US 201302O3752A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0203752 A1 Blough et al. (43) Pub. Date: Aug. 8, 2013

(54) PHENYLMORPHOLINES AND ANALOGUES Publication Classification THEREOF (51) Int. Cl. (76) Inventors: Bruce E. Blough, Raleigh, NC (US); C07D 265/30 (2006.01) Richard Rothman, Ellicott City, MD (52) U.S. Cl. (US); Antonio Landavazo, Raleigh, NC CPC ...... C07D 265/30 (2013.01) (US); Kevin M. Page, Willow Spring, USPC ...... 514/231.2: 544/106; 544/174: 544/163 NC (US); Ann Marie Decker, Durham, NC (US) (57) ABSTRACT (21) Appl. No.: 13/698,892 Provided herein are compounds and prodrugs and methods of (22) PCT Filed: May 20, 2011 preparation of compounds and prodrugs that are capable of functioning as releasers and/or uptake inhibitors of one or (86). PCT No.: PCT/US2011/037361 more monoamine neurotransmitters, including dopamine, serotonin, and norepinephrine. Also provided are pharmaceu S371 (c)(1), tical compositipos1u1ons compris1ng one or more OIf uneseth com (2), (4) Date: Mar. 4, 2013 pounds or prodrugs, which may further comprise one or more Related U.S. Application Data additional therapeutic agents. Also provided are methods of treatment of various conditions that may be responsive to (60) Provisional application No. 61/347,259, filed on May modification of monoamine neutrotransmitter levels, such as 21, 2010. pre-obesity, obesity, addiction, and depression. US 2013/0203752 A1 Aug. 8, 2013

PHENYLMORPHOLINES AND ANALOGUES 0006 Another anorectic, which was prescribed for the THEREOF short-term treatment of obesity, is phenmetrazine Phenmetra Zine is reportedly a potent Substrate for norephinephrine and FEDERALLY SPONSORED RESEARCHOR dopamine transporters and displays stimulant properties DEVELOPMENT similar to those of amphetamines. Some reports indicate that phenmetrazine has been widely abused as a recreational drug 0001. This invention was made with United States Gov and has greater addiction potential than amphetamines. ernment support under DA 12970/0207690,000 awarded by Because of phenmetrazine's high potential for abuse, it was the National Institutes of Health. The United States Govern pulled from the market. ment has certain rights in the invention. 0007 Subsequently, phendimetrazine, a close analogue of FIELD OF THE INVENTION phenmetrazine with a methyl Substituent on the amine, was released onto the market as an anorectic. Recent research has 0002 The present application is directed to various com Suggested that phendimetrazine actually exerts its effect via pounds and methods of preparation of compounds that are conversion to phenmetrazine. See Rothman et al., Eur: J. capable of functioning as releasers and/or reuptake inhibitors Pharmacology 447: 51-57 (2002), incorporated herein by of one or more monoamine neurotransmitters, including reference. Thus, as with phenmetrazine, phendimetrazine dopamine, serotonin, and norepinephrine. The application is also has a high potential for abuse. Although it is still available also directed to pharmaceutical compositions comprising one for the treatment of obesity, phendimetrazine is a Class III or more of these compounds, which may also comprise one or controlled substance and there is a high likelihood of abuse of more additional therapeutic agents. It is also directed to meth this drug. ods of treatment of various conditions that may be responsive 0008 Accordingly, there is a need for an anorectic drug to modification of monoamine neurotransmitter levels, such that acts similarly to the aforementioned drugs on the central as pre-obesity, obesity, addiction, and depression. nervous system, but does not provide Such high potential for abuse and/or does not act as an agonist of the 5-HT2 receptor. BACKGROUND OF THE INVENTION Because of their effects on the central nervous system, such 0003) Obesity is a serious public health concern, associ compounds may be useful not only for treating obesity and ated with a number of health conditions. The National Center pre-obesity, but also for other diseases related to the central for Health Statistics reports that 65% of adults are considered nervous system including addiction, depression, and anxiety. to be overweight (pre-obese), with greater than 34% of those BRIEF SUMMARY OF THE INVENTION adults considered to be obese. The incidences of obesity have dramatically increased over the last twenty years, with the 0009. The present invention relates generally to com percentage of obese adults having doubled from 1980 to pounds and prodrugs that may be useful as releasers and/or 2004. Children are at risk as well, with an estimated 17% of reuptake inhibitors of one or more monoamine neurotrans children from age 2-19 classified as obese. Medical condi mitters, including dopamine, serotonin, and norepinephrine. tions commonly associated with obesity include diabetes and It also relates to pharmaceutical formulations of Such com high blood pressure, which may lead to cardiovascular dis pounds and/or prodrugs and to methods of using such com ease, stroke, and premature mortality. pounds, prodrugs, or formulations thereof to treat various 0004. As a result, there has been an increase in demand for conditions that may be responsive to the modulation of neu medications to treat pre-obesity and obesity. One type of rotransmitter levels. medication that is available to treat obesity is anorectics, also 0010. In one aspect, the present invention provides a com known as appetite Suppressants. One well-known anorectic is pound that may modulate the levels of one or more monoam Fen-Phen, which was widely prescribed for weight loss in the ine neurotransmitters. In some embodiments, the invention early 1990s. Fen-Phen is a combination drug that comprises provides a compound according to the following structure: two compounds; namely, fenfluramine and phentermine. Fenfluramine acts via a serotonergic mechanism to increase a user's satiety. Phentermine has a stimulant effect, acting Rs mainly through dopaminergic and noradrenergic mecha nisms to decrease a user's appetite. Fen-Phen, although effec tive in the treatment of obesity, was linked to possible valvular R N r heart disease and pulmonary hypertension in 1997. As a 2 R3 R4 result, fenfluramine and the Fen-Phen combination drug were pulled from the market in 1997. 0005. It is thought that the valvular heart disease and pull 0011 wherein: monary hypertension associated with the use offenfluramine 0012 R is optionally substituted aryl; and its active metabolite norfenfluramine may result from the 0013 R is H or optionally substituted C1-3 alkyl: stimulation of 5-hydroxytryptamine (5-HT) serotonin recep 0.014 R is H, optionally substituted C1-3 alkyl, or ben tors. Studies have shown that, in particular, fenfluramine is a Zyl; potent agonist of a particular type of 5-HT receptor, the 0.015 R is H or optionally substituted C1-3 alkyl; and 5-HT2 receptor, which is present in human cardiac valves. 0016 Rs is H or OH: Phentermine is still available in many countries, including the 0017 R is H or optionally substituted C1-3 alkyl; United States; however, it is classified as a controlled sub 0018 with the proviso that when R is CH and R is stance due to its chemical and pharmacological similarity to phenyl, then (a) the phenyl ring of R is substituted with one amphetamines. One concern with Such compounds is the high or more substituents; or (b) R is substituted C1 alkyl or potential for abuse. optionally substituted C2-C3 alkyl, or (c) one or more of R, US 2013/0203752 A1 Aug. 8, 2013

Rs, and R is not H, or a combination of two or more of (a) 0028 wherein: through (c); or a pharmaceutically acceptable ester, amide, 0029 each R, represents a substituent independently salt, Solvate, prodrug, or isomer thereof. Selected from the group consisting of OH, optionally 0019. In certain embodiments, a compound of the struc substituted C1-4 alkyl, optionally substituted C1-3 ture above is provided, wherein R is phenyl, substituted alkoxy, optionally substituted C2-4 alkenyl, optionally phenyl, naphthyl, or Substituted naphthyl. In some embodi Substituted C2-4 alkynyl, halogen, amino, acylamido, ments, R is a Substituted aryl group (e.g., a Substituted phe CN, CF, NO, N, CONH CO.R. CH-OH, nyl) and R is H. CHOR, NRR, NHCOR, NHCOR, 0020. In some embodiments, a compound is provided hav CONRR, C1-3 alkylthio. RSO, RSO, CFS, ing the structure: and CFSO; and 0.030 c is an integer from 0-7. 0031 or a pharmaceutically acceptable ester, amide, salt, Solvate, prodrug, or isomer thereof. 0032. In some embodiments of the present invention, a 21 compound is provided, wherein R is H or CH. In some (R-, - || Rs embodiments of the invention, a compound is provided wherein R is Hor CH. In certain embodiments, R is option ally substituted C1-3 alkyl. In certain embodiments, one of R N r and R is Hand the other of RandR is optionally substituted R R. R4 C1-3 alkyl. In some embodiments, such compounds may comprise an enantiomeric excess of at least 95% of one iso mer (e.g., the (25-5S) enantiomer). 0021 wherein the substituents areas noted above, except 0033. In one embodiment of the invention, certain com that: pounds are provided, selected from the group consisting of 0022 each R, represents a substituent independently 2-(2-naphthyl)morpholine: 2-methyl-6-phenyl-morpholine: selected from the group consisting of OH, optionally Substi 2-(3-chloro-phenyl)-3-methyl-morpholine: 2-(3-chloro-phe tuted C1-4 alkyl, optionally substituted C1-4 alkoxy, option nyl)-3-methyl-morpholin-2-ol: 2-(3-chloro-phenyl)-5-me ally substituted C2-4 alkenyl, optionally substituted C2-4 thyl-morpholine: 2-(3-chloro-phenyl)-6-methyl-morpho alkynyl, halogen, amino, acylamido, CN, CF, NO, N, line: 2-(3-fluoro-phenyl)-3-methyl-morpholine: 2-(3-fluoro CONH CO.R., CHOH, CHOR, NRR, NHCOR, phenyl)-3-methyl-morpholin-2-ol: 2-(3-fluoro-phenyl)-5- NHCOR, CONRR, C1-3 alkylthio. RSO, RSO, methyl-morpholine; 2-(3-methoxy-phenyl)-5-methyl CFS, and CFSO, wherein R and R are each indepen morpholine: 2-(4-fluorophenyl)morpholine: 2-(4-chloro dently selected from Hor optionally substituted C1-10 alkyl: phenyl)-5-methyl-morpholine: 2-(4-fluoro-phenyl)-5- and methyl-morpholine; 3-methyl-2-phenylmorpholin-2-ol; (0023 b is an integer from 0-5: 3-methyl-2-(2-naphthyl)morpholine: 3-methyl-2-(3'-tolyl) 0024 with the proviso that when R is CH, then (a) b is an morpholine; 3-methyl-2-(3'-tolyl)morpholin-2-ol: 3-methyl integer from 1-5, or (b) R is substituted Clalkyl or optionally 2-(4-tolyl)morpholine: 3-methyl-(4'-fluoro)-2-phenylmor substituted C2-C3 alkyl, or (c) one or more of R. Rs, and R. pholine; 3-methyl-(4-chloro)-2-phenylmorpholine; is not H, or a combination of two or more of (a) through (c), 3-methyl-(4-methoxy)-2-phenylmorpholine: 3-methyl 0025 or a pharmaceutically acceptable ester, amide, salt, (4'-cyano)-2-phenylmorpholine: 3-methyl-(3'-hydroxy)- Solvate, prodrug, or isomer thereof 2-phenylmorpholine: 3-methyl-(3'-methoxy)-2-phenyl 0026. In certain embodiments, a compound of the above morpholine; 3-methyl-(3'-cyano)-2-Phenylmorpholine; formula is provided, wherein b is an integer from 1-5, and 3-methyl-(3',4'-dichloro)-2-phenylmorpholine: 3-methyl each R, is independently selected from the group consisting (3'-chloro-4'-fluoro)-2-Phenylmorpholine: 3-methyl-(3'- of optionally substituted C1-4 alkyl, optionally substituted chloro-4'-methyl)-2-Phenylmorpholine; 5-methyl-2-(3-trif C1-4 alkoxy, halo, OH, CN, and CF. In some embodiments, luoromethyl-phenyl)-morpholine; 5-methyl-2-p-tolyl b is 1 and the R, substituent is located meta or para to the morpholine; 5-methyl-2-m-tolyl-morpholine; 5-methyl-2- morpholine Substituent on the phenyl ring. phenyl-morpholine; 5-methyl-2-(4-trifluoromethyl-phenyl)- 0027. In some embodiments, a compound is provided hav morpholine, or a pharmaceutically acceptable ester, amide, ing the structure: salt, Solvate, prodrug, or isomer thereof. 0034. According to the invention, in some embodiments, the compound is one or more of a dopamine releaser, norepi nephrine releaser, serotonin releaser, dopamine uptake inhibitor, norepinephrine uptake inhibitor, and serotonin 21 uptake inhibitor. In certain embodiments, the compound is a (R-, - Rs dopamine releaser or a dual serotonin and dopamine releaser. N In Some embodiments, the compound is inactive at the 5HT receptor. 0035. In another aspect of the invention is provided a r prodrug of the compounds disclosed herein, comprising a compound having R replaced with a labile protecting group. For example, certain prodrugs of the present invention have the following formula: US 2013/0203752 A1 Aug. 8, 2013

the singular forms “a”, “an”, “the’, include plural referents Rs unless the context clearly dictates otherwise. 0044) Many modifications and other embodiments of the inventions set forth herein will come to mind to one skilled in the art to which these inventions pertain having the benefit of R rR4 the teachings presented in the foregoing description. There fore, it is to be understood that the inventions are not to be X limited to the specific embodiments disclosed and that modi fications and other embodiments are intended to be included 0036 wherein: within the scope of the appended claims Although specific 0037 X is a chemical moiety which, when the prodrug terms are employed herein, they are used in a generic and is administered in vivo, is cleaved in whole or in part to descriptive sense only and not for purposes of limitation. provide a free amine on the morpholine ring; 0045. The present invention provides compounds that may 0038. In some specific embodiments, a prodrug according function to modify the release and/or reuptake of one or more to this structure is provided, wherein X is an amino acid or monoamine neurotransmitters selected from dopamine, nore peptide. pinephrine, and serotonin The invention also provides meth 0039. In some embodiments, a prodrug is provided having ods of preparation and pharmaceutical compositions thereof the formula: It also provides methods for using such compounds to treat a variety of disorders that may be responsive to the modulation of one or more of these neurotransmitters. In particular, the compositions and methods can be used in the treatment of obesity, various drug addictions, and depression. In some embodiments, treatment can comprise the use of a compound of the present invention as a single active agent. In other embodiments, treatment can comprise the use of a compound of the present invention in combination with one or more further active agents. The specific pharmaceutical composi tion (or compositions) used in the invention and the methods of treatment provided by the invention are further described 0040 wherein Rs is optionally substituted C1-10 alkyl, below. optionally substituted C1-10 alkoxy, optionally substi tuted phenyl, optionally Substituted benzyl, or option Definitions ally substituted pyridyl. 0041. In a further aspect of the invention, a pharmaceutical 0046. The term “alkyl as used herein means saturated composition is provided, wherein the composition comprises straight, branched, or cyclic hydrocarbon groups. In particu a compound or prodrug as disclosed herein and one or more lar embodiments, alkyl refers to groups comprising 1 to 10 pharmaceutically acceptable carriers. carbonatoms (“C1-10 alkyl). In further embodiments, alkyl 0042. In a still further aspect of the invention, a method for refers to groups comprising 1 to 8 carbon atoms ("C1-8 treating or delaying the progression of disorders that are alkyl), 1 to 6 carbon atoms (“C1-6 alkyl), 1 to 4 carbon alleviated by modulating monoamine release in a patient atoms (“C1-4 alkyl), or 1 to 3 carbon atoms (“C1-3 alkyl). comprising administering a therapeutically effective amount In other embodiments, alkyl refers to groups comprising 3-10 carbon atoms (“C3-10 alkyl), 3-8 carbon atoms (“C3-8 of at least one compound or prodrug as disclosed herein is alkyl), or 3-6 carbon atoms (“C3-6 alkyl). In specific provided. For example, in certain embodiments, the disorder embodiments, alkyl refers to methyl, ethyl, propyl, isopropyl. is selected from the group consisting of addiction, depression, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, iso obesity, bipolar disorder, attention deficit disorder (ADD), pentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylm attention deficit/hyperactivity disorder (ADHD), hypoactive ethyl 3-methylpenty1, 2,2-dimethylbutyl, and 2,3-dimethyl sexual desire disorder, antidepressant-induced sexual dys butyl. Substituted alkyl refers to alkyl substituted with one or function, orgasmic dysfunction, seasonal affective disorder/ more moieties selected from the group consisting of halo winter depression, mania, bulimia and other eating disorders, (e.g., Cl, F, Br, and I); halogenated alkyl (e.g., CF, 2-Br panic disorders, obsessive compulsive disorder, Schizophre ethyl, CHF, CHC1, CHCF, or CFCF); hydroxyl; amino; nia, Schizo-affective disorder, Parkinson's disease, narco carboxylate; carboxamido; alkylamino: arylamino; alkoxy; lepsy, anxiety disorders, insomnia, chronic pain, migraine aryloxy; nitro; azido: cyano; thio; Sulfonic acid; Sulfate; phos headaches, and restless legs syndrome. phonic acid; phosphate; and phosphonate. DETAILED DESCRIPTION OF THE INVENTION 0047. The term “alkenyl' as used herein means alkyl moi eties wherein at least one saturated C-C bond is replaced by 0043. The present invention now will be described more a double bond. In particular embodiments, alkenyl refers to fully hereinafter with reference to the accompanying figures, groups comprising 2 to 10 carbon atoms (“C2-10 alkenyl). in which some, but not all embodiments of the inventions are In further embodiments, alkenyl refers to groups comprising shown. Indeed, these inventions may be embodied in many 2 to 8 carbon atoms (“C2-8 alkenyl), 2 to 6 carbon atoms different focus and should not be construed as limited to the (“C2-6 alkenyl), or 2 to 4 carbon atoms (“C2-4 alkenyl). In embodiments set forth herein; rather, these embodiments are specific embodiments, alkenyl can be vinyl, allyl, 1-propenyl, provided so that this disclosure will satisfy applicable legal 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, requirements. Like numbers refer to like elements through 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, out. As used in the specification, and in the appended claims, 3-hexenyl, 4-hexenyl, or 5-hexenyl. US 2013/0203752 A1 Aug. 8, 2013

