USOO7776886B2

(12) United States Patent (10) Patent No.: US 7,776,886 B2 Lindsley et al. (45) Date of Patent: Aug. 17, 2010

(54) CYCLOPROPYL PIPERIDINE GLYCINE WO WOOO/25786 * 5/2OOO TRANSPORTER INHIBITORS WO WO O2/O62750 8, 2002 WO WO 03/042174 * 5/2003 WO O3,055478 T 2003 (75) Inventors: Craig W. Lindsley, Schwenksville, PA WO WOO3,088908 10, 2003 (US); David D. Wisnoski, Quakertown, WO WO 2005/0466O1 5, 2005 PA (US); Scott E. Wolkenberg, WO WO 2005/094514 10/2005 Jenkintown, PA (US) WO WO 2005,107469 11, 2005 WO WO 2005/110983 11, 2005 (73) Assignee: Merck Sharp & Dohme Corp., WO WO 2006/067529 6, 2006 Rahway, NJ (US) WO WO 2007/041025 4/2007 WO WO 2007/053400 5/2007 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 256 days. Rogers et al (Brain Res, 493:41-50, 1989).* Brinker (Advances in Carbene Chemistry, vol. 3, 2001, pp. 20-21).* (21) Appl. No.: 11/664,190 Zhao et al (Bioorg Med Chem Lett 16:5968-5972, 2006).* Lindsley et al (Chem Med Chem 1:807-811, 2006).* (22) PCT Filed: Sep. 26, 2005 Zhao et al (Bioorg Med Chem Lett 19:1488-1491, 2009).* Thomson et al (Bioorg Med Chem Lett 19:2235-2239, 2009).* (86). PCT No.: Hovgaard etal (Pharm Res 12:387-392, 1995).* Ulbrich et al (J Med Chem37:953-959, 2002).* S371 (c)(1), Williams etal (Foye's Principles of Medicinal Chemistry, pp. 59-61. (2), (4) Date: Mar. 28, 2007 2001).* Patani etal (Chem Rev 96:3147-3176, 1996).* Cockerham et al (Basic Environmental Toxicology, pp. 201-204. (87) PCT Pub. No.: WO2006/039221 1994).* Wolkenberg, S.E., et. al., Discovery of GlyT1 Inhibitors with PCT Pub. Date: Apr. 13, 2006 Improved Pharmacokinetic Properties, Bioorganic & Medicinal Chemistry Letters (2009), doi:10.1016/j.bmcl. 2009.01.015. (65) Prior Publication Data Copending U.S. Appl. No. 1 1/991,727, filed Sep. 25, 2006, U.S. US 2008/O108663 A1 May 8, 2008 National Stage Entry of PCT/GB06/036989, published as WO 2007/ 041025. Copending U.S. Appl. No. 12/084,027, filed Oct. 27, 2006, U.S. Related U.S. Application Data National Stage Entry of PCT/GB06/041699, published as WO 2007/ (60) Provisional application No. 60/614.942, filed on Sep. O53400. 30, 2004. Copending U.S. Appl. No. 12/085.340, filed Nov. 23, 2006, U.S. National Stage Entry of PCT/GB06/050411, published as WO 2007/ 060484. (51) Int. Cl. Copending U.S. Appl. No. 11/922,074, filed Jun. 13, 2006, U.S. A6 IK 3/445 (2006.01) National Stage Entry of PCT/GB06/002156, published as WO 2006/ CO7D 2II/96 (2006.01) 134341. (52) U.S. Cl...... 514/331; 514/233; 546/184 Supplementary Partial European Search Report for EP Application (58) Field of Classification Search ...... None No. 0580 1197. See application file for complete search history. * cited by examiner (56) References Cited Primary Examiner Brandon J Fetterolf U.S. PATENT DOCUMENTS Assistant Examiner—Craig Ricci (74) Attorney, Agent, or Firm Gerard Devlin; Raynard Yuro 6,303,637 B1 10, 2001 Bao et al. 6,458,790 B2 10, 2002 Palucki 7,071,213 B2 7/2006 Friary (57) ABSTRACT 2006/0276655 A1 12/2006 Blackaby et al. 2007/0105902 A1* 5/2007 Lindsley et al...... 514,317 The present invention is directed to cyclopropyl piperidine 2007/02496.06 A1 10/2007 Lindsley et al. compounds that inhibit the glycine transporter GlyT1 and 2007,0254880 A1 1 1/2007 Blackaby et al. which are useful in the treatment of neurological and psychi 2008, 002101.0 A1 1/2008 Lindsley et al. atric disorders associated with or 2008/0090796 A1 4/2008 Blackaby et al. neuro-transmission dysfunction and diseases in which the FOREIGN PATENT DOCUMENTS glycine transporter GlyT1 is involved. WO WO 96.25397 8, 1996 13 Claims, No Drawings US 7,776,886 B2 1. 2 CYCLOPROPYL PIPERDINE GLYCINE Kuhse J, 1994, Neuron 12:1291). Depending on the actual TRANSPORTER INHIBITORS Subunit composition, glutamate and glycine activate the NMDA with EC50 values in the high nanomolar to CROSS REFERENCE TO RELATED low micromolar range. In addition, the pore of the NMDA APPLICATIONS receptor is impermeable to magnesium. Under normal resting conditions, extracellular magnesium can bind to a site within This application is a U.S. National Phase application under the pore and produce a magnesium block of the channel. This 35 U.S.C. 371 of PCT Application No. PCT/US2005/034301, magnesium block imparts a strong Voltage dependence to the filed Sep. 26, 2005, which claims priority under 35 U.S.C. channel which allows the NMDA receptor to act as a coinci 119 from U.S. Application No. 60/614,942, filed Sep. 30, 10 dence detector requiring the binding of glutamate, glycine, 2004. and the occurrence of postsynaptic depolarization before con ducting current. Of particular interest is the finding that the BACKGROUND OF THE INVENTION psychotomimetic drugs MK-801, PCP, and ketamine all act as open channel blockers of the NMDA receptor-channel by Schizophrenia is a debilitating psychiatric disorder char 15 binding to a site that overlaps with the magnesium binding acterized by a combination of negative (blunted affect, with site. It is apparent that the rich diversity of NMDA receptor drawal, anhedonia) and positive (paranoia, hallucinations, Subunits and regulatory sites provides for a complex assort delusions) symptoms as well as marked cognitive deficits. ment of physiologically and pharmacologically distinct het While the etiology of schizophrenia is currently unknown, the eromeric receptors making the NMDA receptor an ideal tar disease appears to be produced by a complex interaction of get for the design of novel therapeutic compounds. biological, environmental, and genetic factors. Over 40 years The NMDA receptor plays a critical role in a variety of ago it was found that phencyclidine (PCP) induces a psy neurophysiological phenomena, including but not limited to chotic state in humans that is very similar to that observed in synaptic plasticity, cognition, attention and memory (Bliss T Schizophrenic patients. The finding that the main mode of and Collingridge W. 1993, Nature 361:31: Morris RG Met action of PCP is that of a non-competitive antagonist of the 25 al., 1986, Nature 319:774). Psychotomimetic drugs consti N-methyl-D-aspartate (NMDA) subtype of ionotropic tute a wide class of drugs including psychomotor stimulants glutamate receptor stimulated a series of studies that have led (cocaine, amphetamine), hallucinogens (LSD), and NMDA to the development of the NMDA receptor hypofunction receptor antagonists (PCP, ketamine). Of these, only the model of schizophrenia (Jentsch J D and Roth R. H., 1999 NMDA receptor antagonists appear to elicit a robust induc Neuropsychopharmacology, 20:201). 30 tion of the positive, negative, and cognitive symptoms of Fast glutamatergic transmission in the mammalian central Schizophrenia. Controlled studies of ketamine-induced psy nervous system is primarily mediated by the excitatory amino chosis in human subjects, as well as observations of symp acid glutamate acting on ionotropic glutamate receptors (iG toms from patients abusing PCP as a recreational drug, have luRs). The iGluRs are comprised of three major subclasses, produced a convincing list of similarities between NMDA including the C-amino-3-hydroxy-5-methyl-4-isoxazolepro 35 -induced psychosis and Schizophrenia pionic acid (AMPA), kainate, and NMDA receptor subtypes (Jentsch JD and Roth RH, 1999 Neuropsychopharmacology, (Hollmann M and Heinemann S, 1994, Annu. Rev. Neurosci. 20:201). NMDA-receptor antagonists faithfully mimic the 17:31). These three subclasses are multimeric ligand-gated symptoms of schizophrenia to the extent that it is difficult to cation channels which open in response to glutamate binding differentiate the two in the clinic. In addition, NMDA recep to induce a depolarizing excitatory post synaptic current. 40 tor antagonists can exacerbate the symptoms in Schizophren Molecular cloning has revealed that the NMDA receptor fam ics, and can trigger the re-emergence of symptoms in stable ily is composed of two primary subunits, NR1 and NR2. In patients. Finally, the finding that NMDA receptor co- addition a novel inhibitory subunit which is developmentally Such as glycine, D-cycloserine, and D-serine produce benefits regulated termed NR3 has been recently described. A high in schizophrenic patients implicates NMDA receptor hypo degree of molecular diversity exists within each set of sub 45 function in this disorder, and indicate that increasing NMDA units. To date, only one NR1 subunit gene has been cloned; receptor activation may provide atherapeutic benefit (Leider however, alternative splicing of the NR1 gene can produce man E et al., 1996, Biol. Psychiatry 39:213, Javitt D C et al., eight different subunits. In contrast, 4 genes have been cloned 1994, Am. J. Psychiatry 151:1234, Heresco-Levy U, 2000, for the NR2 subunit (NR2A, NR2B, NR2C, and NR2D), Int. J. Neuropsychopharmacol. 