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US20150322069A1 - Phenoxymethyl heterocyclic compounds - Google Patents

Phenoxymethyl heterocyclic compounds Download PDF

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US20150322069A1
US20150322069A1 US14/564,507 US201414564507A US2015322069A1 US 20150322069 A1 US20150322069 A1 US 20150322069A1 US 201414564507 A US201414564507 A US 201414564507A US 2015322069 A1 US2015322069 A1 US 2015322069A1
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pyridin
mmol
dimethyl
phenyl
furan
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Amy Ripka
Gideon Shapiro
Richard Chesworth
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Forum Pharmaceuticals Inc
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Forum Pharmaceuticals Inc
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Publication of US20150322069A1 publication Critical patent/US20150322069A1/en
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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    • A—HUMAN NECESSITIES
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    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P3/04—Anorexiants; Antiobesity agents
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    • A61P3/00—Drugs for disorders of the metabolism
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    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Cyclic phosphodiesterases are intracellular enzymes which, through the hydrolysis of cyclic nucleotides cAMP and cGMP, regulate the levels of these mono phosphate nucleotides which serve as second messengers in the signaling cascade of G-protein coupled receptors.
  • PDEs also play a role in the regulation of downstream cGMP and cAMP dependent kinases which phosphorylate proteins involved in the regulation of synaptic transmission and homeostasis.
  • eleven different PDE families have been identified which are encoded by 21 genes. The PDEs contain a variable N-terminal regulatory domain and a highly conserved C-terminal catalytic domain and differ in their substrate specificity, expression and localization in cellular and tissue compartments, including the CNS.
  • PDE10 is primarily expressed in the brain (caudate nucleus and putamen) and is highly localized in the medium spiny neurons of the striatum, which is one of the principal inputs to the basal ganglia. This localization of PDE10 has led to speculation that it may influence the dopaminergic and glutamatergic pathways both which play roles in the pathology of various psychotic and neurodegenerative disorders.
  • PDE10 has a five-fold greater V max for cGMP than for cAMP and these in vitro kinetic data have lead to the speculation that PDE10 may act as a cAMP-inhibited cGMP phosphodiesterase in vivo (Soderling and Beavo “Regulation of cAMP and cGMP signaling: New phosphodiesterases and new functions,” Curr. Opin. Cell Biol., 2000, 12, 174-179).
  • PDE10 is also one of five phosphodiesterase members to contain a tandem GAF domain at their N-terminus. It is differentiated by the fact that the other GAF containing PDEs (PDE2, 5, 6, and 11) bind cGMP while recent data points to the tight binding of cAMP to the GAF domain of PDE10 (Handa et al. “Crystal structure of the GAF-B domain from human phosphodiesterase 10A complexed with its ligand, cAMP” J. Biol. Chem. 2008, May 13 th , ePub).
  • PDE10 inhibitors have been disclosed for the treatment of a variety of neurological and psychiatric disorders including Parkinson's disease, schizophrenia, Huntington's disease, delusional disorders, drug-induced psychoses, obsessive compulsive and panic disorders (US Patent Application 2003/0032579).
  • Studies in rats (Kostowski et. al “Papaverine drug induced stereotypy and catalepsy and biogenic amines in the brain of the rat” Pharmacol. Biochem. Behav . 1976, 5, 15-17) have showed that papaverine, a selective PDE10 inhibitor, reduces apomorphine induced stereotypes and rat brain dopamine levels and increases haloperidol induced catalepsy. This experiment lends support to the use of a PDE10 inhibitor as an antipsychotic since similar trends are seen with known, marketed antipsychotics.
  • Antipsychotic medications are the mainstay of current treatment for schizophrenia.
  • Conventional or classic antipsychotics typified by haloperidol, were introduced in the mid-1950s and have a proven track record over the last half century in the treatment of schizophrenia. While these drugs are effective against the positive, psychotic symptoms of schizophrenia, they show little benefit in alleviating negative symptoms or the cognitive impairment associated with the disease.
  • drugs such as haloperidol have extreme side effects such as extrapyramidal symptoms (EPS) due to their specific dopamine D2 receptor interaction.
  • EPS extrapyramidal symptoms
  • An even more severe condition characterized by significant, prolonged, abnormal motor movements known as tardive dyskinesia also may emerge with prolonged classic antipsychotic treatment.
  • atypical antipsychotics typified by risperidone and olanzapine and most effectively, clozapine.
  • These atypical antipsychotics are generally characterized by effectiveness against both the positive and negative symptoms associated with schizophrenia, but have little effectiveness against cognitive deficiencies and persisting cognitive impairment remain a serious public health concern (Davis, J. M et al. “Dose response and dose equivalence of antipsychotics.” Journal of Clinical Psychopharmacology , 2004, 24 (2), 192-208; Friedman, J. H. et al “Treatment of psychosis in Parkinson's disease: Safety considerations.” Drug Safety , 2003, 26 (9), 643-659).
  • atypical antipsychotic agents while effective in treating the positive and, to some degree, negative symptoms of schizophrenia, have significant side effects.
  • clozapine which is one of the most clinically effective antipsychotic drugs shows agranulocytosis in approximately 1.5% of patients with fatalities due to this side effect being observed.
  • Other atypical antipsychotic drugs have significant side effects including metabolic side effects (type 2 diabetes, significant weight gain, and dyslipidemia), sexual dysfunction, sedation, and potential cardiovascular side effects that compromise their clinically effectiveness.
  • the disclosure relates compounds which are inhibitors of phosphodiesterase 10.
  • the disclosure further relates to processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function.
  • CNS central nervous system
  • the disclosure also relates to methods for treating neurological, neurodegenerative and psychiatric disorders including but not limited to those comprising cognitive deficits or schizophrenic symptoms.
  • HET is a heterocyclic ring selected from Formulas A29, A31 and A39 below
  • X is selected from optionally substituted aryl and optionally substituted heteroaryl
  • Z is optionally substituted heteroaryl
  • Each R 2 is independently selected from C 1 -C 4 alkyl, or two R 2 groups taken together with the carbon to which they are attached form a 3 membered cycloalkyl ring;
  • alkyl groups are fully saturated whether present on their own or as part of another group (e.g. alkylamino or alkoxy).
  • substituent groups are not further substituted.
  • any group that is defined as being optionally substituted can be singly or independently multiply optionally substituted.
  • HET is selected from Formulas A29 and A31.
  • HET is Formula A29.
  • HET is Formula A31.
  • X is selected from a monocyclic heteroaryl having 5 ring atoms selected from C, O, S and N provided the total number of ring heteroatoms is less than or equal to four and where no more than one of the total number of heteroatoms is oxygen or sulfur, and a monocyclic aromatic ring having 6 atoms selected from C and N provided that not more than 3 ring atoms are N, and where said ring may be optionally and independently substituted with up to two groups selected from C 1 -C 4 alkyl, cycloalkyl, cycloalkyloxy, C 1 -C 4 alkoxy, CF 3 , carboxy, alkoxyalkyl, C 1 -C 4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, alkylsulfonyl and nitro.
  • Examples include but are not limited to 1H-pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-thiatriazolyl, 1,2,3,5-thiatriazolyl, 1,2,3,5-thiatriazolyl, 1,2,3,5-thiatriazolyl, 1,2,3,5-
  • X is a monocyclic heteroaryl having 6 ring atoms selected from C and N provided that not more than 3 ring atoms are N, and where said ring may be optionally and independently substituted with up to two groups selected from C 1 -C 4 alkyl, cycloalkyl, cycloalkyloxy, C 1 -C 4 alkoxy, CF 3 , carboxy, alkoxyalkyl, C 1 -C 4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, alkylsulfonyl and nitro.
  • Examples include but are not limited to 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.
  • X is a monocyclic heteroaryl having 5 ring atoms selected from C, O, S, and N, provided the total number of ring heteroatoms is less than or equal to four and where no more than one of the total number of heteroatoms is oxygen or sulfur and where said ring may be optionally and independently substituted with up to two groups selected from C 1 -C 4 alkyl, cycloalkyl, cycloalkyloxy, C 1 -C 4 alkoxy, CF 3 , carboxy, alkoxyalkyl, C 1 -C 4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, alkylsulfonyl and nitro.
  • Examples include but are not limited to 1H-pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-thiatriazolyl, 1,2,3,5-thiatriazolyl.
  • X is 4-pyridinyl optionally substituted with one group selected from C 1 -C 4 alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, C 1 -C 4 alkoxy, CF 3 , amino, alkylamino, dialkylamino, thioalkyl, halogen, alkylsulfonyl and cyano.
  • X is 4-pyridinyl.
  • X is selected from restricted phenyl.
  • X is selected from a 3,4-disubstituted phenyl, 4-substituted phenyl. and 4-pyridinyl.
  • X is selected from a 3,4-disubstituted phenyl and 4-substituted phenyl.
  • X is selected from 4-pyridinyl and 4-substituted phenyl.
  • X is 4-substituted phenyl.
  • X is 4-methoxyphenyl.
  • X is 4-chlorophenyl.
  • X is 4-cyanophenyl.
  • Z is heteroaryl but is not quinolinyl or pyridyl.
  • Z is heteroaryl but is not quinolinyl.
  • Z is heteroaryl but is not pyridyl.
  • Z is not pyridin-2-yl.
  • Z is not pyridinyl.
  • Z is selected from pyridin-2-yl, imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-b]pyridazin-2-yl, and imidazo[1,2-b]pyridazin-6-yl all of which may be optionally substituted with up to 2 substituents independently selected from C 1 -C 4 alkyl, cycloalkyl, cycloalkyloxy, C 1 -C 4 alkoxy, CF 3 , carboxy, alkoxyalkyl, C 1 -C 4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, alkylsulfonyl and nitro.
  • Z is selected from imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-b]pyridazin-2-yl, and imidazo[1,2-b]pyridazin-6-yl all of which may be optionally substituted with up to 2 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.
  • Z is a 3,5-disubstituted-pyridin-2-yl with each substituent being independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.
  • Z is 5-substituted-pyridin-2-yl with the substituent being independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.
  • Z is imidazo[1,2-a]pyridin-2-yl substituted with up to 2 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.
  • Z is imidazo[1,2-b]pyridazin-2-yl substituted with up to 2 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.
  • Z is imidazo[1,2-b]pyridazin-6-yl substituted with up to 2 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.
  • any Z substituent may be unsubstituted.
  • R 2 is C 1 -C 4 alkyl.
  • R 2 is methyl
  • two R 2 groups taken together form a 3 membered cycloalkyl ring.
  • compositions in the disclosure may be in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable refers to salts prepared from pharmaceutically acceptable non-toxic bases and acids, including inorganic and organic bases and inorganic and organic acids.
  • Salts derived from inorganic bases include lithium, sodium, potassium, magnesium, calcium and zinc.
  • Salts derived from organic bases include ammonia, primary, secondary and tertiary amines, and amino acids.
  • Salts derived from inorganic acids include sulfuric, hydrochloric, phosphoric, hydrobromic.
  • Salts derived from organic acids include C 1-6 alkyl carboxylic acids, di-carboxylic acids and tricarboxylic acids such as acetic acid, proprionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, adipic acid and citric acid, and alkylsulfonic acids such as methanesulphonic, and aryl sulfonic acids such as para-tolouene sulfonic acid and benzene sulfonic acid.
  • Compounds in the disclosure may be in the form of a solvate. This occurs when a compound of Formula (I) has an energetically favorable interaction with a solvent, crystallizes in a manner that it incorporates solvent molecules into the crystal lattice or a complex is formed with solvent molecules in the solid or liquid state.
  • solvents forming solvates are water (hydrates), MeOH, EtOH, iPrOH, and acetone.
  • Polymorphism is the ability of a substance to exist in two or more crystalline phases that have different arrangements and/or conformations of the molecule in the crystal lattice.
  • Compounds in the disclosure may exist as isotopically labeled compounds of Formula (I) where one or more atoms are replaced by atoms having the same atomic number but a different atomic mass from the atomic mass which is predominantly seen in nature.
  • isotopes include, but are not limited to hydrogen isotopes (deuterium, tritium), carbon isotopes ( 11 C, 13 C, 14 C) and nitrogen isotopes ( 13 N, 15 N).
  • substitution with heavier isotopes such as deuterium ( 2 H) may offer certain therapeutic advantages resulting from greater metabolic stability which could be preferable and lead to longer in vivo half-life or dose reduction in a mammal or human.
  • Prodrugs of compounds embodied by Formula (I) are also within the scope of this disclosure. Particular derivatives of compounds of Formula (I) which may have little to negligible pharmacological activity themselves, can, when administered to a mammal or human, be converted into compounds of Formula (I) having the desired biological activity.
  • Compounds in the disclosure and their pharmaceutically acceptable salts, prodrugs, as well as metabolites of the compounds may also be used to treat certain eating disorders, obesity, compulsive gambling, sexual disorders, narcolepsy, sleep disorders, diabetes, metabolic syndrome, neurodegenerative disorders and CNS disorders/conditions as well as in smoking cessation treatment.
  • the treatment of CNS disorders and conditions by the compounds of the disclosure can include Huntington's disease, schizophrenia and schizo-affective conditions, delusional disorders, drug-induced psychoses, panic and obsessive compulsive disorders, post-traumatic stress disorders, age-related cognitive decline, attention deficit/hyperactivity disorder, bipolar disorders, personality disorders of the paranoid type, personality disorders of the schizoid type, psychosis induced by alcohol, amphetamines, phencyclidine, opioids hallucinogens or other drug-induced psychosis, dyskinesia or choreiform conditions including dyskinesia induced by dopamine agonists, dopaminergic therapies, psychosis associated with Parkinson's disease, psychotic symptoms associated with other neurodegenerative disorders including Alzheimer's disease, dystonic conditions such as idiopathic dystonia, drug-induced dystonia, torsion dystonia, and tardive dyskinesia, mood disorders including major depressive episodes, post-stroke depression, minor depressive disorder, premen
  • compounds of the disclosure may be used for the treatment of eating disorders, obesity, compulsive gambling, sexual disorders, narcolepsy, sleep disorders as well as in smoking cessation treatment.
  • compounds of the disclosure may be used for the treatment of obesity, schizophrenia, schizo-affective conditions, Huntington's disease, dystonic conditions and tardive dyskinesia.
  • compounds of the disclosure may be used for the treatment of schizophrenia, schizo-affective conditions, Huntington's disease and obesity.
  • compounds of the disclosure may be used for the treatment of schizophrenia and schizo-affective conditions.
  • compounds of the disclosure may be used for the treatment of Huntington's disease.
  • compounds of the disclosure may be used for the treatment of obesity and metabolic syndrome.
  • Compounds of the disclosure may also be used in mammals and humans in conjunction with conventional antipsychotic medications including but not limited to Clozapine, Olanzapine, Risperidone, Ziprasidone, Haloperidol, Aripiprazole, Sertindole and Quetiapine.
  • conventional antipsychotic medications including but not limited to Clozapine, Olanzapine, Risperidone, Ziprasidone, Haloperidol, Aripiprazole, Sertindole and Quetiapine.
  • the combination of a compound of Formula (I) with a subtherapeutic dose of an aforementioned conventional antipsychotic medication may afford certain treatment advantages including improved side effect profiles and lower dosing requirements.
  • Alkyl is meant to denote a linear or branched saturated or unsaturated aliphatic C 1 -C 8 hydrocarbon which can be optionally substituted with up to 3 fluorine atoms and, if specified, substituted with other groups. Unsaturation in the form of a double or triple carbon-carbon bond may be internal or terminally located and in the case of a double bond both cis and trans isomers are included. Examples of alkyl groups include but are not limited to methyl, trifluoromethyl, ethyl, trifluoroethyl, isobutyl, neopentyl, cis- and trans-2-butenyl, isobutenyl, propargyl.
  • C 1 -C 4 alkyl is the subset of alkyl limited to a total of up to 4 carbon atoms.
  • C x -C y includes all subsets, e.g., C 1 -C 4 includes C 1 -C 2 , C 2 -C 4 , C 1 -C 3 etc.
  • Acyl is an alkyl-C(O)— group wherein alkyl is as defined above.
  • Examples of acyl groups include acetyl and proprionyl.
  • Alkoxy is an alkyl-O— group wherein alkyl is as defined above.
  • C 1 -C 4 alkoxy is the subset of alkyl-O— where the subset of alkyl is limited to a total of up to 4 carbon atoms.
  • alkoxy groups include methoxy, trifluoromethoxy, ethoxy, trifluoroethoxy, and propoxy.
  • Alkoxyalkyl is an alkyl-O—(C 1 -C 4 alkyl)- group wherein alkyl is as defined above.
  • alkoxyalkyl groups include methoxymethyl and ethoxymethyl.
  • Alkoxyalkyloxy is an alkoxy-alkyl-O— group wherein alkoxy and alkyl are as defined above.
  • alkoxyalkyloxy groups include methoxymethyloxy (CH 3 OCH 2 O—) and methoxyethyloxy (CH 3 OCH 2 CH 2 O—) groups.
  • Alkylthio is alkyl-S— group wherein alkyl is as defined above.
  • Alkylthio includes C 1 -C 4 alkylathio.
  • Alkylsulfonyl is alkyl-SO 2 — wherein alkyl is as defined above.
  • Alkylsulfonyl includes C 1 -C 4 alkylsulfonyl.
  • Alkylamino is alkyl-NH— wherein alkyl is as defined above.
  • Alkylamino includes C 1 -C 4 alkylamino.
  • Dialkylamino is (alkyl) 2 -N— wherein alkyl is as defined above.
  • Amido is H 2 NC(O)—
  • Alkylamido is alkyl-NHC(O)— wherein alkyl is as defined above.
  • Dialkylamido is (alkyl) 2 -NC(O)— wherein alkyl is as defined above.
  • Aromatic is heteroaryl or aryl wherein heteroaryl and aryl are as defined below.
  • Aryl is a phenyl or napthyl group.
  • Aryl groups may be optionally and independently substituted with up to three groups selected from halogen, CF 3 , CN, NO 2 , OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH 2 CH 2 OCH 3 , —OC(O)R a , —OC(O)OR a , —OC(O)NHR a , —OC(O)N(R a ), —SR a , —S(O)R a , —NH 2 , —NHR a , —N(R a )(R b ), —NHC(O)R a
  • Arylalkyl is an aryl-alkyl- group wherein aryl and alkyl are as defined above.
  • Aryloxy is an aryl-O— group wherein aryl is as defined above.
  • Arylalkoxy is an aryl-(C 1 -C 4 alkyl)-O— group wherein aryl is as defined above.
  • Carboxy is a CO 2 H or CO 2 R c group wherein R c is independently chosen from, alkyl, C 1 -C 4 alkyl, cycloalkyl, arylalkyl, cycloalkylalkyl, CF 3 , and alkoxyalkyl, wherein alkyl is as defined above.
  • Cycloalkyl is a C 3 -C 7 cyclic non-aromatic hydrocarbon which may contain a single double bond and is optionally and independently substituted with up to three groups selected from alkyl, alkoxy, hydroxyl and oxo.
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexanonyl.
  • Cycloalkyloxy is a cycloalkyl-O— group wherein cycloalkyl is as defined above. Examples include cyclopropyloxy, cyclobutyloxy and cyclopentyloxy. C 3 -C 6 cycloalkyloxy is the subset of cycloalkyl-O— where cycloalkyl contains 3-6 carbon atoms.
  • Cycloalkylalkyl is a cycloalkyl-(C 1 -C 4 alkyl)- group. Examples include cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl and cyclohexylethyl.
  • Cycloalkylalkoxy is a cycloalkyl-(C 1 -C 4 alkyl)-O— group wherein cycloalkyl and alkyl are as defined above.
  • Examples of cycloalkylalkoxy groups include cyclopropylmethoxy, cyclopentylmethoxy and cyclohexylmethoxy.
  • Halogen is F, Cl, Br or I.
  • Heteroaryl is a tetrazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, a mono or bicyclic aromatic ring system, or a heterobicyclic ring system with one aromatic ring having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C.
  • heteroaryl groups include but are not limited to thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyrrazolyl, imidazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, pyrimidinyl, pyrazinyl, indolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, benzthiadiazololyl, benzoxadiazolyl and benzimidazolyl.
  • Heteroaryl groups may be optionally and independently substituted with up to 3 substituents independently selected from halogen, CF 3 , CN, NO 2 , OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH 2 CH 2 OCH 3 , —OC(O)R a , —OC(O)O R a , —OC(O)NHR a , —OC(O)N(R a ), —SR a , —S(O)R a , —NH 2 , —NHR a , —N(R a )(R b ), —NHC(O)R a , —N(R a ) C(O)
  • Heteroarylalkyl is a heteroaryl-(C 1 -C 4 alkyl)- group wherein heteroaryl and alkyl are as defined above.
  • heteroarylalkyl groups include 4-pyridinylmethyl and 4-pyridinylethyl.
  • Heteroaryloxy is a heteroaryl-O group wherein heteroaryl is as defined above.
  • Heteroarylalkoxy is a heteroaryl-(C 1 -C 4 alkyl)-O— group wherein heteroaryl and alkoxy are as defined above.
  • heteroarylalkyl groups include 4-pyridinylmethoxy and 4-pyridinylethoxy.
  • Heterobicyclic ring system is a ring system having 8-10 atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than carbon and provided that at least one of the rings is aromatic; said bicyclic ring may be optionally and independently substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, C 3 -C 6 cycloalkyloxy, cycloalkylalkyl, halogen, nitro, alkylsulfonyl and cyano.
  • Examples of 8-10 membered heterobicyclic ring systems include but are not limited to 1,5-naphthyridyl, 1,2,3,4-tetrahydro-1,5-naphthyridyl 1,6-naphthyridyl, 1,2,3,4-tetrahydro-1,6-naphthyridyl 1,7-naphthyridyl, 1,2,3,4-tetrahydro-1,7-naphthyridinyl 1,8-naphthyridyl, 1,2,3,4-tetrahydro-1,8-naphthyridyl, 2,6-naphthyridyl, 2,7-naphthyridyl, cinnolyl, isoquinolyl, tetrahydroisoquinolinyl, phthalazyl, quinazolyl, 1,2,3,4-tetrahydroquinazolinyl, quinolyl
  • Heterocycloalkyl is a non-aromatic, monocyclic or bicyclic saturated or partially unsaturated ring system comprising 5-10 ring atoms selected from C, N, O and S, provided that not more than 2 ring atoms in any single ring are other than C.
  • the nitrogen may be substituted with an alkyl, acyl, —C(O)O-alkyl, —C(O)NH(alkyl) or a —C(O)N(alkyl) 2 group.
  • Heterocycloalkyl groups may be optionally and independently substituted with hydroxy, alkyl and alkoxy groups and may contain up to two oxo groups.
  • Heterocycloalkyl groups may be linked to the rest of the molecule via either carbon or nitrogen ring atoms.
  • heterocycloalkyl groups include tetrahydrofuranyl, tetrahydrothienyl, tetrahydro-2H-pyran, tetrahydro-2H-thiopyranyl, pyrrolidinyl, pyrrolidonyl, succinimidyl, piperidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, morpholin-3-one, thiomorpholinyl, thiomorpholin-3-one, 2,5-diazabicyclo[2.2.2]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, octahydro-1H-pyrido[1,2-a]pyrazine, 3-thia-6-azabicyclo[3.1.1]heptane and 3-oxa-6-azabicyclo[3.1.1]
  • Heterocycloalkylalkyl is a heterocycloalkyl-(C 1 -C 4 alkyl)- group wherein heterocycloalkyl is as defined above.
  • Heterocycloalkyloxy is a heterocycloalkyl-O— group wherein heterocycloalkyl is as defined above.
  • Heterocycloalkylalkoxy is a heterocycloalkyl-(C 1 -C 4 alkyl)-O— group wherein heterocycloalkyl is as defined above.
  • Oxo is a —C(O)— group.
  • Phenyl is a benzene ring which may be optionally and independently substituted with up to three groups selected from halogen, CF 3 , CN, NO 2 , OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH 2 CH 2 OCH 3 , —OC(O)R a , —OC(O)OR a , —OC(O)NHR a , —OC(O)N(R a ), —SR a , —S(O)R a , —NH 2 , —NHR a , —N(R a )(R b ), —NHC(O)R a , —N(ROC(O)R
  • Restricted phenyl is a benzene ring which may be optionally and independently substituted with up to three groups selected from halogen, CF 3 , CN, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH 2 CH 2 OCH 3 , —OC(O)R a , —OC(O)OR a , —OC(O)N(R a ), —N(R a )(R b ), —NHC(O)R a , —N(R a )C(O)R b , —NHC(O)OR a , —N(R a )C(O)OR b , —C(O)N(R a )(R b ), —COR a wherein R a and R b are independently chosen from alky
  • the 1,2 disubstituted heterocyclic compounds of Formula I may be prepared from multi-step organic synthesis routes from commercially available starting materials by one skilled in the art of organic synthesis using established organic synthetic procedures.
  • Non-commercially available phenyl acetic acids can be made from commercially available starting materials via methods known by one skilled in the art of organic synthesis. Such methods include synthesis from the corresponding aryl acids via. the Wolff rearrangement using diazomethane.
  • Reactive groups not involved in the above processes can be protected with standard protecting groups during the reactions and removed by standard procedures (T. W. Greene & P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley-Interscience) known to those of ordinary skill in the art.
  • Presently preferred protecting groups include methyl, benzyl, MEM, acetate and tetrahydropyranyl for the hydroxyl moiety, and BOC, Cbz, trifluoroacetamide and benzyl for the amino moiety, methyl, ethyl, tert-butyl and benzyl esters for the carboxylic acid moiety.
  • Practitioners in the art will also recognize that the order of certain chemical reactions can be changed. Practitioners of the art will also note that alternative reagents and conditions exist for various chemical steps.
  • the reaction was heated at reflux for 3 h, upon which the reaction mixture was filtered through a pad of Celite® and the filtrate was diluted with EtOAc (100 mL), washed with water (50 mL), brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain the crude product.
  • reaction was refluxed for 3 h and monitored by TLC. Upon complete consumption of the starting material, the reaction mixture was filtered through a bed of Celite® washing with ethyl acetate. The organic layer was then washed with water, brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexanes on 230-400 mesh silica gel to afford 4-(4-(benzyloxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (8.3 g, 60.2%) as a light orange color solid.
  • the reaction mixture was quenched with a saturated NH 4 Cl solution and extracted with EtOAc (2 ⁇ 100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo to obtain the crude product.
  • the crude material was purified via silica gel column chromatography eluting with 15% EtOAc in hexanes to afford 4-(4-methyl-4-(trimethylsilyloxy) pent-2-ynoyl)benzonitrile (3.8 g, 68%) as a yellow oil.
  • Tosyl chloride (12.5 g, 65.6 mmol) was added to a solution of 2,3,5-trimethylpyridine 1-oxide (6.0 g, 43.7 mmol), and triethylamine (6.6 g, 65.6 mmol) in DCM (60 ml) at RT under an atmosphere of nitrogen.
  • the reaction mixture was heated to reflux and reflux was maintained 4 h (reaction was monitored by TLC).
  • the reaction was quenched with water and extracted with DCM. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Methanesulfonic acid (445.0 mg, 4.6 mmol) was added to a solution of 4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.01 g, 4.6 mmol) in DCM (3 ml) and diethyl ether (150 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h and the solids were removed by filtration.
  • 1,3-Dichloroacetone (22.9 g, 180.3 mmol) was added to a solution of 2-amino pyridine (10 g, 106.3 mmol) in acetonitrile (200 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). Upon completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water and adjusted the pH to 7.5 with sodium bicarbonate solution which was extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Methanesulfonic acid (531 mg, 5.5 mmol) was added to a solution of 4-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.5 g, 5.5 mmol) in DCM (5 ml) and diethyl ether (150 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred for a further 4 h at RT.
  • Bromoacetaldehyde diethylacetal (36.5 g, 216 mmol) was added to a solution of aq.cHBr (7.2 ml) and then heated to reflux for 30 min. The mixture was then cooled to 0° C., upon which ethanol (236 ml), sodium bicarbonate (8.09 g, 95 mmol) and 6-chloropyridazin-3-amine (4 g, 30 mmol) were added. The mixture was heated to 80° C. for 3 h (reaction was monitored by TLC) and then allowed to cool to RT. The mixture was concentrated under reduced pressure, diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • 6-Chloroimidazo[1,2-b]pyridazine (5.0 g, 32 mmol) was added to a solution of methanol (75 ml) and acetonitrile (75 ml) in a steel bomb at RT under nitrogen bubbling.
  • Triethylamine (4.0 g, 39.4 mmol)
  • BINAP 2.0 g, 3.0 mmol
  • bisacetonitrile palladium dichloride 0.854 g, 3.0 mmol
  • Methanesulfonic acid 54 mg, 0.5 mmol was added to a solution of compound 4-(4-(imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (250 mg, 0.5 mmol) in DCM (2 ml) and diethyl ether (20 mL) at RT under an atmosphere of nitrogen.
  • 1,3-Dichloroacetone (21.4 g, 168.0 mmol) was added to a solution of 6-chloropyridazin-3-amine (10 g, 77.2 mmol) in acetonitrile (200 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). The volatiles were removed under reduced pressure and the reaction mixture was diluted with water. The pH was adjusted to ⁇ 7.5 with sodium bicarbonate solution and then extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Methanesulfonic acid (34.8 mg, 0.36 mmol) was added to a solution of compound 4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (160 mg, 0.36 mmol) in DCM (3 ml) and diethyl ether (15 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h, upon which the mixture was filtered and the solids were washed with 20% DCM in diethyl ether.
  • reaction mixture was diluted with water and extracted with EtOAc; the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • residue was purified by flash column chromatography using 22% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(3-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl) (0.70 g, 35%,) as yellow solid.
  • Methanesulfonic acid 158 mg, 1.6 mmol was added to a solution of compound 4-(3-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl) (700 mg, 1.6 mmol) in DCM (0.5 ml) and diethyl ether (15 mL) at RT under an atmosphere of nitrogen.
  • Methanesulfonic acid (309 mg, 3.2 mmol) was added to a solution of compound 4-(3-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.4 g, 3.2 mmol) in DCM (5 ml) and diethyl ether (30 mL) at RT under an atmosphere of nitrogen.
