Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• This invention relates to novel nitrogen substituted imidazo[4, 5-c]pyrazole compounds and pharmaceutical compositions, and to methods for the treatment of psychiatric disorders and neurological diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders, as well as treatment of immunological, cardiovascular or heart- related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.
• the present invention relates to novel imidazopyrimidines and imidazopyridines, pharmaceutical compositions containing such compounds and their use in treating psychiatric disorders, neurological diseases, immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.
• Corticotropin releasing hormone or factor (herein referred to as CRH or CRF) , a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin(POMC) -derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat . Acad. Sci . (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has
• CRF cerebral spinal fluid
• CRF produces anxiogenic effects in animals and interactions between benzodiazepine / non- benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D.R. Britton et al., Life Sci . 31:363 (1982); C.W. Berridge and A.J. Dunn Regul . Peptides 16:83 (1986)].
• CRF receptor antagonist ( ⁇ - helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces "anxiolytic-like" effects qualitatively ⁇ similar to the benzodiazepines [for review see G.F. Koob and K.T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E.B. De Souza and C.B. Nemeroff eds., CRC Press p221 (1990)].
• Several publications describe corticotropin releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases. Examples of such publications include DuPont Merck PCT application US94/11050, Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and Pfizer EP 778277 Al.
• European Patent Application Number 190457 Al discloses 3-methyl-imidazo [4,5-c] pyrazole derivatives which have the general formula shown below.
• the compounds have an intense depressant activity on the central nervous system, including anticonvulsant, sedative, analgesic and hypot ermizing.
• PCT Patent Application WO 91/11999 discloses angiotensin II antagonists having the general formula shown below. These compounds also have utility as treatments for cognitive dysfunctions, depression, anxiety and dysphoric mental states .
• novel nitrogen substituted imidazo [4, 5-c]pyrazoles which are described in detail below, have not been previously reported as corticotropin releasing factor antagonist compounds useful in the treatment of psychiatric disorders and neurological diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.
• the present invention provides novel compounds which bind to corticotropin releasing factor receptors, thereby altering the anxiogenic effects of CRF secretion.
• the compounds of the present invention are useful for the treatment of psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in mammals.
• the present invention provides novel compounds of formulae (I) and (II) (described below) which are useful as antagonists of the corticotropin releasing factor.
• the compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress CRF hypersecretion.
• the present invention also includes pharmaceutical compositions containing such compounds of formulae (I) and (II) , and methods of using such compounds for the suppression of CRF hypersecretion, and/or for the treatment of anxiogenic disorders.
• the present invention provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; post- traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression;
• Huntington's disease gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH) ; obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g.
• cerebral ischemia such as cerebral hippocampal ischemia
• excitotoxic neuronal damage e.g., epilepsy
• stroke immune dysfunctions including stress induced immune dysfunctions (e.g.. stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs)
• muscular spasms e.g.. stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs
• muscular spasms e.g.. stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress
• the present invention provides novel compounds of Formulae (I) and (II) :
• R 1 is selected from H, Ci-C ⁇ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, where such haloalkyl is substituted with 1-6 halogens, C3-C6 cycloalkyl, C 4 -C 8 cycloalkylalkyl, C1-C6 alkoxy, aryl, heteroaryl or heterocyclyl;
• R 2 is C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalkyl, where each group can be optionally substituted with 1 to 3 substituents independently selected at each occurrence from C ⁇ -C6 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C6 cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, NR ⁇ R 7 , OR 7 , thiol, S(0) n R 9 / COR 7 , C02R 7 , OC(0)R 9 , NR 8 COR 7 , NR 8 CONR 6 R 7 , or S(0) n R 9 , COR 7 , C0 2 R 7 , CONR 6 R 7 ; or C ] _-C haloalkyl, where C ⁇ -C
• n is independently at each occurrence 0, 1, or 2;
• R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-Cg alkynyl, C ⁇ _- C ⁇ haloalkyl, where such haloalkyl is substituted with 1-6 halogens, C3-C6 cycloalkyl, C2-C10 alkoxyalkyl, C1-C6 hydroxyalkyl, cyano, OR 6 , thiol, S(0) n R 9 , NR 6 R 7 , aryl, or heteroaryl;
• R 4 is phenyl, pyridyl, pyrimidyl, triazinyl, furanyl, naphthyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl , benzothiazolyl, isoxazolyl, 2,3-dihydrobenzofuranyl, 2,3- dihydrobenzothienyl, 1,2-ber ⁇ zopyranyl, 3 , 4-dihydro-
• each R 4 is attached via an unsaturated carbon atom and each R 4 may be optionally substituted with 1 to 4 R ⁇ groups ;
• R 5 is independently at each occurrence selected from
• R 6 and R 7 are independently at each occurrence selected from:
• Ci-Cio alkyl C3-C10 alkenyl, C3-C10 alkynyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, or C4-C12 cycloalkylalkyl, each optionally substituted with 1-6 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 haloalkyl, cyano, nitro, OR 12 , thiol, S(0) n R 9 COR 12 , CO2R! 2 , NR 8 COR 12 ,
• R 8 is independently at each occurrence selected from H, C1-C4 alkyl, C3-C8 alkenyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl; or phenyl or phenyl (C1-C4 alkyl), each optionally substituted with 1-3 substitutents selected from C1-C4 alkyl, halogen, C1-C4 haloalkyl optionally substituted with 1-6 halogens, C1-C4 alkoxy, OH;
• R 9 is independently at each occurrence selected from H, C1-C4 alkyl, C2-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl; or phenyl or phenyl (C1-C4 alkyl), each optionally substituted with 1-3 substitutents selected from C1-C4 alkyl, halogen, C1-C4 haloalkyl optionally substituted with 1-6 halogens, C1-C4 alkoxy, OH;
• R 10 is H, C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C ⁇ -C4 alkyl), heteroaryl, heteroaryl (C1-C4 alkyl), heterocyclyl, heterocyclyl (C1-
• R 11 and R 12 are independently at each occurrence selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C4- C7 cycloalkylalkyl, or C1-C4 haloalkyl optionally substituted with 1-6 halogens; or phenyl or phenyl (C1-C4 alkyl), each optionally substituted with 1-3 substitutents selected from C1-C4 alkyl, halogen, C1-C4 haloalkyl optionally substituted with 1-6 halogens, C1-C4 alkoxy, OH;
• aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from R 13 ;
• heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, 2,3- dihydrobenzofuranyl, 2,3- dihydrobenzothienyl, or indazolyl, each optionally substituted with 1 to 4 substituents independently selected from at each occurrence R 13 ;
• heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from R 13 ;
• R1 3 is independently at each occurrence selected from Ci-Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, where C1 . -C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl are optionally substituted with 1-3 substituents independently selected at each occurrence from C1-C4 alkyl, nitro, halogen, cyano, NR 8 R 9 , NR 8 COR 9 , NR 8 C ⁇ 2R 9 ,
• the present invention provides novel compounds of Formulae (I) and (II) wherein: R 4 is phenyl, pyridyl or pyrimidyl, each optionally substituted by 1 to 4 R ⁇ groups.
