USOO9029407B2

(12) United States Patent (10) Patent No.: US 9,029.407 B2 Rao et al. (45) Date of Patent: May 12, 2015

(54) AMINOTHIAZOLE MODULATORS OF WO 2010, 118291 A2 10/2010 BETA-3-ADRENORECEPTOR WO 2010, 147830 A2 12/2010 WO 2010, 147830 A3 12/2010 (71) Applicant: Auspex Pharmaceuticals, Inc., La Jolla, OTHER PUBLICATIONS CA (US) Kushner, D.J. et al., “Pharmacological Uses and Perspectives of (72) Inventors: Tadimeti Rao, San Diego, CA (US); Heavy Water and Deuterated Compounds', Can. J. Physiol. Chengzhi Zhang, San Diego, CA (US) Pharmacol., (1999), pp. 79-88, vol. 77. Bauer, L.A. et al., “Influence of Long-term Infusions on Lidocaine (73) Assignee: Auspex Pharmaceuticals, Inc., La Jolla, Kinetics”. Clin. Pharmacol. Ther. (1982), pp. 433-437, vol. 31(4). CA (US) Borgstrom, L. et al., “Comparative Pharmacokinetics of Unlabeled and Deuterium-Labeled Terbutaline: Demonstration of a Small Iso (*) Notice: Subject to any disclaimer, the term of this tope Effect”, Jorunal of Pharmaceutical Sciences, Nov. (1988), pp. patent is extended or adjusted under 35 952-954, vol. 77(11). U.S.C. 154(b) by 0 days. Browne, T.R., “Chapter 2. Isotope Effect: Implications for Pharma ceutical Investigations'. Elsevier, Amsterdam (1997), pp. 13-18. (21) Appl. No.: 13/921,723 Browne, T.R. et al., “Pharmacokinetic Equivalence of Stable-iso tope-labeled and Unlabeled Drugs. Phenobarbital in Man”. J. Clin. (22) Filed: Jun. 19, 2013 Pharmacol., (1982), pp. 309-315, vol. 22. Burm, A.G.L. et al., “Pharmacokinetics of Lidocaine and Prior Publication Data Bupivacaine and Stable Isotope Labelled Analogues: A Study in (65) Healthy Volunteers'. Biopharmaceutics & Drug Disposition, (1988), US 2013/0281498A1 Oct. 24, 2013 pp. 85-95, vol. 9. Elison, C. et al., “Effect of Deuteration of N-CH3S Group on Potency and Enzymatic N-Demethylation of Morphine”. Science, (Oct. 13, Related U.S. Application Data 1961), pp. 1078-1079, vol. 134(3485). Farmer, P.B. et al., “Synthesis, Metabolism, and Antitumor Activity (62) Division of application No. 12/796,781, filed on Jun.9, of Deuterated Analogues of 1-(2-Chloroethyl)-3-cyclohexyl-1- 2010. nitrosourea'. Journal of Medicinal Chemistry, (1978), pp. 514-520, Provisional application No. 61/186,965, filed on Jun. vol. 21(6). (60) Fisher, M.B. et al., “The Complexities Inherent in Attempts to 15, 2009. Decrease Drug Clearance by Blocking Sites of CYP-mediated Metabolism'. Current Opinion in Drug Discovery & Development, (51) Int. C. (2006), pp. 101-109, vol. 9(1). A6 IK3I/425 (2006.01) Foster, A.B., “Deuterium Isotope Effects in Studies of Drug Metabo C07D 277/40 (2006.01) lism'. Trends in Pharmacological Sciences, (Dec. 1984), pp. 524 C07D 277/22 (2006.01) 527, vol. 5(12). A6 IK3I/426 (2006.01) Helfenbein, J. et al., “Isotopic Effect Study of Propofol Deuteration A6 IK 45/06 (2006.01) on the Metabolism, Activity, and Toxicity of the Anesthetic'. J. Med. (52) U.S. C. Chem. (2002), pp. 5806-5808, vol. 45. CPC ...... C07D 277/40 (2013.01); C07D 277/22 (Continued) (2013.01); A61 K3I/426 (2013.01); A61 K 45/06 (2013.01) (58) Field of Classification Search Primary Examiner — Nyeemah A Grazier USPC ...... 514/370 (74) Attorney, Agent, or Firm — Dennis A. Bennett See application file for complete search history. (57) ABSTRACT (56) References Cited The present invention relates to new aminothiazole modula U.S. PATENT DOCUMENTS tors of beta-3-adrenoreceptor activity, pharmaceutical com 6,221,335 B1 4/2001 Foster positions thereof, and methods of use thereof. 6,346,532 B1 2/2002 Maruyama et al. 6,440,710 B1 8/2002 Keinan et al. 6,603,008 B1 8, 2003 Ando et al. Formula I 7,517,990 B2 4/2009 Ito et al. 2002fOO13372 A1 1/2002 Ekins 2007/O197695 A1 8/2007 Potyen R is 2008, OO33011 A1 2/2008 Tung R - N1 R10 Rii R12 s RIs O R20 R9 N R21 2008, 0214633 A1 9/2008 Kawazoe et al. s N O 2009, OO18207 A1 1/2009 Gant et al. S 2009/0093.529 A1 4/2009 Takasu et al. ea R13 R14 R. R. 2009,0306215 A1 12, 2009 Czarnik N Rs R54 R22 2010/0286275 A1 1 1/2010 Zhang R 3 R4 Rs R. R. R23 FOREIGN PATENT DOCUMENTS

EP 1440969 A1 T 2004 WO 95/26325 A2 10, 1995 30 Claims, No Drawings US 9,029.407 B2 Page 2