  • N-Chloro succinimide (329 g, 2.46 mmol) was added to a solution of 2-(chloromethyl)imidazo[1,2-a]pyridine (450 mg, 2.2 mmol) in DCM (15 ml) at RT under an atmosphere of nitrogen. Stirring was continued for 2 h (reaction was monitored by TLC) upon which the reaction mixture was diluted with DCM and washed with water and brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Methanesulfonic acid (50.5 mg, 0.52 mmol) was added to a solution of 4-(4-((3-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (250 mg, 0.52 mmol) in DCM (2.5 ml) and diethyl ether (25 mL) at RT under an atmosphere of nitrogen.
  • 2-Chloro-5-methylpyridine (10 g, 78 mmol) was added to a solution of methanol (75 ml) and acetonitrile (75 ml) in steel bomb at RT under nitrogen bubbling followed by the addition of triethylamine (11.8 g, 117 mmol), BINAP (970 mg, 1.5 mmol) and bisacetonitrile palladium dichloride (0.4 g, 1.5 mmol).
  • the mixture was heated to 100° C. and this temperature was maintained over night (the reaction was monitored by TLC).
  • the reaction mixture was filter through Celite® bed and washing with ethyl acetate. The filtrate was washed with water and brine.
  • Methanesulfonic acid (462 mg, 4.8 mmol) was added to a solution of 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (2.0 g, 4.8 mmol) in DCM (5 ml) and diethyl ether (50 mL) at RT under an atmosphere of nitrogen.
  • Methanesulfonic acid 36 mg, 0.3 mmol was added to a solution of 4-(5,5-dimethyl-3-(4-((5-methylpyridin-2-yl)methoxy)phenyl)-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (150 mg, 0.3 mmol) in DCM (5 ml) and diethyl ether (50 mL) at RT under an atmosphere of nitrogen.
  • Trimethylsilyl chloride (1.06 g, 9.8 mmol) was added to a stirred solution of 2-oxobutanoic acid (10.0 g, 98.0 mmol) in 2,2-dimethoxypropane (90 ml) and methanol (20 ml). The mixture was stirred for 18 hours at RT (the reaction was monitored by TLC) upon which the mixture was concentrated under reduced pressure afford crude methyl 2-oxobutanoate (8.0 g) as a brown liquid.
  • 1 H NMR 200 MHz, CDCl 3 : ⁇ 3.85 (s, 3H), 2.9 (q, 2H), 1.15 (t, 1H), 6.8 (t, 1H), 4.75 (s, 2H).
  • Methyl 3-bromo-2-oxobutanoate (6.5 g, 34.3 mmol) was added to a stirred solution of 2-aminopyridine (4.0 g, 42.5 mmol) in acetonitrile (100 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). The mixture was concentrated in vacuo and the residue was diluted with water and the pH was to 7.5 using sodium bicarbonate solution. The mixture was extracted with EtOAc; the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • 1,3-Dichloroacetone (17.6 g, 138.3 mmol) was added to a solution of 6-methylpyridin-2-amine (10 g, 92.5 mmol) in acetonitrile (200 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). The mixture was concentrated under reduced pressure, the residue was diluted with water, and the pH was adjusted to 7.5 with sodium bicarbonate solution. The mixture was extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Methanesulfonic acid (53.1 mg, 0.5 mmol) was added to a solution of 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (250 g, 0.5 mmol) in DCM (2.5 ml) and diethyl ether (50 mL) at RT under an atmosphere of nitrogen.
  • 1,3-Dichloroacetone (7.4 g, 58.3 mmol) was added to a solution of 5-chloropyridin-2-amine (5.0 g, 38.9 mmol) in acetonitrile (100 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). Upon completion of the reaction as judged by TLC, the mixture was concentrated under reduced pressure. The residue was diluted with water and the pH was adjusted to 7.5 with sodium bicarbonate solution. The mixture was extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Methanesulfonic acid (53.1 mg, 0.5 mmol) was added to a solution of compound 4-(4-((6-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (250 g, 0.5 mmol) in DCM (2.5 ml) and diethyl ether (50 mL) at RT under an atmosphere of nitrogen.
  • the present disclosure includes pharmaceutical composition for treating a subject having a neurological disorder comprising a therapeutically effective amount of a compound of Formula (I), a derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.
  • the pharmaceutical compositions can be administered in a variety of dosage forms including, but not limited to, a solid dosage form or in a liquid dosage form, an oral dosage form, a parenteral dosage form, an intranasal dosage form, a suppository, a lozenge, a troche, buccal, a controlled release dosage form, a pulsed release dosage form, an immediate release dosage form, an intravenous solution, a suspension or combinations thereof.
  • the dosage can be an oral dosage form that is a controlled release dosage form.
  • the oral dosage form can be a tablet or a caplet.
  • the compounds can be administered, for example, by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.
  • oral or parenteral routes including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.
  • the compounds or pharmaceutical compositions comprising the compounds are delivered to a desired site, such as the brain, by continuous injection via a shunt.
  • the compound in another embodiment, can be administered parenterally, such as intravenous (IV) administration.
  • the formulations for administration will commonly comprise a solution of the compound of the Formula (I) dissolved in a pharmaceutically acceptable carrier.
  • acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride.
  • sterile fixed oils can conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter.
  • These formulations may be sterilized by conventional, well known sterilization techniques.
  • the formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
  • concentration of compound of Formula (I) in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs.
  • the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.
  • a compound of Formula (I) can be administered by introduction into the central nervous system of the subject, e.g., into the cerbrospinal fluid of the subject.
  • the formulations for administration will commonly comprise a solution of the compound of Formula (I) dissolved in a pharmaceutically acceptable carrier.
  • the compound of Formula (I) is introduced intrathecally, e.g., into a cerebral ventricle, the lumbar area, or the cisterna magna.
  • the compound of Formula (I) is introduced intraocularly, to thereby contact retinal ganglion cells.
  • the pharmaceutically acceptable formulations can easily be suspended in aqueous vehicles and introduced through conventional hypodermic needles or using infusion pumps. Prior to introduction, the formulations can be sterilized with, preferably, gamma radiation or electron beam sterilization.
  • the pharmaceutical composition comprising a compound of Formula (I) is administered into a subject intrathecally.
  • intrathecal administration is intended to include delivering a pharmaceutical composition comprising a compound of Formula (I) directly into the cerebrospinal fluid of a subject, by techniques including lateral cerebroventricular injection through a burrhole or cisternal or lumbar puncture or the like (described in Lazorthes et al. Advances in Drug Delivery Systems and Applications in Neurosurgery, 143-192 and Omaya et al., Cancer Drug Delivery, 1: 169-179, the contents of which are incorporated herein by reference).
  • lumbar region is intended to include the area between the third and fourth lumbar (lower back) vertebrae.
  • ceisterna magna is intended to include the area where the skull ends and the spinal cord begins at the back of the head.
  • cervical ventricle is intended to include the cavities in the brain that are continuous with the central canal of the spinal cord.
  • Administration of a compound of Formula (I) to any of the above mentioned sites can be achieved by direct injection of the pharmaceutical composition comprising the compound of Formula (I) or by the use of infusion pumps.
  • the pharmaceutical compositions can be formulated in liquid solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution.
  • compositions may be formulated in solid form and re-dissolved or suspended immediately prior to use. Lyophilized forms are also included.
  • the injection can be, for example, in the form of a bolus injection or continuous infusion (e.g., using infusion pumps) of pharmaceutical composition.
  • the pharmaceutical composition comprising a compound of Formula (I) is administered by lateral cerebro ventricular injection into the brain of a subject.
  • the injection can be made, for example, through a burr hole made in the subject's skull.
  • the encapsulated therapeutic agent is administered through a surgically inserted shunt into the cerebral ventricle of a subject.
  • the injection can be made into the lateral ventricles, which are larger, even though injection into the third and fourth smaller ventricles can also be made.
  • the pharmaceutical composition is administered by injection into the cisterna magna, or lumbar area of a subject.
  • the compounds will generally be provided in unit dosage forms of a tablet, pill, dragee, lozenge or capsule; as a powder or granules; or as an aqueous solution, suspension, liquid, gels, syrup, slurry, etc. suitable for ingestion by the patient.
  • Tablets for oral use may include the active ingredients mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives.
  • suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • compositions for oral use can be obtained through combination of a compound of Formula (I) with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores.
  • Suitable solid excipients in addition to those previously mentioned are carbohydrate or protein fillers that include, but are not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen.
  • disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.
  • Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredients is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
  • suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth
  • a wetting agent such as lecithin.
  • Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
  • the suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient are cocoa butter and polyethylene glycols.
  • the compounds can be delivered transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, or aerosols.
  • Aqueous suspensions can contain a compound of Formula (I) in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia , and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbi
  • a suspending agent such as sodium carboxymethylcellulose,
  • the aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin.
  • preservatives such as ethyl or n-propyl p-hydroxybenzoate
  • coloring agents such as a coloring agent
  • flavoring agents such as aqueous suspension
  • sweetening agents such as sucrose, aspartame or saccharin.
  • Formulations can be adjusted for osmolarity.
  • Oil suspensions can be formulated by suspending a compound of Formula (I) in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these.
  • the oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose.
  • These formulations can be preserved by the addition of an antioxidant such as ascorbic acid.
  • an injectable oil vehicle see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997.
  • the pharmaceutical formulations can also be in the form of oil-in-water emulsions.
  • the oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate.
  • the emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or transcutaneous delivery (e.g., subcutaneously or intramuscularly), intramuscular injection or a transdermal patch.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable dose will be in the range of 0.01 to 100 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 10 mg per kilogram body weight per day.
  • the desired dose is preferably presented once daily, but may be dosed as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day.
  • the compounds can be administered as the sole active agent, or in combination with other known therapeutics to be beneficial in the treatment of neurological disorders.
  • the administering physician can provide a method of treatment that is prophylactic or therapeutic by adjusting the amount and timing of drug administration on the basis of observations of one or more symptoms (e.g., motor or cognitive function as measured by standard clinical scales or assessments) of the disorder being treated.
  • a pharmaceutical composition After a pharmaceutical composition has been formulated in an acceptable carrier, it can be placed in an appropriate container and labeled for treatment of an indicated condition.
  • labeling would include, e.g., instructions concerning the amount, frequency and method of administration.
  • mice Male C57BL/6J mice (Charles River; 20-25 g) were used for all assays except prepulse inhibition (PPI) which used male DBA/2N mice (Charles River, 20-25 g). For all studies, animals were housed five/cage on a 12-h light/dark cycle with food and water available ad libitum.
  • PPI prepulse inhibition
  • Training consisted of repeated pairings of the light (conditioned stimulus) followed by a shock (unconditioned stimulus). For each trial the light was presented for 5 sec followed by a 0.5 mA shock that would terminate if the mouse crossed to the other chamber or after 10 seconds. The intertrial interval was set to 20 seconds. Each training and test session consisted a four min habituation period followed by 30 trials.
  • mice were individually placed into the test chambers (StartleMonitor, Kinder Scientific, Poway Calif.). The animals were given a five min acclimation period to the test chambers with the background noise level set to 65 decibel (dB) which remained for the entire test session. Following acclimation, four successive trials 120 dB pulse for 40 msec were presented, however these trials were not included in data analysis. The mice were then subjected to five different types of trials in random order: pulse alone (120 dB for 40 msec), no stimulus and three different prepulse+pulse trials with the prepulse set at 67, 69 or 74 dB for 20 msec followed a 100 msec later by a 120 dB pulse for 40 msec.
  • Percent PPI was calculated according to the following formula: (1 ⁇ (startle response to prepulse+pulse)/startle response to pulse alone)) ⁇ 100.
  • mice were individually placed into test cages for a 30 min habituation period. Following habituation to test cages, baseline activity was recorded for 60 min. Mice were then briefly removed and administered test compound and placed immediately back into the test cage. At 5 min prior to test time mice were again briefly removed from test cages and administered MK-801 (0.3 mg/kg, i.p. in 0.9% saline) and then immediately placed back into test cages and activity level recorded 1 hour. Activity level was measured as distance travelled in centimeters (Ethovision tracking software, Noldus Inc. Wageningen, Netherlands).
  • mice were placed on a wire mesh screen set at a 60 degree angle with their heads facing upwards and the latency to move or break stance was recorded. Animals were given three trials per time point with a 30 sec cut-off per trial.
  • a one-way or two-way ANOVA was used to evaluate overall differences between treatments and a Tukey's post-hoc test or Student's t-test was used to evaluate differences between treatment groups for the one-way ANOVA and a Bonferroni test was used for the two-way ANOVA.
  • the criterion for statistical significance was set to p ⁇ 0.05.
  • the reaction was terminated by denaturing the PDE enzyme (at 70° C.) after which [ 3 H]-5′-AMP was converted to [ 3 H]-adenosine by adding 25 ⁇ l snake venom nucleotidase and incubating for 10 minutes (at 37° C.). Adenosine, being neutral, was separated from charged cAMP or AMP by the addition of 200 ⁇ l Dowex resin. Samples were shaken for 20 minutes then centrifuged for 3 minutes at 2,500 r.p.m. 50 ⁇ l of supernatant was removed and added to 200 ⁇ l of MicroScint-20 in white plates (Greiner 96-well Optiplate) and shaken for 30 minutes before reading on Perkin Elmer TopCount Scintillation Counter.

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Abstract

Phenoxymethyl compounds that inhibit at least one phosphodiesterase 10 are described as are pharmaceutical compositions containing such compounds an methods for treating various CNS disorders by administering such compounds to a patient in need thereof.

Description

    PRIORITY
  • This application is a continuation of U.S. patent application Ser. No. 13/722,595, filed Dec. 20, 2012, entitled “Phenoxymethyl Heterocyclic Compounds,” which is a divisional application of U.S. patent application Ser. No. 12/642,026, filed Dec. 18, 2009, now U.S. Pat. No. 8,343,973, entitled “Phenoxymethyl Heterocyclic Compounds,” which claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 61/176,413, filed May 7, 2009, entitled “Vicinal Substituted Heterocyclic Compounds.” The entire contents of these priority applications are incorporated herein by reference.
    • BACKGROUND
  • Cyclic phosphodiesterases are intracellular enzymes which, through the hydrolysis of cyclic nucleotides cAMP and cGMP, regulate the levels of these mono phosphate nucleotides which serve as second messengers in the signaling cascade of G-protein coupled receptors. In neurons, PDEs also play a role in the regulation of downstream cGMP and cAMP dependent kinases which phosphorylate proteins involved in the regulation of synaptic transmission and homeostasis. To date, eleven different PDE families have been identified which are encoded by 21 genes. The PDEs contain a variable N-terminal regulatory domain and a highly conserved C-terminal catalytic domain and differ in their substrate specificity, expression and localization in cellular and tissue compartments, including the CNS.
  • The discovery of a new PDE family, PDE10, was reported simultaneously by three groups in 1999 (Soderling et al. “Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A” Proc. Natl Sci. 1999, 96, 7071-7076; Loughney et al. “Isolation and characterization of PDE10A, a novel human 3′,5′-cyclic nucleotide phosphodiesterase” Gene 1999, 234, 109-117; Fujishige et al. “Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A)” J. Biol. Chem. 1999, 274, 18438-18445). The human PDE10 sequence is highly homologous to both the rat and mouse variants with 95% amino acid identity overall, and 98% identity conserved in the catalytic region.
  • PDE10 is primarily expressed in the brain (caudate nucleus and putamen) and is highly localized in the medium spiny neurons of the striatum, which is one of the principal inputs to the basal ganglia. This localization of PDE10 has led to speculation that it may influence the dopaminergic and glutamatergic pathways both which play roles in the pathology of various psychotic and neurodegenerative disorders.
  • PDE10 hydrolyzes both cAMP (Km=0.05 uM) and cGMP (Km=3 uM) (Soderling et al. “Isolation and Characterization of a dual-substrate phosphodiesterase gene family: PDE10.” Proc. Natl Sci. USA 1999, 96(12), 7071-7076). In addition, PDE10 has a five-fold greater Vmax for cGMP than for cAMP and these in vitro kinetic data have lead to the speculation that PDE10 may act as a cAMP-inhibited cGMP phosphodiesterase in vivo (Soderling and Beavo “Regulation of cAMP and cGMP signaling: New phosphodiesterases and new functions,” Curr. Opin. Cell Biol., 2000, 12, 174-179).
  • PDE10 is also one of five phosphodiesterase members to contain a tandem GAF domain at their N-terminus. It is differentiated by the fact that the other GAF containing PDEs (PDE2, 5, 6, and 11) bind cGMP while recent data points to the tight binding of cAMP to the GAF domain of PDE10 (Handa et al. “Crystal structure of the GAF-B domain from human phosphodiesterase 10A complexed with its ligand, cAMP” J. Biol. Chem. 2008, May 13th, ePub).
  • PDE10 inhibitors have been disclosed for the treatment of a variety of neurological and psychiatric disorders including Parkinson's disease, schizophrenia, Huntington's disease, delusional disorders, drug-induced psychoses, obsessive compulsive and panic disorders (US Patent Application 2003/0032579). Studies in rats (Kostowski et. al “Papaverine drug induced stereotypy and catalepsy and biogenic amines in the brain of the rat” Pharmacol. Biochem. Behav. 1976, 5, 15-17) have showed that papaverine, a selective PDE10 inhibitor, reduces apomorphine induced stereotypes and rat brain dopamine levels and increases haloperidol induced catalepsy. This experiment lends support to the use of a PDE10 inhibitor as an antipsychotic since similar trends are seen with known, marketed antipsychotics.
  • Antipsychotic medications are the mainstay of current treatment for schizophrenia. Conventional or classic antipsychotics, typified by haloperidol, were introduced in the mid-1950s and have a proven track record over the last half century in the treatment of schizophrenia. While these drugs are effective against the positive, psychotic symptoms of schizophrenia, they show little benefit in alleviating negative symptoms or the cognitive impairment associated with the disease. In addition, drugs such as haloperidol have extreme side effects such as extrapyramidal symptoms (EPS) due to their specific dopamine D2 receptor interaction. An even more severe condition characterized by significant, prolonged, abnormal motor movements known as tardive dyskinesia also may emerge with prolonged classic antipsychotic treatment.
  • The 1990s saw the development of several new drugs for schizophrenia, referred to as atypical antipsychotics, typified by risperidone and olanzapine and most effectively, clozapine. These atypical antipsychotics are generally characterized by effectiveness against both the positive and negative symptoms associated with schizophrenia, but have little effectiveness against cognitive deficiencies and persisting cognitive impairment remain a serious public health concern (Davis, J. M et al. “Dose response and dose equivalence of antipsychotics.” Journal of Clinical Psychopharmacology, 2004, 24 (2), 192-208; Friedman, J. H. et al “Treatment of psychosis in Parkinson's disease: Safety considerations.” Drug Safety, 2003, 26 (9), 643-659). In addition, the atypical antipsychotic agents, while effective in treating the positive and, to some degree, negative symptoms of schizophrenia, have significant side effects. For example, clozapine which is one of the most clinically effective antipsychotic drugs shows agranulocytosis in approximately 1.5% of patients with fatalities due to this side effect being observed. Other atypical antipsychotic drugs have significant side effects including metabolic side effects (type 2 diabetes, significant weight gain, and dyslipidemia), sexual dysfunction, sedation, and potential cardiovascular side effects that compromise their clinically effectiveness. In the large, recently published NIH sponsored CATIE study, (Lieberman et al “The Clinical Antipsychotic Trials Of Intervention Effectiveness (CATIE) Schizophrenia Trial: clinical comparison of subgroups with and without the metabolic syndrome.” Schizophrenia Research, 2005, 80 (1), 9-43) 74% of patients discontinued use of their antipsychotic medication within 18 months due to a number of factors including poor tolerability or incomplete efficacy. Therefore, a substantial clinical need still exists for more effective and better tolerated antipsychotic mediations possibly through the use of PDE10 inhibitors.
    • BRIEF SUMMARY
  • The disclosure relates compounds which are inhibitors of phosphodiesterase 10. The disclosure further relates to processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function. The disclosure also relates to methods for treating neurological, neurodegenerative and psychiatric disorders including but not limited to those comprising cognitive deficits or schizophrenic symptoms.
  • Described herein are compounds of Formula (I) that are inhibitors of at least one phosphodiesterase 10:
  • Figure US20150322069A1-20151112-C00001
    • Wherein:
  • HET is a heterocyclic ring selected from Formulas A29, A31 and A39 below
  • Figure US20150322069A1-20151112-C00002
  • and the left most radical is connected to the X group;
    X is selected from optionally substituted aryl and optionally substituted heteroaryl;
    Z is optionally substituted heteroaryl;
    Each R2 is independently selected from C1-C4 alkyl, or two R2 groups taken together with the carbon to which they are attached form a 3 membered cycloalkyl ring;
  • In one embodiment, alkyl groups are fully saturated whether present on their own or as part of another group (e.g. alkylamino or alkoxy).
  • In certain embodiments, substituent groups are not further substituted.
  • In various embodiments, any group that is defined as being optionally substituted can be singly or independently multiply optionally substituted.
  • In one embodiment, HET is selected from Formulas A29 and A31.
  • In another embodiment, HET is Formula A29.
  • In another embodiment, HET is Formula A31.
  • In one embodiment, X is selected from a monocyclic heteroaryl having 5 ring atoms selected from C, O, S and N provided the total number of ring heteroatoms is less than or equal to four and where no more than one of the total number of heteroatoms is oxygen or sulfur, and a monocyclic aromatic ring having 6 atoms selected from C and N provided that not more than 3 ring atoms are N, and where said ring may be optionally and independently substituted with up to two groups selected from C1-C4 alkyl, cycloalkyl, cycloalkyloxy, C1-C4 alkoxy, CF3, carboxy, alkoxyalkyl, C1-C4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, alkylsulfonyl and nitro. Examples include but are not limited to 1H-pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-thiatriazolyl, 1,2,3,5-thiatriazolyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.
  • In a further embodiment, X is a monocyclic heteroaryl having 6 ring atoms selected from C and N provided that not more than 3 ring atoms are N, and where said ring may be optionally and independently substituted with up to two groups selected from C1-C4 alkyl, cycloalkyl, cycloalkyloxy, C1-C4 alkoxy, CF3, carboxy, alkoxyalkyl, C1-C4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, alkylsulfonyl and nitro. Examples include but are not limited to 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.
  • In a further embodiment, X is a monocyclic heteroaryl having 5 ring atoms selected from C, O, S, and N, provided the total number of ring heteroatoms is less than or equal to four and where no more than one of the total number of heteroatoms is oxygen or sulfur and where said ring may be optionally and independently substituted with up to two groups selected from C1-C4 alkyl, cycloalkyl, cycloalkyloxy, C1-C4 alkoxy, CF3, carboxy, alkoxyalkyl, C1-C4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, alkylsulfonyl and nitro. Examples include but are not limited to 1H-pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-thiatriazolyl, 1,2,3,5-thiatriazolyl.
  • In a further embodiment, X is 4-pyridinyl optionally substituted with one group selected from C1-C4 alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, C1-C4 alkoxy, CF3, amino, alkylamino, dialkylamino, thioalkyl, halogen, alkylsulfonyl and cyano.
  • In a further embodiment, X is 4-pyridinyl.
  • In another embodiment X is selected from restricted phenyl.
  • In a further embodiment, X is selected from a 3,4-disubstituted phenyl, 4-substituted phenyl. and 4-pyridinyl.
  • In a further embodiment, X is selected from a 3,4-disubstituted phenyl and 4-substituted phenyl.
  • In another embodiment, X is selected from 4-pyridinyl and 4-substituted phenyl.
  • In an additional embodiment, X is 4-substituted phenyl.
  • In a further embodiment, X is 4-methoxyphenyl.
  • In another embodiment, X is 4-chlorophenyl.
  • In another embodiment, X is 4-cyanophenyl.
  • In one embodiment, Z is heteroaryl but is not quinolinyl or pyridyl.
  • In one embodiment, Z is heteroaryl but is not quinolinyl.
  • In one embodiment, Z is heteroaryl but is not pyridyl.
  • In one embodiment, Z is not pyridin-2-yl.
  • In one embodiment, Z is not pyridinyl.
  • In another embodiment, Z is selected from pyridin-2-yl, imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-b]pyridazin-2-yl, and imidazo[1,2-b]pyridazin-6-yl all of which may be optionally substituted with up to 2 substituents independently selected from C1-C4 alkyl, cycloalkyl, cycloalkyloxy, C1-C4 alkoxy, CF3, carboxy, alkoxyalkyl, C1-C4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, alkylsulfonyl and nitro.
  • In a further embodiment, Z is selected from imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-b]pyridazin-2-yl, and imidazo[1,2-b]pyridazin-6-yl all of which may be optionally substituted with up to 2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.
  • In a further embodiment, Z is a 3,5-disubstituted-pyridin-2-yl with each substituent being independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.
  • Figure US20150322069A1-20151112-C00003
  • In a further embodiment, Z is 5-substituted-pyridin-2-yl with the substituent being independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.
  • Figure US20150322069A1-20151112-C00004
  • In an additional embodiment, Z is imidazo[1,2-a]pyridin-2-yl substituted with up to 2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.
  • In an additional embodiment, Z is imidazo[1,2-b]pyridazin-2-yl substituted with up to 2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.
  • In an additional embodiment, Z is imidazo[1,2-b]pyridazin-6-yl substituted with up to 2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.
  • In a further embodiment, any Z substituent may be unsubstituted.
  • In one embodiment, R2 is C1-C4 alkyl.
  • In another embodiment, R2 is methyl.
  • In another embodiment, two R2 groups taken together form a 3 membered cycloalkyl ring.
  • Compounds of the disclosure may contain asymmetric centers and exist as different enantiomers or diastereomers or a combination of these therein. All enantiomeric, diastereomeric forms of Formula (I) are embodied herein.
  • Compounds in the disclosure may be in the form of pharmaceutically acceptable salts. The phrase “pharmaceutically acceptable” refers to salts prepared from pharmaceutically acceptable non-toxic bases and acids, including inorganic and organic bases and inorganic and organic acids. Salts derived from inorganic bases include lithium, sodium, potassium, magnesium, calcium and zinc. Salts derived from organic bases include ammonia, primary, secondary and tertiary amines, and amino acids. Salts derived from inorganic acids include sulfuric, hydrochloric, phosphoric, hydrobromic. Salts derived from organic acids include C1-6 alkyl carboxylic acids, di-carboxylic acids and tricarboxylic acids such as acetic acid, proprionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, adipic acid and citric acid, and alkylsulfonic acids such as methanesulphonic, and aryl sulfonic acids such as para-tolouene sulfonic acid and benzene sulfonic acid.
  • Compounds in the disclosure may be in the form of a solvate. This occurs when a compound of Formula (I) has an energetically favorable interaction with a solvent, crystallizes in a manner that it incorporates solvent molecules into the crystal lattice or a complex is formed with solvent molecules in the solid or liquid state. Examples of solvents forming solvates are water (hydrates), MeOH, EtOH, iPrOH, and acetone.
  • Compounds in the disclosure may exist in different crystal forms known as polymorphs. Polymorphism is the ability of a substance to exist in two or more crystalline phases that have different arrangements and/or conformations of the molecule in the crystal lattice.
  • Compounds in the disclosure may exist as isotopically labeled compounds of Formula (I) where one or more atoms are replaced by atoms having the same atomic number but a different atomic mass from the atomic mass which is predominantly seen in nature. Examples of isotopes include, but are not limited to hydrogen isotopes (deuterium, tritium), carbon isotopes (11C, 13C, 14C) and nitrogen isotopes (13N, 15N). For example, substitution with heavier isotopes such as deuterium (2H) may offer certain therapeutic advantages resulting from greater metabolic stability which could be preferable and lead to longer in vivo half-life or dose reduction in a mammal or human.
  • Prodrugs of compounds embodied by Formula (I) are also within the scope of this disclosure. Particular derivatives of compounds of Formula (I) which may have little to negligible pharmacological activity themselves, can, when administered to a mammal or human, be converted into compounds of Formula (I) having the desired biological activity.
  • Compounds in the disclosure and their pharmaceutically acceptable salts, prodrugs, as well as metabolites of the compounds, may also be used to treat certain eating disorders, obesity, compulsive gambling, sexual disorders, narcolepsy, sleep disorders, diabetes, metabolic syndrome, neurodegenerative disorders and CNS disorders/conditions as well as in smoking cessation treatment.
  • In one embodiment the treatment of CNS disorders and conditions by the compounds of the disclosure can include Huntington's disease, schizophrenia and schizo-affective conditions, delusional disorders, drug-induced psychoses, panic and obsessive compulsive disorders, post-traumatic stress disorders, age-related cognitive decline, attention deficit/hyperactivity disorder, bipolar disorders, personality disorders of the paranoid type, personality disorders of the schizoid type, psychosis induced by alcohol, amphetamines, phencyclidine, opioids hallucinogens or other drug-induced psychosis, dyskinesia or choreiform conditions including dyskinesia induced by dopamine agonists, dopaminergic therapies, psychosis associated with Parkinson's disease, psychotic symptoms associated with other neurodegenerative disorders including Alzheimer's disease, dystonic conditions such as idiopathic dystonia, drug-induced dystonia, torsion dystonia, and tardive dyskinesia, mood disorders including major depressive episodes, post-stroke depression, minor depressive disorder, premenstrual dysphoric disorder, dementia including but not limited to multi-infarct dementia, AIDS-related dementia, and neurodegenerative dementia.
  • In another embodiment, compounds of the disclosure may be used for the treatment of eating disorders, obesity, compulsive gambling, sexual disorders, narcolepsy, sleep disorders as well as in smoking cessation treatment.
  • In a further embodiment, compounds of the disclosure may be used for the treatment of obesity, schizophrenia, schizo-affective conditions, Huntington's disease, dystonic conditions and tardive dyskinesia.
  • In another embodiment, compounds of the disclosure may be used for the treatment of schizophrenia, schizo-affective conditions, Huntington's disease and obesity.
  • In a further embodiment, compounds of the disclosure may be used for the treatment of schizophrenia and schizo-affective conditions.
  • In an additional embodiment, compounds of the disclosure may be used for the treatment of Huntington's disease.
  • In another embodiment, compounds of the disclosure may be used for the treatment of obesity and metabolic syndrome.
  • Compounds of the disclosure may also be used in mammals and humans in conjunction with conventional antipsychotic medications including but not limited to Clozapine, Olanzapine, Risperidone, Ziprasidone, Haloperidol, Aripiprazole, Sertindole and Quetiapine. The combination of a compound of Formula (I) with a subtherapeutic dose of an aforementioned conventional antipsychotic medication may afford certain treatment advantages including improved side effect profiles and lower dosing requirements.
