WO2007133756A2 - Crf1 receptor ligands comprising heteroaryl fused bicycles - Google Patents

Crf1 receptor ligands comprising heteroaryl fused bicycles Download PDF

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Publication number
WO2007133756A2
WO2007133756A2 PCT/US2007/011588 US2007011588W WO2007133756A2 WO 2007133756 A2 WO2007133756 A2 WO 2007133756A2 US 2007011588 W US2007011588 W US 2007011588W WO 2007133756 A2 WO2007133756 A2 WO 2007133756A2
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Prior art keywords
pyrrolo
compound
salt
ethyl
crf
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PCT/US2007/011588
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French (fr)
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WO2007133756A3 (en
Inventor
Raymond F. Horvath
Lu Yan Zhang
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Neurogen Corporation
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Publication of WO2007133756A3 publication Critical patent/WO2007133756A3/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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to novel substituted heteroaryl fused pyridine, pyrazine, and pyrimidine compounds that bind with high selectivity and/ or high affinity to CRF (Corticotropin Releasing Factor), preferably CRFl, receptors. It also relates to pharmaceutical compositions comprising such compounds and to their use in the treatment of psychiatric disorders and neurological diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders, as well as treatment of immunological, cardiovascular or heart-related diseases and digestive disorders including colonic hypersensitivity associated with psychopathological disturbance and stress, including Irritable Bowel Syndrome (IBS). Additionally this invention relates to the use such compounds as probes for the localization of CRF receptors in cells and tissues.
  • CRF Corticotropin Releasing Factor
  • Corticotropin releasing factor is a peptide that acts by binding to and modulating the signal transduction activities of specific cell surface receptors, including CRFl receptors and CRF2 receptors. CRF receptors are believed to play a significant role in integrating responses to stresss.
  • CRF has been shown to be involved in psychiatric disorders and neurological diseases including depression, anxiety-related disorders, gastrointestinal disorders and feeding disorders.
  • novel compounds of Formula I (below), and pharmaceutical compositions comprising such compounds and at least one pharmaceutically acceptable carrier or excipient.
  • Such compounds bind to cell surface receptors, preferably G-coupled protein receptors, especially CRF receptors (including CRFl and CRF2 receptors) and most preferably CRFl receptors.
  • CRF receptors including CRFl and CRF2 receptors
  • preferred compounds exhibit high affinity for CRF receptors, preferably CRF 1 receptors.
  • preferred compounds also exhibit high specificity for CRF receptors (i.e., they exhibit high selectivity compared to their binding to non-CRF receptors). Preferably they exhibit high specificity for CRF 1 receptors.
  • the invention provides compounds and pharmaceutically acceptable salts thereof that are of Formula I
  • R is H, Ci-C 4 alkyl, halogen, cyano, Cl-6 cycloalkyl, or S(O) n C 1 -C 4 alkyl;
  • Ar is optionally substituted aryl or heteroaryl
  • Z3 is optionally substituted nitrogen or carbon; the group:
  • n 0, I, or 2.
  • the invention further provides methods of treating patients suffering from certain disorders with a therapeutically effective amount of at least one compound provided herein.
  • disorders include CNS disorders, particularly affective disorders, anxiety disorders, stress-related disorders, eating disorders and substance abuse.
  • the patient suffering from these disorders may be a human or other animal (preferably a mammal), such as a domesticated companion animal (pet) or a livestock animal.
  • Preferred compounds for such therapeutic purposes are those that antagonize the binding of CRF to CRP receptors (preferably CRFl, or less preferably CRF2 receptors).
  • the ability of compounds to act as antagonists can be measured as an IC 50 value as described below.
  • the present invention provides pharmaceutical compositions comprising at least one compound or salt of Formula 1 (preferably at least one compound or salt of Table I) or the pharmaceutically acceptable salts (as defined below) thereof, which compositions are useful for the treatment of the above-recited disorders.
  • the invention further provides methods of treating patients suffering from any of the above- recited disorders with an effective amount of a compound or composition provided herein.
  • this invention relates to the use of the compounds provided (particularly labeled compounds) as probes for the localization of receptors in cells and tissues and as standards and reagents for use in determining the receptor-binding characteristics of test compounds.
  • Preferred compounds exhibit a half-maximal inhibitory concentration (IC 50 ) of less than 5 micromolar in the standard in vitro CRFl receptor binding assay provided in Example 7 below.
  • Particularly preferred compounds exhibit an IC 50 of about 1 micromolar or less, still more preferably an IC 50 of about 100 nanomolar or less even more preferably an IC 50 of about 10 nanomolar or less.
  • Certain particularly preferred compounds exhibit an IC 50 of 1 nanomolar or less in such standard binding assay.
  • Table I sets forth compounds of Formula I numbered 1 to 562, many of which are prophetic. Reference herein or in the claims to a "compound or salt of Table I” encompases any of these numbered compounds and the pharmaceutically acceptable salts of each. "MoI. Wt.” is the calculated molecular weight for each compound. TABLEI
  • Chlral 493.69 3- ⁇ 6-ethyl-1-[(1S)-2-methoxy-1-methylethyl]-3- methyl-1H-pyrrolo[3,2-b]pyridin-5-yl ⁇ -6- isopropyl-N-(3-morpholi ⁇ -4-y1propyl)pyridin- 2-amine
  • AU compounds listed above may be characterized at least by 1 H-NMR and one of the following LCMS methods:
  • MS conditions Electrospray positive ionization; capillary voltage 3.5kV; cone voltage 30V; desolvation and source temperature 250 0 C and 100 0 C respectively; mass range 120-800 with a scan time of 0.5 seconds and an inter scan delay of 0.1 min.
  • a Perkin Elmer HPLC system (tow Series 200 micro LC pumps, pump A and pump B, with a Series 200 autosampler) is used to perform flow injection.
  • Mobile phase is a combination of 85% methanol (pump B) with 15% of water (pump A).
  • the flow rate is 1.0 mL/min; and the injection volume is 3 ⁇ l.
  • MS instrumentation LC-MS experiments are performed using a Sciex 150MA Mass Spectrometer.
  • Ion source is Heated Nebulizer (atmosphere pressure chemical ionization). The mass range is 100-1000 amu. Both positive and negative modes are in place.
  • Nebulizer current is 2.0 mA, and the temperature is 350 0 C.
  • the Nebulizer gas is 10, and the Curtain gas is 12.
  • the declustering potential is 30 V.
  • the Focusing potential is 200 V, and the entrance potential is -10 V.
  • Nebulizer current is -2.0 mA, and the temperature is 350 0 C.
  • the Nebulizer gas is 10, and the Curtain gas is 12.
  • the declustering potential is -30 V.
  • the Focusing potential is -200 V, and the entrance potential is 10 V.
  • HPLC Instrumentation HPl 100 PUMP, HPIlOO UV detector with 220 nm, HTS/PAL autosampler from Leap Technology, data acquired by Micromass Ma
  • HPLC conditions Synergi 2U HYDRO-RP 20 x 4.0mm column, flow rate 1.0 mL/min, injection volume 5 ⁇ L.
  • MS conditions Scan m/z 100-1200, capillary voltage 3000V, cone voltage 25V, desolvation 200 0 C and source temperature 100 0 C.
  • Compounds of and salts of Formula I are useful in treating a variety of conditions including affective disorders, anxiety disorders, stress disorders, eating disorders, and drug addiction. Hence they each may be used in the manufacture of a medicament for the treatment of each such condition.
  • Affective disorders include all types of depression, bipolar disorder, cyclothymia, and dysthymia.
  • Anxiety disorders include generalized anxiety disorder, panic, phobias and obsessive-compulsive disorder.
  • Compounds of and salts of Formula I are useful in treating symptoms of affective disorders and anxiety disorders. These syptoms include increased awakenings, increased REM density, and related sleep disorders (e.g., insomnia) and dermatologic conditions including atopic dermatitis, urticaria and psoriasis.
  • Stress-related disorders include post-traumatic stress disorder, hemorrhagic stress, stress-induced psychotic episodes, psychosocial dwarfism, stress headaches, stress-induced immune systems disorders such as stress-induced fever, and stress-related sleep disorders.
  • Eating disorders include anorexia nervosa, bulimia nervosa, and obesity.
  • Compounds provided herein are also useful in the treatment (e.g., symptomatic treatment) of a variety of neurological disorders including supranuclear palsy, AIDS related dementias, multiinfarct dementia, neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, head trauma, spinal cord trauma, ischemic neuronal damage, amyotrophic lateral sclerosis, disorders of pain perception such as fibromyalgia and epilepsy.
  • neurological disorders including supranuclear palsy, AIDS related dementias, multiinfarct dementia, neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, head trauma, spinal cord trauma, ischemic neuronal damage, amyotrophic lateral sclerosis, disorders of pain perception such as fibromyalgia and epilepsy.
  • compounds and salts of Formula I are useful in the treatment (e.g., symptomatic treatment) of a number of gastrointestinal, cardiovascular, hormonal, autoimmune and inflammatory conditions.
  • Such conditions include irritable bowel syndrome (IBS), ulcers, Crohn's disease, spastic colon, diarrhea, post operative ilius, and colonic hypersensitivity associated with psychopathological disturbances or stress; hypertension, tachycardia, congestive heart failure, infertility, and euthyroid sick syndrome; and inflammatory conditions effected by or associated with rheumatoid arthritis, osteoarthritis, pain, asthma, psoriasis and allergies.
  • IBS irritable bowel syndrome
  • ulcers Crohn's disease
  • spastic colon diarrhea
  • post operative ilius and colonic hypersensitivity associated with psychopathological disturbances or stress
  • hypertension tachycardia
  • congestive heart failure congestive heart failure
  • infertility infertility
  • euthyroid sick syndrome
  • Compounds and salts of Formula I are also useful as modulators of the CRFl receptor in the treatment of animal disorders associated with aberrant CRF levels.
  • Such conditions include porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs, psychosocial dwarfism and hypoglycemia.
  • Typical subjects to which compounds of Formula I may be administered include mammals, preferably primates, most preferably humans.
  • mammals preferably primates, most preferably humans.
  • livestock such as cattle, sheep, goats, cows, swine and the like; poultry such as chickens, ducks, geese, turkeys, and the like; and other domesticated animals particularly pets such as dogs and cats.
  • rodents e.g. mice, rats, hamsters
  • rabbits, primates, and swine such as inbred pigs and the like.
  • body fluids e.g., blood, plasma, serum, CSF, lymph, cellular interstitial fluid, aqueous humor, saliva, synovial fluid, feces, or urine
  • cell and tissue samples of the above subjects are suitable for use.
  • Test compounds e.g., a potential pharmaceutical
  • Labeled compounds provided herein are also useful as tracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
  • PET positron emission tomography
  • SPECT single photon emission computerized tomography
  • More particularly compounds provided herein are useful for demonstrating the presence of CRF receptors in cell or tissue samples. This may be done by preparing a plurality of matched cell or tissue samples, at least one of which is prepared as an experiment sample and at least one of which is prepared as a control sample.
  • the experimental sample is prepared by contacting (under conditions that permit binding of CRF to CRF receptors within cell and tissue samples) at least one of the matched cell or tissue samples that has not previously been contacted with any compound or salt provided herein with an experimental solution comprising the detectably-labeled preparation of the selected compound or salt at a first measured molar concentration.
  • control sample is prepared by in the same manner as the experimental sample and is incubated in a solution that contains the same ingredients as the experimental solution but that also contains an unlabelled preparation of the same compound or salt provided herein at a molar concentration that is greater than the first measured molar concentration.
  • the experimental and control samples are then washed to remove unbound detectably-labeled compound.
  • the amount of detectably-labeled compound remaining bound to each sample is then measured and the amount of detectably-labeled compound in the experimental and control samples is compared.
  • a comparison that indicates the detection of a greater amount of detectable label in the at least one washed experimental sample than is detected in any of the at least one washed control samples demonstrates the presence of CRP receptors in that experimental sample.
  • the detectably-labeled compound used in this procedure may be labeled with any detectable label, such as a radioactive label, a biological tag such as biotin (which can be detected by binding to detectably-labeled avidin), an enzyme (e.g., alkaline phosphatase, beta galactosidase, or a like enzyme that can be detected its activity in a colorimetric assay) or a directly or indirectly luminescent label.
  • tissue sections are used in this procedure and the detectably-labeled compound is radiolabeled
  • the boxmd, labeled compound may be detected autoradiographically to generate an autoradiogram.
  • the amount of detectable label in an experimental or control sample may be measured by viewing the autoradiograms and comparing the exposure density of the autoradiograms.
  • the present invention also pertains to methods of inhibiting the binding of CRF to CRF receptors (preferably CFRl receptors) which methods involve contacting a solution containing a compound provided herein with cells expressing CRF receptors, wherein the compound is present in the solution at a concentration sufficient to inhibit CRF binding to CRF receptors in vitro.
  • This method includes inhibiting the binding of CRF to CRF receptors in vivo, e.g., in a patient given an amount of a compound or salt of Formula I (preferably of Table I) that would be sufficient to inhibit the binding of CRF to CRF receptors in vitro.
  • such methods are useful in treating physiological disorders associated with excess concentrations of CRF.
  • the amount of a compound that would be sufficient to inhibit the binding of CRF to the CRF receptor in vitro may be readily determined via a CRF receptor binding assay (see, e.g., Example 7), or from the IC 5 0 determined using a CRF receptor functional assay, such as the standard assay of CRF receptor activity of Example 6.
  • the CRF receptors used to determine in vitro binding may be obtained from a variety of sources, e.g., from cells that naturally express CRF receptors, e.g. IMR32 cells, or from cells expressing cloned human CRF receptors.
  • the present invention also pertains to methods for altering the activity of CRF receptors, said method comprising exposing cells expressing such receptors to an effective amount of a compound provided herein, wherein the compound is present in the solution at a concentration sufficient to specifically alter the signal transduction activity in response to CRF in cells expressing CRF receptors in vitro.
  • Preferred cells for this purpose are those that express high levels of CRF receptors (i.e., equal to or greater than the number of CRFl receptors per cell found in differentiated IMR-32 human neuroblastoma cells), with IMR-32 cells being particularly preferred for testing the concentration of a compound required to alter the activity of CRFl receptors.
  • This method includes altering the signal transduction activity of CRF receptors in vivo, e.g., in a patient given an amount of a compound or salt of Formula I (preferably of Table I) that would be sufficient to alter the signal transduction activity in response to CRF in cells expressing CRF receptors in vitro.
  • the amount of a compound that would be sufficient to alter the signal transduction activity of CRF receptors in response to CRF in vitro may also be determined via an assay of CRF receptor mediated signal transduction, such as an assay wherein the binding of CRF to a cell surface CRF receptor effects a changes in reporter gene expression.
  • the present invention also pertains to packaged pharmaceutical compositions for treating disorders responsive to CRF receptor modulation, e.g., eating disorders, depression or stress.
  • the packaged pharmaceutical compositions include a container holding dosage units comprising a therapeutically effective amount of at least one compound or salt of Formula I (preferably of Table I) and instructions for using the treating disorder responsive to CRFl receptor modulation in the patient.
  • Suitable substituents include, for example, halogen, cyano, amino, hydroxy, nitro, azido, carboxamido, -COOH, SO 2 NH 2 , alkyl (e.g., d-Cgalkyl), alkenyl (e.g., C 2 -C 8 alkenyl), alkynyl (e.g., C 2 -C 8 alkynyl), alkoxy (e.g., Ci-Cgalkoxy), alkyl ether (e.g., C 2 -C 8 alkyl ether), alkylthio (e.g., Ci- C 8 alkylthio), haloalkyl (e.g., Ci-Cghaloalkyl), hydroxyalkyl (e.g., Ci-Cghydroxyalkyl), aminoalkyl (e.g., Ci-C 8 aminoalkyl), haloalkoxy (e.g., Ci-Cghaloalkoxy), alkan
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -CONH 2 is attached through the carbon atom.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, and where specified, having the specified number of carbon atoms.
  • Ci-C 6 alkyl indicates an alkyl group having from 1 to 6 carbon atoms.
  • Alkyl groups include groups having from 1 to 8 carbon atoms (Ci-
  • Csalkyl from 1 to 6 carbon atoms (Ci-C ⁇ alkyl) and from 1 to 4 carbon atoms (Cj-C 4 alkyl), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
  • preferred alkyl groups are methyl, ethyl, propyl, butyl, and 3-pentyl.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • a "heteroatom” is an atom other than carbon, such as oxygen, sulfur or nitrogen.
  • aryl refers to a group that comprises at least one aromatic ring. Examples of aryl groups include phenyl and naphthyl.
  • heteroaryl refers to a group that comprises at least one aromatic ring having from 1 to 4 heteroatoms. When the total number of S and 0 atoms in a heteroaryl group exceeds 1, then these heteroatoms are not adjacent to one another; preferably the total number of S and 0 atoms in a heteroaryl is not more than 1, 2 or 3, more preferably 1 or 2 and most preferably not more than 1.
  • heteroaryl groups include pyridyl, furanyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, thienyl, thiazolyl, triazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinoline.
  • optically active forms such as by resolution of racemic forms (racemates), by asymmetric synthesis, or by synthesis from optically active starting materials. Resolution of the racemates can be accomplished, for example, by conventional methods such as by crystallization in the presence of a resolving agent, or by chromatography, using, e.g., a chiral HPLC column.
  • compounds with carbon-carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified.
  • a compound can exist in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms.
  • Recited compounds are further intended to encompass compounds in which one or more atoms are replaced with an isotope (i.e., an atom having the same atomic number but a different mass number).
  • isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11 C, 13 C, and 14 C.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making non-toxic acid or base salts thereof, and further refers to pharmaceutically acceptable solvates of such compounds and such salts.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, malefic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH 2 >n-COOH where n is 0-4, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable. Lists of additional suitable salts maybe found, e.g., in Remington 's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, PA, p. 1418 (1985).
  • prodrugs of the compounds of the recited Formulas are provided herein.
  • a "prodrug” is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a patient, to produce a compound a formula provided herein.
  • a prodrug may be an acylated derivative of a compound as provided herein.
  • Prodrugs include compounds wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, amino, o ⁇ sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, esters such as acetate, formate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein.
  • Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to yield the parent compounds.
  • terapéuticaally effective amount means an amount of a compound or salt of Table I that is effective, when administered to a human or non-human patient, to provide a therapeutic benefit such as an amelioration of symptoms, e.g., an amount effective to antagonize the effects of pathogenic levels of CRF or to treat the symptoms of any of the disorders listed above under the subheading "Methods of Treament". It will be apparent that the therapeutic benefit may be apparent after administration of a single dose, or may become apparent following repeated administration of the therapeutically effective dose according to a predetermined regimen, depending upon the indication for which the compound is administered.
  • Compounds of Formula I may be administered orally, topically, transdermally, parenterally, by inhalation or spray or rectally or vaginally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrathecal and like types of injection or infusion techniques.
  • a pharmaceutical formulation comprising a compound provided herein and a pharmaceutically acceptable carrier.
  • One or more compounds of Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
  • compositions containing compounds of Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or 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, flavoring agents, coloring 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 that 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, e.g., starch, gelatin or acacia, and lubricating agents, e.g., 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 monosterate or glyceryl distearate may be employed.
  • 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 ingredient is mixed with water or an oil medium, e.g., peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium e.g., peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, e.g., sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, 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, e.g., polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, e.g., 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,
  • the aqueous suspensions may also contain one or more preservatives, e.g., 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 or saccharin.
  • preservatives e.g., ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents e.g., ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents e.g., n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, e.g., arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, e.g., beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. 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., sodium EDTA
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium EDTA, sodium sulfate, sodium bicarbonate
  • compositions provided herein may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, e.g., olive oil or arachis oil, or a mineral oil, e.g., liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally- occurring gums, e.g., gum acacia or gum tragacanth, naturally-occurring phosphatides, e.g., soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, e.g., sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, e.g., polyoxyethylene sorbitan monoleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, e.g., glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable dilutent or solvent, e.g., as a solution in 1 ,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • 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.
  • Compounds of Formula I may also be administered in the form of suppositories, e.g., for rectal administration of the drug.
  • suppositories e.g., for rectal administration of the drug.
  • suitable non-irritating excipient that is solid at ordinary temperatures but liquid at body temperature and will therefore melt in the body to release the drug.
  • Such materials include cocoa butter and polyethylene glycols.
  • Compounds of Formula I may be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • one or more adjuvants such as preservatives, buffering agents, or local anesthetics can also be present in the vehicle.
  • Dosage levels of the order of from about 0.05 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions, preferred dosages range from about 0.1 to about 30 mg per kg and more preferably from about 0.5 to about 5 mg per kg per subject per day.
  • 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. Dosage unit forms will generally contain between from about 0.1 mg to about 750 mg of an active ingredient.
  • Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most CNS and gastrointestinal disorders, a dosage regimen of four times daily, preferably three times daily, more preferably two times daily and most preferably once daily is contemplated. For the treatment of stress and depression a dosage regimen of 1 or 2 times daily is particularly preferred.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration,- route of administration, and rate of excretion, drug combination (i.e. other drugs being used to treat the patient) and the severity of the particular disease undergoing therapy.
  • Preferred compounds of Formula I will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, such that the preferred oral dosage forms discussed above can provide therapeutically effective levels of the compound in vivo. Penetration of the blood brain barrier is necessary for most compounds used to treat CNS disorders, while low brain levels of compounds used to treat periphereal disorders are generally preferred. Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to predict compound toxicity, with non-toxic compounds being preferred. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound, e.g., intravenously.
  • Percentage of serum protein binding may be predicted from albumin binding assays. Examples of such assays are described in a review by Oravcova, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27). Preferred compounds exhibit reversible serum protein binding. Preferably this binding is less than 99%, more preferably less than 95%, even more preferably less than 90%, and most preferably less than 80%.
  • Frequency of administration is generally inversely proportional to the in vivo half-life of a compound.
  • In vivo half-lives of compounds may be predicted from in vitro assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127). Preferred half lives are those allowing for a preferred frequency of administration.
  • preferred compounds of Formula I exhibit activity in the standard in vitro CRF receptor binding assay specified in Example 7 below.
  • References herein to "standard in vitro receptor binding assay” are intended to refer to this standard assay protocol.
  • preferred compounds of Formula I preferably of Table I
  • the compounds and salts of Formula I may be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described in Scheme I. Those skilled in the art will recognize that the starting materials may be varied and additional steps employed in order to obtain particular compounds and salts of Formula I (preferably of Table I).
  • Step A 2,6-Dichloropyrazine (11.7g), (S)-(+)-l-methoxy-2-propylamine (7g) and EtaN (15 mL) in EtOH (100 mL) are heated at 105 0 C for 2 days. The mixture is evaporated and dissolved in EtOAc and washed with sat. NaHCO 3 , H 2 O and dried. Evaporation affords 2- chloro-6-[(S)-l-methoxy-2-propyl]aminopyrazine.
  • Step C 3-Bromo-2-chloro-6-[(S)-l-methoxy-2- ⁇ ropyl]aminopyrazine (10.7g) and 2- methoxy-6-isopropyl-3-pyridineboronic acid (9.7g) are dissolved in DME (25OmL). After lOmin of degassing, tetrakis(triphenylphosphine)palladium(0) (2.2g) is added, followed by 1 min of degassing. Upon addition of an aqueous IN sodium carbonate solution (76mL), the reaction mixture is heated at 90 0 C for 12h.
  • Step E 3- ⁇ 5-Bromo-2-chloro-6-[(S)-l-methoxy-2-pro ⁇ yl]aminopyrazin-3-yl ⁇ -2-methoxy-6- isopropylpyridine (4.3 g) is dissolved in DMSO (50 ml). Upon addition of NaH (60%, 0.8g), the reaction mixture is stirred at 25 0 C for 30 min before allyl bromide (1.7 mL) is added. The reaction mixture is stirred at 25 0 C for 2h. Subsequently, the crude mixture is put into water (25OmL), extracted with EtOAc/hexane (1 :4, 2x250mL), and dried over sodium sulfate.
  • Step F 3- ⁇ 5-Bromo-2-chloro-6-[(S)-N-allyl-l-methoxy-2-propyl]aminopyrazin-3-yl ⁇ -2- methoxy-6-isopropylpyridine (4.6g) is dissolved in DMF (8OmL). After lOmin of degassing, Pd(OAc) 2 (225mg) is added, followed by 1 min of degassing. Upon addition of potassium carbonate (4.1 g) and Bn 4 NBr (4.Og), the reaction mixture is heated at 90 0 C for Ih.
