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Definitions

• FAAH fatty acid amide hydrolase
• FAAH fatty acid amide hydrolase
• Fatty acid amide hydrolase is an enzyme that is abundantly expressed throughout the CNS (Freund et al. Physiol. Rev. 2003; 83:1017-1066) as well as in peripheral tissues, such as, for example, in the pancreas, brain, kidney , skeletal muscle, placenta, and liver (Giang, D. K. et al., Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 2238-2242; Cravatt et al. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 29, 10821-10826).
• FAAH hydrolyzes the fatty acid amide (FAA) family of endogenous signaling lipids.
• fatty acid amides include the N- acylethanolamides (AEs) and fatty acid primary amides (FAPAs).
• NAEs include anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA).
• FAPAs includes 9- -octadecenamide or oleamide.
• fatty acid amide family of endogenous signaling lipids is N-acyl taurines that have also been shown to be elevated upon FAAH deletion or inhibition and appear to act on transient receptor potential (TRP) family of calcium channels, although the functional consequences are not yet clear (Saghatelian A, et al. Biochemistry. 2004, 43:14332-9, Saghatelian A, et al. Biochemistry, 2006, 45:9007 -9015).
• TRP transient receptor potential
• FAAH can also hydrolyze certain fatty acid esters, such as, for example, 2- arachidonylglycerol (2-AG) another endocannabinoid (Mechoulam et al. Biochem. Pharmacol. 1995; 50:83-90; Stella et ai. Nature, 1997; 388:773-778; Suguria et al. Biochem. Biophys. Res. Commun. 1995; 215:89-97).
• FAAH inhibitor compounds may be peripherally restricted and may not substantially affect neural disorders, such as, for example, depression and anxiety.
• cannabinoid receptors has also been shown to reduce the progression of atherosclerosis in animal models (see Steffens et al. Nature, 2005, 434, 782-786; and Steffens et al, Curr Opin. Lipid., 2006, 17, 519-526).
• cannabinergic fatty acid amides e.g., anandamide
• Inhibition of FAAH also leads to elevation of palmitoylethanolamide which is thought to work, in part, through activation of the peroxisome proliferator-activated receptor a (PPAR- a) to regulate multiple pathways including, for example, pain perception in neuropathic and inflammatory conditions such as convulsions, neurotoxicity, spacticity and to reduce inflammation, for example, in atopic eczema and arthritis (LoVerme J et al. The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol Pharmacol 2005, 67, 15-19; LoVerme J et al. The search for the palmitoylethanolamide receptor.
• PPAR- a peroxisome proliferator-activated receptor a
• inhibition of FAAH is useful for the treatment of various pain and inflammatory conditions, such as osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia.
• fatty acid amides such as, for example, OEA
• PPAR- a peroxisome proliferator-activated receptor a
• human adipose tissue has been shown to bind and metabolize endocannabinoids such as anandamide and 2-arachidonylglycerol (see Spoto et al., Biochimie 2006, 88, 1889-1897; and Matias et al., J. Clin. Endocrin. & Met., 2006, 91, 3171-3180).
• endocannabinoids such as anandamide and 2-arachidonylglycerol
• FAAH inhibitors do not cause adverse side effects such as rash, fatigue, headache, erectile
• FAAH fatty acid amides
• hydrolysis by FAAH is considered to be one of the essential steps in the regulation of fatty acid amide levels in the central nervous system as well as in peripheral tissues and fluids.
• the broad distribution of FAAH combined with the broad array of biological effects of fatty acid amides suggests that inhibition of FAAH leads to altered levels of fatty acid amides in many tissues and fluids and may be useful to treat many different conditions.
• FAAH inhibitors increase the levels of endogenous fatty acid amides.
• FAAH inhibitors block the degradation of endocannabinoids and increase the tissue levels of these endogenous
• FAAH inhibitors can be used in this respect in the prevention and treatment of pathologies in which endogenous cannabinoids and or any other substrates metabolized by the FAAH enzyme are involved.
• FAAH inhibitors that are biologically compatible could be effective pharmaceutical compounds when formulated as therapeutic agents for any clinical indication where FAAH enzymatic inhibition is desired, hi some embodiments, FAAH activity in peripheral tissues can be preferentially inhibited.
• FAAH inhibitors that do substantially cross the blood-brain-barrier can be used to preferentially inhibit FAAH activity in peripheral tissues.
• FAAH inhibitors that preferentially inhibit FAAH activity in peripheral tissues can minimize the effects of FAAH inhibition in the central nervous system. In some embodiments, it is preferred to inhibit FAAH activity in peripheral tissues and minimize FAAH inhibition in the central nervous system.
• the present invention is directed to certain Aza-Indole derivatives which are useful as inhibitors of Fatty Acid Amide Hydrolase (FAAH).
• Fatty Acid Amide Hydrolase FAAH
• the invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia, as well as acute pain, migraine, sleep disorder, Alzheimer disease, and Parkinson's disease.
• the invention is directed to a compound of the formula I:
• n 0, 1 or 2;
• is selected from C or N;
• X2 is S or SO or S0 2 ;
• Rj is selected from the group consisting of:
• choice (2), and the aryl or HETi of choices (3), (4), (5) and (6) are optionally di-substituted with substituents selected from hydroxyl, halo, CF3 and OCH3; selected from the group consisting
• Rg is selected from the group consisting of
• R9 and Rio are each independently selected from the group consisting of
• R9 and Rio are joined together to form a ring with the atoms to which they are attached there is formed a heterocyclic ring of 4 to 7 atoms, said ring containing 1 , 2, 3 or 4 heteroatoms selected from N, O and S, said ring being optionally mono or di-substituted with substituents independently selected from halo, hydroxyl, oxo, Ci-4alkyl, hydroxyCi-4alkyl, haloCi-4alkyl, -C(0)-Ci-4alkyl, -S(0)nCi- 4alkyl, and C(0)-NRaRb, wherein Ra and Rb are each independently selected from hydrogen and methyl,
• Rj 1, R12, Ri3, i4, R]5, R ⁇ , Rl7 > Rl8 > Rl > are each independently selected from H and Ci_4alkyl, optionally substituted with hydroxyl, and
• R20 is selected from H and C ⁇ . 4 alkyl optionally substituted with aryl, HET6, optionally substituted with hydroxyl or 1-4 methyl groups,
• R ⁇ i and R12 or R13 and R14 or R1 and R20 can be joined together to form a ring with the atoms to which they are attached there is formed a 5-membered heterocyclic ring of 4 to 7 atoms, said ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, said ring being optionally mono or di-substituted with substituents independently selected from halo, hydroxyl, oxo, C] trustee 4alkyl, hydroxyCi- 4 alkyl, haloCi- 4 alkyl, -C(0)-Ci_4alkyl and -S(0)nCi_4alkyl;
• R3 is selected from the group consisting of:
• R4, R5 and R6 are each independently selected from the group consisting of:
• choice (7), and the aryl or HET5 of choices (3), (4), (5) and (6) are optionally mono or di-substituted with substituents selected from hydroxyl, halo, CF3 and OCH3;
• R7 is selected from the group consisting of:
• choices (3) and (4) are each optionally mono or di-substituted with substituents selected from hydroxyl, C 3 personally6cycloalkyl 5 -C(0)-NH2, phenyl and HET9,
• R ⁇ is selected from the group consisting of:
• choice (2) is optionally mono or di-substituted with substituents selected from hydroxyl, halo, CF3 and OCH 3 .
