Patent Grant
7153854
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).
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, WO03/000679 and the like. However, there remains a need for novel compounds that inhibit PDE-IV with minimal side effects. Although some pyrrolopyridazine derivatives having the inhibitory activity of hydroxymethylglutaryl (HMG) CoA reductase have been known, for example, in WO91/18903, pyrrolopyridazine derivatives having the inhibitory activity of PDE-IV have not been known.
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
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
that may include the following ones;
More preferred compounds of formula (I) are those in which:
Most preferred compounds of formula (I) are those in which:
Preferred concrete compound of formula (I) is:
More preferred concrete compound of formula (I) is:
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,
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
The term “protected amino” means an amino group bonded to the amino-protecting group. Example of such amino-protectnig group include lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.); lower alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.); optionally substituted aryl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.); phthalimide; and the like. Further example of amino-protecting group are well-known in organic synthesis and are 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:
Syitable “halocarbonyl” may include chlorocarbonyl, bromocarbonyl, and the like.
Suitable “cyclo(lower)alkyl” and “cyclo(lower)alkyl moeity” may include one having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
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
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, pyrrolidinylcarnbonyloxy, 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, isopropoxy, 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 descried 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):
(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
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.
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 (32.5 g) as a pale brown solid.
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
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
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
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
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
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
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.
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
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.
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
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
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
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
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
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
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
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
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 (5.56 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 partitined between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 1 L) eluting with hexane-ethyl acetate=50-1, 20-1, 10-1, and 8-1 to give 1-tert-butyl 7-ethyl 2-acetylheptanedioate (27.3 g, 75.4%) as colorless oil.
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
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
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
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.
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
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
NMR (300 MHz, CDCl3, δ): 0.79 (3H, t, J=7.5 Hz), 1.22 (6H, d, J=7.5 Hz), 3.36–3.54 (1H, m), 3.88 (2H, q, J=75 Hz), 7.26–7.44 (4H, m)
Preparation 27
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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, 756, and 7.85 (4H, m)
MS (ESI+): m/z 275 (M+H)
Preparation 49
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
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
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
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
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
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
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
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
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
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
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
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
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
NMR (CDCl3, δ): 1.23 (3H, t, 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=1.71 Hz), 7.37 (1H, m), 8.03 (1H, m), 8.73 (1H, m), 8.92 (1H, m)
Preparation 63
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
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
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
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
NMR (CDCl3, δ): 1.23–1.37 (9H, m), 1.55–1.68 (11H, s), 2.01 (2H, m), 2.18 (3H, s), 2.29 (2H, t, J=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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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%).
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 (32.5 g). The residue was dissolved in hexane-ethyl acetate=2-1 (200 mL) and was added silica gel (65 g) therein. After stirring for 30 minutes at ambient temperature, the mixture was 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%).
NMR (CDCl3, δ): 1.50 (9H, s), 3.41 (2H, s), 3.43 (3H, s), 4.08 (2H, s)
Preparation 131
To a mixture of 3-formylbenzoic acid (500 mg) and p-toluenesulfonylmethyl isocyanide (715 mg) in methanol (20 mL) was added potassium carbonate (1.38 g) and 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).
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).
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
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, J=7 Hz), 4.11 (2H, q, J=7 Hz), 7.86 (1H, s), 8.03 (1H, s)
Preparation 134
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 suspensin of magnesium chloride (1.46 g) in tetrahydrofuran (10 ml) was added a solution of ethyl 3-oxo-4-phenylbutanoate (2.0 g) in tetrahydrofuran (10 ml) and the mixture was cooled to 0° C., then pyridine (2.5 ml) was added. The mixture was stirred at 20° C. for 30 minutes, then a solution of 4-fluorobenzoyl chloride (2.44 g) in tetrahydrofuran (10 ml) was added at 0° C. After stirring at 20° C. for 2 hours, the mixure was partitoned between 0.5N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. 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.