  • Step G (S)-3-Chloro-2-(6-isopropyl-2-methoxy-pyridin-3-yl)-5-(2-methoxy-l-methyl- ethyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazine (2.Ig) and tetrakis(triphenylphosphme)palladiurn(0) (60 mg) is dissolved in anhydrous THF (1OmL). Upon addition of trimethlaluminum (2M in toluene, 5.3mL) the reaction mixture is heated to 65 0 C for 8h. Subsequently, the crude reaction mixture is cooled to room temperature and poured into icy water saturated with sodium-potassium tartrate.
  • Step H The product of step G (4.6g) in 4N hydrochloric acid (4OmL) is heated at 75 0 C for 18 h. The reaction mixture is cooled to 0 0 C, neutralized with aqueous 50% NaOH and extracted with dichloromethane (3x15mL). The combined extract is washed with water (35mL) the brine (35mL) and dried over sodium sulfate. Silica gel chromatography affords purified product.
  • Step I The product of step H (4.4g) is dissolved in dicloromethane (4OmL). Triflic anhydride (2.6mL) is added gradually at - 5 0 C, and then triethylamine (3.4mL) is added.
  • Step J The product of step I (400mg) is dissolved in toluene (5mL). After 10 min of degassing, tetrakis(triphenylphosphine)palladium(0) (35mg) is added, followed by 1 min of degassing.
  • Step A 2,5-dibromo-3-methylpyridine (18.9Og) and the previously described 2-ethyl-6- methoxy-3 -pyridine boronic acid (13.7Og) are dissolved in DME (20OmL). After degassing, tetrakis(t ⁇ iphenylphos ⁇ hine)palladium (0) (3.6Og) is added. A second degassing is followed by addition of a 5N sodium carbonate solution (3OmL) whereupon the reaction is heated to 80 0 C for 16h. The yellowish mixture is then put into water (50OmL), extracted with DCM (2x300mL), and dried over sodium sulfate. Purification on silica gel affords the coupled product.
  • Step B The purified compound (6.4Og) of step A and (i?)-l-methoxy-2-armnopropane (2.04g) are dissolved in toluene (8OmL) and briefly degassed. Subsequently, Pd 2 (dba> 3
  • Step C The amino compound of step B is dissolved in chloroform (20OmL) and NBS (0.9- 1.0 eq.) is added in portions until TCL control verifies full conversion of the starting material. Subsequently, the yellowish mixture is put into water (20OmL), extracted with DCM (3x10OmL), and dried over magnesium sulfate. Purification on silica gel affords the bromide.
  • Step D The purified bromide (7.59g) of step C and allyl bromide (2.04mL) are dissolved in DMF (10OmL). Sodium hydride (1.16g) is added in 3 portions and the reaction is stirred for 90 min at rt.
  • Step E The allyl compound (7.89g) of step D, tetrabutylammonium bromide (5.85g), palladium acetate (0.4Ig), and potassium carbonate (7.53g) are dissolved in DMF (15OmL).
  • Step A ( ⁇ )-2-Amino-3-methoxy-propan-l-ol hydrochloride (CAS#: 148278-96-0) (6.74g) and imidazole(13.7g) are taken in anhydrous methylene chloride (300ml). TBDMSCl (22.7g) is added in one portion. The reaction is carried on overnight. The reaction mixture is washed with water (200mlx3) and dried with Na 2 SO 4 . Concentration removes all volatiles. The crude product is used for next step reaction without further purification.
  • Step B A mixture of the known bromide (6.4g, 0.02mol), amine (1.5equiv.), BINAP (1.Og), Pd 2 (dba) 3 (0.6g), NaO-?-Bu(4.0g) in toluene(80ml) is heated at 85 °C under N 2 atmosphere overnight. The reaction mixture is cooled to room temperature and quenched with water. The resulting mixture is separated and extracted with ethyl acetate. The combine organic layers are washed with brine and dried with Na 2 SO 4 . Silica gel flash chromatography with hexane/ethyl acetate gives purified product.
  • Step C The starting material (7.3g) is taken in anhydrous CHCl 3 (100ml). 1.0 equivalent of
  • Step D Starting material (5.9g) is taken in anhydrous THF (100ml). Allyl iodide (3.6ml) is added followed by the addition of KO- ⁇ -Bu/THF solution (1.0M, 44ml) at room temperature.
  • Step E The crude product (6.4g) of previous reaction is taken in DMF (60ml) followed by the addition of tetrabutylammonium bromide (4.4g), K 2 CO 3 (4.6g), Pd(OAc) 2 (13 Omg). The resulting mixture is heated at 85 0 C under N 2 atmosphere for one hour. The reaction mixture is cooled to room temperature and diluted with water. The resulting mixture is extracted with ethyl acetate. The combine organic layers are washed with brine and dried with Na 2 SO 4 .
  • Step F Starting material (5.4g) is taken in THF (60ml) followed by the addition of tetrabutylammonium fluoride (2 equiv.) at room temperature. The reaction is complete after 2 hours. The reaction mixture is washed with water, brine and dried with Na 2 SO 4 . Silica gel flash chromatography with hexane/ethyl acetate gives purified product.
  • Step G Starting material (1.Ig) is taken in anhydrous methylene chloride (50ml) followed by the addition of [Bis(2-methoxyethyl)amino]sulfur trifluoride (2 equiv.) at room temperature. The reaction is stirred at room temperature overnight. The reaction mixture is carefully quenched with ice-water. The resulting mixture is separated and extracted with methylene chloride and dried with Na 2 SO 4 . Silica gel flash chromatography with hexane/ethyl acetate affords the title compound.
  • Step B The allylic compound (892mg) of step A, tetrabutylammonium bromide (575mg), palladium acetate (40mg), and potassium carbonate (737mg) are dissolved in DMF (1OmL). After heating to 80 0 C for 30 min. the mixture is worked-up according to step A. Purification on silica gel affords the Heck-product.
  • Step C The Heck product (356mg) of step B is dissolved in THF (2.5mL) and added to a solution of t-BuLi (1.05mL, 1.7N in pentane) in THF (8.5mL) at -78 0 C.
  • Step D The methyl product of step C (238mg) and the known 2-zjopropyl-6-methoxy-5- pyridine boronic acid (158mg) are dissolved in DME (5.OmL). After degassing, tetrakis(triphenylphosphine)palladium (0) (77mg) is added. A second degassing is followed by addition of a IN sodium carbonate solution (1.35mL) whereupon the reaction is heated to
  • Step E The Suzuki product of step D is dissolved in THF (5.OmL). After addition of TBAF monohydrate (650mg), the reaction mixture is stirred for 30 min. Subsequently, the yellow solution is put into water (10OmL), extracted with DCM (3x10OmL), and dried over magnesium sulfate. Purification on silica gel affords the title compound.
  • Step A TBDMSCl (2Og) is added to a cold (O 0 C) solution of 4-hydroxy-2-butanone (17.6g), DMAP (200mg), imidazole (10.8g) in DMF (160ml). The reaction mixture is warmed naturally to room temperature and stirred for 24 hours. The reaction mixture is added with water and extracted with ethyl acetate and dried with Na 2 SO 4 . Purification by column with hexane/ethyl acetate gives product.
  • Step B Triethyl phosphonoacetate (17.3ml) is added as a solution of THF (30ml) to a cold (0 0 C) suspension of NaH (0.131mol) in anhydrous THF (80ml). The resulting mixture is stirred at 0 0 C for 1 hour before ketone (17.67g) is added as a solution of THF (10ml). The reaction is continued at room temperature for another 2 hours. Saturated aqueous NH4C1 is carefully added and separated. Aqueous layer is extracted with ether. The combined organic layers are washed with water, brine.
  • Step C Starting material (21.3g) is treated with DIBAL-H(1.0M in toluene, 196ml) at 0 0 C for 6 hours. Water is carefully added to quench the excess DIBAL. The reaction mixture is filtered and washed with ethyl acetate. The filtrate is concentrated to afford the crude product. Rf: 0.4(hexane/ethyl acetate: 3:1).
  • Step D Starting material (8.75g) is taken in anhydrous methylene chloride (110ml), triethylamine is added.
  • Step E 2,6-dichloropyridine (17g) and CH 3 NH 2 aqueous solution (40%, 26.8g) are taken in THF (100ml) in a sealed tube and is heated at 8O0C for 24 hours. The reaction is cooled to room temperature and diluted with water. The resulting mixture is separated and extracted with ethyl acetate. The combined organic layers are washed with brine and dried with Na 2 SO 4 . The crude product is used for the next step reaction without further purification. LCMS: 143.3 (M+H) +
  • Step F A mixture of 2-chloro-6-methylarnino-pyridine (3.56, 0.025mol), 2-methoxy-6- isopropyl-3-pyridylboronic acid (6.33g), Pd(PPh 3 J 4 (577mg), aqueous Na 2 CO 3 solution (1.0M, 50ml), and toluene (50ml) is heated at 100 0 C under the N2 atmosphere overnight. The reaction mixture is cooled to room temperature and separated. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine and dried with Na 2 SO 4 . The crude product is used for the next step reaction without further purification.
  • Step G The crude starting material is taken in anhydrous CHCI3 (100ml). 4.0 equivalent of NBS is added in one portion at O 0 C. The reaction is complete in 0.5 hour. The reaction mixture is washed with water and dried with Na2SO 4 . Purification by flash column with hexane/ethyl acetate gives product as clear oil. LCMS: m/z 496.1 (M+H) + Step H: NaH (795mg, 60% in mineral oil) is added to a solution of starting material (6.34g) in anhydrous DMF (100ml) and stirred at room temperature for lOminutes.
  • Step I A mixture of bromide (9.26g), tetrabutylammonium bromide (5.95g), K 2 CO 3 (0.12g), Pd(OAc) 2 (LOg) in DMF(80ml) is heated at 8O 0 C under N2 atmosphere for 20 minutes. The reaction mixture is cooled to room temperature and diluted with water. The resulting mixture is extracted with ethyl acetate. The combine organic layers are washed with brine and dried with Na 2 SO 4 . Purification by flash column with hexane/ethyl acetate gives product as clear oil.
  • Step K Starting material (1.26g) is taken in THF (50ml) followed by the addition of tetrabutylammonium fluoride (1.5 equiv.) at room temperature. The reaction is complete after 4 hours. The reaction mixture is washed with water, brine and dried with Na 2 SO 4 . Silica gel chromatography with hexane/ethyl acetate affords the title compound.
  • chemiluminescent ELISA system cAMP- Screen ® , Applied Biosystems, Bedford, MA
  • cAMP- Screen ® 3 ',5 '-cyclic AMP
  • IMR32 cells (ATCC CCL 127) are grown to confluence in one or more T-175 flasks, each flask is split evenly into the wells of two pre-coated 96-well cAMP-Screen ® assay plates prior to the test treatment and ELISA, each plate is then incubated for 16 hours and assayed.
  • the following assay is referred to herein and in the claims as a standard in vitro CRF receptor binding assay.
  • the CRF receptor binding is performed using a modified version of the assay described by Grigoriadis and De Souza (Methods in Neurosciences, Vol. 5, 1991).
  • IMR-32 human neuroblastoma cells a cell-line that naturally expresses the CRFl receptor, are grown in IMR-32 Medium (see preceeding Example). The cells are grown to confluence and split three times (all splits and harvest are carried out using NO-ZYME — JRH Biosciences, Cat# 59226).
  • the cells are first split 1:2, incubated for 3 days and split 1 :3, and finally incubated for 4 days and split 1 :5.
  • the cells are then incubated for an additional 4 days before being differentiated by treatment with 5-bromo- 2'deoxyuridine (BrdU, Sigma, Cat# B9285).
  • the medium is replaced every 3-4 days with IMR-32 medium w/2.5uM BrdU and the cells are harvested after 10 days of BrdU treatment and washed with calcium and magnesium- free PBS. .
  • receptor containing membranes To prepare receptor containing membranes, cells are homogenized in wash buffer (50 mM Tris HCl, 10 mM MgCl 2 , 2 mM EGTA, pH 7.4) and centrifuged at 48,000 x g for 10 minutes at 4 0 C. The pellet is re-suspended in wash buffer, and the homogenization and centrifugation steps are performed two additional times.
  • wash buffer 50 mM Tris HCl, 10 mM MgCl 2 , 2 mM EGTA, pH 7.4
  • Membrane pellets (containing CRF receptors) are re-suspended in 50 mM Tris buffer pH 7.7 containing 10 mM MgCl 2 and 2 mM EDTA and centrifuged for 10 minutes at 48,00Og. Membranes are washed again and brought to a final concentration of 1500 ug/ml in binding buffer (Tris buffer above with 0.1 % BSA, 15 mM bacitracin and 0.01 mg/ml aprotinin.).
  • ⁇ L of the membrane preparation are added to 96 well microtube plates containing 100 ⁇ L of l25 I-sauvagine (SA 2200 Ci/mmol, final concentration of 100 pM) and 50 ⁇ L of test compound. Binding is carried out at room temperature for 2 hours. Plates are then harvested on a BRANDEL 96 well cell harvester and filters are counted for gamma emissions on a Wallac 1205 BETAPLATE liquid scintillation counter. Non-specific binding is defined by 1 raM cold CRF. IC 50 values are calculated with the nonlinear curve fitting program RS/1 (BBN Software Products Corp., Cambridge, MA).
  • the binding affinity (expressed as IC 50 value) for those compounds and salts of Table I that have been tested generally ranges from about 0.5 nanomolar to about 10 micromolar.
  • Preferred compounds or salts of Formula I exhibit IC 50 values of less than or equal to 1.5 micromolar, more preferred compounds or salts exhibit IC 50 values of less than 500 nanomolar, still more preferred compounds or salts exhibit IC 50 values of less than 100 nanomolar, and most preferred compounds or salts are those othat exhibit IC5 0 values of less than 10 nanomolar.
  • Preferred of these compounds or salts are those of Table I.
  • Example 8 Evaluation of mechanism-based inhibition of Cytochrome P450 (CYP) 1A2, 2C8, 2C9, 2C19, 2D6 and 3A4 in human liver microsomes
  • Compound or salt at 1, 2.5, 5, 10, 25, and less preferably 50 ⁇ M are preincubated with pooled human liver microsomes 1) in the presence and 2) in the absence of NADPH (final cone. 1 niM) in a shaking water bath at 37°C for 30 minutes. After 10-fold dilution of the preincubation mixture with 0.1M phosphate buffer, pH 7.4, containing a selective CYP probe substrate and NADPH (final cone. 1 mM), residual enzyme activity is measured and the extent of the inhibition shift between the two treatments is evaluated. A concentration- dependent and statistically significant decrease in each particular CYP activity in the presence vs. absence of NADPH indicates mechanism-based inhibition of that CYP isozyme.
  • CYP 1A2 furafylline
  • CYP2C8 phenelzine
  • CYP2C9 tienilic acid
  • CYP2C19 ticlopidine
  • CYP2D6 paroxetine
  • ribefradil CYP3 A4
  • LC-MS dexadextrorphan
  • LC-MS/MS 4'-hydroxytolbutamide, desethylamodiaquine,4- acetamidophenol, 4-hydroxy-S-mephenytoin
  • HPLC 6 ⁇ - hydroxytestosterone
  • a mechanism based inhibitor ot the isozyme will show concentration dependence and a statistically significant decrease (student's t-test: p ⁇ 0.05) in activity after 30 minutes preincubation with NADPH as compared to preincubation in the absence of NADPH.
  • Preferred compounds or salts of Formula I do not cause nausea or vomiting when administered to a patient in a therapeutically effective amount.
  • a convenient measure of this property is absence of emesis in more than 1 out of six dogs within one, preferably 3, or less preferably 6 hours of administration of a dose selected from 1, 30, 100, 300, and 1000mg/kg of body weight.
  • Such absence of emesis is determined as follows: Doses of compound or salt are administered by oral intubation using a flexible tube fitted onto a syringe and utilizing a flush of approximately 10 mL of distilled water. Dogs are fed Certified Canine Diet, No. 5007 (PMI Nutrition International, St. Louis, MO) ad libitum in 400 gram amounts for approximately 4 hours daily.
  • Example 10 Preparation of radiolabeled probe compounds
  • the compounds and salts of Formula I are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope.
  • the radioisotope is preferably selected from of at least one of carbon (preferably 14 C), hydrogen (preferably 3 H), sulfur (preferably 35 S), or iodine (preferably 125 I).
  • radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds.
  • a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds.
  • suppliers include Amersham Corporation, Arlington Heights, IL; Cambridge Isotope Laboratories, Inc. Andover, MA; SRI International, Menlo Park, CA; Wizard Laboratories, West Sacramento, CA; ChemSyn Laboratories, Lexena, KS; American Radiolabeled Chemicals, Inc., St. Louis,, MO; and Moravek Biochemicals Inc., Brea, CA.
  • Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the unlabeled compound as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.
  • Example 11 Receptor autoradiography
  • Receptor autoradiography (receptor mapping) is carried out in vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York, using radiolabeled compounds provided herein prepared as described in the preceeding schemes and the preceding Example.
  • Example 12 Microsomal in vitro half-life
  • Compound half-life values may be determined via the following standard liver microsomal half-life assay. Pooled Human liver microsomes are obtained from XenoTech LLC, 3800 Cambridge St. Kansas's City, Kansas, 66103 (catalog # H0610). Such liver microsomes may also be obtained from In Vitro Technologies, 1450 South Rolling Road, Baltamore, MD 21227, or from Tissue Transformation Technologies, Edison Corporate Center, 175 May Street, Suite 600, Edison, NJ 08837. Reactions are preformed as follows: Reagents:
  • Phosphate buffer 19 mL 0.1 M NaH 2 PO 4 , 81 mL O.l Na 2 HPO 4 , adjusted to pH 7.4 with
  • CoFactor Mixture 16.2 mg NADP, 45.4 mg Glucose-6-phosphate in 4 mL 100 mM MgCk- Glucose-6-phosphate dehydrogenase: 214.3 ⁇ L glucose-6-phos ⁇ hate dehydrogenase suspension (Boehringer-Mariheim catalog no. 0737224, distributed by Roche Molecular Biochemicals, 9115 Hague Road, P.O. Box 50414, Indianapolis, IN 46250) is diluted into 1285.7 ⁇ L distilled water. Starting Reaction Mixture; 3 mL CoFactor Mixture, 1.2 mL Glucose-6-phosphate dehydrogenase. Reaction:
  • test reactions are prepared, each containing 25 ⁇ L microsomes, 5 ⁇ L of a 100 uM solution of test compound, and 399 ⁇ L 0.1 M phosphate buffer.
  • a seventh reaction is prepared as a positive control containing 25 ⁇ L microsomes, 399 ⁇ L 0.1 M phosphate buffer, and 5 ⁇ L of a 100 uM solution of a compound with known metabolic properties (e.g. diazepam or clozepine). Reactions are preincubated at 39°C for 10 minutes.
  • 71 ⁇ L Starting Reaction Mixture is added to 5 of the 6 test reactions and to the positive control, 71 ⁇ L 100 mM MgC ⁇ is added to the sixth test reaction, which is used as a negative control.
  • Preferred compounds exhibit in vitro tj /2 values of greater than 10 minutes and less than 4 hours. Most preferred compounds exhibit in vitro t ⁇ a values of between 30 minutes and 1 hour in human liver microsomes.
  • the most preferred compounds and salts of Formula I are suitable for pharmaceutical use in treating human patients. Accordingly, such preferred compounds are non-toxic. They do not exhibit single or multiple dose acute or long-term toxicity, mutagenicity (e.g., as determined in a bacterial reverse mutation assay such as an Ames test), teratogenicity, tumorogenicity, or the like, and rarely trigger adverse effects (side effects) when administered at therapeutically effective dosages.
  • administering does not result in prolongation of heart QT intervals (i.e., as determined by electrocardiography, e.g., in guinea pigs, minipigs or dogs).
  • such doses of such preferred compounds When administered daily for 5 or preferably ten days, such doses of such preferred compounds also do riot cause liver enlargement resulting in an increase of liver to body weight ratio of more than 100%, preferably not more than 75% and more preferably not more than 50% over matched controls in laboratory rodents (e.g., mice or rats). In another aspect such doses of such preferred compounds also preferably do not cause liver enlargement resulting in an increase of liver to body weight ratio of more than 50%, more preferably preferably not more than 25%, and most preferably not more than 10% over matched untreated controls in dogs or other non- rodent mammals.
  • such doses of such preferred compounds also preferably do not promote the release of liver enzymes (e.g., ALT, LDH, or AST) from hepatocytes in vivo.
  • liver enzymes e.g., ALT, LDH, or AST
  • such doses do not elevate serum levels of such enzymes by more than 100%, more preferably not by more than 75% and most preferably not by more than 50% over matched untreated controls in laboratory rodents.
  • concentrations (in culture media or other such solutions that are contacted and incubated with cells in vitro) equivalent to two, fold, preferably five-fold, and most preferably ten-fold the minimum in vivo therapeutic concentration do not cause release of any of such liver enzymes from hepatocytes into culture medium in vitro above baseline levels seen in media from untreated cells.
  • preferred compounds exert their receptor-modulatory effects with high selectivity. This means that they do not bind to certain other receptors (other than CRF, preferably CRFl, receptors) with high affinity, but rather only bind to, activate, or inhibit the activity of such other receptors with affinity constants (note: greater affinity constants indicate weaker binding) of greater than 100 nanomolar, preferably greater than 1 micromolar, more preferably greater than 10 micromolar and most preferably greater than 100 micromolar.
  • Such receptors preferably are selected from the group consisting of a) ion channel receptors, (preferably sodium ion channel receptors), b) neurotransmitter receptors (preferably selected from alpha- and beta-adrenergic receptors, muscarinic receptors - most preferably ml, m2, or m3 receptors, dopamine receptors, GABAA receptors and metabotropic glutamate receptors), c) histamine receptors, d) cytokine receptors (preferably selected from interleukin receptors, most preferably IL-8 receptors), e) bioactive peptide receptors (preferably selected from NPY and VIP receptors), f) neurokinin receptors g) bradykinin receptors (preferably selected from BKl receptors and BK2 receptors), and h) hormone receptors (preferably selected from thyrotropin releasing hormone receptors and melanocyte-concentrating hormone receptors).
  • ion channel receptors preferably sodium ion channel receptors

Abstract

Substituted heteroaryl fused pyridine and pyrazine compounds that act as selective modulators of CRFl receptors are provided. These compounds are useful in the treatment of a number of CNS and periphereal disorders, particularly stress, anxiety, depression, cardiovascular disorders, gastrointestinal disorders, and eating disorders. Methods of treatment of such disorders as well as packaged pharmaceutical compositions are also provided. Compounds provided herein are also useful as probes for the localization of CRF receptors and as standards in assays for CRF receptor binding. Methods of using the compounds in receptor localization studies are given.

Description

CRFl RECEPTOR LIGANDS COMPRISING HETEROARYL FUSED BICYCLES
Related Applications
This application claims the benefit of U.S. provisional patent application Ser. No. 60/747,241 filed May 15, 2006. The disclosure of the aforementioned provisional patent application is incorporated herein in its entirety by this reference.
FIELD OF THE INVENTION
The present invention relates to novel substituted heteroaryl fused pyridine, pyrazine, and pyrimidine compounds that bind with high selectivity and/ or high affinity to CRF (Corticotropin Releasing Factor), preferably CRFl, receptors. It also relates to pharmaceutical compositions comprising such compounds and to their use in the treatment of psychiatric disorders and neurological diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders, as well as treatment of immunological, cardiovascular or heart-related diseases and digestive disorders including colonic hypersensitivity associated with psychopathological disturbance and stress, including Irritable Bowel Syndrome (IBS). Additionally this invention relates to the use such compounds as probes for the localization of CRF receptors in cells and tissues.
BACKGROUND OF THE INVENTION
Corticotropin releasing factor (CRF), is a peptide that acts by binding to and modulating the signal transduction activities of specific cell surface receptors, including CRFl receptors and CRF2 receptors. CRF receptors are believed to play a significant role in integrating responses to stresss.
CRF has been shown to be involved in psychiatric disorders and neurological diseases including depression, anxiety-related disorders, gastrointestinal disorders and feeding disorders.