(56) References Cited Haskins, N.J., “The Application of Stable Isotopes in Biomedical Research'. Biomedical Mass Spectrometry, (1982), pp. 269-277, vol. OTHER PUBLICATIONS 9(7). Honma, S. et al., “The Metabolism of Roxatidine Acetate Hydrochlo Lee, H. et al., “Deuterium Magic Angle Spinning Studies of Sub ride, Liberation of Deuteerium from the Piperidine Ring during strates Bound to Cytochrome P450”, Biochemistry, (1999), pp. Hydroxylation”. Drug Metabolism and Disposition, (1987), pp. 551 10808-10813, vol. 38. 559, vol. 15(4). Mamada, K.K. et al., “Pharmacokinetic Equivalence of Deuterium Pieniaszek, Jr., H.J. et al. “Moricizine Bioavailability via Simulta Labeled and Unlabeled Phenytoin'. Drug Metabolism and Disposi neous, Dual, Stable Isotope Administration: Bioecuivalence Impli tion, (1986), pp. 509-511, vol. 14(4). cations”. J. Clin. Pharmacol, (1999), pp. 817-825, vol. 39. Tonn, G.R. et al., “Simultaneous Analysis of Diphenhydramine and a Nelson, S.D. et al., “The Use of Deuterium Isotope Effects to Probe Stable Isotope Analog (2H10)Diphenhydramine Using Capillary the Active Site Properties, Mechanism, of Cytochrome P450-Cata Gass Chromatography with Mass Selective Detection in Biological lyzed Reactions, and Mechanisms of Metabolically Dependent Tox Fluids from Chronically Instrumented Pregnant Ewes”. Biological icity'. Drug Metabolism and Disposition, (2003) pp. 1481-1498, vol. Mass Spectrometry, (1993), pp. 633-642, vol. 22. 31(12). Wolen, R.L., “The Application of Stable Isotopes to Studies of Drug Nelson, S.D. et al., “Primary and B-Secondary Deuterium Isotope Bioavailability and Bioecuivalence'. J. Clin. Pharmacol., (1986), pp. Effects in N-Deethylation Reactions”, Journal of Medicinal Chem 419-424, vol. 26. istry, (1975), pp. 1062-1065, vol. 18(11). International Preliminary Report on Patentability of WO 2010/ Pohl, L.R. et al., “Determination of Toxic Pathways of Metabolism 147830, Rao T. et al., “Aminothiazole Modulators of Beta-3- by Deuterium Substitution”. Drug Metabolism Reviews, (1984), pp. Adrenoreceptor'. Publication Date Dec. 23, 2010. Goble, S.D. et al., “Heterocyclic Acetamide and Benzamide Deriva 1335-1351, vol. 15(7). tives as Potent and Selective Beta-3-Adrenergic Receptor Agonists Rampe, D. et al., “Deuterated Analogs of Verapamil and Nifedipine. with Improved Rodent Pharmacokinetic Profiles'. Bioorganic & Synthesis and Biological Activity”. Eur, J. Med. Chem. (1993), pp. Medicinal Chemistry Letters, (2010), pp. 1895-1899, vol. 20. 259-263, vol. 28. Takasu, T. et al., “Effect of (R)-2-(2-Aminothiazol-4-yl)-4-(2-(2- Baillie, T.A., “The Use of Stable Isotopes in Pharmacological hydroxy-2-phenylethyl)aminoethyl Acetanilide (YM178), a Novel Research'. Pharmacological Reivews, (1981), pp. 81-132, vol.33(2). Selective Beta-3-Adrenoceptor Agonist, on Bladder Function'. The Browne, T.R., "Stable Isotope Techniques in Early Drug Develop Journal of Pharmacology and Experimental Therapeutics, (2007), pp. ment: An Economic Evaluation'. J. Clin. Pharmacol., (1998), pp. 642-647, vol. 321(2). 213-220, vol. 38. van Gelderen, E.M. et al., “An Exploratory Comparison of the Single Cherrah, Y. et al., “Study of Deuterium Isotope Effects on Protein Dose Pharmacokinetics of the Beta-3-Adrenoceptor Agonist Binding by Gas Chromatography/Mass Specgtrometry. Caffeine and Mirabegron in Healthy CYP2D6 Poor and Extensive Metabolizers”. Deuterated Isotopomers'. Biomedical and Environmental Mass Clin. Pharmacol. Ther. Abstract PIII-65, (2009), p. S88, vol. Spectrometry, (1987), pp. 653-657, vol. 14. 85(Supp. 1). Dyck, L.E. et al., “Effcts of Deuterium Substitution on the Catabo Foster, A.B., Deuterium Isotope Effects in the Metabolism of Drugs lism of Beta-Phenylethylamine: An In Vivo Study”. Journal of and Xenobiotics: Implications for Drug Design, Adv. Drug Res., Neurochemistry, (1986), pp. 399-404, vol. 46(2). Academic Press, London, GB, vol. 14, Jan. 1, 1985, pp. 1-40. Gouyette, A., “Synthesis of Deuterium-labelled Elliptinium and its Rao et al., Aminothiazole Modulators of Beta-3-Adrenoreceptor, Use in Metabolic Studies'. Biomedical and Environmental Mass Auspex Pharmaceuticals, Inc., U.S. Appl. No. 12/796,781—Prosecu Spectrometry, (1988), pp. 243-247, vol. 15. tion History, Downloaded Jun. 11, 2013. US 9,029.407 B2 1. 2 AMINOTHAZOLE MODULATORS OF state of that reaction. Once the transition state is reached, the BETA-3-ADRENORECEPTOR molecules can either revert to the original reactants, or form new bonds giving rise to reaction products. A catalyst facili This application is a division of U.S. patent application Ser. tates a reaction process by lowering the activation energy No. 12/796,781, filed Jun. 9, 2010, which claims the benefit of 5 leading to a transition State. Enzymes are examples of bio priority of U.S. provisional application No. 61/186,965, filed logical catalysts. Jun. 15, 2009, the disclosures of which are hereby incorpo Carbon-hydrogen bond strength is directly proportional to rated by reference as if written herein in its entirety. the absolute value of the ground-state vibrational energy of Disclosed herein are new substituted aminothiazole com the bond. This vibrational energy depends on the mass of the pounds, pharmaceutical compositions made thereof, and 10 methods to modulate beta-3-adrenoreceptor activity in a sub atoms that form the bond, and increases as the mass of one or ject are also provided for, for the treatment of disorders such both of the atoms making the bond increases. Since deuterium as overactive bladder, irritable bowel syndrome, type 2 dia (D) has twice the mass of protium (H), a C-D bond is stron betes, and obesity. ger than the corresponding C–H bond. If a C-H bond is Mirabegron (YM-178, CAS #223673-61-8), 2-amino-N- 15 broken during a rate-determining step in a chemical reaction 4-2-(2R)-2-hydroxy-2-phenylethylaminoethylphe (i.e. the step with the highest transition State energy), then nyl-4-thiazoleacetamide, is a beta-3-adrenoreceptoragonist. Substituting a deuterium for that protium will cause a Mirabegron is currently under investigation for the treatment decrease in the reaction rate. This phenomenon is known as of overactive bladder, irritable bowel syndrome, type 2 dia the Deuterium Kinetic Isotope Effect (DKIE). The magnitude betes, and obesity (US 2009093529; US 2008214633; and of the DKIE can be expressed as the ratio between the rates of Takasu et al., J. Pharmacol. Exp. Ther. 2007, 321(2), 642 a given reaction in which a C H bond is broken, and the 647). same reaction where deuterium is substituted for protium. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more. Substitution of tritium for HN 9 25 hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects X. N O Deuterium (HorD) is a stable and non-radioactive isotope e of hydrogen which has approximately twice the mass of pro \llul N tium ("H), the most common isotope of hydrogen. Deuterium H 30 oxide (DO or "heavy water) looks and tastes like HO, but has different physical properties. Mirabegron When pure DO is given to rodents, it is readily absorbed. The quantity of deuterium required to induce toxicity is Mirabegron is subject to CYP3A4 and CYP2D6-mediated extremely high. When about 0-15% of the body water has oxidative cleavage (van Gelderen et al., Clin Pharmacol Ther 35 been replaced by D.O, animals are healthy but are unable to 2009, 85 (Suppl. 1), Abst PIII-65). Mean Cand mean AUC gain weight as fast as the control (untreated) group. When were slightly higher in poor metabolizers compared to exten about 15-20% of the body water has been replaced with D.O. sive metabolizers as reflected by a longert (van Gelderenet the animals become excitable. When about 20-25% of the al., Clin Pharmacol Ther 2009, 85(Suppl. 1), Abst PIII-65). body water has been replaced with DO, the animals become Intersubject variability was generally higher in poor metabo 40 so excitable that they go into frequent convulsions when lizers (van Gelderen et al., Clin Pharmacol Ther 2009, stimulated. Skin lesions, ulcers on the paws and muzzles, and 85 (Suppl. 1), Abst PIII-65). necrosis of the tails appear. The animals also become very Deuterium Kinetic Isotope Effect aggressive. When about 30% of the body water has been In order to eliminate foreign Substances such as therapeutic replaced with DO, the animals refuse to eat and become agents, the animal body expresses various enzymes, such as 45 comatose. Their body weight drops sharply and their meta the cytochrome Paso enzymes (CYPs), esterases, proteases, bolic rates drop far below normal, with death occurring at reductases, dehydrogenases, and monoamine oxidases, to about 30 to about 35% replacement with D.O.The effects are react with and convert these foreign Substances to more polar reversible unless more than thirty percent of the previous intermediates or metabolites for renal excretion. Such meta body weight has been lost due to D.O. Studies have also bolic reactions frequently involve the oxidation of a carbon 50 shown that the use of DO can delay the growth of cancer cells hydrogen (C H) bond to either a carbon-oxygen (C–O) or and enhance the cytotoxicity of certain antineoplastic agents. a carbon-carbon (C C) L-bond. The resultant metabolites Deuteration of pharmaceuticals to improve pharmacoki may be stable or unstable under physiological conditions, and netics (PK), pharmacodynamics (PD), and toxicity profiles can have Substantially different pharmacokinetic, pharmaco has been demonstrated previously with some classes of drugs. dynamic, and acute and long-term toxicity profiles relative to 55 For example, the DKIE was used to decrease the hepatotox the parent compounds. For most drugs, such oxidations are icity of halothane, presumably by limiting the production of generally rapid and ultimately lead to administration of mul reactive species such as trifluoroacetyl chloride. However, tiple or high daily doses. this method may not be applicable to all drug classes. For The relationship between the activation energy and the rate example, deuterium incorporation can lead to metabolic of reaction may be quantified by the Arrhenius equation, 60 Switching. Metabolic Switching occurs when Xenogens, k=Ae'. The Arrhenius equation states that, at a given sequestered by Phase I enzymes, bind transiently and re-bind temperature, the rate of a chemical reaction depends expo in a variety of conformations prior to the chemical reaction nentially on the activation energy (E). (e.g., oxidation). Metabolic switching is enabled by the rela The transition state in a reaction is a short lived state along tively vast size of binding pockets in many Phase I enzymes the reaction pathway during which the original bonds have 65 and the promiscuous nature of many metabolic reactions. stretched to their limit. By definition, the activation energy Metabolic switching can lead to different proportions of E. for a reaction is the energy required to reach the transition known metabolites as well as altogether new metabolites. US 9,029.407 B2 3 4 This new metabolic profile may impart more or less toxicity. Certain compounds disclosed herein may possess useful Such pitfalls are non-obvious and are not predictable a priori beta-3-adrenoreceptor modulating activity, and may be used for any drug class. in the treatment or prophylaxis of a disorder in which beta Mirabegron is a beta-3-adrenoreceptor agonist. The car bon-hydrogen bonds of mirabegron contain a naturally occur 3-adrenoreceptors play an active role. Thus, certain embodi ring distribution of hydrogen isotopes, namely Horprotium ments also provide pharmaceutical compositions comprising (about 99.984.4%), Hordeuterium (about 0.0156%), and H one or more compounds disclosed herein together with a or tritium (in the range between about 0.5 and 67 tritium pharmaceutically acceptable carrier, as well as methods of atoms per 10' protium atoms). Increased levels of deuterium making and using the compounds and compositions. Certain embodiments provide methods for modulating beta-3- incorporation may produce a detectable Deuterium Kinetic 10 Isotope Effect (DKIE) that could effect the pharmacokinetic, adrenoreceptor activity. Other embodiments provide methods pharmacologic and/or toxicologic profiles of mirabegron in for treating a beta-3-adrenoreceptor-mediated disorder in a comparison with mirabegron having naturally occurring lev patient in need of Such treatment, comprising administering els of deuterium. to said patient a therapeutically effective amount of a com Based on discoveries made in our laboratory, as well as 15 pound or composition according to the present invention. considering the literature, mirabegron is likely metabolized in Also provided is the use of certain compounds disclosed humans at the methylene group alpha to the carbonyl group, herein for use in the manufacture of a medicament for the the N-methylene groups, the benzylic methylene group, and prevention or treatment of a disorder ameliorated by modu the O-methine group. The current approach has the potential lating beta-3-adrenoreceptor activity. to prevent metabolism at this site. Other sites on the molecule The compounds as disclosed herein may also contain less may also undergo transformations leading to metabolites prevalent isotopes for other elements, including, but not lim with as-yet-unknown pharmacology/toxicology. Limiting the ited to, C or ''C for carbon, S, S, or S for sulfur, 'N production of these metabolites has the potential to decrease for nitrogen, and 'O or "O for oxygen. the danger of the administration of such drugs and may even allow increased dosage and/or increased efficacy. All of these In certain embodiments, the compound disclosed herein transformations can occur through polymorphically-ex 25 may expose apatient to a maximum of about 0.000005% DO pressed enzymes, exacerbating interpatient variability. Fur or about 0.00001% DHO, assuming that all of the C-D bonds ther, some disorders are best treated when the subject is in the compound as disclosed herein are metabolized and released as DO or DHO. In certain embodiments, the levels medicated around the clock or for an extended period of time. of DO shown to cause toxicity in animals is much greater For all of the foregoing reasons, a medicine with a longer 30 half-life may result in greater efficacy and cost savings. Vari than even the maximum limit of exposure caused by admin ous deuteration patterns can be used to (a) reduce or eliminate istration of the deuterium enriched compound as disclosed unwanted metabolites, (b) increase the half-life of the parent herein. Thus, in certain embodiments, the deuterium-en drug, (c) decrease the number of doses needed to achieve a riched compound disclosed herein should not cause any addi desired effect, (d) decrease the amount of a dose needed to 35 tional toxicity due to the formation of DO or DHO upon drug achieve a desired effect, (e) increase the formation of active metabolism. metabolites, if any are formed, (f) decrease the production of In certain embodiments, the deuterated compounds dis deleterious metabolites in specific tissues, and/or (g) create a closed herein maintain the beneficial aspects of the corre more effective drug and/or a safer drug for polypharmacy, sponding non-isotopically enriched molecules while Substan whether the polypharmacy be intentional or not. The deutera 40 tially increasing the maximum tolerated dose, decreasing tion approach has the strong potential to slow the metabolism toxicity, increasing the half-life (T), lowering the maxi of mirabegron and attenuate interpatient variability. mum plasma concentration (C) of the minimum effica Novel compounds and pharmaceutical compositions, cer cious dose (MED), lowering the efficacious dose and thus tain of which have been found to modulate beta-3-adrenore decreasing the non-mechanism-related toxicity, and/or low ceptor activity have been discovered, together with methods 45 ering the probability of drug-drug interactions. of synthesizing and using the compounds, including methods In certain embodiments, if Ro-R2 are deuterium, then at for the treatment of beta-3-adrenoreceptor-mediated disor least one of R-Rs are deuterium. ders in a patient by administering the compounds as disclosed All publications and references cited herein are expressly herein. incorporated herein by reference in their entirety. However, In certain embodiments of the present invention, com 50 with respect to any similar or identical terms found in both the pounds have structural Formula I: incorporated publications or references and those explicitly put forth or defined in this document, then those terms defi nitions or meanings explicitly put forth in this document shall (I) control in all respects. 