(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 partitoned between ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 3-(4-fluorobenzoyl)-4-oxopentanoate (964 mg) as an oil.
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 partitoned between ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 7-(4-fluorobenzoyl)-8-oxononanoate (983 mg) as an oil.
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 partitoned between ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 8-acetyl-9-oxodecanoate (5.5 g) as an oil.
(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 (3.52 g) as an oil.
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 partitoned between ethyl acetate and water. The organic layer was separated, washed with water, aqueous sodium bicarbonate and brine, dried over MgSO4 (magnesium sulfate), and evaporated to give ethyl 7-(4-cyanobenzoyl)-8-oxononanoate (2.25 g) as an oil.
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 (6.55 g) in dimethoxyethane (50 mL) was refluxed for 5 minutes. After cooling the mixture, a solution of benzyl chloridocarbonate (5.25 g) in dimethoxyethane (30 mL), and the resulting mixture was refluxed for 1 hour. The reaction was quenched by adding 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).
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).
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 1.5 hours at room temperature. Ethyl acetate (20 mL) and water (20 mL) were added, and the mixture was filtered through celite. The filtrate was diluted with ethyl acetate (80 mL) and water (30 mL), and organic extract was washed with water (30 mL), 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 (1.57 g, 70.1%).
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).
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 (5.33 g).
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).
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 sufate, and evaporated to give a dark orange oil. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-25 to 8-5 afforded 2-(trimethylsilyl)ethyl 3-(methylsulfonyl)-2-oxopropanoate as a pale brown oil (8.37 g).
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).
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
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).
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).
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 brmown oil. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-20 to 4-5 afforded methyl 7-(1-methyl-1H-pyrrol-2-yl)-7-oxoheptanoate as a colorless oil (615 mg).
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.
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).
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).
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 (11.5 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).
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).
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).
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).
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
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
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
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
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).
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).
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).
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
NMR (CDCl3, δ): 1.47 (9H, s), 2.46 (3H, s), 2.68 (3H, s), 3.68 (2H, s)
Preparation 168
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
NMR (CDCl3, δ): 1.47 (9H, s), 2.07 (3H, s), 3.31 (2H, s), 3.58 (2H, s)
Preparation 170
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
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
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
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
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
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).
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
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)
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.
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.
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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.
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.
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)
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)
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)
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)
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.
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.
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
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)
NMR (300 MHz, CDCl3, δ): 0.78 (3H, t, J=7.5 Hz), 1.38 (6H, d, J=7.5 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
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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).
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)
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)
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)
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
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
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
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
NMR (CDCl3, δ): 1.23 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.38–1.50 (2H, m), 1.50–1.63 (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
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
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
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)
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
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
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
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)
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
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)
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)
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
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
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
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
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
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)
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
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
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).
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)
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)
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 partitined between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica 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%).
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.
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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).
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
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
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
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
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
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
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)
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)
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
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
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)
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
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
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
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
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
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
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
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)
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
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
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
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
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
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=11 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
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
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
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
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
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
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
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), 854(1H, s), 8.77(1H, s)
MS: (m/z) 388 (M+), 390(M++2), 114(bp)
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)
NMR (CDCl3, δ): 1.30–1.70 (5H, overlappoed 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)
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)
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)
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)
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)
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)
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)
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)
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
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
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.
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, 15 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.
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=8.5 Hz), 7.33 (1H, d, J=8.5 Hz), 7.35 (1H, d, J=8.5 Hz), 7.63 (1H, d, J=15 Hz).
MS (ESI−): m/z 385 (M−H).
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)
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.
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.
NMR (300 MHz, CDCl3, δ): 0.89 (3H, t, J=7.5 Hz), 1.41 (6H, d, J=7.5 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
NMR (300 MHz, CDCl3, δ): 0.78 (3H, t, J=7.5 Hz), 1.43 (6H, d, J=7.5 Hz), 3.29–3.41 (1H, m), 3.95 (2H, q, J=7.5 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)
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.