SUMMARY OF THE INVENTION
The invention provides novel compounds of Formula I (below), and pharmaceutical compositions comprising such compounds and at least one pharmaceutically acceptable carrier or excipient. Such compounds bind to cell surface receptors, preferably G-coupled protein receptors, especially CRF receptors (including CRFl and CRF2 receptors) and most preferably CRFl receptors. Preferred compounds exhibit high affinity for CRF receptors, preferably CRF 1 receptors. Additionally, preferred compounds also exhibit high specificity for CRF receptors (i.e., they exhibit high selectivity compared to their binding to non-CRF receptors). Preferably they exhibit high specificity for CRF 1 receptors.
Thus, in certain aspects, the invention provides compounds and pharmaceutically acceptable salts thereof that are of Formula I
Figure imgf000003_0001
wherein:
R is H, Ci-C4 alkyl, halogen, cyano, Cl-6 cycloalkyl, or S(O)nC1-C4 alkyl;
Ar is optionally substituted aryl or heteroaryl;
Z3 is optionally substituted nitrogen or carbon; the group:
Figure imgf000003_0002
represents a saturated, unsaturated or aromatic 5-membered ring system, wherein one of Z] and Z2 represents nitrogen; and n = 0, I, or 2.
The invention further provides methods of treating patients suffering from certain disorders with a therapeutically effective amount of at least one compound provided herein. These disorders include CNS disorders, particularly affective disorders, anxiety disorders, stress-related disorders, eating disorders and substance abuse. The patient suffering from these disorders may be a human or other animal (preferably a mammal), such as a domesticated companion animal (pet) or a livestock animal. Preferred compounds for such therapeutic purposes are those that antagonize the binding of CRF to CRP receptors (preferably CRFl, or less preferably CRF2 receptors). The ability of compounds to act as antagonists can be measured as an IC50 value as described below. According to yet another aspect, the present invention provides pharmaceutical compositions comprising at least one compound or salt of Formula 1 (preferably at least one compound or salt of Table I) or the pharmaceutically acceptable salts (as defined below) thereof, which compositions are useful for the treatment of the above-recited disorders. The invention further provides methods of treating patients suffering from any of the above- recited disorders with an effective amount of a compound or composition provided herein.
Additionally this invention relates to the use of the compounds provided (particularly labeled compounds) as probes for the localization of receptors in cells and tissues and as standards and reagents for use in determining the receptor-binding characteristics of test compounds. Preferred compounds exhibit a half-maximal inhibitory concentration (IC50) of less than 5 micromolar in the standard in vitro CRFl receptor binding assay provided in Example 7 below. Particularly preferred compounds exhibit an IC50 of about 1 micromolar or less, still more preferably an IC50 of about 100 nanomolar or less even more preferably an IC50 of about 10 nanomolar or less. Certain particularly preferred compounds exhibit an IC50 of 1 nanomolar or less in such standard binding assay.
DETAILED DESCRIPTION OF THE INVENTION Exemplified compounds
Table I sets forth compounds of Formula I numbered 1 to 562, many of which are prophetic. Reference herein or in the claims to a "compound or salt of Table I" encompases any of these numbered compounds and the pharmaceutically acceptable salts of each. "MoI. Wt." is the calculated molecular weight for each compound. TABLEI
Figure imgf000005_0001
Figure imgf000006_0001
8. 417.52 (1S,2S)-2-{2-[2-methoxy-4-(1H-pyrazol-1-
Chiral yl)phenyl]-3,7-dimethyl-5H-pyτrolo[2,3- b]pyrazin-5-yl}cyclohexanol
Figure imgf000007_0001
394.56 (3R)-3-[2-ethyl-3-(2-ethyl-6-isopropylpyridin-3- yl)-5-methyl-5H-pyrrolo[2,3-b]pyrazin-7- yl]pentan-1-ol
Figure imgf000007_0002
10. Chiral 451.61 N-{2-[(3-{6-ethyl-1 -[{1 S)-2-methoxy-1 -
"O methy1ethy1]-3-methy1-1H-pyrrolo[3,2- b]pyridin-5-y1}-6-isopropylpyridin-2- y1)amϊπolethyt}acetamide
Figure imgf000007_0003
11. 368.48 (2R)-2-[3-(6-lsopropy)-2-methoxypyridin-3-yl)-
2,5-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7- yl]butan-1-ol
Figure imgf000007_0004
Figure imgf000008_0001
Figure imgf000009_0001
20. 382.51 (2R)-2-[2-ethyf-3-{6-isopropyl-2- methoxypyrldin-3-yl)-5-methyl-5H-pyrrolo[2,3- b] pyrazin-7-yl]butan-1 -ol
Figure imgf000010_0001
21. 431.55 5-(6-lsopropyl-2-methoxypyridin-3-yl)-1-[(1S)-
Chiral 2-methoxy-1 -methy1ethyl]-3-methyl-6- (methy1sulfonyl}-1H-pyrrolo[3,2-b]pyridine
Figure imgf000010_0002
22. 365.52 (2R)-2-[5-ethyl-6-(2-ethyl-6-isopropylpyridin-3- yl)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-3- yl]propan-1-ol
Figure imgf000010_0003
23. 459.61 5-[2-ethoxy-6-ethyl-5-(methylsulfonyl)pyridin- 3-ylJ-1 -[{1 R)-1 -(methoxymethyl)propyl]-3,6- dimethyl-1H-pyrrolo[3,2-b]pyridine
Figure imgf000010_0004
-
Figure imgf000011_0001
28. 365.52 6-ethy1-5-(6-isopropyt-2-methylpyridin-3-yl)-1-
Chiral [(1 S)-2-mβthoxy-1 -methylethy1]-3-methyM H- pyrrolo[3,2-b]pyridine
Figure imgf000012_0001
29. 421.49 1-(2,5-difluorobenzyl)-5-(6-isopropyl-2- methoxypyridin-3-yl)-3,6-dimethyl-1H- pyrrolo[3,2-b]pyridine
Figure imgf000012_0002
30. 367.50 (2S)-2-{2-ethyl-3-[6-isopropyl-2-
(methylamino)pyridin-3-yl]-5-methyl-5H- pyrrolo[2,3-b]pyrazin-7-yl}propan-1-ol
Figure imgf000012_0003
31. 424.54 2-[(6-ethyl-5-{1-[(1S)-2-methoxy-1- methylethyl]-3,6-dimethyl-1H-pyrrolo[3,2- b]pyridin-5-yl}pyridin-2-yl)oxy]-N- methylpropanamide
Figure imgf000012_0004
32. 405.50 (2R,3R)-3-{2-[2-methoxy-4-(1 H-pyτazol-1 -
Chiral yl)phenyl]-3,7-dlmethyl-5H-pyrrolo[2,3- b]pyrazin-5-yl}pentan-2-ol
Figure imgf000013_0001
33. 381.52 (3R)-3-[5-(6-isopropyl-2-methoxypyridin-3-yl)-
3,6-dimethy1-1H-pyrrolo[3,2-b]pyridin-1- yt]pentan-1-ol
Figure imgf000013_0002
34. 382.51 (3R)-3-[3-(6-ethoxy-2-ethylpyridin-3-yl)-2- ethyI-5-methy1-5H-pyrτolo[2,3-b]pyrazin-7- yl]butan-1-ol
Figure imgf000013_0003
35. Chiral 391.48 (3R)-3-{2-[2-πiethoxy-4-(1 H-pyrazol-1- yl)phenyl]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5-yl}butan-1-ol
Figure imgf000013_0004
R)-1 -
Figure imgf000014_0001
din-1 -
Figure imgf000015_0001
-
Figure imgf000016_0001
Figure imgf000017_0001
H-
Figure imgf000018_0001
n-3-yl)-3,6-
Figure imgf000019_0001
60. 380.54 (2S)-2-{5-βthyi-6-[β-isopropyl-2- (methy!amino)pyridin-3-yl]-1 -methyl-1 H- pyrrolo[2,3-b]pyridin-3-yl}butan-1-ol
Figure imgf000020_0001
61. 2-(2-chloro-6-iso
Chiral 386.92 propylpyridin-3-yl)-5-[(1R)-1-
(methoxymethyl)propyl]-3,7-dimethyl-5H- pyrrolo[2,3-b]pyrazine
Figure imgf000020_0002
62. 352.48 (2R)-2-{5-[6-isopropyl-2-(methylamiπo)pyridiπ-
3-yl]-3,6-diniethyl-1H-pyrroloI3,2-b]pyrldln-1- yl}propan-1-ol
Figure imgf000020_0003
63. 352.48 (2R)-2-[3-(2-ethyl-6-isopiOpy1pyridin-3-yl}-2,5- dimethyt-5H-pyrrolo[2,3-b]pyrazin-7- yl]propan-1-ol
Figure imgf000020_0004
Figure imgf000021_0001
68. 378.47 [(6-ethyJ-5-{1 -[(1 S)-2-methoxy-1 -methylβthyl]-
3,6-dlmethy1-1H-pyιτolo[3,2-bJpyridln-5- yl}pyτidin-2-y1)oxy]acθtonitrilθ
Figure imgf000022_0001
69. 381.52 (2R)-2-[6-{6-ethoxy-2-ethylpyridin-3-yl)-5- ethyl-1 -mβthyl-1 H-pyτrolo[2,3-b]pyridin-3- y>]butan-1-ol
Figure imgf000022_0002
70. 366.51 (3R)-3-{5-[6-isopropyl-2-(methylamino)pyriclin-
3-yl]-3,6-dimethyl-1H-pyrrolo[3,2-b]pyridin-1- yl}butan-1-ol
Figure imgf000022_0003
71. 381.53 (2R)-2-{3-[6-isopropyl-2-(πiethyIamino)pyridin-
3-yl]-2,5-dJmethyl-5H-pyrrolo[2,3-b]pyrazin-7- yl}ρentan-1-ol
Figure imgf000022_0004
Figure imgf000023_0001
76. 3B1.53 (2S)-2-{2-ethyl-3-[6-isopropyl-2-
(methy)amino)pyridin-3-y1]-5-mβthyl-5H- pyrrolo[2,3-b]pyrazin-7-yl}butan-1-ol
Figure imgf000024_0001
77. 367.50 (3S)-3-{2-[6-isopropyl-2-(methylamino)pyridin-
3-yl]-3,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-5- yl}butan-1-ol
Figure imgf000024_0002
78. 382.51 <3R)-3-[3-ethy1-2-(6-isopropy1-2- methoxypyridin-3-yI)-7-methyl-5H-pyrrolo[2,3- b]pyrazin-5-yl]butan-1-ol
Figure imgf000024_0003
79. 380.54 (2R)-2-{5-[6-isopropyl-2-(methylamino)pyridin-
3-yl]-3,6-dimethyl-1 H-pyrrolo[3,2-b]pyridin-1- yl}pentan-1-ol
Figure imgf000024_0004
80. 405.50 (2S,3S)-3-{2-[2-mβthoxy-4-(1 H-pyrazol-1 -
Chiral yl)pheny1]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5-yl}pentaπ-2-ol
Figure imgf000025_0001
81. 366.51 2-[3-etrιyl-2-{6-isopropyl-2-methyl-3-pyridinyl)-
7-methy1-5H-pyrrolo[2,3-b]pyrazin-5-yl]-1- butanol
Figure imgf000025_0002
82. 403.49 (1 R,2R)-2-{2-[2-methoxy-4-(1 H-pyrazol-1 -
Chiral yl)phenyl]-3,7-dimethyf-5H-pyjτolo[2,3- b]pyrazin-5-yl}cyclopentanol
Figure imgf000025_0003
83. 368.48 (2S)-2-[2-(6-ethoxy-2-ethylpyridiπ-3-yl)-3-ethyl-
7-methyI-5H-pyrrolo[2,3-b)pyrazin-5- yl]propan-1-ol
Figure imgf000025_0004
Figure imgf000026_0001
88. Chiral 446.59 3-{6-ethyl-1 -[(1 S)-2-mβthoxy-1 -methylethyl]-3- methyl-1H-pyrrolo[3,2-b]pyridin-5-yl}-N-(2- furylmethyl)-6-isopropylpyridin-2-amine
Figure imgf000027_0001
89. 391.48 (2R)-1 -{2-[2-methoxy-4-(1 H-pyrazol-1 -
Chiral yl)phenyl]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5-yl}butan-2-ol
Figure imgf000027_0002
90. 409.57 5-(2-isopropoxy-6-isopropylpyridiπ-3-yl)-1- [(1 R)-1 -(methoxymethyl)propyl]-3,6-dimethyl- 1 H-pyrrolo[3,2-b]pyridine
Figure imgf000027_0003
91. 452.60 6-ethyl-2-isopropoxy-5-{1-[(1 R)-1- (methoxymethyl)propyl]-3,6-dimθthyl-1H- pyrrolo[3,2-b]pyridin-5-yl}-N- methylnicotinamide
Figure imgf000027_0004
H-
Figure imgf000028_0001
96. 463.58 5-[2-ethyl-6-isopropoxy-5-(1H-tetrazol-5- yl)pyridin-3-yl]-1-[(1 R)-1- (methoxymethy1)propyl]-3,6-dimethyl-1H- pyrroloI3,2-b] pyridine
Figure imgf000029_0001
97. 465.79 5-(2-chloro-6-isopropylpyridin-3-yl)-1-[(1S)-2-
Chiral methoxy-1 -methylethyl]-3-methyl-1 H- pyrrolo[3,2-b]pyridine-6-carboπitrile
Figure imgf000029_0002
98. 403.49 (1 S,3R)-3-{2-[2-methoxy-4-(1 H-pyrazol-1 -
Chiral yl)phenyl]-3,7-dimethyl-SH-pyrrolo[2,3- b]pyrazin-5-yl}cyclopentanol
Figure imgf000029_0003
99. 380.54 (3S)-3-[3-ethyl-2-(2-ethyl-6-isopropylpyrldIn-3- yl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-5- yl]butan-1-ol
Figure imgf000029_0004
100. 379.54 5-(β-Isopropyl-2-methy1pyridin-3-yl)-1-[(1R)-1-
Chiral (methoxymethyl)butyll-3,6-dimβthyl-1H- pyrrolo[3,2-b]pyrldlne
Figure imgf000030_0001
101. 396.54 (2R)-2-[3-(6-ethoxy-2-ethylpyridin-3-y1)-2- ethyl-5-methyl-5H-pyrrolo[2,3-b]pyrazin-7- yl]pentan-1-ol
Figure imgf000030_0002
102. 406.53 2-ethoxy-6-ethyl-5-{6-ethyl-1-[(1S)-2-methoxy-
Chiral 1-methylethyl]-3-methyl-1H-pyrrolo[3,2- b]pyridin-5-yl>nicotinonitrile
Figure imgf000030_0003
103. 396.54 (2S)-2-[2-(6-ethoxy-2-ethylpyridin-3-yl)-3-ethyi-
7-methyl-5H-pyrrolo[213-blpyrazin-5- yl]pentan-1-ol
Figure imgf000030_0004
104. 405.50 4-{2-[2-methoxy-4-(1H-pyrazol-1-y1)pheny1]-
3,7-dimethyl-5H-pyrrolo[2,3-b3pyrazin-5-yl}-2- methylbutan-2-ol
Figure imgf000031_0001
105. 454.40 1-(2,6-dichlorobeπzyl)-5-(6-isopropyl-2- methoxypyridin-3-yl)-3,6-dimethyl-1H- pyrrolo[3,2-b]pyridlne
Figure imgf000031_0002
106. 396.54 (3R)-3-[3-(6-ethoxy-2-ethylpyridin-3-yl)-2- ethyl-5-methyl-5H-pyrrolo[2,3-b]pyrazin-7- yl]pentan-1-ol
Figure imgf000031_0003
107. 392.50 8-{6-ethyl-1-[(1S)-2-methoxy-1-methylethyl]-3-
Chiral methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-5- isopropyltetrazolo[1 ,5-a]ρyridine
Figure imgf000031_0004
Figure imgf000032_0001
, 5-
Figure imgf000033_0001
116. 381.52 (2R)-2-[5-ethy1-6^isopropyl-2-
Chiral inethoxypyridin-3-yl)-1-methyl-1 H-pyrrolo[2,3- bjpyridi n-3-yl]butan-1 -ol
Figure imgf000034_0001
117. 366.50 5-(4-isopropyl-2-methoxypheπyl)-1-[(1R)-1-
Chiral (methoxymet hy1)propy1]-3-methyl-1 H- pyrrolo[3,2-b]pyridine
Figure imgf000034_0002
118. 396.54 (2R)-2-[3-ethyl-2-(6-isopropyl-2- methoxypyridin-3-yl>7-methyl-5H-pyrrolo[2,3- b] pyrazi n-5-yl] pe ntan-1 -ol
Figure imgf000034_0003
119. 380.54 (2S)-2-[3-ethyl-2-(2-ethyl-6-isopropylpyridin-3- yl)-7-methyl-5H-pyrrolo[2,3-b]pyra-:in-5- yl)butan-1-ol
Figure imgf000034_0004
120. 381.52 (3S)-3-[6-(6-isopropy1-2-methoxypyridin-3-yl)- 1 ,5-dimethyl-i H-pyrrolo[2,3-b]pyridin-3- yl]pentan-1-ol
Figure imgf000035_0001
121. 420.60 6-ethyl-5-(6-lsopropy1-2-pyrrolIdln-1-ylpyrldln-
Chiral 3-yl)-1 -[(1 S)-2-mβthoxy-1 -methylethyl]-3- methyl-1 H-pyrrolo[3,2-b]pyridine
Figure imgf000035_0002
122. 367.49 5-(6-ethoxy-2-methylpyridin-3-yl)-6-ethyl-1-
Chiral I(1S)-2-methoxy-1-methylethyl]-3-methyl-1H- pyrrolo[3,2-b]pyridine
Figure imgf000035_0003
123. 435.57 S-(6-isopropyl-2-methoxypyridin-3-yl)-3,6- dimethyl-1 -(2-naρhthy1methyl)-1 H-pyrrolo[3,2- b]pyridine
Figure imgf000035_0004
124. 380.54 (3R)-3-{5-ethyl-6-[6-isopropyl-2- (methylamino)pyridin-3-yl]-1-methyl-1H- pyrrolo[2,3-b]pyridin-3-yl}butan-1 -ol
Figure imgf000036_0001
125. 392.54 6-cyclopropyl-5-(4-isopropyl-2-
Chiral methoxyρhenyl)-1-[(1 S)-2-methoxy-1 - methylethyl]-3-methy1-1H-pyτrolo[3,2- b]pyridine
Figure imgf000036_0002
126. 367.50 (2R)-2-[5-ethyl-6-(6-isopropyl-2- methoxypyridln-3-yl)-1-metliyl-1H-pyrrolo[2,3- b]pyr!din-3-yl]propan-1 -ol
Figure imgf000036_0003
127. 365.52 5-(2-ethy1-6-isopropylpyridin-3-yl)-1-[(1R)-1-
Chiral (tnethoxymethyl)proρyl]-3-methyl-1 H- pyrrolo[3,2-b]pyridiπe
Figure imgf000036_0004
128. 381.51 (2S)-2-[5-{6-lsopropyl-2-methoxy-3-pyridinyl)- 3,6-dimethyMH-pyrrolo[3,2-b]pyrldin-1-yl]-3- methyl-1-butanol
Figure imgf000037_0001
129. 414.55 5-(6-isopropyl-2-methoxypyridin-3-yl)-3,6- dimethyl-1 -(1 -pyridf n-2-y1propyf)-1 H- pyrrolo[3,2-b] pyridine
Figure imgf000037_0002
130. 526.67 6-ethyl-5-{6-ethyl-1-[2-ιnethoxy-1- (methoxymethyl)ethy1]-3-methyl-1 H- pyrrolo[3,2-b]pyridin-5-yl}-2-Isopropoxy-N-(2- methoxyethyl)nicotinamide
Figure imgf000037_0003
131. 381.52 (3S)-3-t5-(6-ethoxy-2-ethylpyridin-3-yI)-6-ethyI-
3-methyl-1H-pyrroloI3,2-b]pyridin-1-yl]butan-
1-ol
Figure imgf000037_0004
Figure imgf000038_0001
H-
Figure imgf000039_0001
140. 380.53 6-isopropyi-3-{1 -[( 1 R)-1 -
Chiral (methoxymethyl)propyt]-3-methyl-1 H- pynrolo[3,2-b]pyridin-5-yl}-N,N- dimethytpyridiπ-2-am!ne
Figure imgf000040_0001
141. Chiral 405.50 (3S)-3-{2-[2-methoxy-4-(1 H-pyrazol-1 - yl)phenyl]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5-yl}pentaπ-1-ol
Figure imgf000040_0002
142. 353.47 (2R)-2-{2-[6-isopropyl-2-(methylamino)pyridin-
3-yl]-3,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-5- yl}propan-1-ol
Figure imgf000040_0003
143. 405.50 (2S,3R)-2-{2-[2-methoxy-4-{1 H-pyrazol-1 -
Chiral yl)phenyl]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5-yl}pentan-3-ol
Figure imgf000040_0004
144. 395.55 (3R)-3-[5-(6-ethoxy-2-ethylpyridin-3-yl)-6- ethyl-3-methyJ-1H-pyrrolo[3,2-b]pyridin-1- yl]pentan-1-ol
Figure imgf000041_0001
145. 368.48 (2R}-2-[3-(6-ethoxy-2-ethy1pyridin-3-yl}-2- ethyl-5-methyl-5H-pyτrolo[2,3-b]pyrazϊn-7- yl]propan-1-ol
Figure imgf000041_0002
146. 396.54 (3R)-3-[3-ethyt-2-(6-Isopropyl-2- methoxypyridln-3-yl)-7-methyl-5H-pyrrolo[2,3- b] pyrazin-5-y1]pentan-1 -ol
Figure imgf000041_0003
147. 381.53 (3R)-3-{3-[6-isopropyl-2-(methylamino)pyridin-
3-y1]-2,5-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7- yl}pentan-1-ol
Figure imgf000041_0004
Figure imgf000042_0001
152. 397.52 6-ethyl-5-{2-ethyl-6-methoxypyridin-3-yl)-1-[2- methoxy-1-(methoxymethyl)ethyl]-3-methyl- 1 H-pyrrolo[3,2-b]pyridine
Figure imgf000043_0001
153. 381.52 (3R)-3-[6-(6-isopropyl-2-methoxypyridin-3-yl)-
1,5-dimethyt-1H-pyrrolo[2,3-blpyridin-3- yl]pentan-1-ol
Figure imgf000043_0002
154. 367.50 (3S)-3-{3-[6-isopropy1-2-(methylamino)pyridin-
3-yl]-2,5-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7- ylJ-butan-1-ol
Figure imgf000043_0003
155. 368.48 (2R)-2-[2-ethyl-3-(6-isopropyl-2- methoxypyridi n-3-yl)-5-methyl-5HI-pyrrol o[2,3- b]pyrazin-7-yl]propan-1-ol
Figure imgf000043_0004
156. 380.53 N-ethyl-β-isopropyl-3-{1-[(1 RM -
Chiral (methoxymβthy))propyl]-3-mβthyl-1 H- pyrrolo[3,2-b]pyτidln-5-yl}pyridln-2-amlne
Figure imgf000044_0001
157. 394.56 (3R)-3-[3-ethyl-2-{2-ethyl-6-isopropy1pyridin-3- yl)-7-methy1-5H-pyrrolo[2,3-blpyrazin-5- yl]pentan-1-ol
Figure imgf000044_0002
158. 394.56 6-isopropyl-3-{1-[(1R)-1- (methoxymethyl)propyl]-3,6-dimethyl-1H- pyrrolo[3,2-b]pyτidin-5-yl}-N,N- dimethylpyridin-2-amlne
Figure imgf000044_0003
159. 385.51 1-benzyl-5-(6-isopropyl-2-methoxypyridin-3- y1)-3,6-dimethyl-1H-pyrrolo[3,2-b]pyridine
Figure imgf000044_0004
-[(1 R)- 1 -
Figure imgf000045_0001
H-
Figure imgf000046_0001
-[(1 S)-2-
Figure imgf000047_0001
172. 395.55 (3S)-3-[6-ethyl-5-(6-isopropy1-2- mθthoxypyridin-3-y1)-3-methyl-1 H-pyιτolo[3,2- b]pyridin-1-yl]pentan-1-ol
Figure imgf000048_0001
173. 366.51 6-isopropyl-3-{1-[(1R)-1-
Chiral (methoxymathyl)propyl]-3-methyl-1H- pyrrolo[3,2-b]pyridin-5-yl}-N-methylpyridin-2- amiπe
Figure imgf000048_0002
174. 365.51 (2R)-2-[6-ethyl-5^-isopropyI-2-methyl-3- pyridiπyl)-3-methyl-1H-pyrrolo[3,2-b]pyridiπ-1- yl]-1-butanol
Figure imgf000048_0003
175. 381.52 (2R)-2-[6-(6-isopropyl-2-methoxypyridin-3-yl)- 1 ,5-dimethyl-1 H-pyrrolo[2,3-b]pyridin-3- yl]pentan-1-ol
Figure imgf000048_0004
Figure imgf000049_0001
-
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
192. 380.54 (2R)-2-[2-{2-ethyl-6-isopropy1-5-methylpyridin-
3-yl)-3,7-dlmethyl-5H-pyιτolo[2,3-b]pyrazIn-5- yl]butan-1-ol
Figure imgf000053_0001
193. 366.50 (2S)-2-(e-ethyl-5-[6-isopropyl-2-
