyl acetatec-hexane (1-5), and to the solution was added silica gel. The mixture was filtered, and the filtrate was evaporated to give 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 1.29 (3H, t, J=7 Hz), 2.76 (2H, q, J=7 Hz), 3.97 (3H, s), 5.73 (2H, s, br), 5.93 (1H, d, J=5 Hz), 6.62 (1H, d, J=5 Hz), 7.73 (1H, d, J=8 Hz), 7.84 (1H, d, J=8 Hz), 8.02 (1H, s).
Preparation 338
To a solution of dimethyl 2-bromoterephthalate (1.04 g) in methanol (10 mL) was added 1 N sodium hydroxide (5.71 mL) at room temperature. After stirring for 1.5 hour, the reaction was quenched by adding 1 N hydrochloric acid (7 mL). White crystals were formed. Water (10 mL) was added to aid crystalyzation. The crystals were collected by filtration, washed with water, and dried in the air. 3-Bromo-4-(methoxycarbonyl)benzoic acid was obtained as white crystals (532 mg).
3-bromo-4-(methoxycarbonyl)benzoic acid
1H-NMR (DMSO-d6) δ 3.89 (3H, s), 7.87 (1H, d, J=8 Hz), 8.01 (1H, d, J=8 Hz), 8.17 (1H, s).
Preparation 339
A mixture of 2-[2-(2-chloroethoxy)ethoxy]ethyl acetate (6.23 g) and sodium iodide (22.2 g) in acetone (60 mL) was refluxed for 4 hours. The mixture was further refluxed for 4 hours after adding sodium iodide (11.0 g). The solvent was evaporated off, and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was washed with 10% sodium thiosulfate and brine, dried over MgSO4, and evaporated to give 2-[2-(2-iodoethoxy)ethoxy]ethyl acetate as a pale yellow oil (9.74 g).
2-[2-(2-iodoethoxy)ethoxy]ethyl acetate
1H-NMR (CDCl3) δ 2.09 (3H, s), 3.27 (2H, t, J=7 Hz), 3.65-3.78 (8H, m), 4.24 (2H, m).
Preparation 340
A solution of 1-tert-butyl 7-ethyl 2-[(5-methyl-3-isoxazolyl)carbonyl]heptanedioate (126 mg) in trifluoroacetic acid (1 mL) was stirred for 1.5 hour at room temperature. The volatile was evaporated off, and azeotroped with toluene to give 7-ethoxy-2-[(5-methyl-3-isoxazolyl)carbonyl]-7-oxoheptanoic acid as a pale orange oil (106 mg).
7-ethoxy-2-[(5-methyl-3-isoxazolyl)carbonyl]-7-oxoheptanoic acid
1H-NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.41 (2H, m), 1.65 (2H, m), 2.02 (2H, m), 2.30 (2H, m), 2.50 (3H, s), 2.55 (1H, s, br), 4.10 (2H, q, J=7 Hz), 4.47 (1H, t, J=7 Hz), 6.40 (1H, s). MS (ESI+): m/z 296.22 (M−H) and 593.52 (2M−H)
Preparation 341
To a suspension of dimethyl sulfone (5.43 g) in tetrahydrofuran (10 mL) was added 1.59 M n-butyl lithium (36.3 mL) in a dryice-acetone bath under a nitrogen atmosphere. After stirring for 0.5 hour, a solution of methyl methoxyacetate (2.00 g) in tetrahydrofuran (5 mL) was added. The resulting mixture was stirred for 2 hours in the bath and allowed to warm to room temperature over 2 hours. The mixture was partitioned between EtOAc and 4 N hydrochloric acid. The reaction was quenched by adding 4 N hydrochloric acid in EtOAc (15 mL). The mixture was partitioned between EtOAc (100 mL) and brine (100 mL). The aqueous layer was washed with EtOAc (100 mL, five times). The organic layer was combined, and the combined extracts were dried over MgSO4, and evaporated. Flash silica gel column chromatography (EtOAc-hexane=50-200 to 300-100) afforded 2-(methylsulfonyl)-1-methoxyethanone as a colorless oil (2.24 g).
1-methoxy-3-(methylsulfonyl)acetone
1H-NMR (CDCl3) δ 2.99 (3H, s), 3.08 (2H, s), 3.47 (3H, s), 4.19 (2H, s).
The following compound(s) was (were) obtained in a similar manner to that of Example 1.
EXAMPLE 392
ethyl 4-[3-bromo-4-(methoxycarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate
1H-NMR (CDCl3) δ 0.98 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.61 (3H, s), 3.04 (2H, q, J=7 Hz), 3.98 (3H, s), 4.05 (2H, q, J=7 Hz), 6.29 (1H, d, J=5 Hz), 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-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
1H-NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 2.98 (2H, q, J=7 Hz), 3.18 (3H, s), 3.45 (3H, s), 4.59 (2H, s), 6.25 (1H, d, J=5 Hz), 6.71 (1H, d, J=5 Hz), 7.65 (1H, t, J=8 Hz), 7.78 (1H, d, J=8 Hz), 7.94 (1H, d, J=8 Hz), 7.99 (1H, s). MS (ESI+): m/z 370 (M+H)
The following compound(s) was (were) obtained in a similar manner to that of Example 16.
EXAMPLE 394
5-{4-[3-(aminocarbonyl)phenyl]-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H-NMR (CDCl3) δ 1.02 (4H, m), 1.28 (3H, t, J=7 Hz), 1.70 (2H, m), 2.37 (2H, m), 2.92 (2H, q, J=7 Hz), 5.87 (1H, d, J=5 Hz), 6.66 (1H, d, J=5 Hz), 7.46-7.67 (5H, m), 7.96-8.08 (3H, m).
The following compound(s) was (were) obtained in a similar manner to that of Example 21.
EXAMPLE 395
ethyl 4-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (CDCl3) δ 1.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.65-1.78 (2H, m), 2.22 (2H, t, J=7 Hz), 2.40-2.52 (2H, m), 2.58 (3H, s), 3.03 (2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.86 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.25 (1H, d, J=5 Hz), 7.36 (1H, s), 8.53 (1H, d, J=5 Hz). MS (ESI+): m/z 386.
EXAMPLE 396
ethyl 3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.30-2.39 (2H, m), 2.57 (3H, s), 2.74-2.83 (2H, m), 3.03 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.88 (1H, d, J=4 Hz), 6.55 (1H, d, J=4 Hz), 7.24 (1H, d, J=5 Hz), 7.35 (1H, s), 8.53 (1H, d, J=5 Hz). MS (ESI+): m/z 372.
EXAMPLE 397
ethyl 5-[2-benzyl-4-(2-chloro-4-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.30-1.50 (4H, m), 2.10 (2H, t, J=7 Hz), 2.23-2.35 (2H, m), 3.04 (2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 4.21 (2H, s), 5.88 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.14-7.32 (7H, m), 8.50 (1H, d, J=5 Hz).
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 1.37 (3H, t, J=7 Hz), 2.42 (3H, s), 2.61 (3H, s), 2.78-2.88 (2H, m), 3.03 (2H, q, J=7 Hz), 3.46-3.57 (2H, m), 3.71 (3H, s), 3.95 (2H, s), 5.87 (1H, d, J=4 Hz), 6.52 (1H, d, J=4 Hz), 7.54 (1H, s), 8.43 (1H, d, J=2 Hz), 8.53 (1H, d, J=2 Hz). MS (ESI+): m/z 368.
EXAMPLE 399
ethyl[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.51 (3H, s), 3.03 (2H, q, J=7 Hz), 3.43 (2H, s), 4.12 (2H, q, J=7 Hz), 5.99 (1H, d, J=4 Hz), 6.58 (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-[(acetyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.16 (3H, s), 2.32-2.42 (2H, m), 2.44 (3H, s), 2.77-2.90 (2H, m), 3.03 (2H, q, J=7 Hz), 4.12 (2H, q, 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-[(acetyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.64-1.78 (2H, m), 2.10-2.23 (2H, m), 2.17 (3H, s), 2.43 (3H, s), 2.43-2.58 (2H, m), 3.02 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.33 (2H, s), 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-[(acetyloxy)methyl]-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.60 (4H, m), 2.16 (2H, t, J=7 Hz), 2.17 (3H, s), 2.40-2.52 (2H, m), 3.03 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.29 (2H, s), 5.88 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.60-7.68 (3H, m), 7.75-7.83 (1H, m). MS (ESI+): m/z 448.
EXAMPLE 403
ethyl 4-[2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (CDCl3) δ 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.65-1.82 (2H, m), 2.17 (3H, s), 2.21 (2H, t, J=7 Hz), 2.45-2.63 (2H, m), 3.02 (2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.33 (2H, s), 5.95 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.90 (1H, m), 8.57 (1H, d, J=2 Hz), 8.80 (1H, d, J=2 Hz). MS (ESI+): m/z 488 490.
EXAMPLE 404
ethyl 3-[2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]propanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.16 (3H, s), 2.36 (2H, t, J=7 Hz), 2.77-2.95 (2H, m), 3.02 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 5.31 (2H, s), 5.96 (1H, d, J=4 Hz), 6.64 (1H, d, J=4 Hz), 7.88 (1H, s), 8.56 (1H, m), 8.80 (1H, m). MS (ESI+): m/z 474 476.
EXAMPLE 405
ethyl 3-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate
1H NMR (CDCl3) δ 0.88-1.06 (2H, m), 1.19 (3H, t, J=7 Hz), 1.15-1.36 (3H, m), 1.37 (3H, t, J=7 Hz), 1.58-1.85 (6H, m), 2.42 (2H, m), 2.43 (3H, s), 2.83-2.97 (2H, m), 3.05 (2H, q, J=7 Hz), 3.38 (2H, d, J=7 Hz), 4.06 (2H, q, J=7 Hz), 4.66 (2H, s), 5.91 (1H, d, J=4 Hz), 6.58 (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-ethylpyrrolo[1,2-b]pyridazin-3-yl}propanoate
1H NMR (CDCl3) δ 0.85-1.06 (2H, m), 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.16-1.46 (3H, m), 1.55-1.84 (6H, m), 2.43 (2H, t, J=7 Hz), 2.82-3.00 (2H, m), 3.06 (2H, q, J=7 Hz), 3.37 (2H, d, J=7 Hz), 4.06 (2H, q, J=7 Hz), 4.66 (2H, s), 5.93 (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-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoate
1H NMR (CDCl3) δ 0.87-1.06 (2H, m), 1.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.16-1.46 (3H, m), 1.50-1.85 (8H, m), 2.23 (2H, t, J=7 Hz), 2.55-2.75 (2H, m), 3.04 (2H, q, J=7 Hz), 3.38 (2H, d, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.67 (2H, s), 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), 0.53-0.65 (2H, m), 1.10-1.20 (1H, m), 1.19 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.65-1.80 (2H, m), 2.14-2.30 (2H, m), 2.43 (3H, s), 2.57-2.74 (2H, m), 3.05 (2H, q, J=7 Hz), 3.43 (2H, d, J=7 Hz), 4.03 (2H, q, J=7 Hz), 4.74 (2H, s), 5.90 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.53 (1H, s), 8.43 (1H, s), 8.54 (1H, s). 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), 0.54-0.63 (2H, m), 1.10-1.20 (1H, m), 1.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.40-2.50 (2H, m), 2.43 (3H, s), 2.86-2.98 (2H, m), 3.05 (2H, q, J=7 Hz), 3.42 (2H, d, J=7 Hz), 4.06 (2H, q, J=7 Hz), 4.71 (2H, s), 5.92 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.52 (1H, s), 8.42 (1H, s), 8.54 (1H, s). MS (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 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.44 (2H, t, J=7 Hz), 2.82-2.98 (2H, m), 3.05 (2H, q, J=7 Hz), 3.38 (3H, s), 3.58 (2H, m), 3.76 (2H, m), 4.05 (2H, q, J=7 Hz), 4.76 (2H, s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.87 (1H, m), 8.54 (1H, s), 8.79 (1H, s). MS (ESI+): m/z 490 492.
EXAMPLE 411
4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine
1H NMR (CDCl3) δ 1.39 (3H, t, J=7 Hz), 2.54 (3H, s), 3.04 (2H, q, J=7 Hz), 6.39 (1H, s), 6.51 (1H, d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 8.17 (1H, m), 8.76 (1H, d, J=2 Hz), 8.86 (1H, d, J=2 Hz). MS (ESI+): m/z 316 318.
EXAMPLE 412
ethyl 4-[2-[(acetyloxy)methyl]-4-(5-chloro-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (300 MHz, CDCl3) δ 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.70 (2H, tt, J=7, 7 Hz), 2.17 (3H, s), 2.20 (2H, t, J=7 Hz), 2.45-2.54 (2H, m), 3.02 (2H, q, J=7 Hz), 4.04 (2H, q, J=7 Hz), 5.33 (2H, s), 5.94 (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), 8.70 (1H, d, J=2 Hz).
EXAMPLE 413
ethyl 5-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (300 MHz, CDCl3) δ 0.23-0.26 (2H, m), 0.54-0.59 (2H, m), 1.07-1.16 (1H, m), 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.41-1.56 (4H, m), 2.17 (2H, t, J=7 Hz), 2.53-2.64 (2H, m), 3.03 (2H, q, J=7 Hz), 3.41 (2H, d, J=7 Hz), 4.09 (2H, q, J=7 Hz), 4.70 (2H, s), 5.90 (1H, d, J=5 Hz), 6.58 (1H, d, J=5 Hz), 7.72 (1H, s), 8.51 (1H, s), 8.68 (1H, s).
EXAMPLE 414
ethyl 4-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoate
1H NMR (300 MHz, CDCl3) δ 0.24 (2H, dt, J=7, 7 Hz), 0.56 (2H, dt, J=7, 7 Hz), 1.07-1.15 (1H, m), 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.72 (2H, tt, J=7, 7 Hz), 2.21 (2H, t, J=7 Hz), 2.55-2.66 (2H, m), 3.02 (2H, q, J=7 Hz), 3.43 (2H, d, J=7 Hz), 4.04 (2H, q, J=7 Hz), 4.73 (2H, s), 5.91 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.74 (1H, dd, J=2, 2 Hz), 8.52 (1H, d, J=2 Hz), 8.68 (1H, d, J=2 Hz).
EXAMPLE 415
ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (300 MHz, CDCl3) δ 0.92 (6H, d, J=7 Hz), 1.26 (3H, t, J=7 Hz), 1.34 (3H, t, J=7 Hz), 1.38-1.56 (4H, m), 1.92 (1H, qt, J=7, 7 Hz), 2.15 (2H, t, J=7 Hz), 2.51-2.63 (2H, m), 3.03 (2H, q, J=7 Hz), 3.33 (2H, d, J=7 Hz), 4.09 (2H, q, J=7 Hz), 4.65 (2H, s), 5.90 (1H, d, J=7 Hz), 6.59 (1H, d, J=7 Hz), 7.88 (1H, dd, J=2, 2 Hz), 8.55 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz).
EXAMPLE 416
ethyl 3-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate
1H NMR (300 MHz, CDCl3) δ 0.92 (6H, d, J=7 Hz), 1.19 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.91 (1H, qt, J=7, 7 Hz), 2.41 (2H, t, J=8 Hz), 2.84-2.94 (2H, m), 3.03 (2H, q, J=7 Hz), 3.35 (2H, d, J=7H), 4.05 (2H, q, J=7 Hz), 4.68 (2H, s), 5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.72 (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-[(acetyloxy)methyl]-4-(3-chlorophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]propanoate
1H NMR (300 MHz, CDCl3) δ 1.19 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 2.15 (3H, s), 2.33 (2H, t, J=8 Hz), 2.82 (2H, t, J=8 Hz), 3.02 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 5.31 (2H, s), 5.97 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.23-7.26 (1H, m), 7.37 (1H, s), 7.44-7.46 (2H, m).
EXAMPLE 418
ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (300 MHz, CDCl3) δ 0.92 (6H, d, J=7 Hz), 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.71 (2H, tt, J=8, 8 Hz), 1.91 (1H, qt, J=7, 7 Hz), 2.20 (2H, t, J=8 Hz), 2.56-2.66 (2H, m), 3.03 (2H, q, J=7 Hz), 3.34 (2H, d, J=7 Hz), 4.05 (2H, q, J=7 Hz), 4.69 (2H, s), 5.91 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.89 (1H, s), 8.56 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).
EXAMPLE 419
2,4-bis(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazine
1H NMR (CDCl3) δ 1.45 (3H, t, J=7 Hz), 3.14 (2H, q, J=7 Hz), 6.66 (1H, d, J=4 Hz), 6.86 (1H, d, J=4 Hz), 6.91 (1H, s), 8.23 (1H, m), 8.48 (1H, m), 8.77 (1H, m), 8.83 (1H, m), 8.94 (1H, d, J=2 Hz), 9.18 (1H, d, J=2 Hz).
EXAMPLE 420
ethyl 4-[2-[(acetyloxy)methyl]-4-(3-chlorophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (CDCl3) δ 1.19 (3H, t, J=8 Hz), 1.34 (3H, t, J=8 Hz), 1.63-1.76 (2H, m), 2.10-2.22 (5H, m), 2.45-2.55 (2H, m), 3.01 (2H, q, J=8 Hz), 4.04 (2H, q, J=8 Hz), 5.32 (2H, s), 5.95 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.21-7.29 (1H, overlapped with CDCl3), 7.36 (1H, br s), 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 1.23 (3H, t, J=8 Hz), 1.33-1.60 (7H, m), 1.55-1.70 (2H, m), 2.17 (2H, t, J=8 Hz), 2.46-2.64 (2H, m), 3.04 (2H, d, J=8 Hz), 3.46 (3H, s), 3.90 (3H, s), 4.09 (2H, q, J=8 Hz), 4.62 (2H, s), 5.93 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.23 (1H, m), 8.22 (1H, d, J=1 Hz), 8.40 (1H, d, J=3 Hz). MS (ESI+): m/z 426 (M+H).
EXAMPLE 422
ethyl 5-[7-ethyl-4-(5-methoxy-3-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=8 Hz), 1.33-1.62 (7H, m), 2.18 (2H, t, J=8 Hz), 2.38-2.49 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 3.90 (3H, s), 4.08 (2H, q, J=8 Hz), 5.89 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.21 (1H, m), 8.21 (1H, 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 1.20 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 2.40 (2H, t, J=8 Hz), 2.81-2.96 (2H, m), 3.04 (2H, d, J=8 Hz), 3.47 (3H, s), 3.90 (3H, s), 4.05 (2H, q, J=8 Hz), 4.65 (2H, s), 5.96 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.21 (1H, m), 8.23 (1H, br s), 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 1.20 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 1.64-1.79 (2H, m), 2.14-2.24 (2H, m), 2.53-2.66 (2H, m), 3.04 (2H, d, J=8 Hz), 3.47 (3H, s), 3.90 (3H, s), 4.04 (2H, q, J=8 Hz), 4.67 (2H, br s), 5.94 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.23 (1H, m), 8.22 (1H, d, J=1 Hz), 8.40 (1H, d, J=3 Hz). MS (ESI+): m/z 412 (M+H).
EXAMPLE 425
ethyl 5-[7-ethyl-2-(methoxymethyl)-4-(5-pyrimidinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=8 Hz), 1.30-1.62 (7H, m), 2.19 (2H, t, J=8 Hz), 2.46-2.60 (2H, m), 3.04 (2H, d, J=8 Hz), 3.47 (3H, s), 3.90 (3H, s), 4.09 (2H, q, J=8 Hz), 4.63 (2H, s), 5.90 (1H, d, J=5 Hz), 6.61 (1H, d, J=5 Hz), 8.80 (2H, s), 9.34 (1H, s). 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 1.21 (3H, t, J=8 Hz), 1.37 (3H, t, J=8 Hz), 1.62-1.76 (2H, m), 2.21 (2H, t, J=8 Hz), 2.49-2.67 (2H, m), 3.04 (2H, d, J=8 Hz), 3.46 (3H, s), 4.06 (2H, q, J=8 Hz), 4.67 (2H, br s), 5.92 (1H, d, J=5 Hz), 6.61 (1H, d, J=5 Hz), 7.74 (1H, m), 8.53 (1H, d, J=1 Hz), 8.69 (1H, d, J=2 Hz). MS (ESI+): m/z 414 (M−H).
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 1.20 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 2.40 (2H, t, J=8 Hz), 2.82-2.94 (2H, m), 3.04 (2H, d, J=8 Hz), 3.47 (3H, s), 4.06 (2H, q, J=8 Hz), 4.65 (2H, s), 5.93 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.73 (1H, br s), 8.51 (1H, br s), 8.70 (1H, br s). MS (ESI+): m/z 402 (M+H).
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 1.23 (3H, t, J=8 Hz), 1.34-1.60 (7H, m), 2.19 (2H, t, J=8 Hz), 2.47-2.64 (2H, m), 3.04 (2H, d, J=8 Hz), 3.46 (3H, s), 4.10 (2H, q, J=8 Hz), 4.62 (2H, s), 5.90 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.73 (1H, m), 8.51 (1H, br s), 8.68 (1H, br s). MS (ESI+): m/z 426 (M+H).
EXAMPLE 429
methyl 2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazine-3-carboxylate
mp 122-123 deg.
1H NMR (CDCl3) δ 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), 7.93 (1H, t, J=1 Hz), 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)ethyl acetate
1H-NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 2.05 (3H, s), 2.42 (3H, s), 2.59 (3H, s), 2.75 (2H, m), 3.00 (2H, q, J=7 Hz), 3.39-3.48 (4H, m), 3.54 (2H, m), 3.63 (2H, m), 4.16 (2H, m), 5.86 (1H, d, J=5 Hz), 6.52 (1H, d, J=5 Hz), 7.50 (1H, m), 8.43 (1H, m), 8.52 (1H, m).
EXAMPLE 431
ethyl (2E)-4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-2-butenoate
1H-NMR (CDCl3) δ 1.27 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 2.49 (3H, s), 3.02 (2H, q, J=7 Hz), 3.30 (2H, m), 4.16 (2H, q, J=7 Hz), 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), 7.65 (1H, s), 7.75 (1H, m).
EXAMPLE 432
ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (300 MHz, CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.65-1.78 (2H, m), 2.23 (2H, t, J=7 Hz), 2.54-2.72 (2H, m), 3.04 (2H, q, J=7 Hz), 3.46 (3H, s), 4.06 (2H, q, J=7 Hz), 4.66 (2H, s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.89 (1H, m), 8.55 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz). MS (ESI+): m/z 460 462.
EXAMPLE 433
ethyl 4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate
1H NMR (CDCl3) δ 0.99 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 2.63 (3H, s), 3.05 (2H, q, J=8 Hz), 4.07(2H, q, J=8 Hz), 6.27 (1H, d, J=5 Hz), 6.70 (1H, d, J=5 Hz), 7.30 (1H, dd, J=5, 1 Hz), 7.41 (1H, br s), 8.49 (1H, d, J=5 Hz). MS (ESI+): m/z 344 (M+H).
The following compound(s) was (were) obtained in a similar manner to that of Example 76.
EXAMPLE 434