3:243, Tsai G. et al., 1998, some of which exhibit alternative splicing (Hollmann Mand 50 Biol. Psychiatry 44:1081). A large number of studies in ani Heinemann S, 1994, Annu. Rev. Neurosci. 17:31). These mal models lend support to the NMDA hypofunction hypoth multiple subunits form heteromeric glutamate-gated ion esis of Schizophrenia. Recent generation of a mutant mouse channels. While the precise subunit stoichiometry of the natu expressing only 5% of normal levels of the NMDA NR1 rally occurring receptor remains unknown, both the NR1 and subunit have shown that this decrease in functional NMDA NR2 subunits are required for the expression of functionally 55 receptors induces a state very similar to that observed in other active receptor-channel complexes in mammalian expression animal models of schizophrenia (Mohn A Ret al., 1999, Cell systems. Activation of the NMDA receptor requires the bind 98:427). Besides schizophrenia, dysfunction of glutamater ing of both glutamate and glycine (Johnson JW and Ascher P. gic pathways has been implicated in a number of disease 1987, Nature 325:529). Interestingly, the binding sites for states in the human central nervous system (CNS) including these two co-agonists exist on separate Subunits as deter 60 but not limited to cognitive deficits, dementia, Parkinson mined by site-directed mutagenesis studies (Laube B, Hirai disease, Alzheimer disease and bipolar disorder. H. Sturgess M, Betz Hand Kuhse J, 1997, Neuron 18:493). NMDA receptor function can be modulated by altering the On the NR2A and NR2B subunits, a binding pocket for availability of the co- glycine. This approach has the glutamate is formed by interactions between the N-terminus critical advantage of maintaining activity-dependent activa of the receptor and the extracellular loops. Analogous experi 65 tion of the NMDA receptor because an increase in the synap ments have placed the glycine binding site in a homologous tic concentration of glycine will not produce an activation of region of the NR1 subunit (Kuryatov A. Laube B. Betz Hand NMDA receptors in the absence of glutamate. Since synaptic US 7,776,886 B2 3 4 glutamate levels are tightly maintained by high affinity trans ated with glutamatergic neurotransmission dysfunction and port mechanisms, an increased activation of the glycine site diseases in which the glycine transporter GlyT1 is involved. will only enhance the NMDA component of activated syn apses. Clinical trials in which high doses of glycine were DETAILED DESCRIPTION OF THE INVENTION administered orally as an add-on to standard neuroleptic therapy showed an improvement of the symptoms of schizo The present invention is directed to compounds of the phrenia patients (Javitt et al. Int. J. Neuropsychopharmacol. formula I: (2001) 4: 385-391). One way to increase synaptic glycine levels without administering exogenous glycine is to inhibit its removal from the synapse. Evidence that this approach 10 would be useful in treating schizophrenia comes from a double-blind placebo controlled study in which sarcosine was administered to patients suffering from Schizophrenia, but who were poorly responsive to antipsychotic drugs. A ben 15 eficial effect was observed on positive, negative and cognitive symptoms, indicating that inhibition of glycine re-uptake is a reasonable approach to the treatment of Schizophrenia. Two specific glycine transporters, GlyT1 and GlyT2 have been identified and shown to belong to the Na/Cl dependent family of neurotransmitter transporters which includes tau rine, Y-amino-butyric acid (GABA), proline, monoamines wherein: and orphan transporters (Smith K E et al., 1992, Neuron R is selected from the group consisting of: 8:927; Borowsky Bet al., 1993, Neuron 10:851; Liu Q Ret (1) phenyl, which is substituted with R", Rand R*, al., 1993, J. Biol. Chem. 268:22802; Kim K M et al., 1994, 25 (2) heterocycle, which is substituted with R", RandR, Mol. Pharmacol. 45:608; Morrow JA et al., 1998, FEBS Lett. (3) Cisalkyl, which is unsubstituted or substituted with 439:334; Nelson N, 1998, J. Neurochem. 71:1785). GlyT1 1-6 halogen, hydroxy, NR'R'', phenyl or heterocycle, and GlyT2 have been isolated from different species and where the phenyl or heterocycle is substituted with R', R shown to have only 50% identity at the amino acid level. They and R, also have a different pattern of expression in mammalian 30 (4) Cecycloalkyl, which is unsubstituted or substituted central nervous system with GlyT2 being expressed in spinal with 1-6 halogen, hydroxy or NR'R'', cord, brainstem and cerebellum and GlyT1 present in these wherein R'' and R'' are independently selected from: regions as well as forebrain areas such as cortex, hippocam (a) hydrogen, pus, septum and thalamus (Smith K E et al., 1992, Neuron 35 (b) - Calkyl, which is unsubstituted or substituted with 8:927; Borowsky Bet al., 1993, Neuron 10:851; Liu Q Ret hydroxy, 1-6 fluoro or - NR'R'', where R'' and R' al., 1993, J. Biol. Chem. 268:22802). At the cellular level, are independently selected from hydrogen and GlyT2 has been reported to be expressed by glycinergic nerve —Calkyl, endings in rat spinal cord whereas GlyT1 appears to be pref (c) —C-cycloalkyl, which is unsubstituted or substituted erentially expressed by glial cells (Zafra F et al., 1995, J. 40 with hydroxy, 1-6 fluoro or - NR'R'', Neurosci. 15:3952). These expression studies have led to the (d) benzyl, conclusion that GlyT2 is predominantly responsible for gly (e) phenyl, and cine uptake at glycinergic synapses whereas GlyT1 is (5)—Calkyl-(C-cycloalkyl), which is unsubstituted or involved in monitoring glycine concentration in the vicinity substituted with 1-6 halogen, hydroxy or NR'R'': of NMDA receptor expressing synapses. Recent functional 45 R", Rand Rare independently selected from the group studies in rat have shown that blockade of GlyT1 with the consisting of: potent inhibitor (N-3-(4-fluorophenyl)-3-(4-phenylphe (1) hydrogen, noxy)propyl)sarcosine (NFPS) potentiates NMDA receptor (2) halogen, activity and NMDA receptor-dependent long-term potentia (3) —Calkyl, which is unsubstituted or substituted with: tion in rat (Bergeron R et al., 1998, PNAS USA 95:15730; 50 (a) 1-6 halogen, Kinney Get al., 2003, J. Neurosci. 23:7586). Furthermore, (b) phenyl, NFPS has been reported to enhance pre-pulse inhibition in (c) C3-cycloalkyl, or mice, a measure of sensory gating that is known to be defi (d) NRIORI s cient in schizophrenia patients (Kinney G. et al., 2003, J. 55 (4) —O—Calkyl, which is unsubstituted or substituted Neurosci. 23:7586). These physiological effects of GlyT1 in with 1-6 halogen, forebrain regions together with clinical reports showing the (5) hydroxy, beneficial effects of GlyT1 inhibitor sarcosine in improving (6) —SCF, symptoms in schizophrenia patients (Tsai and Coyle WO99/ (7) SCHF, 52519) indicate that selective GlyT1 uptake inhibitors repre (8)—SCH, sent a new class of antipsychotic drugs. 60 (9) COR, wherein R is independently selected from: SUMMARY OF THE INVENTION (a) hydrogen, (b) - Calkyl, which is unsubstituted or substituted with The present invention is directed to compounds that inhibit 65 1-6 fluoro, the glycine transporter GlyT1 and which are useful in the (c) benzyl, and treatment of neurological and psychiatric disorders associ (d) phenyl, US 7,776,886 B2 6 (10) - CN, An embodiment of the present invention includes com (11) -SOR, pounds wherein R is Calkyl and R is hydrogen or (12) - SO, NR'R'', C1-alkyl. (13) NR'R'', Within this embodiment, the present invention includes (14) CONR'R'', and compounds wherein R is C-alkyl in the (S) configuration (15) - NO; and R is hydrogen. Also within this embodiment, the present invention R is Coalkyl or C-cycloalkyl, which are independently includes compounds wherein R is methyl and R is hydro unsubstituted or substituted with 1-6 halogen, hydroxyl, gen. -NR'R'', or heterocycle, which is substituted with R', 10 Also within this embodiment, the present invention R2 and R2; includes compounds wherein R is methyl and R is methyl. Rand Rare independently selected from the group consist Also within this embodiment, the present invention ing of includes compounds wherein Rishydrogen and R is hydro (1) hydrogen, and gen. (2) Calkyl, which is unsubstituted or substituted with 15 An embodiment of the present invention includes com halogen or hydroxyl, or R and R taken together form a pounds wherein m is Zero. C-cycloalkyl ring: Within this embodiment, the present invention includes compounds of the formula Ic: A is selected from the group consisting of (1) —O—, and (2) NR' : Ic m is zero or one, whereby when m is zero R is attached R R5 l directly to the carbonyl: N R2 H and pharmaceutically acceptable salts thereof and individual 25 enantiomers and diastereomers thereof. An embodiment of the present invention includes com pounds of the formula Ia: o==o 30 R3 Ia