(methy1amino)pyridin-3-yl]-3-methyl-1H- pyrrolo[3,2-b]pyridin-1-yl}propan-1-ol
Figure imgf000053_0002
194. 382.51 (3R)-3-[2-(6-ethoxy-2-ethylpyridin-3-yl)-3- ethyl-7-methyl-5H-pyrrolo[2,3-b]pyraziπ-5- yl]butan-1-ol
Figure imgf000053_0003
195. Chiral 391.48 (3S)-3-{2-[2-methoxy-4-(1 H-pyrazol-1 - yl)phenyl]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5-yl}butan-1 -ol
Figure imgf000053_0004
196. Chiral 375.87 6-chloro-1-[(1S)-2-fluoro-1-
(methoxymethyl)ethy1]-5-(6-lsopropylpyridin-
3-yl)-3-methyl-1H-pyrrolo[3,2-b]pyridine
Figure imgf000054_0001
197. 396.54 (2R)-2-[2-{6-βthoxy-2-θthylpyridin-3-yl)-3- ethyl-7-methyl-5H-pyrrolo[2,3-b]pyrazin-5- yl]pentan-1-ol
Figure imgf000054_0002
198. 395.55 (2S)-2-[5-ethy!-6-{6-isopropy1-2- methoxypyridiπ-3-yl)-1 -methyl-1 H-pyrrolo[2,3- b]pyrldIn-3-yl]pentan-1-ol
Figure imgf000054_0003
199. 367.50 (2R)-2-{3-[6-isopropyl-2-(methylamino)pyridin-
3-yl]-2,5-dimethyI-5H-pyrrolo[2,3-b]pyrazin-7- yi}butan-1-ol
Figure imgf000054_0004
200. 366.51 (3R)-3-{6-[6-lsopropyl-2-(methylamino)pyridin- 3-y)]-1 ,5-dimethyl-1 H-pyrrolo[2,3-b]pyriclln-3- yl}butan-1-ol
Figure imgf000055_0001
201. 406.57 5-(6-lsopropy1-2-pyπrolidln-1-ylpyτldin-3-y1)-1-
Chiral [(1 R)-1-(methoxymethy1)propyl]-3-methy1-1 H- pyrrolo[3,2-b]pyridine
Figure imgf000055_0002
202. 420.60 5-(6-isopropyi-2-piperidin-1-ylpyridin-3-yl)-1-
Chiral [(1 R)-1-(methoxymethyl)propyl]-3-methyl-1 H- pyrrolo[3,2-b]pyridiπe
Figure imgf000055_0003
203. 403.49 (1S,2S)-2-{2-[2-methoxy-4-(1H-pyrazoM-
Chiral yl)phenyl]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5-yl}cyclopentaπol
Figure imgf000055_0004
204. 417.52 (1 R,2S)-1-cyclopropyt-1-{2-[2-methoxy-4-(1 H-
Chiral pyrazol-1-yl)phenyl]-3,7-dimethyl-5H- pyrrolo[2,3-b]pyrazin-5-yl}propaπ-2-ol
Figure imgf000056_0001
205. 367.50 (2R)-2-{2-ethyl-3-[6-isopropy1-2-
(methy1amino)pyιϊdin-3-yl]-5-methyi-5H- pyrrolo[2,3-b]pyrazin-7-yl}propan-1-ol
Figure imgf000056_0002
206. 405.50 (2R,3S)-2-{2-[2-methoxy-4-(1 H-pyrazol-1-
Chiral yl)phenyl)-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5-yl}pentan-3-ol
Figure imgf000056_0003
207. 405.50 (2R)-2-{2-[2-methoxy-4-(1H-pyrarol-1-
Chiral yl)pheny1]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5-yl}-3-methylbutan-1-ol
Figure imgf000056_0004
H-
Figure imgf000057_0001
212. 438.57 6-ethyl-2-isopropoxy-5-{1 -1(1 R)-1 -
(methoxymethyl)propy1]-3,6-dImethyl-1H- pyrrolo[3,2-b]pyridin-5-yl}πicotinamide
Figure imgf000058_0001
213. 395.55 (2S)-2-[6-ethyl-5-(6-isopropyl-2- methoxypyridin-3-yl)-3-methyl-1H-pyrrolo[3,2- bjpyrl din-1 -yl]pentan-1 -ol
Figure imgf000058_0002
214. 393.58 (2S)-2-[6-ethyl-5-(2-ethy1-6-isopropylpyridin-3- yl)-3-methyl-1 H-pyrrolo[3,2-b]pyridin-1 - yl]pentan-1-ol
Figure imgf000058_0003
215. 395.55 (2R)-2-{3-ethyl-2-[6-isopropyl-2-
(methylamino)pyridin-3-yl]-7-methyI-5H- pyrrolo[2,3-b]pyrazin-5-yl}pentan-1-ol
Figure imgf000058_0004
216. 366.51 (2S)-2-{6-βthyl-5-[6-isopropyl-2-
(methylamlno)pyridin-3-yl]-3-methyl-1H- pyrrolo[3,2-b]pyridin-1-yl}propan-1-ol
Figure imgf000059_0001
217. 353.47 (2R)-2-{3-[6-isopropyl-2-(methylamiπo)pyridin-
3-yl]-2,5-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7- yl}propan-1-ol
Figure imgf000059_0002
218. 323.44 5-{6-isopropylpyrϊdin-3-yl)-1-{2-methoxyethy1)- 3,6-dimethyl-1 H-pyrrolo[3,2-b]pyridine
Figure imgf000059_0003
219. 396.54 (3R)-3-l2-(6-ethoxy-2-ethylpyridin-3-yl)-3- ethyl-7-methyl-5H-pyrrolo[2,3-b]pyrazin-5- y]]pentan-1-ol
Figure imgf000059_0004
220. 403.49 (2S)-2-cyclopropyl-2-{2-[2-methoxy-4-(1H-
Chiral pyrazol-1 -yl)phenylI-3,7-dimethyl-5H- pyrrolo[2,3-b]pyrazin-5-y1}ethanol
Figure imgf000060_0001
221. 399.53 5-(6-isopropyl-2-methoxypyridin-3-y1)-3,6- dimethyl-1-(1-phenylethyl)-1H-pyrro!o[3,2- bjpyridine
Figure imgf000060_0002
222. 335.49 6-ethyl-1-isopropyl-5-(6-isopropyl-2- methylpyridin-3-yl)-3-methyl-1H-pyrrolo[3,2- b] pyridine
Figure imgf000060_0003
223. 394.56 (3S)-3-[2-ethyl-3-(2-ethyl-6-isopropylpyridin-3- yl)-5-methyl-5H-pyrrolo[2,3-blpyrazin-7- yl]pentan-1-ol
Figure imgf000060_0004
224. 380.54 (3R)-3-{6-[6-isopropyl-2-(methylamino)pyridin- 3-ylJ-1 r5-dlmethyl-1 H-pyrrolo[2,3-b]pyrldin-3- yl}pentan-1-ol
Figure imgf000061_0001
225. 425.57 5-[6-isopropyi-2-(2-methoxyethoxy)pyridin-3- yl]-1-[(1R)-1-(methoxymethyl)propyl]-3,6- dimethyl-1 H-pyrrolo[3,2-b]pyτidine
Figure imgf000061_0002
226. 3S1.53 (3S)-3-{3-[β-isopropyl-2-(methylamino)pyridin-
3-yl]-2,5-dimethyi-5H-pyrrolo[2,3-b]pyrazin-7- yl}ρentan-1-ol
Figure imgf000061_0003
227. 381.53 (3S)-3-{3-ethyl-2-[6-isopropyl-2-
(methylamino)pyridϊn-3-yl3-7-methyl-5H- pyrrolo[2,3-b]pyrazin-5-yl}butan-1-ol
Figure imgf000061_0004
228. 380.54 (2S)-2-[2-(2.ethyl-6-Isopropy1pyridiπ-3-yl)-3,7- dlmethyl-5H-pyrrolo[2,3-b]pyrazin-5- yl]pentan-1-ol
Figure imgf000062_0001
229. Chiral 417.52 cis-4-{2-[2-methoxy-4-(1 H-pyrazol-1- yl)ρhenyl]-3,7-dimethyl-5H-pyτrolo[2,3- b]pyrazin-5-yl}cyclohexanol
Figure imgf000062_0002
230. 383.49 5-{2-ethyl-6-mβthoxypyridin-3-yl)-1-[2- methoxy-1-(πiethoxymethy1)ethyl]-3,6- dimethyl-1 H-pyrrolo[3,2-b]pyridine
Figure imgf000062_0003
231. 368.48 (2R)-2-[3-ethyl-2-(6-isopropyl-2- methoxypyridin-3-yl)-7-methyl-5H-pyrrolo[2,3- b]pyraziπ-5-yt]propaπ-1-ol
Figure imgf000062_0004
, 5-
Figure imgf000063_0001
236. 356.44 5-[(1R)-2-fluoro-1-(methoxymethyl)ethyl]-2-(6-
Chiral isopropy1pyridin-3-yl)-3,7-dimethyl-5H- pyrrolo[2,3-b]pyτazine
Figure imgf000064_0001
237. 382.51 <2S)-2-[2-ethyl-3-{6-isopropyt-2- methoxypyridin-3-yl)-5-methyl-5H-pyrrolo[2,3- b]pyrazin-7-yl]butan-1-ol
Figure imgf000064_0002
238. 381.53 (2R)-2-{3-ethy1-2-[6-isopropyl-2-
(methylamino)pyridin-3-yl]-7-methyl-5H- pyrrolo[2,3-b]pyrazin-5-yl}butan-1-ol
Figure imgf000064_0003
239. 417.52 (1R,3R)-3-{2-[2-methoxy-4-(1H-pyrazol-1-
Chiral yl)phenyl]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5-yl}cycIohexanol
Figure imgf000064_0004
H-
H-pyrazol-1 -
Figure imgf000065_0001
Figure imgf000066_0001
-[(1 RH -
Figure imgf000067_0001
252. 391.48 (2R,3S)-3-{2-[2-methoxy-4-(1 H-pyrazol-1 -
Chiral yi)phenyl]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5-yt}butan-2-ol
Figure imgf000068_0001
253. 347.50 5-(2-ethyl-6-isopropylpyrldin-3-yl)-3)6- dimethyl-1 -(1 -methylenepropyl>-1 H- pyrrolo[3,2-b]pyridine
Figure imgf000068_0002
254. 395.55 (3R)-3-[6-ethyl-5-{6-isopropyl-2- methoxypyιϊdin-3-yl)-3-methyl-1 H-pyrrolo[3,2- b]pyridin-1-yl]pentan-1-ol
Figure imgf000068_0003
255. 395.55 (2R)-2-[5-ethyl-6-(6-isopropyl-2- methoxypyridin-3-yl)-1-methyl-1H-pyrrolo[2,3- b]pyridiπ-3-yl]pentan-1-ol
Figure imgf000068_0004
256. 380.54 {2S)-2-[3-(2-ethyI-6-isopropylpyridin-3-yl)-2l5- dimethyl-5H-pyrrolo[2,3-b]pyrazin-7- yl]pentan-1-ol
Figure imgf000069_0001
257. 381.53 (2S)-2-{3-[6-isopropy1-2-(methylamino)pyridln-
3-yl]-2,5-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7- yl}pentan-1-ol
Figure imgf000069_0002
258. 380.54 (3S)-3-{6-ethyl-5-[6-isopropyl-2-
(methylamino)pyridin-3-yl]-3-methyl-1H- pyrrolo[3,2-b]pyridin-1-yl}butan-1-ol
Figure imgf000069_0003
259. 367.50 (2S)-2-{3-ethy1-2-[6-isopfopyl-2-
(methylamino)pyridin-3-yl]-7-methyl-SH- pyrrolo[2,3-b]pyτazin-5-yl}propan-1-ol
Figure imgf000069_0004
Figure imgf000070_0001
264. 353.46 5-(2-ethy1-6-methoκypyridln-3-yl)-1-[(1R)-2- methoxy-1-methylethyl]-3,6-dimethyl-1H- pyrrolo[3,2-b]pyrldlne
Figure imgf000071_0001
265. 417.52 (1R,2R)-2-{2-[2-metrκ>xy-4-(1 H-pyrazol-1-
Chiral yl)phβnyl3-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5-y)}cyclohexanol
Figure imgf000071_0002
266. 445.58 6-ethyl-5-[2-ethyl-6-methoxy-5-
Chiral (methylsulfonyl)pyridin-3-yl]-1-[(1S)-2- methoxy-1 -methylethy)]-3-methyl-1 H- pyrrolo[3,2-b]pyridiπe
Figure imgf000071_0003
267. 397.52 5-<6-ethoxy-2-ethylpyridin-3-yt)-1-[2-methoxy-
1-(methoxymethyl)ethyl]-3l6-dimθthyl-1H- pyrrolo[3,2-b]pyridine
Figure imgf000071_0004
268. 351.49 (2S)-2-[5-(6-isopropyl-2-methyl-3-pyridiny1)-
3,6-dimethyl-1H-pyrrolo[3,2-b]pyridin-1-yl]-1- butanol
Figure imgf000072_0001
269. 369.48 6-ethyl-1-[(1S)-2-fluoro-1-methylethyl]-5-(6-
Chlral isopropyl-2-methoxypyridiπ-3-y1)-3-methyl-1H- pyrrolo[3,2-b]pyridlne
Figure imgf000072_0002
270. 393.58 (2R)-2-[5-ethyl-6-{2-ethyl-6-isopropy1pyridin-3- yl)-1-methyl-1 H-pyrrolo[2,3-b]pyridin-3- yl]pentan-1-ol
Figure imgf000072_0003
271. 393.58 (3R)-3-[5-ethyl-6-(2-ethyl-6-isopropylpyridin-3- yl)-1-nrιethyl-1 H-pyrrolo[2,3-b]pyridin-3- yl]pentan-1-ol
Figure imgf000072_0004
272. 366.51 (2S)-2-{6-[6-isopropyl-2-{methylamlno)pyridln-
3-yl]-1,5-dimethyl-1H-pyrrolo[2,3-b]pyridin-3- yl}butan-1-ol
Figure imgf000073_0001
273. 366.51 (2R)-2-{5-ethyl-6-[6-isopropyl-2-
(methylamino)pyrldln-3-yl]-1-methyl-1H- pyrrolo[2,3-b]pyridin-3-yl}propan-1-oI
Figure imgf000073_0002
274. 354.46 (2R)-2-[2-(6-ethoxy.2-ethylpyridin-3-yl)-3,7- dimethyl-5H-pyrrolo[2,3-b]pyraziπ-5- yl]propaπ-1-ol
Figure imgf000073_0003
275. 381.52 (2R)-2-[5-(6-ethoxy-2-ethyIpyridin-3-yl)-6- ethyl-3-methyl-1 H-pyrrolo[3,2-b]pyridin-1 - yl]butan-1-ol
Figure imgf000073_0004
Figure imgf000074_0001
Figure imgf000075_0001
284. 354.45 5-(2,4-dimethoxyphenyl)-1-[(1R)-1- (methoxymethyl)propyt]-3-methyl-1 H- pyrrolo[3,2-b]pyridine
Figure imgf000076_0001
285. 385.48 3-{S-[(1 R)-2-fluoro-1 -{methoxymethyl)ethyl]-
Chiral 3,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-2-yl}-6- isopropyl-N-methylpyrtdin-2-amine
Figure imgf000076_0002
286. 3S4.46 (2R)-2-[3-(6-ethoxy-2-ethylpyridlπ-3-yl)-2,5- dimethy1-5H-pyrrolo[2,3-b]pyrazin-7- yl]propan-1-ol
Figure imgf000076_0003
287. 382.51 (3R)-3-[3-(6-isopropyl-2-methoxypyridin-3-yl)-
2,5-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7- y1]pentan-1-ol
Figure imgf000076_0004
288. 475.61 6-ethyl-5-[2-ethyl-6-methoxy-5- (methylsulf onyl)pyridin-3-yl]-1 -[2-methoxy-1 - (methoxymethyl)ethy1]-3-methyl-1 H- pyrrolo[3,2-b]pyridine
Figure imgf000077_0001
289. 381.53 (3R)-3-{2-ethyl-3-[6-lsopropy1-2-
(methylamlno)pyrldin-3-yl]-5-methyl-5H- pyrrolo[2,3-b]pyrazin-7-yl>butan-1-ol
Figure imgf000077_0002
290. 367.49 5-(6-ethoxy-2-methylpyridin-3-yi)-1-[(1R)-1-
Chiral (methoxymethyl)propyl]-3,6-dimethyl-1H- pyrrolo[3,2-b]pyridiπe
Figure imgf000077_0003
291. 437.63 N'-(3-{6-ethyl-1 -[(1 S)-2-methoxy-1 -
Chiral methylethylJ-3-methyl-1H-pyrrolo[3,2- b]pyridin-5-yl}-6-isopropylpyridin-2-yl)-N,N- dimethy1ethane-1,2-diamine
Figure imgf000077_0004
Figure imgf000078_0001
Figure imgf000079_0001
300. 380.49 (2S)-2-_2-{2-ethyl-6-isopropylpyridin-3-yl)-3,7-
Chiral dimethyl-5H-pyrrolo[2,3-b]pyrazin-5- yljbutanoic acid
Figure imgf000080_0001
301. 368.48 (2S)-2-[2-ethyl-3-(6-isopropyl-2- methoxypyridin-3-yl)-5-methyl-5H-pyrrolo[2,3- b] pyrazi n-7-yl] propa n-1 -ol
Figure imgf000080_0002
302. 417.52 (1S,3R)-3-<2-[2-methoxy-4-(1 H-pyrazol-1 -
Chiral yl)phenyl]-3,7-dimethy1-5H-pyrrolo[2,3- b]pyrazin-5-yl}cyclohexanol
Figure imgf000080_0003
303. 368.43 (2S)-2-[3-(6-ethoxy-2-ethylpyτϊdin-3-yl}-2-ethy1-
5-methyl-5H-pyrrolo[2,3-b]pyra2in-7- yl]propan-1-ol
Figure imgf000080_0004
304. 366.51 (2R)-2-{5-[6-isopropyl-2-(methylamino)pyridin-
3-yl]-3,6-dimethyl-1H-pyrrolo[3,2-b]pyridin-1- yl}butan-1-ol
Figure imgf000081_0001
305. 380.54 (2S)-2-[2-ethyl-3-(2-ethyl-6-isopropylpyridin-3- yl)-5-methyl-5H-pyrrolo[2,3-b]pyrazin-7- yl]butan-1-ol
Figure imgf000081_0002
306. 368.50 3-ethyl-5-[(1 R)- 1 -(fluoromethyl)propyl]-2-(6-
Chiral isopropyl-2-methylpyridin-3-yl)-7-methyl-5H- pyrrolo[2,3-b]pyrazine
Figure imgf000081_0003
307. 424.54 2-ethoxy-6-ethyl-5-{1-t(1 R)-1-
(methoxymethyl)propyl]-3,6-dimethyl-1H- pyrrolo[3,2-b]pyridin-5-yl}nicotinamlde
Figure imgf000081_0004
308. 368.48 (3S)-3-[3-(6-isopropyl-2-methoxypyridin-3-yl)-
2,5-dlmethyl-5H-pyτro1o[2,3-b]pyrazin-7- yl]butaπ-1-ol
Figure imgf000082_0001
309. 380.54 (3R)-3-{6-ethyl-5-[6-isopropyl-2-
(methy1amino)pyτidin-3-yl)-3-methyl-1H- pyrrolo[3,2-bjpyridin-1-yl}butan-1-ol
Figure imgf000082_0002
310. 405.50 (2R,3S)-3-{2-[2-methoxy-4-(1H-pyτazol-1-
Chiral yl)phenyl]-3,7-dimethy1-5H-pyrrolo[2,3- b]pyrazin-5-yl}pentan-2-ol
Figure imgf000082_0003
311. 379.54 SM2-ethyl-6-isopropy1pyr!din-3-yl)-1-[(1S)-1-
Chiral (methoxymethy1)propyl]-3,6-dlmethyl-1H- pyrrolo[3,2-b]pyridine
Figure imgf000082_0004
312. 353.47 (2S)-2-[6-{6-isopropyl-2-methoxypyridin-3-y1)-
1,5-dimethyl-1H-pyrrolo[2,3-b]pyridin-3- y1]propan-1-ol
Figure imgf000083_0001
313. 368.48 (3S)-3-[2-(6-isopropy1-2-methoxypyridiπ-3-y1)-
3,7-dimethyl-5H-pyrτolo[2,3-b]pyrazin-5- yl]butan-1-ol
Figure imgf000083_0002
314. 380.54 (2R)-2-[3-ethyl-2-(2-ethyl-6-isopropylpyridiπ-3- ylJ-T-methyl-SH-pyrrolop.S-blpyrazin-S- yl]butaπ-1-ol
Figure imgf000083_0003
315. 381.52 (2S)-2-[6-ethyl-5-(6-isopropyl-2- methoxypyridin-3-yl)-3-methy1-1 H-pyrro!o[3,2- b]pyridin-1-yl]butaπ-1-ol
Figure imgf000083_0004
316. 367.49 5-{6-ethoxy-2-ethytpyridin-3-yl)-1 -[(1 R)-2-
Chiral methoxy-1 -methylethyl]-3,6-dimethyl-1 H- pyrrolo[3,2-b]pyridine
Figure imgf000084_0001
317. 380.54 (3R)-3-{5-[6-isopropyl-2-(methylamiπo)pyridin- 3-yl]-3,6-dim ethyl-1 H-pyrrolo[3, 2-b] pyri d i n-1 - yl}pentan-1-ol
Figure imgf000084_0002
318. 395.55 (2S)-2-{2-ethyl-3-[6-isopropy1-2-
(methylamino)pyridin-3-yl]-5-methy1-5H- pyrrolo[2,3-b]pyrazin-7-yl}pentan-1-ol
Figure imgf000084_0003
319. 379.55 {2R)-2-[6-<2-ethyl-6-isopropytpyridin-3-yl )-1 ,5- dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl]pentan-
1-ol
Figure imgf000084_0004
Figure imgf000085_0001
Figure imgf000086_0001
328. 353.47 (2S)-2-{3-[6-isopropyl-2-(methylamlπo)pyridlπ-
3-yl]-2,5-dimethyt-5H-pyrrolo[2,3-b]pyrazIn-7- yl}propaπ-1-ol
Figure imgf000087_0001
329. 434.62 5-{β-isopropyl-2-piperidin-1-ylpyridiπ-3-yl)-1- [(1R)-1-(methoxyrηethyl)propyll-3,6-dimethyl- 1 H-pyrrolo[3,2-b]pyridine
Figure imgf000087_0002
330. 450.62 3-{6-ethyi-1 -[(1 S)-2-methoxy-1-methylethyl]-3- methyt-1H-pyrrolo[3,2-b]pyridin-5-yl}-6- isopropyl-N-[(2S)-tetrahydrofuran-2- ylmethyl]pyridin-2-amine
Figure imgf000087_0003
331. 395.55 (3S)-3-[5-ethyl-6-(6-isopropyl-2- methoxypyri din-3-yI)-1 -methyl-1 H-pyrrolo[2,3- b]pyridin-3-yl]pentan-1-ol
Figure imgf000087_0004
332. 436.60 6-ethyl-5-(5-isopropyl-2-morpholin-4- ylpyridin-3-ylH -[(1S)-2-methoxy-1- methylethyl]-3-methy1-1H-pyrrolo[3,2- b]pyridine
Figure imgf000088_0001
333. 391.56 5-(2-cyclopropyl-6-isopropylpyridin-3-yl)-6- ethyl-1-[(1S)-2-methoxy-1-methylethyl]-3- methyl-1 H-pyrrolo[3,2-b]pyridinβ
Figure imgf000088_0002
334. 352.48 (2S)-2-[3-{2-ethyl-6-isopropylpyridin-3-yl)-2,5- dimethy1-5H-pyrrolo[2,3-b]pyrazin-7- yl]propaπ-1-ol
Figure imgf000088_0003
335. 394.56 (2S)-2-{6-ethyl-5-[6-isopropyl-2-
(methylamino)pyridin-3-ylJ-3-methyl-1H- pyrrolo[3,2-b]pyridin-1-yl}pentan-1-ol
Figure imgf000088_0004
Figure imgf000089_0001
340. 453.58 methyl 6-ethyl-2-isopropoxy-5-{1 -[(1 R)-1 - (rnethoxymethyi)propyl]-3,6-dimethyl-1H- pyrrolo[3,2-b]pyridin-5-yl}nicotiπate
Figure imgf000090_0001
341. 354.46 (2S)-2-[3-{6-isopropyl-2-nnethoxypyτldln-3-y1)-
2,5-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7- yl]propaπ-1-ol
Figure imgf000090_0002
342. 380.54 (2R)-2-[2-(2-ethyl-6-isopropylpyridin-3-yl)-3,7- dimethyl-5H-pyrrolo[2,3-b]pyrazin-5- yl]pentan-1-ol
Figure imgf000090_0003
343. 382.51 (2R)-2-[3-{6-ethoxy-2-ethylpyridin-3-yl)-2,5- dimethyl-5H-pyrrolo[2,3-b]pyrazin-7- yl]pentan-1-ol
Figure imgf000090_0004
344. 438.57 2-ethoxy-6-ethyl-5-{1-[(1 R)-1- (methoxymethyl)propyl]-3,6-dImethyl-1H- pyrrolo[3,2-b]pyridiπ-5-yl)-N- methylnicotlπamide
Figure imgf000091_0001
345. 379.55 (3S)-3-[5-ethyl-6-(2-ethyl-6-isopropylpyridin-3- yl)-1-methyl-1 H-pyrrolo[2,3-b]pyridin-3- yl]butan-1-ol
Figure imgf000091_0002
346. 417.52 1-({2-[2-methoxy-4-{1H-pyrazol-1-yl)phenyll-
3,7-dimethyl-5H-pyrrolo[2,3-b]pyraziπ-5- yl}methy1)cyclopentanol
Figure imgf000091_0003
347. 405.50 (2S,3R)-3-{2-[2-methoxy-4-(1 H-pyrazol-1 -
Chiral yl)pheπy1]-3,7-dimβthyl-5H-pyrrolo[2,3- b]pyrazin-5-yi}pentan-2-ol
Figure imgf000091_0004
348. 403.49 (1 S,3S)-3-{2-[2-methoxy-4-(1 H-pyrazol-1 -
Chiral yl)phθπyl]-3,7-d!methyl-5H-pyτrolo[2,3- b]pyrazin-5-y1}cyclopentanol
Figure imgf000092_0001
349. 379.55 (3R)-3-[5-ethyl-6-(2-ethyl-6-isopropylpyridϊn-3- yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3- yl]butan-1-ol
Figure imgf000092_0002
350. 395.54 5-(6-isopropyl-2-methoxypyrldln-3-yl)-1-[(1S)-
Chiral 1-(methoxyRiethyl)-2-methylpropyl]-3,6- dimet hy 1-1 H-pyrrolo[3,2-b] pyridine
Figure imgf000092_0003
351. 353.46 (2R)-2-[5-(6-ethoxy-2-methyl-3-pyridiny1)-3,6- dimethyl-1 H-pyrrolo[3,2-b]pyridin-1 -yl]-1 - butanol
Figure imgf000092_0004
352. Chiral 424.59 6-Isopropyl-N-{2-methoxyethyl)-3-{1-[(1R)-1- (methoxymethy1)propyl]-3-methyI-1 H- pyrrolo[3,2-blpyridin-5-yl}-N-methylpyridin-2- amine
Figure imgf000093_0001
353. 381.52 5-(6-isopropyl-2-methoxypyridln-3-yl)-1-[{1S)-
Chiral 1-(methoxymothyl)propyl]-3,6-dimethyl-1H- pyrrolo[3,2-b]pyridine
Figure imgf000093_0002
354. 367.50 (3S)-3-[5-(6-isopropyl-2-methoxypyridin-3-yl)-
3,6-dimethyl-1H-pyrrolo[3,2-b]pyιϊdin-1- yl]butan-1-ol
Figure imgf000093_0003
355. 424.59 3-<6-βthyl-1 -[(1 S)-2-methoxy-1 -methylethyll-3-
Chiral methyl-1H-pyrrolo[3,2-b]pyrldln-5-yl}-6- isopropyl-N-(2-methoxyethyl)pyridin-2-amine
Figure imgf000093_0004
Figure imgf000094_0001
Figure imgf000095_0001
364. 391.48 (2R)-4-{2-[2-mβthoxy-4-(1 H-pyrazol-1-
Chiral yl)pheny1]-3,7-dimethyl-5H-pyrrolo[2,3- b] py razi n-5-yl} butan-2-ol
Figure imgf000096_0001
365. 391.48 (2S)-2-{2-[2-methoxy-4-<1H-pyrazol-1-
Chiral yl)phenyl]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5-yl}butaπ-1-ol
