OA16797A - Deuterated 1-Piperazino-3-Phenyl-Indanes for treatment of Schizophrenia. - Google Patents

Abstract

The present invention relates to deuterated 1-piperazino-3-phenyl-indanes and salts thereof with activity at dopamine receptors D1 and D2 as well as the 5HT2 receptors in the central nervous system, to medicaments comprising such compounds as active ingredients, to the use of such compounds in the treatment of diseases in the central nervous system, and to methods of treatment comprising administration of such compounds. <img file="OA16797A_A0001.tif"/>

Description

DEUTERATED 1-PIPERAZINO-3-PHENYL INDAN ES FOR TREATMENT OF SCHIZOPHRENIA

This application daims priority to U.S. Provisional Application Nos. 61/498,651, filed on June 20, 2011, and 61/537,103, filed on September 21,2011, the entirety of each of which is incorporated herein by référencé.

Ail patents, patent applications and publications cited herein are hereby incorporated by référencé in their entirety. The disclosures of these publications in their entireties are hereby incorporated by référencé into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.

FIELD OF THE INVENTION

The présent invention relates to deuterated 1-piperazino-3-phenyl-indanes and salts thereof with activity at dopamine Di and D₂ receptors as well as the serotonin 5HT₂ receptors in the central nervous System, to médicaments comprising such compounds as active ingrédients, and to the use of such compounds in the treatment of diseases in the central nervous system.

BACKGROUND OF THE INVENTION

Throughout this application, various publications are referenced in full. The disclosures of these publications are hereby incorporated by référencé into this application to describe more fully the state of the art to which this invention pertains.

4-((1R,3S)-6-Chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine and salts thereof, pharmaceutical compositions containing these salts and the medical use thereof, including treatment of schizophrenia or other diseases involving psychotic symptoms, are disclosed in W02005/016900. 4-((1 R,3S)-6-Chloro-3-phenyl-indan-1 -yl)-1,2,2-trimethyl-piperazine has the general formula (X), hereinafter referred to as Compound (X)

EP 638 073 recites a group of trans isomers of 3-aryl-1-(1-piperazinyl)indanes substituted in the 2- and/or 3-position of the piperazine ring. The compounds are described as

- 1 16797 having high affinity for dopamine Di and D₂ receptors and the 5-HT₂ receptors and are suggested to be useful for treatment of several diseases in the central nervous System, including schizophrenia.

The enantiomer of formula (X) above has been described by Begeso et al. in J. Med. Chem., 1995, 38, page 4380-4392, in the form of the fumarate sait, see table 5, compound (-)38. This publication concludes that the (-)-enantiomer of compound 38 is a potent Di/D₂ antagonist showing some Di selectivity in vitro. The compound is also described as a potent 5HT₂ antagonist. It is aiso mentioned that the compound does not induce catalepsy in rats.

The aetiology of schizophrenia is not known, but the dopamine hypothesis of schizophrenia (Carlsson, Am. J. Psychiatry 1978, 135, 164-173), formuiated in the early 1960s, has provided a theoretical framework for understanding the biological mechanisms underlying this disorder. ln its simplest form, the dopamine hypothesis states that schizophrenia is associated with a hyperdopaminergic state, a notion which is supported by the fact that ali antipsychotic drugs on the market today exert some dopamine D₂ receptor antagonism (Seeman Science and Medicine 1995, 2, 28-37). However, whereas it is generally accepted that antagonism of dopamine D₂ receptors in the limbic régions of the brain plays a key rôle in the treatment of positive symptoms of schizophrenia, the blockade of D₂ receptors in striatal régions of the brain causes extrapyramidal symptoms (EPS). As described in EP 638 073 a profile of mixed dopamine Di/D₂ receptor inhibition has been observed with some so-called atypical antipsychotic compounds, in partîcularwith clozapine (8-chloro-11-(4methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine), used in treatment of schizophrénie patients.

Further, sélective Ü! antagonists hâve been connected to treatment of sleep disorders and alcohol abuse (D.N. Eder, Current Opinion in Investigationai Drugs, 2002 3(2):284-288).

Dopamine may also play an important rôle in the aetiology of affective disorders (P. Willner, Brain. Res. Rev. 1983, 6, 211-224, 225-236 and 237-246; Bogeso et al, J. Med. Chem., 1985, 28, 1817-1828).

In EP 638 073 is described how compounds having affinity for 5-HT₂ receptors, in particular 5-HT₂a receptor antagonists, hâve been suggested for treatment of different diseases, such as schizophrenia including the négative symptoms in schizophrénie patients, dépréssion, anxiety, sleep disturbance, migraine attacks and neuroleptic-induced parkinsonism. 5-HT_2A receptor antagonism has also been suggested to reduce the incidence of extrapyramidal side effects induced by classical neuroleptics (Balsara et al. Psychopharmacology 1979, 62, 67-69).

-216797

An isotopic substitution of one or more hydrogen atoms (H) by deuterium atoms (D) in a compound may give rise to a kinetic isotope effect which may influence the reaction rate, e.g. metabolism of the compound. This is particularly the case when the isotopic replacement is in a chemical bond that is broken or formed in a rate limiting step. In such a case, the change is termed a primary isotope effect. When the isotopic substitution(s) are not involved in one or more bonds that are broken a smaller rate change, termed the secondary isotope effect may be observed.

SUMMARY OF THE INVENTION

The présent invention provides compounds wherein one or more hydrogen atoms atoms (H) in one or more of the metabolic sites M1, M2 and M3 of Compound (X) hâve been substituted by deuterium atoms (D),

In one aspect, the invention provides a compound of formula Y:

R⁸ (Y) wherein, R¹ - R¹⁰ are independently hydrogen or deuterium, and wherein at least one of R¹-R¹⁰ comprises at least about 50% deuterium, or a pharmaceutically acceptable acid addition sait thereof.

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

In another aspect, the invention provides for uses of a compound of formula (Y) or a pharmaceutical composition comprising a compound of formula (Y) in the treatment of psychosis, other diseases involving psychotic symptoms, psychotic disorders or diseases that présent with psychotic symptoms.

-316797

In yet another aspect, the invention provides for the manufacture of a médicament comprising a compound of formula (Y) for treatment of psychosis, other diseases involving psychotic symptoms, psychotic disorders or diseases that présent with psychotic symptoms.

In still another aspect, the invention provides for methods of treating psychosis, other diseases involving psychotic symptoms, psychotic disorders or diseases that présent with psychotic symptoms comprising administration of an effective amount of a compound of formula (Y) or a pharmaceutically composition comprising a compound of formula (Y) to a subject in need thereof.

In still another aspect, the invention provides a compound of formula

In still another aspect, the invention provides a process for the préparation of compound

BINAP]Rh(l)BF₄.

In still another aspect, the invention provides a process for the préparation of compound (1 R,3S)-(IV) tartrate comprising, treatment of racemic trans-1-(6-chloro-3-phenyl(d_s)-indan-1yl)“1(cG), 2, 2-trimethyl-piperazine with L-(+)-tartarie acid.

Still other objects and advantages of the invention will become apparent to those of skill in the art from the disclosure herein, which is simply illustrative and not restrictive. Thus, other embodiments will be recognized by the skilled artisan without departing from the spirit and scope of the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows major metabolic sites of Compound (X).

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FIG. 2 shows Compound (I) and Compound (XI), each as the (1R,3S)-enantiomer.

FIG. 3 shows NMR spectra of Compound (II) and Compound (V). Selected régions of the proton-decoupled and proton- and deuterium-decoupled ¹³C NMR spectra of Compound (II) [Fig. 3A] and Compound (V) [Fig. 3B] are shown.

FIG. 4 shows the mass spectrum of Compound (IV).