R2 wherein R. R. Rand Rare defined herein; s 35 or a pharmaceutically acceptable salt thereof oran individual enantiomer or diastereomer thereof. Further within this embodiment, the present invention includes compounds wherein R is selected from the group consisting of: o==o 40 (1) phenyl, which is substituted with R", Rand R*, R3 (2) furanyl, which is substituted with R", Rand R, (3) Cisalkyl, which is unsubstituted or substituted with 1-6 halogen, phenyl or NR'R'', where the phenyl is sub wherein R. R. A. and mare defined herein; stituted with R, R and R*, or a pharmaceutically acceptable salt thereof oran individual 45 (4) Cecycloalkyl, which is unsubstituted or substituted enantiomer or diastereomer thereof. with 1-6 halogen, hydroxy or NR'R'', and An embodiment of the present invention includes com R", R” and R are independently selected from the group pounds of the formula Ib: consisting of: (1) hydrogen, 50 (2) halogen, Ib (3) —Calkyl, R O (4) —)—Calkyl, R2 (5)—CF, s 55 (6) - OCF, (7). OCHF, (8)—SCF, (9)-SCHF, and (10) - NH. o==o 60 Also further within this embodiment, the present invention R3 includes compounds wherein R is phenylorfuranyland R*, R” and R are independently selected from the group con sisting of: wherein R is Calkyl, and R. R. A. and m are defined (1) hydrogen, herein; 65 (2) halogen, or a pharmaceutically acceptable salt thereof oran individual (3) —Calkyl, enantiomer or diastereomer thereof. US 7,776,886 B2 7 8 (5) —CF,