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)
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 metanol solution (536 mg) and the mixture was heated under reflux for 2 hours. The solution was acidified to pH 4 with 1N hydrochloric acid and extracted with chloroform. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. To the residue in ethanol (5 mL) was added 1N sodium hydroxide 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)
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.
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)
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.
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
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
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).
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)
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%).
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.
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)
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)
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)
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)
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)
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)
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)
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)
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).
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)
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)
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)
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)
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)
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 (1H, m)
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)
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.
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)
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)
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)
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)
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%)
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)
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%)
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.
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)
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%)
NMR (CDCl3, δ): 1.39 (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)
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-(methyl sulfonyl)-2-(1-pyrrolidinyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile as an yellow oil, which was crystalyzed upon standing (112 mg, 89.6%).
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.
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)
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)
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.
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)
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 chromatograpy eluting with a mixture of toluene and ethyl acetate (10:1) to give ethyl 2-benzyl-7-chloro-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (285 mg) as an yellow oil.
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)
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.
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)
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 chromatograpy eluting with a mixture of toluene and ethyl acetate (10:1) to give ethyl[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate (34 mg) as an yellow oil.
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)
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.
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).
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.
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)
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 chromatograpy 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.
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)
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.
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)
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.
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)
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)
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.
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)
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)
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.
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)
To a solution of ethyl 6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate (1.5 g) in tetrahydrofuran (15 ml) was added 2N potassium hydroxide (7.4 ml), followed by methanol (7.4 ml). After stirring at 50° C. for 2 hours and 60° C. for 3 hours, the mixture was partitioned between 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 chromatograpy 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.
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)
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)
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.
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)
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 diisobutylalminum hydride (0.277 mL) in toluene (24 mL) in a dryice-acetone bath. After addition, the mixture was stirred for 2 hours (−10° C.). The reaction 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).
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.
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)
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)
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)
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 (3.5 mg, 10.2%).
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)
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%).
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)
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).
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)
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%).
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)
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 (361 mg, 72.6%).
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)
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%).
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)
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 25 hours at room temperature. The mixture was stirred for futher 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%).
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)
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%).
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)
To methanol (1 mL) was added 60% sodium hydride (6.51 mg) at room temperature. Then, 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-2-yl trifluoromethanesulfonate (70.0 mg) was added to the mixture. The 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%).
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)
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 adiding 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%)
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)
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%).
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)
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 mehtyl iodide (25.9 mg). The mixture was further stirred for 1 hour after adding 60% sodium hydride (3.0 mg) and methyl iodide (25.9 mg). The mixture was partitioned between ethyl acetate 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).
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)
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)
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%).
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.
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)
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%).
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)
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 ehtyl 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%)
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)
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 2.5 hours. The reaction mixture was cooled under an ice-bath, and quenched by adding concentrated hydrochloric (5 mL). The mixture was partitioned between ethyl acetate (20 mL) and water (10 mL), and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated to 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%).
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)
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%).
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)
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%).
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.
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)
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%)
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)
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%).
NMR (CDCl3, δ): 0.97–1.26 (36H, 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)
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%).
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)
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 mixtrure was further stirred for 50 minutes after adding 2,3,4,6-tetra-O-acetyl-beta-D-galactosyl bromide (114 mg), silver carbonate (154 mg). The mixture was filtered through celite, and the filtrate was paritiotned between ethyl acetate and water. The 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%).
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)
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%).
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.
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)
NMR (CDCl3, δ): 1.24 (3H, t, J=7 Hz), 1.34–1.50 (5H, m), 1.54 (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)
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[5.40]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.
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)
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 yello solid.
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)
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)
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 mixure became clear solution. The solution was filtered through membrane filter, washed with water (0.4 mL×3), and was freezedried for 15 hours to give 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid sodium salt (612 mg, 98.2%) as a pale yellow powder.