• R 1 is selected from H, Ci-C ⁇ alkyl, C ⁇ _- C6 haloalkyl, where such haloalkyl is substituted with 1-6 halogens, C3-C6 cycloalkyl, or aryl.
• the present invention provides novel compounds of Formulae (I) and (II), wherein: R 1 is selected from H, C ⁇ _-C6 alkyl, CT.- C6 haloalkyl, where such haloalkyl is substituted with
• R 4 is phenyl, pyridyl or pyrimidyl, each optionally substituted by 1 to 4 R5 groups.
• the present invention provides novel compounds of Formula (I) and (II), wherein the compound is selected from the group:
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of compounds of Formulae (I) and (II) .
• the present invention provides a method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals, comprising: administering to the mammal a therapeutically effective amount of compounds of Formulae (I) and (II) .
• the compounds herein described may have asymmetric centers.
• the present invention is intended to include all isotopes of atoms occurring in the present compounds .
• Isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include tritium and deuterium.
• Isotopes of carbon include C-13 and C-14.
• alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
• alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
• haloalkyl examples include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl .
• Alkoxy represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.
• Cycloalkyl is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl.
• Alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl.
• Alkynyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl.
• Halo or "halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
• carbocycle or “carbocyclic residue” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7-to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic.
• carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, ada antyl, cyclooctyl, [3.3.
• heterocyclic system is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic) , and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
• the nitrogen and sulfur heteroatoms may optionally be oxidized.
• the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
• the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
• a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1.
• aromatic heterocyclic system is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, 0 and S. It is preferred that the total number of S and 0 atoms in the aromatic heterocycle is not more than 1.
• heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl , benzoxazolyl , benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzi idazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1, 5, 2-dithiazinyl, dihydrofuro[2,3--]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, ind
• Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, IH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
• amino acid as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids (e.g., L-amino acids), modified and unusual amino acids (e.g., D-amino acids), as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides. 5: 342-429, the teaching of which is hereby incorporated by reference.
• Natural protein occurring amino acids include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanin ⁇ ., serine, threonine, tyrosine, tyrosine, tryptophan, proline, and valine.
• Natural non-protein amino acids include, but are not limited to arginosuccinic acid, citrulline, cysteine sulfinic acid, 3,4-dihydroxyphenylalanine, homocysteine, homoserine, ornithine, 3-monoiodotyrosine, 3, 5-diiodotryosine, 3, 5, 5'-triiodothyronine, and 3, 3 ' , 5, 5 '-tetraiodothyronine.
• Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, 2, 4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, S-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3 , 4-dehydroproline, N, N-dimethylaminoglycine, N- ethylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4- (aminomethyl) -cyclohexanecarboxylic acid, 2-, 3-, and 4- (aminomethyl) -benzoic acid, 1-aminocyclopentanecarboxy
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
• inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric
• organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
• such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
• Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
• prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc..) the compounds of the present invention may be delivered in prodrug form.
• the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same.
• Prodrugs are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject.
• Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
• Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
• Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
• Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
• Substituted is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group (s) , provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
• “Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host.
• the combination of compounds is preferably a synergi_stic combination.
• Synergy as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.
• a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds.
• Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
• terapéuticaally effective amount of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.
• These cyclizations are preferrably conducted in aqueous media and at elevated temperatures up to boiling.
• Hal'CH2CH(CN)Hal may be cyclized with the hydrazines of formula R 4 NHNH2 • Hal and Hal ' may be independently selected from chlorine, bromine or iodine.
• Hal ' may be independently selected from chlorine, bromine or iodine.
• R 1 is larger than methyl.
• Amides of formula (IV) may then be converted, in the presence of a reducing agent, to the substituted amino pyrazoles of formula (V) .
• Reducing agents include, but are not limited to, lithium aluminum hydride and borane. Reactions are generally run in ethereal solvents, for example tetrahydrofuran and diethyl ether. The reductions are carried out for a period of time between 1 hour and 4 days, and at room temperature or elevated temperature up to reflux in order to effect the reaction.
• borane it may be employed as a complex, for example, but not limited to, borane-methyl sulfide complex, borane-piperidine complex, borane-pyridine complex, and borane- tetrahydrofuran complex.
• compounds of formula (V) may be nitrosated in the presence of acid and a suitable nitrosating agent such as, but not limited to, isoamyl nitrite in an alcoholic solvent such as methanol, ethanol, or isopropanol.
• a suitable nitrosating agent such as, but not limited to, isoamyl nitrite in an alcoholic solvent such as methanol, ethanol, or isopropanol.
• Cyclization to imidazopyrazoles of formula (VII) may be accomplished by refluxing precursors of formula (VI) in the presence of a base such as, but not limited to, pyridine or other non-nucleophilic organic base for a period of time between 1 hour and 3 days and at a temperature ranging from room temperature up to the boiling point of the base or co-solvent employed.
• a base such as, but not limited to, pyridine or other non-nucleophilic organic base
• Cosolvents such as, but not limited to, tetrahydrofuran may be used, however, it may be preferrable to conduct the cyclizations in the absence of cosolvent.
• Compounds of formula (VII) are expected to exist as- a mixture of imidazole tautomers, and one skilled in the art will immediately recognize this.
• Leaving groups may include, but are not limited to, bromo, chloro, iodo, cyano, alkoxy, methanesulfonyl, and p- toluenesulfonyl.
• Possible bases include, but are not limited to, the sodium, lithium or potassium bis (trimethylsilyl) amides, sodium or potassium hydride, alkyl lithiums and alkyl grignards and inorganic bases such as sodium, potassium and lithium hydroxide.
• the reactions are optionally conducted at room temperature or at elevated temperatures up to the boiling point of a cosolvent.
• inert solvents may be employed, for example, dimethylformamide, dimethylsulfoxide, toluene, tetrahydrofuran, diethyl ether, and methylene chloride.
• the reactions may be successfully performed in glass reaction vessels or polypropylene wells, and one skilled in the art of organic chemistry will readily understand the optimal combinations of above conditions for effecting this transformation, or can consult the text of Larock, R.C. ( Comprehensive Organic Transformations, VCH Publishers, New York, 1989) .
• the experimental conditions taught herein will selectively provide the desired regiomer represented by compounds of formula (I) .
• compounds of formula (I) may be formed from compounds of formula (VII) by treatment with a base and subsequent addition to the carbon-carbon double bond of an ⁇ , ⁇ -unsaturated carboxylic acid derivative, ketone, aldehyde, or nitrile; a process commonly accepted as the Michael reaction.