FIG. 5 shows formation of the métabolite Compound (XI) by metabolism of Compound (X) and Compound (I) (0.1 microM) in cryopreserved dog hépatocytes (n=2 the bars represent max and min results).

FIG. 6 shows formation of the métabolite Compound (XI) by metabolism of Compound (X) and Compound (I) (1 microM) in cryopreserved dog hépatocytes (n=2 the bars represent max and min results).

FIG. 7 shows formation of the desmethyl métabolite by metabolism of Compound (II), (IV) and (X) (1 micro M) in human liver microsomes (n=3, the bars represent standard déviation).

FIG. 8 shows formation of the desmethyl métabolite by metabolism of Compound (II), (IV) and (X) (10 micro M) in human liver microsomes (n=3, the bars represent standard déviation).

[0001] FIG. 9 shows formation of the desmethyl métabolite by metabolism of Compound (III) (10 micro M) in human liver microsomes (n=3, the bars represent standard déviation).

FIG. 10 shows formation of the desmethyl métabolite by metabolism of Compound (V) (10 micro M) in human liver microsomes (n=3, the bars represent standard déviation).

FIG. 11 shows formation of the desmethyl métabolite by metabolism of Compound (VI) (10 micro M) in human liver microsomes (n=3, the bars represent standard déviation).

FIG. 12 shows formation of the desmethyl métabolite by metabolism of Compound (VII) (10 micro M) in human liver microsomes (n=3, the bars represent standard déviation).

FIG. 13 shows shows the chemical structure of compounds (l)-(VII), (X)-(XI), and (XIX)(XXI).

FIG. 14 shows formation of the desmethyl métabolite by metabolism of Compound (II) and (X) (10 micro M) by recombinant human liver CYP2C19 (n=3, the standard déviation).

FIG. 15 shows formation of the desmethyl métabolite by metabolism of Compound (IV) and Compound (X) (1 micro M) by recombinant human liver CYP2C19 (n=3, the bars represent standard déviation).

FIG. 16 shows PCP-induced hyperactivity in mice for compound (IV).

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FIG. 17 shows cataleptic response in rats for compound (IV).

FIG. 18 shows X-ray diffractograms on two batches of hydrogen tartrate sait of Compound (IV).

DETAILED DESCRIPTION OF THE INVENTION

Atypical antipsychotics hâve been the subject of numerous studies by the pharmaceutical industry, and hâve shown promise in treating mental disorders such as schizophrenia, bipolar disorder, dementia, anxiety disorder and obsessive-compulsive disorder (OCD). The mechanism of action of these agents remains unknown; however ali antipsychotics work to some degree on the dopamine system. Most atypical antipsychotics exhibit activity at dopamine subtype receptors 1 and 2 (D, and D₂, respectively), and at the serotonin receptors subtype 2 (5-HT₂). In some cases, the atypical désignation 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 profiles: the atypical antipsychotics are not ail the same J. Psychiatr. Pract. 2007,13(1): 13-24; herein incorporated by référencé 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), olanzapine (Zyprexa), paliperidone (Invega), perospirone (Lullan), quetiapine (Seroquel), remoxipride (Roxiam), rispéridone (Risperdal), sertindole (Serdolect), supliride (Sulpirid, Eglonyl), ziprasidone (Geodon, Zeldox), and zotepine (Nipolept). Several others are currently under development. Because the mechanism of atypical antipsychotics is not well understood, side effects associated with these drugs hâve been difficult to design around. Thus, there is a need for additional antipsychotic thérapies with potential for reduced side effect and/or improved therapeutic profile relative to existing thérapies.

[0002] In one aspect, the présent invention provides compounds wherein one or more hydrogen atoms (H) in one or more of the metabolic sites M1, M2 and M3 of Compound (X) hâve been substituted 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; 8,076,342; U.S. Patent Publication Nos. 2008/0269248; 2010/0069676; 2011/0178094; 2011/0207744; WO 2005/016900; EP 0 638 073; and J. Med. Chem. 1995, 38, 4380-4392; each herein incorporated by référencé in its entirety.

The kinetic isotope effect may potentially influence the rate of metabolism at one or more of the metabolic sites M1, M2, and M3 indicated in Figure 1. The inventors ofthe présent invention hâve identified three major metabolic sites of 4-((1R,3S)-6-chloro-3-phenyl-indan-1-616797 yl)-1,2,2-trimethyl-piperazine (Compound (X)) denoted herein as M1, M2 and M3 and indicated in Figure 1.

Deutération of a compound at a site subject to oxidative metabolism may, in some cases reduce the rate of metabolism for a compound due to the primary isotope effect. If the C-H bond cleavage step is rate limiting, a significant isotope effect may be observed. However, if other steps drive the rate of metabolism for a compound, the C-H bond cleavage step is not rate limiting and the isotope effect may be of little significance. Additionally, a négative isotope effect can be observed where reaction rate is increased upon substitution with deutérium. Thus, incorporation of deuterium at a site subject to oxidative 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 référencé in its entirety). The impact of deuterium incorporation is unpredictable does not work for many drugs or classes of drugs. Decreased metabolic clearance has been observed with some deuterated compounds relative to non-deuterated dérivatives; whereas metabolism of other compounds has been unimpacted. Examples of studies indicating lack of predictability 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. Chem. 1991, 34, 2871-2876; Can. J. Physiol. Pharmacol. 1999, 79-88; Silverman, R. B., The Organic Chemistry of Drug Design and Drug Action, 2^nd Ed. (2004), 422; Curr. Opin. Drug Dev. 2006, 9,101-109; Chemical Res. Tox. 2008,1672; Harbeson, S.L and Tung, R.D. “Deuterium in Drug Discovery and Development, in Ann. Rep. Med. Chem. 2011,46, 404-418; each herein incorporated by référencé in its entirety. Even incorporation deuterium at known sites of metabolism has an unpredictable impact on metabolic profile. Metabolic switching may resuit wherein the metabolic profile of a particular drug is changed due to deuterium incorporation, thus leading to different proportions of (or different) métabolites than observed with a non-deuterated anlog of the same drug. The new metabolic profile may resuit in a distinct toxicological profile of the deuterated analog. Adding to the potential complications of deuterium incorporation is the possibility of deuterium/hydrogen exchange in the physiological environment (Adv. Drug. Res. 1985,14,1-40; herein incorporated by référencé in its entirety). [0003] In some embodiments, isotopic substitution of one or more hydrogen atoms in Compound (X) by deuterium atoms has given rise to a kinetic isotope effect that influences the rate of metabolism.

The isotopic substitution of hydrogen atoms in Compound (X) by deuterium atoms results in less metabolism of the deuterated compound as shown to occur in dog hépatocytes where for instance an approximately 50% decrease in formation of the desmethyl métabolite

- 716797 (Compound (XI)) from Compound (I) (Figure 2) was noted in comparison to the formation of Compound (XI) from the metabolism of Compound (X).

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

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

The desmetyl métabolite (Compound (XI)) is known to hâve hERG affinity and thus potentially contribute to QTc prolongation. As mentioned above, deutération of the free phenyl optionally in combination with deutération of the 1-methyl group (Compound (II) and (IV)), surprisingly reduces the amount of the desmethyl métabolite produced in human liver microsomes as compared to the non-deuterated compound (Compound (X)). Accordingly and without being bound by theory, it is anticipated that there will be less interaction with the hERG channel and résultant lower burden on the heart when dosing the deuterated variants of Compound (X) [e.g., compounds of formula (Y)] compared to when dosing Compound (X).

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

[0004] Définitions

The term compound(s) of the invention as used herein means Compounds (Y), (I), (II), (III), (IV), (V), (VI), and/or(VII), and may include salts, hydrates and/or solvatés thereof. The compounds of the présent invention are prepared in different forms, such as salts, hydrates, and/or solvatés, and the invention includes compositions and methods encompassing ail variant forms of the compounds.