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)
A solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (100 mg), triethylamime (29.4 mg), and diphenylphosphoryl azide (79.9 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.
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)
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)
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)
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.
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.
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)
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)
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)
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
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)
A solution of 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (50 mg) in dioxane (1.5 mL) in a sealed tube was added 50% dimethylamine in water (1.5 mL). The mixture was heated at 175° C. overnight. The cooled reaction mixture was concentrated in vacuo. The residue was dissolved in water (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%).
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)
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).
NMR (CDCl3, δ): 1.43 (6H, d, J=7 Hz), 2.65 (2H, t, J=7 Hz), 3.42 (1H, m), 3.53 (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)
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 ⅓ 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 yelow solid (340 mg, 67.9%).
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)
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 (3.5 atm) at ambient temperature. After 12 hours, the mixture was stood overnight. To the mixture was added 10% palladium on carbon (900 mg) and was stirred under hydrogen atomosphere (3.5 atm) at ambient temperature for 8 hours. The mixture was filtered 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%).
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.
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
NMR (CDCl3, δ): 1.30 (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
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)
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%).
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.
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)
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).
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.
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
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).
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)
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).
NMR (CDCl3, δ): 1.24 (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.
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)
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)
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)
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)
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 filtereed off and washed with ethyl acetate. The filtrates were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1–2:1) to give 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol as an yellow oil (478 mg).
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)
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).
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
A mixture of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol (65 mg), trimethyloxonium tetrafluoroborate (275 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).
NMR (CDCl3, δ): 00.90–1.32 (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
To a solution of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol (55 mg) and triethylamine (19.9 mg) in dichloromethane (3 mL) was added methanesulfonyl chloride (16.5 mg) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. The solution was washed with brine, dried over magnesium 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).
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
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-animopyridine (20 mg) and the reaction mixture was stirred for 10 minutes. 4-Dimethylaminopyridine (2 mg) was added and the reaction mixture was stirred at room temperature for 15 hours. The mixture was diluted with water and extracted with ethyl 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.
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.
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)
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)
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=75 Hz), 8.24 (1H, d, J=5 Hz), 8.53 (1H, d, J=6 Hz)
MS: (m/z) 510 (M++H), 80 (bp)
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)
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 partitioend 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%).
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.
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)
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 mixrure 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).
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)
A mixture of ethyl 5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(methylsulfonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate (50.0 mg), benzylamine (29.8 mg) in dichloromathane (1 mL) was stirred for 20 hour at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, and evaporated. Preparative thin layer 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).
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.
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)
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 (5.5 mg) in an ice-water bath. After 20 minutes, to the mixture was added 2-bromoethyl acetate (31 mg) at the temperature. After 15 minutes, the reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was 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).
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.
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.
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)
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).
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)
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).
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.
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)
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)
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)
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)
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)
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)
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.
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 (13.3 g).
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
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
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
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
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
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
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
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
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
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
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).
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
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
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
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
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
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), 9.33 (1H, d, J=2 Hz).
MS (ESI+): m/z 526.
Preparation 195
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
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
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
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
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
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
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
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
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
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
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
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
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), 9.39 (1H, d, J=2 Hz).
MS (ESI+): m/z 426.
Preparation 208
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
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
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
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
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
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
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
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, t, 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
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.
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.
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.
1H NMR (CDCl3) δ 1.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.67–1.78 (2H, m), 2.22 (2H, t, J=7 Hz), 2.42–2.54 (2H, m), 2.59 (3H, s), 3.01 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.87 (1H, m), 8.54 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz).
MS (ESI+): m/z 430 432.
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.
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.
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), 9.33 (1H, d, J=2 Hz).
MS (ESI+): m/z 500.
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).
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.
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).
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).
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.
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.
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.
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.
1H NMR (CDCl3) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.30–1.58 (4H, m), 2.13 (2H, t, J=7 Hz), 2.18 (3H, s), 2.44 (3H, s), 2.40–2.55 (2H, m), 3.02 (2H, q, 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.