    • DEFINITIONS
  • Alkyl is meant to denote a linear or branched saturated or unsaturated aliphatic C1-C8 hydrocarbon which can be optionally substituted with up to 3 fluorine atoms and, if specified, substituted with other groups. Unsaturation in the form of a double or triple carbon-carbon bond may be internal or terminally located and in the case of a double bond both cis and trans isomers are included. Examples of alkyl groups include but are not limited to methyl, trifluoromethyl, ethyl, trifluoroethyl, isobutyl, neopentyl, cis- and trans-2-butenyl, isobutenyl, propargyl. C1-C4 alkyl is the subset of alkyl limited to a total of up to 4 carbon atoms.
  • In each case in which a size range for the number of atoms in a ring or chain is disclosed, all subsets are disclosed. Thus, Cx-Cy includes all subsets, e.g., C1-C4 includes C1-C2, C2-C4, C1-C3 etc.
  • Acyl is an alkyl-C(O)— group wherein alkyl is as defined above. Examples of acyl groups include acetyl and proprionyl.
  • Alkoxy is an alkyl-O— group wherein alkyl is as defined above. C1-C4 alkoxy is the subset of alkyl-O— where the subset of alkyl is limited to a total of up to 4 carbon atoms. Examples of alkoxy groups include methoxy, trifluoromethoxy, ethoxy, trifluoroethoxy, and propoxy.
  • Alkoxyalkyl is an alkyl-O—(C1-C4 alkyl)- group wherein alkyl is as defined above. Examples of alkoxyalkyl groups include methoxymethyl and ethoxymethyl.
  • Alkoxyalkyloxy is an alkoxy-alkyl-O— group wherein alkoxy and alkyl are as defined above. Examples of alkoxyalkyloxy groups include methoxymethyloxy (CH3OCH2O—) and methoxyethyloxy (CH3OCH2CH2O—) groups.
  • Alkylthio is alkyl-S— group wherein alkyl is as defined above. Alkylthio includes C1-C4 alkylathio.
  • Alkylsulfonyl is alkyl-SO2— wherein alkyl is as defined above. Alkylsulfonyl includes C1-C4 alkylsulfonyl.
  • Alkylamino is alkyl-NH— wherein alkyl is as defined above. Alkylamino includes C1-C4 alkylamino.
  • Dialkylamino is (alkyl)2-N— wherein alkyl is as defined above.
  • Amido is H2NC(O)—
  • Alkylamido is alkyl-NHC(O)— wherein alkyl is as defined above.
  • Dialkylamido is (alkyl)2-NC(O)— wherein alkyl is as defined above.
  • Aromatic is heteroaryl or aryl wherein heteroaryl and aryl are as defined below.
  • Aryl is a phenyl or napthyl group. Aryl groups may be optionally and independently substituted with up to three groups selected from halogen, CF3, CN, NO2, OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH2CH2OCH3, —OC(O)Ra, —OC(O)ORa, —OC(O)NHRa, —OC(O)N(Ra), —SRa, —S(O)Ra, —NH2, —NHRa, —N(Ra)(Rb), —NHC(O)Ra, —N(Ra)C(O)Rb, —NHC(O)ORa, —N(ROC(O)ORb, —N(Ra)C(O)NH(Rb), —N(ROC(O)NH(Rb)2, —C(O)NH2, —C(O)NHRa, —C(O)N(Ra)(Rb), —CO2H, —CO2Ra, —CORa wherein Ra and Rb are independently chosen from alkyl, alkoxyalkyl, —CH2CH2OH, —CH2CH2OMe, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each of which is optionally and independently substituted with up to three groups selected from only halogen, Me, Et, iPr, tBu, unsubstituted cyclopropyl, unsubstituted cyclobutyl, CN, NO2, NH2, CF3, NHMe, NMe2, OMe, OCF3, each of which are attached via carbon-carbon or carbon-nitrogen or carbon-oxygen single bonds; or Ra and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring.
  • Arylalkyl is an aryl-alkyl- group wherein aryl and alkyl are as defined above.
  • Aryloxy is an aryl-O— group wherein aryl is as defined above.
  • Arylalkoxy is an aryl-(C1-C4 alkyl)-O— group wherein aryl is as defined above.
  • Carboxy is a CO2H or CO2Rc group wherein Rc is independently chosen from, alkyl, C1-C4 alkyl, cycloalkyl, arylalkyl, cycloalkylalkyl, CF3, and alkoxyalkyl, wherein alkyl is as defined above.
  • Cycloalkyl is a C3-C7 cyclic non-aromatic hydrocarbon which may contain a single double bond and is optionally and independently substituted with up to three groups selected from alkyl, alkoxy, hydroxyl and oxo. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexanonyl.
  • Cycloalkyloxy is a cycloalkyl-O— group wherein cycloalkyl is as defined above. Examples include cyclopropyloxy, cyclobutyloxy and cyclopentyloxy. C3-C6 cycloalkyloxy is the subset of cycloalkyl-O— where cycloalkyl contains 3-6 carbon atoms.
  • Cycloalkylalkyl is a cycloalkyl-(C1-C4 alkyl)- group. Examples include cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl and cyclohexylethyl.
  • Cycloalkylalkoxy is a cycloalkyl-(C1-C4 alkyl)-O— group wherein cycloalkyl and alkyl are as defined above. Examples of cycloalkylalkoxy groups include cyclopropylmethoxy, cyclopentylmethoxy and cyclohexylmethoxy.
  • Halogen is F, Cl, Br or I.
  • Heteroaryl is a tetrazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, a mono or bicyclic aromatic ring system, or a heterobicyclic ring system with one aromatic ring having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C. Examples of heteroaryl groups include but are not limited to thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyrrazolyl, imidazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, pyrimidinyl, pyrazinyl, indolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, benzthiadiazololyl, benzoxadiazolyl and benzimidazolyl. Heteroaryl groups may be optionally and independently substituted with up to 3 substituents independently selected from halogen, CF3, CN, NO2, OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH2CH2OCH3, —OC(O)Ra, —OC(O)O Ra, —OC(O)NHRa, —OC(O)N(Ra), —SRa, —S(O)Ra, —NH2, —NHRa, —N(Ra)(Rb), —NHC(O)Ra, —N(Ra) C(O)Rb, —NHC(O)ORa, —N(Ra)C(O)ORb, —N(Ra)C(O)NH(Rb), —N(Ra)C(O)NH(Rb)2, —C(O)NH2, —C(O)NHRa, —C(O)N(Ra)(Rb), —CO2H, —CO2Ra, —CORa wherein Ra and Rb are independently chosen from alkyl, alkoxyalkyl, —CH2CH2OH, —CH2CH2OMe, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each of which is optionally and independently substituted with up to three groups selected from only halogen, Me, Et, iPr, tBu, unsubstituted cyclopropyl, unsubstituted cyclobutyl, CN, NO2, NH2, CF3, NHMe, NMe2, OMe, OCF3, each of which are attached via carbon-carbon or carbon-nitrogen or carbon-oxygen single bonds; or Ra and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring.
  • Heteroarylalkyl is a heteroaryl-(C1-C4 alkyl)- group wherein heteroaryl and alkyl are as defined above. Examples of heteroarylalkyl groups include 4-pyridinylmethyl and 4-pyridinylethyl.
  • Heteroaryloxy is a heteroaryl-O group wherein heteroaryl is as defined above.
  • Heteroarylalkoxy is a heteroaryl-(C1-C4 alkyl)-O— group wherein heteroaryl and alkoxy are as defined above. Examples of heteroarylalkyl groups include 4-pyridinylmethoxy and 4-pyridinylethoxy.
  • Heterobicyclic ring system is a ring system having 8-10 atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than carbon and provided that at least one of the rings is aromatic; said bicyclic ring may be optionally and independently substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, C3-C6 cycloalkyloxy, cycloalkylalkyl, halogen, nitro, alkylsulfonyl and cyano. Examples of 8-10 membered heterobicyclic ring systems include but are not limited to 1,5-naphthyridyl, 1,2,3,4-tetrahydro-1,5-naphthyridyl 1,6-naphthyridyl, 1,2,3,4-tetrahydro-1,6-naphthyridyl 1,7-naphthyridyl, 1,2,3,4-tetrahydro-1,7-naphthyridinyl 1,8-naphthyridyl, 1,2,3,4-tetrahydro-1,8-naphthyridyl, 2,6-naphthyridyl, 2,7-naphthyridyl, cinnolyl, isoquinolyl, tetrahydroisoquinolinyl, phthalazyl, quinazolyl, 1,2,3,4-tetrahydroquinazolinyl, quinolyl, tetrahydroquinolinyl, quinoxalyl, tetrahydroquinoxalinyl, benzo[d][1,2,3]triazyl, benzo[e][1,2,4]triazyl, pyrido[2,3-b]pyrazyl, pyrido[2,3-c]pyridazyl, pyrido[2,3-d]pyrimidyl, pyrido[3,2-b]pyrazyl, pyrido[3,2-c]pyridazyl, pyrido[3,2-d]pyrimidyl, pyrido[3,4-b]pyrazyl, pyrido[3,4-c]pyridazyl, pyrido[3,4-d]pyrimidyl, pyrido[4,3-b]pyrazyl, pyrido[4,3-c]pyridazyl, pyrido[4,3-d]pyrimidyl, quinazolyl, 1H-benzo[d][1,2,3]triazoyl, 1H-benzo[d]imidazoyl, 1H-indazoyl, 1H-indoyl, 2H-benzo[d][1,2,3]triazoyl, 2H-pyrazolo[3,4-b]pyridinyl, 2H-pyrazolo[4,3-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, benzo[b]thienyl, benzo[c][1,2,5]oxadiazyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]isothiazoyl, benzo[d]isoxazoyl, benzo[d]oxazoyl, benzo[d]thiazoyl, benzofuryl, imidazo[1,2-a]pyrazyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidyl, imidazo[1,2-b]pyridazyl, imidazo[1,2-c]pyrimidyl, imidazo[1,5-a]pyrazyl, imidazo[1,5-a]pyridinyl, imidazo[1,5-a]pyrimidyl, imidazo[1,5-b]pyridazyl, imidazo[1,5-c]pyrimidyl, indolizyl, pyrazolo[1,5-a]pyrazyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidyl, pyrazolo[1,5-b]pyridazine, pyrazolo[1,5-c]pyrimidine, pyrrolo[1,2-a]pyrazine, pyrrolo[1,2-a]pyrimidyl, pyrrolo[1,2-b]pyridazyl, pyrrolo[1,2-c]pyrimidyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 2H-indazoyl, 3H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, benzo[c]isothiazyl, benzo[c]isoxazyl, furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, isothiazolo[4,5-b]pyridinyl, isothiazolo[4,5-c]pyridinyl, isothiazolo[5,4-b]pyridinyl, isothiazolo[5,4-c]pyridinyl, isoxazolo[4,5-b]pyridinyl, isoxazolo[4,5-c]pyridinyl, isoxazolo[5,4-b]pyridinyl, isoxazolo[5,4-c]pyridinyl, oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-b]pyridinyl, oxazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridiyl, thiazolo[4,5-c]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[5,4-c]pyridinyl, thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl and thieno[3,2-c]pyridinyl.
  • Heterocycloalkyl is a non-aromatic, monocyclic or bicyclic saturated or partially unsaturated ring system comprising 5-10 ring atoms selected from C, N, O and S, provided that not more than 2 ring atoms in any single ring are other than C. In the case where the heterocycloalkyl group contains a nitrogen atom the nitrogen may be substituted with an alkyl, acyl, —C(O)O-alkyl, —C(O)NH(alkyl) or a —C(O)N(alkyl)2 group. Heterocycloalkyl groups may be optionally and independently substituted with hydroxy, alkyl and alkoxy groups and may contain up to two oxo groups. Heterocycloalkyl groups may be linked to the rest of the molecule via either carbon or nitrogen ring atoms. Examples of heterocycloalkyl groups include tetrahydrofuranyl, tetrahydrothienyl, tetrahydro-2H-pyran, tetrahydro-2H-thiopyranyl, pyrrolidinyl, pyrrolidonyl, succinimidyl, piperidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, morpholin-3-one, thiomorpholinyl, thiomorpholin-3-one, 2,5-diazabicyclo[2.2.2]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, octahydro-1H-pyrido[1,2-a]pyrazine, 3-thia-6-azabicyclo[3.1.1]heptane and 3-oxa-6-azabicyclo[3.1.1]heptanyl.
  • Heterocycloalkylalkyl is a heterocycloalkyl-(C1-C4 alkyl)- group wherein heterocycloalkyl is as defined above.
  • Heterocycloalkyloxy is a heterocycloalkyl-O— group wherein heterocycloalkyl is as defined above.
  • Heterocycloalkylalkoxy is a heterocycloalkyl-(C1-C4 alkyl)-O— group wherein heterocycloalkyl is as defined above.
  • Oxo is a —C(O)— group.
  • Phenyl is a benzene ring which may be optionally and independently substituted with up to three groups selected from halogen, CF3, CN, NO2, OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH2CH2OCH3, —OC(O)Ra, —OC(O)ORa, —OC(O)NHRa, —OC(O)N(Ra), —SRa, —S(O)Ra, —NH2, —NHRa, —N(Ra)(Rb), —NHC(O)Ra, —N(ROC(O)Rb, —NHC(O)ORa, —N(Ra)C(O)ORb, —N(Ra)C(O)NH(Rb), —N(ROC(O)NH(Rb)2, —C(O)NH2, —C(O)NHRa, —C(O)N(Ra)(Rb), —CO2H, —CO2Ra, —CORa wherein Ra and Rb are independently chosen from alkyl, alkoxyalkyl, —CH2CH2OH, —CH2CH2OMe, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each of which is optionally and independently substituted with up to three groups selected from only halogen, Me, Et, iPr, tBu, unsubstituted cyclopropyl, unsubstituted cyclobutyl, CN, NO2, NH2, CF3, NHMe, NMe2, OMe, OCF3, each of which are attached via carbon-carbon or carbon-nitrogen or carbon-oxygen single bonds; or Ra and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring.
  • Restricted phenyl is a benzene ring which may be optionally and independently substituted with up to three groups selected from halogen, CF3, CN, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH2CH2OCH3, —OC(O)Ra, —OC(O)ORa, —OC(O)N(Ra), —N(Ra)(Rb), —NHC(O)Ra, —N(Ra)C(O)Rb, —NHC(O)ORa, —N(Ra)C(O)ORb, —C(O)N(Ra)(Rb), —CORa wherein Ra and Rb are independently chosen from alkyl, alkoxyalkyl, —CH2CH2OH, —CH2CH2OMe, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each of which is optionally and independently substituted with up to three groups selected from only halogen, Me, Et, iPr, tBu, unsubstituted cyclopropyl, unsubstituted cyclobutyl, CN, NO2, NH2, CF3, NHMe, NMe2, OMe, OCF3, each of which are attached via carbon-carbon or carbon-nitrogen or carbon-oxygen single bonds; or Ra and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring.
  • Abbreviations used in the following examples and preparations include:
      • Ac Acyl (Me-C(O)—)
      • AcN Acetonitrile
      • BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
      • Bn Benzyl
      • Celite® Diatomaceous earth
      • DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene
      • DCC N.N′, Dicyclohexylcarbodiimide
      • DCM Dichloromethane
      • DIEA Di-isopropylethyl amine
      • DIPEA Di-isopropylethyl amine
      • DMAP 4-Dimethylaminopyridine
      • DMF Dimethylformamide
      • DMP Dess Martin Periodinane
      • DMSO Dimethyl sulfoxide
      • Dppf 1,4-Bis(diphenylphosphino) ferrocene
      • EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride
      • Et3N Triethylamine
      • g gram(s)
      • h Hour(s)
      • hr Hour(s)
      • HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
      • HMDS Hexamethyldisilazide
      • HOBt 1-Hydroxybenzotriazole
      • HPLC High Pressure Liquid Chromatography
      • HRMS High resolution mass spectrometry
      • i.v. Intravenous
      • KHMDS Potassium Hexamethydisilazide
      • LDA Lithium Di-isopropylamide
      • m Multiplet
      • m- meta
      • MEM Methoxyethoxymethyl
      • MeOH Methyl Alcohol or Methanol
      • min Minute(s)
      • mmol millimoles
      • mmole millimoles
      • Ms Mesylate
      • MS Mass Spectrometry
      • MW Molecular Weight
      • NBS N-Bromosuccinamide
      • NIS N-Iodosuccinamide
      • NMR Nuclear Magnetic Resonance
      • NMM N-Methyl Morpholine
      • NMP N-Methyl-2-pyrrolidone
      • o ortho
      • o/n overnight
      • P para
      • PCC Pyridinium Chlorochromate
      • PEPPSI 1,3-Bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridinyl) palladium(II) dichloride
      • PhNTf2 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide
      • POPd Dihydrogen dichlorobis(di-tert-butylphosphinito-kp) palladate (2-)
      • p.s.i. Pounds per square inch
      • PPA Polyphosphoric acid
      • PPAA 1-Propanephosphonic Acid Cyclic Anhydride
      • PTSA p-Toluenesulfonic acid
      • PyBOP® Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
      • RT (or rt) room temperature (about 20-25° C.)
      • s Singlet
      • sat. Saturated
      • t Triplet
      • TBAF Tetra-butyl ammonium fluoride
      • TEA Triethylamine
      • TFA Trifluoroacetic Acid
      • THF Tetrahydrofuran
      • TLC Thin layer chromatography
      • TMS Trimethylsilyl
      • Tf Triflate
      • Tof-MS Time of Flight Mass Spectrometry
      • Ts Tosylate
      • v/v volume/volume
      • wt/v weight/volume
    DETAILED DESCRIPTION
  • The 1,2 disubstituted heterocyclic compounds of Formula I may be prepared from multi-step organic synthesis routes from commercially available starting materials by one skilled in the art of organic synthesis using established organic synthetic procedures. Non-commercially available phenyl acetic acids can be made from commercially available starting materials via methods known by one skilled in the art of organic synthesis. Such methods include synthesis from the corresponding aryl acids via. the Wolff rearrangement using diazomethane.
  • Compounds of the disclosure where HET is A29 and A31 may be prepared generally as depicted in Schemes 1-8 below.
  • Compounds of the disclosure of Formula (I) wherein HET is A29 and X=phenyl or heteroaryl (each respectively optionally substituted) thus having general Formula LIV may be prepared generally as depicted in Scheme 1:
  • Figure US20150322069A1-20151112-C00005
  • Alternatively, compounds of the disclosure of Formula (I) wherein HET is A29 and X=phenyl or heteroaryl (each respectively optionally substituted) and thus having general Formula LIV may also be prepared generally as depicted in Scheme 2:
  • Figure US20150322069A1-20151112-C00006
  • Intermediate compounds of Formula LXIII may alternatively be synthesized as depicted in Scheme 3.
  • Figure US20150322069A1-20151112-C00007
  • Compounds of the disclosure of Formula (I) wherein HET is A31 and X=phenyl or heteroaryl (each optionally substituted) are as described previously and thus having general Formula LXXIV may be prepared generally as depicted in Scheme 4:
  • Figure US20150322069A1-20151112-C00008
  • The general synthesis of heterocyclic chloride intermediates (Z—CH2—Cl) where Z corresponds to an imidazo[1,2-a]pyrid-2-yl is depicted in Scheme 5.
  • Figure US20150322069A1-20151112-C00009
  • The general synthesis of heterocyclic chloride intermediates (Z—CH2—Cl) where Z corresponds to an imidazo[1,2-b]pyridazin-6-yl is depicted in Scheme 6.
  • Figure US20150322069A1-20151112-C00010
  • The general synthesis of heterocyclic chloride intermediates (Z—CH2—Cl) where Z corresponds to an imidazo[1,2-b]pyridazin-2-yl is depicted in Scheme 7.
  • Figure US20150322069A1-20151112-C00011
  • The general synthesis of heterocyclic chloride intermediates (Z—CH2—Cl) where Z corresponds to either a 5-substituted-pyridin-2-yl or a 3,5-disubstituted-lpyridin-2-yl is depicted in Scheme 8.
  • Figure US20150322069A1-20151112-C00012
  • Reactive groups not involved in the above processes can be protected with standard protecting groups during the reactions and removed by standard procedures (T. W. Greene & P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley-Interscience) known to those of ordinary skill in the art. Presently preferred protecting groups include methyl, benzyl, MEM, acetate and tetrahydropyranyl for the hydroxyl moiety, and BOC, Cbz, trifluoroacetamide and benzyl for the amino moiety, methyl, ethyl, tert-butyl and benzyl esters for the carboxylic acid moiety. Practitioners in the art will also recognize that the order of certain chemical reactions can be changed. Practitioners of the art will also note that alternative reagents and conditions exist for various chemical steps.
    • Experimental Procedures
  • The synthesis of N-methoxy-N-methylcarboxamides from their corresponding carboxylic acids is known by those of ordinary skill in the art. A representative procedure is described below, where is selected from
  • Figure US20150322069A1-20151112-C00013
  • To a stirred solution of carboxylic acid (1 eq., 3 mmol) in DCM (50 mL) was added HATU (1.5 eq, 4.5 mmol), N-methoxy methylamine (1.5 eq, 4.5 mmol) and TEA (3 eq., 9 mmol) at RT under nitrogen atmosphere. The reaction mixture was then stirred at RT for 3 h. The reaction mixture was diluted with water and the aqueous layer was extracted with DCM (3×50 mL). The combined organic extracts were washed with water (50 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford the corresponding N-methoxy-N-methylcarboxamide.
    • HPLC Conditions Condition-A: Column: Acquity BEH C-18 (50×2.1 mm, 1.7μ,)
      • Column Temp: 25° C.
      • Mobile Phase A/B: Acetonitrile (0.025% TFA) and water
      • Flow Rate: 0.50 mL/Min
    4-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile
  • Figure US20150322069A1-20151112-C00014
  • To a suspension of NaH (0.9 g) in THF at RT was added 3-hydroxy-3-methyl-2-butanone (1 g) and ethyl methyl 4-cyanobenzoate (1.58 g). The resultant mixture was refluxed overnight, upon which the reaction was quenched with 12N HCl (6 mL). MgSO4 (excess) was added until the organic phase became clear. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 4-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (0.63 g).
    • Synthesis of 4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one 4-Methoxy-N-methoxy-N-methylbenzamide
  • Figure US20150322069A1-20151112-C00015
  • To a stirred solution of 4-methoxybenzoic acid (10.0 g, 65.70 mmol) in DCM (50 mL) were added EDCI (18.90 g, 98.60 mmol), HOBT (10.0 g, 65.70 mmol), N-methoxy methylamine (13.0 g, 131.40 mmol) and DIPEA (34.3 mL, 197.20 mmol) at RT under a nitrogen atmosphere. The reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and the aqueous layer was extracted with DCM (3×100 mL). The combined organic extracts were washed with water (2×100 mL), brine (2×50 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford crude product. The crude material was purified by flash column chromatography using 20% ethyl acetate in hexane and silica gel (230-400 Mesh) to afford N,4-dimethoxy-N-methylbenzamide (11.0 g, 86%) as a colorless liquid.
    • 4-Hydroxy-1-(4-methoxyphenyl)-4-methylpent-2-yn-1-one
  • Figure US20150322069A1-20151112-C00016
  • To a stirred solution of 2-methylbut-3-yn-2-ol (2.15 g, 25.6 mmol) in dry THF (80 mL) was added n-BuLi (24.0 mL, 38.7 mmol, 1.6 M in hexane) drop wise at −20° C. under an inert atmosphere for a period of 10 min. After being stirred for 30 min at −20° C., a solution of N,4-dimethoxy-N-methylbenzamide (2.5 g, 12.8 mmol) in dry THF (10 mL) was added to reaction mixture and stirring was continued for an additional 3 h at −20° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (100 mL), brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 4-hydroxy-1-(4-methoxyphenyl)-4-methylpent-2-yn-1-one (2.25 g, 81%) as a colorless liquid.
    • 5-(4-Methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
  • Figure US20150322069A1-20151112-C00017
  • To 4-hydroxy-1-(4-methoxyphenyl)-4-methylpent-2-yn-1-one (10 g, 45.8 mmol) was added methanolic ammonia (50 mL) at room temperature and the reaction mixture was stirred overnight. The mixture was concentrated under reduced pressure and 50% aqueous acetic acid was added. The resultant mixture was heated at reflux for 4 hours. The pH was adjusted to 8 with saturated ammonium chloride solution and extracted with DCM. The combined organics were washed with water and brine solution, dried over sodium sulphate, filtered, concentrated under reduced pressure and washed with heptane to afford 5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (8.6 g, 86%) as white solid. 1H NMR (500 MHz, d6-DMSO): δ 7.99 (d, 2H), 7.15 (d, 2H), 6.20 (s, 1H), 3.89 (s, 3H). 1.42 (s, 6H). MS: [M+H]+: m/z=218.1.
    • 4-Bromo-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
  • Figure US20150322069A1-20151112-C00018
  • To a stirred solution of 5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (5.5 g, 0.025 mol) in CHCl3 (100 mL) was added NBS (6.733 g, 0.038 mol) portion wise at RT. The reaction mixture was stirred for 2 h at RT. The reaction mixture was diluted with DCM (100 mL), washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered and then concentrated in vacuo to obtain the crude product. The crude material was purified via by flash column chromatography using 25% ethyl acetate in hexane and silica gel (230-400 Mesh) to afford 4-bromo-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (4.6 g, 65%) as a solid.
    • 4-(4-(Benzyloxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
  • Figure US20150322069A1-20151112-C00019
  • 4-Bromo-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2 g, 6.7 mol), 2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.43 g, 0.0067 mol), and Cs2CO3 (11 g, 0.034 mol) in toluene (25 mL) and water (8 mL) was degassed, Pd (dppf) Cl2 (1.1 g, 0.0013 mol) was added under an inert atmosphere and the mixture degassed once again. The reaction was heated at reflux for 3 h, upon which the reaction mixture was filtered through a pad of Celite® and the filtrate was diluted with EtOAc (100 mL), washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by flash column chromatography using 30% ethyl acetate in hexane and silica gel (230-400 Mesh), Rf=0.30 to afford 4-(4-(benzyloxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.3 g, 73%) as solid. 1H NMR (500 MHz, d6-DMSO): δ 8.42 (d, J=7.6 Hz, 1H), 8.06-7.99 (m, 2H), 7.95 (t, J=7.2 Hz, 1H), 7.72 (t, J=7.2 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H); 7.18 (d, J=7.4 Hz, 2H), 7.12 (d, J=7.2 Hz, 2H), 6.89 (d, J=7.2 Hz, 2H), 5.38 (s, 2H), 3.79 (s, 3H). 1.42 (s, 6H). MS: [M+H]+: m/z=452.1; [M+Na]+: m/z=474.2.
    • 4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
  • Figure US20150322069A1-20151112-C00020
  • 5% Palladium on carbon (7.0 g) was added to a solution 4-(4-(benzyloxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (19 g, 42.1 mmol) in methanol (25 ml) at RT under an atmosphere of nitrogen. The nitrogen atmosphere was changed to an atmosphere of hydrogen. The reaction mixture was stirred under an atmosphere of hydrogen at RT for 4 h (the reaction was monitored by TLC). The reaction mixtures was filtered over through a pad of Celite®, washed with methanol, concentrated in vacuo and the resultant residue was slurried with heptane. The solid was filtered & dried under vacuum to afford 4-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (14.0 g, 95%,) as light yellow solid. 1H NMR, 500 MHz, DMSO-d6: δ 9.5 (bs, 1H), 7.55 (d, 2H), 7.05 (d, 2H), 7.0 (d, 2H), 6.75 (d, 2H), 3.8 (s, 3H), 1.4 (s, 6H). MS: [M+H]: m/z=311.2. HPLC: (98.8%, Eclipse XDB-C18, 150×4.6 mm, Sum. Mobile Phase: 0.1% TFA in Water. (A). ACN (B), Flow rate: 1.5 ml/min).
    • Synthesis of 5-(4-Hydroxyphenyl)-2,2-dimethyl-4-(pyridin-4-yl) furan-3(2H)-one Trimethyl (2-methylbut-3-yn-2-yloxy) silane
  • Figure US20150322069A1-20151112-C00021
  • To a stirred solution of 2-methylbut-3-yn-2-ol (20 g, 0.23 mol) in HMDS (42.3 g, 0.261 mol) was added LiClO4 (38.03 g, 0.35 mol) at RT. The reaction mixture was then stirred for additional 30 minutes, diluted with water (100 mL) and then extracted with ether (3×200 mL). The combined ether layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO and filtered. The ether was distilled off at 80° C. to afford trimethyl (2-methylbut-3-yn-2-yloxy) silane (25 g) as an oil.
    • 4-Methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy) pent-2-yn-1-one
  • Figure US20150322069A1-20151112-C00022
  • To a pre-cooled −78° C. stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (5.0 g, 0.03 mol) in dry THF (150 mL), n-BuLi (23.82 mL, 0.03 mol, 1.6 M in hexane) was added dropwise over a period of 10 minutes under an inert atmosphere. The reactions was stirred for 30 minutes at −78° C. and then a solution of N-methoxy-N-methylisonicotinamide (6.34 g, 0.03 mol) in dry THF (30 mL) was added to the reaction mixture and stirring was continued for an additional 40 min at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and finally concentrated in vacuo to obtain a residue. The residue was purified via silica gel column chromatography eluting with 5% EtOAc in hexanes to afford 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy) pent-2-yn-1-one (2.2 g, 27%) as oil.
    • 4-Hydroxy-4-methyl-1-(pyridin-4-yl) pent-2-yn-1-one
  • Figure US20150322069A1-20151112-C00023
  • To a stirred solution of 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy) pent-2-yn-1-one (0.5 g, 1.915 mmol) in DCM (10 mL) was added PTSA (0.47 g, 2.49 mmol) at RT and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with DCM (50 mL). The organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 4-hydroxy-4-methyl-1-(pyridin-4-yl) pent-2-yn-1-one (0.35 g, 96%) as an oil.
    • 2,2-Dimethyl-5-(pyridin-4-yl) furan-3(2H)-one
  • Figure US20150322069A1-20151112-C00024
  • To a stirred solution of 4-hydroxy-4-methyl-1-(pyridin-4-yl) pent-2-yn-1-one (1.49 g, 0.007 mol) in ethanol (15 mL), diethylamine (0.511 g, 0.007 mol) in EtOH (15 mL) was added dropwise at RT. The mixture was then stirred for additional 40 min. The EtOH was evaporated and the mixture was diluted with EtOAc (100 mL). The organic layers were washed with water (50 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 2,2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (1.4 g).