4-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.72-1.84 (2H, m), 2.33 (2H, t, J=7 Hz), 2.47-2.57 (2H, m), 2.58 (3H, s), 3.03 (2H, q, J=7 Hz), 5.88 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.27 (1H, m), 7.38 (1H, s), 8.53 (1H, d, J=5 Hz). MS (ESI−): m/z 356, MS (ESI+): m/z 358.
EXAMPLE 435
3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 2.36-2.47 (2H, m), 2.58 (3H, s), 2.76-2.88 (2H, m), 3.03 (2H, q, J=7 Hz), 5.89 (1H, d, J=4 Hz), 6.55 (1H, d, J=4 Hz), 7.25 (1H, d, J=5 Hz), 7.35 (1H, s), 8.53 (1H, d, J=5 Hz).
EXAMPLE 436
4-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.30-1.42 (2H, m), 1.35 (9H, s), 1.63-1.76 (2H, m), 2.22-2.37 (4H, m), 3.93 (1H, d, J=17 Hz), 4.12 (2H, q, J=7 Hz), 4.29 (1H, d, J=17 Hz), 7.22 (2H, d, J=8 Hz), 7.26-7.36 (4H, m), 7.50 (1H, s), 8.42 (1H, d, J=5 Hz). MS (ESI−): m/z 418, MS (ESI+): m/z 420.
EXAMPLE 437
3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoic acid
1H NMR (CDCl3) δ 1.36 (3H, t, J=7 Hz), 2.06 (2H, t, J=7 Hz), 2.78 (2H, t, J=7 Hz), 3.04 (2H, q, J=7 Hz), 5.99 (1H, d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 7.28 (1H, d, J=5 Hz), 7.41 (1H, s), 7.45-7.55 (5H, m), 8.53 (1H, d, J=5 Hz). MS (ESI−): m/z 404, MS (ESI+): m/z 406.
EXAMPLE 438
5-[2-benzyl-4-(2-chloro-4-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.16-1.32 (2H, m), 1.39 (3H, t, J=7 Hz), 1.38-1.53 (2H, m), 2.15 (2H, t, J=7 Hz), 2.30-2.40 (2H, m), 3.06 (2H, q, J=7 Hz), 4.21 (2H, s), 5.88 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.18-7.35 (7H, m), 8.49 (1H, d, J=5 Hz). MS (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 1.37 (3H, t, J=7 Hz), 2.44 (3H, s), 2.59 (3H, s), 2.74-2.92 (2H, m), 3.02 (2H, q, J=7 Hz), 3.54-3.66 (2H, m), 3.93 (2H, m), 5.82 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.63 (1H, s), 8.52 (1H, s), 8.56 (1H, s).
EXAMPLE 440
{2-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}acetic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 2.80 (2H, t, J=7 Hz), 3.03 (2H, q, J=7 Hz), 3.20 (2H, t, J=7 Hz), 3.72 (3H, s), 6.01 (1H, d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 7.42 (1H, d, J=5 Hz), 7.45-7.60 (6H, m), 8.57 (1H, d, J=5 Hz).
EXAMPLE 441
[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 2.55 (3H, s), 2.97-3.10 (2H, m), 3.30-3.62 (2H, m), 5.97 (1H, m), 6.57 (1H, m), 8.03 (1H, s), 8.69 (1H, s), 8.77 (1H, s). MS (ESI+): m/z 374 376.
EXAMPLE 442
3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 2.33-2.50 (2H, m), 2.42 (3H, s), 2.80-3.00 (2H, m), 3.06 (2H, q, J=7 Hz), 4.72 (2H, s), 4.83 (2H, s), 5.92 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.36 (2H, d, J=7 Hz), 7.55 (1H, s), 8.41 (1H, s), 8.44 (2H, d, J=7 Hz), 8.53 (1H, s). MS (ESI+): m/z 429 431.
EXAMPLE 443
3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 2.42 (3H, s), 2.40-2.55 (2H, m), 2.83-3.12 (2H, m), 3.03 (2H, q, J=7 Hz), 4.84 (2H, s), 4.91 (2H, m), 5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.57 (1H, s), 8.42 (1H, s), 8.48-8.55 (3H, m), 8.76 (1H, s). MS (ESI+): m/z 432.
EXAMPLE 444
3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 2.43 (3H, s), 2.50-2.60 (2H, m), 2.88-3.05 (2H, m), 3.03 (2H, q, J=7 Hz), 4.81 (2H, s), 4.87 (2H, s), 5.82 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.27 (1H, m), 7.48 (1H, d, J=8 Hz), 7.56 (1H, s), 7.77 (1H, t, J=8 Hz), 8.43 (1H, s), 8.54 (2H, m).
EXAMPLE 445
4-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoic acid
1H NMR (CDCl3) δ 1.40 (3H, t, J=7 Hz), 1.70-1.85 (2H, m), 2.16-2.31 (2H, m), 2.44 (3H, s), 2.53-2.83 (2H, m), 3.05 (2H, q, J=7 Hz), 4.72 (2H, s), 4.83-4.98 (2H, m), 5.92 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.30 (2H, d, J=7 Hz), 7.57 (1H, s), 8.38-8.55 (4H, m). MS (ESI−): m/z 443, MS (ESI+): m/z 445.
EXAMPLE 446
5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 2.20 (2H, t, J=7 Hz), 2.52-2.68 (2H, m), 3.04 (2H, q, J=7 Hz), 4.69 (2H, s), 4.78 (2H, s), 5.93 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.35 (2H, d, J=6 Hz), 7.88 (1H, m), 8.54 (2H, d, J=6 Hz), 8.55 (1H, m), 8.79 (1H, m).
EXAMPLE 447
5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.40-1.62 (4H, m), 2.17 (2H, t, J=7 Hz), 2.50-2.67 (2H, m), 3.04 (2H, q, J=7 Hz), 4.69 (2H, s), 4.76 (2H, s), 5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.32-7.38 (1H, m), 7.77 (1H, d, J=8 Hz), 7.88 (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-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.48-1.67 (4H, m), 2.26 (2H, t, J=7 Hz), 2.53-2.75 (2H, m), 3.03 (2H, q, J=7 Hz), 4.82 (2H, s), 4.83 (2H, s), 5.90 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.26-7.34 (1H, m), 7.53 (1H, d, J=8 Hz), 7.75-7.83 (1H, m), 7.87 (1H, m), 8.55 (1H, d, J=2 Hz), 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-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.45-1.64 (4H, m), 2.23 (2H, t, J=7 Hz), 2.53-2.72 (2H, m), 3.03 (2H, q, J=7 Hz), 4.83 (2H, s), 4.87 (2H, s), 5.93 (1H, d, 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-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoic acid
1H NMR (CDCl3) δ 1.39 (3H, t, J=7 Hz), 1.69-1.84 (2H, m), 2.27 (2H, t, J=7 Hz), 2.56-2.80 (2H, m), 3.02 (2H, q, J=7 Hz), 4.73 (2H, s), 4.92 (2H, m), 5.94 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.31 (2H, d, J=6 Hz), 7.90 (1H, m), 8.46 (2H, d, J=6 Hz), 8.57 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz). MS (ESI−): m/z 507 509, MS (ESI+): m/z 509 511.
EXAMPLE 451
4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.66-1.83 (2H, m), 2.26 (2H, t, J=7 Hz), 2.53-2.77 (2H, m), 3.04 (2H, q, J=7 Hz), 4.71 (2H, s), 4.86 (2H, m), 5.92 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.33 (1H, m), 7.78 (1H, d, J=8 Hz), 7.90 (1H, m), 8.50 (1H, m), 8.56 (1H, d, J=2 Hz), 8.60 (1H, s), 8.78 (1H, d, J=2 Hz). MS (ESI+): m/z 509 511.
EXAMPLE 452
4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.70-1.85 (2H, m), 2.23-2.34 (2H, m), 2.57-2.76 (2H, m), 3.03 (2H, q, J=7 Hz), 4.81 (2H, s), 4.90 (2H, m), 5.91 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.28 (1H, m), 7.49 (1H, d, J=7 Hz), 7.77 (1H, t, J=8 Hz), 7.88 (1H, m), 8.55 (1H, d, J=2 Hz), 8.57 (1H, m), 8.74 (1H, d, J=2 Hz). MS (ESI+): m/z 509 511.
EXAMPLE 453
4-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoic acid
1H NMR (CDCl3) δ 0.22 (2H, m), 0.57 (2H, m), 1.07-1.22 (1H, m), 1.37 (3H, t, J=7 Hz), 1.72-1.87 (2H, m), 2.28 (2H, t, J=7 Hz), 2.58-2.77 (2H, m), 3.03 (2H, q, J=7 Hz), 3.41 (2H, d, J=7 Hz), 4.72 (2H, s), 5.92 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.93 (1H, m), 8.56 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz). MS (ESI−): m/z 470 472, MS (ESI+): m/z 472 474.
EXAMPLE 454
4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.68-1.83 (2H, m), 2.27 (2H, t, J=7 Hz), 2.56-2.78 (2H, m), 3.03 (2H, q, J=7 Hz), 4.84 (2H, s), 4.92 (2H, m), 5.94 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.91 (1H, m), 8.51 (2H, m), 8.56 (1H, d, J=2 Hz), 8.76 (2H, m). MS (ESI−): m/z 508 510, MS (ESI+): m/z 510 512.
EXAMPLE 455
3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid
1H NMR (CDCl3) δ 1.39 (3H, t, J=7 Hz), 2.38 (2H, t, J=7 Hz), 2.83-2.98 (2H, m), 3.07 (2H, q, J=7 Hz), 4.74 (2H, s), 4.83 (2H, s), 5.95 (1H, d, J=4 Hz), 6.65 (1H, 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}butanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.68-1.83 (2H, m), 2.28 (2H, t, J=7 Hz), 2.53-2.76 (2H, m), 3.02 (2H, q, J=7 Hz), 3.75 (2H, m), 3.79 (2H, m), 4.78 (2H, s), 5.93 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.90 (1H, s), 8.56 (1H, s), 8.78 (1H, s). MS (ESI−): m/z 460 462, MS (ESI+): m/z 462 464.
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 0.88-1.06 (2H, m), 1.10-1.36 (3H, m), 1.37 (3H, t, J=7 Hz), 1.58-1.85 (6H, m), 2.42 (3H, s), 2.48-2.60 (2H, m), 2.80-3.02 (2H, m), 3.04 (2H, q, J=7 Hz), 3.39 (2H, d, J=7 Hz), 4.67 (2H, m), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.57 (1H, s), 8.42 (1H, s), 8.53 (1H, s). MS (ESI−): m/z 434, MS (ESI+): m/z 436.
EXAMPLE 458
3-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}propanoic acid
1H NMR (CDCl3) δ 0.88-1.05 (2H, m), 1.10-1.36 (3H, m), 1.37 (3H, t, J=7 Hz), 1.56-1.83 (6H, m), 2.51 (2H, t, J=7 Hz), 2.80-3.07 (2H, m), 3.06 (2H, q, J=7 Hz), 3.37 (2H, d, J=7 Hz), 4.67 (2H, s), 5.93 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 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-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoic acid
1H NMR (CDCl3) δ 0.86-1.03 (2H, m), 1.10-1.35 (3H, m), 1.37 (3H, t, J=7 Hz), 1.60-1.82 (8H, m), 2.28 (2H, t, J=7 Hz), 2.55-2.76 (2H, m), 3.05 (2H, q, J=7 Hz), 3.36 (2H, d, J=7 Hz), 4.67 (2H, s), 5.92 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 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]butanoic acid
1H NMR (CDCl3) δ 0.22-0.32 (2H, m), 0.55-0.63 (2H, m), 1.10-1.22 (1H, m), 1.37 (3H, t, J=7 Hz), 1.73-1.86 (2H, m), 2.20-2.35 (2H, m), 2.46 (3H, s), 2.55-2.86 (2H, m), 3.04 (2H, q, J=7 Hz), 3.43 (2H, d, J=7 Hz), 4.70-4.85 (2H, m), 5.88 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.62 (1H, s), 8.42 (1H, s), 8.46 (1H, s). MS (ESI+): m/z 408.
EXAMPLE 461
3-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid
1H NMR (CDCl3) δ 0.23-0.35 (2H, m), 0.54-0.65 (2H, m), 1.08-1.24 (1H, m), 1.37 (3H, t, J=7 Hz), 2.43 (3H, s), 2.50-2.65 (2H, m), 2.70-3.05 (2H, m), 3.04 (2H, q, J=7 Hz), 3.44 (2H, d, J=7 Hz), 4.74 (2H, s), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.56 (1H, s), 8.42 (1H, s), 8.53 (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 1.37 (3H, t, J=7 Hz), 2.48-2.62 (2H, m), 2.83-3.02 (2H, m), 3.02 (2H, q, J=7 Hz), 3.37 (3H, s), 3.60 (2H, m), 3.73 (2H, m), 4.75 (2H, s), 5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.89 (1H, m), 8.55 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz). MS (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)pentanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.35-1.65 (4H, m), 2.23 (2H, t, J=7 Hz), 2.40-2.56 (2H, m), 3.02 (2H, q, J=7 Hz), 3.48-3.57 (4H, m), 3.60-3.78 (4H, m), 5.33 (2H, s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.89 (1H, m), 8.56 (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-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.36 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.22 (2H, t, J=7 Hz), 2.42-2.57 (2H, m), 2.97 (6H, s), 3.03 (2H, q, J=7 Hz), 5.30 (2H, s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.89 (1H, s), 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[1,2-b]pyridazin-3-yl)pentanoic acid
1H NMR (CDCl3) δ 1.36 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 1.82-1.97 (4H, m), 2.23 (2H, t, J=7 Hz), 2.43-2.58 (2H, m), 3.03 (2H, q, J=7 Hz), 3.37-3.52 (4H, m), 5.31 (2H, s), 5.93 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.88 (1H, m), 8.54 (1H, 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}pentanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.40-1.58 (4H, m), 2.18 (2H, t, J=7 Hz), 2.32-2.53 (2H, m), 3.04 (2H, q, J=7 Hz), 3.37 (3H, s), 5.36 (2H, s), 5.92 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.16-7.40 (5H, m), 7.87 (1H, s), 8.52 (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)butanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.65-1.84 (2H, m), 2.27 (2H, t, J=7 Hz), 2.45-2.68 (2H, m), 3.04 (2H, q, J=7 Hz), 3.53 (4H, m), 3.69 (4H, m), 5.36 (2H, s), 5.95 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.91 (1H, m), 8.55 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).
EXAMPLE 468
4-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H NMR (CDCl3) δ 1.36 (3H, t, J=7 Hz), 1.66-1.82 (2H, m), 2.27 (2H, t, J=7 Hz), 2.46-2.68 (2H, m), 2.97 (6H, s), 3.04 (2H, q, J=7 Hz), 5.33 (2H, s), 5.94 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.92 (1H, m), 8.56 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).
EXAMPLE 469
3-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]propanoic acid
1H NMR (CDCl3) δ 1.36 (3H, t, J=7 Hz), 2.45 (2H, t, J=7 Hz), 2.82-2.96 (2H, m), 2.97 (6H, s), 3.03 (2H, q, J=7 Hz), 5.33 (2H, s), 5.96 (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-thiomorpholinyl)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (300 MHz, CDCl3) δ 1.36 (3H, t, J=7 Hz), 1.42-1.56 (4H, m), 2.26 (2H, t, J=7 Hz), 2.48-2.61 (2H, m), 3.01 (2H, q, J=7 Hz), 3.10 (4H, t, J=6 Hz), 3.19 (4H, t, J=6 Hz), 3.85 (2H, s), 5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.89 (1H, dd, J=2, 2 Hz), 8.56 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz). MS (m/z) 550 (M+H).
EXAMPLE 471
5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (300 MHz, CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.43-1.58 (4H, m), 2.24 (2H, t, J=7 Hz), 2.49-2.61 (2H, m), 2.66 (4H, t, J=4 Hz), 2.86 (4H, t, J=4 Hz), 3.02 (2H, q, J=7 Hz), 3.68 (2H, s), 5.89 (1H, d, J=5 Hz), 6.58 (1H, d, J=5 Hz), 7.90 (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-piperazinyl]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoic acid
1H NMR (300 MHz, CDCl3) δ 1.34 (3H, t, J=7 Hz), 1.41-1.57 (4H, m), 2.21 (2H, t, J=6 Hz), 2.43-2.57 (2H, m), 2.80-2.84 (4H, m), 2.91-3.00 (6H, m), 3.65 (2H, s), 3.83 (2H, m), 5.88 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.88 (1H, s), 8.55 (1H, s), 8.77 (1H, s). MS (m/z) 545 (M+H).
EXAMPLE 473
4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H NMR (300 MHz, CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.72 (2H, tt, J=7, 7 Hz), 2.26 (2H, t, J=7 Hz), 2.53-2.68 (6H, m), 2.87-2.90 (4H, m), 3.02 (2H, q, J=7 Hz), 3.72 (2H, s), 5.91 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.78 (1H, dd, J=2, 2 Hz), 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-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoic acid
1H NMR (300 MHz, CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.73 (2H, tt, J=7, 7 Hz), 2.25 (2H, t, J=7 Hz), 2.57-2.73 (2H, m), 3.04 (2H, q, J=7 Hz), 4.72 (2H, s), 4.89 (2H, s), 5.93 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.31 (2H, d, J=6 Hz), 7.76 (1H, dd, J=2, 2 Hz), 8.46 (2H, d, J=6 Hz), 8.53 (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]butanoic acid
1H NMR (300 MHz, CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.73 (2H, tt, J=7, 7 Hz), 2.26 (2H, t, J=7 Hz), 2.54-2.72 (6H, m), 3.03 (2H, q, J=7 Hz), 3.66-3.73 (6H, m), 5.90 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.79 (1H, s), 8.53 (1H, s), 8.67 (1H, s). MS (m/z) 443 (M+H).
EXAMPLE 476
5-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (300 MHz, CDCl3) δ 0.24 (2H, dt, J=7, 7 Hz), 0.57 (2H, dt, J=7, 7 Hz), 1.07-1.17 (1H, m), 1.38 (3H, t, J=7 Hz), 1.45-1.61 (4H, m), 2.23 (2H, t, J=7 Hz), 2.52-2.66 (2H, m), 3.02 (2H, q, J=7 Hz), 3.41 (2H, d, J=7 Hz), 4.70 (2H, s), 5.90 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.74 (1H, dd, J=2, 2 Hz), 8.52 (1H, d, J=2 Hz), 8.68 (1H, d, J=2 Hz). MS (m/z) 442 (M+H).
EXAMPLE 477
4-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoic acid
1H NMR (300 MHz, CDCl3) δ 0.23 (2H, dt, J=6, 6 Hz), 0.56 (2H, dt, J=6, 6 Hz), 1.05-1.17 (1H, m), 1.37 (3H, t, J=7 Hz), 1.75 (2H, tt, J=7, 7 Hz), 2.28 (2H, t, J=7 Hz), 2.57-2.70 (2H, m), 3.03 (2H, q, J=7 Hz), 3.42 (2H, d, J=7 Hz), 4.73 (2H, s), 5.91 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.77 (1H, dd, J=2, 2 Hz), 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-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (300 MHz, CDCl3) δ 0.93 (6H, d, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.42-1.59 (4H, m), 1.92 (1H, qt, J=7, 7 Hz), 2.24 (2H, t, J=7 Hz), 2.48-2.69 (2H, m), 3.03 (2H, q, J=7 Hz), 3.33 (2H, d, J=7 Hz), 4.66 (2H, s), 5.91 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.90 (1H, dd, J=2, 2 Hz), 8.56 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz). MS (m/z) 489 (M+H).
EXAMPLE 479
3-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid
1H NMR (300 MHz, CDCl3) δ 0.92 (6H, d, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.91 (1H, qt, J=7, 7 Hz), 2.49 (2H, t, J=8 Hz), 2.82-2.98 (2H, m), 3.03 (2H, q, J=7 Hz), 3.35 (2H, d, J=7 Hz), 4.69 (2H, s), 5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.72 (1H, dd, J=2, 2 Hz), 851 (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 1.36 (3H, t, J=7 Hz), 2.55 (2H, t, J=8 Hz), 2.66 (4H, br s), 2.79-2.97 (2H, m), 3.02 (2H, q, J=7 Hz), 3.70-3.74 (6H, m), 5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 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-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H NMR (300 MHz, CDCl3) δ 1.36 (3H, t, J=7 Hz), 1.73 (2H, tt, J=7, 7 Hz), 2.26 (2H, t, J=7 Hz), 2.57-2.70 (6H, m), 3.02 (2H, q, J=7 Hz), 3.69 (6H, m), 5.90 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.93 (1H, dd, J=2, 2 Hz), 8.57 (1H, d, J=2 Hz), 8.77(1H, d, J=2 Hz). MS (m/z) 488 (M+H).
EXAMPLE 482
4-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylamino)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoic acid
1H NMR (300 MHz, CDCl3) δ 0.54-0.60 (2H, m), 0.74-0.79 (2H, m), 1.38 (3H, t, J=7 Hz), 1.65 (2H, tt, J=6, 6 Hz), 2.21 (2H, t, J=6 Hz), 2.45-2.55 (2H, m), 3.03 (2H, q, J=7 Hz), 4.30 (2H, s), 5.04 (1H, br s), 5.93 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.73 (1H, dd, J=2, 2 Hz), 8.52 (1H, d, J=2 Hz), 8.69(1H, d, J=2 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)pentanoic acid
1H NMR (300 MHz, CDCl3) δ 1.36 (3H, t, J=7 Hz), 1.42-1.56 (4H, m), 2.22 (2H, br s), 2.34-2.48 (2H, m), 3.03 (2H, q, J=7 Hz), 3.38-3.43 (2H, br s), 4.23-4.50 (4H, m), 5.93 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 6.89-6.97 (3H, m), 7.23-7.30 (2H, m), 7.85 (1H, s), 8.52 (1H, s), 8.78 (1H, s). MS (m/z) 552 (M+H).
EXAMPLE 484
5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(2-hydroxyethyl)(methyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoic acid
1H NMR (300 MHz, CDCl3) δ 1.36 (3H, t, J=7 Hz), 1.34-1.54 (4H, m), 2.15-2.26 (2H, m), 2.33-2.52 (2H, m), 2.98 (2H, q, J=7 Hz), 3.16 (3H, s), 3.59-3.72 (2H, m), 3.99-4.10 (2H, m), 4.70 (2H, s), 5.94 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.85 (1H, s), 8.51 (1H, s), 8.73 (1H, s). MS (m/z) 490 (M+H).
EXAMPLE 485
5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(1-piperidinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (300 MHz, CDCl3) δ 1.36 (3H, t, J=7 Hz), 1.39-1.51 (6H, m), 1.62-1.71 (4H, m), 2.19 (2H, t, J=6 Hz), 2.52-2.65 (2H, m), 2.78-2.91 (4H, m), 3.10 (2H, q, J=7 Hz), 3.65 (2H, s), 5.89 (1H, d, J=5 Hz), 6.58 (1H, d, J=5 Hz), 7.88 (1H, s), 8.55 (1H, s), 8.76 (1H, s). MS (m/z) 500 (M+H).
EXAMPLE 486
3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid
1H NMR (300 MHz, CDCl3) δ 1.37 (3H, t, J=7 Hz), 2.52 (2H, t, J=8 Hz), 2.68 (4H, t, J=5 Hz), 2.81-2.95 (6H, m), 3.02 (2H, q, J=7 Hz), 3.74 (2H, s), 5.92 (1H, d, J=5 Hz), 6.61 (1H, d, J=5 Hz), 7.89 (1H, dd, J=2, 2 Hz), 8.55 (1H, d, J=2 Hz), 8.79 (1H, d, J=2 Hz). MS (m/z) 490 (M+H).
EXAMPLE 487