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.
1H NMR (CDCl3) δ 1.19 (3H, t, J=7 Hz), 1.26 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.42 (2H, t, J=7 Hz), 2.84–2.97 (2H, m), 3.07 (2H, q, J=7 Hz), 3.47 (3H, s), 3.97 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.36 (1H, d, J=3 Hz), 4.66 (2H, s), 4.77 (1H, d, J=3 Hz), 5.95 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.92 (1H, m), 8.54 (1H, d, J=2 Hz), 8.95 (1H, d, J=2 Hz).
MS (ESI+): m/z 438.
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.
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.
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.
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.
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.
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).
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.
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.
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 filterred off and washed with chloroform. The filtrates were evaporated in vacuo to give 5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]nicotinic acid as yellow oil (272 mg)
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), 9.37 (1H, d, J=2 Hz).
MS (ESI−): m/z 408, MS (ESI+): m/z410.
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)
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.
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)
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).
To a solution of ethyl 5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (55 mg), 37% formaldehyde solution (277 mg) and sodium cyanoborohydride (27.3 mg) in acetnitrile (1 mL) and methanol (1 mL) was added acetic acid (2 drops) and the mixture was stirred at ambient temperature for 2 hours. The solution was diluted with saturated sodium bicarbonate solution and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-{4-[5-(dimethylamino)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate as yellow oil (36.5 mg)
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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), 8.58 (2H, d, J=7 Hz).
MS (ESI+): m/z 487.
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.
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 (1J, d, J=5 Hz), 6.56 (1H, d, J=5 Hz), 7.60 (2H, m), 7.67 (1H, s), 7.75 (1H, m)
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).
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).
A solution of ethyl 5-[2-[(2-tert-butoxy-2-oxoethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (60 mg) in tifluoroacetic acid (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).
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.
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).
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), 3.48–3.57 (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 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.52 (1H, s), 8.43 (1H, d, J=2 Hz), 8.54 (1H, d, J=2 Hz).
MS (ESI+): m/z 523.
The following compound(s) was(were) obtained in substantially the same manner as that of Example 330.
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), 7.53 (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.
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), 8.53 (1H, d, J=2 Hz).
MS (ESI+): m/z 485.
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 (995 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).
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.
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).
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.
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).
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), 7.50 (1H, s), 8.40 (1H, d, J=2 Hz), 8.54 (1H, d, J=2 Hz).
MS (ESI+): m/z 437.
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)
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.
A mixture of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (75 mg), benzoic acid (27.9 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (54.7 mg) and 1-hydroxybenotriazole (38.5 mg) in dimethylformamide (2 mL) was stirred at ambient temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. 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).
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.
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.
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).
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).
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 (18.5 mg) in dichloromethane (1 mL) was added methanesulfonyl chloride (20.9 mg) under an ice bath. After stirring for 1 hour, to the mixture was added 1-methylpiperazine (27.0 mg). The mixture was stirred for 0.5 hour under an ice bath and overnight at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. Preparative silicagel thin layer chromatography (chloroform-methanol=20-1) afforded ethyl 5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-methyl-1-piperazinyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate as an yellow gum (52.4 mg, 63.5%).
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 Hz9, 7.87 (1H, m), 8.54 (1H, m), 8.77 (1H, m).
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%).
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).
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%).
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
1H NMR (CDCl3) 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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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 produt 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)
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.
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)
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)
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)
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.
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).
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).
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).
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).
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.
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.
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.
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.
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.
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.
1H NMR (CDCl3) δ 1.32 (3H, t, J=7 Hz), 1.90 2H, m), 2.26 (3H, s), 2.57–2.278 (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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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), 7.38 (1H, t, J=8 Hz), 7.52 (1H, br d, J=8 Hz), 7.60 (1H, br d, J=8 Hz), 7.79 (1H, br s).