0048. The term “alkynyl as used herein means alkyl moi groups have been replaced, either with a different atom or a eties wherein at least one saturated C-C bond is replaced by different functional, generally giving rise to a compound with a triple bond. In particular embodiments, alkynyl refers to similar properties. groups comprising 2 to 10 carbon atoms (“C2-10 alkynyl). 0059. The term "derivative' as used herein means a com In further embodiments, alkynyl refers to groups comprising pound that is formed from a similar, beginning compound by 2 to 8 carbon atoms (“C2-8 alkynyl), 2 to 6 carbon atoms attaching another molecule or atom to the beginning com (“C2-6 alkynyl), or 2 to 4 carbonatoms (“C2-4 alkynyl). In pound. Further, derivatives, according to the invention, specific embodiments, alkynyl can be ethynyl, 1-propynyl, encompass one or more compounds formed from a precursor 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, compound through addition of one or more atoms or mol 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, ecules or through combining two or more precursor com 3-hexynyl, 4-hexynyl, or 5-hexynyl. pounds. 0049. The term “alkoxy” as used herein means straight or 0060. The term “prodrug” as used herein means any com branched chain alkyl groups linked by an oxygen atom (i.e., pound which, when administered to a mammal, is converted —O-alkyl), wherein alkyl is as described above. In particular in whole or in part to a compound of the invention. embodiments, alkoxy refers to oxygen-linked groups com 0061. The term “active metabolite' as used herein means a prising 1 to 10 carbon atoms (“C1-10 alkoxy”). In further physiologically active compound which results from the embodiments, alkoxy refers to oxygen-linked groups com metabolism of a compound of the invention, or a prodrug prising 1 to 8 carbon atoms (“C1-8 alkoxy), 1 to 6 carbon thereof, when such compound or prodrug is administered to a atoms (“C1-6 alkoxy”), 1 to 4 carbon atoms (“C1-4 alkoxy”) mammal or 1 to 3 carbon atoms (“C1-3 alkoxy”). 0062. The terms “therapeutically effective amount’ or 0050. The term “arylas used herein means a stable mono “therapeutically effective dose' as used herein are inter cyclic, bicyclic, or tricyclic carbon ring of up to 8 members in changeable and mean a concentration of a compound accord each ring, wherein at least one ring is aromatic as defined by ing to the invention, or a biologically active variant thereof, the Hickel 4n+2 rule. Exemplary aryl groups according to the sufficient to elicit the desired therapeutic effect according to invention include phenyl and naphthyl. the methods of treatment described herein. 0063. The term “pharmaceutically acceptable carrier as 0051. The term “halo' or “halogen' as used herein means used herein means a carrier that is conventionally used in the fluorine, chlorine, bromine, or iodine. art to facilitate the storage, administration, and/or the healing 0052. The term “alkylthio' as used herein means a thio effect of a biologically active agent. group with one or more alkyl substituents, where alkyl is 0064. The term “intermittent administration” as used defined as above. herein means administration of a therapeutically effective 0053. The term “acylamido” refers to an amide group with dose of a composition according to the invention, followed by one or more acyl substituents, where acyl is as defined below. a time period of discontinuance, which is then followed by 0054 The term “acyl as used herein means a group another administration of a therapeutically effective dose, formed by removing the hydroxyl group from a carboxylic and so forth. acid, in which the non-carbonyl moiety of the group is 0065. The term “neurotransmitter” as used herein encom selected from straight, branched, or cyclic alkyl or lower passes monoamine neurotransmitters and neuromodulators. alkyl; alkoxyalkyl including methoxymethyl, aralkyl includ In particular, the term neurotransmitter as used herein ing benzyl, aryloxyalkyl Such as phenoxymethyl: aryl includ includes, but is not limited to, dopamine, norepinephrine, and ing phenyl optionally Substituted with halogen, C1-6 alkyl or serotonin. C1-6 alkoxy; sulfonate esters such as alkyl or aralkylsulfonyl including methanesulfonyl: mono-, di-, or triphosphate ester; Active Agents trityl or monomethoxytrityl; substituted benzyl; trialkylsilyl such as dimethyl-t-butylsilyl or diphenylmethylsilyl. 0066. The present invention provides compounds, meth 0055. The terms “aralkyl and “arylalkyl as used herein ods of preparation of the compounds, pharmaceutical com mean an aryl group as defined above linked to the molecule positions, and methods of treatment of various conditions through an alkyl group as defined above. using such compounds and pharmaceutical compositions. 0056. The term "amino” as used herein means a moiety 0067. In some embodiments, morpholine compounds represented by the structure NR, and includes primary according to Formula I are provided, amines, and secondary and tertiary amines Substituted by alkyl (i.e., alkylamino). Thus, R may represent two hydrogen Formula I atoms, two alkyl moieties, or one hydrogen atom and one Rs alkyl moiety. 0057 The term “cycloalkyl means a non-aromatic, monocyclic or polycyclic ring comprising carbon and hydro gen atoms. Substituted cycloalkyl refers to alkyl substituted r R N. R4 with one or more moieties selected from the group consisting of halo (e.g., Cl, F, Br, and I); halogenated alkyl (e.g., CF 2-Br-ethyl, CHF, CHC1, CHCF, or CFCF); hydroxyl: 0068 wherein: amino; carboxylate; carboxamido; alkylamino: arylamino; 0069 R is optionally substituted aryl (e.g., naphthyl or alkoxy: aryloxy; nitro; azido; cyano; thio; Sulfonic acid; Sul phenyl); fate; phosphonic acid; phosphate, and phosphonate. 0070 R is H or optionally substituted C1-3 alkyl; 0058. The term “analogue' as used herein means a com 0071 R is H, optionally substituted C1-3 alkyl, or ben pound in which one or more individual atoms or functional Zyl; US 2013/0203752 A1 Aug. 8, 2013

0072 R is H or optionally substituted C1-3 alkyl: Substituted C2-4 alkynyl, halogen, amino, acylamido, (0073 R is Hor OH; and CN, CF, NO, N, CONH CO.R., CHOH, 0074 R is H or optionally substituted C1-3 alkyl: CHOR, NRR, NHCOR, NHCOR, 0075 with the proviso that when R is CH and R is CONRR, C1-3 alkylthio. RSO, RSO, CFS, phenyl, then (a) the phenyl ring of R is substituted with and CFSO, wherein R and Rs are each indepen one or more substituents; or (b) R is substituted Clalkyl dently selected from H or optionally substituted C1-10 or optionally substituted C2-C3 alkyl, or (c) one or more alkyl: of R. Rs, and R is not H, or a combination of two or I0086 b is an integer from 0-5; and more of (a) through (c); with the proviso that when R is CH, then (a) b is an integer 0076 or a pharmaceutically acceptable ester, amide, from 1-5, or (b) R is substituted C1 alkyl or optionally salt, Solvate, prodrug, or isomer thereof. substituted C2-C3 alkyl, or (c) one or more of R. Rs, and R. 0077. In some preferred embodiments, a compound of is not H, or a combination of two or more of (a) through (c), Formula I is provided wherein R is aryl substituted at one or or a pharmaceutically acceptable ester, amide, salt, Solvate, more available sites. Where multiple substitutions are present prodrug, or isomer thereof. on R, multiple different types of substituents may be utilized. I0087. In some preferred embodiments, b=0 or 1. In certain The one or more Substituents present on R may include, but embodiments, b=1 and R, is selected from the group consist are not limited to, OH, optionally substituted C1-4 alkyl, ing of CH, F, and Cl. In certain embodiments, the R, sub optionally substituted C1-4 alkoxy, optionally substituted stituent is located meta or para to the morpholine Substituent C2-4 alkenyl, optionally substituted C2-4 alkynyl, halogen, on the phenyl ring. amino, acylamido, CN, CF, NO, N, CONH2, COR, I0088. In another particular embodiment, the compound of CHOH, CHOR, NRR, NHCOR, NHCOR, Formula I may be represented by Formula III: CONRR, C1-3 alkylthio. RSO, RSO, CFS, and CFSO, wherein R and R are each independently selected from H or optionally substituted C1-10 alkyl. 0078. In some preferred embodiments, a compound of Formula I is provided wherein R is H. In some preferred Formula III embodiments, a compound of Formula I is provided wherein R is C1-3alkyl (e.g., CH). In some preferred embodiments, 21 a compound of Formula I is provided wherein R is H. In (R)- - R5 Some preferred embodiments, a compound of Formula I is N R6 provided wherein R is H. In some preferred embodiments, a compound of Formula I is provided wherein R is C1-3 alkyl (e.g., CH). In some preferred embodiments, a compound of DC Formula I is provided wherein Rs is H. In some preferred embodiments, a compound of Formula I is provided wherein Rs is OH. In one particular embodiment, the compound of Formula I may be represented by Formula II.

0089 wherein: 0090 R is H or optionally substituted C1-3 alkyl; 0091 R is H, optionally substituted C1-3 alkyl, or ben Formula II Zyl; 21 0092 R is H or optionally substituted C1-3 alkyl: (R)-H | Rs I0093 R is H or OH: N R6 0094 R is H or optionally substituted C1-3 alkyl: 0.095 each R, represents a substituent independently Selected from the group consisting of OH, optionally R R. R4 substituted C1-4 alkyl, optionally substituted C1-3 alkoxy, optionally substituted C2-4 alkenyl, optionally Substituted C2-4 alkynyl, halogen, amino, acylamido, CN, CF, NO, N, CONH CO.R. CH-OH, CHOR, NRR, NHCOR, NHCOR, 0079 wherein: CONRR, C1-3 alkylthio. RSO, RSO, CFS, 0080 R is H or optionally substituted C1-3 alkyl: and CFSO; and I0081 R is H, optionally substituted C1-3 alkyl, or ben (0.096 c is an integer from 0-7, Zyl; 0097 or a pharmaceutically acceptable ester, amide, I0082 R is H or optionally substituted C1-3 alkyl: salt, Solvate, prodrug, or isomer thereof. 0.083 R is H or OH: 0098. In some embodiments of the present invention, I0084 R is H or optionally substituted C1-3 alkyl; therapeutically inactive prodrugs are provided. Prodrugs are I0085 each R, represents a substituent independently compounds which, when administered to a mammal, are con Selected from the group consisting of OH, optionally verted in whole or in part to a compound of the invention. In substituted C1-4 alkyl, optionally substituted C 1-4 most embodiments, the prodrugs are pharmacologically inert alkoxy, optionally substituted C2-4 alkenyl, optionally chemical derivatives that can be converted in vivo to the active US 2013/0203752 A1 Aug. 8, 2013

drug molecules to exert a therapeutic effect. Any of the com 0102 Prodrugs of the present invention may be repre pounds described herein can be administered as a prodrug to sented by Formula IV: increase the activity, bioavailability, or stability of the com pound or to otherwise alter the properties of the compound. Typical examples of prodrugs include compounds that have Formula IV biologically labile protecting groups on a functional moiety Rs of the active compound. In preferred embodiments, the nitro gen atom of the morpholine in Formulas I-III above is func R r tionalized with such a chemical moiety. Prodrugs include, but R R4 are not limited to, compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, X hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, and/or dephosphorylated to pro Zn duce the active compound. (0103 wherein: 0099. A number of prodrug ligands are known. In general, 0104 R. R. R. Rs, and R are the same as indicated alkylation, acylation, or other lipophilic modification of one above for Formula I; or more heteroatoms of the compound. Such as a free amine or 0105 X is a chemical moiety, wherein each X may be carboxylic acid residue, may reduce polarity and allow for the the same or different; compounds passage into cells. The means by which the 0106 n is an integer from 0 to 50, preferably 1 to 10; modification of one or more heteroatoms of the compound is 0.107 Z is a chemical moiety that acts as an adjuvant, performed may vary, and typical methods for Such modifica wherein each Z may be the same or different, and tions are familiar to one of skill in the art of organic synthesis. wherein each Z is different from at least one X; and For example, general reaction conditions for the alkylation 0.108 m is an integer from 0 to 50. and acylation of heteroatoms are well known and can be 0109. In some embodiments, X may be alkyl. In some modified for application to the compounds provided herein. embodiments, when R is CH, R is phenyl, R-R are H. n=1, and m=0, X is not CH. In some, but not all, embodi 0100. In some prodrug embodiments, the amine of the ments of Formula IV, when R is phenyl, the phenyl ring is morpholine ring of any one of Formulas I-III is modified to substituted with one or more substituents and/or one or more provide a prodrug. Examples of Substituent groups that can of R. Rs, and R is not H. replace one or more hydrogenatoms on the free amine and/or 0110. The chemical moiety constituting X may be any carboxylic acid moiety include, but are not limited to, the chemical moiety that, while bound to the compound, following: aryl; Steroids; carbohydrates (including Sugars); decreases the pharmacological activity of the compound in 1.2-diacylglycerol; alcohols; acyl (including lower acyl); comparison to the free compound. In some embodiments, X alkyl (including lower alkyl); Sulfonate ester (including alkyl is any pharmaceutically acceptable chemical moiety which, or arylalkyl Sulfonyl. Such as methanesulfonyl and benzyl, when the prodrug is administered in vivo, is cleaved in whole wherein the phenyl group is optionally substituted with one or or in part to provide a free amine on the morpholine ring. more Substituents as provided in the definition of an aryl given Exemplary chemical moieties include, but are not limited to, herein); optionally Substituted arylsulfonyl: lipids (including peptides, carbohydrates (including Sugars), lipids, nucleo phospholipids); phosphotidylcholine; phosphocholine; sides, nucleic acids, and vitamins, aryl groups; steroids; 1.2- diacylglycerol; alcohols; optionally Substituted acyl groups amino acid residues or derivatives; amino acid acyl residues (including lower acyl); optionally Substituted alkyl groups or derivatives; peptides; cholesterols; or other pharmaceuti (including lower alkyl); Sulfonate esters (including alkyl or cally acceptable leaving groups which, when administered in arylalkyl Sulfonyl. Such as methanesulfonyl and benzyl, vivo, provide the free amine. Any of these moieties can be wherein the phenyl group is optionally substituted with one or used in combination with the disclosed active agents to more Substituents as provided in the definition of an aryl given achieve a desired effect. herein); optionally Substituted arylsulfonyl groups; lipids (in 0101 Prodrugs may be particularly useful according to the cluding phospholipids); phosphotidylcholine; phosphocho present invention, as they may provide a safer alternative for line; amino acid residues or derivatives; amino acid acyl treatment due to the noted high potential for abuse of amphet residues or derivatives; cholesterols; or other pharmaceuti amines and related compounds. Although the therapeutic cally acceptable leaving groups which, when administered in effect of the prodrugs may be similar to that provided by the vivo, provide the free amine and/or carboxylic acid moiety. free compounds, the prodrugs of the present invention may be Peptides include dipeptides, tripeptides, oligopeptides, and stable under conditions commonly used to provide drugs in polypeptides. concentrated form for illicit use. Specifically, using a prodrug 0111. In some preferred embodiments, X is an amino acid. should reduce the risk that pills comprising the prodrug might Where X is an amino acid or peptide, the amino acid(s) may be used to extract the drug and concentrate it or use it via other be naturally occurring or unnatural, non-standard, or syn methods (e.g., via intravenous administration, Snorting, or thetic, and may be either the L- or D enantiomer. Particularly Smoking), because additional steps (i.e., for example, acid preferable amino acids for use in the present invention cleavage and extraction) are required to provide the prodrug include alanine, lysine, serine, phenylalanine, arginine, gly compound in the pure drug form. Additionally, a prodrug cine, glutamic acid, or leucine. In some preferred embodi form may be advantageous in that it may deliver a constant ments of the invention, a prodrug of Formula IV is provided, low dose of the drug which reduces abuse liability by “slow wherein In some preferred embodiments of the invention, a onset, i.e., a pharmacokinetics approach. prodrug of Formula IV is provided, wherein X is a single US 2013/0203752 A1 Aug. 8, 2013

amino acid. In other preferred embodiments, a prodrug of Formula IV is provided, wherein X is a peptide. Formula VI 0112. With regard to peptide conjugates, an iterative approach can be used to identify favorable conjugates by synthesizing and testing single amino acid conjugates and Subsequently extending the peptide by one amino acid at a time. The parent single amino acid prodrug candidate may exhibit more or less desirable characteristics than the subse quent di- or tri-, etc. peptide candidates. The iterative approach can be beneficial in determining whether peptide length influences bioavailability. 0113. In some other embodiments, X may be represented 0119 wherein the substituents are the same as those by the following: indicated for Formula IV, except that: I0120 Rs is optionally substituted C1-10 alkyl, optionally substituted C1-10 alkoxy, optionally substituted phenyl, optionally substituted benzyl, or optionally substituted pyridyl. For example, in certain embodiments, Rs may be, but is not limited to, CH, CHCH phenyl, benzyl, 4-CHNPh. 3-pyridyl, OCH, OCHCH (CH)N(CH), (CH)-N' (CH), O(CH)NH2. O(CH)N(CH), and O(CH)-N-- (CH), or any of the following: x-rr xxy