3-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}pyrrolo[1,2-b]pyridazin-3-yl)propanoic acid
1H NMR (300 MHz, DMSO-d6) δ 1.32 (3H, t, J=7 Hz), 2.40-2.56 (12H, m), 2.58-2.65 (2H, m), 2.94 (2H, q, J=7 Hz), 3.52 (2H, t, J=5 Hz), 3.67 (2H, s), 5.83 (1H, d, J=5 Hz), 6.62 (1H, d, J=5 Hz), 8.25 (1H, dd, J=2, 2 Hz), 8.63 (1H, d, J=2 Hz), 8.86 (1H, d, J=2 Hz). MS (m/z) 517 (M+H).
EXAMPLE 488
4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H NMR (300 MHz, CDCl3) δ 0.91 (6H, d, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.74 (2H, tt, J=8, 8 Hz), 1.91 (1H, qt, J=7, 7 Hz), 2.27 (2H, t, J=8 Hz), 2.56-2.73 (2H, m), 3.03 (2H, q, J=7 Hz), 3.33 (2H, d, J=7 Hz), 4.68 (2H, s), 5.92 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.92 (1H, dd, J=7, 7 Hz), 8.56 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz). MS (m/z) 475 (M+H).
EXAMPLE 489
5-[2-{[2-(benzylamino)-2-oxoethoxy]methyl}-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.33 (3H, t, J=7 Hz), 1.39-1.60 (4H, m), 2.15 (2H, t, J=7 Hz), 2.42 (3H, s), 2.40-2.58 (2H, m), 2.95 (2H, q, J=7 Hz), 4.19 (2H, s), 4.50 (2H, d, J=7 Hz), 4.75 (2H, m), 5.91 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.07 (1H, br), 7.22-7.34 (5H, m), 7.54 (1H, s), 8.40 (1H, s), 8.53 (1H, s). MS (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)pentanoic acid
1H NMR (CDCl3) δ 1.36 (3H, t, J=7 Hz), 1.23-1.60 (4H, m), 2.19 (2H, t, J=7 Hz), 2.28-2.46 (2H, m), 2.42 (3H, s), 2.97 (2H, q, J=7 Hz), 4.37 (2H, m), 5.89 (1H, d, J=4 Hz), 5.90 (1H, m), 6.57 (1H, d, J=4 Hz), 7.42-7.53 (4H, m), 7.90 (2H, d, J=8 Hz), 8.34 (1H, s), 8.53 (1H, s). MS (ESI−): m/z 505, MS (ESI+): m/z 507.
EXAMPLE 491
5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(1-pyrrolidinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (300 MHz, CDCl3) δ 1.35 (3H, t, J=7 Hz), 1.39-1.57 (4H, m), 1.79-1.88 (4H, m), 2.18 (2H, t, J=7 Hz), 2.84-2.89 (6H, m), 3.00 (2H, q, J=7 Hz), 3.89-4.02 (2H, m), 5.88 (1H, d, J=5 Hz), 6.56 (1H, d, J=5 Hz), 7.87 (1H, s), 8.55 (1H, s), 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 1.37 (3H, t, J=8 Hz), 2.39-2.48 (2H, m), 2.83-2.94 (2H, m), 3.03 (2H, q, J=8 Hz), 3.45 (3H, s), 4.65 (2H, s), 5.95 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.24 (1H, m), 7.35 (1H, br s), 7.40-7.46 (2H, m). MS (ESI+): m/z 373 (M+H).
EXAMPLE 493
4-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=8 Hz), 1.64-1.78 (2H, m), 2.24 (2H, t, J=8 Hz), 2.56-2.66 (2H, m), 3.04 (2H, q, J=8 Hz), 3.45 (3H, s), 4.65 (2H, s), 5.94 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.21-7.29 (1H, overlapped with CDCl3), 7.36 (1H, br s), 7.39-7.46 (2H, m). MS (ESI+): m/z 387 (M+H).
EXAMPLE 494
5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-phenyl-1-piperazinyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (300 MHz, CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.41-1.61 (4H, m), 2.22 (2H, t, J=7 Hz), 2.49-2.67 (2H, m), 2.76 (4H, t, J=5 Hz), 3.03 (2H, q, J=7 Hz), 3.20 (4H, t, J=5 Hz), 3.73 (2H, s), 5.89 (1H, d, J=5 Hz), 6.58 (1H, d, J=5 Hz), 6.85 (1H, dd, J=8, 8 Hz), 6.93 (2H, J=8 Hz), 7.25 (2H, J=8 Hz), 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)pentanoic acid
1H NMR (300 MHz, CDCl3) δ 1.28 (3H, t, J=7 Hz), 1.32-1.43 (4H, m), 2.03-2.17 (2H, m), 2.23-2.41 (2H, m), 2.49-2.88 (2H, m), 2.98 (2H, q, J=7 Hz), 3.37 (3H, s), 3.89-3.99 (2H, m), 4.51 (2H, s), 5.91 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.82 (1H, s), 8.47 (1H, s), 8.72 (1H, s).
EXAMPLE 496
5-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
mp 111-112° C. 1H NMR (CDCl3) δ 1.37 (3H, t, J=8 Hz), 1.41-1.60 (4H, m), 2.21 (2H, br t, J=8 Hz), 2.30-2.70 (2H, m), 3.04 (2H, d, J=8 Hz), 3.46 (3H, s), 3.90 (3H, s), 4.63 (2H, br d, J=5 Hz), 5.92 (1H, d, J=5 Hz), 6.58 (2H, d, J=8 Hz), 7.25 (1H, m), 8.22 (1H, d, J=1 Hz), 8.40 (1H, d, J=3 Hz). MS (ESI+): m/z 398 (M+H).
EXAMPLE 497
5-[7-ethyl-4-(5-methoxy-3-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
mp 133-134° C. 1H NMR (CDCl3) δ 1.37 (3H, t, J=8 Hz), 1.40-1.62 (7H, m), 2.24 (2H, t, J=8 Hz), 2.35-2.49 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 3.89 (3H, s), 5.87 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.23 (1H, m), 8.20 (1H, d, J=1 Hz), 8.39 (1H, d, J=3 Hz). 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
mp 164-165° C. 1H NMR (CDCl3) δ 1.37 (3H, t, J=8 Hz), 2.44-2.54 (2H, m), 2.80-3.00 (2H, m), 3.04 (2H, d, J=8 Hz), 3.47 (3H, s), 3.89 (3H, s), 4.66 (2H, br s), 5.95 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.25 (1H, m), 8.22 (1H, d, J=1 Hz), 8.38 (1H, d, J=3 Hz). MS (ESI+): m/z 370 (M+H).
EXAMPLE 499
4-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
mp 140-141° C. 1H NMR (CDCl3) δ 1.38 (3H, t, J=8 Hz), 1.68-1.82 (2H, m), 2.25 (2H, t, J=8 Hz), 2.52-2.75 (2H, m), 3.04 (2H, d, J=8 Hz), 3.46 (3H, s), 3.92 (3H, s), 4.65 (2H, br d, J=7 Hz), 5.94 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.29 (1H, m), 8.23 (1H, d, J=1 Hz), 8.37 (1H, d, J=3 Hz). MS (ESI+): m/z 384 (M+H).
EXAMPLE 500
5-[7-ethyl-2-(methoxymethyl)-4-(5-pyrimidinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=8 Hz), 1.40-1.64 (4H, m), 2.25 (2H, t, J=8 Hz), 2.49-2.61 (2H, m), 3.04 (2H, d, J=8 Hz), 3.47 (3H, s), 4.65 (2H, s), 5.91 (1H, d, J=5 Hz), 6.62 (1H, d, J=5 Hz), 8.82 (2H, s), 9.32 (H, 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]butanoic acid
mp 112-113° C. 1H NMR (CDCl3) δ 1.38 (3H, t, J=8 Hz), 1.66-1.79 (2H, m), 2.28 (2H, t, J=8 Hz), 2.52-2.71 (2H, m), 3.05 (2H, d, J=8 Hz), 3.46 (3H, s), 4.66 (2H, br s), 5.92 (1H, d, J=5 Hz), 6.61 (1H, d, J=5 Hz), 7.77 (1H, m), 8.53 (1H, d, J=1 Hz), 8.67 (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
mp 159-160° C. 1H NMR (CDCl3) δ 1.38 (3H, t, J=8 Hz), 2.47 (2H, br t, J=8 Hz), 2.79-2.98 (2H, m), 3.04 (2H, d, J=8 Hz), 3.47 (3H, s), 4.66 (2H, s), 5.93 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.74 (1H, m), 8.51 (1H, d, J=1 Hz), 8.68 (1H, d, J=3 Hz). 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]pentanoic acid
mp 118-119° C. 1H NMR (CDCl3) δ 1.37 (3H, t, J=8 Hz), 1.40-1.62 (7H, m), 2.24 (2H, t, J=8 Hz), 2.45-2.64 (2H, m), 3.04 (2H, d, J=8 Hz), 3.45 (3H, s), 4.63 (2H, s), 5.91 (1H, d, 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-triazol-4-ylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H-NMR (CDCl3) δ 1.36 (3H, t, J=7 Hz), 1.60 (2H, m), 2.32 (2H, m), 2.46 (2H, m), 3.01 (2H, q, J=7 Hz), 5.75 (2H, m), 5.97 (1H, d, J=5 Hz), 6.66 (1H, d, J=5 Hz), 7.87 (1H, m), 7.97 (1H, s), 8.53 (1H, s), 8.65 (1H, s), 8.69 (1H, s).
EXAMPLE 505
4-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylamino)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoic acid
1H-NMR (CDCl3) δ 0.56 (2H, m), 0.75 (2H, m), 1.38 (3H, t, J=7 Hz), 1.65 (2H, m), 2.21 (2H, m), 2.50 (2H, m), 3.01 (2H, q, J=7 Hz), 3.27 (3H, br), 4.29 (2H, s), 5.93 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.98 (1H, m), 8.55 (1H, m), 8.78 (1H, m). MS (ESI+) m/z: 457 and 459 (M+H)
EXAMPLE 506
4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-oxo-1,3-oxazolidin-3-yl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoic acid
1H-NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.68 (2H, m), 2.31 (2H, m), 2.53 (2H, m), 2.98 (2H, q, J=7 Hz), 3.77 (2H, m), 4.42 (2H, t, J=7 Hz), 4.67 (2H, m), 5.94 (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-(ethoxycarbonyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzoic acid
1H-NMR (CDCl3) δ 1.00 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.62 (3H, s), 3.04 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 6.29 (1H, d, J=5 Hz), 6.68 (1H, d, J=5 Hz), 7.49 (2H, dd, J=2 and 8 Hz), 7.82 (1H, d, J=2 Hz), 8.07 (1H, d, J=8 Hz). MS (ESI+) m/z: 431 and 433 (M+H)
EXAMPLE 508
5-[4-(3-cyanophenyl)-7-ethyl-2-(phenoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H-NMR (CDCl3) δ 1.25-1.49 (7H, m), 2.15 (2H, m), 2.54 (2H, m), 3.02 (2H, q, J=7 Hz), 5.23 (2H, s), 5.86 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 6.98 (1H, t, J=8 Hz), 7.06 (2H, d, J=8 Hz), 7.28 (2H, t, J=8 Hz), 7.60 (2H, m), 7.67 (1H, s), 7.77 (1H, m).
EXAMPLE 509
5-[4-(3-cyanophenyl)-7-ethyl-2-(3-methyl-2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H-NMR (CDCl3) δ 1.14-1.28 (4H, m), 1.37 (3H, t, J=7 Hz), 2.01 (2H, t, J=7 Hz), 2.23 (3H, s), 2.40 (2H, m), 3.02 (2H, q, J=7 Hz), 5.92 (1 J, d, J=5 Hz) (6.64 (1H, d, J=5 Hz), 6.94 (1 J, d, J=5 Hz), 7.33 (1H, d, J=5 Hz), 7.57-7.66 (2H, m), 7.73-7.76 (2H, m).
EXAMPLE 510
(2E)-4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-2-butenoic acid
1H-NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 2.55 (3H, s), 3.03 (2H, q, J=7 Hz), 3.09 (2H, d, J=7 Hz), 5.45 (1H, dt, J=7 and 16 Hz), 6.05 (1H, d, J=5 Hz), 6.25 (1H, d, J=16 Hz), 6.57 (1H, d, J=5 Hz), 7.55 (1H, t, J=8 Hz), 7.66+−7.72 (3H, m). MS (ESI+): m/z 345 (M+H)
EXAMPLE 511
4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.68-1.84 (2H, m), 2.28 (2H, t, J=7 Hz), 2.56-2.74 (2H, m), 3.03 (2H, q, J=7 Hz), 3.46 (3H, s), 4.66 (2H, s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.92 (1H, m), 8.57 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz). MS (ESI−): m/z 430 432, MS (ESI+): m/z 432 434.
The following compound(s) was (were) obtained in a similar manner to that of Example 159.
EXAMPLE 512
ethyl 4-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.35-1.45 (2H, m), 1.88 (2H, t, J=7 Hz), 2.43-2.55 (2H, m), 3.03 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.98 (1H, d, J=4 Hz), 6.65 (1H, d, J=4 Hz), 7.33 (1H, d, J=5 Hz), 7.42-7.55 (6H, m), 8.55 (1H, d, J=5 Hz). MS (ESI+): m/z 448.
EXAMPLE 513
ethyl 3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoate
1H NMR (CDCl3) δ 1.09 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.98-2.08 (2H, m), 2.75-2.85 (2H, m), 3.03 (2H, q, J=7 Hz), 3.92 (2H, q, J=7 Hz), 6.00 (1H, d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 7.32 (1H, d, J=5 Hz), 7.42 (1H, s), 7.43-7.57 (5H, m), 8.55 (1H, d, J=5 Hz). MS (ESI+): m/z 434.
EXAMPLE 514
methyl {2-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}acetate
1H NMR (CDCl3) δ 1.36 (3H, t, J=7 Hz), 2.73-2.85 (2H, t, J=7 Hz), 3.03 (2H, t, J=7 Hz), 3.15 (2H, t, J=7 Hz), 3.74 (2H, s), 4.09 (3H, s), 6.02 (1H, d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 7.39 (1H, m), 7.42-7.60 (6H, m), 8.53 (1H, d, J=5 Hz). MS (ESI+): m/z 450.
EXAMPLE 515
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), 1.36 (3H, t, J=7 Hz), 1.93 (2H, t, J=7 Hz), 2.23 (3H, s), 2.39 (2H, m), 3.03 (2H, q, J=7 Hz), 4.03 (2H, q, J=7 Hz), 5.93 (1H, d, J=5 Hz), 6.64 (1H, d, J=7 Hz), 6.96 (1H, d, J=5 Hz), 7.33 (1H, d, J=5 Hz), 7.60-7.67 (2H, m), 7.72-7.79 (2H, m).
EXAMPLE 516
methyl 5-[4-(3-cyanophenyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H-NMR (CDCl3) δ 1.21-1.47 (7H, m), 2.04 (2H, t, J=7 Hz), 2.60 (2H, m), 3.05 (2H, q, J=7 Hz), 3.61 (3H, s), 5.37 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.13 (1H, m), 7.36 (1H, m), 7.44 (1H, m), 7.62-7.78 (4H, m).
EXAMPLE 517
ethyl 3-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoate
1H-NMR (CDCl3) δ 1.08 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.98 (2H, m), 2.75 (2H, m), 3.02 (2H, q, J=7 Hz), 3.89 (2H, q, J=7 Hz), 5.93 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.41-7.55 (5H, m), 7.57-7.78 (4H, m). MS (ESI+): m/z 424 (M+H)
EXAMPLE 518
ethyl 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H-NMR (CDCl3) δ 1.02-1.25 (7H, m), 1.37 (3H, t, J=7 Hz), 1.88 (2H, t, J=7 Hz), 2.43 (2H, m), 3.01 (2H, q, J=7 Hz), 4.00 (2H, q, J=7 Hz), 5.96 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.29 (1H, m), 7.37-7.54 (8H, m). MS (ESI+): m/z 461
EXAMPLE 519
4-(5-bromo-3-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazine-3-carbonitrile
1H NMR (CDCl3) δ 1.42 (3H, t, J=8 Hz), 3.12 (2H, t, J=8 Hz), 6.65 (1H, d, J=5 Hz), 6.94 (1H, d, J=5 Hz), 7.51-7.59 (3H, m), 7.83-7.91 (2H, m), 8.19 (1H, m), 8.85-8.92 (2H, m). MS (ESI+): m/z 403, 405 (M+H).
The following compound(s) was (were) obtained in a similar manner to that of Example 175.
EXAMPLE 520
5-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.36-1.57 (4H, m), 2.16 (2H, t, J=7 Hz), 2.51-2.62 (2H, m), 3.03 (2H, q, J=7 Hz), 4.69 (2H, s), 4.78 (2H, s), 5.87 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.35 (2H, d, J=5 Hz), 7.61 (2H, d, J=5 Hz), 7.67 (1H, s), 7.77 (1H, m), 8.54 (2H, d, J=5 Hz). MS (ESI−): m/z 467, MS (ESI+): m/z 469.
EXAMPLE 521
5-{4-[3-(aminocarbonyl)phenyl]-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.47-1.68 (4H, m), 2.15-2.40 (2H, m), 2.40-2.56 (1H, m), 2.82-2.96 (1H, m), 3.05 (2H, q, J=7 Hz), 4.68 (2H, s), 4.72 (1H, d, J=17 Hz), 4.93 (1H, d, J=17 Hz), 5.83 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.31 (2H, d, J=5 Hz), 7.39 (1H, br), 7.45 (1H, d, J=8 Hz), 7.58 (1H, t, J=8 Hz), 7.69 (1H, br), 7.77 (1H, br), 7.98 (1H, d, J=8 Hz), 8.57 (2H, d, J=5 Hz). MS (ESI−): m/z 485, MS (ESI+): m/z 487.
EXAMPLE 522
5-{4-(3-cyanophenyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.30-1.57 (4H, m), 2.18 (2H, m), 2.48-2.65 (2H, m), 3.03 (2H, q, J=7 Hz), 4.83 (2H, s), 4.85 (2H, s), 5.86 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.61 (2H, d, J=5 Hz), 7.68 (1H, s), 7.77 (1H, m), 8.53 (2H, d, 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-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.38-1.57 (4H, m), 2.15 (2H, t, J=7 Hz), 2.49-2.62 (2H, m), 3.04 (2H, q, J=7 Hz), 4.69 (2H, s), 4.76 (2H, s), 5.85 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.33 (1H, m), 7.62 (2H, m), 7.67 (1H, s), 7.73-7.82 (2H, m), 8.53 (1H, d, J=5 Hz), 8.67 (1H, s). MS (ESI−): m/z 467, MS (ESI+): m/z 469.
EXAMPLE 524
5-[4-(3-cyanophenyl)-7-ethyl-2-(5-methyl-3-isoxazolyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic 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, q, J=7 Hz), 5.89 (1H, d, J=5 Hz), 6.54 (1H, s), 6.67 (1H, d, J=5 Hz), 7.63 (2H, m), 7.68 (1H, s), 7.78 (1H, m).
EXAMPLE 525
5-[4-(3-cyanophenyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H-NMR (CDCl3) δ 1.23-1.42 (7H, m), 2.07 (2H, t, J=7 Hz), 2.58 (2H, m), 3.03 (2H, q, J=7 Hz), 5.87 (1H, d, J=5 hz), 6.56 (1H, d, J=5 Hz), 7.13 (1H, m), 7.36 (1H, m), 7.43 (1H, d, J=5 Hz), 7.62 (2H, m), 7.70 (1H, s), 7.76 (1H, m).
EXAMPLE 526
3-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoic acid
1H-NMR (CDCl3) δ 1.36 (3H, t, J=7 Hz), 1.99 (2H, m), 2.75 (2H, m), 3.00 (2H, q, J=7 Hz), 5.93 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.42-7.55 (5H, m), 7.57-7.78 (4H, m).
EXAMPLE 527
5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H-NMR (CDCl3) δ 1.03-1.25 (4H, m), 1.36 (3H, t, J=7 Hz), 1.90 (2H, t, J=7 Hz), 2.41 (2H, m), 3.00 (2H, q, J=7 Hz), 5.97 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.28 (1H, m), 7.35-7.54 (8H, m). MS (ESI+): m/z 433 (M+H)
The following compound(s) was (were) obtained in a similar manner to that 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 1.22 (3H, t, J=7 Hz), 1.32-1.46 (5H, m), 1.72 (2H, m), 2.10 (2H, t, J=7 Hz), 2.54 (3H, s), 2.78 (2H, m), 3.03 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 5.89 (1H, d, J=5 Hz), 6.54 (1H, s), 6.66 (1H, d, J=5 Hz), 7.62 (2H, m), 7.67 (1H, s), 7.77 (1H, m).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 176.
EXAMPLE 529
ethyl 4-[4-(aminocarbonyl)-3-bromophenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate
1H-NMR (CDCl3) δ 1.03 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.60 (3H, s), 3.03 (2H, q, J=7 Hz), 4.07 (2H, q, J=7 Hz), 5.83 (1H, s, br), 6.19 (1H, s, br), 6.28 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.46 (1H, d, J=8 Hz), 7.72 (1H, s), 7.77 (1H, d, J=8 Hz).
The following compound(s) was (were) obtained in a similar manner to that of Example 184.
EXAMPLE 530
3-[2-(cyclopentylamino)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
1H-NMR (CDCl3) δ 1.36 (3H, t, J=7 Hz), 1.51-1.80 (6H, m), 2.15 (2H, m), 2.96 (2H, q, J=7 Hz), 3.05 (3H, s), 4.27 (1H, m), 5.94 (1H, d, J=5 Hz), 6.47-6.53 (2H, m), 7.53-7.59 (3H, m), 7.74 (1H, m).
EXAMPLE 531
3-[7-ethyl-2-(methylamino)-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
1H-NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 2.94-3.07 (8H, m), 5.95 (1H, d, J=5 Hz), 6.50 (2H, m), 7.54-7.59 (3H, m), 7.74 (1H, m).
The following compound(s) was (were) obtained in a similar manner to that 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]propanoyl}amino)-6-{1[(2,2-dimethylpropanoyl)oxy]methyl}tetrahydro-2H-pyran-3,4,5-triyl tris(2,2-dimethylpropanoate)
1H-NMR (CDCl3) δ 1.07 (9H, s), 1.11 (9H, s), 1.16 (9H, s), 1.18 (9H, s), 1.37 (3H, t, J=7 Hz), 2.23 (2H, m), 2.84 (2H, m), 3.03 (2H, q, J=7 Hz), 3.48 (3H, s), 3.91-4.21 (3H, m), 4.62-4.67 (2H, m), 5.00-5.26 (3H, m), 5.43 (2H, m), 5.91 (1H, d, J=5 Hz), 6.55 (1H, m, br), 6.62 (1H, d, J=5 Hz), 7.84 (1H, m), 8.51 (1H, m), 8.77 (1H, m).
The following compound(s) was (were) obtained in a similar manner to that of Example 226.
EXAMPLE 533
[4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-3-yl]methanol
1H-NMR (CDCl3) δ 1.40 (3H, t, J=7 Hz), 2.53 (1H, t, J=7 Hz), 3.07 (2H, q, J=7 Hz), 4.48 (2H, m), 6.23 (1H, d, J=5 Hz), 6.62 (1H, m), 6.71 (1H, d, J=5 Hz), 7.10 (1H, d, J=5 Hz), 7.46-7.52 (3H, m), 7.61 (1H, m), 7.64 (1H, m).
EXAMPLE 534
[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methanol
1H NMR (CDCl3) δ 1.38 (3H, t, J=8 Hz), 3.05 (2H, q, J=8 Hz), 3.45-3.55 (4H, m), 4.40 (2H, br d, J=7 Hz), 4.77 (2H, br s), 6.22 (1H, d, J=5 Hz), 6.70 (1H, d, J=5 Hz), 8.11 (1H, m), 8.74 (1H, br s), 8.80 (1H, d, J=2 Hz). MS (ESI+): m/z 302 (M+H).
The following compound(s) was (were) obtained in a similar manner to that of Example 227.
EXAMPLE 535
(2R,3S,4S,5R,6R)-2-[(acetyloxy)methyl]-6-({5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentyl}oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate
1H-NMR (CDCl3) δ 0.82-1.18 (6H, m), 1.37 (3H, t, J=7 Hz), 1.92-2.17 (14H, m), 2.35 (2H, m), 3.01 (2H, q, J=7 Hz), 3.16 (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), 5.35 (1H, m), 5.90 (1H, d, J=5 Hz), 6.62 (1H, d, J=5 Hz), 7.44-7.53 (5H, m), 7.60-7.80 (4H, m).
The following compound(s) was (were) obtained in a similar manner to that of 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 1.19 (3H, t, J=7 Hz), 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 (2H, q, J=7 Hz), 3.71 (1H, t, J=5 Hz), 4.05 (2H, q, J=7 Hz), 4.89 (2H, d, J=5 Hz), 5.98 (1H, d, J=4 Hz), 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 1.24 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.62-1.78 (2H, m), 2.16-2.28 (2H, m), 2.36-2.53 (2H, m), 2.44 (3H, s), 3.06 (2H, q, J=7 Hz), 3.86 (1H, t, J=7 Hz), 4.12 (2H, q, 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 1.26 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.46-1.65 (4H, m), 2.16 (2H, t, J=7 Hz), 2.32-2.44 (2H, m), 3.04 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.86 (2H, s), 5.91 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.58-7.68 (3H, m), 7.75-7.82 (1H, m). MS (ESI+): m/z 406.
