NZ618222B2 - Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia - Google Patents

Abstract

Disclosed are deuterated 1-piperazino-3-phenyl-indanes of formula Y and salts thereof with activity at dopamine receptors D1 and D2 as well as the 5HT2 receptors in the central nervous system. Also disclosed are medicaments comprising such compounds as active ingredients, the use of such compounds in the treatment of diseases in the central nervous system including schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, bipolar disorder, or mania in bipolar disorder, and the use of the compounds in the manufacture of medicaments for the treatment of these conditions. n the treatment of diseases in the central nervous system including schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, bipolar disorder, or mania in bipolar disorder, and the use of the compounds in the manufacture of medicaments for the treatment of these conditions.

Description

DEUTERATED 1-PIPERAZIN0PHENYL INDANES FOR TREATMENT OF SCHIZOPHRENIA This application claims priority to U.S. Provisional Application Nos. ,651, filed on June 20, 2011, and 61/537,103, filed on ber 21, 2011, the entirety ofeach of which is incorporated herein by reference.

All patents, patent ations and publications cited herein are hereby incorporated by reference in their entirety. The disclosures ofthese publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state ofthe art as known to those skilled therein as ofthe date ofthe invention described and claimed herein.

FIELD OF THE INVENTION The present invention relates to deuterated 1-piperazinophenyl-indanes and salts thereofwith activity at dopamine D1 and D2 receptors as well as the nin 5HT2 receptors in the central nervous system, to medicaments comprising such compounds as active ients, and to the use ofsuch compounds in the treatment ofdiseases in the central nervous system.

BACKGROUND OF THE INVENTION Throughout this application, various ations are referenced in full. The disclosures ofthese publications are hereby orated by reference into this application to describe more fully the state ofthe art to which this invention pertains. 4-((1R,3S)Chlorophenyl-indanyl)-1 ,2,2-trimethyl-piperazine and salts thereof, pharmaceutical compositions containing these salts and the medical use thereof, including treatment ofschizophrenia or other es involving psychotic symptoms, are sed in W02005/016900. 4-((1R,3S)Chlorophenyl-indanyl)-1,2,2-trimethylpiperazine has the l formula (X), hereinafter referred to as Compound (X) wo 2012/176066 EP 638 073 recites a group oftrans isomers of3-aryl(1-piperazinyl)indanes substituted in the 2- and/or 3-position ofthe piperazine ring. The compounds are described as having high affinity for ne D1 and D2 receptors and the 5-HT2 receptors and are suggested to be useful for treatment ofseveral diseases in the central nervous system, including schizophrenia.

The enantiomer offormula (X) above has been described by Boges0 et al. in J Med. Chern., 1995, 38, page 4380-4392, in the form ofthe fumarate salt, see table 5, compound (-)-38. This publication concludes that the (-)-enantiomer ound 38 is a potent DdD2 antagonist showing some D 1 selectivity in vitro. The compound is also described as a potent 5-HT2 antagonist. It is also mentioned that the compound does not induce catalepsy in rats.

The aetiology ofschizophrenia is not known, but the dopamine hypothesis of phrenia (Carlsson, Am. J atry 1978, 135, 164-173), formulated in the early 1960s, has ed a tical framework for understanding the biological mechanisms ying this disorder. In its simplest form, the ne hypothesis states that schizophrenia is associated with a hyperdopaminergic state, a notion which is supported by the fact that all antipsychotic drugs on the market today exert some dopamine D2 receptor antagonism (Seeman e and Medicine 1995, 2, 28-37). However, whereas it is generally accepted that antagonism ofdopamine D2 receptors in the limbic regions ofthe brain plays a key role in the ent ofpositive symptoms ofschizophrenia, the de ofD2 receptors in striatal regions ofthe brain causes extrapyramidal symptoms (EPS). As described in EP 638 073 a profile ofmixed dopamine DdD2 receptor inhibition has been observed with some so-called "atypical" antipsychotic compounds, in particular with clozapine (8-chloro(4- methylpiperazinyl)-5H-dibenzo[b,e][1,4]diazepine), used in treatment ofschizophrenic patients.

] According to a first aspect, the present invention provides a compound of formula AH26(9680189_1):RTK R1 N R8 (Y) wherein, R1 – R10 are independently hydrogen or deuterium, wherein R6-R10 are each deuterium, wherein at least one of R1-R10 comprises at least about 50% deuterium, or a pharmaceutically able acid on salt thereof. [0013b] According to a second aspect, the present invention provides a pharmaceutical composition comprising the nd according to the first aspect above and one or more pharmaceutically able carriers, diluents, or excipients. [0013c] According to a third aspect, the present invention provides use of the compound ing to the first aspect above, or the composition according to the second aspect above for the manufacture of a ment for treatment of psychosis, other diseases involving psychotic symptoms, psychotic disorders or diseases that present with psychotic symptoms. [0013d] ing to a fourth aspect, the present invention provides a compound of formula D (S)-(XV). [0013e] According to a fifth aspect, the present invention provides a process for the preparation of compound AH26(9680189_1):RTK D (S)-(XV) comprising treating compound D D D D D (XIV) with [(S)-BINAP]Rh(I)BF4. [0013f] According to a sixth aspect, the present ion es a process for the preparation of compound D D D D D (XIV) comprising a) treatment of D OTf D D D (XII) with bis(pinacolato) diboron, and b) treatment with 2-bromochlorobenzaldehyde.

AH26(9680189_1):RTK [0013g] According to a seventh , the present invention provides a process for the preparation of compound D (1R,3S)-(IV) tartrate comprising treatment of racemic trans(6-chlorophenyl(d5)-indanyl)-1(d3), 2, 2-trimethyl-piperazine with L-(+)-tartaric acid.

In one aspect, the invention es a compound of formula Y: AH26(9680189_1):RTK wo 2012/176066 R8 (Y) wherein, R1- R10 are independently hydrogen or deuterium, and wherein at least one ofR1- R10 comprises at least about 50% deuterium, or a pharmaceutically acceptable acid addition salt thereof.

In another aspect, the invention provides pharmaceutical compositions comprising a compound offormula (Y) and one or more pharmaceutically acceptable carriers, diluents, or ents.

In another aspect, the invention provides for uses ofa compound ula (Y) or a ceutical composition sing a compound of formula (Y) in the treatment of psychosis, other es involving psychotic symptoms, psychotic disorders or diseases that present with psychotic symptoms.

In yet another aspect, the invention provides for the manufacture of a medicament comprising a compound offormula (Y) for treatment ofpsychosis, other diseases involving psychotic symptoms, psychotic disorders or diseases that present with psychotic ms.

In still another aspect, the invention provides for methods oftreating psychosis, other es involving psychotic ms, psychotic disorders or diseases that present with psychotic symptoms comprising administration ofan effective amount ofa compound of formula (Y) or a pharmaceutically composition comprising a nd offormula (Y) to a subject in need thereof. wo 2012/176066 In still another aspect, the invention provides a compound offormula D (S)-(XV).

In still another , the ion provides a process for the preparation of compound D (S)-(XV) comprising treating compound (XIV) with [(S)-BINAP]Rh(I)BF4.

In still another aspect, the invention provides a process for the preparation of compound (1R,3S)-(IV) tartrate comprising, treatment of racemic trans(6-chloro (d5)-indanyl)-l(d3), 2, 2-trimethyl-piperazine with L-(+)-tartaric acid.

Still other objects and advantages ofthe invention will become apparent to those ofskill in the art from the disclosure herein, which is simply illustrative and not restrictive.

Thus, other embodiments will be recognized by the d artisan without departing from the spirit and scope ofthe ion.

BRIEF DESCRIPTION OF THE FIGURES shows major metabolic sites ofCompound (X). shows Compound (I) and Compound (XI), each as the (1R,3S)-enantiomer. shows NMR spectra ofCompound (II) and Compound (V). Selected regions ofthe proton-decoupled and - and deuterium-decoupled 13C NMR spectra of Compound (II) [Fig. 3A] and Compound (V) [Fig. 3B] are shown. shows the mass spectrum of Compound (IV). shows formation ofthe metabolite Compound (XI) by metabolism of Compound (X) and Compound (I) (0.1 microM) in cryopreserved dog hepatocytes (n=2 the bars ent max and min results). wo 2012/176066 shows formation ofthe metabolite Compound (XI) by metabolism of Compound (X) and Compound (I) (1 microM) in cryopreserved dog cytes (n=2 the bars represent max and min results). shows ion ofthe desmethyl metabolite by metabolism ofCompound (II), (IV) and (X) (1 micro M) in human liver microsomes (n=3, the bars represent standard deviation). shows formation ofthe desmethyl metabolite by metabolism ofCompound (II), (IV) and (X) (10 micro M) in human liver microsomes (n=3, the bars represent standard deviation). shows ion ofthe desmethyl metabolite by metabolism ofCompound (III) (10 micro M) in human liver microsomes (n=3, the bars represent rd deviation). shows formation ofthe desmethyl metabolite by metabolism of Compound (V) (10 micro M) in human liver microsomes (n=3, the bars represent standard deviation). shows formation ofthe desmethyl metabolite by metabolism of Compound (VI) (10 micro M) in human liver omes (n=3, the bars represent standard deviation). shows formation ofthe desmethyl metabolite by metabolism of Compound (VII) (10 micro M) in human liver microsomes (n=3, the bars represent standard deviation). shows shows the chemical structure ofcompounds (I)-(VII), (X)-(XI), and (XXI). shows formation ofthe desmethyl lite by metabolism of Compound (II) and (X) (10 micro M) by recombinant human liver CYP2C19 (n=3, the rd deviation). shows formation ofthe desmethyl metabolite by metabolism of Compound (IV) and Compound (X) (1 micro M) by inant human liver CYP2C 19 (n=3, the bars represent standard ion). shows PCP-induced hyperactivity in mice for compound (IV). shows cataleptic response in rats for compound (IV). shows X-ray diffractograms on two batches of hydrogen tartrate salt of Compound (IV).

DETAILED DESCRIPTION OF THE INVENTION wo 2012/176066 Atypical antipsychotics have been the subject ofnumerous studies by the pharmaceutical industry, and have shown promise in treating mental disorders such as schizophrenia, r disorder, dementia, anxiety disorder and obsessive-compulsive disorder (OCD). The mechanism of action ofthese agents remains unknown; r all antipsychotics work to some degree on the dopamine system. Most atypical antipsychotics exhibit activity at dopamine subtype receptors 1 and 2 (D1 and D2, respectively), and at the serotonin receptors subtype 2 (5-HT2). In some cases, the "atypical" designation was assigned to antipsychotics that did not induce extrapyramidal side effects; however it has been shown that some atypical antipsychotics still induce extrapyramidal side effects, albeit to a lesser degree that that observed with typical antipsychotics (Weiden, P.J., "EPS es: the atypical antipsychotics are not all the same" J atr. Pract. 2007, 13(1): 13-24; herein incorporated by reference in its entirety). Approved atypical antipsychotics include, for example, amisulpride (Solian), aripiprazole (Abilify), asenapine (Saphris), blonanserin (Lonasen), clotiapine (Entumine), clozapine (Clozaril), iloperidone (Fanapt), lurasidone (Latuda), mosapramine (Cremin), pine (Zyprexa), paliperidone a), perospirone (Lullan), quetiapine (Seroquel), pride (Roxiam), risperidone (Risperdal), sertindole (Serdolect), supliride (Sulpirid, Eglonyl), ziprasidone (Geodon, Zeldox), and zotepine (Nipolept). Several others are currently under pment. Because the ism of atypical antipsychotics is not well understood, side effects associated with these drugs have been difficult to design around. Thus, there is a need for additional ychotic therapies with potential for reduced side effect and/or improved therapeutic profile relative to existing therapies.

In one aspect, the t ion es compounds wherein one or more hydrogen atoms (H) in one or more ofthe metabolic sites M 1, M2 and M3 ofCompound (X) have been tuted by deuterium atoms (D). Compound (X) and variants thereof are described in, for example U.S. Patent Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240; 342; U.S. Patent Publication Nos. 2008/0269248; 201 0/0069676; 2011/0178094; 2011/0207744; ; EP 0 638 073; and J Med. Chern. 1995, 38, 4380-4392; each herein incorporated by reference in its entirety.

The kinetic isotope effect may potentially influence the rate ofmetabolism at one or more ofthe metabolic sites M1, M2, and M3 indicated in Figure 1. The inventors ofthe t invention have identified three major metabolic sites of4-((1R,3S)chloro wo 2012/176066 2012/001386 phenyl-indanyl)-1,2,2-trimethyl-piperazine (Compound (X)) denoted herein as M1, M2 and M3 and indicated in Figure 1.

Deuteration ofa compound at a site subject to oxidative metabolism may, in some cases reduce the rate ofmetabolism for a nd due to the primary isotope effect. Ifthe C-H bond cleavage step is rate limiting, a significant isotope effect may be observed.

However, ifother steps drive the rate ofmetabolism for a compound, the C-H bond cleavage step is not rate limiting and the isotope effect may be of little significance. Additionally, a negative isotope effect can be observed where reaction rate is sed upon substitution with deuterium. Thus, incorporation ofdeuterium at a site subject to ive enzymatic metabolism does not predictably impact pharmacokinetics (See, for example, U.S. Pat. No. 7,678,914; Drug Metab. Dispos. 1986, 14, 509; Arch. Toxicol. 1990, 64, 109; Int. Arch.

Occup. Environ. Health 1993, 65(Suppl. 1): S139; each herein incorporated by reference in its entirety). The impact ofdeuterium incorporation is unpredictable does not work for many drugs or classes ofdrugs. Decreased metabolic clearance has been ed with some deuterated compounds relative to non-deuterated derivatives; whereas metabolism ofother compounds has been cted. Examples ofstudies indicating lack ofpredictability regarding deuterium incorporation include U.S. Patent No. 6,221,335; J Pharm. Sci. 1975, 64, 367-391; Adv. Drug. Res. 1985, 14, 1-40; J Med. Chern. 1991, 34, 876; Can. J Physiol. cal. 1999, 79-88; Silverman, R. B., The Organic Chemistry ofDrug Design and Drug Action, 2nd Ed. (2004), 422; Curr. Opin. Drug Dev. 2006, 9, 101-109; Chemical Res. Tax. 2008, 1672; Harbeson, S.L and Tung, R.D. "Deuterium in Drug Discovery and Development," in Ann. Rep. Med. Chern. 2011, 46, 404-418; each herein incorporated by reference in its entirety. Even incorporation ium at known sites ofmetabolism has an unpredictable impact on metabolic profile. Metabolic switching may result wherein the metabolic profile ofa ular drug is changed due to deuterium incorporation, thus leading to different tions of(or different) lites than observed with a non-deuterated anlog ofthe same drug. The new metabolic profile may result in a distinct logical profile ofthe deuterated analog. Adding to the potential complications ofdeuterium incorporation is the possibility ofdeuterium/hydrogen exchange in the logical environment (Adv. Drug. Res. 1985, 14, 1-40; herein incorporated by reference in its entirety). wo 2012/176066 In some embodiments, isotopic tution ofone or more hydrogen atoms in Compound (X) by deuterium atoms has given rise to a kinetic isotope effect that influences the rate ofmetabolism.

The isotopic substitution ofhydrogen atoms in Compound (X) by deuterium atoms results in less metabolism ofthe deuterated compound as shown to occur in dog hepatocytes where for instance an approximately 50% decrease in formation ofthe desmethyl metabolite (Compound (XI)) from Compound (I) (Figure 2) was noted in comparison to the formation ofCompound (XI) from the metabolism of Compound (X).