55 R As used herein, the terms below have the meanings indi RSN/ cated. R9 The singular forms “a”, “an', and “the may refer to plural s N O articles unless specifically stated otherwise. S ea The term “about', as used herein, is intended to qualify the N 60 numerical values which it modifies, denoting Such a value as R3 R4 R5 R. variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about should be or a pharmaceutically acceptable salt thereof, wherein: understood to mean that range which would encompass the R-R are independently selected from the group consist 65 recited value and the range which would be included by ing of hydrogen and deuterium; and rounding up or downto that figure as well, taking into account at least one of R-R is deuterium. significant figures. US 9,029.407 B2 5 6 When ranges of values are disclosed, and the notation single, double, or triple unless otherwise specified. A dashed “from n ... to n' or “n-n' is used, where n and n are the line between two atoms in a drawing of a molecule indicates numbers, then unless otherwise specified, this notation is that an additional bond may be present or absent at that intended to include the numbers themselves and the range position. between them. This range may be integral or continuous The term “disorder as used herein is intended to be gen between and including the end values. erally synonymous, and is used interchangeably with, the The term “deuterium enrichment” refers to the percentage terms “disease”, “syndrome', and “condition' (as in medical of incorporation of deuterium at a given position in a mol condition), in that all reflect an abnormal condition of the ecule in the place of hydrogen. For example, deuterium human or animal body or of one of its parts that impairs enrichment of 1% at a given position means that 1% of mol 10 normal functioning, is typically manifested by distinguishing ecules in a given sample contain deuterium at the specified signs and Symptoms. position. Because the naturally occurring distribution of deu The terms “treat”, “treating, and “treatment” are meant to terium is about 0.0156%, deuterium enrichment at any posi include alleviating or abrogating a disorder or one or more of tion in a compound synthesized using non-enriched starting the symptoms associated with a disorder, or alleviating or materials is about 0.0156%. The deuterium enrichment can 15 eradicating the cause(s) of the disorder itself. As used herein, be determined using conventional analytical methods known reference to “treatment of a disorder is intended to include to one of ordinary skill in the art, including mass spectrometry prevention. The terms “prevent”, “preventing, and “preven and nuclear magnetic resonance spectroscopy. tion” refer to a method of delaying or precluding the onset of The term “is/are deuterium, when used to describe a given a disorder, and/or its attendant symptoms, barring a subject position in a molecule Such as R-R or the symbol “D’. from acquiring a disorder or reducing a subject’s risk of when used to represent a given position in a drawing of a acquiring a disorder. molecular structure, means that the specified position is The term “therapeutically effective amount” refers to the enriched with deuterium above the naturally occurring distri amount of a compound that, when administered, is sufficient bution of deuterium. In one embodiment deuterium enrich to prevent development of oralleviate to some extent, one or ment is no less than about 1%, in another no less than about 25 more of the symptoms of the disorder being treated. The term 5%, in another no less than about 10%, in another no less than “therapeutically effective amount” also refers to the amount about 20%, in another no less than about 50%, in another no of a compound that is sufficient to elicit the biological or less than about 70%, in another no less than about 80%, in medical response of a cell, tissue, system, animal, or human another no less than about 90%, or in another no less than that is being sought by a researcher, Veterinarian, medical about 98% of deuterium at the specified position. 30 doctor, or clinician. The term “isotopic enrichment” refers to the percentage of The term “subject” refers to an animal, including, but not incorporation of a less prevalent isotope of an element at a limited to, a primate (e.g., human, monkey, chimpanzee, given position in a molecule in the place of the more prevalent gorilla, and the like), rodents (e.g., rats, mice, gerbils, ham isotope of the element. sters, ferrets, and the like), lagomorphs, Swine (e.g., pig, The term “non-isotopically enriched refers to a molecule 35 miniature pig), equine, canine, feline, and the like. The terms in which the percentages of the various isotopes are Substan “subject' and “patient” are used interchangeably herein in tially the same as the naturally occurring percentages. reference, for example, to a mammalian Subject, such as a Asymmetric centers exist in the compounds disclosed human patient. herein. These centers are designated by the symbols “R” or The term “combination therapy’ means the administration 'S', depending on the configuration of Substituents around 40 of two or more therapeutic agents to treat a therapeutic dis the chiral carbonatom. It should be understood that the inven order described in the present disclosure. Such administration tion encompasses all Stereochemical isomeric forms, includ encompasses co-administration of these therapeutic agents in ing diastereomeric, enantiomeric, and epimeric forms, as a Substantially simultaneous manner, Such as in a single cap well as D-isomers and L-isomers, and mixtures thereof. Indi Sule having a fixed ratio of active ingredients or in multiple, vidual stereoisomers of compounds can be prepared syntheti 45 separate capsules for each active ingredient. In addition, Such cally from commercially available starting materials which administration also encompasses use of each type of thera contain chiral centers or by preparation of mixtures of enan peutic agent in a sequential manner. In either case, the treat tiomeric products followed by separation Such as conversion ment regimen will provide beneficial effects of the drug com to a mixture of diastereomers followed by separation or bination in treating the disorders described herein. recrystallization, chromatographic techniques, direct separa 50 The term “beta-3-adrenoreceptor refers to a member of tion of enantiomers on chiral chromatographic columns, or the family of receptors which mediate the physiological any other appropriate method known in the art. Starting com actions of the hormones adrenaline and noradrenaiine. Sub pounds of particular Stereochemistry are either commercially types of the adrenoreceptors, alpha-1, alpha-2, beta-1, beta-2, available or can be made and resolved by techniques known in and beta-3, can be identified on the basis of their pharmaco the art. Additionally, the compounds disclosed herein may 55 logical properties and physiological effects. Beta-3-adreno exist as geometric isomers. The present invention includes all ceptors are known to occur in adipose tissue and the gas cis, trans, syn, anti, entgegen (E), and Zusammen (Z) isomers trointestinal tract. Beta-3-adrenoceptor agonists are thought as well as the appropriate mixtures thereof. Additionally, to be useful as thermogenic anti-obesity agents and as anti compounds may exist as tautomers; all tautomeric isomers diabetic agents. Additionally, beta-3-adrenoreceptor signal are provided by this invention. Additionally, the compounds 60 ing is known to induce relaxant effects on the human detrusor disclosed herein can exist in unsolvated as well as Solvated muscle. Thus, selective stimulation of beta-3-adrenoceptors forms with pharmaceutically acceptable solvents such as in the human bladder would be expected to cause bladder water, ethanol, and the like. In general, the Solvated forms are relaxation, and as Such it may represent a novel strategy in the considered equivalent to the unsolvated forms. treatment of overactive bladder. The term “bond refers to a covalent linkage between two 65 The term “beta-3-adrenoreceptor-mediated disorder. atoms, or two moieties when the atoms joined by the bond are refers to a disorder that is characterized by abnormal beta-3- considered to be part of larger substructure. A bond may be adrenoreceptor activity, or normal beta-3-adrenoreceptor US 9,029.407 B2 7 8 activity that when modulated ameliorates other abnormal bio The terms “active ingredient”, “active compound', and chemical processes. A beta-3-adrenoreceptor-mediated dis “active substance” refer to a compound, which is adminis order may be completely or partially mediated by modulating tered, alone or in combination with one or more pharmaceu beta-3-adrenoreceptor activity. In particular, a beta-3-adreno tically acceptable excipients or carriers, to a subject for treat receptor-mediated disorder is one in which modulation of 5 ing, preventing, or ameliorating one or more symptoms of a beta-3-adrenoreceptor activity results in some effect on the disorder. underlying disorder e.g., administration of a beta-3-adreno The terms “drug”, “therapeutic agent, and “chemothera receptor modulator results in Some improvement in at least peutic agent” refer to a compound, or a pharmaceutical com Some of the patients being treated. position thereof, which is administered to a subject for treat The term “beta-3-adrenoreceptor modulator, refers to the 10 ing, preventing, or ameliorating one or more symptoms of a ability of a compound disclosed hereinto alter the function of disorder. beta-3-adrenoreceptors. A beta-3-adrenoreceptor modulator The term “release controlling excipient” refers to an may activate the activity of a beta-3-adrenoreceptor, may excipient whose primary function is to modify the duration or activate or inhibit the activity of a beta-3-adrenoreceptor place of release of the active Substance from a dosage form as depending on the concentration of the compound exposed to 15 compared with a conventional immediate release dosage the beta-3-adrenoreceptor, or may inhibit the activity of a form. beta-3-adrenoreceptor. Such activation or inhibition may be The term “nonrelease controlling excipient” refers to an contingent on the occurrence of a specific event. Such as excipient whose primary function do not include modifying activation of a signal transduction pathway, and/or may be the duration or place of release of the active substance from a manifest only in particular cell types. The term “beta-3- 20 dosage form as compared with a conventional immediate adrenoreceptor modulator also refers to altering the function release dosage form. of a beta-3-adrenoreceptor by increasing or decreasing the The term “prodrug” refers to a compound functional probability that a complex forms between a beta-3-adrenore derivative of the compound as disclosed herein and is readily ceptor and a natural binding partner. A beta-3-adrenoreceptor convertible into the parent compound in vivo. Prodrugs are modulator may increase the probability that such a complex 25 often useful because, in Some situations, they may be easier to forms between the beta-3-adrenoreceptor and the natural administer than the parent compound. They may, for instance, binding partner, may increase or decrease the probability that be bioavailable by oral administration whereas the parent a complex forms between the beta-3-adrenoreceptor and the compound is not. The prodrug may also have enhanced solu natural binding partner depending on the concentration of the bility in pharmaceutical compositions over the parent com compound exposed to the beta-3-adrenoreceptor, and or may 30 pound. A prodrug may be converted into the parent drug by decrease the probability that a complex forms between the various mechanisms, including enzymatic processes and beta-3-adrenoreceptor and the natural binding partner. In metabolic hydrolysis. See Harper, Progress in Drug Research Some embodiments, modulation of beta-3-adrenoreceptors 1962, 4, 221–294; Morozowich et al. in “Design of Biophar may be assessed using the method described in US maceutical Properties through Prodrugs and Analogs. Roche 2009093529; US 2008214633; and Takasu et al., J. Pharma- 35 Ed., APHA Acad. Pharm. Sci. 1977: “Bioreversible Carriers col. Exp. Ther: 2007, 321(2), 642-647. in Drug in Drug Design, Theory and Application. Roche Ed., The term “modulating beta-3-adrenoreceptor activity” or APHA Acad. Pharm. Sci. 1987: “Design of Prodrugs.” Bund “modulation of beta-3-adrenoreceptor activity” refers to gaard, Elsevier, 1985; Wang et al., Curr: Pharm. Design 1999, altering the function of beta-3-adrenoreceptors by adminin 5,265-287: Pauletti et al., Adv. Drug. Delivery Rev. 1997,27, stering a beta-3-adrenoreceptor modulator. 40 235-256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365; The term “therapeutically acceptable' refers to those com Gaignault et al., Pract. Med. Chem. 1996, 671-696; pounds (or salts, prodrugs, tautomers, Zwitterionic forms, Asgharnejad in “Transport Processes in Pharmaceutical Sys etc.) which are suitable for use in contact with the tissues of tems. Amidon et al., Ed., Marcell Dekker, 185-218, 2000; patients without excessive toxicity, irritation, allergic Balant et al., Eur: J. Drug Metab. Pharmacokinet. 1990, 15, response, immunogenecity, are commensurate with a reason- 45 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, able benefit/risk ratio, and are effective for their intended use. 39, 183-209: Browne, Clin. Neuropharmacol. 1997, 20, 1-12; The term “pharmaceutically acceptable carrier”, “pharma Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39: Bundgaard, ceutically acceptable excipient”, “physiologically acceptable Controlled Drug Delivery 1987, 17, 179–96: Bundgaard, Adv. carrier, or “physiologically acceptable excipient” refers to a Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al., Adv. Drug pharmaceutically-acceptable material, composition, or 50 Delivery Rev. 1996, 19, 115-130; Fleisher et al., Methods vehicle, such as a liquid or Solid filler, diluent, excipient, Enzymol. 1985, 112,360-381: Farquhar et al., J. Pharm. Sci. Solvent, or encapsulating material. Each component must be 1983, 72, 324-325; Freeman et al., J. Chem. Soc., Chem. “pharmaceutically acceptable' in the sense of being compat Commun. 1991, 875-877: Friis and Bundgaard, Eur: J. ible with the other ingredients of a pharmaceutical formula Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. tion. It must also be suitable for use in contact with the tissue 55 Prop. Prodrugs Analogs, 1977, 409–421; Nathwani and or organ of humans and animals without excessive toxicity, Wood, Drugs 1993, 45,866-94: Sinhababu and Thakker, Adv. irritation, allergic response, immunogenecity, or other prob Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs lems or complications, commensurate with a reasonable ben 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, efit/risk ratio. See, Remington. The Science and Practice of 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131 Pharmacy, 21st Edition; Lippincott Williams & Wilkins: 60 148; Valentino and Borchardt, Drug Discovery Today 1997.2, Philadelphia, Pa., 2005; Handbook of Pharmaceutical 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, Excipients, 5th Edition; Rowe et al., Eds. The Pharmaceuti 39, 63-80; Waller et al., Br. J. Clin. Pharmac. 1989, 28, cal Press and the American Pharmaceutical Association: 497-507. 