(6) - OCF, Id (7) OCHF R R5 O (8)—SCF, 5 R2a (9)-SCHF, and H 1N14--R2b (10) -NH. 2é Also further within this embodiment, the present invention N R2c includes compounds wherein R is phenyl and R. R. and 10 R* are independently selected from the group consisting of: O O (1) hydrogen, (2) fluoro, (3) chloro, 15 wherein R. R. R. R. Rand Rare defined herein; (4) bromo, and pharmaceutically acceptable salts thereof and individual (5) –OCH, enantiomers and diastereomers thereof. Within this embodiment, the present invention includes (6)—CF, compounds of the formula Id' (7) -NH. 2O Also further within this embodiment, the present invention is directed to compounds wherein R is phenyl and R', R’ O Id and Rare independently selected from the group consisting R2a of: 25 S4 (1) hydrogen, N -R (2) fluoro, 2éR2c (3) chloro, and N (4) bromo. 30 O O Also further within this embodiment, the present invention is directed to compounds wherein R is phenyl and R', R’ and Rare independently selected from the group consisting of: 35 wherein R. R. R. and Rare defined herein; (1) hydrogen, and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. (2) fluoro, and Also within this embodiment, the present invention (3) chloro. includes compounds of the formula Id": Also further within this embodiment, the present invention 40 is directed to compounds wherein R is phenyl and R', R’ and Rare independently selected from the group consisting R O Id" of: s R2a (1) hydrogen, and 45 S4 (2) fluoro. N -R Also further within this embodiment, the present invention 2éR2c is directed to compounds wherein R is phenyl and R', R’ N and Rare independently selected from the group consisting so OR FO of: (1) hydrogen, and (2) chloro. Also further within this embodiment, the present invention ss wherein R. R. R. Rand Rare defined herein; is directed to compounds wherein R is selected from the and pharmaceutically acceptable salts thereof and individual group consisting of enantiomers and diastereomers thereof. (1) 2,3-difluorophenyl, An embodiment of the present invention includes com pounds wherein R is Calkyl. (2) 2,4-difluorophenyl, 60 Within this embodiment, the present invention includes (3) 2,4-dichlorophenyl, compounds wherein R is —CHCH (4) 2-chloro-4-fluorophenyl, Within this embodiment, the present invention includes (5) 2-chloro-6-fluorophenyl, and compounds wherein R is —CHCF. Within this embodiment, the present invention includes (6) 2-chloro-4,6-difluorophenyl, 65 compounds wherein R is —(CH2)CHs. Within this embodiment the present invention includes Within this embodiment, the present invention includes compounds of the formula Id: compounds wherein R is —CH(CH4). US 7,776,886 B2 9 10 Also within this embodiment, the present invention alinyl, tetrahydropyranyl, tetrazolyl, tetraZolopyridyl, thia includes compounds wherein R is cyclopropyl. diazolyl, thiazolyl, thienyl, triazolyl, and N-oxides thereof, Specific embodiments of the present invention include a and wherein the Saturated heterocyclic moieties include aze compound which is selected from the group consisting of the tidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, pip Subject compounds of the Examples herein and pharmaceu eridinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahy tically acceptable salts thereof and individual enantiomers drofuranyl, tetrahydrothienyl, thiomorpholinyl, and diastereomers thereof. dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydroben The compounds of the present invention may contain one Zothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihy or more chiral centers and can thus occur as racemates and droimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihy racemic mixtures, single enantiomers, diastereomeric mix 10 droisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, tures and individual diastereomers. Additional asymmetric dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihy centers may be present depending upon the nature of the dropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihy various Substituents on the molecule. Each Such asymmetric drotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihy center will independently produce two optical isomers and it drothienyl, dihydrotriazolyl, dihydroazetidinyl, and is intended that all of the possible optical isomers and dias 15 methylenedioxybenzoyl, and N-oxides thereof. In embodi tereomers in mixtures and as pure or partially purified com ments of the present invention, heterocycle is an unsaturated pounds are included within the ambit of this invention. The heterocyclic moiety ("heteroaryl') which is pyridyl or pyrim present invention is meant to comprehend all Such isomeric idyl or a saturated heterocyclic moiety which is piperidine or forms of these compounds. Formula I shows the structure of aZetidine. the class of compounds without preferred stereochemistry. The term “pharmaceutically acceptable salts' refers to The independent syntheses of these diastereomers or their salts prepared from pharmaceutically acceptable non-toxic chromatographic separations may be achieved as known in bases or acids including inorganic or organic bases and inor the art by appropriate modification of the methodology dis ganic or organic acids. Salts derived from inorganic bases closed herein. Their absolute stereochemistry may be deter include aluminum, ammonium, calcium, copper, ferric, fer mined by the X-ray crystallography of crystalline products or 25 rous, lithium, magnesium, manganic salts, manganous, crystalline intermediates which are derivatized, if necessary, potassium, Sodium, zinc, and the like. Particularly preferred with a reagent containing an asymmetric center of known are the ammonium, calcium, magnesium, potassium, and absolute configuration. Sodium salts. Salts in the solid form may exist in more than If desired, racemic mixtures of the compounds may be one crystal structure, and may also be in the form of hydrates. separated so that the individual enantiomers are isolated. The 30 Salts derived from pharmaceutically acceptable organic non separation can be carried out by methods well known in the toxic bases include salts of primary, secondary, and tertiary art, such as the coupling of a racemic mixture of compounds amines, substituted amines including naturally occurring to an enantiomerically pure compound to form a diastereo Substituted amines, cyclic amines, and basic ion exchange meric mixture, followed by separation of the individual dias resins, such as arginine, betaine, caffeine, choline, N,N'- tereomers by standard methods, such as fractional crystalli 35 dibenzylethylene-diamine, diethylamine, 2-diethylaminoet Zation or chromatography. The coupling reaction is often the hanol, 2-dimethylamino-ethanol, ethanolamine, ethylenedi formation of salts using an enantiomerically pure acid or amine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, base. The diasteromeric derivatives may then be converted to glucosamine, histidine, hydrabamine, isopropylamine, the pure enantiomers by cleavage of the added chiral residue. lysine, methylglucamine, morpholine, piperazine, piperi The racemic mixture of the compounds can also be separated 40 dine, polyamine resins, procaine, purines, theobromine, tri directly by chromatographic methods utilizing chiral station ethylamine, trimethylamine, tripropylamine, tromethamine, ary phases, which methods are well known in the art. and the like. When the compound of the present invention is Alternatively, any enantiomer of a compound may be basic, salts may be prepared from pharmaceutically accept obtained by Stereoselective synthesis using optically pure able non-toxic acids, including inorganic and organic acids. starting materials or reagents of known configuration by 45 Such acids include acetic, benzenesulfonic, benzoic, cam methods well known in the art. phorsulfonic, citric, ethanesulfonic, fumaric, gluconic, As appreciated by those of skill in the art, halo or halogen glutamic, hydrobromic, hydrochloric, isethionic, lactic, as used herein are intended to include fluoro, chloro, bromo maleic, malic, mandelic, methanesulfonic, mucic, nitric, and iodo. Similarly, C as in Calkyl is defined to identify pamoic, pantothenic, phosphoric, succinic, Sulfuric, tartaric, the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or 50 p-toluenesulfonic acid, and the like. Particularly preferred are branched arrangement, such that Cisalkyl specifically citric, hydrobromic, hydrochloric, maleic, phosphoric, Sulfu includes methyl, ethyl, n-propyl, iso-propyl. n-butyl, iso-bu ric, fumaric, and tartaric acids. It will be understood that, as tyl, tert-butyl, pentyl, hexyl, heptyl and octyl. A group which used herein, references to the compounds of the present is designated as being independently Substituted with Sub invention are meant to also include the pharmaceutically stituents may be independently substituted with multiple 55 acceptable salts. numbers of such substituents. The term "heterocycle” as used Exemplifying the invention is the use of the compounds herein includes both unsaturated and Saturated heterocyclic disclosed in the Examples and herein. Specific compounds moieties, wherein the unsaturated heterocyclic moieties (i.e. within the present invention include a compound which "heteroaryl’) include benzoimidazolyl, benzimidazolonyl, selected from the group consisting of the compounds dis benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriaz 60 closed in the following Examples and pharmaceutically olyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, acceptable salts thereof and individual diastereomers thereof. cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazi The Subject compounds are useful in a method of inhibiting nyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, the glycine transporter GlyT1 activity in a patient such as a isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, mammal in need of Such inhibition comprising the adminis oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazi 65 tration of an effective amount of the compound. The present nyl, pyrazolyl pyridazinyl, pyridopyridinyl, pyridazinyl, invention is directed to the use of the compounds disclosed pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinox herein as inhibitors of the glycine transporter GlyT1 activity. US 7,776,886 B2 11 12 In addition to primates, especially humans, a variety of other with Tris base) with or without the compounds of the present mammals can be treated according to the method of the invention for 1 minute. Then 30 microliters of ''C-glycine present invention. diluted with TBIA was added to each well to give a final The present invention is further directed to a method for the concentration of 10 micromolar. After incubation at room manufacture of a medicament for inhibiting glycine trans temperature for 3 hours, the Cytostar Scintillating microplates porter GlyT1 activity in humans and animals comprising were sealed and counted on a Top Count Scintillation counter combining a compound of the present invention with a phar (Packard). Non-specific uptake of ''C-glycine was deter maceutical carrier or diluent. mined in the presence of 10 mM unlabeled glycine. I'C) The Subject treated in the present methods is generally a taurine uptake experiments were performed according to the mammal, preferably a human being, male or female, in whom 10 same protocol except that 10 mM unlabeled taurine was used inhibition of glycine transporter GlyT1 activity is desired. to determine non-specific