Deuteration ofthe free phenyl, optionally in combination with deuteration ofthe 1-methyl group (Compound (II) and (IV)), surprisingly reduces the amount ofthe desmethyl metabolite produced in human liver microsomes as compared to the non-deuterated compound (Compound (X)). Also surprisingly, deuteration ofthe 1-methyl group impacted metabolism in dog but not human hepatocytes, thus indicative ofthe unpredictability of deuteration on pharmacological properties.

The effect ofthe reduced metabolism is higher bioavailability ofthe deuterated, parent compound and less metabolite formation. Without being bound by theory, based on the results described in the experimental section ofthis ation the same effect is ed to show up after multiple dosing in humans, allowing for lower doses to be stered to humans i.e. less burden to the entire body, e.g. the liver, and a less frequent dosing.

The yl metabolite (Compound (XI)) is known to have hERG affinity and thus ially contribute to QTc prolongation. As mentioned above, deuteration ofthe free phenyl optionally in combination with deuteration ofthe 1-methyl group und (II) and (IV)), surprisingly reduces the amount ofthe desmethyl metabolite produced in human liver microsomes as ed to the uterated nd (Compound (X)). Accordingly and without being bound by theory, it is anticipated that there will be less interaction with the hERG channel and resultant lower burden on the heart when dosing the deuterated ts of nd (X) [e.g., compounds offormula (Y)] compared to when dosing Compound (X).

The invention is further detailed in the exemplary embodiments provided herein.

Definitions The term "compound(s) ofthe invention" as used herein means nds (Y), (I), (II), (III), (IV), (V), (VI), and/or (VII), and may include salts, hydrates and/or solvates thereof. The compounds ofthe present invention are prepared in different forms, such as wo 76066 salts, hydrates, and/or solvates, and the invention includes compositions and methods encompassing all variant forms ofthe compounds.

The term "composition(s) ofthe ion" as used herein means compositions comprising Compounds (Y), (I), (II), (III), (IV), (V), (VI), and/or (VII), or salts, hydrates, and solvates thereof. The compositions ofthe invention may further se one or more chemical components such as, for example, excipients, diluents, vehicles or carriers.

The term "method(s) ofthe invention" as used herein means methods comprising treatment with the compounds and/or compositions ofthe invention.

As used herein the term "about" is used herein to mean approximately, roughly, , or in the region of. When the term " is used in ction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of20 t up or down (higher or lower).

An "effective amount", "sufficient amount" or "therapeutically effective " as used herein is an amount ofa compound that is sufficient to effect beneficial or desired results, including clinical results. As such, the effective amount may be sufficient, for example, to reduce or ameliorate the severity and/or duration ofan affliction or condition, or one or more symptoms thereof, prevent the ement ofconditions related to an affliction or condition, prevent the recurrence, development, or onset ofone or more symptoms associated with an affliction or condition, or enhance or otherwise improve the prophylactic or therapeutic effect(s) her therapy. An effective amount also includes the amount of the compound that avoids or substantially attenuates undesirable side effects.

As used herein and as well understood in the art, ment" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or d al results may include, but are not limited to, alleviation or amelioration ofone or more symptoms or conditions, diminution of extent of disease, a stabilized (i.e., not worsening) state ofdisease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation ofthe disease state and remission (whether partial or total), whether detectable or ctable. "Treatment" can also mean prolonging survival as compared to expected survival ifnot ing treatment.

The term "in need thereof'refers to the need for symptomatic or asymptomatic relief from a condition such as, for example, psychosis or a psychotic disorder. The subject wo 2012/176066 in need thereofmay or may not be undergoing treatment for conditions related to, for e, sis or a psychotic disorder.

The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a compound is administered. Non-limiting examples ofsuch pharmaceutical carriers include liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carriers may also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In on, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used. Other examples able pharmaceutical carriers are described in Remington: The Science and Practice ofPharmacy, 21st Edition (University of the Sciences in Philadelphia, ed., Lippincott Williams & Wilkins 2005). (hereby incorporated by reference in its entirety).

The terms "animal," "subject" and "patient" as used herein include all s of the animal kingdom including, but not limited to, s, animals (e.g., cats, dogs, horses, swine, etc.) and humans.

The term "isotopic variant" as used herein means a compound obtained by substituting one or more hydrogen in a parent compound not comprising deuterium atoms by deuterium atoms.

It is recognized that elements are present in natural isotopic abundances in most synthetic compounds, and result in inherent incorporation ofdeuterium. However, the natural ic abundance ofhydrogen isotopes such as deuterium is immaterial (about ) relative to the degree ofstable isotopic substitution ofcompounds indicated herein.

Thus, as used herein, designation ofan atom as deuterium at a position indicates that the abundance ofdeuterium is significantly greater than the natural nce ofdeuterium.

Any atom not designated as a particular isotope is intended to ent any stable isotope of that atom, as will be apparent to the rily skilled artisan.

Compounds (Y) are isotopic ts of Compound (X).

In some ments, compounds (I), (II), (III), (IV), (V), (VI) and (VII) are ic ts of Compound (X).

M1 is a site ofCompound (X) susceptible to lism; M1 consists of-CH2- in the 6-position ofthe piperazine ofCompound (X).

M2 is a site of compound (X) susceptible to metabolism; M2 consists oftheN- bound methyl ofthe piperazine ofCompound (X). wo 2012/176066 M3 is a site ofCompound (X) susceptible to metabolism; M3 consists ofthe phenyl group ofCompound (X).

Parent compound is the chemical compound which is the basis for its tives obtained either by substitution or breakdown, e.g. metabolic breakdown. In the context ofthe present invention the parent compound is the Active Pharmaceutical Ingredient (API).

In some embodiments, any atom not designated as deuterium is t at its natural isotopic abundance. In some embodiments, any hydrogen atom not designated as deuterium is present at less than 1% isotopic abundance ofdeuterium.

In one aspect, the invention provides a compound offormula (Y): RB (Y) wherein, R1 - R10 are independently hydrogen or deuterium, wherein at least one ofR1-R10 comprises at least about 50% ium, or a pharmaceutically acceptable acid addition salt thereof.

In another aspect, the invention provides pharmaceutical compositions comprising a nd ula (Y) and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In another aspect, the invention provides for uses ofa compound offormula (Y) or a pharmaceutical composition comprising a compound of formula (Y) in the treatment of psychosis, other diseases involving psychotic symptoms, psychotic ers or es that present with psychotic ms.

In yet another aspect, the invention provides for the manufacture of a medicament comprising a compound offormula (Y) for ent ofpsychosis, other diseases ing psychotic symptoms, psychotic disorders or diseases that present with tic symptoms. wo 2012/176066 In still another aspect, the invention provides for methods oftreating psychosis, other es involving psychotic symptoms, psychotic disorders or diseases that present with psychotic symptoms comprising administration ofan effective amount ofa compound of a (Y) or a ceutically composition comprising a compound offormula (Y).

In some embodiments, the compound is racemic. In some embodiments, the compound is enantiomerically enriched.

In some embodiments, the compound is selected from the group consisting of (J-- (J-I :::::- Cl f :::::- Cl f ~ D ~ (1R,3S)-(I), D (1R,3S)-(II), "tY (J- rN N :::::- Cl Cl f (1R,3S)-(III), D (1R,3S)-(IV), wo 2012/176066 DDfD DtfD Dty y N Cl f Cl t ~ D =- (1R,3S)-(V), D (1R,3S)-(VI), and DtyD I ::::-N Cl f D (1R,3S)-(VII).

In some embodiments, R1 and R2 comprise deuterium, R3-R5 comprise deuterium, or R6-R10 comprise deuterium.

In some embodiments, R1 and R2 comprise deuterium. In some embodiments, R1 and R2 comprise deuterium and R3-R5 comprise hydrogen.

In some ments, R3-R5 comprise deuterium. In some embodiments, R3-R5 comprise hydrogen.

In some ments, R6-R10 comprise deuterium. In some embodiments, R6-R10 comprise deuterium and R3-R5 comprise hydrogen.

In some embodiments, R1-R5 se deuterium.

In some embodiments, R1, R2, and R6-R10 comprise deuterium.

In some ments, R3-R10 comprise deuterium.

In some embodiments, R1-R10 comprise deuterium. wo 2012/176066 (J-I Cl 1 In some ments, the compound is D (1R,3S)-(II) or D (1R,3S)-(IV).

(J-I Cl 1 In some embodiments, the compound is D (1R,3S)-(II). wo 2012/176066 2012/001386 In some embodiments, the compound is (1R,3S)-(III).

In some embodiments, the compound is D (1R,3S)-(IV).

In some embodiments, the compound is (1R,3S)-(V). wo 2012/176066 In some embodiments, the compound is D (1R,3S)-(VI).

In some embodiments, the compound is D (1R,3S)- (VII).

In some embodiments, at least about 75% ofthe compound has a deuterium atom at each on designated as deuterium, and any atom not designated as deuterium is present at about its natural isotopic abundance.

In some embodiments, at least about 85% ofthe compound has a deuterium atom at each position designated as deuterium, and any atom not designated as ium is present at about its natural isotopic abundance.

In some embodiments, at least about 90% ofthe nd has a deuterium atom at each position designated as deuterium, and any atom not designated as deuterium is present at about its natural isotopic abundance.

In some embodiments, the compound is a salt selected from the group consisting rate, maleate, succinate, and tartrate. In some ments, the compound is a fumarate salt. In some embodiments, the compound is a hydrogen fumarate salt. In some wo 2012/176066 2012/001386 embodiments, the compound is a maleate salt. In some embodiments, the compound is a hydrogen maleate salt.

In some embodiments, the compound is a succinate salt. In some embodiments, the compound is a hydrogen succinate salt. In some ments, the compound is a tartrate salt. In some embodiments, the compound is the hydrogen tartrate salt.

In some embodiments, the compound is the hydrogen tartrate salt of(1R,3S)-(IV).

In some embodiments, the psychosis or disease involving psychotic symptoms is schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, bipolar disorder, or mania in bipolar disorder.

In some embodiments, the psychosis or disease involving psychotic symptoms is schizophrenia.

In some ments, the methods further comprise administration ofwith one or more neuroleptic agents.

In some ments, the uses further comprise use of a one or more neuroleptic agents.

In some embodiments, the neuroleptic agent is selected from the group consisting ofsertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and ant.

In some ments, administration is oral, sublingual, or buccal. In some embodiments, administration is oral.

In some ments, the subject is a mammal. In some embodiments, the subject is a rodent, cat, dog, monkey, horse, swine, , or human. In some embodiments, the subject is a rodent, cat, dog, monkey, bovine or human. In some embodiments, the subject is a mouse, rat, cat, dog, monkey, or human. In some embodiments, the subject is a mouse, rat, dog, monkey, or human. In some embodiments, the subject is a mouse, rat, dog, or human. In some embodiments, the subject is a mouse, rat or a human. In some embodiments, the subject is a dog or a human. In some embodiments, the subject is a human.

In some embodiments, ation ofa position as "D" in a compound has a minimum ium incorporation ofgreater than about 40% at that position. In some ments, designation ofa position as "D" in a compound has a m deuterium incorporation ofgreater than about 50% at that position. In some embodiments, designation ofa position as "D" in a compound has a minimum deuterium incorporation ter than about 60% at that position. In some embodiments, ation ofa position as "D" in a wo 2012/176066 compound has a minimum deuterium incorporation ofgreater than about 65% at that position. In some embodiments, designation ofa position as "D" in a compound has a m deuterium incorporation ter than about 70% at that position. In some ments, designation ofa position as "D" in a compound has a minimum deuterium incorporation ter than about 75% at that position. In some embodiments, designation ofa position as "D" in a compound has a minimum deuterium incorporation ofgreater than about 80% at that position. In some embodiments, designation ofa position as "D" in a compound has a minimum deuterium incorporation ofgreater than about 85% at that position. In some embodiments, designation ofa position as "D" in a compound has a minimum deuterium oration ofgreater than about 90% at that position. In some embodiments, designation ofa position as "D" in a compound has a minimum deuterium incorporation ofgreater than about 95% at that position. In some embodiments, designation ofa position as "D" in a compound has a minimum deuterium incorporation ofgreater than about 97% at that position. In some embodiments, designation ofa position as "D" in a compound has a minimum deuterium oration ofgreater than about 99% at that position. ceutically Acceptable Salts The present invention also comprises salts ofthe compounds, lly, pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts. Acid addition salts include salts ofinorganic acids as well as organic acids.

Representative examples able inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.

Representative es ofsuitable organic acids e formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, hylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, benzoic , glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline and the like. Further examples maceutically acceptable nic or organic acid addition salts include the pharmaceutically acceptable salts listed in Berge, S.M. et al., J. Pharm. Sci. 1977, 66, 2, and Gould, P.L., Int. J. Pharmaceutics 1986, 33, 201-217; the contents ofeach are hereby incorporated by reference. wo 76066 Furthermore, the compounds ofthis invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, l and the like. In l, the solvated forms are considered comparable to the unsolvated forms for the purposes ofthis invention.

Headings and sub-headings are used herein for convenience only, and should not be construed as limiting the invention in any way.

The use ofany and all examples, or exemplary language (including "for ce", "for example", "e.g.", and "as such") in the present specification is intended merely to better illuminate the invention, and does not pose a limitation on the scope ofinvention unless otherwise ted.

The use ofthe terms "a" and "an" and "the" and similar referents in the context of describing the ion are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

Unless otherwise indicated, all exact values provided herein are representative of corresponding approximate values (e.g., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also provide a corresponding approximate measurement, modified by "about," where appropriate).

The description herein ofany aspect or aspect ofthe invention using terms such as "comprising", "having," "including," or "containing" with reference to an element or elements is intended to provide support for a similar aspect or aspect ofthe invention that "consists of',"consists essentially of',or "substantially comprises" that particular element or elements, unless otherwise stated or clearly contradicted by context.

Exemplary syntheses ofthe compounds ofthe invention can be readily achieved by methods described, for example, U.S. Patent Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240; 8,076,342; U.S. Patent Publication Nos. 2008/0269248; 069676; 2011/0178094; 2011/0207744; ; EP 0 638 073; andJ. Med. Chern. 1995, 38, 392; each herein incorporated by nce in its entirety. Such s, and r methods can be performed using deuterated reagents and/or intermediates, and/or introducing ium atoms to a chemical structure according to protocols known in the art.

Further exemplary methods of synthesis include conversion none A to intermediate C via treatment of3-bromochloro-indanone (A; for references on this material, see: Boges0 EP 35363 AI 19810909 and Kehler, Juhl, Puschl, WO 2008025361; each herein incorporated by reference in its entirety) with a base such as triethylamine in a wo 2012/176066 solvent such as tetrahydrofuran at ambient temperature e 1). Removal ofthe precipitated amine romide salt by filtration and concentration ofthe filtrate will afford 6-chloro-indenone (B). This al can be reacted with phenyl-d5-boronic acid in the presence ofapproximately 1 equivalent ofa base such as triethylamine and a catalytic amount ofa 1:1 mixture of b)2]BF4 (bis(norbomadiene)rhodium(!) tetrafluoroborate) and c BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)in a suitable solvent (e.g. approximately 10:1 solvent mixture of 1,4-dioxane and water) under an atmosphere ofargon at elevated ature (e.g. about 100°C). Work-up will afford racemic 6-chlorophenyld5-indanone (C).

Scheme 1. Exemplary synthesis ofintermediate C. a~ Cl~ ~ UJ A B D C (racemate) Treatment of6-chlorophenyl-d5-indanone (C) with a reductive base such as sodium borohydride (~2 lents) in a ~10:1 solvent mixture oftetrahydrofuran and water at low temperature (approximately -15 °C) will lead to reduction ofthe carbonyl group to the corresponding alcohol (Scheme 2). Work-up will afford racemic cischlorophenylindanol (D). Treatment ofthis material with vinyl butyrate (approximately 5 equivalents) and Novozym 435® in a solvent such as di-iso-propyl ether at ambient temperature will afford (1S,3S)chlorophenyl-indanol (E) after work-up.