Figure imgf000096_0002
366. 367.50 (2R)-2-[5-{6-ethoxy-2-ethytpyridin-3-yl)-6- ethyl-3-methyl-1H-pyrrolo[3,2-b]pyridin-1- yl]propan-1-ol
Figure imgf000096_0003
367. 381.53 (2R)-2-{2-[6-isopropy)-2-(methylamino)pyridin-
3-yl]-3,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-5- yl}pentan-1-ol
Figure imgf000096_0004
368. 403.49 (2R)-2-cyclopropyl-2-(2-[2-methoxy-4-(1H-
Chiral pyrazol-1-yl)phenyl]-3,7-dlmethyl-5H- pyrrolo[2,3-b]pyrazin-5-yl}ethanol
Figure imgf000097_0001
369. 417.52 (1 S.2R)-1 -cyclopropyl-1 -{2-[2-methoxy-4-{1 H-
Chiral pyrazol-1-yl)phenyl]-3,7-dimethyl-5H- pyrrolo[2,3-b]pyrazin-5-yl}propaπ-2-ol
370. 391.48 (2S)-4-{2-[2-methoxy-4-(1 H-pyrazol-1 -
Chiral yl)phenyl]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyraziπ-5-yl}butan-2-ol
Figure imgf000097_0003
371. 413.56 5-(6-isopropyl-2-methoxypyridin-3-yl)-3,6- dimethyl-1-(1-phenylpropyl)-1H-pyrrolo[3,2- bjpyridine
Figure imgf000097_0004
372. 395.54 5-(2-ethoxy-6-isopropy1pyridin-3-yl)-6-ethyl-1-
Chiral 1(1 S)-2-methoxy-1 -methylethyl]-3-methyl-1 H- pyτrolo[3,2-b]pyτidine
Figure imgf000098_0001
373. 367.49 (2S)-2-l5-(6-isopropyl-2-methoxypyridin-3-yl)-
Chiral 3,6-dimethyl-1H-pyrrolo[3,2-b]pyridiπ-1- yl]butan-1-ol
Figure imgf000098_0002
374. 382.51 (2R)-2-[3-(6-isopropyl-2-methoxypyridin-3-yl)-
2,5-dimBthyl-5H-pyrrolo[2,3-b]pyraziπ-7- yl]peπtan-1-ol
Figure imgf000098_0003
375. 365.52 (3S)-3-[6-(2-ethyl-6-isopropylpyridin-3-yl)-1,5- dimethy1-1H-pyrrolo[2,3-b]pyridin-3-ylJbutan- 1-ol
Figure imgf000098_0004
H-
-
Figure imgf000099_0001
Figure imgf000100_0001
384. 417.52 (1R,3S)-3-{2-[2-methoxy-4-<1H-pyrazol-1-
Chiral yl)phenyl]-3,7-dimethyi-5H-pyrrolo[2,3- b]pyraziπ-5-yl}cyclohβxanol
Figure imgf000101_0001
385. 396.53 5-(4-isopropyl-2,6-dimethoxyphenyl)-1-[(1R)-1-
Chiral (methoxymethyl)propyi]-3-methyl-1 H- pyrrolo[3,2-b]pyridine
Figure imgf000101_0002
386. 391.48 (2SM -{2-[2-methoxy-4-(1 H-pyrazol-1 -
Chiral yl)phenyl]-3,7-dimethy1-5H-pyrrolo[2,3- b]pyrazi n-5-yl}butan-2-ol
Figure imgf000101_0003
387. 394.56 (3S)-3-{5-ethyl-6-[6-isopropyl-2- (methylamino)pyridin-3-yl]-1 -methyl-1 H- pyrrolo[2,3-b]pyridin-3-y1}pentan-1-ol
Figure imgf000101_0004
H-
Figure imgf000102_0001
392. 339.45 6-ethyl-1 -[(1 S)-2-fluoro-1-methy1ethyl]-5-(6-
Chiral isopropylpyridin-3-yl)-3-tnethyl-1 H- pyrrolo[3,2-bjpyridine
Figure imgf000103_0001
393. 382.51 (2S)-2-[3-(6-isopropy1-2-methoxypyridln-3-yi)-
2,5-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7- yl]pentan-1-ol
Figure imgf000103_0002
394. 393.57 6-ethyl-5-(6-isopropyl-2-propylpyridin-3-yl)-1-
Chiral [(1S)-2-methoxy-1-iτiethylethyl]-3-methyl-1H- pyrrolo[3,2-b] pyridine
Figure imgf000103_0003
395. 381.52 (3R)-3-[6-ethyl-5-(6-isopropyl-2- methoxypyrjdin-3-yl)-3-methyl-1H-pyrrolo[3,2- b]pyridin-1-yl]butan-1-ol
Figure imgf000103_0004
-[(1 S)- H- .
Figure imgf000104_0001
400. Chiral 404.91 3-{6-chloro-1-[(1S)-2-fluoro-1- (methoxymethy1)ethyl]-3-methyM H- pyrrolo[3,2-b]pyridin-5-yl}-6-isopropyI-N- methylpyridin-2-amiπβ
Figure imgf000105_0001
401. 380.54 (3S)-3-{6-[6-isopropyl-2-(methy1amino)pyridin- 3-yl]-1 ,5-dimethyl-1 H-pyrrolo[2,3-b]pyridin-3- yl}pentan-1-ol
Figure imgf000105_0002
402. 335.49 1-isobutyl-5-(6-isopropyl-2-methylpyridiπ-3- yl)-3,6-dimethyl-1 H-pyrrolo[3,2-b]pyridϊ ne
Figure imgf000105_0003
403. Chiral 403.49 (1R,3R)-3-{2-[2-methoxy-4-(1H-pyrazol-1- yl)phenyl]-3,7-dimethyt-5H-pyrrolo[2,3- b]pyrazin-5-yl}cyclopentanol
Figure imgf000105_0004
404. 397.95 5-{2-chloro-6-isopropyIpyriclin-3-yl)-6-
Chiral cyclopropyl-1 -[(1 S)-2-mβthoxy-1 -methylethyl]- 3-mβthyl-1 H-pyrrolo[3,2-b]pyridinβ
Figure imgf000106_0001
405. 379.55 (2S>-2-[5-ethyl-6-(2-ethy1-6-isopropy1pyriciin-3- yl)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-3- yl]butan-1-ol
Figure imgf000106_0002
406. 380.54 (2R)-2-[3K2-ethy1-6-isopropylpyridin-3-yl)-2,5- dimethyl-5H-pyrrolo[2,3-b]pyrazin-7- yl]pentaπ-1-ol
Figure imgf000106_0003
407. 393.58 (3S)-3-[6-ethyl-5-{2-ethy1-6-isopropylpyridin-3- yl)-3-methyl-1H-pyrrolo[3,2-b]pyridin-1- yl]pentaπ-1-ol
Figure imgf000106_0004
Figure imgf000107_0001
412. 395.54 5-{2-lsopropoxy-6-isopropylpyriclin-3-yl)-1-
Chiral [(1 R)-1-(methoxymetliyl)propyl]-3-mettiyl-1 H- pyrroloI3,2-b)pyrldi πe
Figure imgf000108_0001
413. 351.49 5-(2-ethyl-6-isopropy1pyrldln-3-yl)-1-(2- methoxyethyl)-3tθ-dimethyl-1H-pyrrolo[3,2- b]pyridine
Figure imgf000108_0002
414. 445.58 5-[2-ethoxy-6-ethy1-5-(methylsulfonyl)pyridin- 3-yl]-1 -[(1 R)-1 -(methoxymethyl)propyl]-3- methyl-1 H-pyrrolo[3,2-b]pyridine
Figure imgf000108_0003
415. 391.48 1-{2-[2-methoxy~4-(1H-pyrazol-1-yl)phenyl]-
3,7-dimethyl-5H-pyrroloI2,3-b]pyrarin-5-yl}-2- methylpropan-2-ol
Figure imgf000108_0004
416. 366.51 (2R)-2-[3-ethyl-2-(2-ethyl-6-lsopropylpyridin-3- y1)-7-methy1-5H-pyrrolo[2,3-b]pyrazin-5- yl]ρropan-1-ol
Figure imgf000109_0001
417. 394.56 (2R)-2-{6-ethyl-5-[6-isopropy1-2-
(methylamino)pyridin-3-yl]-3-methyl-1H- pyrrolo[3,2-b]pyridin-1-yl}pentan-1-ol
Figure imgf000109_0002
418. 395.55 (2R)-2-[5-(6-ethoxy-2-ethylpyridin-3-yl)-6- ethyl-3-methy1-1 H-pyrrolo[3,2-b]pyridin-1- yl]pentan-1-ol
Figure imgf000109_0003
419. 382.51 (3S)-3-t2-ethyl-3-(6-isopropyl-2- methoxypyridin-3-yl)-5-methyl-5H-pyrτolo[2,3- b]pyrazin-7-yl]butan-1-ol
Figure imgf000109_0004
420. 380.54 (2R)-2-{6-[6-lsopropyl-2-(methylamino)pyridin-
3-yl]-1,5-dimethy1-1H-pyrrolo[2,3-b]pyridin-3- yl}pentan-1-ol
Figure imgf000110_0001
421. 363.50 5-{2-ethyl-6-isopropy1pyridin-3-yl)-1-[1-
(methoxymβthyl)vlnyl]-3,6-climethyl-1H- pyrrolo[3,2-b]pyridine
Figure imgf000110_0002
422. 465.64 6-isopropyl-3-{1-[(1 R)-1-
Chiral (methoxymethyl)propyl]-3-methyl-1 H- pyrrolo[3,2-b]pyridin-5-y1}-N-(2-morpholin-4- ylethyl)pyridin-2-amlne
Figure imgf000110_0003
423. 367.50 (3R)-3-[5-(6-isopropyl-2-methoxypyridin-3-yl)- 3,6-dimethyl-1 H-pyrrolo[3,2-b]pyridin-1 - yl]butan-1-ol
Figure imgf000110_0004
Figure imgf000111_0001
428. 381.52 (2S)-2-[5-ethyl-β-{6-isopropyl-2- methoxypyridin-3-yl)-1-inethyl-1H-pyrrolo[2,3- b]pyridin-3-y1]butan-1 -ol
Figure imgf000112_0001
429. Chlral 493.69 3-{6-ethyl-1-[(1S)-2-methoxy-1-methylethyl]-3- methyl-1H-pyrrolo[3,2-b]pyridin-5-yl}-6- isopropyl-N-(3-morpholiπ-4-y1propyl)pyridin- 2-amine
Figure imgf000112_0002
430. 393.58 (2S)-2-[5-ethyl-6-(2-ethyl-6-isopropylpyridin-3- yf)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-3- y1]peπtan-1-ol
Figure imgf000112_0003
431. 352.48 (2S)-2-[2-(2-ethyl-6-isopropylpyridin-3-yl)-3,7- dimethyt-5H-pyrrolo[2,3-b]pyrazin-5- yl]propan-1-ol
Figure imgf000112_0004
Figure imgf000113_0001
H-
-[(1R)-I-
Figure imgf000114_0001
440. 396.54 (2S)-2-[3-(6-ethoxy-2-ethy1pyridin-3-yl)-2-ethyi-
5-methyl-5H-pyrrolo[2,3-b]pyrazin-7- yl]pentaπ-1-ol
Figure imgf000115_0001
441. 381.53 (3S)-3-{2-[6-isopropyl-2-(methy1amino)pyridin-
3-yl]-3,7-dimethyt-5H-pyrrolo[2,3-b]pyrazin-5- yl}pentan-1-ol
Figure imgf000115_0002
442. 381.51 (2R)-2-[5-(2-ethyl-6-isopropyl-3-pyridinyl)-3,6- dimethyl-1H-pyπrolo[3,2-b]pyridin-1-yl]-3- methqxy-1-propanol
Figure imgf000115_0003
443. 367.50 (2S)-2-[5-{6-ethoxy-2-ethylpyridin-3-yl)-3,6- dimethyl-1H-pyrrolo[3,2-b]pyridin-1-yl]butan-
1-Ol
Figure imgf000115_0004
444. 394.56 (2S)-2-{5-ethyl-6-[6-isopropyl-2- (methylamino)pyridin-3-yl]-1 -methyl-1 H- pyrrolo[2,3-b]pyridin-3-y1}pentan-1-ol
Figure imgf000116_0001
445. 382.51 (2R)-2-I3-ethyl-2-(6-isopropy1-2- mβthoxypyrldin-3-yl)-7-methyl-5H-pyrrolo[2,3- b]ρyrazin-5-yl]butan-1-ol
Figure imgf000116_0002
446. 366.51 (2S)-2-{5-[6-lsopropyl-2-(methylamiπo)pyridiπ- 3-yl]-3,6-dimethyl-1 H-pyrrolo[3,2-b]pyridin-1 - yl}butan-1-ol
Figure imgf000116_0003
447. 393.58 (3R)-3-[6-ethyl-5-(2-ethyl-6-isopropylpyridin-3- yl)-3-methyl-1 H-pyrrolo[3,2-b]pyridin-1- yl]peπtan-1-ol
Figure imgf000116_0004
448. 380.49 (2R)-2-[2-(2-ethyl-6-isopropy1pyridin-3-yl)-3,7-
Chiral dimethy1-5H-pyττolo[2,3-b]pyrazin-5- yl]butanolc acid
Figure imgf000117_0001
449. 393.58 (3S)-3-[5-ethyl-6-(2-ethy1.6-isopropy1pyridin-3- yl)-1-methyl-1H-pyτroloI2,3-b]pyτidin-3- y1]pentan-1-ol
Figure imgf000117_0002
450. 368.48 (2R)-2-[2-(6-isopropyl-2-methoxypyridin-3-yl)-
3,7-dlmethy1-5H-pyrrolo[2,3-b]pyraziπ-5- yl]butan-1-ol
Figure imgf000117_0003
451. 365.52 (3R)-3-[5-(2-ethyl-6-isopropylpyridin-3-yl)-3,6- dimethyl-1 H-pyrrolo[3,2-b]pyrtdin-1 -yljbutan- 1-ol
Figure imgf000117_0004
452. 379.50 6-cyclopropyl-5-{2-ethyl-6-methoxypyrlclln-3-
Chiral yl )-1 -1(1 S)-2-methoxy-1 -methylethyl]-3-methyl- 1 H-pyrrolo[3,2-b]pyridine
Figure imgf000118_0001
453. 367.50 (3R)-3-{3-[6-isopropyl-2-(methylamino)pyridin-
3-yl]-2,5-dimethyl-5H-pyrrolo[2,3-b]pyra-:in-7- yl}butan-1-ol
Figure imgf000118_0002
454. 372.44 (2R)-2-[3-fluoro-2-(6-isopropyl-2-methoxy-3- pyridinyl)-7-methyi-5H-pyrrolot2,3-b]pyrazin-
5-ylJ-1-butaπol
Figure imgf000118_0003
455. 395.55 (2R)-2-{2-ethyl-3-[6-isopropyI-2-
(methylamino)pyridin-3-yl]-5-methyl-5H- pyrrolo[2,3-b]pyrazin-7-yl}pentan-1-ol
Figure imgf000118_0004
456. 381.52 (3R)-3-[6-(6-ethoxy-2-ethylpyridin-3-y1>-5- ethyl-1-methyl-1H-pyrrolo[2,3-b]pyridin-3- yl]butan-1-ol
Figure imgf000119_0001
457. 367.50 (2S)-2-[5-ethyl-6-(6-isopropyl-2- methoxypyridin-3-yl)-1 -methyl-1 H-pyrrol o[2,3- b]pyridin-3-yl]propan-1-ol
Figure imgf000119_0002
458. 411.54 5-[6-isopropyl-2-(2-methoxyethoxy)pyridin-3-
Chiral yl]-1-[(1R)-1-(methoxymethyl)propyl]-3- methyl-1 H-pyrrolo[3,2-blpyrldine
Figure imgf000119_0003
459. 405.50 (2S)-2-{2-[2-methoxy-4-(1H-pyrazol-1-
Chiral y1)phenyl]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5-yl}-3-methylbutan-1 -ol
Figure imgf000119_0004
H-
Figure imgf000120_0001
Figure imgf000122_0001
472. 394.56 N-βthyl-6-lsopropyl-3-{1 -[(1 R)-1 -
Chiral (methoxymethyl)propyl]-3-methyl-1 H- pyπrolo[3,2-b]pyrIdin-5-yl}-N-methylpyrldin-2- amine
Figure imgf000123_0001
473. 393.57 5-(6-isopropyl-2-methoxypyridin-3-yl)-3,6- dimethyl-1-(1-propylbutyl)-1H-pyrrolo[3,2- bjpyridine
Figure imgf000123_0002
474. 382.51 (2S)-2-[2-(6-isopropy1-2-methoxypyridin-3-yl)-
3,7-dimethyI-5H-pyrrolo[2,3-b]pyrazin-5- yl]pentan-1-ol
Figure imgf000123_0003
475. 396.54 (2S)-2-[3-ethyl-2-(6-isopropy[-2- methoxypyridin-3-yl)-7-methyl-5H-pyrrolo[2,3- b]pyrazin-5-yl]peπtaπ-1-ol
Figure imgf000123_0004
-[(1 R)-2-
Figure imgf000124_0001
480. 353.47 (2S)-2-{2-[6-isopropyl-2-(methylamino)pyridin-
3-yl]-3F7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-5- yl}propan-1-ol
Figure imgf000125_0001
481. 367.51 6-ethyl-5-(2-ethyl-6-isopropy1pyridln-3-yl)-1-
Chiral [(1S)-2-fluoro-1-methylethyl]-3-methyl-1H- pyrrolo[3,2-b] pyridine
Figure imgf000125_0002
482. 366.51 (3S)-3-{6-[6-isopropyl-2-{methylamino)pyridin- 3-yl]-1,5-dimethyl-1H-pyrrolo[2,3-b]pyridin-3- yl}butaπ-1 -ol
Figure imgf000125_0003
483. 382.51 (3S)-3-[3-θthyl-2-(6-isopropyl-2- methoxypyridln-3-yl)-7-methyl-5H-pyrrolo[2,3- b]pyrazi n-5-yl]butan-1 -ol
Figure imgf000125_0004
484. 371.90 (2S)-2-[5-(2-chloro-6-isopropylpyr!dlπ-3-yl)-6- ethyl-3-methyl-1 H-pyrrolo[3,2-b)pyridln-1 - y1]propan-1-ol
Figure imgf000126_0001
485. 365.52 (2R)-2-[6-ethyl-5-(2-ethyl-6-isopropy1pyridin-3- ylJ-S-mβthyl-IH-pyrroloIS.Σ-blpyridin-i- yl]propan-1-ol
Figure imgf000126_0002
486. 367.49 5-(6-isopropyl-2-methoxypyridin-3-yl)-1-[(1R)-
Chiral 1-(methoxymethyl)propyl]-3-methyl-1H- pyrrolo[3,2-b]pyridine
Figure imgf000126_0003
487. Chiral 479.66 6-isopropy|.3-{1 -[(1 RH - (methoxymethyl)propyl]-3-methyl-1H- pyrrolo[3,2-b]pyridin-5-yl}-N-(3-morpholiπ-4- ylpropyI)pyridin-2-amiπθ
Figure imgf000126_0004
Figure imgf000127_0001
492. Chiral 403.93 6-chloro-5-(2-ethyl-6-lsopropy1pyrldin-3-yl)-1- [{1S}-2-fluoro-1-(methoxymethyl)ethyl]-3- methyl-1 H-pyrrolo[3,2-b]ρyridinβ
Figure imgf000128_0001
493. 391.48 (2S,3S)-3-{2-[2-methoxy-4-(1 H-pyrazoi-1 -
Chiral yl)phenyl]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyraziπ-5-yl}butan-2-ol
Figure imgf000128_0002
494. 352.48 2-(6-isopropy1-2-methylpyridin-3-yl)-5-[(1S)-2-
Chiral methoxy-1 -methylethyl]-3,7-dimethy1-5H- pyrrolo[2,3-b]pyrazi ne
Figure imgf000128_0003
495. 436.60 5-(6-isopropyl-2-morpholin-4-ylpyridin-3-yl)-1- [(1 R)-1 -(methoxymethyl)proρyl]-3,6-dimethy1- 1 H-pyrrolo[3,2-b]pyridine
Figure imgf000128_0004
Figure imgf000129_0001
Figure imgf000130_0001
504. 391.48 <2S,3R)-3-{2-[2-methoxy-4-(1H-pyrazol-1-
Chiral yl)phenyl]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5-yl}butan-2-ol
Figure imgf000131_0001
505. 468.59 6-ethyl-5-{6-ethy[-1 -[2-methoxy-1- (methoxymethyl)ethy1]-3-meth.yl-1 H- pyrrolo[3,2-b]pyridin-5-yl}-2- isopropoxynicotinamide
Figure imgf000131_0002
506. 377.49 5-(4-isopropyl-2-methoxypheny1)-1-[(1S)-2-
Chiral methoxy-1-methylethyl]-3-methyl-1 H- pyrrolo[3,2-b]pyridine-6-carbonitrilβ
Figure imgf000131_0003
507. 367.50 (2S)-2-[6-(6-isopropyl-2-methoxypyridin-3-yI)-
1,5-dimethyl-1H-pyrrolo[2,3-b]pyridin-3- yl]butan-1-ol
Figure imgf000131_0004
Figure imgf000132_0001
Figure imgf000133_0001
-
Figure imgf000134_0001
520. 395.54 5-(2-ethoxy-6-Isopropylpyridin-3-yI)-1 -[(1 R)-I-
(methoxymethyl)propyl]-3,6-dlmethyl-1H- pyrτolo[3,2-b]pyr!dine
Figure imgf000135_0001
521. 382.51 (2R)-2-[2-{6-isopropy1-2-methoxypyridin-3-y1)-
3,7-dimethyt-5H-pyrrolo[2,3-b]pyrazin-5- yl]pβntan-1-ol
Figure imgf000135_0002
522. Chiral 405.50 (3R)-3-<2-[2-methoxy-4-(1 H-pyrazol-1 ■ yl)phenyl]-3,7-dImethyl-5H-pyrrolo[2,3- b]pyrazin-5-yl}pentan-1-ol
Figure imgf000135_0003
523. 367.51 6-ethyl-1-[(1R)-1-(fluoromethyl)propyl]-5-(6-
Chiral isopropy1-2-methylpyridln-3-yl)-3-methyl-1 H- pyrrolo[3,2-b]pyridine
Figure imgf000135_0004
Figure imgf000136_0001
528. 382.51 (2S)-2-[3-ethy1-2-{6-isopropyl-2- methoxypyridin-3-y))-7-methyl-5H-pyrrolo[2,3- b] pyrazin-5-yllbutan-1 -ol
Figure imgf000137_0001
529. 380.54 (3S)-3-[2-{2-ethyl-6-isopropylpyridin-3-yl)-3,7- dimethyl-5H-pyrrolo[2,3-b]pyrazin-5- yl]pentan-1-ol
Figure imgf000137_0002
530. 382.51 (2S)-2-[3-{β-ethoxy-2-ethylpyridin-3-yl)-2,5- dimethyl-5H-pyrrolo[2,3-b]pyrazin-7- yl]peπtan-1-ol
Figure imgf000137_0003
531. 379.54 6-ethyl-5-(6-isopropyl-2-methylpyridin-3-yl)-1-
Chira) [(1 R)-1 -(methoxymethy1)propyl]-3-methyl-1 H» pyrrolo[3,2-b]pyridine
Figure imgf000137_0004
Figure imgf000138_0001
536. 380.54 (3R)-3-[2-ethyt-3-{2-ethyl-6-isopropylpyridin-3- yl)-5-methy1-5H-pyτrolol2,3-b]pyrazln-7- yl]butan-1-ol
Figure imgf000139_0001
537. 394.56 (2R)-2-{5-ethyt-6-[6-isopropy1-2- (methy)amino)pyridin-3-yl]-1 -methyl-1 H- pyrrolo[2,3-b]pyridln-3-yl}pentan-1-ol
Figure imgf000139_0002
538. 352.48 (2R)-2-[2-(2-ethy1-6-isopropylpyridiπ-3-yl)-3,7- dimethy1-5H-pyrrolo[2,3-b]pyrazin-5- yl]propan-1-ol
Figure imgf000139_0003
539. 367.50 (2R)-2-[5-(θ-isopropyl-2-methoxypyridin-3-yl)-
3,6-dimethyl-1H-pyrrolo[3,2-bJpyridin-1- yl]butan-1-ol
Figure imgf000139_0004
540. 1 ■
Chiral 405.50 (2S,3S)-2-{2-[2-methoxy-4-(1 H-pyrazol- yl)phenyl]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyτazln-5-y1}pentan-3-ol
Figure imgf000140_0001
541. 392.50 2-[(6-ethyl-5-{1-[(1S)-2-methoxy-1- methylethyl]-3,6-dimethyl-1H-pyrrolo[3,2- b]pyridin-5-yl}pyridin-2-yl)oκy]propanenitrile
Figure imgf000140_0002
542. 381.52 (2S)-2-[5-(6-isopropyl-2-methoxypyridin-3-yl)-
3,6-dimethyl-1H-pyrrolo[3,2-b]pyridin-1- yl]pentan-1-ol
Figure imgf000140_0003
543. 380.54 (2S)-2-{6-[6-isopropyl-2-(methylamino)pyridin- 3-yl]-1 ,5-dimethyl-1 H-pyrrolo[2,3-b]pyridin-3- yl}pentaπ-1-ol
544. 368.48 (2S)-2-[3-{6-isopropy1-2-methoxypyriclin-3-y1)-
2,5-dimethy1-5H-pyrrolo[2,3-b]pyrazin-7- yl]butan-1-ol
Figure imgf000141_0001
545. 364.49 (2R)-2-[2-{2-ethy1-6-isopropylpyridln-3-yl)-3,7-
Chiral dimβthy1-5H-pyrrolo[2,3-b]pyrazin-5-y1]butanal
Figure imgf000141_0002
546. 381.53 (3R)-3-{2-[6-isopropyl-2-(methylamino)pyridin-
3-yl]-3,7-dlmethy1-5H-pyrrolo[2,3-b]pyraziπ-5- yl}pentan-1-ol
Figure imgf000141_0003
547. 381.52 (2R)-2-[6-(6-ethoxy-2-ethylpyridin-3-yl)-1,5- dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl]pentan-
1-ol
Figure imgf000141_0004
Figure imgf000142_0001
552. 379.55 (3R)-3-[6-ethyl-5-(2-ethyl-6-isopropy1pyridln-3- yl)-3-methyl-1 H-pyrrolo[3,2-b]pyridiπ-1 - yl]butan-1-ol
Figure imgf000143_0001
553. 393.53 6-cyclopropy1-5-($-isopropyl-2-
Chiral methoxypyridi n-3-yl)-1-[(1 S)-2-methoxy-1 - methylethyl]-3-methyl-1 H-pyrrolo[3,2- b]pyridine
Figure imgf000143_0002
554. 367.50 (2R)-2-{2-[6-isopropyl-2-(methylamino)pyridin-
3-yl]-3,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-5- yl}butan-1-ol
Figure imgf000143_0003
555. 381.52 (2S)-2-[5-(6-ethoxy-2-ethylpyridin-3-yl)-3,6- dimethyl-1H-pyrrolo[3,2-b]pyridin-1-yl]pentan-
1-ol
Figure imgf000143_0004
556. 417.52 (1 S,2R)-2-{2-[2-methoxy-4-{1 H-pyrazol-1-
Chiral yl)pheny1]-3,7-dimethyI-5H-pyrrolo[2,3- b]pyraziπ-5-yl}cyclohexanol
Figure imgf000144_0001
557. 380.54 (2S)-2-{5-[6-isopropyl-2-(methylamiπo)pyridin-
3-yl]-3,6-dimethyl-1H-pyrrolo[3,2-b]pyridin-1- yl}pentan-1-ol
Figure imgf000144_0002
558. 379.55 (2R)-2-[6-ethyl-5-(2-ethyl-6-isopropylpyridin-3- yl )-3-methyI-1 H-pyrrolo[3,2-b]pyridin-1- yl]butan-1-ol
Figure imgf000144_0003
559. 368.50 3-{6-ethyl-1-[(1S)-2-fluoro-1-methylethyl]-3-
Chiral methyi-1 H-pyrrolo[3,2-b]pyridin-5-yl}-6- isopropyl-N-methylpyridin-2-amine
Figure imgf000144_0004
Figure imgf000145_0001
AU compounds listed above may be characterized at least by 1H-NMR and one of the following LCMS methods:
