Patent Application
20080081812
The present invention relates to a novel heteroaryl-pyrazole compound which is effective as a cannabinoid CB1 receptor inverse agonist or antagonist.
The World Health Organization (WHO) recently reported that obesity has become a global epidemic, posing a serious threat to public health because of the increased risk of associated health problems (See Report of a WHO Consultation on Obesity: Obesity-Preventing and Managing a Global Epidemic; World Health Organization: Geneva, 1997). Obesity is characterized by excess body fat, especially visceral fat, and constitutes a pro-inflammatory state eventually leading to serious health consequences. There are growing evidences that obesity as a chronic disease cannot be cured by short-term dieting or exercise alone, but additional pharmacological treatments would lead to higher success rates.
CB1 cannabinoid receptor belongs to G-protein-coupled receptor (GPCR) type and is coupled to inhibitory G proteins (G(i/o)) to inhibit certain adenylyl cyclase isozymes, leading to decreased cAMP production, decreased Ca2+ conductance, increased K+ conductance, and increased mitogen-activated protein kinase activity (See Di Marzo et al., Nat. Rev. Drug Discovery 2004, 3, 771-784; Rhee, M. H. et al., J. Neurochem. 1998, 71, 1525-1534). The major physiological effect of cannabinoids (in the central nervous system (CNS) and neuronal tissues) is the modulation of neurotransmitter release via activation of presynaptic CB1 receptors located on distinct types of axon terminals throughout the brain (See Howlett, A. C. et al., Neuropharmacology 2004, 47 (Suppl. 1), 345-358).
The CB1 receptor is mainly expressed in several brain areas including the limbic system (amygdala, hippocampus), hypothalamus, cerebral cortex, cerebellum, and basal ganglia. In the cerebellum and basal ganglia cannabinoids modulate the locomotor activity. In the limbic system, cannabinoids influence learning, memory, emotion, and motivation, and through activation of CB1 receptors in the limbic system-hypothalamus axis, cannabinoids have an important role in the control of appetite. Moreover, lower levels of CB1 receptors can also be found in peripheral tissues including urinary bladder, testis, prostate, GI tract, heart, lung, adrenal gland, parotid gland, bone marrow, uterus, ovary, and adipose tissue (See Cota, D. et al., J. Clin. Invest. 2003, 112, 423-431; Ravinet Trillou, C. et al., Int. J. Obes. Relat. Metab. Disord. 2004, 28, 640-648; Galiegue, S. et al., Eur. J. Biochem. 1995, 232, 54-61; Howlett, A. C. et al., Pharmacol. Rev. 2002, 54, 161-202).
Many preclinical in vitro and in vivo experiments have shown that CB1 receptor antagonists can influence energy homeostasis by central and peripheral mechanisms and may represent promising targets to treat diseases that are characterized by impaired energy balance. Already the first published studies with rimonabant (SR141716) in both rodents (See Amone, M. et al., Psychopharmacology (Berlin) 1997, 132, 104-106) and primates (See Simiand, J.; Keane, M.; Keane, P. E.; Soubrie, P. Behav. Pharmacol. 1998, 9, 179-181) showed clear differentiation, i.e., marked effects on sweet food intake versus marginal effects on regular chow intake or water drinking. Many other preclinical “proof of concept” studies have been performed in the meantime with several CB agonists and antagonists to further uncover the amount and mode of contribution of cannabinergic system modulators to energy homeostasis. Almost all of those studies have been recently reviewed (See Smith, R. A. et al., IDrugs 2005, 8, 53-66).
Considering the important impact of obesity on public health and the lack of any efficient and viable drug to cure it, it is no surprise that CB1 antagonists are currently the subject of intense studies, which were published in several reviews (See Adam, J. et al., Expert Opin. Ther. Patents, 2002, 12(10), 1475-1489; Hertzog, D. L. Expert Opin. Ther. Patents, 2004, 14(10), 1435-1452; Lange, J. H. M. et al., Drug Discov. Today, 2005, 10, 693-702; Bishop, M. J. J. Med. Chem., 2006, 49(14), 4008-4016).
It is a primary object of the present invention to provide a novel heteroaryl-pyrazole compound of formula (I) or a pharmaceutically acceptable salt thereof, which is effective as a cannabinoid CB1 receptor inverse agonist or antagonist, useful for preventing or treating obesity and obesity-related metabolic disorders.
It is another object of the present invention to provide a method for preparing the inventive compound.
It is another object of the present invention to provide a pharmaceutical composition for preventing or treating obesity and obesity-related metabolic disorders, comprising the inventive compound as an active ingredient.
The above and other objects and features of the present invention will become apparent from the following description of the invention, when taken in conjunction with the accompanying drawing, which show:
In accordance with one aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof and a method for preparing same:
wherein:
R1 is hydrogen, C1-5 alkyl, substituted C1-5 alkyl, C2-4 alkenyl, substituted C2-4 alkenyl, C2-4 alkynyl, substituted C2-4 alkynyl, halogen, or —(CH2)n—C3-5 carbocycle, n being 0 or 1;
R2 is hydrogen, NR3R4, carbocycle, substituted carbocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, C1-8 alkyl optionally substituted with hydroxy, acyloxy, C1-6 alkoxy, substituted C1-6 alkoxy; C3-5 alkenyloxy, substituted C3-5 alkenyloxy; C3-5 alkynyloxy, substituted C3-5 alkynyloxy; aryloxy, substituted aryloxy; heteroaryloxy, substituted heteroaryloxy or halogen, C2-6 alkenyl optionally substituted with alkoxy or halogen, C2-6 alkynyl optionally substituted with alkoxy or halogen, —(CH2)m—C3-6 carbocycle optionally substituted with alkoxy or halogen, or —(CH2)m—R5, m being 1 or 2;
R3 and R4 are each independently hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C3-7 cycloalkyl, substituted C3-7 cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl; or
R3 and R4, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered saturated or unsaturated heterocyclic ring which is optionally substituted with one or more C1-3 alkyl, benzyl, phenyl, C1-3 alkoxy or halogen;
R5 is phenyl, furanyl, benzofuranyl, thienyl, benzothienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridizinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, 1,4-benzodioxanyl or benzo[1,3]dioxolyl, each being optionally substituted with one or more halogen, C1-3 alkyl or C1-2 alkoxy, each optionally having one to three fluorine substitutes;
R6, R7, R8, R9, R10 and R11, are each independently hydrogen, halogen, C1-3 alkyl, C1-3 alkoxy or trifluoromethyl;
X, Y and Z are each independently selected from the group consisting of —C(R12)═, —O—, —N═, —N(R13)— and —S— to form an aromatic heterocycle together with Q and T;
Q and T are each independently
with the proviso that both Q and T can not be simultaneously
and
R12 and R13 are each independently hydrogen, NR3R4, carbocycle, substituted carbcycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, C1-8 alkyl optionally substituted with alkoxy or halogen, C2-6 alkenyl optionally substituted with alkoxy or halogen, C2-6 alkynyl optionally substituted with alkoxy or halogen, —(CH2)m—C3-6 carbocycle optionally substituted with alkoxy or halogen, or —(CH2)m—R5, m being 1 or 2, and R3, R4 and R5 having the same meaning as defined above; or
R2 and R12 are bonded together to form a 4- to 10-membered saturated or unsaturated carbocyclic or heterocyclic ring which is optionally substituted with one or more C1-3 alkyl, benzyl, phenyl, C1-3 alkoxy or halogen.
The aromatic heterocycles formed by X, Y, Z, Q and T encompass, for example, oxazole, isoxazole, thiazole, isothiazole, pyrazole, triazole, oxadiazole, thiadiazole and tetrazole.
It is to be understood that the present invention also includes a pharmaceutically acceptable salt and an addition salt of the inventive compound, such as a hydrochloride, hydrobromide or trifluoroacetate addition salt and a sodium, potassium and magnesium salt.
The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are incorporated within the scope of the present invention.
One embodiment of the present invention is to provide a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:
wherein R1, R2, R6, R7, R8, R9, R10, and R11 have the same meanings as defined in claim 1; with the proviso that when R1 is C1-5 alkyl, R2 represents (i) or (ii):
wherein, R1a is C1-6 alkyl, substituted C1-6 alkyl; C2-4 alkenyl, substituted C2-4 alkenyl; C2-4 alkynyl, substituted C2-4 alkynyl; CN, carboxy, aminocarbonyl; aryl, substituted aryl; heteroaryl, substituted heteroaryl;
wherein R1b is hydrogen, acyl, C1-6 alkyl, substituted C1-6 alkyl; C3-5 alkenyl, substituted C3-5 alkenyl; C3-5 alkynyl, substituted C3-5 alkynyl; aryl, substituted aryl; heteroaryl, substituted heteroaryl.
Another embodiment of the present invention is to provide a compound of formula (Ib) or a pharmaceutically acceptable salt thereof:
wherein R1, R2, R6, R7, R8, R9, R10 and R11 have the same meanings as defined above.
A further embodiment of the present invention is provide a compound of formula (Ic) or a pharmaceutically acceptable salt thereof:
wherein R1, R2, R6, R7, R8, R9, R10 and R11 have the same meanings as defined above.
A still another embodiment of the present invention is to provide a compound of formula (Id) or a pharmaceutically acceptable salt thereof:
wherein, R1, R2, R6, R7, R8, R9, R10, R11 and R13 have the same meanings as defined above.
The present invention also provides a compound of formula (Ie) or (If) or a pharmaceutically acceptable salt thereof:
wherein R1, R2, R6, R7, R8, R9, R10, R11 and R13 have the same meanings as defined above.
A further embodiment of the present invention is to provide a compound of formula (Ig) or a pharmaceutically acceptable salt thereof:
wherein R1, R2, R6, R7, R8, R9, R10, R11 and R12 have the same meanings as defined above.
A still another embodiment of the present invention is to provide a compound of formula (Ih) or a pharmaceutically acceptable salt thereof:
wherein R1, R2, R6, R7, R8, R9, R10, R11 and R12 have the same meanings as defined above.
As used herein, the term “alkyl” refers to a straight or branched chain saturated hydrocarbon radical. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl and hexyl.
As used herein, the term “substituted alkyl” refers to a straight or branched chain saturated hydrocarbon radical, which is optionally substituted with one or more substituents selected from the group consisting of C1-3 alkyl optionally having one to three fluorine substituents, C2-3 alkenyl, C2-3 alkynyl, C1-2 alkoxy optionally having one to three fluorine substituents, sulfanyl, sulfinyl, sulfonyl, oxo, hydroxy, mercapto, amino, guanidino, carboxy, aminocarbonyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, aminosulfonyl, sulfonylamino, carboxyamide, ureido, nitro, cyano and halogen.
As used herein, the term “alkenyl” refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond. Examples of “alkenyl” as used herein include, but are not limited to, ethenyl and propenyl.
As used herein, the term “substituted alkenyl” refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond, which has optional substituents selected from the group consisting of C1-3 alkyl optionally having one to three fluorine substituents, amino, aryl, cyano and halogen.
As used herein, the term “alkynyl” refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond. Examples of “alkynyl” as used herein include, but are not limited to, acetylenyl and 1-propynyl.
As used herein, the term “substituted alkynyl” refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond, optionally having one or more substituents selected from the group consisting of C1-3 alkyl optionally having one to three fluorine substituents, amino, aryl and halogen.
As used herein, the term “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
As used herein, the term “carbocycle” refers to a non-aromatic cyclic hydrocarbon radical composed of three to seven carbon atoms. Five- to seven-membered rings may contain a double bond in the ring structure. Exemplary “carbocycle” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cycloheptyl.
As used herein, the term “substituted carbocycle” refers to a non-aromatic cyclic hydrocarbon radical composed by three to seven carbon atoms, which is optionally substituted with one or more substituents selected from the group consisting of C1-3 alkyl optionally having one to three fluorine substituents, C2-3 alkenyl, C2-3 alkynyl, C1-2 alkoxy optionally having one to three fluorine substituents, sulfanyl, sulfinyl, sulfonyl, oxo, hydroxy, mercapto, amino, guanidino, carboxy, aminocarbonyl, aryl, aryloxy, heteroaryl, heterocyclic, aminosulfonyl, sulfonylamino, carboxyamide, nitro, ureido, cyano and halogen.
As used herein, the term “aryl” refers to an optionally substituted benzene ring or refers to a ring system which may result by fusing one or more optional substituents. Exemplary optional substituents include substituted C1-3 alkyl, substituted C2-3 alkenyl, substituted C2-3 alkynyl, heteroaryl, heterocyclic, aryl, alkoxy optionally having one to three fluorine substituents, aryloxy, aralkoxy, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, sulfanyl, sulfinyl, sulfonyl, aminosulfonyl, sulfonylamino, carboxyamide, aminocarbonyl, carboxy, oxo, hydroxy, mercapto, amino, nitro, cyano, halogen, or ureido. Such a ring or ring system may be optionally fused to aryl rings (including benzene rings) optionally having one or more substituents, carbocycle rings or heterocyclic rings.
Examples of “aryl” groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, indanyl, anthracyl or phenanthryl, as well as substituted derivatives thereof.
As used herein, the term “heteroaryl” refers to an optionally substituted monocyclic five to six-membered aromatic ring containing one or more heteroatomic substitutions selected from S, SO, SO2, O, N, or N-oxide, or refers to such an aromatic ring fused to one or more rings such as heteroaryl rings, aryl rings, heterocyclic rings, or carbocycle rings (e.g., a bicyclic or tricyclic ring system), each having optional substituents. Examples of optional substituents are selected from the group consisting of substituted C1-3 alkyl, substituted C2-3 alkenyl, substituted C2-3 alkynyl, heteroaryl, heterocyclic, aryl, C1-3 alkoxy optionally having one to three fluorine substituents, aryloxy, aralkoxy, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, sulfanyl, sulfinyl, sulfonyl, aminosulfonyl, sulfonylamino, carboxyamide, aminocarbonyl, carboxy, oxo, hydroxy, mercapto, amino, nitro, cyano, halogen or ureido. Examples of “heteroaryl” groups used herein include, but are not limited to, benzoimidazolyl, benzothiazolyl, benzoisothiazolyl, benzothiophenyl, benzopyrazinyl, benzotriazolyl, benzo[1,4]dioxanyl, benzofuranyl, 9H-a-carbolinyl, cinnolinyl, furanyl, furo[2,3-b]pyridinyl, imidazolyl, imidazolidinyl, imidazopyridinyl, isoxazolyl, isothiazolyl, isoquinolinyl, indolyl, indazolyl, indolizinyl, naphthyridinyl, oxazolyl, oxothiadiazolyl, oxadiazolyl, phthalazinyl, pyridyl, pyrrolyl, purinyl, pteridinyl, phenazinyl, pyrazolyl, pyridyl, pyrazolopyrimidinyl, pyrrolizinyl, pyridazyl, pyrazinyl, pyrimidyl, 4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]-quinolin-4-yl, quinoxalinyl, quinazolinyl, quinolinyl, quinolizinyl, thiophenyl, triazolyl, triazinyl, tetrazolopyrimidinyl, triazolopyrimidinyl, tetrazolyl, thiazolyl, thiazolidinyl, and substituted versions thereof.
As used herein, the term “heterocyclic” refers to a three to seven-membered ring containing one or more heteroatomic moieties selected from S, SO, SO2, O, N, or N-oxide, optionally substituted with one or more substituents selected from the group which includes substituted C1-3 alkyl, substituted C2-3 alkenyl, substituted C2-3 alkynyl, heteroaryl, heterocyclic, aryl, C1-3 alkoxy optionally having one to three fluorine substituents, aryloxy, aralkoxy, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, sulfanyl, sulfinyl, sulfonyl, aminosulfonyl, sulfonylamino, carboxyamide, aminocarbonyl, carboxy, oxo, hydroxy, mercapto, amino, nitro, cyano, halogen, and ureido. Such a ring can be saturated or have one or more degrees of unsaturation. Such a ring may be optionally fused to one or more “heterocyclic” ring(s), aryl ring(s), heteroaryl ring(s) or carbocycle ring(s), each having optional substituents.
Examples of “heterocyclic” moieties include, but are not limited to, 1,4-dioxanyl, 1,3-dioxanyl, pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl, imidazolidine-2,4-dionepiperidinyl, piperazinyl, piperazine-2,5-dionyl, morpholinyl, dihydropyranyl, dihydrocinnolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]-dioxepinyl, tetrahydropyranyl, 2,3-dihydrofuranyl, 2,3-dihydrobenzofuranyl, dihydroisoxazolyl, tetrahydrobenzodiazepinyl, tetrahydroquinolinyl, tetrahydrofuranyl, tetrahydronaphthyridinyl, tetrahydropurinyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, tetrahydroquinoxalinyl, tetrahydropyridinyl, tetrahydrocarbolinyl, 4H-benzo[1,3]-dioxinyl, benzo[1,3]dioxonyl, 2,2-difluorobenzo-[1,3]-dioxonyl, 2,3-dihydro-phthalazine-1,4-dionyl, and isoindole-1,3-dionyl.
As used herein, the term “alkoxy” refers to the group —ORa, where Ra is alkyl as defined above. Exemplary alkoxy groups useful in the present invention include, but are not limited to, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and t-butoxy.
As used herein, the term “alkenyloxy” refers to the group —ORb, where Rb is alkenyl as defined above.
As used herein, the term “alkynyloxy” refers to the group —ORc, where Rc is alkynyl as defined above.
As used herein, the term “aralkoxy” refers to the group —ORaRd, wherein Ra is alkyl and Rd is aryl as defined above.
As used herein, the term “aryloxy” refers to the group —ORd, wherein Rd is aryl as defined above.
As used herein, the term “heteroaryloxy” refers to the group —ORe, where Re is heteroaryl as defined above.
As used herein, the term “mercapto” refers to the group —SH. As used herein, the term “sulfonyl” refers to the group —SRf, wherein Rf is substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
As used herein, the term “sulfonyl” refers to the group —S—(O)Rf, wherein Rf is substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
As used herein, the term “sulfonyl” refers to the group —S(O)2Rf, wherein Rf is substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
As used herein, the term “oxo” refers to the group ═O.
As used herein, the term “hydroxyl” refers to the group —OH.
As used herein, the term “amino” refers to the group —NH2. The amino group is optionally substituted with substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
As used herein, the term “cyano” refers to the group —CN.
As used herein, the term “aminosulfonyl” refers to the group —S(O)2NH2. The aminosulfonyl group is optionally substituted with substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
As used herein, the term “sulfonylamino” refers to the group —NHS(O)2Rf wherein Rf is substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
As used herein, the term “carboxyamide” refers to the group —NHC(O)Rf wherein Rf is substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
As used herein, the term “carboxy” refers to the group —C(O)OH. The carboxy group is optionally substituted with substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
As used herein, the term “aminocarbonyl” refers to the group —C(O)NH2. The aminocarbonyl group is optionally substituted with substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
As used herein, the term “ureido” refers to the group —NHC(O)NHRg wherein Rg is hydrogen, alkyl, carbocycle or aryl as defined above.
As used herein, the term “guanidine” refers to the group —NHC(═NH)NH2.
As used herein, the term “acyl” refers to the group —C(O)Rh, wherein Rh is alkyl, carbocycle, or heterocyclic as defined herein.
As used herein, the term “aroyl” refers to the group —C(O)Rd, wherein Rd is aryl as defined herein.
As used herein, the term “heteroaroyl” refers to the group —C(O)Re, wherein Re is heteroaryl as defined herein.
As used herein, the term “acyloxy” refers to the group —OC(O)Rh, wherein Rh is alkyl, carbocycle, or heterocyclic as defined herein.
As used herein, the term “aroyloxy” refers to the group —OC(O)Rd, wherein Rd is aryl as defined herein.
As used herein, the term “heteroaroyloxy” refers to the group —OC(O)Re, wherein Re is heteroaryl as defined herein.
Preferred compounds useful in the present invention are selected from the group consisting of:
General Synthetic Sequence
The following synthetic schemes are merely illustrative of the methods by which the compounds of the invention may be prepared and are not intended to limit the scope of the invention as defined in the appended claims.
The compound of formula (Ia) may be prepared by (i) reacting a carboxylic acid derivative (5) with a hydrazide compound (7) or a semicarbazide compound (12) in the presence of a coupling agent, e.g., 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDCI), 4-dimethylaminopyridine (DMAP), and (ii) cyclizing the resulting product using a dehydrating agent to obtain an 1,3,4-oxadiazole compound of formula (Ia), as shown in Reaction Scheme 1.
wherein, R1 to R4 have the same meanings as defined above.
The cyclization may be conducted using Burgess reagent as a dehydrating agent while applying microwave irradiation thereon (See Leber, J. D. et al., WO 2005/032550), or using triphenylphosphine with carbon tetrachloride and a base such triethylamine in a suitable solvent such as acetonitrile and THF.
The carboxylic acid derivative (5) used as a starting material in preparing the compound of formula (Ia) may be prepared by a conventional method, e.g., by treating an acetophenone derivative (1) with an organic base such as lithium hexamethyldisilazide (LHMDS) to produce a corresponding alkali metal salt (2), reacting the resulting salt with an equimolar amount of diethyl oxalate to provide a ketoester salt (3), reacting the salt (3) with a hydrazine derivative in refluxing acetic acid to obtain a pyrazole-3-carboxylic ester (4), and transforming the ester (4) into an acid form (5) using an alkaline agent such as potassium hydroxide or lithium hydroxide, followed by acidification (See Barth, F. et al., U.S. Pat. No. 5,462,960), as shown in Reaction Scheme 2.
The hydrazide compound (7) which may be used in preparing the compound of formula (Ia) may be prepared by treating an ester or a carboxylic acid with hydrazine, and also, the semicarbazide compound (12) may be prepared by treating carbamyl chloride or isocynate with hydrazine, as shown in Reaction Scheme 3.
wherein, R1 to R4 have the same meanings as defined above.
The compound of formula (Ib) may be prepared by (i) reacting a carboxylic acid derivative (5) with a hydrazide compound (7) in the presence of coupling agents, e.g., EDCI, DMAP, and (ii) cyclizing the resulting product using a Lawesson's reagent, which can be conducted with microwave irradiation (See Kiryanov, A. A., Sampson, P., Seed, A. J., J. Org. Chem. 2001, 665, 7925-7929), as shown in Reaction Scheme 4.
As demonstrated above, the acylhydrazide intermediate (9) is also available through a coupling of the hydrazide (A) with a corresponding acid in the presence of coupling reagents: DMAP, EDCI; EDCI, 1-hydroxybezotriazole (HOBt), N-methyl morpholine (NMM) In turn, the requisite hydrazide (A) is prepared by treating ester (4) with hydrazine in refluxing ethanol (EtOH).
The compound of formula (Ic) may be prepared by (i) reacting a nitrile intermediate (19) with hydroxylamine in a solvent, e.g., MeOH, (ii) acylating the resulting N-hydroxyamidine (20) with an activated carboxylic acid in the presence of a coupling agent, e.g., dicyclohexylcarbodiimide (DCC), EDCI or 1,1-carbonyldiimidazole (CDI), and (iii) cyclizing the acylated compound (21) in the presence of a base by heating, e.g., microwave irradiation, as shown in Reaction Scheme 5.
wherein, R1 and R2 have the same meanings as defined above.
In Reaction Scheme 5, step (i) may be conducted in heated methyl alcohol. The acylation of step (ii) may be conducted in the presence of a suitable base such as triethylamine (TEA) or N-methyl morpholine (NMM) in a solvent such as methylene chloride, THF or acetonitrile. The cyclization step (iii) may be conducted in a solvent such as acetonitrile or THF, and exemplary bases which may be used in this step include pyridine, N,N-diisopropylethylamine or tetrabutylammonium fluoride. Also, the process of isolating N-acyloxyamidine (21) may be omitted, in case N-hydroxyamidine (20) was converted to 1,2,4-oxadiazole (Ic) in a continuous process (See, Colandrea, V. J. et al., WO 2005/058848).
The nitrile intermediate (19) used in preparing the compound of formula (Ic) may be prepared by [3+2] cycloaddition reaction disclosed in J. Med. Chem. 1999, 42, 769-776, as shown in Reaction Scheme 6.
The compound of formula (Id) may be prepared by reacting a nitrile intermediate (19) with a hydrazide compound (7) in the presence of a catalyst such as potassium carbonate in a suitable solvent such as 1-butanol under a reflux condition, to obtain a triazole, as shown in Reaction Scheme 7.
wherein, R2 has the same meaning as defined above.
The compound of formula (Ie) or (If) may be prepared by reacting a nitrile intermediate (19) with sodium azide in the presence of a base (e.g., ammonium chloride) in a solvent (e.g., N,N-dimethylformamide: DMF) with microwave irradiation, according to [3+2] cycloaddition reaction, to obtain a tetrazole, which may be alkylated by a reaction with an alkyl halide in the presence of potassium carbonate in DMF to obtain alkyl tetrazoles, as shown in Reaction Scheme 8.
In Reaction Scheme 8, when RX is a primary alkyl halide, the alkylation can be conducted at room temperature. However, when a secondary alkyl halide is used, the reaction is preferably conducted at 80° C.
Also, the alkylation of the tetrazole may be conducted using an aliphatic alcohol in the presence of diisopropylazodicarboxylate (DIAD) and triphenylphosphine (PPh3) in THF at 0° C., as shown in Reaction Scheme 9.
Alternatively, the compound of formula (If) may be prepared by treating acyl chloride (17) with an amine in the presence of triethylamine in methylene chloride to produce an amide (26) and reacting the resulting amide with hydrazoic acid in the presence of phosphorus pentachloride in toluene as shown in Reaction Scheme 10.
The compound of formula (Ig) may be prepared by (i) reacting a carboxylic acid intermediate (5) with an aminoketone (27) in the presence of a coupling reagent, e.g. EDCI, DMAP, and (ii) cyclizing the resulting product (28) using a dehydrating agent to obtain an oxazole compound of formula (Ig), as shown in Reaction Scheme 11.
wherein R2 and R12 have the same meanings as defined above.
The aminoketone compound (27) or (32) which may be used in preparing the compound of formula (Ig) may be prepared as shown in Reaction Scheme 12. The starting N-Boc protected aminoacid (29) is converted into the corresponding Weinreb amide (30) using N,O-dimethylhydroxylamine hydrochloride in the presence of coupling reagents such as EDCI, HOBt, NMM in an appropriate solvent such as dichloromethane (DCM) or DMF. The Weinreb amide (30) may be transformed into a corresponding ketone (31) by action of a Grignard reagent in an appropriate solvent such as ether or THF under N2 atmosphere. Then final deprotection of Boc group using either trifluoroacetic acid (TFA) or HCl may provide a corresponding aminoketone (27) or (32) in a salt form, respectively.
The compound of formula (Ih) may be prepared by (i) reacting a carboxylic acid intermediate (5) with an aminoketone (27) or (32) in the presence of a coupling reagent, e.g. EDCI, DMAP, and (ii) cyclizing the resulting product (28) using a Lawesson's reagent, which may be conducted with microwave irradiation (See Kiryanov, A. A., Sampson, P., Seed, A. J., J. Org. Chem. 2001, 665, 7925-7929), as shown in Reaction Scheme 13.
Further derivatization may be started with activated 4-pyrazole intermediate such as the bromomethyl derivative (33) as illustrated in Reaction Scheme 14. Thus, hydroxyl group is introduced by reacting the bromo derivative (33) with sodium acetate, and subsequent hydrolysis of the acetate (34). Oxidation of the alcohol (35) to aldehyde (36) is achieved by action of an oxidant such as Dess-Martin periodinane.
A bromide of structure (33) may be utilized to provide the corresponding cyanide (37) by reaction with sodium cyanide in a mixture of acetonitrile and water. A bromide (33) also undergoes acetylenylation to afford a 4-(3-(trimethylsilyl)prop-2-ynyl)-pyrazole (38), which is further desilylated in the presence of TBAF to provide a 4-(prop-2-ynyl)-pyrazole (39) as shown in Reaction Scheme 15.
A bromide of structure (33) may be further utilized by reacting a bromide (33) with various primary or secondary amines in the presence of a suitable base such as diisopropylethylamine (DIPEA) in a suitable solvent such as acetonitrile to afford the corresponding amines of structure (40) as described in Reaction Scheme 16.
Further derivatization may be conducted on a bromide of structure (33) by reacting a bromide (33) with a pyrrole or various azoles including pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole in the presence of a base such as sodium hydride in an appropriate solvent such as THF.
A derivatization may come from alkylation of the anion of pyrrolidin-2-one, succinimide, or oxazolidini-2-one with a bromide of structure (33) to lead to the corresponding alkylated products (42), (43), or (44), respectively as depicted in Reaction Scheme (18).
Another derivatization may come from alkylation of the anion of hydroxyl-aryl or hydroxyl-hetero-aryl such as phenol or pyridin-2-ol with a bromide of structure (33) to produce the corresponding alkylated products (45) or (46), respectively as demonstrated in Reaction Scheme 19.
Another derivatization may result from a nucleophilic sulfur reagent such as potassium thioacetate or sodium thiomethoxide with a bromide of structure (33). For example, a bromide (33) is smoothly converted to a thioacetate (47) in a suitable solvent such as DMF at ambient temperature. A thioacetate of structure (47) may be used to prepare the corresponding thiol. Another example includes reacting a bromide of structure (33, X═Cl) with sodium thiomethoxide in heated DMF to generate a disulfide of structure (48) as shown in Reaction Scheme 20.
An alcohol of structure (35) can be alkylated with an alkyl iodide or an alkyl bromide in the presence of a suitable base such as sodium hydride (Williamson ether synthesis conditions) to furnish the corresponding ether of structure (49). Also, an alcohol of structure (35) may be converted into the corresponding fluoride of structure (50) by action of a fluorinating agent such as diethylaminosulfur trifluoride (DAST) in an appropriate solvent such as methylene chloride at ambient temperature. On the other hand, Burgess reagent may convert an alcohol of structure (35) to the corresponding carbamate of structure (51) as described in Reaction Scheme 21.
An aldehyde of structure (36) previously prepared as shown in Reaction Scheme 14 may be treated with a fluorinating agent such as DAST to provide the corresponding difluoromethyl-pyrazole (52). Also, an aldehyde of structure (36) may be treated with a Grignard reagent such as methylmagnesium bromide to afford the corresponding alcohol of structure (53), which is further alkylated with an alkyl iodide or an alkyl bromide in the presence of a suitable base such as sodium hydride (Williamson ether synthesis conditions) to furnish the corresponding ether of structure (54). In addition, an alcohol of structure (53) may be treated with Burgess reagent to furnish a carbamate (56) as well as an olefin of structure (55). Also, an alcohol of structure (53) may be oxidized by an appropriate oxidizing agent such as Dess-Martin periodinane to give the corresponding ketone of structure (57). Finally, an alcohol of structure (53) may be treated with a fluorinating agent such as DAST to give a fluoride of structure (58) as described in Reaction Scheme 22.
A ketone of structure (57) may be further reacted with a Grignard reagent such as methylmagnesium bromide to provide the alcohol of structure (59), which may be dehydrated by using a suitable dehydrating agent such as Burgess reagent to give the corresponding olefin of structure (60) as demonstrated in Reaction Scheme 23.
The compounds containing 1,2,4-triazole at C-4 on pyrazole may be obtained by a series of reaction sequence involving a key intermediate bromide of structure (61). Thus, a bromide of structure (61), which is obtained by reaction of a pyrazole of structure (4) with N-bromosuccinimide (NBS) in the presence of a catalytic amount of AIBN, may be reacted with 1H-1,2,4-triazole in the presence of a suitable base such as sodium hydride in a suitable solvent such as THF to furnish 1,2,4-triazole of structure (62). Hydrolysis of an ester (62) may provide the corresponding acid of structure (63). Activation of an acid of structure (63) followed by coupling with a hydrazide in the presence of an appropriate base such as triethylamine may produce an acylhydrazide of structure (64). As an alternative, hydrazynolysis of an ester (62) may provide the corresponding hydrazide, which may be coupled with a particular acid in the presence of coupling reagents such as EDCI, HOBt and NMM to provide an acylhydrazide of structure (64).
The cyclization may be conducted using Burgess reagent as a dehydrating agent while applying microwave irradiation thereon, or using triphenylphosphine with carbon tetrachloride and a base such as triethylamine in a suitable solvent such as acetonitrile and THF, or alternatively using phosphorus(III) oxychloride in a solvent such as acetonitrile or 1,4-dioxane at reflux temperature to give an oxadiazole of structure (65). On the other hand, a compound of formula (66) may be prepared by cyclizing the acylhydrazide intermediate (64) using a Lawesson's reagent, which may be conducted with microwave irradiation as shown in Reaction Scheme 24.
The 4-cyclopropyl-pyrazole compound may be prepared as shown in Reaction Scheme 25. Thus, 4-bromo-pyrazole of structure (68), which may be prepared by following a generic procedure (Andrew G. Horti et al, J. Med. Chem. 2003, 46, 642-645), may be coupled with a cyclopropylboronic acid under Suzuki-Miyaura coupling reaction conditions to afford a 4-cyclopropyl-pyrazole of structure (69). The ester (69) may undergo a series of reaction sequence previously described to give rise to an oxadiazole of structure (72). The thiadiazole compound of formula (73) may be prepared by cyclizing the acylhydrazide intermediate (71) using a Lawesson's reagent, which may be conducted with microwave irradiation as shown in Reaction Scheme 25.
The 4-ethynyl-pyrazole compound of structure (75) may be prepared through two steps from a starting aldehyde of structure (36). Thus, an aldehyde of structure (36) prepared in Reaction Scheme 14 may be converted to a corresponding 4-(2,2-dibromovinyl)-pyrazole (74), which could be treated with a suitable base such as potassium hexamethyldisilazane (KHMDS) at −78° C. in an appropriate solvent such as THF to afford a 4-ethynyl-pyrazole of structure (75). A compound of structure (75) may be further alkylated by action of a base such as lithium hexamethyldisilazide (LHMDS) with an alkylating agent such as methyl iodide in an appropriate solvent such as THF to produce 4-(prop-1-ynyl)-pyrazole of structure (76) as shown in Reaction Scheme 26.
The requisite cyclopropanecarboxylic acid (80) as a coupling partner of a hydrazide such as structure (70) for the preparation of an oxadiazole as well as a thiadiazole may be prepared by following a known procedure involving three steps starting from a benzyl bromide of structure (77): i) cyanation, ii) cyclopropanation, iii) hydrolysis of the resulting cyanide of structure (79) [Imbimbo, B. P., J. Med. Chem. 2005, 48, 5707-7520] as described in Reaction Scheme 27.
wherein A is carbon or nitrogen; R is halogen, C1-C6 alkyl, C1-C4 alkoxy, NRiRj, carbocycle, heterocycle, aryl, or heteroaryl; and Ri and Rj are independently hydrogen, C1-4 alkyl or C3-5 carbocycle.
Alternatively, a requisite cyclopropanecarboxylic acid such as structure (85) may be provided by following a known method [Krawczyk, H., Synlett., 2005, 17, 2648-2652]. Thus, a commercially available 3-bromodihydrofuran-2(3H)-one (81) may undergo Arbuzov reaction to afford diethyl 2-oxotetrahydrofuran-3-ylphosphonate (82), which could be alkylated with an alkyl bromide or an alkyl iodide in the presence of a suitable base such as lithium diisopropylamide (LDA) in an appropriate solvent such as THF to give a compound of structure (83). Treatment of a lactone compound of structure (83) with in situ generated sodium ethoxide in refluxed THF would afford a cyclopropanecarboxylic ester of structure (84), which in turn could be hydrolyzed to a corresponding cyclopropanecarboxylic acid (85) as shown in Reaction Scheme 28.
As an alternative scaffold, a pyrazole of structure (88) may be prepared by treatment of 1,3-dione of structure (87) with hydrazine at reflux temperature. In turn, a 1,3-dione of structure (87) in equilibrium with a keto-enol of structure (88) may be obtained by treating an ester of structure (4) with a methyl ketone such as 3,3-dimethylbutan-2-one (86) in the presence of a base such as sodium amide. On the other hand, an isoxazole (90) or its isomer (91) may be prepared by treatment of 1,3-dione of structure (87) with hydroxylamine. These two isomers may be separated by preparative HPLC as shown in Reaction Scheme 29.
Further derivatization on a thiadiazole compound may be done in a similar fashion as done on an oxadiazole compound as illustrated in Reaction Scheme 14. Thus, as shown in Reaction Scheme 30, bromination may be achieved by NBS in the presence of either benzoyl peroxide or AIBN. Subsequently, hydroxyl group is introduced by reacting a bromide of structure (92) with sodium acetate followed by subsequent hydrolysis of the acetate (93). Oxidation of the alcohol (94) to aldehyde (95) may be achieved by action of a mild oxidant such as Dess-Martin periodinane.
All the other transformations demonstrated in Reaction Scheme 15-24, and Reaction Scheme 26 can be applied on a thiadiazole compound to prepare inventive compounds in a similar way.
The inventive heteroaryl-pyrazole compound of formula (I) is effective as a cannabinoid CB1 receptor inverse agonist or antagonist, thereby preventing or treating obesity and obesity-related metabolic disorders.
Accordingly, the present invention provides a pharmaceutical composition for preventing or treating obesity and obesity-related metabolic disorders, which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
Further, the present invention provides a method for preventing or treating obesity and obesity-related metabolic disorders in a mammal, which comprises administering the compound of formula (I) of claim 1 to the mammal.
Also, the present invention provides a method for inhibiting cannabinoid CB1 receptor in a mammal, which comprises administering the compound of formula (I) of claim 1 to the mammal.
As used herein, the term “obesity-related metabolic disorders” refers to chronic diseases that require treatment to reduce the excessive health risks associated with obesity and exemplary disorders include type 2 diabetes mellitus, cardiovascular and hypertension, hyperlipidaemia, fibrinolytic abnormalities.