Scheme 2. ary synthesis ofintermediate E.

Cl Cl Cl D D D D D D C (racemate) D (cis-racemate) E ((1 S,3S)-enantiomer) wo 2012/176066 Alternatively, performing the sequence from A to E using phenyl boronic acid or 4,4,5,5-tetramethylphenyl-[1,3,2]dioxaborolane instead of4,4,5,5-tetramethyld5- phenyl-[1,3,2]dioxaborolane will lead to (1S,3S)chlorophenyl-indanol cheme Scheme 3. Exemplary synthesis ofintermediate E'.

Cl-yy( Cl A E' ((1S,3S)-enantiomer) Further alternative synthetic methods to obtain E' are disclosed in the patent literature (Dahl, Wohlk Nielsen, Suteu, Robin, Brosen W02006/086984 AI; Bang-Andersen, Boges0, , Svane, Dahl, Howells, Lyngso, Mow /016901 AI; each herein incorporated by reference in its entirety). These procedures rely on benzyl cyanide as one of the substrates. Using benzyl cyanide-d7 (commercially available from Aldrich, catalog# ) or phenyl-d5-acetonitrile (commercially available from Aldrich g# 495859 or from CDN catalog# D-5340 or from Kanto catalog# 27) the same procedure may lead toE (Scheme 4). As alternatives to the commercial sources, benzyl cyanide-d7 and phenyl-d5-acetonitrile can be prepared sodium cyanide and benzyl-d7 chloride (commercially available from Aldrich, catalog# ) and benzyl-2,3,4,5,6-d5 chloride (commercially available from Aldrich, catalog# 485764), respectively.

Scheme 4. Exemplary synthesis ofintermediates E and E'. wo 2012/176066 benzyl cyanide E' ((1 S,3S)-enantiomer) R Cl D D --- D D D D R = D: benzyl cyanide-d7 R = H: phenyl-d5-acetonitrile E ((1S,3S)-enantiomer) Treatment ofE with approximately 4 equivalents ofdi-iso-propylethylamine and approximately 2 equivalents methanesulphonic anhydride in tetrahydrofuran at approximately -18 oc followed by slow heating to approximately -5 oc and subsequent treatment with approximately 4 equivalents 2,2-dimethyl-piperazine will lead to the formation of ,3S)- 6-chlorophenyl-d5-indanyl)-3,3-dimethyl-piperazine (F) that can be ed after the reaction (Scheme 5). Alternatively, one can t alcohol E to the corresponding chloride, predominantly with retention ofconfiguration at Clleading to (1S,3S)chlorod5-phenylindan (E"; similarly E' can be converted to (1S,3S)chlorophenyl-indan (E"')).

Chloride E" can be reacted with 2,2-dimethyl-piperazine to afford F. The final step can be med as described for the preparation ofCompound (I)•butanedioic acid salt by the use ofiodomethane to give Compound (II) or d3-iodomethane to give Compound (IV), respectively. atively, as bed below, the methyl group or d3-methyl group can be installed by refluxing in HCHO/HCOOH or DCDO/DCOOD, respectively.

Scheme 5. Exemplary sis ofintermediates F and Compounds (II) and (IV). wo 2012/176066 cY CYRI N N Cl Cl f Cl f"' D D D D D D D D D D E ((1 S,3S)-enantiomer) F ((1 R,3S)-enantiomer) R =CH3: Compound (II) R =CD3: Compound (IV) (2-Aminomethyl-propyl)-carbamic acid tert-butyl ester (G) can be prepared from 2-methyl-propane-1,2-diamine and di-tert-butyl dicarbonate (alternatively, G is claimed to be commercially available: Prime catalog# POIMB4; Rovathin catalog# NX45401). Reaction ofG with a haloacetyl halide such as either chloroacetyl chloride or cetyl e will give [2-(2-chloro-acetylamino)methyl-propyl]-carbamic acid tert-butyl ester or [2-(2-bromo-acetylamino)methyl-propyl]-carbamic acid tert-butyl ester (H), respectively e 6). Treatment ofeither variant ofH with acid followed by base will lead to the formation of6,6-dimethyl-piperazineone (I). This material can be reduced to 2,2-dimethyl-5,5-d2-piperazine (J) by treatment with lithium aluminium deuteride.

Scheme 6. Exemplary synthesis ofintermediate J. 2-methylpropane-1 diamine G H J Alternatively, J can be prepared from 2-aminomethyl-propionic acid. on of2-aminomethyl-propionic acid and di-tert-butyl onate will afford 2-tertbutoxycarbonylaminomethyl-propionic acid (K) (Scheme 7). The acid functionality can be converted to the corresponding Weinreb amide by on with O,N-dimethylhydroxylamine in the presence ofa suitable coupling reagent such as 2-(1H zotriazolyl)-1 ,1 ,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU) or 1-ethyl(3-dimethylaminopropyl) carbodiimide (EDC) to afford [1-(methoxy- wo 76066 methyl-carbamoyl)methyl-ethyl]-carbamic acid tert-butyl ester (L). ive ion of the Weinreb amide leads to (1,1-dimethyloxo-ethyl)-carbamic acid tert-butyl ester (M).

Reductive amination involving aldehyde M and amino-acetic acid methyl ester can be used to prepare (2-tert-butoxycarbonylaminomethyl-propylamino)-acetic acid methyl ester (N).

Treatment ofcarbamate-ester N with a suitable acid, such as trifluoroacetic acid, will lead to the formation ofpiperazinone I that upon treatment with lithium aluminium deuteride gives piperazine J.

Scheme 7. Alternative ary synthesis ofintermediate J. oyo't oyo't oyo't ~Nf ""f ""f ""f HO 0 HO 0 '-.,.N 0 H 0 2-aminomethyl- OMe propionic acid K L M oyo't ""f l~t D1:~t MeO~~ N N H H N J Using J instead of2,2-dimethyl-piperazine as described for the conversion ofE to Compounds (II) and (IV) will lead to Compounds (VI) and Compound (VII), respectively.

Similarly, using E' and J instead of2,2-dimethyl-piperazine and E will lead to Compound (III) and Compound (V). wo 2012/176066 In r aspect, the invention provides a process for the preparation of compound D (S)-(XV) comprising treating nd (XIV) with [(S)-BINAP]Rh(I)BF4.

In another aspect, the invention provides a process ofthe preparation of compound (1R,3S)-(IV) tartrate sing treatment of racemic trans(6-chloro phenyl(d5)-indanyl)-l(d3), 2, ethyl-piperazine with L-(+)-tartaric acid.

In some embodiments, racemic trans-!-(6-chlorophenyl(d5)-indanyl)-1 ( d3), 2, 2-trimethyl-piperazine is generated from the corresponding succinate salt f.

In some ments, racemic trans(6-chlorophenyl(d5)-indanyl)-l(d3), 2, 2-trimethyl-piperazine succinate is generated from the maleate salt of racemic trans(6- chlorophenyl(d5)-indanyl)-3,3-dimethyl-piperazine.

In some embodiments, acetophenone-d5is converted to an enol ether. In some ments, the enol ether is a silyl enol ether. In some embodiments, the enol ether of acetophenone-d5is converted to the ponding vinyl boronate. In some embodiments, the enol ether ofacetophenone-d5is treated with bis(pinacolato)diboron. In some embodiments, the vinyl boronate is treated with 2-halochlorobenzaldehyde.

In some embodiments, the compounds exist as racemates. In some embodiments, the compounds exist in r than about 70% enantiomeric excess. In some embodiments, the compounds exist in greater than about 75% enantiomeric excess. In some embodiments, the compounds exist in greater than about 80% enantiomeric excess. In some embodiments, the compounds exist in greater than about 85% enantiomeric excess. In some embodiments, the compounds exist in greater than about 90% enantiomeric excess. In some embodiments, the compounds exist in greater than about 92% enantiomeric excess. In some embodiments, the compounds exist in greater than about 95% enantiomeric excess. In some embodiments, the compounds exist in greater than about 97% enantiomeric excess. In some embodiments, the compounds exist in greater than about 99% enantiomeric excess.

Pharmaceutical compositions wo 2012/176066 The present invention further provides pharmaceutical compositions comprising a therapeutically effective amount ofthe compounds ofthe present invention and a pharmaceutically acceptable carrier or diluent.

The compounds ofthe invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or le doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with tional techniques such as those disclosed in Remington: The e and Practice ofPharmacy, 21st n (University ofthe Sciences in Philadelphia, ed., Lippincott Williams & Wilkins 2005).. r exemplary itions of the nds ofthe invention are described in, for example, U.S. Patent Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240; 8,076,342; U.S. Patent Publication Nos. 2008/0269248; 2010/0069676; 2011/0178094; 2011/0207744; ; EP 0 638 073; andJ. Med.

Chern. 1995, 38, 4380-4392; each herein incorporated by reference in its entirety.

The pharmaceutical compositions may be specifically ated for administration by any suitable route such as oral, nasal, topical (including buccal and sublingual), and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) . It will be appreciated that the route will depend on the general condition and age ofthe t to be treated, the nature ofthe condition to be treated and the active ingredient.

The daily dose ofthe compounds ofthe invention, calculated as the free base, is suitably from about 1.0 to about 160 mg/day, more suitably from about 1 to about 100 mg, e.g. preferably from about 2 to about 55, such as from about 2 to about 15 mg, e.g. from about 3 to about 10 mg. In some ments, the daily dose is from about 0.1 mg to about 500 mg. In some ments, the daily dose is from about 1 mg to about 500 mg. In some embodiments, the daily dose is from about 1 mg to about 400 mg. In some embodiments, the daily dose is from about 1 mg to about 300 mg. In some embodiments, the daily dose is from about 1 mg to about 200 mg. In some embodiments, the daily dose is from about 1 mg to about 160 mg. In some embodiments, the daily dose is from about 1 mg to about 100 mg. In some embodiments, the daily dose is from about 1 mg to about 60 mg. In some embodiments, the daily dose is from about 2 mg to about 30 mg. In some embodiments, the daily dose is from about 2 mg to about 15 mg. In some embodiments, the daily dose is from about 3 mg to about 10 mg. In some embodiments, the daily dose is about 60 mg. In some wo 2012/176066 embodiments, the daily dose is about 50 mg. In some embodiments, the daily dose is about 40 mg. In some embodiments, the daily dose is about 30 mg. In some embodiments, the daily dose is about 20 mg. In some embodiments, the daily dose is about 10 mg. In some embodiments, the daily dose is about 5 mg. In some embodiments, the daily dose is about 3 mg. In some embodiments, the daily dose is about 2 mg. In some embodiments, the daily dose is about 1 mg.

For eral routes such as intravenous, hecal, intramuscular and similar administration, typical doses are in the order ofhalfthe dose employed for oral administration.

The nds ofthis invention are lly utilized as the free substance or as a pharmaceutically acceptable salt thereof. Examples ofsuitable organic and inorganic acids are described herein.

In some embodiments, the composition comprises a cyclodextrin. In some embodiments, the composition comprises a cyclodextrin in water. In some embodiments, the cyclodextrin is hydroxypropyl-~-cyclodextrin. In some embodiments, the composition comprises hydroxypropyl-~-cyclodextrin in water.

Treatment ofDisorders The invention also relates to the medical use ofcompounds ofthe present invention, such as for the treatment ofa disease in the central nervous system, including psychosis, in particular schizophrenia or other diseases involving psychotic symptoms, such as, e.g., Schizophrenia, Schizophreniform Disorder, Schizoaffective er, Delusional Disorder, BriefPsychotic Disorder, Shared Psychotic Disorder as well other psychotic disorders or diseases that present with psychotic symptoms, e.g. bipolar disorder, such as mania in bipolar disorder. Compounds and/or compositions ofthe invention can further be used in treatment ofdisorders such as those described in, for example, U.S. Patent Nos. ,807,855; 7,648,991; 7,767,683; 7,772,240; 8,076,342; U.S. Patent Publication Nos. 2008/0269248; 069676; 2011/0178094; 2011/0207744; WO 16900; EP 0 638 073; and J Med. Chern. 1995, 38, 4380-4392; each herein incorporated by nce in its entirety. The invention also relates to the l use ofcompounds ofthe present invention as combination therapy in conjunction with other therapeutic agents such as those described in, for example, U.S. Patent Nos. 855; 7,648,991; 7,767,683; 7,772,240; 8,076,342; U.S. Patent Publication Nos. 2008/0269248; 2010/0069676; 2011/0178094; 2011/0207744; wo 76066 WO 16900; EP 0 638 073; and J Med. Chern. 1995, 38, 4380-4392; each herein incorporated by reference in its entirety.

It will recognized that one or more features ofany embodiments disclosed herein may be combined and/or nged within the scope ofthe invention to produce further embodiments that are also within the scope ofthe invention.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments ofthe invention described herein. Such equivalents are intended to be within the scope ofthe present invention.

The invention is further described by the following non-limiting Examples.

EXAMPLES Examples are provided below to facilitate a more complete understanding ofthe invention. The following examples illustrate the exemplary modes ofmaking and practicing the invention. However, the scope ofthe invention is not limited to specific embodiments disclosed in these Examples, which are for purposes ofillustration only, since alternative methods can be utilized to obtain similar results.

Purification of compounds by chromatography refers to the application ofsilica gel chromatography using either manual flash chromatography or ted flash chromatography, lly performed using eluent gradients from heptanes to ethyl acetate or mixtures ofethyl acetate, triethylamine and methanol.

Description ofLCMS Methods.

Compounds (I), (II), (III), (IV), (V), (VI) and (VII) were terized by LCMS using the ing methods (Table 1): Table 1: Methods for LCMS Analysis Methods WXV-ABS, WXV-ABIO, and WXV-AB30 Equipment t 1100 LCMS system with ELS Detector d WuXiAB25 Agilent 1200 LCMS system with ELS or] Pump Gl311A Degasser Gl379A Well-plate Autosampler Gl367A Column Oven Gl316A DAD Gl315B MSD Gl946C or Gl956A [method WuXiAB25 6110] ELSD Alltech ELSD 800 [method WuXiAB25 Aligentl200] Column YMC ODS-AQ [method WuXiAB25 t TC-Cl8] Particle size 5 micrometer Pore size 12 urn Dimension 50* 2.0 mm ID d WuXiAB25 50*2.1 mm ID] Injection volume 2 microL wo 2012/176066 Column temperature 50°C Flow 0.8 mL/min Mobile phases A 0.1% TFA in water B 0.05% TFA in acetonitrile Total run time 4.5 min Gradient linear UV Detection Wavelength 254nm ELSD ion Temperature: 50°C Gas Pressure: 3.2 bar Time Gradient WXV-ABOS 0 min 95 %A5%B 3.5 min O%A 100% B 3.55 min B WXV-ABIO 0 min 90%A 10% B 3.4 min 100%B 3.5 min 100%B 3.51 min 90%A 10% B WXV-AB30 0 min 70%A30%B 3.2 min O%A 100% B 3.5 min O%A 100%B 3.55 min 70%A30%B WuXiAB25 0 min 75%A25%B 3.4 min 0 %A 100%B 4 min 0 %A 100%B 4.01 min 75%A25%B 4.5 min 75%A25%B Method 131 Equipment Sciex API150EX equipped with APPI-source operating in ve ion mode LC-MS were run on a Sciex APII50EX equipped with APPI-source operating in posi-tive ion mode. The HPLC consisted adzu Dvp LC pumps, SPD-M20A PDA detector (operating at 254 nM) and SCL-1 OA system controller. Autosampler was Gilson Autosampler Gilson 215 Column Oven Jones Chromatography 7990R ELSD Sedere Sedex 85 Column Waters Symmetry C-18 Particle size 3.5 micrometer Dimension 30 * 4.6 mm ID Injection volume 10 microL Column temperature 60°C Flow 3.0 mL/min Mobile phases A 0.05% TFA in water B 0.05% TFA in methanol Total run time 2.8 min Gradient non-linear UV Detection Wavelength 254nm ELSD Detection Temperature: 50°C Gas Pressure: 4.4 bar Time Gradient 0.01 min 17% B inA 0.27 min 28% B inA 0.53 min 39% B inA 0.80 min 50% B inA 1.07 min 59% B inA 1.34 min 68% B inA 1.60 min 78% B inA 1.87 min 86% B inA 2.14 min 93% B inA 2.38 min 100%B 2.40 min 17% B inA wo 2012/176066 2.80 min 17% B inA Description ofChiral HPLC methods The omeric purity was assayed on a Hewlett d 1100 series system equipped with a diode array detector and using ChemStation for LC Rev. A.08.03[847]. The HPLC method parameters are described in the table below (Table 2). Compound (X) has a retention time around 13.6-13.7 min while its enantiomer, 4-((1S,3R)chlorophenyl-indanyl)-1,2,2- trimethyl-piperazine, elutes at 8.5-8.6 min.