    • 4-Bromo-2,2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one
  • Figure US20150322069A1-20151112-C00025
  • To a stirred solution of 2,2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (0.81 g, 4.28 mmol) in CHCl3 (20 mL), NBS (1.3 g, 7.28 mmol) was added portionwise at RT. The reaction mixture was then stirred for 2 h and diluted with DCM (100 mL). The organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-2,2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (0.25 g, 21%) as a solid
    • 4-(4-(Benzyloxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one
  • Figure US20150322069A1-20151112-C00026
  • A solution of 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (10.0 g, 37.2 mmol), 2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.8 g, 44.7 mmol), and Cs2CO3 (36.27 g, 111.6 mmol) in toluene (100 mL) and water (50 mL) was degassed. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(11) (2.7 g, 3.7 mmol) was added under an inert atmosphere and again degassed. Then the reaction was refluxed for 3 h and monitored by TLC. Upon complete consumption of the starting material, the reaction mixture was filtered through a bed of Celite® washing with ethyl acetate. The organic layer was then washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexanes on 230-400 mesh silica gel to afford 4-(4-(benzyloxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (8.3 g, 60.2%) as a light orange color solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.2 (d, 2H), 7.85 (d, 2H), 7.6 (d, 4H), 7.4 (t, 1H), 7.15 (d, 2H), 7.05 (d, 2H), 5.1 (s, 2H), 1.45 (s, 6H). MS: [M+H]+: m/z=396.0. HPLC: (97.5%, Column: Eclipse XDB-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water. (A). ACN (B), Flow rate: 1.5 ml/min).
    • 5-(4-Hydroxyphenyl)-2,2-dimethyl-4-(pyridin-4-yl) furan-3(2H)-one
  • Figure US20150322069A1-20151112-C00027
  • To a stirred solution of 5-(4-(benzyloxy)phenyl)-2,2-dimethyl-4-(pyridin-4-yl) furan-3(2H)-one (620 mg, 0.001 mmol) in MeOH (15 mL) was added Pd (OH)2 (120 mg, 0.85 mmol) at RT under an inert atmosphere. The reaction mixture was stirred under a hydrogen atmosphere for 1 h. The reaction mixture was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(4-hydroxyphenyl)-2,2-dimethyl-4-(pyridin-4-yl) furan-3(2H)-one (280 mg, 60%) as a solid.
    • Synthesis of 4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile 4-Cyano-N-methoxy-N-methylbenzamide
  • Figure US20150322069A1-20151112-C00028
  • To a stirred solution of 4-cyanobenzoic acid (5.0 g, 34.0 mmol) in DCM (75 mL) were added HATU (19.40 g, 51.0 mmol), N-methoxy, N-methylamine (4.90 g, 51.0 mmol) and TEA (14.30 mL, 102.0 mmol) at RT under a nitrogen atmosphere. The reaction mixture was then stirred at RT for 3 h, diluted with water and the aqueous layer was extracted with DCM (3×100 mL). The combined organic extracts were washed with water (60 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford 4-cyano-N-methoxy-N-methylbenzamide (6.2 g, 96%) as a yellow color oil.
    • 4-(4-Methyl-4-(trimethylsilyloxy) pent-2-ynoyl)benzonitrile
  • Figure US20150322069A1-20151112-C00029
  • To a −78° C. stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (3.3 g, 20.00 mmol) in dry THF (45 mL), n-BuLi (4.1 mL, 9.00 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at −78° C., and then a solution of 4-cyano-N-methoxy-N-methylbenzamide (2.0 g, 10.00 mmol) in dry THF (15 mL) was added to the reaction mixture and stirring was continued for an additional 1 h at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 15% EtOAc in hexanes to afford 4-(4-methyl-4-(trimethylsilyloxy) pent-2-ynoyl)benzonitrile (3.8 g, 68%) as a yellow oil.
    • 4-(4-Hydroxy-4-methylpent-2-ynoyl)benzonitrile
  • Figure US20150322069A1-20151112-C00030
  • To a stirred solution of 4-(4-methyl-4-(trimethylsilyloxy) pent-2-ynoyl)benzonitrile (1.7 g, 5.00 mmol) in DCM (15 mL) was added PTSA (1.70 g, 8.90 mmol) at RT and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 4-(4-hydroxy-4-methylpent-2-ynoyl)benzonitrile (1.20 g) as a yellow oil.
    • 4-(5,5-Dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile
  • Figure US20150322069A1-20151112-C00031
  • To a stirred solution of crude 4-(4-hydroxy-4-methylpent-2-ynoyl)benzonitrile (1.2 g, 5.60 mmol) in ethanol (12 mL), a solution of diethyl amine (0.58 mL, 5.60 mmol) in EtOH (5 mL) was added dropwise at RT. The reaction mixture was then stirred for additional 1 h. The ethanol was removed and the mixture then diluted with EtOAc (50 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford crude 4-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.2 g) as a light green semi solid which was taken on to the next step without further purification.
    • 4-(3-Bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile
  • Figure US20150322069A1-20151112-C00032
  • To a stirred solution of 4-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.2 g, 5.60 mmol) in CHCl3 (12 mL), NBS (1.1 g, 6.00 mmol) was added portionwise at RT. The reaction mixture was then stirred for 3 h and diluted with DCM (100 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(3-bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (0.50 g, 31%) as an off white solid.
    • 4-(3-(4-(benzyloxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile
  • Figure US20150322069A1-20151112-C00033
  • A solution of 4-(3-bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (29.0 g, 107.4 mmol), 2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (34.7 g, 118.8 mmol), and Cs2CO3 (104.7 g, 322.2 mmol) in toluene (200 mL) and water (50 mL) was degassed. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (8.5 g, 10 mmol) was added under an inert atmosphere and the solution was again degassed. The reaction was then refluxed for 3 h and monitored for completion by TLC. Upon complete consumption of the starting material, the reaction mixture was filtered through a bed of Celite® washing with ethyl acetate. The organic layer was then washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane on 230-400 mesh silica gel (Rf=0.3) to afford 4-(3-(4-(benzyloxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (31.5 g, 74.25%) as solid. 1H NMR: 500 MHz, DMSO-d6: δ 7.95 (d, 2H), 7.75 (d, 2H), 7.5 (d, 4H), 7.35 (t, 1H), 7.15 (d, 2H), 7.05 (d, 2H), 5.1 (s, 2H), 1.45 (s, 6H). MS: [M+H]+: m/z=396.0. HPLC: (99.5%, Eclipse XDB-C18, 150×4.6 mm, Sum. Mobile Phase: 0.1% TFA in Water. (A). ACN (B), Flow rate: 1.5 ml/min).
    • 4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile
  • Figure US20150322069A1-20151112-C00034
  • Boron tribromide (3.4 g, 15.8 mmol) was added to a solution of 44344-(benzyloxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (2.5 g, 6.3 mmol) in DCM at 0° C. & the mixture was stirred for 1 h (reaction was monitored by TLC). Upon complete consumption of the starting material, the mixture was quenched with chilled water and extracted with DCM, The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 4-(3-(4-hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.8 g, 93.2%,) as yellow solid. 1H NMR: 500 MHz, CDCl3: δ 9.6 (s, 1H), 7.95 (d, 2H), 7.75 (d, 2H), 7.0 (d, 2H), 6.75 (d, 2H), 1.5 (s, 6H).
    • 2,3,5-Trimethylpyridine 1-oxide
  • Figure US20150322069A1-20151112-C00035
  • 3-Chloro per benzoic acid (10 g, 164.2 mmol) was added to a solution of 2,3,5-trimethylpyridine (10 g, 82.1 mmol) in DCM at 0° C. and the mixture was stirred at RT for 8 h (the reaction was monitored by TLC). The reaction was quenched with sodium bicarbonate solution and stirred for 1 h at RT. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2,3,5-trimethylpyridine 1-oxide (6.5 g, 58.0%,) as a brown solid. 1H NMR: 200 MHz, CDCl3: δ 8.15 (s, 1H), 7.15 (s, 1H), 2.55 (s, 3H), 2.35 (s, 3H), 2.25 (s, 3H). MS: [M+H]+: m/z=311.2.
    • 2-(Chloromethyl)-3,5-dimethylpyridine
  • Figure US20150322069A1-20151112-C00036
  • Tosyl chloride (12.5 g, 65.6 mmol) was added to a solution of 2,3,5-trimethylpyridine 1-oxide (6.0 g, 43.7 mmol), and triethylamine (6.6 g, 65.6 mmol) in DCM (60 ml) at RT under an atmosphere of nitrogen. The reaction mixture was heated to reflux and reflux was maintained 4 h (reaction was monitored by TLC). The reaction was quenched with water and extracted with DCM. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexanes and silica gel (230-400 Mesh) to afford 2-(chloromethyl)-3,5-dimethylpyridine (4.5 g, 66.1%,) as a brown thick syrup. 1H NMR: 200 MHz, CDCl3: δ 8.15 (s, 1H), 7.45 (s, 1H), 4.75 (s, 2H), 2.35 (s, 3H), 2.25 (s, 3H). MS: [M+H]+: m/z=156.3.
    • 4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
  • Figure US20150322069A1-20151112-C00037
  • 4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (3.0 g, 9.6 mmol) was added to a mixture of cesium carbonate (12.6 g, 38.6 mmol) and DMF (1000 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl)-3,5-dimethylpyridine (2.25 g, 14.5 mmol) was added. The reaction mixture was heated for 4 h at 80° C. (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-(3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (3.2 g, 65.3%,) as an off-white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.2 (s, 1H), 7.65 (d, 2H), 7.45 (s, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.2 (s, 2H), 3.8 (s, 3H), 2.35 (s, 3H), 2.3 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=430.4. HPLC (96.3%, Condition-A).
    • 4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one methanesulfonate
  • Figure US20150322069A1-20151112-C00038
  • Methanesulfonic acid (445.0 mg, 4.6 mmol) was added to a solution of 4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.01 g, 4.6 mmol) in DCM (3 ml) and diethyl ether (150 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h and the solids were removed by filtration. The solid was washed with 20% DCM in diethyl ether and dried under vacuo to afford 4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one methanesulfonate (2.1 g, 87%) as a white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.2 (s, 1H), 7.65 (d, 2H), 7.45 (s, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.2 (s, 2H), 3.8 (s, 3H), 2.35 (s, 3H), 2.3 (s, 3H), 1.45 (s, 6H), HPLC: (98.9%, Condition-A).
    • 2-(Chloromethyl) imidazo[1,2-a]pyridine
  • Figure US20150322069A1-20151112-C00039
  • 1,3-Dichloroacetone (22.9 g, 180.3 mmol) was added to a solution of 2-amino pyridine (10 g, 106.3 mmol) in acetonitrile (200 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). Upon completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water and adjusted the pH to 7.5 with sodium bicarbonate solution which was extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 12% ethyl acetate in n-hexanes and silica gel (230-400 mesh) to afford 2-(chloromethyl) imidazo[1,2-a]pyridine (8.0 g, 47.9%,) as pale yellow solid. 1H NMR: 200 MHz, CDCl3: δ 8.15 (d, 1H), 7.6 (dd, 2H), 7.1 (t, 1H), 6.8 (t, 1H), 4.75 (s, 2H). MS: [M+H]+: m/z=167.2.
    • 4-(4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
  • Figure US20150322069A1-20151112-C00040
  • 4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.5 g, 8.06 mmol) was added to a mixture of cesium carbonate (10.5 g, 32.2 mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 30 min, upon which 2-(chloromethyl) imidazo[1,2-a]pyridine (2.4 g, 12.0 mmol) was added. The mixture was heated at 80° C. for 4 h (reaction was monitored by TLC). The reaction mixture was allowed to cool to RT, diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh), to afford 4-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.8 g, 77.7%,) as Off-white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.55 (d, 1H), 8.0 (s, 1H), 7.55 (Ar, 3H), 7.3-6.85 (Ar, 8H), 5.15 (s, 2H) 3.85 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=441.2. HPLC: (97.3%, Condition-A).
    • 4-(4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one methanesulfonate
  • Figure US20150322069A1-20151112-C00041
  • Methanesulfonic acid (531 mg, 5.5 mmol) was added to a solution of 4-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.5 g, 5.5 mmol) in DCM (5 ml) and diethyl ether (150 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred for a further 4 h at RT. The solids were collected by filtration, washed with 20% DCM in diethyl ether and dried in vacuo to afford 4-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one methanesulfonate (2.4 g, 82.7%,) as white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.75 (d, 1H), 8.1 (s, 1H), 7.65 (Ar, 3H), 7.3-6.85 (Ar, 8H), 5.2 (s, 2H) 3.85 (s, 3H), 1.25 (s, 6H), HPLC: (98.8%, Condition-A).
    • 6-Chloroimidazo[1,2-b]pyridazine
  • Figure US20150322069A1-20151112-C00042
  • Bromoacetaldehyde diethylacetal (36.5 g, 216 mmol) was added to a solution of aq.cHBr (7.2 ml) and then heated to reflux for 30 min. The mixture was then cooled to 0° C., upon which ethanol (236 ml), sodium bicarbonate (8.09 g, 95 mmol) and 6-chloropyridazin-3-amine (4 g, 30 mmol) were added. The mixture was heated to 80° C. for 3 h (reaction was monitored by TLC) and then allowed to cool to RT. The mixture was concentrated under reduced pressure, diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in n-hexane and silica gel (230-400 mesh), to afford 6-chloroimidazo[1,2-b]pyridazine (4.0 g, 85.2%,) as Off-white solid. 1H NMR: 200 MHz, CDCl3: δ 7.4-7.2 (Ar, 4H), 3.85 (q, 1H), 3.4 (q, 1H), 3.2 (q, 2H), 1.35 (t, 3H), 1.1 (t, 3H). MS: [M+H]+: m/z=154.3.
    • Methylimidazo[1,2-b]pyridazine-6-carboxylate
  • Figure US20150322069A1-20151112-C00043
  • 6-Chloroimidazo[1,2-b]pyridazine (5.0 g, 32 mmol) was added to a solution of methanol (75 ml) and acetonitrile (75 ml) in a steel bomb at RT under nitrogen bubbling. Triethylamine (4.0 g, 39.4 mmol), BINAP (2.0 g, 3.0 mmol) and bisacetonitrile palladium dichloride (0.854 g, 3.0 mmol) were then added to the mixture. The mixture was heated to 100° C. which was maintained for approximately 10 hours (the reaction was monitored by TLC). The reaction mixture was filtered through a bed of Celite® washing with ethyl acetate. The organics were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford methyl imidazo[1,2-b]pyridazine-6-carboxylate (2.5 g, 43%,) as an off-white solid. 1H NMR: 200 MHz, DMSO-d63: δ 8.55 (s, 1H), 8.3 (d, 1H), 7.95 (s, 1H), 7.55 (d, 1H), 3.95 (s, 3H). MS: [M+H]+: m/z=177.9.
    • Imidazo[1,2-b]pyridazin-6-ylmethanol
  • Figure US20150322069A1-20151112-C00044
  • Sodium borohydride (1.1 g, 31.1 mmol) was added to a solution of methyl imidazo[1,2-b]pyridazine-6-carboxylate (2.4 g, 15.5 mmol) in THF (35 mL) and methanol (2.5 ml) at RT. The reaction mixture was stirred at RT for 2 h (the reaction was monitored by TLC) upon which the mixture was concentrated under reduced pressure. The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford imidazo[1,2-b]pyridazin-6-ylmethanol (1.6 g, 81%,) as a white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.5 (s, 1H), 8.3 (d, 1H), 7.9 (s, 1H), 7.55 (d, 1H), 5.65 (t, 1H), 4.6 (d, 2H). MS: [M+H]+: m/z=311.2.
    • 6-(Chloromethyl) imidazo[1,2-b]pyridazine
  • Figure US20150322069A1-20151112-C00045
  • Thionyl chloride (10 ml) was added to imidazo[1,2-b]pyridazin-6-ylmethanol (1.5 g, 9.0 mmol) at 20° C. under an atmosphere of nitrogen at RT. The reaction mixture was stirred at reflux for 3 h (the reaction was monitored by TLC) upon which the volatiles were removed under reduced pressure. The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 6-(chloromethyl) imidazo[1,2-b]pyridazine (1.2 g, 69%,) as an off-white solid. 1H NMR, 200 MHz, DMSO-d6: δ 8.35 (s, 1H), 8.3 (d, 1H), 7.85 (s, 1H), 7.35 (d, 1H), 4.95 (s, 2H). MS: [M+H]+: m/z=149.9.
    • 4-(4-(Imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
  • Figure US20150322069A1-20151112-C00046
  • 4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (1.2 g, 3.8 mmol) was added to a mixture of cesium carbonate (3.7 g, 11.6 mmol) and DMF (25 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 6-(chloromethyl) imidazo[1,2-b]pyridazine (0.96 g, 5 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 30% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-(imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (0.8 g, 47%,) as Off-white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.35 (s, 1H), 8.2 (d, 1H), 7.8 (s, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.3 (s, 2H) 3.9 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=442.1. HPLC: (95.8%, Condition-A).
    • 4-(4-(Imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one methanesulfonate
  • Figure US20150322069A1-20151112-C00047
  • Methanesulfonic acid (54 mg, 0.5 mmol) was added to a solution of compound 4-(4-(imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (250 mg, 0.5 mmol) in DCM (2 ml) and diethyl ether (20 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h upon which the mixture was filtered and the solids were washed with 20% DCM in diethyl ether and dried in vacuo to afford 4-(4-(imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one methanesulfonate (240 mg, 80.0%,) as an off-white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.55 (s, 1H), 8.35 (d, 1H), 78.1 (s, 1H), 7.65 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.35 (s, 2H) 3.9 (s, 3H), 2.35 (s, 3H), 1.45 (s, 6H). HPLC: (98.3%, Condition-A).
    • 6-Chloro-2-(chloromethyl) imidazo[1,2-b]pyridazine
  • Figure US20150322069A1-20151112-C00048
  • 1,3-Dichloroacetone (21.4 g, 168.0 mmol) was added to a solution of 6-chloropyridazin-3-amine (10 g, 77.2 mmol) in acetonitrile (200 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). The volatiles were removed under reduced pressure and the reaction mixture was diluted with water. The pH was adjusted to ˜7.5 with sodium bicarbonate solution and then extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 14% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 6-chloro-2-(chloromethyl) imidazo[1,2-b]pyridazine (6.0 g, 64.1%,) as white solid. 1H NMR: 200 MHz, CDCl3: δ 8.0 (s, 1H), 7.9 (d, 1H), 7.1 (d, 1H), 4.75 (s, 2H). MS: [M+H]+: m/z=202.8.
    • 4-(4-((6-Chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
  • Figure US20150322069A1-20151112-C00049
  • 4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (200 mg, 0.64 mmol) was added to a mixture of cesium carbonate (838 mg, 2.5 mmol) and DMF (5 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 6-chloro-2-(chloromethyl) imidazo[1,2-b]pyridazine (196 mg, 9.6 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc; the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The organic residue was purified by flash column chromatography using 30% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl) methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (180 mg, 63.0%,) as an off-white solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.45 (s, 1H), 8.2 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.25 (s, 2H) 3.8 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=476.7. HPLC: (96.7%, Condition-A).
    • 4-(4-(Imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
  • Figure US20150322069A1-20151112-C00050
  • Palladium hydroxide (36 mg) was added to a solution of 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (180 mg, 0.37 mmol) and diethyl amine (28 mg, 0.37) in methanol (25 ml) at RT under an atmosphere of nitrogen. The nitrogen atmosphere was exchanged for hydrogen and was stirred at RT for 2 h (the reaction was monitored by TLC). The compound was filtered through a bed of Celite® bed washing with methanol. The filtrate was concentrated under reduced pressure to afford 4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (160 mg, 96.7%,) as a white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.45 (s, 1H), 8.4 (s, 1H) 8.15 (d, 1H), 7.55 (d, 2H), 7.25 (d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.25 (s, 2H) 3.8 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=442.3. HPLC: (97.4%, Condition-A).
    • 4-(4-(Imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one methanesulfonate
  • Figure US20150322069A1-20151112-C00051
  • Methanesulfonic acid (34.8 mg, 0.36 mmol) was added to a solution of compound 4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (160 mg, 0.36 mmol) in DCM (3 ml) and diethyl ether (15 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h, upon which the mixture was filtered and the solids were washed with 20% DCM in diethyl ether. The solids were dried under vacuo to afford 4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one methanesulfonate (110 mg, 56%,) as a white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.45 (s, 1H), 8.4 (s, 1H) 8.15 (d, 1H), 7.55 (d, 2H), 7.25 (d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.25 (s, 2H) 3.8 (s, 3H), 2.35 (s, 3H), 1.25 (s, 6H), HPLC: (98.5%, Condition-A).
    • 4-(3-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile
  • Figure US20150322069A1-20151112-C00052
  • 4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.5 g, 4.9 mmol) was added to a mixture of carbonate (6.3 g, 19.6 mmol) and DMF (100 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl)-3,5-dimethylpyridine (1.14 g, 7.3 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc; the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 22% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(3-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl) (0.70 g, 35%,) as yellow solid. 1H NMR, 200 MHz, CDCl3: δ 7.45-6.8 (Ar, 11H), 4.9 (d, 1H), 4.6 (d, 1H), 3.75 (s, 3H), 3.2 (d, 2H) 3.1 (q, 1H), 2.5 (q, 1H) 0.95 (t, 6H). MS: [M+H]+: m/z=425.2. HPLC: (96.3%, Condition-A).
    • 4-(3-(4-((3,5-Dimethylpyridin-2-yl)methoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile methanesulfonate
  • Figure US20150322069A1-20151112-C00053
  • Methanesulfonic acid (158 mg, 1.6 mmol) was added to a solution of compound 4-(3-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl) (700 mg, 1.6 mmol) in DCM (0.5 ml) and diethyl ether (15 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h upon which, the mixture was filtered and the solids were washed with 20% DCM in diethyl ether and dried in vacuo to afford 4-(3-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile methanesulfonate (2.1 g, 75%,) as a white solid. 1H NMR: 200 MHz, CDCl3: δ 8.2 (d, 1H), 7.5 (t, 1H), 7.3-6.8 (Ar, 9H) 5.1 (s, 2H), 4.05 (s, 2H), 3.8 (s, 3H), HPLC: (97.1%, Condition-A).
    • 4-(3-(4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile
  • Figure US20150322069A1-20151112-C00054
  • 4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (3.15 g, 10.3 mmol) was added to a mixture of cesium carbonate (13.4 g, 41.3 mmol) and DMF (100 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl) imidazo[1,2-a]pyridine (2.0 g, 12.3 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(3-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (2.7 g, 60%,) as an off-white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.55 (d, 1H), 8.0 (s, 1H), 7.55 (Ar, 3H), 7.3-6.85 (Ar, 8H), 5.15 (s, 2H), 1.25 (s, 6H). MS: [M+H]+: m/z=436.2. HPLC: (97.3%, Condition-A).
    • 4-(3-(4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile methanesulfonate
  • Figure US20150322069A1-20151112-C00055
  • Methanesulfonic acid (309 mg, 3.2 mmol) was added to a solution of compound 4-(3-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.4 g, 3.2 mmol) in DCM (5 ml) and diethyl ether (30 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h upon which it was filtered and the solids were washed with 20% DCM in diethyl ether and dried in vacuo to afford 4-(3-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile methanesulfonate (1.1 g, 64%,) as a white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.55 (d, 1H), 8.0 (s, 1H), 7.55 (Ar, 3H), 7.3-6.85 (Ar, 8H), 5.15 (s, 2H) 2.15 (s, 3H), 1.25 (s, 6H), HPLC: (98.5%, Condition-A).
    • 3-Chloro-2-(chloromethyl)imidazo[1,2-a]pyridine
  • Figure US20150322069A1-20151112-C00056
  • N-Chloro succinimide (329 g, 2.46 mmol) was added to a solution of 2-(chloromethyl)imidazo[1,2-a]pyridine (450 mg, 2.2 mmol) in DCM (15 ml) at RT under an atmosphere of nitrogen. Stirring was continued for 2 h (reaction was monitored by TLC) upon which the reaction mixture was diluted with DCM and washed with water and brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 3-chloro-2-(chloromethyl) imidazo[1,2-a]pyridine (400 mg, 76%,) as Off-white solid. 1H NMR: 200 MHz, CDCl3: δ 8.4 (d, 1H), 7.7 (d, 1H), 7.5 (t, 1H), 7.1 (t, 1H), 4.85 (s, 2H). MS: [M+H]+: m/z=201.8. HPLC: (98.3%, Condition-A).
    • 4-(4-((3-Chloroimidazo[1,2-a]pyridin-2-yl) methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
  • Figure US20150322069A1-20151112-C00057
  • 4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (200 mg, 0.64 mmol) was added to a mixture of cesium carbonate (843 mg, 2.5 mmol) and DMF (20 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min, upon which 3-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (183 mg, 0.77 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC) upon which, the mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 18% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-((3-chloroimidazo[1,2-a]pyridin-2-yl) methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (250 mg, 81%,) as an off-white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.4 (d, 1H), 7.7 (d, 1H), 7.55 (Ar, 3H), 7.7-6.9 (Ar, 10H), 5.2 (s, 2H) 3.8 (s, 3H), 1.4 (s, 6H). MS: [M+H]+: m/z=470.7. HPLC: (97.2%, Condition-A).
    • 4-(4-((3-Chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one methanesulfonate
  • Figure US20150322069A1-20151112-C00058
  • Methanesulfonic acid (50.5 mg, 0.52 mmol) was added to a solution of 4-(4-((3-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (250 mg, 0.52 mmol) in DCM (2.5 ml) and diethyl ether (25 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h upon which the compound was filtered, washed with 20% DCM in diethyl ether and dried in vacuo to afford 4-(4-((3-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one methanesulfonate (260 mg, 86%,) as white solid. 1H NMR: 500 MHz, δ 8.55 (d, 1H), 8.0 (s, 1H), 7.65 (Ar, 3H), 7.3-6.85 (Ar, 7H), 5.2 (s, 2H) 3.85 (s, 3H), 2.15 (s, 3H) 1.25 (s, 6H), HPLC: (98.8%, Condition-A).
    • Methyl 5-methylpicolinate
  • Figure US20150322069A1-20151112-C00059
  • 2-Chloro-5-methylpyridine (10 g, 78 mmol) was added to a solution of methanol (75 ml) and acetonitrile (75 ml) in steel bomb at RT under nitrogen bubbling followed by the addition of triethylamine (11.8 g, 117 mmol), BINAP (970 mg, 1.5 mmol) and bisacetonitrile palladium dichloride (0.4 g, 1.5 mmol). The mixture was heated to 100° C. and this temperature was maintained over night (the reaction was monitored by TLC). The reaction mixture was filter through Celite® bed and washing with ethyl acetate. The filtrate was washed with water and brine. The organic layer was concentrated under reduced pressure and purified by flash column chromatography using 10% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford methyl 5-methylpicolinate (6.5 g, 55%,) as an off-white solid. 1H NMR: 200 MHz, CDCl3: δ 8.6 (s, 1H), 8.0 (d, 1H), 7.65 (d, 1H), 4.05 (s, 3H), 2.4 (s, 3H). MS: [M+H]+: m/z=151.9.
    • (5-Methylpyridin-2-yl) methanol
  • Figure US20150322069A1-20151112-C00060
  • Sodium borohydride (4.5 g, 115. mmol) was added to a solution of methyl 5-methylpicolinate (6.0 g, 39.5 mmol) in THF (60 mL) and methanol (6 ml) at RT. The reaction mixture was stirred at RT for 2 h (the reaction was monitored by TLC). The mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The organic layer was concentrated under vacuo to afford (5-methylpyridin-2-yl) methanol (3.5 g, 72.9%,) as an off-white solid. 1H NMR: 200 MHz, CDCl3: δ 8.5 (s, 1H), 7.7 (d, 1H), 7.15 (d, 1H), 5.0 (s, 3H), 3.4 (s, 3H). MS: [M+H]+: m/z=124.0.
    • 2-(Chloromethyl)-5-methylpyridine
  • Figure US20150322069A1-20151112-C00061
  • Thionyl chloride (30 ml) was added to (5-methylpyridin-2-yl) methanol (3.0 g, 24.3 mmol) at 20° C. under nitrogen. The reaction mixture was stirred at reflux for 3 h (the reaction was monitored by TLC). The reaction mixture was concentrated under reduced pressure upon which it was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 6% ethyl acetate in n-hexane and silica gel (230-400 mesh), to afford 2-(chloromethyl)-5-methylpyridine (2.5 g, 73%,) as an off-white solid. 1H NMR: 200 MHz, CDCl3: δ 8.4 (s, 1H), 7.5 (d, 1H), 7.3 (d, 1H), 4.6 (s, 2H), 2.3 (s, 3H). MS: [M+H]+: m/z=142.2.
    • 5-(4-Methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-one
  • Figure US20150322069A1-20151112-C00062
  • 4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.0, 6.5 mmol) was added to a mixture of cesium carbonate (10.5 g, 32.2 mmol) and DMF (50 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min, upon which 2-(chloromethyl)-5-methylpyridine (1.36 g, 9.6 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture allowed to cool, diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh), to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3 (2H)-one (2.0 g, 76.9%,) as an off-white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.4 (s, 1H), 7.6 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.2 (s, 2H) 3.8 (s, 3H), 2.3 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=415.2. HPLC: (97.5%, Condition-A).
    • 5-(4-Methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-one methanesulfonate
  • Figure US20150322069A1-20151112-C00063
  • Methanesulfonic acid (462 mg, 4.8 mmol) was added to a solution of 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (2.0 g, 4.8 mmol) in DCM (5 ml) and diethyl ether (50 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h upon which the solids were collected by filtration, washed with 20% DCM in diethyl ether and dried in vacuo to afford 5-(4-Methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-one methanesulfonate (2.0 g, 90.9%,) as a white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.5 (s, 1H), 7.6 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.2 (s, 2H) 3.8 (s, 3H), 2.35 (s, 3H), 2.3 (s, 3H), 1.45 (s, 6H), HPLC: (99.3%, Condition-A).