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

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

-816797

As used herein the term “about is used herein to mean approximately, roughly, around, or in the région of. When the term “about” is used in conjunction 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 of 20 percent up or down (higher or lower).

An “effective amount, “sufficient amount” or “therapeutically effective amount” as used herein is an amount of a compound that is sufficient to effect bénéficiai 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 of an affliction or condition, or one or more symptoms thereof, prevent the advancement of conditions related to an affliction or condition, prevent the récurrence, development, or onset of one or more symptoms associated with an affliction or condition, or enhance or otherwise improve the prophylactic or therapeutic effect(s) of another therapy. An effective amount also includes the amount of the compound that avoids or substantïally atténuâtes undesirable side effects.

As used herein and as well understood in the art, treatment is an approach for obtaining bénéficiai or desired results, including clinical results. Bénéficiai or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminution of extent of disease, a stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state and rémission (whether partial or total), whether détectable or undetectable. Treatment can also mean prolonging survival as compared to expected survival if not receiving 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 in need thereof may or may not be undergoing treatment for conditions related to, for example, psychosis or a psychotic disorder.

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

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The terms animal, subject and patient as used herein include ail members of the animal kingdom including, but not limited to, mammals, animais (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 éléments are présent in natural isotopic abundances in most synthetic compounds, and resuit in inhérent incorporation of deuterium. However, the natural isotopic abundance of hydrogen isotopes such as deuterium is immaterial (about 0.015%) relative to the degree of stable isotopic substitution of compounds indicated herein. Thus, as used herein, désignation of an atom as deuterium at a position indicates that the abundance of deuterium is significantly greater than the natural abundance of deuterium. Any atom not designated as a particular isotope is intended to represent any stable isotope of that atom, as will be apparent to the ordinarily skilled artisan.

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

In some embodiments, compounds (I), (II), (III), (IV), (V), (VI) and (VII) are isotopic variants of Compound (X).

M1 is a site of Compound (X) susceptible to metabolism; M1 consiste of -CH₂- in the 6position of the piperazine of Compound (X).

M2 is a site of compound (X) susceptible to metabolism; M2 consists of the N-bound methyl of the piperazine of Compound (X).

M3 is a site of Compound (X) susceptible to metabolism; M3 consists of the phenyl group of Compound (X).

Parent compound is the chemical compound which is the basis for its dérivatives obtained either by substitution or breakdown, e.g. metabolic breakdown. In the context of the présent invention the parent compound is the Active Pharmaceutical Ingrédient (API).

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

In one aspect, the invention provides a compound of formula (Y):

- 1016797

wherein, R¹ - R¹⁰ are independently hydrogen or deuterium, wherein at least one of R¹-R¹⁰ comprises at least about 50% deuterium, or a pharmaceutically acceptable acid addition sait thereof.

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

[0005] In another aspect, the invention provides for uses of a compound of formula (Y) or a pharmaceutical composition comprising a compound of formula (Y) in the treatment of psychosis, other diseases involving psychotic symptoms, psychotic disorders or diseases that présent with psychotic symptoms.

In yet another aspect, the invention provides for the manufacture of a médicament comprising a compound of formula (Y) for treatment of psychosis, other diseases involving psychotic symptoms, psychotic disorders or diseases that présent with psychotic symptoms.

In still another aspect, the invention provides for methods of treating psychosis, other diseases involving psychotic symptoms, psychotic disorders or diseases that présent with psychotic symptoms comprising administration of an effective amount of a compound of formula (Y) or a pharmaceutically composition comprising a compound of formula (Y).

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

- Il 16797

In some embodiments, the compound is selected from the group consisting of

- 12 16797

(1F?,3S)-(VI), and

Rt°

R³-R⁵ comprise deuterium, or R⁶In some embodiments, R¹ and R^z comprise deuterium, 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 embodiments, R³-R⁵ comprise deuterium. In some embodiments, R³-R⁵ comprise hydrogen.

In some embodiments, R®-R^w comprise deuterium. In some embodiments, R⁶-R¹⁰ comprise deuterium and R³-R⁵ comprise hydrogen.

In some embodiments, R¹-R⁵ comprise deuterium.

In some embodiments, R¹, R², and R^e-R¹⁰ comprise deuterium.

In some embodiments, R³-R¹⁰ comprise deuterium.

In some embodiments, R¹-R¹⁰ comprise deuterium.

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In some embodiments, the compound is

I416797

[0007] ln some embodiments, the compound is

(1R,3S)-(V).

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In some embodiments, at least about 75% of the compound has a deuterium atom at each position designated as deuterium, and any atom not designated as deuterium is présent at 5 about its natural isotopic abundance.

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

In some embodiments, 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 présent at about its natural isotopic abundance.

In some embodiments, the compound is a sait selected from the group consisting of fumarate, maleate, succinate, and tartrate. In some embodiments, the compound is a fumarate sait. In some embodiments, the compound is a hydrogen fumarate sait. In some embodiments,

- I616797 the compound is a maleate sait. In some embodiments, the compound is a hydrogen maleate sait.

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

In some embodiments, the compound is the hydrogen tartrate sait of (1 R,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 embodiments, the methods further comprise administration of with one or more neuroleptic agents.

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

In some embodiments, the neuroleptic agent is selected from the group consisting of sertindole, olanzapine, rispéridone, quetiapine, ariplprazole, haloperidol, clozapine, ziprasidone and osanetant.

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

In some embodiments, the subject is a mammal. In some embodiments, the subject is a rodent, cat, dog, monkey, horse, swine, bovine, 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, désignation of a position as “D in a compound has a minimum deuterium incorporation of greater than about 40% at that position. In some embodiments, désignation of a position as “D in a compound has a minimum deuterium incorporation of greater than about 50% at that position. In some embodiments, désignation of a position as “D in a compound has a minimum deuterium incorporation of greater than about 60% at that position. In some embodiments, désignation of a position as “D in a compound has a minimum deuterium incorporation of greater than about 65% at that position. In some embodiments, désignation of a position as “D” in a compound has a minimum deuterium incorporation of

- 1716797 greater than about 70% at that position. In some embodiments, désignation of a position as “D in a compound has a minimum deuterium incorporation of greater than about 75% at that position. In some embodiments, désignation of a position as “D in a compound has a minimum deuterium incorporation of greater than about 80% at that position. In some embodiments, désignation of a position as “D” in a compound has a minimum deuterium incorporation of greater than about 85% at that position. In some embodiments, désignation of a position as “D” in a compound has a minimum deuterium incorporation of greater than about 90% at that position. In some embodiments, désignation of a position as “D in a compound has a minimum deuterium incorporation of greater than about 95% at that position. In some embodiments, désignation of a position as “D in a compound has a minimum deuterium incorporation of greater than about 97% at that position. In some embodiments, désignation of a position as “D in a compound has a minimum deuterium incorporation of greater than about 99% at that position.

Pharmaceutically Acceptable Salts

The présent invention also comprises salts of the compounds, typically, pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts. Acid addition salts include salts of inorganic acids as well as organic acids.

Représentative examples of sultable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Représentative examples of suitable organic acids include 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, tartane, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline and the like. Further examples of pharmaceutically acceptable inorganic 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 of each are hereby incorporated by reference.

Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, éthanol and the like. In general, the solvated forms are considered comparable to the unsolvated forms for the purposes of this invention.

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

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The use of any and ail examples, or exemplary language (including “for instance”, “for example, “e.g., and “as such) in the présent spécification is intended merely to better illuminate the invention, and does not pose a limitation on the scope of invention unless otherwise indicated.