The pharmaceutical composition may be administered orally, intramuscularly or subcutaneously. The formulation for oral administration may take various forms such as a syrup, tablet, capsule, cream and lozenge. A syrup formulation will generally contain a suspension or solution of the compound or its salt in a liquid carrier, e.g., ethanol, peanut oil, olive oil, glycerine or water, optionally with a flavoring or coloring agent. When the composition is in the form of a tablet, any one of pharmaceutical carriers routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. When the composition is in the form of a capsule, any of the routine encapsulation procedures may be employed, e.g., using the aforementioned carriers in a hard gelatin capsule shell. When the composition is formulated in the form of a soft gelatin shell capsule, any of the pharmaceutical carrier routinely used for preparing dispersions or suspensions may be prepared using an aqueous gum, cellulose, silicate or oil. The formulation for intramuscular or subcutaneous administration may take a liquid form such as a solution, suspension and emulsion which includes aqueous solvents such as water, physiological saline and Ringer's solution; or lipophilic solvents such as fatty oil, sesame oil, corn oil and synthetic fatty acid ester.
Preferably the composition is formulated in a specific dosage form for a particular patient.
Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg of the compound of Formula (I) or its pharmaceutically acceptable salt.
The suitable daily dosage for oral administration is about 0.01 mg/Kg to 40 mg/Kg of the compound of Formula (I) or its pharmaceutically acceptable salt, may be administered 1 to 6 times a day, depending on the patient's condition.
As used herein the symbols and conventions used describing the processes, schemes and examples of the present invention are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.
Hz (Hertz) TLC (thin layer chromatography)
Tr (retention time) RP (reverse phase)
MeOH (methanol) i-PrOH (isopropanol)
TFA (trifluoroacetic acid) TEA (triethylamine)
EtOH (ethanol) THF (tetrahydrofuran)
DMSO (dimethylsulfoxide) EtOAc (ethyl acetate)
DCM (dichloromethane) HOAc (acetic acid)
DMF (N,N-dimethylformamide) Ac (acetyl)
CDI (1,1-carbonyldiimidazole) Bn (benzyl)
HOSu (N-hydroxysuccinimide)
HOBT (1-hydroxybenzotriazole)
Boc (tert-butyloxycarbonyl)
mCPBA (meta-chloroperbenzoic acid)
FMOC (9-fluorenylmethoxycarbonyl)
DCC (dicyclohexylcarbodiimide)
Cbz (benzyloxycarbonyl)
NMM (N-methyl morpholine)
HOAt (1-hydroxy-7-azabenzotriazole)
TBAF (tetra-n-butylammonium fluoride)
THP (tetrahydro-2H-pyran-2-yl)
DMAP (4-dimethylaminopyridine)
HPLC (high pressure liquid chromatography)
BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride);
EDCI (1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride)
HBTU (O-Benzotriazolel-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate)
AIBN (α,α′-azobis(isobutyronitrile))
MeI (iodomethane)
LDA (lithium diisopropylamide)
DIPEA (diisopropylethylamine)
NaSMe (sodium thiomethoxide)
All references to ether are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in ° C. (degrees Centigrade). All reactions are conducted under an inert atmosphere at room temperature unless otherwise noted, and all solvents are of the highest available purity unless otherwise indicated.
Microwave reaction was conducted with a Biotage microwave reactor.
1H NMR spectra were recorded on either a Jeol ECX-400, or a Jeol JNM-LA300 spectrometer. Chemical shifts were expressed in parts per million (ppm, δ units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad).
Mass spectra were obtained with either a Micromass, Quattro LC Triple Quadruple Tandem Mass Spectometer, ESI or Agilent, 1100 LC/MSD, ESI.
For preparative HPLC, ca 100 mg of a product was injected in 1 mL of DMSO onto a SunFire™ Prep C18 OBD 5 um 19×100 mm Column with a 10 min gradient from 10% CH3CN to 90% CH3CN in H2O. Flash chromatography was carried using Merck silica gel 60 (230-400 mesh). Most of the reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light using a 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution.
Added to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (0.40 g, 1.05 mmol), N-butanoyl-hydrazine (0.11 g, 1.05 mmol) and EDCI (0.24 g, 1.26 mmol) dissolved in DCM (11 ml), was DMAP (0.15 g, 1.26 mmol) in one portion at room temperature. The reaction mixture was stirred at room temperature for 6 hrs, and then treated with 10% aq. HCl. The organic layer was collected, and evaporated under a vacuum. The crude mixture was further purified by preparative HPLC, to obtain 0.38 g (0.81 mmol, 77%) of the title compound as yellow solid.
1H NMR (400 MHz, CDCl3) δ 7.40 (br s, 1H), 7.31-7.27 (m, 4H), 7.08-7.03 (m, 2H), 2.33 (s, 3H), 2.31 (t, J=7.8 Hz, 2H), 1.72 (m, 2H), 0.97 (t, J=7.3 Hz, 3H).
MH+ 463.
N-butanoyl-N′-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl]-hydrazine (0.35 g, 0.75 mmol) obtained in Step 1 was added to a microwave reactor containing Burgess reagent (0.45 g, 1.88 mmol) in THF (2 mL). The capped reactor was placed in a microwave reactor and the mixture was irradiated at 140° C. for 15 min. The reaction product was purified by preparative HPLC to provide the title compound (0.21 g, 0.46 mmol, 61%) as yellow solid.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.3 Hz, 1H), 7.34-7.28 (m, 4H), 7.09-7.13 (m, 2H), 2.90 (t, J=7.6 Hz, 2H), 2.45 (s, 3H), 1.88 (m, 2H), 1.03 (t, J=7.6 Hz, 3H).
MH+ 447.
The following compounds of Examples 2 to 344 were obtained by using corresponding starting materials and repeating the procedure of Example 1.
1H NMR (400 MHz, CDCl3) δ 8.78 (d, J=7.43 Hz, 1H), 8.01 (d, J=5.04 Hz, 1H), 7.41 (d, J=1.84 Hz, 1H), 7.37-7.29 (m, 4H), 7.11 (d, J=8.72 Hz, 2H), 2.48 (s, 3H).
MH+ 482.
1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=1.84 Hz, 1H), 7.37-7.29 (m, 4H), 7.11 (dt, J=2.28, 8.24 Hz, 2H), 2.63 (s, 3H), 2.46 (s, 3H).
MH+ 419.
1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=1.84 Hz, 1H), 7.37-7.29 (m, 4H), 7.12 (dt, J=2.28, 8.24 Hz, 2H), 2.94 (t, J=7.56 Hz, 2H), 2.46 (s, 3H), 1.85 (m, 2H), 1.45 (m, 2H), 0.96 (t, J=7.36 Hz, 3H).
MH+ 461.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=1.84 Hz, 1H), 7.37-7.29 (m, 4H), 7.11 (dt, J=2.28, 8.24 Hz, 2H), 3.39 (m, 1H), 2.45 (s, 3H), 2.14 (m, 2H), 2.04 (m, 2H), 1.84 (m, 2H), 1.71 (m, 2H).
MH+ 473.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=1.84 Hz, 1H), 7.37-7.29 (m, 4H), 7.11 (dt, J=2.28, 8.24 Hz, 2H), 3.00 (m, 1H), 2.44 (s, 3H), 2.16-2.12 (m, 2H), 1.87-1.81 (m, 2H), 1.78-1.65 (m, 3H), 1.44-1.28 (m, 3H).
MH+ 487.
MH+ 445.
MH+ 471.
1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=2.3 Hz, 1H), 7.34-7.28 (m, 4H), 7.13-7.09 (m, 2H), 4.01 (m, 1H), 2.62-2.52 (m, 2H), 2.49 (s, 3H), 2.47-2.39 (m, 2H), 2.20-2.00 (m, 2H).
MH+ 459.
1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 8.76 (m, 1H), 7.43 (d, J=1.84 Hz, 1H), 7.39 (d, J=8.68 Hz, 1H), 7.36-7.30 (m, 4H), 7.15 (d, J=8.24 Hz, 2H), 2.55 (s, 3H).
MH+ 483.
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=4.12 Hz, 1H), 7.66 (dt, J=1.84, 7.80 Hz, 1H), 7.41 (d, J=1.84 Hz, 1H), 7.35-7.29 (m, 5H), 7.20 (dd, J=5.04, 7.32 Hz, 1H), 7.13-7.09 (m, 2H), 4.52 (s, 2H), 2.45 (s, 3H).
MH+ 496.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.28 Hz, 1H), 7.38-7.29 (m, 4H), 7.13-7.09 (m, 2H), 3.28 (m, 1H), 2.44 (s, 3H), 1.46 (d, J=6.88 Hz, 6H).
MH+ 447.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=2.28 Hz, 1H), 7.38-7.30 (m, 4H), 7.13-7.10 (m, 2H), 2.96 (m, 1H), 2.46 (s, 3H), 1.93-1.79 (m, 2H), 0.94 (t, J=7.32 Hz, 3H).
MH+ 475.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=1.84 Hz, 1H), 7.38-7.27 (m, 9H), 7.12-7.08 (m, 2H), 4.29 (s, 2H), 2.43 (s, 3H).
MH+ 495.
1H NMR (300 MHz, CDCl3) δ 8.22-8.18 (m, 2H), 7.57-7.49 (m, 3H), 7.45-7.44 (m, 1H), 7.41-7.32 (m, 4H), 7.16-7.12 (m, 2H), 2.51 (s, 3H).
MH+ 483.
1H-NMR (300 MHz, CDCl3) δ 8.16-8.12 (m, 2H), 7.52-7.48 (m, 2H), 7.45-7.44 (m, 1H), 7.37-7.32 (m, 4H), 7.16-7.12 (m, 2H), 2.50 (s, 3H).
MH+ 517.
1H-NMR (400 MHz, CDCl3) δ 7.70 (d, J=7.7 Hz, 1H), 7.64-7.62 (m, 2H), 7.47-7.42 (m, 2H), 7.40-7.38 (m, 1H), 7.36-7.30 (m, 4H), 7.16-7.13 (m, 2H), 2.53 (s, 3H).
MH+ 521.
1H-NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.37-7.30 (m, 4H), 7.13-7.10 (m, 2H), 2.93 (t, J=7.8 Hz, 2H), 2.46 (s, 3H), 1.90-1.83 (m, 2H), 1.45-1.32 (m, 4H), 0.91 (t, J=7.3 Hz, 3H).
MH+ 475.
1H-NMR (400 MHz, CDCl3) δ 7.43-7.41 (m, 1H), 7.37-7.29 (m, 4H), 7.13-7.10 (m, 2H), 3.23-3.16 (m, 1H), 2.45 (s, 3H), 2.21-2.14 (m, 4H), 1.98-1.89 (m, 2H), 1.85-1.79 (m, 2H), 1.68-1.53 (m, 4H).
MH+ 501.
1H-NMR (400 MHz, CDCl3) δ 8.04 (d, J=8.4 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.44 (d, J=2.2 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.39-7.31 (m, 4H), 7.15-7.12 (m, 2H), 2.51 (s, 3H).
MH+ 548.
1H-NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.3 Hz, 1H), 7.37-7.29 (m, 4H), 7.14-7.10 (m, 2H), 2.93 (d, J=7.3 Hz, 2H), 2.46 (s, 3H), 2.45-2.39 (m, 1H), 1.90-1.82 (m, 2H), 1.71-1.63 (m, 2H), 1.61-1.54 (m, 2H), 1.35-1.26 (m, 2H).
MH+ 487.
1H-NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.37-7.30 (m, 4H), 7.13-7.10 (m, 2H), 4.08-4.03 (m, 2H), 3.59-3.52 (m, 2H), 3.29-3.21 (m, 1H), 2.45 (s, 3H), 2.10-2.05 (m, 4H).
MH+ 489.
1H-NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.37-7.29 (m, 4H), 7.13-7.10 (m, 2H), 2.82 (d, J=7.3 Hz, 2H), 2.46 (s, 3H), 1.98-1.87 (m, 1H), 1.79-1.63 (m, 4H), 1.31-1.03 (m, 6H).
MH+ 501.
1H-NMR (400 MHz, CDCl3) δ 7.45-7.42 (m, 1H), 7.34-7.29 (m, 4H), 7.13-7.10 (m, 2H), 5.28-5.24 (m, 1H), 4.10-4.04 (m, 1H), 3.99-3.96 (m, 1H), 2.45 (s, 3H), 2.42-2.33 (m, 2H), 2.25-2.14 (m, 1H), 2.11-2.00 (m, 1H).
MH+ 475.
1H-NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 2H), 7.42 (d, J=2.3 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 7.33-7.30 (m, 1H), 7.07-7.04 (m, 2H), 3.86-3.77 (m, 1H), 2.61-2.51 (m, 2H), 2.49-2.41 (m, 2H), 2.45 (s, 3H), 2.16-2.00 (m, 2H).
MH+ 503.
1H-NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 2H), 7.42 (d, J=2.3 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.32-7.29 (m, 1H), 7.07-7.03 (m, 2H), 3.43-3.35 (m, 1H), 2.45 (s, 3H), 2.19-2.11 (m, 2H), 2.08-1.99 (m, 2H), 1.89-1.80 (m, 2H), 1.75-1.67 (m, 2H).
MH+ 517.
1H-NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 2H), 7.42 (d, J=2.3 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.32-7.29 (m, 1H), 7.06-7.03 (m, 2H), 3.03-2.96 (m, 1H), 2.45 (s, 3H), 2.17-2.12 (m, 2H), 1.88-1.83 (m, 2H) 1.76-1.66 (m, 4H), 1.45-1.26 (m, 2H).
MH+ 531.
1H-NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.34-7.30 (m, 3H), 7.13-7.09 (m, 2H), 3.16-3.07 (m, 1H), 2.45 (s, 3H), 2.00-1.89 (m, 1H), 1.80-1.70 (m, 1H), 1.43 (d, J=6.9 Hz, 3H), 0.97 (t, J=7.4 Hz, 3H).
MH+ 461.
1H-NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.38-7.30 (m, 4H), 7.13-7.09 (m, 2H), 3.24-3.15 (m, 1H), 2.45 (s, 3H), 1.95-1.86 (m, 1H), 1.71-1.63 (m, 1H), 1.46-1.32 (m, 5H), 0.92 (t, J=7.4 Hz, 3H).
MH+ 475.
1H-NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.38-7.30 (m, 4H), 7.13-7.09 (m, 2H), 3.22-3.13 (m, 1H), 2.45 (s, 3H), 1.95-1.89 (m, 1H), 1.73-1.64 (m, 1H), 1.42 (d, J=6.9 Hz, 3H), 1.38-1.25 (m, 4H), 0.91-1.87 (m, 3H).
MH+ 489.
1H-NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.42-7.41 (m, 1H), 7.39-7.37 m, 1H), 7.33-7.30 (m, 1H), 7.05-7.03 (m, 2H), 2.45 (s, 3H), 1.50 (s, 9H).
MH+ 505.
1H-NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.34-7.30 (m, 3H), 7.12-7.09 (m, 2H), 2.45 (s, 3H), 1.52 (s, 9H).
MH+ 461.
1H-NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.37-7.30 (m, 4H), 7.13-7.09 (m, 2H), 2.87 (d, J=6.9 Hz, 2H), 2.45 (s, 3H), 2.29-2.24 (m, 2H), 1.29-1.21 (m, 1H), 0.64-0.60 (m, 2H), 0.36-0.32 (m, 2H).
MH+ 459.
1H-NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.37-7.30 (m, 4H), 7.13-7.09 (m, 2H), 2.92-2.85 (m, 1H), 2.45 (s, 3H), 2.28-2.24 (m, 2H), 1.94-1.91 (m, 2H), 1.71-1.63 (m, 2H), 1.17-1.08 (m, 3H), 0.87 (s, 9H).
MH+ 543.
1H-NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 2H), 7.42-7.41 (m, 1H), 7.36 (d, J=8.7 Hz, 1H), 7.31 (dd, J=8.7, 2.3 Hz, 1H), 7.07-7.03 (m, 2H), 3.23-3.15 (m, 1H), 2.45 (s, 3H), 2.21-2.14 (m, 2H), 1.98-1.89 (m, 2H), 1.84-1.79 (m, 2H), 1.69-1.52 (m, 6H).
MH+ 545.
1H-NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 2H), 7.41-7.40 (m, 1H), 7.36 (d, J=8.7 Hz, 1H), 7.30 (dd, J=8.7, 2.3 Hz, 1H), 7.07-7.03 (m, 2H), 3.02-2.96 (m, 1H), 2.94-2.89 (m, 2H), 2.22-2.13 (m, 2H), 1.87-1.84 (m, 2H), 1.76-1.67 (m, 2H), 1.45-1.20 (m, 7H).
MH+ 545.
1H-NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 2H), 7.42-7.41 (m, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.30 (dd, J=8.2, 2.3 Hz, 1H), 7.09-7.05 (m, 2H), 3.86-3.77 (m, 1H), 2.91-2.85 (m, 2H), 2.61-2.51 (m, 2H), 2.49-2.40 (m, 2H), 2.19-1.99 (m, 2H), 1.25-1.21 (m, 3H).
MH+ 517.
1H-NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 2H), 7.41-7.40 (m, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.32-7.29 (m, 1H), 7.07-7.03 (m, 2H), 3.45-3.35 (m, 1H), 2.90-2.84 (m, 2H), 2.19-2.11 (m, 2H), 2.08-1.99 (m, 2H), 1.89-1.80 (m, 2H), 1.75-1.65 m, 2H), 1.25-1.20 (m, 3H).
MH+ 531.
1H-NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 2H), 7.41-7.40 (m, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.32-7.29 (m, 1H), 7.07-7.03 (m, 2H), 2.88-2.82 (m, 2H), 1.50 (s, 9H), 1.25-1.18 (m, 3H).
MH+ 519.
1H-NMR (300 MHz, CDCl3) δ 7.50-7.46 (m, 2H), 7.42-7.41 (m, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.33-7.29 (m, 1H), 7.07-7.03 (m, 2H), 3.21-3.14 (m, 1H), 2.45 (s, 3H), 1.96-1.89 (m, 1H), 1.71-1.64 (m, 1H), 1.43 (d, J=7.0 Hz, 3H), 1.34-1.32 (m, 4H), 0.91-0.86 (m, 3H).
MH+ 533.
1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=2.3 Hz, 1H), 7.37-7.23 (m, 9H), 7.12-7.09 (m, 2H), 4.45 (m, 1H), 2.42 (s, 3H), 1.82 (d, J=7.3 Hz, 3H).
(M+Na)+ 531.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.3 Hz, 1H), 7.35-7.28 (m, 4H), 7.13-7.09 (m, 2H), 3.81 (m, 4H), 3.62 (m, 4H), 2.41 (s, 3H).
MH+ 490.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=1.8 Hz, 1H), 7.34-7.27 (m, 4H), 7.13-7.09 (m, 2H), 4.62 (br d, J=8.2 Hz, 1H), 3.68 (m, 1H), 2.42 (s, 3H), 2.15-2.07 (m, 2H), 1.78-1.70 (m, 2H), 1.67-1.59 (m, 1H), 1.47-1.18 (m, 7H).
MH+ 502.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=2.3 Hz, 1H), 7.38-7.29 (m, 4H), 7.14-7.10 (m, 2H), 3.20 (m, 1H), 2.46 (s, 3H), 2.25-2.15 (m, 3H), 1.87-1.79 (m, 2H), 1.47-1.35 (m, 2H), 0.93 (d, J=6.4 Hz, 3H).
MH+ 501.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=2.3 Hz, 1H), 7.38-7.29 (m, 4H), 7.14-7.10 (m, 2H), 3.01 (m, 1H), 2.45 (s, 3H), 2.17-2.13 (m, 2H), 1.91-1.33 (m, 7H), 0.95 (d, J=6.4 Hz, 3H).
MH+ 501.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=1.8 Hz, 1H), 7.38-7.09 (m, 4H), 7.13-7.10 (m, 2H), 3.25 (m, 1H), 2.46 (s, 3H), 2.26 (m, 1H), 2.05 (m, 1H), 1.92-1.57 (m, 5H), 1.49-1.40 (m, 2H), 0.92 (d, J=6.9 Hz, 3H).
MH+ 501.
MH+ 476.
MH+ 485.
MH+ 501.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=2.3 Hz, 1H), 7.38-7.30 (m, 4H), 7.14-7.10 (m, 2H), 5.76 (s, 2H), 3.79 (m, 1H), 2.89 (d, J=8.2 Hz, 2H), 2.45 (s, 3H).
MH+ 471.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=1.8 Hz, 1H), 7.38-7.30 (m, 4H), 7.14-7.10 (m, 2H), 3.34 (m, 1H), 2.74 (m, 1H), 2.46 (s, 3H), 2.40 (m, 1H), 2.05-1.98 (m, 2H), 1.65-1.21 (m, 6H).
MH+ 499.
1H NMR (300 MHz, CDCl3) δ 7.43 (d, J=2.22 Hz, 2H), 7.38-7.24 (m, 5H), 7.24-7.19 (m, 3H), 7.13-7.10 (m, 2H), 3.48-3.43 (m, 1H), 3.37-3.30 (m, 1H), 2.95-2.88 (dd, J=13.56, 8.79 Hz, 1H), 2.45 (s, 3H), 1.40 (d, J=6.93 Hz, 3H).
MH+ 525.
1H NMR (300 MHz, CDCl3) δ 7.43-7.13 (m, 5H), 7.13-7.10 (m, 2H), 3.15-3.13 (m, 1H), 2.46 (s, 3H), 2.26-2.33 (m, 1H), 2.04-1.97 (m, 3H), 1.81-1.75 (m, 3H), 1.41 (d, J=7.14 Hz, 3H).
MH+ 503.
1H NMR (300 MHz, CDCl3) δ 7.50-7.47 (m, 2H), 7.42-7.41 (m, 1H), 7.38-7.28 (m, 2H), 7.09-7.06 (m, 2H), 2.92-2.80 (m, 4H), 1.99-1.88 (m, 1H), 1.80-1.62 (m, 4H), 1.26-1.04 (m, 9H).
MH+ 560.
1H NMR (300 MHz, CDCl3) δ 7.50-7.47 (m, 2H), 7.43-7.30 (m, 3H), 7.07-7.04 (m, 2H), 2.82 (d, J=6.9 Hz, 2H), 2.46 (s, 3H), 1.99-1.87 (m, 1H), 1.79-1.61 (m, 4H), 1.25-1.04 (m, 6H).
MH+ 545.
1H NMR (300 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.41-7.40 (m, 1H), 7.38-7.28 (m, 2H), 7.08-7.05 (m, 2H), 3.21-3.13 (m, 1H), 2.91-2.83 (m, 2H), 1.98-1.88 (m, 1H), 1.75-1.65 (m, 1H), 1.43 (d, J=6.9 Hz, 3H), 1.37-1.28 (m, 4H), 1.23 (t, J=7.3 Hz, 3H), 0.91-0.86 (m, 3H).
MH+ 547.
1H NMR (300 MHz, CDCl3) δ 7.42-7.40 (m, 1H), 7.37-7.28 (m, 4H), 7.15-7.11 (m, 2H), 2.89-2.82 (m, 2H), 1.50 (s, 9H), 1.23 (t, J=7.3 Hz, 3H).
MH+ 475.
1H NMR (300 MHz, CDCl3) δ 7.42-7.40 (m, 1H), 7.38-7.27 (m, 4H), 7.15-7.12 (m, 2H), 3.04-2.96 (m, 1H), 2.91-2.83 (m, 2H), 2.18-2.13 (m, 2H), 1.84-1.61 (m, 6H), 1.44-1.34 (m, 2H), 1.23 (t, J=7.3 Hz, 3H).
MH+ 501.
1H NMR (400 MHz, CDCl3) δ 7.42-7.31 (m, 5H), 7.12-7.10 (m, 2H), 2.44 (s, 3H), 1.83 (q, J=7.6 Hz, 2H), 1.47 (s, 6H), 0.87 (t, J=7.6 Hz, 3H).
MH+ 475.
1H NMR (300 MHz, CDCl3) δ 7.43-7.12 (m, 5H), 7.13-7.11 (m, 2H), 3.15-3.13 (m, 1H), 2.46 (s, 3H), 1.89-1.73 (m, 1H), 1.70-1.50 (m, 4H), 1.44-1.40 (m, 4H), 1.41 (d, J=7.23 Hz, 3H).
MH+ 503.
1H NMR (300 MHz, CDCl3) δ 7.44-7.12 (m, 5H), 7.13-7.12 (m, 2H), 3.11-3.12 (m, 1H), 2.49 (s, 3H), 1.92-1.73 (m, 2H), 1.72-1.50 (m, 5H), 1.44-1.40 (m, 4H), 1.44 (d, J=7.21 Hz, 3H).
MH+ 517.
1H NMR (300 MHz, CDCl3) δ 7.55-7.53 (m, 2H), 7.39-7.34 (m, 2H), 7.26-7.20 (m, 2H), 7.13-7.12 (m, 1H), 2.51 (s, 3H), 1.92-1.73 (m, 1H), 1.74-1.50 (m, 5H), 1.45 (s, 6H), 1.43-1.40 (m, 3H).
MH+ 517.
1H NMR (300 MHz, CDCl3) δ 7.55-7.53 (m, 2H), 7.39-7.34 (m, 2H), 7.26-7.20 (m, 2H), 7.13-7.12 (m, 1H), 2.54 (s, 3H), 1.97-1.88 (m, 1H), 1.74-1.50 (m, 6H), 1.45 (s, 6H), 1.43-1.40 (m, 3H).
MH+ 531.
1H NMR (400 MHz, CDCl3) δ 7.43-7.31 (m, 5H), 7.14-7.10 (m, 2H), 2.69 (d, J=7.8 Hz, 1H), 2.46 (s, 3H), 1.86 (s, 1H), 1.78 (d, J=7.8 Hz, 1H).
MH+ 527.
1H NMR (400 MHz, CDCl3) δ 7.41-7.30 (m, 5H), 7.12-7.08 (m, 2H), 3.98 (m, 1H), 3.04 (s, 3H), 2.41 (s, 3H), 1.88-1.80 (m, 4H), 1.70-1.05 (m, 6H).
MH+ 516.
1H NMR (400 MHz, CDCl3) δ 7.42-7.39 (m, 3H), 7.35-7.29 (m, 6H), 7.08 (m, 2H), 2.38 (s, 3H), 1.79 (dd, J=7.1, 4.6 Hz, 2H), 1.45 (dd, J=7.1, 4.6 Hz, 2H).
MH+ 555.
1H NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.37-7.29 (m, 4H), 7.15-7.12 (m, 2H), 3.84-3.80 (m, 1H), 2.91-2.85 (m, 2H), 2.61-2.52 (m, 2H), 2.48-2.40 (m, 2H), 2.17-2.02 (m, 2H), 1.23 (t, J=7.2 Hz, 3H).
MH+ 473.
1H NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.38-7.29 (m, 4H), 7.15-7.12 (m, 2H), 3.43-3.35 (m, 1H), 2.90-2.84 (m, 2H), 2.19-2.08 (m, 2H), 2.06-1.99 (m, 2H), 1.88-1.80 (m, 2H), 1.75-1.68 (m, 2H), 1.23 (t, J=7.2 Hz, 3H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.41-7.40 (m, 1H), 7.37-7.28 (m, 4H), 7.15-7.11 (m, 2H), 3.23-3.15 (m, 1H), 2.90-2.84 (m, 2H), 2.22-2.15 (m, 2H), 1.98-1.89 (m, 2H), 1.85-1.78 (m, 2H), 1.69-1.52 (m, 6H), 1.22 (t, J=7.3 Hz, 3H).
MH+ 515.
1H NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.41-7.27 (m, 8H), 7.15-7.08 (m, 2H), 2.38 (s, 3H), 1.78 (dd, J=7.0, 5.0 Hz, 2H), 1.48 (dd, J=7.0, 5.0 Hz, 2H).
MH+ 521.
1H NMR (400 MHz, CDCl3) δ 7.41-7.40 (m, 1H), 7.38-7.29 (m, 4H), 7.15-7.11 (m, 2H), 3.15-3.06 (m, 1H), 2.90-2.84 (m, 2H), 2.01-1.90 (m, 1H), 1.80-1.69 (m, 1H), 1.43 (d, J=6.88 Hz, 3H), 1.23 (t, J=7.3 Hz, 3H), 0.98 (t, J=7.3 Hz, 3H).
MH+ 475.
1H NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.42-7.41 (m, 2H), 7.36 (d, J=8.28 Hz, 1H), 7.32-7.29 (m, 1H), 7.08-7.05 (m, 2H), 3.16-3.06 (m, 1H), 2.90-2.84 (m, 2H), 2.01-1.90 (m, 1H), 1.80-1.69 (m, 1H), 1.43 (d, J=7.32 Hz, 3H), 1.23 (t, J=7.32 Hz, 3H), 0.98 (t, J=7.32 Hz, 3H).
MH+ 519.
1H NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.41 (d, J=2.28 Hz, 1H), 7.36 (d, J=8.24 Hz, 1H), 7.30 (dd, J=8.24, 2.28 Hz, 1H), 7.08-7.05 (m, 2H), 3.22-3.15 (m, 1H), 2.90-2.84 (m, 2H), 2.22-2.15 (m, 2H), 1.98-1.89 (m, 2H), 1.85-1.79 (m, 2H), 1.68-1.53 (m, 6H), 1.23 (t, J=7.8 Hz, 3H).
MH+ 560.
1H NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 2H), 7.42 (d, J=2.32 Hz, 1H), 7.37 (d, J=8.72 Hz, 1H), 7.32 (dd, J=8.68, 2.28 Hz, 1H), 7.07-7.03 (m, 2H), 3.16-3.07 (m, 1H), 2.45 (s, 3H), 2.00-1.90 (m, 1H), 1.80-1.70 (m, 2H), 1.43 (d, J=6.88 Hz, 3H), 0.97 (t, J=7.32 Hz, 3H).
MH+ 505.
1H NMR (400 MHz, CDCl3) δ 7.48-7.45 (m, 2H), 7.37 (d, J=2.32 Hz, 1H), 7.35-7.30 (m, 4H), 7.29-7.20 (m, 3H), 7.05-7.01 (m, 2H), 2.83-2.78 (m, 2H), 1.90 (s, 6H), 1.18 (t, J=7.32 Hz, 3H).
MH+ 581.
1H NMR (400 MHz, CDCl3) δ 7.41-7.29 (m, 7H), 7.12-7.08 (m, 2H), 3.15 (s, 3H), 2.41 (s, 3H), 1.51 (s, 9H).
MH+ 490.
1H NMR (400 MHz, CDCl3) δ 7.40-7.38 (d, J=2 Hz, 1H), 7.36-7.27 (m, 7H), 7.26-7.21 (m, 1H), 7.10-7.07 (m, 2H), 2.42 (s, 3H), 1.90 (s, 6H).
MH+ 523.
1H NMR (400 MHz, CDCl3) δ 7.40-7.38 (m, 1H), 7.35-7.27 (m, 6H), 7.26-7.21 (m, 1H), 7.10-7.07 (m, 2H), 2.42 (s, 3H), 1.88 (s, 6H).
MH+ 559.
1H NMR (400 MHz, CDCl3) δ 7.90-7.89 (m, 1H), 7.55-7.51 (m, 1H), 7.43-7.29 (m, 5H), 7.11-7.07 (m, 2H), 6.79-6.74 (m, 2H), 2.37 (s, 3H), 1.99 (s, 6H).
MH+ 542.
1H NMR (400 MHz, CDCl3) δ 8.00 (m, 1H), 7.77-7.74 (m, 1H), 7.40-7.26 (m, 5H), 7.10-7.08 (m, 2H), 6.88-6.86 (d, J=9.2 Hz, 1H), 2.41 (s, 3H), 2.02 (s, 6H).
MH+ 610.
1H NMR (400 MHz, CDCl3) δ 7.45-7.27 (m, 6H), 7.14-7.10 (m, 2H), 2.45 (s, 3H), 1.50 (s, 9H).
MH+ 427.
1H NMR (400 MHz, CDCl3) δ 7.45-7.27 (m, 6H), 7.16-7.11 (m, 2H), 3.12 (sextet, J=6.8 Hz, 1H), 2.47 (s, 3H), 1.95 (septet, J=6.8 Hz, 1H), 1.75 (septet, J=6.8 Hz, 1H), 1.43 (d, J=7.2 Hz, 3H), 0.97 (t, J=7.4 Hz, 3H).
MH+ 427.
1H NMR (400 MHz, CDCl3) δ 7.46-7.26 (m, 6H), 7.18-7.11 (m, 2H), 3.01-2.98 (m, 1H), 2.47 (s, 3H), 2.41-2.20 (m, 2H), 1.91-1.83 (m, 2H), 1.80-1.65 (m, 3H), 1.48-1.24 (m, 4H).
MH+ 453.
1H NMR (400 MHz, CDCl3) δ 7.43-7.38 (m, 2H), 7.34-7.30 (m, 3H), 7.15-7.09 (m, 2H), 2.44 (s, 3H), 1.78 (m, 2H), 1.47 (s, 6H), 1.25 (m, 4H), 0.87 (t, J=7.0 Hz, 3H).
MH+ 503.
1H NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 2H), 7.38-7.36 (m, 1H), 7.34-7.29 (m, 2H), 7.14-7.12 (m, 2H), 3.24-3.15 (m, 1H), 2.90-2.84 (m, 2H), 1.96-1.87 (m, 2H), 1.71-1.65 (m, 2H), 1.44-1.42 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.6 Hz, 3H).
MH+ 489.
1H NMR (400 MHz, CDCl3) δ 7.44-7.26 (m, 6H), 7.18-7.10 (m, 2H), 3.82 (quintet, J=8.8 Hz, 1H), 2.63-2.51 (m, 2H), 2.50-2.48 (m, 4H), 2.19-2.01 (m, 2H).
MH+ 425.
1H NMR (400 MHz, CDCl3) δ 7.47-7.28 (m, 6H), 7.14-7.10 (m, 2H), 2.45 (s, 3H), 1.84 (quartet, J=7.2 Hz, 2H), 1.46 (s, 6H), 0.87 (t, J=7.6 Hz, 3H).
MH+ 441.
1H NMR (400 MHz, CDCl3) δ 7.46-7.28 (m, 6H), 7.18-7.11 (m, 2H), 3.18 (sextet, J=6.8 Hz, 1H), 2.47 (s, 3H), 1.96-1.88 (m, 1H), 1.75-1.62 (m, 1H), 1.43 (d, J=6.8 Hz, 3H), 1.39-1.28 (m, 4H), 0.90 (t, J=7.2 Hz, 3H).
MH+ 455.
1H NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.42 (d, J=2.4 Hz, 1H), 7.38-7.36 (d, J=8.4 Hz, 1H), 7.30 (dd, J=8.4, 2.4 Hz, 1H), 7.06-7.04 (m, 2H), 3.22-3.17 (m, 1H), 2.45 (s, 3H), 1.92-1.89 (m, 1H), 1.68-1.66 (m, 1H), 1.43-1.42 (m, 3H), 1.41-1.37 (m, 2H), 0.93 (t, J=7.6 Hz, 3H).
MH+ 519.
1H NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 2H), 7.41 (d, J=2.0 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.32-7.29 (m, 1H), 7.08-7.05 (m, 2H), 3.22-3.17 (m, 1H), 2.90-2.84 (m, 2H), 1.93-1.88 (m, 1H), 1.70-1.64 (m, 1H), 1.44-1.42 (d, J=6.8 Hz, 3H), 1.41-1.35 (m, 2H), 1.23 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.6 Hz, 3H).
MH+ 533.
1H NMR (400 MHz, CDCl3) δ 7.46-7.27 (m, 6H), 7.30-7.11 (m, 2H), 2.45 (s, 3H), 1.83-1.74 (m, 2H), 1.47 (s, 6H), 1.33-1.18 (m, 4H), 0.88 (t, J=6.8 Hz, 3H).
MH+ 469.
1H NMR (400 MHz, CDCl3) δ 7.44-7.20 (m, 11H), 7.12-7.07 (m, 2H), 2.43 (s, 3H), 1.90 (s, 6H).
MH+ 489.
1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=8.4 Hz, 2H), 7.32 (d, J=6.4 Hz, 2H), 7.22 (d, J=6.4 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 2.41 (s, 3H), 1.86 (q, J=7.2 Hz, 2H), 1.48 (s, 6H), 0.88 (t, J=7.2 Hz, 3H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.55-7.52 (m, 2H), 7.33-7.30 (m, 2H), 7.23-7.20 (m, 2H), 7.08-7.05 (m, 2H), 3.08-2.98 (m, 1H), 2.41 (s, 3H), 2.18-2.14 (m, 2H), 1.90-1.85 (m, 2H), 1.77-1.68 (m, 2H), 1.46-1.25 (m, 3H).
MH+ 499.
1H NMR (400 MHz, CDCl3) δ 7.55-7.53 (m, 2H), 7.33-7.30 (m, 2H), 7.23-7.20 (m, 2H), 7.08-7.06 (m, 2H), 3.15-3.13 (m, 1H), 2.42 (s, 3H), 1.98-1.92 (m, 2H), 1.79-1.75 (m, 2H), 1.45 (d, J=6.8 Hz, 3H), 0.99 (t, J=7.2 Hz, 3H).
MH+ 473.
1H NMR (400 MHz, CDCl3) δ 7.42-7.30 (m, 5H), 7.15-7.09 (m, 2H), 4.00 (br d, 5.6 Hz, 2H), 3.67 (s, 2H), 2.44 (s, 3H), 1.56 (s, 3H), 1.51 (s, 3H).
MH+ 517.
1H NMR (400 MHz, CDCl3) δ 7.42-7.31 (m, 5H), 7.14-7.10 (m, 2H), 3.23 (s, 3H), 2.45 (s, 3H), 1.74 (s, 6H).
MH+ 477.
1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=2.4 Hz, 1H), 7.39-7.32 (m, 3H), 7.31-7.28 (m, 2H), 7.20-7.16 (m, 2H), 2.46 (s, 3H), 1.84 (q, J=7.6 Hz, 2H), 1.47 (s, 6H), 0.88 (t, J=7.2 Hz, 3H).