uptake. To determine potencies, a The term “therapeutically effective amount’ means the range of concentrations of the compounds of the present amount of the subject compound that will elicit the biological invention was added to the cells, followed by the fixed con or medical response of a tissue, System, animal or human that centration of ''Clglycine. The concentration of the present is being sought by the researcher, Veterinarian, medical doc 15 compound that inhibited half of the specific uptake of ''C tor or other clinician. It is recognized that one skilled in the art glycine (ICso value) was determined from the assay data by may affect the neurological and psychiatric disorders by treat non-linear curve fitting. ing a patient presently afflicted with the disorders or by pro In particular, the compounds of the following examples phylactically treating a patient afflicted with such disorders had activity in inhibiting specific uptake of ''Clglycine in with an effective amount of the compound of the present the aforementioned assay, generally with an ICso value of less invention. As used herein, the terms “treatment” and “treat than about 10 micromolar. Preferred compounds within the ing refer to all processes wherein there may be a slowing, present invention had activity in inhibiting specific uptake of interrupting, arresting, controlling, or stopping of the pro '''Clglycine in the aforementioned assay with an ICso value gression of the neurological and psychiatric disorders of less than about 1 micromolar. These compounds were described herein, but does not necessarily indicate a total 25 selective for ''Clglycineuptake (by GlyT1 in the JAR cells) elimination of all disorder symptoms, as well as the prophy compared to '''Ctaurine uptake (by the taurine transporter lactic therapy to retard the progression or reduce the risk of TauT in the JAR cells). Such a result is indicative of the the noted conditions, particularly in a patient who is predis intrinsic activity of the compounds in use as inhibitors of posed to such disease or disorder. GlyT1 transporter activity. The term “composition” as used herein is intended to 30 The NMDA receptor is central to a wide range of CNS encompass a product comprising the specified ingredients in processes, and plays a role in a variety of disease states in the specified amounts, as well as any product which results, humans or other species. The action of GlyT1 transporters directly or indirectly, from combination of the specified affects the local concentration of glycine around NMDA ingredients in the specified amounts. Such term in relation to receptors. Selective GlyT1 inhibitors slow the removal of pharmaceutical composition, is intended to encompass a 35 glycine from the synapse, causing the level of synaptic gly product comprising the active ingredient(s), and the inert cine to rise. This in turn increases the occupancy of the gly ingredient(s) that make up the carrier, as well as any product cine binding site on the NMDA receptor, which increases which results, directly or indirectly, from combination, com activation of the NMDA receptor following glutamate release plexation or aggregation of any two or more of the ingredi from the presynaptic terminal. Because a certain amount of ents, or from dissociation of one or more of the ingredients, or 40 glycine is needed for the efficient functioning of NMDA from other types of reactions or interactions of one or more of receptors, any change to that local concentration can affect the ingredients. Accordingly, the pharmaceutical composi NMDA-mediated neurotransmission. Changes in NMDA tions of the present invention encompass any composition mediated neurotransmission have been implicated in certain made by admixing a compound of the present invention and a neuropsychiatric disorders such as dementia, depression and pharmaceutically acceptable carrier. By “pharmaceutically 45 psychoses, for example Schizophrenia, and learning and acceptable' it is meant the carrier, diluent or excipient must memory disorders, for example attention deficit disorders and be compatible with the other ingredients of the formulation autism. and not deleterious to the recipient thereof. The compounds of the present invention have utility in The terms “administration of and or “administering a treating a variety of neurological and psychiatric disorders compound should be understood to mean providing a com 50 associated with glutamatergic neurotransmission dysfunc pound of the invention or a prodrug of a compound of the tion, including one or more of the following conditions or invention to the individual in need of treatment. diseases: Schizophrenia or psychosis including schizophrenia The utility of the compounds in accordance with the (paranoid, disorganized, catatonic or undifferentiated), present invention as inhibiting the glycine transporter activ schizophreniform disorder, schizoaffective disorder, delu ity, in particular GlyT1 activity, may be demonstrated by 55 sional disorder, brief psychotic disorder, shared psychotic methodology known in the art. Human placental choriocar disorder, psychotic disorder due to a general medical condi cinoma cells (JAR cells (ATCC No. HTB-144)) endog tion and Substance-induced or drug-induced (phencyclidine, enously expressing GlyT1 were cultured in 96-well Cytostar ketamine and other dissociative anaesthetics, amphetamine scintillating microplates (Amershaam Biosciences) in RPMI and other psychoStimulants and cocaine) psychosispsychotic 1640 medium containing 10% fetal calfserum in the presence 60 disorder, psychosis associated with affective disorders, brief of penicillin (100 micrograms/milliliter) and streptomycin reactive psychosis, Schizoaffective psychosis, "schizophre (100 micrograms/milliliter). Cells were grown at 37°C. in a nia-spectrum” disorders such as Schizoid or schizotypal per humidified atmosphere of 5% CO2 for 40-48 hours before the Sonality disorders, or illness associated with psychosis (Such assay. Culture medium was removed from the Cytostar plate, as major depression, manic depressive (bipolar) disorder, and JAR cells were incubated with 30 microliters of TB 1A 65 Alzheimer's disease and post-traumatic stress syndrome), buffer (120 mM. NaCl, 2 mM KC1, 1 mM CaCl, 1 mM including both the positive and the negative symptoms of MgCl, 10 mM HEPES, 5 mM L-alanine, pH 7.5 adjusted Schizophrenia and other psychoses; cognitive disorders US 7,776,886 B2 13 14 including dementia (associated with Alzheimer's disease, ing phobia and post traumatic stress disorder, cognitive dis ischemia, multi-infarct dementia, trauma, Vascular problems orders associated with dementia, AIDS dementia, or stroke, HIV disease, Parkinson's disease, Huntington's Alzheimer's, Parkinson's, Huntington's disease, spasticity, disease, Pick's disease, Creutzfeldt-Jacob disease, perinatal myoclonus, muscle spasm, tinnitus and hearing impairment hypoxia, other general medical conditions or Substance and loss are of particular importance. abuse); delirium, amnestic disorders or age related cognitive In a specific embodiment, the present invention provides a decline; anxiety disorders including acute stress disorder, method for treating cognitive disorders, comprising: admin agoraphobia, generalized anxiety disorder, obsessive-com istering to a patient in need thereof an effective amount of a pulsive disorder, panic attack, panic disorder, post-traumatic compound of the present invention. Particular cognitive dis stress disorder, separation anxiety disorder, Social phobia, 10 orders are dementia, delirium, amnestic disorders and age specific phobia, Substance-induced anxiety disorder and related cognitive decline. At present, the text revision of the anxiety due to a general medical condition; Substance-related fourth edition of the Diagnostic and Statistical Manual of disorders and addictive behaviors (including Substance-in Mental Disorders (DSM-IV-TR) (2000, American Psychiat duced delirium, persisting dementia, persisting amnestic dis ric Association, Washington D.C.) provides a diagnostic tool order, psychotic disorder or anxiety disorder, tolerance, 15 that includes cognitive disorders including dementia, dependence or withdrawal from Substances including alco delirium, amnestic disorders and age-related cognitive hol, amphetamines, cannabis, cocaine, hallucinogens, inhal decline. As used herein, the term “cognitive disorders' ants, nicotine, , phencyclidine, sedatives, hypnotics or includes treatment of those mental disorders as described in anxiolytics); obesity, bulimia nervosa and compulsive eating DSM-IV-TR. The skilled artisan will recognize that there are disorders; bipolar disorders, mood disorders including alternative nomenclatures, noSologies and classification sys depressive disorders; depression including unipolar depres tems for mental disorders, and that these systems evolve with Sion, seasonal depression and post-partum depression, pre medical and Scientific progress. Thus the term “cognitive menstrual syndrome (PMS) and premenstrual dysphoric dis disorders' is intended to include like disorders that are order (PDD), mood disorders due to a general medical described in other diagnostic Sources. condition, and Substance-induced mood disorders; learning 25 In another specific embodiment, the present invention pro disorders, pervasive developmental disorder including autis vides a method for treating anxiety disorders, comprising: tic disorder, attention disorders including attention-deficit administering to a patient in need thereofan effective amount hyperactivity disorder (ADHD) and conduct disorder; of a compound of the present invention. Particular anxiety NMDA receptor-related disorders such as autism, depression, disorders are generalized anxiety disorder, obsessive-com benign forgetfulness, childhood learning disorders and 30 pulsive disorder and panic attack. At present, the text revision closed head injury; movement disorders, including akinesias of the fourth edition of the Diagnostic and Statistical Manual and akinetic-rigid syndromes (including Parkinson's disease, of Mental Disorders (DSM-IV-TR) (2000, American Psychi drug-induced parkinsonism, postencephalitic parkinsonism, atric Association, Washington D.C.) provides a diagnostic progressive Supranuclearpalsy, multiple system atrophy, cor tool that includes anxiety disorders are generalized anxiety ticobasal degeneration, parkinsonism-ALS dementia com 35 disorder, obsessive-compulsive disorder and panic attack. As plex and basal ganglia calcification), -induced used herein, the term “anxiety disorders' includes treatment parkinsonism (Such as neuroleptic-induced parkinsonism, of those mental disorders as described in DSM-IV-TR. The neuroleptic malignant syndrome, neuroleptic-induced acute skilled artisan will recognize that there are alternative nomen dystonia, neuroleptic-induced acute akathisia, neuroleptic clatures, noSologies and classification systems for mental induced tardive dyskinesia and medication-induced postural 40 disorders, and that these systems evolve with medical and tremor), Gilles de la Tourette’s syndrome, epilepsy, muscular scientific progress. Thus the term "anxiety disorders” is spasms and disorders associated with muscular spasticity or intended to include like disorders that are described in other weakness including tremors; dyskinesias including tremor diagnostic sources. (such as rest tremor, postural tremor and intention tremor), In another specific embodiment, the present invention pro chorea (such as