Table 2: Methods for Chiral HPLC Analysis Sample Preparation 1-3 mg/mL in hexane/2-propanol (80/20 v/v) : Chiralpak ADH 5microm 250 x 4.6mm Column Temperature (°C): 30 Injection (microL): 5 Detection: 240,8 Wavelength, Bandwidth( nm): Total me 30 min Flow Rate (mL.min-1): 0.6 hexane/2-propanol/diethylamine/propionic acid Mobile Phase 90/10/0.2/2 Example 1 Preparation of4-((1R,3S)chlorophenyl-indanyl)methyl-d3- 2,2-dimethyl-piperazine•butanedioic acid (Compound (I)•butanedioic acid salt).

Scheme 8. Synthesis ofCompound (I). cY• HCI Cl r"' Cl 1-((1 R,3S)Chlorophenyl-indanyl)- nd (I) butanedioic acid salt 3,3-dimethyl-piperazine hydrochloride (Compound (XI) hydrochloride) wo 2012/176066 I-((IR,3S)Chlorophenyl-indan-I-yl)-3,3-dimethyl-piperazine hydrochloride (II. I g) was dissolved in a mixture oftoluene (74 mL) and water (74 mL). Preparation of I- ((IR,3S)chlorophenyl-indan-I-yl)-3,3-dimethyl-piperazine hloride is disclosed in the patent literature (Dahl, Wohlk Nielsen, Suteu, Robin, Brosen W02006/086984 AI; Bang-Andersen, Boges0, Jensen, Svane, Dahl, Howells, Lyngso, Mow W02005/0I690I AI; each herein incorporated by nce in its entirety). I2.0 M ssium hydroxide in water (5.38 mL), N-butylammonium bromide (I.42 g), and d3-iodomethane (Aldrich catalog# I76036; 2.4 mL) were added and the mixture was stirred at room temperature for I8 hours (Scheme 8). The mixture was filtered through a glass filter into a separatory funnel. The solid on the filter was washed with toluene (50 mL) into the separatory funnel. The aqueous layer was ted with toluene (IOO mL) and the ed organic layers were washed with concentrated aqueous ammonia (IOO mL) and subsequently with water (IOO mL) before it was dried over sodium sulfate, filtered, and concentrated in vacuum affording a slightly yellow oil. The oil was cooled to -78°C under vacuum which fied the oil. Upon warming to room temperature the oil became a semi-solid.

This material was dissolved in acetone (30 mL); in a separate flask butanedioic acid (3.46 g) was suspended in acetone (30 mL) and warmed to reflux (not all ofthe diacid went into solution). The acid suspension was added to the solution ofthe crude product and onal acetone (50 mL) was added to the butanedioic acid residue and then poured into solution. The mixture was stirred overnight. Partial precipitation had occurred overnight, and the mixture was concentrated in vacuum. The residue was re-dissolved in acetone (70 mL) and warmed to reflux and allowed to cool to room temperature and d for 2 hours.

The mixture was ed affording 4-((IR,3S)chlorophenyl-indan-I-yl)-I- methyl-d3-2,2-dimethyl-piperazine•butanedioic acid (Compound (I)•butanedioic acid salt; 7.6I g). LC-MS (method 13I): RT(UV) 1.57 min; UV/ELS purity IOO%/IOO%; mass ed 358.0. Incorporation ofthree deuterium atoms >99 %. The proton-decoupled Be NMR spectrum showed a heptet around 36.4 ppm corresponding to the deuterated M2 lic site; this signal collapsed to a singlet in the proton- and deuterium-decoupled Be NMR spectrum. All other signals were singlets in both spectra. Optical purity >95% ee.

Example 2 Alternative method ofpreparation of4-((IR,3S)chlorophenyl- indan-I-yl)-I-methyl-d3-2,2-dimethyl-piperazine•butanedioic acid (Compound (I)•butanedioic acid salt) wo 2012/176066 The free base of 1-((1R,3S)chlorophenyl-indanyl)-3,3-dimethylpiperazine was prepared from the corresponding hydrochloride salt by ioning 23.4 g of the salt between a mixture ofwater (1 00 mL), trated aqueous potassium ide (40 mL), and toluene (250 mL). The organic layer was washed with a mixture ofwater (50 mL) and concentrated aqueous potassium hydroxide (10 mL). The combined aqueous layers were extracted with toluene (75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuum affording the free base of 1-((1R,3S)chlorophenylindanyl )-3,3-dimethyl-piperazine (21.0 g) as a colorless oil. This material was dissolved in a mixture oftoluene (150 mL) and water (150 mL), before 12.0 M aqueous potassium hydroxide (11.3 mL), tetra-N-butylammonium bromide (2.98 g), and d3-iodomethane (4.9 mL) were added and mixture was stirred at room temperature for 18 hours.

Work-up and purification was performed as described above and afforded 4- ((1R,3S)chlorophenyl-indanyl)methyl-d3-2,2-dimethyl-piperazine•butanedioic acid und (I)•butanedioic acid salt; 14.34 g; 48.9%).

Example 3 Preparation of4-((1R,3S)chlorophenyl-d5-indanyl)-1,2,2- trimethyl-piperazine (Compound (II)) and ,3S)chlorophenyl-d5-indanyl) methyl-d3-2,2-dimethyl-piperazine (Compound (IV)).

Hl1fr:iH{H-64t To a solution ofcompound A (57 g) in tetrahydrofuran (600 mL) was added triethylamine (30 mL) dropwise over 30 min. The on mixture was kept at room ature for 3 hours. The precipitated solid was filtered and the filtrate was trated in vacuo. The residue was reprecipitated from l ether to afford compound B (31 g) as a yellow solid. To a solution ofcompound phenyl-d5-boronic acid (25 g) in 1,4-dioxane/water (900 mL/ 90 mL) was added [Rh(ndb)2]BF4 (1.3 g), racemic BINAP (2.1 g) and triethylamine (14 mL), then the reaction mixture was kept at room temperature for 2 hours under N 2 . Then compound indenone (19 g) was added, and the resulting mixture was heated to 100 oc for 3 hours. The itated solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by chromatography to afford indanone C (10 g).

Scheme 9. Synthesis ofCompound C. wo 2012/176066 Cl~ auj I~ - I~ I A B D*B'D - D D ~ D D ~ D C (racemate) D D A' B' 13.4 kg 3-Bromochloro-indanone (A; for references on this material, see: Boges0 EP 35363 AI 19810909 and Kehler, Juhl, Puschl, WO 2008025361; each herein orated by reference in its entirety) was dissolved in tetrahydrofuran (170.8 L), and the solution was cooled to 0-5 oc (Scheme 9). Triethylamine (9.1 L) was added over 0.5h. The mixture was stirred at 0-5 oc for 5 hours before an additional portion oftriethylamine (2.48 L) was added over 0.5 hour, and stirring was continued for 2 hours. The e was filtered, and the filtrate was concentrated to 30 L before n-heptane (102 L) was added. The volume was reduced to 60 L. More n-heptane (203 L) was added, and the mixture was stirred for 1 hour. Silica gel (17.2 kg) was added. The mixture was filtered, and the residual solid was washed with n-heptane (100 L). The ed filtrates were concentrated to 30 Land stirred at 0-5 oc for 1 hour. The mixture was centrifuged, and the residual solid was dried to afford 6-chloro-indenone (compound B; 2.42 kg) sufficiently pure for the next step. 2-Methyl-tetrahydrofuran (85 L) and methyl acetamide (12.4 L) were added to a reactor followed by potassium acetate (10.9 kg) and bis(pinacolato)diboron (14.8 kg). The resulting mixture was stirred for 0.5 hour. Pd(dppf)Clz-DCM (0.91 kg) was added ed by bromobenzene-d5 (9.0 kg) and yl-tetrahydrofuran (12.2 L). The mixture was heated to 80-85 oc for 3 hours, before the temperature was reduced to ambient ature. The crude mixture was filtered via kieselguhr and silica gel. The filter-cake was washed with 2-methyl-tetrahydrofuran (31 L). The combined filtrates were trated to approximately 25 L while maintaining the temperature below 35 °C. n-Heptane (52 L) and 7% aqueous NaHC03 (31 L) were added, and the mixture was stirred for 0.5 hour. The organic layer was stirred with 7% aqueous NaHC03 (31 L) for 0.5 hour. The combined aqueous layers were ted with n-heptane (22 L) over 0.5 hour. The combined organic extracts were washed with 25% aqueous NaCl (50 L) over 0.5 hour. The organic layer was wo 2012/176066 concentrated while maintaining the temperature below 35°C to afford 4,4,5,5-tetramethyl d5-phenyl-[1,3,2]dioxaborolane (compound B'; 10.5 kg) sufficiently pure for the next step.

To a reactor was added sequentially 1,4-dioxane (85 L), 6-chloro-indenone (compound B; 9.09 kg prepared in a similar manner to the one described above), 1,5- cyclooctadiene (0.2 L), bis(norbomadiene)rhodium(I) tetrafluoroborate (0.52 kg), triethylamine (5.5 L), 5-tetramethyld5-phenyl-[1,3,2]dioxaborolane (compound B'; 6.5 kg), and 1,4-dioxane (26 L). The e was heated to 48-53 oc and stirred at that temperature for 5 hours. The reaction was quenched by the addition of2M aqueous HCl (13 kg). Then n-heptane (110 L), methyl tert-butyl ether (32 L), and water (90 L) were added, and the resulting mixture was stirred for 0.3 hour. The organic layer was washed with water (90 L) over 0.3 hour. The combined aqueous layers were extracted with a mixture ofmethyl tert-butyl ether (30 L) and n-heptane (57 L) over 0.3 hour. The combined organic layers were filtered through silica gel (13 kg). The filter-cake was washed with a 2:1 mixture ofn-heptane and methyl tert-butyl ether (19.5 kg). The filtrate was concentrated to approximately 25 L. n- Heptane (45 L) was added, and the volume was reduced to approximately 25 L. n-Heptane (45 L) was added, and the volume was reduced to approximately 35 L. The mixture was d at 0-5 oc for 3 hours. The e was centrifuged, and the residual solid was dried to afford racemic 6-chlorod5-phenyl-indanone und C; 8.4 kg) sufficiently pure for the next step.

Tetrahydrofuran (90 L) was added to a r followed by water (10 L) and 6- chlorod5-phenyl-indanone und C; 7.73 kg) (Scheme 10). The mixture was cooled to -35 - -30 °C. Sodium borohydride (1.5 kg) was added portion-wise while maintaining the ature at -30 °C. The resulting mixture was stirred at -30 oc for 5 hours before it was allowed to warm to ambient temperature. Excess sodium borohydride was quenched by the addition of2M aqueous HCl (7.6 kg) while maintaining the temperature below 45 °C. Water (17 L) and methyl tert-butyl ether (67 L) were added and the e was d for 0.3 hour. The aq layer was extracted with methyl tert-butyl ether (39 L) over 0.3 hour. The combined organic layers were washed with brine (36 kg) over 0.3 hour.

The organic layer was filtered h silica gel (6,4 kg). The filter-cake was washed with methyl tert-butyl ether (20 L). The combined filtrates were concentrated to approximately 30 L while ining the temperature below 45 °C. n-Heptane (55 L) was added and the resulting mixture was concentrated to approximately 30 L while maintaining the temperature below 45 °C. The resulting mixture was stirred at 0-5 oc for 2 hours. The mixture was wo 2012/176066 centrifuged, and the filter-cake was washed with n-heptane (12 L) before it was fuged again. The residual solid was dried to afford crude D. 4.87 kg ofthis material was dissolved in methyl tert-butyl ether (20 L) and dried over Na2S04 (2 kg) over 0.25 hour. The mixture was filtered, and the filter-cake was washed with methyl tert-butyl ether (4.4 L). The combined filtrate was concentrated to approximately 20 L while maintaining the temperature below 45 °C. n-Heptane (32 L) was added and the e was to approximately 25 L while maintaining the temperature below 45 °C. n-Heptane (16 L) was added and the mixture was to approximately 20 L while maintaining the temperature below 45 °C. The solid was filtered offand dried to afford racemic cischlorod5-phenyl-indanol (compound D; 4.99 kg) sufficiently pure for the next step.

Scheme 10. sis and resolution ofCompound E.

Cl Cl Cl D - D D D D D D D D D C (racemate) D (cis-racemate) E ((1 S,3S)-enantiomer) To a solution ofracemic cischlorod5-phenyl-indanol (compound D; 50 g) in 2-isopropoxypropane (200 mL) was added vinyl butyrate (120 mL) and Novozym-435 (15 g). The mixture was kept at ambient temperature for 2 days. The solid was filtered off. The filtrate was ated and purified by chromatography on silica gel to afford (1S,3S) chlorod5-phenyl-indanol (compound E; 13 g) sufficiently pure for the next step.

To a solution of (1 S,3S)chlorod5-phenyl-indanol (compound E; 7 g) in THF (100 mL) was treated with SOCb (6.6 g) at t temperature overnight. The mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over Na2S04, filtered, and trated in vacuo to afford the intermediate chloride (7.5 g). 3.5 g ofthis material was dissolved in 2- butanone (50 mL) and reacted with 2,2-dimethyl-piperazine (1.7 g) in the presence ofK2C03 (2.7 g) at reflux overnight. The solid was filtered off. The te was concentrated in vacuo and the residue was purified by preparative HPLC on a Shimadzu FRC-1 OA instrument fitted with a i C18 column (250mm*50mm, 10 microm) using water and acetonitrile wo 2012/176066 ining 0.1 %TFA, v/v) as the eluent to afford 1-((1R,3S)chlorod5-phenyl-indan yl)-3,3-dimethyl-piperazine und F; 2.6 g) sufficiently pure for the next step.

To a solution of 1-((1R,3S)chlorod5-phenyl-indanyl)-3,3-dimethylpiperazine (compound F; 2.2 g) in HCHO/HCOOH (3 mL/3 mL) was refluxed overnight. The volatiles were removed in vacuo. The residue was partitioned n ethyl acetate and 10% aq NaOH. The organic layer was dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford 4-((1R,3S)chlorod5- phenyl-indanyl)-1 ,2,2-trimethyl-piperazine (Compound (II); 1.89 g). LC-MS (method WXV-AB05): RT(UV) 2.43 min; UV/ELS purity 95.1 %/99.6%; mass observed 360.2.