0114. As noted, Z may be a chemical moiety that acts as an adjuvant. Exemplary chemical moieties that may comprise Z include those indicated for X, above (e.g., peptides, amino 0121. In some embodiments, compounds or prodrugs with acids, carbohydrates, vitamins) Further examples of Z may be one or more chiral centers are provided. While racemic mix found, for example, in U.S. Patent Application Publication tures of compounds or prodrugs of the invention may be 2009/0192093 to Mickle et al., incorporated by reference active, selective, and bioavailable, isolated isomers may be of herein in its entirety. interest as well. 0115. In preferred embodiments, m=0, which is repre 0.122 The compounds and prodrugs disclosed herein as sented by Formula V: active agents may contain chiral centers, which may be either of the (R) or (S) configuration, or which may comprise a mixture thereof. Accordingly, the present invention also includes stereoisomers of the compounds and prodrugs described herein, where applicable, either individually or Formula V admixed in any proportions. Stereoisomers may include, but Rs are not limited to, enantiomers, diastereomers, racemic mix R R6 tures, and combinations thereof Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating R R4 isomers of compounds and prodrugs of the present invention. X Isomers may include geometric isomers. Examples of geo metric isomers include, but are not limited to, cis isomers or trans isomers across a double bond. Other isomers are con 0116 wherein the substituents are the same as those templated among the compounds of the present invention. indicated for Formula IV. The isomers may be used either in pure form or in admixture 0117. In preferred embodiments, when R is CH, R is with other isomers of the compounds described herein. phenyl, R-R are H, and n=1, X is not CH. I0123. The compounds of the present invention may be 0118. In some preferred embodiments, prodrugs of the compounds according to Formulas I-III with one or more present invention may be represented by the following for chiral centers, which may be either of the (R) or (S) configu mula: ration, or which may comprise a mixture thereof The carbon US 2013/0203752 A1 Aug. 8, 2013

to which R and Rs are connected may be either of the R or S may be either of the R or S configuration. Accordingly, the configuration. When R is a substituent other than H, the present invention includes both racemic mixtures of prodrugs carbon to which R is connected is a chiral center and may be of Formula IV and isolated isomers of Formula IV. Where either of the R or S configuration. When R is a substituent more than one chiral center is present in a compound of the other than H, the carbon to which R is connected to is a chiral invention, Some, none, or all of the chiral centers may be center and may be either of the R or S configuration. When R. enantiomerically enriched. Thus, mixtures of a compound of is a substituent other than H, the carbon to which R is con Formula IV may be racemic with respect to one or more chiral nected is a chiral center and may be either of the R or S centers and/or enantiomerically enriched with respect to one configuration. The present invention includes both racemic or more chiral centers. mixtures of a compound of Formula I and isolated isomers of I0126. In some preferred embodiments, an enantiomeri Formulas I-III. Where more than one chiral center is present cally enriched sample of a prodrug of Formula IV is provided in a compound of the invention, some, none, or all of the chiral wherein the carbon to which R and Rs are attached is (R) or centers may be enantiomerically enriched. Thus, mixtures of (S). In some preferred embodiments, an enantiomerically a compound of Formulas I-III may be racemic with respect to enriched sample of a prodrug of Formula IV is provided one or more chiral centers and/or enantiomerically enriched wherein the carbon to which R is attached is (R) or (S). In with respect to one or more chiral centers. Some preferred embodiments, an enantiomerically enriched 0.124. In some preferred embodiments, an enantiomeri sample of a prodrug of Formula IV is provided wherein the cally enriched sample of a compound of Formulas I-III is carbon to which R is attached is (R) or (S). In some preferred provided wherein the carbon to which R and Rs are attached embodiments, an enantiomerically enriched sample of a pro is (R) or (S). In some preferred embodiments, an enantiomeri drug of Formula IV is provided wherein both the carbon to cally enriched sample of a compound of Formulas I-III is which R and Rs are attached and the carbon to which R is provided wherein the carbon to which R is attached is (R) or attached are independently (R) or (S) (e.g., (R, S), (S,R), (R, (S). In some preferred embodiments, an enantiomerically R), or (S,S)). In some preferred embodiments, an enantio enriched sample of a compound of Formulas I-III is provided merically enriched sample of a prodrug of Formula IV is wherein the carbon to which R is attached is (R) or (S). In provided wherein both the carbon to which R and Rs are Some preferred embodiments, an enantiomerically enriched attached and the carbon to which R is attached are indepen sample of a compound of Formulas I-III is provided wherein dently (R) or (S) (e.g., (R, S), (S,R), (R,R), or (S,S)). In some the compound to which R is attached is (R) or (S). In some preferred embodiments, an enantiomerically enriched sample preferred embodiments, an enantiomerically enriched sample of a prodrug of Formula IV is provided wherein both the of a compound of Formulas I-III is provided wherein both the carbon to which R is attached and the carbon to which R is carbon to which RandR is attached and the carbon to which attached are independently (R) or (S) (e.g., (R, S), (S,R), (R, R is attached are independently (R) or (S) (e.g., (R, S), (S,R), R), or (S,S)). (R,R), or (S,S)). In some preferred embodiments, an enan I0127. Various methods are known in the art for preparing tiomerically enriched sample of a compound of Formulas optically active fauns and determining activity. Such methods I-III is provided wherein both the carbon to which R and Rs include standard tests described herein and other similar tests is attached and the carbon to which R is attached are inde which are well known in the art. Examples of methods that pendently (R) or (S) (e.g., (R, S), (S,R), (R,R), or (S,S)). In can be used to obtain optical isomers of the compounds Some preferred embodiments, an enantiomerically enriched according to the present invention include the following: sample of a compound of Formulas I-III is provided wherein I0128 i) physical separation of crystals whereby macro both the carbon to which RandR is attached and the carbon scopic crystals of the individual enantiomers are manually to which R is attached are independently (R) or (S) (e.g., (R, separated. This technique may particularly be used when S), (S,R), (R,R), or (S,S)). In some preferred embodiments, crystals of the separate enantiomers exist (i.e., the material is an enantiomerically enriched sample of a compound of For a conglomerate), and the crystals are visually distinct; mulas I-III is provided wherein both the carbon to which R is I0129 ii) simultaneous crystallization whereby the indi attached and the carbon to which R is attached are indepen vidual enantiomers are separately crystallized from a solution dently (R) or (S) (e.g., (R, S), (S,R), (R, R), or (S,S)). of the racemate, possible only if the latteris a conglomerate in Obviously, compounds are within the scope of the present the solid state; invention wherein one, two, three, or four chiral centers are 0.130 iii) enzymatic resolutions whereby partial or com provided on the morpholine ring. Accordingly, various enan plete separation of a racemate by virtue of differing rates of tiomerically enriched compounds may be provided, wherein reaction for the enantiomers with an enzyme; the compounds may be racemic with respect to one or more I0131 iv) enzymatic asymmetric synthesis, a synthetic chiral centers and/or enantiomerically enriched with respect technique whereby at least one step of the synthesis uses an to one or more chiral centers. enzymatic reaction to obtain an enantiomerically pure or 0.125. The prodrugs of the present invention may be pro enriched synthetic precursor of the desired enantiomer; drugs according to Formula IV with one or more chiral cen I0132 v) chemical asymmetric synthesis whereby the ters, which may be either of the (R) or (S) configuration, or desired enantiomer is synthesized from an achiral precursor which may comprise a mixture thereof The carbon to which under conditions that produce asymmetry (i.e., chirality) in R and Rs are connected may be either of the R or S configu the product, which may be achieved using chiral catalysts or ration. When R is a substituent other than H, the carbon to chiral auxiliaries; which R is connected is chiral and may be either of the Ror 0.133 vi) diastereomer separations whereby a racemic S configuration. When R is a substituent other than H, the compound is reacted with an enantiomerically pure reagent carbon to which R is connected to is chiral and may be either (the chiral auxiliary) that converts the individual enantiomers of the R or S configuration. When R is a substituent other to diastereomers. The resulting diastereomers are then sepa than H, the carbon to which R is connected to is chiral and rated by chromatography or crystallization by virtue of their US 2013/0203752 A1 Aug. 8, 2013

now more distinct structural differences and the chiral auxil 0.143 Although various stereoisomers may be represented iary later removed to obtain the desired enantiomer; by the previous formulas, one particularly preferred configu 0134 vii) first- and second-order asymmetric transforma ration of Foilinula I is represented by Formula VII: tions whereby diastereomers from the racemate equilibrate to yield a preponderance in Solution of the diastereomer from the desired enantiomer or where preferential crystallization Formula VII of the diastereomer from the desired enantiomer perturbs the Rs equilibrium such that eventually in principle all the material is R1a -O R6 converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomers; R2 NR3 R4 0135 viii) kinetic resolutions comprising partial or com plete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction 0144 or a pharmaceutically acceptable ester, amide, salt, rates of the enantiomers with a chiral, non-racemic reagent or Solvate, prodrug, or isomer thereof. catalyst under kinetic conditions; 0145. In an alternative embodiment, a preferred configu 0.136 ix) enantiospecific synthesis from non-racemic pre ration of Formula I is represented by Formula VIII, wherein cursors whereby the desired enantiomer is obtained from R is not H: non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; Formula VIII 0.137 x) chiral liquid chromatography whereby the enan tiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase. The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; 0138 xi) chiral gas chromatography whereby the race 0146 or a pharmaceutically acceptable ester, amide, salt, mate is volatilized and enantiomers are separated by virtue of solvate, prodrug, or isomer thereof. their differing interactions in the gaseous mobile phase with a I0147 In one embodiment, R is not H and a chiral center column containing a fixed non-racemic chiral adsorbent exists both at the carbon to which R and Rs are attached, and phase; at the carbon alpha to the amine of the morpholine ring (to 0139 xii) extraction with chiral solvents whereby the enantiomers are separated by virtue of preferential dissolu which R is attached), as shown below in Formula IX: tion of one enantiomer into a particular chiral solvent; and 0140 xiii) transport across chiral membranes whereby a Formula IX racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one con taining the racemate, and a driving force Such as concentra tion or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one enantiomer of the racemate to pass through. 0141. The compound optionally may be provided in a 0.148 or a pharmaceutically acceptable ester, amide, salt, composition that is enantiomerically enriched, Such as a mix Solvate, prodrug, or isomer thereof. ture of enantiomers in which one enantiomer is present in 0.149 Inanother embodiment, an alternative enantiomer is excess, in particular, to the extent of 95% or more, 96% or provided, represented by Formula X: more, 97% or more, 98% or more, or 99% or more, including 100%. 0142. In some embodiments, a compound of Formula I or Formula X a prodrug of Formula V is provided, wherein the compound Rs contains one or more chiral centers. Specifically, the carbon to which R and Rs is attached is a chiral center, and may have eitheran R or S configuration. Depending on the Substituents h R6 on the compound, other chiral centers may be present in the R 2 NR3 R4 compound as well. In some embodiments, the compound is provided in a composition that is enantiomerically enriched. One preferred configuration is represented below in Figure 0150 or a pharmaceutically acceptable ester, amide, salt, VII. The chiral center(s) present in the compounds may be Solvate, prodrug, or isomer thereof. designated as either R or S, depending on the specific Sub 0151. These compounds or prodrugs, wherein two chiral stituents on the chiral center. For example, in Formula VII centers are present in the molecule, may be (R,R), (S,S), below, when R is phenyl and Rs is H, the carbon center is (RS), or (S,R) isomers. The “trans’ compounds, wherein one designated as R, whereas when R is phenyland Rs is OH, the of R and R is above the plane of the molecule and one of R carbon center is designated as S. and R is below the plane of the molecule are encompassed by US 2013/0203752 A1 Aug. 8, 2013

the invention. The “cis' compounds, wherein R and R are maleic, oxaloacetic, methanesulfonic, ethanesulfonic, p-tolu both above the plane of the molecule, or wherein R and R enesulfonic, benzenesulfonic, and isethionic acids. Other are both below the plane of the molecule, are also within the useful acid addition salts include propionic acid, glycolic purview of this invention. In these compounds, as noted acid, oxalic acid, malic acid, malonic acid, benzoic acid, above, the identity of the Substituents comprising R and Rs cinnamic acid, mandelic acid, Salicylic acid, and the like. will determine whether the carbon center to which these Particular example of pharmaceutically acceptable salts Substituents are attached is designated as R or S. include, but are not limited to, Sulfates, pyrosulfates, bisul 0152. As noted above, the carbon centers to which R. R. fates, sulfites, bisulfites, phosphates, monohydrogenphos and Rare attached may be chiral, when these substituents are phates, dihydrogenphosphates, metaphosphates, pyrophos not H. Compounds wherein one or more of the four carbons phates, chlorides, bromides, iodides, acetates, propionates, on the morpholine ring are chiral are encompassed within the decanoates, caprylates, acrylates, formates, isobutyrates, present invention. Compounds that are enantiomerically caproates, heptanoates, propiolates, oxalates, malonates, suc enriched with regard to zero, one, two, three, or all four cinates, Suberates, sebacates, fumarates, maleates, butyne-1, carbon centers on the morpholine ring are encompassed. All 4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, isomeric combinations are encompassed within the present methylbenzoates, dinitrobenzoates, hydroxybenzoates, invention. methoxyenzoates, phthalates, Sulfonates, Xylenesulfonates, 0153. The terms (R), (S), (R,R), (S,S), (R.S) and (S,R) as phenylacetates, phenylpropionates, phenylbutyrates, citrates, used herein mean that the composition contains a greater lactates, Y-hydroxybutyrates, glycolates, tartrates, methane proportion of the named isomer of the compound or prodrug Sulfonates, propanesulfonates, naphthalene-1-sulfonates, in relation to other isomers. In a preferred embodiment these naphthalene-2-sulfonates, and mandelates. terms indicate that the composition contains at least 90% by 0157 An acid addition salt may be reconverted to the free weight of the named isomer and 10% by weight or less of the base by treatment with a suitable base. Preparation of basic one or more other isomers; or more preferably about 95% by salts of acid moieties which may be present on a compound or weight of the named isomer and 5% or less of the one or more prodrug useful according to the present invention may be other isomers. In some embodiments, the composition may prepared in a similar manner using a pharmaceutically contain at least 99% by weight of the named isomer and 1% acceptable base, such as sodium hydroxide, potassium or less by weight of the one or more other isomers, or may hydroxide, ammonium hydroxide, calcium hydroxide, tri contain 100% by weight of the named isomer and 0% by ethylamine, or the like. weight of the one of more other isomers. These percentages 0158 Esters of the active agent compounds according to are based on the total amount of the compound of the present the present invention may be prepared through functionaliza invention present in the composition. tion of hydroxyl and/or carboxyl groups that may be present 0154 Additional chiral centers may be present in the com within the molecular structure of the compound or prodrug. pounds and prodrugs of the present invention. Compound Amides and prodrugs may also be prepared using techniques samples wherein the compounds contain any of the afore known to those skilled in the art. For example, amides may be mentioned chiral centers may be racemic or may be enantio prepared from esters, using Suitable amine reactants, or they merically enriched. Where more than one chiral center is may be prepared from anhydride or an acid chloride by reac present in a compound or prodrug of the invention, Some, tion with ammonia or a lower alkyl amine. Moreover, esters none, or all of the chiral centers may be enantiomerically and amides of compounds and prodrugs of the invention can enriched. Thus, they may be racemic with respect to one or be made by reaction with a carbonylating agent (e.g., ethyl more chiral centers and/or enantiomerically enriched with formate, acetic anhydride, methoxyacetyl chloride, benzoyl respect to one or more chiral centers. chloride, methyl isocyanate, ethyl chloroformate, methane 0155 The compounds and prodrugs of the present inven Sulfonyl chloride) and a Suitable base (e.g., 4-dimethylami tion may be utilized perse or in the form of a pharmaceuti nopyridine, pyridine, triethylamine, potassium carbonate) in cally acceptable ester, amide, salt, Solvate, prodrug, or iso a suitable organic solvent (e.g., tetrahydrofuran, acetone, mer. For example, the compound or prodrug may be provided methanol, pyridine, N,N-dimethylformamide) at a tempera as a pharmaceutically acceptable salt. If used, a salt of the ture of 0° C. to 60° C. Prodrugs are typically prepared by drug compound or prodrug should be both pharmacologically covalent attachment of a moiety, which results in a compound and pharmaceutically acceptable, but non-pharmaceutically that is therapeutically inactive until modified by an individu acceptable salts may conveniently be used to prepare the free als metabolic system. Examples of pharmaceutically accept active compound, prodrug, or pharmaceutically acceptable able Solvates include, but are not limited to, compounds salts thereof and are not excluded from the scope of this according to the invention in combination with water, isopro invention. Such pharmacologically and pharmaceutically panol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, acceptable salts can be prepared by reaction of the drug with or ethanolamine. an organic or inorganic acid, using standard methods detailed 0159. In the case of solid compositions, it is understood in the literature. that the compounds and prodrugs used in the methods of the 0156 Examples of pharmaceutically acceptable salts of invention may exist in different forms. For example, the com the compounds and prodrugs useful according to the inven pounds or prodrugs may exist in stable and metastable crys tion include acid addition salts. Salts of non-pharmaceuti talline forms and isotropic and amorphous forms, all of which cally acceptable acids, however, may be useful, for example, are intended to be within the scope of the present invention. in the preparation and purification of the compounds. Suitable 0160 If a compound or prodrug useful as an active agent acid addition salts according to the present invention include according to the invention is a base, the desired salt may be organic and inorganic acids. Preferred salts include those prepared by any suitable method known to the art, including formed from hydrochloric, hydrobromic, sulfuric, phospho treatment of the free base with an inorganic acid, such as ric, citric, tartaric, lactic, pyruvic, acetic. Succinic, fumaric, hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric US 2013/0203752 A1 Aug. 8, 2013