MH+ 441.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.4 Hz, 1H), 7.38-7.32 (m, 3H), 7.31-7.28 (m, 2H), 7.20-7.16 (m, 2H), 2.46 (s, 3H), 1.51 (s, 9H).
MH+ 427.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.0 Hz, 1H), 7.36-7.32 (m, 3H), 7.30-7.28 (m, 2H), 7.19-7.17 (m, 2H), 3.04-2.97 (m, 1H), 2.47 (s, 3H), 2.17-2.13 (m, 2H), 1.88-1.84 (m, 2H), 1.77-1.67 (m, 3H), 1.45-1.29 (m, 3H).
MH+ 453.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.0 Hz, 1H), 7.37-7.31 (m, 3H), 7.30-7.26 (m, 2H), 7.20-7.16 (m, 2H), 3.15-3.09 (m, 1H), 2.47 (s, 3H), 1.99-1.90 (m, 1H), 1.81-1.72 (m, 1H), 1.44 (d, J=6.8 Hz, 3H), 0.98 (t, J=7.6 Hz, 3H).
MH+ 427.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.0 Hz, 1H), 7.36-7.32 (m, 3H), 7.30-7.27 (m, 2H), 7.20-7.17 (m, 2H), 3.87-3.78 (m, 1H), 2.62-2.52 (m, 2H), 2.49-2.41 (m, 5H), 2.17-2.03 (m, 2H).
MH+ 425.
1H NMR (400 MHz, CDCl3) δ 7.56-7.55 (m, 2H), 7.39-7.31 (m, 2H), 7.23-7.21 (m, 2H), 7.08-7.06 (m, 2H), 2.41 (s, 3H), 1.52 (s, 9H).
MH+ 473.
1H NMR (400 MHz, CDCl3) δ 7.46-7.43 (m, 3H), 7.41-7.38 (m, 1H), 7.36-7.31 (m, 2H), 7.07-7.04 (m, 2H), 2.5 (s, 3H), 1.50 (s, 9H).
MH+ 471.
1H NMR (400 MHz, CDCl3) δ 7.46-7.43 (m, 3H), 7.41-7.39 (m, 1H), 7.38-7.34 (m, 2H), 7.07-7.05 (m, 2H), 3.02-2.97 (m, 1H), 2.46 (s, 3H), 2.16-2.12 (m, 2H), 1.88-1.84 (m, 2H), 1.77-1.58 (m, 2H), 1.41-1.25 (m, 4H).
MH+ 497.
1H NMR (400 MHz, CDCl3) δ 7.46-7.42 (m, 3H), 7.41-7.39 (m, 1H), 7.38-7.33 (m, 2H), 7.08-7.06 (m, 2H), 3.86-3.77 (m, 1H), 2.63-2.48 (m, 2H), 2.50 (s, 3H), 2.44-2.40 (m, 2H), 2.18-1.98 (m, 2H).
MH+ 469.
1H NMR (400 MHz, CDCl3) δ 7.47-7.31 (m, 6H), 7.08-7.05 (m, 2H), 3.16-3.07 (m, 1H), 2.49 (s, 3H), 2.01-1.90 (m, 1H), 1.80-1.69 (m, 1H), 1.43 (d, J=7.2 Hz, 3H), 0.97 (t, J=7.6 Hz, 3H).
MH+ 471.
1H NMR (400 MHz, CDCl3) δ 7.46-7.42 (m, 2H), 7.41-7.31 (m, 4H), 7.07-7.04 (m, 2H), 2.45 (s, 3H), 1.83 (q, J=7.6 Hz, 2H), 1.46 (s, 6H), 0.87 (t, J=7.6 Hz, 3H).
MH+ 485.
1H NMR (400 MHz, CDCl3) δ 7.40 (m, 1H), 7.35-7.29 (m, 8H), 7.10-7.06 (m, 2H), 3.09 (m, 2H), 2.73 (m, 2H), 2.40 (s, 3H), 2.25 (s, 1H), 2.02 (m, 1H).
MH+ 569.
1H NMR (400 MHz, CDCl3) δ 7.48-7.40 (m, 5H), 7.35-7.28 (m, 4H), 7.06-7.02 (m, 2H), 2.79 (q, J=7.2 Hz, 2H), 1.79 (dd, J=7.2, 4.8 Hz, 2H), 1.45 (dd, J=7.2, 4.8 Hz, 2H), 1.16 (t, J=7.2 Hz, 3H).
MH+ 613.
1H NMR (400 MHz, CDCl3) δ 7.43-7.25 (m, 10H), 7.12-7.08 (m, 2H), 2.39 (s, 3H), 1.79 (m, 2H), 1.44 (m, 2H).
MH+ 521.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, 1H, J=2.4 Hz), 7.38 (d, 1H, J=8.8 Hz), 7.34-7.31 (m, 2H), 7.29-7.25 (m, 1H), 7.21-7.20 (m, 1H), 7.03 (dt, 1H, J=7.6 Hz, 1.2 Hz), 2.45 (s, 3H), 1.50 (s, 9H).
MH+ 461.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, 1H, J=2.4 Hz), 7.37 (d, 1H, J=7.6 Hz), 7.34-7.31 (m, 2H), 7.29-7.25 (m, 1H), 7.21-7.20 (m, 1H), 7.03 (dt, 1H, J=8.0 Hz, 1.2 Hz), 3.14-3.09 (m, 1H), 2.46 (s, 3H), 1.98-1.91 (m, 1H), 1.78-1.73 (m, 1H), 1.43 (d, 3H), 0.97 (t, 3H).
MH+ 461.
1H NMR (400 MHz, CDCl3) δ 7.43 (dd, 1H, J=2.0 Hz, 0.4 Hz), 7.36 (d, 1H, J=8.0 Hz), 7.35-7.32 (m, 2H), 7.31-7.25 (m, 1H), 7.22-7.21 (m, 1H), 7.04 (dt, 1H, J=7.6 Hz, 1.2 Hz), 3.82 (m, 1H), 2.59-2.51 (m, 2H), 2.48-2.42 (m, 2H), 2.47 (s, 3H), 2.14-2.05 (m, 2H).
MH+ 461.
1H NMR (400 MHz, CDCl3) δ 7.42-7.32 (m, 5H), 7.14-7.10 (m, 2H), 3.40 (q, J=7.2 Hz, 2H), 2.45 (s, 3H), 1.74 (s, 6H), 1.16 (t, J=7.2 Hz, 3H).
MH+ 491.
1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.8 Hz, 2H), 7.31 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 2.40 (s, 3H), 1.51 (s, 9H).
MH+ 427.
1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.8 Hz, 2H), 7.31 (d, J=8.8 Hz, 2H), 7.21 (d, J=9.2 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 3.16-3.11 (m, 1H), 2.42 (s, 3H), 1.99-1.92 (m, 1H), 1.80-1.73 (m, 1H), 1.45 (d, J=7.2 Hz, 3H), 0.99 (t, J=7.6 Hz, 3H).
MH+ 427.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.35-7.29 (m, 4H), 7.18 (d, J=8.8 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 2.34 (s, 3H), 1.82-1.79 (m, 2H), 1.48-1.45 (m, 2H).
MH+ 521.
1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.4 Hz, 2H), 7.31 (d, J=9.2 Hz, 2H), 7.22 (d, J=9.2 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 2.40 (s, 3H), 1.85 (q, J=Hz, 2H), 1.48 (s, 6H), 0.88 (t, J=7.6 Hz, 3H).
MH+ 441.
1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=2.4 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.35-7.32 (m, 2H), 7.31-7.25 (m, 1H), 7.21-7.20 (m, 1H), 7.04 (dt, J=7.2 Hz, 1.2 Hz, 1H), 3.04-3.00 (m, 1H), 2.46 (s, 3H), 2.17-2.13 (m, 2H), 1.88-1.84 (m, 2H), 1.77-1.67 (m, 3H), 1.46-1.26 (m, 3H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=2.4 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.34-7.31 (m, 2H), 7.29-7.25 (m, 1H), 7.21-7.20 (m, 1H), 7.03 (dt, J=7.6 Hz, 1.6 Hz 1H), 2.45 (s, 3H), 1.83 (q, 2H, J=7.6 Hz), 1.46 (s, 6H), 0.88 (t, J=7.2 Hz, 3H).
MH+ 477.
1H NMR (400 MHz, CDCl3) δ 7.49-7.43 (m, 3H), 7.39-7.25 (m, 7H), 7.05-7.02 (m, 2H), 2.76 (quartet, J=7.6 Hz, 2H), 1.77 (m, 2H), 1.48 (m, 2H), 1.15 (t, J=7.6 Hz, 3H).
MH+ 581.
1H NMR (400 MHz, CDCl3) δ 7.49-7.45 (m, 2H), 7.41-7.35 (m, 2H), 7.31-7.27 (m, 1H), 7.07-7.03 (m, 2H), 2.84 (quartet, J=7.6 Hz, 2H), 1.83 (quartet, J=7.2 Hz, 2H), 1.46 (s, 6H), 1.22 (t, J=7.2 Hz, 3H), 0.87 (t, J=7.6 Hz, 3H).
MH+ 535.
1H NMR (400 MHz, CDCl3) δ 7.49-7.45 (m, 2H), 7.42-7.39 (m, 1H), 7.37-7.33 (m, 1H), 7.31-7.27 (m, 1H), 7.08-7.04 (m, 2H), 7.08-7.04 (m, 2H), 2.90 (quartet, J=7.6 Hz, 2H), 2.56 (br d, J=3.6 Hz, 1H), 2.49-2.37 (m, 1H), 2.20-2.02 (m, 1H), 1.95-1.85 (m, 1H), 1.70-1.18 (m, 9H).
MH+ 559.
1H NMR (400 MHz, CDCl3) δ 7.49-7.45 (m, 2H), 7.41-7.28 (m, 3H), 7.08-7.04 (m, 2H), 3.28 (quintet, J=6.8 Hz, 1H), 2.86 (quartet, J=6.8 Hz, 2H), 1.46 (d, J=6.8 Hz, 6H), 1.22 (t, J=7.6 Hz, 3H).
MH+ 506.
1H NMR (400 MHz, CDCl3) δ 7.50-7.45 (m, 2H), 7.41-7.27 (m, 3H), 7.08-7.04 (m, 2H), 2.99-2.91 (m, 1H), 2.86 (quartet, J=7.6 Hz, 2H), 1.94-1.74 (m, 4H), 1.22 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.6 Hz, 3H).
MH+ 534.
1H NMR (400 MHz, CDCl3) δ 7.49-7.45 (m, 2H), 7.41-7.36 (m, 2H), 7.31-7.29 (m, 1H), 7.07-7.03 (m, 2H), 2.85 (quartet, J=7.2 Hz, 2H), 2.32-2.25 (m, 2H), 1.68-1.45 (m, 8H), 1.40 (s, 3H), 1.21 (t, J=7.6 Hz, 3H).
MH+ 561.
1H NMR (400 MHz, CDCl3) δ 7.42-7.38 (m, 3H), 7.35-7.28 (m, 4H), 7.07 (m, 2H), 6.87 (m, 2H), 3.79 (s, 3H), 2.54 (s, 3H), 1.73 (dd, J=7.2, 4.4 Hz, 2H), 1.42 (dd, J=7.2, 4.4 Hz, 2H).
MH+ 551.
1H NMR (400 MHz, CDCl3) δ 7.44-7.39 (m, 3H), 7.36-7.25 (m, 5H), 7.07 (m, 2H), 2.35 (s, 3H), 1.94 (dd, J=7.6, 5.2 Hz, 2H), 1.48 (dd, J=7.6, 5.2 Hz, 2H).
MH+ 589.
1H NMR (400 MHz, CDCl3) δ 7.39-7.25 (m, 7H), 7.14 (m, 2H), 7.08 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 1.73 (dd, J=7.2, 4.4 Hz, 2H), 1.44 (dd, J=7.2, 4.4 Hz, 2H).
MH+ 535.
1H NMR (400 MHz, CDCl3) δ 7.41 (br d, J=2.0 Hz, 1H), 7.38-7.30 (m, 4H), 7.10 (m, 2H), 2.42 (s, 3H), 1.63 (m, 2H), 1.61 (m, 2H).
MH+ 513.
1H NMR (400 MHz, CDCl3) δ 7.42-7.37 (m, 3H), 7.34-7.27 (m, 6H), 7.11-7.07 (m, 2H), 2.78 (quartet, J=7.6 Hz, 2H), 1.79 (m, 2H), 1.44 (m, 2H), 1.16 (t, J=7.6 Hz, 3H).
MH+ 571.
1H NMR (400 MHz, CDCl3) δ 7.45-7.40 (m, 4H), 7.39-7.34 (m, 4H), 7.33-7.31 (m, 2H), 7.05 (d, 2H, J=8.4 Hz), 2.80 (q, 2H, J=7.2 Hz), 1.82-1.79 (m, 2H), 1.47-1.44 (m, 2H), 1.17 (t, 3H, J=7.2 Hz).
MH+ 581.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.0 Hz, 1H), 7.38-7.30 (m, 4H), 7.10 (m, 2H), 2.81 (m, 4H), 2.44 (s, 3H), 2.16 (m, 2H).
MH+ 527.
1H NMR (400 MHz, CDCl3) δ 7.42 (br d, J=2.0 Hz, 1H), 7.36-7.30 (m, 4H), 7.11 (m, 2H), 3.84 (q, J=9.6 Hz, 2H), 2.45 (s, 3H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.53-7.50 (m, 1H), 7.34-7.23 (m, 9H), 7.10-7.07 (m, 1H), 3.14-3.04 (m, 2H), 2.78-2.69 (m, 2H), 2.40 (s, 3H), 2.26-2.18 (m, 2H).
MH+ 571.
1H NMR (400 MHz, CDCl3) δ 7.42-7.47 (m, 2H), 7.33-7.25 (m, 5H), 7.07-7.04 (m, 2H), 6.85-6.81 (m, 2H), 3.79 (s, 3H), 2.37 (s, 3H), 1.78 (m, 2H), 1.43 (m, 2H).
MH+ 553.
1H NMR (400 MHz, CDCl3) δ 7.54-7.49 (m, 1H), 7.34-7.22 (m, 4H), 7.14-7.10 (m, 2H), 2.44 (s, 3H), 1.49 (s, 9H).
MH+ 463.
1H NMR (400 MHz, CDCl3) δ 7.41-7.39 (m, 1H), 7.37-7.33 (m, 1H), 7.29-7.24 (m, 1H), 7.11-7.06 (m, 2H), 6.86-6.83 (m, 2H), 3.79 (s, 3H), 2.42 (s, 3H), 1.49 (s, 9H).
MH+ 457.
1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.33-7.24 (m, 4H), 7.15-7.10 (m, 2H), 3.85-3.75 (m, 1H), 2.61-2.50 (m, 2H), 2.48-2.39 (m, 5H), 2.24-2.02 (m, 2H).
MH+ 461.
1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.33-7.22 (m, 4H), 7.14-7.09 (m, 2H), 3.05-2.94 (m, 1H), 2.45 (s, 3H), 2.18-2.10 (m, 2H), 1.89-1.80 (m, 2H), 1.79-1.63 (m, 2H), 1.45-1.25 (m, 4H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.53-7.49 (m, 1H), 7.42-7.37 (m, 2H), 7.32-7.22 (m, 6H), 7.12-7.06 (m, 2H), 2.83 (s, 3H), 1.78 (m, 2H), 1.39 (m, 2H).
MH+ 557.
1H NMR (400 MHz, CDCl3) δ 7.43-7.36 (m, 4H), 7.34-7.26 (m, 6H), 7.14-7.10 (m, 2H), 2.80 (q, 2H), 1.84-1.78 (m, 2H), 1.46-1.43 (m, 2H), 1.73 (t, 3H, J=7.2 Hz).
MH+ 537.
1H NMR (400 MHz, CDCl3) δ 7.45-7.42 (m, 1H), 7.40-7.36 (m, 1H), 7.35-7.27 (m, 4H), 7.16-7.13 (m, 2H), 2.87 (q, 2H), 1.50 (s, 9H), 1.24 (t, 3H, J=7.2 Hz).
MH+ 442.
1H NMR (400 MHz, CDCl3) δ 7.43-7.40 (m, 1H), 7.39-7.36 (m, 1H), 7.35-7.28 (m, 4H), 7.17-7.14 (m, 2H), 3.86-3.77 (m, 1H), 2.88 (q, 2H), 2.62-2.52 (m, 2H), 2.49-2.40 (m, 2H), 2.18-2.01 (m, 2H), 1.24 (t, 3H, J=7.6 Hz).
MH+ 439.
1H NMR (400 MHz, CDCl3) δ 7.41-7.35 (m, 2H), 7.34-7.26 (m, 6H), 7.27-7.25 (m, 2H), 7.13-7.09 (m, 2H), 3.12-3.06 (m, 2H), 2.81 (q, 2H), 2.78-2.70 (m, 2H), 2.30-2.19 (m, 1H), 2.07-1.97 (m, 1H), 1.19 (t, 3H, J=7.2 Hz).
MH+ 551.
1H NMR (400 MHz, CDCl3) δ 7.39 (br d, J=2.0 Hz, 1H), 7.37-7.22 (m, 9H), 7.08 (m, 2H), 4.17 (t, J=7.6 Hz, 2H), 2.42 (s, 3H), 2.37 (m, 1H), 2.12 (m, 1H), 0.97 (t, J=7.2 Hz, 3H).
MH+ 523.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=2.0 Hz, 1H), 7.36-7.18 (m, 9H), 7.11 (m, 2H), 3.44 (m, 1H), 3.20 (m, 2H), 2.42 (s, 3H), 1.36 (d, J=6.8 Hz).
MH+ 523.
1H NMR (400 MHz, CDCl3) δ 7.48-7.45 (m, 2H), 7.38-7.26 (m, 8H), 7.09 (d, J=8.8 Hz, 2H), 2.77 (q, J=7.2 Hz, 2H), 1.79-1.76 (m, 2H), 1.48-1.46 (m, 2H), 1.14 (t, J=7.6 Hz, 3H).
MH+ 537.
1H NMR (400 MHz, CDCl3) δ 7.38-7.34 (m, 3H), 7.32-7.26 (m, 4H), 7.16-7.13 (m, 2H), 7.09 (d, J=8.4 Hz, 2H), 2.77 (q, J=7.2 Hz, 2H), 2.33 (s, 3H), 1.76-1.73 (m, 2H), 1.45-1.42 (m, 2H), 1.14 (t, J=7.2 Hz, 3H).
MH+ 549.
1H NMR (400 MHz, CDCl3) δ 7.43-7.38 (m, 3H), 7.34-7.26 (m, 4H), 7.09 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 3.79 (s, 3H), 2.77 (q, J=7.6 Hz, 2H), 1.75-1.72 (m, 2H), 1.44-1.41 (m, 2H), 1.14 (t, J=7.2 Hz, 3H).
MH+ 565.
1H NMR (400 MHz, CDCl3) δ 7.44-7.42 (m, 2H), 7.39-7.27 (m, 6H), 7.09 (d, J=8.4 Hz, 2H), 2.75 (q, J=7.6 Hz, 2H), 1.97-1.94 (m, 2H), 1.50-1.47 (m, 2H), 1.12 (t, J=7.6 Hz, 3H).
MH+ 605.
1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=2.0 Hz, 1H), 7.34-7.25 (m, 8H), 7.09 (d, J=8.8 Hz, 2H), 3.11-3.05 (m, 2H), 2.82-2.70 (m, 4H), 2.30-2.18 (m, 1H), 2.06-1.97 (m, 1H), 1.16 (t, J=7.2 Hz, 3H).
MH+ 585.
1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=2.4 Hz, 1H), 7.36-7.28 (m, 4H), 7.12 (d, J=8.8 Hz, 2H), 2.84 (q, J=7.6 Hz, 2H), 1.67-1.61 (m, 4H), 1.21 (t, J=7.2 Hz, 3H).
MH+ 527.
1H NMR (400 MHz, CDCl3) δ 7.59-7.57 (m, 1H), 7.41-7.34 (m, 2H), 7.30-7.25 (m, 3H), 7.16-7.12 (m, 2H), 3.02-2.97 (m, 1H), 2.46 (s, 3H), 2.16-2.12 (m, 2H), 1.88-1.84 (m, 2H), 1.73-1.71 (m, 2H), 1.41-1.33 (m, 4H).
MH+ 497.
1H NMR (400 MHz, CDCl3) δ 7.59-7.57 (m, 1H), 7.43-7.35 (m, 2H), 7.30-7.26 (m, 3H), 7.15-7.12 (m, 2H), 2.45 (s, 3H), 1.50 (s, 9H).
MH+ 471.
1H NMR (400 MHz, CDCl3) δ 7.58-7.56 (m, 1H), 7.42-7.36 (m, 4H), 7.34-7.25 (m, 5H), 7.13-7.09 (m, 2H), 2.39 (s, 3H), 1.80-1.77 (m, 2H), 1.45-1.42 (m, 2H).
MH+ 565.
1H NMR (400 MHz, CDCl3) δ 7.58-7.55 (m, 1H), 7.37-7.25 (m, 9H), 7.18-7.09 (m, 2H), 3.12-3.06 (m, 2H), 2.78-2.70 (m, 2H), 2.41 (s, 3H), 2.27-2.20 (m, 1H), 2.04-1.99 (m, 1H).
MH+ 579.
1H NMR (400 MHz, CDCl3) δ 7.36-7.35 (m, 1H), 7.34-7.33 (m, 1H), 7.31-7.30 (m, 1H), 7.29-7.28 (m, 2H), 7.22-7.19 (m, 2H), 2.43 (s, 3H), 1.49 (s, 9H).
MH+ 461.
1H NMR (400 MHz, CDCl3) δ 7.41-7.38 (m, 2H), 7.36-7.33 (m, 2H), 7.32-7.29 (m, 3H), 7.28-7.26 (m, 2H), 7.20-7.17 (m, 2H), 2.37 (s, 3H), 1.80-1.77 (m, 2H), 1.44-1.41 (m, 2H).
MH+ 555.
1H NMR (400 MHz, CDCl3) δ 7.35-7.34 (m, 1H), 7.33-7.32 (m, 2H), 7.31-7.29 (m, 4H), 7.28-7.27 (m, 2H), 7.20-7.16 (m, 2H), 3.12-3.06 (m, 2H), 2.77-2.69 (m, 2H), 2.25 (s, 3H), 2.24-2.18 (m, 1H), 2.05-1.97 (m, 1H).
MH+ 569.
1H NMR (400 MHz, CDCl3) δ 7.59-7.56 (m, 1H), 7.40-7.30 (m, 2H), 7.29-7.27 (m, 3H), 7.24-7.12 (m, 2H), 3.83-3.78 (m, 1H), 2.58-2.53 (m, 2H), 2.51 (s, 3H), 2.47-2.41 (m, 2H), 2.15-1.03 (m, 2H).
MH+ 469.
1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=2.4 Hz, 1H), 7.35-7.29 (m, 4H), 7.12 (d, J=8.8 Hz, 2H), 2.43 (s, 3H), 1.50 (s, 9H).
MH+ 461.
1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=2.0 Hz, 1H), 7.35-7.30 (m, 4H), 7.13 (d, J=8.8 Hz, 2H), 3.83-3.79 (m, 1H), 2.58-2.51 (m, 2H), 2.47-2.42 (m, 5H), 2.14-2.05 (m, 2H).
MH+ 459.
1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=2.0 Hz, 1H), 7.35-7.29 (m, 4H), 7.13 (d, J=8.8 Hz, 2H), 3.02-2.97 (m, 1H), 2.45 (s, 3H), 2.16-2.12 (m, 2H), 1.87-1.83 (m, 2H), 1.76-1.66 (m, 3H), 1.44-1.29 (m, 3H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.47 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 7.35-7.28 (m, 6H), 7.10 (d, J=8.4 Hz, 2H), 2.38 (s, 3H), 1.80-1.77 (m, 2H), 1.46-1.43 (m, 2H).
MH+ 557.
1H NMR (400 MHz, CDCl3) δ 7.47 (d, J=2.4 Hz, 1H), 7.34-7.27 (m, 8H), 7.09 (d, J=8.4 Hz, 2H), 3.12-3.05 (m, 2H), 2.78-2.70 (m, 2H), 2.39 (s, 3H), 2.24-2.19 (m, 1H), 2.05-1.18 (m, 1H).
MH+ 571.
1H NMR (400 MHz, CDCl3) δ 7.42-7.39 (m, 1H), 7.38-7.35 (m, 1H), 7.33-7.26 (m, 4H), 7.16-7.12 (m, 2H), 3.02-2.95 (m, 1H), 2.88 (q, 2H), 2.16-2.12 (m, 2H), 1.87-1.83 (m, 2H), 1.76-1.66 (m, 3H), 1.44-1.26 (m, 3H), 1.23 (t, J=7.6 Hz, 3H).
MH+ 467.
1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=2.4 Hz, 2H), 7.42-7.39 (m, 2H), 7.34 (d, J=8.4 Hz, 1H), 7.16-7.12 (m, 2H), 6.96 (dd, J=8.8 Hz, 2.4 Hz, 1H), 2.38 (s, 3H), 1.51 (s, 9H).
MH+ 461.
1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=2.4 Hz, 2H), 7.42-7.39 (m, 2H), 7.34 (d, J=8.4 Hz, 1H), 7.16-7.12 (m, 2H), 6.96 (dd, J=8.8 Hz, 2.4 Hz, 1H), 3.86-3.81 (m, 1H), 2.59-2.54 (m, 2H), 2.51-2.45 (m, 2H), 2.40 (s, 3H), 2.18-2.07 (m, 2H).
MH+ 459.
1H NMR (400 MHz, CDCl3) δ 7.42-7.36 (m, 2H), 7.34-7.24 (m, 3H), 7.08-7.03 (m, 2H), 6.90-6.80 (m, 4H), 3.78 (s, 6H), 2.35 (d, J=4.0 Hz, 3H), 1.81-1.71 (m, 2H), 1.45-1.38 (m, 2H).
MH+ 547.
1H NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.40 (br d, J=2.0 Hz, 1H), 7.37-7.28 (m, 2H), 7.07-7.04 (m, 2H), 2.83 (q, J=7.6 Hz, 2H), 1.64 (m, 2H), 1.61 (m, 2H), 1.21 (t, J=7.6 Hz, 3H).
MH+ 571.
1H NMR (400 MHz, CDCl3) δ 7.47-7.25 (m, 8H), 7.04-7.00 (m, 2H), 2.74 (q, J=7.6 Hz, 2H), 1.95 (dd, J=7.4, 5.0 Hz, 2H), 1.49 (dd, J=7.4, 5.0 Hz, 2H), 1.12 (t, J=7.6 Hz, 3H).
MH+ 647.
1H NMR (400 MHz, CDCl3) δ 7.47-7.44 (m, 2H), 7.42-7.39 (m, 2H), 7.38-7.27 (m, 3H), 7.04-7.00 (m, 2H), 6.88-6.86 (m, 2H), 3.79 (s, 3H), 2.76 (q, J=7.6 Hz, 2H), 1.74 (dd, J=7.2, 4.8 Hz, 2H), 1.42 (dd, J=7.2, 4.8 Hz, 2H), 1.14 (t, J=7.6 Hz, 3H).
MH+ 609.
1H NMR (400 MHz, CDCl3) δ 7.47-7.44 (m, 2H), 7.38-7.27 (m, 5H), 7.16-7.14 (m, 2H), 7.04-7.00 (m, 2H), 2.76 (q, J=7.6 Hz, 2H), 2.31 (s, 3H), 1.74 (dd, J=7.2, 4.8 Hz, 2H), 1.44 (dd, J=7.2, 4.8 Hz, 2H), 1.14 (t, J=7.6 Hz, 3H).
MH+ 593.
1H NMR (400 MHz, CDCl3) δ 7.48-7.44 (m, 4H), 7.38-7.27 (m, 6H), 7.04-7.00 (m, 2H), 2.76 (q, J=7.6 Hz, 2H), 1.77 (dd, J=7.2, 4.8 Hz, 2H), 1.47 (dd, J=7.2, 4.8 Hz, 2H), 1.14 (t, J=7.6 Hz, 3H).
MH+ 579.
1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=2.0 Hz, 1H), 7.31-7.24 (m, 4H), 7.14 (d, J=8.8 Hz, 2H), 3.48-3.43 (m, 1H), 1.49 (s, 9H), 1.26 (d, J=7.2 Hz, 6H).
MH+ 489.
1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=2.4 Hz, 1H), 7.31-7.23 (m, 4H), 7.15 (d, J=8.4 Hz, 2H), 3.85-3.76 (m, 1H), 3.54-3.47 (m, 1H), 2.60-2.40 (m, 3H), 2.18-2.00 (m, 3H), 1.27 (d, J=7.2 Hz, 6H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=2.4 Hz, 1H), 7.31-7.22 (m, 4H), 7.15 (d, J=8.0 Hz, 2H), 3.52-3.45 (m, 1H), 3.02-2.95 (m, 1H), 2.16-2.12 (m, 2H), 1.87-1.83 (m, 2H), 1.75-1.65 (m, 3H), 1.44-1.29 (m, 3H), 1.26 (d, J=6.8 Hz, 6H).
MH+ 515.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=8.4 Hz, 2H), 7.37 (d, J=2.0 Hz, 1H), 7.33-7.23 (m, 6H), 7.11 (d, J=8.4 Hz, 2H), 3.40-3.33 (m, 1H), 1.80-1.77 (m, 2H), 1.46-1.43 (m, 2H), 1.20 (d, J=7.2 Hz, 6H).
MH+ 585.
1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=2.0 Hz, 1H), 7.31-7.22 (m, 8H), 7.11 (d, J=8.4 Hz, 2H), 3.43-3.36 (m, 1H), 3.11-3.05 (m, 2H), 2.77-2.70 (m, 2H), 2.28-2.21 (m, 1H), 2.05-1.97 (m, 1H), 1.19 (d, J=7.2 Hz, 6H).
MH+ 599.
1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=2.4 Hz, 1H), 7.37-7.27 (m, 4H), 7.11 (d, J=8.4 Hz, 2H), 2.81-2.77 (m, 2H), 1.66-1.57 (m, 2H), 1.49 (s, 9H), 0.88 (t, J=7.2 Hz, 3H).
MH+ 489.
1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=2.0 Hz, 1H), 7.35-7.27 (m, 4H), 7.12 (d, J=8.0 Hz, 2H), 3.82-3.78 (m, 1H), 2.84-2.80 (m, 2H), 2.58-2.50 (m, 2H), 2.48-2.42 (m, 2H), 2.16-2.05 (m, 2H), 1.65-1.59 (m, 2H), 0.88 (t, J=7.2 Hz, 3H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=2.0 Hz, 1H), 7.35-7.27 (m, 4H), 7.12 (d, J=8.4 Hz, 2H), 3.02-2.94 (m, 1H), 2.83-2.79 (m, 2H), 2.17-2.12 (m, 2H), 1.87-1.83 (m, 2H), 1.75-1.57 (m, 4H), 1.44-1.25 (m, 4H), 0.88 (t, J=7.2 Hz, 3H).
MH+ 515.
1H NMR (400 MHz, CDCl3) δ 7.42-7.38 (m, 3H), 7.34-7.26 (m, 6H), 7.09 (d, J=8.8 Hz, 2H), 2.74-2.70 (m, 2H), 1.80-1.77 (m, 2H), 1.58-1.50 (m, 2H), 1.46-1.43 (m, 2H), 0.82 (t, J=7.6 Hz, 3H).
MH+ 585.
1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=2.4 Hz, 1H), 7.33-7.26 (m, 8H), 7.08 (d, J=8.8 Hz, 2H), 3.11-3.04 (m, 2H), 2.77-2.70 (m, 4H), 2.27-2.20 (m, 1H), 2.04-2.00 (m, 1H), 1.61-1.53 (m, 2H), 0.85 (t, J=7.2 Hz, 3H).
MH+ 599.
1H NMR (400 MHz, CDCl3) δ 7.46-7.38 (m, 4H), 7.37 (d, J=2.4 Hz, 1H), 7.34-7.26 (m, 4H), 7.23-7.19 (m, 1H), 7.03-6.95 (m, 2H), 2.91 (m, 2H), 2.77 (q, J=7.6 Hz, 2H), 2.24 (m, 2H), 1.83 (m, 4H), 1.15 (t, J=7.6 Hz, 3H).
MH+ 607.
1H NMR (400 MHz, CDCl3) δ 7.46-7.44 (m, 2H), 7.35-7.25 (m, 7H), 7.04-7.01 (m, 2H), 2.88 (m, 2H), 2.78 (q, J=7.6 Hz, 2H), 2.19 (m, 2H), 1.83 (m, 4H), 1.16 (t, J=7.6 Hz, 3H).
MH+ 641.
1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.33-7.26 (m, 4H), 7.16 (d, J=8.8 Hz, 2H), 3.48-3.41 (m, 1H), 1.66-1.63 (m, 4H), 1.28 (d, J=7.2 Hz, 6H).
MH+ 541.
1H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 7.30-7.22 (m, 4H), 7.06 (d, J=8.8 Hz, 2H), 2.74-2.71 (m, 2H), 1.58-1.52 (m, 6H), 0.82 (t, J=7.2 Hz, 2H).
MH+ 541.
To a solution of ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate (1 g, 2.4 mmol) in methylene chloride (30 ml) at room temperature was added bromine (4.9 ml, prepared 1.0 M solution in methylenechlordie, 4.9 mmol) dropwisely. The reaction mixture was stirred at room temperature for 1 hour and the resulting solution was diluted with ethyl ether (50 ml). The reaction mixture was quenched with saturated sodium bicarbonate solution (30 ml) and extracted with ethyl ether (50 ml twice). The organic solution was evaporated under reduced pressure, and crude residue was purified with silica gel column (hexane/ethyl acetate=5/1) to recover starting material (401 mg, 40%) and produce the title compound (520 mg, 45% yield) as white solid.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.0 Hz, 1H), 7.37 (d, J=8.4, 2H), 7.35-7.31 (m, 3H), 7.21-7.19 (m, 2H), 4.50 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H).
MH+ 473.
To a solution of ethyl 4-bromo-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate (68) (500 mg, 1.1 mmol) in aqueous toluene, tetrakis(triphenylphsophine)palladium (122 mg, 0.11 mmol) and potassium carbonate (510 mg, 3.9 mmol) were added. The reaction mixture was placed under microwave irradiation with the temperature set to 140° C. The resulting solution was filtered with syringe filter, and then solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography to obtain the title compound (283 mg, 44%) as white solid.
1H NMR (400 MHz, CDCl3) δ 7.46-7.43 (m, 1H), 7.38-7.35 (m, 4H), 7.13-7.11 (m, 2H), 4.48 (q, J=7.1 Hz, 2H), 2.02-1.98 (m, 1H), 1.44 (t, J=7.1, 3H), 1.26-1.23 (m, 1H), 0.89-0.86 (m, 1H).
MH+ 436.
1H NMR (400 MHz, CDCl3) δ 7.52-7.48 (m, 2H), 7.31-7.22 (m, 2H), 7.17-7.04 (m, 1H), 7.02-7.00 (m, 2H), 3.08-2.98 (m, 1H), 2.18-2.14 (m, 2H), 1.90-1.85 (m, 2H), 1.77-1.68 (m, 2H), 1.46-1.25 (m, 4H), 0.63-0.60 (m, 2H), 0.38-0.34 (m, 2H).
MH+ 515.
1H NMR (400 MHz, CDCl3) δ 7.55-7.50 (m, 2H), 7.37-7.31 (m, 2H), 7.22-7.20 (m, 1H), 7.15-7.10 (m, 2H), 1.45 (m, 1H), 1.34 (s, 9H), 0.62-0.59 (m, 2H), 0.38-0.34 (m, 2H).
MH+ 489.
1H NMR (400 MHz, CDCl3) δ 7.54-7.51 (m, 2H), 7.33-7.31 (m, 2H), 7.20-7.17 (m, 1H), 7.14-7.11 (m, 2H), 3.25-2.22 (m, 1H), 1.50 (m, 1H), 1.45-1.44 (m, 4H), 1.37-1.30 (m, 2H), 0.61-0.59 (m, 2H), 0.37-0.34 (m, 2H).
MH+ 487.
To the solution of bromide (33) (2.7 g, 4.614 mmol) in DMF (20 mL) was added sodium acetate (1.13 mg, 13.842 mmol). The reaction mixture was heated for 12 hrs at 60° C. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: hexane/EtOAc=3/1) provided 1.75 g (76%) of desired acetate as solid.
1H NMR (400 MHz, CDCl3) δ 7.51-7.47 (m, 2H), 7.44-7.39 (m, 1H), 7.40-7.38 (m, 1H), 7.35-7.32 (m, 1H), 7.25-7.06 (m, 2H), 5.30 (s, 2H), 2.03 (s, 3H), 1.49 (s, 9H).
MH+ 563.
1H NMR (400 MHz, CDCl3) δ 7.44-7.43 (m, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.35-7.32 (m, 3H), 7.15-7.13 (m, 2H), 5.30 (s, 2H), 2.03 (s, 3H), 1.50 (s, 9H).
MH+ 519.
1H NMR (300 MHz, CDCl3) δ 7.42-7.38 (m, 3H), 7.35-7.31 (m, 6H), 7.12 (d, J=8.4 Hz, 2H), 5.24 (s, 2H), 1.99 (s, 3H), 1.81-1.77 (m, 2H), 1.48-1.46 (m, 2H).
MH+ 615.
1H NMR (400 MHz, CDCl3) δ 7.93-7.91 (m, 2H), 7.56-7.52 (m, 1H), 7.45-7.26 (m, 7H), 7.19-7.17 (m, 2H), 5.58 (s, 2H), 1.46 (s, 9H).
MH+ 581.
To the solution of acetate (34) (1.57 g, 3.020 mmol) in THF(9 mL)/MeOH(9 mL)/H2O(2 mL) was added LiOH monohydrate (380 mg, 9.060 mmol). The reaction mixture was stirred for 12 hrs at room temperature. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide 1.37 g (95%) of desired alcohol (35) as solid. The obtained acid was used without further purification.