EXAMPLE 539
ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (CDCl3) δ 1.25 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.64-1.79 (2H, m), 2.23 (2H, t, J=7 Hz), 2.42-2.53 (2H, m), 3.04 (2H, q, J=7 Hz), 4.10 (2H, q, J=7 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 1.20 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.32 (2H, m), 2.68-2.90 (2H, m), 3.03 (2H, q, J=7 Hz), 4.10 (2H, m), 4.89 (2H, s), 6.03 (1H, m), 6.65 (1H, m), 7.90 (1H, m), 8.58 (1H, m), 8.83 (1H, m). 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 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.67 (2H, tt, J=7, 7 Hz), 2.20 (2H, t, J=7 Hz), 2.37-2.79 (2H, m), 3.04 (2H, q, J=7 Hz), 3.77 (1H, t, J=4 Hz), 4.07 (2H, q, J=7 Hz), 4.91 (2H, d, J=4 Hz), 5.96 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.73 (1H, dd, J=2, 2 Hz), 8.52 (1H, d, J=2 Hz), 8.70 (1H, d, J=2 Hz).
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 1.20 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.31 (2H, t, J=8 Hz), 2.85 (2H, t, J=8 Hz), 3.04 (2H, q, J=7 Hz), 3.69-3.75 (1H, br s), 4.06 (2H, q, J=7 Hz), 4.88 (2H, s), 6.00 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.23-7.26 (1H, m), 7.36 (1H, s), 7.44-7.46 (2H, m).
EXAMPLE 543
ethyl 4-[4-(3-chlorophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (CDCl3) δ 1.21 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 1.57 (3H, s), 1.59-1.74 (2H, m), 2.20 (2H, t, J=8 Hz), 2.37-2.47 (2H, m), 3.03 (2H, q, J=8 Hz), 3.84 (1H, t, J=5 Hz), 4.06 (2H, q, J=8 Hz), 4.39 (2H, d, J=5 Hz), 5.32 (2H, s), 5.96 (1H, d, J=5 Hz), 6.56 (1H, d, J=5 Hz), 7.21-7.29 (1H, overlappled with CDCl3), 736 (1H, br s), 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-one
1H NMR (CDCl3) δ 1.42 (3H, t, J=8 Hz), 3.11 (2H, q, J=8 Hz), 5.32 (2H, s), 6.87 (1H, d, J=5 Hz), 6.99 (1H, d, J=5 Hz), 8.20 (1H, m), 8.83-8.87 (2H, m). MS (ESI+): m/z 358, 360 (M+H).
4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid
1H NMR (CDCl3-CD3OD) δ 1.40 (3H, t, J=8 Hz), 3.09 (2H, q, J=8 Hz), 4.93 (2H, s), 6.34 (1H, d, J=5 Hz), 6.79 (1H, d, J=5 Hz), 7.96 (1H, m), 8.55 (1H, br s), 8.73 (1H, br s). 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-pyran-2-yl]propanamide
1H-NMR (DMSO-d6) δ 1.30 (3H, t, J=7 Hz), 2.21 (1H, m), 2.96 (2H, q, J=7 Hz), 3.25-3.45 (8H, m), 3.66 (1H, m), 4.40 (1H, m), 4.55-4.67 (5H, m), 4.75 (1H, m), 5.85 (1H, d, J=5 Hz), 6.66 (1H, d, J=5 Hz), 8.23 (1H, m), 8.33 (1H, d, br, J=7 Hz), 8.61 (1H, m), 8.84 (1H, m).
EXAMPLE 546
3-[7-ethyl-2-phenyl-3-(5-{[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}pentyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
1H-NMR (CDCl3) δ 0.85-1.38 (6H, m), 1.46 (3H, t, J=7 Hz), 2.13 (2H, m), 2.38 (2H, m), 2.65 (1H, m), 2.73 (1H, m), 3.02 (2H, q, J=7 Hz), 3.23 (1H, m), 3.48-3.70 (4H, m), 3.804.01 (3H, m), 4.13 (1H, m), 5.90 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.42-7.55 (5H, m), 7.60-7.79 (4H, m).
The following compound(s) was (were) obtained in a similar manner to that of Example 235.
EXAMPLE 547
N-(2-aminoethyl)-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanamide
1H-NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 2.29 (2H, m), 2.72-3.07 (6H, m), 333 (2H, q, J=7 Hz), 3.49 (3H, s), 4.68 (2H, s), 5.93 (1H, d, J=5 Hz), 6.06 (1H, m, br), 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 compound(s) was (were) obtained in a similar manner to that of Example 268.
EXAMPLE 548
ethyl 3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoate
1H NMR (CDCl3) δ 1.15 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.37 (2H, t, J=7 Hz), 2.43 (3H, s), 2.86-3.01 (2H, m), 3.03 (2H, q, J=7 Hz), 3.99 (2H, q, J=7 Hz), 4.68 (2H, s), 4.81 (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), 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-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoate
1H NMR (CDCl3) δ 1.16 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.39 (2H, t, J=7 Hz), 2.43 (3H, s), 2.88-3.03 (2H, m), 3.04 (2H, q, J=7 Hz), 4.01 (2H, q, J=7 Hz), 4.83 (2H, s), 4.90 (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-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoate
1H NMR (CDCl3) δ 1.15 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.40 (2H, t, J=7 Hz), 2.42 (3H, s), 2.88-3.00 (2H, m), 3.03 (2H, q, J=7 Hz), 3.99 (2H, q, J=7 Hz), 4.79 (2H, s), 4.86 (2H, s), 5.92 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.16-7.23 (1H, m), 7.45-7.53 (2H, m), 7.68 (1H, m), 8.42 (1H, m), 8.53 (2H, m). MS (ESI+): m/z 459.
EXAMPLE 551
ethyl 4-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate
1H NMR (CDCl3) δ 1.18 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.60-1.80 (2H, m), 2.13-2.25 (2H, m), 2.43 (3H, s), 2.53-2.76 (2H, m), 3.03 (2H, q, J=7 Hz), 4.03 (2H, q, J=7 Hz), 4.68 (2H, s), 4.83 (2H, m), 5.92 (1H, d, J=4 Hz), 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-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (CDCl3) δ 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.35-1.57 (4H, m), 2.11 (2H, t, J=7 Hz), 2.53-2.65 (2H, m), 3.03 (2H, q, J=7 Hz), 4.03 (2H, q, J=7 Hz), 4.67 (2H, s), 4.78 (2H, s), 5.87 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.28 (2H, d, J=5 Hz), 7.61 (2H, m), 7.66 (1H, s), 7.78 (1H, m), 8.58 (2H, d, J=5 Hz). MS (ESI+): m/z 497.
EXAMPLE 553
ethyl 5-{4-(3-cyanophenyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (CDCl3) δ 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.35-1.58 (4H, m), 2.11 (2H, t, J=7 Hz), 2.55-2.65 (2H, m), 3.03 (2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 4.82 (2H, s), 4.86 (2H, s), 5.86 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.62 (2H, m), 7.67 (1H, s), 7.78 (1H, m), 8.51 (2H, m), 8.74 (1H, s). MS (ESI+): m/z 498.
EXAMPLE 554 
ethyl 5-{4-(3-cyanophenyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (CDCl3) δ 1.22 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.32-1.66 (4H, m), 2.10 (2H, t, J=7 Hz), 2.48-2.60 (2H, m), 3.03 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.66 (2H, s), 4.75 (2H, s), 5.86 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.28 (1H, m), 7.58-7.63 (2H, m), 7.66 (1H, s), 7.66-7.80 (2H, m), 8.54 (1H, m), 8.62 (1H, m). MS (ESI+): m/z 497.
EXAMPLE 555 
ethyl 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.62 (4H, m), 2.16 (2H, t, J=7 Hz), 2.53-2.71 (2H, m), 3.05 (2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 4.67 (2H, s), 4.78 (2H, s), 5.93 (1H, d, J=4 Hz), 6.63 (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-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.40 (3H, t, J=7 Hz), 1.30-1.60 (4H, m), 2.15 (2H, t, J=7 Hz), 2.50-2.68 (2H, m), 3.06 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.68 (2H, s), 4.78 (2H, s), 5.95 (1H, m), 6.63 (1H, m), 7.24-7.38 (1H, m), 7.75 (1H, m), 7.89 (1H, m), 8.58 (2H, s), 8.64 (1H, s), 8.80 (1H, s). MS (ESI+): m/z 551 553.
EXAMPLE 557
ethyl 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (CDCl3) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.58 (4H, m), 2.12 (2H, t, J=7 Hz), 2.53-2.68 (2H, m), 3.03 (2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 4.78 (2H, s), 4.84 (2H, s), 5.92 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.22 (1H, m), 7.48 (1H, d, J=8 Hz), 7.68-7.75 (1H, m), 7.88 (1H, m), 8.57 (2H, m), 8.78 (1H, d, J=2 Hz).
EXAMPLE 558
ethyl 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (CDCl3) δ 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.62 (4H, m), 2.15 (2H, t, J=7 Hz), 2.53-2.72 (2H, m), 3.05 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.82 (2H, s), 4.86 (2H, s), 5.94 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.88 (1H, m), 8.52 (2H, m), 8.55 (1H, d, J=2 Hz), 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-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate
1H NMR (CDCl3) δ 1.19 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.60-1.80 (2H, m), 2.22 (2H, t, J=7 Hz), 2.55-2.74 (2H, m), 3.05 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 4.69 (2H, s), 4.83 (2H, s), 5.96 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.30 (2H, d, J=6 Hz), 7.88 (1H, m), 8.56 (2H, d, J=6 Hz), 8.57 (1H, m), 8.80 (1H, m). MS (ESI+): m/z 537 539.
EXAMPLE 560
ethyl 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.55-1.82 (2H, m), 2.18 (2H, t, J=7 Hz), 2.52-2.72 (2H, m), 3.05 (2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 4.68 (2H, s), 4.83 (2H, s), 5.94 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.28 (1H, m), 7.73 (1H, d, J=8 Hz), 7.88 (1H, m), 8.54 (2H, m), 8.62 (1H, s), 8.79 (1H, s)
EXAMPLE 561
ethyl 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate
1H NMR (CDCl3) δ 1.26 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.63-1.82 (2H, m), 2.18 (2H, t, J=7 Hz), 2.55-2.75 (2H, m), 3.06 (2H, q, J=7 Hz), 4.00 (2H, q, J=7 Hz), 4.80 (2H, s), 4.88 (2H, s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.22 (1H, m), 7.48 (1H, d, J=8 Hz), 7.71 (1H, t, J=8 Hz), 7.89 (1H, m), 8.55 (2H, m), 8.78 (1H, d, J=2 Hz). MS (ESI+): m/z 537 539.
EXAMPLE 562
ethyl 4-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[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), 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.69-1.82 (2H, m), 2.21 (2H, t, J=7 Hz), 2.56-2.72 (2H, m), 3.03 (2H, q, J=7 Hz), 3.42 (2H, d, J=7 Hz), 4.04 (2H, q, J=7 Hz), 4.73 (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-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate
1H NMR (CDCl3) δ 1.19 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.70-1.82 (2H, m), 2.23 (2H, t, J=7 Hz), 2.56-2.76 (2H, m), 3.06 (2H, q, J=7 Hz), 4.04 (2H, q, J=7 Hz), 4.84 (2H, s), 4.95 (2H, m), 5.94 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.89 (1H, m), 8.50 (2H, m), 8.56 (1H, s), 8.74 (1H, s), 8.79 (1H, m). MS (ESI+): m/z 538 540.
EXAMPLE 564
ethyl 3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoate
1H NMR (CDCl3) δ 1.16 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.41 (2H, t, J=7 Hz), 2.85-3.07 (2H, m), 3.06 (2H, q, J=7 Hz), 4.02 (2H, q, J=7 Hz), 4.68 (2H, s), 4.81 (2H, s), 5.95 (1H, d, J=4 Hz), 6.65 (1H, d, J=4 Hz), 7.31 (2H, d, J=6 Hz), 7.87 (1H, m), 8.55 (1H, m), 8.56 (2H, d, J=6 Hz), 8.79 (1H, d, J=2 Hz). MS (ESI+): m/z 523 525.
EXAMPLE 565
ethyl 4-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)butanoate
1H NMR (CDCl3) δ 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.46-1.93 (8H, m), 2.21 (2H, t, J=7 Hz), 2.55-2.76 (2H, m), 3.02 (2H, q, J=7 Hz), 3.46-3.56 (1H, m), 3.60-3.68 (1H, m), 3.74-3.82 (2H, m), 3.83-3.96 (2H, m), 4.03 (2H, q, J=7 Hz), 4.63 (1H, m), 4.77 (2H, s), 5.91 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.89 (1H, m), 8.56 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).
EXAMPLE 566
ethyl 4-{4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate
1H NMR (300 MHz, CDCl3) δ 1.19 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.70 (2H, t, J=7 Hz), 2.19 (2H, t, J=7 Hz), 2.55-2.67 (2H, m), 3.04 (2H, q, J=7 Hz), 4.03 (2H, q, J=7 Hz), 4.69 (2H, s), 4.83 (2H, s), 5.94 (1H, d, J=5 Hz), 6.63(1H, d, J=5 Hz), 7.29 (2H, d, J=6 Hz), 7.73 (1H, dd, J=2, 2 Hz), 8.52 (1H, d, J=2 Hz), 8.58 (2H, d, J=6 Hz), 8.69 (1H, d, J=2 Hz).
EXAMPLE 567
ethyl 3-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate
1H NMR (CDCl3) δ 1.20 (3H, t, J=8 Hz), 1.37 (3H, t, J=8 Hz), 2.33-2.44 (2H, m), 2.84-2.94 (2H, m), 3.03 (2H, q, J=8 Hz), 3.45 (3H, s), 4.05 (2H, q, J=8 Hz), 4.64 (2H, s), 5.94 (1H, d, J=5 Hz), 6.58 (1H, d, J=5 Hz), 7.21-7.29 (1H, overlappled with CDCl3), 7.36 (1H, br s), 7.38-7.46 (2H, m).
EXAMPLE 568
ethyl 4-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (CDCl3) δ 1.20 (3H, t, J=8 Hz), 1.37 (3H, t, J=8 Hz), 1.62-1.78 (2H, m), 2.14-2.28 (2H, m), 2.53-2.66 (2H, m), 3.04 (2H, q, J=8 Hz), 3.46 (3H, s), 4.04 (2H, q, J=8 Hz), 4.65 (2H, s), 5.93 (1H, d, J=5 Hz), 6.58 (1H, d, J=5 Hz), 7.21-7.29 (1H, overlappled with CDCl3), 7.36 (1H, br s), 7.39-7.46 (2H, m).
The following compound(s) was (were) obtained in a similar manner to that of Example 272.
EXAMPLE 569
ethyl 5-{4-(5-bromo-3-pyridinyl)-2-[(1,1-dioxido-4-thiomorpholinyl)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (300 MHz, CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.39-1.53 (4H, m), 2.19 (2H, t, J=7 Hz), 2.50-2.61 (2H, m), 3.00 (2H, q, J=7 Hz), 3.10 (4H, t, J=6 Hz), 3.21 (4H, t, J=6 Hz), 3.85 (2H, s), 4.10 (2H, q, J=7 Hz), 5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.88 (1H, dd, J=2, 2 Hz), 8.55 (1H, d, J=2 Hz), 8.80 (1H, d, J=2 Hz).
EXAMPLE 570
ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (300 MHz, CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.41-1.54 (4H, m), 2.19 (2H, t, J=7 Hz), 2.50-2.61 (2H, m), 2.66 (4H, t, J=4 Hz), 2.85 (4H, t, J=4 Hz), 3.01 (2H, q, J=7 Hz), 3.67 (2H, s), 4.10 (2H, q, J=7H), 5.88 (H, d, J=5 Hz), 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-piperazinyl]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate
1H NMR (300 MHz, CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.40-1.55 (4H, m), 2.18 (2H, t, J=7 Hz), 2.48-2.66 (12H, m), 3.02 (2H, q, J=7 Hz), 3.61 (2H, t, J=5 Hz), 3.66 (2H, s), 4.10 (2H, q, J=7 Hz), 5.88 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.88 (1H, dd, J=2, 2 Hz), 8.55 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).
EXAMPLE 572
ethyl 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (300 MHz, CDCl3) δ 1.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.70 (2H, t, J=7, 7 Hz), 2.19 (2H, t, J=7 Hz), 2.50-2.67 (6H, m), 2.86 (4H, t, J=5 Hz), 3.02 (2H, q, J=7 Hz), 3.70 (2H, s), 4.05 (2H, q, J=5 Hz), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.74 (1H, dd, J=2, 2 Hz), 8.52 (1H, d, J=2 Hz), 8.68 (1H, d, J=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 1.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.72 (2H, tt, J=7, 7 Hz), 2.20 (2H, t, J=7 Hz), 2.56-2.69 (6H, m), 3.02 (2H, q, J=7 Hz), 3.68-3.71 (6H, m), 4.05 (2H, q, J=7 Hz) 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.74 (1H, dd, J=2, 2 Hz), 8.53 (1H, d, J=2 Hz), 8.69 (1H, d, J=2 Hz).
EXAMPLE 574
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 1.21 (3H, t, J=7 Hz), 1.34 (3H, t, J=7 Hz), 2.47-2.54 (2H, m), 2.59 (4H, t, J=5 Hz), 2.81-2.95 (2H, m), 3.02 (2H, q, J=7 Hz), 3.67 (4H, t, J=5 Hz), 3.69 (2H, s), 4.07 (2H, q, J=7 Hz), 5.90 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.88 (1H, dd, J=2, 2 Hz), 8.55 (1H, d, J=2 Hz), 8.79 (1H, d, J=2 Hz).
EXAMPLE 575
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 1.21 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.73 (2H, tt, J=7, 7 Hz), 2.20 (2H, t, J=7 Hz), 2.55-2.69 (6H, m), 3.02 (2H, q, J=7 Hz), 3.69 (4H, t, J=5 Hz), 4.05 (2H, q, J=7 Hz), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.89 (1H, dd, J=2, 2 Hz), 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-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoate
1H NMR (300 MHz, CDCl3) δ 0.46-0.52 (4H, m), 1.21 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.71 (2H, tt, J=8, 8 Hz), 2.21 (2H, t, J=8 Hz), 2.32-2.39 (1H, m), 2.45-2.54 (2H, m), 3.04 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 4.07 (2H, s), 5.89 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.72 (1H, dd, J=2, 2 Hz), 8.50 (1H, 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 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.56 (4H, m), 2.18 (2H, t, J=8 Hz), 2.41-2.52 (2H, m), 3.04 (2H, q, J=7 Hz), 3.19 (2H, t, J=5 Hz), 4.07 (2H, s), 4.09 (2H, q, J=7 Hz), 4.17 (2H, t, J=5 Hz), 5.90 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 6.92-6.98 (3H, m), 7.29-7.32 (2H, m), 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 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.42-1.63 (4H, m), 2.20 (2H, t, J=8 Hz), 2.38 (3H, s), 2.53-2.64 (2H, m), 2.75 (2H, t, J=5 Hz), 3.02 (2H, q, J=7 Hz), 3.66 (2H, t, J=5 Hz), 3.77 (2H, s), 4.10 (2H, q, J=7 Hz), 5.90 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.88 (1H, dd, J=2, 2 Hz), 8.55 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).
EXAMPLE 579
ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(1-piperidinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
15 1H NMR (300 MHz, CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.42-1.58 (6H, m), 1.69 (4H, tt, J=5, 5 Hz), 2.18 (2H, t, J=8 Hz), 2.53-2.64 (2H, m), 3.02 (2H, q, J=7 Hz), 3.19 (4H, t, J=5 Hz), 3.60 (2H, s), 4.07 (2H, q, J=7 Hz), 5.86 (1H, d, J=5 Hz), 6.54 (1H, d, J=5 Hz), 7.89 (1H, dd, J=2, 2 Hz), 8.56 (1H, d, J=2 Hz), 8.75 (1H, d, J=2 Hz).
EXAMPLE 580
ethyl 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate
1H NMR (300 MHz, CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.46 (2H, t, J=8 Hz), 2.64 (4H, t, J=5 Hz), 2.86 (6H, m), 3.02 (2H, q, J=7 Hz), 3.69 (2H, s), 4.06 (2H, q, J=7 Hz), 5.91 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.88 (1H, dd, J=2, 2 Hz), 856(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-piperazinyl]methyl}pyrrolo[1,2-b]pyridazin-3-yl)propanoate
1H NMR (300 MHz, CDCl3) δ 1.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.46-2.63 (12H, m), 2.80-2.94 (2H, m), 3.03 (2H, q, J=7 Hz), 3.61 (2H, t, J=5 Hz), 3.70 (2H, s), 4.08 (2H, q, 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-pyrrolidinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (300 MHz, CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.55 (4H, m), 1.75-1.80 (4H, m), 2.19 (2H, t, J=7 Hz), 2.54-2.66 (6H, m), 3.02 (2H, q, J=7 Hz), 3.76-3.81 (2H, m), 4.10 (2H, q, J=7 Hz), 5.87 (1H, d, J=5 Hz), 6.55 (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-piperazinyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (300 MHz, CDCl3) δ 1.21 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.41-1.54 (4H, m), 2.17 (2H, t, J=7 Hz), 2.53-2.68 (2H, m), 2.75 (4H, t, J=5 Hz), 3.03 (2H, q, J=7 Hz), 3.19 (4H, t, J=5 Hz), 3.73 (2H, s), 4.07 (2H, q, J=7 Hz), 5.89 (1H, d, J=5 Hz), 6.58 (H, d, J=5 Hz), 6.85 (1H, dd, J=8, 8 Hz), 6.93 (2H, J=2.08 Hz), 7.25 (2H, J=8 Hz), 7.89 (1H, dd, J=2, 2 Hz), 8.56 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).
EXAMPLE 584
ethyl 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(2-methoxyethyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate
1H NMR (300 MHz, CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.41-1.60 (4H, m), 2.19 (2H, t, J=7 Hz), 2.43-2.52 (2H, m), 2.96 (2H, t, J=5 Hz), 3.03 (2H, q, J=7 Hz), 3.40 (3H, s), 3.58 (2H, t, J=5 Hz), 3.99 (2H, s), 4.10 (2H, q, J=7 Hz), 5.89 (1H, d, J=5 Hz), 6.56 (1H, d, J=5 Hz), 7.87 (1H, dd, J=2, 2 Hz), 8.54 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).