2005; and Handbook of Pharmaceutical Additives, 3rd Edi The compounds disclosed herein can exist as therapeuti tion; Ash and Ash Eds. Gower Publishing Company: 2007; 65 cally acceptable salts. The term “pharmaceutically accept Pharmaceutical Preformulation and Formulation, Gibson able salt”, as used herein, represents salts or Zwitterionic Ed., CRC Press LLC: Boca Raton, Fla., 2004). forms of the compounds disclosed herein which are therapeu US 9,029.407 B2 10 tically acceptable as defined herein. The salts can be prepared fying, encapsulating, entrapping or compression processes. during the final isolation and purification of the compounds or The pharmaceutical compositions may also be formulated as separately by reacting the appropriate compound with a Suit a modified release dosage form, including delayed-, able acid or base. Therapeutically acceptable salts include extended-, prolonged-, Sustained-, pulsatile-, controlled acid and basic addition salts. For a more complete discussion accelerated- and fast-, targeted-, programmed-release, and of the preparation and selection of salts, refer to “Handbook gastric retention dosage forms. These dosage forms can be of Pharmaceutical Salts, Properties, and Use.” Stah and Wer prepared according to conventional methods and techniques muth, Ed., (Wiley-VCH and VHCA, Zurich, 2002) and Berge known to those skilled in the art (see, Remington. The Science et al., J. Pharm. Sci. 1977, 66, 1-19. and Practice of Pharmacy, supra; Modified-Release Drug Suitable acids for use in the preparation of pharmaceuti 10 cally acceptable salts include, but are not limited to, acetic Deliver Technology, Rathbone et al., Eds. Drugs and the acid, 2,2-dichloroacetic acid, acylated amino acids, adipic Pharmaceutical Science, Marcel Dekker, Inc.: New York, acid, alginic acid, ascorbic acid, L-aspartic acid, benzene N.Y., 2002; Vol. 126). Sulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric The compositions include those suitable for oral, acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)- 15 parenteral (including Subcutaneous, intradermal, intramuscu camphor-10-Sulfonic acid, capric acid, caproic acid, caprylic lar, intravenous, intraarticular, and intramedullary), intraperi acid, cinnamic acid, citric acid, cyclamic acid, cyclohexane toneal, transmucosal, transdermal, rectal and topical (includ Sulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic ing dermal, buccal, Sublingual and intraocular) acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, administration although the most Suitable route may depend formic acid, fumaric acid, galactaric acid, gentisic acid, glu upon for example the condition and disorder of the recipient. coheptonic acid, D-gluconic acid, D-glucuronic acid, The compositions may conveniently be presented in unit dos L-glutamic acid, C-OXO-glutaric acid, glycolic acid, hippuric age form and may be prepared by any of the methods well acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, known in the art of pharmacy. Typically, these methods (+)-L-lactic acid, (t)-DL-lactic acid, lactobionic acid, lauric include the step of bringing into association a compound of acid, maleic acid, (-)-L-malic acid, malonic acid, (+)-DL 25 the Subject invention or a pharmaceutically salt, prodrug, or mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic solvate thereof (“active ingredient') with the carrier which acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naph constitutes one or more accessory ingredients. In general, the thoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, compositions are prepared by uniformly and intimately oxalic acid, palmitic acid, pamoic acid, perchloric acid, phos bringing into association the active ingredient with liquid phoric acid, L-pyroglutamic acid, Saccharic acid, salicylic 30 carriers or finely divided solid carriers or both and then, if acid, 4-amino-salicylic acid, sebacic acid, Stearic acid, suc necessary, shaping the product into the desired formulation. cinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thio Formulations of the compounds disclosed herein suitable cyanic acid, p-toluenesulfonic acid, undecylenic acid, and for oral administration may be presented as discrete units Valeric acid. Such as capsules, cachets or tablets each containing a prede Suitable bases for use in the preparation of pharmaceuti 35 termined amount of the active ingredient, as a powder or cally acceptable salts, including, but not limited to, inorganic granules; as a solution or a suspension in an aqueous liquid or bases, such as magnesium hydroxide, calcium hydroxide, a non-aqueous liquid; or as an oil-in-water liquid emulsion or potassium hydroxide, Zinc hydroxide, or sodium hydroxide; a water-in-oil liquid emulsion. The active ingredient may also and organic bases, such as primary, secondary, tertiary, and be presented as a bolus, electuary or paste. quaternary, aliphatic and aromatic amines, including L-argi 40 Pharmaceutical preparations which can be used orally nine, benethamine, benzathine, choline, deanol, diethanola include tablets, push-fit capsules made of gelatin, as well as mine, diethylamine, dimethylamine, dipropylamine, diiso soft, sealed capsules made of gelatin and a plasticizer, Such as propylamine, 2-(diethylamino)-ethanol, ethanolamine, glycerol or sorbitol. Tablets may be made by compression or ethylamine, ethylenediamine, isopropylamine, N-methyl molding, optionally with one or more accessory ingredients. glucamine, hydrabamine, 1H-imidazole, L-lysine, morpho 45 Compressed tablets may be prepared by compressing in a line, 4-(2-hydroxyethyl)-morpholine, methylamine, piperi Suitable machine the active ingredient in a free-flowing form dine, piperazine, propylamine, pyrrolidine, 1-(2- Such as a powder or granules, optionally mixed with binders, hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, inert diluents, or lubricating, Surface active or dispersing isoquinoline, secondary amines, triethanolamine, trimethy agents. Molded tablets may be made by molding in a Suitable lamine, triethylamine, N-methyl-D-glucamine, 2-amino-2- 50 machine a mixture of the powdered compound moistened (hydroxymethyl)-1,3-propanediol, and tromethamine. with an inert liquid diluent. The tablets may optionally be While it may be possible for the compounds of the subject coated or scored and may be formulated so as to provide slow invention to be administered as the raw chemical, it is also or controlled release of the active ingredient therein. All for possible to present them as a pharmaceutical composition. mulations for oral administration should be in dosages Suit Accordingly, provided herein are pharmaceutical composi 55 able for Such administration. The push-fit capsules can con tions which comprise one or more of certain compounds tain the active ingredients in admixture with filler such as disclosed herein, or one or more pharmaceutically acceptable lactose, binders such as starches, and/or lubricants such as salts, prodrugs, or Solvates thereof, together with one or more talc or magnesium Stearate and, optionally, stabilizers. In soft pharmaceutically acceptable carriers thereof and optionally capsules, the active compounds may be dissolved or Sus one or more other therapeutic ingredients. Proper formulation 60 pended in Suitable liquids, such as fatty oils, liquid paraffin, or is dependent upon the route of administration chosen. Any of liquid polyethylene glycols. In addition, stabilizers may be the well-known techniques, carriers, and excipients may be added. Dragee cores are provided with Suitable coatings. For used as Suitable and as understood in the art; e.g., in Reming this purpose, concentrated Sugar Solutions may be used, ton’s Pharmaceutical Sciences. The pharmaceutical compo which may optionally contain gum arabic, talc, polyvinyl sitions disclosed herein may be manufactured in any manner 65 pyrrolidone, carbopol gel, polyethylene glycol, and/or tita known in the art, e.g., by means of conventional mixing, nium dioxide, lacquer Solutions, and Suitable organic solvents dissolving, granulating, dragee-making, levigating, emulsi or solvent mixtures. Dyestuffs or pigments may be added to US 9,029.407 B2 11 12 the tablets or dragee coatings for identification or to charac other convenient means of delivering an aerosol spray. Pres terize different combinations of active compound doses. Surized packs may comprise a suitable propellant Such as The compounds may be formulated for parenteral admin dichlorodifluoromethane, trichlorofluoromethane, dichlo istration by injection, e.g., by bolus injection or continuous rotetrafluoroethane, carbon dioxide or other suitable gas. In infusion. Formulations for injection may be presented in unit the case of a pressurized aerosol, the dosage unit may be dosage form, e.g., in ampoules or in multi-dose containers, determined by providing a valve to deliver a metered amount. with an added preservative. The compositions may take Such Alternatively, for administration by inhalation or insufflation, forms as Suspensions, Solutions or emulsions in oily or aque the compounds according to the invention may take the form ous vehicles, and may contain formulatory agents such as ofa dry powder composition, for example a powder mix of the Suspending, stabilizing and/or dispersing agents. The formu 10 compound and a suitable powder base such as lactose or lations may be presented in unit-dose or multi-dose contain starch. The powder composition may be presented in unit ers, for example sealed ampoules and vials, and may be stored dosage form, in for example, capsules, cartridges, gelatin or in powder form or in a freeze-dried (lyophilized) condition blister packs from which the powder may be administered requiring only the addition of the sterile liquid carrier, for with the aid of an inhalator or insufflator. example, saline or sterile pyrogen-free water, immediately 15 Preferred unit dosage formulations are those containing an prior to use. Extemporaneous injection solutions and Suspen effective dose, as herein below recited, or an appropriate sions may be prepared from Sterile powders, granules and fraction thereof, of the active ingredient. tablets of the kind previously described. Compounds may be administered orally or via injection at Formulations for parenteral administration include aque a dose of from 0.1 to 500 mg/kg per day. The dose range for ous and non-aqueous (oily) sterile injection solutions of the adult humans is generally from 5 mg to 2 g/day. Tablets or active compounds which may contain antioxidants, buffers, other forms of presentation provided in discrete units may bacteriostats and solutes which render the formulation iso conveniently contain an amount of one or more compounds tonic with the blood of the intended recipient; and aqueous which is effective at Such dosage or as a multiple of the same, and non-aqueous sterile Suspensions which may include Sus for instance, units containing 5 mg to 500 mg, usually around pending agents and thickening agents. Suitable lipophilic 25 10 mg to 200 mg. Solvents or vehicles include fatty oils such as sesame oil, or The amount of active ingredient that may be combined synthetic fatty acid esters, such as ethyl oleate or triglycer with the carrier materials to produce a single dosage form will ides, or liposomes. Aqueous injection Suspensions may con vary depending upon the host treated and the particular mode tain Substances which increase the Viscosity of the Suspen of administration. Sion, such as Sodium carboxymethyl cellulose, Sorbitol, or 30 The compounds can be administered in various modes, e.g. dextran. Optionally, the Suspension may also contain Suitable orally, topically, or by injection. The precise amount of com stabilizers or agents which increase the solubility of the com pound administered to a patient will be the responsibility of pounds to allow for the preparation of highly concentrated the attendant physician. The specific dose level for any par Solutions. ticular patient will depend upon a variety of factors including In addition to the formulations described previously, the 35 the activity of the specific compound employed, the age, body compounds may also be formulated as a depot preparation. weight, general health, sex, diets, time of administration, Such long acting formulations may be administered by route of administration, rate of excretion, drug combination, implantation (for example Subcutaneously or intramuscu the precise disorder being treated, and the severity of the larly) or by intramuscular injection. Thus, for example, the disorder being treated. Also, the route of administration may compounds may be formulated with Suitable polymeric or 40 vary depending on the disorder and its severity. hydrophobic materials (for example as an emulsion in an In the case wherein the patient’s condition does not acceptable oil) or ion exchange resins, or as sparingly soluble improve, upon the doctor's discretion the administration of derivatives, for example, as a sparingly soluble salt. the compounds may be administered chronically, that is, for For buccal or Sublingual administration, the compositions an extended period of time, including throughout the duration may take the form of tablets, lozenges, pastilles, or gels 45 of the patient’s life in order to ameliorate or otherwise control formulated in conventional manner. Such compositions may or limit the symptoms of the patient’s disorder. comprise the active ingredient in a flavored basis Such as In the case wherein the patient's status does improve, upon Sucrose and acacia or tragacanth. the doctor's discretion the administration of the compounds The compounds may also be formulated in rectal compo may be given continuously or temporarily Suspended for a sitions such as Suppositories or retention enemas, e.g., con 50 certain length of time (i.e., a "drug holiday'). taining conventional Suppository bases such as cocoa butter, Once improvement of the patients conditions has polyethylene glycol, or other glycerides. occurred, a maintenance dose is administered if necessary. Certain compounds disclosed herein may be administered Subsequently, the dosage or the frequency of administration, topically, that is by non-systemic administration. This or both, can be reduced, as a function of the symptoms, to a includes the application of a compound disclosed herein 55 level at which the improved disorder is retained. Patients can, externally to the epidermis or the buccal cavity and the instil however, require intermittent treatment on a long-term basis lation of Sucha compound into the ear, eye and nose, such that upon any recurrence of symptoms. the compound does not significantly enter the blood stream. Disclosed herein are methods of treating a beta-3-adreno In contrast, Systemic administration refers to oral, intrave receptor-mediated disorder comprising administering to a nous, intraperitoneal and intramuscular administration. 