1H NMR (400 MHz, CDCl3) δ 7.45-7.44 (m, 1H), 7.34-7.32 (m, 4H), 7.16-7.14 (m, 2H), 4.82-4.78 (m, 1H), 4.72-4.70 (m, 2H), 1.51 (s, 9H).
MH+ 478.
1H NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.44-7.43 (m, 1H), 7.33-7.32 (m, 2H), 7.08-7.06 (m, 2H), 4.69 (s, 2H), 1.50 (s, 9H).
MH+ 521.
1H NMR (400 MHz, CDCl3) δ 7.43-7.39 (m, 3H), 7.35-7.30 (m, 6H), 7.12 (d, J=8.4 Hz, 2H), 4.66 (s, 2H), 1.82-1.79 (m, 2H), 1.50-1.47 (m, 2H).
MH+ 573.
To the solution of alcohol (35) (100 mg, 0.209 mmol) and Dess-Martin periodinane (132 mg, 0.313 mmol) in CH2Cl2 (5 mL) was stirred at room temperature. The reaction mixture was filtered off the white solid and then diluted with CH2Cl2 (50 mL) and washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: hexane/EtOAc=3/1) provided 78 mg (78%) of desired aldehyde (36) as solid.
1H NMR (400 MHz, CDCl3) δ 10.65 (s, 1H), 7.46-7.45 (m, 1H), 7.38-7.31 (m, 4H), 7.36-7.23 (m, 2H), 1.52 (s, 9H).
MH+ 475.
1H NMR (400 MHz, CDCl3) δ 10.63 (s, 1H), 7.48-7.44 (m, 3H), 7.35-7.33 (m, 2H), 7.18-7.15 (m, 2H), 1.50 (s, 9H).
MH+ 519.
1H NMR (300 MHz, CDCl3) δ 10.55 (s, 1H), 7.45-7.41 (m, 3H), 7.36-7.30 (m, 6H), 7.23 (d, J=8.6 Hz, 2H), 1.85-1.81 (m, 2H), 1.52-1.48 (m, 2H).
MH+ 571.
To the suspension of alcohol (35) (120 mg, 0.251 mmol), NaH (20 mg, 60% dispersion in mineral oil) in DMF (5 mL) was stirred at room temperature. After 1 hr, the reaction mixture was added MeI (40 μL, 0.33 mmol) and stirred for 12 hrs. The reaction mixture was filtered off the white solid and then extracted with EtOAc (50 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: hexane/EtOAc=4/1) provided 103 mg (84%) of desired ether (49) as solid.
1H NMR (400 MHz, CDCl3) δ 7.45-7.44 (m, 1H), 7.36-7.31 (m, 4H), 7.26-7.23 (m, 2H), 4.66 (s, 2H), 3.48 (s, 3H), 1.50 (s, 9H).
MH+ 491.
1H NMR (400 MHz, CDCl3) δ 7.45-7.36 (m, 1H), 7.34-7.31 (m, 4H), 7.28-7.26 (m, 2H), 4.70 (s, 2H), 3.60 (t, J=6.4 Hz, 2H), 1.66-1.57 (m, 2H), 1.50 (s, 9H), 1.41-1.26 (m, 2H), 0.91 (t, J=7.6 Hz, 3H).
MH+ 533.
To the solution of aldehyde (36) (100 mg, 0.210 mmol) in THF (5 mL) was added methyl magnesium bromide (200 L, 3.0M solution in diethylether). The reaction mixture was stirred for 12 hrs at room temperature. H2O (20 mL) was added to the reaction mixture and then extracted with CH2Cl2 (50 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: hexane/EtOAc=2/1) provided 83 mg (80%) of desired secondary alcohol (53) as solid.
1H NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.34-7.29 (m, 4H), 7.13-7.10 (m, 2H), 5.72 (d, J=11.6 Hz, 1H), 4.86-4.78 (m, 1H), 1.61 (d, J=7.2 Hz, 3H), 1.51 (s, 9H).
MH+ 491.
1H NMR (400 MHz, CDCl3) δ 7.48-7.46 (m, 2H), 7.42-7.41 (m, 1H), 7.31-7.29 (m, 2H), 7.06-7.03 (m, 2H), 4.83-4.78 (m, 1H), 1.60-1.59 (m, 3H), 1.50 (s, 9H).
MH+ 535.
1H NMR (400 MHz, CDCl3) δ 7.43-7.40 (m, 3H), 7.35-7.29 (m, 6H), 7.09 (d, J=8.4 Hz, 2H), 4.78 (q, J=6.8 Hz, 1H), 1.85-1.77 (m, 2H), 1.56 (d, J=6.8 Hz, 3H), 1.51-1.46 (m, 2H).
MH+ 587.
To the solution of secondary alcohol (53) (50 mg, 0.101 mmol) in CH2Cl2 (3 mL) in Falcon tube was added DAST (27 L, 0.202 mmol). The reaction mixture was stirred for 2 hrs at room temperature. Saturated NaHCO3 (30 mL) was added to the reaction mixture. After 1 hr, the organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: hexane/EtOAc=2/1) provided 40 mg (80%) of desired product (58) as solid.
1H NMR (400 MHz, CDCl3) δ 7.42 (bs, 1H), 7.32-7.29 (m, 4H), 7.25-7.22 (m, 2H), 6.49 (q, J=6.8 Hz, 1H), 1.61 (d, J=6.4 Hz, 3H), 1.50 (s, 9H).
MH+ 493.
1H NMR (400 MHz, CDCl3) δ 7.48-7.46 (m, 2H), 7.41-7.40 (m, 1H), 7.31-7.30 (m, 2H), 7.05-7.03 (m, 2H), 4.82-4.80 (m, 1H), 1.60-1.58 (m, 3H), 1.50 (s, 9H).
MH+ 537.
1H NMR (400 MHz, CDCl3) δ 7.45-7.41 (m, 3H), 7.36-7.30 (m, 6H), 7.22 (d, J=8.4 Hz, 2H), 6.43-6.27 (m, 1H), 1.82-1.80 (m, 2H), 1.58-1.51 (m, 3H), 1.49-1.47 (m, 2H).
MH+ 589.
To the solution of secondary alcohol (53) (150 mg, 0.305 mmol) and Dess-Martin periodinane (155 mg, 0.366 mmol) in CH2Cl2 (5 mL) was stirred at room temperature. The reaction mixture was filtered off the white solid and then diluted with CH2Cl2 (50 mL) and washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: hexane/EtOAc=2/1) provided 117 mg (78%) of desired ketone (57) as solid.
1H NMR (400 MHz, CDCl3) δ 7.44-7.43 (m, 1H), 7.35-7.30 (m, 4H), 7.23-7.19 (m, 2H), 2.40 (s, 3H), 1.50 (s, 9H).
MH+ 489.
1H NMR (400 MHz, CDCl3) δ 7.48-7.45 (m, 2H), 7.43-7.42 (m, 1H), 7.32-7.31 (m, 2H), 7.15-7.11 (m, 2H), 2.39 (s, 3H), 1.49 (s, 9H).
MH+ 533.
1H NMR (400 MHz, CDCl3) δ 7.36-7.34 (m, 3H), 7.28-7.23 (m, 6H), 7.12 (d, J=8.8 Hz, 2H), 2.25 (s, 3H), 1.76-1.73 (m, 2H), 1.43-1.40 (m, 2H).
MH+ 585.
To the solution of ketone (57) (65 mg, 0.132 mmol) and 3-chloroperoxybenzoic acid (77% max) (66 mg) in CH2Cl2 (10 mL) was stirred at rt. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: hexane/EtOAc=5/1) provided 42 mg (63%) of desired acetate as solid.
1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=8.4 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.39-7.36 (m, 1H), 7.33-7.29 (m, 2H), 7.16-7.12 (m, 2H), 2.37 (s, 3H), 1.48 (s, 9H).
MH+ 505.
To the solution of ketone (57) (40 mg, 0.082 mmol) in THF (5 mL) was added methyl magnesium bromide (100 L, 3.0M solution in diethylether). The reaction mixture was stirred for 12 hrs at room temperature. H2O (20 mL) was added to the reaction mixture and then extracted with CH2Cl2 (50 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: hexane/EtOAc=2/1) provided 33 mg (80%) of desired tertiary alcohol (59) as solid.
1H NMR (400 MHz, CDCl3) δ 7.39-7.38 (m, 1H), 7.29-7.17 (m, 6H), 6.77 (s, 1H), 1.51 (s, 9H), 1.42 (s, 6H).
MH+ 505.
1H NMR (400 MHz, CDCl3) δ 7.44-7.41 (m, 2H), 7.38 (d, J=2.0 Hz, 1H), 7.21 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.11-7.09 (m, 2H), 1.50 (s, 9H), 1.41 (s, 6H).
(MH+-H2O) 531.
To the solution of tertiary alcohol (59) (52 mg, 0.103 mmol) and Burgess reagent (50 mg, 0.206 mmol) in THF (5 mL) was irradiated in a microwave reactor (Biotage) for 10 minutes at 150° C. The organic layer was washed with brine and dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: hexane/EtOAc=4/1) provided 49 mg (98%) of desired product (60) as solid.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=2.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.32 (dd, J=8.4, 2.4 Hz, 1H), 7.28-7.26 (m, 2H), 7.14-7.10 (m, 2H), 5.28-5.27 (m, 1H), 4.99-4.98 (m, 1H), 2.02 (s, 3H), 1.48 (s, 9H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.43-7.37 (m, 3H), 7.39 (d, J=8.4 Hz, 1H), 7.31 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.06-7.03 (m, 2H), 5.27-5.26 (m, 1H), 4.98-4.97 (m, 1H), 2.01 (s, 3H), 1.47 (s, 9H).
MH+ 531.
To the solution of alcohol (35) (200 mg, 0.418 mmol) in CH2Cl2 (5 mL) in Falcon tube was added (diethylamino)sulfur trifluoride (DAST, 110 L, 0.836 mmol). The reaction mixture was stirred for 2 hrs at room temperature. Saturated NaHCO3 (30 mL) was added to the reaction mixture. After 1 hr, the organic extract was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: hexane/EtOAc=4/1) provided 106 mg (53%) of desired fluoride (50) as solid.
1H NMR (400 MHz, CDCl3) δ 7.47-7.46 (m, 1H), 7.38-7.32 (m, 4H), 7.24-7.20 (m, 2H), 5.67 (d, J=48.8 Hz, 2H), 1.50 (s, 9H).
MH+ 479.
1H NMR (400 MHz, CDCl3) δ 7.51-7.49 (m, 2H), 7.45-7.44 (m, 1H), 7.38-7.32 (m, 2H), 7.15-7.13 (m, 2H), 5.65 (d, J=48.8 Hz, 2H), 1.48 (s, 9H).
MH+ 523.
1H NMR (300 MHz, CDCl3) δ 7.45-7.39 (m, 3H), 7.36-7.31 (m, 6H), 7.20 (d, J=8.5 Hz, 2H), 5.67 (s, 1H), 5.51 (s, 1H), 1.82-1.78 (m, 2H), 1.49-1.45 (m, 2H).
MH+ 575.
To the solution of aldehyde (36) (50 mg, 0.105 mmol) in CH2Cl2 (5 mL) in Falcon tube was added (diethylamino)sulfur trifluoride (DAST, 30 L, 0.210 mmol). The reaction mixture was stirred for 2 hrs at room temperature. Saturated NaHCO3 (30 mL) was added to the reaction mixture. After 1 hr, the organic extract was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: hexane/EtOAc=4/1) provided 25 mg (48%) of desired difluoride (52) as solid.
1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=53.6 Hz, 1H), 7.45-7.44 (m, 1H), 7.37-7.30 (m, 4H), 7.27-7.24 (m, 2H), 1.50 (s, 9H).
MH+ 497.
1H NMR (400 MHz, CDCl3) δ 7.45-7.41 (m, 3H), 7.36-7.31 (m, 7H), 7.25 (d, J=8.8 Hz, 2H), 1.83-1.80 (m, 2H), 1.51-1.48 (m, 2H).
MH+ 593.
To the suspension of secondary alcohol (53) (50 mg, 0.101 mmol), NaH (25 mg, 60% dispersion in mineral oil) in DMF (5 mL) was stirred at room temperature. After 1 hr, the reaction mixture was added MeI (20 μL, 0.33 mmol) and stirred for 12 hrs. The reaction mixture was filtered off the white solid and then extracted with EtOAc (50 mL). The organic extract was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: Hexane/EtOAc=2/1) provided 42 mg (82%) of desired product (54) as solid.
1H NMR (400 MHz, CDCl3) δ 7.41-7.40 (m, 1H), 7.30-7.22 (m, 6H), 5.27 (q, J=6.4 Hz, 1H), 3.27 (s, 3H), 1.50 (s, 9H), 1.39 (d, J=6.8 Hz, 3H).
MH+ 505.
To the solution of secondary alcohol (53) (50 mg, 0.093 mmol) and Burgess reagent (45 mg, 0.186 mmol) in THF (5 mL) was irradiated in a microwave reactor (Biotage) for 10 minutes at 150° C. The organic extract was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: hexane/EtOAc=4/1) provided 15 mg (55, 31%) and 16 mg (56, 29%) as solid.
1H NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.34-7.28 (m, 4H), 7.20-7.18 (m, 2H), 7.12-7.04 (m, 1H), 5.41 (dd, J=18.0, 1.2 Hz, 1H), 5.25 (dd, J=11.6, 1.2 Hz, 1H), 1.50 (s, 9H).
MH+ 473.
1H NMR (400 MHz, CDCl3) δ 7.48-7.44 (m, 2H), 7.42-7.40 (m, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.29 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.13-7.09 (m, 2H), 7.07-7.02 (m, 1H), 5.40 (dd, J=18.0, 1.2 Hz, 1H), 5.13 (dd, J=11.6, 1.2 Hz, 1H), 1.49 (s, 9H).
MH+ 517.
1H NMR (400 MHz, CDCl3) δ 7.42-7.39 (m, 3H), 7.38-7.23 (m, 6H), 7.16 (d, J=8.8 Hz, 2H), 7.01-6.84 (m, 1H), 5.39 (d, J=18 Hz, 1H), 5.22 (d, J=12 Hz, 1H), 1.81-1.77 (m, 2H), 1.50-1.42 (m, 2H).
MH+ 569.
1H NMR (400 MHz, CDCl3) δ 7.51-7.49 (m, 2H), 7.47-7.44 (m, 1H), 7.41-7.40 (m, 1H), 7.31-7.29 (m, 2H), 7.23-7.21 (m, 1H), 5.10-4.90 (m, 1H), 3.62 (s, 3H), 1.54 (s, 3H), 1.50 (s, 9H).
MH+ 592.
1H NMR (400 MHz, CDCl3) δ 7.44-7.40 (m, 3H), 7.36-7.33 (m, 4H), 7.31-7.27 (m, 4H), 5.0-4.94 (m, 1H), 3.60 (s, 3H), 1.85-1.74 (m, 2H), 1.50-1.40 (m, 4H).
MH+ 644.
1H NMR (400 MHz, CDCl3) δ 7.44-7.41 (m, 1H), 7.38-7.27 (m, 6H), 6.86-6.78 (m, 1H), 4.41 (d, J=6.8 Hz, 2H), 3.60 (s, 3H), 1.50 (s, 9H).
MH+ 536.
To the solution of bromide (33) (150 mg, 0.277 mmol) in DMF (5 mL) was added phenol (40 mg, 0.415 mmol), Cs2CO3 (202 mg, 0.622 mmol). The reaction mixture was refluxed for 12 hrs at room temperature. Reaction mixture was filtered off the white solid and then extracted with EtOAc (50 mL). The organic extract was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: hexane/EtOAc=5/1) provided 86 mg (56%) of desired ether (45) as solid.
1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=2.0 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.33 (dd, J=8.4, 2.0 Hz, 1H), 7.30-7.22 (m, 6H), 6.97-6.95 (m, 3H), 5.27 (s, 2H), 1.44 (s, 9H).
MH+ 553.
1H NMR (400 MHz, CDCl3) δ 8.11-8.09 (m, 1H), 7.56-7.53 (m, 1H), 7.44-7.41 (m, 2H), 7.34-7.32 (m, 1H), 7.28-7.19 (m, 4H), 6.88-6.86 (m, 1H), 6.73-6.71 (m, 1H), 5.52 (s, 2H), 1.52 (s, 9H).
MH+ 554.
1H NMR (400 MHz, CDCl3) δ 7.42-7.30 (m, 5H), 7.14-7.08 (m, 2H), 3.29 (t, J=6.6 Hz, 2H), 2.45 (s, 3H), 1.74 (s, 6H), 1.53 (m, 2H), 0.87 (t, J=7.2 Hz, 3H).
MH+ 505.
1H NMR (400 MHz, CDCl3) δ 7.42 (br d, J=2.0 Hz, 2H), 7.39-7.26 (m, 9H), 7.14-7.10 (m, 2H), 4.75 (dd, J=6.0, 8.0 Hz, 1H), 4.66 (d, J=11.6 Hz, 1H), 4.49 (d, J=11.6 Hz, 1H), 2.46 (s, 3H), 2.09 (m, 1H), 1.97 (m, 1H), 1.48 (m, 1H), 1.31 (m, 3H), 0.87 (t, J=7.2 Hz, 3H).
MH+ 581.
1H NMR (400 MHz, CDCl3) δ 7.42 (br d, J=2.0 Hz, 1H), 7.40-7.31 (m, 4H), 7.13-7.10 (m, 2H), 5.86 (m, 1H), 5.26 (br d, J=17.2 Hz, 1H), 5.10 (br d, J=10.4 Hz, 1H), 3.92 (dt, J=5.2, 1.6 Hz, 2H), 2.45 (s, 3H), 1.77 (s, 6H).
MH+ 503.
1H NMR (400 MHz, CDCl3) δ 7.43-7.22 (m, 5H), 7.01-6.98 (m, 2H), 5.79 (m, 1H), 5.17 (dd, J=17.2, 1.4 Hz, 1H), 5.03 (dd, J=10.4, 1.4 Hz, 1H), 3.86 (d, J=6.8 Hz, 2H), 2.78 (q, J=7.6 Hz, 2H), 1.70 (s, 6H), 1.16 (t, J=7.6 Hz, 3H).
MH+ 561.
1H NMR (400 MHz, CDCl3) δ 7.35-7.22 (m, 5H), 7.08-7.04 (m, 2H), 5.79 (m, 1H), 5.17 (dd, J=17.2, 1.4 Hz, 1H), 5.03 (dd, J=10.4, 1.4 Hz, 1H), 3.86 (d, J=6.8 Hz, 2H), 2.78 (q, J=7.6 Hz, 2H), 1.70 (s, 6H), 1.16 (t, J=7.6 Hz, 3H).
MH+ 517.
MH+ 580.
1H NMR (400 MHz, CDCl3) δ 7.42-7.26 (m, 5H), 7.14-7.10 (m, 2H), 4.75 (dd, J=6.0, 8.0 Hz, 1H), 2.46 (s, 3H), 2.09 (m, 1H), 1.97 (m, 1H), 1.48 (m, 1H), 1.31 (m, 3H), 0.87 (t, J=7.2 Hz, 3H).
MH+ 491.
MH+ 556.
1H NMR (400 MHz, CDCl3) δ 7.40 (br d, J=2.0 Hz), 7.37-7.29 (m, 4H), 7.12-7.09 (m, 2H), 3.31 (t, J=6.8 Hz, 2H), 2.43 (s, 3H), 1.72 (s, 6H), 1.49 (m, 2H), 1.31 (m, 2H), 0.84 (t, J=7.2 Hz, 3H).
MH+ 519.
1H NMR (400 MHz, CDCl3) δ 7.40 (br d, J=2.0 Hz, 1H), 7.38-7.30 (m, 4H), 7.10 (m, 2H), 3.30 (t, J=6.8 Hz, 2H), 2.44 (s, 3H), 1.72 (s, 6H), 1.50 (m, 2H), 1.25 (m, 4H), 0.83 (t, J=5.2 Hz, 3H).
MH+ 533.
1H NMR (400 MHz, CDCl3) δ 7.42 (br d, J=2.0 Hz, 1H), 7.37-7.20 (m, 9H), 7.10 (m, 2H), 4.43 (s, 2H), 2.43 (s, 3H), 1.83 (s, 6H).
MH+ 553.
1H NMR (400 MHz, CDCl3) δ 7.42-7.30 (s, 5H), 7.12-7.09 (m, 2H), 2.44 (s, 3H), 2.09 (s, 3H), 1.90 (s, 6H).
MH+ 505.
1H NMR (400 MHz, CDCl3) δ 7.43-7.31 (m, 5H), 7.13-7.10 (m, 2H), 2.45 (s, 3H), 1.77 (s, 6H).
MH+ 463.
1H NMR (400 MHz, CDCl3) δ 7.46-7.18 (m, 7H), 7.12-6.94 (m, 4H), 4.51 (s, 2H), 2.43 (s, 3H), 1.83 (s, 6H).
MH+ 571.
1H NMR (400 MHz, CDCl3) δ 7.42-7.22 (m, 6H), 7.20-7.09 (m, 5H), 4.42 (s, 2H), 2.43 (s, 3H), 1.82 (s, 6H).
MH+ 587.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=2.0 Hz, 1H), 7.36-7.30 (m, 4H), 7.11 (m, 2H), 4.53 (q, J=7.2 Hz, 2H), 2.47 (s, 3H), 1.45 (t, J=7.2 Hz, 3H).
MH+ 477.
1H NMR (400 MHz, CDCl3) δ 7.58 (m, 2H), 7.44-7.29 (m, 8H), 7.10 (m, 2H), 3.49 (s, 3H), 2.44 (s, 3H).
MH+ 593.
1H NMR (400 MHz, CDCl3) δ 7.42-7.31 (m, 5H), 7.12-7.10 (m, 2H), 4.32 (s, 2H), 2.44 (s, 3H), 1.52 (s, 6H).
MH+ 519.
1H NMR (400 MHz, CDCl3) δ 7.44-7.32 (m, 5H), 7.14-7.13 (m, 2H), 3.85 (s, 2H), 2.45 (s, 3H), 1.47 (s, 6H).
MH+ 477.
1H NMR (300 MHz, CDCl3) δ 7.43-7.23 (m, 9H), 7.17-7.04 (m, 3H), 5.11 (s, 2H), 3.93 (s, 2H), 2.12 (s, 3H), 1.21 (s, 6H).
MH+ 567.
1H NMR (400 MHz, CDCl3) δ 7.59-7.31 (m, 9H), 7.13-7.10 (m, 2H), 4.58 (s, 2H), 3.70 (s, 2H), 2.42 (s, 3H), 1.53 (s, 6H).
MH+ 635.
1H NMR (400 MHz, CDCl3) δ 7.44-7.32 (m, 5H), 7.24-7.11 (m, 6H), 4.48 (s, 2H), 3.60 (s, 2H), 2.42 (s, 3H), 1.51 (s, 6H).
MH+ 601.
The experimental procedure was followed by the method of Bruno P. Imbimbo et al [J. Med. Chem. 2005, 48, 5707-7520]. A solution of 3-chlorobenzylbromide (5 g, 24.3 mmol) and sodium cyanide (1.3 g, 26.8 mmol) in ethanol (50 ml) was heated to 80° C. for 2 hours. After resulting solution was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in water and organic layer was extracted with ethyl acetate. The solution was evaporated and crude compound was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to yield 2-(3-chlorophenyl)acetonitrile (3.2 g, 87% yield) as colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.36-7.32 (m, 1H), 7.20-7.17 (m, 3H), 7.06-7.04 (m, 1H), 3.68 (s, 2H).
To a solution of 2-(3-chlorophenyl)acetonitrile (3.2 g, 21 mmol) and 1,2-dibromoethane (3 mL, 35 mmol) in toluene (20 ml), 35% sodium hydroxide and tetrabutylammonium iodide (400 mg, 1.3 mmol) were added. The mixture was vigorously stirred at room temperature for 4 hours. The resulting solution was diluted with water and extracted with ethyl acetate. The organic solution was concentrated to afford brown oil. Chromatography on silica gel (hexane/ethyl acetate=5/1) afforded 1-(3-chlorophenyl)cyclopropanecarbonitrile (2.1 g, 56% yield) as light yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.38-7.34 (m, 1H), 7.21-7.18 (m, 3H), 7.07-7.03 (m, 1H), 0.98-0.96 (m, 2H), 0.74-0.72 (m, 2H).
To a solution of 1-(3-chlorophenyl)cyclopropanecarbonitrile (2.1 g, 11.8 mmol) in methanol (10 ml), 35% NaOH (40 ml) was added and the mixture was heated to 100° C. for 8 hours. After cooling to room temperature, the resulting solution was evaporated under reduced pressure. And the aqueous layer was washed with ethyl ether, acidified with 2N HCl, and extracted organic layer with ethyl acetate. The organic solution was dried over magnesium sulfate, evaporated volatile solvent and dried under vacuum to obtain 1-(3-chlorophenyl)cyclopropanecarboxylic acid (1.8 g, 77% yield) as white solid.
1H NMR (400 MHz, CDCl3) δ 7.55-7.48 (m, 4H), 7.33-7.31 (m, 2H), 7.25-7.17 (m, 3H), 7.14-7.11 (m, 3H), 2.35 (s, 3H), 1.86-1.84 (m, 2H), 1.34-1.29 (m, 2H).
MH+ 555.
1H NMR (400 MHz, CDCl3) δ 7.56-7.48 (m, 4H), 7.33-7.32 (m, 2H), 7.25-7.19 (m, 3H), 7.13-7.10 (m, 3H), 2.85 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H).
MH+ 569.
The experimental procedure was followed by the method of Henryk Krawczyk et al [Synlett 2005, 17, 2648-2652]. A solution of -diethoxyphosphoryl-lactone (5 g, 22.5 mmol) in THF (10 ml) was added dropwise under nitrogen atmosphere at −78° C. to a stirred solution of LDA (13.7 ml, 1.8 M in tetrahydrofuran/heptane/ethylbenzene, 24.8 mmol). When the addition was completed the reaction mixture was warmed to 0° C. and stirred for 30 minutes. The reaction mixture was cooled down to −78° C. and ally bromide (2.45 ml, 18.7 mmol) was added. The stirring was continued for 1 hour at this temperature and then the reaction mixture was warmed to room temperature and stirred for overnight. The mixture was quenched and acidified using 1N HCl solution and extracted with methylenechloride (30 ml twice). The crude products was purified by column chromatography (silica gel, acetone/methylenechloride=1/5) to produce diethyl 3-allyl-2-oxotetrahydrofuran-3-ylphosphonate (4.5 g, 76%) as colorless oil.
1H NMR (400 MHz, CDCl3) δ 5.71-5.70 (m, 1H), 5.03-4.97 (m, 2H), 4.35-4.25 (m, 2H), 4.08-4.06 (m, 6H), 2.40-2.38 (m, 1H), 2.32-2.30 (m, 2H), 1.97-1.95 (m, 1H), 1.13-1.10 (m, 9H).
To a suspension of sodium hydride (686 mg, 60% in mineral oil, 17.2 mmol) and diethyl 3-allyl-2-oxotetrahydrofuran-3-ylphosphonate (4.5 g, 17.2 mmol) in THF (15 ml) was added dropwise under nitrogen atmosphere at room temperature a solution of ethanol (1.1 ml, 18.9 mmol) in THF (5 ml). The reaction mixture was stirred for 30 minutes and then was heated at reflux for 10 hours. After cooling to room temperature saturated ammonium chloride was added and extracted organic layer with ethyl ether. The residue was dried with magnesium sulfate. Without further purification, the ester was hydrolyzed with sodium hydroxide (1.4 g, 34 mmol) in aqueous acetonitrile (20 ml) at 60° C. for overnight. The reaction mixture was cooled down to room temperature. After acidification of the resulting solution with 1H HCl, organic layer was extracted with ethyl ether. The solution was dried with magnesium sulfate, and then it was evaporated under reduced pressure. Product was dried under vacuum to produce crude title compound (1.4 g, 65% yield) as light yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.57-7.47 (m, 4H), 7.34-7.32 (m, 2H), 7.26-7.19 (m, 3H), 7.14-7.10 (m, 3H), 5.71-5.68 (m, 1H), 5.03-4.97 (m, 2H), 2.85 (q, J=7.6 Hz, 2H), 2.23-2.20 (m, 2H), 1.23 (t, J=7.6 Hz, 3H), 0.84 (dd, J=4.4, 6.8 Hz, 2H), 0.43 (dd, J=4.4.68 Hz, 2H).
MH+ 543.
To a solution of carbontetrabromide (313 mg, 0.94 mmol) in methylene chloride (15 ml) at 0° C. was added triphenylphosphine (248 mg, 0.95 mmol). The reaction mixture was stirred at 0° C. for 10 minutes and then 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carbaldehyde (300 mg, 0.63 mmol) in methylenechloride (10 ml) was added slowly. The reaction temperature was warmed slowly to room temperature and stirred overnight. The resulting solution was quenched with saturated ammonium chloride and extracted organic layer with ethyl ether (50 ml twice). After evaporation, crude residue was purified with silica gel column (hexane/ethyl acetate=5/1) to recover starting material (110 mg, 37%) and produce 2-tert-butyl-5-(5-(4-chlorophenyl)-4-(2,2-dibromovinyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazole (230 mg, 58% yield) as white solid.
1H NMR (400 MHz, CDCl3) δ 7.51-7.48 (m, 1H), 7.47 (s, 1H), 7.36-7.32 (m, 2H), 7.30-7.28 (m, 1H), 7.18 (d, J=8.68 Hz, 1H), 7.14-7.10 (m, 2H), 1.34 (s, 9H).
MH+ 631.
To a solution of 2-tert-butyl-5-(5-(4-chlorophenyl)-4-(2,2-dibromovinyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazole (230 mg, 0.36 mmol) in tetrahydrofuran (10 ml) at 78° C., potassium bis(trimethysilyl)amide (1.46 ml, 0.5 M solution in tetahydrofuran, 0.73 mmol) was added slowly. After stirring for 20 minutes at 78° C., the resulting solution was quenched with saturated ammonium chloride (5 ml). After warming up to room temperature, the solution was diluted with ethyl ether, and then the organic layer was extracted with ethyl acetate (50 ml twice). After evaporation, crude residue was purified with silica gel column (hexane/ethyl acetate=5/1) to obtain title compound (150 mg, 91% yield) as light yellow solid.
1H NMR (400 MHz, CDCl3) δ 7.54-7.49 (m, 2H), 7.34-7.31 (m, 2H), 7.20-7.17 (m, 1H), 7.15-7.11 (m, 2H), 3.06 (s, 1H), 1.35 (s, 9H).
MH+ 471.
To a solution of 2-tert-butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-ethynyl-1H-pyrazol-3-yl)-1,3,4-oxadiazole (100 mg, 0.21 mmol) in tetrahydrofuran (15 ml) at 78° C., lithium bis(trimethylsilyl)amide (0.23 ml, 1.0 M solution in tetrahydrofuran, 0.23 mmol) was added slowly not to warm up the reaction solution. After stirring at 78° C. for 10 minutes, iodomethane (0.04 ml, 0.7 mmol) was added quickly. The resulting solution was stirred for 20 minutes, and then it was warmed up to room temperature slowly. After quenching with saturated ammonium solution, the organic layer was separated with ethyl acetate. The organic solution was evaporated in reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1 to hexane/ethyl acetate=5/1) to produce title compound (13 mg, 13% yield) as light yellow solid.
1H NMR (400 MHz, CDCl3) δ 7.55-7.49 (m, 2H), 7.35-7.31 (m, 2H), 7.21-7.17 (m, 1H), 7.16-7.11 (m, 2H), 1.89 (s, 1H), 1.35 (s, 9H).
MH+ 485.
1H NMR (400 MHz, CDCl3) δ 7.56-7.44 (m, 4H), 7.34-7.32 (m, 2H), 7.27-7.20 (m, 3H), 7.15-7.10 (m, 3H), 2.91 (q, J=7.8 Hz, 2H), 2.23-2.20 (m, 2H), 1.57-1.53 (m, 2H), 1.33-1.30 (m, 2H), 1.27 (t, J=7.8 Hz, 3H), 0.98 (t, J=7.4 Hz, 3H), 0.86-0.82 (m, 2H), 0.45-0.41 (m, 2H).
MH+ 545.
To a solution of ethylyltrimethylsilane (0.26 ml, 1.85 mmol) in tetrahydrofuran (10 ml) at 78° C. was added butyllithium (0.74 ml, 2.5 M in hexane, 1.85 mmol) slowly. The reaction mixture was stirred at 78° C. for 10 minutes and then 2-(4-(bromomethyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-5-tert-butyl-1,3,4-oxadiazole (500 mg, 0.92 mmol) in tetrahydrofuran (5 ml) was added slowly at 78° C. The reaction temperature was warmed slowly to room temperature for 5 hours and stirred 1 hour at room temperature. The resulting solution was quenched with saturated ammonium chloride and extracted organic layer with ethyl acetate (50 ml twice). After evaporation, crude residue was purified with silica gel column (hexane/ethyl acetate=5/1) to produce 2-tert-butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(3-(trimethylsilyl)prop-2-ynyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazole (370 mg, 72% yield) as white solid.
1H NMR (400 MHz, CDCl3) δ 7.54-7.49 (m, 2H), 7.33-7.31 (m, 2H), 7.20-7.17 (m, 1H), 7.14-7.11 (m, 2H), 4.00 (s, 2H), 1.57 (s, 9H), 0.11 (s, 9H).
MH+ 559.
To a solution of 2-tert-butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(3-(trimethylsilyl)prop-2-ynyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazole (300 mg, 0.46 mmol) in tetrahydrofuran (5 ml) at 0° C. was added tetrabutylammonium fluoride (0.7 ml, 1.0 M in tetrahydrofuran, 0.7 mmol). After reaction mixture was warmed up to room temperature, it was stirred for 10 minutes. After the resulting solution was diluted with ether (20 ml), water was added (10 ml). Organic layer was separated with ethyl acetate (20 ml twice). After evaporation, crude residue was purified with silica gel column (hexane/ethyl acetate=7/1 to hexane/ethyl acetate 5/1). The less polar compound 2-tert-butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(propa-1,2-dienyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazole was obtained as light yellow solid (87 mg, 34% yield). And relatively more polar compound 2-tert-butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(prop-2-ynyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazole was produced as yellow solid (140 mg, 54% yield).
1H NMR (400 MHz, CDCl3) δ 7.41-7.40 (dd, J=0.4, 2.4 Hz, 1H), 7.34-7.32 (m, 1H), 7.30-7.25 (m, 3H), 7.18-7.16 (m, 2H), 6.83 (t, J=7.2 Hz, 1H), 4.59 (d, J=6.8 Hz, 2H), 1.49 (s, 9H).
MH+ 485.
1H NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 2H), 7.35-7.32 (m, 2H), 7.29-7.26 (m, 3H), 3.02-2.93 (m, 2H), 1.49 (s, 9H), 1.51 (m, 1H).
MH+ 485.
1H NMR (400 MHz, CDCl3) δ 7.49-7.41 (m, 3H), 7.36-7.30 (m, 2H), 7.07-7.04 (m, 2H), 2.84 (q, J=7.6 Hz, 2H), 2.03-1.95 (m, 2H), 1.94-1.91 (m, 2H), 1.21 (t, J=7.6 Hz, 3H).
MH+ 528.
1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J=0.4, 2.4 Hz, 1H), 7.36-7.30 (m, 4H), 7.12-7.08 (m, 2H), 2.42 (s, 3H), 2.03-1.90 (m, 4H).
MH+ 470.
1H NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.34-7.27 (m, 4H), 7.14-7.10 (m, 2H), 2.86 (q, J=10.0 Hz, 2H), 1.97 (dd, J=4.6, 2.7 Hz, 2H), 1.04 (dd, J=4.6, 2.7 Hz, 2H), 1.21 (t, J=10.0, 3H).
MH+ 484.
1H NMR (400 MHz, CDCl3) δ 8.45 (m, 1H), 7.43-7.40 (m, 3H), 7.34-7.31 (m, 4H), 7.20-7.18 (m, 1H), 7.12-7.08 (m, 2H), 2.43 (s, 3H), 2.02-1.92 (m, 4H).
MH+ 523.
A solution of cyclopropyl cyanide (2 g, 30 mmol) in THF (30 ml) was added dropwise under nitrogen atmosphere at −78° C. to a stirred solution of LDA (18 ml, 1.8 M in tetrahydrofuran/heptane/ethylbenzene, 33 mmol). The reaction mixture was stirred 20 minutes at −78° C. and then benzylbromide (7 ml, 60 mmol) in tetrahydrofuran (20 ml) was added at −78° C. After stirring for 30 minutes, the reaction mixture was warmed to room temperature. The stirring was continued for 3 hours at this temperature and then the mixture was quenched using saturated ammonium chloride solution and extracted with ethyl ether. The organic solution was dried with magnesium sulfate. Without further purification, the nitrile compound was hydrolyzed with 35% aqueous sodium hydroxide solution (20 ml) in methanol (30 ml) at 100° C. for 8 hours. After reaction complete, methanol was evaporated under reduced pressure. After washing aqueous solution with diethyl ether (30 ml twice), resulting solution was acidified using 3N HCl. With diethyl ether, the organic phase was worked-up and evaporated under reduced pressure to obtained the title compound (3.2 g, 61%) as light yellow solid.
1H NMR (400 MHz, CDCl3) δ 7.35-7.17 (m, 5H), 2.98 (s, 2H), 1.34 (dd, J=4, 6.8 Hz, 2H), 0.87 (dd, J=4.0, 6.8 Hz, 2H).
1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=2 Hz, 1H), 7.35-7.26 (m, 6H), 7.21-7.17 (m, 3H), 7.09-7.07 (m, 2H), 3.22 (s, 2H), 2.38 (s, 3H), 1.44-1.41 (m, 2H), 1.07-1.04 (m, 2H).