    • 4-(5,5-Dimethyl-3-(4-((5-methylpyridin-2-yl)methoxy)phenyl)-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile
  • Figure US20150322069A1-20151112-C00064
  • 4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (0.4 g, 1.3 mmol) was added to a mixture of cesium carbonate (1.7 g, 5.2 mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 30 minutes upon which afford 2-(chloromethyl)-5-methylpyridine (306 mg, 1.9 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 25% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(5,5-dimethyl-3-(4-((5-methylpyridin-2-yl)methoxy)phenyl)-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (160 mg, 30.1%,) as an off-white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.4 (s, 1H), 7.6 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.2 (s, 2H), 2.3 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=411.2. HPLC: (97.3%, Condition-A).
    • 4-(5,5-Dimethyl-3-(4-((5-methylpyridin-2-yl)methoxy)phenyl)-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile methanesulfonate
  • Figure US20150322069A1-20151112-C00065
  • Methanesulfonic acid (36 mg, 0.3 mmol) was added to a solution of 4-(5,5-dimethyl-3-(4-((5-methylpyridin-2-yl)methoxy)phenyl)-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (150 mg, 0.3 mmol) in DCM (5 ml) and diethyl ether (50 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h upon which the solids were collected by filtration, washed with 20% DCM in diethyl ether, dried in vacuo to afford 4-(5,5-dimethyl-3-(4-((5-methylpyridin-2-yl)methoxy)phenyl)-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile methanesulfonate (120 mg, 67.0%,) as a white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.5 (s, 1H), 7.6 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.2 (s, 2H), 2.35 (s, 3H), 2.3 (s, 3H), 1.45 (s, 6H). HPLC: (98.3%, Condition-A).
    • Methyl 2-oxobutanoate
  • Figure US20150322069A1-20151112-C00066
  • Trimethylsilyl chloride (1.06 g, 9.8 mmol) was added to a stirred solution of 2-oxobutanoic acid (10.0 g, 98.0 mmol) in 2,2-dimethoxypropane (90 ml) and methanol (20 ml). The mixture was stirred for 18 hours at RT (the reaction was monitored by TLC) upon which the mixture was concentrated under reduced pressure afford crude methyl 2-oxobutanoate (8.0 g) as a brown liquid. 1H NMR: 200 MHz, CDCl3: δ 3.85 (s, 3H), 2.9 (q, 2H), 1.15 (t, 1H), 6.8 (t, 1H), 4.75 (s, 2H).
    • Methyl 3-bromo-2-oxobutanoate
  • Figure US20150322069A1-20151112-C00067
  • Copper bromide (30.0 g, 137 mmol) was added to a stirred solution of methyl 2-oxobutanoate (8.0 g, 68.9 mmol) in ethyl acetate (150 ml) and chloroform (100 ml). The mixture was stirred for 18 hours at reflux (the reaction was monitored by TLC). The mixture was filtered and washed with ethyl acetate and the filtrates were concentrated in vacuo to afford crude methyl 3-bromo-2-oxobutanoate (6.5 g) as a colorless liquid. 1H NMR: 200 MHz, CDCl3: δ 5.2 (q, 1H), 3.9 (s, 3H), 1.8 (d, 3H).
    • Methyl 3-methylimidazo[1,2-a]pyridine-2-carboxylate
  • Figure US20150322069A1-20151112-C00068
  • Methyl 3-bromo-2-oxobutanoate (6.5 g, 34.3 mmol) was added to a stirred solution of 2-aminopyridine (4.0 g, 42.5 mmol) in acetonitrile (100 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). The mixture was concentrated in vacuo and the residue was diluted with water and the pH was to 7.5 using sodium bicarbonate solution. The mixture was extracted with EtOAc; the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 8% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford methyl 3-methylimidazo[1,2-a]pyridine-2-carboxylate (2.0 g, 25.1%,) as a pale yellow solid. 1H NMR: 200 MHz, CDCl3: δ 7.95 (d, 1H), 7.7 (d, 1H), 7.25 (t, 1H), 6.8 (t, 1H), 4.0 (s, 3H), 2.8 (s, 3H). MS: [M+H]+: m/z=191.1.
    • (3-Methylimidazo[1,2-a]pyridin-2-yl)methanol
  • Figure US20150322069A1-20151112-C00069
  • Sodium borohydride (1.5 g, 41.6 mmol) was added to a solution of methyl 3-methylimidazo[1,2-a]pyridine-2-carboxylate (2.0 g, 10.5 mmol) in THF (50 mL) and methanol (2.5 ml) at RT. The reaction mixture was stirred at RT for 2 h (the reaction was monitored by TLC) upon which the mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (3-methylimidazo[1,2-a]pyridin-2-yl)methanol (0.8 g, 47.05%,) as off-white solid. 1H NMR: 200 MHz, CDCl3: δ 7.45 (d, 1H), 7.6 (d, 1H), 7.2 (t, 1H), 6.8 (t, 1H), 4.85 (s, 2H), 2.45 (s, 3H). MS: [M+H]+: m/z=162.9.
    • 2-(Chloromethyl)-3-methylimidazo[1,2-a]pyridine
  • Figure US20150322069A1-20151112-C00070
  • Thionyl chloride (10 ml) was added to (3-methylimidazo[1,2-a]pyridin-2-yl)methanol (0.8 g, 4.9 mmol) at 20° C. under an atmosphere of nitrogen. The reaction mixture was stirred at reflux for 3 h (the reaction was monitored by TLC). The mixture was concentrated under reduced pressure, the residue was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 6% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 2-(chloroethyl)-3-methylimidazo[1,2-a]pyridine (400 mg, 45.4%,) as an off-white solid. 1H NMR: 200 MHz, CDCl3: δ 8.15 (s, 1H), 7.6 (s, 1H), 7.55 (d, 1H), 7.15 (d, 1H), 4.75 (s, 2H). MS: [M+H]+: m/z=181.3.
    • 5-(4-Methoxyphenyl)-2,2-dimethyl-4-(4-((3-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one
  • Figure US20150322069A1-20151112-C00071
  • 4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (0.1 g, 0.32 mmol) was added to a mixture of cesium carbonate (0.52 g, 1.62 mmol) and DMF (20 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl)-3-methylimidazo[1,2-a]pyridine (87 mg, 0.48 mmol) was added. The mixture was heated at for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((3-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (2.8 g, 77%,) as an off-white solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.25 (d, 1H), 7.45 (d, 3H), 7.25 (t, 1H), 7.15-6.95 (Ar, 7H), 5.2 (s, 2H), 3.85 (s, 3H), 2.45 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=455.3. HPLC: (96.3%, Condition-A).
    • 2-(Chloromethyl)-5-methylimidazo[1,2-a]pyridine
  • Figure US20150322069A1-20151112-C00072
  • 1,3-Dichloroacetone (17.6 g, 138.3 mmol) was added to a solution of 6-methylpyridin-2-amine (10 g, 92.5 mmol) in acetonitrile (200 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). The mixture was concentrated under reduced pressure, the residue was diluted with water, and the pH was adjusted to 7.5 with sodium bicarbonate solution. The mixture was extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (7.0 g, 70.7%,) as a pale yellow solid. 1H NMR: 200 MHz, CDCl3: δ 8.15 (s, 1H), 7.6 (dd, 2H), 7.1 (t, 1H), 6.8 (t, 1H), 4.95 (s, 2H), 2.6 (s, 3H). MS: [M+H]+: m/z=181.5.
    • 5-(4-Methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one
  • Figure US20150322069A1-20151112-C00073
  • 4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (250 mg, 0.8 mmol) was added to a mixture of cesium carbonate (1.05 g, 3.22 mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 30 minutes upon which 2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (218 mg, 1.2 mmol) was added. The mixture was heated at for 4 h (the reaction was monitored by TLC) upon which the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (280 mg, 77.7%,) as a light yellow solid. 1H NMR: 500 MHz, DMSO-d6: δ 7.95 (s, 1H), 7.6 (d, 2H), 7.4 (d, 1H), 7.25 (t, 1H), 7.2 (d, 3H), 7.15 (d, 2H), 7.0 (d, 2H), 6.8 (d, 1H), 5.2 (s, 2H) 3.85 (s, 3H), 2.6 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=455.6. HPLC: (97.3%, Condition-A).
    • 5-(4-Methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one methanesulfonate
  • Figure US20150322069A1-20151112-C00074
  • Methanesulfonic acid (53.1 mg, 0.5 mmol) was added to a solution of 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (250 g, 0.5 mmol) in DCM (2.5 ml) and diethyl ether (50 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h upon which, the solids were collected by filtration, washed with 20% DCM in diethyl ether, dried in vacuo to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one methanesulfonate (240 mg, 82.7%,) as white solid. 1H NMR: 500 MHz, DMSO-d6: δ 7.95 (s, 1H), 7.6 (d, 2H), 7.4 (d, 1H), 7.25 (t, 1H), 7.2 (d, 3H), 7.15 (d, 2H), 7.0 (d, 2H), 6.8 (d, 1H), 5.2 (s, 2H) 3.85 (s, 3H), 2.6 (s, 3H), 2.5 (s, 3H), 1.25 (s, 6H), HPLC: (98.4%, Condition-A).
    • 6-Chloro-2-(chloromethyl)imidazo[1,2-a]pyridine
  • Figure US20150322069A1-20151112-C00075
  • 1,3-Dichloroacetone (7.4 g, 58.3 mmol) was added to a solution of 5-chloropyridin-2-amine (5.0 g, 38.9 mmol) in acetonitrile (100 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). Upon completion of the reaction as judged by TLC, the mixture was concentrated under reduced pressure. The residue was diluted with water and the pH was adjusted to 7.5 with sodium bicarbonate solution. The mixture was extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 6-chloro-2-(chloromethyl) imidazo[1,2-a]pyridine (1.5 g, 30%,) as a pale yellow solid. 1H NMR: 200 MHz, CDCl3: δ 8.0 (d, 1H), 7.6 (dd, 2H), 6.8 (d, 1H), 4.75 (s, 2H). MS: [M+H]+: m/z=201.9.
    • 4-(4-((6-Chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
  • Figure US20150322069A1-20151112-C00076
  • 4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (300 mg, 0.96 mmol) was added to a mixture of cesium carbonate (1.05 g, 3.8 mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 30 minutes, upon which 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (201 mg, 1.4 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). Upon completion of the reaction as judged by TLC, the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-((6-chloroimidazo[1,2-a]pyridin-2-yl) methoxy)phenyl)-5-(4-methoxy phenyl)-2,2-dimethylfuran-3(2H)-one (180 mg, 39.3%,) as a white solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.85 (s, 1H), 8.0 (s, 1H), 7.6 (d, 3H), 7.3 (d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.15 (s, 2H) 3.8 (s, 3H), 1.4 (s, 6H). MS: [M+H]+: m/z=475. HPLC: (98.0%, Condition-A).
    • 4-(4-((6-Chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one methanesulfonate
  • Figure US20150322069A1-20151112-C00077
  • Methanesulfonic acid (53.1 mg, 0.5 mmol) was added to a solution of compound 4-(4-((6-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (250 g, 0.5 mmol) in DCM (2.5 ml) and diethyl ether (50 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h upon which the solids were collected by filtration, washed with 20% DCM in diethyl ether and dried in vacuo to afford 4-(4-((6-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one methanesulfonate (240 mg, 82%,) as a white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.8 (s, 1H), 8.3 (s, 1H), 8.0 (s, 1H), 7.6 (d, 2H), 7.4 (d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H) 5.35 (s, 2H), 3.8 (s, 3H), 2.3 (s, 3H), 1.4 (s, 6H), HPLC: (99.3%, Condition-A).
    • Tables
  • In the following tables, if a specific example contains multiple instances of R2, they will be separated by commas in the table (e.g. Me, Me or Et, Me). If the R2 column contains a value “-group-” e.g. “-cyclopropyl-”, then both R2 values are taken together to be a spiro ring.
  • In a further aspect the compounds of the disclosure are embodied in with distinct examples listed in the table below taken from Formula (I):
  • Example # HET X Z R2
    1 A29
    Figure US20150322069A1-20151112-C00078
    Figure US20150322069A1-20151112-C00079
         		Me, Me
    2 A29
    Figure US20150322069A1-20151112-C00080
    Figure US20150322069A1-20151112-C00081
         		Me, Me
    3 A29
    Figure US20150322069A1-20151112-C00082
    Figure US20150322069A1-20151112-C00083
         		Me, Me
    4 A29
    Figure US20150322069A1-20151112-C00084
    Figure US20150322069A1-20151112-C00085
         		Me, Me
    5 A29
    Figure US20150322069A1-20151112-C00086
    Figure US20150322069A1-20151112-C00087
         		Me, Me
    6 A29
    Figure US20150322069A1-20151112-C00088
    Figure US20150322069A1-20151112-C00089
         		Me, Me
    7 A29
    Figure US20150322069A1-20151112-C00090
    Figure US20150322069A1-20151112-C00091
         		Me, Me
    8 A29
    Figure US20150322069A1-20151112-C00092
    Figure US20150322069A1-20151112-C00093
         		Me, Me
    9 A29
    Figure US20150322069A1-20151112-C00094
    Figure US20150322069A1-20151112-C00095
         		Me, Me
    10 A29
    Figure US20150322069A1-20151112-C00096
    Figure US20150322069A1-20151112-C00097
         		Me, Me
    11 A29
    Figure US20150322069A1-20151112-C00098
    Figure US20150322069A1-20151112-C00099
         		Me, Me
    12 A29
    Figure US20150322069A1-20151112-C00100
    Figure US20150322069A1-20151112-C00101
         		Me, Me
    13 A29
    Figure US20150322069A1-20151112-C00102
    Figure US20150322069A1-20151112-C00103
         		Me, Me
    14 A29
    Figure US20150322069A1-20151112-C00104
    Figure US20150322069A1-20151112-C00105
         		Me, Me
    15 A29
    Figure US20150322069A1-20151112-C00106
    Figure US20150322069A1-20151112-C00107
         		Me, Me
    16 A29
    Figure US20150322069A1-20151112-C00108
    Figure US20150322069A1-20151112-C00109
         		Me, Me
    17 A29
    Figure US20150322069A1-20151112-C00110
    Figure US20150322069A1-20151112-C00111
         		Me, Me
    18 A29
    Figure US20150322069A1-20151112-C00112
    Figure US20150322069A1-20151112-C00113
         		Me, Me
    19 A29
    Figure US20150322069A1-20151112-C00114
    Figure US20150322069A1-20151112-C00115
         		Me, Me
    20 A29
    Figure US20150322069A1-20151112-C00116
    Figure US20150322069A1-20151112-C00117
         		Me, Me
    21 A29
    Figure US20150322069A1-20151112-C00118
    Figure US20150322069A1-20151112-C00119
         		Me, Me
    22 A29
    Figure US20150322069A1-20151112-C00120
    Figure US20150322069A1-20151112-C00121
         		Me, Me
    23 A29
    Figure US20150322069A1-20151112-C00122
    Figure US20150322069A1-20151112-C00123
         		Me, Me
    24 A29
    Figure US20150322069A1-20151112-C00124
    Figure US20150322069A1-20151112-C00125
         		Me, Me
    25 A29
    Figure US20150322069A1-20151112-C00126
    Figure US20150322069A1-20151112-C00127
         		Me, Me
    26 A29
    Figure US20150322069A1-20151112-C00128
    Figure US20150322069A1-20151112-C00129
         		Me, Me
    27 A29
    Figure US20150322069A1-20151112-C00130
    Figure US20150322069A1-20151112-C00131
         		Me, Me
    28 A29
    Figure US20150322069A1-20151112-C00132
    Figure US20150322069A1-20151112-C00133
         		Me, Me
    29 A29
    Figure US20150322069A1-20151112-C00134
    Figure US20150322069A1-20151112-C00135
         		Me, Me
    30 A29
    Figure US20150322069A1-20151112-C00136
    Figure US20150322069A1-20151112-C00137
         		Me, Me
    31 A29
    Figure US20150322069A1-20151112-C00138
    Figure US20150322069A1-20151112-C00139
         		Me, Me
    32 A29
    Figure US20150322069A1-20151112-C00140
    Figure US20150322069A1-20151112-C00141
         		Me, Me
    33 A29
    Figure US20150322069A1-20151112-C00142
    Figure US20150322069A1-20151112-C00143
         		Me, Me
    34 A29
    Figure US20150322069A1-20151112-C00144
    Figure US20150322069A1-20151112-C00145
         		Me, Me
    35 A29
    Figure US20150322069A1-20151112-C00146
    Figure US20150322069A1-20151112-C00147
         		Me, Me
    36 A29
    Figure US20150322069A1-20151112-C00148
    Figure US20150322069A1-20151112-C00149
         		Me, Me
    37 A29
    Figure US20150322069A1-20151112-C00150
    Figure US20150322069A1-20151112-C00151
         		Me, Me
    38 A29
    Figure US20150322069A1-20151112-C00152
    Figure US20150322069A1-20151112-C00153
         		Me, Me
    39 A29
    Figure US20150322069A1-20151112-C00154
    Figure US20150322069A1-20151112-C00155
         		Me, Me
    40 A29
    Figure US20150322069A1-20151112-C00156
    Figure US20150322069A1-20151112-C00157
         		Me, Me
    41 A29
    Figure US20150322069A1-20151112-C00158
    Figure US20150322069A1-20151112-C00159
         		Me, Me
    42 A29
    Figure US20150322069A1-20151112-C00160
    Figure US20150322069A1-20151112-C00161
         		Me, Me
    43 A29
    Figure US20150322069A1-20151112-C00162
    Figure US20150322069A1-20151112-C00163
         		Me, Me
    44 A29
    Figure US20150322069A1-20151112-C00164
    Figure US20150322069A1-20151112-C00165
         		Me, Me
    45 A29
    Figure US20150322069A1-20151112-C00166
    Figure US20150322069A1-20151112-C00167
         		Me, Me
    46 A29
    Figure US20150322069A1-20151112-C00168
    Figure US20150322069A1-20151112-C00169
         		Me, Me
    47 A29
    Figure US20150322069A1-20151112-C00170
    Figure US20150322069A1-20151112-C00171
         		Me, Me
    48 A29
    Figure US20150322069A1-20151112-C00172
    Figure US20150322069A1-20151112-C00173
         		Me, Me
    49 A29
    Figure US20150322069A1-20151112-C00174
    Figure US20150322069A1-20151112-C00175
         		Me, Me
    50 A29
    Figure US20150322069A1-20151112-C00176
    Figure US20150322069A1-20151112-C00177
         		Me, Me
    51 A29
    Figure US20150322069A1-20151112-C00178
    Figure US20150322069A1-20151112-C00179
         		Me, Me
    52 A29
    Figure US20150322069A1-20151112-C00180
    Figure US20150322069A1-20151112-C00181
         		Me, Me
    53 A29
    Figure US20150322069A1-20151112-C00182
    Figure US20150322069A1-20151112-C00183
         		Me, Me
    54 A29
    Figure US20150322069A1-20151112-C00184
    Figure US20150322069A1-20151112-C00185
         		Me, Me
    55 A29
    Figure US20150322069A1-20151112-C00186
    Figure US20150322069A1-20151112-C00187
         		Me, Me
    56 A29
    Figure US20150322069A1-20151112-C00188
    Figure US20150322069A1-20151112-C00189
         		Me, Me
    57 A29
    Figure US20150322069A1-20151112-C00190
    Figure US20150322069A1-20151112-C00191
         		Me, Me
    58 A29
    Figure US20150322069A1-20151112-C00192
    Figure US20150322069A1-20151112-C00193
         		Me, Me
    59 A29
    Figure US20150322069A1-20151112-C00194
    Figure US20150322069A1-20151112-C00195
         		Me, Me
    60 A29
    Figure US20150322069A1-20151112-C00196
    Figure US20150322069A1-20151112-C00197
         		Me, Me
    61 A29
    Figure US20150322069A1-20151112-C00198
    Figure US20150322069A1-20151112-C00199
         		Me, Me
    62 A29
    Figure US20150322069A1-20151112-C00200
    Figure US20150322069A1-20151112-C00201
         		Me, Me
    63 A29
    Figure US20150322069A1-20151112-C00202
    Figure US20150322069A1-20151112-C00203
         		Me, Me
    64 A29
    Figure US20150322069A1-20151112-C00204
    Figure US20150322069A1-20151112-C00205
         		Me, Me
    65 A29
    Figure US20150322069A1-20151112-C00206
    Figure US20150322069A1-20151112-C00207
         		Me, Me
    66 A29
    Figure US20150322069A1-20151112-C00208
    Figure US20150322069A1-20151112-C00209
         		Me, Me
    67 A29
    Figure US20150322069A1-20151112-C00210
    Figure US20150322069A1-20151112-C00211
         		Me, Me
    68 A29
    Figure US20150322069A1-20151112-C00212
    Figure US20150322069A1-20151112-C00213
         		Me, Me
    69 A29
    Figure US20150322069A1-20151112-C00214
    Figure US20150322069A1-20151112-C00215
         		Me, Me
    70 A29
    Figure US20150322069A1-20151112-C00216
    Figure US20150322069A1-20151112-C00217
         		Me, Me
    71 A29
    Figure US20150322069A1-20151112-C00218
    Figure US20150322069A1-20151112-C00219
         		Me, Me
    72 A29
    Figure US20150322069A1-20151112-C00220
    Figure US20150322069A1-20151112-C00221
         		Me, Me
    73 A29
    Figure US20150322069A1-20151112-C00222
    Figure US20150322069A1-20151112-C00223
         		Me, Me
    74 A29
    Figure US20150322069A1-20151112-C00224
    Figure US20150322069A1-20151112-C00225
         		Me, Me
    75 A29
    Figure US20150322069A1-20151112-C00226
    Figure US20150322069A1-20151112-C00227
         		Me, Me
    76 A29
    Figure US20150322069A1-20151112-C00228
    Figure US20150322069A1-20151112-C00229
         		Me, Me
    77 A29
    Figure US20150322069A1-20151112-C00230
    Figure US20150322069A1-20151112-C00231
         		Me, Me
    78 A29
    Figure US20150322069A1-20151112-C00232
    Figure US20150322069A1-20151112-C00233
         		Me, Me
    79 A29
    Figure US20150322069A1-20151112-C00234
    Figure US20150322069A1-20151112-C00235
         		Me, Me
    80 A29
    Figure US20150322069A1-20151112-C00236
    Figure US20150322069A1-20151112-C00237
         		Me, Me
    81 A29
    Figure US20150322069A1-20151112-C00238
    Figure US20150322069A1-20151112-C00239
         		Me, Me
    82 A29
    Figure US20150322069A1-20151112-C00240
    Figure US20150322069A1-20151112-C00241
         		Me, Me
    83 A29
    Figure US20150322069A1-20151112-C00242
    Figure US20150322069A1-20151112-C00243
         		Me, Me
    84 A29
    Figure US20150322069A1-20151112-C00244
    Figure US20150322069A1-20151112-C00245
         		Me, Me
    85 A29
    Figure US20150322069A1-20151112-C00246
    Figure US20150322069A1-20151112-C00247
         		Me, Me
    86 A29
    Figure US20150322069A1-20151112-C00248
    Figure US20150322069A1-20151112-C00249
         		Me, Me
    87 A29
    Figure US20150322069A1-20151112-C00250
    Figure US20150322069A1-20151112-C00251
         		Me, Me
    88 A29
    Figure US20150322069A1-20151112-C00252
    Figure US20150322069A1-20151112-C00253
         		Me, Me
    89 A29
    Figure US20150322069A1-20151112-C00254
    Figure US20150322069A1-20151112-C00255
         		Me, Me
    90 A29
    Figure US20150322069A1-20151112-C00256
    Figure US20150322069A1-20151112-C00257
         		Me, Me
    91 A29
    Figure US20150322069A1-20151112-C00258
    Figure US20150322069A1-20151112-C00259
         		Me, Me
    92 A29
    Figure US20150322069A1-20151112-C00260
    Figure US20150322069A1-20151112-C00261
         		Me, Me
    93 A29
    Figure US20150322069A1-20151112-C00262
    Figure US20150322069A1-20151112-C00263
         		Me, Me
    94 A29
    Figure US20150322069A1-20151112-C00264
    Figure US20150322069A1-20151112-C00265
         		Me, Me
    95 A29
    Figure US20150322069A1-20151112-C00266
    Figure US20150322069A1-20151112-C00267
         		Me, Me
    96 A29
    Figure US20150322069A1-20151112-C00268
    Figure US20150322069A1-20151112-C00269
         		Me, Me
    97 A29
    Figure US20150322069A1-20151112-C00270
    Figure US20150322069A1-20151112-C00271
         		Me, Me
    98 A29
    Figure US20150322069A1-20151112-C00272
    Figure US20150322069A1-20151112-C00273
         		Me, Me
    99 A29
    Figure US20150322069A1-20151112-C00274
    Figure US20150322069A1-20151112-C00275
         		Me, Me
    100 A29
    Figure US20150322069A1-20151112-C00276
    Figure US20150322069A1-20151112-C00277
         		Me, Me
    101 A29
    Figure US20150322069A1-20151112-C00278
    Figure US20150322069A1-20151112-C00279
         		Me, Me
    102 A29
    Figure US20150322069A1-20151112-C00280
    Figure US20150322069A1-20151112-C00281
         		Me, Me
    103 A29
    Figure US20150322069A1-20151112-C00282
    Figure US20150322069A1-20151112-C00283
         		Me, Me
    104 A29
    Figure US20150322069A1-20151112-C00284
    Figure US20150322069A1-20151112-C00285
         		Me, Me
    105 A29
    Figure US20150322069A1-20151112-C00286
    Figure US20150322069A1-20151112-C00287
         		Me, Me
    106 A29
    Figure US20150322069A1-20151112-C00288
    Figure US20150322069A1-20151112-C00289
         		Me, Me
    107 A29
    Figure US20150322069A1-20151112-C00290
    Figure US20150322069A1-20151112-C00291
         		Me, Me
    108 A29
    Figure US20150322069A1-20151112-C00292
    Figure US20150322069A1-20151112-C00293
         		Me, Me
    109 A29
    Figure US20150322069A1-20151112-C00294
    Figure US20150322069A1-20151112-C00295
         		Me, Me
    110 A29
    Figure US20150322069A1-20151112-C00296
    Figure US20150322069A1-20151112-C00297
         		Me, Me
    111 A29
    Figure US20150322069A1-20151112-C00298
    Figure US20150322069A1-20151112-C00299
         		Me, Me
    121 A29
    Figure US20150322069A1-20151112-C00300
    Figure US20150322069A1-20151112-C00301
         		Me, Me
    122 A29
    Figure US20150322069A1-20151112-C00302
    Figure US20150322069A1-20151112-C00303
         		Me, Me
    123 A29
    Figure US20150322069A1-20151112-C00304
    Figure US20150322069A1-20151112-C00305
         		Me, Me
    124 A29
    Figure US20150322069A1-20151112-C00306
    Figure US20150322069A1-20151112-C00307
         		Me, Me
    125 A29
    Figure US20150322069A1-20151112-C00308
    Figure US20150322069A1-20151112-C00309
         		Me, Me
    126 A29
    Figure US20150322069A1-20151112-C00310
    Figure US20150322069A1-20151112-C00311
         		Me, Me
    127 A29
    Figure US20150322069A1-20151112-C00312
    Figure US20150322069A1-20151112-C00313
         		Me, Me
    128 A29
    Figure US20150322069A1-20151112-C00314
    Figure US20150322069A1-20151112-C00315
         		Me, Me
    129 A29
    Figure US20150322069A1-20151112-C00316
    Figure US20150322069A1-20151112-C00317
         		Me, Me
    130 A29
    Figure US20150322069A1-20151112-C00318
    Figure US20150322069A1-20151112-C00319
         		Me, Me
    131 A29
    Figure US20150322069A1-20151112-C00320
    Figure US20150322069A1-20151112-C00321
         		Me, Me
    132 A29
    Figure US20150322069A1-20151112-C00322
    Figure US20150322069A1-20151112-C00323
         		Me, Me
    133 A29
    Figure US20150322069A1-20151112-C00324
    Figure US20150322069A1-20151112-C00325
         		Me, Me
    134 A29
    Figure US20150322069A1-20151112-C00326
    Figure US20150322069A1-20151112-C00327
         		Me, Me
    135 A29
    Figure US20150322069A1-20151112-C00328
    Figure US20150322069A1-20151112-C00329
         		Me, Me
    136 A29
    Figure US20150322069A1-20151112-C00330
    Figure US20150322069A1-20151112-C00331
         		Me, Me
    137 A29
    Figure US20150322069A1-20151112-C00332
    Figure US20150322069A1-20151112-C00333
         		Me, Me
    138 A29
    Figure US20150322069A1-20151112-C00334
    Figure US20150322069A1-20151112-C00335
         		Me, Me
    139 A29
    Figure US20150322069A1-20151112-C00336
    Figure US20150322069A1-20151112-C00337
         		Me, Me
    140 A29
    Figure US20150322069A1-20151112-C00338
    Figure US20150322069A1-20151112-C00339
         		Me, Me
    141 A29
    Figure US20150322069A1-20151112-C00340
    Figure US20150322069A1-20151112-C00341
         		Me, Me
    142 A29
    Figure US20150322069A1-20151112-C00342
    Figure US20150322069A1-20151112-C00343
         		Me, Me
    143 A29
    Figure US20150322069A1-20151112-C00344
    Figure US20150322069A1-20151112-C00345
         		Me, Me
    144 A29
    Figure US20150322069A1-20151112-C00346
    Figure US20150322069A1-20151112-C00347
         		Me, Me
    145 A29
    Figure US20150322069A1-20151112-C00348
    Figure US20150322069A1-20151112-C00349
         		Me, Me
    146 A29
    Figure US20150322069A1-20151112-C00350
    Figure US20150322069A1-20151112-C00351
         		Me, Me
    147 A29
    Figure US20150322069A1-20151112-C00352
    Figure US20150322069A1-20151112-C00353
         		Me, Me
    148 A29
    Figure US20150322069A1-20151112-C00354
    Figure US20150322069A1-20151112-C00355
         		Me, Me
    149 A29
    Figure US20150322069A1-20151112-C00356
    Figure US20150322069A1-20151112-C00357
         		Me, Me
    150 A29
    Figure US20150322069A1-20151112-C00358
    Figure US20150322069A1-20151112-C00359
         		Me, Me
    151 A29
    Figure US20150322069A1-20151112-C00360
    Figure US20150322069A1-20151112-C00361
         		Me, Me
    152 A29
    Figure US20150322069A1-20151112-C00362
    Figure US20150322069A1-20151112-C00363
         		Me, Me
    153 A29
    Figure US20150322069A1-20151112-C00364
    Figure US20150322069A1-20151112-C00365
         		Me, Me
    154 A29
    Figure US20150322069A1-20151112-C00366
    Figure US20150322069A1-20151112-C00367
         		Me, Me
    155 A29
    Figure US20150322069A1-20151112-C00368
    Figure US20150322069A1-20151112-C00369
         		Me, Me
    156 A29
    Figure US20150322069A1-20151112-C00370
    Figure US20150322069A1-20151112-C00371
         		Me, Me
    157 A29
    Figure US20150322069A1-20151112-C00372
    Figure US20150322069A1-20151112-C00373
         		Me, Me
    158 A29
    Figure US20150322069A1-20151112-C00374
    Figure US20150322069A1-20151112-C00375
         		Me, Me
    159 A29
    Figure US20150322069A1-20151112-C00376
    Figure US20150322069A1-20151112-C00377
         		Me, Me
    160 A29
    Figure US20150322069A1-20151112-C00378
    Figure US20150322069A1-20151112-C00379
         		Me, Me
    161 A29
    Figure US20150322069A1-20151112-C00380