Method 1. HPLC instrumentation: Analyses are performed using a Waters 600 series pump (Waters Corp.), a Waters 996 Diode Array detector and a Gilson 215 auto-sampler (Gilson Inc.). Data are acquired using MassLynx 4.0 software, with OpenLynx processing. - HPLC conditions: 4.6x50mm, XTerra MS Cl 8, 5 mm column (Waters Corp.); UV 10 spectra/sec, 220, 254nm; flow rate 4.0 mL/min; injection volume 1-10 μl; Gradient conditions - Mobile phase A 95% Water, 5% Methanol with 0.05% Formic acid; Mobile phase B 95% methanol, 5% Water with 0.025% Formic acid; Gradient: Time (min) %B
0 5 0.01 5
1.0 100
2.0 100
2.1 5
MS instrumentation: LC-MS experiments are performed using a Waters ZMD II Mass Spectrometer.
MS conditions: Electrospray positive ionization; capillary voltage 3.5kV; cone voltage 30V; desolvation and source temperature 250 0C and 100 0C respectively; mass range 120-800 with a scan time of 0.5 seconds and an inter scan delay of 0.1 min. Method 2. Flow Injection Condition:
A Perkin Elmer HPLC system (tow Series 200 micro LC pumps, pump A and pump B, with a Series 200 autosampler) is used to perform flow injection. Mobile phase is a combination of 85% methanol (pump B) with 15% of water (pump A). The flow rate is 1.0 mL/min; and the injection volume is 3 μl. MS instrumentation: LC-MS experiments are performed using a Sciex 150MA Mass Spectrometer.
MS conditions: Ion source is Heated Nebulizer (atmosphere pressure chemical ionization). The mass range is 100-1000 amu. Both positive and negative modes are in place. For positive ion mode, Nebulizer current is 2.0 mA, and the temperature is 350 0C. The Nebulizer gas is 10, and the Curtain gas is 12. The declustering potential is 30 V. The Focusing potential is 200 V, and the entrance potential is -10 V. For negative ion mode, Nebulizer current is -2.0 mA, and the temperature is 350 0C. The Nebulizer gas is 10, and the Curtain gas is 12. The declustering potential is -30 V. The Focusing potential is -200 V, and the entrance potential is 10 V.
Method 3.
HPLC Instrumentation: HPl 100 PUMP, HPIlOO UV detector with 220 nm, HTS/PAL autosampler from Leap Technology, data acquired by Micromass Ma
HPLC conditions: Synergi 2U HYDRO-RP 20 x 4.0mm column, flow rate 1.0 mL/min, injection volume 5 μL.
Gradient conditions: 0.1% formic acid in aqueous acetonitrile, 10-90% acetonitrile over 3 min, then 100% acetonitrile, end at 5 min. MS instrumentation: Micromass LCT-TOF MS
MS conditions: Scan m/z 100-1200, capillary voltage 3000V, cone voltage 25V, desolvation 200 0C and source temperature 100 0C.
Methods of treatment
Compounds of and salts of Formula I (preferably of Table I) are useful in treating a variety of conditions including affective disorders, anxiety disorders, stress disorders, eating disorders, and drug addiction. Hence they each may be used in the manufacture of a medicament for the treatment of each such condition.
Affective disorders include all types of depression, bipolar disorder, cyclothymia, and dysthymia. Anxiety disorders include generalized anxiety disorder, panic, phobias and obsessive-compulsive disorder. Compounds of and salts of Formula I (preferably of Table I) are useful in treating symptoms of affective disorders and anxiety disorders. These syptoms include increased awakenings, increased REM density, and related sleep disorders (e.g., insomnia) and dermatologic conditions including atopic dermatitis, urticaria and psoriasis.
Stress-related disorders include post-traumatic stress disorder, hemorrhagic stress, stress-induced psychotic episodes, psychosocial dwarfism, stress headaches, stress-induced immune systems disorders such as stress-induced fever, and stress-related sleep disorders. Eating disorders include anorexia nervosa, bulimia nervosa, and obesity.
Compounds provided herein are also useful in the treatment (e.g., symptomatic treatment) of a variety of neurological disorders including supranuclear palsy, AIDS related dementias, multiinfarct dementia, neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, head trauma, spinal cord trauma, ischemic neuronal damage, amyotrophic lateral sclerosis, disorders of pain perception such as fibromyalgia and epilepsy.
Additionally compounds and salts of Formula I (preferably of Table I) are useful in the treatment (e.g., symptomatic treatment) of a number of gastrointestinal, cardiovascular, hormonal, autoimmune and inflammatory conditions. Such conditions include irritable bowel syndrome (IBS), ulcers, Crohn's disease, spastic colon, diarrhea, post operative ilius, and colonic hypersensitivity associated with psychopathological disturbances or stress; hypertension, tachycardia, congestive heart failure, infertility, and euthyroid sick syndrome; and inflammatory conditions effected by or associated with rheumatoid arthritis, osteoarthritis, pain, asthma, psoriasis and allergies. Compounds and salts of Formula I (preferably of Table I) are also useful as modulators of the CRFl receptor in the treatment of animal disorders associated with aberrant CRF levels. Such conditions include porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs, psychosocial dwarfism and hypoglycemia.
Typical subjects to which compounds of Formula I (preferably of Table I) may be administered include mammals, preferably primates, most preferably humans. For veterinary applications, a wide variety of subjects are suitable, e.g. livestock such as cattle, sheep, goats, cows, swine and the like; poultry such as chickens, ducks, geese, turkeys, and the like; and other domesticated animals particularly pets such as dogs and cats. For diagnostic or research applications, a wide variety of mammals are suitable subjects including rodents (e.g. mice, rats, hamsters), rabbits, primates, and swine such as inbred pigs and the like. Additionally, for in vitro applications, such as in vitro diagnostic and research applications, body fluids (e.g., blood, plasma, serum, CSF, lymph, cellular interstitial fluid, aqueous humor, saliva, synovial fluid, feces, or urine) and cell and tissue samples of the above subjects are suitable for use.
Compounds provided herein are also useful as standards and reagents in determining the ability of test compounds (e.g., a potential pharmaceutical) to bind to a CRF receptor. Labeled compounds provided herein are also useful as tracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
More particularly compounds provided herein are useful for demonstrating the presence of CRF receptors in cell or tissue samples. This may be done by preparing a plurality of matched cell or tissue samples, at least one of which is prepared as an experiment sample and at least one of which is prepared as a control sample. The experimental sample is prepared by contacting (under conditions that permit binding of CRF to CRF receptors within cell and tissue samples) at least one of the matched cell or tissue samples that has not previously been contacted with any compound or salt provided herein with an experimental solution comprising the detectably-labeled preparation of the selected compound or salt at a first measured molar concentration. The control sample is prepared by in the same manner as the experimental sample and is incubated in a solution that contains the same ingredients as the experimental solution but that also contains an unlabelled preparation of the same compound or salt provided herein at a molar concentration that is greater than the first measured molar concentration.
The experimental and control samples are then washed to remove unbound detectably-labeled compound. The amount of detectably-labeled compound remaining bound to each sample is then measured and the amount of detectably-labeled compound in the experimental and control samples is compared. A comparison that indicates the detection of a greater amount of detectable label in the at least one washed experimental sample than is detected in any of the at least one washed control samples demonstrates the presence of CRP receptors in that experimental sample. The detectably-labeled compound used in this procedure may be labeled with any detectable label, such as a radioactive label, a biological tag such as biotin (which can be detected by binding to detectably-labeled avidin), an enzyme (e.g., alkaline phosphatase, beta galactosidase, or a like enzyme that can be detected its activity in a colorimetric assay) or a directly or indirectly luminescent label. When tissue sections are used in this procedure and the detectably-labeled compound is radiolabeled, the boxmd, labeled compound may be detected autoradiographically to generate an autoradiogram. When autoradiography is used, the amount of detectable label in an experimental or control sample may be measured by viewing the autoradiograms and comparing the exposure density of the autoradiograms.
The present invention also pertains to methods of inhibiting the binding of CRF to CRF receptors (preferably CFRl receptors) which methods involve contacting a solution containing a compound provided herein with cells expressing CRF receptors, wherein the compound is present in the solution at a concentration sufficient to inhibit CRF binding to CRF receptors in vitro. This method includes inhibiting the binding of CRF to CRF receptors in vivo, e.g., in a patient given an amount of a compound or salt of Formula I (preferably of Table I) that would be sufficient to inhibit the binding of CRF to CRF receptors in vitro. In one embodiment, such methods are useful in treating physiological disorders associated with excess concentrations of CRF. The amount of a compound that would be sufficient to inhibit the binding of CRF to the CRF receptor in vitro may be readily determined via a CRF receptor binding assay (see, e.g., Example 7), or from the IC50 determined using a CRF receptor functional assay, such as the standard assay of CRF receptor activity of Example 6. The CRF receptors used to determine in vitro binding may be obtained from a variety of sources, e.g., from cells that naturally express CRF receptors, e.g. IMR32 cells, or from cells expressing cloned human CRF receptors.
The present invention also pertains to methods for altering the activity of CRF receptors, said method comprising exposing cells expressing such receptors to an effective amount of a compound provided herein, wherein the compound is present in the solution at a concentration sufficient to specifically alter the signal transduction activity in response to CRF in cells expressing CRF receptors in vitro. Preferred cells for this purpose are those that express high levels of CRF receptors (i.e., equal to or greater than the number of CRFl receptors per cell found in differentiated IMR-32 human neuroblastoma cells), with IMR-32 cells being particularly preferred for testing the concentration of a compound required to alter the activity of CRFl receptors. This method includes altering the signal transduction activity of CRF receptors in vivo, e.g., in a patient given an amount of a compound or salt of Formula I (preferably of Table I) that would be sufficient to alter the signal transduction activity in response to CRF in cells expressing CRF receptors in vitro. The amount of a compound that would be sufficient to alter the signal transduction activity of CRF receptors in response to CRF in vitro may also be determined via an assay of CRF receptor mediated signal transduction, such as an assay wherein the binding of CRF to a cell surface CRF receptor effects a changes in reporter gene expression.
The present invention also pertains to packaged pharmaceutical compositions for treating disorders responsive to CRF receptor modulation, e.g., eating disorders, depression or stress. The packaged pharmaceutical compositions include a container holding dosage units comprising a therapeutically effective amount of at least one compound or salt of Formula I (preferably of Table I) and instructions for using the treating disorder responsive to CRFl receptor modulation in the patient. Chemical description and terminology
The compounds herein are generally described using standard nomenclature. The phrase "optionally substituted" indicates that a group may either be unsubstituted or substituted at one or more of any of the available positions, typically 1, 2, 3, 4, or 5 positions, by one or more suitable substituents such as those disclosed herein. Suitable substituents include, for example, halogen, cyano, amino, hydroxy, nitro, azido, carboxamido, -COOH, SO2NH2, alkyl (e.g., d-Cgalkyl), alkenyl (e.g., C2-C8alkenyl), alkynyl (e.g., C2-C8 alkynyl), alkoxy (e.g., Ci-Cgalkoxy), alkyl ether (e.g., C2-C8alkyl ether), alkylthio (e.g., Ci- C8alkylthio), haloalkyl (e.g., Ci-Cghaloalkyl), hydroxyalkyl (e.g., Ci-Cghydroxyalkyl), aminoalkyl (e.g., Ci-C8aminoalkyl), haloalkoxy (e.g., Ci-Cghaloalkoxy), alkanoyl (e.g., Q- Csalkanoyl), alkanone (e.g., Ci-Cgalkanone), alkanoyloxy (e.g., Ci-Cgalkanoyloxy), alkoxycarbonyl (e.g., Ci-Cgalkoxycarbonyl), mono- and di-(Ci-C8alkyl)amino, mono- and di- (Ci-C8alkyl)aminoCi-C8alkyl, mono- and di-(Ci-Cgalkyl)carboxamido, mono- and di-(Ci- C8alkyl)sulfonamido, alkylsulfinyl (e.g., Ci-Cgalkylsulfinyl), alkylsulfonyl (e.g., Cj- Cgalkylsulfonyl), aryl (e.g., phenyl), arylalkyl (e.g., (Cβ-CigarytyCi-Cgalkyl, such as benzyl and phenethyl), aryloxy (e.g., Cό-Cigaryloxy such as phenoxy), arylalkoxy (e.g., (Ce- Ci8aryl)Ci-Cgalkoxy) and/or 3- to 8-membered heterocyclic groups such as coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino or pyrrolidinyl. Certain groups within the formulas provided herein are optionally substituted with from 1 to 3, 1 to 4 or 1 to 5 independently selected substituents.
A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, and where specified, having the specified number of carbon atoms. Thus, the term Ci-C6alkyl, as used herein, indicates an alkyl group having from 1 to 6 carbon atoms. Alkyl groups include groups having from 1 to 8 carbon atoms (Ci-
Csalkyl), from 1 to 6 carbon atoms (Ci-Cβalkyl) and from 1 to 4 carbon atoms (Cj-C4alkyl), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. In certain embodiments, preferred alkyl groups are methyl, ethyl, propyl, butyl, and 3-pentyl.
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
A "heteroatom" is an atom other than carbon, such as oxygen, sulfur or nitrogen.
The term "aryl" refers to a group that comprises at least one aromatic ring. Examples of aryl groups include phenyl and naphthyl.
The term "heteroaryl" refers to a group that comprises at least one aromatic ring having from 1 to 4 heteroatoms. When the total number of S and 0 atoms in a heteroaryl group exceeds 1, then these heteroatoms are not adjacent to one another; preferably the total number of S and 0 atoms in a heteroaryl is not more than 1, 2 or 3, more preferably 1 or 2 and most preferably not more than 1. Examples of heteroaryl groups include pyridyl, furanyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, thienyl, thiazolyl, triazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinoline.
For compounds having asymmetric centers, it should be understood that (unless otherwise specified) all of the optical isomers and mixtures thereof are encompassed. Such compounds containing asymmetric substitutions may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms (racemates), by asymmetric synthesis, or by synthesis from optically active starting materials. Resolution of the racemates can be accomplished, for example, by conventional methods such as by crystallization in the presence of a resolving agent, or by chromatography, using, e.g., a chiral HPLC column. In addition, compounds with carbon-carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound can exist in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. Recited compounds are further intended to encompass compounds in which one or more atoms are replaced with an isotope (i.e., an atom having the same atomic number but a different mass number). By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11C, 13C, and 14C. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making non-toxic acid or base salts thereof, and further refers to pharmaceutically acceptable solvates of such compounds and such salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, malefic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2>n-COOH where n is 0-4, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable. Lists of additional suitable salts maybe found, e.g., in Remington 's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, p. 1418 (1985).
It will be apparent that each compound provided herein may, but need not, be formulated as a solvate (e.g., hydrate), ester or non-covalent complex. In addition, the various crystal forms and polymorphs of each are within the scope of the present invention. Also provided herein are prodrugs of the compounds of the recited Formulas. A "prodrug" is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a patient, to produce a compound a formula provided herein. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, amino, oτ sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters such as acetate, formate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to yield the parent compounds.