MH+ 535.
1H NMR (400 MHz, CDCl3) δ 7.48-7.44 (m, 2H), 7.41 (d, J=2 Hz, 1H), 7.37-7.25 (m, 5H), 7.23-7.17 (m, 2H), 7.05-7.02 (m, 2H), 3.31 (s, 2H), 2.81 (q, J=7.6 Hz, 2H), 1.44-1.41 (m 2H), 1.96 (t, J=7.6 Hz, 3H), 1.06-1.05 (m, 2H).
MH+ 551.
1H NMR (400 MHz, CDCl3) δ 7.44-7.42 (m, 1H), 7.34-7.30 (m, 6H), 7.20-7.11 (m, 4H), 2.86 (q, J=9.9 Hz, 2H), 2.12 (dd, J=9.3, 6.1, 2H), 1.98 (dd, J=9.3, 6.1, 2H), 1.26 (t, J=9.9 Hz, 3H).
MH+ 597.
1H NMR (400 MHz, CDCl3) δ 7.47-7.44 (m, 2H), 7.40 (d, J=2.1 Hz, 1H), 7.37-7.31 (m, 2H), 7.30 (d, J=2.4 Hz, 1H), 7.27-7.23 (m, 4H), 7.05-7.03 (m, 2H), 2.77 (q, J=7.7 Hz, 2H), 1.94 (dd, J=9.2, 6.2 Hz, 2H), 1.46 (dd, J=9.2, 6.2 Hz, 2H), 1.19 (t, J=7.7 Hz, 3H).
MH+ 615.
1H NMR (400 MHz, CDCl3) δ 7.48-7.45 (m, 3H), 7.38-7.35 (m, 2H), 7.29-7.22 (m, 4H), 7.04-7.01 (m, 2H), 2.23 (s, 3H), 1.92 (dd, J=9.2, 6.7 Hz, 2H), 1.51 (dd, J=9.2, 6.7 Hz, 2H).
MH+ 539.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2 Hz, 2H), 7.36 (d, J=8.4 Hz, 1H), 7.33-7.23 (m, 3H), 7.11-7.08 (m, 2H), 2.41 (s, 3H), 1.61 (s, 3H), 1.42-1.40 (m, 2H), 0.97-0.94 (m, 2H).
MH+ 459.
1H NMR (400 MHz, CDCl3) δ 7.47-7.45 (m, 2H), 7.40 (d, J=3.6 Hz, 1H), 7.35-7.27 (m, 2H), 7.06-7.04 (m, 2H), 2.83 (q, J=7.6 Hz, 2H), 1.62 (s, 3H), 1.45-1.42 (m, 2H), 1.22 (t, J=7.6 Hz, 3H), 0.96-0.95 (m, 2H).
MH+ 517.
1H NMR (400 MHz, CDCl3) δ 7.44-7.42 (m, 1H), 7.34-7.31 (m, 4H), 7.14-7.10 (m, 2H), 2.45 (s, 3H), 1.90 (q, J=9.7 Hz, 2H), 1.39 (dd, J=9.3, 6.2 Hz, 2H), 1.11 (t, J=9.7 Hz, 3H), 1.06 (dd, J=9.3, 6.2 Hz).
MH+ 473.
1H NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.34-7.29 (m, 4H), 7.16-7.11 (m, 2H), 2.89 (q, J=9.8 Hz, 2H), 1.90 (q, J=9.6 Hz, 2H), 1.38 (dd, J=9.3, 6.2 Hz, 2H), 1.27 (t, J=9.8 Hz, 3H), 1.03 (t, J=9.6 Hz, 3H), 1.01 (dd, J=9.3, 6.2 Hz).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.44-7.42 (m, 1H), 7.33-7.30 (m, 4H), 7.14-7.11 (m, 2H), 2.91 (q, J=9.8 Hz, 2H), 1.91 (q, J=9.6 Hz, 2H), 1.36 (dd, J=9.3, 6.2 Hz, 2H), 1.27 (t, J=9.8 Hz, 3H), 1.03 (t, J=9.6 Hz, 3H), 1.01 (dd, J=9.3, 6.2 Hz).
MH+ 531.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.4 Hz, 1H), 7.34-7.28 (m, 4H), 7.23-7.20 (m, 3H), 7.10-7.07 (m, 2H), 3.24 (s, 2H), 2.39 (s, 3H), 1.45 (dd, J=2, 6.8 Hz, 2H), 1.07 (dd, J=2, 6.8 Hz, 2H).
MH+ 571.
1H NMR (400 MHz, CDCl3) δ 7.51-7.45 (m, 2H), 7.40 (d, J=2 Hz, 1H), 7.34-7.26 (m, 3H), 7.23-7.20 (m, 3H), 7.05-6.96 (m, 2H), 3.24 (s, 2H), 2.80 (q, J=7.6 Hz, 2H), 1.46 (dd, J=5.2, 7.2 Hz, 2H), 1.25 (t, J=7.6 Hz, 3H), 1.06 (dd, J=4.8, 6.8 Hz, 2H).
MH+ 629.
1H NMR (400 MHz, CDCl3) δ 7.46-7.38 (m, 2H), 7.34-7.27 (m, 5H), 7.16-7.06 (m, 4H), 2.74 (q, J=7.6 Hz, 2H), 1.89-1.82 (m, 2H), 1.51-1.45 (m, 2H), 1.12 (t, J=7.2 Hz, 3H).
MH+ 553.
1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.4 HZ, 1H), 7.32-7.27 (m, 3H), 7.13-7.09 (m, 2H), 2.84 (q, J=7.6 Hz, 2H), 1.61 (s, 3H), 1.40 (dd, J=4.4, 6.8 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H), 0.95 (dd, J=4.4, 6.8 Hz, 2H).
MH+ 473.
MH+ 513.
MH+ 557.
1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J=0.4, 2.4 Hz, 1H), 7.36-7.30 (m, 4H), 7.13-7.09 (m, 2H), 2.46 (s, 3H), 2.35 (s, 3H), 1.78 (dd, J=4.8, 8.4 Hz, 2H), 1.66 (dd, J=4.8, 8.4 Hz, 2H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.0, 1H), 7.35-7.28 (m, 4H), 7.10-7.08 (m, 2H), 2.42 (s, 3H), 1.39 (s, 6H), 1.33-1.30 (m, 2H), 1.27-1.23 (m, 2H).
MH+ 503.
1H NMR (400 MHz, CDCl3) δ 7.41-7.41 (m, 1H), 7.35-7.29 (m, 4H), 7.12-7.08 (m, 2H), 3.86 (q, J=6.4 Hz, 1H), 2.42 (s, 3H), 1.38 (d, J=6.4 Hz, 3H), 1.33-1.30 (m, 2H), 1.27-1.23 (m, 2H).
MH+ 489.
MH+ 491.
To the suspension of bromide (33) (150 mg, 0.28 mmol) in CH3CN (5 mL) was added N-ethylmethylamine (30 μL, 0.33 mmol) and DIPEA (63 μL, 0.36 mmol). The reaction mixture was stirred for 12 hrs at room temperature. H2O (25 mL) was added to the reaction mixture and then extracted with EtOAc (50 mL). The organic extract was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by Prep-LC (Gilson) provided 83 mg (58%) of desired amine as solid.
1H NMR (400 MHz, CDCl3) δ 7.42-7.27 (m, 7H), 3.78 (s, 2H), 2.51-2.43 (m, 2H), 2.13 (s, 3H), 1.51 (s, 9H), 0.99 (t, J=6.8 Hz, 3H).
MH+ 518.
1H NMR (400 MHz, CDCl3) δ 7.44-7.26 (m, 7H), 3.58 (s, 2H), 2.38 (br s, 4H), 1.60-1.45 (m, 15H).
MH+ 546.
1H NMR (400 MHz, CDCl3) δ 7.45-7.29 (m, 7H), 4.91 (s, 2H), 3.60-3.49 (m, 4H), 1.99-1.90 (m, 4H), 1.51 (s, 9H).
MH+ 532.
1H NMR (400 MHz, CDCl3) δ 7.43-7.41 (m, 1H), 7.38-7.27 (m, 4H), 6.98-6.81 (m, 2H), 4.92 (s, 2H), 3.77-3.51 (m, 8H), 2.51-2.39 (m, 8H), 1.50 (s, 9H).
MH+ 548.
1H NMR (400 MHz, CDCl3) δ 7.47-7.28 (m, 7H), 4.01 (s, 2H), 3.03 (s, 1H), 1.51 (s, 9H), 1.10 (s, 9H).
MH+ 534.
1H NMR (400 MHz, CDCl3) δ 7.43-7.31 (m, 7H), 3.95 (s, 2H), 3.20-3.07 (m, 1H), 1.51 (s, 9H), 1.05 (s, 6H).
MH+ 518.
NaH (15 mg, 0.36 mmol, 60% dispersion in mineral oil) was added to the solution of 1,2,4-triazole (23 mg, 0.33 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred for 30 min at 0° C. The solution of bromide (33) (150 mg, 0.28 mmol) in THF (5 mL) was added to the reaction mixture. The reaction mixture was warmed up to room temperature and stirred for 12 hrs at room temperature. H2O (25 mL) was added to the reaction mixture and then extracted with EtOAc (50 mL). The organic extract was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by Prep-LC (Gilson) provided 70 mg (47%) of desired product as solid.
1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.99 (s, 1H), 7.49-7.44 (m, 3H), 7.49-7.29 (m, 4H), 5.59 (s, 2H), 1.48 (s, 9H).
MH+ 530.
1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.43-7.33 (m, 5H), 7.10-7.05 (m, 2H), 7.01 (t, J=6.8 Hz, 1H), 6.92 (t, J=1.2 Hz, 1H), 5.47 (s, 2H), 1.49 (s, 9H).
MH+ 527.
1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=2.0 Hz, 1H), 7.49-7.47 (m, 1H), 7.42-7.28 (m, 7H), 6.18 (t, J=2.0 Hz, 1H), 5.54 (s, 2H), 1.47 (s, 9H).
MH+ 527.
1H NMR (400 MHz, CDCl3) δ 7.45-7.27 (m, 7H), 6.45-6.39 (m, 2H), 5.92-5.85 (m, 2H), 5.53 (s, 2H), 1.51 (s, 9H).
MH+ 528.
1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.44-7.43 (m, 1H), 7.36 (d, J=0.4 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.31-7.27 (m, 2H), 7.16-7.13 (m, 2H), 6.07 (s, 2H), 1.47 (s, 9H).
MH+ 531.
1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 7.46-7.29 (m, 7H), 5.777 (s, 2H), 1.49 (s, 9H).
MH+ 531.
1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.49-7.31 (m, 5H), 7.09-7.03 (m, 2H), 6.07 (s, 2H), 1.47 (s, 9H).
MH+ 573.
1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 7.52-7.31 (m, 7H), 5.77 (s, 2H), 1.48 (s, 9H).
MH+ 573.
1H NMR (400 MHz, CDCl3) δ 8.21 (d, J=1.2 Hz, 1H), 7.66 (d, J=0.8 Hz, 1H), 7.44 (dd, J=1.6 Hz, 0.8 Hz, 1H), 7.42-7.29 (m, 6H), 5.76 (s, 2H), 1.48 (s, 9H).
MH+ 530.
To the suspension of bromide (33) (150 mg, 0.28 mmol) in acetone (10 mL) was added succimide (35 mg, 0.33 mmol) and K2CO3 (60 mg, 0.42 mmol). The reaction mixture was refluxed for 12 hrs and cooled to room temperature. H2O (25 mL) was added to the reaction mixture and then extracted with EtOAc (50 mL). The organic extract was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by Prep-LC (Gilson) provided 99 mg (64%) of desired product as solid.
1H NMR (400 MHz, CDCl3) δ 7.36-7.16 (m, 7H), 4.99 (s, 2H), 2.33 (s, 4H), 1.47 (s, 9H).
MH+ 560.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=2.0 Hz, 1H), 7.36-7.27 (m, 4H), 7.13-7.09 (m, 2H), 4.87 (s, 2H), 3.26 (t, J=6.8 Hz, 2H), 2.12 (t, J=8.0 Hz, 2H), 1.68-1.65 (m, 2H), 1.50 (s, 9H).
MH+ 544.
1H NMR (400 MHz, CDCl3) δ 7.45-7.41 (m, 1H), 7.37-7.28 (m, 4H), 7.18-7.15 (m, 2H), 4.75 (s, 2H), 4.13 (t, J=8.0 Hz, 2H), 3.62 (t, J=8.0 Hz, 2H), 1.50 (s, 9H).
MH+ 546.
To the solution of bromide (33) (150 mg, 0.28 mmol) in DMF (3 mL) was added KSAc (48 mg, 0.42 mmol). The reaction mixture was refluxed for 12 hrs at room temperature. The reaction mixture was diluted with EtOAc (25 mL) and washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by Prep-LC (Gilson) provided 45 mg (30%) of desired thioacetate as solid.
1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=2.4 Hz, 1H), 7.38-7.26 (m, 5H), 7.16-7.12 (m, 2H), 4.40 (s, 2H), 2.26 (s, 3H), 1.49 (s, 9H).
MH+ 535.
To the solution of thioacetate (47) (337 mg, 0.63 mmol) in H2O/1,4-dioxane/THF (5 mL/5 mL/5 mL) was added NaOH (100 mg, 2.52 mmol). The reaction mixture was stirred for 12 hrs at room temperature. The reaction mixture was diluted with aq. saturated NH4Cl solution and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by normal phase column chromatography (Biotage) provided 93 mg (30%) of desired thiol as solid.
1H NMR (400 MHz, CDCl3) δ 7.42-7.37 (m, 2H), 7.34-7.27 (m, 3H), 7.25-7.21 (m, 2H), 4.03 (s, 2H), 3.69 (s, 1H), 1.48 (s, 9H).
MH+ 493.
To the solution of bromide (33) (1.0 g, 1.85 mmol) in CH3CN (20 mL) was added KCN (0.24 g, 3.70 mmol) and 18-crown-6 (0.20 g, 0.74 mmol). The reaction mixture was refluxed for 12 hrs. The reaction mixture was cooled to room temperature and diluted with brine. The aqueous layer was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by normal phase column chromatography (Biotage) provided 0.66 g (74%) of desired cyanide as solid.
1H NMR (400 MHz, CDCl3) δ 7.45-7.32 (m, 5H), 7.21-7.18 (m, 2H), 4.05 (s, 2H), 1.51 (s, 9H).
MH+ 488.
To the solution of bromide (33) (150 mg, 0.28 mmol) in DMF (3 mL) was added NaSMe (28 mg, 0.36 mmol). The reaction mixture was heated for 12 hrs at 100° C. and then cooled to room temperature. The reaction mixture was diluted with EtOAc (25 mL) and washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by Prep-LC (Gilson) provided 51 mg (35%) of desired disulfide as solid.
1H NMR (400 MHz, CDCl3) δ 7.34-7.26 (m, 5H), 7.19-7.16 (m, 1H), 7.15-7.10 (m, 1H), 4.03 (s, 2H), 2.47 (s, 3H), 2.08 (s, 3H), 1.49 (s, 9H).
MH+ 519.
NaH (0.37 g, 9.21 mmol, 60% dispersion in mineral oil) was added to the solution of 1,2,4-triazole (0.51 g, 7.37 mmol) in THF (30 mL) at 0° C. The reaction mixture was stirred for 1 hr at 0° C. The solution of bromide (61) (3 g, 6.14 mmol) in THF (15 mL) was added to the reaction mixture. The reaction mixture was warmed up to room temperature, stirred for 1 hr at room temperature and for 12 hrs at 45° C. The reaction mixture was cooled to room temperature. H2O (100 mL) was added to the reaction mixture and then extracted with EtOAc (150 mL). The organic extract was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (Biotage, Eluent: 12% EtOAc/Hexane→EtOAc (Gradient)) provided 1.35 g (46%) of desired triazole (62) as solid.
1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.09 (s, 1H), 7.41-7.27 (m, 7H), 5.48 (s, 2H), 4.44 (quartet, J=7.2 Hz, 2H), 1.398 (t, J=7.2 Hz, 3H).
MH+ 478.
To the solution of bromide (62) (500 mg, 1.05 mmol) in THF (5 mL)/H2O (15 mL) was added LiOH monohydrate (132 mg, 3.15 mmol). The reaction mixture was refluxed for 2 hrs and cooled to room temperature. The reaction mixture was acidified with aq. 1N HCl solution and extracted with 30% MeOH/CHCl3. The organic extract was dried over anhydrous MgSO4, filtered, concentrated and dried in vacuo to provide 470 mg (100%) of desired acid (63) as solid. The obtained acid was used without further purification.
To the solution of acid (63) (330 mg, 0.74 mmol) in CH2Cl2 (10 mL) was added oxalyl chloride (77 μL, 0.88 mmol) and the catalytic amount of DMF. The reaction mixture was stirred for 1 hr and concentrated in vacuo. The residue (crude acyl chloride) was diluted with CH2Cl2 (10 mL) and pivalohydrazide (128 mg, 1.10 mmol) and triethylamine (0.31 mL, 2.21 mmol) was added. The reaction mixture was stirred for 2 hrs at room temperature. The reaction mixture was concentrated in vacuo and diluted with EtOAc (50 mL). The organic layer was washed with aq. 1N HCl and aq. sat'd NaHCO3 solution, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by Prep-LC (Gilson) provided 244 mg (61%) of desired diamide as solid.
A solution of diamide (200 mg, 0.37 mmol) and Burgess reagent (217 mg, 0.91 mmol) in THF (3 mL) was irradiated in a microwave reactor (Biotage) for 1 hr at 160° C. Purification by Prep-LC (Gilson) provided 155 mg (79%) of desired oxadiazole as solid.
1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.99 (s, 1H), 7.46-7.28 (m, 11H), 5.54 (s, 2H), 1.78 (m, 2H), 1.47 (m, 2H).
MH+ 624.
1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.88 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.60 (dd, J=8.4 Hz, 2.4 Hz, 1H), 7.50-7.39 (m, 4H), 5.52 (s, 2H), 1.66 (s, 4H).
MH+ 582.
1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.89 (s, 1H), 7.88-7.80 (m, 2H), 7.59 (dd, J=8.4 Hz, 2.4 Hz, 1H), 7.50-7.39 (m, 4H), 5.53 (s, 2H), 3.95-3.89 (m, 1H), 2.47-2.30 (m, 4H), 2.15-1.87 (m, 2H).
MH+ 528.
1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.89 (s, 1H), 7.85-7.78 (m, 2H), 7.59 (dd, J=8.4 Hz, 2.4 Hz, 1H), 7.51-7.38 (m, 4H), 5.52 (s, 2H), 3.08-2.99 (m, 1H), 2.07-1.97 (m, 2H), 1.79-1.69 (m, 2H), 1.68-1.33 (m, 6H).
MH+ 556.
1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.94 (s, 1H), 7.89-7.78 (m, 2H), 7.60-7.55 (m, 1H), 7.48-7.26 (m, 8H), 5.52 (s, 2H), 1.69-1.64 (m, 2H), 1.55-1.47 (m, 2H).
MH+ 588.
1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.88 (s, 1H), 7.84-7.76 (m, 2H), 7.57 (dd, J=8.4 Hz, 2.4 Hz, 1H), 7.48-7.43 (m, 2H), 7.43-7.36 (m, 8H), 7.30-7.24 (m, 2H), 7.18-7.12 (m, 2H), 5.52 (s, 2H), 2.26 (s, 3H), 1.65-1.59 (m, 2H), 1.48-1.41 (m, 2H).
MH+ 603.
1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.88 (s, 1H), 7.85-7.74 (m, 2H), 7.57 (dd, J=8.4 Hz, 2.4 Hz, 1H), 7.50-7.29 (m, 6H), 6.91-6.84 (m, 2H), 5.47 (s, 2H), 3.72 (s, 3H), 1.65-1.56 (m, 2H), 1.46-1.39 (m, 2H).
MH+ 619.
1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.87 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.57 (dd, J=8.4 Hz, 2.4 Hz, 1H), 7.49-7.25 (m, 5H), 5.46 (s, 2H), 1.83-1.74 (m, 2H), 1.60-1.51 (m, 2H).
MH+ 656.
1H NMR (300 MHz, CDCl3) δ 8.47 (s, 1H), 7.91 (s, 1H), 7.89-7.79 (m, 2H), 7.61 (dd, J=8.4 Hz, 2.4 Hz, 1H), 7.51-7.39 (m, 4H), 5.54 (s, 2H), 2.81-2.63 (m, 4H), 2.15-2.03 (m, 4H).
MH+ 594.
1H NMR (300 MHz, CDCl3) δ 8.42 (s, 1H), 7.89 (s, 1H), 7.86-7.75 (m, 2H), 7.58 (dd, J=8.7 Hz, 2.1 Hz, 1H), 7.50-7.31 (m, 8H), 5.49 (s, 2H), 3.01-2.83 (m, 2H), 2.76-2.62 (m, 2H), 2.15-1.85 (m, 2H).
MH+ 636.
1H NMR (300 MHz, CDCl3) δ 8.41 (s, 1H), 7.88 (s, 1H), 7.85-7.76 (m, 2H), 7.57 (dd, J=8.7 Hz, 2.1 Hz, 1H), 7.50-7.31 (m, 9H), 5.48 (s, 2H), 2.73-2.65 (m, 2H), 2.21-2.11 (m, 2H), 1.80-1.65 (m, 4H).
MH+ 618.
1H NMR (300 MHz, CDCl3) δ 8.42 (s, 1H), 7.88 (s, 1H), 7.86-7.77 (m, 2H), 7.58 (dd, J=8.7 Hz, 2.1 Hz, 1H), 7.52-7.31 (m, 8H), 5.48 (s, 2H), 2.74-2.63 (2H), 2.20-2.09 (m, 2H), 1.84-1.62 (m, 4H).
MH+ 650.
1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.05 (s, 1H), 7.49-7.32 (m, 8H), 5.64 (s, 2H), 1.51 (s, 9H), 1.45 (s, 9H).
MH+ 494.
1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.89 (s, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.59 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.50-7.76 (m, 4H), 5.50 (s, 2H), 1.50 (s, 3H), 1.26-1.19 (m, 2H), 1.05-0.99 (m, 2H).
MH+ 528.
1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.89 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.63-7.55 (m, 3H), 7.38-7.30 (m, 2H), 5.52 (s, 2H), 1.73 (s, 4H).
MH+ 624.
1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.88 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.63-7.43 (m, 3H), 7.47-7.39 (m, 4H), 7.35-7.29 (m, 2H), 5.48 (s, 2H), 1.70-1.63 (m, 2H), 1.53-1.46 (m, 2H).
MH+ 666.
1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.89 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.63-7.57 (m, 3H), 7.37-7.31 (m, 2H), 5.51 (s, 2H), 1.37 (s, 9H).
MH+ 572.
To the solution of cyanide (200 mg, 0.41 mmol) in DMF (2 mL) was added NaN3 (320 mg, 4.93 mmol) and NH4Cl (264 mg, 4.93 mmol) and the reaction mixture was irradiated in a microwave reactor (Biotage) for 20 min at 180° C. The reaction mixture was cooled to room temperature and diluted with 30% MeOH/CHCl3. The organic layer was washed with aq. saturated NaHCO3 solution. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by Prep-LC (Gilson) provided 87 mg (40%) of desired tetrazole as solid.
1H NMR (400 MHz, CDCl3) δ 7.46-7.28 (m, 7H), 4.34 (s, 2H), 2.91 (d, J=29.2 Hz, 1H), 1.54 (s, 9H).
MH+ 529.
1H NMR (400 MHz, CDCl3) δ 7.47-7.42 (m, 3H), 7.35-7.29 (m, 4H), 4.32 (s, 2H), 4.25 (s, 3H), 1.45 (s, 9H).
MH+ 543.
1H NMR (400 MHz, CDCl3) δ 7.42-7.37 (m, 2H), 7.31-7.23 (m, 3H), 7.18-7.14 (m, 2H), 4.48 (s, 2H), 4.22 (s, 3H), 1.45 (s, 9H).
MH+ 543.
To a solution of ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate (3.0 g, 7.6 mmol) in acetic acid (30 ml) at room temperature was bubbled chlorine gas for 10 minutes. The reaction mixture was stirred at room temperature for 2 hours and the resulting solution was quenched with water (100 ml). The organic solution was extracted with diethyl ether (100 ml×2). With saturated sodium bicarbonate solution, remained acetic acid was removed and organic phase was evaporated with reduced pressure. The crude residue was purified with silica gel column (hexane/ethyl acetate=5/1) to produce title compound (3.1 g, 95% yield) as white solid.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.0 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.35-7.32 (m, 3H), 7.20-7.18 (m, 2H), 4.48 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H).
MH+ 430.
A solution of ethyl 4-chloro-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate (3.1 g, 7.2 mmol) in ethyl alcohol (30 ml) was added hydrazine (5 ml, 64% solution in water) in one portion. The reaction mixture was refluxed 100° C. for 6 hours, and then cooled down to room temperature. After volatile solvent was removed in reduced pressure, the residue was purified with silica gel column (5% methanol in methylene chloride) to obtained title compound (3 g, quantitatively) as slightly yellow solid.
MH+ 415.
1H NMR (400 MHz, CDCl3) δ 7.44-7.38 (m, 1H), 7.40-7.33 (m, 4H), 7.25-7.22 (m, 2H), 4.06-4.02 (m, 1H), 2.61-2.57 (m, 2H), 2.54-2.48 (m, 2H), 2.18-2.07 (m, 2H).
MH+ 481.
1H NMR (400 MHz, CDCl3) δ 7.45-7.44 (m, 1H), 7.38-7.33 (m, 4H), 7.26-7.22 (m, 2H), 1.86 (q, J=7.2 Hz, 2H), 1.56 (s, 3H), 1.50 (s, 3H), 0.89 (t, J=7.2 Hz, 3H).
MH+ 497.
1H NMR (400 MHz, CDCl3) δ 7.45-7.40 (m, 2H), 7.38-7.33 (m, 3H), 7.26-7.22 (m, 2H), 3.26-3.24 (m, 1H), 2.20-1.86 (m, 4H), 1.58-1.44 (m, 6H).
MH+ 509.
1H NMR (400 MHz, CDCl3) δ 7.45-7.41 (m, 2H), 7.38-7.26 (m, 3H), 7.25-7.22 (m, 2H), 3.39-3.34 (m, 1H), 1.87-1.75 (m, 2H), 1.46 (d, J=6.8 Hz, 3H), 0.99 (t, J=7.2 Hz).
MH+ 483.
1H NMR (400 MHz, CDCl3) δ 7.48-7.41 (m, 2H), 7.39-7.24 (m, 3H), 7.23-7.19 (m, 2H), 1.57 (s, 9H).
MH+ 483.
To a solution of ethyl 4-bromo-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate (3.5 g, 7.37 mmol) in methanol (50 ml) at room temperature was added potassium hydroxide (830 mg, 14.8 mmol) in one portion. The reaction mixture was warmed to 100° C. and then stirred for 5 hours. The resulting solution was cooled down to room temperature and then evaporated the volatile solvent. The residue was acidified with 10% hydrochloric acid and then filtered using water and hexane. The filtrated solid was dried under vacuum to obtain the title compound (3.2 g, 97%) as pale yellow solid.
MH+ 446.
1H NMR (400 MHz, CDCl3) δ 7.50-7.41 (m, 2H), 7.37-7.24 (m, 3H), 7.23-7.19 (m, 2H), 1.57 (s, 9H).
MH+ 527.
1H NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.40-7.37 (m, 1H), 7.35-7.32 (m, 3H), 7.25-7.21 (m, 2H), 3.14-3.10 (m, 1H), 1.96-1.90 (m, 1H), 1.79-1.71 (m, 1H), 1.43 (dd, J=2.8, 7.2 Hz, 3H), 0.91 (m, 3H).
MH+ 527.
1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=2.0 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.35-7.32 (m, 3H), 7.25-7.21 (m, 2H), 3.87-3.78 (m, 1H), 2.60-2.42 (m, 4H), 2.17-2.05 (m, 2H).
MH+ 525.
1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J=2.0, 3.6 Hz, 1H), 7.38 (dd, J=3.2, 8.4 Hz, 1H), 7.36-7.32 (m, 3H), 7.26-7.21 (m, 2H), 3.04-2.98 (m, 1H), 2.16-2.12 (m, 2H), 1.86-1.76 (m, 2H), 1.73-1.67 (m, 3H), 1.45-1.33 (m, 3H).
MH+ 553.
1H NMR (400 MHz, CDCl3) δ 7.43-7.39 (m, 2H), 7.35-7.32 (m, 3H), 7.23-7.21 (m, 2H), 1.58-1.68 (dq, J=7.6, 49.2 Hz, 2H), 1.46 (s, 3H), 1.36 (s, 3H), 0.90-0.78 (dt, J=7.6, 31.6 Hz, 3H).
MH+ 541.
1H NMR (400 MHz, CDCl3) δ 7.42-7.37 (m, 1H), 7.35-7.10 (m, 4H), 7.29-7.27 (m, 3H), 7.24-7.18 (m, 2H), 7.12-7.09 (m, 1H), 1.88 (s, 3H), 1.72 (s, 3H)
MH+ 623.
1H NMR (400 MHz, CDCl3) δ 7.44-7.41 (m, 1H), 7.37-7.32 (m, 4H), 7.27-7.24 (m, 3H), 7.21-7.18 (m, 2H), 7.12-7.08 (m, 1H), 1.96 (dd, J=9.2, 6.7 Hz, 2H), 1.45 (dd, J=9.2, 6.7 Hz, 2H)
MH+ 621.
N-cyclobutanoyl-N′-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl]-hydrazine (0.14 g, 0.29 mmol) was added to a microwave reactor containing Lawesson's reagent (0.18 g, 0.44 mmol) in 1,4-dioxane (3 mL). The capped reactor was placed into a microwave reactor and the mixture was heated at 180° C. for 15 min, and the process was repeated one more time. The reaction mixture was then purified by preparative HPLC to provide the title compound (60 mg, 0.16 mmol, 43%) as yellow solid.
1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=2.3 Hz, 1H), 7.34-7.28 (m, 4H), 7.13-7.09 (m, 2H), 4.01 (m, 1H), 2.62-2.52 (m, 2H), 2.49 (s, 3H), 2.47-2.39 (m, 2H), 2.20-2.00 (m, 2H).
MH+ 475.
The following compounds of Examples 346 to 547 were obtained by using corresponding starting materials and repeating the procedure of Example 345.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=1.84 Hz, 1H), 7.34-7.28 (m, 4H), 7.11 (dt, J=2.28, 8.24 Hz, 2H), 3.60 (m, 1H), 2.49 (s, 3H), 2.26 (m, 2H), 1.94-1.81 (m, 4H), 1.74 (m, 2H).
MH+ 489.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=1.84 Hz, 1H), 7.37-7.29 (m, 4H), 7.11 (dt, J=2.28, 8.24 Hz, 2H), 2.99 (m, 1H), 2.44 (s, 3H), 2.16-2.12 (m, 2H), 1.87-1.81 (m, 2H), 1.78-1.65 (m, 3H), 1.44-1.28 (m, 3H).
MH+ 487.
MH+ 461.
MH+ 486.
1H-NMR (400 MHz, CDCl3) δ 9.64 (d, J=1.40 Hz, 1H), 8.67 (d, J=2.28 Hz, 1H), 8.64 (dd, J=1.40, 2.32 Hz, 1H), 7.44 (d, J=1.84 Hz, 1H), 7.36-7.29 (m, 4H), 7.15-7.11 (m, 2H), 2.56 (s, 3H).
MH+ 499.
1H-NMR (400 MHz, CDCl3) δ 7.58 (dd, J=0.92, 3.68 Hz, 1H), 7.50 (dd, J=1.36, 5.04 Hz, 1H), 7.44 (d, J=1.84 Hz, 1H), 7.36-7.29 (m, 4H), 7.15-7.11 (m, 3H), 2.52 (s, 3H).
MH+ 503.
1H-NMR (400 MHz, CDCl3) δ 8.59 (d, J=5.04 Hz, 1H), 7.66 (dt, J=1.84, 7.76 Hz, 1H), 7.41 (d, J=1.84 Hz, 1H), 7.36 (d, J=7.76 Hz, 1H), 7.33-7.28 (m, 4H), 7.20 (dd, J=5.04, 7.32 Hz, 1H), 7.13-7.09 (m, 2H), 4.66 (s, 2H), 2.48 (s, 3H).
MH+ 512.
1H-NMR (400 MHz, CDCl3) δ 7.42 (d, J=1.84 Hz, 1H), 7.33-7.28 (m, 3H), 7.13-7.09 (m, 2H), 3.50 (m, 1H), 2.49 (s, 3H), 1.47 (d, J=6.88 Hz, 6H).
MH+ 463.
1H-NMR (400 MHz, CDCl3) δ 7.40 (br s, 1H), 7.34-7.28 (m, 9H), 7.16-7.12 (m, 2H), 4.45 (s, 2H), 2.48 (s, 3H).
MH+ 511.
1H-NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.34-7.29 (m, 4H), 7.13-7.10 (m, 2H), 3.14 (t, J=7.8 Hz, 2H), 2.49 (s, 3H), 1.85-1.79 (m, 2H), 1.52-1.42 (m, 2H), 0.97 (t, J=7.3 Hz, 3H).
MH+ 477.
1H-NMR (300 MHz, CDCl3) δ 8.05-8.01 (m, 2H), 7.51-7.48 (m, 3H), 7.45-7.44 (m, 1H), 7.35-7.31 (m, 4H), 7.16-7.12 (m, 2H), 2.55 (s, 3H).
MH+ 497.
1H-NMR (300 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.35-7.28 (m, 4H), 7.13-7.10 (m, 2H), 3.14 (d, J=7.5, 2H), 2.50 (s, 3H), 2.36-2.26 (m, 1H), 1.88-1.84 (m, 2H), 1.71-1.54 (m, 4H), 1.37-1.25 (m, 2H).
MH+ 503.
1H-NMR (300 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.35-7.30 (m, 4H), 7.14-7.10 (m, 2H), 4.11-4.07 (m, 2H), 3.63-3.55 (m, 2H), 3.50-3.40 (m, 1H), 2.50 (s, 3H), 2.14-2.11 (m, 2H), 2.05-1.92 (m, 2H).
MH+ 505.
1H-NMR (300 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.35-7.30 (m, 4H), 7.13-7.10 (m, 2H), 5.43-5.39 (m, 1H), 4.11-4.04 (m, 1H), 4.00-3.93 (m, 1H), 2.52-2.47 (m, 1H), 2.49 (s, 3H), 2.37-2.28 (m, 1H), 2.09-2.03 (m, 2H).
MH+ 491.
1H-NMR (400 MHz, CDCl3) δ 7.42 (d, J=1.84 Hz, 1H), 7.35-7.29 (m, 4H), 7.13-7.10 (m, 2H), 2.82 (s, 3H), 2.48 (s, 3H).
MH+ 435.
1H-NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.34-7.29 (m, 4H), 7.13-7.10 (m, 2H), 3.14 (t, J=7.8 Hz, 2H), 2.49 (s, 3H), 1.88-1.81 (m, 2H), 1.43-1.38 (m, 4H), 0.91 (t, J=7.3 Hz, 3H).
MH+ 491.
1H-NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.34-7.31 (m, 4H), 7.13-7.10 (m, 2H), 3.47-3.43 (m, 1H), 2.47 (s, 3H), 2.22-2.17 (m, 4H), 1.87-1.79 (m, 4H), 1.70-1.59 (m, 4H).
MH+ 517.
1H-NMR (400 MHz, CDCl3) δ 8.40 (d, J=8.4 Hz, 1H), 7.57 (d, J=2.2 Hz, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.42 (d, J=2.2 Hz, 1H), 7.37-7.31 (m, 4H), 7.16-7.12 (m, 2H), 2.55 (s, 3H).
MH+ 564.
1H-NMR (400 MHz, CDCl3) δ 7.50-7.45 (m, 2H), 7.43-7.42 (m, 1H), 7.34-7.28 (m, 2H), 7.07-7.02 (m, 2H), 4.06-3.96 (m, 1H), 2.61-2.52 (m, 2H), 2.50 (s, 3H), 2.46-2.38 (m, 2H), 2.18-1.99 (m, 2H).
MH+ 519.
1H-NMR (400 MHz, CDCl3) δ 7.42 (bs, 1H), 7.34-7.29 (m, 4H), 7.12-7.10 (m, 2H), 3.02 (d, J=6.4 Hz, 2H), 2.50 (s, 3H), 1.82-1.64 (m, 5H), 1.30-1.02 (m, 6H).
MH+ 517.
1H-NMR (400 MHz, CDCl3) δ 7.49-7.45 (m, 2H), 7.43-7.42 (m, 1H), 7.34-7.28 (m, 2H), 7.07-7.03 (m, 2H), 3.64-3.57 (m, 1H), 2.49 (s, 3H), 2.29-2.21 (m, 2H), 1.94-1.82 (m, 4H), 1.79-1.69 (m, 2H).
MH+ 533.
1H-NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.40-7.28 (m, 4H), 7.13-7.10 (m, 2H), 3.36-3.27 (m, 1H), 2.50 (s, 3H), 1.91-1.73 (m, 2H), 1.44 (d, J=6.9 Hz, 3H), 0.98 (t, J=7.3 Hz, 3H).
MH+ 477.
1H-NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.34-7.28 (m, 4H), 7.13-7.10 (m, 2H), 3.45-3.37 (m, 1H), 2.49 (s, 3H), 1.84-1.67 (m, 2H), 1.44 (d, J=6.9 Hz, 3H), 1.41-1.33 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).
MH+ 491.
1H-NMR (400 MHz, CDCl3) δ 7.49-7.45 (m, 2H), 7.43-7.42 (m, 1H), 7.33-7.28 (m, 2H), 7.07-7.04 (m, 2H), 2.49 (s, 3H), 1.53 (s, 9H).
MH+ 521.