• Bases and optional inert cosolvents may be selected from those identified ( vide supra) .
• One skilled in the art of organic synthesis will readily appreciate the utility of the Michael reaction, and may consult the teachings of House, H.O. (Modern Synthetic Reactions, W.A. Benjamin, Inc., Menlo Park, CA. , 1972, p 595).
• OR 6 or SR 6 may be preferably conducted with oxophilic alkylating agents such as, but not limited to, the trialkyloxonium tetrafluoroborates and/or thiophilic alkylating agents such as, but not limited to, dialkyl sulfates.
• oxophilic alkylating agents such as, but not limited to, the trialkyloxonium tetrafluoroborates and/or thiophilic alkylating agents such as, but not limited to, dialkyl sulfates.
• Reactions to afford compounds of formula (II), where G is 0 or S and the pyrazole nitrogen is substituted (Scheme 2) as R 1 ⁇ are more preferably effected by treatment of compounds of formula (I, R 3 is OH or SH) with a base such as, but not limited to, potassium hydroxide in a solvent such as acetone or other inert solvent with a reagent R 10 -X where X is a leaving group ( vide supra) .
• a base such as, but not limited to, potassium hydroxide in a solvent such as acetone or other inert solvent
• R 10 -X where X is a leaving group
• novel substituted bicyclic imidazo [4, 5-c] pyrazoles of formula (I) and (II) of this invention can be prepared by one of the general schemes outlined above. See Schemes 1-2.
• Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride) , alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide) , alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di- isopropylamide) , alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide) , trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine) .
• alkali metal hydrides preferably sodium hydride
• alkali metal alkoxides (1 to 6 carbons) preferably sodium methoxide or sodium ethoxide
• alkaline earth metal hydrides alkali metal dialkylamides (preferably lithium di- isopropylamide)
• Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile) , dialkyl ethers (preferably diethyl ether) , cyclic ethers (preferably tetrahydrofuran or 1, 4-dioxane) , N,N-dialkylformamides (preferably dimethylformamide) , N,N-dialkylacetamides (preferably dimethylacetamide) , cyclic amides (preferably N- methylpyrrolidin-2-one) , dialkylsulfoxides (preferably di ethylsulfoxide) , aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane) .
• dialkyl ethers preferably diethyl ether
• cyclic ethers preferably tetrahydrofuran or 1, 4-di
• Preferred reaction temperatures range from -20 to 100°C.
• Intermediates (b) may then be treated with a boronic acid or a boronic acid ester of the formula R 4 B(OH) 2 or R 4 B(OR a ) (OR b ) (where R a and R b are lower alkyl ( 1 to 6 carbons ) or together R a and R b are lower alkylene (2 to 12 carbons) in the presence of a metal catalyst with or without a base in an inert solvent to give compounds of Formula (II) .
• Metal catalysts include, but are not limited to salts or phosphine complexes of Cu, Pd or Ni (e.g.
• Bases may include, but are not limited to, alkaline earth metal carbonates, alkaline earth metal bicarbonates, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal hydrides (preferably sodium hydride) , alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide) , alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) , alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide) , trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably
• Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile) , dialkyl ethers (preferably diethyl ether) , cyclic ethers (preferably tetrahydrofuran or 1, 4-dioxane) , N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide) , cyclic amides (preferably N- methylpyrrolidin-2-one) , dialkylsulfoxides (preferably dimethylsulfoxide) , aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane) .
• Preferred reaction temperatures range from -80°C to
• Bases may include, but are not limited to, alkaline earth metal carbonates, alkaline earth metal bicarbonates, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal hydrides (preferably sodium hydride) , alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide) , alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di- isopropylamide) , alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide) , trialkyl amines (preferably N,N-di-isopropyl-N-eth)
• Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile) , dialkyl ethers (preferably diethyl ether) , cyclic ethers (preferably tetrahydrofuran or 1, 4-dioxane) , N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide) , cyclic amides (preferably N- methylpyrrolidin-2-one) , dialkylsulfoxides (preferably dimethylsulfoxide) , aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane) .
• Preferred reaction temperatures range from -80°C to
• Bases may include, but are not limited to, alkaline earth metal carbonates, alkaline earth metal bicarbonates, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal hydrides (preferably sodium hydride) , alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide) , alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) , alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide) , trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or tri
• Inert solvents may include, but are not limited -to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile) , dialkyl ethers (preferably diethyl ether) , cyclic ethers (preferably tetrahydrofuran or 1, 4-dioxane) , N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide) , cyclic amides (preferably N- methylpyrrolidin-2-one) , dialkylsulfoxides (preferably dimethylsulfoxide) , aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane) .
• Preferred reaction temperatures range from -80°C to 150°C.
• Example 1 Preparation of 4-Cyclopropylmethyl-3 , 5- dimethyl-1- (2,4, 6-trichloro) henyl imidazo [4,5- clpyrazole: Step A: ⁇ -Aminocrotononitrile (14.68 g, 0.18 mol) was dissolved in 1.0N HCI (500 ml) and treated with 2,4, 6-trichlorophenylhydrazine (36 g, 0.17 mol). The reaction was refluxed 4h, cooled, and decanted into a 2 liter beaker.
• Step B The product from Part A (14.0 g, 0.05 mol) was suspended in acetic anhydride (40 ml) and allowed to stir at room temperature. The reaction became homogeneous after 20 minutes and was stirred 40 additional minutes, then transferred to a slurry of ice (600 ml) . The resultant precipitate was stirred lh, filtered and dried to constant weight, affording 14.22 g (88%) of acetylated product, mp 210.0-211.0°C. 1- R NMR
• the heterogeneous mixture was diluted with water (400 ml) and diethyl ether (350 ml) and transferred to a separatory funnel. The mixture was partitioned and the aqueous layer reextracted with diethyl ether (2 X 100 ml) . The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in-vacuo. Column chromatography on silica gel (450 g) , eluting with hexanes/ethyl acetate (2/1) afforded the substituted amino pyrazole, 5.89 g (c. 40%) as a white crystalline solid, mp 81.5-83.5°C. ⁇ -H NMR (300 MHz,
• Step D The product from Step C (7.78 g, 25.54 mmol) was dissolved in ethanol (100 ml) , cooled to 0°C, and treated with l.ON HCI (0.5 ml) and isoamyl nitrite (3.42 ml, 25.54 mmol). The reaction was stirred 5 hours before final concentration in-vacuo to remove solvent. Purification via column chromatography (600 g) eluting with hexanes/ethyl acetate (1/2) yielded a violet crystalline solid, 7.14 g (87%), mp 180.0-181.0°C. !H
• Part E The product from Part D (7.82 g, 0.023 mol) was dissolved in pyridine (50 ml) and the homogeneous solution refluxed 8 hours.