Sydenham's chorea, Huntington's disease, 45 vides a method for treating schizophrenia or psychosis com benign hereditary chorea, neuroacanthocytosis, symptomatic prising: administering to a patient in need thereofan effective chorea, drug-induced chorea and hemibalism), myoclonus amount of a compound of the present invention. Particular (including generalised myoclonus and focal myoclonus), tics Schizophrenia or psychosis pathologies are paranoid, disor (including simpletics, complex tics and symptomatic tics), ganized, catatonic or undifferentiated Schizophrenia and Sub and dystonia (including generalised dystonia Such as iodio 50 stance-induced psychotic disorder. At present, the text revi pathic dystonia, drug-induced dystonia, symptomatic dysto sion of the fourth edition of the Diagnostic and Statistical nia and paroxymal dystonia, and focal dystonia Such as ble Manual of Mental Disorders (DSM-IV-TR) (2000, American pharospasm, oromandibular dystonia, spasmodic dysphonia, Psychiatric Association, Washington D.C.) provides a diag spasmodic torticollis, axial dystonia, dystonic writer's cramp nostic tool that includes paranoid, disorganized, catatonic or and hemiplegic dystonia); urinary incontinence; neuronal 55 undifferentiated Schizophrenia and Substance-induced psy damage including ocular damage, retinopathy or macular chotic disorder. As used herein, the term "schizophrenia or degeneration of the eye, tinnitus, hearing impairment and psychosis' includes treatment of those mental disorders as loss, and brain edema; emesis; and sleep disorders including described in DSM-IV-TR. The skilled artisan will recognize insomnia and narcolepsy. that there are alternative nomenclatures, noSologies and clas Of the disorders above, the treatment of schizophrenia, 60 sification systems for mental disorders, and that these systems bipolar disorder, depression including unipolar depression, evolve with medical and scientific progress. Thus the term seasonal depression and post-partum depression, premen “schizophrenia or psychosis” is intended to include like dis strual syndrome (PMS) and premenstrual dysphoric disorder orders that are described in other diagnostic sources. (PDD), learning disorders, pervasive developmental disorder In another specific embodiment, the present invention pro including autistic disorder, attention disorders including 65 vides a method for treating Substance-related disorders and Attention-Deficit/Hyperactivity Disorder, autism, tic disor addictive behaviors, comprising: administering to a patient in ders including Tourette's disorder, anxiety disorders includ need thereof an effective amount of a compound of the US 7,776,886 B2 15 16 present invention. Particular substance-related disorders and bination of the drugs together are safer or more effective than addictive behaviors are persisting dementia, persisting either drug alone. Such other drug(s) may be administered, by amnestic disorder, psychotic disorder or anxiety disorder a route and in an amount commonly used therefor, contem induced by Substance abuse; and tolerance of dependence on poraneously or sequentially with a compound of the present or withdrawal from substances of abuse. At present, the text invention. When a compound of the present invention is used revision of the fourth edition of the Diagnostic and Statistical contemporaneously with one or more other drugs, a pharma Manual of Mental Disorders (DSM-IV-TR) (2000, American ceutical composition in unit dosage form containing Such Psychiatric Association, Washington D.C.) provides a diag other drugs and the compound of the present invention is nostic tool that includes persisting dementia, persisting preferred. However, the combination therapy may also amnestic disorder, psychotic disorder or anxiety disorder 10 includes therapies in which the compound of the present induced by Substance abuse; and tolerance of dependence on invention and one or more other drugs are administered on or withdrawal from substances of abuse. As used herein, the different overlapping schedules. It is also contemplated that term "substance-related disorders and addictive behaviors’ when used in combination with one or more other active includes treatment of those mental disorders as described in ingredients, the compounds of the present invention and the DSM-IV-TR. The skilled artisan will recognize that there are 15 other active ingredients may be used in lowerdoses than when alternative nomenclatures, noSologies and classification sys each is used singly. Accordingly, the pharmaceutical compo tems for mental disorders, and that these systems evolve with sitions of the present invention include those that contain one medical and Scientific progress. Thus the term 'substance or more other active ingredients, in addition to a compound of related disorders and addictive behaviors' is intended to the present invention. include like disorders that are described in other diagnostic The above combinations include combinations of a com SOUCS. pound of the present invention not only with one other active In another specific embodiment, the present invention pro compound, but also with two or more other active com vides a method for treating pain, comprising: administering to pounds. Likewise, compounds of the present invention may a patient in need thereof an effective amount of a compound be used in combination with other drugs that are used in the of the present invention. Particular pain embodiments are 25 prevention, treatment, control, amelioration, or reduction of bone and joint pain (osteoarthritis), repetitive motion pain, risk of the diseases or conditions for which compounds of the dental pain, cancer pain, myofascial pain (muscular injury, present invention are useful. Such other drugs may be admin fibromyalgia), perioperative pain (general Surgery, gyneco istered, by a route and in an amount commonly used therefor, logical), chronic pain and neuropathic pain. contemporaneously or sequentially with a compound of the In another specific embodiment, the present invention pro 30 present invention. When a compound of the present invention vides a method for treating obesity or eating disorders asso is used contemporaneously with one or more other drugs, a ciated with excessive food intake and complications associ pharmaceutical composition containing such other drugs in ated therewith, comprising: administering to a patient in need addition to the compound of the present invention is pre thereof an effective amount of a compound of the present ferred. Accordingly, the pharmaceutical compositions of the invention. At present, obesity is included in the tenth edition 35 present invention include those that also contain one or more of the International Classification of Diseases and Related other active ingredients, in addition to a compound of the Health Problems (ICD-10) (1992 World Health Organiza present invention. tion) as a general medical condition. The text revision of the The weight ratio of the compound of the present invention fourth edition of the Diagnostic and Statistical Manual of to the second active ingredient may be varied and will depend Mental Disorders (DSM-IV-TR) (2000, American Psychiat 40 upon the effective dose of each ingredient. Generally, an ric Association, Washington D.C.) provides a diagnostic tool effective dose of each will be used. Thus, for example, when that includes obesity in the presence of psychological factors a compound of the present invention is combined with affecting medical condition. As used herein, the term “obesity another agent, the weight ratio of the compound of the present or eating disorders associated with excessive food intake invention to the other agent will generally range from about includes treatment of those medical conditions and disorders 45 1000:1 to about 1:1000, preferably about 200:1 to about described in ICD-10 and DSM-IV-TR. The skilled artisan 1:200. Combinations of a compound of the present invention will recognize that there are alternative nomenclatures, noso and other active ingredients will generally also be within the logies and classification systems for general medical condi aforementioned range, but in each case, an effective dose of tions, and that these systems evolve with medical and Scien each active ingredient should be used. tific progress. Thus the term “obesity or eating disorders 50 In Such combinations the compound of the present inven associated with excessive food intake' is intended to include tion and other active agents may be administered separately like conditions and disorders that are described in other diag or in conjunction. In addition, the administration of one ele nostic sources. ment may be prior to, concurrent to, or Subsequent to the The subject compounds are further useful in a method for administration of other agent(s). the prevention, treatment, control, amelioration, or reduca 55 Accordingly, the Subject compounds may be used alone or tion of risk of the diseases, disorders and conditions noted in combination with other agents which are known to be herein. beneficial in the subject indications or other drugs that affect The subject compounds are further useful in a method for receptors or enzymes that either increase the efficacy, safety, the prevention, treatment, control, amelioration, or reduction convenience, or reduce unwanted side effects or toxicity of of risk of the aforementioned diseases, disorders and condi 60 the compounds of the present invention. The Subject com tions in combination with other agents, including an inhibitor pound and the other agent may be co-administered, either in of glycine transporter GlyT1 activity. concomitant therapy or in a fixed combination. The compounds of the present invention may be used in In one embodiment, the Subject compound may be combination with one or more other drugs in the treatment, employed in combination with anti-Alzheimer's agents, beta prevention, control, amelioration, or reduction of risk of dis 65 secretase inhibitors, gamma-secretase inhibitors, HMG-CoA eases or conditions for which compounds of the present reductase inhibitors, NSAID’s including ibuprofen, vitamin invention or the other drugs may have utility, where the com E. and anti-amyloid antibodies. US 7,776,886 B2 17 18 In another embodiment, the Subject compound may be azine hydrochloride, mesoridazine besylate, thioridazine employed in combination with sedatives, hypnotics, anxi hydrochloride, acetophenazine maleate, fluiphenazine hydro olytics, antipsychotics, antianxiety agents, cyclopyrrolones, chloride, flurphenazine enathate, fluiphenazine decanoate, tri imidazopyridines, pyrazolopyrimidines, minor tranquilizers, fluoperazine hydrochloride, thiothixene hydrochloride, halo agonists and antagonists, melatonergic agents, peridol decanoate, loxapine Succinate and molindone benzodiazepines, barbiturates, 5HT-2 antagonists, and the hydrochloride. Perphenazine, chlorprothixene, clozapine, like. Such as: adinazolam, allobarbital, alonimid, alprazolam, haloperidol, pimozide and risperidone are commonly used in amisulpride, amitriptyline, amobarbital, amoxapine, arip a non-salt form. Thus, the Subject compound may be iprazole, bentazepam, benzoctamine, brotizolam, bupropion, employed in combination with acetophenazine, alenternol, buspirione, butabarbital, butalbital, capuride, carbocloral, 10 aripiprazole, amisulpride, benzhexol, bromocriptine, chloral betaine, chloral hydrate, clomipramine, clonazepam, biperiden, chlorpromazine, chlorprothicene, clozapine, diaz