1H-NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.34-7.29 (m, 4H), 7.14-7.10 (m, 2H), 3.03 (d, J=7.3 Hz, 2H), 2.50 (s, 3H), 1.25-1.14 (m, 1H), 0.69-0.64 (m, 2H), 0.40-0.35 (m, 2H).
MH+ 475.
1H-NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.37-7.28 (m, 4H), 7.13-7.10 (m, 2H), 3.14-3.08 (m, 1H), 2.49 (s, 3H), 2.31-2.28 (m, 2H), 1.95-1.92 (m, 2H), 1.66-1.52 (m, 4H), 1.25-1.04 (m, 1H), 0.89 (s, 9H).
MH+ 559.
1H-NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.38-7.28 (m, 4H), 7.14-7.10 (m, 2H), 2.50 (s, 3H), 1.53 (s, 9H).
MH+ 477.
1H-NMR (400 MHz, CDCl3) δ 7.50-7.45 (m, 2H), 7.43-7.42 (m, 1H), 7.34-7.28 (m, 2H), 7.07-7.03 (m, 2H), 3.22-3.16 (m, 1H), 2.49 (s, 3H), 2.22-2.17 (m, 2H), 1.90-1.84 (m, 2H), 1.78-1.28 (m, 6H).
MH+ 547.
1H-NMR (400 MHz, CDCl3) δ 7.49-7.45 (m, 2H), 7.42-7.41 (m, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.30-7.28 (m, 1H), 7.09-7.05 (m, 2H), 3.21-3.15 (m, 1H), 2.95-2.89 (m, 2H), 2.23-2.18 (m, 2H), 1.90-1.84 (m, 2H), 1.78-1.28 (m, 6H), 1.26-1.22 (m, 3H).
MH+ 561.
1H-NMR (400 MHz, CDCl3) δ 7.49-7.45 (m, 2H), 7.42-7.41 (m, 1H), 7.34-7.28 (m, 2H), 7.08-7.05 (m, 2H), 4.05-3.96 (m, 1H), 2.95-2.89 (m, 2H), 2.60-2.52 (m, 2H), 2.49-2.39 (m, 2H), 2.18-2.00 (m, 2H), 1.30-1.22 (m, 3H).
MH+ 533.
1H-NMR (400 MHz, CDCl3) δ 7.49-7.45 (m, 2H), 7.42-7.41 (m, 1H), 7.34-7.28 (m, 2H), 7.08-7.05 (m, 2H), 3.64-3.56 (m, 1H), 2.95-2.89 (m, 2H), 2.29-2.22 (m, 2H), 1.95-1.82 (m, 4H), 1.79-1.70 (m, 2H), 1.26-1.22 (m, 3H).
MH+ 547.
1H-NMR (400 MHz, CDCl3) δ 7.49-7.45 (m, 2H), 7.42-7.41 (m, 1H), 7.34-7.28 (m, 2H), 7.08-7.05 (m, 2H), 2.95-2.89 (m, 2H), 1.56 (s, 9H), 1.28-1.24 (m, 3H).
MH+ 535.
1H-NMR (300 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.43-7.42 (m, 1H), 7.35-7.28 (m, 2H), 7.06-7.04 (m, 2H), 3.47-3.37 (m, 1H), 2.49 (s, 3H), 2.24-2.18 (m, 2H), 1.87-1.60 (m, 10H).
MH+ 561.
1H-NMR (300 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.35-7.28 (m, 4H), 7.13-7.10 (m, 2H), 3.42-3.35 (m, 1H), 2.50 (s, 3H), 1.78-1.73 (m, 2H), 1.44 (d, J=6.7 Hz, 3H), 1.34-1.32 (m, 4H), 0.90-0.85 (m, 3H).
MH+ 505.
1H-NMR (300 MHz, CDCl3) δ 7.49-7.45 (m, 2H), 7.43-7.42 (m, 1H), 7.35-7.28 (m, 2H), 7.07-7.03 (m, 2H), 3.44-3.35 (m, 1H), 2.50 (s, 3H), 1.85-1.69 (m, 2H), 4.44 (d, J=6.7 Hz, 3H), 1.36-1.25 (m, 4H), 0.90-0.85 (m, 3H).
MH+ 549.
1H NMR (400 MHz, CDCl3) δ 7.40-7.23 (m, 10H), 7.12-7.08 (m, 2H), 4.64 (m, 1H), 2.48 (s, 3H), 1.87 (d, J=7.4 Hz, 3H).
MH+ 525.
MH+ 518.
MH+ 501.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=1.8 Hz), 7.34-7.28 (m, 4H), 7.15-7.10 (m, 2), 5.80 (s, 2H), 4.05 (m, 1H), 4.06 (m, 2H), 4.05 (m, 2H), 2.49 (s, 3H).
MH+ 487.
1H NMR (300 MHz, CDCl3) δ 7.43 (d, J=2.34 Hz, 2H), 7.38-7.24 (m, 5H), 7.24-7.19 (m, 3H), 7.12-7.10 (m, 2H), 3.48-3.43 (m, 1H), 3.37-3.30 (m, 1H), 2.95-2.88 (m, 1H), 2.50 (s, 3H), 1.46 (d, J=6.78 Hz, 3H).
MH+ 541.
1H NMR (300 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.42-7.41 (m, 1H), 7.36-7.27 (m, 2H), 7.08-7.05 (m, 2H), 3.02 (d, J=6.6 Hz, 2H), 2.96-2.88 (m, 2H), 1.85-1.65 (m, 7H), 1.27-1.04 (m, 7H).
MH+ 576.
1H NMR (300 MHz, CDCl3) δ 7.50-7.45 (m, 2H), 7.43-7.42 (m, 1H), 7.36-7.28 (m, 2H), 7.06-7.03 (m, 2H), 3.03 (d, J=6.6 Hz, 2H), 2.49 (s, 3H), 1.88-1.62 (m, 7H), 1.23-1.02 (m, 4H).
MH+ 561.
1H NMR (300 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.42-7.41 (m, 1H), 7.35-7.27 (m, 2H), 7.09-7.05 (m, 2H), 3.41-3.34 (m, 1H), 2.96-2.88 (m, 2H), 1.83-1.73 (m, 2H), 1.44 (d, J=6.9 Hz, 3H), 1.36-1.23 (m, 7H), 0.90-0.86 (m, 3H).
MH+ 563.
1H NMR (300 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.35-7.27 (m, 4H), 7.15-7.12 (m, 2H), 2.95-2.88 (m, 2H), 1.53 (s, 9H), 1.26 (t, J=7.3 Hz, 3H).
MH+ 491.
MH+ 517.
1H NMR (300 MHz, CDCl3) δ 7.42-7.11 (m, 5H), 7.15-7.11 (m, 2H), 3.12-3.10 (m, 1H), 2.44 (s, 3H), 1.90-1.73 (m, 1H), 1.70-1.50 (m, 4H), 1.44-1.40 (m, 4H), 1.41 (d, J=7.0 Hz, 3H).
MH+ 519.
1H NMR (300 MHz, CDCl3) δ 7.42-7.11 (m, 5H), 7.09-7.02 (m, 2H), 3.22-3.19 (m, 1H), 2.42 (s, 3H), 1.91-1.72 (m, 2H), 1.69-1.50 (m, 5H), 1.44-1.40 (m, 4H), 1.44 (d, J=7.33 Hz, 3H).
MH+ 531.
1H NMR (300 MHz, CDCl3) δ 7.56-7.53 (m, 2H), 7.39-7.33 (m, 2H), 7.25-7.20 (m, 2H), 7.11-7.08 (m, 1H), 2.50 (s, 3H), 1.90-1.88 (m, 1H), 1.74-1.50 (m, 4H), 1.45 (s, 6H), 1.43-1.40 (m, 4H).
MH+ 531.
1H NMR (300 MHz, CDCl3) δ 7.56-7.53 (m, 2H), 7.38-7.34 (m, 2H), 7.26-7.20 (m, 2H), 7.15-7.12 (m, 1H), 2.54 (s, 3H), 1.97-1.87 (m, 1H), 1.74-1.50 (m, 6H), 1.44 (s, 6H), 1.43-1.40 (m, 3H).
MH+ 547.
1H NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.35-7.28 (m, 4H), 7.15-7.12 (m, 2H), 4.03-3.98 (m, 1H), 2.94-2.89 (m, 2H), 2.60-2.52 (m, 2H), 2.49-2.39 (m, 2H), 2.16-2.01 (m, 2H), 1.25 (t, J=7.2 Hz, 3H).
MH+ 489.
1H NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.34-7.28 (m, 4H), 7.14-7.12 (m, 2H), 3.62-3.58 (m, 1H), 2.94-2.89 (m, 2H), 2.30-2.23 (m, 2H), 1.95-1.70 (m, 6H), 1.25 (t, J=7.2 Hz, 3H).
MH+ 503.
1H NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.34-7.27 (m, 4H), 7.15-7.11 (m, 2H), 3.43-3.38 (m, 1H), 2.94-2.89 (m, 2H), 2.24-2.18 (m, 2H), 1.90-1.79 (m, 4H), 1.70-1.57 (m, 6H), 1.24 (t, J=7.3 Hz, 3H).
MH+ 531.
1H NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.34-7.27 (m, 4H), 7.15-7.10 (m, 2H), 3.35-3.26 (m, 1H), 2.95-2.89 (m, 2H), 1.92-1.73 (m, 2H), 1.45 (d, J=6.88 Hz, 3H), 1.25 (t, J=7.32 Hz, 3H), 0.98 (t, J=7.36 Hz, 3H).
MH+ 491.
1H NMR (400 MHz, CDCl3) δ 7.49-7.45 (m, 2H), 7.42 (d, J=1.84 Hz, 1H), 7.33 (d, J=8.28 Hz, 1H), 7.29 (dd, J=8.24, 1.81 Hz, 1H), 7.08-7.05 (m, 2H), 3.34-3.28 (m, 1H), 2.95-2.89 (m, 2H), 1.90-1.75 (m, 2H), 1.45 (d, J=6.88 Hz, 3H), 1.25 (t, J=7.32 Hz, 3H), 1.98 (t, J=7.32 Hz, 3H).
MH+ 535.
1H NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.41 (d, J=1.84 Hz, 1H), 7.33 (d, J=8.24 Hz, 1H), 7.29 (dd, J=8.24, 1.84 Hz, 1H), 7.10-7.05 (m, 2H), 3.43-3.37 (m, 1H), 2.95-2.89 (m, 2H), 2.25-2.19 (m, 2H), 1.90-1.79 (m, 4H), 1.70-1.57 (m, 6H), 1.24 (t, J=7.32 Hz, 3H).
MH+ 575.
1H NMR (400 MHz, CDCl3) δ 7.42-7.38 (m, 1H), 7.36-7.27 (m, 7H), 7.26-7.21 (m, 1H), 7.11-7.01 (m, 2H), 2.50 (s, 3H), 1.95 (s, 6H).
MH+ 539.
1H NMR (400 MHz, CDCl3) δ 7.41-7.38 (m, 1H), 7.35-7.27 (m, 6H), 7.26-7.21 (m, 1H), 7.11-7.09 (m, 2H), 2.50 (s, 3H), 1.91 (s, 6H).
MH+ 575.
1H NMR (400 MHz, CDCl3) δ 7.48-7.46 (m, 2H), 7.42 (bs, 1H), 7.34-7.29 (m, 2H), 7.06-7.04 (m, 2H), 3.34-3.29 (m, 1H), 2.50 (s, 3H), 1.87-1.76 (m, 2H), 1.44 (d, J=6.8 Hz, 3H), 0.98 (t, J=7.6 Hz, 3H).
MH+ 522.
1H NMR (400 MHz, CDCl3) δ 7.48-7.46 (m, 2H), 7.42-7.38 (m, 3H), 7.34-7.30 (m, 2H), 7.27-7.22 (m, 3H), 7.06-7.04 (m, 2H), 2.92-2.90 (m, 2H), 1.94 (s, 6H), 1.27 (t, J=7.6 Hz, 3H).
MH+ 598.
1H NMR (400 MHz, CDCl3) δ 7.44-7.24 (m, 6H), 7.18-7.12 (m, 2H), 2.51 (s, 3H), 1.53 (s, 9H).
MH+ 443.
1H NMR (400 MHz, CDCl3) δ 7.42 (m, 1H), 7.35-7.30 (m, 4H), 7.34-7.30 (m, 2H), 2.50 (s, 3H), 1.77 (m, 2H), 1.50 (s, 6H), 1.26 (m, 4H), 0.86 (t, J=6.8 Hz, 3H).
MH+ 519.
1H NMR (400 MHz, CDCl3) δ 7.42-7.26 (m, 6H), 7.14-7.09 (m, 2H), 3.31 (sextet, J=6.8 Hz, 1H), 2.50 (s, 3H), 1.80-1.72 (m, 2H), 1.44 (d, J=7.2 Hz, 3H), 0.97 (t, J=7.6 Hz, 3H).
MH+ 443.
1H NMR (400 MHz, CDCl3) δ 7.43-7.26 (m, 6H), 7.15-7.05 (m, 2H), 3.25-3.17 (m, 1H), 2.51 (s, 3H), 2.26-2.17 (m, 2H), 1.93-1.80 (m, 2H), 1.80-1.72 (m, 1H), 1.68-1.53 (m, 2H), 1.52-1.38 (m, 2H), 1.38-1.26 (m, 1H).
MH+ 469.
1H NMR (400 MHz, CDCl3) δ 7.43-7.27 (m, 6H), 7.15-7.07 (m, 2H), 4.01 (quintet, J=8.8 Hz, 1H), 2.61-2.38 (m, 7H), 2.19-2.01 (m, 2H).
MH+ 441.
1H NMR (400 MHz, CDCl3) δ 7.43-7.26 (m, 6H), 7.16-7.10 (m, 2H), 2.52 (s, 3H), 1.83 (quartet, J=7.6 Hz, 2H), 1.46 (s, 6H), 0.87 (t, J=7.6 Hz, 3H).
MH+ 457.
1H NMR (400 MHz, CDCl3) δ 7.42-7.27 (m, 6H), 7.18-7.12 (m, 2H), 3.39 (sextet, J=6.8 Hz, 1H), 2.51 (s, 3H), 1.85-1.69 (m, 3H), 1.44 (d, J=7.2 Hz, 2H), 1.42-1.25 (m, 4H), 0.89 (t, J=6.8 Hz, 3H).
MH+ 471.
1H NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 2H), 7.34-7.30 (m, 4H), 7.15-7.12 (m, 2H), 3.43-3.38 (m, 1H), 2.95-2.90 (m, 2H), 1.84-1.67 (m, 4H), 1.46-1.44 (m, 2H), 1.25 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.6 Hz, 3H).
MH+ 505.
1H NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.43-7.42 (m, 1H), 7.34-7.31 (m, 2H), 7.06-7.04 (m, 2H), 3.44-3.38 (m, 1H), 2.49 (s, 3H), 1.84-1.66 (m, 4H), 1.44 (d, J=6.8 Hz, 3H), 1.41-1.36 (m, 2H), 0.93 (t, J=7.2 Hz, 3H).
MH+ 536.
1H NMR (400 MHz, CDCl3) δ 7.48-7.46 (m, 2H), 7.42-7.41 (m, 1H), 7.34-7.28 (m, 2H), 7.08-7.06 (m, 2H), 3.43-3.37 (m, 1H), 2.95-2.89 (m, 2H), 1.83-1.67 (m, 4H), 1.45-1.43 (d, J=6.8 Hz, 3H), 1.41-1.34 (m, 2H), 1.25 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.2 Hz, 3H).
MH+ 549.
1H NMR (400 MHz, CDCl3) δ 7.46-7.27 (m, 6H), 7.30-7.11 (m, 2H), 2.45 (s, 3H), 1.83-1.74 (m, 2H), 1.47 (s, 6H), 1.33-1.18 (m, 4H), 0.88 (t, J=6.8 Hz, 3H).
MH+ 485.
1H NMR (400 MHz, CDCl3) δ 7.43-7.21 (m, 11H), 7.19-7.09 (m, 2H), 2.51 (s, 3H), 1.94 (s, 6H).
MH+ 505.
1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=8.8 Hz, 2H), 7.31 (d, J=6.4 Hz, 2H), 7.20 (d, J=6.4 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 2.47 (s, 3H), 1.85 (q, J=7.2 Hz, 2H), 1.50 (s, 6H), 0.90 (t, J=7.2 Hz, 3H).
MH+ 503.
1H NMR (400 MHz, CDCl3) δ 7.55-7.53 (m, 2H), 7.35-7.30 (m, 2H), 7.26-7.20 (m, 2H), 7.09-7.06 (m, 2H), 3.35-3.23 (m, 1H), 2.46 (s, 3H), 1.97-1.91 (m, 2H), 1.71-1.40 (m, 2H), 1.42 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.2 Hz, 3H).
MH+ 489.
1H NMR (400 MHz, CDCl3) δ 7.44 (m, 1H), 7.36-7.32 (m, 4H), 7.16-7.12 (m, 2H), 7.28 (s, 3H), 2.51 (s, 3H), 1.74 (s, 6H).
MH+ 493.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.0 Hz, 1H), 7.35-7.32 (m, 3H), 7.31 (s, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.21-7.17 (m, 2H), 2.52 (s, 3H), 1.84 (q, J=8.0 Hz, 2H), 1.49 (s, 6H), 0.88 (t, J=7.2 Hz, 3H).
MH+ 457.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.4 Hz, 1H), 7.35-7.32 (m, 3H), 7.31 (s, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.21-7.17 (m, 2H), 2.51 (s, 3H), 1.53 (s, 9H).
MH+ 443.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.0 Hz, 1H), 7.35-7.32 (m, 3H), 7.31 (s, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.21-7.17 (m, 2H), 3.39-3.28 (m, 1H), 2.52 (s, 3H), 1.89-1.75 (m, 2H), 1.45 (d, J=6.8 Hz, 3H), 0.98 (t, J=7.2 Hz, 3H).
MH+ 443.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.4 Hz, 1H), 7.35-7.32 (m, 3H), 7.31 (s, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.20-7.17 (m, 2H), 4.05-3.97 (m, 1H), 2.61-2.38 (m, 7H), 2.16-2.03 (m, 2H).
MH+ 441.
1H NMR (400 MHz, CDCl3) δ 7.55-7.54 (m, 2H), 7.32-7.31 (m, 2H), 7.26-7.20 (m, 2H), 7.08-7.06 (m, 2H), 3.81-3.79 (m, 1H), 2.57-2.53 (m, 2H), 2.49-2.45 (m, 2H), 2.42 (s, 3H), 2.17-2.04 (m, 2H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.46-7.43 (m, 3H), 7.41-7.38 (m, 1H), 7.36-7.31 (m, 2H), 7.07-7.04 (m, 2H), 2.5 (s, 3H), 1.50 (s, 9H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.45-7.41 (m, 3H), 7.40-7.38 (m, 1H), 7.37-7.32 (m, 2H), 7.07-7.05 (m, 2H), 3.22-3.15 (m, 1H), 2.50 (s, 3H), 2.21-2.18 (m, 2H), 1.89-1.84 (m, 2H), 1.77-1.65 (m, 1H), 1.64-1.55 (m, 2H), 1.50-1.40 (m, 2H), 1.35-1.29 (m, 1H).
MH+ 513.
1H NMR (400 MHz, CDCl3) δ 7.45-7.31 (m, 6H), 7.07-7.05 (m, 2H), 4.03-3.98 (m, 1H), 2.59-2.52 (m, 2H), 2.51 (s, 3H), 2.50-2.40 (m, 2H), 2.16-2.02 (m, 2H).
MH+ 485.
1H NMR (400 MHz, CDCl3) δ 7.46-7.29 (m, 6H), 7.08-7.05 (m, 2H), 3.34-3.29 (m, 1H), 2.50 (s, 3H), 1.89-1.76 (m, 1H), 1.44 (d, J=6.8 Hz, 3H), 0.98 (t, J=7.6 Hz, 3H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.46-7.29 (m, 6H), 7.08-7.05 (m, 2H), 2.51 (s, 3H), 1.83 (q, J=7.6 Hz, 2H), 1.49 (s, 6H), 0.88 (t, J=7.6 Hz, 3H).
MH+ 501.
1H NMR (400 MHz, CDCl3) δ 7.44-5.28 (m, 9H), 7.15-7.08 (m, 2H), 2.46 (s, 3H), 1.94 (m, 2H), 1.50 (m, 2H).
MH+ 571.
1H NMR (400 MHz, CDCl3) δ 7.40 (m, 1H), 7.35-7.25 (m, 8H), 7.12-7.08 (m, 2H), 3.08 (m, 2H), 2.85 (m, 2H), 2.49 (s, 3H), 2.38 (m, 1H), 2.02 (m, 1H).
MH+ 585.
1H NMR (400 MHz, CDCl3) δ 7.48-7.31 (m, 9H), 7.06-7.02 (m, 2H), 2.87 (q, J=7.2 Hz, 2H), 1.95 (dd, J=7.2, 4.8 Hz, 2H), 1.50 (dd, J=7.2, 4.8 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H).
MH+ 629.
1H NMR (400 MHz, CDCl3) δ 7.46-7.26 (m, 10H), 7.14-7.08 (m, 2H), 2.47 (s, 3H), 1.98-1.92 (m, 2H), 1.54-1.48 (m, 2H).
MH+ 536.
1H NMR (400 MHz, CDCl3) δ 7.43 (dd, J=2.4 Hz, 1.8 Hz, 1H), 7.35-7.31 (m, 3H), 7.30-7.24 (m, 2H), 7.22-7.21 (m, 1H), 7.05 (dt, J=8.0 Hz, 1.2 Hz, 1H), 2.51 (s, 3H), 1.53 (s, 9H).
MH+ 477.
1H NMR (400 MHz, CDCl3) δ 7.43 (dd, J=2.4 Hz, 1.8 Hz, 1H), 7.35-7.31 (m, 3H), 7.30-7.26 (m, 2H), 7.22-7.21 (m, 1H), 7.03 (dt, J=7.6 Hz, 1.6 Hz, 1H), 3.34-3.29 (m, 1H), 2.50 (s, 3H), 1.87-1.76 (m, 1H), 1.44 (d, 3H), 0.98 (t, 3H).
MH+ 477.
1H NMR (400 MHz, CDCl3) δ 7.43 (dd, J=2.0 Hz, 0.4 Hz, 1H), 7.35-7.31 (m, 3H), 7.30-7.24 (m, 2H), 7.22-7.21 (m, 1H), 7.04 (dt, J=7.6 Hz, 1.2 Hz, 1H), 4.01 (m, 1H), 2.60-2.52 (m, 2H), 2.50 (s, 3H), 2.46-2.41 (m, 2H), 2.41-2.03 (m, 2H).
MH+ 475.
1H NMR (400 MHz, CDCl3) δ 7.42 (br d, J=2.0 Hz, 1H), 7.36-7.29 (m, 4H), 7.14-7.10 (m, 2H), 3.45 (q, J=7.2 Hz, 2H), 2.50 (s, 3H), 1.74 (s, 6H), 1.19 (t, J=7.2 Hz, 3H).
MH+ 507.
1H NMR (400 MHz, CDCl3) δ 7.43 (dd, 1H, J=2.0 Hz, 0.4 Hz), 7.35-7.31 (m, 3H), 7.30-7.24 (m, 2H), 7.22-7.21 (m, 1H), 7.04 (dt, 1H, J=7.6 Hz, 1.6 Hz), 3.24-3.16 (m, 1H), 2.51 (s, 3H), 2.22-2.02 (m, 2H), 1.90-1.75 (m, 3H), 1.66-1.56 (m, 2H), 1.51-1.26 (m, 3H).
MH+ 502.
1H NMR (400 MHz, CDCl3) δ 7.43 (dd, 1H, J=2.0 Hz, 0.4 Hz), 7.34-7.31 (m, 3H), 7.29-7.24 (m, 2H), 7.22-7.21 (m, 1H), 7.04 (dt, 1H, J=7.6 Hz, 1.2 Hz), δ 2.50 (s, 3H), 1.83 (q, 2H, J=7.6 Hz), 1.49 (s, 6H), 0.88 (t, 3H, J=7.2 Hz).
MH+ 491.
1H NMR (400 MHz, CDCl3) δ 7.55-7.49 (m, 2H), 7.36-7.31 (m, 2H), 7.21-7.16 (m, 1H), 7.11-7.01 (m, 2H), 3.14-3.10 (m, 1H), 2.14-2.12 (m, 2H), 1.91-1.87 (m, 2H), 1.78-1.70 (m, 2H), 1.44-1.20 (m, 4H), 0.62-0.60 (m, 2H), 0.37-0.34 (m, 2H).
MH+ 531.
1H NMR (400 MHz, CDCl3) δ 7.56-7.51 (m, 2H), 7.34-7.31 (m, 2H), 7.20-7.17 (m, 1H), 7.15-7.11 (m, 2H), 1.44 (m, 1H), 1.32 (s, 9H), 0.61-0.59 (m, 2H), 0.37-0.34 (m, 2H).
MH+ 505.
1H NMR (400 MHz, CDCl3) δ 7.54-7.51 (m, 2H), 7.33-7.31 (m, 2H), 7.22-7.18 (m, 1H), 7.14-7.11 (m, 2H), 3.25-2.22 (m, 1H), 1.50-1.47 (m, 1H), 1.45-1.44 (m, 4H), 1.37-1.30 (m, 2H), 0.60-0.57 (m, 2H), 0.37-0.35 (m, 2H).
MH+ 503.
1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.8 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.19 (d, J=9.2 Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 2.46 (s, 3H), 1.54 (s, 9H).
MH+ 443.
1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.19 (d, J=158.8 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 3.37-3.28 (m, 1H), 2.46 (s, 3H), 1.91-1.76 (m, 2H), 1.46 (d, J=7.2 Hz, 3H), 0.99 (t, J=7.2 Hz, 3H).
MH+ 443.
1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 4.06-3.08 (m, 1H), 2.62-2.54 (m, 2H), 2.52-2.42 (m, 5H), 2.20-2.02 (m, 2H).
MH+ 441.
1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.8 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 3.24-3.16 (m, 1H), 2.46 (s, 3H), 2.24-2.20 (m, 2H), 1.91-1.86 (m, 2H), 1.79-1.74 (m, 1H), 1.67-1.57 (m, 2H), 1.52-1.26 (m, 3H).
MH+ 469.
1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.8 Hz, 2H), 7.39-7.34 (m, 4H), 7.28-7.24 (m, 2H), 7.14-7.11 (m, 4H), 2.42 (s, 3H), 1.96-1.94 (m, 2H), 1.53-1.50 (m, 2H).
MH+ 537.
1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.8 Hz, 2H), 7.29 (d, J=11.6 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 2.46 (s, 3H), 1.84 (q, J=7.2 Hz, 2H), 1.50 (s, 6H), 0.89 (t, J=0.90 Hz, 3H).
MH+ 457.
1H NMR (400 MHz, CDCl3) δ 7.42 (br d, J=2.0 Hz, 1H), 7.36-7.29 (m, 4H), 7.14-7.10 (m, 2H), 3.35 (t, J=6.8 Hz, 2H), 2.50 (s, 3H), 1.73 (s, 6H), 1.57 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).
MH+ 521.
1H NMR (400 MHz, CDCl3) δ 7.51-7.42 (m, 4H), 7.37-7.27 (m, 6H), 7.05-7.02 (m, 2H), 2.87 (quartet, J=7.6 Hz, 2H), 1.95 (m, 2H), 1.53 (m, 2H), 1.10 (t, J=7.6 Hz, 3H).
MH+ 596.
1H NMR (400 MHz, CDCl3) δ 7.49-7.45 (m, 2H), 7.42-7.40 (m, 1H), 7.32-7.26 (m, 2H), 7.08-7.03 (m, 2H), 2.91 (quartet, J=7.2 Hz, 2H), 1.82 (quartet, J=8.0 Hz, 2H), 1.48 (s, 6H), 1.25 (t, J=7.2 Hz, 3H), 0.88 (t, J=7.2 Hz, 3H).
MH+ 550.
1H NMR (400 MHz, CDCl3) δ 7.49-7.44 (m, 2H), 7.42-7.39 (m, 1H), 7.33-7.26 (m, 2H), 7.08-7.04 (m, 2H), 3.35-3.31 (m, 1H), 2.90 (quartet, J=7.6 Hz, 2H), 2.56 (br d, J=3.6 Hz, 1H), 2.49-2.37 (m, 1H), 2.20-2.02 (m, 1H), 1.95-1.85 (m, 1H), 1.70-1.18 (m, 9H).
MH+ 574.
1H NMR (400 MHz, CDCl3) δ 7.48-7.44 (m, 2H), 7.42-7.39 (m, 1H), 7.33-7.26 (m, 2H), 7.08-7.04 (m, 2H), 3.48 (quintet, J=7.2 Hz, 1H), 2.91 (quartet, J=7.2 Hz, 2H), 1.48 (d, J=6.8 Hz, 6H), 1.24 (t, J=7.2 Hz, 3H).
MH+ 522.
1H NMR (400 MHz, CDCl3) δ 7.48-7.45 (m, 2H), 7.41-7.40 (m, 1H), 7.33-7.26 (m, 2H), 7.08-7.04 (m, 2H), 3.03-3.01 (m, 1H), 2.92 (quartet, J=7.6 Hz, 2H), 1.80-1.45 (m, 4H), 1.24 (t, J=7.6 Hz, 3H), 0.92 (t, J=7.6 Hz, 3H).
MH+ 550.
1H NMR (400 MHz, CDCl3) δ 7.48-7.44 (m, 2H), 7.41-7.40 (m, 1H), 7.33-7.269 (m, 2H), 7.09-7.04 (m, 2H), 2.91 (quartet, J=7.6 Hz, 2H), 2.28-2.18 (m, 2H), 1.75-1.45 (m, 8H), 1.41 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).
MH+ 577.
1H NMR (400 MHz, CDCl3) δ 7.42-7.30 (m, 5H), 7.14-7.10 (m, 2H), 5.90 (m, 1H), 5.30 (br d, J=17.2 Hz, 1H), 5.14 (br d, J=10.4 Hz, 1H), 3.95 (dt, J=5.2, 1.6 Hz, 2H), 2.50 (s, 3H), 1.77 (s, 6H).
MH+ 519.
1H NMR (400 MHz, CDCl3) δ 7.42 (br d, J=2.0 Hz), 7.37-7.29 (m, 4H), 7.13-7.09 (m, 2H), 3.39 (t, J=6.8 Hz, 2H), 2.50 (s, 3H), 1.73 (s, 6H), 1.54 (m, 2H), 1.36 (m, 2H), 0.89 (t, J=7.2 Hz, 3H).
MH+ 535.
1H NMR (400 MHz, CDCl3) δ 7.42-7.37 (m, 3H), 7.31-7.24 (m, 4H), 7.07 (m, 2H), 6.87 (m, 2H), 3.79 (s, 3H), 2.45 (s, 3H), 1.92 (dd, J=7.2, 4.4 Hz, 2H), 1.48 (dd, J=7.2, 4.4 Hz, 2H).
MH+ 567.
1H NMR (400 MHz, CDCl3) δ 7.44-7.42 (m, 2H), 7.38 (t, J=1.2 Hz, 1H), 7.31-7.25 (m, 5H), 7.08 (m, 2H), 2.45 (s, 3H), 2.01 (dd, J=7.6, 5.2 Hz, 2H), 1.54 (dd, J=7.6, 5.2 Hz, 2H).
MH+ 605.
1H NMR (400 MHz, CDCl3) δ 7.38-7.25 (m, 7H), 7.14 (m, 2H), 7.08 (m, 2H), 2.46 (s, 3H), 2.33 (s, 3H), 1.94 (dd, J=7.2, 4.4 Hz, 2H), 1.50 (dd, J=7.2, 4.4 Hz, 2H).
MH+ 551.
1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J=2.0, 0.4 Hz, 1H), 7.34-7.28 (m, 4H), 7.11 (m, 2H), 3.36 (t, J=6.4 Hz, 2H), 2.49 (s, 3H), 1.72 (s, 6H), 1.50 (m, 2H), 1.27 (m, 4H), 0.87 (t, J=5.2 Hz, 3H).
MH+ 549.
1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J=1.6, 0.8 Hz, 1H), 7.33-7.29 (m, 4H), 7.10 (m, 2H), 2.48 (s, 3H), 1.72 (m, 2H), 1.64 (m, 2H).
MH+ 529.
1H NMR (400 MHz, CDCl3) δ 7.44-7.40 (m, 2H), 7.38-7.36 (m, 1H), 7.34-7.27 (m, 4H), 7.26-7.23 (m, 2H), 7.12-7.08 (m, 2H), 2.87 (quartet, J=7.6 Hz, 2H), 1.93 (m, 2H), 1.50 (m, 2H), 1.23 (t, J=7.6 Hz, 3H).
MH+ 587.
1H NMR (400 MHz, CDCl3) δ 7.45-7.41 (m, 4H), 7.37-7.35 (m, 2H), 7.34-7.31 (m, 2H), 7.29-7.24 (m, 2H), 7.05 (d, J=8.8 Hz, 2H), 2.88 (q, J=7.2 Hz, 2H), 1.96-1.93 (m, 2H), 1.52-1.49 (m, JAB=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H).
MH+ 597.
1H NMR (400 MHz, CDCl3) δ 7.42 (m, 1H), 7.34-7.30 (m, 4H), 7.11 (m, 2H), 2.83 (m, 4H), 2.51 (s, 3H), 2.17 (m, 2H).
MH+ 543.
1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J=1.6, 0.4 Hz, 1H), 7.34-7.30 (m, 4H), 7.11 (m, 2H), 4.01 (q, J=10.0 Hz, 2H), 2.50 (s, 3H).
+503.
1H NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.35-7.26 (m, 6H), 7.21-7.17 (m, 3H), 7.10-7.08 (m, 2H), 3.30 (s, 2H), 2.45 (s, 3H), 1.50-1.47 (m, 2H), 1.19-1.16 (m, 2H).
MH+ 595.
1H NMR (400 MHz, CDCl3) δ 7.46-7.44 (m, 2H), 7.39 (d, J=1.2 Hz, 1H), 7.30-7.23 (m, 6H), 7.21-7.18 (m, 1H), 7.05-7.03 (m, 2H), 3.30 (s, 2H), 2.87 (q, J=7.6 Hz, 2H), 1.51-1.48 (m, 2H), 1.23 (t, J=7.6 Hz, 3H), 1.19-1.16 (m, 2H).
MH+ 611.
1H NMR (400 MHz, CDCl3) δ 7.41 (dd, J=0.8, 2 Hz, 2H), 7.33-7.28 (m, 4H), 7.14-7.09 (m, 2H), 2.47 (s, 3H), 1.64 (s, 3H), 1.42-1.40 (m, 2H), 1.08-1.05 (m, 2H).
MH+ 475.
1H NMR (400 MHz, CDCl3) δ 7.47-7.45 (m, 2H), 7.40 (d, J=2 Hz, 1H), 7.32-7.26 (m, 2H), 7.07-7.05 (m, 2H), 2.90 (q, J=7.2 Hz, 2H), 1.64 (s, 3H), 1.46-1.40 (m, 2H), 1.23 (t, J=7.2 Hz, 3H), 1.08-1.06 (m, 2H).
MH+ 535.
1H NMR (400 MHz, CDCl3) δ 7.42-7.41 (m, 1H), 7.32-7.28 (m, 4H), 7.23-7.20 (m, 3H), 7.11-7.07 (m, 2H), 3.25 (s, 2H), 2.45 (s, 3H), 1.47 (dd, J=4.8, 6.8 Hz, 2H), 1.72 (dd, J=4.8, 6.8 Hz, 2H).
MH+ 587.
1H NMR (400 MHz, CDCl3) δ 7.48-7.44 (m, 2H), 7.40-7.39 (m, 1H), 7.32-7.26 (m, 3H), 7.23-7.20 (m, 3H), 7.06-7.02 (m, 2H), 3.25 (s, 2H), 2.86 (q, J=7.5 Hz, 2H), 1.49-1.46 (m, 2H), 1.36-1.27 (m, 5H).
MH+ 645.
1H NMR (400 MHz, CDCl3) δ 7.46-7.39 (m, 4H), 7.37 (dd, J=1.6, 1.2 Hz, 1H), 7.25 (m, 2H), 7.04-7.00 (m, 2H), 6.89-6.85 (m, 2H), 3.80 (s, 3H), 2.87 (q, J=7.6 Hz, 2H), 1.94 (dd, J=7.2, 4.8 Hz, 2H), 1.49 (dd, J=7.2, 4.8 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H).
MH+ 625.
1H NMR (400 MHz, CDCl3) δ 7.46-7.39 (m, 2H), 7.38-7.36 (m, 3H), 7.24 (m, 2H), 7.17-7.14 (m, 2H), 7.06-7.02 (m, 2H), 2.87 (q, J=7.6 Hz, 2H), 1.96 (dd, J=7.2, 4.8 Hz, 2H), 1.52 (dd, J=7.2, 4.8 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H).
MH+ 609.
1H NMR (400 MHz, CDCl3) δ 7.50-7.43 (m, 2H), 7.36-7.29 (m, 4H), 7.24 (m, 2H), 7.04-7.02 (m, 2H), 2.87 (q, J=7.6 Hz, 2H), 1.96 (dd, J=7.2, 4.8 Hz, 2H), 1.54 (dd, J=7.2, 4.8 Hz, 2H), 1.22 (t, J=7.6 Hz, 3H).
MH+ 595.
1H NMR (400 MHz, CDCl3) δ 7.47-7.43 (m, 2H), 7.38 (t, J=1.2 Hz, 1H), 7.30-7.24 (m, 6H), 7.04-7.02 (m, 2H), 3.09 (m, 2H), 2.90 (q, J=7.6 Hz, 2H), 2.56 (m, 2H), 2.36 (m, 1H), 2.02 (m, 1H), 1.24 (t, J=7.6 Hz, 3H).
MH+ 643.