• Part F The product from Part E (0.10 g, 0.32 mmol) was charged to a dry flask, dissolved in anhydrous dimethylformamide (5.0 ml), and treated with sodium hydride (0.03 g, 0.70 mmol). After stirring 5 minutes, the crimson reaction was quenched with cyclopropylmethylbromide (77 ⁇ l, 0.80 mmol). The reaction was heated to 100°C and allowed to stir 30 minutes, whereupon the reaction returned to a golden yellow color. After dilution with water (30 ml) the reaction was extracted with ethyl acetate (4 X 15 ml) . The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in-vacuo.
• Example 3 Preparation of 3 , 5- Dimethyl -4 - [ 1- ( 2 - ethyl ) butane ] - 1- ( 2 , 4 , 6-trichloro ) phenyl imidazo [4 , 5 -c ] pyrazole :
• the product from Example 1 , Part E ( 61 mg, 0.19 mmol) was reacted with sodium hydride (19 mg, 0.48 mmol) and l-bromo-2-ethylbutane (108 ⁇ l, 0.77 mmol) in dimethylformamide (2.0 ml) as described for the preparation of Example 1, Part F.
• Title compound mp 112.0-114.5°C. ⁇ E NMR (300 MHz, CDCI3) ⁇ 7.44 (s, 2H) ,
• Examples 2 and 4-9 given in TABLE 1 may be prepared in the same manner as described for the preparation of Examples 1 and 3, starting with the product from Example 1, Part E and substituting the appropriate electrophile.
• Step A ⁇ -Aminocrotononitrile (11.96 g, 0.15 mol) was dissolved in l.ON HCI (350 ml) and treated with 2,4, 6-trimethylphenylhydrazine, hydrochloride (25.89 g, 0.14 mol). The reaction was refluxed 4h, cooled, and decanted into a 2 liter beaker. The solution was diluted with water (250 ml) and neutralized with 10%
• Step B The product from Part A (10.0 g, 46.40 mmol) was suspended in acetic anhydride (35 ml) and allowed to stir at room temperature. The reaction became homogeneous after 20 minutes and was stirred 40 additional minutes, then transferred to a slurry of ice (500 ml) . The resultant precipitate was stirred 2h, filtered and dried to constant weight, affording 8.14 g
• Step C The product from Step B (8.1 g, 31.47 mmol) was dissolved in anhydrous THF (80 ml) and treated with lithium aluminum hydride (63 ml, 62.94 mmol, 1.0 M/THF) under nitrogen at room temperature. The reaction was stirred 1.5 h at room temperature and 1.0 h at 50°C, and quenched by the addition of 10% sodium hydroxide (10 ml) . The heterogeneous slurry was filtered through celite with copious diethyl ether washings.
• Step D The product from Step C (7.3 g, 29.99 mmol) was dissolved in ethanol (50 ml) , cooled to 0°C, and treated with 1.0 N HCI (14 drops) and isoamyl nitrite (4.02 ml, 29.99 mmol). The reaction was stirred 10 minutes, warmed to room temperature, and stirred an additional 5 hours.
• Step E The product from Step D (7.14 g, 26.21 mmol) was dissolved in anhydrous pyridine (50 ml) and brought to reflux for 8 hours. The reaction was then concentrated in-vacuo to dryness and directly purified by column chromatography on silica gel (600 g) eluting with ethyl acetate/hexanes (2/1) to afford a dark solid,
• Step F The product from Part E (0.125 g, 0.49 mmol) was charged to a dry flask, dissolved in anhydrous dimethylformamide (7.0 ml), and treated with sodium hydride (0.05 g, 1.22 mmol). After stirring 30 minutes, the dark reaction was quenched with benzylbromide (234 ⁇ l, 1.96 mmol) . The reaction was heated to 50°C and allowed to stir 1 hour, whereupon the reaction returned to a golden yellow color. After dilution with water (40 ml) the reaction was extracted with ethyl acetate (4 X 15 ml) . The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in-vacuo .
• Examples 6-10 and 12-36 given in TABLE 1 may be prepared in the same manner as described for the preparation of Example 11, starting with the product from Example 11, Part E, and substituting the appropriate electrophile.
• Part B The product from Part A (15.92 g, 47.86 mmol) was reduced with borane/THF complex (144 ml) in the same manner as described for the preparation of Example 1, Part C to afford an oil, 5.65 g (56%, based on recovered starting material) .
• ⁇ H NMR 300 MHz, CDCI3 ⁇ 7.47 (s, 2H) , 5.36 (s, IH) , 3.08 (bs, IH) , 3.05
• Part C The product from Step B (10.50 g, 32.97 mmol) was dissolved in ethanol (75 ml), cooled to 0°C, and treated with l.ON HCI (0.5 ml) and isoamyl nitrite (4.41 ml, 32.97 mmol). The reaction was stirred 24 hours, cooled to 0°C and the resultant purple precipitate filtered and dried to constant weight to afford 8.64 g (75%). 1H NMR (300 MHz, CDCI3) ⁇ 7.51 (s,
• Part D The product from Part C (8.47 g, 24.36 mmol) was dissolved in pyridine (140 ml) and the homogeneous solution refluxed 14 hours. The reaction was concentrated in-vacuo to remove pyridine and purified via column chromatography on silica gel (800 g) eluting initially with ethyl acetate/hexanes (1/1) to remove unreacted starting material, and then with ethyl acetate to afford desired imidazopyrazole, 2.87 g (36%), mp 221.0-223.0°C.
• X H NMR 300 MHz, CDCI3 ⁇ 8.82 (bs,
• Part E The product from Part D (0.10 g, 0.30 mmol) was reacted with sodium hydride (30 mg, 0.75 mmol) and l-bromo-2-ethylbutane (170 ⁇ l, 1.20 mmol) in dimethylformamide (2.0 ml) as described for the preparation of Example 1, Part F_> Title compound: mp
• reaction was filtered, dried to constant weight, and purified on a silica gel plug (0.70 g) eluting with a solvent gradient from hexanes/ethyl acetate (9/1) to hexanes/ethyl acetate (1/1) to afford title compound, 18.2 mg, mp 144.5-146.0°C .
• Example 105 Example 106 (260 ⁇ l, 2.43 mmol) in dimethylformamide (6.0 ml) as described for the preparation of Example 105.
• Title compound was obtained as a crystalline solid, mp 113-
• Example 105 (300 ⁇ l, 2.43 mmol) in dimethylformamide (6.0 ml) as described for the preparation of Example 105.