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

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

The description herein of any aspect or aspect of the invention using terms such as “comprising, “having, “including, or “containing with référencé to an element or éléments is intended to provide support for a similar aspect or aspect of the invention that “consists of, “consists essentially of, or “substantially comprises that particular element or éléments, unless otherwise stated or clearly contradicted by context.

Exemplary synthèses of the compounds of the 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; 2010/0069676; 2011/0178094; 2011/0207744; WO 2005/016900; EP 0 638 073; and J. Med. Chem. 1995, 38, 4380-4392; each herein incorporated by référencé in its entirety. Such methods, and similar methods can be performed using deuterated reagents and/or intermediates, and/or introducing deuterium atoms to a chemical structure according to protocols known in the art.

Further exemplary methods of synthesis inciude conversion of indanone A to intermediate C via treatment of 3-bromo-6-chloro-indan-1-one (A; for référencés on this material, see: Bogeso EP 35363 A1 19810909 and Kehler, Juhl, Püschl, WO 2008025361; each herein incorporated by référencé in its entirety) with a base such as triethylamine in a solvent such as tetrahydrofuran at ambient température (Scheme 1 ). Removal of the precipitated amine hydrobromide sait by filtration and concentration of the filtrate will afford 6chloro-inden-1-one (B). This material can be reacted with phenyl-cfe-boronic acid in the presence of approximately 1 équivalent of a base such as triethylamine and a catalytic amount of a 1:1 mixture of [Rh(ndb)₂]BF₄ (bis(norbornadiene)rhodium(l) tetrafluoroborate) and racemic BINAP (2,2^l-bis(diphenylphosphino)-1,T-binaphthyl) in a suitable solvent (e.g. approximately 10:1 solvent mixture of 1,4-dioxane and water) under an atmosphère of argon at elevated

- 1916797 température (e.g. about 100°C). Work-up will afford racemic 6-chloro-3-phenyl-cfc-indan-1-one (C).

Scheme 1. Exemplary synthesis of intermediate C.

B

Treatment of 6-chloro-3-phenyl-d5-indan-1-one (C) with a reductive base such as sodium borohydride (-2 équivalents) in a -10:1 solvent mixture of tetrahydrofuran and water at low température (approximately -15 °C) will lead to réduction of the carbonyl group to the corresponding alcohol (Scheme 2). Work-up will afford racemic cis-6-chloro-3-phenyl-indan-1-ol (D). Treatment of this materiel with vinyl butyrate (approximately 5 équivalents) and Novozym

435® in a solvent such as di-iso-propyl ether at ambient température will afford (1S,3S)-6chloro-3-phenyl-indan-1-ol (E) after work-up.

Scheme 2. Exemplary synthesis of intermediate E.

C (racemate)

D (ds-racemate)

E ((1S.3S}-enantionief)

Altematively, performing the sequence from A to E using phenyl boronic acid or 4,4,5,5 tetramethyl-2-phenyl-[1,3,2]dioxaborolane instead of 4,4,5,5-tetramethyl-2-d₅-phenyl[1,3,2]dioxaborolane will lead to (1S,3S)-6-chloro-3-phenyl-indan-1-ol (E’) (Scheme 3).

Scheme 3. Exemplary synthesis of intermediate E’.

-2016797

Further alternative synthetic methods to obtain E’ are disclosed in the patent literature (Dahl, Wohlk Nielsen, Suteu, Robin, Brosen W02006/086984 A1; Bang-Andersen, Bogeso, Jensen, Svane, Dahl, Howells, Lyngso, Mow W02005/016901 A1; each herein incorporated by reference in its entirety). These procedures rely on benzyl cyanide as one of the substrates. Using benzyl cyanide-d? (commercially available from Aldrich, catalog # 495840) or phenyl-cfeacetonitrile (commercially available from Aldrich catalog # 495859 or from CDN catalog # D5340 or from Kanto catalog # 49132-27) the same procedure may lead to E (Scheme 4). As alternatives to the commercial sources, benzyl cyanide-d? and phenyl-c/5-acetonitrile can be prepared sodium cyanide and benzyl-d? chloride (commercially available from Aldrich, catalog # 217336) and benzyl-2,3,4,5,6-d₅ chloride (commercially available from Aldrich, catalog # 485764), respectively.

Scheme 4. Exemplary synthesis of intermediates E and E’.

OH

E ((1S,3S)-enantlomer)

R = D: benzyl cyanîde-φ R = H: phenyl-dj-acetonltrile

Treatment of E with approximately 4 équivalents of di-iso-propylethylamine and approximately 2 équivalents methanesulphonic anhydride in tetrahydrofuran at approximately

-21 16797 °C followed by slow heating to approximately -5 °C and subséquent treatment with approximately 4 équivalents 2,2-dimethyl-piperazine will lead to the formation of 1 -(( 1 R,3S)-6chloro-3-phenyl-d5-indan-1-yl)-3,3-dimethyl-piperazine (F) that can be purified after the reaction (Scheme 5). Alternatively, one can convert alcohol E to the corresponding chloride, predominantly with rétention of configuration at C1 leading to (1S,3S)-1-chloro-3-d₅-phenylindan (E; similariy E’ can be converted to (1S,3S)-1-chloro-3-phenyl-indan (E’”)). Chloride E” can be reacted with 2,2-dimethyl-piperazine to afford F. The final step can be performed as described for the préparation of Compound (l)»butanedioic acid sait by the use of iodomethane to give Compound (II) or d₃-iodomethane to give Compound (IV), respectively. Alternatively, as described below, the methyl group or d₃-methyl group can be installed by refluxing in HCHO/HCOOH or DCDO/DCOOD, respectively.

Scheme 5. Exemplary synthesis of intermediates F and Compounds (II) and (IV).

E ((1S,3S)-enantïomer)

F ((1R,3S}-enantiomer)

R = CH3: Compound (II)

R = CD₃: Compound (IV) (2-Amino-2-methyl-propyl)-carbamic acid tert-butyl ester (G) can be prepared from 2methyl-propane-1,2-diamine and di-tert-butyl dicarbonate (alternatively, G is claimed to be commercially available: Prime catalog # POI-1362-MB4; Rovathin catalog # NX45401). Reaction of G with a haloacetyl halide such as either chloroacetyl chloride or bromoacetyl bromide will give [2-(2-chloro-acetylamino)-2-methyl-propyl]-carbamic acid tert-butyl ester or [2(2-bromo-acetylamino)-2-methyl-propyl]-carbamic acid tert-butyl ester (H), respectively (Scheme 6). Treatment of either variant of H with acid followed by base will lead to the formation of 6,6-dimethyl-piperazine-2-one (I). This material can be reduced to 2,2-dimethyl5,5-d₂-piperazine (J) by treatment with lithium aluminium deuteride.

Scheme 6. Exemplary synthesis of intermediate J.

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h₂n

2-<nethyiprapane-1,2diamine

Alternatîvely, J can be prepared from 2-amino-2-methyl-propionic acid. Reaction of 2amino-2-methyl-propionic acid and di-fert-butyl dicarbonate will afford 2-tertbutoxycarbonylamino-2-methyl-propionic acid (K) (Scheme 7). The acid functionality can be converted to the corresponding Weinreb amide by reaction with Ο,Ν-dimethyl-hydroxylamine in the presence of a suitable coupling reagent such as 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3tetramethyl uranium hexafluorophosphate methanaminium (HATU) or 1-ethyl-3-(3dimethylaminopropyl) carbodîimide (EDC) to afford [1-(methoxy-methyl-carbamoyl)-1-methylethyl]-carbamic acid fert-butyl ester (L). Sélective réduction of the Weinreb amide leads to (1,ΙΙΟ dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (M). Reductive amination involving aldéhyde M and amino-acetic acid methyl ester can be used to préparé (2-tertbutoxycarbonylamino-2-methyl-propylamino)-acetic acid methyl ester (N). Treatment of carbamate-ester N with a suitable acid, such as trifluoroacetic acid, wiil lead to the formation of piperazinone I that upon treatment with lithium aluminium deuteride gives piperazine J.