The term "therapeutically effective amount" means an amount of a compound or salt of Table I that is effective, when administered to a human or non-human patient, to provide a therapeutic benefit such as an amelioration of symptoms, e.g., an amount effective to antagonize the effects of pathogenic levels of CRF or to treat the symptoms of any of the disorders listed above under the subheading "Methods of Treament". It will be apparent that the therapeutic benefit may be apparent after administration of a single dose, or may become apparent following repeated administration of the therapeutically effective dose according to a predetermined regimen, depending upon the indication for which the compound is administered.
Pharmaceutical Preparations Compounds of Formula I (preferably of Table I) may be administered orally, topically, transdermally, parenterally, by inhalation or spray or rectally or vaginally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrathecal and like types of injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound provided herein and a pharmaceutically acceptable carrier. One or more compounds of Formula I (preferably of Table I) may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of Formula I (preferably of Table I) may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or 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, flavoring agents, coloring 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 that are suitable for the manufacture of • tablets. These 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, e.g., starch, gelatin or acacia, and lubricating agents, e.g., 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. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
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 ingredient is mixed with water or an oil medium, e.g., peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, e.g., sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, 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, e.g., polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, e.g., 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, e.g., polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, e.g., 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 or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, e.g., arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, e.g., beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. 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. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, e.g., sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions provided herein may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, e.g., olive oil or arachis oil, or a mineral oil, e.g., liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, e.g., gum acacia or gum tragacanth, naturally-occurring phosphatides, e.g., soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, e.g., sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, e.g., polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, e.g., glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable dilutent or solvent, e.g., as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, 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. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of Formula I (preferably of Table I) may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at body temperature and will therefore melt in the body to release the drug. Such materials include cocoa butter and polyethylene glycols.
Compounds of Formula I (preferably of Table I) may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, one or more adjuvants such as preservatives, buffering agents, or local anesthetics can also be present in the vehicle. Dosage levels of the order of from about 0.05 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions, preferred dosages range from about 0.1 to about 30 mg per kg and more preferably from about 0.5 to about 5 mg per kg per subject per day. 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. Dosage unit forms will generally contain between from about 0.1 mg to about 750 mg of an active ingredient.
Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most CNS and gastrointestinal disorders, a dosage regimen of four times daily, preferably three times daily, more preferably two times daily and most preferably once daily is contemplated. For the treatment of stress and depression a dosage regimen of 1 or 2 times daily is particularly preferred.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration,- route of administration, and rate of excretion, drug combination (i.e. other drugs being used to treat the patient) and the severity of the particular disease undergoing therapy.
Preferred compounds of Formula I (preferably of Table I) will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, such that the preferred oral dosage forms discussed above can provide therapeutically effective levels of the compound in vivo. Penetration of the blood brain barrier is necessary for most compounds used to treat CNS disorders, while low brain levels of compounds used to treat periphereal disorders are generally preferred. Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to predict compound toxicity, with non-toxic compounds being preferred. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound, e.g., intravenously.
Percentage of serum protein binding may be predicted from albumin binding assays. Examples of such assays are described in a review by Oravcova, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27). Preferred compounds exhibit reversible serum protein binding. Preferably this binding is less than 99%, more preferably less than 95%, even more preferably less than 90%, and most preferably less than 80%.
Frequency of administration is generally inversely proportional to the in vivo half-life of a compound. In vivo half-lives of compounds may be predicted from in vitro assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127). Preferred half lives are those allowing for a preferred frequency of administration.
As discussed above, preferred compounds of Formula I (preferably of Table I) exhibit activity in the standard in vitro CRF receptor binding assay specified in Example 7 below. References herein to "standard in vitro receptor binding assay" are intended to refer to this standard assay protocol. Generally preferred compounds of Formula I (preferably of Table I) have an IC50 (half-maximal inhibitory concentration) of about 1 micromolar or less, still more preferably and IC50 of about 100 nanomolar or less even more preferably an IC50 of about 10 nanomolar or less or even 1 nanomolar or less in such a defined standard in vitro CRF receptor binding assay. Preparation of Compounds
The compounds and salts of Formula I (preferably of Table I) may be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described in Scheme I. Those skilled in the art will recognize that the starting materials may be varied and additional steps employed in order to obtain particular compounds and salts of Formula I (preferably of Table I).
Scheme I
Figure imgf000159_0001
ROOH
Figure imgf000159_0002
Figure imgf000159_0003
11 12 13
Scheme Il
C r
Figure imgf000160_0001
14 15 16 17
Figure imgf000160_0002
18 19 21 22
Scheme III
Figure imgf000160_0003
23 24 25 26
PQCi3 ,
Figure imgf000160_0004
EXAMPLES
The following examples serve to further illustrate methods for preparing compounds and salts of Formula I (preferably of Table I). Additional synthetic methods relating to the synthesis of compounds and salts of Formula I (preferably of Table I) have been published in copending United States Patent Application publication 20050113379, US Serial No. 10/933,834, filed September 3, 2004, entitled "Heteroaryl fused pyridines, pyrazines and pyrimidines as CRFl receptor ligands" in the disclosure of the Examples (through Example 49) in numbered paragraphs 0284-0863, pages 17-90, which disclosure is hereby incorporated by reference for its teachings of such synthetic methods. Example 1: Synthesis of 2-(2-ethyI-6-isopropylpyridin-3-yl)-5-((lS)-2-methoxy-l- methylethyI]-3,7-dimethyl-5H-pyrrolo[2,3-b]pyrazine
Figure imgf000161_0001
ArB(OH)2
Pd(PPh3J4
Step C
Figure imgf000161_0002
Step A: 2,6-Dichloropyrazine (11.7g), (S)-(+)-l-methoxy-2-propylamine (7g) and EtaN (15 mL) in EtOH (100 mL) are heated at 105 0C for 2 days. The mixture is evaporated and dissolved in EtOAc and washed with sat. NaHCO3, H2O and dried. Evaporation affords 2- chloro-6-[(S)-l-methoxy-2-propyl]aminopyrazine. LCMS: m/z 202.3 and 204.3 (MH-H)+ Step B: 2-Chloro-6-[(S)-l-methoxy-2-propyl]aminopyrazine (8.3g) is dissolved in CHCI3 (25OmL). Upon addition of NBS (7.33g), the reaction mixture is stirred at 25 0C for 30 min. Subsequently, the crude mixture is evaporated, dissolved in EtOAc/hexane (1 A, 50OmL), washed with water and dried over sodium sulfate. Purification on silica gel affords 3-bromo- 2-chloro-6-[(S)-l-methoxy-2-propyl]aminopyrazine. LCMS: m/z 280.2, 282.2 and 284.2 (M+H)+
Step C: 3-Bromo-2-chloro-6-[(S)-l-methoxy-2-ρropyl]aminopyrazine (10.7g) and 2- methoxy-6-isopropyl-3-pyridineboronic acid (9.7g) are dissolved in DME (25OmL). After lOmin of degassing, tetrakis(triphenylphosphine)palladium(0) (2.2g) is added, followed by 1 min of degassing. Upon addition of an aqueous IN sodium carbonate solution (76mL), the reaction mixture is heated at 90 0C for 12h. Subsequently, the crude mixture is put into water (80OmL), extracted with EtOAc/hexane (1:1, 3x250mL), and dried over sodium sulfate. Purification on silica gel affords 3-{2-chloro-6-[(S)-l-methoxy-2-propyl]aminopyrazin-3-yl}- ^ 2-methoxy-6-isoproρylρyridine. LCMS: m/z 351.3 and 353.3 (M+H)+ Step D: 3-{2-Chloro-6-[(S)-l-methoxy-2-propyl]aminopyrazin-3-yl}-2-methoxy-6- isopropylpyridine (4.85g) is dissolved in CHCl3 (6OmL). Upon addition of NBS (2.46g), the reaction mixture is stirred at 25 0C for 30 min. Subsequently, the crude mixture is evaporated, dissolved in EtOAc/hexane (1 :4, 25OmL), washed with water and dried over sodium sulfate, Purification on silica gel affords 3-{5-bromo-2-chloro-6-[(S)-l-methoxy-2- proρyl]aminopyrazin-3-yl}-2-methoxy-6-isopropylρyridine. LCMS: m/z 429.2, 431.2 and
433.2 (M+H)+
Step E: 3- {5-Bromo-2-chloro-6-[(S)-l-methoxy-2-proρyl]aminopyrazin-3-yl}-2-methoxy-6- isopropylpyridine (4.3 g) is dissolved in DMSO (50 ml). Upon addition of NaH (60%, 0.8g), the reaction mixture is stirred at 25 0C for 30 min before allyl bromide (1.7 mL) is added. The reaction mixture is stirred at 25 0C for 2h. Subsequently, the crude mixture is put into water (25OmL), extracted with EtOAc/hexane (1 :4, 2x250mL), and dried over sodium sulfate. Purification on silica gel affords 3-{5-bromo-2-chloro-6-[(S)-N-allyl-l-methoxy-2- ρroρyl]aminopyrazin-3-yl}-2-methoxy-6-isopropylpyridine . LCMS: m/z 469.3, 471.3 and
473.3 (M+H)+ Step F: 3-{5-Bromo-2-chloro-6-[(S)-N-allyl-l-methoxy-2-propyl]aminopyrazin-3-yl}-2- methoxy-6-isopropylpyridine (4.6g) is dissolved in DMF (8OmL). After lOmin of degassing, Pd(OAc)2 (225mg) is added, followed by 1 min of degassing. Upon addition of potassium carbonate (4.1 g) and Bn4NBr (4.Og), the reaction mixture is heated at 90 0C for Ih. Subsequently, the crude mixture is put into water (50OmL), extracted with EtOAc/hexane (1 :2, 3x15OmL), and dried over sodium sulfate. Purification on silica gel affords (S)-3- chloro-2-(6-isopropyl-2-rnethoxy-pyridin-3 -yl)-5-(2-methoxy- 1 -methyl-ethyl)-7-methyl-5H- pyrrolo[2,3-b]ρyrazine. LCMS: m/z 389.4 and 391.4 (M+H)+
Step G: (S)-3-Chloro-2-(6-isopropyl-2-methoxy-pyridin-3-yl)-5-(2-methoxy-l-methyl- ethyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazine (2.Ig) and tetrakis(triphenylphosphme)palladiurn(0) (60 mg) is dissolved in anhydrous THF (1OmL). Upon addition of trimethlaluminum (2M in toluene, 5.3mL) the reaction mixture is heated to 650C for 8h. Subsequently, the crude reaction mixture is cooled to room temperature and poured into icy water saturated with sodium-potassium tartrate. The organic layer is separated after stirring the mixture for 4 hours and the aqueous is extracted with ethyl acetate. The combined organic extract is washed with water then brine and dried over sodium sulfate. Silica gel chromatography affords purified product.
Step H: The product of step G (4.6g) in 4N hydrochloric acid (4OmL) is heated at 75 0C for 18 h. The reaction mixture is cooled to 00C, neutralized with aqueous 50% NaOH and extracted with dichloromethane (3x15mL). The combined extract is washed with water (35mL) the brine (35mL) and dried over sodium sulfate. Silica gel chromatography affords purified product. Step I: The product of step H (4.4g) is dissolved in dicloromethane (4OmL). Triflic anhydride (2.6mL) is added gradually at - 5 0C, and then triethylamine (3.4mL) is added. The reaction mixture is warmed to ambient temperature and stirred for Ih. The mixture is washed with saturated sodium bicarbonate solution (2x30mL), water (2x30rnL) and brine (2OmL), and then dried over sodium sulfate. Silica gel chromatography affords purified product. Step J: The product of step I (400mg) is dissolved in toluene (5mL). After 10 min of degassing, tetrakis(triphenylphosphine)palladium(0) (35mg) is added, followed by 1 min of degassing. Upon addition of triethylborane (IN in hexane, 3 mL) and aqueous IN sodium carbonate solution (2mL), the reaction mixture is heated at 110 0C for 36h. Subsequently, the crude mixture is put into water (1OmL), extracted with EtOAc/hexane (1 :3, 3x25mL), and dried over sodium sulfate. Purification on silica gel affords 2-(2-ethyl-6-isopropylpyridin-3- yl)-5-[(lS)-2-methoxy-l-methylethyl]-3s7-dimethyl-5H-pyrrolo[2,3-b]pyrazine. LCMS: m/z 367.4 (M+H)+ Example 2: Synthesis of 5-(2-ethyl-6-methoxypyridin-3-yl)-l-((2JΪ)-2- methoxy-l-methylethyl)-3, 6-dimethyl-lH-pyrrolo[3,2-b]pyridine
Figure imgf000164_0001
Step A: 2,5-dibromo-3-methylpyridine (18.9Og) and the previously described 2-ethyl-6- methoxy-3 -pyridine boronic acid (13.7Og) are dissolved in DME (20OmL). After degassing, tetrakis(tτiphenylphosρhine)palladium (0) (3.6Og) is added. A second degassing is followed by addition of a 5N sodium carbonate solution (3OmL) whereupon the reaction is heated to 80 0C for 16h. The yellowish mixture is then put into water (50OmL), extracted with DCM (2x300mL), and dried over sodium sulfate. Purification on silica gel affords the coupled product. LCMS: m/z 306.94 (M+H)+ Step B: The purified compound (6.4Og) of step A and (i?)-l-methoxy-2-armnopropane (2.04g) are dissolved in toluene (8OmL) and briefly degassed. Subsequently, Pd2(dba>3
(1.03g), røc-2,2'-bis(diphenylphosphino)-l,r-binaphthyl (0.76g), and sodium tert-butoxidβ (2.81 g) are added before the mixture is heated to 70 0C for 16h. The black solution is then put into water (40OmL) and saturated sodium bicarbonate solution (10OmL)3 extracted with dichloromethane (3x3OOmL), and dried over magnesium sulfate. Flushing the crude material through a plug of silica gel affords the 5-aminopyridine as a semi-crude that is used in step C. LCMS: m/z 316.35 (M+H)+
Step C: The amino compound of step B is dissolved in chloroform (20OmL) and NBS (0.9- 1.0 eq.) is added in portions until TCL control verifies full conversion of the starting material. Subsequently, the yellowish mixture is put into water (20OmL), extracted with DCM (3x10OmL), and dried over magnesium sulfate. Purification on silica gel affords the bromide. LCMS: m/z 394.21 (M+H)+ Step D: The purified bromide (7.59g) of step C and allyl bromide (2.04mL) are dissolved in DMF (10OmL). Sodium hydride (1.16g) is added in 3 portions and the reaction is stirred for 90 min at rt. After TLC control confirms some starting material is still remaining, 0.25 equivalents of both reagents are added to drive the reaction to completion. The mixture is then put into water (50OmL) and extracted with ethyl ether (2x30OmL). The combined organic layers are washed with water (10OmL), dried over magnesium sulfate, and purified on silica gel to afford the allylated amine. LCMS: m/z 434.23 (M+H) Step E: The allyl compound (7.89g) of step D, tetrabutylammonium bromide (5.85g), palladium acetate (0.4Ig), and potassium carbonate (7.53g) are dissolved in DMF (15OmL). After heating to 80 0C for 30 min, the mixture is worked-up according to step D. Final purification on silica gel affords the title compound. . LCMS: m/z 354.39 (M+H) Example 3: Synthesis of 5-(2-ethyl-6-methoxypyridin-3-yl)-l-[(lS)-2-fluoro-l- (methoxymethyl) ethyl]-3,6-dimethyl-lH-pyrrolo[3,2-b]pyridine
Figure imgf000165_0001
Step A: (Λ)-2-Amino-3-methoxy-propan-l-ol hydrochloride (CAS#: 148278-96-0) (6.74g) and imidazole(13.7g) are taken in anhydrous methylene chloride (300ml). TBDMSCl (22.7g) is added in one portion. The reaction is carried on overnight. The reaction mixture is washed with water (200mlx3) and dried with Na2SO4. Concentration removes all volatiles. The crude product is used for next step reaction without further purification.
Step B: A mixture of the known bromide (6.4g, 0.02mol), amine (1.5equiv.), BINAP (1.Og), Pd2(dba)3 (0.6g), NaO-?-Bu(4.0g) in toluene(80ml) is heated at 85 °C under N2 atmosphere overnight. The reaction mixture is cooled to room temperature and quenched with water. The resulting mixture is separated and extracted with ethyl acetate. The combine organic layers are washed with brine and dried with Na2SO4. Silica gel flash chromatography with hexane/ethyl acetate gives purified product.
Step C: The starting material (7.3g) is taken in anhydrous CHCl3 (100ml). 1.0 equivalent of
NBS is added in one portion at 0 0C. The reaction is complete in 0.5 hour. The reaction mixture is washed with brine and dried with Na2SO4. Silica gel flash chromatography with hexane/ethyl acetate gives purified product.
Step D: Starting material (5.9g) is taken in anhydrous THF (100ml). Allyl iodide (3.6ml) is added followed by the addition of KO-Λ-Bu/THF solution (1.0M, 44ml) at room temperature.
The reaction is stirred at room temperature for 3 hours. The reaction mixture is quenched with water. The resulting mixture is separated and extracted with ethyl acetate. The combine organic layers are washed with brine and dried with Na2SO4. Silica gel flash chromatography with hexane/ethyl acetate gives purified product.
Step E: The crude product (6.4g) of previous reaction is taken in DMF (60ml) followed by the addition of tetrabutylammonium bromide (4.4g), K2CO3 (4.6g), Pd(OAc)2(13 Omg). The resulting mixture is heated at 85 0C under N2 atmosphere for one hour. The reaction mixture is cooled to room temperature and diluted with water. The resulting mixture is extracted with ethyl acetate. The combine organic layers are washed with brine and dried with Na2SO4.
Silica gel flash chromatography with hexane/ethyl acetate gives purified product.
Step F: Starting material (5.4g) is taken in THF (60ml) followed by the addition of tetrabutylammonium fluoride (2 equiv.) at room temperature. The reaction is complete after 2 hours. The reaction mixture is washed with water, brine and dried with Na2SO4. Silica gel flash chromatography with hexane/ethyl acetate gives purified product.
Step G: Starting material (1.Ig) is taken in anhydrous methylene chloride (50ml) followed by the addition of [Bis(2-methoxyethyl)amino]sulfur trifluoride (2 equiv.) at room temperature. The reaction is stirred at room temperature overnight. The reaction mixture is carefully quenched with ice-water. The resulting mixture is separated and extracted with methylene chloride and dried with Na2SO4. Silica gel flash chromatography with hexane/ethyl acetate affords the title compound. LCMS: m/z 372.4 (M+H)+ Example 4: Synthesis of 2-[2-ethyI-3-(6-isopropyl-2-methoxypyridin-3-yl)-5-methyl-5H- pyrrolo[2,3-b]pyrazinr7-yl]propaii-l-ol
OTBDMS
Figure imgf000167_0001
Figure imgf000167_0002
Figure imgf000167_0003
Step A: The known 2,6-dibromo-3-chloro-5-methylaminopyrazine (55Omg) and the shown allylic bromide (560mg, synthesized identically to the Me-regioisomer described by Enders et al., Synlett 2002, 2280) are dissolved in DMF (1OmL). After addition of sodium hydride (91mg), .the dark red reaction mixture is stirred for 15 min. Subsequently, the mixture is put into water (20OmL) and sat. sodium bicarbonate (100ml), extracted with ethyl ether (2xl00mL), and dried over magnesium sulfate. Purification on silica gel affords the allylic compound. TLC: Rf= 0.69 (EE/hex = 1/6)
Step B: The allylic compound (892mg) of step A, tetrabutylammonium bromide (575mg), palladium acetate (40mg), and potassium carbonate (737mg) are dissolved in DMF (1OmL). After heating to 80 0C for 30 min. the mixture is worked-up according to step A. Purification on silica gel affords the Heck-product. LCMS: m/z 417.93 (M+H)+ Step C: The Heck product (356mg) of step B is dissolved in THF (2.5mL) and added to a solution of t-BuLi (1.05mL, 1.7N in pentane) in THF (8.5mL) at -78 0C. After being stirred for 10 min, ethyl iodide (0.2mL) is added and the reaction mixture is stirred for another Ih at -78 °C. Subsequently, the mixture is put into water (10OmL) and sat. sodium bicarbonate (50ml), extracted with DCM (3x10OmL), and dried over magnesium sulfate. Purification on silica gel affords the ethyl derivative.
Step D: The methyl product of step C (238mg) and the known 2-zjopropyl-6-methoxy-5- pyridine boronic acid (158mg) are dissolved in DME (5.OmL). After degassing, tetrakis(triphenylphosphine)palladium (0) (77mg) is added. A second degassing is followed by addition of a IN sodium carbonate solution (1.35mL) whereupon the reaction is heated to
80 0C for 3h. The yellowish mixture is then put into water (10OmL), extracted with DCM
(3x10OmL), and dried over magnesium sulfate. Purification on silica gel affords the coupled product.
Step E: The Suzuki product of step D is dissolved in THF (5.OmL). After addition of TBAF monohydrate (650mg), the reaction mixture is stirred for 30 min. Subsequently, the yellow solution is put into water (10OmL), extracted with DCM (3x10OmL), and dried over magnesium sulfate. Purification on silica gel affords the title compound.
Example 5: Synthesis of 2-[5-ethyl-6-(6-isopropyl-2-methoxypyridtn-3-yl)-l-methyl-lH- pyrrolo[2,3-b]pyridin-3-yl]butan-l-ol
Figure imgf000168_0001
Step A: TBDMSCl (2Og) is added to a cold (O0C) solution of 4-hydroxy-2-butanone (17.6g), DMAP (200mg), imidazole (10.8g) in DMF (160ml). The reaction mixture is warmed naturally to room temperature and stirred for 24 hours. The reaction mixture is added with water and extracted with ethyl acetate and dried with Na2SO4. Purification by column with hexane/ethyl acetate gives product. Rf: 0.4(hexane/ethyl acetate: 8:1) Step B: Triethyl phosphonoacetate (17.3ml) is added as a solution of THF (30ml) to a cold (00C) suspension of NaH (0.131mol) in anhydrous THF (80ml). The resulting mixture is stirred at 00C for 1 hour before ketone (17.67g) is added as a solution of THF (10ml). The reaction is continued at room temperature for another 2 hours. Saturated aqueous NH4C1 is carefully added and separated. Aqueous layer is extracted with ether. The combined organic layers are washed with water, brine. Purification by column with hexane/ethyl acetate gives product. Rf: 0.4(hexane/ethyl acetate: 15:1) Step C: Starting material (21.3g) is treated with DIBAL-H(1.0M in toluene, 196ml) at 00C for 6 hours. Water is carefully added to quench the excess DIBAL. The reaction mixture is filtered and washed with ethyl acetate. The filtrate is concentrated to afford the crude product. Rf: 0.4(hexane/ethyl acetate: 3:1). Step D: Starting material (8.75g) is taken in anhydrous methylene chloride (110ml), triethylamine is added. The resulting mixture is cooled to -4O0C. MsCl is added dropwise and the reaction is continued for 1 hour at -400C before LiBr (13.2g) is added as a solution of THF (120ml). The resulting reaction mixture is warmed naturally to room temperature and continued for another 1 hour. The reaction is quenched with water and separated. Aqueous layer is extracted with ether. The combined organic layers are washed with brine and dried with Na2SCv The crude product can be used for the next step reaction without further purification. Rf: 0.4(hexane/ethyl acetate: 20:1).
Step E: 2,6-dichloropyridine (17g) and CH3NH2 aqueous solution (40%, 26.8g) are taken in THF (100ml) in a sealed tube and is heated at 8O0C for 24 hours. The reaction is cooled to room temperature and diluted with water. The resulting mixture is separated and extracted with ethyl acetate. The combined organic layers are washed with brine and dried with Na2SO4. The crude product is used for the next step reaction without further purification. LCMS: 143.3 (M+H)+
Step F: A mixture of 2-chloro-6-methylarnino-pyridine (3.56, 0.025mol), 2-methoxy-6- isopropyl-3-pyridylboronic acid (6.33g), Pd(PPh3J4 (577mg), aqueous Na2CO3 solution (1.0M, 50ml), and toluene (50ml) is heated at 1000C under the N2 atmosphere overnight. The reaction mixture is cooled to room temperature and separated. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine and dried with Na2SO4. The crude product is used for the next step reaction without further purification. Rf: 0.4(hexane/ethyl acetate: 4:1). Step G: The crude starting material is taken in anhydrous CHCI3 (100ml). 4.0 equivalent of NBS is added in one portion at O0C. The reaction is complete in 0.5 hour. The reaction mixture is washed with water and dried with Na2SO4. Purification by flash column with hexane/ethyl acetate gives product as clear oil. LCMS: m/z 496.1 (M+H)+ Step H: NaH (795mg, 60% in mineral oil) is added to a solution of starting material (6.34g) in anhydrous DMF (100ml) and stirred at room temperature for lOminutes. Bromide (4.93g) prepared in Step D is added dropwise and the resulting mixture is stirred for 3 hours. The reaction mixture is carefully quenched with water. The resulting mixture is extracted with ethyl acetate. The combine organic layers are washed with brine and dried with Na2S O4. Purification by flash column with hexane/ethyl acetate gives product as clear oil. Rf: 0.4(hexane/ethyl acetate: 12:1).