• Title compound was obtained as a viscous oil. !H NMR (300 MHz, CDCI3) ⁇ 7.44 (s, 2H) , 4.30 (m, IH) , 2.56 (s, 3H) ,
• Example 38 Part D (0.02 g, 0.06 mmol) was reacted with sodium bis (trimethylsilyl) amide (152 ⁇ l, 0.09 mmol, 0.6M/toluene) and 4- ethylsulfonylbenzyl chloride (121 ⁇ l, 0.12 mmol as a 1.0 M solution in DMF) in dimethylformamide (0.6 ml) in a 2.0 ml polypropylene well as described for the preparation of Example 40.
• Title compound was obtained as a crystalline solid, mp 194.0-196.0°C.
• Example 38 The compound prepared in Example 38, Part D (330 mg, 1.0 mmol) was dissolved in anhydrous dimethylformamide (10 mL) , and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 4.17 mL, 2.5 mmol) was added. The solution was heated to 60°C for one hour, then bromodiphenylmethane (988 mg, 4.0 mmol) was added and the reaction held at 100°C for 63 hours. The reaction was then cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo.
• sodium bis (trimethylsilyl) amide 0.6 M in toluene, 4.17 mL, 2.5 mmol
• Example Banana, Part D 200 mg, 0.61 mmol was dissolved in anhydrous dimethylformamide (6 mL) , and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 2.50 mL,
• Example Banana, Part D The compound prepared in Example Banana, Part D (330 mg, 1.0 mmol) was dissolved in anhydrous dimethylformamide (10 mL) , and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 4.17 mL, 2.5 mmol) was added. The solution was heated to 60°C for one hour, then bromoeye1opentane (596 mg, 4.0 mmol) was added and the reaction held at 100°C for 63 hours. The reaction was then cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo.
• Step A Sodium hydride (60% in mineral oil, 6.30 g, 157 mmol) was rinsed free of oil with cyclohexane, fresh cyclohexane was added (200 mL) , and this suspension was heated to reflux. A solution of ethyl propionate (15.3 g, 150 mmol) and acetonitrile (6.77 g, 165 mmol) in cyclohexane (30 mL) was then added to the sodium hydride suspension over 10 minutes, the reaction was held at reflux for 16 hours, and cooled to room temperature. The reaction was extracted with water, and the resulting aqueous solution acidified to pH 4 with 10% HCI.
• Step B The compound prepared in Step A (5.16 g, 17.8 mmol) was suspended in propionic anhydride (11.4 mL, 88.8 mmol) at room temperature and allowed to stir for 2 hours, resulting in a homogeneous solution. Ice was added and the reaction stirred for 5 hours, causing a solid to form. The off-white solid was isolated by filtration to leave the product (5.52 g, 90%), mp 145-
• Step C The compound prepared in Step B (5.47 g, 15.8 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) . To this suspension was added borane/THF complex (47.3 mL, 47.3 mmol), and the reaction was refluxed for 16 hours. The reaction was cooled to room temperature and excess borane was quenched with 10% NaOH (15 mL) until off-gassing ceased. The reaction was diluted with water and diethyl ether, the layers separated and the organic phase washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and reduced in vacuo to leave a white solid, mp 138-
• Step D The compound prepared in Step C was suspended in ethanol (30 mL) , and 15 drops of 10% HCI were added. Upon addition of the HCI significant off- gassing occurred, and at the completion of the off- gassing the reaction mixture was homogeneous. Isoamyl nitrite (2.1 mL, 15.7 mmol) was then added, and the solution darkened upon addition. The solution was stirred at room temperature for 16 hours, then reduced to dryness in vacuo to give a dark oil. This residue was purified by column chromatography (gradient elution of 25-50% ethyl acetate/hexanes) to give the final product as purple crystals (1.66 g, 29% from amide), mp
• Step E The compound prepared in Step D (1.56 g, 4.31 mmol) was dissolved in anhydrous pyridine (20 mL) and the solution heated to reflux for 16 hours. The solvent was removed in vacuo and the residue purified by column chromatography (50% ethyl acetate/hexanes) to afford the product as a brown solid. This solid was washed with ethyl ether to leave the product as a tan solid (517 mg, 35%), mp 242-243.5°C.
• Step F The compound prepared in Step E (80 mg, 0.23 mmol) was dissolved in anhydrous dimethylformamide (2.5 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 0.97 mL, 0.58 mmol) was added. The solution was heated to 60°C for one hour, then 1-bromobutane (0.10 mL, 0.92 mmol) was added. The reaction was held at 60°C for one hour, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column chromatography (25% ethyl acetate/hexanes) to give the final product as a crystalline solid (53 mg, 58%) , mp
• Example 152 80 mg, 0.23 mmol was dissolved in anhydrous dimethylformamide (2.5 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 0.97 mL,
• Example 152 The compound prepared in Step E, Example 152 (145 mg, 0.42 mmol) was dissolved in anhydrous dimethylformamide (4 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 1.76 mL,
• Step A A solution of methoxyacetonitrile (16.3 g, 0.23 mol) and acetonitrile (8.21 g, 0.20 mol) in tetrahydrofuran (50 mL) was added slowly at room temperature to potassium t-butoxide (IM in THF, 180 mL, 0.18 mol). A thick slurry resulted during the addition, and additional tetrahydrofuran (70 mL) was added. The reaction was heated to reflux for 24 hours, and was then slowly hydrolyzed with water (100 mL) . This mixture was then extracted with dichloromethane, and the organic phase was dried over anhydrous magnesium sulfate, filtered and reduced in vacuo to leave a brown oil.
• IM in THF 180 mL, 0.18 mol
• This oil was then purified by vacuum distillation to give the ⁇ -aminoacrylonitrile as a light yellow solid (13.0 g, 116 mmol, 50%).
• IN HCI 200 mL
• 2,4, 6-trichlorophenylhydrazine 16.3 g, 77.0 mmol
• the reaction was cooled to room temperature and the supernatant aqueous phase was decanted and neutralized with 10% NaOH, producing an oil that solidifies upon stirring.
• the solid was isolated by filtration, then redissolved in IN HCI and filtered to remove dark solids. The solution was neutralized to recover the product as a tan solid.
• Step B The compound prepared in Step A (5.61 g, 18.3 mmol) was suspended in propionic anhydride (11.7 mL, 91.5 mmol) at room temperature and allowed to stir for 20 hours, resulting in a homogeneous solution. Ice was added and the reaction stirred for 5 hours, then diethyl ether was added and the phases were separated, the organic phase washed with saturated aqueous NaHC0 3 , then saturated aqueous Na 2 C0 3 , then dried over anhydrous magnesium sulfate and reduced in vacuo to leave an oil. Ice was added to this oil and stirred for four hours, causing a solid to form.