acid, phosphoric acid and the like, or with an organic acid, TABLE 1-continued Such as acetic acid, maleic acid, Succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic Representative Compounds of the Invention acid, Salicylic acid, pyranosidyl acids such as glucuronic acid and galacturonic acid, alpha-hydroxy acids such as citric acid R2 R3 R R5 R74 R7B R7C R7D R7. and tartaric acid, amino acids such as aspartic acid and CH, H H H H CHCH CHCH H CH, H H H H CHCH CHCH glutamic acid, aromatic acids such as benzoic acid and cin CH H H H CH-CH CH-CH CHCH H namic acid, Sulfonic acids such a p-toluenesulfonic acid or CH, H H H H CHCH CHCH CHCH ethanesulfonic acid, or the like. CH, H H H CHCH H CHCH H CHCH CH H H H CHCH H CHCH CHCH 0161 If a compound or prodrug described herein as an CH H H H CHCH H CHCH CHCH active agent is an acid, the desired salt may be prepared by any CH H H H CH-CH CH-CH CH-CH CHCH suitable method known to the art, including treatment of the CH, H H H CHCH H CHCH CH-CH CHCH free acid with an inorganic or organic base, such as an amine CH H H H CH-CH CHCH CHCH CHCH CH H H H CH-CH CH-CH CH-CH CH-CH CHCH (primary, secondary or tertiary), an alkali metal or alkaline CH, H H H C H H earth metal hydroxide or the like. Illustrative examples of CH, H H H H C H Suitable salts include organic salts derived from amino acids CH, H H H H H C H Such as glycine and arginine, ammonia, primary, secondary CH, H H H C C H CH, H H H C H C H and tertiary amines, and cyclic amines Such as piperidine, CH, H H H C H C morpholine and piperazine, and inorganic salts derived from CH, H H H C H H C Sodium, calcium, potassium, magnesium, manganese, iron, CH, H H H H C C H copper, Zinc, aluminum and lithium. CH, H H H H C C CH, H H H C C C H 0162 Some preferred compounds of the invention include CH, H H H H C C C the following, wherein R and Rs are H, the R substituent on CH, H H H C H C H C the morpholine ring is phenyl and the Substituents on the CH, H H H C H C C CH, H H H C H C C phenyl are varied. CH, H H H C C C C CH, H H H C H C C C CH, H H H C C C C RB CH, H H H C C C C C CH, H H H H H R7C R7. CH, H H H H H CH, H H H H H H Rs CH 3 H O CH 3 H H R7t CH 3 H CH, H H H H H RE CH 3 H H R N. R4 CH 3 H CH 3 H CH 3 H CH 3 H H CH 3 H TABLE 1. CH 3 H CH 3 Representative Compounds of the Invention CH 3 H CH 3 H R2 R3 R R5 R74 R7B R7C R7D R7. CH 3 CH, H H H Br H H H CH H H H CH H H CH, H H H H Br H H CH, H H H H CH H CH, H H H H H Br H CH, H H H H CH H CH, H H H Br Br H H CH H H H CH, CH H CH, H H H Br H Br H CH H H H CH H CH H CH, H H H Br H H Br CH H H H CH H CH CH, H H H Br H H H Br CH, H H H CH, H H CH CH, H H H H Br Br H CH, H H H H CH CH H CH, H H H H Br H Br CH, H H H H CH CH CH, H H H Br Br Br H CH H H H CH, CH CH H CH, H H H H Br Br Br CH, H H H H CH CH CH CH, H H H Br H Br H Br CH H H H CH H CH H CH CH, H H H Br H H Br Br CH H H H CH H CH CH CH, H H H Br H Br Br CH, H H H CH, H CH CH CH, H H H Br Br Br Br CH H H H CH, CH CH CH CH, H H H Br H Br Br Br CH H H H CH CH CH CH CH, H H H Br Br H Br Br CH H H H CH, CH CH CH CH, H H H Br Br Br Br Br CH, H H H CH, CH, CH CH CH CH, H H H OCH, H H H CH H H H CHCH. H H CH, H H H H OCH, H H CH, H H H H CHCH H CH, H H H H H OCH H CH, H H H H H CH-CH H CH H H H OCH OCH H H CH, H H H CHCH, CHCH H CH, H H H OCH, H OCH H CH H H H CH-CH H CH-CH H CH, H H H OCH, H H OCH, CH H H H CHCH. H CHCH CH, H H H OCH, H H H OCH CH H H H CHCH. H H CHCH CH, H H H H OCH OCH H

US 2013/0203752 A1 Aug. 8, 2013 14

TABLE 2-continued dopamine release are desirable because they may be useful for treatment of stimulant (e.g., cocaine and methamphet Representative Compounds of the Invention amine) addiction. 0.165. In certain embodiments, the compounds cause R2 R R Rs R74 R7B R7C R7D R7. release of serotonin. In some embodiments, the compounds H H CH, H H C cause release of dopamine and serotonin. In some of these H H CH, H H C H H H CH, H H C H embodiments, there is little or no norepinephrine release. In H H CH, H H C H Some embodiments, the compounds show little or no activity CH 3 C H at the 5HT receptor. In some embodiments, the compounds CH 3 C of the present invention function as uptake inhibitors of one or H H CH, H C H H H CH, H H C H more monoamine neurotransmitters. In particular embodi H H CH, H H C H ments, the compounds show hybrid activity in that they cause H H CH, H H C H release of one or more monoamines and also cause uptake H H CH, H H C H inhibition of one or more monoamines. For example, in some H H CH, H H C H CH 3 C embodiments, compounds of the present invention act as CH 3 C dopamine and/or norepinephrine releasers and as serotonin H H CH, H C H uptake inhibitors. In certain embodiments, the compounds CH 3 C are serotonin releasers or serotonin uptake inhibitors, but CH 3 C CH 3 C H display little to no activity at the 5HT receptor. CH 3 C 0166 In some embodiments, phenyl ring substitution H H CH, H C H increases serotonin release. In certain embodiments, CH 3 C increased serotonin release is desirable in decreasing the CH 3 C addiction liability commonly demonstrated by dopamine CH 3 C H H CH, H C C H H releasers and some combination dopamine?serotonin releas H H CH, H C H C H CS. H H CH, H C H H C H H CH, H H H H H Compositions H H CH, H H H H H H H CH, H H H H H 0.167 While it is possible for the compounds and prodrugs H H CH, H C H H H H H CH, H H C H H of the present invention to be administered in the raw chemi H H CH, H C C C H cal form, it is preferred for the compounds or prodrugs to be H H CH, H C H C C delivered as a pharmaceutical formulation. Accordingly, H H CH, H H C C C there are provided by the present invention pharmaceutical H H CH, H C C C H H H CH, H C H C C compositions comprising at least one compound capable of H H CH, H C C C inhibiting the reuptake of one or more monoamines. As such, H H CH, H C C C H the formulations of the present invention comprise a com H H CH, H C C C pound of any of the formulas noted herein, as described H H CH, H F C C C C above, or a pharmaceutically acceptable ester, amide, salt, or H H CH, H C C C C H H CH, H C C C C Solvate thereof, together with one or more pharmaceutically H CH, H CF H acceptable carriers therefore, and optionally, other therapeu H CH, H H CF tic ingredients. H H CH, H H H CF 0168 By “pharmaceutically acceptable carrier is CH 3 C F3 C F3 intended a carrier that is conventionally used in the art to H H CH, H CF H CF H H CH, H CF H CF facilitate the storage, administration, and/or the healing effect H H CH, H CF H CF of the agent. The carrier(s) must be pharmaceutically accept H H CH, H H CF CF able in the sense of being compatible with the other ingredi H H CH, H H CF CF ents of the formulation and not unduly deleterious to the CH 3 C F3 C F3 C F3 recipient thereof. A carrier may also reduce any undesirable H H CH, H H CF CF CF side effects of the agent. Such carriers are known in the art. H H CH, H CF H CF CF H H CH, H CF H CF CF See, Wang et al. (1980).J Parent. Drug Assn. 34 (6):452-462, H H CH, H CF H CF CF herein incorporated by reference in its entirety. H H CH, H CF CF CF CF 0169. Adjuvants or accessory ingredients for use in the H H CH, H CF H CF CF CF formulations of the present invention can include any phar H H CH, H CF CF CF CF maceutical ingredient commonly deemed acceptable in the H H CH, H CF CF CF CF CF art, such as binders, fillers, lubricants, disintegrants, diluents, Surfactants, stabilizers, preservatives, flavoring and coloring agents, and the like. The compositions may further include 0164. The compounds of the present invention may dis diluents, buffers, binders, disintegrants, thickeners, lubri play different types of activities. In general, the compounds of cants, preservatives (including antioxidants), flavoring the present invention may function as monoamine neu agents, taste-masking agents, inorganic salts (e.g., sodium rotransmitter releasers, which effectuate the release of one or chloride), antimicrobial agents (e.g., benzalkonium chlo more of dopamine, norepinephrine, and/or serotonin and/or ride), Sweeteners, antistatic agents, Surfactants (e.g., polysor may act as monoamine neurotransmitter uptake inhibitors. In bates such as "TWEEN 20” and "TWEEN 80°, and pluronics certain embodiments, the compounds cause release of such as F68 and F88, available from BASF), sorbitan esters, dopamine. In certain embodiments, compounds that cause lipids (e.g., phospholipids Such as lecithin and other phos US 2013/0203752 A1 Aug. 8, 2013

phatidylcholines, phosphatidylethanolamines, fatty acids and then physically treated to present the formulation in a suitable fatty esters, steroids (e.g., cholesterol)), and chelating agents form for delivery (e.g., shaping into a tablet or forming an (e.g., EDTA, zinc and other such suitable cations). Other aqueous Suspension). exemplary pharmaceutical excipients and/or additives Suit 0.174 Pharmaceutical formulations according to the able for use in the compositions according to the invention are present invention Suitable as oral dosage may take various listed in Remington: The Science & Practice of Pharmacy, forms, such as tablets, capsules, caplets, and wafers (includ 21' ed., Lippincott Williams & Wilkins (2006); in the Physi ing rapidly dissolving or effervescing), each containing a cian's Desk Reference, 64" ed., Thomson PDR (2010); and in predetermined amount of the active agent. The formulations Handbook of Pharmaceutical Excipients, 6" ed., Eds. Ray may also be in the form of a powder or granules, a solution or mond C. Rowe et al., Pharmaceutical Press (2009), which are Suspension in an aqueous or non-aqueous liquid, and as a incorporated herein by reference. liquid emulsion (oil-in-water and water-in-oil). The active 0170 Binders are generally used to facilitate cohesiveness agent may also be delivered as a bolus, electuary, or paste. It of the tablet and ensure the tablet remains intact after com is generally understood that methods of preparations of the pression. Suitable binders include, but are not limited to: above dosage fauns are generally known in the art, and any starch, polysaccharides, gelatin, polyethylene glycol, propy such method would be suitable for the preparation of the lene glycol, waxes, and natural and synthetic gums. Accept respective dosage forms for use in delivery of the compounds able fillers include silicon dioxide, titanium dioxide, alumina, according to the present invention. talc, kaolin, powdered cellulose, and microcrystalline cellu 0.175. A tablet containing a compound or prodrug accord lose, as well as soluble materials, such as mannitol, urea, Sucrose, lactose, dextrose, sodium chloride, and Sorbitol. ing to the present invention may be manufactured by any Lubricants are useful for facilitating tablet manufacture and standard process readily known to one of skill in the art, Such include vegetable oils, glycerin, magnesium Stearate, calcium as, for example, by compression or molding, optionally with Stearate, and Stearic acid. Disintegrants, which are useful for one or more adjuvant or accessory ingredient. The tablets may facilitating disintegration of the tablet, generally include optionally be coated or scored and may be formulated so as to starches, clays, celluloses, algins, gums, and crosslinked poly provide slow or controlled release of the active agent. mers. Diluents, which are generally included to provide bulk 0176 Solid dosage farms may be formulated so as to pro to the tablet, may includedicalcium phosphate, calcium Sul vide a delayed release of the active agent. Such as by appli fate, lactose, cellulose, kaolin, mannitol, Sodium chloride, dry cation of a coating. Delayed release coatings are known in the starch, and powdered sugar. Surfactants suitable for use in the art, and dosage from containing Such may be prepared by any formulation according to the present invention may be known suitable method. Such methods generally include that, anionic, cationic, amphoteric, or nonionic Surface active after preparation of the Solid dosage form (e.g., a tablet or agents. Stabilizers may be included in the formulations to caplet), a delayed release coating composition is applied. inhibit or lessen reactions leading to decomposition of the Application can be by methods such as airless spraying, flu active agent, such as oxidative reactions. idized bed coating, use of a coating pan, or the like. Materials 0171 Formulations of the present invention may include for use as a delayed release coating can be polymeric in short-term, rapid-onset, rapid-offset, controlled release, Sus nature. Such as cellulosic material (e.g., cellulose butyrate tained release, delayed release, and pulsatile release formu phthalate, hydroxypropyl methylcellulosephthalate, and car lations, providing the formulations achieve administration of boxymethyl ethylcellulose), and polymers and copolymers of a compound as described herein. See Remington's Pharma acrylic acid, methacrylic acid, and esters thereof. ceutical Sciences (18" ed.: Mack Publishing Company, 0177 Solid dosage forms according to the present inven Eaton, Pa., 1990), herein incorporated by reference in its tion may also be Sustained release (i.e., releasing the active entirety. agent over a prolonged period of time), and may or may not 0172 Pharmaceutical formulations according to the also be delayed release. Sustained release formulations are present invention are suitable for various modes of delivery, known in the art and are generally prepared by dispersing a including oral, parenteral (including intravenous, intramus drug within a matrix of a gradually degradable or hydrolyZ cular, Subcutaneous, intradermal, and transdermal), topical able material. Such as an insoluble plastic, a hydrophilic poly (including dermal, buccal, and Sublingual), and rectal admin mer, or a fatty compound. Alternatively, a Solid dosage form istration. The most useful and/or beneficial mode of admin may be coated with Such a material. istration can vary, especially depending upon the condition of 0.178 Formulations for parenteral administration include the recipient and the disorder being treated. However, in aqueous and non-aqueous sterile injection solutions, which preferred embodiments, the formulation is for oral delivery, may further contain additional agents, such as anti-oxidants, as oral administration may provide the drug while maintain buffers, bacteriostats, and solutes, which render the formula ing abuse resistance. tions isotonic with the blood of the intended recipient. The 0173 The pharmaceutical formulations may be conve formulations may include aqueous and non-aqueous sterile niently made available in a unit dosage form, whereby Such Suspensions, which contain Suspending agents and thicken formulations may be prepared by any of the methods gener ing agents. Such formulations for patenteral administration ally known in the pharmaceutical arts. Generally speaking, may be presented in unit-dose or multi-dose containers. Such Such methods of preparation comprise combining (by various as, for example, sealed ampoules and vials, and may be stores methods) an active agent, such as the compounds of Formula in a freeze-dried (lyophilized) condition requiring only the I according to the present invention (or a pharmaceutically addition of the sterile liquid carrier, for example, water (for acceptable ester, amide, Salt, or Solvate thereof) or the pro injection), immediately prior to use. Extemporaneous injec drugs of Formula IV, with a suitable carrier or other adjuvant, tion Solutions and Suspensions may be prepared from sterile which may consist of one or more ingredients. The combina powders, granules, and tablets of the kind previously tion of the active ingredient with the one or more adjuvants is described. US 2013/0203752 A1 Aug. 8, 2013

0179 The compounds according to the present invention weight of a compound or prodrug of the invention, typically may also be administered transdermally, wherein the active from about 5% to about 70% by weight, and more typically agent is incorporated into a laminated structure (generally from about 10% to about 50% by weight, and will also depend referred to as a “patch') that is adapted to remain in intimate upon the relative amounts of excipients/additives contained contact with the epidermis of the recipient for a prolonged in the composition. period of time. Typically, Such patches are available as single layer "drug-in-adhesive' patches or as multi-layer patches Combinations where the active agent is contained in a layer separate from 0183 Inspecific embodiments, active agents used in com the adhesive layer. Both types of patches also generally con bination with compounds or prodrugs of the present invention tain a backing layer and a liner that is removed prior to comprise one or more compounds generally recognized as attachment to the skin of the recipient. Transdermal drug useful for treating the conditions discussed herein. In one delivery patches may also be comprised of a reservoir under embodiment, the use of two or more drugs, which may be of lying the backing layer that is separated from the skin of the different therapeutic classes, may enhance efficacy and/or recipient by a semi-permeable membrane and adhesive layer. reduce adverse effects associated with one or more of the Transdeimal drug delivery may occur through passive diffu drugs. sion or may be facilitated using electrotransport or ionto 0.184 For example, in certain embodiments, the present phoresis. invention provides a method for treating pre-obesity and obe 0180 Formulations for rectal delivery of the compounds sity, comprising a combination of a compound or prodrug of of the present invention include rectal Suppositories, creams, the present invention and one or more known antiobesity ointments, and liquids. Suppositories may be presented as the drugs. Common therapeutic classes of obesity drugs include active agent in combination with a carrier generally known in those that decrease food intake by either reducing appetite or the art, Such as polyethylene glycol. Such dosage forms may increasing Satiety, those that decrease nutrient absorption, be designed to disintegrate rapidly or over an extended period and those that increase energy expenditure. In some embodi of time, and the time to complete disintegration can range ments, the compounds disclosed herein, either in a form from a short time, Such as about 10 minutes, to an extended according to any one of Formulas I, II, III, VI, VII, VIII, IX, period of time, Such as about 6 hours. or X or in prodrug form according to Formula IV or Formula 0181. The compounds of the formulas above may be for V, may be used with one or more known antiobesity drugs. mulated in compositions including those Suitable for oral, Examples of known antiobesity drugs include: phentermine, buccal, rectal, topical, nasal, ophthalmic, or parenteral (in which is an appetite suppressant; topiramate, which is an cluding intraperitoneal, intravenous, Subcutaneous, or intra depressant/epilepsy drug that has been shown to interfere muscular injection) administration. The compositions may with binge eating and may result in decreased weight and conveniently be presented in unit dosage form and may be decreased blood pressure; Orlistat (Xenical, Alli(R), which prepared by any of the methods well known in the art of reduces intestinal fat absorption by inhibiting pancreatic pharmacy. All methods include the step of bringing a com lipase: Sibutramine (Reductil or Meridia), which is an pound or prodrug of one of the formulas disclosed herein into anorectic or appetite Suppressant; diethylpropion (diethyl association with a carrier that constitutes one or more acces cathinonefamfepramone, also sold as Anorex.R. Tenuate.(R) sory ingredients. In general, the compositions are prepared by and TepanilR), which is a stimulant marketed as an appetite bringing a compound or prodrug of the invention into asso Suppressant (which functions as a prodrug for ethcathinone); ciation with a liquid carrier to form a solution or a Suspension, Mazindol (Mazanor, Sanorex), which is a tetracyclic stimu or alternatively, bringing a compound or prodrug of the inven lant drug used for short-term treatment of obesity; Rimona tion into association with formulation components Suitable bant (Acomplia), which is a recently developed medication for forming a solid, optionally a particulate product, and then, that is a cannabinoid (CB1) receptor antagonist that acts if warranted, shaping the product into a desired delivery form. centrally on the brain to decrease appetite and may also Solid formulations of the invention, when particulate, will increase energy expenditure; metformin (glucophage) in typically comprise particles with sizes ranging from about 1 people with diabetes mellitus type 2; and Exenatide (Byetta) nanometer to about 500 microns. In general, for solid formu and Pramlintide (Symlin), which both delay gastric emptying lations intended for intravenous administration, particles will and promote a feeling of satiety. Other over-the-counter typically range from about 1 nm to about 10 microns in weight loss products including herbal remedies, laxatives, diameter. diet pills, diuretic drugs, and/or pyruvate may also be com 0182. The amount of the compound or prodrug of any one bined with the compounds and/or prodrugs disclosed herein. of the formulas disclosed herein contained in the formulation The compounds and prodrugs disclosed herein may also be will vary depending the specific compound or prodrug used in combination with non drug-based therapy, including selected, dosage form, target patient population, and other caloric restriction, exercise, and behavioral therapy. considerations, and will be readily determined by one skilled 0185. In other embodiments, the present invention pro in the art. The amount of the compound or prodrug in the vides a method for treating depression comprising adminis formulation will be that amount necessary to deliver a thera tering a combination of a compound or prodrug of the present peutically effective amount of the compound to a patient in invention and one or more known antidepressants. Antide need thereof to achieve at least one of the therapeutic effects pressants useful according to the invention comprise selective associated with the compounds or prodrugs of the invention. serotonin reuptake inhibitors (SSRIs), tricyclics, serotonin In practice, this will vary widely depending upon the particu norepinephrine reuptake inhibitors (5-HT-NE dual reuptake lar compound or prodrug, its activity, the severity of the inhibitors), and norepinephrine and dopamine reuptake condition to be treated, the patient population, the stability of inhibitors (NDRIs). the formulation, and the like. Compositions will generally 0186. In one embodiment, compounds or prodrugs of the contain anywhere from about 1% by weight to about 99% by present invention may be combined with one or more com US 2013/0203752 A1 Aug. 8, 2013