Scheme 7. Alternative exemplary synthesis of intermediate J.

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OMe

L

M

2-amino-2-methyl-

Using J instead of 2,2-dimethyl-piperazine as described for the conversion of E to Compounds (II) and (IV) will lead to Compounds (VI) and Compound (VII), respectively.

Similarly, using E' and J instead of 2,2-dimethyl-piperazine and E will lead to Compound (III) and Compound (V).

In another aspect, the invention provides a process for the préparation of compound

BINAP]Rh(l)BF₄.

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

In some embodiments, racemic trans-1 -(6-chloro-3-phenyl(d_s)-indan-1-yl)-1(d₃), 2, 2trimethyl-piperazine is generated from the corresponding succinate sait thereof.

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In some embodiments, racemic trans-1 -(6-chloro-3-phenyl(d_s)-indan-1-yl)-1(i/3), 2, 2trimethyl-piperazine succinate is generated from the maleate sait of racemic trans-1-(6-chloro3-phenyl(d₅)-indan-1 -yl)-3,3-dimethyl-piperazine.

In some embodiments, acetophenone-cfe is converted to an enol ether. In some embodiments, the enol ether is a silyl enol ether. In some embodiments, the enol ether of acetophenone-d₅ is converted to the corresponding vinyl boronate. In some embodiments, the enol ether of acetophenone-cfe is treated with bis(pinacolato)diboron. In some embodiments, the vinyl boronate is treated with 2-halo-5-chlorobenzaldehyde.

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

Pharmaceutical compositions

The présent invention further provides pharmaceutical compositions comprising a therapeutically effective amount of the compounds of the présent invention and a pharmaceutically acceptable carrier or diluent.

The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple 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 conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 21^st Edition (University of the Sciences in Philadelphia, ed., Lippincott Williams & Wilkins 2005).. Further exemplary compositions of the compounds of the 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; WO 2005/016900; EP 0 638 073; and J. Med. Chem. 1995, 38, 4380-4392; each herein incorporated by reference in its entirety.

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The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as oral, nasal, topical (including buccal and sublingual), and parentéral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route will dépend on the general condition and âge of the subject to be treated, the nature of the condition to be treated and the active ingrédient.

The daily dose of the compounds of the 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 embodiments, the daily dose is from about 0.1 mg to about 500 mg. In some embodiments, 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 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 parentéral routes such as intravenous, intrathecal, intramuscular and stmilar administration, typical doses are in the order of half the dose employed for oral administration.

The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable sait thereof. Examples of suitable 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-D-cyclodextrin. In some embodiments, the composition comprises hydroxypropyl-D-cyclodextrin in water.

Treatment of Disorders

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The invention also relates to the medical use of compounds of the présent invention, such as for the treatment of a disease in the central nervous System, including psychosis, in particular schizophrenia or other diseases involving psychotic symptoms, such as, e.g., Schizophrenia, Schizophreniform Disorder, Schîzoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder as well other psychotic disorders or diseases that présent with psychotic symptoms, e.g. bipolar disorder, such as mania in bipolar disorder. Compounds and/or compositions of the invention can further be used in treatment of disorders such as those 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; WO 2005/016900; EP 0 638 073; and J. Med. Chem. 1995, 38, 4380-4392; each herein incorporated by reference in its entirety. The invention also relates to the medical use of compounds of the présent invention as combination therapy in conjunction with other therapeutic agents such as those 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; WO 2005/016900; EP 0 638 073; and J. Med. Chem. 1995, 38, 4380-4392; each herein incorporated by reference in its entirety.

It will recognized that one or more features of any embodiments disclosed herein may be combined and/or rearranged within the scope 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 expérimentation, many équivalents to the spécifie embodiments of the invention described herein. Such équivalents are intended to be within the scope of the présent invention.

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

EXAMPLES

Examples are provided below to facilitate a more complété understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to spécifie embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results.

Purification of compounds by chromatography refers to the application of silica gel chromatography using either manual flash chromatography or automated flash

-2716797 chromatography, typîcally performed using eluent gradients from heptanes to ethyl acetate or mixtures of ethyl acetate, triethylamine and methanol.

Description of LCMS Methods.

Compounds (I), (II), (III), (IV), (V), (VI) and (VII) were characterized by LCMS using the following methods (Table 1):

Table 1: Methods for LCMS Analysis

Methods WXV-AB5, WXV-AB10, and WXV-AB30

Equipment	Agllcnt 1100 LCMS System with ELS Détecter
	(method WuXiAB25 Agitent 1200 LCMS System with ELS Dctcctor|
	Pump	G1311A
	Degasser	GI379A
	Well-plate Autosampler	G1367A
	Column Oven	G1316A
	DAD	GI315B
	MSD	G1946C or G1956A [method WuXi AB25 6110]
	ELSD	Ailtech ELSD 800 [method WuXiAB25 Aligent 1200]
Column	YMC ODS-AO [method WuXiAB25 AgilentTC-ClS]
	Particlc size	5 micromcter
	Pore size	12 nm
	Dimension	50 * 2.0 mm ID [method WuXÎAB25 50*2.1 mm ID]
Injection volume	2 microL
Column température	50°C
Flow	0.8 mL/min
Mobile phases	A	0.1% TFA in water
	B	0.05% TFA in acetonîtrîlc
	Total run tinte	4.5 min
	Gradient	linear
UV Détection	Wavelength	254 nm
ELSD Détection	Température:	50°C
	Gas Pressure:	3.2 bar

TinteGradient

WXV-AB05	0 min	95 % A 5% B
	3.5 min	0% A 100% B
	3.55 min	95% A 6% B
WXV-AB10	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% A 30% B
	3.2 min	0% A 100% B
	3.5 min	0%A 100%B
	3.55 min	70% A 30% B
WuXIAB25	0 min	75% A 25% B
	3.4 min	0%A 100% B
	4 min	0%A 100% B
	4.01 min	75% A 25% B
	4.5 min	75% A 25% B

-2816797

Mcthod 131

Equipment Column	Scicx ΛΡΙ150ΕΧ equipped with APPl-sourcc operating in positive Ion mode LC-MS were run on a Sciex API 150EX equipped with APPI-source operating in posi-tive ion mode. The HPLC consisted of Shimadzu LClO-ADvp LC pumps, SPD-M20A PDA detector (operating at 254 nM) and SCL-10A System controller. Autosamplcr was Gilson
Autosamplcr Column Ovcn ELSD Waters Symmetry C-l 8	Gilson 215 Jones Chromatography 7990R Sedere Sedex 85
	Particle size	3.5 micrometer
	Dimension	30 * 4.6 mm ID
Injection volume	10 microL
Column température	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 Détection	Wavelength	254 nin
ELSD Détection	Température:	50°C
	Gas Pressure:	4.4 bar
	Time	Gradient
	0.01 min	17% B in A
	0.27 min	28% B in A
	0.53 min	39% B in A
	0.80 min	50% B in A
	1.07 min	59% B in A
	1.34 min	68% B in A
	l .60 min	78% B in A
	1.87 mîn	86% B in A
	2.14 min	93% B in A
	2.38 min	100% B
	2.40 min	17% B in A
	2.80 min	17% B in A

Description of Chiral HPLC methods

The enantiomeric purity was assayed on a Hewlett Packard 1100 sériés 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 rétention time around 13.6-13.7 min while its enantiomer, 4-((1 S,3R)-6-chloro-3-phenyl-indan-1-yl)-1,2,2trimethyl-piperazine, elutes at 8.5-8.6 min.