• Step C The compound prepared in Step B (5.32 g, 14.7 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) . To this suspension was added borane/THF complex (47.3 mL, 47.3 mmol), and the reaction was refluxed for 16 hours. The reaction was cooled to room temperature and excess borane was quenched with 10% NaOH (15 mL) until off-gassing ceased. The reaction was diluted with water and diethyl ether, the layers separated and the organic phase washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and reduced in vacuo to leave an orange oil. This oil was purified by column chromatography (25% ethyl acetate/hexanes) to give a light yellow oil (3.75 g,
• Step D The compound prepared in Step C was dissolved in ethanol (25 mL) , and 15 drops of 10% HCI were added. Isoamyl nitrite (1.7 mL, 12.6 mmol) was then added, and the solution darkened upon addition. The solution was stirred at room temperature for 16 hours, and then reduced to dryness in vacuo to give a dark oil. This residue was purified by column chromatography (gradient elution of 25-50% ethyl acetate/hexanes) to give the final product as a dark blue oil (1.05 g, 26%).
• Step E The compound prepared in Step D (1.05 g, 2.8 mmol) was dissolved in anhydrous pyridine (20 mL) and the solution heated to reflux for 16 hours. The solvent was removed in vacuo and the residue purified by column chromatography (50% ethyl acetate/hexanes) to afford the product as a brown solid. This solid was recrystallized from diethyl ether/ethyl acetate to give the product as a light tan solid (505 mg, 50%) , mp 165.5-167.0°C. *H NMR (300 MHz,CDCl 3 ) ⁇ 8.89 (bs, IH) ,
• Step F The compound prepared in Step E (76 mg, 0.21 mmol) was dissolved in anhydrous dimethylformamide (3 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 0.88 mL, 0.53 mmol) was added. The solution was heated to 60°C for one hour, then 1-bromobutane (0.09 mL, 0.84 mmol) was added. The reaction was held at 60°C for 1.5 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column chromatography (10% ethyl acetate/hexanes) to give the final product as an orange solid (46 mg, 53%), mp 65.5-
• Example 156 (76 mg, 0.21 mmol ) was dissolved in anhydrous dimethylformamide (3 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 0.88 mL, 0.53 mmol) was added. The solution was heated to 60°C for one hour, then ⁇ -bromo-3,4-difluorotoluene (0.11 mL,
• Example 156 (125 mg, 0.35 mmol) was dissolved in anhydrous dimethylformamide (4 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 0.97 mL, 0.58 mmol) was added. The solution was heated to 60°C for one hour, then 2-bromopentane (0.18 mL, 1.39 mmol) was added. The reaction was held at 60°C for 20 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column chromatography (10% ethyl acetate/hexanes) to give the final product as a crystalline solid (34 mg, 23%), mp 100.0-101.5°C.
• Example 159 The compound prepared in Example 159 (2.39 g, 5.56 mmol) was dissolved in dichloromethane and cooled to -
• Part B The product from Part A (12.48 g, 36.00 mmol) was reduced with borane/THF complex (100 ml) in the same manner as described for the preparation of
• Part D The product from Part C (8.56 g, 23.67 mmol) was dissolved in pyridine (143 ml) and the homogeneous solution refluxed 20 hours. The reaction was concentrated in-vacuo to remove pyridine and purified via column chromatography on silica gel (800 g) eluting initially with ethyl acetate/hexanes (1/1) and then hexanes/ethyl acetate (1/2) to afford desired imidazopyrazole, 1.49 g (18%), mp 139-139.5°C.
• 1 H NMR 300 MHz, CDCI3 ⁇ 8.81 (bs, IH) , 7.44 (s, 2H) , 3.13 (m,
• Part E The product from Part D (0.10 g, 0.29 mmol) was reacted with sodium hydride (30 mg, 0.75 mmol) and benzyl bromide (138 ⁇ l, 1.16 mmol) in dimethylformamide (2.0 ml) as described for the preparation of Example 1, Part F.
• Title compound mp
• Dess-Martin periodinane (1.84 g, 4.33 mmol) was dissolved in anhydrous acetonitrile (3 mL) , and to this was added the compound prepared in Example 161 (1.50 g, 3.61 mmol) suspended in anhydrous acetonitrile (60 mL) .
• the reaction was stirred at room temperature for 30 minutes, and was then diluted with diethyl ether.
• the reaction was quenched with 0.5 N NaOH and the phases were separated, the organic phase was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and reduced in vacuo.
• Example 238 The compound prepared in Example 238 (1.38 g, 3.33 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and cooled to -78°C. To this solution was added methylmagnesium bromide (2.11 mL, 3.0 M in diethyl ether, 6.33 mmol) and the reaction was held at -78°C for one hour, then the temperature was gradually increased to room temperature. After three hours at room temperature, the reaction was quenched with 15% aqueous ammonium chloride and diethyl ether was added. The organic phase was dried over anhydrous magnesium sulfate and reduced in vacuo.
• Example 251 Preparation of 3-Acetyl-5-ethyl-4- [1- (1- ethyl) butane] -1- (2, 4, 6-trichloro) phenylimidazo [4, 5-c] pyrazole Dess-Martin periodinane (1.12 g, 2.65 mmol) was suspended in anhydrous dichloromethane (5 mL) and to this solution was added the compound prepared in Example 243 (950 mg, 2.21 mmol) in anhydrous dichloromethane (100 mL) . The reaction was held at room temperature for two hours, and was then quenched with 0.5 N NaOH (200 mL) .
• Examples in Table 2 may be prepared as exemplified above for the preparation of Examples 38, 40, 105-108, 113-118, 152-159, 161, 163-167, 238, 243, and 251.
• Step A The product from Example 11, Part A (10 g, 46.44 mmol) was suspended in propionic anhydride (30 ml) and allowed to stir at room temperature for 2 hours. The reaction was poured onto an ice slurry (500 ml) and stirred overnight. The resultant precipitate was filtered and dried to constant weight to afford 11.92 g
• Step B The product from Step A (11.5 g, 42.37 mmol) was reduced with lithium aluminum hydride (84.75 ml, 84.74 mmol, 1.0 M/THF) as described for the preparation of Example 11, Step C.
• the product was obtained as a clear viscous oil, 10.81 g (99%).
• Step C The product from Step B (10.81 g, 41.99 mmol) was treated with isoamyl nitrite (5.62 ml, 41.99 mmol) as described for the preparation of Example 11, Step D to afford a purple crystalline solid, 9.59 g
• Step D The product from Step C (9.59 g) was refluxed in pyridine (60 ml) for 16 hours, as described for the preparation of Example 11, Step E. Chromatography on silica gel (700 g) eluting with hexanes/ethyl acetate (1/1) yielded recovery of 2.38 g of starting material, while elution with ethyl acetate alone afforded the desired product, 3.41 g (50% based on recovered starting material) . !H NMR (300 MHz, CDCI3) ⁇
• Step E The product from Step D (0.25 g, 0.93 mmol) was treated with sodium hydride (93 mg, 2.32 mmol) and benzyl bromide (443 ⁇ l, 3.7 mmol) in anhydrous dimethylformamide (15 ml) as described for the preparation of Example 11, Step F.