• R2 is selected from the group consisting of:
• R9 and Rio are each independently selected from the group consisting of
• R9 and RJ O are joined together to form a ring with the atoms to which they are attached there is formed a heterocyclic ring of 4 to 7 atoms, said ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S 5 said ring being optionally mono or di-substituted with substituents independently selected from halo, hydroxyl, oxo, Ci-4alkyl, ydroxyCi ⁇ alk l, haloCi-4alkyl, ⁇ €(0>Ci-4alkyi ; ⁇ S(0)nCi- 4alkyl, and C(0)-NRaRb, wherein Ra and Rb are each independently selected from hydrogen and methyl, wherein R2 choices (2), (3), (4), (5), (6), (7), (8), (9) and (10) are each optionally mono or di- substituted with substituents independently selected from the group consisting of:
• Ri ⁇ , R12, R3 . 3, Rl4, Ri5, Rl6 > ⁇ -17» Rl8 > are each independently selected from H and Ci-4alkyl, optionally substituted with hydroxyl, and
• R20 is selected from H and Ci_ 4 alkyl optionally substituted with aryl, HETg, optionally substituted with hydroxyl or 1-4 methyl groups, or
• R ⁇ i and R12 or R13 and R14 or R19 and R20 can be joined together to form a ring with the atoms to which they are attached there is formed a 5-membered heterocyclic ring of 4 to 7 atoms, said ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, said ring being optionally mono or di-substituted with substituents independently selected from halo, hydroxyl, oxo, Ci_ 4alkyl, hydroxyC]-4alkyl, haloCl ⁇ alkyl, -C(0)-Ci-4alkyl and ⁇ S(0)nCi- 4 alkyl.
• substituents independently selected from halo, hydroxyl, oxo, Ci_ 4alkyl, hydroxyC]-4alkyl, haloCl ⁇ alkyl, -C(0)-Ci-4alkyl and ⁇ S(0)nCi- 4 alkyl.
• R2 is selected from the group consisting of:
• R9 and Rio are each independently selected from the group consisting of
• R9 and Rjo are joined together to form a ring with the atoms to which they are attached there is formed a heterocyclic ring of 5 or 6 atoms, said ring containing 1 , or 2 heteroatoms selected from N, O and S, said ring being optionally mono or di- substituted with substituents independently selected from hydroxyl, -C(0)-Ci_ 4alkyl, and C(0)-NRaRb, wherein Ra and Rb are each independently selected from hydrogen and methyl,
• R2 choices (1), (2) and (3) are each optionally mono or di-substituted with substituents independently selected from the group consisting of:
• RJ I , i2, Rl3 > Rl4, Rl5 > j6 > R-17s Rl8 > are eacn independently selected from H and Ci_4alkyl, optionally substituted with hydroxyl.
• R9 and Rio are each independently selected from the group consisting of
• R9 and Rio are joined together to form a ring with the atoms to which they are attached there is formed a heterocyclic ring of 5 or 6 atoms, said ring containing 1, or 2 heteroatoms selected from N, O and S, said ring being optionally mono or di- substituted with substituents independently selected from hydroxyl, -C(0)-Ci- 4alkyl, and C(0)-NRaRb, wherein Ra and Rb are each independently selected from hydrogen and methyl,
• R2 choices (1), (2) and (3) are each optionally mono or di-substituted with substituents independently selected from the group consisting of:
• R3 is selected from the group consisting of:
• choices (1) and (2) are each optionally mono or di-substituted with substituents independently selected from the group consisting of:
• R3 is an optionally substituted:
• R4 and R5 are each hydrogen.
• R7 is selected from the group consisting of:
• choice (3) is optionally mono or di-substituted with substituents selected from hydroxyl, C3_6cycloalkyl, -C(0)-NH2 ; phenyl and HET9.
• n 0, 1 or 2;
• R ⁇ is selected from the group consisting of:
• choice (2) is optionally mono or di-substituted with substituents selected from hydroxyl, halo, CF3 and OCH 3 ;
• R.2 is selected from the group consisting of:
• R9 and Rio are each independently selected from the group consisting of
• R9 and R]o are joined together to form a ring with the atoms to which they are attached there is formed a heterocyclic ring of 5 or 6 atoms, said ring containing 1, or 2 heteroatoms selected from N, O and S, said ring being optionally mono or di- substituted with substituents independently selected from hydroxyl, -C(0)-Ci_ 4alkyl, and C(0)-NRaRb, wherein Ra and Rb are each independently selected from hydrogen and methyl,
• R2 choices (1), (2) and (3) are each optionally mono or di-substituted with substituents independently selected from the group consisting of:
• R3 is selected from the group consisting of:
• choices (1) and (2) are each optionally mono or di-substituted with substituents independently selected from the group consisting of:
• Rg is selected from the group consisting of:
• choice (7), and the aryl or HET5 of choices (3), (4), (5) and (6) are optionally mono or di-substituted with substituents selected from hydroxyl, halo, CF3 and OCH3; and
• R7 is selected from the group consisting of:
• choice (3) is optionally mono or di-substituted with substituents selected from hydroxyl, C 3 -6cycloalkyl, -C(0)-N]3 ⁇ 4 5 phenyl and HET9.
• substituents selected from hydroxyl, C 3 -6cycloalkyl, -C(0)-N]3 ⁇ 4 5 phenyl and HET9.