    Figure US20150322069A1-20151112-C00381
         		Me, Me
    162 A29
    Figure US20150322069A1-20151112-C00382
    Figure US20150322069A1-20151112-C00383
         		Me, Me
    163 A29
    Figure US20150322069A1-20151112-C00384
    Figure US20150322069A1-20151112-C00385
         		Me, Me
    164 A29
    Figure US20150322069A1-20151112-C00386
    Figure US20150322069A1-20151112-C00387
         		Me, Me
    165 A29
    Figure US20150322069A1-20151112-C00388
    Figure US20150322069A1-20151112-C00389
         		Me, Me
    166 A29
    Figure US20150322069A1-20151112-C00390
    Figure US20150322069A1-20151112-C00391
         		Me, Me
    167 A29
    Figure US20150322069A1-20151112-C00392
    Figure US20150322069A1-20151112-C00393
         		Me, Me
    168 A29
    Figure US20150322069A1-20151112-C00394
    Figure US20150322069A1-20151112-C00395
         		Me, Me
    169 A29
    Figure US20150322069A1-20151112-C00396
    Figure US20150322069A1-20151112-C00397
         		Me, Me
    170 A29
    Figure US20150322069A1-20151112-C00398
    Figure US20150322069A1-20151112-C00399
         		Me, Me
    171 A29
    Figure US20150322069A1-20151112-C00400
    Figure US20150322069A1-20151112-C00401
         		Me, Me
    172 A29
    Figure US20150322069A1-20151112-C00402
    Figure US20150322069A1-20151112-C00403
         		Me, Me
    173 A29
    Figure US20150322069A1-20151112-C00404
    Figure US20150322069A1-20151112-C00405
         		Me, Me
    174 A29
    Figure US20150322069A1-20151112-C00406
    Figure US20150322069A1-20151112-C00407
         		Me, Me
    175 A29
    Figure US20150322069A1-20151112-C00408
    Figure US20150322069A1-20151112-C00409
         		Me, Me
    176 A29
    Figure US20150322069A1-20151112-C00410
    Figure US20150322069A1-20151112-C00411
         		Me, Me
    177 A29
    Figure US20150322069A1-20151112-C00412
    Figure US20150322069A1-20151112-C00413
         		Me, Me
    178 A29
    Figure US20150322069A1-20151112-C00414
    Figure US20150322069A1-20151112-C00415
         		Me, Me
    179 A29
    Figure US20150322069A1-20151112-C00416
    Figure US20150322069A1-20151112-C00417
         		Me, Me
    180 A29
    Figure US20150322069A1-20151112-C00418
    Figure US20150322069A1-20151112-C00419
         		Me, Me
    181 A29
    Figure US20150322069A1-20151112-C00420
    Figure US20150322069A1-20151112-C00421
         		Me, Me
    182 A29
    Figure US20150322069A1-20151112-C00422
    Figure US20150322069A1-20151112-C00423
         		Me, Me
    183 A29
    Figure US20150322069A1-20151112-C00424
    Figure US20150322069A1-20151112-C00425
         		Me, Me
    184 A29
    Figure US20150322069A1-20151112-C00426
    Figure US20150322069A1-20151112-C00427
         		Me, Me
    185 A29
    Figure US20150322069A1-20151112-C00428
    Figure US20150322069A1-20151112-C00429
         		Me, Me
    186 A29
    Figure US20150322069A1-20151112-C00430
    Figure US20150322069A1-20151112-C00431
         		Me, Me
    187 A29
    Figure US20150322069A1-20151112-C00432
    Figure US20150322069A1-20151112-C00433
         		Me, Me
    188 A29
    Figure US20150322069A1-20151112-C00434
    Figure US20150322069A1-20151112-C00435
         		Me, Me
    189 A29
    Figure US20150322069A1-20151112-C00436
    Figure US20150322069A1-20151112-C00437
         		Me, Me
    190 A29
    Figure US20150322069A1-20151112-C00438
    Figure US20150322069A1-20151112-C00439
         		Me, Me
    191 A29
    Figure US20150322069A1-20151112-C00440
    Figure US20150322069A1-20151112-C00441
         		Me, Me
    192 A29
    Figure US20150322069A1-20151112-C00442
    Figure US20150322069A1-20151112-C00443
         		Me, Me
    193 A29
    Figure US20150322069A1-20151112-C00444
    Figure US20150322069A1-20151112-C00445
         		Me, Me
    194 A29
    Figure US20150322069A1-20151112-C00446
    Figure US20150322069A1-20151112-C00447
         		Me, Me
    195 A29
    Figure US20150322069A1-20151112-C00448
    Figure US20150322069A1-20151112-C00449
         		Me, Me
    196 A29
    Figure US20150322069A1-20151112-C00450
    Figure US20150322069A1-20151112-C00451
         		Me, Me
    197 A29
    Figure US20150322069A1-20151112-C00452
    Figure US20150322069A1-20151112-C00453
         		Me, Me
    198 A29
    Figure US20150322069A1-20151112-C00454
    Figure US20150322069A1-20151112-C00455
         		Me, Me
    199 A29
    Figure US20150322069A1-20151112-C00456
    Figure US20150322069A1-20151112-C00457
         		Me, Me
    200 A29
    Figure US20150322069A1-20151112-C00458
    Figure US20150322069A1-20151112-C00459
         		Me, Me
    201 A29
    Figure US20150322069A1-20151112-C00460
    Figure US20150322069A1-20151112-C00461
         		Me, Me
    202 A29
    Figure US20150322069A1-20151112-C00462
    Figure US20150322069A1-20151112-C00463
         		Me, Me
    203 A29
    Figure US20150322069A1-20151112-C00464
    Figure US20150322069A1-20151112-C00465
         		Me, Me
    204 A29
    Figure US20150322069A1-20151112-C00466
    Figure US20150322069A1-20151112-C00467
         		Me, Me
    205 A29
    Figure US20150322069A1-20151112-C00468
    Figure US20150322069A1-20151112-C00469
         		Me, Me
    206 A29
    Figure US20150322069A1-20151112-C00470
    Figure US20150322069A1-20151112-C00471
         		Me, Me
    207 A29
    Figure US20150322069A1-20151112-C00472
    Figure US20150322069A1-20151112-C00473
         		Me, Me
    211 A29
    Figure US20150322069A1-20151112-C00474
    Figure US20150322069A1-20151112-C00475
         		Me, Me
    212 A29
    Figure US20150322069A1-20151112-C00476
    Figure US20150322069A1-20151112-C00477
         		Me, Me
    213 A29
    Figure US20150322069A1-20151112-C00478
    Figure US20150322069A1-20151112-C00479
         		Me, Me
    214 A29
    Figure US20150322069A1-20151112-C00480
    Figure US20150322069A1-20151112-C00481
         		Me, Me
    215 A29
    Figure US20150322069A1-20151112-C00482
    Figure US20150322069A1-20151112-C00483
         		Me, Me
    216 A29
    Figure US20150322069A1-20151112-C00484
    Figure US20150322069A1-20151112-C00485
         		Me, Me
    217 A29
    Figure US20150322069A1-20151112-C00486
    Figure US20150322069A1-20151112-C00487
         		Me, Me
    218 A29
    Figure US20150322069A1-20151112-C00488
    Figure US20150322069A1-20151112-C00489
         		Me, Me
    219 A29
    Figure US20150322069A1-20151112-C00490
    Figure US20150322069A1-20151112-C00491
         		Me, Me
    220 A29
    Figure US20150322069A1-20151112-C00492
    Figure US20150322069A1-20151112-C00493
         		Me, Me
    221 A29
    Figure US20150322069A1-20151112-C00494
    Figure US20150322069A1-20151112-C00495
         		Me, Me
    222 A29
    Figure US20150322069A1-20151112-C00496
    Figure US20150322069A1-20151112-C00497
         		Me, Me
    223 A29
    Figure US20150322069A1-20151112-C00498
    Figure US20150322069A1-20151112-C00499
         		Me, Me
    224 A29
    Figure US20150322069A1-20151112-C00500
    Figure US20150322069A1-20151112-C00501
         		Me, Me
    225 A29
    Figure US20150322069A1-20151112-C00502
    Figure US20150322069A1-20151112-C00503
         		Me, Me
    226 A29
    Figure US20150322069A1-20151112-C00504
    Figure US20150322069A1-20151112-C00505
         		Me, Me
    227 A29
    Figure US20150322069A1-20151112-C00506
    Figure US20150322069A1-20151112-C00507
         		Me, Me
    228 A29
    Figure US20150322069A1-20151112-C00508
    Figure US20150322069A1-20151112-C00509
         		Me, Me
    229 A29
    Figure US20150322069A1-20151112-C00510
    Figure US20150322069A1-20151112-C00511
         		Me, Me
    230 A29
    Figure US20150322069A1-20151112-C00512
    Figure US20150322069A1-20151112-C00513
         		Me, Me
    231 A29
    Figure US20150322069A1-20151112-C00514
    Figure US20150322069A1-20151112-C00515
         		Me, Me
    232 A29
    Figure US20150322069A1-20151112-C00516
    Figure US20150322069A1-20151112-C00517
         		Me, Me
    233 A29
    Figure US20150322069A1-20151112-C00518
    Figure US20150322069A1-20151112-C00519
         		Me, Me
    234 A29
    Figure US20150322069A1-20151112-C00520
    Figure US20150322069A1-20151112-C00521
         		Me, Me
    235 A29
    Figure US20150322069A1-20151112-C00522
    Figure US20150322069A1-20151112-C00523
         		Me, Me
    236 A29
    Figure US20150322069A1-20151112-C00524
    Figure US20150322069A1-20151112-C00525
         		Me, Me
    237 A29
    Figure US20150322069A1-20151112-C00526
    Figure US20150322069A1-20151112-C00527
         		Me, Me
    238 A29
    Figure US20150322069A1-20151112-C00528
    Figure US20150322069A1-20151112-C00529
         		Me, Me
    239 A29
    Figure US20150322069A1-20151112-C00530
    Figure US20150322069A1-20151112-C00531
         		Me, Me
    240 A29
    Figure US20150322069A1-20151112-C00532
    Figure US20150322069A1-20151112-C00533
         		Me, Me
    241 A29
    Figure US20150322069A1-20151112-C00534
    Figure US20150322069A1-20151112-C00535
         		Me, Me
    242 A29
    Figure US20150322069A1-20151112-C00536
    Figure US20150322069A1-20151112-C00537
         		Me, Me
    243 A29
    Figure US20150322069A1-20151112-C00538
    Figure US20150322069A1-20151112-C00539
         		Me, Me
    244 A29
    Figure US20150322069A1-20151112-C00540
    Figure US20150322069A1-20151112-C00541
         		Me, Me
    245 A29
    Figure US20150322069A1-20151112-C00542
    Figure US20150322069A1-20151112-C00543
         		Me, Me
    246 A29
    Figure US20150322069A1-20151112-C00544
    Figure US20150322069A1-20151112-C00545
         		Me, Me
    247 A29
    Figure US20150322069A1-20151112-C00546
    Figure US20150322069A1-20151112-C00547
         		Me, Me
    248 A29
    Figure US20150322069A1-20151112-C00548
    Figure US20150322069A1-20151112-C00549
         		Me, Me
    249 A29
    Figure US20150322069A1-20151112-C00550
    Figure US20150322069A1-20151112-C00551
         		Me, Me
    250 A29
    Figure US20150322069A1-20151112-C00552
    Figure US20150322069A1-20151112-C00553
         		Me, Me
    251 A29
    Figure US20150322069A1-20151112-C00554
    Figure US20150322069A1-20151112-C00555
         		Me, Me
    252 A29
    Figure US20150322069A1-20151112-C00556
    Figure US20150322069A1-20151112-C00557
         		Me, Me
    253 A31
    Figure US20150322069A1-20151112-C00558
    Figure US20150322069A1-20151112-C00559
         		Me, Me
    254 A31
    Figure US20150322069A1-20151112-C00560
    Figure US20150322069A1-20151112-C00561
         		Me, Me
    255 A31
    Figure US20150322069A1-20151112-C00562
    Figure US20150322069A1-20151112-C00563
         		Me, Me
    256 A31
    Figure US20150322069A1-20151112-C00564
    Figure US20150322069A1-20151112-C00565
         		Me, Me
    257 A31
    Figure US20150322069A1-20151112-C00566
    Figure US20150322069A1-20151112-C00567
         		Me, Me
    258 A31
    Figure US20150322069A1-20151112-C00568
    Figure US20150322069A1-20151112-C00569
         		Me, Me
    259 A31
    Figure US20150322069A1-20151112-C00570
    Figure US20150322069A1-20151112-C00571
         		Me, Me
    260 A31
    Figure US20150322069A1-20151112-C00572
    Figure US20150322069A1-20151112-C00573
         		Me, Me
    261 A31
    Figure US20150322069A1-20151112-C00574
    Figure US20150322069A1-20151112-C00575
         		Me, Me
    262 A31
    Figure US20150322069A1-20151112-C00576
    Figure US20150322069A1-20151112-C00577
         		Me, Me
    263 A31
    Figure US20150322069A1-20151112-C00578
    Figure US20150322069A1-20151112-C00579
         		Me, Me
    264 A31
    Figure US20150322069A1-20151112-C00580
    Figure US20150322069A1-20151112-C00581
         		Me, Me
    265 A31
    Figure US20150322069A1-20151112-C00582
    Figure US20150322069A1-20151112-C00583
         		Me, Me
    266 A31
    Figure US20150322069A1-20151112-C00584
    Figure US20150322069A1-20151112-C00585
         		Me, Me
    267 A31
    Figure US20150322069A1-20151112-C00586
    Figure US20150322069A1-20151112-C00587
         		Me, Me
    268 A31
    Figure US20150322069A1-20151112-C00588
    Figure US20150322069A1-20151112-C00589
         		Me, Me
    269 A31
    Figure US20150322069A1-20151112-C00590
    Figure US20150322069A1-20151112-C00591
         		Me, Me
    270 A31
    Figure US20150322069A1-20151112-C00592
    Figure US20150322069A1-20151112-C00593
         		Me, Me
    271 A31
    Figure US20150322069A1-20151112-C00594
    Figure US20150322069A1-20151112-C00595
         		Me, Me
    272 A31
    Figure US20150322069A1-20151112-C00596
    Figure US20150322069A1-20151112-C00597
         		Me, Me
    273 A31
    Figure US20150322069A1-20151112-C00598
    Figure US20150322069A1-20151112-C00599
         		Me, Me
    274 A31
    Figure US20150322069A1-20151112-C00600
    Figure US20150322069A1-20151112-C00601
         		Me, Me
    275 A31
    Figure US20150322069A1-20151112-C00602
    Figure US20150322069A1-20151112-C00603
         		Me, Me
    276 A31
    Figure US20150322069A1-20151112-C00604
    Figure US20150322069A1-20151112-C00605
         		Me, Me
    277 A31
    Figure US20150322069A1-20151112-C00606
    Figure US20150322069A1-20151112-C00607
         		Me, Me
    278 A31
    Figure US20150322069A1-20151112-C00608
    Figure US20150322069A1-20151112-C00609
         		Me, Me
    279 A31
    Figure US20150322069A1-20151112-C00610
    Figure US20150322069A1-20151112-C00611
         		Me, Me
    280 A31
    Figure US20150322069A1-20151112-C00612
    Figure US20150322069A1-20151112-C00613
         		Me, Me
    281 A31
    Figure US20150322069A1-20151112-C00614
    Figure US20150322069A1-20151112-C00615
         		Me, Me
    282 A31
    Figure US20150322069A1-20151112-C00616
    Figure US20150322069A1-20151112-C00617
         		Me, Me
    283 A31
    Figure US20150322069A1-20151112-C00618
    Figure US20150322069A1-20151112-C00619
         		Me, Me
    284 A31
    Figure US20150322069A1-20151112-C00620
    Figure US20150322069A1-20151112-C00621
         		Me, Me
    285 A31
    Figure US20150322069A1-20151112-C00622
    Figure US20150322069A1-20151112-C00623
         		Me, Me
    286 A31
    Figure US20150322069A1-20151112-C00624
    Figure US20150322069A1-20151112-C00625
         		Me, Me
    287 A31
    Figure US20150322069A1-20151112-C00626
    Figure US20150322069A1-20151112-C00627
         		Me, Me
    288 A31
    Figure US20150322069A1-20151112-C00628
    Figure US20150322069A1-20151112-C00629
         		Me, Me
    289 A31
    Figure US20150322069A1-20151112-C00630
    Figure US20150322069A1-20151112-C00631
         		Me, Me
    290 A31
    Figure US20150322069A1-20151112-C00632
    Figure US20150322069A1-20151112-C00633
         		Me, Me
    291 A31
    Figure US20150322069A1-20151112-C00634
    Figure US20150322069A1-20151112-C00635
         		Me, Me
    292 A31
    Figure US20150322069A1-20151112-C00636
    Figure US20150322069A1-20151112-C00637
         		Me, Me
    293 A31
    Figure US20150322069A1-20151112-C00638
    Figure US20150322069A1-20151112-C00639
         		Me, Me
    294 A31
    Figure US20150322069A1-20151112-C00640
    Figure US20150322069A1-20151112-C00641
         		Me, Me
    295 A31
    Figure US20150322069A1-20151112-C00642
    Figure US20150322069A1-20151112-C00643
         		Me, Me
    296 A31
    Figure US20150322069A1-20151112-C00644
    Figure US20150322069A1-20151112-C00645
         		Me, Me
    297 A31
    Figure US20150322069A1-20151112-C00646
    Figure US20150322069A1-20151112-C00647
         		Me, Me
    298 A31
    Figure US20150322069A1-20151112-C00648
    Figure US20150322069A1-20151112-C00649
         		Me, Me
    299 A31
    Figure US20150322069A1-20151112-C00650
    Figure US20150322069A1-20151112-C00651
         		Me, Me
    300 A31
    Figure US20150322069A1-20151112-C00652
    Figure US20150322069A1-20151112-C00653
         		Me, Me
    301 A31
    Figure US20150322069A1-20151112-C00654
    Figure US20150322069A1-20151112-C00655
         		Me, Me
    302 A31
    Figure US20150322069A1-20151112-C00656
    Figure US20150322069A1-20151112-C00657
         		Me, Me
    303 A31
    Figure US20150322069A1-20151112-C00658
    Figure US20150322069A1-20151112-C00659
         		Me, Me
    304 A31
    Figure US20150322069A1-20151112-C00660
    Figure US20150322069A1-20151112-C00661
         		Me, Me
    305 A31
    Figure US20150322069A1-20151112-C00662
    Figure US20150322069A1-20151112-C00663
         		Me, Me
    306 A31
    Figure US20150322069A1-20151112-C00664
    Figure US20150322069A1-20151112-C00665
         		Me, Me
    307 A31
    Figure US20150322069A1-20151112-C00666
    Figure US20150322069A1-20151112-C00667
         		Me, Me
    308 A31
    Figure US20150322069A1-20151112-C00668
    Figure US20150322069A1-20151112-C00669
         		Me, Me
    309 A31
    Figure US20150322069A1-20151112-C00670
    Figure US20150322069A1-20151112-C00671
         		Me, Me
    310 A31
    Figure US20150322069A1-20151112-C00672
    Figure US20150322069A1-20151112-C00673
         		Me, Me
    311 A31
    Figure US20150322069A1-20151112-C00674
    Figure US20150322069A1-20151112-C00675
         		Me, Me
    312 A31
    Figure US20150322069A1-20151112-C00676
    Figure US20150322069A1-20151112-C00677
         		Me, Me
    313 A31
    Figure US20150322069A1-20151112-C00678
    Figure US20150322069A1-20151112-C00679
         		Me, Me
    314 A31
    Figure US20150322069A1-20151112-C00680
    Figure US20150322069A1-20151112-C00681
         		Me, Me
    315 A31
    Figure US20150322069A1-20151112-C00682
    Figure US20150322069A1-20151112-C00683
         		Me, Me
    316 A31
    Figure US20150322069A1-20151112-C00684
    Figure US20150322069A1-20151112-C00685
         		Me, Me
    317 A31
    Figure US20150322069A1-20151112-C00686
    Figure US20150322069A1-20151112-C00687
         		Me, Me
    318 A31
    Figure US20150322069A1-20151112-C00688
    Figure US20150322069A1-20151112-C00689
         		Me, Me
    319 A31
    Figure US20150322069A1-20151112-C00690
    Figure US20150322069A1-20151112-C00691
         		Me, Me
    320 A31
    Figure US20150322069A1-20151112-C00692
    Figure US20150322069A1-20151112-C00693
         		Me, Me
    321 A31
    Figure US20150322069A1-20151112-C00694
    Figure US20150322069A1-20151112-C00695
         		Me, Me
    322 A31
    Figure US20150322069A1-20151112-C00696
    Figure US20150322069A1-20151112-C00697
         		Me, Me
    323 A31
    Figure US20150322069A1-20151112-C00698
    Figure US20150322069A1-20151112-C00699
         		Me, Me
    324 A31
    Figure US20150322069A1-20151112-C00700
    Figure US20150322069A1-20151112-C00701
         		Me, Me
    325 A31
    Figure US20150322069A1-20151112-C00702
    Figure US20150322069A1-20151112-C00703
         		Me, Me
    326 A31
    Figure US20150322069A1-20151112-C00704
    Figure US20150322069A1-20151112-C00705
         		Me, Me
    327 A31
    Figure US20150322069A1-20151112-C00706
    Figure US20150322069A1-20151112-C00707
         		Me, Me
    328 A31
    Figure US20150322069A1-20151112-C00708
    Figure US20150322069A1-20151112-C00709
         		Me, Me
    329 A31
    Figure US20150322069A1-20151112-C00710
    Figure US20150322069A1-20151112-C00711
         		Me, Me
    330 A31
    Figure US20150322069A1-20151112-C00712
    Figure US20150322069A1-20151112-C00713
         		Me, Me
    331 A31
    Figure US20150322069A1-20151112-C00714
    Figure US20150322069A1-20151112-C00715
         		Me, Me
    332 A31
    Figure US20150322069A1-20151112-C00716
    Figure US20150322069A1-20151112-C00717
         		Me, Me
    333 A31
    Figure US20150322069A1-20151112-C00718
    Figure US20150322069A1-20151112-C00719
         		Me, Me
    334 A31
    Figure US20150322069A1-20151112-C00720
    Figure US20150322069A1-20151112-C00721
         		Me, Me
    335 A31
    Figure US20150322069A1-20151112-C00722
    Figure US20150322069A1-20151112-C00723
         		Me, Me
    336 A31
    Figure US20150322069A1-20151112-C00724
    Figure US20150322069A1-20151112-C00725
         		Me, Me
    337 A31
    Figure US20150322069A1-20151112-C00726
    Figure US20150322069A1-20151112-C00727
         		Me, Me
    338 A31
    Figure US20150322069A1-20151112-C00728
    Figure US20150322069A1-20151112-C00729
         		Me, Me
    339 A31
    Figure US20150322069A1-20151112-C00730
    Figure US20150322069A1-20151112-C00731
         		Me, Me
    340 A31
    Figure US20150322069A1-20151112-C00732
    Figure US20150322069A1-20151112-C00733
         		Me
    341 A31
    Figure US20150322069A1-20151112-C00734
    Figure US20150322069A1-20151112-C00735
         		Me, Me
    342 A31
    Figure US20150322069A1-20151112-C00736
    Figure US20150322069A1-20151112-C00737
         		Me, Me
    343 A31
    Figure US20150322069A1-20151112-C00738
    Figure US20150322069A1-20151112-C00739
         		Me, Me
    344 A31
    Figure US20150322069A1-20151112-C00740
    Figure US20150322069A1-20151112-C00741
         		Me, Me
    345 A31
    Figure US20150322069A1-20151112-C00742
    Figure US20150322069A1-20151112-C00743
         		Me, Me
    346 A31
    Figure US20150322069A1-20151112-C00744
    Figure US20150322069A1-20151112-C00745
         		Me, Me
    347 A31
    Figure US20150322069A1-20151112-C00746
    Figure US20150322069A1-20151112-C00747
         		Me, Me
    348 A31
    Figure US20150322069A1-20151112-C00748
    Figure US20150322069A1-20151112-C00749
         		Me, Me
    349 A31
    Figure US20150322069A1-20151112-C00750
    Figure US20150322069A1-20151112-C00751
         		Me, Me
    350 A31
    Figure US20150322069A1-20151112-C00752
    Figure US20150322069A1-20151112-C00753
         		Me, Me
    351 A31
    Figure US20150322069A1-20151112-C00754
    Figure US20150322069A1-20151112-C00755
         		Me, Me
    352 A31
    Figure US20150322069A1-20151112-C00756
    Figure US20150322069A1-20151112-C00757
         		Me, Me
    353 A31
    Figure US20150322069A1-20151112-C00758
    Figure US20150322069A1-20151112-C00759
         		Me, Me
    354 A31
    Figure US20150322069A1-20151112-C00760
    Figure US20150322069A1-20151112-C00761
         		Me, Me
    355 A31
    Figure US20150322069A1-20151112-C00762
    Figure US20150322069A1-20151112-C00763
         		Me, Me
    356 A31
    Figure US20150322069A1-20151112-C00764
    Figure US20150322069A1-20151112-C00765
         		Me, Me
    357 A31
    Figure US20150322069A1-20151112-C00766
    Figure US20150322069A1-20151112-C00767
         		Me, Me
    358 A31
    Figure US20150322069A1-20151112-C00768
    Figure US20150322069A1-20151112-C00769
         		Me, Me
    359 A31
    Figure US20150322069A1-20151112-C00770
    Figure US20150322069A1-20151112-C00771
         		Me, Me
    360 A31
    Figure US20150322069A1-20151112-C00772
    Figure US20150322069A1-20151112-C00773
         		Me, Me
    361 A31
    Figure US20150322069A1-20151112-C00774
    Figure US20150322069A1-20151112-C00775
         		Me, Me
    362 A31
    Figure US20150322069A1-20151112-C00776
    Figure US20150322069A1-20151112-C00777
         		Me, Me
    363 A31
    Figure US20150322069A1-20151112-C00778
    Figure US20150322069A1-20151112-C00779
         		Me, Me
    364 A31
    Figure US20150322069A1-20151112-C00780
    Figure US20150322069A1-20151112-C00781
         		Me, Me
    365 A31
    Figure US20150322069A1-20151112-C00782
    Figure US20150322069A1-20151112-C00783
         		Me, Me
    366 A31
    Figure US20150322069A1-20151112-C00784
    Figure US20150322069A1-20151112-C00785
         		Me, Me
    367 A31
    Figure US20150322069A1-20151112-C00786
    Figure US20150322069A1-20151112-C00787
         		Me, Me
    368 A31
    Figure US20150322069A1-20151112-C00788
    Figure US20150322069A1-20151112-C00789
         		Me, Me
    369 A31
    Figure US20150322069A1-20151112-C00790
    Figure US20150322069A1-20151112-C00791
         		Me, Me
    370 A31
    Figure US20150322069A1-20151112-C00792
    Figure US20150322069A1-20151112-C00793
         		Me, Me
    371 A31
    Figure US20150322069A1-20151112-C00794
    Figure US20150322069A1-20151112-C00795
         		Me, Me
    372 A31
    Figure US20150322069A1-20151112-C00796
    Figure US20150322069A1-20151112-C00797
         		Me, Me
    373 A31
    Figure US20150322069A1-20151112-C00798
    Figure US20150322069A1-20151112-C00799
         		Me, Me
    374 A31
    Figure US20150322069A1-20151112-C00800
    Figure US20150322069A1-20151112-C00801
         		Me, Me
    375 A31
    Figure US20150322069A1-20151112-C00802
    Figure US20150322069A1-20151112-C00803
         		Me, Me
    376 A31
    Figure US20150322069A1-20151112-C00804
    Figure US20150322069A1-20151112-C00805
         		Me, Me
    377 A31
    Figure US20150322069A1-20151112-C00806
    Figure US20150322069A1-20151112-C00807
         		Me, Me
    378 A31
    Figure US20150322069A1-20151112-C00808
    Figure US20150322069A1-20151112-C00809
         		Me, Me
    379 A31
    Figure US20150322069A1-20151112-C00810
    Figure US20150322069A1-20151112-C00811
         		Me, Me
    380 A31
    Figure US20150322069A1-20151112-C00812
    Figure US20150322069A1-20151112-C00813
         		Me, Me
    381 A31
    Figure US20150322069A1-20151112-C00814
    Figure US20150322069A1-20151112-C00815
         		Me, Me
    382 A31
    Figure US20150322069A1-20151112-C00816
    Figure US20150322069A1-20151112-C00817
         		Me, Me
    383 A31
    Figure US20150322069A1-20151112-C00818
    Figure US20150322069A1-20151112-C00819
         		Me, Me
    384 A31
    Figure US20150322069A1-20151112-C00820
    Figure US20150322069A1-20151112-C00821
         		Me, Me
    385 A31
    Figure US20150322069A1-20151112-C00822
    Figure US20150322069A1-20151112-C00823
         		Me, Me
    386 A31
    Figure US20150322069A1-20151112-C00824
    Figure US20150322069A1-20151112-C00825
         		Me, Me
    387 A31
    Figure US20150322069A1-20151112-C00826
    Figure US20150322069A1-20151112-C00827
         		Me, Me
    388 A31
    Figure US20150322069A1-20151112-C00828
    Figure US20150322069A1-20151112-C00829
         		Me, Me
    389 A31
    Figure US20150322069A1-20151112-C00830
    Figure US20150322069A1-20151112-C00831
         		Me, Me
    390 A31
    Figure US20150322069A1-20151112-C00832
    Figure US20150322069A1-20151112-C00833
         		Me, Me
    391 A31
    Figure US20150322069A1-20151112-C00834
    Figure US20150322069A1-20151112-C00835
         		Me, Me
    392 A31
    Figure US20150322069A1-20151112-C00836
    Figure US20150322069A1-20151112-C00837
         		Me, Me
    393 A31
    Figure US20150322069A1-20151112-C00838
    Figure US20150322069A1-20151112-C00839
         		Me, Me
    394 A31
    Figure US20150322069A1-20151112-C00840
    Figure US20150322069A1-20151112-C00841
         		Me, Me
    395 A31
    Figure US20150322069A1-20151112-C00842
    Figure US20150322069A1-20151112-C00843
         		Me, Me
    396 A31
    Figure US20150322069A1-20151112-C00844
    Figure US20150322069A1-20151112-C00845
         		Me, Me
    397 A31
    Figure US20150322069A1-20151112-C00846
    Figure US20150322069A1-20151112-C00847
         		Me, Me
    398 A31
    Figure US20150322069A1-20151112-C00848
    Figure US20150322069A1-20151112-C00849
         		Me, Me
    399 A31
    Figure US20150322069A1-20151112-C00850
    Figure US20150322069A1-20151112-C00851
         		Me, Me
    400 A31
    Figure US20150322069A1-20151112-C00852
    Figure US20150322069A1-20151112-C00853
         		Me, Me
    401 A31
    Figure US20150322069A1-20151112-C00854
    Figure US20150322069A1-20151112-C00855
         		Me, Me
    402 A31
    Figure US20150322069A1-20151112-C00856
    Figure US20150322069A1-20151112-C00857
         		Me, Me
    403 A31
    Figure US20150322069A1-20151112-C00858
    Figure US20150322069A1-20151112-C00859
         		Me, Me
    404 A31
    Figure US20150322069A1-20151112-C00860
    Figure US20150322069A1-20151112-C00861
         		Me, Me
    405 A31
    Figure US20150322069A1-20151112-C00862
    Figure US20150322069A1-20151112-C00863
         		Me, Me
    406 A31
    Figure US20150322069A1-20151112-C00864
    Figure US20150322069A1-20151112-C00865
         		Me, Me
    407 A31
    Figure US20150322069A1-20151112-C00866
    Figure US20150322069A1-20151112-C00867
         		Me, Me
    408 A31
    Figure US20150322069A1-20151112-C00868
    Figure US20150322069A1-20151112-C00869
         		Me, Me
    409 A31
    Figure US20150322069A1-20151112-C00870
    Figure US20150322069A1-20151112-C00871
         		Me, Me
    410 A31
    Figure US20150322069A1-20151112-C00872
    Figure US20150322069A1-20151112-C00873
         		Me, Me
    411 A31
    Figure US20150322069A1-20151112-C00874
    Figure US20150322069A1-20151112-C00875
         		Me, Me
    412 A31