60 Subject having or Suspected of having Such a disorder, a Formulations suitable for topical administration include therapeutically effective amount of a compound as disclosed liquid or semi-liquid preparations suitable for penetration herein or a pharmaceutically acceptable salt, Solvate, or pro through the skin to the site of inflammation Such as gels, drug thereof. liniments, lotions, creams, ointments or pastes, and drops Beta-3-adrenoreceptor-mediated disorders, include, but Suitable for administration to the eye, ear or nose. 65 are not limited to, overactive bladder, irritable bowel syn For administration by inhalation, compounds may be drome, type 2 diabetes, obesity, hyperglycemia, hyper delivered from an insufflator, nebulizer pressurized packs or lipemia, pain associated with irritable bowel syndrome, US 9,029.407 B2 13 14 motility dysfunction, excessive gastrointestinal secretion, Examples of monoamine oxidase isoforms in a mamma nonspecific diarrhea, neurogenic inflammation, regulation of lian subject include, but are not limited to, MAO, and intraocular pressure, triglyceridemia, diabetic complications MAO. Such as retinopathy, nephropathy, neuropathy, cataracts, The inhibition of the cytochrome Paso isoform is measured coronary heart diseases, and arteriosclerosis, osteoporosis, by the method of Ko et al., British Journal of Clinical Phar gastrointestinal disorders, inflammatory gastrointestinal dis macology 2000, 49, 343-351. The inhibition of the MAO orders, treatment and/or prophylaxis of atherosclerosis, isoform is measured by the method of Weyler et al., J. Biol hyperinsulinemia, depression, muscle wasting, urinary Chem. 1985, 260, 13199-13207. The inhibition of the MAO incontinence, wound-healing, and/or any disorder which can isoform is measured by the method of Uebelhacket al., Phar lessened, alleviated, or prevented by administering a beta-3- 10 macopsychiatry, 1998, 31, 187-192. adrenoreceptor modulator. Examples of polymorphically-expressed cytochrome Paso In certain embodiments, a method of treating a beta-3- isoforms in a mammalian Subject include, but are not limited adrenoreceptor-mediated disorder comprises administering to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. to the subject a therapeutically effective amount of a com 15 The metabolic activities of liver microsomes, cytochrome pound as disclosed herein, or a pharmaceutically acceptable Paso isoforms, and monoamine oxidase isoforms are mea sured by the methods described herein. salt, Solvate, or prodrug thereof. So as to affect: (1) decreased Examples of improved disorder-control and/or disorder inter-individual variation in plasma levels of the compound or eradication endpoints, or improved clinical effects include, a metabolite thereof; (2) increased average plasma levels of but are not limited to, reduction of glucose AUC, reduction of the compound or decreased average plasma levels of at least HbA1C, lowered fasting blood glucose levels, decreased one metabolite of the compound per dosage unit; (3) plasma triglyceride levels, improved glycemic control, decreased inhibition of, and/or metabolism by at least one reduced body weight, percent reduction of body weight, cytochrome Paso or monoamine oxidase isoform in the Sub reduced visceral fat area, increased high-density lipoprotein ject; (4) decreased metabolism via at least one polymorphi 25 cholesterol, reduced very-low-density lipoprotein choles cally-expressed cytochrome Paso isoform in the Subject; (5) at terol, reduced food intake, reduced number of incontinence least one statistically-significantly improved disorder-control episodes per week, reduced number of micturitions per day, increased Volume Voided per micturition, improved patient and/or disorder-eradication endpoint; (6) an improved clini perception of urgency symptoms, improved King's Health cal effect during the treatment of the disorder, (7) prevention 30 Questionnaire quality of life instrument scores, decreased of recurrence, or delay of decline or appearance, of abnormal colonic transit and visceral sensitivity, reduced urgency, alimentary or hepatic parameters as the primary clinical ben firmer Stools, alleviation of abdominal pain and discomfort, efit, or (8) reduction or elimination of deleterious changes in and decreased postprandial nausea and bloating. any diagnostic hepatobiliary function endpoints, as compared 35 Examples of diagnostic hepatobiliary function endpoints to the corresponding non-isotopically enriched compound. include, but are not limited to, alanine aminotransferase In certain embodiments, inter-individual variation in (ALT), serum glutamic-pyruvic transaminase (“SGPT), plasma levels of the compounds as disclosed herein, or aspartate aminotransferase (AST or “SGOT), ALT/AST metabolites thereof, is decreased; average plasma levels of ratios, serum aldolase, alkaline phosphatase (ALP), ammo the compound as disclosed herein are increased; average 40 nia levels, bilirubin, gamma-glutamyl transpeptidase plasma levels of a metabolite of the compound as disclosed (“GGTP” “Y-GTP or “GGT), leucine aminopeptidase herein are decreased; inhibition of a cytochrome Paso or (“LAP), liver biopsy, liver ultrasonography, liver nuclear monoamine oxidase isoform by a compound as disclosed scan, 5'-nucleotidase, and blood protein. Hepatobiliary end herein is decreased; or metabolism of the compound as dis points are compared to the stated normal levels as given in closed herein by at least one polymorphically-expressed 45 “Diagnostic and Laboratory Test Reference', 4' edition, cytochrome Paso isoform is decreased; by greater than about Mosby, 1999. These assays are run by accredited laboratories 5%, greater than about 10%, greater than about 20%, greater according to standard protocol. than about 30%, greater than about 40%, or by greater than Besides being useful for human treatment, certain com about 50% as compared to the corresponding non-isotopi pounds and formulations disclosed herein may also be useful cally enriched compound. 50 for veterinary treatment of companion animals, exotic ani Plasma levels of the compound as disclosed herein, or mals and farm animals, including mammals, rodents, and the metabolites thereof, may be measured using the methods like. More preferred animals include horses, dogs, and cats. described by Li et al. Rapid Communications in Mass Spec Combination Therapy trometry 2005, 19, 1943-1950; and any references cited in The compounds disclosed herein may also be combined or and any modifications made thereof. 55 used in combination with other agents useful in the treatment Examples of cytochrome Paso isoforms in a mammalian of beta-3-adrenoreceptor-mediated disorders. Or, by way of subject include, but are not limited to, CYP1A1, CYP1A2, example only, the therapeutic effectiveness of one of the CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, compounds described herein may be enhanced by adminis CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, 60 tration of an adjuvant (i.e., by itself the adjuvant may only CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, have minimal therapeutic benefit, but in combination with CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Such other agents, adjuvants, or drugs, may be adminis 65 tered, by a route and in an amount commonly used therefor, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, simultaneously or sequentially with a compound as disclosed CYP27A1, CYP27B1, CYP39, CYP46, and CYP51. herein. When a compound as disclosed herein is used con US 9,029.407 B2 15 16 temporaneously with one or more other drugs, a pharmaceu Sartan, eprosartan, irbesartan, losartan, telmisartan or Valsar tical composition containing Such other drugs in addition to tan; renin inhibitors, for example aliskiren, terlakiren, the compound disclosed herein may be utilized, but is not ditekiren, RO-66-1132 or RO-66-1 168; b-adrenergic recep required. tor blockers, for example acebutolol, atenolol, betaxolol, In certain embodiments, the compounds disclosed herein bisoprolol, metoprolol, nadolol, propranolol, Sotalol or can be combined with one or more dipeptidyl peptidase IV timolol; inotropic agents, for example digoxin, dobutamine inhibitors, anti-diabetic agents, hypolipidemic agents, anti or milrinone; calcium channel blockers, for example amlo obesity or appetite regulating agents, anti-hypertensive dipine, bepridil, diltiazem, felodipine, nicardipine, nimo agents, urologicals, urinary antispasmodics, H1 receptor dipine, nifedipine, nisoldipine or Verapamil; aldosterone antagonists, H, K ATPase inhibitors, and alimentary motil 10 receptor antagonists; and aldosterone synthase inhibitors. ity modulators. In certain embodiments, the compounds disclosed herein In certain embodiments, the compounds disclosed herein can be combined with one or more urologicals, including, but can be combined with one or more dipeptidyl peptidase IV not limited to, acetohydroxamic acid, collagen, dimethyl Sul inhibitors, including, but not limited to, Vildagliptin, saxa foxide, magnesium hydroxide, pentosan polysulfate, gliptin, Sitagliptin, linagliptin, and alogliptin. 15 phenaZopyridine, phenyl salicylate. Succinimide, and botuli Examples of anti-diabetic agents include insulin, insulin num toxin A. derivatives and mimetics; insulin secretagogues, for example In certain embodiments, the compounds disclosed herein Sulfonylureas (e.g. glipizide, glyburide or amaryl); insulino can be combined with one or more urinary antispasmodics, tropic Sulfonylurea receptor ligands, for example megli including, but not limited to, tolterodine, darifenacin, eme tinides (e.g. nateglinide or repaglinide); insulin sensitisers, pronium, flavoxate, fesoterodine, meladrazine, oxybutynin, for example protein tyrosine phosphatase-1B (PTP-1B) propiverine, Solifenacin, terodiline, and trospium. inhibitors (e.g. PTP-112); G8K3 (glycogen synthase kinase In certain embodiments, the compounds disclosed herein 3) inhibitors, for example 8B-517955, 8B4195052, can be combined with one or more H1-receptor antagonists, 8B-216763, NN-57-05441 or NN-57-05445; RXR ligands, 25 including, but not limited to, levocetirizine, desloratadine, for example GW-0791 or AGN-194204; sodium-dependent and fexofenadine, astemizole, terfenadine, loratadine, and glucose cotransporter inhibitors, for example T-1095; glyco cetirizine. gen phosphorylase A inhibitors, for example BAY R3401; In further embodiments, the compounds disclosed herein biguanides, for example metformin; alpha-glucosidase can be combined with one or more H, K ATPase inhibitors, inhibitors, for example acarbose, GLP-1 (glucagon like pep 30 including, but not limited to, esomeprazole, lanSoprazole, tide-1), GLP-1 analogues and mimetics, for example exen omeprazole, pantoprazole, rabeprazole, and tenatoprazole. din-4: AGE breakers; and thiazolidone derivatives, for In yet further embodiments, the compounds disclosed example glitaZone, pioglitazone, rosiglitaZone or (R)-1-(4- herein can be combined with one or more alimentary motility 5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl modulators, including, but not limited to, alosetron, methoxy-benzenesulfonyl-2,3-dihydro-1H-indole-2-car 35 cilansetron, domperidone, metoclopramide, itopride, boxylic acid (compound 4 of Example 19 of WO 03/043985) cisapride, renzapride, Zacopride, octreotide, naloxone, eryth or a non-glitazone type PPAR-agonist (e.g. GI-262570). romycin, and bethanechol. Examples of hypolipidemic agents include 3-hydroxy-3- The compounds disclosed herein can also be administered methyl-glutaryl coenzyme A (HMGCoA) reductase inhibi 40 in combination with other classes of compounds, including, tors, for example lovastatin, pitavastatin, simvastatin, pravas but not limited to, norepinephrine reuptake inhibitors (NRIs) tatin, cerivastatin, mevastatin, Velostatin, fluvastatin, Such as atomoxetine; dopamine reuptake inhibitors (DARIs), dalvastatin, atorvastatin, rosuvastatin or rivastatin: squalene Such as methylphenidate; serotonin-norepinephrine reuptake synthase inhibitors: FXR (farnesoid X receptor) ligands; inhibitors (SNRIs), such as milnacipran; sedatives, such as LXR (liver X receptor) ligands; cholestyramine; fibrates: 45 diazepham; norepinephrine-dopamine reuptake inhibitor nicotinic acid; and aspirin. (NDRIs), Such as bupropion; serotonin-norepinephrine Examples of anti-obesity/appetite-regulating agents dopamine-reuptake-inhibitors (SNDRIs), such as Venlafax include phentermine, leptin, bromocriptine, dexamphet ine; monoamine oxidase inhibitors, such as selegiline; hypo amine, amphetamine, fenfluramine, dexfenfluramine, thalamic phospholipids; opioids, such as tramadol; Sibutramine, orlistat, dexfenfluramine, mazindol, phenter 50 thromboxane receptor antagonists, such as ifetroban, potas mine, phendimetrazine, diethylpropion, fluoxetine, bupro sium channel openers; thrombin inhibitors, such as hirudin; pion, topiramate, diethylpropion, benzphetamine, phenylpro hypothalamic phospholipids; growth factor inhibitors. Such panolamine or ecopipam, ephedrine, pseudoephedrine and as modulators of PDGF activity; platelet activating factor cannabinoid receptor antagonists e.g. rimonabant. (PAF) antagonists; anti-platelet agents, such as GPIIb/IIIa Examples of anti-hypertensive agents include loop diuret 55 blockers (e.g., abdximab, eptifibatide, and tirofiban), P2Y ics, for example ethacrynic acid, furosemide or torsemide; (AC) antagonists (e.g., clopidogrel, ticlopidine and CS-747), diuretics, for example thiazide derivatives, chlorithiazide, and aspirin; anticoagulants, such as warfarin; low molecular hydrochlorothiazide or amiloride; angiotensin converting weight heparins, such as enoxaparin; Factor VIIa Inhibitors enzyme (ACE) inhibitors, for example benazepril, captopril, 60 and Factor Xa Inhibitors; bile acid sequestrants. Such as ques enalapril, fosinopril, lisinopril, moexipril, perinodopril, tran; niacin; anti-atherosclerotic agents, such as ACAT inhibi quinapril, ramipril or trandolapril; Na-K-ATPase mem tors; MTP Inhibitors; calcium channel blockers, such as brane pump inhibitors, for example digoxin; neutralendopep amlodipine besylate; potassium channel activators; alpha tidase (NEP) inhibitors, for example thiorphan, terteo-thior muscarinic agents; beta-muscarinic agents, such as carvedilol phan or SQ29072: ECE inhibitors, for example SLV306; dual 65 and metoprolol; antiarrhythmic agents; thrombolytic agents, ACE/NEP inhibitors, for example omapatrilat, sampatrilator Such as tissue plasminogen activator (tPA), recombinant tRA, fasidotril; angiotensin II antagonists, for example cande streptokinase, urokinase, prourokinase, and anisoylated plas US 9,029.407 B2 17 18 minogen Streptokinase activator complex (APSAC); miner ders in a human or animal Subject in need of Such treatment alocorticoid receptor antagonists, such as Spironolactone and comprising administering to said subject an amount of a eplerenone; growth hormone secretagogues; aP2 inhibitors; compound disclosed herein effective to reduce or prevent said phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., disorder in the subject, in combination with at least one addi cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil. tional agent for the treatment of said disorder. In a related Vardenafil); protein tyrosine kinase inhibitors; antiinflamma aspect, certain embodiments provide therapeutic composi tories; antiproliferatives, such as methotrexate, FK506 (tac tions comprising at least one compound disclosed herein in rolimus, Prograf), mycophenolate mofetil: chemotherapeutic combination with one or more additional agents for the treat agents; immunosuppressants; anticancer agents and cyto ment of beta-3-adrenoreceptor-mediated disorders. toxic agents (e.g., alkylating agents, such as nitrogen mus- 10 General Synthetic Methods for Preparing Compounds tards, alkyl Sulfonates, nitrosoureas, ethylenimines, and tria- Isotopic hydrogen can be introduced into a compound as Zenes); antimetabolites, such as folate antagonists, purine disclosed herein by synthetic techniques that employ deuter analogues, and pyrridine analogues; antibiotics, such as ated reagents, whereby incorporation rates are pre-deter anthracyclines, bleomycins, mitomycin, dactinomycin, and mined; and/or by exchange techniques, wherein incorpora plicamycin; enzymes, such as L-asparaginase; farnesyl-pro- 15 tion rates are determined by equilibrium conditions, and may tein transferase inhibitors; hormonal agents, such as gluco- be highly variable depending on the reaction conditions. Syn corticoids (e.g., cortisone), estrogens/antiestrogens, andro- thetic techniques, where tritium or deuterium is directly and gens/antiandrogens, progestins, and luteinizing hormone- specifically inserted by tritiated or deuterated reagents of releasing hormone anatagonists, and octreotide acetate; known isotopic content, may yield high tritium or deuterium microtubule-disruptor agents, such as ecteinascidins; micro- 20 abundance, but can be limited by the chemistry required. tubule-stablizing agents, such as pacitaxel, docetaxel, and Exchange techniques, on the other hand, may yield lower epothilones A-F; plant-derived products, such as Vinca alka- tritium or deuterium incorporation, often with the isotope loids, epipodophyllotoxins, and taxanes; and topoisomerase being distributed over many sites on the molecule. inhibitors; prenyl-protein transferase inhibitors; and The compounds as disclosed herein can be prepared by cyclosporins; steroids, such as prednisone and dexametha- 25 methods known to one of skill in the art and routine modifi Sone; cytotoxic drugs, such as azathiprine and cyclophospha- cations thereof, and/or following procedures similar to those mide; TNF-alpha inhibitors, such as tenidap; anti-TNF anti- described herein and routine modifications thereof, and/or bodies or soluble TNF receptor, such as etanercept, procedures found in US 2009093529 and US 2008214633, rapamycin, and leflunimide; and cyclooxygenase-2 (COX-2) which are hereby incorporated in their entirety, and refer inhibitors, such as celecoxib and rofecoxib; and miscella- 30 ences cited therein and routine modifications thereof. Com neous agents such as, hydroxyurea, procarbazine, mitotane, pounds as disclosed herein can also be prepared as shown in hexamethylmelamine, gold compounds, platinum coordina- any of the following schemes and routine modifications tion complexes, such as cisplatin, satraplatin, and carbopl- thereof. atin. The following schemes can be used to practice the present Thus, in another aspect, certain embodiments provide 35 invention. Any position shown as hydrogen may optionally be methods for treating beta-3-adrenoreceptor-mediated disor- replaced with deuterium.