• n 0, 1 or 2;
• Rl is selected from the group consisting of:
• choice (2) is optionally mono or di-substituted with substituents selected from hydroxyl, halo, CF3 and OCH3;
• R2 is selected from the group consisting of:
• R9 and Rio are each independently selected from the group consisting of
• R9 and Rio are joined together to form a ring with the atoms to which they are attached there is formed a heterocyclic ring of 5 or 6 atoms, said ring containing 1 , or 2 heteroatoms selected from N, O and S, said ring being optionally mono or di- substituted with substituents independently selected from hydroxyl, -C(0)-Ci ⁇
• Ra and Rb are each independently selected from hydrogen and methyl
• R2 choices (1), (2) and (3) are each optionally mono or di-substituted with substituents independently selected from the group consisting of:
• R13, R14, R17, Ri g are each independently selected from H and Ci_4alkyl, optionally substituted with hydroxyl.
• R3 is selected from
• R3 is optionally mono or di substituted with substituents selected from the group consisting of halo and methyl.
• g is selected from the group consisting of:
• choice (7), and the aryl or HET5 of choices (3), (4), (5) and (6) are optionally mono or di-substituted with substituents selected from hydroxyl, halo, CF3 and OCH3; and
• R7 is selected from the group consisting of:
• choice (3) is optionally mono or di-substituted with substituents selected from hydroxyl, C3 ⁇ 6cycloalkyl, ⁇ C(0)-NH2, phenyl and HET9.
• the invention is directed to pharmaceutical compositions which comprise an inert carrier and a compound of Formula lor a pharmaceutically acceptable salt thereof.
• the invention is directed to a method of treating a F AAH mediated diease in a patient in need of such treatment comprising: administration to a patient in need of such treatment of a therapeutically effective amount of a compound of formula I, according to claim 1 and a pharmaceutically acceptable carrier.
• a method of treating a disease is selected from osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, pain, fibromyalgia, pain, migraine, sleep disorder, Alzheimer Disease, and Parkinson's Disease comprising: administration to a patient in need of such treatment of a therapeutically effective amount of a compound of formula I, and a pharmaceutically acceptable carrier.
• the invention is directed to the use of a compound according of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a physiological disorder associated with an excess of FAAH in a mammal.
• the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers,
• racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
• the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or
• any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known
• the present invention also includes all pharmaceutically acceptable isotopic variations of a compound of the Formula I in which one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
• the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
• different isotopic forms of hydrogen (H) include protium (lH) and deuterium (SET).
• Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
• Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
• isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as 2H and 3H, carbon such as 1 lC, 13c and I4c, nitrogen such as 1 ]Sf and 15N 5 oxygen such as 15o, 170 and 18o, phosphorus such as 32p ; sulfur such as 35s, fluorine such as 18F, iodine such as 23j and 125i s and chlorine such as 36C1.
• Certain isotopically-labelled compounds of Formula I for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
• radioactive isotopes tritium i.e. H
• carbon-14 i.e. He
• substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
• Isotopically-labelled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labelled reagents in place of the non- labelled reagent previously employed.
• halogen or "halo” includes F, CI, Br, and I.
• alkyl means linear or branched structures and combinations thereof, having the indicated number of carbon atoms.
• Ci_6alkyl includes methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl.
• alkoxy means alkoxy groups of a straight, branched or cyclic configuration having the indicated number of carbon atoms.
• Ci-galkoxy for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
• alkylthio means alkylthio groups having the indicated number of carbon atoms of a straight, branched or cyclic configuration.
• Ci-galkylthio for example, includes methylthio, propylthio, isopropylthio, and the like.
• alkenyl means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon double bond, wherein hydrogen may be replaced by an additional carbon-to-carbon double bond.
• C2-6alkenyl for example, includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like.
• aJkynyl means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon triple bond.
• C3- 6alkynyl for example, includes propynyl, 1-methylethynyl, butynyl and the like.
• cycloalkyl means mono-, bi- or tri-cyclic structures, optionally combined with linear or branched structures, the indicated number of carbon atoms.
• cycloalkyl groups include cyclopropyl, cyclopentyl, cycloheptyl, adamantyl,
• aryl is defined as a mono- or bi-cyclic aromatic ring system and includes, for example, phenyl, naphthyl, and the like.
• aralkyl means an alkyl group as defined above of 1 to 6 carbon atoms with an aryl group as defined above substituted for one of the alkyl hydrogen atoms, for example, benzyl and the like.
• aryloxy means an aryl group as defined above attached to a molecule by an oxygen atom (aryl-O) and includes, for example, phenoxy, naphthoxy and the like.
• aralkoxy means an aralkyl group as defined above attached to a molecule by an oxygen atom (aralkyl-O) and includes, for example, benzyloxy, and the like.
• arylthio is defined as an aryl group as defined above attached to a molecule by a sulfur atom (aryl-S) and includes, for example, thiophenyoxy, thionaphthoxy and the like.
• aroyl means an aryl group as defined above attached to a molecule by an carbonyl group (aryl-C(O)-) and includes, for example, benzoyl, naphthoyl and the like.
• aroyloxy means an aroyl group as defined above attached to a molecule by an oxygen atom (aroyl-O) and includes, for example, benzoyloxy or benzoxy, naphthoyloxy and the like.
• HET such as in “ ⁇ ”, ' ⁇ 2 ", ⁇ ⁇ 3 ", ' ⁇ 4", "HET 5 n , "HET6", “HET7”, “HET 8 “ or “HET 9”
• ⁇ ⁇
• ⁇ ⁇
• ⁇ ⁇
• ⁇ ⁇
• ⁇ ⁇
• 3 ⁇
• ' ⁇ 4 ⁇
• HET 5 n ⁇
• HET6 HET7
• HET 8 or “HET 9”
• the Het group shall be defined to include the N-oxide.
• HET is a 5- or 6-membered aromatic or non- aromatic monocyclic ring containing 1-3 heteroatoms selected from O, S and N, for example, pyridine, pyrimidine, pyridazine, furan, thiophene, thiazole, oxazole, isooxazole and the like
• HET is a 9- or 10-membered aromatic or partially aromatic bicyclic ring containing 1-3 heteroatoms selected from O, S, and N, for example, benzofuran, benzothiophene, indole, pyranopyrrole, benzopyran, quionoline, benzocyclohexyl, naphtyridine and the like.
• HAT also includes the following: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazoiyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thiazo
• HET is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, thienyl, pyrrolyl, oxazolyl, and oxadiazole;
• each reference to a group is independent of all other references to the same group when referred to in the Specification.
• the definitions of HEX are independent of each other and Rl and R may be different HEX groups, for example furan and thiophene.