Table 2: Methods for Chiral HPLC Analysis

Sample Préparation

1-3 mg/mL in hexane/2-propanol (80/20 v/v)

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Column;	Chiralpak ADH Smicrom 250 x 4.6mm
Column Température (°C):	30
Injection (microL):	5
Détection: Wavelength, Bandwidth( nm);	240, 8
Total run-time	30 min
Flow Rate (mL.mîn‘1):	0.6
Mobile Phase	hexane/2-propanol/diethylamine/propionic acid 90/10/0.2/2

Example 1 Préparation of 4-((1 R.SSj-e-chloro-S-phenyl-indan-l-ylJ-l-methyl-a'j-S^dimethyl-piperazine’butanedioic acid (Compound (l)*butanedioic acid sait).

Scheme 8. Synthesis of Compound (1).

1-{(1fï,3S)-6>Chloro-3-phenyt-lndan-1-yl)- Compound (I) butanedioic acid sait

3,3-dlmathyl-piperazina hydrochloride (Compound (XI) hydrochloride)

1-((1R,3S)-6-Chloro-3-phenyl-indan-1-yl)-3,3-dimethyl-piperazine hydrochloride (11.1 g) was dissolved in a mixture of toluene (74 mL) and water (74 mL). Préparation of 1-((1 R,3S)-6chloro-3-phenyl-indan-1-yl)-3,3-dimethyl-piperazine hydrochloride is disclosed in the patent literature (Dahl, Wohlk Nielsen, Suteu, Robin, Brasen W02006/086984 A1; Bang-Andersen,

Bagesa, Jensen, Svane, Dahl, Howells, Lyngsa, Mow W02005/016901 A1; each herein incorporated by référencé in its entirety). 12.0 M of potassium hydroxide in water (5.38 mL), tetra-N-butylammonium bromide (1.42 g), and ds-iodomethane (Aldrich catalog # 176036; 2.4 mL) were added and the mixture was stirred at room température for 18 hours (Scheme 8). The mixture was filtered through a glass filter into a separatory funnel. The solid on the filter was

-3016797 washed with toluene (50 mL) into the separatory tunnel. The aqueous layer was extracted with toluene (100 mL) and the combined organic layers were washed with concentrated aqueous ammonia (100 mL) and subsequently with water (100 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 solidified the oil. Upon warming to room température 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 ail of the diacid went into solution). The acid suspension was added to the solution of the crude product and additional acetone (50 mL) was added to the butanedioic acid residue and then poured into solution. The mixture was stirred ovemight. Partial précipitation had occurred ovemight, 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 température and stirred for 2 hours.

The mixture was filtered affording 4-((1 R,3S)-6-chloro-3-phenyl-indan-1 -yl)-1-methyl-d3-

2,2-dimethyl-piperazine*butanedioic acid (Compound (l)’butanedioic acid sait; 7.61 g). LC-MS (method 131): RT(UV) 1.57 min; UV/ELS purity 100%/100%; mass observed 358.0. Incorporation of three deuterium atoms >99 %. The proton-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. Ail other signais were singlets in both spectra. Optical purity >95% ee.

Example 2 Alternative method of préparation of 4-((1R,3S)-6-chloro-3-phenyl-indan-1ylj-l-methyl-c/^^-dimethyl-piperazine'butanedioic acid (Compound (l)’butanedioic acid sait)

The free base of 1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3-dimethyl-piperazine was prepared from the corresponding hydrochloride sait by partitioning 23.4 g of the sait between a mixture of water (100 mL), concentrated aqueous potassium hydroxide (40 mL), and toluene (250 mL). The organic layer was washed with a mixture of water (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)-6-chloro-3-phenyl-indan-1-yl)-3,3dimethyl-piperazine (21.0 g) as a colorless oil. This material was dissolved in a mixture of toluene (150 mL) and water (150 mL), before 12.0 M aqueous potassium hydroxide (11.3 mL), tetra-A/-butylammonium bromide (2.98 g), and cG-iodomethane (4.9 mL) were added and mixture was stirred at room température for 18 hours.

-31 16797

Work-up and purification was performed as described above and afforded 4-((1 R,3S)-6chloro-3-phenyl-indan-1 -yl)-1 -methyl-d₃-2,2-dimethyl-piperazine*butanedioic acid (Compound (l)*butanedioic acid sait; 14.34 g; 48.9%).

Example 3 Préparation of 4-((1R,3S)-6-chloro-3-phenyl-d5-indan-1-yl)-1,2,2-trimethylpiperazine (Compound (II)) and 4-((1R,3S)-6-chloro-3-phenyl-d5-indan-1-yl)-1-methyl-d3-2.2dimethyl-piperazine (Compound (IV)).

To a solution of compound A (57 g) in tetrahydrofuran (600 mL) was added triethylamîne (30 mL) dropwise over 30 min. The reaction mixture was kept at room température for 3 hours. The precipitated solid was filtered and the filtrate was concentrated in vacuo. The residue was reprecipitated from diethyl ether to afford compound B (31 g) as a yellow solid. To a solution of compound phenyl-ds-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 triethylamîne (14 mL), then the reaction mixture was kept at room température for 2 hours under N₂. Then compound indenone (19 g) was added, and the resulting mixture was heated to 100 °C for 3 hours. The precipitated 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 of Compound C.

13.4 kg 3-Bromo-6-chloro-indan-1-one (A; for référencés on this material, see: Bogeso EP 35363 A1 19810909 and Kehler, Juhl, Püschl, WO 2008025361 ; each herein incorporated by référencé in ils entirety) was dissolved in tetrahydrofuran (170.8 L), and the solution was cooled to 0-5 °C (Scheme 9). Triethylamîne (9.1 L) was added over 0.5h. The mixture was stirred at 0-5 °C for 5 hours before an additional portion of triethylamîne (2.48 L) was added over 0.5 hour, and stirring was continued for 2 hours. The mixture was filtered, and the filtrate was concentrated to 30 L before n-heptane (102 L) was added. The volume was reduced to 60

-3216797

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 fiitered, and the residual solid was washed with n-heptane (100 L). The combined filtrâtes were concentrated to 30 L and stirred at 0-5 °C for 1 hour. The mixture was centrifuged, and the residual solid was dried to afford 6-chloro-inden-1-one (compound B; 2.42 kg) sufficiently pure for the next step.

2-Methyl-tetrahydrofuran (85 L) and A/,N-dimethyl 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)Cl2-DCM (0.91 kg) was added followed by bromobenzene-ds (9.0 kg) and 2-methyl-tetrahydrofuran (12.2 L). The mixture was heated to 80-85 °C for 3 hours, before the température was reduced to ambient température. The crude mixture was fiitered via kieselguhr and silica gel. The filter-cake was washed with 2-methyltetrahydrofuran (31 L). The combined filtrâtes were concentrated to approximately 25 L while maintaining the température below 35 °C. n-Heptane (52 L) and 7% aqueous NaHCO₃ (31 L) were added, and the mixture was stirred for 0.5 hour. The organic layer was stirred with 7% aqueous NaHCO₃ (31 L) for 0.5 hour. The combined aqueous layers were extracted with nheptane (22 L) over 0.5 hour. The combined organic extracts were washed with 25% aqueous NaCI (50 L) over 0.5 hour. The organic layer was concentrated while maintaining the température below 35°C to afford 4,4,5,5-tetramethyl-2-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-inden-1-one (compound B; 9.09 kg prepared in a similar manner to the one described above), 1,5cyclooctadiene (0.2 L), bis(norbornadiene)rhodium(l) tetrafluoroborate (0.52 kg), triethylamine (5.5 L), 4,4,5,5-tetramethyl-2-d5-phenyl-[1,3,2]dioxaborolane (compound B’; 6.5 kg), and 1,4dioxane (26 L). The mixture was heated to 48-53 °C and stirred at that température for 5 hours. The réaction was quenched by the addition of 2M aqueous HCl (13 kg). Then n-heptane (110 L), methyl terf-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 of methyl fert-butyl ether (30 L) and nheptane (57 L) over 0.3 hour. The combined organic layers were fiitered through silica gel (13 kg). The filter-cake was washed with a 2:1 mixture of n-heptane and methyl terf-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 stirred at 0-5 °C for 3 hours. The mixture was centrifuged, and the residual solid was dried to afford racemic 6-chloro-3-dsphenyl-indan-1-one (compound C; 8.4 kg) sufficiently pure for the next step.