cloperidone, cloraZepate, chlordiazepoxide, clorethate, chlo epam, fenoldopam, fluiphenazine, haloperidol, levodopa, rpromazine, clozapine, cyprazepam, desipramine, dex levodopa with benserazide, levodopa with carbidopa, clamol, diazepam, dichloralphenaZone, divalproex, diphen lisuride, loxapine, mesoridazine, molindolone, naxagolide, hydramine, doxepin, estazolam, ethchlorVynol, etomidate, 15 olanzapine, pergolide, perphenazine, pimozide, pramipexole, fenobam, flunitrazepam, flupentixol, fluphenazine, flu quetiapine, risperidone, Sulpiride, tetraberiazine, trihex razepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, yphenidyl, thioridazine, thiothixene, trifluoperazine or halazepam, haloperidol, hydroxy Zine, imipramine, lithium, Ziprasidone. lorazepam, lormetazepam, maprotiline, mecloqualone, mela In another embodiment, the Subject compound may be tonin, mephobarbital, meprobamate, methaqualone, employed in combination with an anti-depressant or anti midaflur, midazolam, nefazodone, nisobamate, nitrazepam, anxiety agent, including norepinephrine reuptake inhibitors nortriptyline, olanzapine, oxazepam, paraldehyde, paroxet (including tertiary amine tricyclics and secondary amine tri ine, pentobarbital, perlapine, perphenazine, phenelzine, phe cyclics), selective serotonin reuptake inhibitors (SSRIs), nobarbital, prazepam, promethazine, propofol, protriptyline, monoamine oxidase inhibitors (MAOIs), reversible inhibi quazepam, quetiapine, reclazepam, risperidone, roletamide, 25 tors of monoamine oxidase (RIMAS), serotonin and norad secobarbital, Sertraline, Suproclone, temazepam, thior renaline reuptake inhibitors (SNRIs), corticotropin releasing idazine, thiothixene, tracazolate, tranylcypromaine, traZ factor (CRF) antagonists, C.-adrenoreceptor antagonists, neu odone, triazolam, trepipam, tricetamide, triclofos, trifluop rokinin-1 receptor antagonists, atypical anti-depressants, erazine, trimetozine, trimipramine, uldazepam, Venlafaxine, benzodiazepines, -HTL agonists or antagonists, especially Zaleplon, Ziprasidone, Zolazepam, Zolpidem, and salts 30 -HT, partial agonists, and corticotropin releasing factor thereof, and combinations thereof, and the like, or the subject (CRF) antagonists. Specific agents include: amitriptyline, compound may be administered in conjunction with the use clomipramine, doxepin, imipramine and trimipramine: of physical methods such as with light therapy or electrical amoxapine, desipramine, maprotiline, nortriptyline and pro stimulation. triptyline; fluoxetine, fluvoxamine, paroxetine and Sertraline; In another embodiment, the Subject compound may be 35 isocarboxazid, phenelZine, tranylcypromine and selegiline; employed in combination with levodopa (with or without a moclobemide: Venlafaxine; dulloxetine; aprepitant; bupro selective extracerebral decarboxylase inhibitor such as carbi pion, lithium, nefazodone, traZodone and viloxazine; alpra dopa or benserazide), Such as biperiden (op Zolam, chlordiazepoxide, clonazepam, chloraZepate, diaz tionally as its hydrochloride or lactate salt) and trihex epam, halazepam, loraZepam, oxazepam and prazepam, yphenidyl (benzhexol) hydrochloride, COMT inhibitors such 40 buspirone, flesinoxan, gepirone and ipsapirone, and pharma as entacapone, MOA-B inhibitors, antioxidants, A2a adenos ceutically acceptable salts thereof. ine receptor antagonists, agonists, NMDA recep The compounds of the present invention may be adminis tor antagonists, serotonin receptor antagonists and dopamine tered by oral, parenteral (e.g., intramuscular, intraperitoneal, receptor agonists such as alentemol, bromocriptine, intravenous, ICV, intracisternal injection or infusion, Subcu fenoldopam, lisuride, naxagolide, pergolide and pramipex 45 taneous injection, or implant), by inhalation spray, nasal, ole. It will be appreciated that the may be in vaginal, rectal, Sublingual, or topical routes of administration the form of a pharmaceutically acceptable salt, for example, and may be formulated, alone or together, in Suitable dosage alentemol hydrobromide, bromocriptine mesylate, unit formulations containing conventional non-toxic pharma fenoldopam mesylate, naxagolide hydrochloride and per ceutically acceptable carriers, adjuvants and vehicles appro golide mesylate. Lisuride and pramipexol are commonly used 50 priate for each route of administration. In addition to the in a non-salt form. treatment of warm-blooded animals such as mice, rats, In another embodiment, the Subject compound may be horses, cattle, sheep, dogs, cats, monkeys, etc., the com employed in combination with a compound from the phe pounds of the invention are effective for use in humans. nothiazine, thioxanthene, heterocyclic dibenzazepine, buty The term “composition” as used herein is intended to rophenone, diphenylbutylpiperidine and indolone classes of 55 encompass a product comprising specified ingredients in pre neuroleptic agent. Suitable examples of phenothiazines determined amounts or proportions, as well as any product include chlorpromazine, mesoridazine, thioridazine, which results, directly or indirectly, from combination of the acetophenazine, fluiphenazine, perphenazine and trifluopera specified ingredients in the specified amounts. This term in zine. Suitable examples of thioxanthenes include chlorpro relation to pharmaceutical compositions is intended to thixene and thiothixene. An example of a dibenzazepine is 60 encompass a product comprising one or more active ingredi clozapine. An example of abutyrophenone is haloperidol. An ents, and an optional carrier comprising inert ingredients, as example of a diphenylbutylpiperidine is pimozide. An well as any product which results, directly or indirectly, from example of an indolone is molindolone. Other neuroleptic combination, complexation or aggregation of any two or agents include loxapine, Sulpiride and risperidone. It will be more of the ingredients, or from dissociation of one or more appreciated that the neuroleptic agents when used in combi 65 of the ingredients, or from other types of reactions or inter nation with the subject compound may be in the form of a actions of one or more of the ingredients. In general, pharma pharmaceutically acceptable salt, for example, chlorprom ceutical compositions are prepared by uniformly and inti US 7,776,886 B2 19 20 mately bringing the active ingredient into association with a hydroxybenzotriazole: THF tetrahydrofuran; MeOH metha liquid carrier or a finely divided solid carrier or both, and then, nol; DIEA diisopropylethylamine. if necessary, shaping the product into the desired formulation. Several methods for preparing the compounds of this In the pharmaceutical composition the active object com invention are illustrated in the following Schemes and pound is included in an amount Sufficient to produce the Examples. Starting materials and the requisite intermediates desired effect upon the process or condition of diseases. Accordingly, the pharmaceutical compositions of the present are in Some cases commercially available, or can be prepared invention encompass any composition made by admixing a according to literature procedures or as illustrated herein. compound of the present invention and a pharmaceutically The compounds of this invention may be prepared by acceptable carrier. 10 employing reactions as shown in the following schemes, in Pharmaceutical compositions intended for oral use may be addition to other standard manipulations that are known in the prepared according to any method known to the art for the literature or exemplified in the experimental procedures. Sub manufacture of pharmaceutical compositions and Such com stituent numbering as shown in the schemes does not neces positions may contain one or more agents selected from the 15 sarily correlate to that used in the claims and often, for clarity, group consisting of Sweetening agents, flavoring agents, col a single Substituent is shown attached to the compound where oring agents and preserving agents in order to provide phar multiple substituents are allowed under the definitions here maceutically elegant and palatable preparations. Tablets con inabove. Reactions used to generate the compounds of this tain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are Suitable for invention are prepared by employing reactions as shown in the manufacture of tablets. The tablets may be uncoated or the schemes and examples herein, in addition to other stan they may be coated by known techniques to delay disintegra dard manipulations such as ester hydrolysis, cleavage of pro tion and absorption in the gastrointestinal tract and thereby tecting groups, etc., as may be known in the literature or provide a Sustained action over alonger period. Compositions exemplified in the experimental procedures. for oral use may also be presented as hard gelatin capsules 25 In some cases the final product may be further modified, for wherein the active ingredients are mixed with an inert solid example, by manipulation of Substituents. These manipula diluent, for example, calcium carbonate, calcium phosphate tions may include, but are not limited to, reduction, oxidation, or kaolin, or as Softgelatin capsules wherein the active ingre alkylation, acylation, and hydrolysis reactions which are dient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions, commonly known to those skilled in the art. In some cases the oily suspensions, dispersible powders or granules, oil-in-wa 30 order of carrying out the foregoing reaction schemes may be ter emulsions, and sterile injectable aqueous or oleagenous varied to facilitate the reaction or to avoid unwanted reaction Suspension may be prepared by standard methods known in products. The following examples are provided so that the the art. invention might be more fully understood. These examples are illustrative only and should not be construed as limiting In the treatment of conditions which require inhibition of 35 glycine transporter GlyT1 activity an appropriate dosage the invention in any way. level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to 40 CN about 100) mg/kg per day. A Suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per 1. KHMDS day, or about 0.1 to 50 mg/kg per day. Within this range the --- dosage may be 0.05 to 0.5,0.5 to 5 or 5 to 50 mg/kg per day. N For oral administration, the compositions are preferably pro 45 vided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15. 20, 25, O1. O -k Br 50, 75, 100, 150, 200,250, 300,400, 500, 600, 750, 800, 900, I-1 and 1000 milligrams of the active ingredient for the symp CN tomatic adjustment of the dosage to the patient to be treated. 50 The compounds may be administered on a regimen of 1 to 4 1. HC times per day, preferably once or twice per day. This dosage He regimen may be adjusted to provide the optimal therapeutic 2. RSOCI response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient 55 N -k 2 may be varied and will depend upon a variety of factors es including the activity of the specific compound employed, the I-2 metabolic stability and length of action of that compound, the CN age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the 60 severity of the particular condition, and the host undergoing Ra-Ni therapy. --H. Abbreviations used in the description of the chemistry and o==o in the Examples that follow are: DCM dichloromethane: R3 KHMDS potassium bis(trimethylsilyl)amide: EDCI 1-3- 65 (dimethyl-amino)propyl-3-ethylcarbodiimide hydrochlo I-3 ride; EtOAc ethyl acetate; Ra Ni Raney Nickel; HOBt US 7,776,886 B2 21