• Xhe ability of the compounds of Formula I to selectively inhibit FAAH makes them useful for treating, preventing or reversing the progression of a variety of inflammatory and non-inflammatory diseases and conditions.
• FAAH enzymatic activity examples include, for example, Alzheimer's Disease,
• FAAH activity includes, for example, multiple sclerosis, retinitis,
• amyotrophic lateral sclerosis amyotrophic lateral sclerosis, immunodeficiency virus-induced encephalitis, attention-deficit hyperactivity disorder, pain, nociceptive pain, neuropathic pain, inflammatory pain,
• noninflammatory pain painful hemorrhagic cystitis, obesity, hyperlipidemia, metabolic disorders, feeding and fasting, alteration of appetite, stress, memory, aging, hypertension, septic shock, cardiogenic shock, intestinal inflammation and motility, irritable bowel
• activity include, for example, pain, depression, anxiety, generalized anxiety disorder (GAD), obsessive compulsive disorders, stress, stress urinary incontinence, attention deficit
• hyperactivity disorders schizophrenia, psychosis, Parkinson's disease, muscle spasticity, epilepsy, diskenesia, seizure disorders, jet lag, and insomnia.
• FAAH inhibitors can also be used in the treatment of a variety of metabolic syndromes, diseases, disorders and/or conditions, including but not limited to, insulin
• FAAH inhibitors are useful in the treatment of a variety of painful conditions.
• non-inflammatory pain characterized by non-inflammatory pain, inflammatory pain, peripheral neuropathic pain, central pain, deafferentiation pain, chronic nociceptive pain, stimulus of nociceptive receptors, phantom and transient acute pain.
• Inhibition of FAAH activity can also be used in the treatment of a variety of conditions involving inflammation. These conditions include, but are not limited to arthritis (such as rheumatoid arthritis, shoulder tendonitis or bursitis, gouty arthritis, and aolymyalgia rheumatica), organ-specific inflammatory diseases (such as thyroiditis, hepatitis,
• inflammatory bowel diseases include asthma, other autoimmune diseases (such as multiple sclerosis), chronic obstructive pulmonary disease (COPD), allergic rhinitis, and
• FAAH inhibitors are useful in preventing neurodegeneration or for neuroprotection.
• FAAH inhibitors may be useful for treating glaucoma.
• FAAH inhibitors can be used to treat or reduce the risk of EMDs, which include, but are not limited to, obesity, appetite disorders, overweight, cellulite, Type I and Type II diabetes, hyperglycemia, dyslipidemia, steatohepatitis, liver steatosis, non-alcoholic steatohepatitis, Syndrome X, insulin resistance, diabetic
• dyslipidemia anorexia, bulimia, anorexia nervosa, hyperlipidemia, hypertriglyceridemia, atherosclerosis, arteriosclerosis, inflammatory disorders or conditions, Alzheimer's disease, Crohn's disease, vascular inflammation, inflammatory bowel disorders, rheumatoid arthritis, asthma, thrombosis, or cachexia.
• FAAH inhibitors can be used to treat or reduce the risk of insulin resistance syndrome and diabetes, i.e., both primary essential diabetes such as Type I Diabetes or Type II Diabetes and secondary nonessential diabetes.
• Administering a composition containing a therapeutically effective amount of an in vivo FAAH inhibitor reduces the severity of a symptom of diabetes or the risk of developing a symptom of diabetes, such as atherosclerosis, hypertension, hyperlipidemia, liver steatosis, nephropathy, neuropathy, retinopathy, foot ulceration, or cataracts.
• FAAH inhibitors can be used to treat food abuse behaviors, especially those liable to cause excess weight, e.g., bulimia, appetite for sugars or fats, and non-insulin-dependent diabetes.
• FAAH inhibitors can be used to treat a subject suffering from an EMD and also suffers from a depressive disorder or from an anxiety disorder.
• the subject is diagnosed as suffering from the depressive or psychiatric disorder prior to administration of the FAAH inhibitor composition.
• FAAH inhibitor that is therapeutically effective for both the EMD and the depressive or anxiety disorder is administered to the subject.
• the subject to be treated is human.
• the methods can also be used to treat non-human mammals.
• Animal models of EMDs such as those described in, e.g., U.S. Pat. No. 6,946,491 are particularly useful.
• FAAH inhibitor compositions can also be used to decrease body- weight in individuals wishing to decrease their body weight for cosmetic, but not necessarily medical considerations.
• a FAAH inhibitor composition can be administered in combination with a drug for lowering circulating cholesterol levels (e.g., statins, niacin, fibric acid derivatives, or bile acid binding resins).
• a drug for lowering circulating cholesterol levels e.g., statins, niacin, fibric acid derivatives, or bile acid binding resins.
• FAAH inhibitor compositions can also be used in combination with a weight loss drug, e.g., orlistat or an appetite suppressant such as diethylpropion, mazindole, orlistat, phendimetrazine, phentermine, or sibutramine.
• treating encompasses not only treating a patient to relieve the patient of the signs and symptoms of the disease or condition but also prophylactically treating an asymptomatic patient to prevent the onset of the disease or condition or preventing, slowing or reversing the progression of the disease or condition.
• amount effective for treating is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
• the term also encompasses the amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
• CC1 4 carbon tetrachloride
• DIBAL diisobutyl aluminum hydride
• Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
• the present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomencally pure forms and pharmaceutically acceptable salts thereof.
• Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
• compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
• pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium,, potassium, and sodium salts.
• Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamme, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
• basic ion exchange resins such
• salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
• acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethio ic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
• Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
• prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature and the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to a variety of factors including the age, weight, general healtli, sex, diet, time of administration, rate of excretion, drug combination and response of the individual patient. In general, the daily dose from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg. On the other hand, it may be necessary to use dosages outside these limits in some cases.
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
• a formulation intended for oral administration to humans may contain from about 0.5 mg to about 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
• Dosage unit forms will generally contain from about 1 mg to about 2 g of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
• the compound of Formula I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
• parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrastemal injection or infusion techniques.
• the compound of the invention is effective in the treatment of humans.
• compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, solutions, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs,
• Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
• Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
• the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water-miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• water-miscible solvents such as propylene glycol, PEGs and ethanol
• an oil medium for example peanut oil, liquid paraffin, or olive oil.
• Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example
• heptadecaethyleneoxycetanol or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
• the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
• Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
• a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
• the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
• the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example
• polyoxyethylene sorbitan monooleate polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening and flavouring agents.
• Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
• the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-accep table diluent or solvent, for example as a solution in 1,3 -butane diol.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• the compounds of Formula I may also be administered in the form of suppositories for rectal administration of the drug.
• These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• Such materials are cocoa butter and polyethylene glycols.
• Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
• the compounds of the invention underwent pharmacological evaluations to determine their inhibitoiy effect on the enzyme FAAH (Fatty Acid Amide Hydrolase).
• Human FAAH cDNA (Accession No: NM_001441.1) was purchased from Origene (Rockville, MD). The full length FAAH was subcloned into the mammalian expression vector, pcDEF.neo, using Xbal and EcoRl restriction sites and used for stable cell line generation.
• Murine accession number NM_010173
• Rat FAAH accession number NM_024132
• RT-PCR reverse transcriptase polymerase chain reaction
• the resulting PCR product was ligated into pCR4 TOPO and DNA sequence confirmed.
• the full length murine FAAH was subcloned into the mammalian expression vector, pcDEFneo using either EcoRl (murine) or Kpnl and EcoRI (rat) restriction sites.
• Chinese hamster ovary cells were transfected following manufacturers protocol
• AMAXA AMAXA
• cells were trypsinized and transferred to 96 well plates in Iscove's DMEM media supplemented with 2mM Glutamine, 10% fetal calf serum, 1 mg/ml geneticin and HT Supplement (0.1 mM sodium hypoxanthine, 0.016 mM thymidine) in order to isolate single clones.
• HT Supplement 0.1 mM sodium hypoxanthine, 0.016 mM thymidine
• FAAH activity was assessed using a whole cell fluorescent anandamide assay, modified from Ramarao et al (2005). Following removal of tissue culture media cells were dislodged following addition of Cellstripper (Mediatech, Inc.
• CHO cells expressing FAAH were used to prepare either crude cell lysate or microsome fractions.
• tissue culture media was decanted, the monolayer washed three times with Ca ⁇ Mg ' " " free PBS and cells recovered after 15 min in enzyme free dissociation media (Millipore Corp, Billerica, MA).
• Cells were collected by centrifuging at 2000 rpm for 15 min. and the cell pellet re-suspended with 50 mM HEPES (pH 7.4) containing ImM EDTA and the protease inhibitors aprotinin (1 mg/ml) and leupeptin (100 ⁇ ).
• the suspension was sonicated at 4°C and the cell lysate recovered after centrifuging at 12,000xg (14,600rpm, SS34 rotor) for 20 min at 4°C to form a crude pellet of cell debris, nuclei, peroxisomes, lysosomes, and mitochondria; the supernatant or cell lysate was used for FAAH enzyme assay.
• microsomes fractions enriched in FAAH were prepared by centrifuging the cell lysate further at 27,000 rpm (100,000 x g) in SW28 rotor for 50 minutes at 4°C.
• the pellet containing FAAH- enriched microsomes was re-suspend in 50 mM HEPES, (pH 7,4) 1 mM EDTA, and any remaining DNA sheared by passage of material through a 23 gauge needle and aliquots of enzyme were store at -80°C prior to use.
• Assays are performed on either cell lysate or microsome fractions prepared as described or in whole cell format employing either the fluorescent substrate AAMCA (Cayman chemical, Ann Arbor, MI,) or 3 H-anandamide ([ETHANOLAMINE- 1-3H] American
• the cell lysate or microsome assay is performed in black PerkinElmer OptiPlates-384F by adding FAAH_CHO (whole cell (human whole cell or human WC), cell lysate (human cell lysate or human LY) or microsome) in assay buffer (50 mM
• Whole cell assay is conducted with cells harvested after rinsing tissue culture flasks three times with Ca ++ Mg ++ free PBS, incubating for 10 min in Enzyme free dissociation media and centrifuging for 5minutes at l,000rpm in table top centrifuge. Cells are resuspended in assay buffer at desired cell number in (4xl0 4 cells/assay in 96-well format; lxl0 4 cells/assay in 384- well format) and assayed as described.
• assays are performed using anandamide [ethanolamine l-.sup.3H] (specific activity of 10 Ci/mmol) diluted with cold anandamide to achieve a final assay concentration of 1 ⁇ anandamide (-50,000 cpm).
• Enzyme (CHO cell lysate, brain or liver homogenate) is incubated in assay buffer (50 niM Phosphate, pH 8.0, 1 mM EDTA, 200 mM KC1, 0.2% glycerol, 0.1 % fatty acid free BSA) with inhibitor at 25°C for 30 minutes.
• the reaction was terminated by addition of 2 volumes of chloroform: methanol (1 :1) and mixed by vortexing. Following a centrifugation step, 2000 rpm for 10 min. at room temperature, the aqueous phase containing the released 3 H-ethanolamide was recovered and quantitated by liquid scintillation as a reflection of FAAH enzyme activity.
• A4 lJ'-disnlfanediy bis(4-chIorobeiizene')
• A4 Commercially available from Fisher Scientific
• A5 2,2 '-disulfaoed iylbis(5-chlo ropyr .dine) (A5) 1
• Step A3-1 4-(lH-pYrrolof2,3- ⁇ 1pyridin-2-Yl)faenzenesu fonamide
• A3-1 2-bromo-lH-pyrrolo[2,3- bjpyridine (250mg s 1.269mmol), (4-sulfamolyphenyl)boronic acid (503mg 5 1.776mmpl), and cesium carbonate (2538 ⁇ , 2.54mraol, IM aqueous solution) were dissolved in DMF (6.4mL) and the resulting mixture was degassed with nitrogen for 10 minutes.
• Step A3-2 2-f2-fmethoxymethyi ' )phenyll-lH-pyrrolof2,3-Mpyridine
• Step A7-1 4- ⁇ 3-f(4-chlorophenvI)suifanyll-lH-pyrrolof2,3-Mpyridin-2-yl
• A7 4-(lH-pyrrolo[2,3-Z!]pyridin-2-yl)benzenesulfonamide (35mg, 0.064mmol) and NaH (95% wt ⁇ 3.23mg, 0.128mmol) were dissolved in anahydrous DMF (320 ⁇ ) at 0°C and stirred for 5 minutes before the addition of l,l'-disulfanediylbis(4-chlorobenzene) (46.0mg, 0.160mmol).