The following compound(s) was (were) obtained in a similar manner to that of Example 385.
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 1.37 (3H, 1, J=7 Hz), 2.25-3.10 (6H, m), 3.49 (3H, s), 3.58 (4H, m), 3.81 (2H, m), 4.55 (2H, s), 5.97 (1H, d, J=5 Hz), 6.54 (1H, s), 6.64 (1H, d, J=5 Hz), 7.93 (1H, m), 8.52 (1H, m), 8.78 (1H, m).
EXAMPLE 586
tert-butyl [2-({3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoyl}amino)ethyl]carbamate
1H-NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.43 (9H, s), 2.26 (2H, m), 2.88 (2H, m), 3.04 (2H, q, J=7 Hz), 3.20 (2H, m), 3.28 (2H, m), 3.48 (3H, s), 4.67 (2H, s), 4.85 (1H, s, br), 5.93 (1H, d, J=5 Hz), 6.20 (1H, s, br), 6.63 (1H, d, J=5 Hz), 7.88 (1H, m), 8.53 (1H, m), 8.79 (1H, m).
The following compound(s) was (were) obtained in a similar manner to that of Example 330.
EXAMPLE 587
ethyl 5-[2-{[2-(benzylamino)-2-oxoethoxy]methyl}-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.22 (3H, t, J=7 Hz), 1.34 (3H, t, J=7 Hz), 1.33-1.55 (4H, m), 2.12 (2H, t, J=7 Hz), 2.43 (3H, s), 2.40-2.56 (2H, m), 2.96 (2H, q, J=7 Hz), 4.07 (2H, q, J=7 Hz), 4.19 (2H, s), 4.52 (2H, d, J=7 Hz), 4.76 (2H, s), 5.93 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.06 (1H, br), 7.23-7.38 (5H, m), 7.49 (1H, s), 8.40 (1H, s), 8.54 (1H, s). MS (ESI+): m/z 543.
The following compound(s) was (were) obtained in a similar manner to that of Example 333.
EXAMPLE 588
ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4H-1,2,4-triazol-4-ylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H-NMR (CDCl3) δ 1.22-1.34 (6H, m), 1.67 (2H, m), 2.23 (2H, m), 2.51 (2H, m), 2.98 (2H, q, J=7 Hz), 4.21 (2H, q, J=7 Hz), 5.67 (2H, m), 5.97 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.85 (1H, m), 7.96 (1H, s), 8.34 (1H, s), 8.53 (1H, m), 8.79 (1H, m).
The following compound(s) was (were) obtained in a similar manner to that of Example 336.
EXAMPLE 589
ethyl 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(phenylsulfonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.26-1.57 (4H, m), 2.16 (2H, t, J=7 Hz), 2.33-2.46 (2H, m), 2.42 (3H, s), 2.98 (2H, q, J=7 Hz), 4.11 (2H, q, J=7 Hz), 4.38 (2H, m), 5.91 (1H, br), 5.92 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.43-7.55 (4H, m), 7.93 (2H, d, J=8 Hz), 8.33 (1H, d, J=2 Hz), 8.54 (1H, d, J=2 Hz). MS (ESI+): m/z 535.
The following compound(s) was (were) obtained in a similar manner to that of Example 340.
EXAMPLE 590
ethyl 4-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylamino)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoate
1H-NMR (CDCl3) δ 0.48 (4H, m), 1.19 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.70 (2H, t, J=7 Hz), 2.22 (2H, m), 2.50 (2H, m), 2.95-3.07 (3H, m), 3.96-4.12 (4H, m), 5.90 (1H, d, J=5 Hz), 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 ethyl[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate (600 mg) under ice-water cooling and the mixture was stirred at 0° C. for 2 hours. To the mixture was added potassium sodium tartrate solution and the insolubles were filtered off. After evaporation of solvent, the residue was partitioned between AcOEt and water. The organic layer was separated, washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (5:1-1:1) to give 2-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]ethanol as yellow oil (246 mg).
2-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]ethanol
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 2.60 (3H, s), 2.72-2.84 (2H, m), 3.03 (2H, q, J=7 Hz), 3.65 (2H, t, J=7 Hz), 5.89 (1H, d, J=4 Hz), 6.55 (1H, d, J=4 Hz), 7.91 (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-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoic acid (1.07 g), diphenylphosphoryl azide (1.14 g) and Et3N (0.576 mL) in BuOH (30 mL) was heated under reflux for 2 hours. After evaporation of solvent, the residue was partitioned between AcOEt and water. The organic layer was separated, washed with aq NaHCO3 solution and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-3:1) to give tert-butyl {2-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]ethyl}carbamate as yellow oil (450 mg).
tert-butyl {2-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]ethyl}carbamate
1H NMR (CDCl3) δ 1.37 (9H, s), 1.37 (3H, t, J=7 Hz), 2.64 (3H, s), 2.62-2.75 (2H, m), 3.03 (2H, q, J=7 Hz), 3.10-3.27 (2H, m), 4.40-4.52 (1H, m), 5.89 (1H, d, J=4 Hz), 6.55 (1H, d, J=4 Hz), 7.89 (1H, m), 8.53 (1H, m), 8.77 (1H, m).
EXAMPLE 593
To a suspension of 60% NaH (74 mg) in DMF (3 mL) was added ethyl 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate (200 mg) under ice-water cooling, and the mixture was stirred at 0° C. for 0.5 hour. To this was added 3-(bromomethyl)pyridine hydrobromide (234 mg) under ice-water cooling, and the mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between AcOEt and water. The aqueous layer was separated, acidified to pH 3-4 with HCl and extracted with AcOEt. The organic layer was washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of CHCl3 and MeOH (100:1-20:1) to give 3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid as a yellow powder (110 mg).
3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid
1H NMR (CDCl3) δ 1.39 (3H, t, J=7 Hz), 2.41 (2H, t, J=7 Hz), 2.80-2.98 (2H, m), 3.04 (2H, q, J=7 Hz), 4.70 (2H, s), 4.83 (2H, s), 5.93 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.32-7.38 (1H, m), 7.81 (1H, d, J=8 Hz), 7.87 (1H, m), 8.52 (1H, d, J=8 Hz), 8.53 (1H, d, J=2 Hz), 8.63 (1H, s), 8.77 (1H, d, J=2 Hz).
The following compound(s) was (were) obtained in a similar manner to that of Example 593.
EXAMPLE 594
4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-methoxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.72-1.83 (2H, m), 2.28 (2H, t, J=7 Hz), 2.60-2.77 (2H, m), 3.03 (2H, q, J=7 Hz), 3.39 (3H, s), 3.62 (2H, m), 3.77 (2H, m), 4.75 (2H, s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.92 (1H, m), 8.56 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz). MS (ESI−): m/z 474 476, MS (ESI+): m/z 476 478.
EXAMPLE 595
3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 2.48-2.62 (2H, m), 2.98-3.10 (2H, m), 3.05 (2H, q, J=7 Hz), 4.82 (2H, s), 4.88 (2H, s), 5.94 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.27 (1H, m), 7.48 (1H, d, J=8 Hz), 7.77 (1H, t, J=8 Hz), 7.90 (1H, m), 8.56 (2H, m), 8.80 (1H, m). MS (ESI+): m/z 495 497.
EXAMPLE 596
3-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}propanoic acid
1H NMR (CDCl3) δ 0.25 (2H, m), 0.58 (2H, m), 1.12 (1H, m), 1.37 (3H, t, J=7 Hz), 2.40-2.63 (2H, m), 2.85-3.05 (2H, m), 3.02 (2H, q, J=7 Hz), 3.42 (2H, d, J=7 Hz), 4.73 (2H, s), 5.93 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.89 (1H, m), 8.55 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz). MS (ESI−): m/z 456 458, MS (ESI+): m/z 458 460.
EXAMPLE 597
3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 2.48 (2H, t, J=7 Hz), 2.85-3.09 (2H, m), 3.06 (2H, q, J=7 Hz), 4.84 (2H, s), 4.92 (2H, s), 5.96 (1H, d, J=4 Hz), 6.65 (1H, d, J=4 Hz), 7.90 (1H, m), 8.48-8.62 (3H, m), 8.77 (2H, m).
EXAMPLE 598
A mixture of ethyl 4-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)butanoate (89 mg) and pyridinium p-toluenesulfonate (0.8 mg) in MeOH (5 mL) was heated under reflux for 2 hours. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (10:1-1:1) to give ethyl 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-hydroxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate as yellow oil (69 mg).
ethyl 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-hydroxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate
1H NMR (CDCl3) δ 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.69-1.84 (2H, m), 2.22 (2H, t, J=7 Hz), 2.53-2.72 (2H, m), 3.03 (2H, q, J=7 Hz), 3.76 (2H, m), 3.83 (2H, m), 4.07 (2H, q, J=7 Hz), 4.79 (2H, s), 5.93 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.89 (1H, m), 8.56 (1H, d, J=2 Hz), 8.79 (1H, d, J=2 Hz). MS (ESI+): m/z 490 492.
EXAMPLE 599
To a suspension of 60% NaH (695 mg) in DMF (3 mL) was added ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate 5 (200 mg) under ice-water cooling and the mixture was stirred at 0° C. for 0.5 hour. To this was added 4-morpholinecarbonyl chloride (659 mg) and the mixture was stirred at ambient temperature for 15 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-1:1) to give [4-(5-bromo-3-pyridinyl)-3-(5-ethoxy-5-oxopentyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methyl 4-morpholinecarboxylate as yellow oil (75 mg).
[4-(5-bromo-3-pyridinyl)-3-(5-ethoxy-5-oxopentyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methyl 4-morpholinecarboxylate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.60 (4H, m), 2.18 (2H, t, J=7 Hz), 2.42-2.54 (2H, m), 3.03 (2H, q, J=7 Hz), 3.53-3.57 (4H, m), 3.63-3.78 (4H, m), 4.09 (2H, q, J=7 Hz), 5.33 (2H, s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.87 (1H, m), 8.54 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz). MS (ESI+): m/z 573 575.
The following compound(s) was (were) obtained in a similar manner to that of Example 599.
EXAMPLE 600
ethyl 5-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.35-1.60 (4H, m), 2.17 (2H, t, J=7 Hz), 2.44-2.57 (2H, m), 2.98 (6H, s), 3.03 (2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 5.30 (2H, s), 5.93 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.87 (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-oxopentyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methyl 1-pyrrolidinecarboxylate
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.38-1.60 (4H, m), 1.86-1.98 (4H, m), 2.17 (2H, t, J=7 Hz), 2.44-2.57 (2H, m), 3.03 (2H, q, J=7 Hz), 3.36-3.52 (4H, m), 4.11 (2H, q, J=7 Hz), 5.32 (2H, s), 5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.87 (1H, m), 8.55 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).
EXAMPLE 602
ethyl 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[({[methyl(phenyl)amino]carbonyl}oxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate
1H NMR (CDCl3) δ 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.32-1.57 (4H, m), 2.13 (2H, t, J=7 Hz), 2.33-2.48 (2H, m), 3.03 (2H, q, J=7 Hz), 3.38 (3H, s), 4.08 (2H, q, J=7 Hz), 5.34 (2H, s), 5.92 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.20-7.38 (5H, m), 7.83 (1H, s), 8.49 (1H, s), 8.77 (1H, s).
EXAMPLE 603
[4-(5-bromo-3-pyridinyl)-3-(4-ethoxy-4-oxobutyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methyl 4-morpholinecarboxylate
1H NMR (CDCl3) δ 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.63-1.80 (2H, m), 2.22 (2H, t, J=7 Hz), 2.44-2.65 (2H, m), 3.03 (2H, q, J=7 Hz), 3.54 (4H, m), 3.68 (4H, m), 4.05 (2H, q, J=7 Hz), δ 37 (2H, s), 5.94 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.87 (1H, m), 8.55 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz). MS (ESI+): m/z 559 561.
EXAMPLE 604
ethyl 4-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H NMR (CDCl3) δ 1.20 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.66-1.79 (2H, m), 2.20 (2H, t, J=7 Hz), 2.46-2.62 (2H, m), 2.97 (6H, s), 3.03 (2H, q, J=7 Hz), 4.04 (2H, q, J=7 Hz), 5.34 (2H, s), 5.93 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.89 (1H, m), 8.56 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz). MS (ESI+): m/z 517 519.
EXAMPLE 605
ethyl 3-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]propanoate
1H NMR (CDCl3) δ 1.20 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 2.37 (2H, t, J=7 Hz), 2.82-2.93 (2H, m), 2.97 (6H, s), 3.03 (2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.32 (2H, s), 5.96 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.88 (1H, m), 8.54 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).
EXAMPLE 606
To a solution of sodium hydride (93.1 mg) in DMF (4 mL) was added ethyl 3-[4-(3-chlorophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate (150 mg) under ice water cooling and the mixture was stirred at this temperature for 1 hour. To this was added 4-(bromomethyl)pyridine hydrobromide (196 mg) and the mixture was stirred for 1 hour at ambient temperature. The reaction was quenched by adding water. The mixture was extracted with CHCl3. The organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of CHCl3-MeOH=30-1 to give 3-{4-(3-chlorophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid (18 mg) as a yellow solid.
3-{4-(3-chlorophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid
1H NMR (300 MHz, CDCl3) δ 1.39 (3H, t, J=7 Hz), 2.33 (2H, t, J=7 Hz), 2.84-2.91 (2H, m), 3.04 (2H, q, J=7 Hz), 4.73 (2H, s), 4.82 (2H, s), 5.96 (1H, d, J=5 Hz), 6.62 (1H, d, J=5 Hz), 7.23-7.26 (1H, m), 7.36-7.38 (3H, m), 7.42-7.44 (2H, m), 8.41 (2H, d, J=5 Hz). MS (m/z) 450 (M+H).
The following compound(s) was (were) obtained in a similar manner to that of Example 606.
EXAMPLE 607
3-{4-(3-chlorophenyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid
1H NMR (300 MHz, CDCl3) δ 1.39 (3H, t, J=7 Hz), 2.32-2.38 (2H, m), 2.84-2.92 (2H, m), 3.04 (2H, q, J=7 Hz), 4.70 (2H, s), 4.82 (2H, s), 5.94 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.21-7.24 (1H, m), 7.31-7.36 (2H, m), 7.40-7.42 (2H, m), 7.80 (2H, d, J=8 Hz), 8.51 (1H, d, J=5 Hz), 8.64 (1H, s).
EXAMPLE 608
3-{4-(3-chlorophenyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid
1H NMR (300 MHz, CDCl3) δ 1.38 (3H, t, J=7 Hz), 2.42 (2H, t, J=7 Hz), 2.91-2.97 (2H, m), 3.03 (2H, q, J=7 Hz), 4.83 (2H, s), 4.90 (2H, s), 5.96 (2H, d, J=5 Hz), 6.62 (2H, d, J=5 Hz), 7.23-7.26 (1H, m), 7.36 (1H, s), 7.43-7.44 (2H, m), 8.51-8.53 (2H, m), 8.75 (1H, s).
EXAMPLE 609
A solution of 5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (15 mg) in MeOH was added 10% Pd/C (2 mg). The mixture was stirred under hydrogen atomosphere (1 atm) for 6 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was triturated with hexane to give 5-[7-ethyl-4-(2-ethyl-4-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (14 mg) as an yellow solid.
5-[7-ethyl-4-(2-ethyl-4-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H NMR (CDCl3) δ 1.29-1.64 (10H, m), 2.18-2.30 (2H, m), 2.45-2.48 (2H, m), 2.56 (3H, s), 2.91-3.06 (4H, m), 5.84 (1H, d, J=5 Hz), 6.53 (1H, d, J=16 Hz), 6.51 (1H, d, J=5 Hz), 7.25-7.32 (2H, m), 8.69 (1H, br s).
EXAMPLE 610
To a solution of ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate (70.0 mg) in toluene (1 mL) was added tributylphosphine (0.098 mL), 1,3-oxazolidin-2-one (34.1 mg) in that order in an ice bath. After stirring for 5 minutes, to the mixture was added 1,1′-(azodicarbonyl)dipiperidine (98.9 mg). The mixture was stirred for 10 minutes in the bath, and 8 hours at room temperature. Hexane (5 mL) was added, and the mixture was filtered. The filtrate was evaporated. Preparative thin layer chromatography (ethyl acetate-hexane=1-1) afforded ethyl 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-oxo-1,3-oxazolidin-3-yl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate as an yellow gum (25.0 mg).
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 1.20 (3H, t, J=7 Hz), 1.369 (3H, t, J=7 Hz), 1.65 (3H, t, J=7 Hz), 2.25 (2H, t, J=7 Hz), 2.51 (2H, m), 2.99 (2H, q, J=7 Hz), 3.79 (2H, t, J=7 Hz), 4.04 (2H, q, J=7 Hz), 4.43 (2H, t, J=7 Hz), 4.69 (2H, m), 5.95 (1H, d, J=5 Hz), 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-(ethoxycarbonyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzoic acid (50.0 mg) in tetrahydrofuran (1 mL) was added a solution of 1 M borane-tetrahydrofuran complex (0.348 mL) in an ice bath. After stirring for 2 hours at room temperature, additional solution of the borane-tetrahydrofuran complex (0.348 mL) was added. The mixture was stirred for 15 hours at room temperature. The mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with water, saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and evaporated to give ethyl 4-[3-bromo-4-(hydroxymethyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow oil (54.2 mg).
ethyl 4-[3-bromo-4-(hydroxymethyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate
1H-NMR (CDCl3) δ 0.99 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.59 (3H, s), 3.03 (2H, q, J=7 Hz), 4.07 (2H, q, J=7 Hz), 4.82 (2H, s), 6.33 (1H, d, J=5 Hz), 6.66 (1H, d, J=5 Hz), 7.44 (1H, d, J=8 Hz), 7.58 (1H, d, J=8 Hz), 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 hour, The solvent was evaporated off. Preparative thin layer chromatography (CHCl3-MeOH=20-1) afforded the desired product as an yellow gum (54.1 mg). The gum was dissolved in 1 N HCl (1 mL), and the solution was lyophilized to give a dark green gum, which was crystalyzed upon standing. The crystal was triturated in diisopropyl ether to give 2-(2-{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy}ethoxy)ethanol hydrochloride as an yellow powder (403 mg).
2-(2-{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy}ethoxy)ethanol hydrochloride
1H-NMR (DMSO-d6): 1.29 (3H, t, J=7 Hz), 2.51 (3H, s), 2.56 (3H, s), 2.62 (2H, m), 2.94 (2H, q, J=7 Hz), 3.30-3.47 (10H, m), 5.84 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 8.26 (1H, m), 8.77 (1H, m), 8.85 (1H, m).
EXAMPLE 613
A mixture of ethyl 5-[2-(bromomethyl)-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (70.0 mg), phenol (21.1 mg), and pottassium carbonate (31.0 mg) in N,N-dimethylformamide was stirred for 25 hours at room temperature. The mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with water, saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and evaporated to give ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-(phenoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow gum (775 mg, 108%).
ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-(phenoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate
1H-NMR (CDCl3) δ 1.21 (3H, t, J=7 Hz), 1.35-1.53 (7H, m), 2.07 (2H, m), 2.54 (2H, m), 3.03 (2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.24 (2H, s), 5.86 (1H, d, J=5 Hz), 6.65 (1H, d, J=5 Hz), 6.80-7.01 (3H, m), 7.03 (2H, d, J=9 Hz), 7.32 (2H, t, J=9 Hz), 7.55-7.63 (2H, m), 7.67 (1H, s), 7.76 (1H, m). MS (ESI+): m/z 482 (M+H)
EXAMPLE 614
A mixture of 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-2-yl trifluoromethanesulfonate (50.0 mg), 3-furylboronic acid (23.6 mg), dichlorobis(triphenylphosphine)palladium (3.71 mg), and 2 N sodium carbonate (44.8 mg in 0.2 mL of water) in dioxane was stirred for 20 minutes at 85° C. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried, and evaporated. Preparative thin layer chromatography (EtOAc-hexane=1-1) afforded 3-[7-ethyl-2-(2-furyl)-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile as an orange solid (11.5 mg).