Incorporation offive deuterium atoms >95 %. The proton-decoupled Be NMR spectrum showed three triplets around 126.1, 127.2, and 128.2 ppm corresponding to the ated M3 metabolic sites; these signal collapsed to three ts in the proton- and deuteriumdecoupled Be NMR spectrum. All other signals were singlets in both spectra. Optical purity >95% ee.

To a solution of 1-((1R,3S)chlorod5-phenyl-indanyl)-3,3-dimethylpiperazine (compound F; 3.0 g) in DCDO/DCOOD (4 mL/4 mL) was refluxed overnight. The volatiles were removed in vacuo. The residue was partitioned between ethyl e and 10% aq NaOH. The organic layer was dried over Na2S04, filtered, and concentrated in vacuo. The e was ed by chromatography on silica gel to afford 4-((1R,3S)chlorod5- phenyl-indanyl)d3-methyl-2,2-diimethyl-piperazine (Compound (IV); 2.14 g). LC-MS (method WXV-AB10): RT(UV) 2.06 min; UV/ELS purity 98%/100%; mass observed 363.3.

Incorporation t deuterium atoms >94 %. The proton-decoupled Be NMR spectrum showed a heptet around 36.4 ppm corresponding to the deuterated M2 metabolic site; this signal collapsed to a singlet in the - and deuterium-decoupled Be NMR spectrum. The proton-decoupled Be NMR spectrum further showed three triplets around 126.1, 127.2, and 128.2 ppm corresponding to the deuterated M3 metabolic sites; these signal collapsed to three ts in the proton- and deuterium-decoupled Be NMR spectrum. All other signals were singlets in both spectra. Optical purity >95% ee.

Example 4: Preparation of4-((1R,3S)chlorophenyl-indanyl)-1 ,2,2- trimethyl-piperazine-6,6-d2 (Compound (III)), ,3S)chlorophenyl-indanyl) methyl-d3-2,2-dimethyl-piperazine-6,6-d2 (Compound (V)), 4-(( 1R,3 S)chlorophenyl-d5- indanyl)methyl-d3-2,2-dimethyl-piperazine-6,6-d2 (Compound (VI)), and 4-((1R,3S) chlorophenyl-d5-indanyl)-1 ,2,2-trimethyl-piperazine-6,6-d2(Compound (VII). wo 2012/176066 2-Aminomethyl-propionic acid (50.0 g) was suspended in a mixture of methanol and triethylamine (9:1, 1.2 L) (Scheme 11). 1M aqueous NaOH (450 mL) was added with stirring until all solid was ved. Di-tert-butyl dicarbonate (Boc20; 214.0 g) was added, and the mixture was stirred at ambient temperature overnight. The organic volatiles were d in vacuo. EtOAc (500 mL) was added. The organic layer was washed with brine and dried over , filtered, then concentrated to afford 2-tertbutoxycarbonylaminomethyl-propionic acid und K; 90 g) as a white solid which was used directly in next step directly.

Scheme 11. Synthesis ofintermediate J. oyo't oyo't oyo't ~Nf ""f ""f ""f HO 0 HO 0 -........_N 0 H 0 2-aminomethyl- OMe propionic acid K L M oyo't ""f l~t D1:~t MeOY'~ N N H H N J A mixture ofafford 2-tert-butoxycarbonylaminomethyl-propionic acid (compound K; 60.0 g) and 1-ethyl-3(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC·HCl; 86.4 g) in dichloromethane (900 mL) was stirred at ambient temperature, then N,O-dimethyl hydroxylamine hydrochloride (35.3 g) and triethylamine (150 mL) were added.

The resulting e was stirred at ambient temperature for 3 days. Water was added and most ofvolatiles were removed in vacuo. The residue was partitioned between DCM and aqueous NaHC03. The organic layer was washed with 3M aqueous HCl, uently with brine before it was dried over , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give [1-(methoxy-methyl-carbamoyl)methyl- wo 2012/176066 ethyl]-carbamic acid tert-butyl ester (compound L; 28.2 g) as a white solid sufficiently pure for the next step.

Lithium aluminum hydride (7.8 g) was added to a stirred solution of [1-(methoxymethyl-carbamoyl )methyl-ethyl]-carbamic acid tert-butyl ester (compound L; 42.0 g) in dry diethyl ether (1.5 L) at -40 °C. Then stirred at that ature for about 5 min. Excess LiAlH4 was quenched with a solution ofpotassium hydrogen sulfate in water. The ing mixture was partitioned between EtOAc and 3M aqueous HCL The c layer was washed with sat. aqueous NaHC03, dried over Na2S04, filtered, and concentrated in vacuo to afford (1,1-dimethyloxo-ethyl)-carbamic acid tert-butyl ester (compound M; 29 g) sufficiently pure for the next step. acetic acid methyl ester hydrochloride (80.6 g) and Et3N (160 mL) were ved in DCM (1000 mL) and stirred for 15 min to liberate the amine from the salt. Then a solution of 1,1-dimethyloxo-ethyl)-carbamic acid tert-butyl ester (compound M; 29.0 g) in DCM (600 mL) was added. The resulting mixture was d for 0.5 hour at ambient temperature before NaBH(OAc)3 (102 g) was added and the mixture was stirred at ambient temperature overnight. Sat. aqueous NaHC03 was added. The s layer was extracted with DCM. The ed organic layers were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford (2-tertbutoxycarbonylaminomethyl-propylamino )-acetic acid methyl ester (compound N; 26.5 g) as white solid which was used directly in the next step.

A mixture ert-butoxycarbonylaminomethyl-propylamino)-acetic acid methyl ester (compound N; 26.5 g) in DCM (800 mL) was stirred at ambient temperature, TFA (180 mL) was added ise. The mixture was stirred at 30-40 oc for 5h before it was concentrated in vacuo. The residue was partitioned between dissolved toluene and water. The c layer was dried over Na2S04, filtered, and concentrated in vacuo. The residual solid was ved in a mixture of ethanol (400 mL) and methanol (90 mL). K2C03 (207 g) was added and the mixture was refluxed overnight. The mixture was cooled to room temperature.

DCM (2500 mL) was added, and the mixture was stirred for 1 hour at ambient temperature.

The solid was filtered off, and the filtrate was concentrated in vacuo to afford 6,6-dimethylpiperazinone (Compound I; 5.85 g) as a white solid sufficiently pure for the next step.

A solution of6,6-dimethyl-piperazinone (Compound I; 3.6 g) in THF (20 mL) was stirred at 0 °C. Lithium aluminum deuteride (LiAlD4; 3.6 g) was added then the mixture was refluxed overnight. The mixture was cooled to ambient temperature and Na2S04 was wo 2012/176066 added. The e was stirred for 0.5h before most ofthe volatiles were removed in vacuo.

The residue was suspended in a saturated solution ofHCl in EtOAc at ambient temperature for 0.5 hour. The solid was filtered offand dried to afford to give 2,2-d2-6,6-dimethylpiperazine as the his-hydrochloride salt (Compound l2HC1; 5.3 g) sufficiently pure for the next step.

HLt~,}H-t+4-8~:;-l:- To a solution ofcompound E' (5 g) in THF (50 mL) was added SOClz (4.7 g), and the resulting mixture was stirred overnight at ambient temperature (Scheme 12). The mixture was poured into ice-water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to afford the corresponding chloride (5.3 g) which was used directly in the next step. 3.3 g ofthis material was dissolved in 2-butanone (50 mL) and reacted with 2,2-d2-6,6-dimethyl-piperazine (Compound J; 3 g) in the presence ofK2C03 (8.28 g) at reflux overnight. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC on a Shimadzu A instrument fitted with a y C18 column (250mm*50mm, 10 microm) using water and acetonitrile (containing 0.1 %TFA, v/v) as the eluents to afford 1-((1R,3S) chlorophenyl-indanyl)-3,3-d2-5,5-dimethyl-piperazine (Compound 0; 1.7 g).

Scheme 12. Synthesis ofCompound (III) and Compound (V).

DtYD D1:~t DtY DtyDDfo N N N ~ f f J Cl f Cl Cl =- =- =- E' ((1 S,3S)-enantiomer) 0 S)-enantiomer) Compound (Ill) Compound (V) A on of 1-((1R,3S)chlorophenyl-indanyl)-3,3-d2-5,5-dimethylpiperazine (Compound 0; 0.5 g) in HCHO/HCOOH (1 mL/1 mL) was refluxed overnight.

The les were removed in vacuo. The residue was partitioned between EtOAc and 10% aqueous NaOH. The organic layer was dried over Na2S04, ed, and concentrated in vacuo. The residue was ed by tography on silica gel to afford 4-((1R,3S) chlorophenyl-indanyl)-1,2,2-trimethyl-piperazine-6,6-d2 (Compound (III); 0.33 g). LCMS (method WXV-AB30): RT(UV) 1.42 min; UV/ELS purity 100%/100%; mass observed 357.2. oration oftwo deuterium atoms >97 %. The proton-decoupled 13C NMR wo 2012/176066 spectrum showed a quintet around 49.5 ppm corresponding to the deuterated M1 metabolic site; this signal collapsed to a singlet in the proton- and deuterium-decoupled 13C NMR spectrum. The proton-decoupled 13C NMR spectrum further showed three triplets around 126.1, 127.2, and 128.2 ppm corresponding to the deuterated M3 metabolic sites; these signal collapsed to three singlets in the proton- and deuterium-decoupled 13C NMR spectrum. All other s were singlets in both spectra. Optical purity >95% ee.

A solution of ,3S)chlorophenyl-indanyl)-3,3-d2-5,5-dimethylpiperazine (Compound 0; 0.7 g) in DCDO/DCOOD (1 mL/1 mL) was ed overnight.

The volatiles were removed in vacuo. The residue was partitioned n EtOAc and 10% aqueous NaOH. The organic layer was dried over Na2S04, filtered, and trated in vacuo. The residue was purified by chromatography on silica gel to afford 4-((1R,3S) chlorophenyl-indanyl)methyl-d3-2,2-dimethyl-piperazine-6,6-d2 (Compound (V); 0.49 g). LC-MS (method WXVAB25): RT(UV) 2.13 min; UV/ELS purity 100%/100%; mass observed 360.2. Incorporation offive deuterium atoms >95 %. The -decoupled 13C NMR spectrum showed a heptet around 36.4 ppm corresponding to the deuterated M2 metabolic site; this signal collapsed to a singlet in the proton- and deuterium-decoupled 13C NMR spectrum. The proton-decoupled 13C NMR spectrum further showed a quintet around 49.5 ppm corresponding to the deuterated M 1 metabolic site; this signal collapsed to a singlet in the proton- and deuterium-decoupled 13C NMR um. All other signals were singlets in both spectra. Optical purity >95% ee.

To a solution of (1 S,3S)chlorod5-phenyl-indanol (compound E; 7 g) in THF (100 mL) was treated with SOCb (6.6 g) at ambient ature overnight (Scheme 13).

The mixture was poured into ice-cold water, and extracted with ethyl acetate. The c layer was washed with brine. The organic layer was dried over , filtered, and concentrated in vacuo to afford the intermediate chloride (7 .5 g).

Scheme 13. Synthesis ofCompound (VI) and Compound (VII). wo 2012/176066 DDi-D Dty (yD I Cl --- N N Cl f Cl f Cl ~ D D D D D D D D E ((1 S,3S)-enantiomer) P ((1R,3S)-enantiomer) Compound (VI) Compound (VII) 1.8 g ofthis material was dissolved in 2-butanone (30 mL) and reacted with 2,2- d2-6,6-dimethyl-piperazine (Compound J; 1.4 g) in the presence ofK2C03 (5.5 g) at reflux overnight. The solid was filtered off. The filtrate was trated in vacuo. The residue was purified by preparative HPLC on a Shimadzu FRC-1 OA instrument fitted with a Synergy C18 column (250mm*50mm, 10 microm) using water and acetonitrile (containing 0.1 %TFA, v/v) as the eluents to afford 1-((1R,3S)Chlorod5-phenyl-indanyl)-3,3-d2-5,5-dimethylpiperazine (Compound P; 1.7 g).

A solution of 1-((1R,3S)Chlorod5-phenyl-indanyl)-3,3-d2-5,5-dimethylpiperazine (Compound P; 1 g) in DCDO/DCOOD (1.5 mL/1.5 mL) was refluxed overnight.

The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 10% aq NaOH. The organic layer was dried over Na2S04, ed, and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford 4-((1R,3S)chlorod5- -indanyl)d3-methyl-2,2-dimethyl-piperazine-6,6-d2 (Compound (VI); 0.55 g).

LC-MS (method WuXiAB25): RT(UV) 2.13 min; UV/ELS purity 98.2%/100%; mass observed 365.2. Incorporation often deuterium atoms >91 %. The proton-decoupled 13C NMR spectrum showed a heptet around 36.4 ppm corresponding to the deuterated M2 metabolic site; this signal sed to a singlet in the proton- and deuterium-decoupled 13C NMR spectrum. The proton-decoupled 13C NMR spectrum further showed a quintet around 49.5 ppm corresponding to the deuterated M 1 lic site; this signal collapsed to a singlet in the proton- and ium-decoupled 13C NMR spectrum. The -decoupled 13C NMR spectrum further showed three triplets around 126.1, 127.2, and 128.2 ppm corresponding to the deuterated M3 metabolic sites; these signal collapsed to three singlets in the proton- and deuterium-decoupled 13C NMR spectrum. All other signals were singlets in both spectra.

Optical purity >95% ee. wo 2012/176066 A solution of 1-((1R,3S)chlorod5-phenyl-indanyl)-3,3-d2-5,5-dimethylpiperazine (Compound P; 0.7 g) in HCHO/HCOOH (1 mL/1 mL) was refluxed ght.

The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 10% s NaOH. The organic layer was dried over Na2S04, filtered, and concentrated in vacuo. The e was purified by tography on silica gel to afford 4-((1R,3S) chlorod5-phenyl-indanyl)methyl-2,2-dimethyl-piperazine-6,6-d2 (Compound (VII); 0.47 g). LC-MS (method WXV-AB30): RT(UV) 1.33 min; UV/ELS purity 97.4%/100%; mass observed 362.3. Incorporation ofseven deuterium atoms >93 %=. The protondecoupled 13C NMR spectrum showed a quintet around 49.5 ppm corresponding to the deuterated M1 metabolic site; this signal collapsed to a singlet in the - and deuteriumdecoupled 13C NMR um. The proton-decoupled 13C NMR spectrum further showed three triplets around 126.1, 127.2, and 128.2 ppm corresponding to the deuterated M3 metabolic sites; these signal collapsed to three ts in the proton- and deuteriumdecoupled 13C NMR spectrum. All other signals were singlets in both spectra. Optical purity >95% ee.

Example 5: Description ofNMR determination ofthe on(s) bearing deuterium rather than hydrogen NMR spectra were recorded on a Broker 600-Avance-III spectrometer ed with a 5 mm TCI obe operating at 150.91 MHz for 13C. The solvent CDCh was used as internal reference for the proton-decoupled experiments, while the proton- and inverse gated deuterium-decoupled spectra were recorded using gated lock. Difference(s) between the two spectra for the compounds ofthe invention determine(s) the position(s) ofthe deuterium atoms. When combining this information summarized in the table below (Table 3) with the electrospray mass spectrometry data that determined degree ofdeuteration, the structures of the compounds ofthe invention can be ed unambiguously.

Table 3: Carbon NMR data for compounds.