• Step A8-1 4-f3-ifS-chIoropyridiB"2-vt)suIfanYll-lH-pyrrolo[2,3- ⁇ lPYridin-2- vUbenzenesuifonamide
• A8 4-(lH-pyrrolo[2,3-Z>]pyridin-2-yl)benzenesulfonamide (7 tag, 0.026mmol) and NaH (95% wt, 1.3mg, 0.051mmol) were dissolved in anahydrous DMF (128 ⁇ .) at 0°C and stirred for 5 minutes before the addition of 2,2'-disulfanediylbis(5-chloropyridine) (18.52mg, 0.064mmol).
• reaction mixture was allowed to warm to room temperature over 7 hours and was quenched with the drop-wise addition of 0.5mL of water.
• the crude reaction mixture was syringe filtered and purified by reverse phase chromatography. The appropriate fractions were lyophilized to afford 0.2mg of a white solid. !
• Step A9-1 3- ⁇ ( 4-chlorophenYDsulfanvil -2-i2-(methoxyniethyl ' >phenyn - lH-py r rolo ⁇ 2,3-b] pyridine
• A9 2-[2-(methoxymethyl)phenyl]-lH-pyrrolo[2,3-d]pyridine (50mg, 0.210mmol), 2-[(4- chIorophenyl)sulfanyI]-IH ⁇ isoindole-l,3(2H)-dione (66.9mg, 0.23 Immol), and magnesium bromide
• Step Bl-1 2-bromo-3-ff4-chIoropheByi)sulfanvn-lH-Pyrrolot2,3- ⁇ lpyridine
• Bl 2-bromo-7- azaindole (1.026g; 5.2 mmol), A5 (1.66g; 5.75mmol) and Magnesium bromide (40mg; 0.217mmol) was dissolved in DMAc (lOmL) and heated to 60-70C °C for 3 hours under a nitrogen atmosphere. The reaction mixture was then cooled back to ambient temperature. Aqueous Sodium hydroxide (1.0N; lOmL) was added slowly via addition funnel during which time the product precipitated out as a white solid.
• Step B2-1 2 ⁇ bromo-3 ⁇ f (5-chloropy ridin-2-yI)su)fanYll - lH-pyrrolo ⁇ 2,3-b] pyridine
• B2 2-bromo-7- azaindole (0.5g; 2.54mmol) and A6 (0.81g; 2.79mmol; l . leq) was dissolved in DMF (lOmL). Sodium hydride (0.3 l g; 7.61mmol; 3 eq; 60wt% in mineral oil) was then added and the resulting solution was heated to 40 °C for 3 hours under a nitrogen atmosphere.
• the crude reaction mixture was cooled back to ambient temperature and water (20mL0 was added during which time product precipitated as a white solid.
• the crude product was filtered, washed with water (2x20mL) and purified by silica gel chromatography to yield 200 mg of a white solid.
• Step B4-1 2-fl.3-beMzodioxoI-5-vn-3-K4-chloropbenvnsuIfanyn-lH-pyrrolor2.3- ⁇ Pyridine
• B4 2-bromo-3-[(4-chlorophenyl)sulfanyl]-lH-pyrrolo[2,3-/j]pyridine
• Bl 50 mg, 0.15 mmol
• cesium carbonate 96 mg, 0.294 mmol
• l,3-benzodioxol-5-ylboronic acid (B3) 48 mg, 0.29 mmol
• PdCl 2 (dppf)CH 2 Cl 2 (12 mg, 0.015 mmol) were dissolved in a degassed solution of tetrahydrofura water (2: 1, 1.5 mL) and placed under argon atmosphere.
• the resulting solution was heated to 100 °C for 0.5 hours using microwave irradiation.
• the crude reaction mixture was then filtered over a celite pad, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated in vacuo.
• the crude product was purified using reverse phase chromatography. The appropriate fractions were extracted into ethyl acetate and washed with saturated sodium bicarbonate and brine to yield 34 mg of a white solid.
• Step B5-1 2-(l,3-ben3 ⁇ 4odioxol-5-yl)-3-[(5-chioropyridin-2-yl)sulfanyll-lH-pyrroIof2,3-j>lPYridine (B5): 2-bromo-3-[(5-chloropyridin-2-yl)sulfanyl]-lH ⁇ pyrrolo[2,3-ij]pyridine (B2) (50 mg, 0.14 mmol), cesium carbonate (96 mg, 0.294 mmol), l,3-benzodioxol-5-ylboronic acid (B3) (48 mg, 0.29 mmol), and PdCl 2 (dppf)CH 2 Cl 2 (12 mg, 0.015 mmol) were dissolved in a degassed solution of tetrahydrofuran:water (2: 1, 1.5 mL) and placed under argon atmosphere.
• the resulting solution was heated to 100 °C for 0.5 hours using microwave irradiation.
• the crude reaction mixture was then filtered over a celite pad, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated in vacuo.
• the crude product was purified using reverse phase chromatography. The appropriate fractions were extracted into ethyl acetate and washed with saturated sodium bicarbonate and brine to yield 34 mg of a white solid.
• Step C2-1 Prepared from B47 via amide coupling reaction.
• Step C6- 1
• Step H4-1 diastereomers was purified by reverse phase chromatography and the appropriate fractions were collected and lyophilized to afford 20 mg of a white solid.
• C3 fra»5-4-ammocycIohexanol (C3): Commercially available from Sigma Aldrich,
• the flask was then fitted with an air condenser and placed under balloon CO atm.
• the reaction flask was vacuum purged with CO 3X.
• the reaction was then heated to 80 deg overnight.
• the reaction mixture was then cooled and diluted with EtOAc and 3M LiCl.
• the layers were separated and the organic layer was washed with 3M LiCl (2X) and brine.
• the organic layer was dried over sodium sulfate, filtered and concentrated to yield a brown oil. This brown oil was taken up in dichloromethane and heated. The mixture is allowed to cool and precipitated solid is filtered off to yield 150 mg of pure product.
• Step C4-1 3-ff4-chIorophenyl)suIfanyl]-N-(fra «y-4-hYdroxycYclohexyI -lH-pyrroIof2,3- ⁇ lpYridine- 2-carboxainide
• C4 3-[(4-chlorophenyl)sulfanyl3-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid (C2) (25 mg, 0.082 mmol) and trans 4-aminocyclohexanol (C3) (28.3 mg, 0.246 mmol) were stirred in DMF (820 ⁇ ).
• Step C6-1 f3-i(4-chlorophenyI)sulfaiiyll-lH-pYrro)of2,3-f>lpyridin-2-yll(4-hydroxYpiperidin-l- vDmethanoae (C6): 3-[(4-chlorophenyl)sulfanyl]-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid (C2) (15 mg, 0.049 mmol) and 4-bydroxy piperidine (4.98 mg, 0.049 mmol) appropriate amine were stirred in DMF (492 ⁇ ).