pounds that are serotonin reuptake inhibitors. Serotonin LUDIOMILR), or PSYMIONR), bupropion (WELL reuptake inhibitors increase the extracellular level of the sero BUTRINR) or ZYBANR), and radafaxine. tonin by inhibiting its reuptake into the presynaptic cell, 0189 Further non-limiting examples of specific antide which increases the level of serotonin available to bind to and pressants useful according to the invention include tricyclics stimulate the postsynaptic receptor. Examples of SSRIs Such as amitriptyline, nortriptyline, and desipramine; seroto include fluoxetine (PROZAC(R) paroxetine (PAXIL(R), ser nin-norepinephrine reuptake inhibitors such as Venlafaxine traline (ZOLOFTR), citalopram (CELEXAR), escitalopram (EFFEXORR), duloxetine (CYMBALTAR), and milnacip (LEXAPROR), nefazodone (SERZONER) and fluvoxamine ran; tetracyclics such as maprotiline and mirtazapine; and (LUVOX(R). other classes of compounds, including triazolopyridines Such as traZodone. 0187. In another embodiment, compounds or prodrugs of 0190. The above compounds and classes of compounds the present invention may be combined with one or more are only examples of the types of active agents that can be compounds that at least partially inhibit the function of used in combination with a compound or prodrug of the monoamine oxidase. Monoamine oxidase inhibitors present invention for the treatment of mood disorders, sleep (MAOIs) comprise a class of compounds understood to act by disorders, or attention deficit disorders and are not intended to inhibiting the activity of monoamine oxidase, an enzyme be limiting of the invention. Rather, various further active generally found in the brain and liver of the human body, agents can be combined with one or more compounds of the which functions to breakdown monoamine compounds, typi present invention according to the invention. For example, cally through deamination. There are two isoforms of any drug generally recognized as being an antidepressant, monoamine oxidase inhibitors, MAO-A and MAO-B. The antinarcoleptic, or ADHD treatment can be used in combina MAO-A isoform preferentially deaminates monoamines tion with one or more compounds of the present invention. typically occurring as neurotransmitters (e.g., serotonin, Moreover, it is possible according to the invention to combine melatonin, epinephrine, norepinephrine, and dopamine). two or more additional active agents with one or more com Thus, MAOIs have been historically prescribed as antidepres pounds or prodrugs of the present invention for treatment of sants and for treatment of other social disorders, such as the noted conditions. agoraphobia and social anxiety. The MAO-B isoform prefer 0191 Non-limiting examples of further active agents that entially deaminates phenylethylamine and trace amines can be combined with compounds of the present invention Dopamine is equally deaminated by both isofouns. The activ include: mood stabilizers (such as lithium, olanzipine, Vera ity of MAOIs may be reversible or non-reversible and MAOIs pamil, quetiapine, lamotrigine, carbamazepine, Valproate, may be selective for a specific isoform. For example, the oXcarbazepine, risperidone, aripiprazole, and Ziprasidone); MAOI moclobemide (also known as Manerix or Aurorix) is antipsychotics (such as haloperidol and other butyrophe known to be approximately three times more selective for nones, chlorpromazine, fluphenazine, perphenazine, MAO-Athan MAO-B. Any compound generally recognized prochlorperazine, and other phenothiazines, and clozapine); as being an MAOI may be useful according to the present serotonin receptor antagonist (5-HT2 and 5-HT3 antagonists) invention. Non-limiting examples of MAOIs useful in com (such as ondansetron, tropisetron, katenserin, methysergide, bination with compounds or prodrugs of the present invention cyproheptadine, and pizotifen); serotonin receptor agonists for preparing compositions according to the invention include (5-HT1A receptor agonists) (such as buspirone); stimulants the following: isocarboxazid (MARPLANR); moclobemide such as caffeine, ADDERALL(R), methylphenidate (META (Aurorix, Manerix, or Moclodura); phenelzine (NARDIL(R): DATER, RITALINR, or CONCERTAR), pemoline (CY tranylcypromine (PARNATE(R); selegiline (ELDEPRYL(R), LERTR), or modafinil (PROVIGIL(R); and gamma-hy EMSAMCR, or 1-deprenyl); lazabemide: nialamide: iproni droxybutyrate (GHB) (XYREMR). Although the above azid (marsilid, iprozid, ipronid, rivivol, or propilniaZida); compounds are described in terms of classes of compounds iproclozide, toloxatone; harmala; brofaromine (Consonar); and specific compounds, it is understood that there is substan benmoxin (Neuralex); and certain tryptamines, such as tial overlap between certain classes of compounds (such as 5-MeO-DMT (5-Methoxy-N,N-dimethyltryptamine) or between mood stabilizers, antipsychotics, antidepressants, 5-MeO-AMT (5-methoxy-O-methyltryptamine). and serotonin receptor antagonists). Thus, specific com 0188 According to still another embodiment of the inven pounds exemplifying a specific class of compounds may also tion, compounds or prodrugs of any one of the formulas properly be identified with one or more further classes of disclosed herein may be combined with one or more com compounds. Accordingly, the above classifications should pounds that are norepinephrine reuptake inhibitors (NRIs). not be viewed as limiting the scope of the types of compounds NRIs are also known as noradrenaline reuptake inhibitors useful in combination with compounds and prodrugs of the (NARIS) and generally function to elevate the level of nore present invention for treating the conditions described herein. pinephrine in the central nervous system (CNS) by inhibiting 0.192 Since the compounds and prodrugs of the present reuptake of norepinephrine from the synaptic cleft into the invention may also be useful in the treatment of stimulant presynaptic neuronal terminal. Norepinephrine is a cat (e.g., cocaine and/or methamphetamine) addiction, they may echolamine and phenylethylamine that functions as a neu be combined with other drugs for the treatment of addiction. rotransmitter and is known to affect many conditions. Any For example, drugs that are commonly used for the treatment compound typically recognized as inhibiting the reuptake of of methamphetamine addiction include, but are not limited to, norepinephrine in the CNS can be used according to the bupropion, modafinil, Ibogaine, Mirtzapine, dextroamphet present invention. Non-limiting examples of NRIs useful amine, monoamine reuptake inhibitors (such as indatraline, according to the invention comprise atomoxetine (STRAT fluoxetine, bupropion and imipramine), and amino acids. TERAR), reboxetine (EDRONAX(R), VESTRAR, or NORE Although cocaine replacement therapies to treat addiction are BOX(R), viloxazine (EMOVITR, VIVALANR, being researched, there is currently no FDA-approved treat VIVARINTR, or VIVILANR), maprotiline (DEPRILEPTR), ment for cocaine addiction. US 2013/0203752 A1 Aug. 8, 2013

0193 Combinations of compounds or prodrugs of the rotransmitter release and uptake inhibition. For example, in present invention with other therapeutic agents are also some embodiments, the invention provides for the use of included in the present invention, wherein the condition to be compounds or prodrugs of the present invention to treat dis treated is any condition that may be responsive to the inhibi eases responsive to dopamine and norepinephrine release tion of dopamine, serotonin and/or norepinephrine reuptake. and/or serotonin uptake inhibition. 0194 The compound or prodrug of any of the formulas 0198 Obesity has its common meaning, e.g., the medical disclosed herein and the one or more other therapeutic agents condition that exists when an individual has accumulated may be contained within a single composition or alternatively excess body fat, which may lead to a variety of related health may be administered concurrently or sequentially (consecu problems, and which is characterized by a body mass index tively) in any order. For sequential administration, each of the (BMI) of 30 kg/m or more. Pre-obesity, also known as over compound or prodrug of the formulas disclosed herein and weight, refers to the condition wherein an individual's BMI is the one or more other therapeutic agents can be formulated in between 25 kg/m and 30 kg/m. its own pharmaceutical composition, each of which is to be 0199 Addiction has its common meaning, e.g., the condi administered sequentially, in any order. Alternatively, the tion that exists when an individual persists in the use of a compound or prodrug of the formulas disclosed herein and Substance despite impairment or distress related to the use of the one or more other therapeutic agents can be formulated the Substance. In preferred embodiments, the compounds and together. The compositions may be formulated for oral, sys prodrugs of the present invention show a slow onset and long temic, topical, intravenous, intraparenteral, intravaginal, duration of activity. These features make the compounds and intraocular, transbuccal, transmucosal, or transdermal admin prodrugs of the present invention particularly suitable for the istration. treatment of addiction to abused substances, which com monly exhibit a fast onset and/or short duration of activity. Methods of Use Administration of compounds or prodrugs of the present 0.195. In a further embodiment, the present invention pro invention to Subjects with addiction to one or more substances vides a method for treating or delaying the progression of may be particularly Suited for the treatment of cocaine, meth disorders that are alleviated by the modulation of neurotrans amphetamine, and nicotine addiction. mitter levels in a patient, the method comprising administer 0200. The compounds and prodrugs of the present inven ing a therapeutically effective amount of at least one com tion may also be applicable to treating depression and depres pound or prodrug of the formulas disclosed herein to the sive conditions in animals, particularly humans and other patient. mammals, and associated effects of these conditions. Depres 0196. In particular, the present invention relates to the field sion has its common meaning, e.g., a common mental disor of treating pre-obesity and obesity in animals, particularly der that presents with depressed mood, loss of interest or humans and other mammals, and associated effects of these pleasure, feelings of guilt or low self-worth, disturbed sleep conditions. It may also relate to the treatment of other condi or appetite, low energy, and poor concentration or a mental tions that may benefit from modulation of neurotransmitter state characterized by a pessimistic sense of inadequacy and levels. For example, it may relate to treatment of depression a despondent lack of activity. Physical changes, such as and associated disorders, as well as cocaine and/or metham insomnia, anorexia, weight loss, and decreased energy and phetamine addictions. It may particularly relate to the treat libido can also occur as a result of depression. Depression ment of conditions that may benefit from the release and/or includes dysthymic disorder or dysthymia, defined as a reuptake inhibition of one or more of dopamine, norepineph chronic low-grade depression and major depression as well as rine, and serotonin. In some embodiments, the compounds other stages or levels of depression. It also includes post and prodrugs of the present invention are selective for one or partum depression. more monoamine transporter. In some embodiments, the 0201 The compounds or prodrugs of the present invention compounds bind more strongly to the dopamine and/or sero may also be used for other conditions that may be responsive tonin transporters than to the norepinephrine transporters. to release or inhibition of reuptake of one or more type of 0197) In some embodiments, the present invention may neurotransmitter. In some embodiments, the compounds or relate to the use of compounds or prodrugs of the present prodrugs may be used to treat patients for conditions that are invention to treat diseases that are responsive to the modula responsive to the release or uptake inhibition of dopamine, tion of the level of one or more monoamine neurotransmitter. norepinephrine, and/or serotonin. For example, in some For example, in Some embodiments, the invention provides embodiments, compounds or prodrugs of the present inven for the use of compounds or prodrugs of the present invention tion may be used to treat patients with bipolar disorder, atten to treat diseases responsive to one or more of dopamine, tion deficit disorder (ADD), attention-deficit/hyperactivity serotonin, and/or norepinephrine release. In some embodi disorder (ADHD), hypoactive sexual desire disorder, antide ments, the invention provides for the use of compounds or pressant-induced sexual dysfunction, orgasmic dysfunction, prodrugs of the present invention to treat diseases responsive seasonal affective disorder/winter depression, obesity and to dopamine release. In some embodiments, the invention food addiction, mania, bulimia and other eating disorders, provides for the use of compounds or prodrugs of the present panic disorders, obsessive compulsive disorder, Schizophre invention to treat diseases responsive to joint dopamine and nia, Schizo-affective disorder, Parkinson's disease, narco serotonin release. In some embodiments, the invention pro lepsy, anxiety disorders, insomnia, chronic pain, migraine vides for the use of compounds or prodrugs of the present headaches, and restless legs syndrome. invention to treat diseases responsive to one or more of 0202 The method of treatment generally includes admin dopamine, serotonin, and/or norepinephrine uptake inhibi istering a therapeutically effective amount of a compound or tion. In certain embodiments, the invention provides for the prodrug of a formula disclosed herein, optionally in a phar use of compounds or prodrugs of the present invention to treat maceutical composition including one or more pharmaceuti diseases responsive to a combination of monamine neu cally acceptable carriers. The therapeutically effective US 2013/0203752 A1 Aug. 8, 2013

amount is preferably sufficient to cause the release of one or 0208. The compounds and prodrugs of the invention may more neurotransmitter and/or inhibit the uptake of one or be used with other types of therapy, including those which are more neurotransmitter. The therapeutically effective amount non-drug based. For example, obesity is commonly treated is further preferably sufficient to cause some relief to the using one or more therapeutics in combination with behav patient in the symptoms of the disorder for which the patient ioral treatment (e.g., diet and exercise changes), which may is being treated. lead to a better outcome than using a drug alone. Depression 0203 For example, in one embodiment, a method of treat is commonly treated with some combination of therapeutics ing pre-obesity or obesity is provided. In such methods, a and some sort of psychotherapy. Thus, in Some embodiments, therapeutically effective amount of a compound or prodrug of the methods of the present invention comprise administering the present invention to treat a patient with pre-obesity or to a Subject a compound or prodrug of the invention that that obesity may be that amount capable of effecting the release is capable of modulating neurotransmitter levels in conjunc and/or reuptake of one or more monoamine neurotransmitter. tion with one or more other types of non-drug-based therapy. Such compound or prodrug may cause the patient to experi ence decreased appetite and/or may create a sensation of EXAMPLES fullness. The method of treating pre-obesity or obesity may 0209 Certain compounds in the Examples Section are be used to attain or maintain a patients weight loss. referred to with an alphanumerical designation. The com 0204. In another embodiment, a method of treating pound structure for these compounds can be found, for cocaine addiction is provided. In Such methods, a therapeu example, in the specific synthesis examples, Schemes 1-3, or tically effective amount of a compound or prodrug of the present invention to treat a patient with cocaine addiction may in the data tables provided herein. be that amount capable of exerting some dopaminergic effect. Example 1 Cocaine functions by inhibiting the reuptake of dopamine by blocking the dopamine transporter that transports excess Representative Preparation of Compounds of the dopamine back into the presynaptic cell. It has a fast onset of activity and short duration. Chronic cocaine use produces a Present Invention Preparation of PAL-583 withdrawal syndrome that is associated with depletion of 0210 dopamine and deficits in dopaminergic signaling By provid ing a compound or prodrug of the present invention with slow onset and long duration of activity, the compound or prodrug O may be able to reverse dopaminergic deficits in chronic cocaine users. CH3 + 0205. In another embodiment, a method of treating depression is provided. A therapeutically effective amount of Br a compound or prodrug of the present invention to treat a HC-EN patient with depression may be that amount capable of pro HN -e- viding some relief from Symptoms such as changes in mood, 40° C. feelings of intense sadness and despair, mental slowing, loss of concentration, pessimistic worry, agitation, and self-dep OH recation and/or from physical changes such as insomnia, anorexia and weight loss, and decreased energy and libido. The levels of one or more of dopamine, norepinephrine, and serotonin may be low in Subjects with depression and thus, HC N) increase in the release of or inhibition of the uptake of any of these monoamines by the appropriate transporter may be effective to adjust the monoamine levels and treat the Symp 0211. A 0.4 M solution of 2-Bromopropiophenone (1.54 toms of depression. mL, 1 eq) in acetonitrile (26 mL) was mixed in a 50 mL round 0206. The therapeutically effective dosage amount of any bottom flask under N (g). Ethanolamine (1.25 mL, 2 eq) was specific formulation will vary somewhat from drug to drug, added changing the color of Solution from olive green to patient to patient, and will depend upon factors such as the amber and forming a precipitate. The reaction was refluxed at condition of the patient and the route of delivery. When 40° C. for 3.5 hrs and then cooled to room temperature to stir administered conjointly with other pharmaceutically active overnight. The next morning the orange-yellow mixture with agents, even less of the compound or prodrug of the invention precipitate was refluxed at 40°C. for 2 hrs. After cooling to may be therapeutically effective. Furthermore, the therapeu room temperature the reaction was diluted with ethylacetate, tically effective amount may vary depending on the specific washed with saturated sodium bicarbonate (2x50 mL), water condition to be treated. (2x50 mL), brine (2x50 mL), and then dried over anhydrous 0207. The compound or prodrug of the invention can be sodium sulfate. After filtration the volatiles were removed administered once or several times a day or according to any under reduced pressure affording 0.807 g (40%) of crude other intermittent administration schedule. The daily dose product. Purified on 12 g column (ISCO) using a system of can be administered either by a single dose in the form of an chloroform (A)/9:1 methanol: ammonium hydroxide (B) individual dosage unit or several Smaller dosage units or by with a 20-30% gradient (B). Fractions 8-10 were collected multiple administration of Subdivided dosages at certain and concentrated under reduced pressure affording 0.351 g intervals. Possible routes of delivery include buccally, subcu (18%) of purified product. The free base was salted with taneously, transdermally, intramuscularly, intravenously, 0.2108 g of fumaric acid and recrystalized using methanol/ orally, or by inhalation. ether yielding 0.2135 g of final product. US 2013/0203752 A1 Aug. 8, 2013 20