Ml (methylene group@ ~49.5 M3 (phenyl group@ ~126.1 ppm, M2 (methyl group @ ~36.4 ppm) ppm) ~127.2 (2C), and~128.2 (2C)) CNMR CNMR CNMR proton- and 13CNMR proton- and 13CNMR proton- and 13C NMR proton- deuterium- proton- deuterium- proton- deuterium- Cmpd. decoupled decoupled decoupled decoupled decoupled decoupled (I) heptet singlet singlet singlet singlets singlets (II) singlet singlet singlet singlet 3 triplets 3 singlets (III) t singlet quintet singlet 3 singlets 3 singlets wo 2012/176066 (IV) heptet singlet singlet t 3 triplets 3 singlets (V) heptet singlet quintet singlet 3 singlets 3 singlets (VI) heptet singlet quintet singlet 3 triplets 3 singlets (VII) singlet singlet quintet singlet 3 triplets 3 singlets Only NMR signals that 'change'as a consequence ofthe presence ofD rather than H in the compounds ofthe invention are included in the table.

Relevant s ofthe 13C proton-decoupled (lower spectrum) and 13C proton- and deuterium-decoupled (upper spectrum) NMR spectra ofCompound (II) and Compound (V) are shown in Figure 3 as representative examples. Selected regions ofthe protondecoupled and proton- and deuterium-decoupled 13C NMR spectra of nd (II) [Fig. 3A] and Compound (V) [Fig. 3B].

Example 6: Description ofthe electrospray mass spectrometry to determine degree ofdeuteration Instrumentation: Mass a ic, aqueous solutions ofthe compounds were obtained on a Hewlett Packard quadrupole mass spectrometer model1100 LC-MSD. Liquid chromatography was performed on an Agilent 1100 HPLC-system coupled to the mass spectrometer.

Experimental: Solutions ofthe samples were made by dissolving . 2 mg substance in 2 mL methanol+ 18 mL 10 mM ammonium formate pH 3.0. Subsequently the solutions were diluted 100-fold prior to analysis. In order to get a " peak, the samples were chromatographed using a Waters X-bridge C18, 3.5 microm (150x2.1mm) column, and 0.1% trifluoroacetic acid I acetonitrile 50/50 as mobile phase. This ure gave one peak ofthe compound ofinterest g at ca. 3.6 min, containing both the deuterated compounds ofthe invension as well as small quantities ofdeuterium-deficient species. The mass spectra obtained from these peaks were used to evaluate the speciation ofthe target molecules. The results were ed in percent ofthe total amount ofsubstance, adding up to 100%. The actual potency ofthe compounds were not analyzed, merely the relative content ofthe deuterium ent s.

As a representative example, the mass spectrum ofCompound (IV) is shown in Figure 4. The isotopic n ofthe protonated Compound (V) [M+H t with mass 363.1u (362.1u + l.Ou) and the isotope ions 363.1u, 364.1u, 365.1u and 366.1u was in the ratio 100: .3 : 34.9: 7.9; calculation for CzoH22NzClDs gives the ratio 100: 25.2: 34.9: 8.3.

Furthermore, Dranalogs and the D3-analogs were observed at masses 362.1u and 358.1u, respectively. The signals at 364u, 365u and 366u are primarily due to protonated molecules wo 2012/176066 containing 13C and/or 37Cl isotopes instead of 12C and 35Cl (due to the natural distribution).

This data shows that the incorporation ofeight deuterium atoms was greater than 94 %. e 7: Experimental Binding Assays Description ofhuman D2 binding assay The assay was performed as a SPA-based competition-binding in a 50 mM Tris pH 7.4 assay buffer containing 120 mM NaCl, 5 mM KCl, 4 mM MgCb, 1.5 mM CaCb, 1 mMEDTA. 1.5 nM 3H-raclopride (Perkin Elmer, NET 975) was mixed with test compound before addition of20 microg ofa homogenised human D2 receptor ne-preparation and 0,25 mg SPA beads (WGA RPNQ 0001, Amersham) in a total volume of90 microL. The assay plates were under agitation incubated for 60 minutes at room temperature and subsequently counted in a scintillation r (TriLux, Wallac). The total binding, which comprised approximately 15% ofadded radioligand, was defined using assay buffer, whereas the non-specific binding was defined in the ce of 10 microM haloperidol. The non-specific binding constituted approximately 10% ofthe total binding.

Data points were expressed in t ofthe specific binding of 3H-Raclopride and the IC50 values ntration causing 50 percent inhibition of 3H-raclopride specific binding) were determined by non-linear regression analysis using a sigmoidal variable slope curve fitting. The dissociation constant (Ki) was calculated from the Cheng Prusoff on (Ki = IC50/(1 +(L!Kn)), where the concentration offree radioligand Lis approximated to the concentration d 3H-raclopride in the assay. The Kn of 3H-raclopride was determined to 1.5 nM from two independent saturation assays each performed with triplicate determinations. ption ofhuman D1 binding assay The assay was performed as a SPA-based ition-binding in a 50 mM Tris pH 7.4 assay buffer containing 120 mM NaCl, 5 mM KCl, 4 mM MgCb, 1,5 mM CaCb, 1 mM EDTA. Approximately 1 nM 3H-SCH23390 (Perkin Elmer, NET 930) was mixed with test compound before addition of2,5 microg ofa homogenized human D1 receptor membrane-preparation and 0,25 mg SPA beads (WGA RPNQ 0001, Amersham) in a total volume of60 microL.

The assay plates were under agitation incubated for 60 minutes at room ature before the plates were centrifuged and subsequently counted in a scintillation counter x, Wallac). The total g, which comprised approximately 15% ofadded wo 2012/176066 radioligand, was defined using assay buffer whereas the non-specific binding was d in the presence of 10 microM haloperidol.

Data points were expressed in percent ofthe specific binding and the IC50 values ntration g 50 percent inhibition ofspecific binding) and were determined by non-linear regression analysis using a sigmoidal variable slope curve g. The dissociation constant (Ki) was calculated from the Cheng Prusoffequation (Ki = IC50/(1 +(L!Kn)), where the concentration offree igand L is approximated to the concentration ofadded radioligand in the assay.

Description ofhuman 5-HT2A binding The experiment was carried out at Cerep Contract Laboratories (Cat. ref.# 471).

Compound (I) was also tested in an in vivo set up trating central effects of the compound. By in vivo binding, the compound'sin vivo affinity for D2 receptors was assessed and occupancy of 60% ofthe target was observed. Occupancy ofD2 ors is closely linked to antipsychotic s in animal models and in patients.

Description of in vivo binding to D2 receptors in rat brain In vivo binding was carried out according to Andersen et al (Eur J Pharmacal, (1987) 144:1-6; herein incorporated by reference in its entirety) with a few modifications (Kapur S. et al, J Pharm Exp Ther, 2003, 305, 625- 631; herein incorporated by reference in its entirety). Briefly, 6 rats (male Wistar, 180-200 g) were treated with 20 mg/kg test compound subcutaneous 30 minutes before receiving 9.4 micro Ci eHJ-raclopride intravenously via the tail vein. 15 minutes after the injection ofthe radio ligand the animals were killed by cervical dislocation, the brain quickly removed and striatum and cerebellum dissected out and nized in 5 mL (cerebellum in 20 mL) ice-cold buffer (50 mM K3P04, pH 7.4). 1.0 mL ofthe homogenate was filtered through 0.1% PEl- soaked Whatman GF/C filters. This was completed within 60 seconds subsequent to the decapitation. Filters were washed 2 times with 5 mL ice-cold buffer and counted in a scintillation counter. A group ofvehicle treated animals was used to determine clopride total binding in um and ecific binding in cerebellum. The homogenate was measured for protein content by the BCA n determination assay (Smith P.K. et al (1985) Anal. Biochem., 150: 6-85; herein incorporated by reference in its entirety). wo 76066 e 8: Investigation ofthe metabolism of4-((1R,3S)chlorophenylindanyl )-1,2,2-trimethyl-piperazine (Compound (X)) and 4-((1R,3S)chlorophenylindanyl )methyl-d3-2,2-dimethyl-piperazine (Compound (I)) Cryopreserved dog (male Beagle dog) cytes (1 million cells/mL in suspension, 50 microL/well) were pre-incubated for 15 minutes in a 96 well plate at 37°C water bath in DMEM high glucose buffered with 1M HEPES. The cell suspension was added with 50 microL test compounds (final tration 0.1 or 1 microM of4-((1R,3S)chloro- 3-phenyl-indanyl)-1,2,2-trimethyl-piperazine (Compound (X)) or 4-((1R,3S)chloro phenyl-indanyl)methyl-d3-2,2-dimethyl-piperazine (Compound (I)) and further incubated for 0, 15, 45, 75 and 120 minutes. The reaction was stopped by addition of 100 microL acetonitrile to the cell suspension, and the s were then removed for LC-MS is ofthe desmethyl metabolite (Compound (XI)). Data were expressed as MS area relative to an internal standard.

The results (Figure 5 and Figure 6) show that the amount ofthe desmethyl metabolite (Compound (XI)) produced in cryopreserved dog hepatocytes is lower from the deuterated form (Compound (I)) than from the parent compound (Compound (X)), both at a concentration of 0.1 micro M (Figure 5) and at a concentration of 1 micro M (Figure 6).

Example 9: Pharmacological testing ofCompounds. ,3S)chlorophenyl-indanyl)-l-d3-methyl-2,2-dimethyl-piperazine (Compound (I)): 4-((1R,3S)chlorophenyl-indanyl)-l-d3-methyl-2,2-dimethyl-piperazine (Compound (I)) was tested in three in vitro assays for dopamine D1, dopamine D2 and serotonin 5-HTzA affinity.

The experiments were carried out as in the section Binding assays. The experimental results showed the following ties for 4-((1R,3S)chlorophenyl-indan- 1-yl)methyl-d3-2,2-dimethyl-piperazine: D1: Ki log mean= 7.5 nM (pKi 0.88 +/- 0.15) D2 : Ki log mean= 34 nM (pKi 1.54 +/- 0.11) 5HTzA: IC50 = 1.14 nM These binding affinities indicate that Compound (I) has biological activity likely to exert ychotic effect.

Pharmacological testing ofCompound (II) and Compound (IV) wo 2012/176066 The ments were carried out as described in the section "Binding assays".

The mental results for the two compounds are provided below.

Compounds (II) and Compound (IV) were tested in two in vitro assays for dopamine D 1 and dopamine D2 affinity.

Compound (IV): D1: Ki log mean= 26.1 nM (pKi 1.42 +/- 0.03) D2 : Ki log mean= 26.7 nM (pKi 1.43 +/- 0.04) Compound (II): D1: Ki log mean= 23.2 nM (pKi 1.37 +/- 0.03) D2 : Ki log mean= 26.5 nM (pKi 1.42 +/- 0.03) These binding ties indicate that Compound (II) and (IV) have biological activity likely to exert antipsychotic effect.

Compound (II) and (IV) were also tested in an in vivo set up demonstrating central effects ofthe compound. By in vivo g, the compound'sin vivo affinity for D2 receptors was assessed and occupancy of70% (Compound (IV)) and 75% (Compound (II)) ofthe target was observed. Occupancy ofD2 ors is closely linked to antipsychotic effects in animal models and in patients.

Compounds (I)- (VII) and (X) were assayed in a side-by-side is at Cerep Contract Laboratories (Cat. Refs.# 44, 46 and 471). Results ofreceptor binding is listed in Table 4.

Table 4. Binding ofCompounds to D1, D2 and 5-HT2a. alternative human D1 alternative human D2 Cmpd. receptor binding (Ki) receptor binding (Ki) human 5-HT2A (ICso) (I) 0.10 nM 7.6nM 0.37 nM; 1.14 nM* (II) 0.20nM 6.8nM 1.1 nM (III) 0.36nM 7.6nM 1.1 nM (IV) 0.05 nM lOnM 0.25 nM (V) 0.10 nM 4.8nM 0.61 nM (VI) 0.10 nM 3.7nM 0.24 nM (VII) 0.14 nM 5.2nM 0.33 nM (X) 0.22nM 7nM 0.79 nM * Compound (I) was tested twice in this assay.

Example 10: Metabolismlnvestigations in pooled human liver microsomes (HLM) wo 2012/176066 Pooled human liver microsomes (50 donors, from Xenotech) were incubated with 1 microM or 10 microM ofcompound at 37 °C. The incubation mixture ned 50 mM Tris-HCl, 154 mM KCl, 5 mM MgCb and a NADPH regenerating system (1 mM NADP+, 5 mM isocitric acid, 1 unit/mL ric dehydrogenase, from Sigma-Aldrich). The protein concentration was 0.2 mg/mL and the final volume was 0.5 mL. Following a 10 minute preincubation , the reaction was initiated by adding Compound. After 0, 15, 30, 60, 90, 120 and 180 minutes, the ons were terminated by transferring the subcellular fraction to 0.5 mL ofstopping reagent containing internal standard. The incubations were carried out in triplicate. The samples were centrifuged at 4000 g (4 °C, 15 min) and the atants were analysed by HPLC-MS/MS. Data were sed as MS area relative to an internal standard.

The results are shown as the mean oftriplicate determinations± SD. Figure 7 and Figure 8 show that the amount ofthe desmethyl metabolite produced in human liver microsomes is lower from the deuterated form (Compound (II) and Compound (IV)) than from the non-deuterated compound (Compound (X)), both at a tration of 1 microM (Figure 7) and at a concentration of 10 microM (Figure 8). Results for Compound (III) are shown in Figure 9. Results for Compounds (V)- (VII) are shown in Figs. 10-12, respectively. The desmethyl metabolites ofcompounds (II), (IV) and (X) are compounds (XX) and (XI), respectively (see Figure 13).

Investigations using recombinant human liver CYP2C19 and CYP3A4 Recombinant human liver CYP2C19 or CYP3A4 isoenzymes (from BD biosciences) were incubated with 1 microM or 10 microM Compound (X), Compound (II) or Compound (IV) at 37 °C. The incubation mixture contained 50 mM Cl, 154 mM KCl, mM MgCb and a NADPH regenerating system (1 mM NADP+, 5 mM isocitric acid, 1 unit/mL isocitric dehydrogenase, from Sigma-Aldrich). The protein concentration was 0.5 mg/mL and the final volume was 0.5 mL. ing a 10 minutes pre-incubation, the reaction was initiated by adding Compound (X), Compound (II) and/or Compound (IV).

After 0, 15, 30, 60, 90, 120 and 180 minutes the reactions were ated by transferring the subcellular fraction to 0.5 mL of stopping reagent containing internal standard. The incubations were carried out in cate. The samples were centrifuged at 4000 g ( 4 °C, 15 minutes) and the supernatants were analyzed by HPLC-MS/MS. Data were expressed as MS area relative to an al standard.

The results (Figure 14 and Figure 15) show that the amount ofthe desmethyl metabolite produced following tion with recombinant human liver CYP2C19 enzymes wo 2012/176066 is lower from the deuterated forms (Compound (II) and Compound (IV)) than from the terated compound (Compound (X)), both at a concentration of 10 micro M (Figure 14, Compound (II)) and at a concentration of 1 micro M (Figure 15, Compound (IV)).

Corresponding results were obtained for Compound (II) at a concentration of 1 micro M and for Compound (IV) at a concentration of 10 micro M.

Correspondingly, the amount ofthe hyl metabolite produced by incubation with recombinant human liver CYP3A4 enzymes is lower from the deuterated forms (Compound (II) and (IV)) than from the non-deuterated compound (Compound (X)), both at a concentration of 1 micro M and 10 micro M.

Example 11: Pharmacology of Compound (IV).