• Title compound 200.0 mg (60%), mp 96.5-98°C, ⁇ E NMR (300 MHz, CDCI3) ⁇
• Step B The compound prepared in Step A (4.0g, 14.0 mmol) was suspended in propionic anhydride (9.0 mL, 69.8 mmol) at room temperature and was allowed to stir for 16 hours. Ice was then added and the reaction stirred for 5 hours. Diethyl ether was added and the phases were separated. The organic phase was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and reduced in vacuo to leave a thick oil. This residue was purified by column chromatography (50% ethyl acetate/hexanes) to give the final product as a solid (4.2 g, 88%), mp 107-110°C.
• Step C The compound prepared in Step B (4.1 g, 12.0 mmol) was suspended in tetrahydrofuran (30 mL) . To this suspension was added borane/THF complex (36.0 mL, 36.0 mmol), and the reaction refluxed for 3 hours. The reaction was cooled to room temperature and excess borane was quenched with 10% NaOH (10 mL) until off- gassing ceased and the reaction was diluted with water and diethyl ether. The layers were separated and the organic phase was washed with saturated sodium chloride, dried over anhydrous anhydrous magnesium sulfate, and reduced in vacuo. This residue was purified by column chromatography (25% ethyl acetate/hexanes) to provide the final product as a white solid (3.46 g, 88%), mp
• Step D The compound prepared in Step C (2.76 g, 8.40 mmol) was suspended in ethanol (20 mL) , and 15 drops of 10% HCI were added. Upon addition of the HCI significant off-gassing occurred, and at the completion of the off-gassing the reaction mixture was homogeneous. Isoamyl nitrite (1.35 mL, 10.1 mmol) was then added, and the solution darkened upon addition. The solution was stirred at room temperature for 16 hours, and then reduced to dryness in vacuo.
• Step E The compound prepared in Step D (2.06 g,
• Step F The compound prepared in Step E (500 mg, 1.47 mmol) was dissolved in anhydrous dimethylformamide (15 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 6.1 mL, 3.68 mmol) was added. The solution was heated to 60°C for one hour, then 1-bromobutane (0.63 mL, 5.88 mmol) was added. The reaction was held at 60°C for 4 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo .
• Example 325 (50 mg, 0.15 mmol) was dissolved in anhydrous dimethylformamide (1 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 0.61 mL, 0.37 mmol) was added. The solution was heated to 60°C for one hour, then ⁇ -bromo-3, 4- difluorotoluene (0.075 mL, 0.59 mmol) was added. The reaction was held at 60°C for 4 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase was washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column chromatography (33% ethyl
• Example 325 (110 mg, 0.32 mmol) was dissolved in anhydrous dimethylformamide (4 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 1.3 mL, 0.8 mmol) was added. The solution was heated to 60°C for one hour, then 3-bromohexane (211 mg,
• the reaction was held at 100°C for 64 hours, then cooled to room temperature and diluted with water and diethyl ether. The layers were separated and the organic phase was washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column chromatography (33% ethyl acetate/hexanes) to give the final product as an oil (27 mg, 20%) .
• Step A ⁇ -Aminocrotonitrile (4.53 g, 0.06 mol) was dissolved in l.ON HCI (90 ml) and treated with 2-chloro- 4-methylhydrazine (8.66 g, 0.06 mol). The reaction was allowed to reflux for 6h, cooled, and decanted into a 2 liter beaker. The solution was diluted with water (250 ml) and neutralized with 10% NaOH. The resulting
• Step B The compound prepared in Step A (0.97 g, 4.37 mmol) was suspended in propionic anhydride (2.8 mL, 21.9 mmol) at room temperature and allowed to stir for 16 hours. Ice was added and the reaction stirred for 24 hours. Diethyl ether was added and the phases separated. The organic phase was washed with saturated sodium chloride and dried over anhydrous magnesium sulfate and reduced in vacuo to leave a thick oil. This residue was purified by column chromatography (50% ethyl acetate/hexanes) to give the final product as a solid
• Step C The compoimd prepared in Step B (0.94 g,
• Step D The compound prepared in Step C (0.69 g, 2.62 mmol) was suspended in ethanol (10 mL) , and 15 drops of 10% HCI were added. Upon addition of the HCI significant off-gassing occurred, and at the completion of the off-gassing the reaction mixture was homogeneous. Isoamyl nitrite (0.42 mL, 3.14 mmol) was then added, and the solution darkened upon addition. The solution was stirred at room temperature for 16 hours, and then reduced to dryness in vacuo.
• Step E The compound prepared in Step D (0.34 g, 1.15 mmol) was dissolved in anhydrous pyridine (5 mL) and the solution heated to reflux for 16 hours. The solvent was removed in vacuo and the residue purified by column chromatography (75% ethyl acetate/hexanes) to afford the product as a brown solid (0.2 g, 60%). This product was used in further reactions directly, however a sample was further purified for analytical purposes by washing briefly with diethyl ether to remove a brown oily residue, leaving the final product as an off-white solid, mp 178-180°C.
• Step F The compound prepared in Step E (50 mg, 0.18 mmol) was dissolved in anhydrous dimethylformamide (1.5 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 0.75 mL, 0.45 mmol) was added. The solution was heated to 60°C for one hour, then 1-bromobutane
• Example 329 (116 mg, 0.42 mmol) was dissolved in anhydrous dimethylformamide (3.5 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 1.75 mL, 1.05 mmol) was added. The solution was heated to 60°C for one hour, then 2-bromopentane
• Step B The compound prepared in Step A (4.0 g, 14.5 mmol) was dissolved in propionic anhydride (9.3 L, 72.5 mmol) at room temperature and was allowed to stir for 16 hours. Ice was then added and the reaction stirred for 5 hours. The solid product was removed by filtration, washed with water, and dried in vacuo to leave the final product as a yellow solid (3.75 g, 78%), mp 135-138°C.
• Step C The compound prepared in Step B (3.63 g, 10.9 mmol) was suspended in tetrahydrofuran (30 mL) . To this suspension was added borane/THF complex (32.8 mL, 32.8 mmol), and the reaction refluxed for one hour, then held at room temperature for 16 hours. Excess borane was quenched with 10% NaOH (10 mL) until off-gassing ceased and the reaction was diluted with water and diethyl ether. The layers were separated and the organic phase as washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and reduced in vacuo. This residue was purified by column chromatography (25% ethyl acetate/hexanes) to provide the final product as a white solid (2.73 g, 79%), mp
• Step D The compound prepared in Step C (2.83 g, 8.91 mmol) was suspended in ethanol (22 mL) , and 15 drops of 10% HCI were added. Upon addition of the HCI significant off-gassing occurred, and at the completion of the off-gassing the reaction mixture was homogeneous. Isoamyl nitrite (1.4 mL, 10.7 mmol) was then added, and the solution darkened upon addition. The solution was stirred at room temperature for 16 hours, and then reduced to dryness in vacuo. Hexanes were added to the residual oil and a yellow precipitate formed.