Preparation 245
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
1H NMR (CDCl3) δ 1.24 (3H, t, J=8 Hz), 1.27–1.40 (1H, 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
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
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
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
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
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
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
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
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
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
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 Prepatration 78.
Preparation 257
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
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
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
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
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
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
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
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
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
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
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
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
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), 4.85–4.93 (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
1H NMR (300 MHz, CDCl3) δ 0.75–0.86 (2H, m), 0.95–1.15 (3H, m), 1.24 (3H, t, J=57 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
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
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
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
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
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
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
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
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
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
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
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
1H NMR (DMSO-d6) δ 7.60 (1H, s), 8.78 (2H, s), 8.88 (2H, s), 9.30 (2H, s).
Preparation 283
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
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
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
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
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
1H NMR (CDCl3) δ 1.23 (3H, t, J=8 Hz), 1.25–1.45 (2H, m), 1.55–1.70 (2H, m), δ 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
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
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
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
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 (1H, m), 9.31 (1H, m).
Preparation 293
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
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
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
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
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
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
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
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
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
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
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
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
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
Preparation 307
Preparation 308
Preparation 309
The following compound(s) was(were) obtained in a similar manner to that of Praparation 159.
Preparation 310
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
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
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
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
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
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
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
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
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
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
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
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 (4.45 g).
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).
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 filterred 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).
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).
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).
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 neutrolized 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).
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).
1H NMR (300 MHz, CDCl3) δ 3.03 (4H, t, J=5 Hz), 3.33 (4H, t, J=5 Hz).
MS (m/z) 136 (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.
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 betwwen 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 (10.5 g) as a pale brown oil.
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 (10.5 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), 13.8 (1H, br s).
1H NMR (300 MHz, DMSO-d6) δ 8.30 (1H, dd, J=3, 3 Hz), 8.88 (1H, d, J=3 Hz), 9.01 (1H, d, J=3 Hz), 13.8 (1H, br s).
The following compound(s) was(were) obtained in a similar manner to that of Preparation 332.
Preparation 333
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
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).
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.
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 miutes. After stirring for 1 hour, (aminooxy)(diphenyl)phosphine oxide (340 mg) was added portionwise over 40 minutes. The resulting mixture was stirred for 1 hour in the bath. The reaction was quenched by adding water (10 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (two times) and brine, dried over magnesium sulfate, and evaporated. The residue was dissolved in ethyl acetatec-hexane (1-5), and to the solution was added silicagel. The mixture was filtered, and the filtrate was evaporated to give methyl 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-2-bromobenzoate as an orange solid (310 mg).
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).
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 partitioend 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).
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).
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 59352 (2M−H).
Preparation 341
To a suspension of dimethyl sulfone (5.43 g) in tetrahydrofuran (10 mL) was addded 1.59 M n-butyl lithium (36.3 mL) in a dryice-acetone bath under a nitrogen 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 silicagel column chromatography (EtOAc-hexane=50-200 to 300-100) afforded 2-(methylsulfonyl)-1-methoxyethanone as a colorless oil (2.24 g).
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.
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).
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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).
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).
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).
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).
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).
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).
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).
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).
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, overlappled with CDCl3), 7.36 (1H, br s), 7.38–7.46 (2H, m).
MS (ESI+): m/z 443 (M+H).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.
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.
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.
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).
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.
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.
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.
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).
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).
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.
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.
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.
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).
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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).
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).
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).
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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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), 8.51 (1H, d, J=2 Hz), 8.69 (1H, d, J=2 Hz).
MS (m/z) 416 (M+H).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.
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.
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).
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).
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, overlappled with CDCl3), 7.36 (1H, br s), 7.39–7.46 (2H, m).
MS (ESI+): m/z 387 (M+H).
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).
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).
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).
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).
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).
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).
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 (1H, s).
MS (ESI+): m/z 369 (M+H).
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).
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).
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).
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).
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)
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).
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)
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).