    Figure US20150322069A1-20151112-C00876
    Figure US20150322069A1-20151112-C00877
         		Me, Me
    413 A31
    Figure US20150322069A1-20151112-C00878
    Figure US20150322069A1-20151112-C00879
         		Me, Me
    414 A31
    Figure US20150322069A1-20151112-C00880
    Figure US20150322069A1-20151112-C00881
         		Me, Me
    415 A31
    Figure US20150322069A1-20151112-C00882
    Figure US20150322069A1-20151112-C00883
         		Me, Me
    416 A31
    Figure US20150322069A1-20151112-C00884
    Figure US20150322069A1-20151112-C00885
         		Me, Me
    417 A31
    Figure US20150322069A1-20151112-C00886
    Figure US20150322069A1-20151112-C00887
         		Me, Me
    418 A31
    Figure US20150322069A1-20151112-C00888
    Figure US20150322069A1-20151112-C00889
         		Me, Me
    419 A31
    Figure US20150322069A1-20151112-C00890
    Figure US20150322069A1-20151112-C00891
         		Me, Me
    420 A31
    Figure US20150322069A1-20151112-C00892
    Figure US20150322069A1-20151112-C00893
         		Me, Me
    421 A31
    Figure US20150322069A1-20151112-C00894
    Figure US20150322069A1-20151112-C00895
         		Me, Me
    422 A31
    Figure US20150322069A1-20151112-C00896
    Figure US20150322069A1-20151112-C00897
         		Me, Me
    423 A31
    Figure US20150322069A1-20151112-C00898
    Figure US20150322069A1-20151112-C00899
         		Me, Me
    424 A31
    Figure US20150322069A1-20151112-C00900
    Figure US20150322069A1-20151112-C00901
         		Me, Me
    425 A31
    Figure US20150322069A1-20151112-C00902
    Figure US20150322069A1-20151112-C00903
         		Me, Me
    426 A31
    Figure US20150322069A1-20151112-C00904
    Figure US20150322069A1-20151112-C00905
         		Me, Me
    427 A31
    Figure US20150322069A1-20151112-C00906
    Figure US20150322069A1-20151112-C00907
         		Me, Me
    428 A31
    Figure US20150322069A1-20151112-C00908
    Figure US20150322069A1-20151112-C00909
         		Me, Me
    429 A31
    Figure US20150322069A1-20151112-C00910
    Figure US20150322069A1-20151112-C00911
         		Me, Me
    430 A31
    Figure US20150322069A1-20151112-C00912
    Figure US20150322069A1-20151112-C00913
         		Me, Me
    431 A31
    Figure US20150322069A1-20151112-C00914
    Figure US20150322069A1-20151112-C00915
         		Me, Me
    432 A31
    Figure US20150322069A1-20151112-C00916
    Figure US20150322069A1-20151112-C00917
         		Me, Me
    433 A31
    Figure US20150322069A1-20151112-C00918
    Figure US20150322069A1-20151112-C00919
         		Me, Me
    434 A31
    Figure US20150322069A1-20151112-C00920
    Figure US20150322069A1-20151112-C00921
         		Me, Me
    435 A31
    Figure US20150322069A1-20151112-C00922
    Figure US20150322069A1-20151112-C00923
         		Me, Me
    436 A31
    Figure US20150322069A1-20151112-C00924
    Figure US20150322069A1-20151112-C00925
         		Me, Me
    437 A31
    Figure US20150322069A1-20151112-C00926
    Figure US20150322069A1-20151112-C00927
         		Me, Me
    438 A31
    Figure US20150322069A1-20151112-C00928
    Figure US20150322069A1-20151112-C00929
         		Me, Me
    439 A31
    Figure US20150322069A1-20151112-C00930
    Figure US20150322069A1-20151112-C00931
         		Me, Me
    440 A31
    Figure US20150322069A1-20151112-C00932
    Figure US20150322069A1-20151112-C00933
         		Me, Me
    441 A31
    Figure US20150322069A1-20151112-C00934
    Figure US20150322069A1-20151112-C00935
         		Me, Me
    442 A31
    Figure US20150322069A1-20151112-C00936
    Figure US20150322069A1-20151112-C00937
         		Me, Me
    443 A31
    Figure US20150322069A1-20151112-C00938
    Figure US20150322069A1-20151112-C00939
         		Me, Me
    444 A31
    Figure US20150322069A1-20151112-C00940
    Figure US20150322069A1-20151112-C00941
         		Me, Me
    445 A31
    Figure US20150322069A1-20151112-C00942
    Figure US20150322069A1-20151112-C00943
         		Me, Me
    446 A31
    Figure US20150322069A1-20151112-C00944
    Figure US20150322069A1-20151112-C00945
         		Me, Me
    447 A31
    Figure US20150322069A1-20151112-C00946
    Figure US20150322069A1-20151112-C00947
         		Me, Me
    448 A31
    Figure US20150322069A1-20151112-C00948
    Figure US20150322069A1-20151112-C00949
         		Me, Me
    449 A31
    Figure US20150322069A1-20151112-C00950
    Figure US20150322069A1-20151112-C00951
         		Me, Me
    450 A31
    Figure US20150322069A1-20151112-C00952
    Figure US20150322069A1-20151112-C00953
         		Me, Me
    451 A31
    Figure US20150322069A1-20151112-C00954
    Figure US20150322069A1-20151112-C00955
         		Me, Me
    452 A31
    Figure US20150322069A1-20151112-C00956
    Figure US20150322069A1-20151112-C00957
         		Me, Me
    453 A31
    Figure US20150322069A1-20151112-C00958
    Figure US20150322069A1-20151112-C00959
         		Me, Me
    454 A31
    Figure US20150322069A1-20151112-C00960
    Figure US20150322069A1-20151112-C00961
         		Me, Me
    455 A31
    Figure US20150322069A1-20151112-C00962
    Figure US20150322069A1-20151112-C00963
         		Me, Me
    456 A31
    Figure US20150322069A1-20151112-C00964
    Figure US20150322069A1-20151112-C00965
         		Me, Me
    457 A31
    Figure US20150322069A1-20151112-C00966
    Figure US20150322069A1-20151112-C00967
         		Me, Me
    458 A31
    Figure US20150322069A1-20151112-C00968
    Figure US20150322069A1-20151112-C00969
         		Me, Me
    459 A31
    Figure US20150322069A1-20151112-C00970
    Figure US20150322069A1-20151112-C00971
         		Me, Me
    460 A31
    Figure US20150322069A1-20151112-C00972
    Figure US20150322069A1-20151112-C00973
         		Me, Me
    461 A31
    Figure US20150322069A1-20151112-C00974
    Figure US20150322069A1-20151112-C00975
         		Me, Me
    462 A31
    Figure US20150322069A1-20151112-C00976
    Figure US20150322069A1-20151112-C00977
         		Me, Me
    463 A31
    Figure US20150322069A1-20151112-C00978
    Figure US20150322069A1-20151112-C00979
         		Me, Me
    464 A31
    Figure US20150322069A1-20151112-C00980
    Figure US20150322069A1-20151112-C00981
         		Me, Me
    465 A31
    Figure US20150322069A1-20151112-C00982
    Figure US20150322069A1-20151112-C00983
         		Me, Me
    466 A31
    Figure US20150322069A1-20151112-C00984
    Figure US20150322069A1-20151112-C00985
         		Me, Me
    467 A31
    Figure US20150322069A1-20151112-C00986
    Figure US20150322069A1-20151112-C00987
         		Me, Me
    468 A31
    Figure US20150322069A1-20151112-C00988
    Figure US20150322069A1-20151112-C00989
         		Me, Me
    469 A31
    Figure US20150322069A1-20151112-C00990
    Figure US20150322069A1-20151112-C00991
         		Me, Me
    470 A31
    Figure US20150322069A1-20151112-C00992
    Figure US20150322069A1-20151112-C00993
         		Me, Me
    471 A31
    Figure US20150322069A1-20151112-C00994
    Figure US20150322069A1-20151112-C00995
         		Me, Me
    472 A31
    Figure US20150322069A1-20151112-C00996
    Figure US20150322069A1-20151112-C00997
         		Me, Me
    473 A31
    Figure US20150322069A1-20151112-C00998
    Figure US20150322069A1-20151112-C00999
         		Me, Me
    474 A31
    Figure US20150322069A1-20151112-C01000
    Figure US20150322069A1-20151112-C01001
         		Me, Me
    475 A31
    Figure US20150322069A1-20151112-C01002
    Figure US20150322069A1-20151112-C01003
         		Me, Me
    476 A31
    Figure US20150322069A1-20151112-C01004
    Figure US20150322069A1-20151112-C01005
         		Me, Me
    477 A31
    Figure US20150322069A1-20151112-C01006
    Figure US20150322069A1-20151112-C01007
         		Me, Me
    478 A31
    Figure US20150322069A1-20151112-C01008
    Figure US20150322069A1-20151112-C01009
         		Me, Me
    479 A31
    Figure US20150322069A1-20151112-C01010
    Figure US20150322069A1-20151112-C01011
         		Me, Me
    480 A31
    Figure US20150322069A1-20151112-C01012
    Figure US20150322069A1-20151112-C01013
         		Me, Me
    481 A31
    Figure US20150322069A1-20151112-C01014
    Figure US20150322069A1-20151112-C01015
         		Me, Me
    482 A31
    Figure US20150322069A1-20151112-C01016
    Figure US20150322069A1-20151112-C01017
         		Me, Me
    483 A31
    Figure US20150322069A1-20151112-C01018
    Figure US20150322069A1-20151112-C01019
         		Me, Me
    484 A31
    Figure US20150322069A1-20151112-C01020
    Figure US20150322069A1-20151112-C01021
         		Me, Me
    485 A31
    Figure US20150322069A1-20151112-C01022
    Figure US20150322069A1-20151112-C01023
         		Me, Me
    486 A31
    Figure US20150322069A1-20151112-C01024
    Figure US20150322069A1-20151112-C01025
         		Me, Me
    487 A31
    Figure US20150322069A1-20151112-C01026
    Figure US20150322069A1-20151112-C01027
         		Me, Me
    488 A31
    Figure US20150322069A1-20151112-C01028
    Figure US20150322069A1-20151112-C01029
         		Me, Me
    489 A31
    Figure US20150322069A1-20151112-C01030
    Figure US20150322069A1-20151112-C01031
         		Me, Me
    490 A31
    Figure US20150322069A1-20151112-C01032
    Figure US20150322069A1-20151112-C01033
         		Me, Me
    491 A31
    Figure US20150322069A1-20151112-C01034
    Figure US20150322069A1-20151112-C01035
         		Me, Me
    492 A31
    Figure US20150322069A1-20151112-C01036
    Figure US20150322069A1-20151112-C01037
         		Me, Me
    493 A29
    Figure US20150322069A1-20151112-C01038
    Figure US20150322069A1-20151112-C01039
         		--cyclopropyl--
    494 A29
    Figure US20150322069A1-20151112-C01040
    Figure US20150322069A1-20151112-C01041
         		--cyclopropyl--
    495 A29
    Figure US20150322069A1-20151112-C01042
    Figure US20150322069A1-20151112-C01043
         		--cyclopropyl--
    496 A29
    Figure US20150322069A1-20151112-C01044
    Figure US20150322069A1-20151112-C01045
         		--cyclopropyl--
    497 A29
    Figure US20150322069A1-20151112-C01046
    Figure US20150322069A1-20151112-C01047
         		--cyclopropyl--
    498 A29
    Figure US20150322069A1-20151112-C01048
    Figure US20150322069A1-20151112-C01049
         		--cyclopropyl--
    499 A29
    Figure US20150322069A1-20151112-C01050
    Figure US20150322069A1-20151112-C01051
         		--cyclopropyl--
    500 A29
    Figure US20150322069A1-20151112-C01052
    Figure US20150322069A1-20151112-C01053
         		--cyclopropyl--
    501 A29
    Figure US20150322069A1-20151112-C01054
    Figure US20150322069A1-20151112-C01055
         		--cyclopropyl--
    502 A29
    Figure US20150322069A1-20151112-C01056
    Figure US20150322069A1-20151112-C01057
         		--cyclopropyl--
    503 A29
    Figure US20150322069A1-20151112-C01058
    Figure US20150322069A1-20151112-C01059
         		--cyclopropyl--
    504 A29
    Figure US20150322069A1-20151112-C01060
    Figure US20150322069A1-20151112-C01061
         		--cyclopropyl--
    505 A29
    Figure US20150322069A1-20151112-C01062
    Figure US20150322069A1-20151112-C01063
         		--cyclopropyl--
    506 A29
    Figure US20150322069A1-20151112-C01064
    Figure US20150322069A1-20151112-C01065
         		--cyclopropyl--
    507 A29
    Figure US20150322069A1-20151112-C01066
    Figure US20150322069A1-20151112-C01067
         		--cyclopropyl--
    508 A29
    Figure US20150322069A1-20151112-C01068
    Figure US20150322069A1-20151112-C01069
         		--cyclopropyl--
    509 A29
    Figure US20150322069A1-20151112-C01070
    Figure US20150322069A1-20151112-C01071
         		--cyclopropyl--
    510 A29
    Figure US20150322069A1-20151112-C01072
    Figure US20150322069A1-20151112-C01073
         		--cyclopropyl--
    511 A29
    Figure US20150322069A1-20151112-C01074
    Figure US20150322069A1-20151112-C01075
         		--cyclopropyl--
    512 A29
    Figure US20150322069A1-20151112-C01076
    Figure US20150322069A1-20151112-C01077
         		--cyclopropyl-
    513 A29
    Figure US20150322069A1-20151112-C01078
    Figure US20150322069A1-20151112-C01079
         		--cyclopropyl--
    514 A29
    Figure US20150322069A1-20151112-C01080
    Figure US20150322069A1-20151112-C01081
         		--cyclopropyl--
    515 A29
    Figure US20150322069A1-20151112-C01082
    Figure US20150322069A1-20151112-C01083
         		--cyclopropyl--
    516 A29
    Figure US20150322069A1-20151112-C01084
    Figure US20150322069A1-20151112-C01085
         		--cyclopropyl--
    517 A29
    Figure US20150322069A1-20151112-C01086
    Figure US20150322069A1-20151112-C01087
         		--cyclopropyl--
    518 A29
    Figure US20150322069A1-20151112-C01088
    Figure US20150322069A1-20151112-C01089
         		--cyclopropyl--
    519 A29
    Figure US20150322069A1-20151112-C01090
    Figure US20150322069A1-20151112-C01091
         		--cyclopropyl--
    520 A29
    Figure US20150322069A1-20151112-C01092
    Figure US20150322069A1-20151112-C01093
         		--cyclopropyl--
    521 A29
    Figure US20150322069A1-20151112-C01094
    Figure US20150322069A1-20151112-C01095
         		--cyclopropyl--
    522 A29
    Figure US20150322069A1-20151112-C01096
    Figure US20150322069A1-20151112-C01097
         		--cyclopropyl--
    523 A29
    Figure US20150322069A1-20151112-C01098
    Figure US20150322069A1-20151112-C01099
         		--cyclopropyl--
    524 A29
    Figure US20150322069A1-20151112-C01100
    Figure US20150322069A1-20151112-C01101
         		--cyclopropyl--
    525 A29
    Figure US20150322069A1-20151112-C01102
    Figure US20150322069A1-20151112-C01103
         		--cyclopropyl--
    526 A29
    Figure US20150322069A1-20151112-C01104
    Figure US20150322069A1-20151112-C01105
         		--cyclopropyl--
    527 A29
    Figure US20150322069A1-20151112-C01106
    Figure US20150322069A1-20151112-C01107
         		--cyclopropyl--
    528 A29
    Figure US20150322069A1-20151112-C01108
    Figure US20150322069A1-20151112-C01109
         		--cyclopropyl--
    529 A29
    Figure US20150322069A1-20151112-C01110
    Figure US20150322069A1-20151112-C01111
         		--cyclopropyl--
    530 A29
    Figure US20150322069A1-20151112-C01112
    Figure US20150322069A1-20151112-C01113
         		--cyclopropyl--
    531 A29
    Figure US20150322069A1-20151112-C01114
    Figure US20150322069A1-20151112-C01115
         		--cyclopropyl--
    532 A29
    Figure US20150322069A1-20151112-C01116
    Figure US20150322069A1-20151112-C01117
         		--cyclopropyl--
    533 A29
    Figure US20150322069A1-20151112-C01118
    Figure US20150322069A1-20151112-C01119
         		--cyclopropyl--
    534 A29
    Figure US20150322069A1-20151112-C01120
    Figure US20150322069A1-20151112-C01121
         		--cyclopropyl--
    535 A29
    Figure US20150322069A1-20151112-C01122
    Figure US20150322069A1-20151112-C01123
         		--cyclopropyl--
    536 A29
    Figure US20150322069A1-20151112-C01124
    Figure US20150322069A1-20151112-C01125
         		--cyclopropyl--
    537 A29
    Figure US20150322069A1-20151112-C01126
    Figure US20150322069A1-20151112-C01127
         		--cyclopropyl--
    538 A29
    Figure US20150322069A1-20151112-C01128
    Figure US20150322069A1-20151112-C01129
         		--cyclopropyl--
    539 A29
    Figure US20150322069A1-20151112-C01130
    Figure US20150322069A1-20151112-C01131
         		--cyclopropyl--
    540 A29
    Figure US20150322069A1-20151112-C01132
    Figure US20150322069A1-20151112-C01133
         		--cyclopropyl--
    541 A29
    Figure US20150322069A1-20151112-C01134
    Figure US20150322069A1-20151112-C01135
         		--cyclopropyl--
    542 A29
    Figure US20150322069A1-20151112-C01136
    Figure US20150322069A1-20151112-C01137
         		--cyclopropyl--
    543 A29
    Figure US20150322069A1-20151112-C01138
    Figure US20150322069A1-20151112-C01139
         		--cyclopropyl--
    544 A29
    Figure US20150322069A1-20151112-C01140
    Figure US20150322069A1-20151112-C01141
         		--cyclopropyl--
    545 A29
    Figure US20150322069A1-20151112-C01142
    Figure US20150322069A1-20151112-C01143
         		--cyclopropyl--
    546 A29
    Figure US20150322069A1-20151112-C01144
    Figure US20150322069A1-20151112-C01145
         		--cyclopropyl--
    547 A29
    Figure US20150322069A1-20151112-C01146
    Figure US20150322069A1-20151112-C01147
         		--cyclopropyl--
    548 A29
    Figure US20150322069A1-20151112-C01148
    Figure US20150322069A1-20151112-C01149
         		--cyclopropyl--
    549 A29
    Figure US20150322069A1-20151112-C01150
    Figure US20150322069A1-20151112-C01151
         		--cyclopropyl--
    550 A29
    Figure US20150322069A1-20151112-C01152
    Figure US20150322069A1-20151112-C01153
         		--cyclopropyl--
    551 A29
    Figure US20150322069A1-20151112-C01154
    Figure US20150322069A1-20151112-C01155
         		--cyclopropyl--
    552 A29
    Figure US20150322069A1-20151112-C01156
    Figure US20150322069A1-20151112-C01157
         		--cyclopropyl--
    553 A29
    Figure US20150322069A1-20151112-C01158
    Figure US20150322069A1-20151112-C01159
         		--cyclopropyl--
    554 A29
    Figure US20150322069A1-20151112-C01160
    Figure US20150322069A1-20151112-C01161
         		--cyclopropyl--
    555 A29
    Figure US20150322069A1-20151112-C01162
    Figure US20150322069A1-20151112-C01163
         		--cyclopropyl--
    556 A29
    Figure US20150322069A1-20151112-C01164
    Figure US20150322069A1-20151112-C01165
         		--cyclopropyl--
    557 A29
    Figure US20150322069A1-20151112-C01166
    Figure US20150322069A1-20151112-C01167
         		--cyclopropyl--
    558 A29
    Figure US20150322069A1-20151112-C01168
    Figure US20150322069A1-20151112-C01169
         		--cyclopropyl--
    559 A29
    Figure US20150322069A1-20151112-C01170
    Figure US20150322069A1-20151112-C01171
         		--cyclopropyl--
    560 A29
    Figure US20150322069A1-20151112-C01172
    Figure US20150322069A1-20151112-C01173
         		--cyclopropyl--
    561 A29
    Figure US20150322069A1-20151112-C01174
    Figure US20150322069A1-20151112-C01175
         		--cyclopropyl--
    562 A29
    Figure US20150322069A1-20151112-C01176
    Figure US20150322069A1-20151112-C01177
         		--cyclopropyl--
    563 A29
    Figure US20150322069A1-20151112-C01178
    Figure US20150322069A1-20151112-C01179
         		--cyclopropyl--
    564 A29
    Figure US20150322069A1-20151112-C01180
    Figure US20150322069A1-20151112-C01181
         		--cyclopropyl--
    565 A29
    Figure US20150322069A1-20151112-C01182
    Figure US20150322069A1-20151112-C01183
         		--cyclopropyl--
    566 A29
    Figure US20150322069A1-20151112-C01184
    Figure US20150322069A1-20151112-C01185
         		--cyclopropyl--
    567 A29
    Figure US20150322069A1-20151112-C01186
    Figure US20150322069A1-20151112-C01187
         		--cyclopropyl--
    568 A29
    Figure US20150322069A1-20151112-C01188
    Figure US20150322069A1-20151112-C01189
         		--cyclopropyl--
    569 A29
    Figure US20150322069A1-20151112-C01190
    Figure US20150322069A1-20151112-C01191
         		--cyclopropyl--
    570 A29
    Figure US20150322069A1-20151112-C01192
    Figure US20150322069A1-20151112-C01193
         		--cyclopropyl--
    571 A29
    Figure US20150322069A1-20151112-C01194
    Figure US20150322069A1-20151112-C01195
         		--cyclopropyl--
    572 A29
    Figure US20150322069A1-20151112-C01196
    Figure US20150322069A1-20151112-C01197
         		--cyclopropyl--
    573 A29
    Figure US20150322069A1-20151112-C01198
    Figure US20150322069A1-20151112-C01199
         		--cyclopropyl--
    574 A29
    Figure US20150322069A1-20151112-C01200
    Figure US20150322069A1-20151112-C01201
         		--cyclopropyl--
    575 A29
    Figure US20150322069A1-20151112-C01202
    Figure US20150322069A1-20151112-C01203
         		--cyclopropyl--
    576 A29
    Figure US20150322069A1-20151112-C01204
    Figure US20150322069A1-20151112-C01205
         		--cyclopropyl--
    577 A29
    Figure US20150322069A1-20151112-C01206
    Figure US20150322069A1-20151112-C01207
         		--cyclopropyl--
    578 A29
    Figure US20150322069A1-20151112-C01208
    Figure US20150322069A1-20151112-C01209
         		--cyclopropyl--
    579 A29
    Figure US20150322069A1-20151112-C01210
    Figure US20150322069A1-20151112-C01211
         		--cyclopropyl--
    580 A29
    Figure US20150322069A1-20151112-C01212
    Figure US20150322069A1-20151112-C01213
         		--cyclopropyl--
    581 A29
    Figure US20150322069A1-20151112-C01214
    Figure US20150322069A1-20151112-C01215
         		--cyclopropyl--
    582 A29
    Figure US20150322069A1-20151112-C01216
    Figure US20150322069A1-20151112-C01217
         		--cyclopropyl--
    583 A29
    Figure US20150322069A1-20151112-C01218
    Figure US20150322069A1-20151112-C01219
         		--cyclopropyl--
    584 A29
    Figure US20150322069A1-20151112-C01220
    Figure US20150322069A1-20151112-C01221
         		--cyclopropyl--
    585 A29
    Figure US20150322069A1-20151112-C01222
    Figure US20150322069A1-20151112-C01223
         		--cyclopropyl--
    586 A29
    Figure US20150322069A1-20151112-C01224
    Figure US20150322069A1-20151112-C01225
         		--cyclopropyl--
    587 A29
    Figure US20150322069A1-20151112-C01226
    Figure US20150322069A1-20151112-C01227
         		--cyclopropyl--
    588 A29
    Figure US20150322069A1-20151112-C01228
    Figure US20150322069A1-20151112-C01229
         		--cyclopropyl--
    589 A29
    Figure US20150322069A1-20151112-C01230
    Figure US20150322069A1-20151112-C01231
         		--cyclopropyl--
    590 A29
    Figure US20150322069A1-20151112-C01232
    Figure US20150322069A1-20151112-C01233
         		--cyclopropyl--
    591 A29
    Figure US20150322069A1-20151112-C01234
    Figure US20150322069A1-20151112-C01235
         		--cyclopropyl--
    592 A29
    Figure US20150322069A1-20151112-C01236
    Figure US20150322069A1-20151112-C01237
         		--cyclopropyl--
    593 A29
    Figure US20150322069A1-20151112-C01238
    Figure US20150322069A1-20151112-C01239
         		--cyclopropyl--
    594 A29
    Figure US20150322069A1-20151112-C01240
    Figure US20150322069A1-20151112-C01241
         		--cyclopropyl--
    595 A29
    Figure US20150322069A1-20151112-C01242
    Figure US20150322069A1-20151112-C01243
         		--cyclopropyl--
    596 A29
    Figure US20150322069A1-20151112-C01244
    Figure US20150322069A1-20151112-C01245
         		--cyclopropyl--
    597 A29
    Figure US20150322069A1-20151112-C01246
    Figure US20150322069A1-20151112-C01247
         		--cyclopropyl--
    598 A29
    Figure US20150322069A1-20151112-C01248
    Figure US20150322069A1-20151112-C01249
         		--cyclopropyl--
    599 A29
    Figure US20150322069A1-20151112-C01250
    Figure US20150322069A1-20151112-C01251
         		--cyclopropyl--
    600 A29
    Figure US20150322069A1-20151112-C01252
    Figure US20150322069A1-20151112-C01253
         		--cyclopropyl--
    601 A29
    Figure US20150322069A1-20151112-C01254
    Figure US20150322069A1-20151112-C01255
         		--cyclopropyl--
    602 A29
    Figure US20150322069A1-20151112-C01256
    Figure US20150322069A1-20151112-C01257
         		--cyclopropyl--
    603 A29
    Figure US20150322069A1-20151112-C01258
    Figure US20150322069A1-20151112-C01259
         		--cyclopropyl--
    604 A29
    Figure US20150322069A1-20151112-C01260
    Figure US20150322069A1-20151112-C01261
         		--cyclopropyl--
    605 A29
    Figure US20150322069A1-20151112-C01262
    Figure US20150322069A1-20151112-C01263
         		--cyclopropyl--
    606 A29
    Figure US20150322069A1-20151112-C01264
    Figure US20150322069A1-20151112-C01265
         		--cyclopropyl--
    607 A29
    Figure US20150322069A1-20151112-C01266
    Figure US20150322069A1-20151112-C01267
         		--cyclopropyl--
    608 A29
    Figure US20150322069A1-20151112-C01268
    Figure US20150322069A1-20151112-C01269
         		--cyclopropyl--
    609 A29
    Figure US20150322069A1-20151112-C01270
    Figure US20150322069A1-20151112-C01271
         		--cyclopropyl--
    610 A29
    Figure US20150322069A1-20151112-C01272
    Figure US20150322069A1-20151112-C01273
         		--cyclopropyl--
    611 A29
    Figure US20150322069A1-20151112-C01274
    Figure US20150322069A1-20151112-C01275
         		--cyclopropyl--
    612 A29
    Figure US20150322069A1-20151112-C01276
    Figure US20150322069A1-20151112-C01277
         		--cyclopropyl--
    613 A29
    Figure US20150322069A1-20151112-C01278
    Figure US20150322069A1-20151112-C01279
         		--cyclopropyl--
    614 A29
    Figure US20150322069A1-20151112-C01280
    Figure US20150322069A1-20151112-C01281
         		--cyclopropyl--
    615 A29
    Figure US20150322069A1-20151112-C01282
    Figure US20150322069A1-20151112-C01283
         		--cyclopropyl--
    616 A29
    Figure US20150322069A1-20151112-C01284
    Figure US20150322069A1-20151112-C01285
         		--cyclopropyl--
    617 A29
    Figure US20150322069A1-20151112-C01286
    Figure US20150322069A1-20151112-C01287
         		--cyclopropyl--
    618 A29
    Figure US20150322069A1-20151112-C01288
    Figure US20150322069A1-20151112-C01289
         		--cyclopropyl--
    619 A29
    Figure US20150322069A1-20151112-C01290
    Figure US20150322069A1-20151112-C01291
         		--cyclopropyl--
    620 A29
    Figure US20150322069A1-20151112-C01292
    Figure US20150322069A1-20151112-C01293
         		--cyclopropyl--
    621 A29
    Figure US20150322069A1-20151112-C01294
    Figure US20150322069A1-20151112-C01295
         		--cyclopropyl--
    622 A29
    Figure US20150322069A1-20151112-C01296
    Figure US20150322069A1-20151112-C01297
         		--cyclopropyl--
    623 A29
    Figure US20150322069A1-20151112-C01298
    Figure US20150322069A1-20151112-C01299
         		--cyclopropyl--
    624 A29
    Figure US20150322069A1-20151112-C01300
    Figure US20150322069A1-20151112-C01301
         		--cyclopropyl--
    625 A29
    Figure US20150322069A1-20151112-C01302
    Figure US20150322069A1-20151112-C01303
         		--cyclopropyl--
    626 A29
    Figure US20150322069A1-20151112-C01304
    Figure US20150322069A1-20151112-C01305
         		--cyclopropyl--
    627 A29
    Figure US20150322069A1-20151112-C01306
    Figure US20150322069A1-20151112-C01307
         		--cyclopropyl--
    628 A29
    Figure US20150322069A1-20151112-C01308
    Figure US20150322069A1-20151112-C01309
         		--cyclopropyl--
    629 A29
    Figure US20150322069A1-20151112-C01310
    Figure US20150322069A1-20151112-C01311
         		--cyclopropyl--
    630 A29
    Figure US20150322069A1-20151112-C01312
    Figure US20150322069A1-20151112-C01313
         		--cyclopropyl--
    631 A29
    Figure US20150322069A1-20151112-C01314
    Figure US20150322069A1-20151112-C01315
         		--cyclopropyl--
    632 A29
    Figure US20150322069A1-20151112-C01316
    Figure US20150322069A1-20151112-C01317
         		--cyclopropyl--
    633 A29
    Figure US20150322069A1-20151112-C01318
    Figure US20150322069A1-20151112-C01319
         		--cyclopropyl--
    634 A29
    Figure US20150322069A1-20151112-C01320
    Figure US20150322069A1-20151112-C01321
         		--cyclopropyl--
    635 A29
    Figure US20150322069A1-20151112-C01322
    Figure US20150322069A1-20151112-C01323
         		--cyclopropyl--
    636 A29
    Figure US20150322069A1-20151112-C01324
    Figure US20150322069A1-20151112-C01325
         		--cyclopropyl--
    637 A29
    Figure US20150322069A1-20151112-C01326
    Figure US20150322069A1-20151112-C01327
         		--cyclopropyl--
    638 A29
    Figure US20150322069A1-20151112-C01328
    Figure US20150322069A1-20151112-C01329
         		--cyclopropyl--
    639 A29
    Figure US20150322069A1-20151112-C01330
    Figure US20150322069A1-20151112-C01331
         		--cyclopropyl--
    640 A29
    Figure US20150322069A1-20151112-C01332
    Figure US20150322069A1-20151112-C01333
         		--cyclopropyl--
    641 A29
    Figure US20150322069A1-20151112-C01334
    Figure US20150322069A1-20151112-C01335
         		--cyclopropyl--
    642 A29
    Figure US20150322069A1-20151112-C01336
    Figure US20150322069A1-20151112-C01337
         		--cyclopropyl--
    643 A29
    Figure US20150322069A1-20151112-C01338
    Figure US20150322069A1-20151112-C01339
         		--cyclopropyl--
    644 A29
    Figure US20150322069A1-20151112-C01340
    Figure US20150322069A1-20151112-C01341
         		--cyclopropyl-
    645 A29
    Figure US20150322069A1-20151112-C01342
    Figure US20150322069A1-20151112-C01343
         		--cyclopropyl--
    646 A29
    Figure US20150322069A1-20151112-C01344
    Figure US20150322069A1-20151112-C01345
         		--cyclopropyl--
    647 A29
    Figure US20150322069A1-20151112-C01346
    Figure US20150322069A1-20151112-C01347
         		--cyclopropyl--
    648 A29