3-[7-ethyl-2-(2-furyl)-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
1H-NMR (CDCl3) δ 1.40 (3H, t, J=7 Hz), 3.10 (2H, q, J=7 Hz), 3.20 (3H, s), 6.30 (1H, d, J=5 Hz), 6.63 (1H, m), 6.87 (1H, d, J=5 Hz), 6.95 (1H, m), 7.60-7.73 (4H, m), 8.79 (1H, m).
EXAMPLE 615
To a solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (100 mg) in tetrahydrofurane (1 mL) was added 1 M borane-tetrahydrofurane comples (0.708 mL) in an ice bath under a nitrogen atmosphere. The mixture was stirred for 4 hours in the bath and 1 hour at room temperature. The reaction was quenched by adding 1 N hydrochloric acid (1 mL). The mixture was partitioned between EtOAc (10 mL) and 1 N hydrochloric acid (5 mL). The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated. Preparative thin layer chromatography eluting with acetone-hexane=1-2 afforded 3-[7-ethyl-3-(5-hydroxypentyl)-2-phenylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile as an yellow gum (104 mg).
3-[7-ethyl-3-(5-hydroxypentyl)-2-phenylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile
1H-NMR (CDCl3) δ 0.98-1.17 (6H, m), 1.36 (3H, t, J=7 Hz), 2.38 (2H, m), 2.58 (2H, m), 3.34 (2H, m), 5.89 (1H, d, J=5 Hz), 6.62 (1H, d, J=5 Hz), 7.45-7.53 (5H, m), 7.55-7.67 (4H, m). MS (ESI+): m/z 410 (M+H)
The following compound(s) was (were) obtained in a similar manner to that of Preparation 24.
Preparation 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), 4.57 (1H, s), 8.00 (0.15H, br s), 8.23 (0.15H, br s), 8.60-8.91 (2H, m).
Preparation 344
1-tert-butyl 8-ethyl 2-acetyl-2-[(6-cyano-3-pyridinyl)carbonyl]octanedioate
1H NMR (CDCl3) δ 1.22-1.46 (16H, m), 1.55-1.70 (2H, m), 2.17-2.34 (4H, m), 2.48 (3H, s), 4.14 (2H, q, J=8 Hz), 7.77 (1H, br d, J=8 Hz), 8.17 (1H, dd, J=8, 2 Hz), 8.97 (1H, d, J=2 Hz).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 78.
Preparation 345
ethyl 7-[(6-cyano-3-pyridinyl)carbonyl]-8-oxononanoate
1H NMR (CDCl3) δ 1.20-1.45 (7H, m), 1.52-1.70 (2H, m), 1.92-2.14 (2H, m), 2.17-2.39 (5H, m), 4.11 (2H, q, J=8 Hz), 4.40 (1H, t, J=8 Hz), 7.84 (1H, br d, J=8 Hz), 8.39 (1H, m), 9.23 (1H, br s).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 130.
Preparation 346
ethyl 4-methoxy-3-oxobutanoate
1H NMR (CDCl3) δ 1.28 (3H, t, J=8 Hz), 3.42 (3H, s), 3.51 (2H, s), 4.09 (2H, s), 4.20 (2H, q, J=8 Hz).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 338.
Preparation 347
benzyl 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-5-bromobenzoate
1H-NMR (CDCl3) δ 1.28 (3H, t, J=7 Hz), 2.75 (2H, q, J=7 Hz), 5.37 (2H, s), 5.73 (2H, s), 5.94 (1H, d, J=5 Hz), 6.66 (1H, d, J=5 Hz), 7.35-7.48 (5H, m), 7.99 (1H, s), 8.33 (1H, s), 8.38 (1H, s).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 321.
Preparation 348
benzyl 3-bromo-5-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate
1H-NMR (CDCl3) δ 1.29 (3H, t, J=7 Hz), 2.72 (2H, q, J=7 Hz), 5.37 (2H, s), 6.09 (1H, m), 6.78 (1H, m), 7.33-7.45 (5H, m), 8.15 (1H, s), 8.33 (1H, s), 8.45 (1H, s).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 310.
Preparation 349
benzyl 3-bromo-5-(chlorocarbonyl)benzoate
Preparation 350
To a solution of benzyl 3-bromo-5-iodobenzoate (1.00 g) in THF (10 mL) was added 0.76 M isopropyl magnesium bromide (3.16 mL) in an ice bath under a nitrogen atmosphere. After stirring for 0.5 hour, the mixture was poured onto dryice. The mixture was warmed to room temperature over 1 hour. The mixture was partitioned between EtOAc and 1 N HCl. The organic layer was washed with brine, dried over MgSO4, and evaporated. Flash silica gel column chromatography (chloroform-methanol=50-0 to 50-2) afforded 3-benzyloxycarbonyl-5-bromobenzoic acid as a white solid (273 mg).
3-[(benzyloxy)carbonyl]-5-bromobenzoic acid
1H-NMR (DMSO-d6) δ 5.39 (2H, s), 7.30-7.52 (5H, m), 8.29 (2H, s), 8.43 (1H, s).
Preparation 351
A mixture of 3-bromo-5-iodobenzoic acid (5.00 g) and N,N-dimethylformamide (0.059 mL) in dichloromethane (50 mL) was added oxalyl chloride (1.47 mL) in an ice bath under a nitrogen atmosphere. After stirring for 1 hour, the volatile was evaporated off. The residue was dissolved in dichloromethane (50 mL), and to the solution was added bensyl alcohol (1.82 g) followed by triethyl amine (3.2 mL) in the ice bath. The mixture was stirred for 2 hours at room temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with water (two times), satd. NaHCO3, and brine, dried over MgSO4 and evaporated. Flash silica gel column chromatography (EtOAc-hexanes=1/200 to 20/200) afforded benzyl 3-bromo-5-iodobenzoate as white crystals (5.95 g).
benzyl 3-bromo-5-iodobenzoate
1H-NMR (CDCl3) δ 5.35 (3H, s), 7.35-7.68 (5H, m), 8.04 (1H, s), 8.16 (1H, m), 8.30 (1H, s).
The following compound(s) was (were) obtained in a similar manner to that of Example 1.
EXAMPLE 615
benzyl 3-bromo-5-[7-ethyl-2-methyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoate
1H-NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 2.88 (3H, s), 3.05 (3H, s), 3.06 (2H, q, J=7 Hz), 5.35 (2H, s), 6.15 (1H, d, J=5 Hz), 6.72 (1H, d, J=5 Hz), 7.33-7.45 (5H, m), 7.68 (1H, m), 7.94 (1H, m), 8.28 (1H, m).
EXAMPLE 616
4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazine-3-carbonitrile
1H NMR (CDCl3) δ 1.42 (3H, t, J=8 Hz), 3.12 (2H, q, 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), 7.82-7.91 (3H, m), 7.93-8.01 (2H, m).
EXAMPLE 617
2-tert-butyl-4-(3-chlorophenyl)-7-ethylpyrrolo[1,2-b]pyridazine-3-carbonitrile
1H NMR (CDCl3) δ 1.38 (3H, t, J=8 Hz), 1.60 (9H, s), 3.05 (2H, q, J=8 Hz), 6.48 (1H, d, J=5 Hz), 6.77 (1H, d, J=5 Hz), 7.45-7.54 (3H, m), 7.60 (1H, br s).
The following compound(s) was (were) obtained in a similar manner to that of reparation 78.
EXAMPLE 618
ethyl 6-[4-(6-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate
1H NMR (CDCl3) δ 1.15-1.64 (12H, m), 2.21 (1H, t, J=8 Hz), 2.32-2.44 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 4.10 (2H, q, J=8 Hz), 5.79 (1H, d, J=5 Hz), 6.54 (1H, d, J=5 Hz), 7.85 (1H, br s), 8.30 (1H, br d, J=8 Hz), 8.72 (1H, br s). MS (ESI+): m/z 405 (M+H).
The following compound(s) was (were) obtained in a similar manner to that of Example 21.
EXAMPLE 619
ethyl 4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazine-3-carboxylate
1H NMR (CDCl3) δ 1.04 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 3.06 (2H, q, J=8 Hz), 3.39 (3H, s), 4.10 (2H, q, J=8 Hz), 4.76 (2H, s), 6.33 (1H, d, J=5 Hz), 6.74 (1H, d, J=5 Hz), 7.96 (1H, br s), 8.61 (1H, br s), 8.78 (1H, d, J=2 Hz). MS (ESI+): m/z 418, 420 (M+H).
The following compound(s) was (were) obtained in a similar manner to that of Example 76.
EXAMPLE 620
3-bromo-5-[7-ethyl-2-methyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid
1H-NMR (CDCl3+CD3OD) δ 1.38 (3H, t, J=7 Hz), 2.86 (3H, s), 3.05 (3H, s), 3.06 (2H, q, J=7 Hz), 6.19 (1H, d, J=5 Hz), 6.71 (1H, d, J=5 Hz), 7.53 (1H, s), 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 1.39 (3H, t, J=8 Hz), 3.07 (2H, q, J=8 Hz), 3.51 (3H, s), 4.65 (2H, s), 5.96 (1H, d, J=15 Hz), 6.27 (1H, d, J=5 Hz), 6.74 (1H, d, J=5 Hz), 7.68 (1H, d, J=15 Hz), 7.93 (1H, m), 8.57 (1H, d, J=1 Hz), 8.70 (1H, d, J=2 Hz). MS (ESI+): m/z 416, 418 (M+H).
EXAMPLE 622
6-[4-(6-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoic acid
1H NMR (CDCl3) δ 1.15-1.69 (9H, m), 1.90-2.50 (4H, m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 5.80 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.84 (1H, dd, J=8, 2 Hz), 8.28 (1H, d, J=8 Hz), 8.51 (1H, d, J=2 Hz). MS (ESI+): m/z 377 (M+H).
EXAMPLE 622-2
6-{4-[6-(aminocarbonyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid
1H NMR (CDCl3) δ 1.16-1.51 (9H, m), 2.10-2.24 (2H, m), 2.35-2.47 (2H, m), 2.58 (3H, s), 3.01 (2H, q, J=8 Hz), 5.85 (1H, d, J=5 Hz), 6.54 (1H, d, J=5 Hz), 7.22 (1H, br s), 7.90 (1H, dd, J=8, 1 Hz), 8.01 (1H, br s), 8.34 (1H, d, J=8 Hz), 8.61 (1H, d, J=1 Hz). MS (ESI+): m/z 395 (M+H).
The following compound(s) was (were) obtained in a similar manner to that of Example 147.
EXAMPLE 623
ethyl (2E)-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylate
1H NMR (CDCl3) δ 1.27 (3H, t, J=8 Hz), 1.39 (3H, t, J=8 Hz), 3.06 (2H, q, J=8 Hz), 3.51 (3H, s), 4.17 (2H, q, J=8 Hz), 4.64 (2H, s), 5.97 (1H, d, J=15 Hz), 6.24 (1H, d, J=5 Hz), 6.73 (1H, d, J=5 Hz), 7.51 (1H, d, J=15 Hz), 7.91 (1H, br s), 8.57 (1H, br s), 8.70 (1H, br s). MS (ESI+): m/z 444, 446 (M+H).
The following compound(s) was (were) obtained in a similar manner to that of Example 200.
EXAMPLE 624
[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]methanol
1H NMR (CDCl3) δ 1.38 (3H, t, J=8 Hz), 3.05 (2H, q, J=8 Hz), 3.45-3.55 (4H, m), 4.40 (2H, br d, J=7 Hz), 4.77 (2H, br s), 6.22 (1H, d, J=5 Hz), 6.70 (1H, d, J=5 Hz), 8.11 (1H, m), 8.74 (1H, br s), 8.80 (1H, d, J=2 Hz). MS (ESI+): m/z 376, 378 (M+H).
The following compound(s) was (were) obtained in a similar manner to that of Example 205.
EXAMPLE 625
(4E)-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]4-pentenoic acid
1H NMR (CDCl3) δ 1.37 (3H, t, J=8 Hz), 2.26-2.43 (4H, m), 2.50 (3H, s), 3.01 (2H, q, J=8 Hz), 5.40 (1H, dt, J=15, 7 Hz), 6.05 (1H, d, J=5 Hz), 6.20 (1H, d, J=15 Hz), 6.56 (1H, d, J=5 Hz), 7.28 (1H, br d, J=5 Hz), 7.39 (1H, br s), 8.47 (1H, br d, J=5 Hz). MS (ESI+): m/z 370 (M+H).
EXAMPLE 625-2
(4Z)-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-4-pentenoic acid
1H NMR (CDCl3) δ 1.39 (3H, t, J=8 Hz), 1.87-2.00 (2H, m), 2.12 (2H, t, J=8 Hz), 2.42 (3H, s), 3.03 (2H, q, J=8 Hz), 5.58 (1H, dt, J=10, 8 Hz), 6.17 (1H, d, J=5 Hz), 6.26 (1H, br d, J=10 Hz), 6.60 (1H, d, J=5 Hz), 7.35 (1H, br d, J=5 Hz), 7.44 (1H, br s), 8.48 (1H, br d, J=5 Hz). MS (ESI+): m/z 370 (M+H).
The following compound(s) was (were) obtained in a similar manner to that of Example 220.
EXAMPLE 626
4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid
1H NMR (CDCl3) δ 1.39 (3H, t, J=8 Hz), 3.06 (2H, q, J=8 Hz), 3.44 (3H, s), 4.82 (2H, s), 6.36 (1H, d, J=5 Hz), 6.77 (1H, d, J=5 Hz), 8.09 (1H, br s), 8.65 (1H, br s), 8.72 (1H, br s). MS (ESI+): m/z 390, 392 (M+H).
EXAMPLE 627
4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=8 Hz), 2.70 (3H, s), 3.06 (2H, q, J=8 Hz), 6.26 (1H, d, J=5 Hz), 6.72 (1H, d, J=5 Hz), 7.32 (1H, dd, J=5, 1 Hz), 7.43 (1H, br s), 8.50 (1H, d, J=5 Hz). MS (ESI+): m/z 316 (M+H).
The following compound(s) was (were) obtained in a similar manner to that of Example 244.
EXAMPLE 628
4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carbaldehyde
1H NMR (CDCl3) δ 1.39 (3H, t, J=8 Hz), 2.81 (3H, s), 3.09 (2H, q, J=8 Hz), 6.43 (1H, d, J=5 Hz), 6.78 (1H, d, J=5 Hz), 7.34 (1H, br d, J=5 Hz), 7.46 (1H, br s), 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]pyridazine-3-carbaldehyde
1H NMR (CDCl3) δ 1.41 (3H, t, J=8 Hz), 3.14 (2H, q, J=8 Hz), 3.55 (3H, s), 4.94 (2H, s), 6.50 (1H, d, J=5 Hz), 6.84 (1H, d, J=5 Hz), 7.95 (1H, br s), 8.12 (1H, br s), 8.84 (1H, br s), 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° C., and a solution of ethyl 4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (428 mg, 1.31 mmol) in N,N-dimethylformamide (0.7 mL) was added. The resulting mixture was warmed to 50° C., and stirred for 45 min. Since the starting material was remained, a solution of phosphorus oxychloride (621 mg, 0.67 mmol) in N,N-dimethylformamide (0.2 mL) was added, and the mixture was stirred for 15 min. The resulting mixture was poured into ice-cooled water (10 mL), and extracted with ethyl acetate (30 mL). The organic layer was washed with water and saturated sodium bicarbonate. All the aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give a blue oil. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-20 to 1-10 afforded ethyl 4-(4-fluorophenyl)-7-formyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow oil, which was crystalized upon standing (360 mg, 77.5%).
1H-NMR (CDCl3) δ 1.02 (3H, t, J=7 Hz), 1.41 (6H, d, J=7 Hz), 3.29 (1H, septet, J=7 Hz), 4.10 (2H, q, J=7 Hz), 6.42 (1H, d, J=5 Hz), 7.20 (2H, t, J=9 Hz), 7.45-7.51 (3H, m), 10.56 (1H, s). MS (ESI+): m/z 355 (M+H)
EXAMPLE 631
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, a solution of ethyl 4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (200 mg, 0.613 mmol) in dichloroethane (0.5 mL) was added. The resulting mixture was stirred for 3 days at room temperature. The mixture was partitioned between ethyl acetate (30 mL) and water (5 mL), and the organic layer was washed with saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, and evaporated to give an orange gum. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-20 to 1-10 afforded ethyl 7-acetyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow gum (144 mg, 63.8%).
1H-NMR (CDCl3) δ 1.00 (3H, t, J=7 Hz), 1.41 (6H, d, J=7 Hz), 2.88 (3H, s), 3.09 (1H, septet, J=7 Hz), 4.09 (2H, q, J=7 Hz), 6.40 (1H, d, J=5 Hz), 7.19 (2H, t, J=9 Hz), 7.46 (2H, dd, J=3 and 9 Hz), 7.57 (2H, d, J=7 Hz). MS (ESI+): m/z 369 (M+H)
EXAMPLE 632
A solution of ethyl 4-(4-fluorophenyl)-7-formyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (100 mg, 0.282 mmol) and sodium borohydride (10.7 mg, 0.282 mmol) in ethanol (1 mL) was stirred for 0.5 h under an ice bath. The mixture was partitioned between ethyl acetate (10 mL) and water (5 mL), and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give ethyl 4-(4-fluorophenyl)-7-hydroxymethyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow gum (89.1 mg, 89.1%).
1H-NMR (CDCl3) δ 0.97 (3H, t, J=7 Hz), 1.37 (6H, J=7 Hz), 3.25-3.37 (2H, m), 4.04 (2H, q, J=7 Hz), 5.06 (1H, d, J=7 Hz), 6.32 (1H, d, J=5 Hz), 6.78 (1H, d, J=5 Hz), 7.19 (2H, t, J=9 Hz), 7.46 (2H, d, J=4 and 9 Hz).
EXAMPLE 633
To a solution of ethyl 4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (80.0 mg, 0.245 mmol) and N,N-dimethylaminopyridine (29.9 mg, 0.245 mmol) in N,N-dimethylformamide (0.5 mL) was added 3,7-dinitro-5-(trifluoromethyl)dibenzo[b,d]thiophenium trifluoromethanesulfonate (120 mg, 0.245 mmol) at −20° C. The resulting mixture was stirred for 45 min at 0° C. and 12 h at room temperature. Water (5 mL) and ethyl acetate (10 mL) were added, and the resulting mixture was filtered. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give a brown gum. Flash silica gel column chromatography eluting with toluene-hexane=1-5 to 4-5 afforded ethyl 4-(4-fluorophenyl)-2-isopropyl-7-trifluoromethylpyrrolo[1,2-b]pyridazine-3-carboxylate product as an yellow gum (46.7 mg, 48.3%).
1H-NMR (CDCl3) δ 1.00 (3H, t, J=7 Hz), 1.38 (6H, d, J=7 Hz), 3.26 (1H, septet, J=7 Hz), 4.08 (2H, q, J=7 Hz), 6.33 (1H, d, J=5 Hz), 7.12 (H, 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-fluorophenyl)-7-formyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (200 mg, 0.564 mmol), hydroxylamine hydrochloride (51.0 mg, 0.734 mmol), and sodium formate (69.1 mg, 1.02 mmol) in formic acid (2 mL) were refluxed for 2 h. The mixture was evaporated to give a green gum. The gum was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate (5 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give a green gum. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-10 to 1-8 gave ethyl 7-cyano-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow crystal (144 mg, 72.6%).
1H-NMR (CDCl3) δ 1.01 (3H, t, J=7 Hz), 1.41 (6H, d, J=7 Hz), 3.26 (1H, septet, J=7 Hz), 4.09 (2H, q, 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). MS (ESI+): m/z 398 (M+HCOOH+H)
EXAMPLE 635
A solution of ethyl 7-cyano-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (70.4 mg, 0.200 mmol) in sulfuric acid (1 mL) was stirred for 50 min at 70° C. The solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give a brown gum. Preparative silica gel thin layer chromatography eluting with ethyl acetate-hexane=1-1 afforded ethyl 7-aminocarbonyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate as an orange solid (5.2 mg, 7.0%).
1H-NMR (CDCl3) δ 0.99 (3H, t, J=7 Hz), 1.41 (6H, d, J=7 Hz), 3.41 (1H, septet, J=7 Hz), 4.08 (2H, q, J=7 Hz), 5.93 (1H, br s), 6.46 (1H, d, J=5 Hz), 7.45 (2H, t, J=9 Hz), 7.28 (1H, d, J=5 Hz), 8.90 (1H, br s).
EXAMPLE 636
To a mixture of ethyl 4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (100 mg, 0.306 mmol) and ammonium thiocyanate (28.0 mg, 0.368 mmol) in methanol (100 mL) was added cerium ammonium nitrate (386 mg, 0.705 mmol) under an ice bath. The mixture was stirred for 30 min. The mixture was stirred for additional 10 min after adding ammonium thiocyanate (8.2 mg, 0.107 mmol). Water (5 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give a deep green gum. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-10 to 3-20 afforded ethyl ethyl 4-(4-fluorophenyl)-2-isopropyl-7-thiocyanatopyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow gum (89.6 mg, 82.3%).
1H-NMR (CDCl3) δ 1.01 (3H, t, J=7 Hz), 1.46 (6H, d, J=7 Hz), 3.36 (1H, septet, J=7 Hz), 4.08 (2H, q, J=7 Hz), 6.23 (1H, d, J=5 Hz), 7.14-7.22 (3H, m), 7.16 (2H, t, J=9 Hz), 7.46 (2H, dd, J=4 and 9 Hz).
EXAMPLE 637
To a solution of ethyl 4-(4-fluorophenyl)-2-isopropyl-7-thiocyanatopyrrolo[1,2-b]pyridazine-3-carboxylate (77.7 mg, 0.219 mmol) in methanol (0.7 mL) was added 85% potassium hydroxide (0.3 mg, 0.004 mmol) at room temperature. After stirring for 5 min, the mixture was partitioned between ethyl acetate (20 mL) and water (5 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give an yellow gum. Preparative silica gel thin layer chromatography eluting with ethyl acetate-hexane=1-7 afforded ethyl 4-(4-fluorophenyl)-2-isopropyl-7-(methylthio)pyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow gum (35.9 mg, 44.1%).
1H-NMR (CDCl3) δ 0.98 (3H, t, J=7 Hz), 1.41 (6H, d, J=7 Hz), 2.52 (3H, s), 3.32 (1H, septet, J=7 Hz), 4.05 (2H, q, J=7 Hz), 6.35 (1H, d, J=5 Hz), 6.89 (1H, d, J=5 Hz), 7.16 (2H, t, J=9 Hz), 7.44 (2H, d, J=4 and 9 Hz). MS (ESI+): m/z 373 (M+H)
The following compound(s) was (were) obtained in a similar manner to that of 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 1.41 (3H, t, J=8 Hz), 2.91-3.11 (6H, m), 3.78 (3H, s), 6.09 (1H, d, J=5 Hz), 6.38 (1H, dd, J=8, 3 Hz), 6.52 (1H, d, J=8 Hz), 6.59 (1H, d, J=5 Hz), 6.77 (1H, br s), 7.56 (1H, t, J=8 Hz), 7.67 (1H, br d, J=8 Hz), 7.70-7.77 (2H, m).
EXAMPLE 639
4-(3-ethyl-6H-indeno[1,2-e]pyrrolo[1,2-b]pyridazin-11-yl)benzonitrile
1H NMR (CDCl3) δ 1.43 (3H, t, J=8 Hz), 3.09 (2H, q, J=8 Hz), 4.11 (3H, s), 6.14 (1H, d, J=5 Hz), 6.64 (1H, d, J=5 Hz), 6.71 (1H, d, J=8 Hz), 7.07 (1H, t, J=8 Hz), 7.20-7.30 (1H, overlapped with 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 compound(s) was (were) obtained in a similar manner to that of Preparation 24.
Preparation 352
ethyl 4-methoxy-2-[(5-methyl-3-pyridinyl)carbonyl]-3-oxobutanoate
1H NMR (CDCl3) δ 0.97, 1.26 (3H, t, J=7 Hz), 2.40 (3H, s), 3.24, 3.35, 3.49 (3H, s), 3.98-4.20 (2H, m), 4.11, 4.20, 4.54 (2H, s), 5.70 (1H, s), 7.67, 7.92, 8.02, 8.50-8.66, 8.77, 8.89 (3H, m).