0212 Preparation of PAL-587 0215 Preparation of PAL-589

O O CH3Cl2 CH3Cl2 CH + Br-Br - - - CH + Br-Br - - -

F CH O O CH CH3

Br Br

F CH3

0213 1-(3-fluorophenyl)propan-1-one (4.53 g, 1 eq) and 0216) 1-(3-methylphenyl)propan-1-one (8.746 g, 1 eq) bromine (1.53 mL, 1 eq) were combined and stirred in 50 mL and bromine (3.04 mL, 1 eq) were combined and stirred in of methylene chloride overnight at room temperature. The 100 mL of methylene chloride overnight at room tempera next day the mixture was washed with water (4x50 mL), brine ture. The next day the mixture was washed with water (4x50 (2x50 mL), and dried over anhydrous sodium sulfate. After mL), brine (2x50 mL), and dried over anhydrous sodium filtration the volatiles were removed under reduced pressure sulfate. After filtration the volatiles were removed under affording 6.435 g (94%) of crude 2-bromo-1-(3-fluorophe reduced pressure affording 12.923 g (96%) of crude 2-bromo nyl)propan-1-one. 1-(3-methylphenyl)propan-1-one.

HC-EN HC-EN CH + HN2 \ -e-40° C. CH + H2HN \ -as40° C. OH OH Br Br

F CH

OH OH O O F D H3C D H3C N H3C N

0214. A 0.4 M solution of 2-bromo-1-(3-fluorophenyl) 0217. A 0.4 M solution of 2-bromo-1-(3-methylphenyl) propan-1-one (3.05 g, 1 eq) in acetonitrile (33 mL) was mixed propan-1-one (6.57g, 1 eq) in acetonitrile (72 mL) was mixed in a 100 mL round bottom flask under N (g). Ethanolamine in a 250 mL round bottom flask under N (g). Ethanolamine (1.6 mL, 2eq) was added and stirred/refluxed for 6 hrs at 40° (3.5 mL, 2 eq) was added and stirred/refluxed for 6 hrs at 40° C. After cooling to room temperature overnight the Volatiles C. After cooling to room temperature overnight the Volatiles were removed under reduced pressure, the residue was then were removed under reduced pressure, the residue was then taken up in ethylacetate, washed with Saturated Sodium bicar taken up in ethylacetate, washed with Saturated Sodium bicar bonate (3x50 mL), brine (2x50 mL), and dried over anhy bonate (3x50 mL), brine (2x50 mL), and dried over anhy drous sodium sulfate. After filtration the volatiles were drous sodium sulfate. After filtration the volatiles were removed under reduced pressure affording 1.464 g (53%) of removed under reduced pressure affording 3.777 g (63%) of crude product. Purified on 12 g column (ISCO) using a sys crude product. Purified on 12 g column (ISCO) using a sys tem of methylene chloride (A)/methanol (B) with a 20-30% tem of methylene chloride (A)/methanol (B) with a 20-30% gradient (B). Fractions 13-32 were collected and concen gradient (B). Product fractions were collected and concen trated under reduced pressure affording 0.638 g (23%) of trated under reduced pressure affording 1.183 g (20%) of purified product. The free base was salted with 0.3506 g of purified product. The free base was salted with 0.6624 g of fumaric acid and recrystalized using methanol/ethyl acetate fumaric acid and recrystalized using methanol/ethyl acetate, yielding 0.5672 g of final product. yielding 0.3459 g of final product. US 2013/0203752 A1 Aug. 8, 2013 21

0218. Preparation of PAL-590 diluted with water, chilled to 0°C., made basic by adding 40% aqueous sodium hydroxide (tested with litmus), extracted with methylene chloride (3x25 mL), dried over anhydrous O sodium sulfate, filtered, and volatiles removed under reduced CH + H2HN HeHC-EN pressure to afford 0.200 g of solid residue. The intermediate 40° C. residue dissolved in methylene chloride was then added drop \-on wise to 4.8 mL of concentrated sulfuric acid at 0° C. and Br stirred overnight. The next morning the reaction was poured into ice water, the layers were separated, and the aqueous C layer was chilled to 0°C. The aqueous layer was then made basic with 40% aqueous sodium hydroxide (tested with lit OH mus), extracted with methylene chloride (3x25 mL), dried O over anhydrous sodium sulfate, filtered, and volatiles removed under reduced pressure to afford 0.172 g of oil. The C D oil was then dissolved in methylene chloride and 0.0681 g of H3C N fumaric acid in methanol was added to form the fumarate salt of the product. Anal. Calcd for 2CHCNOCHOI: C 66.36, H 7.28, N5.95: Found: C 66.12, H 7.29, N 5.85. 1H 0219. A 0.4 M solution of 2-bromo-1-(3-chlorophenyl) NMR (300 MHz, MeOH) 8 ppm 1.01 (d. J=6.78 Hz, 3H) propan-1-one (4.22g, 1 eq) in acetonitrile (43 mL) was mixed 3.20-3.41 (m, 3H) 3.84-3.99 (m. 1H) 4.13 (d. J=14.32 Hz, in a 100 mL round bottom flask under N, (g). Ethanolamine 1H)4.32 (d. J=10.17 Hz, 1H)6.70 (s, 1H) 7.39 (s, 5H). (2.05 mL, 2 eq) was added and stirred/refluxed for 6 hrs at 40° C. After cooling to room temperature overnight the Volatiles Preparation of PAL-593 were removed under reduced pressure, the residue was then taken up in ethylacetate, washed with Saturated Sodium bicar 0222 bonate (3x50 mL), brine (2x50 mL), and dried over anhy drous sodium sulfate. After filtration the volatiles were removed under reduced pressure affording 3.319 g (70%) of OH crude product. Purified on 12 g column (ISCO) using a sys O tem of methylene chloride (A)/methanol (B) with a 20-30% F EtOH/H2O (1:1) gradient (B). Product fractions were collected and concen fumarate + NaBH4 trated under reduced pressure affording 0.970 g (20%) of H2SO4 HC N purified product. The free base was salted with 0.4054 g of H fumaric acid and recrystalized using methanol/ethyl acetate, yielding 0.7213 g of final product. O Preparation of PAL-592 0220 F D H3C N H

OH 0223) A solution of 2-(3-fluorophenyl)-3-methylmorpho O lin-2-ol fumarate salt (0.432.6 g. 1 eq) in 1:1 ethanol: water EtOH/HO (1:1) (3.3 mL) was chilled to 0°C. under N, (g). With constant fumarate + NaBH4 H2SO4 stirring, a solution of sodium borohydride (0.2000 g, 4 eq) in water (2.2 mL) was added drop wise. The reaction was HC N allowed to warm to room temperature and stir overnight. The next morning the reaction was chilled to 0°C. and 1.9 mL of concentrated hydrochloric acid was added drop wise. The ethanol was then removed under reduced pressure and the crude mixture was diluted with water, chilled to 0°C., made basic by adding 40% aqueous sodium hydroxide (tested with () litmus), extracted with methylene chloride (3x25 mL), dried HC N over anhydrous sodium sulfate, filtered, and volatiles removed under reduced pressure to afford 0.176 g of clear oil. 0221) A solution of 3-methyl-2-phenylmorpholin-2-ol The inteimediate oil dissolved in methylene chloride was then fumarate salt (0.4646g, 1 eq) in 1:1 ethanol: water (3.6 mL) added drop wise to 1.9 mL of concentrated sulfuric acid at 0° was chilled to 0°C. under N, (g). With constant stirring, a C. and stirred overnight. The next morning the reaction was solution of sodium borohydride (0.2278 g. 4 eq) in water (2.5 poured into ice water, the layers were separated, and the mL) was added drop wise. The reaction was allowed to warm aqueous layer was chilled to 0°C. The aqueous layer was then to room temperature and stir overnight. The next morning the made basic with 40% aqueous sodium hydroxide (tested with reaction was chilled to 0° C. and 2.2 mL of concentrated litmus), extracted with methylene chloride (3x25 mL), dried hydrochloric acid was added drop wise. The ethanol was then over anhydrous sodium sulfate, filtered, and volatiles removed under reduced pressure and the crude mixture was removed under reduced pressure to afford 0.168 g of oil. The US 2013/0203752 A1 Aug. 8, 2013 22 oil was then dissolved in methylene chloride and 0.0626 g of Example 2 fumaric acid in methanol was added to form the fumarate salt of the product. Anal. Calcd for 2CHCFNOCHOI: C Preparation of Additional Compounds 61.65, H 6.37, N 5.53; Found: C 61.67, H 6.36, N 5.53. H Representative Preparation NMR (300 MHz, METHANOL-da) 8 ppm 0.96 (d. J=6.78 Hz, 3H)3.04-3.17 (m, 1H)3.17-3.24 (m. 1H)3.26 (m, 1H) Step 1: Preparation of N-Benzyl-N-(2-hydroxy 3.83 (t, J=1111 Hz, 1H)4.09 (d. J=11.68 Hz, 1H)4.23 (d. ethyl)-1-methyl-2-oxo-2-tolylethylamine J=9.42 Hz, 1H) 6.68 (s, 1H) 7.03-7.24 (m, 3H) 7.39 (dd, J=7.91, 7.16 Hz, 1H). 0227

Preparation of PAL-594 O

0224 Br

--

OH OH O C D fumarate + HN ? 18 THF,h, 50 C. H3C N H EtOH/HO (1:1) NaBH4 --H2SO4

o OH O C D O HC N N H

0225. A solution of 2-(3-chlorophenyl)-3-methylmorpho lin-2-ol fumarate salt (0.3884 g, 1 eq) in 1:1 ethanol: water la (2.8 mL, plus methanol drop wise till dissolved) was chilled to 0°C. under N (g). With constant stirring, a solution of sodium borohydride (0.1710 g, 4 eq) in water (1.8 mL) was 0228. A solution of 2-bromo-2'-acetonaphthone (3 g, 12 added drop wise. The reaction was allowed to warm to room mmol) and 2-benzylaminoethanol (3.64 g. 24.1 mmol) in temperature and stir overnight. The next morning the reaction THF (50 mL) was stirred 18h at 50 C. The mixture was was chilled to 0°C. and 1.7 mL of concentrated hydrochloric concentrated and taken up into ethyl acetate and washed with acid was added drop wise. The ethanol was then removed saturated aqueous NaHCO, water and brine. The organics under reduced pressure and the crude mixture was diluted were dried (MgSO), concentrated and purified by automated with water, chilled to 0°C., made basic by adding 40% flash chromatography (silica gel, 4/1 hexane/ethyl acetate) to aqueous Sodium hydroxide (tested with litmus), extracted yield 4.93 g (84%) of 1a as a white solid. "H NMR (CDC1 with methylene chloride (3x25 mL), dried over anhydrous 300 MHz) & 7.52-7.11 (m,9H), 4.17-4.13 (m, 2H), 3.66-3.59 sodium sulfate, filtered, and volatiles removed under reduced (m,3H), 2.84-2.65 (m, 2H), 2.43-2.33 (m, 4H), 0.96-0.79 (m, pressure to afford 0.247 g of white solid. The solid interme 3H): APCI-MS, calculated for CHNO (M+H)298.4: diate dissolved in methylene chloride was then added drop observed 298.4. wise to 5.1 mL of concentrated sulfuric acid at 0° C. and stirred overnight. The next morning the reaction was poured Step 2: Preparation of N-Benzyl-N-(2-hydroxy into ice water, the layers were separated, and the aqueous ethyl)-2-hydroxy-1-methyl-2-tolylethylamine layer was chilled to 0°C. The aqueous layer was then made 0229 basic with 40% aqueous sodium hydroxide (tested with lit mus), extracted with methylene chloride (3x25 mL), dried over anhydrous sodium sulfate, filtered, and volatiles OH removed under reduced pressure to afford 0.245 g of oil. The oil was then dissolved in methylene chloride and 0.0868 g of OH fumaric acid in methanol was added to form the fumarate salt NaBH4, MeOH N of the product. Anal. Calcd for 2CHCINOCHOI: C la 57.89, H 5.98, N5.19; Found: C 57.75, H 5.88, N5.10. rt, 1 h 0226 H NMR (300 MHz, MeOH)8 ppm 1.06 (d. J=6.78 Hz, 3H)3.17-3.28 (m. 1H)3.27-3.35 (m, 1H)3.34-3.39 (m, 1H)3.93 (t, J=11.87 Hz, 1H)4.19 (d. J=12.43 Hz, 1H)4.32 (d. J=9.80 Hz, 1H)6.79 (s.1H) 737-7.44 (m, 1H)7.47 (d. J=5.27 HZ, 1H) 7.53 (s, 1H). US 2013/0203752 A1 Aug. 8, 2013