PCP-Induced Hyperactivity nd (IV) dose-dependently reverses duced hyperactivity in mice, indicative ofantipsychotic efficacy (Figure 16). Compound (IV) tartrate was administered subcutaneous (s.c.) 30 minutes before the test. PCP hydrochloride (2,3 mg/kg) was administered s.c. just before the test. tor activity was measured for 60 minutes as number ofbeam breaks (counts). Eight to 16 male mice were used in each group. ## indicates P <0.01 versus Vehicle-PCP (One-way analysis ofvariance ] followed by Bonferroni post-hoc test). PCP is ng NMDA receptors and as such is used to model the hypo-glutamatergic state related to schizophrenia. PCP es behavioural effects in animals reminiscent ofpositive, negative, and ive symptoms ofschizophrenia ts (Jentsch, J.D. and Roth, R. H. Neuropsychopharmacology 1999; 20: 201-225; herein incorporated by reference in its entirety). PCP-induced hyperactivity is ly used as an assay for evaluation ofantipsychotic compounds (Jackson, D.M. et al., Pharmacal Biochem Behav. 1994; 48: 465-471; herein incorporated by reference in its entirety).

Catalepsy Catalepsy is thought to reflect drug-induced suppression ofthe ability to initiate a behavioral response. The catalepsy test in rats is a common and widely used preclinical screening test for the EPS liability ofpotentially antipsychotic drugs. Although catalepsy is y assessed following acute drug administration, the test has proven to be a reliable predictor for the propensity ofan antipsychotic drug to induce EPS (that is, pseudo parkinsonism, dystonia) in humans (Elliott, P.J. et al, J . Transm. Park. Dis.Dement.

Sect. 1990; 2: 79-89; herein incorporated by reference in its entirety). wo 2012/176066 nd (IV) dose-dependently induced catalepsy in rats suggestive ofEPS ity. The minimal effective dose inducing catalepsy was 10 mg/kg (Figure 17).

Compound (IV) tartrate was stered s.c. 30 minutes before the test. Eight male e Dawley rats were used in each group. #indicates P <0.05, ##indicates P <0.01 versus vehicle (One-way ANOVA followed by Bonferroni post-hoc test). This dose is 100 times higher than the dose indicating antipsychotic activity (Figure 16).

Example 12: Human Pharmacokinetic Studies.

The pharmacokinetics of Compound (IV) and Compound (X) were compared in a multiple oral dose study in healthy young men. The study ipants received daily doses of3 mg Compound (IV) and 3 mg Compound (X) for 18 days and blood samples were collected for 24 hours (one dosing interval) after the last dose to e the exposure of both compounds and their demethylated metabolites, Compound (XX) and Compound (XI) , respectively.

For all study participants, the area under the time-plasma concentration curve for the dosing interval (AUC 0-24) for Compound (IV) was higher than that for Compound (X), mean 104 h*ng/mL vs 98 h*ng/mL. A consistent shift in the opposite direction was observed for the demethylated lites with mean AUC 0-24 of 117 h*ng/mL and 120 h*ng/ml for Compound (XX) and Compound (XI), respectively.

Example 13: Catalytic oselective synthesis ofketone ediate.

This example discloses the synthesis 6-chlorophenyl(ds)-indanone, Compound (XV), and (S)chlorophenyl-indanone, Compound (XVIII).

(S)chlorophenyl(ds)-indanone, Compound (XV), has proven to be a valuable building block in the synthesis ofdeuterated variants ofCompound (X) where the free phenyl group is deuterated. l Experimental Unless otherwise stated, all reactions were carried out under nitrogen. Reactions were monitored by thin-layer chromatography (TLC) analysis and LC-MS. All reagents were purchased and used without further purification. Spots were visualized by exposure to ultraviolet (UV) light (254 nm), or by staining with a 5 % on ofphosphomolybdenic acid (PMA) in ethanol or basic aqueous ium permanganate (KMn04) and then heating.

Column chromatography was carried out using Merck C60 (40-63 f.lm, 230-240 mesh) silica gel. NMR spectra were recorded at 500 or 600 MHz CH NMR), and calibrated to the residual solvent peak. The following abbreviations are used for NMR data: s, singlet; d, doublet; t, wo 2012/176066 triplet; m, multiplet. ng constants are rounded to nearest 0.5 Hz. Enantiomeric excess was determined by chiral HPLC.

LC-MS method: Acquity UPLC BEH C18 1.7 J.lm column; 2.1 x 50 mm operating at 60°C with flow 1.2 mL/min ofa binary gradient consisting ofwater+ 0.1 %formic acid (A) and acetonitrile+ 5% water+ 0.1 % formic acid (B).

Chiral HPLC method: Phenomenex Lux 5).1 Cellulose-2 column; 250 x 4.6 mm operating at 30°C with flow 0.6 mL/min xane:isopropanol:diethylamine, 90:10:0.1.

Synthesis of(S)chlorophenyl(ds)-indanone (Compound (XV)) (Scheme Scheme 14. Synthesis ofCompound (XV) '}--{ (Pinacoi)Bb "XX' PdCI2(Ph3Pl2 0, ....o D 0 D OTf D B Tf20 Ph3P DIPEA D~ KOPh 1.0 DCM, rt 1.0 0 PhMe, 50°C D D D D D D Step B D Step A: 82% D D (XII) (XIII) CI'C(I~ Br Cl Cl (Ph3P)4Pd 2mol% K2C03 INAP]Rh(I)BF4 EtOH-H20-PhMe D Aoetone, rt 75°C Step D: D Step C D 96% Step B-C: 74% 96% ee (98:2 S:R) D D Overall yield: 58% (XIV) (XV) yl(d5)-vinyl oromethanesulfonate (XII): To a solution ofacetophenone-d5 (1.56 g, 12.5 mmol) in CH2Clz (25.0 mL) was added trifluoromethanesulfonic anhydride (2.52 mL, 15.0 mmol) at room temperature. Then N,N-diisopropylethylamine (3.04 mL, 17.5 mmol) was added dropwise while the reaction mixture was cooled in an ice-water bath. The reaction mixture was allowed to warm to room temperature, and it was stirred for 1.5 h. Trifluoromethanesulfonic anhydride (0.63 mL, 3.74 mmol) was added followed by N,N-diisopropylethylamine (1.09 mL, 6.24 mmol). The reaction mixture was stirred for 2 hours at room temperature. Toluene (25 mL) and silica gel wo 2012/176066 (5 g) was added. The mixture was concentrated in vacuo, and the ing suspension was filtered through a pad of celite. The filter cake was washed with toluene (10 mL), and the filtrate was evaporated to dryness in vacuo to yield crude Compound (XII) (3 .11 g, 82%, purity (NMR): approx. 85%) as a dark oil, that was used t further purification. 1H NMR (600 MHz, CDCh) 8H 5.38 (d, 1H, J = 4.0 Hz), 5.62 (d, 1H, J = 4.0 Hz). 5-chloro(1-phenyl(d5)-vinyl)benzaldehyde (XIV) (Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura, N. JAm. Chern. Soc. 2002, 124, 8001-8006; Simeone, J.P.; Sowa, J.

R. Jr. Tetrahedron 2007, 63, 12646-12654; each herein incorporated by reference in its entirety).

To a solution ofCompound (XII) (3.11 g, 10.3 mmol, purity (NMR): . 85%) in toluene was added triphenylphosphine (108 mg, 0.685 mmol), nacolato)diboron (2.61 g, 10.3 mmol), iphenylphosphine)palladium(II) chloride (240 mg, 0.342 mmol) and potassium phenolate (1.92 g, 14.6 mmol). The reaction mixture was stirred at 50°C for 4 hours. This yielded Compound (XIII) in the mixture, which was not isolated. The mixture was cooled to room temperature, and ethanol (10 mL) and water (5 mL) was added, followed by tetrakis(triphenylphosphine)palladium(O) (495 mg, 0.428 mmol), ium carbonate (4.73 g, 34.2 mmol) and 2-bromochlorobenzaldehyde (1.88 g, 8.56 mmol). The reaction mixture was stirred at 80°C for 16 hours. The mixture was cooled to room temperature, and partitioned n water (50 mL) and toluene (50 mL).

The organic phase was separated and washed with water (50 mL) twice, and brine.

The organic phase was dried over MgS04, filtered and evaporated to dryness in vacuo. The e was subjected to purification by column chromatography eluting with 80:1 nheptane :EtOAc mixture to afford Compound (XIV) (1.66 g, 74%) as an orange oil. 1HNMR(600 MHz, CDCh) 8H 5.28 (d, 1H,J=.5 Hz), 6.00 (d, 1H ,J= 0.5 Hz), 7.30 (d, 1H, J = 8.0 Hz), 7.56 (dd, 1H; J = 2.5, 8.0 Hz), 7.96 (d, 1H, J = 2.5 Hz); 13C NMR (150 MHz, CDCh) 8c 118.7, 126.6 (t, J =24.0 Hz), 127.5, 128.2 (t, J = 24.0 Hz), 128.4 (t, J = 24.0 Hz), 132.5, 133.7, 134.7, 135.7, 140.3, 143.9, 144.8, 190.8; LC-MS (APPI): m/e calc. for C1sH7DsClO [M+Ht 248.1, found 248.1.

(S)Chlorophenyl(ds)-indanone (XV) (Kundu, K.; McCullagh, J. V.; Morehead, A. T. Jr. JAm. Chern. Soc. 2005, 127, 16042-16043; herein incorporated by reference in its entirety). en was bubbled through a N2-flushed solution of((R)-2,2'- bis(diphenylphosphino)-1,1'-binaphthyl)(norbomadiene)rhodium(!) tetrafluoroborate (3 7 mg, wo 2012/176066 0.0404 mmol) in acetone (7.5 mL) for 10 min at room temperature, during which the color of the solution changed from orange to more brownish red. The flask containing the solution was subsequently flushed briefly with N2 gas. Then a solution of(XIV) (526 mg, 2.02 mmol, purity (LC-MS): 95%) in acetone (7.5 mL) was added at room temperature. The reaction mixture was stirred for 24 hours at room ature. The reaction mixture was mixed with silica gel and evaporated to dryness in vacuo. The obtained al was loaded onto a silica gel column and the product was eluted with 10:1 n-heptane:EtOAc mixture to obtain Compound (XV) (495 mg, 96%, 96.0% ee) as a solid. 1H NMR (500 MHz, CDCh) 8H 2.72 (dd, 1H, J = 4.0, 19.5 Hz), 3.27 (dd, 1H, J = 8.0, 19.5 Hz), 4.55 (dd, 1H, J = 4.0, 8.0 Hz), 7.21 (d, 1H; J = 8.0 Hz), 7.52 (dd, 1H, J = 2.0, 8.0 Hz), 7.77 (d, 1H, J = 2.0 Hz); 13C NMR (125 MHz, CDCh) 8c 44.0, 47.2, 123.2, 126.8 (t, J = 24.0 Hz), 127.3 (t, J = 24.0 Hz), 128.7 (t, J = 24.0 Hz), 134.4, 135.1, 138.2, 142.9, 156.0, 206.4; LC-MS (APPI): m/e calc. for C1sH7DsClO [M+Ht 248.1, found 247.6. sis of(S)chlorophenyl-indanone (XVIII) (Scheme 15) Scheme 15. sis ofCompound ) d0 CI'CC0 Tf20 NaOH CI'CCu0 DIPEA + I .-9 I .-9 I .-9 MeOH-H 20, rt DCM, 0°C OH OH Step A: 46% Step B: 97% (XVI) Pd(OAclz (R)-3,5-XyiMeOBIPHEP Proton sponge Cl DMF, 85°C Step C: (XVII) 64% ee (82:18 S:R) Overall yield: 34% (E)(5-chlorohydroxyphenyl)phenylpropenone (XVI): To an ice-cooled solution ofsodium hydroxide (2.34 g, 58.6 mmol) in water (17.0 mL) was added benzaldehyde (0.746g, 7.03 mmol) and then a solution of5-chloro hydroxyacetophenone (1.00 g, 5.86 mmol) in methanol (17.0 mL). The reaction mixture was allowed to warm to room temperature, and it was stirred for 24 hours. The bulk ofthe organic solvent was d by evaporation in vacuo. The s residue was extracted with EtOAc (3 x 30 mL). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over MgS04, filtered and evaporated to dryness in vacuo. The residue was dissolved in a minimum volume of CH2Clz, and n-pentane was added which resulted in wo 2012/176066 precipitation. The obtained suspension was filtered and the precipitate was washed with little cold pentane, and dried in vacuo to afford nd (XVI) (695 mg, 46%) as an orange solid. 1HNMR(500 MHz, CDCh) 8H 6.22 (d, 1H,J= 9.0 Hz), 6.80 (dd, 1H,J= 3.0, 9.0 Hz), 7.33 (t, 1H, J = 7.5 Hz), 7.38-7.42 (m, 4H), 7.60 (d, 2H, J = 7.5 Hz); 8.63 (d, 1H, J = 16.0 Hz); 13C NMR (125 MHz, CDCh) 8c 110.6, 125.2, 127.8, 128.1, 128.8, 128.9, 129.4, 129.6, 1'33.0, 136.4, 137.1, 174.5, 188.2.

Trifluoromethanesulfonic acid 4-chloro((E)-(3-phenyl-acryloyl))-phenyl ester To a solution ofCompound (XVI) (517 mg, 2.00 mmol) in CH2Cb (10.0 mL) was added isopropylethylamine (697 f.lL, 4.00 mmol). Trifluoromethanesulfonic anhydride (437 f.lL, 2.60 mmol) was added dropwise at 0°C. The reaction mixture was stirred for 45 min at 0°C. Sat. aq. NH4Cl (5 mL) and water (10 mL) was added, and the mixture was stirred for minutes. The organic phase was separated, and the aqueous phase was extracted with CH2Cb (10 mL). The combined extracts were dried over MgS04, filtered and evaporated to dryness in vacuo. The residue was purified by column chromatography eluting with 4:1 nheptane :EtOAc to yield (XVII) (757 mg, 97%) as an oil. 1H NMR (500 MHz, CDCh) 8H 7.16 (d, 1H, J = 16.0 Hz), 7.34 (d, 1H, J = 9.0 Hz), 7.40-7.47 (m, 3H), 7.57 (dd, 1H, J = 2.5, 9.0 Hz), .62 (m, 2H), 7.69 (d, 1H, 16.0 Hz), 7.72 (d, 1H, J= 2.5 Hz); 13C NMR (125 MHz, CDCh) 8c 124.1, 124.2, 129.0, 129.2, 130.7, 131.5, 132.8, 134.1, 134.6, 145.2, 147.8, 188.4.

(S)Chlorophenyl-indanone (XVIII) (Minatti, A.; Zheng, X.; Buchwald, S.

L. J. Org. Chern. 2007, 72, 9253-9258; herein incorporated by reference in its entirety).

To a solution ofCompound (XVII) (195 mg, 0.500 mmol) in DMF (2.0 mL) was added -sponge (214 mg, 1.00 mmol), palladium acetate (6 mg, 0.025 mmol) and (R)- 3,5-XylMeOBIPHEP (35 mg, 0.05 mmol) at rt. The reaction mixture was stirred at 85°C for 45 h. The mixture was cooled tort, and diluted with TBME (15 mL). The e was washed three times with water (3 x 20 mL), and the organic phase was dried over MgS04, filtered and evaporated to dryness in vacuo. The residue was subjected to column chromatography eluting with 10:1 n-heptane:EtOAc to yield Compound (XVII) (94 mg, 77%, 64.0% ee). 1HNMR(600MHz, CDCh) 8H2.71 (dd, 1H,J=4.0, 19.5 Hz), 3.25 (dd, 1H,J= 8.0, 19.5 Hz), 4.54 (dd, 1H, J = 4.0, 8.0 Hz), 7.10 (d, 2H, J = 7.0 Hz), 7.20 (d, 1H, J = 8.0 wo 2012/176066 Hz), 7.25 (t, 1H, J = 7.5 Hz), 7.31 (t, 2H, J = 7.5 Hz), 7.50 (dd, 1H, J = 2.0, 8.0 Hz), 7.75 (d, 2H, J = 2.0 Hz); 13C NMR (150 MHz, CDCb) 8c 44.1, 47.2, 123.3, 127.3, 127.6, 128.3, 129.1, 134.4, 135.2, 138.3, 143.1, 156.1, 204.5.