Preparation 353
ethyl 2-[(5-chloro-3-pyridinyl)carbonyl]-4-methoxy-3-oxobutanoate
1H NMR (CDCl3) δ 1.00, 1.06, 1.28, 1.35 (3H, t, J=7 Hz), 3.23, 3.43, 3.49 (3H, s), 4.05-4.33 (2H, m), 4.56 (2H, s), 7.85, 8.05, 8.22, 8.29, 8.58-8.82, 8.85, 9.01, 9.10 (3H, m).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 176.
Preparation 354
tert-butyl 3-bromo-5-({1-[(cyanoacetyl)amino]-5-ethyl-1H-pyrrol-2-yl}carbonyl)benzoate
1H-NMR (CDCl3) δ 1.29 (34H, t, J=7 Hz), 1.60 (9H, s), 2.61 (2H, q, J=7 Hz), 3.64 (2H, s), 6.00 (1H, m), 6.80 (1H, m), 8.03 (1H, m), 8.26 (1H, m), 8.28 (1H, m).
Preparation 355
tert-butyl 3-bromo-5-[(5-ethyl-1-{[(methylsulfonyl)acetyl]amino}-1H-pyrrol-2-yl)carbonyl]benzoate
1H-NMR (CDCl3) δ 1.29 (3H, t, J=7 Hz), 1.60 (9H, s), 2.60 (2H, q, J=7 Hz), 2.92 (3H, s), 4.04 (2H, s), 6.11 (1H, m), 6.78 (1H, m), 8.03 (1H, m), 8.25 (1H, m), 8.27 (1H, m).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 153.
Preparation 356
tert-butyl 3-bromo-5-(chlorocarbonyl)benzoate
The following compound(s) was (were) obtained in a similar manner to that of Preparation 164.
Preparation 357
tert-butyl 3-bromo-5-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate
1H-NMR (CDCl3) δ 1.32 (3H, t, J=7 Hz), 1.61 (9H, s), 2.74 (2H, q, J=7 Hz), 6.10 (1H, m), 6.80 (1H, m), 8.13 (1H, m), 8.26 (1H, m), 8.39 (1H, m), 934 (1H, s, br).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 338.
Preparation 358
tert-butyl 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-5-bromobenzoate
1H-NMR (CDCl3) δ 1.29 (3H, t, J=7 Hz), 1.61 (9H, s), 2.76 (2H, q, J=7 Hz), 5.74 (2H, s, br), 5.93 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 8.05 (1H, m), 8.25 (1H, m), 8.29 (1H, m).
Preparation 359
To a solution of tert-butyl 3-bromo-5-iodobenzoate (4.00 g) in tetrahydrofuran (30 mL) was added 0.76 M isopropylmagnesium bromide (13.7 mL) in an ice-methanol bath under a nitrogen atmosphere. After stirring for 0.5 hour, the mixture was poured onto dryice. The mixture was warmed to room temperature over 1 hour. The mixture was partitioned between EtOAc and 1 N hydrochloric acid. The organic layer was back extracted with 1 N sodium hydroxide (two times). The extract was acidified by adding concentrated hydrochloric acid, and extracted with chloroform (two times). The organic extract was washed with brine, dried over MgSO4, and evaporated to give 3-bromo-5-(tert-butoxycarbonyl)benzoic acid as a pale brown solid (529 mg).
3-bromo-5-(tert-butoxycarbonyl)benzoic acid
1H-NMR (DMSO-d6) δ 1.57 (9H, s), 8.21 (1H, s), 8.25 (1H, s), 8.37 (1H, s).
Preparation 360
To a vigirously stirred suspension of powdered MgSO4 (7.36 g) in dichloromethane (50 mL) was added sulfuric acid (0.758 mL) at room temperature. After stirring for 15 minutes, to the mixture was added 3-bromo-5-iodobenzoic acid (5.00 g) followed by tert-butanol (7.31 mL). The mixture was stirred for 3 days at room temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with satd. NaHCO3 and brine, dried over MgSO4, and evaporated to give tert-butyl 3-bromo-5-iodobenzoate as pale purple crystals (4.44 g).
tert-butyl 3-bromo-5-iodobenzoate
1H-NMR (CDCl3) δ 1.58 (9H, s), 8.00 (1H, m), 8.06 (1H, m), 8.22 (1H, m).
Preparation 361
To a suspension of lithium (316 mg) in ether (10 mL) was added cyclopropylbromide (250 g) in ether (10 mL) over 20 min in a methanol-ice bath under a nitrogen atmosphere. The mixture was stirred for 0.5 hour in an ice bath. The mixture was cooled in a dryice-acetone bath. To the mixture was added a solution of triisopropoxyborane (5.05 g) in tetrahydrofuran (5 mL) over 15 minutes. The mixture was allowed to warm to room temperature over 2 hours. The reaction was quenched by adding hydrochloric acid. The organic solvent was evaporated off, and the residual solution was extracted with ether (30 mL, five times). The combined extract was dried over MgSO4, and evaporated to give a white solid (968 mg). The solid was triturated in cold hexanes to give cyclopropylboronic acid as a white powder (789 mg).
cyclopropylboronic acid
1H-NMR (DMSO-d6) δ−0.40 (1H, m), 0.32 (2H, m), 0.39 (2H, m), 7.28 (2H, s).
The following compound(s) was (were) obtained in a similar manner to that of Example 21.
EXAMPLE 640
ethyl 7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylate
1H NMR (CDCl3) δ 0.99 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.41 (3H, s), 3.06 (2H, q, J=7 Hz), 3.38 (3H, s), 4.06 (2H, q, J=7 Hz), 4.75 (2H, s), 6.33 (1H, d, J=4 Hz), 6.71 (1H, d, J=4 Hz), 7.61 (1H, s), 8.52 (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-(methoxymethyl)pyrrolo[1,2-b]pyridazine-3-carboxylate
1H NMR (300 MHz, CDCl3) δ 1.04 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 3.06 (2H, q, J=7 Hz), 3.39 (3H, s), 4.09 (2H, q, J=7 Hz), 4.76 (2H, s), 6.33 (1H, d, J=4 Hz), 6.75 (1H, d, J=4 Hz), 7.81 (1H, dd, J=2, 2 Hz), 8.57 (1H, d, J=2 Hz), 8.68 (1H, d, J=2 Hz). MS (m/z) 374 (M+1).
The following compound(s) was (were) obtained in a similar manner to that of Example 0.76.
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 1.39 (3H, t, J=7 Hz), 2.43 (3H, s), 3.07 (2H, q, J=7 Hz), 3.51 (3H, s), 4.65 (2H, s), 5.97 (1H, d, J=16 Hz), 6.27 (1H, d, J=4 Hz), 6.71 (1H, d, J=4 Hz), 7.61 (1H, s), 7.72 (1H, d, J=16 Hz), 8.46 (1H, d, J=2 Hz), 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 1.39 (3H, t, J=7 Hz), 3.07 (2H, q, J=7 Hz), 3.51 (3H, s), 4.65 (2H, s), 5.97 (1H, d, J=16 Hz), 6.27 (1H, d, J=4 Hz), 6.75 (1H, d, J=4 Hz), 7.69 (1H, d, J=16 Hz), 7.78 (1H, dd, J=2, 2 Hz), 8.54 (1H, d, J=2 Hz), 8.71 (1H, d, J=2 Hz). MS (m/z) 400 (M+1).
EXAMPLE 644
4-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid
1H-NMR (CDCl3) δ 0.78 (2H, m), 1.10 (2H, m), 1.37 (3H, t, J=7 Hz), 1.73 (2H, m), 1.98 (1H, m), 2.23 (2H, m), 2.62 (2H, m), 3.02 (2H, q, J=7 Hz 9, 3.46 (3H, s), 4.65 (2H, q, J=7 Hz), 5.88 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.36 (1H, m), 8.41 (1H, m), 8.47 (1H, m).
EXAMPLE 645
5-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid
1H-NMR (CDCl3) δ 0.75 (2H, m), 1.08 (2H, m), 1.37 (3H, t, J=7 Hz), 1.40-1.57 (4H, m), 1.96 (1H, m), 2.18 (2H, m), 2.51 (2H, m), 3.02 (2H, q, J=7 Hz), 3.45 (3H, s), 4.61 (2H, m), 5.87 (1H, d, J=5 Hz), 6.56 (1H, d, J=5 Hz), 7.34 (1H, m), 8.39 (1H, m), 8.50 (1H, m).
EXAMPLE 646
3-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid
1H-NMR (DMSO-d6) δ 0.76 (2H, m), 1.08 (2H, m), 1.37 (3H, t, J=7 Hz), 1.95 (1H, m), 2.48 (2H, m), 2.87 (2H, m), 3.02 (2H, q, J=7 Hz), 3.47 (3H, s), 4.66 (2H, m), 5.90 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.35 (1H, m), 8.40 (1H, m), 8.48 (1H, m).
EXAMPLE 647
5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5-oxopentanoic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=8 Hz), 1.73-1.85 (2H, m), 2.26 (2H, t, J=8 Hz), 2.36 (2H, t, J=8 Hz), 2.46 (3H, s), 3.04 (2H, q, J=8 Hz), 6.33 (1H, d, J=5 Hz), 6.70 (1H, d, J=5 Hz), 7.34 (1H, br d), 7.45(1H, br s), 8.53 (1H, d, J=6 Hz).
EXAMPLE 648
(2E)-3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acrylic acid
1H NMR (CDCl3) δ 1.38 (3H, t, J=8 Hz), 2.67 (3H, s), 3.05 (2H, q, J=8 Hz), 5.79 (1H, d, J=15 Hz), 6.19 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.24-7.29 (1H, overlappled with CDCl3), 7.40 (1H, br s), 7.51 (1H, d, J=15 Hz), 8.55 (1H, d, J=5 Hz).
The following compound(s) was (were) obtained in a similar manner to that of Example 146.
EXAMPLE 649
ethyl (2E)-3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acrylate
1H NMR (CDCl3) δ 1.27 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 2.65 (3H, s), 3.04 (2H, q, J=8 Hz), 4.17 (2H, q, J=8 Hz), 5.76 (1H, d, J=15 Hz), 6.16 (1H, d, J=5 Hz), 6.65 (1H, d, J=5 Hz), 7.24-7.29 (1H, overlappled with CDCl3), 7.40 (1H, br s), 7.53 (1H, d, J=15 Hz), 8.53 (1H, d, J=5 Hz). MS (ESI+): m/z 370 (M+H).
The following compound(s) was (were) obtained in a similar manner to that of Example 181.
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 1.36 (3H, t, J=7 Hz), 2.94 (2H, q, J=7 Hz), 6.57 (1H, d, J=5 Hz), 6.72 (1H, d, J=5 Hz), 7.94 (1H, m), 8.20 (1H, m), 8.38 (1H, m).
EXAMPLE 651
tert-butyl 3-bromo-5-[7-ethyl-3-(methylsulfonyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4-yl]benzoate
1H-NMR (CDCl3) δ 1.35 (3H, t, J=7 Hz), 3.02 (2H, q, J=7 Hz), 3.06 (3H, s), 6.24 (1H, d, J=5 Hz), 6.70 (1H, d, J=5 Hz), 7.23 (1H, m), 7.94 (1H, m), 8.25 (1H, m).
The following compound(s) was (were) obtained in a similar manner to that of Example 183.
EXAMPLE 652
tert-butyl 3-bromo-5-(3-cyano-7-ethyl-2-{[(trifluoromethyl)sulfonyl]oxy}pyrrolo[1,2-b]pyridazin-4-yl)benzoate
1H-NMR (CDCl3) δ 1.39 (3H, t, J=7 Hz), 1.61 (9H, s), 3.02 (2H, q, J=7 Hz), 6.81 (1H, d, J=5 Hz), 7.00 (1H, d, J=5 Hz), 7.96 (1H, m), 8.21 (1H, m), 8.33 (1H, m).
EXAMPLE 653
tert-butyl 3-bromo-5-(7-ethyl-3-(methylsulfonyl)-2-{[(trifluoromethyl)sulfonyl]oxy}pyrrolo[1,2-b]pyridazin-4-yl)benzoate
1H-NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 1.59 (9H, s), 3.01 (2H, q, J=7 Hz), 3.22 (3H, s), 6.46 (1H, d, J=5 Hz), 7.12 (1H, d, J=5 Hz), 7.67 (1H, m), 7.90 (1H, m), 8.23 (1H, m).
The following compound(s) was (were) obtained in a similar manner to that of Example 184.
EXAMPLE 654
tert-butyl 3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoate
1H-NMR (CDCl3) δ 1.35 (3H, t, J=7 Hz), 1.60 (9H, s), 2.01 (4H, m), 2.93 (2H, q, J=7 Hz), 3.73 (4H, m), 6.32 (1H, d, J=5 Hz), 6.58 (1H, d, J=7 Hz), 7.86 (1H, m), 8.12 (1H, m), 8.24 (1H, m).
EXAMPLE 655
tert-butyl 3-bromo-5-[7-ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoate
1H-NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 1.58 (9H, s), 1.99 (4H, m), 2.98 (2H, q, J=7 Hz), 3.21 (3H, s), 3.52 (4H, m), 6.30 (1H, d, J=5 Hz), 6.66 (1H, d, J=5 Hz), 7.76 (1H, m), 8.00 (1H, m), 8.19 (1H, m).
The following compound(s) was (were) obtained in a similar manner to that of Example 147.
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 1.27 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 3.07 (2H, q, J=7 Hz), 3.51 (3H, s), 4.18 (2H, q, J=7 Hz), 4.64 (2H, s), 5.97 (1H, d, J=16 Hz), 6.24 (1H, d, J=4 Hz), 6.72 (1H, d, J=4 Hz), 7.61 (1H, d, J=16 Hz), 7.76 (1H, dd, J=2, 2 Hz), 8.54 (1H, d, J=2 Hz), 8.68 (1H, d, J=2 Hz).
The following compound(s) was (were) obtained in a similar manner to that of Example 205.
EXAMPLE 657
(4E)-5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]-4-pentenoic acid
1H NMR (300 MHz, CDCl3) δ 1.38 (3H, t, J=7 Hz), 2.25-2.41 (4H, m), 3.05 (2H, q, J=7 Hz), 3.50 (3H, s), 4.57 (2H, s), 5.53 (1H, dd, J=16, 7 Hz), 6.13 (1H, d, J=4 Hz), 6.36 (1H, d, J=16 Hz), 6.65 (1H, d, J=4 Hz), 7.80 (1H, s), 8.54 (1H, br s), 8.62 (1H, br s). MS (m/z) 400 (M+1).
The following compound(s) was (were) obtained in a similar manner to that of Preparation 153.
EXAMPLE 658
4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carbonyl chloride
The following compound(s) was (were) obtained in a similar manner to that of Example 244.
EXAMPLE 659
7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carbaldehyde
1H NMR (CDCl3) δ 1.40 (3H, t, J=7 Hz), 2.45 (3H, s), 3.12 (2H, q, J=7 Hz), 3.56 (3H, s), 4.96 (2H, s), 6.51 (1H, d, J=4 Hz), 6.80 (1H, d, J=4 Hz), 7.62 (1H, s), 8.54 (1H, s), 8.61 (1H, s), 9.79 (1H, s). MS (ESI+): m/z 310.
EXAMPLE 660
4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazine-3-carbaldehyde
1H NMR (300 MHz, CDCl3) δ 1.41 (3H, t, J=7 Hz), 3.12 (2H, q, J=7 Hz), 3.54 (3H, s), 4.94 (2H, s), 6.50 (1H, d, J=4 Hz), 6.84 (1H, d, J=4 Hz), 7.81 (1 (H, dd, J=2, 2 Hz), 8.59 (1H, d, J=2 Hz), 8.74 (1H, d, J=2 Hz), 9.85 (1H, s).
The following compound(s) was (were) obtained in a similar manner to that of Example 533.
EXAMPLE 661
[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]methanol
1H NMR (CDCl3) δ 1.38 (3H, t, J=7 Hz), 2.43 (3H, s), 3.05 (2H, q, J=7 Hz), 3.52 (3H, s), 4.37-4.51 (2H, br), 4.66-4.78 (2H, br), 6.20 (1H, d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 7.75 (1H, s), 8.54 (1H, s), 8.60 (1H, s). MS (ESI+): m/z 312.
EXAMPLE 662
[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]methanol
1H NMR (300 MHz, CDCl3) δ 1.38 (3H, t, J=7 Hz), 3.05 (2H, q, J=7 Hz), 3.53 (3H, s), 4.41 (2H, d, J=6 Hz), 4.77 (2H, s), 6.22 (1H, d, J=4 Hz), 6.70 (1H, d, J=4 Hz), 7.97 (1H, dd, J=2, 2 Hz), 8.69-8.71 (2H, m). MS (m/z) 332 (M+1).
EXAMPLE 663
A mixture of 7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carbaldehyde (48 mg) and ethyl (triphenylphosphoranylidene)acetate (56.8 mg) in THF (3 mL) was stirred at ambient temperature for 2 hours. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (5:1-2:1) to give ethyl (2E)-3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylate as a 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 1.26 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 2.42 (3H, s), 3.07 (2H, q, J=7 Hz), 3.51 (3H, s), 4.12 (2H, q, J=7 Hz), 4.64 (2H, s), 5.97 (1H, d, J=16 Hz), 6.24 (1H, d, J=4 Hz), 6.70 (1H, d, J=4 Hz), 7.55 (1H, s), 7.63 (1H, d, J=16 Hz), 8.47 (1H, d, J=2 Hz), 8.55 (1H, d, J=2 Hz). MS (ESI+): m/z 380.
EXAMPLE 664
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 (457 mg), and potassium phosphate (104 mg) in toluene-water (1 mL-0.2 mL) was added palladium acetate (1.83 mg). The mixture was stirred for 2 hours at 100° C. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, and evaporated. Preparative silicagel thin layer chromatography (EtOAc-hexanes=1-3) afforded ethyl 4-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoateas an yellow gum (60.9 mg).
ethyl 4-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate
1H-NMR (CDCl3) δ 0.76 (2H, m), 1.07 (2H, m), 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.68 (2H, m), 1.96 (1H, m), 2.17 (2H, m), 2.56 (2H, m), 3.02 (2H, q, J=7 Hz), 3.46 (3H, s), 4.03 (2H, q, J=7 Hz), 4.65 (2H, m), 5.90 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.30 (1H, m), 8.40 (1H, m), 8.51 (1H, m).
The following compound(s) was (were) obtained in a similar manner to that 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), 1.08 (2H, m), 1.23 (3H, t, J=7 Hz), 1.35-1.57 (7H, m), 1.96 (1H, m), 2.16 (2H, t, J=7 Hz), 2.53 (2H, m), 3.03 (2H, q, J=7 Hz), 3.46 (3H, s), 4.08 (2H, q, J=7 Hz), 4.62 (2H, s), 5.89 (1H, d, J=5 Hz), 6.56 (1H, d, J=5 Hz), 7.29 (1H, m), 8.40 (1H, m), 8.52 (1H, m).
EXAMPLE 666
ethyl 3-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate
1H-NMR (CDCl3) δ 0.76 (2H, m), 1.08 (2H, m), 1.19 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.97 (1H, m), 2.38 (2H, m), 2.85 (2H, m), 3.02 (2H, q, J=7 Hz), 3.46 (3H, s), 4.04 (2H, q, J=7 Hz), 4.64 (2H, s), 5.92 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.29 (1H, m), 8.40 (1H, m), 8.53 (1H, m).
EXAMPLE 667
tert-butyl 3-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]-5-cyclopropylbenzoate
1H-NMR (CDCl3) δ 0.81 (2H, m), 1.03 (2H, m), 1.35 (3H, t, J=7 Hz), 1.59 (9H, s), 1.94-2.08 (5H, m), 2.94 (2H, q, J=7 Hz), 3.68-3.77 (4H, m), 6.35 (1H, j, J=5 Hz), 6.55 (1H, d, J=5 Hz), 7.43 (1H, s), 7.84 (1H, s), 7.97 (1H, s).
EXAMPLE 668
A solution of tert-butyl 3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoate (16.0 mg) in trifluoroacetic acid (0.5 mL) was stirred for 0.5 hour at room temperature. The reaction was quenched by adding water. The mixture was neutralized by adding NaOH (pH=3). The mixture was extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and evaporated to give a greenish yellow solid. The solid was triturated in hexanes-CHCl3 (2-1) to afford 3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid as an yellow powder (10.8 mg).
3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid
1H-NMR (CDCl3+CD3OD) δ 1.36 (3H, t, J=7 Hz), 2.01 (4H, m), 2.94 (2H, q, J=7 Hz), 3.72 (4H, m), 636 (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 compound(s) was (were) obtained in a similar manner to that of Example 668.
EXAMPLE 669
3-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]-5-cyclopropylbenzoic acid
1H-NMR (CDCl3+CD3OD) δ 0.81 (2H, m), 1.05 (2H, m), 1.35 (3H, t, J=7 Hz), 2.01 (5H, m), 2.94 (2H, q, J=7 Hz), 7.73 (4H, m), 637 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 6.98 (1H, s), 7.90 (1H, s), 8.08 (1H, s).
EXAMPLE 670
3-bromo-5-[7-ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid
1H-NMR (CDCl3+CD3OD) δ 1.37 (3H, t, J=7 Hz), 1.98 (4H, m), 2.99 (2H, q, J=7 Hz), 3.20 (3H, s), 3.56 (4H, m), 6.32 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.80 (1H, m), 8.08 (1H, m), 8.30 (1H, m).
EXAMPLE 671
To a 3-necked frask containing Zn—Cu couple was added a solution of ethyl 4-iodobutanoate (369 mg) in toluene (3 mL) and N,N-dimethylacetamide (0.2 mL) at ambient temperature under N2. The mixture was stirred at the temperature for 1 h and then at 60° C. for 3 h. A suspension of tetrakis(triphenylphosphine)palladium (44 mg) in toluene (0.5 mL) was added and stirred for 5 min. After removal of an oil bath, the mixture was cooled in an ice-water bath. To this mixture was added a solution of 4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carbonyl chloride (212 mg) in DCM (1 mL) dropwise. After 10 min, the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was partitioned between AcOEt and H2O. The organic layer was washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 80 mL) eluted with hexane-AcOEt=10-1 and 5-1 to give ethyl 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5-oxopentanoate as yellow amorphous (143 mg).
ethyl 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5-oxopentanoate
1H NMR (CDCl3) δ 1.23 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 1.71-1.84 (2H, m), 2.17 (3H, t, J=8 Hz), 2.32 (3H, t, J=8 Hz), 2.46 (3H, s), 3.04 (2H, q, J=8 Hz), 4.06 (2H, q, J=8 Hz), 6.32 (1H, d, J=5 Hz), 6.70 (1H, d, J=5 Hz), 7.32 (1H, dd, J=5, 1), 7.46 (1H, br s), 8.53 (1H, d, J=5 Hz).
EXAMPLE 672
To a solution of 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5-oxopentanoic acid (47 mg) in EtOH (1 mL) was added sodium borohydride (5 mg) in an ice-water bath under N2. After 10 min, the mixture was stirred at ambient temperature. After 1 h, another odium borohydride (5 mg) was added. After 2 h, the reaction mixture was partitioned between CHCl3 and H2O. The aqueous layer was extracted with CHCl3 twice. The combined organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by p-TLC (CHCl3-MeOH=10-1) to give 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5-hydroxypentanoic acid as yellow amorphous (28 mg).
5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5-hydroxypentanoic acid
1H NMR (CDCl3) δ 1.36 (3H, t, J=8 Hz), 1.46-1.83 (3H, m), 1.95 (1H, m), 2.70 (3H, br s), 3.01 (2H, q, J=8 Hz), 4.63 (1H, m), 5.85 (1H, m), 6.55 (1H, d, J=5 Hz), 7.18-7.29 (1H, overlapped with CDCl3), 7.34 (1H, d, J=2 Hz), 8.49 (1H, d, J=5 Hz).