0230. A solution of 1a (4.9 g, 16.5 mmol) in MeOH (150 0234. A solution of 3a (1.86 g. 6.61 mmol) and 1-chloro mL) was treated with NaBH (0.69 g, 18.1 mmol) and the ethyl chloroformate (0.95 mL, 8.72 mmol) in DCE (30 mL) reaction stirred for 1 hat room temperature. The mixture was was refluxed for 1.5 hand then concentrated. The residue was concentrated and the residue was taken up into ethyl acetate dissolved in MeOH (30 mL) and refluxed for 1 h. The mixture and washed with saturated aqueous NaHCO, water and brine. The organic phase was dried (MgSO) and concen was concentrated again and this residue was taken up into trated to generate a quantitative amount of colorless oil (2a). ethyl acetate and washed with saturated aqueous NaHCO, which required no further purification. "H NMR (CDC1300 water and brine, dried (MgSO) and concentrated. The crude MHz) & 7.38-7.09 (m,9H), 4.33 (d. 1H, J=9 Hz), 3.94 (d. 1H, product was purified by automated flash chromatography J=15 Hz), 3.70–3.62 (m, 2H), 3.49 (d. 1H, J=12 Hz), 2.87-2. (silica gel, 10% MeOH/DCM) to yield 572 mg (45%) of pale 83 (m, 2H), 2.67-2.58 (m, 1H), 2.32 (s, 3H), 0.83-0.80 (m, yellow solid. An initial attempt was made to isolate the hydro 3H): APCI-MS, calculated for CHNO (M+H)300.4: chloride salt, but if it wouldn’t crystallize, the mixture was observed 300.5. neutralized and the fumarate salt was formed. After several recrystallization attempts, 66 mg (9%) of pure 4a was Step 3: Preparation of obtained. H NMR (D.O.300 MHz) & 7.20 (d. 2H, J=9 Hz), N-Benzyl-3-methyl-2-tolylmorpholine 7.15 (d. 2H, J=9 Hz), 3.97 (d. 1H, J=9 Hz), 3.89-3.85 (m, 2H), 0231 2.98-2.81 (m, 3H), 2.29 (s.3H), 0.73 (d. 3H, J=6 Hz); ESI MS, calculated for CHNO (M+H)"1923; observed 192. 1; Anal. Calculated for CHNO (with 0.2 mol of water): C, 66.49;H, 7.73; N, 5.54. Found: C, 66.14:H, 7.46; N, 5.31. O N 60% aq. HCl, 0235. The following compounds were prepared based on reflux the above procedure (Steps 1-4) with the indicated modifica 2a -- tions. Characterization data for representative compounds of the present invention is presented below. 3-Methyl-2-(4'-Tolyl)morpholine 0236) "H NMR (CDC1, 300 MHz) & 7.23-7.16 (m, 4H), 3a 4.41 (d. 1H, J=12 Hz), 4.14-4.09 (m, 2H), 3.30-3.19 (m,3H), 2.35 (s.3H), 1.19 (d. 3H, J=9 Hz). 0232 A suspension of 2a (4.9 g, 16.5 mmol) in 60% (v/v) of aqueous HCl solution (150 mL) was introduced to a glass 2-(2-Naphthyl)morpholine hydrochloride (4b, PAL reactor and sealed with a Teflon cap and was heated to 105 C 703) for 18 h. The mixture was made alkaline with solid KOH and extracted with ethyl acetate. The organic phase was washed 0237. The product of the de-benzylation step was recrys with brine, dried (MgSO) and concentrated to yield 5.13 g of tallized from methanol/ether to yield a white solid in 86% brown oil. This crude material was purified by automated yield (1.34g); H NMR (d-DMSO, 300 MHz) & 9.38 (brs, flash chromatography (silica gel, 1/1 hexanes/ethyl acetate) 2H), 7.97-7.93 (m, 4H), 7.58-7.51 (m, 3H), 4.93 (d. 1H, J=9 to obtain 1.86 g (40%) of pale orange solid (3a). H NMR Hz), 4.19-4.15 (m, 1H), 3.98-3.97 (m. 1H), 3.54-3.50 (m, (CDC1300 MHz) & 7.34-7.23 (m, 8H), 7.15 (d. 1H, J=9 Hz), 1H), 3.41-3.28 (m. 1H), 3.20-3.06 (m, 2H); ESI-MS, calcu 4.21-4.10 (m, 2H), 3.85-3.74 (m, 2H), 3.18 (d. 1H, J=15 Hz), lated for CHNO (M+H)"214.3; observed 214.1; Anal. 2.68-2.64 (m, 1H), 2.51-2.38 (m, 2H), 2.34 (s, 3H), 0.97 (d. Calculated (with 0.1 mol water) for CHCINO; C, 66.84; 3H, J=6Hz); ESI-MS, calculated for CHNO (M+H)"282. H, 6.49; N, 5.57. Found: C, 66.75;H, 6.50; N, 5.47. 4; observed 282.4. 3-Methyl-2-(2-Naphthyl)morpholine hydrochloride Step 4: Preparation of 3-Methyl-2-(4-Tolyl)morpholine fumarate (PAL (4c., PAL 704) 747) 0238. The product of the de-benzylation step was recrys tallized from methanol/ether to yield a white solid in 7% yield 0233 (29 mg); H NMR (CDOD, 300 MHz) & 7.95-7.89 (m, 4H), 7.56-7.53 (m,3H), 4.59 (d. 1H, J=9.9 Hz), 4.25-4.24 (m, 1H), 4.11-3.96 (m, 1H), 3.58-3.45 (m,3H), 1.10(d,3H, J=6.9 Hz); 1. HCCHCI)O(CO)C1, A V DCE, reflux, 1.5 h O NH ESI-MS, calculated for CH-NO (M+H)"228.3: observed 2. MeOH, reflux, 1 h 228.1; Anal. Calculated (with 0.2 mol water) for 3a -- CHCINO; C, 67.39;H, 6.94: N, 5.24. Found: C, 67.40;H, 3. Fumaric acid, ether, MeOH, rt, 18 h 6.85: N, 5.26. Fumarate 3-Methyl-(4-Fluoro)-2-Phenylmorpholine (0.5 fumarate) (4d, PAL 748) 4a 0239. The product was isolated as a white solid in 39% yield (99 mg); H NMR (CDOD, 300 MHz) & 743-7.37 (m, 2H), 7.11 (t, 2H, J=9 Hz), 4.24 (d. 1H, J=9 Hz), 4.07 (d. 1H,

US 2013/0203752 A1 Aug. 8, 2013

3.37 (m, 3H), 1.07 (d. 3H, J=6 Hz); 'C NMR (free amine) various compounds is noted and the reagents and intermedi (CDC1, 75 MHz) & 143.0, 140.0, 130.0, 127.0, 123.0, 81.4, ates are represented in Schemes 1, 2, and 3, below. 56.0, 49.8, 46.0, 34.8, 15.4; ESI-MS, calculated for CHCIFNO (M+H)"230.7: observed 230.3: Anal. Calcu General Procedure A. lated for CHC1FNO; C, 49.64;H, 5.30; N, 5.26: Cl, 0256 To a stirring solution under N of the commercially 26.64: F, 7.14. Found: C, 49.41; H, 5.30; N, 5.22; C1, 26.84: F, available amine (1.0 equiv.) in MeOH (dried over 4A molecu 7.07. lar sieves, 0.20 M) was added an aryl epoxide (0.83 equiv.). The reaction mixture was heated to reflux for 4 h and then 3-Methyl-(3'-Chloro-4-Methyl)-2-Phenylmorpho cooled to room temperature. The solution was allowed to stir line hydrochloride (4m, PAL 822) at room temperature for 3 days and then concentrated under 0252. The product was isolated as a white solid in 25% reduced pressure to yield an oily residue which was purified yield (248 mg); H NMR (CDOD,300 MHz) & 7.44 (d. 1H, by flash chromatography on silica gel (10% to 20% MeOH/ J=3 Hz), 7.33 (d. 1H, J-6 Hz), 7.24 (d. 1H, J=6 Hz), 4.36 (d. CHCl gradient) to remove the unreacted starting amine. 1H, J=12 Hz), 4.24-4.17 (m. 1H), 4.02-3.90 (m. 1H), 3.42-3. 36 (m,3H), 2.37 (s.3H), 1.07(d,3H, J=6Hz); CNMR (free General Procedure B. amine) (CDC1, 75 MHz) & 131.0, 128.4, 127.9, 126.2, 85.9, 0257 The secondary amine (1.0 equiv.) was dissolved in a 68.6, 56.5, 46.8, 20.1, 18.7: APCI-MS, calculated for 50%. 60%, or 90% aqueous HCl solution (0.37M) and heated CHCINO (M+H)226.7; observed 226.2: Anal. Calcu to 90° C. overnight under N. The reaction mixture was lated for CH,ClNO; C, 54.98:H, 6.54; N, 5.34; C1, 27.04. allowed to cool to room temperature and poured onto ice Found: C, 55.16;H, 6.52: N, 5.41; C1, 27.18. water. After chilling to 0°C., the solution was carefully bas ified to pH 12 with a 3 Maqueous NaOH solution. After 3-Methyl-(3'-Methoxy)-2-Phenylmorpholine (0.5 warming to room temperature, ether was added and the bipha fumarate) (4n, PAL 823) sic mixture was partitioned in a separatory funnel. The aque 0253) The product was isolated as a white solid in 53% ous portion was extracted twice with EtO and the combined yield (218 mg); H NMR (CDOD,300 MHz) & 7.29 (t, 1H, organic extracts were washed with water and brine and dried J=6 Hz, 9 Hz), 6.95-6.90 (m, 3H), 6.68 (s, 1H), 4.23 (d. 1H, over NaSO. Filtration and concentration under reduced J=9 Hz), 4.13-4.05 (m. 1H), 3.92-3.82 (m, 1H), 3.80 (s.3H), pressure, followed by flash chromatography on silica gel (5% 3.26-3.19 (m, 3H), 0.97 (d. 3H, J=6 Hz); ESI-MS, calculated to 20% MeOH/CHCl gradient) afforded the cyclized prod for CHNO (M+H)"208.3: observed 208.0; Anal. Calcu uct. lated for CHNO: C, 63.38:H, 7.22; N, 5.28. Found: C, 63.35;H, 7.28; N, 5.25. General Procedure C. 0258. The secondary amine (1.0 equiv.) was dissolved in 3-Methyl-(3'-Methoxy)-2-Phenylmorpholine concentrated HSO (0.4 M) and allowed to stand at room (0254 'H NMR (CDC1, 300 MHz) & 7.27-7.22 (m, 2H), temperature overnight. The reaction mixture was then poured 6.93-6.82 (m, 2H), 4.01-3.91 (m, 2H), 3.81 (s, 3H), 3.70 (t, onto ice water. After chilling to 0°C., the solution was care 1H, J=12 Hz), 3.15 (t, 1H, J=12 Hz), 2.96-2.83 (m, 2H), 0.83 fully basified to pH 12 with a 10 Naqueous NaOH solution. (d,3H, J=6 Hz); C NMR (CDC1, 75 MHz) & 160.0, 141.8, After warming to room temperature, ether was added and the 129.6, 120.4, 114.0, 113.3, 86.7, 68.6, 56.5, 55.6, 46.9, 18.7. biphasic mixture was partitioned in a separatory funnel. The aqueous portion was extracted twice with EtO and the com Example 3 bined organic extracts were washed with water and brine and dried over NaSO. Filtration and concentration under Preparation of Additional Compounds reduced pressure, followed by flash chromatography on silica 0255. Additional compounds were prepared according to gel (5% to 20% MeOH/CHCl, gradient) afforded the the following procedures. The procedure used to prepare cyclized product.

Scheme 1 mCPBA, N CHCl2

US 2013/0203752 A1 Aug. 8, 2013 28

(2R,5S)-5-Methyl-2-m-tolyl-morpholine (9c) and (2S,5S)-5-Methyl-2-m-tolyl-morpholine (10c)

o, O 0264 General procedure A was followed using amine 4 (0.56 mL, 7.17 mmol) and epoxide 2c (875 mg. 6.52 mmol) in Me C dry MeOH (22 mL) under N to afford 416 mg (31% yield) of N and amine 8c as a yellow oil. General procedure B was then H followed using amine 8c (416 mg, 1.99 mmol) in 90% aque ous HCl (5.4 mL) under N to afford a mixture of separable isomers in a 1.9:1 (anti:Syn) ratio. Anti isomer 9c. 143 mg (38% yield) isolated as a clear oil. C.?',-11.7 (c 0.0095, MeOH); H NMR (CDC1, 300 MHz) & 7.22-7.10 (m, 4H), 4.38 (dd, J=12.0, 3.0 Hz, 1H), 3.96 (dd, J=12.0, 3.0 Hz, 1H), 3.31 (t, J=21.0, 12.0 Hz, 1H), 3.07 (dd, J=12.0, 3.0 Hz, 1H), -Co 3.03-2.96 (m, 1H), 2.86 (br. t, J-210, 9.0 Hz, 1H), 2.34 (s, 3H), 1.88 (br. s. 1H), 1.02 (d. J=6.0 Hz, 3H); 'C NMR (CDC1, 75 MHz) ppm 140.2, 138.0, 128.4, 128.2, 126.7, (2S.5R)-5-Methyl-2-m-tolyl-morpholine (6c) and 123.2, 78.8, 7.4.3, 53.3, 49.9, 21.4, 17.5: MS (ESI) calcd for (2R,5R)-5-Methyl-2-m-tolyl-morpholine (7c) (M+1)*192.3, found 192.2. The hydrochloride salt had mp 0263 General procedure A was followed using amine 3 194-195°C.; Anal. (CHCINO) C, H, N. Syn isomer 10c: (0.56 mL, 7.17 mmol) and epoxide 2c (875 mg. 6.52 mmol) in 76 mg (20% yield) isolated as a clear oil contaminated with dry MeOH (22 mL) under N, to afford 625 mg (46% yield) of unreacted starting material. The fumarate had mp 168-170 amine 5c as a thick yellow oil. General procedure B was then C.: C-14.5 (c. 0.0020, MeOH); H NMR (CDOD, 300 followed using amine 5c (575 mg, 2.75 mmol) in 90% aque MHz) & 7.30-7.15 (m, 4H), 6.70 (s. 2H), 4.72 (dd, J=9.0, 6.0 ous HCl (7.4 mL) under N to afford a mixture of separable HZ, 1H), 4.10 (dd, J=12.0, 3.0 Hz, 1H), 3.94 (d. J=12.0 Hz, isomers in a 1.4:1 (anti:Syn) ratio. Anti isomer 6c. 166 mg 1H), 3.66-3.58 (m. 1H), 3.27-3.24 (m, 2H), 2.35 (s.3H), 1.55 (32% yield) isolated as a clear oil. C.?'-33.3 (c. 0.00135, (d. J=6.0 Hz, 3H); 'CNMR (CDOD, 75 MHz) ppm 171.5, MeOH); H NMR (CDC1, 300 MHz) & 7.22-7.07 (m, 4H), 139.7, 139.0, 136.2, 130.4, 129.7, 127.7, 1242, 77.1, 69.5, 4.39 (dd, J=9.0, 3.0 Hz, 1H), 3.96 (dd, J=9.0, 3.0 Hz, 1H), 48.2, 44.0, 21.4, 13.6; MS (ESI) calcd for (M+1)*192.3, 3.31 (t, J–21.0, 9.0 Hz, 1H), 3.06 (dd, J=12.0, 3.0 Hz, 1H), found 192.1 (free base); Anal. (CHNOs) C, H, N. 3.02-2.94 (m. 1H), 2.85 (t, J=24.0, 12.0 Hz, 1H), 2.34 (s.3H), 1.96 (br. s. 1H), 1.02 (d. J=6.0 Hz, 3H); 'C NMR (CDC1, 75 MHz) ppm 140.2, 138.0, 128.4, 128.2, 126.7, 123.2, 78.8, 74.3, 53.3, 49.9, 21.4, 17.5; MS (ESI) calcd for (M+1)*192.3, found 192.5. The hydrochloride salt had mp 194-195° C.: , O Anal. (C.H.CINO) C. H. N. Syn isomer 7c. 117 mg (22% C C yield) isolated as a clear oil contaminated with unreacted N and starting material. The fumarate had mp 175-176°C. O'- H 19.2 (c 0.0012, MeOH); H NMR (CDOD, 300 MHz) & 7.30-7.15 (m, 4H), 6.70 (s. 2H), 4.72 (br. t, J=15.0, 6.0 Hz, 1H), 4.08 (dd, J=12.0, 3.0 Hz, 1H), 3.96 (br. d, J=15.0 Hz, 1H), 3.65-3.58 (m, 1H), 3.27-3.24 (m, 2H), 2.35 (s.3H), 1.55 (d. J=6.0 Hz, 3H); 'CNMR (CDOD, 75 MHz) ppm 171.5, 139.7, 138.9, 136.2, 130.4, 129.7, 127.7, 1242, 77.1, 69.5, 48.2, 44.1, 21.4, 13.6; MS (ESI) calcd for (M+1)*192.3, Co. found 192.3 (free base); Anal. (CHNO.0.25 HO) C, H, N. (2S,5R)-2-(3-Chloro-phenyl)-5-methyl-morpholine (6d) and (2R,5R)-2-(3-Chloro-phenyl)-5-methyl morpholine (7d) 0265 General procedure A was followed using amine 3 Me D (0.50 mL, 6.42 mmol) and epoxide 2d (824 mg, 5.33 mmol) A. in dry MeOH (21 mL) under N to afford 649 mg (53% yield) '' and of amine 5d as a thick clear oil. General procedure C was then followed using amine 5d (649 mg, 2.83 mmol) in concen trated HSO (7 mL) to afford a mixture of separable isomers in a 10.3:1 (anti:syn) ratio. Anti isomer 6d: 261 mg (44% yield) as a clear sticky oil.C.'', 42.1 (c 0.0024, MeOH); H NMR (CDC1, 300 MHz) & 7.37 (s, 1H), 7.29-7.20 (m,3H), 4.39 (dd, J=9.0, 3.0 Hz, 1H), 3.96 (dd, J=12.0, 3.0 Hz, 1H), 3.30 (t, J=21.0, 9.0 Hz, 1H), 3.06 (dd, J=12.0, 3.0 Hz, 1H), 3.01-2.92 (m, 1H), 2.79 (t, J–21.0, 9.0 Hz, 1H), 2.01 (br. s. 1H), 1.01 (d.J=6.0Hz,3H); 'CNMR (CDC1, 75 MHz) ppm