-3316797

Tetrahydrofuran (90 L) was added to a reactor followed by water (10 L) and 6-chloro-3d₅-phenyl-indan-1-one (compound 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 température at -35 - -30 °C. The resulting mixture was stirred at -35 - -30 °C for 5 hours before it was allowed to warm to ambient température. Excess sodium borohydride was quenched by the addition of 2M aqueous HCl (7.6 kg) while maintaining the température below 45 °C. Water (17 L) and methyl ferf-butyl ether (67 L) were added and the mixture was stirred for 0.3 hour. The aq layer was extracted with methyl fert-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 through silica gel (6,4 kg). The filter-cake was washed with methyl fert-butyl ether (20 L). The combined filtrâtes were concentrated to approximately 30 L while maintaining the température below 45 °C. n-Heptane (55 L) was added and the resulting mixture was concentrated to approximately 30 L while maintaining the température below 45 °C. The resulting mixture was stirred at 0-5 °C for 2 hours. The mixture was centrifuged, and the filter-cake was washed with n-heptane (12 L) before it was centrifuged again. The residual solid was dried to afford crude D. 4.87 kg of this material was dissolved in methyl fert-butyl ether (20 L) and dried over Na₂SO4 (2 kg) over 0.25 hour. The mixture was filtered, and the filter-cake was washed with methyl fert-butyl ether (4.4 L). The combined filtrate was concentrated to approximately 20 L while maintaining the température below 45 °C. n-Heptane (32 L) was added and the mixture was to approximately 25 L while maintaining the température below 45 °C. n-Heptane (16 L) was added and the mixture was to approximately 20 L while maintaining the température below 45 °C. The solid was filtered off and dried to afford racemic crs-6-chloro-3-d₅-phenyl-indan-1-ol (compound D; 4.99 kg) sufficiently pure for the next step.

Scheme 10. Synthesis and resolution of Compound E.

OH

E ((1S,3S)-enantlomer)

To a solution of racemic c/s-6-chloro-3-d_s-phenyl-indan-1-ol (compound D; 50 g) in 2isopropoxypropane (200 mL) was added vinyl butyrate (120 mL) and Novozym-435 (15 g). The mixture was kept at ambient température for 2 days. The solid was filtered off. The filtrate was

-3416797 evaporated and purified by chromatography on silica gel to afford (1S,3S)-6-chloro-3-d₅-phenylindan-1-ol (compound E; 13 g) sufficiently pure for the next step.

To a solution of (lS,3S)-6-chloro-3-d5-phenyl-indan-1-ol (compound E; 7 g) in THF (100 mL) was treated with SOCI₂ (6.6 g) at ambient température 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 Na₂SO₄, filtered, and concentrated in vacuo to afford the intermediate chloride (7.5 g). 3.5 g of this material was dissolved in 2-butanone (50 mL) and reacted with 2,2-dimethyl-piperazine (1.7 g) in the presence of K2CO3 (2.7 g) at reflux overnight. The solid was filtered off. The filtrate was concentrated in vacuo and the residue was purified by préparative HPLC on a Shimadzu FRC-10A instrument fitted with a Synergi C18 column (250mm*50mm, 10 microm) using water and acetonitrile (containing 0.1%TFA, v/v) as the eluent to afford 1-((1R,3S)-6-chloro-3-d_s-phenyl-indan-1-yl)-3,3-dimethyl-piperazine (compound F; 2.6 g) sufficiently pure for the next step.

To a solution of 1-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-3,3-dimethyl-piperazine (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 between ethyl acetate and 10% aq NaOH. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford 4-((1R,3S)-6-chloro-3-d5-phenyl-indan-1-yl)-

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 of five deuterium atoms >95 %. The proton-decoupled ¹³C NMR spectrum 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. Ail other signais were singlets in both spectra. Optical purity >95% ee.

To a solution of 1-((1R,3S)-6-chloro-3-d₅-phenyl-îndan-1-yl)-3,3-dimethyl-piperazine (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 acetate and 10% aq NaOH. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford 4-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-1c/3-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 of eight deuterium atoms >94 %. The proton-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 three triplets around 126.1, 127.2, and 128.2 ppm corresponding to -3516797 the deuterated M3 metabolic sites; these signal collapsed to three sînglets in the proton- and deuterium-decoupled ¹³C NMR spectrum. Ail other signais were singlets in both spectra. Optical purity >95% ee.

Example 4: Préparation of 4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethylpiperazine-6,6-d₂ (Compound (III)), 4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2dimethyl-piperazine-6,6-d₂ (Compound (V)), 4-((1R,3S)-6-chloro-3-phenyl-d₅-indan-1-yl)-1methyl-d₃-2,2-dimethyl-piperazine-6,6-d2 (Compound (VI)), and 4-((1R,3S)-6-chloro-3-phenylds-indan-1 -yl)-1,2,2-trimethyl-piperazine-6,6-d₂ (Compound (VII).

2-Amino-2-methyl-propionic acid (50.0 g) was suspended in a mixture of methanol and triethylamîne (9:1,1.2 L) (Scheme 11). 1M aqueous NaOH (450 mL) was added with stirring until ail solid was dissolved. Di-tert-butyl dicarbonate (Boc₂0; 214.0 g) was added, and the mixture was stirred at ambient température ovemight. The organic volatiles were removed in vacuo. EtOAc (500 mL) was added. The organic layer was washed with brine and dried over Na₂SO₄, filtered, then concentrated to afford 2-tert-butoxycarbonylamino-2-methyl-propionic acid (compound K; 90 g) as a white solid which was used directly in next step directly.

Scheme 11. Synthesis of intermediate J.

2-amlno-2-methytpropionic acid

K

A mixture of afford 2-tert-butoxycarbonylamino-2-methyl-propionic acid (compound K;

60.0 g) and 1-ethyl-3(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCI; 86.4 g) in dichloromethane (900 mL) was stirred at ambient température, then N,O-dimethyl

-3616797 hydroxylamine hydrochlorïde (35.3 g) and triethylamine (150 mL) were added. The resulting mixture was stirred at ambient température for 3 days. Water was added and most of volatiles were removed in vacuo. The residue was partitioned between DCM and aqueous NaHCO₃. The organic layer was washed with 3M aqueous HCl, subsequently with brine before it was dried over Na₂SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give [1-(methoxy-methyl-carbamoyl)-1-methyl-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-(methoxy-methylcarbamoyl)-1-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 température for about 5 min. Excess LîAIH₄ was quenched with a solution of potassium hydrogen sulfate in water. The resulting mixture was partitioned between EtOAc and 3M aqueous HCl. The organic layer was washed with sat. aqueous NaHCO3, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford (1,1dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (compound M; 29 g) sufficiently pure for the next step.