• Dl 3-iodopyridin-2-amine (Dl): Commercially available from Sigma Aldrich.
• Step D3-1 fra « -4-[(2-aminopyridin-3-yl)ethvnYllcYcIohexanoI (D3): 3-iodopyridin-2-amine (Dl) (2 g, 9.09 mmol), ft3 ⁇ 4ras-4-ethynylcyclohexanol (D2) (1.47 g, 1 1.8 mmol), Cul (87 mg, 0.455 mmol), and PdCl 2 (PPh 3 ) 2 were stirred in anhydrous THF (36.4 ml) under a inert atmosphere.
• D3 3-iodopyridin-2-amine
• D2 ft3 ⁇ 4ras-4-ethynylcyclohexanol
• Cul 87 mg, 0.455 mmol
• PdCl 2 (PPh 3 ) 2 were stirred in anhydrous THF (36.4 ml) under a inert atmosphere.
• Triethylamine (3.80 mL, 27.3 mmol) was added to this solution and the reaction mixture was stirred for 6 hours.
• the crude reaction mixture was diluted with ethylacetate and filtered through celite.
• the resulting solution was concentrated under reduced pressure, and purified by normal phase chromatography (silica gel, 50-100% hexanes-EtOAc) to yield 1.30g of a white solid.
• Step D5-1 ⁇ rfl» -4-i3-f(4-chlorophenyl snifanyll-lH-pyrrolof2,3- ⁇ 1pyridin-2-yl ⁇ cYclohexanol
• D5 A stirring mixture of tr « «i , -4-[(2-aminopyridin-3-yl)ethynyl]cyclohexanol (D3) (100 mg, 0.462 mmol), l,l'-disulfanediylbis(4-chlorobenzene) (A4) (133 mg, 0.462 mmol), and PdCl 2 (8.2 mg, 0.046 mmol) in DMSO was heated to 80°C under an inert atmosphere for 18 hours.
• reaction mixture was then poured into ethylacetate, washed with brine, extracted and concentrated under reduced pressure.
• the crude reaction mixture was then purified by reverse phase chromatography (5%/95% ACN H20 to 95%/5% ACN/H20 over 10 min). Pure fractions were placed on the lyophilizer overnight to yield a white solid.
• Step D6-1 ftwts-4-f3 (5-chIoropyridin-2-yI)sulfanvIl-lH-pyrro ⁇
• step A8-1 Starting from /ra «5-4-(lH-pyrrolo[2,3-i!>]pyridin-2-yl)cyclohexanol (D4) (100 mg, 0.462 mmol) a similar experimental procedure was used as in step A8-1 with the following modification. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine and concentrated under reduced pressure. The reaction mixture was then concentrated under reduced pressure, and purified by normal phase chromatography (silica gel, 50-100% hexanes-EtOAc) to yield D6 as a white solid.
• Step D7-1 4-i3-ff4 ⁇ chIorophenYl)salfanyll-lH-pyrrolor2,3- ⁇ 1PYridin-2-vIicYcIohexanone 007): tr ⁇ ms-4- ⁇ 3-[(4-chlorophenyl)sulfanyl]-lH-pyrrolo[2 5 3-6]pyridin-2-yl ⁇ cyclohexanol (D5) (7 mg, 0.020 mmol), and Dess-Matrin periodinane (8.27 mg, 0.020 mmol) were dissolved in dichloromethane and the reaction mixture was allowed to for 15 mins.
• Step E2-1 3-[f4-chlorophenYi>suIfaavil-2-(2,3-dihydro-l,4-bepzodioxin-6-yl)-7-methYl-7H- py rrolo ⁇ 2.3-b] pyridine
• E2 3-[(4-chlorophenyl)sulfanyl]-2-(2 5 3-dihydro-l ,4-ben2odioxin-6-yl)-lH- pyrro]o[2,3-&]pyridine (B6) (200 mg, 0.506 mmol) was dissolved in anhydrous dimethylfonnamide (5.1 mL) in a sealed tube under argon atmosphere.
• lodomethane (El) (34.8 0.557 mmol) was added dropwise vi syringe and the resulting solution was heated to 85 °C for 4 hours.
• the crude reaction mixture was than cooled to 25 °C arid Hunig's base (265 1 ,52 mmol) was added to neutralize the pH and the resulting the solution was stirred for 10 minutes.
• the crude product was purified using reverse phase chromatography. The appropriate fractions were extracted into ethyl acetate and washed with saturated sodium bicarbonate and brine to yield 172 mg of a yellow solid.
• lodomethane (El) (34.8 ⁇ , 0.557 mmol) was added dropwise via syringe and the resulting solution was allowed to stir at 25 °C for 1.6 hours.
• the crude reaction mixture was filtered over a pad of celite and the crude product was purified using reverse phase chromatography. The appropriate fractions were extracted into ethyl acetate and washed with saturated sodium bicarbonate and brine to yield 1 5 mg of a white solid.
• Step F2-1 3-ff4-chlorophenvBsulfanYil-2-(4-methoxybenzylVlH-PYrroior2,3-&lpyridine
• F2 2- bromo-3-[(4-chlorophenyl)sulfanyl]-lH-pyrrolo[2,3-&]pyridine
• B l 3-bromo-3-[(4-chlorophenyl)sulfanyl]-lH-pyrrolo[2,3-&]pyridine
• B l 3-0.0 mg, 0.088 mmol
• Tetrakis(triphenylphosphine)palladium (10.2 mg, 8.8 ⁇ ) was added in one portion as a solid to the solution.
• Gl tert-butyl 4-iodopiperidine-l-carboxyIate
• G4 Methyl chloroformate
• G6 Methyl bromoacetate
• G6 Commercially available from Fisher Scientific Scheme G: Synthetic Procedures
• Step G2 feff-butyl 4- ⁇ 3-if4-chlorophepyl>suIfanYn-lH-PYrroIoi2.3-j>lpyridm-2-vUpiperidine-l- carboxylate
• G2 tert-buty ⁇ 4-iodopiperidine-l-carboxylate (Gl )(710 mg, 2.82 mmol) was dissolved in degassed THF (4.1 mL) and placed under argon atmosphere. An activated zinc solution (3.0 mL, 2.82 mmol, 0.75 M solution) was added dropwise to the stirring solution and the resulting mixture was stirred at 25 °C for 2 hours.