    Figure US20150322069A1-20151112-C01348
    Figure US20150322069A1-20151112-C01349
         		--cyclopropyl--
    649 A29
    Figure US20150322069A1-20151112-C01350
    Figure US20150322069A1-20151112-C01351
         		--cyclopropyl--
    650 A29
    Figure US20150322069A1-20151112-C01352
    Figure US20150322069A1-20151112-C01353
         		--cyclopropyl--
    651 A29
    Figure US20150322069A1-20151112-C01354
    Figure US20150322069A1-20151112-C01355
         		--cyclopropyl--
    652 A29
    Figure US20150322069A1-20151112-C01356
    Figure US20150322069A1-20151112-C01357
         		--cyclopropyl--
    653 A29
    Figure US20150322069A1-20151112-C01358
    Figure US20150322069A1-20151112-C01359
         		--cyclopropyl--
    654 A29
    Figure US20150322069A1-20151112-C01360
    Figure US20150322069A1-20151112-C01361
         		--cyclopropyl--
    655 A29
    Figure US20150322069A1-20151112-C01362
    Figure US20150322069A1-20151112-C01363
         		--cyclopropyl--
    656 A29
    Figure US20150322069A1-20151112-C01364
    Figure US20150322069A1-20151112-C01365
         		--cyclopropyl--
    657 A29
    Figure US20150322069A1-20151112-C01366
    Figure US20150322069A1-20151112-C01367
         		--cyclopropyl--
    658 A29
    Figure US20150322069A1-20151112-C01368
    Figure US20150322069A1-20151112-C01369
         		--cyclopropyl--
    659 A29
    Figure US20150322069A1-20151112-C01370
    Figure US20150322069A1-20151112-C01371
         		--cyclopropyl--
    660 A29
    Figure US20150322069A1-20151112-C01372
    Figure US20150322069A1-20151112-C01373
         		--cyclopropyl--
    661 A29
    Figure US20150322069A1-20151112-C01374
    Figure US20150322069A1-20151112-C01375
         		--cyclopropyl--
    662 A29
    Figure US20150322069A1-20151112-C01376
    Figure US20150322069A1-20151112-C01377
         		--cyclopropyl--
    663 A29
    Figure US20150322069A1-20151112-C01378
    Figure US20150322069A1-20151112-C01379
         		--cyclopropyl-
    664 A29
    Figure US20150322069A1-20151112-C01380
    Figure US20150322069A1-20151112-C01381
         		--cyclopropyl--
    665 A29
    Figure US20150322069A1-20151112-C01382
    Figure US20150322069A1-20151112-C01383
         		--cyclopropyl--
    666 A29
    Figure US20150322069A1-20151112-C01384
    Figure US20150322069A1-20151112-C01385
         		--cyclopropyl--
    667 A29
    Figure US20150322069A1-20151112-C01386
    Figure US20150322069A1-20151112-C01387
         		--cyclopropyl--
    668 A29
    Figure US20150322069A1-20151112-C01388
    Figure US20150322069A1-20151112-C01389
         		--cyclopropyl--
    669 A29
    Figure US20150322069A1-20151112-C01390
    Figure US20150322069A1-20151112-C01391
         		--cyclopropyl--
    670 A29
    Figure US20150322069A1-20151112-C01392
    Figure US20150322069A1-20151112-C01393
         		--cyclopropyl--
    671 A29
    Figure US20150322069A1-20151112-C01394
    Figure US20150322069A1-20151112-C01395
         		--cyclopropyl--
    672 A29
    Figure US20150322069A1-20151112-C01396
    Figure US20150322069A1-20151112-C01397
         		--cyclopropyl--
    673 A29
    Figure US20150322069A1-20151112-C01398
    Figure US20150322069A1-20151112-C01399
         		--cyclopropyl--
    674 A29
    Figure US20150322069A1-20151112-C01400
    Figure US20150322069A1-20151112-C01401
         		--cyclopropyl--
    675 A29
    Figure US20150322069A1-20151112-C01402
    Figure US20150322069A1-20151112-C01403
         		--cyclopropyl--
    676 A29
    Figure US20150322069A1-20151112-C01404
    Figure US20150322069A1-20151112-C01405
         		--cyclopropyl--
    677 A29
    Figure US20150322069A1-20151112-C01406
    Figure US20150322069A1-20151112-C01407
         		--cyclopropyl--
    678 A29
    Figure US20150322069A1-20151112-C01408
    Figure US20150322069A1-20151112-C01409
         		--cyclopropyl--
    679 A29
    Figure US20150322069A1-20151112-C01410
    Figure US20150322069A1-20151112-C01411
         		--cyclopropyl--
    680 A29
    Figure US20150322069A1-20151112-C01412
    Figure US20150322069A1-20151112-C01413
         		--cyclopropyl--
    681 A29
    Figure US20150322069A1-20151112-C01414
    Figure US20150322069A1-20151112-C01415
         		--cyclopropyl--
    682 A29
    Figure US20150322069A1-20151112-C01416
    Figure US20150322069A1-20151112-C01417
         		--cyclopropyl--
    683 A29
    Figure US20150322069A1-20151112-C01418
    Figure US20150322069A1-20151112-C01419
         		--cyclopropyl--
    684 A29
    Figure US20150322069A1-20151112-C01420
    Figure US20150322069A1-20151112-C01421
         		--cyclopropyl--
    685 A29
    Figure US20150322069A1-20151112-C01422
    Figure US20150322069A1-20151112-C01423
         		--cyclopropyl--
    686 A29
    Figure US20150322069A1-20151112-C01424
    Figure US20150322069A1-20151112-C01425
         		--cyclopropyl--
    687 A29
    Figure US20150322069A1-20151112-C01426
    Figure US20150322069A1-20151112-C01427
         		--cyclopropyl--
    688 A29
    Figure US20150322069A1-20151112-C01428
    Figure US20150322069A1-20151112-C01429
         		--cyclopropyl--
    689 A29
    Figure US20150322069A1-20151112-C01430
    Figure US20150322069A1-20151112-C01431
         		--cyclopropyl--
    690 A29
    Figure US20150322069A1-20151112-C01432
    Figure US20150322069A1-20151112-C01433
         		--cyclopropyl--
    691 A29
    Figure US20150322069A1-20151112-C01434
    Figure US20150322069A1-20151112-C01435
         		--cyclopropyl--
    692 A29
    Figure US20150322069A1-20151112-C01436
    Figure US20150322069A1-20151112-C01437
         		--cyclopropyl--
    693 A29
    Figure US20150322069A1-20151112-C01438
    Figure US20150322069A1-20151112-C01439
         		--cyclopropyl--
    694 A29
    Figure US20150322069A1-20151112-C01440
    Figure US20150322069A1-20151112-C01441
         		--cyclopropyl-
    695 A29
    Figure US20150322069A1-20151112-C01442
    Figure US20150322069A1-20151112-C01443
         		--cyclopropyl--
    696 A29
    Figure US20150322069A1-20151112-C01444
    Figure US20150322069A1-20151112-C01445
         		--cyclopropyl--
    697 A29
    Figure US20150322069A1-20151112-C01446
    Figure US20150322069A1-20151112-C01447
         		--cyclopropyl--
    698 A29
    Figure US20150322069A1-20151112-C01448
    Figure US20150322069A1-20151112-C01449
         		--cyclopropyl--
    699 A29
    Figure US20150322069A1-20151112-C01450
    Figure US20150322069A1-20151112-C01451
         		--cyclopropyl--
    700 A29
    Figure US20150322069A1-20151112-C01452
    Figure US20150322069A1-20151112-C01453
         		--cyclopropyl--
    701 A29
    Figure US20150322069A1-20151112-C01454
    Figure US20150322069A1-20151112-C01455
         		--cyclopropyl--
    702 A29
    Figure US20150322069A1-20151112-C01456
    Figure US20150322069A1-20151112-C01457
         		--cyclopropyl--
    703 A29
    Figure US20150322069A1-20151112-C01458
    Figure US20150322069A1-20151112-C01459
         		--cyclopropyl--
    704 A29
    Figure US20150322069A1-20151112-C01460
    Figure US20150322069A1-20151112-C01461
         		--cyclopropyl--
    705 A29
    Figure US20150322069A1-20151112-C01462
    Figure US20150322069A1-20151112-C01463
         		--cyclopropyl--
    706 A29
    Figure US20150322069A1-20151112-C01464
    Figure US20150322069A1-20151112-C01465
         		--cyclopropyl--
    707 A29
    Figure US20150322069A1-20151112-C01466
    Figure US20150322069A1-20151112-C01467
         		--cyclopropyl--
    708 A29
    Figure US20150322069A1-20151112-C01468
    Figure US20150322069A1-20151112-C01469
         		--cyclopropyl--
    709 A29
    Figure US20150322069A1-20151112-C01470
    Figure US20150322069A1-20151112-C01471
         		--cyclopropyl--
    710 A29
    Figure US20150322069A1-20151112-C01472
    Figure US20150322069A1-20151112-C01473
         		--cyclopropyl--
    711 A29
    Figure US20150322069A1-20151112-C01474
    Figure US20150322069A1-20151112-C01475
         		--cyclopropyl--
    712 A29
    Figure US20150322069A1-20151112-C01476
    Figure US20150322069A1-20151112-C01477
         		--cyclopropyl--
    713 A29
    Figure US20150322069A1-20151112-C01478
    Figure US20150322069A1-20151112-C01479
         		--cyclopropyl--
    714 A29
    Figure US20150322069A1-20151112-C01480
    Figure US20150322069A1-20151112-C01481
         		--cyclopropyl--
    715 A29
    Figure US20150322069A1-20151112-C01482
    Figure US20150322069A1-20151112-C01483
         		--cyclopropyl--
    716 A29
    Figure US20150322069A1-20151112-C01484
    Figure US20150322069A1-20151112-C01485
         		--cyclopropyl--
    717 A29
    Figure US20150322069A1-20151112-C01486
    Figure US20150322069A1-20151112-C01487
         		--cyclopropyl--
    718 A29
    Figure US20150322069A1-20151112-C01488
    Figure US20150322069A1-20151112-C01489
         		--cyclopropyl--
    719 A29
    Figure US20150322069A1-20151112-C01490
    Figure US20150322069A1-20151112-C01491
         		--cyclopropyl--
    720 A29
    Figure US20150322069A1-20151112-C01492
    Figure US20150322069A1-20151112-C01493
         		--cyclopropyl--
    721 A29
    Figure US20150322069A1-20151112-C01494
    Figure US20150322069A1-20151112-C01495
         		--cyclopropyl--
    722 A29
    Figure US20150322069A1-20151112-C01496
    Figure US20150322069A1-20151112-C01497
         		--cyclopropyl--
    723 A29
    Figure US20150322069A1-20151112-C01498
    Figure US20150322069A1-20151112-C01499
         		--cyclopropyl--
    724 A29
    Figure US20150322069A1-20151112-C01500
    Figure US20150322069A1-20151112-C01501
         		--cyclopropyl--
    725 A29
    Figure US20150322069A1-20151112-C01502
    Figure US20150322069A1-20151112-C01503
         		--cyclopropyl--
    726 A29
    Figure US20150322069A1-20151112-C01504
    Figure US20150322069A1-20151112-C01505
         		--cyclopropyl--
    727 A29
    Figure US20150322069A1-20151112-C01506
    Figure US20150322069A1-20151112-C01507
         		--cyclopropyl--
    728 A29
    Figure US20150322069A1-20151112-C01508
    Figure US20150322069A1-20151112-C01509
         		--cyclopropyl--
    729 A29
    Figure US20150322069A1-20151112-C01510
    Figure US20150322069A1-20151112-C01511
         		--cyclopropyl--
    730 A29
    Figure US20150322069A1-20151112-C01512
    Figure US20150322069A1-20151112-C01513
         		--cyclopropyl--
    731 A29
    Figure US20150322069A1-20151112-C01514
    Figure US20150322069A1-20151112-C01515
         		--cyclopropyl--
    732 A29
    Figure US20150322069A1-20151112-C01516
    Figure US20150322069A1-20151112-C01517
         		--cyclopropyl--
    • Dosage and Administration
  • The present disclosure includes pharmaceutical composition for treating a subject having a neurological disorder comprising a therapeutically effective amount of a compound of Formula (I), a derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.
  • The pharmaceutical compositions can be administered in a variety of dosage forms including, but not limited to, a solid dosage form or in a liquid dosage form, an oral dosage form, a parenteral dosage form, an intranasal dosage form, a suppository, a lozenge, a troche, buccal, a controlled release dosage form, a pulsed release dosage form, an immediate release dosage form, an intravenous solution, a suspension or combinations thereof. The dosage can be an oral dosage form that is a controlled release dosage form. The oral dosage form can be a tablet or a caplet. The compounds can be administered, for example, by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration. In one embodiment, the compounds or pharmaceutical compositions comprising the compounds are delivered to a desired site, such as the brain, by continuous injection via a shunt.
  • In another embodiment, the compound can be administered parenterally, such as intravenous (IV) administration. The formulations for administration will commonly comprise a solution of the compound of the Formula (I) dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of compound of Formula (I) in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.
  • In one embodiment, a compound of Formula (I) can be administered by introduction into the central nervous system of the subject, e.g., into the cerbrospinal fluid of the subject. The formulations for administration will commonly comprise a solution of the compound of Formula (I) dissolved in a pharmaceutically acceptable carrier. In certain aspects, the compound of Formula (I) is introduced intrathecally, e.g., into a cerebral ventricle, the lumbar area, or the cisterna magna. In another aspect, the compound of Formula (I) is introduced intraocularly, to thereby contact retinal ganglion cells.
  • The pharmaceutically acceptable formulations can easily be suspended in aqueous vehicles and introduced through conventional hypodermic needles or using infusion pumps. Prior to introduction, the formulations can be sterilized with, preferably, gamma radiation or electron beam sterilization.
  • In one embodiment, the pharmaceutical composition comprising a compound of Formula (I) is administered into a subject intrathecally. As used herein, the term “intrathecal administration” is intended to include delivering a pharmaceutical composition comprising a compound of Formula (I) directly into the cerebrospinal fluid of a subject, by techniques including lateral cerebroventricular injection through a burrhole or cisternal or lumbar puncture or the like (described in Lazorthes et al. Advances in Drug Delivery Systems and Applications in Neurosurgery, 143-192 and Omaya et al., Cancer Drug Delivery, 1: 169-179, the contents of which are incorporated herein by reference). The term “lumbar region” is intended to include the area between the third and fourth lumbar (lower back) vertebrae. The term “cisterna magna” is intended to include the area where the skull ends and the spinal cord begins at the back of the head. The term “cerebral ventricle” is intended to include the cavities in the brain that are continuous with the central canal of the spinal cord. Administration of a compound of Formula (I) to any of the above mentioned sites can be achieved by direct injection of the pharmaceutical composition comprising the compound of Formula (I) or by the use of infusion pumps. For injection, the pharmaceutical compositions can be formulated in liquid solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution. In addition, the pharmaceutical compositions may be formulated in solid form and re-dissolved or suspended immediately prior to use. Lyophilized forms are also included. The injection can be, for example, in the form of a bolus injection or continuous infusion (e.g., using infusion pumps) of pharmaceutical composition.
  • In one embodiment, the pharmaceutical composition comprising a compound of Formula (I) is administered by lateral cerebro ventricular injection into the brain of a subject. The injection can be made, for example, through a burr hole made in the subject's skull. In another embodiment, the encapsulated therapeutic agent is administered through a surgically inserted shunt into the cerebral ventricle of a subject. For example, the injection can be made into the lateral ventricles, which are larger, even though injection into the third and fourth smaller ventricles can also be made.
  • In yet another embodiment, the pharmaceutical composition is administered by injection into the cisterna magna, or lumbar area of a subject.
  • For oral administration, the compounds will generally be provided in unit dosage forms of a tablet, pill, dragee, lozenge or capsule; as a powder or granules; or as an aqueous solution, suspension, liquid, gels, syrup, slurry, etc. suitable for ingestion by the patient. Tablets for oral use may include the active ingredients mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • Pharmaceutical preparations for oral use can be obtained through combination of a compound of Formula (I) with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores. Suitable solid excipients in addition to those previously mentioned are carbohydrate or protein fillers that include, but are not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.
  • Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredients is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • For transmucosal administration (e.g., buccal, rectal, nasal, ocular, etc.), penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
  • The suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
  • The compounds can be delivered transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, or aerosols.
  • The compounds may also be presented as aqueous or liposome formulations. Aqueous suspensions can contain a compound of Formula (I) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.
  • Oil suspensions can be formulated by suspending a compound of Formula (I) in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.
  • In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or transcutaneous delivery (e.g., subcutaneously or intramuscularly), intramuscular injection or a transdermal patch. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • For administration by inhalation, the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • In general a suitable dose will be in the range of 0.01 to 100 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 10 mg per kilogram body weight per day. The desired dose is preferably presented once daily, but may be dosed as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day.
  • The compounds can be administered as the sole active agent, or in combination with other known therapeutics to be beneficial in the treatment of neurological disorders. In any event, the administering physician can provide a method of treatment that is prophylactic or therapeutic by adjusting the amount and timing of drug administration on the basis of observations of one or more symptoms (e.g., motor or cognitive function as measured by standard clinical scales or assessments) of the disorder being treated.
  • Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa. After a pharmaceutical composition has been formulated in an acceptable carrier, it can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of the compounds of Formula (I), such labeling would include, e.g., instructions concerning the amount, frequency and method of administration.
    • Biological Examples In Vivo Methods
  • Subjects:
  • Male C57BL/6J mice (Charles River; 20-25 g) were used for all assays except prepulse inhibition (PPI) which used male DBA/2N mice (Charles River, 20-25 g). For all studies, animals were housed five/cage on a 12-h light/dark cycle with food and water available ad libitum.
  • Conditioned Avoidance Responding:
  • Testing was performed in commercially available avoidance boxes (Kinder Scientific, Poway Calif.). The boxes were divided into two compartments separated by an archway. Each side of the chamber has electronic grid flooring that is equipped to administer footshocks and an overhead light. Training consisted of repeated pairings of the light (conditioned stimulus) followed by a shock (unconditioned stimulus). For each trial the light was presented for 5 sec followed by a 0.5 mA shock that would terminate if the mouse crossed to the other chamber or after 10 seconds. The intertrial interval was set to 20 seconds. Each training and test session consisted a four min habituation period followed by 30 trials. The number of avoidances (mouse crossed to other side during presentation of the light,), escapes (mouse crossed to the other side during presentation of the shock) and failures (mouse did not cross during the entire trial period) were recorded by a computer. For study inclusion an animal had to reach a criterion of at least 80% avoidances for two consecutive test sessions.
  • PPI:
  • Mice were individually placed into the test chambers (StartleMonitor, Kinder Scientific, Poway Calif.). The animals were given a five min acclimation period to the test chambers with the background noise level set to 65 decibel (dB) which remained for the entire test session. Following acclimation, four successive trials 120 dB pulse for 40 msec were presented, however these trials were not included in data analysis. The mice were then subjected to five different types of trials in random order: pulse alone (120 dB for 40 msec), no stimulus and three different prepulse+pulse trials with the prepulse set at 67, 69 or 74 dB for 20 msec followed a 100 msec later by a 120 dB pulse for 40 msec. Each animal received 12 trials for each condition for a total of 60 trials with an average intertrial interval of 15 sec. Percent PPI was calculated according to the following formula: (1−(startle response to prepulse+pulse)/startle response to pulse alone))×100.
  • MK-801-Induced Hyperactivity:
  • After a 30 min acclimatation to the test room mice were individually placed into test cages for a 30 min habituation period. Following habituation to test cages, baseline activity was recorded for 60 min. Mice were then briefly removed and administered test compound and placed immediately back into the test cage. At 5 min prior to test time mice were again briefly removed from test cages and administered MK-801 (0.3 mg/kg, i.p. in 0.9% saline) and then immediately placed back into test cages and activity level recorded 1 hour. Activity level was measured as distance travelled in centimeters (Ethovision tracking software, Noldus Inc. Wageningen, Netherlands).
  • Catalepsy:
  • Mice were placed on a wire mesh screen set at a 60 degree angle with their heads facing upwards and the latency to move or break stance was recorded. Animals were given three trials per time point with a 30 sec cut-off per trial.
  • Data Analysis:
  • A one-way or two-way ANOVA was used to evaluate overall differences between treatments and a Tukey's post-hoc test or Student's t-test was used to evaluate differences between treatment groups for the one-way ANOVA and a Bonferroni test was used for the two-way ANOVA. The criterion for statistical significance was set to p<0.05.
    • In Vitro Methods
  • hPDE10A1 Enzyme Activity:
  • 50 μl samples of serially diluted Human PDE10A1 enzyme were incubated with 50 μl of [3H]-cAMP for 20 minutes (at 37° C.). Reactions were carried out in Greiner 96 deep well 1 ml master-block. The enzyme was diluted in 20 mM Tris HCl pH7.4 and [3H]-cAMP was diluted in 10 mM MgCl2, 40 mM Tris.HCl pH 7.4. The reaction was terminated by denaturing the PDE enzyme (at 70° C.) after which [3H]-5′-AMP was converted to [3H]-adenosine by adding 25 μl snake venom nucleotidase and incubating for 10 minutes (at 37° C.). Adenosine, being neutral, was separated from charged cAMP or AMP by the addition of 200 μl Dowex resin. Samples were shaken for 20 minutes then centrifuged for 3 minutes at 2,500 r.p.m. 50 μl of supernatant was removed and added to 200 μl of MicroScint-20 in white plates (Greiner 96-well Optiplate) and shaken for 30 minutes before reading on Perkin Elmer TopCount Scintillation Counter.
  • hPDE10A1 Enzyme Inhibition:
  • To check inhibition profile 11 μl of serially diluted inhibitor was added to 50 μl of [3H]-cAMP and 50 ul of diluted Human PDE10A1 and assay was carried out as in the enzyme activity assay. Data was analysed using Prism software (GraphPad Inc). Representative compounds of this disclosure are shown in the table below. A compound with the value “A” had an IC50 value less than or equal to 10 nM. A compound with the value “B” had an IC50 value greater than 10 nM and less than 50 nM:
  • hPDE10A1
    Name IC50 Band
    4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5- A
    (4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
    4-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)- A
    5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
    4-(4-(imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)- B
    5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
    4-(4-((6-chloroimidazo[1,2-b]pyridazin-2- B
    yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-
    dimethylfuran-3(2H)-one
    4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)- A
    5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
    4-(3-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)- A
    5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile
    4-(4-((3-chloroimidazo[1,2-a]pyridin-2- A
    yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-
    dimethylfuran-3(2H)-one
    5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin- A
    2-yl)methoxy)phenyl)furan-3(2H)-one
    4-(5,5-dimethyl-3-(4-((5-methylpyridin-2- A
    yl)methoxy)phenyl)-4-oxo-4,5-dihydrofuran-
    2-yl)benzonitrile
    4-(4-((6-chloroimidazo[1,2-a]pyridin-2- A
    yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-
    dimethylfuran-3(2H)-one
    5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((3- B
    methylimidazo[1,2-a]pyridin-2-
    yl)methoxy)phenyl)furan-3(2H)-one
    5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5- A
    methylimidazo[1,2-a]pyridin-2-
    yl)methoxy)phenyl)furan-3(2H)-one

Claims (21)

What is claimed is:
1. A compound of Formula (I) and pharmaceutically acceptable salts thereof,
Figure US20150322069A1-20151112-C01518
wherein:
HET is selected from A29 and A31
Figure US20150322069A1-20151112-C01519
wherein the left most radical is connected to the X group in Formula (I);
X is selected from optionally substituted aryl and optionally substituted heteroaryl, wherein the substituents are selected from C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C1-C4 alkoxy, CF3, carboxy, alkoxyalkyl, C1-C4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, alkylsulfonyl and nitro; and
Z is selected from pyridin-2-yl, imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-b]pyridazin-2-yl, and imidazo[1,2-b]pyridazin-6-yl, each of which can be optionally substituted, wherein the substituents are selected from C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C1-C4 alkoxy, CF3, carboxy, alkoxyalkyl, C1-C4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, alkylsulfonyl and nitro; and
each R2 is independently selected from optionally fluoro substituted C1-C4 alkyl or two R2 groups taken together with the carbon to which they are attached form a 3 membered cycloalkyl ring.
2-35. (canceled)
36. A method for making 4-(4-hydroxyphenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof, the method comprising using Suzuki coupling to obtain 4-(4-hydroxyphenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof from 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one.
37. The method of claim 36, conducted in a polar solvent mixture.
38. The method of claim 37, wherein the polar solvent mixture comprises water.
39. The method of claim 36, conducted in the presence of a catalyst.
40. The method of claim 39, wherein the catalyst is a palladium(0) or palladium(II) catalyst.
41. The method of claim 36 conducted in the presence of a base.
42. The method of claim 41, wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate and cesium carbonate.
43. The method of claim 36, further comprising isolating 4-(4-hydroxyphenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof.
44. A method for making 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof,
the method comprising contacting 4-(4-hydroxyphenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one
with a compound of formula
Figure US20150322069A1-20151112-C01520
to provide 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof.
45. The method of claim 44, conducted in a polar solvent.
46. The method of claim 45, wherein the polar solvent is CH3CN or DMF.
47. The method of claim 44 conducted in the presence of a base.
48. The method of claim 47, wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate and cesium carbonate.
49. The method of claim 44, further comprising isolating 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof.
50. A method for making 4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof,
the method comprising reducing 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one to provide 4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof.
51. The method of claim 50, conducted in the presence of a catalyst.
52. The method of claim 51, wherein the catalyst is a palladium(0) or palladium(II) catalyst.
53. The method of claim 50, conducted in the presence of hydrogen.
54. The method of claim 50, further comprising isolating 4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof.
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