1H NMR (400 MHz, CDCl3) δ 7.46-7.40 (m, 4H), 7.38 (m, 1H), 7.34-7.30 (m, 2H), 7.24 (m, 2H), 7.04-7.02 (m, 2H), 2.87 (q, J=7.6 Hz, 2H), 1.94 (dd, J=7.2, 4.8 Hz, 2H), 1.50 (dd, J=7.2, 4.8 Hz, 2H), 1.22 (t, J=7.6 Hz, 3H).
MH+ 629.
1H NMR (400 MHz, CDCl3) δ 7.46-7.40 (m, 4H), 7.38 (m, 1H), 7.28-7.24 (m, 3H), 7.04-7.02 (m, 2H), 2.87 (q, J=7.6 Hz, 2H), 2.05 (dd, J=7.2, 4.8 Hz, 2H), 1.54 (dd, J=7.2, 4.8 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H).
MH+ 663.
1H NMR (300 MHz, CDCl3) δ 7.50 (d, J=5.5 Hz, 2H), 7.38-7.25 (m, 8H), 7.11 (d, J=8.5 Hz, 2H), 2.88 (q, J=7.4 Hz, 2H), 1.99-1.96 (m, 2H), 1.56-1.53 (m, 2H), 1.23 (t, J=7.4 Hz, 3H).
MH+ 553.
1H NMR (300 MHz, CDCl3) δ 7.39-7.37 (m, 2H), 7.31-7.25 (m, 5H), 7.17-7.14 (m, 2H), 7.11 (d, J=8.6 Hz, 2H), 2.88 (q, J=7.4 Hz, 2H), 2.34 (s, 3H), 1.96-1.93 (m, 2H), 1.53-1.49 (m, 2H), 1.23 (t, J=7.4 Hz, 3H).
MH+ 567.
1H NMR (300 MHz, CDCl3) δ 7.43-7.37 (m, 3H), 7.31-7.25 (m, 4H), 7.11 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 3.80 (s, 3H), 2.88 (q, J=7.4 Hz, 2H), 1.95-1.92 (m, 2H), 1.51-1.48 (m, 2H), 1.23 (t, J=7.4 Hz, 3H).
MH+ 583.
1H NMR (300 MHz, CDCl3) δ 7.47-7.38 (m, 3H), 7.31-7.25 (m, 5H), 7.11 (d, J=8.6 Hz, 2H), 2.88 (q, J=7.4 Hz, 2H), 2.08-2.04 (m, 2H), 1.57-1.53 (m, 2H), 1.23 (t, J=7.3 Hz, 3H).
MH+ 621.
1H NMR (300 MHz, CDCl3) δ 7.41-7.40 (m, 1H), 7.35-7.28 (m, 8H), 7.13 (d, J=8.4 Hz, 2H), 3.13-3.05 (m, 2H), 2.92 (q, J=7.4 Hz, 2H), 2.88-2.78 (m, 2H), 2.40-2.30 (m, 1H), 2.06-1.95 (m, 1H), 1.27 (t, J=7.4 Hz, 3H).
MH+ 601.
1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=1.6 Hz, 1H), 7.33-7.27 (m, 4H), 7.15-7.10 (m, 2H), 2.90 (q, J=7.2 Hz, 2H), 1.64 (s, 3H), 1.44 (dd, J=4.4, 6.8 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H), 1.09 (dd, J=4.4, 6.8 Hz, 2H).
MH+ 489.
1H NMR (400 MHz, CDCl3) δ 7.46-7.41 (m, 4H), 7.37 (m, 1H), 7.32-7.24 (m, 4H), 7.23-7.19 (m, 1H), 7.04-7.01 (m, 2H), 2.90 (q, J=7.6 Hz, 2H), 2.83 (m, 2H), 2.31 (m, 2H), 1.85 (m, 4H), 1.23 (t, J=7.6 Hz, 3H).
MH+ 623.
1H NMR (400 MHz, CDCl3) δ 7.46-7.43 (m, 2H), 7.38-7.35 (m, 3H), 7.28-7.25 (m, 4H), 7.05-7.02 (m, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.82 (m, 2H), 2.27 (m, 2H), 1.86 (m, 4H), 1.23 (t, J=7.6 Hz, 3H).
MH+ 657.
1H NMR (400 MHz, CDCl3) δ 7.50-7.47 (m, 2H), 7.38-7.27 (m, 6H), 7.25-7.24 (m, 2H), 7.10-7.04 (m, 2H), 2.45 (s, 3H), 1.98 (d, J=7.2, 3.6 Hz, 2H), 1.55 (dd, J=7.2, 3.6 Hz, 2H).
MH+ 537.
1H NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.34-7.30 (m, 4H), 7.14-7.10 (m, 2H), 2.48 (s, 3H), 1.89 (q, J=9.7 Hz, 2H), 1.37 (dd, J=9.3, 6.2 Hz, 2H), 1.11 (t, J=9.7 Hz, 3H), 1.06 (dd, J=9.3, 6.2 Hz).
MH+ 489.
1H NMR (400 MHz, CDCl3) δ 7.44-7.42 (m, 1H), 7.34-7.30 (m, 4H), 7.16-7.11 (m, 2H), 2.87 (q, J=9.4 Hz, 2H), 1.93 (q, J=9.7 Hz, 2H), 1.38 (dd, J=9.3, 6.2 Hz, 2H), 1.27 (t, J=9.4 Hz, 3H), 1.03 (t, J=9.7 Hz, 3H), 1.00 (dd, J=9.3, 6.2 Hz).
MH+ 504.
1H NMR (400 MHz, CDCl3) δ 7.49-7.45 (m, 2H), 7.42-7.41 (m, 1H), 7.34-7.29 (m, 2H), 7.10-7.05 (m, 2H), 2.90 (q, J=9.8 Hz, 2H), 1.90 (q, J=9.8 Hz, 2H), 1.38 (dd, J=9.2, 6.2 Hz, 2H), 1.27 (t, J=9.8 Hz, 3H), 1.10 (t, J=9.8 Hz, 3H), 1.03 (dd, J=9.2, 6.2 Hz).
MH+ 547.
1H NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.34-7.30 (m, 4H), 7.14-7.11 (m, 2H), 2.88 (q, J=10.0 Hz, 2H), 2.11-2.05 (m, 2H), 1.99-1.94 (m, 2H), 1.24 (t, J=10.0 Hz, 3H).
MH+ 501.
1H NMR (400 MHz, CDCl3) δ 7.45-7.42 (m, 1H), 7.35-7.30 (m, 6H), 7.20-7.13 (m, 4H), 2.79 (q, J=9.8 Hz, 2H), 2.19 (dd, J=9.4, 6.1, 2H), 2.02 (dd, J=9.4, 6.1, 2H), 1.21 (t, J=9.8 Hz, 3H).
MH+ 613.
1H NMR (400 MHz, CDCl3) δ 7.47-7.44 (m, 2H), 7.39-7.37 (m, 1H), 7.36-7.34 (m, 1H), 7.33-7.32 (m, 1H), 7.29-7.25 (m, 4H), 7.04-7.02 (m, 2H), 2.45 (s, 3H), 1.95 (dd, J=7.2, 4.4 Hz, 2H), 1.53 (dd, J=7.2, 4.4 Hz, 2H).
MH+ 571.
1H NMR (400 MHz, CDCl3) δ 7.47-7.44 (m, 2H), 7.39 (d, J=2.0 Hz, 1H), 7.36-7.32 (m, 2H), 7.30-7.29 (m, 1H), 7.27-7.25 (m, 4H), 7.04-7.02 (m, 2H), 2.78 (q, J=7.6 Hz, 2H), 1.79 (dd, J=7.2, 4.8 Hz, 2H), 1.47 (dd, J=7.2, 4.8 Hz, 2H), 1.17 (t, J=7.6 Hz, 3H).
MH+ 586.
1H NMR (400 MHz, CDCl3) δ 7.48-7.43 (m, 3H), 7.39-7.36 (m, 2H), 7.29-7.22 (m, 4H), 7.05-7.03 (m, 2H), 2.88 (q, J=7.2 Hz, 2H), 1.94 (dd, J=7.2, 4.0 Hz, 2H), 1.52 (dd, J=7.2, 4.0 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H).
MH+ 629.
1H NMR (400 MHz, CDCl3) δ 7.47-7.44 (m, 3H), 7.38-7.35 (m, 2H), 7.29-7.22 (m, 4H), 7.04-7.01 (m, 2H), 2.27 (s, 3H), 1.90 (dd, J=8.3, 6.7 Hz, 2H), 1.44 (dd, J=8.3, 6.7 Hz, 2H).
MH+ 555.
1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=8.4 Hz, 2H), 7.30-7.19 (m, 5H), 7.14-7.12 (m, 2H), 7.07 (d, J=8.4 Hz, 2H), 3.51-3.43 (m, 1H), 1.90-1.88 (m, 2H), 1.45-1.43 (m, 2H), 1.21 (d, J=7.2 Hz, 6H).
MH+ 601.
1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 7.31-7.24 (m, 4H), 7.15 (d, J=8.4 Hz, 2H), 3.59-3.51 (m, 1H), 1.76-1.73 (m, 2H), 1.63-1.60 (m, 2H), 1.28 (d, J=6.8 Hz, 6H).
MH+ 559.
1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.32-7.27 (m, 4H), 7.12 (d, J=8.4 Hz, 2H), 2.87-2.83 (m, 2H), 1.69-1.57 (m, 6H), 0.88 (t, J=7.6 Hz, 2H).
MH+ 559.
1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.32-7.29 (m, 4H), 7.13 (d, J=8.8 Hz, 2H), 2.90 (q, J=7.6 Hz, 2H), 1.78-1.72 (m, 2H), 1.64-1.61 (m, 2H), 1.25 (t, J=7.6 Hz, 3H).
MH+ 545.
1H NMR (400 MHz, CDCl3) δ 7.51-7.44 (m, 1H), 7.37-7.22 (m, 6H), 7.15-7.05 (m, 4H), 2.87 (q, J=7.2 Hz, 2H), 2.05-1.99 (m, 2H), 1.55-1.52 (m, 2H), 1.22 (t, J=7.6 Hz, 3H).
MH+ 571.
1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.99 (s, 1H), 7.45-7.42 (m, 3H), 7.39-7.34 (m, 4H), 5.64 (s, 2H), 1.52 (s, 9H).
MH+ 544.
1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 7.96 (s, 1H), 7.53-7.50 (m, 2H), 7.45-7.44 (m, 1H), 7.39-7.36 (m, 2H), 7.35-7.30 (m, 2H), 5.63 (s, 2H), 1.52 (s, 9H).
MH+ 588.
1H NMR 400 MHz, CDCl3) δ 8.82 (s, 1H), 7.96 (s, 1H), 7.50-7.23 (m, 7H), 5.65 (s, 2H), 4.08-3.93 (m, 1H), 2.63-2.51 (m, 2H), 2.50-2.37 (m, 2H), 2.20-2.01 (m, 2H).
MH+ 542.
1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.16 (s, 1H), 7.49-7.31 (m, 7H), 5.69 (s, 2H), 3.23-3.12 (m, 1H), 2.24-2.15 (m, 2H), 1.98-1.91 (m, 2H), 1.65-1.21 (m, 6H).
MH+ 570.
1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.13 (s, 1H), 7.44-7.24 (m, 11H), 5.29 (s, 2H), 1.99-1.88 (m, 2H), 1.59-1.51 (m, 2H).
MH+ 638.
1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.05 (s, 1H), 7.50-7.46 (m, 2H), 7.42-7.21 (m, 10H), 5.63 (s, 2H), 1.98-1.90 (m, 2H), 1.61-1.53 (m, 2H).
MH+ 604.
1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.04 (s, 1H), 7.47-7.22 (m, 9H), 7.18-7.10 (m, 2H), 5.62 (s, 2H), 2.33 (s, 3H), 1.95-1.88 (m, 2H), 1.56-1.49 (m, 2H).
MH+ 618.
1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.07 (s, 1H), 7.49-7.21 (m, 9H), 6.92-6.83 (m, 2H), 5.64 (s, 2H), 3.78 (s, 3H), 1.98-1.87 (m, 2H), 1.65-1.49 (m, 2H).
MH+ 634.
1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.11 (s, 1H), 7.48-7.22 (m, 9H), 5.64 (s, 2H), 2.09-1.99 (m, 2H), 1.65-1.53 (m, 2H).
MH+ 672.
1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.01 (s, 1H), 7.48-7.28 (m, 7H), 5.65 (s, 2H), 1.83-1.61 (m, 4H).
MH+ 596.
1H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.28 (s, 1H), 7.47-7.45 (m, 1H), 7.43-7.31 (m, 6H), 5.72 (s, 2H), 2.84 (d, J=8.0 Hz, 4H), 2.20 (m, 2H).
MH+ 610.
1H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.28 (s, 1H), 7.43-7.23 (m, 11H), 5.70 (s, 2H), 3.10-3.01 (m, 2H), 2.89-2.78 (m, 2H), 2.42-2.31 (m, 1H), 2.10-1.98 (m, 1H).
MH+ 652.
1H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.34 (s, 1H), 7.45-7.25 (m, 12H), 5.69 (s, 2H), 2.84-2.75 (m, 2H), 2.41-2.32 (m, 2H), 1.95-1.80 (m, 4H).
MH+ 632.
1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 8.29 (s, 1H), 7.43-7.24 (m, 11H), 5.68 (s, 2H), 2.82-2.73 (m, 2H), 2.37-2.26 (m, 2H), 1.92-1.80 (m, 4H).
MH+ 666.
1H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.16 (s, 1H), 7.48-7.29 (m, 7H), 5.68 (s, 2H), 1.65 (s, 3H), 1.45-1.39 (m, 2H), 1.16-1.10 (m, 2H).
MH+ 543.
1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.25 (s, 1H), 7.58-7.54 (m, 2H), 7.47 (d, J=1.6 Hz, 1H), 7.39-7.31 (m, 4H), 5.69 (s, 2H), 1.77-1.65 (m, 4H).
MH+ 640.
1H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 8.18 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.46-7.40 (m, 2H), 7.38-7.24 (m, 8H), 5.67 (s, 2H), 2.05-1.93 (m, 2H), 1.59-1.52 (m, 2H).
MH+ 682.
1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.18 (s, 1H), 7.47-7.31 (m, 8H), 5.71 (s, 2H), 1.54 (s, 9H).
MH+ 510.
1H NMR (400 MHz, CDCl3) δ 7.49-7.45 (m, 2H), 7.44-7.43 (m, 1H), 7.32-7.31 (m, 2H), 7.09-7.06 (m, 2H), 5.39 (s, 2H), 2.00 (s, 3H), 1.51 (s, 9H).
MH+ 579.
1H NMR (400 MHz, CDCl3) δ 7.44-7.43 (m, 1H), 7.34-7.29 (m, 4H), 7.15-7.12 (m, 2H), 5.40 (s, 2H), 2.00 (s, 3H), 1.52 (s, 9H).
MH+ 535.
1H NMR (400 MHz, CDCl3) δ 7.48-7.45 (m, 2H), 7.44-7.43 (m, 1H), 7.30-7.29 (m, 2H), 7.09-7.07 (m, 2H), 4.70 (s, 2H), 1.52 (s, 9H).
MH+ 537.
1H NMR (400 MHz, CDCl3) δ 7.44-7.43 (m 1H), 7.33-7.29 (m, 4H), 7.24-7.12 (m, 2H), 4.70 (s, 2H), 1.54 (2, 9H).
MH+ 493.
1H NMR (400 MHz, CDCl3) δ 7.48-7.46 (m, 2H), 7.45-7.44 (m, 1H), 7.30-7.29 (m, 2H), 7.19-7.17 (m, 2H), 4.73 (s, 2H), 3.47 (s, 3H), 1.52 (s, 9H).
MH+ 551.
1H NMR (400 MHz, CDCl3) δ 7.51-7.45 (m, 3H), 7.33-7.32 (m, 2H), 7.17-7.14 (m, 2H), 5.74 (d, J=48.4 Hz, 2H), 1.53 (s, 9H).
MH+ 539.
1H NMR (400 MHz, CDCl3) δ 8.00-7.99 (m, 1H), 7.43-7.40 (m, 3H), 7.34-7.27 (m, 3H), 7.01-6.99 (m, 2H), 6.42-6.40 (m, 1H), 5.48 (s, 2H), 1.52 (s, 9H).
MH+ 682.
1H NMR (400 MHz, CDCl3) δ 10.80 (s, 1H), 7.48-7.42 (m, 3H), 7.34-7.26 (m, 2H), 7.20-7.07 (m, 2H), 1.53 (s, 9H).
MH+ 535.
1H NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.42-7.41 (m, 1H), 7.30-7.26 (m, 2H), 7.07-7.04 (m, 2H), 4.83-4.78 (m, 1H), 1.59 (d, J=6.8 Hz, 3H), 1.52 (s, 9H).
MH+ 551.
MH+ 507.
MH+ 553.
1H NMR (400 MHz, CDCl3) δ 7.48-7.44 (m, 2H), 7.42-7.40 (m, 1H), 7.29-7.21 (m, 3H), 7.15-7.11 (m, 2H), 5.43 (dd, J=18, 1.6 Hz, 1H), 5.22 (dd, J=11.6, 1.6 Hz, 1H), 1.51 (s, 9H).
MH+ 533.
1H NMR (400 MHz, CDCl3) δ 7.51-7.41 (m, 3H), 7.27-7.22 (m, 4H), 5.02 (bs, 1H), 3.62 (s, 3H), 1.53 (s, 9H), 1.48 (d, J=7.2 Hz, 3H).
MH+ 609.
1H NMR (400 MHz, CDCl3) δ 7.46-7.43 (m, 3H), 7.30-7.29 (m, 2H), 7.15-7.12 (m, 2H), 2.53 (s, 3H), 1.52 (s, 9H).
MH+ 549.
MH+ 565.
1H NMR (400 MHz, CDCl3) δ 7.43-7.39 (m, 3H), 7.34 (d, J=8.4 Hz, 1H), 7.31-7.28 (m, 1H), 7.07-7.03 (m, 2H), 5.29-5.24 (m, 1H), 4.97-4.96 (m, 1H), 2.10 (s, 3H), 1.51 (s, 9H).
MH+ 547.
1H NMR (400 MHz, CDCl3) δ 7.45-7.38 (m, 1H), 7.41-7.34 (m, 4H), 7.25-7.23 (m, 2H), 4.07-4.02 (m, 1H), 2.60-2.56 (m, 2H), 2.54-2.48 (m, 2H), 2.18-2.05 (m, 2H).
MH+ 497.
1H NMR (400 MHz, CDCl3) δ 7.45-7.44 (m, 1H), 7.38-7.33 (m, 4H), 7.26-7.22 (m, 2H), 1.86 (q, J=7.6 Hz, 2H), 1.52 (s, 3H), 1.50 (s, 3H), 0.89 (t, J=7.6 Hz, 3H).
MH+ 514.
1H NMR (400 MHz, CDCl3) δ 7.46-7.40 (m, 2H), 7.37-7.32 (m, 3H), 7.26-7.22 (m, 2H), 3.26-3.24 (m, 1H), 2.22-1.86 (m, 4H), 1.56-1.44 (m, 6H).
MH+ 525.
1H NMR (400 MHz, CDCl3) δ 7.46-7.41 (m, 2H), 7.39-7.26 (m, 3H), 7.24-7.20 (m, 2H), 3.36-3.32 (m, 1H), 1.87-1.75 (m, 2H), 1.48 (d, J=6.9 Hz, 3H), 0.99 (t, J=7.2 Hz).
MH+ 499
1H NMR (400 MHz, CDCl3) δ 7.49-7.41 (m, 2H), 7.38-7.24 (m, 3H), 7.23-7.19 (m, 2H), 1.59 (s, 9H).
MH+ 499.
1H NMR (400 MHz, CDCl3) δ 7.51-7.48 (m, 2H), 7.38-7.27 (m, 3H), 7.23-7.19 (m, 2H), 1.55 (s, 9H).
MH+ 544.
1H NMR (400 MHz, CDCl3) δ 7.44-7.42 (m, 1H), 7.40-7.37 (m, 1H), 7.35-7.32 (m, 3H), 7.25-7.21 (m, 2H), 3.37-3.32 (m, 1H), 1.87-1.76 (m, 2H), 1.45 (d, J=6.8 Hz, 3H), 0.91 (t, J=7.2, 3H).
MH+ 543.
1H NMR (400 MHz, CDCl3) δ 7.44-7.42 (m, 1H), 7.37-7.31 (m, 4H), 7.25-7.22 (m, 2H), 4.12-4.01 (m, 1H), 2.61-2.57 (m, 2H), 2.53-2.39 (m, 2H), 2.19-2.05 (m, 2H).
MH+ 541.
1H NMR (400 MHz, CDCl3) δ 7.43-7.37 (m, 2H), 7.34-7.31 (m, 3H), 7.25-7.21 (m, 2H), 3.02-2.97 (m, 1H), 2.16-2.11 (m, 2H), 1.87-1.76 (m, 2H), 1.73-1.68 (m, 3H), 1.44-1.33 (m, 3H).
MH+ 569.
1H NMR (400 MHz, CDCl3) δ 7.44-7.43 (m, 2H), 7.38-7.33 (m, 3H), 6.99-6.95 (m, 2H), 1.66 (dq, J=28.8, 7.2 Hz, 2H), 1.49 (s, 3H), 1.42 (s, 3H), 0.83 (t, J=18.8, 7.2 Hz, 3H).
MH+ 557.
1H NMR (400 MHz, CDCl3) δ 7.45-7.41 (m, 1H), 7.38-7.33 (m, 4H), 7.27-7.24 (m, 3H), 7.22-7.18 (m, 2H), 7.12-7.08 (m, 1H), 1.92 (s, 3H), 1.81 (s, 3H).
MH+ 639.
1H NMR (400 MHz, CDCl3) δ 7.46-7.42 (m, 1H), 7.39-7.36 (m, 4H), 7.27-7.24 (m, 3H), 7.21-7.18 (m, 2H), 7.12-7.08 (m, 1H), 2.01 (dd, J=9.1, 6.7 Hz, 2H), 1.49 (dd, J=9.1, 6.7 Hz, 2H).
MH+ 635.
Thionyl chloride (1.3 ml, 22.0 mmol) was added to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (2.09 g, 5.5 mmol) in toluene (50 ml) maintained at room temperature. The mixture was refluxed at 110° C. for 2 hours and then cooled to room temperature. The resulting solution was evaporated and dried under a vacuum to produce crude 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride, which are not further purified. 27% aqueous ammonia (2 ml) was added to the solution of crude 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride in methylene chloride (10 ml) at 0° C. After stirring 3 hours at room temperature, the resulting solution was quenched with saturated ammonium chloride which was extracted twice with 50 ml portions of ethyl acetate. After concentrating the extract by evaporation, the crude residue was purified using a silica gel column (hexane/ethyl acetate=1/1), to obtain the title compound (2.07 g, 99%) as white solid.
Added dropwise to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (1.57 g, 4.1 mmol) obtained in Step 1 dissolved in dimethylformamide (10 ml) at 0° C., was phosphoryl chloride (0.72 ml, 8.2 mmol). The resulting mixture was stirred for 20 minutes at 0° C. and then stirred for 1 hour at room temperature. The reaction mixture was quenched with water at 0° C., and an mixture was extracted with ethyl acetate (30 ml twice). After removing the solvent, 5-(4-chloro phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonitrile was obtained by column chromatography as white solid (1.47 g, quantativly).
1H NMR (400 MHz, CDCl3) δ 7.40 (br s, 1H), 7.31-7.27 (m, 4H), 7.08-7.03 (m, 2H), 2.33 (s, 3H), 2.31 (t, J=7.8 Hz, 2H), 1.72 (m, 1H), 0.97 (t, J=7.3 Hz, 3H).
MH+ 463.
Potassium carbonate (0.58 g, 4.14 mmol) was added to a sealed tube containing a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonitrile (1.0 g, 2.76 mmol) obtained in Step 2, hydroxylamine hydrochloride (0.39 g, 5.52 mmol) dissolved in MeOH (16 mL). The mixture was stirred vigorously and heated at 100° C. for 16 hr. The white precipitate formed was filtered and washed twice with cold water. It was further dried under a high vacuum. The filtrate was extracted with chloroform (30 mL×2), dried over MgSO4, filtered and evaporated under a vacuum, to obtain the title product in a compound amount of 1.04 g (2.63 mmol, 95%).
1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.27 (s, 1H), 7.69 (d, J=2.2 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.51 (dd, J=2.2, 8.4 Hz, 1H), 7.41 (br d, J=8.6 Hz, 2H), 7.19 (br d, J=8.6 Hz, 2H), 5.49 (br s, 1H), 2.20 (s, 3H).
MH+ 395.
NMM (0.42 mL, 3.77 mmol) was added to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-hydroxy-4-methyl-1H-pyrazole-3-carboxamid amide (0.30 g, 0.75 mmol) obtained in Step 3, cyclohexylcarboxylic acid (97 mg, 0.75 mmol), HOBt (194 mg, 1.43 mmol) and EDCI (220 mg, 1.13 mmol) dissolved in DCM (7 mL). The mixture was stirred overnight at room temperature. After adding thereto EtOAc (30 mL), the mixture was successively washed with water, saturated NaHCO3 solution (20 mL) and brine (20 mL). The organic layer was isolated, dried over MgSO4, filtered, and concentrated under a vacuum, to obtain 5-(4-chlorophenyl)-N-(cyclohexanecarbonyloxy)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximidamide as a white solid, which was used in the next step without further purification. The crude material was dissolved in pyridine (4 mL), and was subjected to microwave irradiation at 180° C. for 20 min., to remove volatile components under a vacuum. The residue was further purified by reverse phase preparative HPLC, to obtain the title compound as white solid (67 mg, 0.137 mmol, 18% via two steps).
1H NMR (300 MHz, CDCl3) δ 7.42-7.38 (m, 2H), 7.34-7.28 (m, 3H), 7.14-7.09 (m, 2H), 3.06 (m, 1H), 2.39 (s, 3H), 2.14 (m, 2H), 1.88-1.81 (m, 2H), 1.80-1.68 (m, 2H), 1.48-1.25 (m, 4H).
(M+Na)+ 509.
The following compounds of Examples 549 to 564 were obtained by using corresponding starting materials and repeating the procedure of Example 548.
1H NMR (300 MHz, CDCl3) δ 7.42-7.38 (m, 2H), 7.34-7.28 (m, 3H), 7.14-7.09 (m, 2H), 3.45 (m, 1H), 2.39 (s, 3H), 2.20 (m, 2H), 2.06 (m, 2H), 1.86 (m, 2H), 1.72 (m, 2H).
(M+Na)+ 495.
1H NMR (300 MHz, CDCl3) δ 7.42-7.38 (m, 2H), 7.34-7.28 (m, 3H), 7.14-7.09 (m, 2H), 3.01 (m, 1H), 2.40 (s, 3H), 1.99-1.75 (m, 4H), 0.92 (t, J=7.5 Hz, 3H).
(M+Na)+ 497.
1H NMR (300 MHz, CDCl3) δ 7.41-7.27 (m, 10H), 7.13-7.09 (m, 2H), 4.33 (s, 2H), 2.38 (s, 3H), 2.67-2.42 (m, 4H), 2.39 (s, 3H), 2.24-2.02 (m, 2H).
(M+Na)+ 517.
1H NMR (300 MHz, CDCl3) δ 7.42-7.38 (m, 2H), 7.34-7.28 (m, 3H), 7.14-7.10 (m, 2H), 3.86 (m, 1H), 2.67-2.42 (m, 4H), 2.39 (s, 3H), 2.24-2.02 (m, 2H).
(M+Na)+ 481.
1H NMR (300 MHz, CDCl3) δ 7.42-7.37 (m, 2H), 7.32-7.27 (m, 3H), 7.13-7.10 (m, 2H), 3.25 (m, 1H), 2.39 (s, 3H), 2.24-2.15 (m, 2H), 2.01-1.81 (m, 4H), 1.65-1.60 (m, 6H).
(M+Na)+523.
1H NMR (400 MHz, CDCl3) δ 7.41-7.37 (m, 2H), 7.32-7.27 (m, 3H), 7.13-7.10 (m, 2H), 2.89 (d, J=6.88 Hz, 2H), 2.40 (s, 3H), 1.26 (m, 1H), 0.64 (m, 2H), 0.35 (AB q, J=5.04 Hz, 2H).
MH+ 459.
1H NMR (400 MHz, CDCl3) δ 7.41-7.37 (m, 2H), 7.32-7.27 (m, 3H), 7.13-7.10 (m, 2H), 2.98 (d, J=7.80 Hz, 2H), 2.46 (m, 1H), 2.40 (s, 3H), 1.98 (m, 1H), 1.91-1.82 (m, 2H), 1.72-1.52 (m, 4H), 1.36-1.25 (m, 2H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.41-7.37 (m, 2H), 7.32-7.27 (m, 3H), 7.13-7.10 (m, 2H), 2.86 (d, J=7.36 Hz, 2H), 2.40 (s, 3H), 1.98 (m, 1H), 1.80-1.62 (m, 5H), 1.33-1.10 (m, 5H).
MH+ 501.
MH+ 447.
MH+ 445.
1H NMR (400 MHz, CDCl3) δ 7.42-7.37 (m, 2H), 7.33-7.28 (m, 3H), 7.14-7.11 (m, 2H), 3.14 (m, 1H), 2.40 (s, 3H), 2.95 (m, 1H), 1.78 (m, 1H), 1.45 (d, J=6.9 Hz, 3H), 0.97 (t, J=7.6 Hz, 3H).
MH+ 461.
1H NMR (400 MHz, CDCl3) δ 7.40-7.35 (m, 2H), 7.32-7.27 (m, 3H), 7.14-7.11 (m, 2H), 3.25 (m, 1H), 2.39 (s, 3H), 1.91 (m, 1H), 1.70 (m, 1H), 1.43 (d, J=7.3 Hz), 1.36 (m, 1H), 0.92 (t, J=7.3 Hz, 3H).
MH+ 475.
1H NMR (400 MHz, CDCl3) δ 7.43-7.37 (m, 2H), 7.33-7.28 (m, 3H), 7.14-7.11 (m, 2H), 3.23 (m, 1H), 2.40 (s, 3H), 1.98-1.88 (m, 1H), 1.77-1.67 (m, 1H), 1.44 (d, J=6.5 Hz, 3H), 1.39-1.23 (m, 4H), 0.89 (t, J=7.1 Hz, 3H).
MH+ 489.
1H NMR (400 MHz, CDCl3) δ 7.41-7.37 (m, 2H), 7.34-7.27 (m, 3H), 7.14-7.10 (m, 2H), 5.76 (s, 2H), 3.83 (m, 1H), 2.92 (d, J=8.24 Hz, 4H), 2.39 (s, 3H).
MH+ 471.
1H NMR (400 MHz, CDCl3) δ 7.40-7.36 (m, 2H), 7.33-7.27 (m, 3H), 7.12-7.09 (m 2H), 2.37 (s, 3H), 1.99 (m, 1H), 1.73 (m, 1H), 1.54 (m, 1H), 1.23 (d, J=6.0 Hz, 3H), 1.04 (m, 1H).
MH+ 459.
MH+ 495.
A mixture of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonitrile (500 mg, 1.39 mmol), sodium azide (1.08 g, 16.6 mmol) and ammonium chloride (890 mg, 16.6 mmol) dissolved in dimethylformamide (3 ml) was placed in a microwave synthesizer tube, and subjected to microwave irradiation in a Biotage® Initiator was set at 180° C. After 20 minutes, the mixture was quenched with water and extracted with ethyl acetate. The solvent of the extracted organic layer was evaporated off and the residue was purified by reverse phase preparative HPLC, to obtain 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-1H-tetrazole (550 mg, 98%) as white solid.
MH+ 404.
5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-1H-tetrazole (150 mg, 0.37 mmol) obtained in Step 1 was dissolved in dimethylformamide (1 ml), and potassium carbonate (250 mg, 1.85 mmol) and 1-iodopropane (0.07 ml, 1.1 mmol) were added thereto at room temperature. After stirring for 5 hours, the resulting solution was quenched with water (1 ml) and the mixture was three time extracted with 5 ml portion of ethyl acetate. The solvent of the extracted organic layer was evaporated under a reduced pressure and the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=1/7 to hexane/ethyl acetate=1/5), to obtain two compounds, one of which was the title compound (61 mg, 37%) in the form of white solid.
1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=2.28 Hz, 1H), 7.36-7.32 (m, 2H), 7.29 (dd, J=8.72, 2.28 Mz, 1H), 7.18 (d, J=8.68 Hz, 1H), 7.14-7.10 (m, 2H), 4.78 (t, J=7.32 Hz, 2H), 2.46 (s, 3H), 2.03-1.93 (m, 20.94 (t, J=7.32 Hz, 3H).
MH+ 447.
The title compound (62 mg, 37%) was the other compound obtained as white solid in Example 565, which was relatively more polar than the compound of Example 565. 1H NMR (400 MHz, CDCl3) δ 7.41-7.38 (m, 2H), 7.33-7.28 (m, 3H), 7.15-7.12 (m, 2H), 4.66 (t, J=5.16, 2H), 2.46 (s, 3H), 2.17-2.07 (m, 2H), 1.01 (t, J=5.52 Hz, 3H).
MH+ 447.
The following compounds of Examples 567 to 592 were obtained by using corresponding starting materials and repeating the procedure of Example 565 and 566.
1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=2.32 Hz, 1H), 7.35-7.22 (m, 4H), 7.14-7.10 (m, 2H), 4.39 (s, 3H), 2.47 (s, 3H).
MH+ 419.
1H NMR (400 MHz, CDCl3) δ 7.40-7.38 (m, 2H), 7.33-7.27 (m, 3H), 7.14-7.12 (m, 2H), 4.44 (s, 3H), 2.46 (s, 3H).
MH+ 421.
1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=1.71 Hz, 1H), 7.36-7.28 (m, 3H), 7.20 (d, J=6.51 Hz, 1H), 7.14-7.10 (m, 2H), 4.86 (q, J=5.52 Hz, 2H), 2.47 (s, 3H), 1.56 (t, J=5.52 Hz, 3H).
MH+ 433.
1H NMR (400 MHz, CDCl3) δ 7.41-7.38 (m, 2H), 7.33-7.27 (m, 3H), 7.15-7.12 (m, 2H), 4.75 (q, J=7.36 Hz, 2H), 2.46 (s, 3H), 1.71 (t, J=7.36 Hz, 3H).
MH+ 433.
1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=2.32 Hz, 1H), 7.35-7.27 (m, 3H), 7.19 (d, J=8.72 Hz, 1H), 7.14-7.10 (m, 2H), 4.82 (t, J=7.32 Hz, 2H), 2.46 (s, 3H), 1.97-1.89 (m, 2H), 1.55-1.33 (m, 2H), 0.91 (t, J=7.36 Hz, 3H).
MH+ 460.
1H NMR (400 MHz, CDCl3) δ 7.41-7.38 (m, 2H), 7.33-7.27 (m, 3H), 7.15-7.12 (m, 2H), 4.70 (t, J=7.32 Hz, 2H), 2.46 (s, 3H), 2.10-2.03 (m, 2H), 1.44-1.38 (m, 2H), 0.98 (t, J=7.32 Hz, 3H).
MH+ 459.
1H NMR (300 MHz, CDCl3) δ 7.50 (d, J=2.22 Hz, 1H), 7.36-7.27 (m, 3H), 7.19 (d, J=11.24 Hz, 1H), 7.14-7.10 (m, 2H), 4.81 (t, J=9.76 Hz, 2H), 2.46 (s, 3H), 1.97-1.83 (m, 2H), 1.32-1.25 (m, 4H), 0.86-81 (m, 3H).
MH+ 475.
1H NMR (300 MHz, CDCl3) δ 7.42-7.39 (m, 2H), 7.34-7.27 (m, 3H), 7.15-7.12 (m, 2H), 4.69 (t, J=7.14 Hz, 2H), 2.46 (s, 3H), 2.11-2.09 (m, 2H), 1.37-1.36 (m, 4H), 0.92-0.88 (m, 3H).
MH+ 477.
1H NMR (300 MHz, CDCl3) δ 7.49 (d, J=2.19 Hz, 1H), 7.36-7.27 (m, 3H), 7.20 (d, J=8.61 Hz, 1H), 7.14-7.10 (m, 2H), 5.68-5.61 (m, 1H), 2.44 (s, 3H), 1.66 (s, 3H), 1.63 (s, 3H).
MH+ 449.
1H NMR (300 MHz, CDCl3) δ 7.42-7.38 (m, 2H), 7.33-7.27 (m, 3H), 7.15-7.12 (m, 2H), 5.22-5.12 (m, 1H), 2.46 (s, 3H), 1.74 (s, 3H), 1.72 (s, 3H).
MH+ 447.
1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=2.28 Hz, 1H), 7.35-7.27 (m, 3H), 7.20 (d, J=8.72 Hz, 1H), 7.14-7.09 (m, 2H), 5.75-5.67 (m, 1H), 2.44 (s, 3H), 2.24-2.16 (m, 4H), 2.04-1.98 (m, 2H), 1.78-1.68 (m, 2H).
MH+ 473.
1H NMR (400 MHz, CDCl3) δ 7.41-7.36 (m, 2H), 7.33-7.27 (m, 3H), 7.15-7.11 (m, 2H), 5.34-5.27 (m, 1H), 2.44 (s, 3H), 2.37-2.24 (m, 4H), 2.04-1.94 (m, 2H), 1.84-1.73 (m, 2H).
MH+ 473.
1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=2.28 Hz, 1H), 7.36-7.26 (m, 3H), 7.16-7.10 (m, 3H), 5.25-5.17 (m, 1H), 2.42 (s, 3H), 2.19-1.30 (m, 10H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.41-7.38 (m, 2H), 7.35-7.27 (m, 3H), 7.15-7.10 (m, 2H), 4.84-4.76 (m, 1H), 2.45 (s, 3H), 2.31-1.31 (m, 10H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=2.28 Hz, 1H), 7.37-7.26 (m, 8H), 7.19 (d, J=8.24 Hz, 1H), 7.11-7.07 (m, 2H), 6.05 (s, 2H), 2.44 (s, 3H).