-continued -continued R R5 CN R(A)-COCI O n-C2H5SO2Cl NH2 R2N=C=O He DIEA EtN, DCM N O H He N RCOOH, HOBt I-3 DCM, EtN CN 10 O CDI, ROH or RNH Raney-Ni -e- H 15 O -SO I-4 O C

C

NH2

25 C DIEA As illustrated in general Reaction Scheme I for the com pounds of the present invention wherein R is hydrogen and R is hydrogen, a suitably substituted 4-cyanopiperidine is O -k)O deprotonated employing KHMDS, followed by a nucleo 30 I-5 philic aromatic Substitution reaction with (bromomethyl)- O C cyclopropane to provide I-2. Exposure of this material to HCl removes the Boc protecting group to afford the free amine H which is treated with a sulfonyl chloride understandard reac 35 tion conditions to provide the corresponding Sulfonamide. ves r C Hydrogenation employing Ra—Ni under a hydrogen atmo N sphere provides the corresponding amine, which is acylated 2 l(N understandard reactions conditions to deliver the final mate 2 no rial. In this instance, the sulfonyl chlorides, acid chlorides and 40 I-6 carboxylic acids employed were commercially available, as were the starting 4-cyanopiperidines. tert-Butyl 4-cyano-4-(cyclopropylmethyl)piperidine-1-car boxylate (I-2) 45 A solution of tert-butyl 4-cyanopiperidine-1-carboxylate SCHEME 1. I-1 (1.0 g, 4.8 mmol) in THF (20 mL) at room temperature was treated with KHMDS (9.6 mL of a 1.0 M solution in TBF, H. CN 9.6 mmol). After 30 min, (bromomethyl)cyclopropane (0.47 mL, 4.8 mmol) was added dropwise and the mixture was 50 stirred until LCMS indicated the reaction was complete. The Br reaction mixture was poured into Saturated aqueous NHCl (50 mil) and extracted with EtOAc (3x50 mL), and the com N -k KHMDS bined organic extracts were dried (NaSO) and concentrated under reduced pressure to afford tert-butyl 4-cyano-4-(cyclo 1s. 55 propyl-methyl)piperidine-1-carboxylate (I-2, M+H=265.2). I-1 This material was used in Subsequent reactions without fur ther purification. CN 4-(Cyclopropylmethyl)piperidine-4-carbonitrile hydrochlo 60 1. TFA-DCM ride (I-3) He A sample of tert-butyl 4-cyano-4-(cyclopropylmethyl)pi 2. NaOH peridine-1-carboxylate (I-2, 3.6 g. 13.6 mmol) was treated with HCl (40 mL of a 4.0 M solution in dioxane) and stirred at room temperature for 2 h before being concentrated under 65 reduced pressure to afford 4-(cyclopropylmethyl)-piperi -k dine-4-carbonitrile hydrochloride (I-3, M+H=165.1) which was used without further purification. US 7,776,886 B2 23 24 4-(Cyclopropylmethyl)-1-(ethylsulfonyl)piperidine-4-car 2,4-Dichloro-N-4-(cyclopropylmethyl)-1-(ethylsulfonyl) bonitrile (I-4) piperidin-4-yl)methylbenzamide (I-6) A Suspension of 4-(cyclopropylmethyl)piperidine-4-car A solution of 1-4-(cyclopropylmethyl)-1-(ethylsulfonyl) bonitrile hydrochloride (I-3, 2.5g, 12.5 mmol) in CHCl, piperidin-4-yl)methanamine (I-5, 250 mg, 1.0 mmol) in (130 mL) at 0° C. was treated with i-PrNEt (8.7 mL, 50 CHC1 (10 mL) at 0°C. was treated withi-PrNEt (1 mL, 5.7 mmol) and EtSOC1 (1.8 mL, 18.7 mmol) dropwise. After 2h, mmol), 2,4-dichlorobenzoyl chloride (200 uL. 1.43 mmol), the reaction was quenched with the addition of 1 Maqueous and stirred for 15 min before being warmed to room tempera ture. After 1 h, the reaction was quenched with the addition of NaOH (40 mL) and stirred 18 h before being extracted with 1 M aqueous NaOH (10 mL) and stirred 1 h before being CHCl (3x50 mL). The combined organic extracts were 10 extracted with CHCl (3x20 mL). The combined organic dried (NaSO) and concentrated under reduced pressure to extracts were dried (NaSO), concentrated under reduced afford 4-(cyclopropylmethyl)-1-(ethylsulfonyl)piperidine-4- pressure, and purified by reverse phase HPLC to afford 2,4- carbonitrile (I-4, M+H=256.1) as an off-white amorphous dichloro-N-4-(cyclopropylmethyl)-1-(ethylsulfonyl)pip Solid. This material was used in Subsequent reactions without eridin-4-yl)methylbenzamide (I-6) as an off-white amor further purification. 15 phous solid. Analytical LCMS: single peak (214 nm), 3.328 min. 'H NMR (CDC1,300 MHz) & 7.64 (d. J=8.4 Hz, 1 H), 1-4-(Cyclopropylmethyl)-1-(ethylsulfonyl)piperidin-4-yl) 7.46 (s, 1H), 7.35 (d. J=8.4 Hz, 1H), 6.39 (t, J=8 Hz, 1H), 3.63 methanamine (I-5) (d. J–6.3 Hz, 2H), 3.41 (m, 2H), 3.35 (m, 2H), 2.98 (d. J–7.2 A solution of 4-(cyclopropylmethyl)-1-(ethylsulfonyl)pi HZ, 1H), 1.68 (m, 5H), 1.39 (m, 5H), 0.68 (m. 1H), 0.56 (d. peridine-4-carbonitrile (I-4, 3.1 mg, 11.1 mmol) in 2 MNH / J=8 Hz, 1H). HRMS m/z. 433.1091 (CHCINOS+H" MeOH (50 mL) was treated with excess Raney Ni and agi requires 433.1091). The compounds in Table 1 were synthesized as shown in tated under an atmosphere of H. (40 psi) in a Parr apparatus. Reaction Scheme I, but substituting the appropriately substi After 5 h, the reaction was filtered through Celite (MeOH tuted sulfonyl chloride and/or acid chloride/carboxylic acid wash) and concentrated under reduced pressure to afford as described in the Schemes and the foregoing examples. The 1-4-(cyclopropylmethyl)-1-(ethylsulfonyl)-piperidin-4-yl) 25 requisite starting materials were commercially available, methanamine (I-5, M--H=261.2) as a yellow oil. This mate described in the literature or readily synthesized by one rial was used in Subsequent reactions without further purifi skilled in the art of organic synthesis without undue experi cation. mentation.

TABLE 1.

MS Compound Nomenclature M+ 1

2-amino-6-chloro-N-(4- 428.1 HN (cyclopropylmethyl)-1- 2 (propylsulfonyl)piperidin-4- O yl)methylbenzamide

N H C

N le

2-chloro-N-(4- 431.1 (cyclopropylmethyl)-1- (propylsulfonyl)piperidin-4- F yl)methyl-6-fluorobenzamide O

N H C

N le

US 7,776,886 B2 31 32 While the invention has been described and illustrated with (3) —Calkyl, reference to certain particular embodiments thereof, those (4) —CH, and skilled in the art will appreciate that various adaptations, changes, modifications, Substitutions, deletions, or additions (5)-NH. of procedures and protocols may be made without departing 5 4. The compound of claim3 wherein R is phenyland R*, from the spirit and scope of the invention. R” and R are independently selected from the group con What is claimed is: sisting of: 1. A compound of Formula I (1) hydrogen, (2) fluoro, 10 I (3) chloro, R4 R5 Q (4) bromo, R2 (5) —CH, and (6) —NH. s 15 5. The compound of claim 4 wherein R is selected from the group consisting of (1) 2,3-difluorophenyl, O = EO (2) 2,4-difluorophenyl, R3 (3) 2,4-dichlorophenyl, (4) 2-chloro-4-fluorophenyl, wherein R is selected from the group consisting of: (5) 2-chloro-6-fluorophenyl, and (1) phenyl, which is substituted with R', RandR, (6) 2-chloro-4,6-difluorophenyl. (2) furanyl, which is substituted with R', Rand R*, 25 (3) cyclohexyl, which is unsubstituted or substituted with 6. The compound of claim 1 wherein R is Calkyl. 1-6 halogen, hydroxy or —NH2, 7. The compound of claim 6 wherein R is —CHCH. R", Rand R* are independently selected from the group 8. The compound of claim 6 wherein R is cyclopropyl. consisting of: 9. The compound of claim 1 wherein R is hydrogen andR (1) hydrogen, 30 is hydrogen. (2) halogen, 10. A compound which is selected from the group consist (3) —Calkyl, ing of (4) —CF, and (5) – NH; R is Calkyl or cyclopropyl: Rand Rare independently selected from the group consist ing of (1) hydrogen, and (2) Calkyl, which is unsubstituted or substituted with halogen or hydroxyl, or RandR taken togetherform a C-cycloalkyl ring: A is selected from the group consisting of (1) —O—, and (2) - NH-; HN m is zero, whereby R is attached directly to the carbonyl: 45 or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 of the formula Id': NH C O Id 50 R2a sa Á -R 2 55 N R2c OE l EO

NH 60 C or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1 wherein R is phenyl or fura nyl and R, RandR are independently selected from the group consisting of 65 (1) hydrogen, (2) halogen, US 7,776,886 B2 33 34

-continued -continued

10

15

25

30 NH

35 NH

40

C 45

50 US 7,776,886 B2 35 36 11. A compound which is: -continued O C O C 5 H N ves r F H N C Os 10 N es cano