• the resulting zincate solution was then added dropwise via syringe to a solution of 2-bromo-3-[(4-chlorophenyl)suifanyl]-lH-pyrrolo[2,3-3 ⁇ 4]pyridine (Bl)(310 mg, 0.913 mmol) and bis(tri- i-butylphosphine)palladium (46.6 mg, 0.091 mmol) in degassed THF (5.0 mL) under argon atmosphere. The resulting solution was heated to 100 °C for 1 hour using microwave irradiation.
• the crude reaction mixture was then filtered over celite, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated in vacuo.
• the crude product was purified using reverse phase chromatography. The appropriate fractions were extracted into ethyl acetate and washed with saturated sodium bicarbonate and brine to yield 202 mg of a yellow oil.
• Step G3 3-f(4-ehIorophenYl)sulfanvn-2-(piperidiii-4-yl -lH-pyrroloi2,3-i)1pYridine
• G3 tert- butyl 4- ⁇ 3-[(4-chloiOphenyl)sulfanyl]-lH-pyrrolo[2,3-&]pyridin-2-yl ⁇ piperidine-l-carboxylate (35 mg, 0.079 mmol) was dissolved in methylene chloride (1.0 mL) and trifluoroacetic acid (30.4 ⁇ L, 0.394 mmol) was dropwise via syringe.
• Methyl chloroformate (G4) (6.31 L, 0.081 mmol) was added dropwise via syringe and the resulting solution was allowed to stir at 25 °C for 1 hour. The solution was then partitioned between chloroform and water, the combined organic? were dried using sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase chromatography. The appropriate fractions were extracted into ethyl acetate and washed with saturated sodium bicarbonate and brine to yield 26 mg of a colorless oil.
• Methyl bromoacetate (9.4 ⁇ ., 0.102 mmol) was added dropwise to the stirring solution and the resulting solution was allowed to stir at 25 °C for 1 hour.
• the solution was diluted with ethyl acetate and washed with aqueous lithium chloride.
• the organics were dried with sodium sulfate and concentrated in vacuo.
• the crude product was purified using reverse phase chromatography. The appropriate fractions were extracted into ethyl acetate and washed with saturated sodium bicarbonate and brine to yield 35 mg of a colorless oil.
• HI Methyl magnesium bromide (HI) : Commercially available from Fisher Scientific H3 : Lithium aluminum hydride (H3) : Commercially available from Fisher Scientific
• Step H2 4 ⁇ -ff4-chlorophenynsulfanYll-lH-pyrroiof2,3- ⁇ 1pyridin-2-Yl
• reaction mixture was quenched with aqueous ammonium chloride, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated in vacuo.
• the crude product was purified using reverse phase chromatography. The appropriate fractions were extracted into ethyl acetate and washed with saturated sodium bicarbonate and brine to yield 18 mg of a colorless oil.
• Step H4 3-i3-ff4-chlorophenyl)sulfanYll-lH-pyrro oi2,3- ⁇ lpyridin-2-Yl)propan-l-ol
• H4 Ethyl 3- ⁇ 3-[(4-ch]orophenyl)sulfanyl]-lH-pyrrolo[2,3-&]pyridin"2-yl ⁇ propanoate (F3)(25 mg, 0.069 mmol)' was dissolved in anhydrous THF (800 ⁇ ), placed under argon atmosphere and cooled to 0 °C.
• Lithium aluminum hydride (138 ⁇ , 0.14 mmol, 1 M solution) was added dropwise to the stirring solution and the resulting mixture was stirred at 0 °C for 0.5 hours. The reaction mixture was quenched with aqueous sodium potassium tartrate and stirred for 3 hours. The resulting solution was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified using reverse phase chromatography. The appropriate fractions were extracted into ethyl acetate and washed with saturated sodium bicarbonate and brine to yield 13 mg of a white solid.
• Step 13-1 5-i3-r(4-chIorophenyl suIfanyll-lH-nyrrolof2.3- ⁇ 1pyridin-2-YU-lH-indazole (13): 5- ⁇ 3- [(4-chlorophenyl)sulfanyl]-lH-pyrrolo[2,3-b]pyridin-2-yl ⁇ -2-fluorobenzaldehyde, 12 (60 mg, 0.157) was added to a solution of THF (1.0 mL) and hydrazine (50.2 mmol, 1.6 mL). The reaction mixture was heated to 100° for 16 hours. The hydrazine was then removed in vacuo to yield a white solid which was taken up in DCM and stirred.
• J3 Phenyl magnesium bromide (J3) : Commercially available from Fisher Scientific
• Step J2 3-ff4-chlorophenYl)sulfanyll-lH-pyrro of2,3-61pyridine-2-carbaldehyde
• J2 Ethyl 6- bromo-3-[(4-chlorophenyl)sulfanyl]-lH-pyrrolot2,3-3 ⁇ 4]pyridine-2-carboxylate (1.7 g, 4.13 mmol) was dissolved in anhydrous THF (42 mL) and placed under argon atmosphere. Lithium aluminum hydride (12.4 mL, 24.8 mmol, 2 M solution) was added dropwise to the stirring solution and the resulting solution was heated to reflux for 16 hours.
• Step J4 ⁇ 3-ff4-chIorophenYl)suIfanyll-lH-pyrrolof2 -&1pyridin-2-yl)(phenyl)methano
• J4 3-[(4-chlorophenyl)sulfanyl]-lH-pyrrolo[2,3-6]pyridine-2-carbaldehyde (J2) (35 mg, 0.121 mmol) was dissolved in anhydrous THF (1.2 mL) and cooled to 0 °C under argon atmosphere. Phenyl magnesium bromide (303 sL, 0.303 mmol, 1 M solution) was added dropwise via syringe.
• the resulting solution was allowed to stir at 0 °C for 2 hours.
• the reaction mixture was quenched with aqueous ammonium chloride, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated in vacuo.
• the crude product was purified using reverse phase chromatography. The appropriate fractions were extracted into ethyl acetate and washed with saturated sodium bicarbonate and brine to yield 21 mg of a yellow oil.
• Step J6 N-benzYl-t-(3-f(4-chIorophenvI)suIfanvI1-lH-pyrroioi2 - ⁇ lpyridin-2-Ynmethanamme (J6): 3-[(4-chlorophenyl)sulfanyl]-lH-pyrrolo[2 s 3-6]pyridine-2-carbaldehyde (J2) (25 mg, 0.087 mmol) and benzyl amine (46.4 mg, 0.433 mmol) were dissolved in dichloroethane (1.0 mL) and placed under argon atmosphere.

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