Enantioenrichment ound ) by Reprecipitation Compound (XVII) (940 mg, 3.87 mmol, 96% ee) was dissolved in a minimum volume ofboiling ethanol (99% v/v). The resulting solution was allowed to cool slowly tort by placing the glass flask containing the solution in the air. A precipitate formed that was filtered from solution to yield Compound (XVIII) (700 mg, 99.9% ee, 74%). A second crop ofCompound (XVIII) could be obtained by cooling the filtrate in the freezer (-8°C) to yield Compound (XVIII) (80 mg, 98.6% ee, 9%). ical data (NMR and LC-MS) for Compound (XVIII) were the same as those reported above.

Example 14: Large scale production ofCompound (IV) The following process was developed for the large scale production ofthe tartrate salt ofCompound (IV) Scheme 16: Synthesis ofrac-trans(6-Chlorophenyl(d5)-indanyl)-3,3- dimethyl-piperazine maleate OH Cl )< Cl HN\._/NH Cl rY- rY- SOCI2, THF K2C03, MIBK N Cl CI~ 2. maleic acid + ~ D D \ D D D Df::f-~::,..... D (XXII) ) D cis racemate D cis racemate (+15% trans) Mw249.75 Mw 268.20 (XX) (XXIV) C15H8CIOD5 C15H7CI 2D5 (XXV) e Mw 462.00 3+116.07) trans racemate (+8% cis) Procedure: 1.) 2.01 kg (16.9 mol) thionylchloride and 7.2 kg tetrahydrofuran are mixed and the reaction is cooled to 10-15 oc 2.) a solution of2.76 kg (11.1 mol) (XXII) in 7.2 kg THF is slowly added and after completion 5.9 kg tetrahydrofuran is added 3.) the reaction is stirred at 15 oc for approximately 90 hours 4.) 16.7 kg water is cooled to 11 oc and added slowly to the reaction, afterwards 7.8 kg 27.7% aqueous sodium ide is added slowly, followed by 10 kg ethylacetate wo 2012/176066 .) the mixture is stirred for 20-40 minutes 6.) the phases are separated and the organic phase is d to a volume of approximately 6L 7.) 16 kg methyl isobutylketone is added and the volume is reduced to imately 8 L 8.) 1.58 kg (11.4 mol) ium carbonate, 1.69 kg (14.8 mol) 2,2-dimethylpiperazin and 13.6 kg methyl isobutyl ketone are added 9.) the reaction is stirred 35 hours at 90-95 oc .) after cooling to room temperature 11 kg water is added and the mixture is stirred for 30 - 60 minutes 11.) the phases are separated. 13.7 kg water is added to the organic phase and the mixture is stirred slowly for 30 - 60 minutes 12.) the phases are separated and the organic phase is blank ed 13.) 5 kg methyl yl ketone, 7.8 kg water and 5.9 kg 36% aqueous hydrogen de are added and the mixture is stirred at 50 oc for 30- 60 minutes 14.) the phases are separated. 8 kg methyl isobutyl ketone is added to the water phase and the mixture is cooled to 10-15 oc .) a mixture of3.5 kg methyl isobutyl ketone and 7.8 kg 25% aqueous ammonia are slowly added to the mixture and the reaction is stirred at 20-25 oc for 60 - 90 minutes 16.) the phases are separated and the organic phase is washed with 10.5 kg water 17.) the organic phase is reduced to 8 L 18.) 1.19 kg (10.25 mol) maleic acid and 9 kg methyl isobutyl ketone are added and the reaction is afterwards warmed to 75-80 oc 19.) after cooling to 10-15 oc the precipitate is filtered offand washed with 10 kg methyl isobutyl ketone .) the solid is dried in a vacuum oven at 50 oc for approximately 20 hours to give 3.47 kg (68% yield) of(XXV) maleate.

NMR data for (XXV) maleate: 1H-NMR (dmso-d6, 600 MHz, ppm): 8.60 (bs, 2H, maleic acid), 7.39 (d, 1H, J=1.6 Hz), 7.29 (dd, 1H, J=8.0 Hz, J=1.8 Hz), 6.98 (d, 1H, J=8.2 Hz), 6.04 (s, 2H, maleic acid), 4.56 (dd, 1H, J=8.1 Hz, J=4.9 Hz), 4.48 (dd, 1H, J=8.6 Hz, J=6.2 Hz), 3.37 (bs, 1H), 3.16 (bs, 2H), 2.77 (bs, 1H), 2.58-2.50 (m, 3H), 2.31 (d, 1H, J=12.0 Hz), 2.12 (ddd, 1H, J=13.8 Hz, J=8.0 Hz, J=6.0 Hz), 1.33 (s, 3H), 1.31 (s, 3H). wo 76066 Scheme 17: sis ofrac-trans(6-chlorophenyl(d5)-indanyl)-1(d3), 2,2-trimethyl-piperazine succinate rY- rY- 1. NH3 aq., MTBE H H 2. CD31, KOH, H20, MTBE 3. NH3 aq. r9- Cl N 4. AcCI, MTBE i ClmN N . NH3 aq. Cl i + lA 6. succinic acid, acetone OH Df:f~ D ,._ D D D ¢~H D D (XX) 0 (XXIV) (IV) (XXV) Maleate (XXVII)Succinate Mw 462.00 (345.93+116.07) Mw 481.07 (362.98+118.09) trans te (+8% cis) trans racemat Procedure: 1.) 1.1 kg (2.38 mol) (XXV) maleate, 11 L methyl tertbutyl ether, 1.8 L water and 1 L % aqueous ammonia are stirred for 1 - 2 hours 2.) the phases are separated and the organic phase is washed with two times 2 L water 3.) a solution of254 g (3.85 mol) 85% aqueous potassium hydroxide and 1.5 L water is added to the organic phase, followed by addition of450 g (3.11 mol) methyl(d3 )iodide (CD3I) 4.) the reaction is d at 20-25 oc for 16-24 hours .) 2 L water are added and the precipitating by-product is filtered off 6.) 0.8 L water and 0.2 L 25% aqueous ammonia are added to the filtrate and the mixture is stirred for 20 - 40 minutes 7.) the phases are separated and the organic phase is washed with 2 L water 8.) the phases are separated and 38 g (0.48 mol) chloride is added to the organic phase which is stirred for 20 - 40 minutes 9.) 0.8 L water and 0.2 L 25% s ammonia are added and the mixture is stirred for - 40 minutes .) the phases are separated and the organic phase is washed with 2 L water 11.) the organic phase is reduced to dryness and acetone is added 12.) 225 g (1.91 mol) succinic acid and acetone are added so that the reaction volume is approximately 6 - 6.5 L 13.) The reaction is warmed to reflux and afterwards cooled to 5-10 oc wo 2012/176066 14.) The precipitate is filtered offand washed with 1 L acetone .) the solid is dried in a vacuum oven at 50 oc for more than 16 hours to give 630 g (55% yield) of(XXVII) succinate NMR data for (XXVII) succinate: 1H-NMR (dmso-d6, 600 MHz, ppm): 7.33 (d, 1H, J=1.9 Hz), 7.26 (dd, 1H, J=8.1 Hz, J=2.0 Hz), 6.95 (d, 1H, J=8.0 Hz), 4.46 (dd, 1H, J=8.0 Hz, J=5.1 Hz), 4.46 (dd, 1H, J=8.8 Hz, J=5.8 Hz), 2.65-2.56 (m, 4H), .41 (m, 1H), 2.37 (s, 4H, succinic acid), 2.31 (bs, 1H), 2.13 (d, 1H, J=10.9 Hz), 2.02 (ddd, 1H, J=13.7 Hz, J=7.8 Hz, J=6.0 Hz), 1.04 (s, 3H), 1.02 (s, 3H).

Scheme 18: Synthesis of4-((1R,3S)chlorophenyl(d5)-indanyl)-1 (d3),2,2- trimethyl-piperazine L(+)-tartrate c9- po3 (~1. NH3 aq., EtOAc N c9- i N 2. L(+) tartaric acid, acetone N Hoy% Cl + Cl 3. EtOH (recrystallisation) 1 Yield from Lu AF38107: HO'''~~H ~~H D-R-D -"% 1"9 SM gWoHOOg N'<) 0 D D D D (IV) (XXVI) L(+) (IV) tartrate Mw 513.07 (362.98+150.09) XXVII Succinate IOD5, C4H60 Mw 481.07 (362.98+118.09) 6 Procedure: 1.) 1.0 kg (2.08 mol) ) succinate, 8 L ethyl acetate, 2L water and 1L 25% aqueous ammonia are stirred for 0.5- 1 hours 2.) the phases are separated and the organic phase is washed with 2 L water 3.) the organic phase is reduced to approximately 1.5 L 4.) 10 L e and 312 g (2.08 mol) L(+)-tartaric acid are added .) the reaction is warmed to reflux and ards cooled to 5-10 oc 6.) the precipitate is filtered off, washed with 1.2 L acetone 7.) the wet filtercake is recharged and 11 L absolute ethanol are added 8.) the reaction is warmed to reflux and afterwards cooled to 5-10 oc 9.) the precipitate is filtered offand washed with 1.2 L absolute ethanol wo 76066 .) the solid is dried in a vacuum oven at 50 oc for more than 16 hours to give 395 g (37% yield) of(IV) L(+)-tartrate NMR data for (IV) L(+)-tartrate: 1H-NMR (dmso-d6, 600 MHz, ppm): 7.36 (s, 1H), 7.27 (d, 1H, J=8.2 Hz), 6.96 (d, 1H, J=8.2 Hz), 4.50 (dd, 1H, J=8.0 Hz, J=5.1 Hz), 4.45 (dd, 1H, J=8.5 Hz, J=5.8 Hz), 4.07 (s, 2H, tartrate), 2.95 (bs, 1H), 2.77 (bs, 1H), .50 (m, 3H), 2.31 (d, 1H, J=11.7 Hz), 2.04 (ddd, 1H, J=13.7 Hz, J=7.8 Hz, J=6.0 Hz) 1.21 (s, 3H), 1.18 (s, 3H).

Example 15: o-Chemical characterization ofsalts of Compound (IV) n.Ka and log P/D ound (IV) pKa was determined by iometric titration ofthe base at ion strength 0.16 using MeOH as co-solvent. Three series ofthree repeated titrations on the same solution of the sample was performed in a conventional way from low to high pH and a difference curve was created from each ofthese titrations by blank subtraction. The apparent pKa-value at each MeOH:water ratio is calculated from the difference curves, and the pKa value is determined by extrapolation to zero MeOH content.

The lower pKa value is too low to be determined by potentiometric titration as data only were found reliable down to ~3. The high pKa was determined to be 8. 9 + 0.1 The lower pKa was determined by Dip Probe Absorption Spectroscopy detection during titration ofthe base at ion strength 0.16 using MeOH as co-solvent. The change in absorption spectra as a function of ionisation is used to calculate the pKa-value. Two series of three repeated titrations on the same solution ofthe sample was performed from low to high pH, with a photo diode array as additional detection. The apparent lue at each MeOH:water ratio is calculated by Target factor analysis on the change in absorption spectra, and the pKa value is determined by extrapolation to zero MeOH content.

Result : The lower pKa was ined to be 2.5+ 0.1 The logD profile was determined by titration at 27°C and ion th ofapprox. 0.16. A series ofthree repeated titrations on the same sample in solution was performed, from low to high pH. The first titration was performed with a small amount ofn-octanol present in the solution, the second and third with increasing amounts.

A difference curve was created from each e titrations by blank subtraction, and from these difference , the apparent pKa values (poKa) were calculated. From the change in the apparent pKa values (LlpKa) with the n-octanol:water ratio combined with the real pKa value, the LogP value was calculated and the LogD profile was derived. The following values were determined: Log P = 5.4+ 0.4 and Log D74 = 3.9+ 0.4 Melting point determined by DSC The melting point of the (R,R)—hydrogen tartrate salt of Compound (IV) was determined using differential ng calorimetry (DSC), using a TA ments DSC Q1000 heating the sample 5°/minute. The sample was placed in a covered pan with a punched pinhole.

The melting is terized by onset and peak temperature of the melting endotherm, and the enthalpy of fusion is calculated from the area of the peak. Based on the DSC thermogram an onset temperature of 187.4°C and a peak maximum at 189.4°C was found. The py of fusion was 96 J/g corresponding to 49 kJ/mol, however the thermogram is indicative that the melting s under decomposition meaning that the enthalpy probably contain energy other than melting.

Solubility lity of the (R,R)-hydrogen tartrate salt of Compound (IV) was measured in aqueous solutions and in cyclodextrins with the following results (Table 5): Table 5. Solubility of (R,R)-hydrogen tartrate salt of Compound (IV).

Polymorphism One solvent free crystal form of the tartrate has been isolated. The XRPD of this form is shown in Figure 18, and designated herein as "polymorph A".

Salts of Compound (IV) Four salts were ed by precipitation of Compound (IV) from 99% EtOH.

Analytical data are given in the table below (Table 6). -6l- WO 76066 Table 6. Data for salts of Compound (IV) 250°C _H dro-en fumarate C _H dro-en maleate 150.4°C Hydrogen malonate l45.0°C followed by 9.5 4.08 de_radation Hydrogen tartrate 187°C 3.15 —Base *>l<>l<>l<>l< Although the invention has been described and rated in the ing illustrative embodiments, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the details of implementation of the invention can be made without departing from the spirit and scope of the invention, which is d only by the claims that follow. Features of the disclosed embodiments can be combined and/or rearranged in various ways within the scope and spirit of the invention to produce further embodiments that are also within the scope of the invention. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments bed specifically in this disclosure. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims (14)

WE CLAIM:

1. A compound of formula Y: R1 N R8 (Y) wherein, R1 – R10 are independently hydrogen or deuterium, wherein R6-R10 are each deuterium, wherein at least one of R1-R10 ses at least about 50% deuterium, or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1, wherein R3-R5 are each hydrogen.

3. The compound of claim 1, wherein R3-R5 are each deuterium.

4. The compound of claim 2, wherein the nd is D (1R,3S)-(II).

5. The compound of claim 2, wherein the compound is AH26(9680189_1):RTK D N D (1R,3S)-(VII).

6. The compound of claim 3, wherein the compound is D )-(IV).

7. The compound of claim 3, wherein the compound is D N D (1R,3S)-(VI).

8. The compound of claim 1, wherein R1 and R2 are each deuterium. AH26(9680189_1):RTK

9. The compound of claim 8, n R3-R5 are each deuterium.

10. The compound of claim 8, wherein R3-R5 are each hydrogen.

11. The compound of any of claims 1-10, wherein at least about 85% of the compound has a ium atom at each on designated as deuterium, and any atom not designated as deuterium is present at about its natural isotopic abundance.

12. The compound of any of claims 1-11, wherein at least about 90% of the compound has a deuterium atom at each position designated as deuterium, and any atom not designated as deuterium is present at about its natural isotopic abundance.

13. The compound of claim 1, wherein the compound is the hydrogen tartrate salt of D (1R,3S)-(IV).

14. The compound of claim 13, wherein the compound exists in polymorphic form having an XRPD diffraction pattern as indicated in