• Step F The compound prepared in Step E (160 mg, 0.49 mmol) was dissolved in anhydrous dimethylformamide (5 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 2.0 mL, 1.22 mmol) was added. The solution was heated to 60°C for one hour, then 1-bromobutane (0.21 mL, 1.96 mmol) was added. The reaction was held at 60°C for
• Example 331 160 mg, 0.49 mmol was dissolved in anhydrous dimethylformamide (5 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 2.0 mL, 1.22 mmol) was added. The solution was heated to 60°C for one hour, then ⁇ -bromo-3,4- difluorotoluene (0.25 mL, 1.96 mmol) was added. The reaction was held at 60°C for 2.5 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous sodium sulfate, and reduced to dryness in vacuo .
• Example 501 150 mg, 0.45 mmol was dissolved in anhydrous dimethylformamide (5 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 1.9 mL, 1.14 mmol) was added. The solution was heated to
• Example 325 (178 mg, 0.45 mmol) was dissolved in anhydrous dimethylformamide (2.2 mL) . To this solution was added CuBr (9.7 mg, 0.0676 mmol), followed by sodium methoxide (25% in methanol, 0.29 mL, 1.35 mmol). This solution was heated to 155°C for 30 minutes, cooled to room temperature, and diluted with diethyl ether. This solution was shaken with a 20% solution of NH 4 0H in saturated aqueous NH 4 C1, and the ethereal phase was dried over anhydrous magnesium sulfate and reduced in vacuo to leave a brown oil.
• Example 102 The compound prepared in Example 102 (296 mg, 0.74 mmol) was dissolved in anhydrous dimethylformamide (3.5 mL) . To this solution was added CuBr (16 mg, 0.11 mmol), followed by sodium methoxide (25% in methanol,
• Step A To 2-methyl-4-bromoaniline (30.0 g, 161 mmol) at 10°C was added concentrated HCI (400 mL) , and to this solution was added sodium nitrite (13.4 g, 193 mmol) in water (125 mL) , maintaining an internal temperature of -10°C during the addition. The reaction was stirred for an hour at 0-5°C, then tin (II) chloride (90.9 g, 403 mmol) in concentrated HCI (395 mL) was added so as to keep the temperature between 5-8°C; significant foaming occurred during addition. The orange solid was isolated by filtration and dried to give the hydrazine hydrochloride.
• Step B The compound prepared in Step A (13.8 g, 51.7 mmol) was dissolved in propionic anhydride (33.2 mL, 259 mmol) and was allowed to stir for 16 hours at room temperature. Ice was then added and the reaction stirred for 5 hours, then diethyl ether was added and the phases were separated. The organic phase was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and reduced in vacuo to leave a thick oil. This residue was purified by column chromatography (50% ethyl acetate/hexanes) to give the final product as an off-white solid (13.9 g, 83%), mp 119-121°C. ⁇ NMR
• Step C The compound prepared in Step B (13.9 g, 43.0 mmol) was suspended in tetrahydrofuran (150 mL) . To this suspension was added borane/THF complex (129 mL, 129 mmol), and the reaction refluxed for 16 hours. Excess borane was quenched with 10% NaOH (50 mL) until off-gassing ceased and the reaction was diluted with water and diethyl ether. The layers were separated and the organic phase was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and reduced in vacuo to leave the product as a white solid
• Step D The compound prepared in Step C (13.6 g,
• Step E The compound prepared in Step D (11.3 g,
• Step F The compound prepared in Step E (130 mg, 0.41 mmol) was dissolved in anhydrous dimethylformamide (4 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 1.7 mL, 1.02 mmol) was added. The solution was heated to 60°C for one hour, then 1-bromobutane (0.17 mL,
• Step B The compound prepared in Step A (27.3 g, 85.4 mmol) was dissolved in propionic anhydride (54.8 mL, 427 mmol) and was allowed to stir for 2 hours at room temperature. Ice was then added and the reaction stirred for 16 hours, providing the product as a solid. The product was isolated by filtration and dried to leave an off-white solid (29.8 g, 93%), mp 165.5-167.5°C.
• Step C The compound prepared in Step B (29.8 g, 79.1 mmol) was suspended in anhydrous tetrahydrofuran (220 mL) . To this suspension was added borane/THF complex (237 mL, 237 mmol) , and the reaction refluxed for 16 hours. Excess borane was quenched with 10% NaOH (100 mL) until off-gassing ceased, and the reaction was filtered through Celite. Diethyl ether was added and the layers were separated, the organic phase was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and reduced in vacuo to leave the product as a white solid (28.4 g, 99%).
• Step D The compound prepared in Step C (28.3 g, 78.1 mmol) was suspended in ethanol (200 mL) , and one mL of 10% HCI was added. Upon addition of the HCI significant off-gassing occurred, and at the completion of the off-gassing the reaction mixture was homogeneous. Isoamyl nitrite (12.6 mL, 93.8 mmol) was then added, and the solution darkened upon addition. The solution was stirred at room temperature for 16 hours, and then a few drops of triethylamine were added to neutralize the HCI.
• Step E The compound prepared in Step D (18.1 g, 46.2 mmol) was dissolved in anhydrous pyridine (200 mL) and the solution heated to reflux for 16 hours. The solvent was removed in vacuo and the residue purified by column chromatography (gradient elution with 25-50% ethyl acetate/hexanes) to afford the product as a tan solid (13.1 g, 76%) mp 158-160.5°C. *H NMR (300
• Step F The compound prepared in Step E (153 mg, 0.41 mmol) was dissolved in anhydrous dimethylformamide (4 mL) and sodium bis (trimethylsilyl) amide (0.6 M in toluene, 1.7 mL, 1.02 mmol) was added. The solution was heated to 60°C for one hour, then 1-bromobutane (0.17 mL,
• the reaction was held at 80°C for 16 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced in vacuo . The residue was purified by column chromatography (15% ethyl acetate/hexanes) to give the final product as an oil (50 mg, 11%) .
• Example 396 The compound prepared in Example 396 (492 mg, 1.26 mmol) was dissolved in anhydrous toluene (5 mL) and dichlorobis (triphenylphosphine) palladiu (II) (18 mg, 0.025 mmol) was added, followed by tributyKl- ethoxyvinyl) tin (548 mg, 1.52 mmol), and the solution was heated to reflux for 2.5 hours. The reaction was cooled to room temperature and quenched with IN HCI (10 mL) and diethyl ether.
• Examples in Table 3 may be prepared as amply exemplified above for the preparation of Examples 325- 334, 353-357, 396-403, and 408.
• R 4 corresponds to the substitutions exemplified in Table 4 to give initially compounds of formula (III) .

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