Scheme I

R21

R10 R. R. R 22 R10 Ro NH2 R9 2 -e- R13 R14 ON Rs ON R R7 1 3

R10 R. R. Rs. 9H R20 R10 R. R. RIs OH R20 H s H s Ro N R21 Ro N R21

e R13 R14 R16 R17 R13 R14 R16 R17 HN R8 R24 R22 ON R8 R24 R22 R7 R23 R R23 5 4 US 9,029.407 B2 19 20 -continued HN X's O S R19 le R2 OH RINN R10 R. R. s RIs () R20

Ro N R21 NN O S le R13 R14 R16 R17 N Rs R24 R22 R 3 R4 RS R R7 R23 7

Compound 1 is reacted with compound 2 in the presence of -continued an appropriate activating reagent, such as a combination of D D D hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3- HN D ethylcarbodiimide hydrochloride, in the presence of an 2O )=N O appropriate base, such as triethylamine, in an appropriate Saa Solvent. Such as dimethylformamide, to give compound 3. N D Compound 3 is reacted with an appropriate reducing agent, D D D

Such as a combination of 1,3-dimethyl-2-imidazolidinone D and borane, in an appropriate solvent, such as tetrahydrofu- 25 HN O ran, to give compound 4. Compound 4 is reacted with an )=N appropriate reducing agent, Such as a combination of hydro- Saa gen gas, in the presence of an appropriate catalyst, Such as D D palladium on carbon, in an appropriate solvent, such as 30 D R methanol, to give compound 5. Compound 5 is reacted with HN D D D H D., sOH compound 6 in the presence of an appropriate activating )=N O D N reagent, Such as 1-(3-dimethylaminopropyl)-3-ethylcarbodi- S D D imide hydrochloride, in the presence of an appropriate acid, a N D D