## Claims

1. A compound of the formula I or a pharmaceutically acceptable salt thereof, or a prodrug thereof:



wherein
R1 is (1) a mono- or di(lower)alkylamino,
(2) a phenyl,
(3) a saturated or unsaturated 5 to 6 membered heteromonocyclic group selected from the group consisting of a pyrrolidinyl, a pyrrolyl, an oxazolyl, an isooxazolyl, a thiazolyl, a furanyl, a thienyl, and a pyridinyl, or
(4) a lower alkyl optionally substituted by (i) a lower alkoxy or (ii) a saturated 5- or 6-membered heteromonocyclic group selected from the group consisting of a piperazinyl and a morpholinyl, wherein the lower alkoxy is optionally substituted by a cyclo(lower)alkyl or a pyridinyl,

R2 is R7 or -A2-R7,
wherein A2 is —(CH2)n- or —(CH═CH)m-
wherein n is an integer which may range from 2 to 6, and m is an integer of 1 to 2, and
R7 is a hydrogen, a lower alkyl sulfonyl, a carboxy, an esterified carboxy or a pyridinyl,
R3 is (1) a phenyl optionally substituted by a lower alkyl, a cyclo(lower)alkyl, a lower alkoxy, a halogen, a cyano, or a carbamoyl; or
(2) a quinolinyl; or a pyridinyl substituted by a lower alkyl, a cyclo(lower)alkyl, a lower alkoxy, a carbamoyl or a halogen, and

R4 is ethyl.

2. The compound of claim 1, wherein
R1 is a phenyl, a pyrrolyl, an isooxazolyl, a furanyl, a thienyl, a lower alkyl optionally substituted by a lower alkoxy, a piperazinyl or a morpholinyl, wherein a lower alkoxy is optionally substituted by a cyclo(lower)alkyl or a pyridinyl,
R2 is —(CH2)n-R7, wherein n is an integer which may range from 2 to 5, and R7 is a carboxy or an esterified carboxy, and
R3 is (1) a phenyl optionally substituted by a lower alkyl, a cyclo(lower)alkyl, a lower alkoxy, a halogen, a cyano, or a carbamoyl; or (2) a pyridinyl substituted by a lower alkyl, a cyclo(lower)alkyl, a lower alkoxy, a carbamoyl or a halogen.

3. A process for preparing a compound of claim 1 comprising:
(1) reacting a compound (II) of formula




wherein R3 and R4 are as defined in claim 1 or a salt thereof with a compound (III) of formula




wherein R1 and R2 are as defined in claim 1 or a salt thereof to obtain a compound (I) of formula




wherein R1, R2, R3, and R4 are as defined in claim 1 or a salt thereof, or
(2) reacting a compound (V) of formula




wherein R4 is as defined in claim 1 or a salt thereof with a compound (VI) of formula




wherein R1, R2 and R3 are as defined in claim 1 or a salt thereof to obtain a compound (I) of formula




wherein R1, R2, R3 and R4 are as defined in claim 1 or a salt thereof.

4. A pharmaceutical composition comprising:
a compound of claim 1 in admixture with a pharmaceutically acceptable carrier.

5. A method for treating, in a subject, asthma, chronic obstructive pulmonary disease (COPD), fibrotic disease, acute and fulminant hepatitis, hepatic steatosis (alcoholic or non-alcoholic steatohepatitis), chronic (viral or non-viral) hepatitis, hepatic cirrhosis, autoimmune hepatitis, autoimmune inflammatory bowel disease, atopic dermatitis,
the method comprising:
administering a therapeutically effective amount, or a prophylactically effective amount, of the compound of claim 1 to the subject.