Step I: A mixture of bromide (9.26g), tetrabutylammonium bromide (5.95g), K2CO3(0.12g), Pd(OAc)2(LOg) in DMF(80ml) is heated at 8O0C under N2 atmosphere for 20 minutes. The reaction mixture is cooled to room temperature and diluted with water. The resulting mixture is extracted with ethyl acetate. The combine organic layers are washed with brine and dried with Na2SO4. Purification by flash column with hexane/ethyl acetate gives product as clear oil. LCMS: m/z 548.4 (M+H)+ Step J: To a solution of /-BuLi(1.7M/pentane, 7ml)in THF (30ml) at -78°C is added a solution of bromide (3.07g) in THF (5ml). The resulting mixture is stirred at -78°C for 10 minutes before iodoethane (1.4ml) is added. The reaction is continued for 30minutes. The reaction is carefully quenched with EtOH. The resulting mixture is washed with water and brine, dried with Na2SO4. Silica gel chromatography with hexane/ethyl acetate gives purified product. Step K: Starting material (1.26g) is taken in THF (50ml) followed by the addition of tetrabutylammonium fluoride (1.5 equiv.) at room temperature. The reaction is complete after 4 hours. The reaction mixture is washed with water, brine and dried with Na2SO4. Silica gel chromatography with hexane/ethyl acetate affords the title compound.
Example 6: Assay for CRF receptor functional activity
As discussed above, the following assay is referred to herein and in the claims as a standard in vitro CRF receptor functional assay. A chemiluminescent ELISA system (cAMP- Screen®, Applied Biosystems, Bedford, MA) is used according to the manufacturers instructions to quantify the levels of 3 ',5 '-cyclic AMP (cAMP) in extracts prepared from the human neuroblastoma cell line IMR32, which endogenously expresses the human CRFl receptor. IMR32 cells (ATCC CCL 127) are grown to confluence in one or more T-175 flasks, each flask is split evenly into the wells of two pre-coated 96-well cAMP-Screen® assay plates prior to the test treatment and ELISA, each plate is then incubated for 16 hours and assayed. Culture is in IMR-32 Medium: EMEM w/Earle's BSS (JRH Biosciences, Cat# 51411) plus, as supplements, 2mM L-Glutamine, 10% Fetal Bovine Serum, 25mM HEPES (pH 7.2), ImM Sodium Pyruvate and Non-Essential Amino Acids (JRH Biosciences, Cat# 58572) for 16-20 hours. For antagonist mode characterization, compounds are used to dose dependently antagonize the cAMP production response of CRF. An EC6O response of CRF is used to stimulate IMR32 cells to produce cAMP. A co-incubation strategy is used to determine the potency of compounds to reverse the CRF stimulated cAMP response. IC50 and Ki values are calculated using non-linear regression analysis. For agonist mode characterization, compounds are used alone to treat the cells. Example 7: Assay for CRT Receptor Binding Activity
As discussed above, the following assay is referred to herein and in the claims as a standard in vitro CRF receptor binding assay. The CRF receptor binding is performed using a modified version of the assay described by Grigoriadis and De Souza (Methods in Neurosciences, Vol. 5, 1991). IMR-32 human neuroblastoma cells, a cell-line that naturally expresses the CRFl receptor, are grown in IMR-32 Medium (see preceeding Example). The cells are grown to confluence and split three times (all splits and harvest are carried out using NO-ZYME — JRH Biosciences, Cat# 59226). The cells are first split 1:2, incubated for 3 days and split 1 :3, and finally incubated for 4 days and split 1 :5. The cells are then incubated for an additional 4 days before being differentiated by treatment with 5-bromo- 2'deoxyuridine (BrdU, Sigma, Cat# B9285). The medium is replaced every 3-4 days with IMR-32 medium w/2.5uM BrdU and the cells are harvested after 10 days of BrdU treatment and washed with calcium and magnesium- free PBS. .
To prepare receptor containing membranes, cells are homogenized in wash buffer (50 mM Tris HCl, 10 mM MgCl2, 2 mM EGTA, pH 7.4) and centrifuged at 48,000 x g for 10 minutes at 40C. The pellet is re-suspended in wash buffer, and the homogenization and centrifugation steps are performed two additional times.
Membrane pellets (containing CRF receptors) are re-suspended in 50 mM Tris buffer pH 7.7 containing 10 mM MgCl2 and 2 mM EDTA and centrifuged for 10 minutes at 48,00Og. Membranes are washed again and brought to a final concentration of 1500 ug/ml in binding buffer (Tris buffer above with 0.1 % BSA, 15 mM bacitracin and 0.01 mg/ml aprotinin.). For the binding assay, 100 μL of the membrane preparation are added to 96 well microtube plates containing 100 μL of l25I-sauvagine (SA 2200 Ci/mmol, final concentration of 100 pM) and 50 μL of test compound. Binding is carried out at room temperature for 2 hours. Plates are then harvested on a BRANDEL 96 well cell harvester and filters are counted for gamma emissions on a Wallac 1205 BETAPLATE liquid scintillation counter. Non-specific binding is defined by 1 raM cold CRF. IC50 values are calculated with the nonlinear curve fitting program RS/1 (BBN Software Products Corp., Cambridge, MA). The binding affinity (expressed as IC50 value) for those compounds and salts of Table I that have been tested generally ranges from about 0.5 nanomolar to about 10 micromolar. Preferred compounds or salts of Formula I exhibit IC50 values of less than or equal to 1.5 micromolar, more preferred compounds or salts exhibit IC50 values of less than 500 nanomolar, still more preferred compounds or salts exhibit IC50 values of less than 100 nanomolar, and most preferred compounds or salts are those othat exhibit IC50 values of less than 10 nanomolar. Preferred of these compounds or salts are those of Table I.
Example 8: Evaluation of mechanism-based inhibition of Cytochrome P450 (CYP) 1A2, 2C8, 2C9, 2C19, 2D6 and 3A4 in human liver microsomes
Compound or salt at 1, 2.5, 5, 10, 25, and less preferably 50 μM are preincubated with pooled human liver microsomes 1) in the presence and 2) in the absence of NADPH (final cone. 1 niM) in a shaking water bath at 37°C for 30 minutes. After 10-fold dilution of the preincubation mixture with 0.1M phosphate buffer, pH 7.4, containing a selective CYP probe substrate and NADPH (final cone. 1 mM), residual enzyme activity is measured and the extent of the inhibition shift between the two treatments is evaluated. A concentration- dependent and statistically significant decrease in each particular CYP activity in the presence vs. absence of NADPH indicates mechanism-based inhibition of that CYP isozyme. Vehicle and known selective mechanism-based inhibitors of each CYP isozyme are also separartely incubated in parallel with the compound or salt to serve as negative and positive controls. Positive controls include furafylline (CYP 1A2), gemfibrozil glucuronide, or, less preferably, phenelzine (CYP2C8), tienilic acid (CYP2C9), ticlopidine (CYP2C19), paroxetine (CYP2D6), and ribefradil (CYP3 A4). For all CYPs evaluated, the activity tests are conducted under linear conditions as follows:
Figure imgf000172_0001
Figure imgf000173_0001
For each assay, the formation of the CYP specific metabolites is monitored and quantified by LC-MS (dextrorphan), LC-MS/MS (4'-hydroxytolbutamide, desethylamodiaquine,4- acetamidophenol, 4-hydroxy-S-mephenytoin), or HPLC (6β- hydroxytestosterone).
For each isozyme tested, a mechanism based inhibitor ot the isozyme will show concentration dependence and a statistically significant decrease (student's t-test: p<0.05) in activity after 30 minutes preincubation with NADPH as compared to preincubation in the absence of NADPH. Absence of mechanism-based inhibition is demonstrated for each isozyme when no statistically significant changes in one or more (preferably all) of CYPl A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 activities are observed when human liver microsomes are preincubated with a preferred compound or salt of Formula I (preferably of Table I) at concentrations of 1, 2.5, 5, 10, 25, and 50 μM with vs. without NADPH. Example 9: Assay for emesis in dogs
Preferred compounds or salts of Formula I (preferably of Table I) do not cause nausea or vomiting when administered to a patient in a therapeutically effective amount. A convenient measure of this property is absence of emesis in more than 1 out of six dogs within one, preferably 3, or less preferably 6 hours of administration of a dose selected from 1, 30, 100, 300, and 1000mg/kg of body weight. Such absence of emesis is determined as follows: Doses of compound or salt are administered by oral intubation using a flexible tube fitted onto a syringe and utilizing a flush of approximately 10 mL of distilled water. Dogs are fed Certified Canine Diet, No. 5007 (PMI Nutrition International, St. Louis, MO) ad libitum in 400 gram amounts for approximately 4 hours daily. Food is presented at approximately the same time each day. Food is provided 1-2 h prior to dosing. Water is provided ad libitum, via automated watering system. Observations are made 4 times after compound or salt administration at 30 minutes, 1, 3 and 6 hours post dosing. Observed emesis events are recorded during the observation period. Example 10: Preparation of radiolabeled probe compounds The compounds and salts of Formula I (preferably of Table I) are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. The radioisotope is preferably selected from of at least one of carbon (preferably 14C), hydrogen (preferably 3H), sulfur (preferably 35S), or iodine (preferably 125I). Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, IL; Cambridge Isotope Laboratories, Inc. Andover, MA; SRI International, Menlo Park, CA; Wizard Laboratories, West Sacramento, CA; ChemSyn Laboratories, Lexena, KS; American Radiolabeled Chemicals, Inc., St. Louis,, MO; and Moravek Biochemicals Inc., Brea, CA.
Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the unlabeled compound as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate. Example 11: Receptor autoradiography
Receptor autoradiography (receptor mapping) is carried out in vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York, using radiolabeled compounds provided herein prepared as described in the preceeding schemes and the preceding Example. Example 12: Microsomal in vitro half-life
Compound half-life values (tm values) may be determined via the following standard liver microsomal half-life assay. Pooled Human liver microsomes are obtained from XenoTech LLC, 3800 Cambridge St. Kansas's City, Kansas, 66103 (catalog # H0610). Such liver microsomes may also be obtained from In Vitro Technologies, 1450 South Rolling Road, Baltamore, MD 21227, or from Tissue Transformation Technologies, Edison Corporate Center, 175 May Street, Suite 600, Edison, NJ 08837. Reactions are preformed as follows: Reagents:
Phosphate buffer: 19 mL 0.1 M NaH2PO4, 81 mL O.l Na2HPO4, adjusted to pH 7.4 with
H3PO4.
CoFactor Mixture: 16.2 mg NADP, 45.4 mg Glucose-6-phosphate in 4 mL 100 mM MgCk- Glucose-6-phosphate dehydrogenase: 214.3 μL glucose-6-phosρhate dehydrogenase suspension (Boehringer-Mariheim catalog no. 0737224, distributed by Roche Molecular Biochemicals, 9115 Hague Road, P.O. Box 50414, Indianapolis, IN 46250) is diluted into 1285.7 μL distilled water. Starting Reaction Mixture; 3 mL CoFactor Mixture, 1.2 mL Glucose-6-phosphate dehydrogenase. Reaction:
6 test reactions are prepared, each containing 25 μL microsomes, 5 μL of a 100 uM solution of test compound, and 399 μL 0.1 M phosphate buffer. A seventh reaction is prepared as a positive control containing 25 μL microsomes, 399 μL 0.1 M phosphate buffer, and 5 μL of a 100 uM solution of a compound with known metabolic properties (e.g. diazepam or clozepine). Reactions are preincubated at 39°C for 10 minutes. 71 μL Starting Reaction Mixture is added to 5 of the 6 test reactions and to the positive control, 71 μL 100 mM MgC^ is added to the sixth test reaction, which is used as a negative control. At each time point (0, 1, 3, 5, and 10 minutes) 75 μL of each reaction mix is pipetted into a well of a 96-well deep- well plate containing 75 μL ice-cold acetonitrile. Samples are vortexed and centrifuged 10 minutes at 3500 rpm (SORVAL T 6000D centrifuge, HlOOOB rotor). 75 μL of supernatant from each reaction is transferred to a well of a 96-well plate containing 150 μL of a 0.5 uM solution of a compound with a known LCMS profile (internal standard) per well. LCMS analysis of each sample is carried out and the amount of unmetabolized test compound is measured as AUC, compound concentration vs time is plotted, and the tm value of the test compound is extrapolated.
Preferred compounds exhibit in vitro tj/2 values of greater than 10 minutes and less than 4 hours. Most preferred compounds exhibit in vitro t\a values of between 30 minutes and 1 hour in human liver microsomes.
Additional Aspects of Preferred Compounds
The most preferred compounds and salts of Formula I (preferably of Table I) are suitable for pharmaceutical use in treating human patients. Accordingly, such preferred compounds are non-toxic. They do not exhibit single or multiple dose acute or long-term toxicity, mutagenicity (e.g., as determined in a bacterial reverse mutation assay such as an Ames test), teratogenicity, tumorogenicity, or the like, and rarely trigger adverse effects (side effects) when administered at therapeutically effective dosages. Preferably, administration of such preferred compounds at certain doses (i.e., doses yielding therapeutically effective in vivo concentrations or preferably doses of 1, 30, 100, 300, or 1000 mg/kg - 300 being most preferred - administered parenterally or prefrerably orally) does not result in prolongation of heart QT intervals (i.e., as determined by electrocardiography, e.g., in guinea pigs, minipigs or dogs). When administered daily for 5 or preferably ten days, such doses of such preferred compounds also do riot cause liver enlargement resulting in an increase of liver to body weight ratio of more than 100%, preferably not more than 75% and more preferably not more than 50% over matched controls in laboratory rodents (e.g., mice or rats). In another aspect such doses of such preferred compounds also preferably do not cause liver enlargement resulting in an increase of liver to body weight ratio of more than 50%, more preferably preferably not more than 25%, and most preferably not more than 10% over matched untreated controls in dogs or other non- rodent mammals.
In yet another aspect such doses of such preferred compounds also preferably do not promote the release of liver enzymes (e.g., ALT, LDH, or AST) from hepatocytes in vivo. Preferably such doses do not elevate serum levels of such enzymes by more than 100%, more preferably not by more than 75% and most preferably not by more than 50% over matched untreated controls in laboratory rodents. Similarly, concentrations (in culture media or other such solutions that are contacted and incubated with cells in vitro) equivalent to two, fold, preferably five-fold, and most preferably ten-fold the minimum in vivo therapeutic concentration do not cause release of any of such liver enzymes from hepatocytes into culture medium in vitro above baseline levels seen in media from untreated cells.
Because side effects are often due to undesirable receptor activation or antagonism, preferred compounds exert their receptor-modulatory effects with high selectivity. This means that they do not bind to certain other receptors (other than CRF, preferably CRFl, receptors) with high affinity, but rather only bind to, activate, or inhibit the activity of such other receptors with affinity constants (note: greater affinity constants indicate weaker binding) of greater than 100 nanomolar, preferably greater than 1 micromolar, more preferably greater than 10 micromolar and most preferably greater than 100 micromolar. Such receptors preferably are selected from the group consisting of a) ion channel receptors, (preferably sodium ion channel receptors), b) neurotransmitter receptors (preferably selected from alpha- and beta-adrenergic receptors, muscarinic receptors - most preferably ml, m2, or m3 receptors, dopamine receptors, GABAA receptors and metabotropic glutamate receptors), c) histamine receptors, d) cytokine receptors (preferably selected from interleukin receptors, most preferably IL-8 receptors), e) bioactive peptide receptors (preferably selected from NPY and VIP receptors), f) neurokinin receptors g) bradykinin receptors (preferably selected from BKl receptors and BK2 receptors), and h) hormone receptors (preferably selected from thyrotropin releasing hormone receptors and melanocyte-concentrating hormone receptors).

Claims

WHAT IS CLAIMED IS:
1. A compound or salt of Formula I which is a compound or salt of Table I which is ( 1 R,2S)-2- {2-[2-methoxy-4-(l H-pyrazol- 1 -yl)phenyl]-3,7-dimethyl-5H-pyrrolo[2,3- b]pyrazin-5 -yl } cycl ohexanol or a pharmaceutically acceptable salt thereof.
2. A compound or salt of Table I wherein, in a standard in vitro CRF receptor binding assay the compound exhibits an IC50 value of less than or equal to 1 micromolar.
3. A compound or salt of Table I wherein, in a standard in vitro CRF receptor binding assay the compound exhibits an IC50 value of less than or equal to 100 nanomolar.
4. A compound or salt of Table I wherein, in a standard in vitro CRF receptor binding assay, the compound exhibits an IC50 value of less than or equal to 10 nanomolar.
5. A method for treating at least one syptom of an anxiety disorder, a stress- related disorder, or an eating disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt of Table I.
6. A method for treating at least one syptom of an depression or bipolar disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt of Table I.
7. A method for treating anorexia nervosa, bulimia nervosa, or obesity, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt of Table I.
8. A method for treating Irritable Bowel Syndrome or Crohn's disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt of Table I.
9. A method for demonstrating the presence of CRF receptors in cell or tissue samples, said method comprising: preparing a plurality of matched cell or tissue samples; preparing at least one control sample by contacting (under conditions that permit binding of CRF to CRF receptors within cell and tissue samples) at least one of the matched cell or tissue samples (that has not previously been contacted with any compound or salt of any of Claims 1-42) with a control solution comprising a detectably-labeled preparation of a selected compound or salt of Table I at a first measured molar concentration, said control solution further comprising an unlabelled preparation of the selected compound or salt at a second measured molar concentration, which second measured concentration is greater than said first measured concentration; preparing at least one experimental sample by contacting (under conditions that permit binding of CRF to CRF receptors within cell and tissue samples) at least one of the matched cell or tissue samples (that has not previously been contacted with any compound or salt of Table I) with an experimental solution comprising the detectably-labeled preparation of the selected compound or salt at the first measured molar concentration, said experimental solution not further comprising an unlabelled preparation of any compound or salt of Table I at a concentration greater than or equal to said first measured concentration; washing the at least one control sample to remove unbound selected compound or salt to produce at least one washed control sample; washing the at least one experimental sample to remove unbound selected compound or salt to produce at least one washed experimental sample; measuring the amount of detectable label of any remaining bound detectably-labeled selected compound or salt in the at least one washed control sample; measuring the amount detectable label of any remaining bound detectably-labeled selected compound or salt in the at least one washed experimental sample; and comparing the amount of detectable label measured in each of the at least one washed experimental sample to the amount of detectable label measured in each of the at least one washed control sample; wherein, a comparison that indicates the detection of a greater amount of detectable label in the at least one washed experimental sample than is detected in any of the at least one washed control samples demonstrates the presence of CRF receptors in that experimental sample.
10. A method of inhibiting the binding of CRF to a CRFl Receptor, which method comprises: contacting a solution comprising CRF and compound or salt of Table I with a cell expressing the CRF receptor, wherein the compound or salt is present in the solution at a concentration sufficient to inhibit in vitro CRF binding to IMR32 cells.
11. The method of Claim 10 wherein the cell expressing the CRF receptor is a neuronal cell that is contacted in vivo in an animal, and wherein the solution is a body fluid of said animal.
12. The method of Claim 11 wherein the animal is a human patient.
13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and compound or salt of Table I.
14. A package comprising a pharmaceutical composition of claim 13 in a container and further comprising indicia comprising at least one of: instructions for using the composition to treat a patient suffering from an anxiety disorder, or instructions for using the composition to treat a patient suffering from a stress-related disorder, or instructions for using the composition to treat a patient suffering from an eating disorder.
15. A package comprising a pharmaceutical composition of claim 13 in a container and further comprising indicia comprising at least one of: instructions for using the composition to treat a patient suffering from depression or instructions for using the composition to treat a patient suffering from a bipolar disorder.
16. A compound or salt of Table I which, when administered orally to dogs at a dose selected from 1, 30, 100, 300, and 1000mg/kg of body weight, does not produce emesis in more than 1 out of six dogs within three hours of administration.
17. A compound or salt of Table I which, at a concentration selected from 5, 10, 15, 20 and 25 micromolar in in vitro cytochrome P450 assays, does not exhibit mechanism-based inhibition of any of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 activities.
1 S. The compound or salt of claim 17 wherein, the concentration is 25 micromolar.
19. A compound or salt of Table I which, at a concentration selected from 5, 10, 15, 20 and 25 micromolar in an in vitro CYP2C8 assay, does not produce irreversible inhibition of CYP2C8.
20. The method of Claim 5, wherein the symptom of a stress disorder is a sleep disorder or a dermatologic disorder.
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
EP2567959A1 (en) 2011-09-12 2013-03-13 Sanofi 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2020005873A1 (en) * 2018-06-27 2020-01-02 Ptc Therapeutics, Inc. Heterocyclic and heteroaryl compounds for treating huntington's disease
US11382918B2 (en) 2017-06-28 2022-07-12 Ptc Therapeutics, Inc. Methods for treating Huntington's Disease
US11395822B2 (en) 2017-06-28 2022-07-26 Ptc Therapeutics, Inc. Methods for treating Huntington's disease
US11407753B2 (en) 2017-06-05 2022-08-09 Ptc Therapeutics, Inc. Compounds for treating Huntington's disease
US11638706B2 (en) 2015-12-10 2023-05-02 Ptc Therapeutics, Inc. Methods for treating Huntington's disease
US11685746B2 (en) 2018-06-27 2023-06-27 Ptc Therapeutics, Inc. Heteroaryl compounds for treating Huntington's disease
US11780839B2 (en) 2018-03-27 2023-10-10 Ptc Therapeutics, Inc. Compounds for treating Huntington's disease

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6001808A (en) * 1996-08-19 1999-12-14 Metatron, Inc. Method of treating herpes virus infections with spermostatic gramicidin
US20050113379A1 (en) * 2003-09-05 2005-05-26 Ping Ge Heteroaryl fused pyridines, pyrazines and pyrimidines as CRF1 receptor ligands

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6001808A (en) * 1996-08-19 1999-12-14 Metatron, Inc. Method of treating herpes virus infections with spermostatic gramicidin
US20050113379A1 (en) * 2003-09-05 2005-05-26 Ping Ge Heteroaryl fused pyridines, pyrazines and pyrimidines as CRF1 receptor ligands

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
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US11638706B2 (en) 2015-12-10 2023-05-02 Ptc Therapeutics, Inc. Methods for treating Huntington's disease
US11407753B2 (en) 2017-06-05 2022-08-09 Ptc Therapeutics, Inc. Compounds for treating Huntington's disease
US11382918B2 (en) 2017-06-28 2022-07-12 Ptc Therapeutics, Inc. Methods for treating Huntington's Disease
US11395822B2 (en) 2017-06-28 2022-07-26 Ptc Therapeutics, Inc. Methods for treating Huntington's disease
US11780839B2 (en) 2018-03-27 2023-10-10 Ptc Therapeutics, Inc. Compounds for treating Huntington's disease
JP2021528467A (en) * 2018-06-27 2021-10-21 ピーティーシー セラピューティクス， インコーポレイテッド Heterocyclic and heteroaryl compounds for treating Huntington's disease
CN112654625A (en) * 2018-06-27 2021-04-13 Ptc医疗公司 Heterocyclic and heteroaryl compounds for the treatment of huntington's disease
WO2020005873A1 (en) * 2018-06-27 2020-01-02 Ptc Therapeutics, Inc. Heterocyclic and heteroaryl compounds for treating huntington's disease
US11685746B2 (en) 2018-06-27 2023-06-27 Ptc Therapeutics, Inc. Heteroaryl compounds for treating Huntington's disease
US11858941B2 (en) 2018-06-27 2024-01-02 Ptc Therapeutics, Inc. Heterocyclic and heteroaryl compounds for treating Huntington's disease

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