MH+ 496.
1H NMR (400 MHz, CDCl3) δ 7.45-7.43 (m, 2H), 7.39-7.27 (m, 8H), 7.13-7.10 (m, 2H), 5.85 (s, 2H), 2.43 (s, 3H).
MH+ 497.
1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=4.53, 1H), 7.61-7.57 (m, 1H), 7.42 (d, J=2.32 Hz, 1H), 7.33-7.30 (m, 2H), 7.27-7.24 (m, 2H), 7.20-7.17 (m, 2H), 7.11-7.05 (m, 3H), 7.00 (d, J=7.80 Hz, 1H), 6.21 (s, 2H), 2.48 (s, 3H).
MH+ 496.
1H NMR (400 MHz, CDCl3) δ 8.61-8.59 (m, 1H), 7.71-7.66 (m, 1H), 7.40-7.37 (dd, J=5.04, 2.72 Hz, 2H), 7.33-7.26 (m, 4H), 7.18 (d, J=8.24 Hz, 1H), 7.14-7.11 (m, 2H), 6.03 (s, 2H), 2.45 (s, 3H).
MH+ 498.
1H NMR (400 MHz, CDCl3) δ 8.65 (d, J=1.84, 1H), 8.54 (dd, J=4.56, 1.36 Hz, 1H), 7.23-7.70 (m, 1H), 7.50 (d, J=2.32 Hz, 1H), 7.35-7.31 (m, 3H), 7.26-7.20 (m, 2H), 7.11-7.08 (m, 2H), 6.09 (s, 2H), 2.46 (s, 3H).
MH+ 496.
1H NMR (400 MHz, CDCl3) δ 8.76 (d, J=1.84 Hz, 1H), 8.62 (dd, J=5.04, 1.84 Hz, 1H), 7.79-7.76 (m, 1H), 7.39-7.36 (m, 2H), 7.33-7.27 (m, 4H), 7.13-7.10 (m, 2H), 5.88 (s, 2H), 2.43 (s, 3H).
MH+ 498.
1H NMR (400 MHz, CDCl3) δ 8.54-8.52 (m, 2H), 7.48 (d, J=2.28 Hz, 1H), 7.34-7.28 (m, 3H), 7.14-7.07 (m, 5H), 6.07 (s, 2H), 2.47 (s, 3H).
MH+ 496.
1H NMR (400 MHz, CDCl3) δ 8.64-8.62 (m, 2H), 7.40-7.13 (m, 7H), 7.14-7.11 (m, 2H), 5.87 (s, 2H), 2.45 (s, 3H).
MH+ 496.
1H NMR (300 MHz, CDCl3) δ 7.51 (d, J=2.4 Hz, 1H), 7.36-7.26 (m, 3H), 7.18-7.09 (m, 3H), 4.68 (d, J=7.32 Hz, 2H), 2.46 (s, 3H), 2.04-2.00 (m, 1H), 1.68-0.90 (m, 10H).
MH+ 501.
1H NMR (300 MHz, MeOH-d4) δ 7.58-7.55 (m, 2H), 7.47-7.44 (m, 1H), 7.41-7.37 (m, 2H), 7.27-7.23 (m, 2H), 4.60 (d, J=7.14 Hz, 2H), 2.39 (s, 3H), 2.18-2.02 (m, 1H), 1.77-0.86 (m, 10H).
MH+ 501.
1H NMR (300 MHz, CDCl3) δ 7.52 (d, J=2.37 Hz, 1H), 7.36-7.07 (m, 11H), 5.04 (t, J=7.68 Hz, 2H), 3.24 (t, J=7.86 Hz, 2H), 2.39 (s, 3H).
MH+ 508.
1H NMR (300 MHz, CDCl3) δ 7.42-7.39 (m, 2H), 7.34-7.26 (m, 6H), 7.25-7.19 (m, 2H), 7.16-7.11 (m, 2H), 4.92 (t, J=7.68 Hz, 2H), 3.41 (t, J=7.89 Hz, 2H), 2.45 (2, 3H).
MH+ 509.
A mixture of 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-1H-tetrazole (113 mg, 0.28 mmol) obtained in Step 1 of Example 52, furfuryl alcohol (0.05 ml, 0.56 mmol) and triphenylphosphine (146 mg, 0.56 mmol) was dissolved in tetrahydronfuran (3 ml) and cooled down to 0° C. Then, diisopropyl azodicarboxylate (0.11 ml, 0.56 mmol) was slowly added thereto at 0° C. After stirring for 2 hours at room temperature, the resulting solution was quenched with saturated ammonium chloride solution (1 ml). The mixture was extracted with ethyl acetate, and then the solvent of the organic layer was removed under a reduced pressure. The residue contained two regioisomers were separated by silica gel column chromatography (hexane/ethyl acetate=1/5), and repurified by reverse phase preparative HPLC, to obtain two compound, one of which was the title compound (22 mg, 16%).
1H NMR (400 MHz, CDCl3) δ 7.50-7.47 (m, 1H), 7.35-7.23 (m, 6H), 7.14-7.10 (m, 3H), 6.07 (s, 2H), 2.46 (s, 3H).
MH+ 484.
The title compound (24 mg, 18%) was the other regioisomer obtained as white solid in Example 593, which is relatively more polar than the compound of Example 593.
1H NMR (400 MHz, CDCl3) δ 7.48-7.27 (m, 7H), 7.14-7.10 (m, 3H), 5.86 (s, 2H), 2.43 (s, 3H).
MH+ 485.
The following compounds of Examples 595 to 598 were obtained by using corresponding starting materials and repeating the procedure of Example 593 and 594.
1H NMR (400 MHz, CDCl3) δ 7.50-7.51 (m 1H), 7.46 (s, 1H), 7.36-7.31 (m, 4H), 7.25-7.23 (m, 1H), 7.14-7.10 (m, 2H), 6.46 (s, 1H), 5.91 (s, 2H), 2.47 (s, 3H).
MH+ 484.
1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.41-7.37 (m, 3H), 7.32-7.27 (m, 3H), 7.14-7.10 (m, 2H), 6.52 (m, 2H), 5.73 (s, 2H), 2.44 (s, 3H).
MH+ 484.
1H NMR (300 MHz, CDCl3) δ 7.51 (d, J=2.19 Hz, 1H), 7.35-7.30 (m, 4H), 7.26-7.21 (m, 2H), 7.13-7.09 (m, 3H), 6.06 (s, 2H), 2.45 (s, 3H).
MH+ 501.
1H NMR (300 MHz, CDCl3) δ 7.43-7.41 (m, 1H), 7.40-737 (m, 2H), 7.33-7.27 (m, 4H), 7.18 (dd, J=4.95, 1.29 Hz, 1H), 7.14-7.10 (m, 2H), 5.87 (s, 2H), 2.44 (s, 3H).
MH+ 501.
Crude 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (150 mg, 0.37 mmol) was dissolved in methylene chloride (3 ml) at 0° C., and triethyl amine (0.05 ml, 1.11 mmol) and cyclopropyl amine (0.03 ml, 0.56 mmol) were slowly added thereto. The resulting solution was stirred at room temperature for 3 hours, quenched with saturated ammonium chloride solution, extracted with ethyl acetate and filtrated with magnesium sulfate. The crude solution was evaporated and dried under a reduced pressure, to obtain 5-(4-chlorophenyl)-N-cyclopropyl-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, which are not further purified. The resulting product was dissolved in benzene (3 ml), and phosphorus pentachloride (85 mg, 0.41 mmol) was added thereto at room temperature. The solution was stirred for 20 minutes, hydroazoic aicd (1.0 ml, 2.0 M solution in benzene) was added thereto and maintained room temperature for overnight. For completion of the reaction, reaction solution was refluxed for 10 minutes and purified by reverse phase preparative HPLC, to obtain the title compound (83 mg, 50%) as white solid.
1H NMR (300 MHz, CDCl3) δ 7.49-7.47 (m, 1H0, 7.34-7.22 (4H), 7.14-7.11 (m, 2H), 4.44 (m, 1H), 2.44 (s, 3H), 1.46-1.40 (m, 2H), 1.24-1.18 (m, 2H).
MH+ 445.
The following compounds of Examples 600 to 610 were obtained by using corresponding starting material and repeating the procedure of Example 599.
1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=2.32 Hz, 1H), 7.35-7.29 (m, 3H), 7.22 (d, J=8.24 Hz, 1H), 7.13-7.09 (m, 2H), 5.75-5.67 (m, 1H), 2.86-2.75 (m, 2H), 2.62-2.53 (m, 2H), 2.43 (s, 3H), 2.03-1.85 (m, 2H).
MH+ 459.
1H NMR (300 MHz, CDCl3) δ 7.42 (m, 1H), 7.36-7.26 (m, 3H), 7.07-7.04 (m, 2H), 6.91-6.88 (m, 1H), 4.13 (m, 1H), 2.37 (s, 3H), 2.08-2.02 (m, 2H), 1.75-1.52 (m, 8H), 1.27-1.22 (m, 3H), 0.93-0.82 (m, 3H).
MH+ 500.
1H NMR (300 MHz, CDCl3) δ 7.44-7.43 (m, 1H), 7.34-7.26 (m, 4H), 7.07-7.03 (m, 2H), 2.25 (s, 3H), 1.58 (s, 9H).
MH+ 460.
1H NMR (300 MHz, CDCl3) δ 7.43-7.42 (m, 1H), 7.32-7.23 (m, 2H), 7.07-7.04 (m, 2H), 6.94 (m, 1H), 3.41 (q, J=6.96 Hz, 2H), 2.38 (s, 3H), 1.63-1.25 (m, 7H), 0.91-0.85 (m, 4H).
MH+ 489.
1H NMR (300 MHz, CDCl3) δ 7.43-7.41 (m, 1H), 7.31-7.24 (m, 3H), 7.10-7.03 (m, 2H), 6.94-6.92 (m, 1H), 3.41 (q, J=7.14 Hz, 2H), 2.38 (s, 3H), 1.62-0.85 (m, 15H).
MH+ 516.
1H NMR (300 MHz, CDCl3) δ 7.47 (d, J=2.22 Hz, 1H), 7.34-7.28 (m, 4H), 7.15-7.12 (m, 2H), 2.42 (s, 6H), 2.20 (br, 3H), 2.12 (s, 3H), 1.76 (m, 6H).
MH+ 541.
1H NMR (400 MHz, CDCl3) δ 7.50-7.47 (m, 3H), 7.31-7.28 (m, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.06-7.03 (m, 2H), 5.73-5.69 (m, 1H), 2.43 (s, 3H), 2.27-2.16 (m, 4H), 2.06-1.96 (m, 2H), 1.77-1.67 (m, 2H).
MH+ 517.
1H NMR (400 MHz, CDCl3) δ 7.52-7.48 (m, 3H), 7.29-7.26 (m, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.06-7.04 (m, 2H), 5.23-5.18 (m, 1H), 2.42 (s, 3H), 2.18-2.15 (m, 2H), 2.03-2.00 (m, 2H), 1.93-1.90 (m, 2H), 1.41-1.34 (m, 4H).
MH+ 531.
1H NMR (400 MHz, CDCl3) δ 7.51-7.47 (m, 3H), 7.27 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.05-7.03 (m, 2H), 5.43-5.41 (m, 1H), 2.41 (s, 3H), 2.21-2.15 (m, 4H), 1.86-1.82 (m, 2H), 1.66-1.63 (m, 4H), 1.51-1.49 (m, 2H).
MH+ 545.
1H NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 3H), 7.29-7.26 (m, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.08-7.04 (m, 2H), 5.72-5.65 (m, 1H), 2.88-2.82 (m, 2H), 2.22-2.16 (m, 4H), 2.02-1.96 (m, 2H), 1.74-1.67 (m, 2H), 1.16 (t, J=7.6 Hz, 3H).
MH+ 531.
1H NMR (400 MHz, CDCl3) δ 7.47-7.46 (m, 1H), 7.34-7.30 (m, 2H), 7.28-7.26 (m, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.14-7.11 (m, 2H), 5.71-5.67 (m, 1H), 2.85 (q, J=7.6 Hz, 2H), 2.22-2.16 (m, 4H), 2.02-1.97 (m, 2H), 1.73-1.69 (m, 2H), 1.16 (t, J=7.6 Hz, 3H).
MH+ 487.
A solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonitrile (300 mg, 0.83 mmol), cyclopentanecarbohydrazide (116 mg, 0.90 mmol) and potassium carbonate (57 mg, 0.41 mmol) dissolved in 1-butanol (2 ml) was placed in a sealed tube, stirred at room temperature for 10 minutes and then refluxed at 150° C. for 1 day. The mixture was cooled down to room temperature and methanol (4 ml) was added thereto, followed by filtering. The filtrate was purified by reverse phase preparative HPLC, to obtain the title compound as white solid.
1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=2.32 Hz, 1H), 7.35-7.27 (m, 3H), 7.07-7.03 (m, 2H), 3.32-3.23 (m, 1H), 2.25 (s, 3H), 2.17-2.08 (m, 2H), 1.98-1.78 (m, 4H), 1.74-1.67 (m, 2H).
MH+ 472.
The following compounds of Examples 612 to 636 were obtained by using corresponding starting materials and repeating the procedure of Example 611.
1H NMR (400 MHz, CDCl3) δ 7.39-7.35 (m, 2H), 7.32-7.27 (m, 3H), 7.12-7.09 (m, 2H), 2.91-2.84 (m, 1H), 2.43 (s, 3H), 2.17-2.10 (m, 2H), 1.87-1.83 (m, 2H), 1.75-1.73 (m, 1H), 1.67-1.58 (m, 3H), 1.46-1.28 (m, 2H).
MH+ 486.
1H NMR (400 MHz, CDCl3) δ 8.21-8.18 (m, 2H), 7.47-7.42 (m, 4H), 7.35-7.29 (m, 4H), 7.14-7.12 (m, 2H), 2.54 (s, 3H).
MH+ 480.
1H NMR (400 MHz, CDCl3) δ 7.44-7.43 (m, 1H), 7.35-7.81 (m, 4H), 7.31-7.29 (m, 1H), 7.14-7.11 (m, 2H), 7.07-7.03 (m, 2H), 2.25 (s, 3H).
MH+ 486.
1H NMR (400 MHz, CDCl3) δ 7.40-7.35 (m, 2H), 7.32-7.27 (m, 3H), 7.12-7.09 (m 2H), 3.11-3.04 (m, 1H), 2.43 (s, 3H), 2.18-2.12 (m, 2H), 1.89-1.80 (m, 4H), 1.70-1.55 (m, 6H).
MH+ 502.
1H NMR (400 MHz, CDCl3) δ 7.43 (m, 1H), 7.34-7.27 (m, 5H), 7.14-7.10 (m, 2H), 7.07-7.04 (m, 2H), 2.25 (s, 3H).
MH+Na 493.
1H NMR (400 MHz, CDCl3) δ 7.41-7.32 (m, 2H), 7.34-7.27 (m, 3H), 7.08-7.05 (m, 2H), 2.57-2.50 (m, 2H), 2.15 (s, 3H), 1.70-1.65 (m, 2H), 1.01-0.98 (m, 3H).
MH+ 445.
1H NMR (400 MHz, CDCl3) δ 7.40-7.26 (m, 5H), 7.12-7.09 (m 2H), 3.23-3.18 (m, 1H), 2.44 (s, 3H), 1.43 (s, 3H), 1.41 (s, 3H).
MH+ 447.
1H NMR (400 MHz, CDCl3) δ 7.40-7.27 (m, 5H), 7.12-7.09 (m, 2H), 2.41 (s, 3H), 2.10-2.04 (m, 1H), 1.34-1.10 (m, 2H), 1.04-0.99 (m, 2H).
MH+ 445.
1H NMR (400 MHz, CDCl3) δ 7.42-7.26 (m, 5H), 7.14-7.08 (m, 2H), 2.97-2.80 (m, 2H), 1.58-1.48 (m, 1H), 1.33-1.09 (m, 2H), 1.04-1.00 (m, 2H).
MH+ 458.
1H NMR (400 MHz, CDCl3) δ 7.46-7.43 (m, 2H), 7.34-7.27 (m, 3H), 7.07-7.04 (m, 2H), 3.51-3.47 (m, 1H), 2.57-2.52 (m, 2H), 2.38-2.29 (m, 2H), 2.25 (s, 3H), 2.25-1.93 (m, 2H).
MH+ 459.
1H NMR (400 MHz, CDCl3) δ 7.40-7.27 (m, 5H), 7.13-7.09 (m, 2H), 3.10-2.93 (m, 1H), 2.44 (s, 3H), 1.93-1.83 (m, 1H), 1.76-1.67 (m, 1H), 1.39 (d, J=6.9 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H).
MH+ 460.
A solution of 3-(5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-5-cyclopentyl-1H-1,2,4-triazole (400 mg, 0.82 mmol), iodomethane (0.19 ml, 2.5 mmol) and potassium hydroxide (138 mg, 2.5 mmol) dissolved in methanol (3 ml) was placed in a round bottom flask, stirred at room temperature for 1 day. After evaporation of the volatile solvent, the crude residue was purified by column chromatography to obtain the title compound (330 mg, 80%) as white solid.
1H NMR (400 MHz, CDCl3) δ 7.46-7.45 (m, 1H), 7.33-7.27 (m, 3H), 7.22-7.20 (d, J=8.7 Hz, 1H), 7.11-7.08 (m, 2H), 4.11 (s, 3H), 3.28-3.20 (m, 1H), 2.35 (s, 3H), 2.12-2.06 (m, 2H), 1.97-1.78 (m, 2H), 1.73-1.63 (m, 2H).
MH+ 486.
1H NMR (400 MHz, CDCl3) δ 7.46-7.45 (d, J=2.32 Hz, 1H), 7.33-7.27 (m, 3H), 7.22-7.20 (d, J=8.2 Hz, 1H), 7.11-7.08 (m, 2H), 4.12 (s, 3H), 2.83-2.77 (m, 1H), 2.35 (s, 3H), 2.11-2.06 (m, 2H), 1.87-1.82 (m, 2H), 1.74-1.67 (m, 2H), 1.67-1.57 (m, 2H), 1.46-1.28 (m, 4H).
MH+ 500.
1H NMR (400 MHz, CDCl3) δ 7.47-7.46 (d, J=2.3 Hz, 1H), 7.33-7.27 (m, 3H), 7.20-7.18 (d, J=8.2 Hz, 1H), 7.11-7.07 (m, 2H), 4.55-4.50 (q, J=6.9 Hz, 3H), 2.83-2.77 (m, 1H), 2.35 (s, 3H), 2.11-2.05 (m, 2H), 1.87-1.82 (m, 2H), 1.75-1.67 (m, 2H), 1.67-1.57 (m, 2H), 1.47-1.44 (t, J=7.4 Hz, 3H), 1.44-1.28 (m, 4H).
MH+ 515.
1H NMR (400 MHz, CDCl3) δ 7.46-7.45 (d, J=2.3 Hz, 1H), 7.33-7.25 (m, 3H), 7.21-7.19 (d, J=8.2 Hz, 1H), 7.11-7.07 (m, 2H), 5.28-5.22 (m, 1H), 2.85-2.79 (m, 1H), 2.31 (s, 3H), 2.07-2.03 (m, 2H), 1.89-1.81 (m, 2H), 1.73-1.62 (m, 2H), 1.51-1.49 (d, J=6.4 Hz, 6H), 1.49-1.25 (m, 5H).
MH+ 530.
1H NMR (400 MHz, CDCl3) δ 7.46-7.45 (d, J=2.3 Hz, 1H), 7.33-7.25 (m, 3H), 7.21-7.19 (d, J=8.2 Hz, 1H), 7.11-7.07 (m, 2H), 5.28-5.22 (m, 1H), 2.85-2.79 (m, 1H), 2.31 (s, 3H), 2.07-2.03 (m, 2H), 1.89-1.81 (m, 2H), 1.73-1.62 (m, 2H), 1.51-1.49 (d, J=6.4 Hz, 6H), 1.49-1.25 (m, 5H).
MH+ 530.
1H NMR (400 MHz, CDCl3) δ 7.47-7.46 (d, J=2.3 Hz, 1H), 7.34-7.25 (m, 3H), 7.20-7.17 (d, J=8.1 Hz, 1H), 7.10-7.08 (m, 2H), 4.1 (s, 3H), 2.32 (s, 3H), 2.12-2.07 (m, 1H), 1.55-1.04 (m, 2H), 1.00-0.96 (m, 2H).
MH+ 459.
1H NMR (400 MHz, CDCl3) δ 7.47-7.46 (d, J=2.3 Hz, 1H), 7.33-7.25 (m, 3H), 7.20-7.17 (d, J=8.2 Hz, 1H), 7.10-7.08 (m, 2H), 4.53-4.78 (q, J=7.3 Hz, 2H), 2.32 (s, 3H), 2.12-2.07 (m, 1H), 1.47-1.44 (t, J=7.4 Hz, 3H), 1.54-1.03 (m, 2H), 1.00-0.96 (m, 2H).
MH+ 473.
1H NMR (400 MHz, CDCl3) δ 7.46-7.45 (d, J=2.3 Hz, 1H), 7.33-7.25 (m, 3H), 7.20-7.18 (d, J=8.2 Hz, 1H), 7.10-7.08 (m, 2H), 5.28-5.24 (m, 1H) 2.23 (s, 3H), 2.14-2.10 (m, 1H), 1.51-1.49 (d, J=6.4 Hz, 6H), 1.07-1.30 (m, 2H), 0.99-0.95 (m, 2H).
MH+ 487.
1H NMR (400 MHz, CDCl3) δ 7.47-7.44 (d, J=2.3 Hz, 1H), 7.32-7.24 (m, 3H), 7.20-7.18 (d, J=8.6 Hz, 1H), 7.11-7.08 (m, 2H), 4.15 (s, 3H), 2.92-2.87 (m, 1H), 2.34 (s. 3H), 1.91-1.83 (m, 1H), 1.71-1.64 (m, 1H), 1.37-1.36 (d, J=7.3 Hz), 0.94 (t, J=7.3 Hz, 3H).
MH+ 475.
1H NMR (400 MHz, CDCl3) δ 7.47-7.46 (d, J=2.3 Hz, 1H), 7.33-7.24 (m, 3H), 7.20-7.18 (d, J=8.7 Hz, 1H), 7.11-7.08 (m, 2H), 4.55-4.50 (q, J=6.9 Hz, 2H), 2.92-2.87 (m, 1H), 2.34 (s. 3H), 1.91-1.83 (m, 1H), 1.71-1.64 (m, 1H), 1.47-1.44 (t, J=6.8 Hz, 3H), 1.37-1.35 (d, J=7.4 Hz), 0.95-0.91 (t, J=7.3 Hz, 3H).
MH+ 489.
1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=1.8 Hz, 1H), 7.34-7.22 (m, 3H), 7.21-7.19 (d, J=8.2 Hz, 1H), 7.10-7.08 (m, 2H), 5.26-5.22 (m, 1H), 2.91-2.88 (m, 1H), 2.30 (s. 3H), 1.89-1.82 (m, 1H), 1.70-1.64 (m, 1H), 1.51-1.49 (d, 6.4 Hz, 6H), 1.36-1.34 (d, J=7.3 Hz), 0.93-0.90 (t, J=7.3 Hz, 3H).
MH+ 503.
1H NMR (400 MHz, CDCl3) δ 7.47-7.50 (d, J=2.3 Hz, 1H), 7.33-7.23 (m, 3H), 7.22-7.20 (m, 1H), 7.11-7.08 (m, 2H), 4.12 (s, 3H), 3.14-3.08 (m, 1H), 2.37 (s. 3H), 1.40-1.38 (d, J=6.9 Hz, 6H).
MH+ 461.
1H NMR (400 MHz, CDCl3) δ 7.48-7.47 (d, J=2.3 Hz, 1H), 7.33-7.23 (m, 3H), 7.22-7.20 (d, J=8.7 Hz, 1H), 7.11-7.08 (m, 2H), 4.54-4.49 (q, J=7.4 Hz, 2H), 3.20-3.15 (m, 1H), 2.32 (s. 3H), 1.49-1.45 (t, J=7.3 Hz, 3H), 1.41-1.39 (d, J=6.9 Hz, 6H).
MH+ 475.
1H NMR (400 MHz, CDCl3) δ 7.46-7.45 (d, J=2.3 Hz, 1H), 7.33-7.23 (m, 3H), 7.21-7.19 (d, J=8.2 Hz, 1H), 7.11-7.08 (m, 2H), 5.26-5.23 (m, 1H), 3.17-3.10 (m, 1H), 2.31 (s. 3H), 1.51-1.49 (d, J=6.9 Hz, 6H), 1.39-1.37 (d, J=7.3 Hz, 6H).
MH+ 488.
5′-tert-butyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H,1′H-3,3′-bipyrazole
To a solution of sodium amide (215 mg, 5.5 mmol) in THF (5 mL) was added pinacolone (1.0 M THF solution, 5 mL, 5.0 mmol). The reaction mixture was refluxed at 80° C. for 30 min and then ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate (4) (2.05 g, 5.0 mmol) in THF (15 mL) was added. The resulting solution was stirred and refluxed at 80° C. overnight. HCl aquous solution (11.0M, 50 mL) was added and extracted organic layer with ethyl acetate (50 mL twice). The combined organic phase was evaporated under vacuum. The crude residue was further purified by prep HPLC to provide 0.862 g (1.86 mmol, 37%) of the title compound.
1H NMR (400 MHz, CDCl3) δ 7.44-41 (m, 1H), 7.35-7.21 (m, 4H), 7.08-7.03 (m, 2H), 6.54 (s, 1H), 2.36 (s, 3H), 1.24 (s, 9H).
MH+ 463.
To a suspension of 1-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-4,4-dimethylpentane-1,3-dione (555 mg, 1.20 mmol) (B) in EtOH (5.5 mL) was added hydrazine monohydrate (0.12 g, 2.4 mmol). The reaction mixture was refluxed at 90° C. for 6 hours. After cooled down to room temperature, the resulting suspension was dissolved by addition of THF (15 mL) and further purified by prep HPLC to provide 350 mg (0.761 mmol, 63%) of the title compound.
1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=2.8 Hz, 1H), 7.35-7.25 (m, 4H), 7.11 (d, J=11.2 Hz, 2H), 6.54 (br s, 1H), 2.33 (s, 3H), 1.38 (s, 9H).
MH+ 459.
To a 2-(tert-butoxycarbonylamino)acetic acid (800 mg, 4.57 mmol), N,O-dimethylhydroxylamine hydrochloride (535 mg, 5.48 mmol), EDCI (1.05 g, 5.48 mmol), HOBt (740 mg, 5.48 mmol) in DCM (25 mL) was added NMM (2.77 g, 27.42 mmol) at rt. The reaction mixture was stirred overnight. After the reaction was completed, DCM was evaporated in vacuo. The residue was dissolved in MeOH, filtered through a syringe filter, and then purified by reverse-phase prep HPLC to provide the desired product (705 mg, 71%) as white solid
To a tert-butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate (400 mg, 1.83 mmol) in THF (10 mL) was added cyclohexylmagnesium chloride (4.12 mL, 8.24 mmol) portionwise at room temperature under N2 atmosphere. As addition of the Grignard reagent was completed, the reaction mixture was stirred and heated to reflux for an hour. Then the mixture was allowed to cool down to room temperature. The reaction was quenched by adding water (10 mL) slowly. 1N HCl solution (30 mL) was added to the mixture, and extracted with EtOAc (20 mL×3). The combined organic layers were collected and evaporated in vacuo. The crude material was purified by column chromatography (hexane: EtOAc=10:1 to 5:1) to yield the desired product (110 mg, 25%).
To a tert-butyl 2-cyclohexyl-2-oxoethylcarbamate (228 mg, 0.946 mmol) in DCM (5 mL) was added 4M HCl in 1,4-dioxane (5 mL) at room temperature. The reaction continued for an hour at room temperature. The volatiles were removed under vacuum. To the residue (2-amino-1-cyclohexylethanone hydrochloric acid), 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (361 mg, 0.946 mmol), EDCI (272 mg, 1.429 mmol), HOBt (192 mg, 1.429 mmol) in DMF (9 mL) was added NMM (1.0 mL, 9.46 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The residue was purified by reverse-phase prep HPLC to afford the title compound (232 mg, 49%).
5-(4-chlorophenyl)-N-(2-cyclohexyl-2-oxoethyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (116 mg, 0.23 mmol) obtained in Step 3 was added to a microwave reactor containing Burgess reagent (165 mg, 0.689 mmol) in THF (2 mL). The capped reactor was placed in a microwave reactor and the mixture was irradiated at 160° C. for 20 min. The reaction product was purified by reverse-phase prep HPLC to provide the title compound (62 mg, 55%) as white solid.
1H NMR (400 MHz, CDCl3) δ 7.40-7.26 (m, 5H), 7.13-7.09 (m, 2H), 6.86 (d, J=0.93 Hz, 1H), 2.78 (m, 1H), 2.42 (s, 3H), 2.10 (m, 2H), 1.83-1.68 (m, 3H), 1.51-1.25 (m, 5H).
MH+ 486.
The following compounds of Examples 639 to 644 were obtained by using corresponding starting materials and repeating the procedure of Example 638.
1H NMR (300 MHz, CDCl3) δ 7.40-7.28 (m, 5H), 7.14-7.09 (m, 2H), 6.91 (t, J=1.0 Hz, 1H), 2.74 (t, J=7.6 Hz, 2H), 2.42 (s, 3H), 1.70 (m, 2H), 1.40 (m, 2H), 0.94 (t, J=7.3 Hz, 3H).
MH+ 460.
1H NMR (400 MHz, CDCl3) δ 7.40-7.28 (m, 5H), 7.13-7.09 (m, 2H), 6.91 (t, J=1.2 Hz, 1H), 2.78 (q, J=7.5 Hz, 2H), 2.43 (s, 3H), 1.31 (t, J=7.5 Hz, 3H).
MH+ 432.
1H NMR (400 MHz, CDCl3) δ 7.40-7.28 (m, 5H), 7.13-7.09 (m, 2H), 6.92 (br s, 1H), 2.61 (d, J=6.7 Hz, 2H), 2.43 (s, 3H), 2.05 (m, 1H), 0.97 (d, J=6.6 Hz, 6H).
MH+ 460.
1H NMR (400 MHz, CDCl3) δ 7.40-7.27 (m, 5H), 7.14-7.10 (m, 2H), 2.71 (m, 2H), 2.64 (m, 2H), 2.43 (s, 3H), 1.87-1.80 (m, 4H).
MH+ 458.
1H NMR (400 MHz, CDCl3) δ 7.40-7.37 (m, 2H), 7.34-7.28 (m, 3H), 7.14-7.08 (m, 2H), 6.89 (s, 1H), 3.21 (m, 1H), 2.42 (s, 3H), 2.07 (m, 2H), 1.80-1.60 (m, 6H).
MH+ 472.
1H NMR (400 MHz, CDCl3) δ 7.42-7.38 (m, 2H), 7.33-7.26 (m, 3H), 7.12-7.08 (m, 2H), 6.85 (d, J=0.4 Hz, 1H), 2.41 (s, 3H), 1.37 (s, 9H).
MH+ 460.
5-(4-chlorophenyl)-N-(2-cyclohexyl-2-oxoethyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (116 mg, 0.23 mmol) obtained in Step 3 of preparation of oxazole was added to a microwave reactor containing Lawesson's reagent (186 mg, 0.46 mmol) in THF (2 mL). The capped reactor was placed in a microwave reactor and the mixture was irradiated at 1860° C. for 30 min. The reaction product was purified by reverse-phase prep HPLC to provide the title compound (88 mg, 76%) as white solid.
1H NMR (400 MHz, CDCl3) δ 7.59 (br d, J=0.8 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.37-7.27 (m, 4H), 7.13-7.08 (m, 2H), 2.89 (m, 1H), 2.43 (s, 3H), 2.07 (m, 2H), 1.85-1.71 (m, 3H), 1.53-1.34 (m, 5H).
MH+ 502.
The following compounds of Examples 646 to 649 were obtained by using corresponding starting materials and repeating the procedure of Example 645.
1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.40-7.26 (m, 5H), 7.12-7.09 (m, 2H), 2.73 (d, J=7.0 Hz, 2H), 2.44 (s, 3H), 1.90 (m, 1H), 0.97 (d, J=6.8 Hz, 6H).
MH+ 476.
1H NMR (400 MHz, CDCl3) δ 7.41-7.37 (m, 2H), 7.34-7.25 (m, 3H), 7.12-7.08 (m, 2H), 2.84 (d, J=18.8 Hz, 4H), 2.41 (s, 3H), 1.90 (m, 4H).
MH+ 474.
1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.42-7.26 (m, 5H), 7.14-7.09 (m, 2H), 3.31 (m, 1H), 2.44 (s, 3H), 2.16 (m, 2H), 1.90-1.60 (m, 6H).
MH+ 488.
1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=0.4 Hz, 1H), 7.42-7.27 (m, 5H), 7.14-7.10 (m, 2H), 2.44 (s, 3H), 1.43 (s, 9H).
MH+ 476.
A solution of diketone (87) (200 mg, 0.43 mmol) and hydroxylamine hydrochloride (60 mg, 0.86 mmol) in EtOH (5 mL) was irradiated in a microwave reactor (Biotage) for 20 min. at 140° C. Purification by Prep-LC (Gilson) provided 67 mg (34%) of 5-t-butylisoxazole and 28 mg (14%) of 3-t-butylisoxazole as solid.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.4 Hz, 1H), 7.31-7.29 (m, 4H), 7.10 (d, J=9.6 Hz, 2H), 6.47 (s, 1H), 2.38 (s, 3H), 1.38 (s, 9H).
MH+ 460.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=1.6 Hz, 1H), 7.32-7.29 (m, 4H), 7.09 (d, J=4.4 Hz, 2H), 6.62 (s, 1H), 2.36 (s, 3H), 1.38 (s, 9H).
MH+ 460.
A solution of diketone (20 mg, 0.043 mmol), hydroxylamine hydrochloride (9 mg, 0.13 mmol) and Lawesson reagent (52 mg, 0.13 mmol) in 1,4-dioxane (4 mL) was irradiated in a microwave reactor (Biotage) for 20 min. at 140° C. Purification by Prep-LC (Gilson) provided 1 mg (5%) of desired isothiazole as solid.
1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.35-7.28 (m, 4H), 7.09 (d, J=6.4 Hz, 2H), 2.28 (s, 3H), 1.41 (s, 9H).
MH+ 476.
The compounds of the present invention were analyzed for their binding characteristics for CB1 and CB2 and the pharmacological activity thereof in accordance with the method disclosed in [Devane W A, Dysarz F A 3rd, Johnson M R, Melvin L S and Howlett A C, Determination and characterization of a cannabinoid receptor in rat brain, Mol. Pharmacol., 34(5): 605-13 (1998)]. The analysis was performed using [3H]CP-55940 which is a selectively radioactivity-labeled 5-(1,1-dimethyheptyl)-2[5-hydroxy-2-(3-hydroxypropyl)-cyclohexyl]-phenol, purchased from PerkinElmer Life Sciences, Inc. (Boston, Mass., U.S.A.), through a rat CB-1 receptor binding protocol as follows.
The tissue obtained from the brain of SD rats was homogenized with a Dounce homogenate system in TME (50 mM Tris, 3 mM MgCl2 and 1 mM EDTA, pH 7.4) at 4° C., and the homogenate was centrifuged at 48,000 g for 30 min. at 4° C. The pellet was resuspended in 5 ml of TME and the suspension was divided into aliquots and stored at −70° C. until its use in the following assay.
2 ml of the test compound was diluted in dimethylsulphoxide and was added to a deep well of a polypropylene plate, to which 50 μl of [3H]CP-55940 diluted in a ligand buffer solution (0.1% bovine serum albumin(BAS)+TME) was added. The tissue concentrations were determined by Bradford protein analysis, and 148 μl of brain tissue of the required concentration was added to the plate. The plate was covered and placed in a 30° C. incubator for 60 min, and then transformed on GF/B filtermat pretreated in polyethylenimine (PEI) using a cell harvester. Each filter was washed five times and dried at 60° C. for 1 hr. Then, the degree of radioactivity retained by the filter was measured using Wallac Microbeta™ (PerkinElmer Life Sciences, Inc., Massachusetts, U.S.A.) and the activity of the compound for inhibiting CB1 receptor was determined therefrom.
The examples of the present invention were tested in the cannabinoid-1 receptor (CB1R) binding affinity assay (Table 1). All of the preferred examples were shown to have binding affinities in the range of CB1R IC50<1.0 uM. Among them, more than twenty and less than thirty examples of the present invention were shown to have binding affinities in the range of IC50<3.0 nM, while rimonabant (SR141716) showed binding affinity in the range of IC50=5.0 nM.
Male C57BL/6J mice weighing over 38 g were housed 1 per cage on a 12-/12-h light/dark cycle, had free access to food (rodent sterilizable diet) and water, and were experimentally native before testing. Mice were allowed at least 7 days to habituate to the experimental room prior to testing, and testing was conducted during the light period. Mice were maintained and experiments were conducted in accordance with the Institutional Animal Care.
The reference (rimonabant) and the inventive compounds of Examples 132, 155 and 502 were prepared fresh daily by dissolving it in deionized water containing 10% DMSO. By oral administration, animals received at a volume of 10 ml/kg for 14 days. All control animals received 10% DMSO dissolved in deionized water.
The vehicles 10% DMSO treated group were comprised of 5 mice in oral test. There were 6 mice in each of the other experimental groups (n=6 in each group). By oral administration, the losing weight was checked everyday for the drug treated group and the control group.
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.
This application is a continuation-in-part of U.S. Ser. No. 11/541,269 filed on Sep. 29, 2006, which is pending.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11541269 | Sep 2006 | US |
| Child | 11863501 | Sep 2007 | US |