Such as hydrochloric acid, in an appropriate solvent, such as 35 D D H D water, to give a compound 7 of Formula I. P D D Deuterium can be incorporated to different positions syn- HN D thetically, according to the synthetic procedures as shown in )=N O Scheme I, by using appropriate deuterated intermediates. For Saa D D example, to introduce deuterium at one or more positions of 40 N D R7-Ra, compound 1 with the corresponding deuterium Sub- D D D stitutions can be used. To introduce deuterium at one or more P D D positions of Rs and Ro-Ri, compound 2 with the corre- HN D sponding deuterium Substitutions can be used. To introduce 45 )=N O deuterium at one or more positions of Re-R7, trideuterobo- Sna D D D rane can be used. To introduce deuterium at one or more NH D positions of R-Rs, compound 6 with the corresponding deu- D D D terium Substitutions can be used. HN D H gh R Deuterium can be incorporated to various positions having so " D N an exchangeable proton, Such as the amine N-Hs, the amide ) N O D D D N—H, and hydroxyl O. H. via proton-deuterium equilib- Saa N D rium exchange. For example, to introduce deuterium at D D H R-R. R. Ris, or Ro, these protons may be replaced with D D deuterium selectively or non-selectively through a proton- 55 HN D H deuterium exchange method known in the art. 2 O D N The following compounds can generally be made using the )=N scheme described above. Syss P D H 60 D D D P D D R 9DP D H DN D R s D, HN D N )=N O )=N O S D D D D S D D YxssD D D D 65 Yxs H D D D D D D D D US 9,029.407 B2 21 22 -continued -continued

US 9,029.407 B2 27 28 -continued -continued

D D US 9,029.407 B2 29 30 -continued -continued

US 9,029.407 B2 31 32 -continued -continued

D D US 9,029.407 B2 33 34 -continued -continued

g H US 9,029.407 B2 36 -continued -continued D OH HN S HN )=N O S S D D H YxD D D - OH H N 2. NO 10 XO D S H 15 H N uNO D NO OH u HN H N )=N O S D D 2 N 25 H D NO

D OH u HN S D H N 30 NO oD D OH 35 NO H N 40 NO oD D u D H S D H N

D D D D 45 NO o D D OH HN D H N )=N O 50 O S D D D D 2 N )= H D N D D D D, OH 55 H NS D NO o D D g 60 NO H N D rH 65 NO uu oD D US 9,029.407 B2 37 38 -continued -continued

H N H N O D N NO oD D oD D

N H 10 O D N NO oD D oD D D D 15 H N NO NO oD D o D D

H N 25 NO NO o D D oD D

H N H N NO 30 Jul.O oD D 35 H N H N NO JuO oD D 40

H N H N O JuNO 45 u

H N O O 50 Ju N lu

D D D H D, 55 H N O O DYYS Y Yo Y D D D N D Jul. N D

60 D D HN H N O O DY8X, a YD a Ju N 65 US 9,029.407 B2 39 40

-continued -continued US 9,029.407 B2 41 42 -continued -continued D D D D H D H H N s H N s O XD O u D D Ju D D D D D D O H H H N H N g 10 O O Ju D D Ju D

D S H 15 H H N DD H N s O O D u 2.D D g H O H H N H N O O DD 25 Ju 2.D D D H D S H H N s H N DDDD DDDD O 30 O u D D 2.D D O H 35 H H N a H N g O O Ju D 2.D D 40 D D D D S H H N D H H N s O DDDDD O u DRRR 45 Ju reD D D H O H N g H H N O Ju DD 50 uO reD D D H DRRRpRRD D D D H N S H 9 55 H N O DD O u D D D D O.D D 60 reD D D H H N g g H H N DDDDDDDD O O D D D D Ju 65 re 2.D D US 9,029.407 B2 43 44 -continued -continued D D HN 9 H N

DD D S N Ju N D D D D O H H N 10 S Ju N N 2.D D H N D S H 15 SJu D D N N H N 2.D D H S u N

D D 25 N N H 2.D D S D s H N 30 O.D D H N N 2.D D S O H 35 N loD D

H N N 2.D D 40 S D D ss H S N loD D

D H N DD 45 N 2.D D S H N i.D D 50 D H N N 2.D D S D H Ju 55 N H N

N S 2.D D 60 Ju H N H N

S 2. N 65 Ju N US 9,029.407 B2 45 46 -continued stop the reactions. Samples are centrifuged at 12,000 RPM D D OH for 10 minutes to precipitate proteins. Supernatants are trans ferred to microcentrifuge tubes and stored for LC/MS/MS analysis of the degradation half-life of the test compounds. In Vitro Metabolism. Using Human Cytochrome Paso Enzymes The cytochrome Paso enzymes are expressed from the cor responding human cDNA using abaculovirus expression sys tem (BD Biosciences, San Jose, Calif.). A 0.25 milliliter 10 reaction mixture containing 0.8 milligrams per milliliter pro tein, 1.3 millimolar NADP", 3.3 millimolar glucose-6-phos phate, 0.4 U/mL glucose-6-phosphate dehydrogenase, 3.3 millimolar magnesium chloride and 0.2 millimolar of a com pound as disclosed herein, the corresponding non-isotopi 15 cally enriched compound or standard or control in 100 milli molar potassium phosphate (pH 7.4) is incubated at 37°C. for 20 minutes. After incubation, the reaction is stopped by the addition of an appropriate solvent (e.g., acetonitrile, 20% trichloroacetic acid, 94% acetonitrile/6% glacial acetic acid, 70% perchloric acid, 94% acetonitrile/6% glacial acetic acid) and centrifuged (10,000 g) for 3 minutes. The supernatant is analyzed by HPLC/MS/MS.

25 Cytochrome P4so Standard CYP1A2 Phenacetin CYP2A6 Coumarin CYP2B6 'C-(S)-mephenytoin CYP2C8 Paclitaxel 30 CYP2C9 Diclofenac CYP2C19 'C-(S)-mephenytoin CYP2D6 (+/-)-Bufuralol CYP2E1 ChlorZoxazone CYP3A4 Testosterone CYP4A 'C-Lauric acid 35 Monoamine Oxidase A Inhibition and Oxidative Turnover The procedure is carried out using the methods described by Weyler et al., Journal of Biological Chemistry 1985, 260, 40 13199-13207, which is hereby incorporated by reference in its entirety. Monoamine oxidase A activity is measured spec trophotometrically by monitoring the increase in absorbance at 314 nm on oxidation of kynuramine with formation of 4-hydroxyquinoline. The measurements are carried out, at 45 30°C., in 50 mM sodium phosphate buffer, pH 7.2, contain ing 0.2% Triton X-100 (monoamine oxidase assay buffer), Changes in the metabolic properties of the compounds plus 1 mM kynuramine, and the desired amount of enzyme in disclosed herein as compared to their non-isotopically 1 mL total volume. enriched analogs can be shown using the following assays. Monooamine Oxidase B Inhibition and Oxidative Turnover Compounds listed above which have not yet been made and/ 50 or tested are predicted to have changed metabolic properties The procedure is carried out as described in Uebelhacket al., Pharmacopsychiatry 1998, 31(5), 187-192, which is as shown by one or more of these assays as well. hereby incorporated by reference in its entirety. Biological Activity Assays Isolated Rat Bladder Smooth Muscle Relaxation Test 55 The procedure is carried out as described in US In Vitro Liver Microsomal Stability Assay 2009093529, which is hereby incorporated by reference in its Liver microsomal stability assays are conducted at 1 mg entirety. per mL liver microsome protein with an NADPH-generating Rat Rythmic Bladder Contraction Measurement Test system in 2% sodium bicarbonate (2.2 mM NADPH, 25.6 The procedure is carried out as described in US mM glucose 6-phosphate, 6 units per mL glucose 6-phos 60 2009093529, which is hereby incorporated by reference in its phate dehydrogenase and 3.3 mM magnesium chloride). Test entirety. compounds are prepared as solutions in 20% acetonitrile water and added to the assay mixture (final assay concentra Measurement of Urination Function of Model Rats Suffering tion 5 microgram per mL) and incubated at 37° C. Final from Overactive Bladder Induced by Cyclophosphamide concentration of acetonitrile in the assay should be <1%. 65 The procedure is carried out as described in US Aliquots (50 uL) are taken out at times 0, 15, 30, 45, and 60 2009093529, which is hereby incorporated by reference in its minutes, and diluted with ice cold acetonitrile (200 uL) to entirety. US 9,029.407 B2 47 48 Hypoglycemic Test in kk Mice The procedure is carried out as described in US (I)

2008214633, which is hereby incorporated by reference in its entirety. Relaxant Activity in Isolated Human Bladder Smooth Muscle The procedure is carried out as described in Takasu et al., J. Pharmacol. Exp. Ther: 2007, 321(2), 642-647, which is hereby incorporated by reference in its entirety. Rythmic Isovolumetric Reflex Bladder Contraction The procedure is carried out as described in Takasu et al., J. 10 Pharmacol. Exp. Ther: 2007, 321(2), 642-647, which is hereby incorporated by reference in its entirety. or a pharmaceutically acceptable salt thereof, wherein: cAMP Accumulation Assay R-R are independently selected from the group consist The procedure is carried out as described in Takasu et al., J. ing of hydrogen and deuterium; and Pharmacol. Exp. Ther: 2007, 321(2), 642-647, which is 15 at least one of R-R is deuterium. hereby incorporated by reference in its entirety. 2. The method as recited in claim 1 wherein said disorder is Chinese Hampster Ovary Cell Adrenoreceptor Transfection selected from the group consisting of overactive bladder, Assay irritable bowel syndrome, type 2 diabetes, and obesity. The procedure is carried out as described in U.S. Pat. No. 6.251.925, which is hereby incorporated by reference in its 3. The method as recited in claim 1 wherein said compound entirety. has a structural formula selected from the group consisting of Radioligand Binding Assay The procedure is carried out as described in Hicks et al., J. D D D D OD P Pharm. Exp. Therapeutics 2007, 323(1), 202-209, which is D hereby incorporated by reference in its entirety. 25 O Cyclic AMP Assay D The procedure is carried out as described in Hicks et al., J. D D-X DR Pharm. Exp. Therapeutics 2007, 323(1), 202-209, which is SD D hereby incorporated by reference in its entirety. D D D In Vitro Urinary Bladder Tissue Assay 30 HN The procedure is carried out as described in Hicks et al., J. Pharm. Exp. Therapeutics 2007, 323(1), 202-209, which is hereby incorporated by reference in its entirety. NOD In Vivo Acetic Acid-Evoked Bladder Irritation in Dog D -D D The procedure is carried out as described in Hicks et al., J. 35 Pharm. Exp. Therapeutics 2007, 323(1), 202-209, which is D D D hereby incorporated by reference in its entirety. H Antidiabetic Efficacy Studies O The procedure is carried out as described in Uehiling et al., )-D D1X D D J. Med. Chem. 2006, 49, 2758-2771, which is hereby incor 40 D D ND porated by reference in its entirety. D D