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 (1J, d, J=5 Hz)(, 6.64 (1H, d, J=5 Hz), 6.94 (1J, d, J=5 Hz), 7.33 (1H, d, J=5 Hz), 7.57–7.66 (2H, m), 7.73–7.76 (2H, m).
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)
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.
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.
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.
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.
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).
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).
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)
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
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.
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.
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.
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.
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.
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).
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).
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).
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.
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.
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.
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).
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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).
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).
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), 7.36 (1H, br s), 7.39–7.47 (2H, m).
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).
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).
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).
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), 3.80–4.01 (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.
1H-NMR (CDCl3) δ 1.37 (3H, t, J=7 Hz), 2.29 (2H, m), 2.72–3.07 (6H, m), 3.33 (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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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).
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.
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.
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)
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.
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.
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.
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.
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).
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).
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).
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.
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).
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 (1H, 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).
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).
1H NMR (300 MHz, CDCl3) δ 1.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.70 (2H, tt, J=7, 7 Hz), 2.19 (2H, t, J=7 Hz), 2.50–2.67 (6H, m), 2.86 (4H, t, J=5 Hz), 3.02 (2H, q, J=7 Hz), 3.70 (2H, s), 4.05 (2H, q, J=5 Hz), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.74 (1H, dd, J=2, 2 Hz), 8.52 (1H, d, J=2 Hz), 8.68 (1H, d, J=2 Hz).
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).
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).
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).
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).
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).
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).
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), 8.56 (1H, d, J=2 Hz), 8.80 (1H, d, J=2 Hz).
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).
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).
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 (1H, d, J=5 Hz), 6.85 (1H, dd, J=8, 8 Hz), 6.93 (2H, J=8 Hz), 7.25 (2H, J=8 Hz), 7.89 (1H, dd, J=2, 2 Hz), 8.56 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).
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.
1H-NMR (CDCl3) δ 1.37 (3H, t, 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).
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.
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.
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.
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.
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).
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 filterred 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).
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.
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).
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).
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).
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.
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.
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.
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.
1H NMR (CDCl3) 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).
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).
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.
To a suspension of 60% NaH (69.5 mg) in DMF (3 mL) was added ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (200 mg) under 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).
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.
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.
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).
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).
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), 5.37 (2H, s), 5.94 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.87 (1H, m), 8.55 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).
MS (ESI+): m/z 559 561.
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.
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).
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.
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.
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).
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).
A solution of 5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (15 mg) in MeOH was added 10% Pd/C (2 mg). The mixture was stirred under under hydrogen atomosphere (1 atm) for 6 h. The reaction mixture was filtered through Celite and the filtrate was concentrarted in vacuo. The residue was triturated with hexane to give 5-[7-ethyl-4-(2-ethyl-4-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (14 mg) as an yellow solid.
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).
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).
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).
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 parititioned 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).
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).
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) affroded 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 (40.3 mg).
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).
A mixture of ethyl 5-[2-(bromomethyl)-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (70.0 mg), phenol (21.1 mg), and pottassium carbonate (31.0 mg) in N,N-dimethylformamide was stirred for 2.5 hours at room temperature. The mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with water, saturated sodium bicarbonate, and brine, dried over 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%).
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)
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).
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).
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).
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
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 (0.5H, br s), 8.23 (0.5H, br s), 8.60–8.91 (2H, m).
Preparation 344
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
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
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
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
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
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 silicagel column chromatography (chloroform-methanol=50-0 to 50-2) afforded 3-benzyloxycarbonyl-5-bromobenzoic acid as a white solid (273 mg).
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 aicd (5.00 g) and N,N-dimethylformamide (0.059 mL) in dichloromethane (50 mL) was added oxalyl chloride (1.47 mL) in an ice bath under a nitrogen atmosphere. After stirring for 1 hour, the volatile was evaporated off. The residue was dissolved in dichloromethane (50 mL), and to the solution was added bensyl alcohol (1.82 g) followe by triethyl amine (3.2 mL) in the ice bath. The mixture was stirred for 2 hours at room temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with water (two times), satd. NaHCO3, and brine, dried over MgSO4 and evaporated. Flash silicagel columnc hromatography (EtOAc-hexanes=1/200 to 20/200) afforded benzyl 3-bromo-5-iodobenzoate as white crystals (5.95 g).