US 2013/0203752 A1 Aug. 8, 2013 36

(2R,6R)-2-Methyl-6-phenyl-morpholine (23a) and in dry MeOH (21 mL) under N to afford 663 mg (55% yield) (2S,6R)-2-Methyl-6-phenyl-morpholine (24a) of amine 22d as a thick pale yellow oil. General procedure C 0280 General procedure A was followed using amine 18 was then followed using amine 22d (663 mg, 2.89 mmol) in (0.50 mL, 6.35 mmol) and epoxide 2a (0.60 mL, 5.27 mmol) concentrated HSO (72 mL) to afford 406 mg (66% yield) of in dry MeCH (32 mL) under N to afford 446 mg (43% yield) inseparable morpholines 23d and 24d as a clear Sticky oil in a of amine 22a as a pale yellow oil. General procedure B was 3:1 (syn:anti) ratio. C.?', 22.2 (c. 0.0037, MeOH), MS then followed using amine 22a (446 mg, 2.28 mmol) in 50% (ESI) calcd for (M+1)"212.7, found 212.1. The fumarate had aqueous HCl (6.2 mL) under N to afford 89.1 mg (22% yield) mp 136-137° C.; Anal. (C.H.CINOs) C, H, N. of inseparable morpholines 23a and 24a as a clear Sticky oil in a 3:1 (syn:anti) ratio. C.?' -23.6 (c 0.00165, MeOH); MS Example 4 (APCI) calcd for (M+1)*178.2, found 178.2. The fumarate had mp 131-133° C.; Anal. (CHNO.0.2 HO) C, H, N. DA, NE, 5-HT Release Assays 0283. A series of compounds were assayed for release of dopamine, serotonin, and norepinephrine as well as for activ ity at the 5-HT, receptor. This data is shown below in Table 3. C '', A. 10 -- DA, NE and 5-HT Release Assays N H (0284. HMPP" was used as the radioligand for both the DA and NE release assays, because this method led to an improved signal-to-noise ratio. Rat caudate (for DA release) or whole brain minus cerebellum and caudate (for NE and 5-HT release), was homogenized in ice-cold 10% sucrose containing 1 uM reserpine. Nomifensine (100 nM) and Cyr. GBR12935 (100 nM) were added to the sucrose solution for H5-HT release experiments to block any potential H5 HT reuptake into NE and DA nerve terminals. For the DA (2S,6S)-2-(3-Chloro-phenyl)-6-methyl-morpholine release assay, 100 nM desipramine and 100 nM citalopram (20d) and (2R,6S)-2-(3-Chloro-phenyl)-6-methyl were added to block HMPP" uptake into NE and 5-HT morpholine (21d) nerves. For the NE release assay, 50 nM GBR12935 and 100 nM. citalopram were added to block HMPP" uptake into 0281 General procedure A was followed using amine 17 DA and 5-HT nerves. After 12 strokes with a Potter-Elvehjem (0.50 mL, 6.35 mmol) and epoxide 2d (814 mg, 5.27 mmol) homogenizer, homogenates were centrifuged at 1000xg for in dry MeOH (21 mL) under N, to afford 787 mg (65% yield) 10 min at 0-4°C. and the supernatants were retained on ice of amine 19d as a thick clear oil. General procedure C was (synaptosomal preparation). then followed using amine 19d (787 mg, 3.43 mmol) in con centrated HSO (8.6 mL) to afford 354 mg (49% yield) of 0285 Synaptosomal preparations were incubated to inseparable morpholines 20d and 21d as a clear Sticky oil in a steady state with 5 nM (HMPP (60 min) or 5 nM H5-HT 3:1 (syn:anti) ratio. C.?'-37.7 (c 0.0022, MeOH); MS (60 min) in Krebs-phosphate buffer (without BSA) (pH 7.4), which contained 154.4 mM NaCl, 2.9 mM KC1, 1.1 mM (ESI) calcd for (M+1)"212.7, found 212.1. The fumarate had CaCl, 0.83 mM MgCl, 5 mM glucose, 1 mg/mL ascorbic mp 136-137° C. Anal (CHCINOs) C, H, N. acid, 50LM pargyline plus 1 M reserpine in a polypropylene beaker with stirring at 25°C. with the appropriate blockers. After incubation to steady state, 850 ul of synaptosomes preloaded with HIligand were added to 12x75 mm polysty rene test tubes that contained 150 ul test drug in uptake buffer plus 1 mg/ml BSA. After 5 min (H5-HT) or 30 min (NE and DA assays) the release reaction was terminated by dilution with 4 ml wash buffer (10 mM Tris-HCl pH 7.4 containing 0 9% NaCl at 25°C.) followed by rapid vacuum filtration over Whatman GF/B filters using a Brandel Harvester. The filters were rinsed twice with 4 ml wash buffer using the Brandel O w Harvester, and the retained tritium was counted by a Taurus liquid scintillation counter at 40% efficiency after an over C eC Ds night extraction in 3 ml Cytoscint (ICN). N H Substrate Reversal Experiments 0286 For substrate reversal experiments, test drugs were (2R,6R)-2-(3-Chloro-phenyl)-6-methyl-morpholine tested at approximately EDso doses in the absence and pres (23d) and (2S,6R)-2-(3-Chloro-phenyl)-6-methyl ence of blockers (250 nM GBR1209 for DAT, 166 nM morpholine (24d) desipramine for NET, 100 nM fluoxetine for SERT). Sub 0282 General procedure A was followed using amine 18 strate activity was detected by a significant reversal of the (0.50 mL, 6.35 mmol) and epoxide 2d (815 mg, 5.27 mmol) releasing effect of the test drug. US 2013/0203752 A1 Aug. 8, 2013 37

Data Analysis and Statistics reference), ECso values were determined using the nonlinear least squares curve fitting program MLAB-PC (Civilized 0287. As previously described (Rothman R B, Baumann Software, Bethesda, Md.). In substrate reversal experiments, MH, Dersch CM, Romero DV, Rice KC, Carroll F I and statistical significance was determined using the Students Partilla J S Synapse 39: 32-41 (2001), incorporated herein by t-teSt. TABLE 3

Monoamine Release and 5HT Activity of a Series of Phenmetrazine Analogs

Release 5-HT2 Activity

EC50 nm or % (10 l M Agonist Antagonist

Compound DA 5-HT NE (% (a) 10M) (% at 1 IM)

131 7765 50 O

87 3246 37 O 42

PALS6

415 inactive 63 O

', O

N H

PAL 57

1457 Inactive 349 O

^, O

w N H

PAL60

29% O% 69% O% 6% OH O

N

PALS83 US 2013/0203752 A1 Aug. 8, 2013

TABLE 3-continued

Monoamine Release and 5HT. Activity of a Series of Phenmetrazine Analogs Release 5-HT2B Activity EC50 nm or % G, 10 IIM Agonist Antagonist Compound DA 5-HT NE (% (a) 10 IM) (% at 1 IM) 34% 6% 67% O O OH O F D N H

PALS87

28% S6% 47% 12 OH

N) H

PALS89

39% 41% 62% 16 OH O C D N H

PALS90

100% 95% 93%

PALS93

100% 95% 82% 28

PALS94

98% 31% 96% 12

N H

PAL632 US 2013/0203752 A1 Aug. 8, 2013 39

TABLE 3-continued

Monoamine Release and 5HT. Activi of a Series of Phenmetrazine Analogs Release 5-HT2B Activity EC50 nm or % G, 10 IIM Agonist Antagonist Compound DA 5-HT NE (% (a) 10 IM) (% at 1 IM) F 95% 88% 100% O%

N

PAL635 * denotes relative configuration

0288 An additional series of compounds of the present TABLE 4-continued invention, having the stereochemistry indicated in the figure above Table 4 below, was synthesized and tested for dopam Comparison of the DA, 5-HT, and NE Releasing ine, serotonin, and norepinephrine release, as well as for Activity of a Series of Phenmetrazine Analogs serotonin uptake inhibition. The initial set of compounds was based on PAL-56, which is (+)-phenmetrazine, and which was found to be an effective DA/5HT releaser. The (-)-isomer S. N is also active as a releaser, but is not as potent. The two cis compounds were weaker uptake inhibitors. Adding substitu YX-H ents to the phenyl ring resulted in improvements in 5HT 2 R release, such as the 3-chloro compounds (PAL-594), shown in Table 4. The data in Table 4 is shown either as %EC50 of PALi R X,Y DA Rel 5HT Rel 5HTUp NE Rel release or the EC50 value has been calculated in nM. Two of 786 Me 3CN 99% 99% 100% 788 Me 3,4-diCl 60% 95% 98% the compounds, PAL-704 and PAL-788, show unique and 821 Me 4F,3Cl 94% 71.9% 80% interesting hybrid activity in that they are DA/NE releasers, 823 Me 3OMe 96% 78% 86% but are 5HT uptake inhibitors. 1001 H 2CF3 64% 25% SO% TABLE 4 0289 An additional set of compounds, wherein all com pounds have a CH group at the Ra position, was generated, Comparison of the DA, 5-HT, and NE Releasing and tested for dopamine release, dopamine reuptake, seroto Activity of a Series of Phenmetrazine Analogs nin release, and norepinephrine release. In all cases, the (2S, 5S)-analog was more active as a releaser, as shown in Table 5. The other isomers were either inactive or uptake inhibitors, s'Y- the potency depending on the Substituent (not shown). TABLE 5 YX 2 R Comparison of the DA, 5-HT, and NE Releasing Activity of a Series of (2S,5S)-5-methyl-2-phenylmorpolines PALi R X,Y DA Rel 5HT Rel 5HTUp NE Rel

56 Me H 87nM 3246 nM 38 nM 593 Me 3F 43 nM 2558 nM 30 nM ~" 594 Me 3C 27 M 301 nM 75 nM 632 H H 86 nM 20260 nM 79 nM N -N- 635 H 4F 529 nM 2403 nM 285 nM YX-H 678 H Naphthyl 79% 92% 88% 21 704 Me Naphthyl 111 nM 105 nM 203 nM 747 Me 4Me 91% 79% 95% PALii X,Y DA Rel DAUp SHT Rel NE Rel 748 Me 4F 98% 94% 93% 730 H 212 107 79 749 Me 4C 88% 76% 93% 738 3C 58 23 65 751 Me 4OMe. SO% 64% 84% 880 3OMe. 56% 100% 76% 772 Me 4CN O% 53% 100% 886 3Me 86% 98% 88% 773 Me 3Me 98% 82% 80% 890 3F 96% 89% 96% 780 Me 3OH 97% 70% 100% 895 3CF 45% 100% 770, US 2013/0203752 A1 Aug. 8, 2013 40

TABLE 5-continued 4. The compound according to claim 1, having the formula: Comparison of the DA, 5-HT, and NE Releasing of a Series of (2S,5S)-5-methyl-2-phenylmorpolines Activi 21 CH3 (R-, - || Rs r N R6 N xx N N YX 2 R. N. R.

PALii X,Y DA Rel DA Up 5HT Rel NE Rel wherein: 899 4C 90% 76% 65% each R, represents a Substituent independently selected 903 4F 65% 100% 100% from the group consisting of OH, optionally substituted 910 4CF 15% 80% 15% C1-4 alkyl, optionally substituted C1-4 alkoxy, option 914 4Me 88% 88% 81% ally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, halogen, acylamido, CN, CF, N. CONH CO.R., CHOH, CHOR, NHCOR, NHCOR, CONRR, C1-3 alkylthio, RSO, 1. A compound according to the formula: RSO, CFS, and CFSO, wherein R and Rs are each independently selected from H or optionally sub stituted C1-10 alkyl; and Rs b is an integer from 0-5: R6 with the proviso that when R is CH, then: (a) b is an integer from 1-5; or (b) one or more of R. Rs, and R is not H; or a combination of both (a) and (b): R N, R4 or a pharmaceutically acceptable ester, amide, salt, Solvate, or isomer thereof. 5. The compound according to claim 4, wherein b is an integer from 1-5, and each R, is independently selected from wherein: the group consisting of optionally Substituted C1-4 alkyl, R is optionally substituted aryl, wherein the substituents optionally substituted C1-4 alkoxy, halo, OH, CN, and CF. are selected from the group consisting of OH, optionally 6. The compound according to claim 5, wherein b is 1 and substituted C1-4 alkyl, optionally substituted C1-4 the R-7 Substituent is located meta or para to the morpholine alkoxy, optionally substituted C2-4 alkenyl, optionally Substituent on the phenyl ring. Substituted C2-4 alkynyl, halogen, acylamido, CN, CF, 7. The compound according to claim 1, having the formula: N. CONH CO.R., CHOH, CHOR, NHCOR, NHCOR, CONRR, C1-3 alkylthio, RSO, RSO, CFS, and CFSO, wherein R and R are 21 each independently selected from H or optionally sub (R-, - Rs stituted C1-10 alkyl: R is H or optionally substituted C1-3 alkyl: N r R is H: R R. R4 R is H or optionally substituted C1-3 alkyl; and wherein: Rs is Hor OH: each R, represents a Substituent independently selected R is H or optionally substituted C 1-3 alkyl: from the group consisting of OH, optionally substituted C 1-4 alkyl, optionally substituted C1-3 alkoxy, option with the proviso that when R is CH andR is phenyl, then: ally substituted C2-4 alkenyl, optionally substituted (a) the phenyl ring of R is substituted with one or more C2-4 alkynyl, halogen, acylamido, CN, CFs, N. Substituents; or (b) one or more of R. Rs, and R is not CONH CO.R. CH-OH, CHOR, NHCOR, H; or a combination of both (a) and (b): NHCOR, CONRR, C1-3 alkylthio, RSO, and wherein at least one of the R. R. and R. Substituents is RSO, CFS, and CFSO; and not H; c is an integer from 0-7. or a pharmaceutically acceptable ester, amide, salt, Solvate, or a pharmaceutically acceptable ester, amide, salt, Solvate, or isomer thereof. or isomer thereof 8. The compound according to claim 1, wherein R is Hor 2. The compound of claim 1, wherein R is phenyl, substi CH. tuted phenyl, naphthyl, or substituted naphthyl. 9. The compound according to claim 1, wherein R is Hor CH. 3. The compound of claim 1, wherein R is H and R is 10. The compound according to claim 1, wherein R is substituted aryl. optionally substituted C1-3 alkyl. US 2013/0203752 A1 Aug. 8, 2013

11. The compound according to claim 1, wherein one of R2 18. A prodrug of a compound according to claim 1, having and R is Hand the other of RandR is optionally substituted the formula: C1-3 alkyl. 12. The compound of claim 10, wherein the compound Rs comprises an enantiomeric excess of at least 95% of the R R6 (2S-5S) enantiomer. 13. The compound of claim 1, wherein the compound is selected from the group consisting of: R2 R4 2-methyl-6-phenyl-morpholine; X 2-(3-chloro-phenyl)-3-methyl-morpholine; 2-(3-chloro-phenyl)-3-methyl-morpholin-2-ol; wherein: 2-(3-chloro-phenyl)-5-methyl-morpholine; X is a chemical moiety which, when the prodrug is admin 2-(3-chloro-phenyl)-6-methyl-morpholine; istered in vivo, is cleaved in whole or in part to provide 2-(3-fluoro-phenyl)-3-methyl-morpholine; a free amine on the morpholine ring. 19. The prodrug of claim 18, wherein X is an amino acid or 2-(3-fluoro-phenyl)-3-methyl-morpholin-2-ol; peptide. 2-(3-fluoro-phenyl)-5-methyl-morpholine; 20. The prodrug of claim 18, having the formula: 2-(3-methoxy-phenyl)-5-methyl-morpholine: 2-(4-chloro-phenyl)-5-methyl-morpholine; 2-(4-fluoro-phenyl)-5-methyl-morpholine; 3-methyl-2-phenylmorpholin-2-ol; 3-methyl-2-(2-naphthyl)morpholine; 3-methyl-2-(3'-tolyl)morpholine; 3-methyl-2-(3'-tolyl)morpholin-2-ol; 3-methyl-2-(4-tolyl)morpholine; 3-methyl-(4-fluoro)-2-phenylmorpholine; wherein Rs is optionally substituted C1-10 alkyl, option 3-methyl-(4-chloro)-2-phenylmorpholine; ally substituted C1-10 alkoxy, optionally substituted phenyl, optionally Substituted benzyl, or optionally Sub 3-methyl-(4-methoxy)-2-phenylmorpholine: stituted pyridyl. 3-methyl-(4-cyano)-2-phenylmorpholine; 21. A pharmaceutical composition comprising a com 3-methyl-(3'-hydroxy)-2-phenylmorpholine; pound according to claim 1, and one or more pharmaceuti 3-methyl-(3'-methoxy)-2-phenylmorpholine: cally acceptable carriers. 3-methyl-(3'-cyano)-2-Phenylmorpholine; 22. A method for treating or delaying the progression of disorders that are alleviated by modulating monoamine 3-methyl-(3',4'-dichloro)-2-phenylmorpholine: release in a patient comprising administering a therapeuti 3-methyl-(3'-chloro-4'-fluoro)-2-Phenylmorpholine; cally effective amount of at least one compound according to 3-methyl-(3'-chloro-4'-methyl)-2-Phenylmorpholine: claim 1. 23. The method of claim 22, wherein the disorder is 5-methyl-2-(3-trifluoromethyl-phenyl)-morpholine; selected from the group consisting of addiction, depression, 5-methyl-2-p-tolyl-morpholine: obesity, bipolar disorder, attention deficit disorder (ADD), 5-methyl-2-m-tolyl-morpholine; attention deficit/hyperactivity disorder (ADHD), hypoactive 5-methyl-2-phenyl-morpholine; sexual desire disorder, antidepressant-induced sexual dys function, orgasmic dysfunction, seasonal affective disorder/ 5-methyl-2-(4-trifluoromethyl-phenyl)-morpholine, winter depression, mania, bulimia and other eating disorders, or a pharmaceutically acceptable ester, amide, salt, Solvate, panic disorders, obsessive compulsive disorder, Schizophre or isomer thereof. nia, Schizo-affective disorder, Parkinson's disease, narco 14. The compound according to claim 1, wherein the com lepsy, anxiety disorders, insomnia, chronic pain, migraine pound is one or more of a dopamine releaser, norepinephrine headaches, and restless legs syndrome. releaser, serotonin releaser, dopamine uptake inhibitor, nore 24. The compound according to claim 4, wherein R is Hor pinephrine uptake inhibitor, and serotonin uptake inhibitor. CH. 15. The compound according to claim 1, wherein the com 25. The compound according to claim 7, wherein R is Hor pound is a dopamine releaser or a dual serotonin and dopam CH. ine releaser. 26. The compound according to claim 4, wherein R is Hor CH. 16. The compound according to claim 1, wherein the com 27. The compound according to claim 7, wherein R is Hor pound is inactive at the 5HT receptor. CH. 17. A prodrug of a compound according to claim 1, com 28. The compound according to claim 4, wherein one of R2 prising a compound according to claim 1 having R replaced and R is Hand the other of RandR is optionally substituted with a labile protecting group. C1-3 alkyl. US 2013/0203752 A1 Aug. 8, 2013 42

29. The compound according to claim 7, wherein one of R and R is Hand the other of RandR is optionally substituted C1-3 alkyl. 30. A pharmaceutical composition comprising a prodrug according to claim 17, and one or more pharmaceutically acceptable carriers. 31. A method for treating or delaying the progression of disorders that are alleviated by modulating monoamine release in a patient comprising administering a therapeuti cally effective amount of at least one prodrug according to claim 17. 32. The method of claim 31, wherein the disorder is selected from the group consisting of addiction, depression, obesity, bipolar disorder, attention deficit disorder (ADD), attention deficit/hyperactivity disorder (ADHD), hypoactive sexual desire disorder, antidepressant-induced sexual dys function, orgasmic dysfunction, seasonal affective disorder/ winter depression, mania, bulimia and other eating disorders, panic disorders, obsessive compulsive disorder, Schizophre nia, Schizo-affective disorder, Parkinson's disease, narco lepsy, anxiety disorders, insomnia, chronic pain, migraine headaches, and restless legs syndrome. k k k k k