Rodent Infrared Thermography Studies D D D The procedure is carried out as described in Uehiling et al., H J. Med. Chem. 2006, 49, 2758-2771, which is hereby incor O porated by reference in its entirety. 45 )- D1X D D In Vitro Functional Assay D D D ND The procedure is carried out as described in Uehiling et al., D D J. Med. Chem. 2006, 49, 2758-2771, which is hereby incor D D D porated by reference in its entirety. H From the foregoing description, one skilled in the art can 50 O ascertain the essential characteristics of this invention, and )- D D without departing from the spirit and scope thereof, can make D D various changes and modifications of the invention to adapt it D D ND to various usages and conditions. D 55 H N Drox What is claimed is: O 1. A method of treatment of a disorder selected from the group consisting of overactive bladder, irritable bowel syn -D D drome, type 2 diabetes, obesity, hyperglycemia, hyper D D ND lipemia, motility dysfunction, excessive gastrointestinal 60 D secretion, nonspecific diarrhea, triglyceridemia, retinopathy, nephropathy, neuropathy, cataracts, coronary heart diseases, H N arteriosclerosis, osteoporosis, atherosclerosis, hyperinsuline O mia, depression, muscle wasting, urinary incontinence, and - D wound-healing, comprising the administration, to a patient in 65 D D ND need thereof, of a therapeutically effective amount of a com D pound of structural Formula I US 9,029.407 B2 49 50 -continued -continued

US 9,029.407 B2 55 56 -continued -continued

H N HN O uNO D S SY D D HN H 10 O N O DYYX Y. Yi Y )- D D D S D N D D D D D 15 H N NO D - H N NO 25 D -

H N 30

D 35 H N

D D D 40

2-- D D H N

NO 45 N D -

H N NO 50 D -

H N 55

NO N D - 60 H N

NO 65 N D - - US 9,029.407 B2 57 58 -continued -continued

HN

N

O N - N 15

O N

O D D D N N D D D

D D D 35 D D

OO D N oD D ND 40 D D D

N D D

5 O N )- C.OD D ND 55 HN O N D D 60 DDD DDD p DDD

O D N D D ND D

US 9,029.407 B2 61 62 -continued -continued

US 9,029.407 B2 63 64 -continued -continued

D D OH US 9,029.407 B2 65 66 -continued -continued

D D H N H O 5 D D D NO N oD D

H N 10 H O - Da-- a - Da NO N o D D 15 D D H N H N JuNO D D H N 2.- H N 25 NO D D o D D

H H N )- O 30 D N D D NO i.D D

D D 35 H N H N NO D D NO o oD D 40

H N H N

NO 45 oD D 2-,D D

H N 50 Ju 2.,D D NO

H N 55 H N NO JuNO oD D 60 H N H N

D D JuNO 65 JuNO

US 9,029.407 B2 69 70 -continued -continued D D D OH P D D H N HN O Sks N

H N O

Susu, N H

HN D )=N O S-sus2 N H

H N Susu,O

H N O Sea D D

HN )-oD O orcDD D D NN H N

S

D ND

H N O Q-Sks N D D OH HN D NH )=N YYOO YaYYYYX Y-S Y Sna N H D D 60 P D D D. OH HN D NH s )=N O DDDDD D D s Mus D 65

US 9,029.407 B2 73 74 -continued 5. The method as recited in claim 3 wherein each position D D R SH represented as D has deuterium enrichment of no less than HN about 50%. )=N O 5 6. The method as recited in claim 3 wherein each position * ---- D D represented as D has deuterium enrichment of no less than H about 90%. HN D D H gH 7. The method as recited in claim 3 wherein each position 2 N represented as D has deuterium enrichment of no less than

)=N O DXo D 10 about 98%. 8. The method as recited in claim3 wherein said compound * ---- H has a structural formula selected from the group consisting of D D H S. HN N D D D, OH H s S)=N Sun-2 N so H N N H )=N O s D D OH S D D D D HN 2O 2 N

S-sus)=N O ro D D D D gH

HN NH s 25 Sna D D D D )=N O N Susu, D D D D D D N D D D, OH H HN s gH 30 N O HN o s

S-N-1s)=N O OrixD D DXo D S^k.D D H D D H HN

D OH and 55 HN s

H D OH S)=N OrixD D s HN s S^

S)=N O Or 60 D D OH H SS- HN N H )=N O S 2 D D 4. The method as recited in claim 3 wherein each position 65 N represented as D has deuterium enrichment of no less than about 10%.

US 9,029.407 B2 77 78 -continued 16. The method as recited in claim 14 wherein said anti D OH obesity or appetite-regulating agent is selected from the HN S group consisting of phentermine, leptin, bromocriptine, dex amphetamine, amphetamine, fenfluramine, dexfenfluramine, )– N O Or Sibutramine, orlistat, dexfenfluramine, mazindol, phenter S Q--- N mine, phendimetrazine, diethylpropion, fluoxetine, bupro pion, topiramate, diethylpropion, benzphetamine, phenylpro panolamine, ecopipam, ephedrine, and pseudoephedrine. 9. The method as recited in claim 8 wherein said compound has the structural formula: 17. The method as recited in claim 14 wherein said anti 10 hypertensive agent is selected from the group consisting of ethacrynic acid, furosemide, torsemide, chlorithiazide, HN D D D. OH hydrochlorothiazide, amiloride, benazepril, captopril, enala H 8 pril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, X's O N - ramipril, trandolapril, digoxin, thiorphan, terteo-thiorphan, S 15 e D D D D SQ29072, SLV306, omapatrilat, sampatrilat, fasidotril, can N H desartan, eprosartan, irbesartan, losartan, telmisartan, Valsar D D tan, alliskiren, terlakiren, ditekiren, RO-66-1132, RO-66 1168, acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, 10. The method as recited in claim 8 wherein said com nadolol, propranolol, Sotalol, timolol, digoxin, dobutamine, pound has the structural formula: milrinone, amlodipine, bepridil, diltiazem, felodipine, nicar dipine, nimodipine, nifedipine, nisoldipine, and Verapamil. 18. The method as recited in claim 14 wherein said uro HN g H logical is selected from the group consisting of acetohydrox 25 amic acid, collagen, dimethyl Sulfoxide, magnesium hydrox Xy o ide, pentosan polysulfate, phenazopyridine, phenyl salicylate, succinimide, and botulinum toxin A. 19. The method as recited in claim 14 wherein said urinary antispasmodic is selected from the group consisting of 30 tolterodine, darifenacin, emepronium, flavoxate, fesoterod ine, meladrazine, oxybutynin, propiverine, Solifenacin, 11. The method as recited in claim 8 wherein said com terodiline, and trospium. pound has the structural formula: 20. The method as recited in claim 14 wherein said H1-re ceptor antagonist is selected from the group consisting of 35 levocetirizine, desloratadine, and feXofenadine, astemizole, HN D D H g H N terfenadine, loratadine, and cetirizine. NN O 21. The method as recited in claim 14 wherein said H+, S e D D K+-ATPase inhibitor is selected from the group consisting of N esomeprazole, lanSoprazole, omeprazole, pantoprazole, H 40 rabeprazole, and tenatoprazole. 22. The method as recited in claim 14 wherein said alimen 12. The method as recited in claim 8 wherein said com tary motility modulator is selected from the group consisting pound has the structural formula: oftegaserod, alosetron, cilansetron, domperidone, metoclo pramide, itopride, cisapride, renZapride, Zacopride, oct 45 reotide, naloxone, erythromycin, and bethanechol. HN D D H R 9 23. The method as recited in claim 1, further resulting in at N least one effect selected from the group consisting of NN O a. decreased inter-individual variation in plasma levels of S said compound or a metabolite thereofas compared to \llul N D D D D 50 the non-isotopically enriched compound; H b. increased average plasma levels of said compound per dosage unit thereofas compared to the non-isotopically 13. The method as recited in claim 1 further comprising the enriched compound; administration of an additional therapeutic agent. c. decreased average plasma levels of at least one metabo 14. The method as recited in claim 13 wherein said addi 55 lite of said compound per dosage unit thereofas com tional therapeutic agent is selected from the group consisting pared to the non-isotopically enriched compound; of dipeptidyl peptidase IV inhibitors, anti-diabetic agents, d. increased average plasma levels of at least one metabo hypolipidemic agents, anti-obesity or appetite regulating lite of said compound per dosage unit thereofas com agents, anti-hypertensive agents, urologicals, urinary antis pared to the non-isotopically enriched compound; and pasmodics, H1 receptor antagonists, H, K ATPase inhibi 60 e. an improved clinical effect during the treatment in said tors, and alimentary motility modulators. Subject per dosage unit thereofas compared to the non 15. The method as recited in claim 14 wherein said hypo isotopically enriched compound. lipidemic agent is selected from the group consisting of lov 24. The method as recited in claim 1, further resulting in at astatin, pitavastatin, simvastatin, pravastatin, cerivastatin, least two effects selected from the group consisting of mevastatin, Velostatin, fluvastatin, dalvastatin, atorvastatin, 65 a. decreased inter-individual variation in plasma levels of rosuvastatin, rivastatin, cholestyramine, fibrates, nicotinic said compound or a metabolite thereofas compared to acid, and aspirin. the non-isotopically enriched compound; US 9,029.407 B2 79 80 b. increased average plasma levels of said compound per the group consisting of CYP1A1, CYP1A2, CYP1B1, dosage unit thereofas compared to the non-isotopically CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, enriched compound; CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1. c. decreased average plasma levels of at least one metabo CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, lite of said compound per dosage unit thereofas com CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, pared to the non-isotopically enriched compound; CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, d. increased average plasma levels of at least one metabo CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, lite of said compound per dosage unit thereofas com CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, pared to the non-isotopically enriched compound; and CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, e. an improved clinical effect during the treatment in said 10 Subject per dosage unit thereofas compared to the non CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO, and isotopically enriched compound. MAO. 29. The method as recited in claim 1, wherein the method 25. The method as recited in claim 1, wherein the method reduces a deleterious change in a diagnostic hepatobiliary effects a decreased metabolism of the compound per dosage function endpoint, as compared to the corresponding non unit thereof by at least one polymorphically-expressed cyto 15 chrome Paso isoform in the subject, as compared to the cor isotopically enriched compound. responding non-isotopically enriched compound. 30. The method as recited in claim 29, wherein the diag 26. The method as recited in claim 25, wherein the cyto nostic hepatobiliary function endpoint is selected from the chrome Paso isoform is selected from the group consisting of group consisting of alanine aminotransferase (ALT), serum CYP2C8, CYP2C9, CYP2C19, and CYP2D6. glutamic-pyruvic transaminase (“SGPT), aspartate ami 27. The method as recited claim 1, wherein said compound notransferase (AST,” “SGOT), ALT/AST ratios, serum is characterized by decreased inhibition of at least one cyto aldolase, alkaline phosphatase (ALP), ammonia levels, chrome Paso or monoamine oxidase isoform in said subject bilirubin, gamma-glutamyl transpeptidase (“GGTP per dosage unit thereofas compared to the non-isotopically “Y-GTP “GGT), leucine aminopeptidase (“LAP), liver enriched compound. 25 biopsy, liver ultrasonography, liver nuclear Scan, 5'-nucleoti 28. The method as recited in claim 27, wherein said cyto dase, and blood protein. chrome Paso or monoamine oxidase isoform is selected from k k k k k