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.
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).
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).
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 Preparation 78.
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.
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.
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).
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).
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).
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.
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.
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.
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).
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.
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).
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.
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).
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).
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 10=7 Hz), 4.10 (2H, q, J=7 Hz), 6.42 (1H, d, J=5 Hz), 7.20 (2H, t, J=9 Hz), 7.45–7.51 (3H, m), 10.56 (1H, s).
MS (ESI+): m/z 355 (M+H)
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)
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 evaporateed 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).
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 temperatue. Water (5 mL) and ethyl acetate (10 mL) were added, and the resulting mixture was filtered. The organic layer was washed with brine, dried over anhydrous 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 (1H, d, J=5 Hz), 7.19 (2H, t, J=9 Hz), 7.47 (2H, d, J=4 and 9 Hz).
MS (ESI+): m/z 395 (M+H)
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)
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).
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).
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.
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).
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
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
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
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
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
The following compound(s) was(were) obtained in a similar manner to that of Preparation 164.
Preparation 357
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), 9.34 (1H, s, br).
The following compound(s) was(were) obtained in a similar manner to that of Preparation 338.
Preparation 358
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).
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 poudered 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).
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 (2.50 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 alowed to warme to room temperature over 2 hours. The reaction was quenced by adding hydrochloric acid. The organic solvent was evaporated off, and the residual 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).
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.
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.
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 076.
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.
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).
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 Hz9, 3.46 (3H, s), 4.65 (2H, q, J=7 Hz), 5.88 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.36 (1H, m), 8.41 (1H, m), 8.47 (1H, m).
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).
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).
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).
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.
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.
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).
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.
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).
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.
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).
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.
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.
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.
The following compound(s) was(were) obtained in a similar manner to that of Example 244.
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.
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 (1H, dd, J=2, 2 Hz), 8.59 (1H, d, J=2 Hz), 8.74 (1H, d, J=2 Hz), 9.85 (1H, s).
The following compound(s) was(were) obtained in a similar manner to that of Example 533.
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.
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).
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).
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.
To a mixture of ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate (75.0 mg), cyclopropylboronic acid (18.2 mg), tricyclohexylphosphine (4.57 mg), and potassium phosphate (104 mg) in toluene-water (1 mL-0.2 mL) was added palladium acetate (1.83 mg). The mixture was stirred for 2 hours at 100° C. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, and evaporated. Preparative silicagel thin layer chtomatography (EtOAc-hexanes=1-3) afforded ethyl 4-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoateas an yellow gum (60.9 mg).
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.
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).
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).
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).
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).
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), 6.36 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.92 (1H, m), 8.23 (1H, m), 8.35 (1H, m).
The following compound(s) was(were) obtained in a similar manner to that of Example 668.
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), 6.37 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 6.98 (1H, s), 7.90 (1H, s), 8.08 (1H, s).
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).
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).
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).
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).
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).
| Number | Date | Country | Kind |
|---|---|---|---|
| 2003900189 | Jan 2003 | AU | national |
| 2003903628 | Jul 2003 | AU | national |
| Number | Name | Date | Kind |
|---|---|---|---|
| 6472389 | Ohtani et al. | Oct 2002 | B1 |
| 20050075342 | Abe et al. | Apr 2005 | A1 |
| Number | Date | Country |
|---|---|---|
| 2 792 938 | Nov 2000 | FR |
| WO 9118903 | Dec 1991 | WO |
| WO 9118903 | Dec 1991 | WO |
| WO 03082208 | Oct 2003 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20050075342 A1 | Apr 2005 | US |