Amino-acetic acid methyl ester hydrochloride (80.6 g) and Et₃N (160 mL) were dissolved in DCM (1000 mL) and stirred for 15 min to liberale the amine from the sait. Then a solution of 1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (compound M; 29.0 g) in DCM (600 mL) was added. The resulting mixture was stirred for 0.5 hour at ambient température before NaBH(OAc)a (102 g) was added and the mixture was stirred at ambient température overnight. Sat. aqueous NaHCO₃ was added. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford (2-tert-butoxycarbonylamino-2-methylpropylamino)-acetic acid methyl ester (compound N; 26.5 g) as white solid which was used directly in the next step.

A mixture of (2-tert-butoxycarbonylamino-2-methyl-propylamino)-acetic acid methyl ester (compound N; 26.5 g) in DCM (800 mL) was stirred at ambient température, TFA (180 mL) was added drop-wise. The mixture was stirred at 30-40 °C for 5h before it was concentrated in vacuo. The residue was partitioned between dissolved toluene and water. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residual solid was dissolved in a mixture of éthanol (400 mL) and methanol (90 mL). K₂CO₃ (207 g) was added and the mixture was refluxed overnight. The mixture was cooled to room température. DCM (2500 mL) was added, and the mixture was stirred for 1 hour at ambient température. The solid was filtered off, and the filtrate was concentrated in vacuo to afford 6,6-dimethyl-piperazin-2-one (Compound I; 5.85 g) as a white solid sufficiently pure for the next step.

-3716797

A solution of 6,6-dimethyl-piperazin-2-one (Compound I; 3.6 g) in THF (20 mL) was stirred at 0 °C. Lithium aluminum deuteride (LiAID₄; 3.6 g) was added then the mixture was refluxed overnight. The mixture was cooled to ambient température and Na₂SO₄ was added. The mixture was stirred for 0,5h before most of the volatiles were removed in vacuo. The residue was suspended in a saturated solution of HCl in EtOAc at ambient température for 0.5 hour. The solid was filtered off and dried to afford to give 2,2-d₂-6,6-dimethyl-piperazine as the bis-hydrochloride sait (Compound J-2HCI; 5.3 g) sufficiently pure for the next step.

To a solution of compound E’ (5 g) in THF (50 mL) was added SOCI₂ (4.7 g), and the resulting mixture was stirred overnight at ambient température (Scheme 12). The mixture was poured înto îce-water and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the corresponding chloride (5.3 g) which was used directly in the next step. 3.3 g of this 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 of K_ZCO₃ (8.28 g) at reflux overnight. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by préparative HPLC on a Shimadzu FRC-10A instrument fitted with a Synergy C18 column (250mm*50mm, 10 mlcrom) using water and acetonitrile (containing 0.1%TFA, v/v) as the eluents to afford 1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3d₂-5,5-dimethyl-piperazine (Compound O; 1.7 g).

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

E (( 1 S.3S)*enanUomer)

O (( 1R,3SJ-onantkxnef )

Compound (III)

Compound (V)

A solution of 1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3-d2-5,5-dimethyl-piperazine (Compound O; 0.5 g) in HCHO/HCOOH (1 mL/1 mL) was refluxed overnight. The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 10% aqueous NaOH. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford 4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-

1,2,2-trimethyl-piperazine-6,6-d₂ (Compound (III); 0.33 g). LC-MS (method WXV-AB30): RT(UV) 1.42 min; UV/ELS purity 100%/100%; mass observed 357.2. Incorporation of two

-3816797 deuterium atoms >97 %. The proton-decoupled 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 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. Ali other signais were singlets in both spectra. Optical purity >95% ee.

A solution of 1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine (Compound O; 0.7 g) in DCDO/DCOOD (1 mL/1 mL) was refluxed overnight. The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 10% aqueous NaOH. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford 4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1methyl-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 of five deuterium atoms >95 %. The proton-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 M1 metabolic site; this signal collapsed to a singlet in the proton- and deuterium-decoupled ¹³C NMR spectrum. Ali other signais were singlets in both spectra. Optical purity >95% ee.

To a solution of (1S,3S)-6-chloro-3-d₅-phenyl-indan-1-ol (compound E; 7 g) in THF (100 mL) was treated with SOCI₂ (6.6 g) at ambient température overnight (Scheme 13). 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 Na₂SO₄, filtered, and concentrated in vacuo to afford the intermediate chloride (7.5 g).

Scheme 13. Synthesis of Compound (VI) and Compound (VII).

-3916797

E ((1S,3S)-ônarrti orner)

P ((lR.3S)-enantiôfner)

Compound (VI)

Compound (Vil)

1.8 g of this material was dissolved in 2-butanone (30 mL) and reacted with 2,2-d₂-6,6dimethyl-piperazine (Compound J; 1.4 g) in the presence of K₂CO₃ (5.5 g) at reflux overnight. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by préparative HPLC on a Shimadzu FRC-10A 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-((1 R,3S)-6-Chloro-3-d₅-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine (Compound P; 1.7 g).

A solution of 1-((1 R,3S)-6-Chloro-3-d5-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine (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 Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford 4-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-1c/₃-methyl-2₁2-dimethyl-piperazine-6₁6-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 of ten 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 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 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. Ail other signais were singlets in both spectra. Optical purity >95% ee.

A solution of 1-{(1R,3S)-6-chloro-3-d5-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine (Compound P; 0.7 g) in HCHO/HCOOH (1 mL/1 mL) was refluxed overnight. The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 10% aqueous NaOH. The -4016797 organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford 4-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-1methyl-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 of seven deuterium atoms >93 %=. The proton-decoupled 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 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. Ail other signais were singlets in both spectra. Optical purity >95% ee.

Example 5: Description of NMR détermination of the position(s) bearinq deuterium rather than hydrogen

NMR spectra were recorded on a Bruker 600-Avance-lll spectrometer equipped with a 5 mm TCI cryoprobe operating at 150.91 MHz for ¹³C. The solvent CDCI₃ was used as internai reference for the proton-decoupled experiments, while the proton- and inverse gated deuteriumdecoupled spectra were recorded using gated lock. Difference(s) between the two spectra for the compounds of the invention determine(s) the position(s) of the deuterium atoms. When combining this information summarized in the table below (Table 3) with the electrospray mass spectrometry data that determined degree of deutération, the structures of the compounds of the invention can be assigned unambiguously.

Table 3: Carbon NMR data for compounds.

M3 (phenyl group @

-126.1 ppm, -127.2

M2 (methyl group @ -36.4 ppm)	M1 (methylene group @ -49.5 ppm)	(2C), and -128.2 (2C))
		13C		13c		13c
		NMR		NMR		NMR
		proton-		proton-		proton-
		and	13C	and	13c	and
		deuteri	NMR	deuteri	NMR	deuteri
	13C NMR	um-	proton-	um-	proton-	um-
Cm	proton-	decoupl	decoupl	decoupl	decoupl	decoupl
pd.	decoupled	ed	ed	ed	ed	ed

-41 16797

(i)	heptet	singlet	singlet	singlet	singlets	singlets
(II)	singlet	singlet	singlet	singlet	3 triplets	3 singlets
(III)	singlet	singlet	quintet	singlet	3 singlets	3 singlets
(IV)	heptet	singlet	singlet	singlet	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 signais that ‘change’ as a conséquence of the presence of D rather than H in the compounds of the invention are included in the table.

Relevant régions of the ^{* * * 5 * * * * 10 * * 13 * 15}C proton-decoupled (lower spectrum) and ¹³C proton- and deuterium-decoupled (upper spectrum) NMR spectra of Compound (II) and Compound (V) are shown in Figure 3 as représentative examples. Selected régions of the proton-decoupled and proton- and deuterium-decoupled ¹³C NMR spectra of Compound (II) [Fig. 3A] and Compound (V) [Fig. 3B].

Example 6: Description of the electrospray mass spectrometry to détermine degree of deutération

Instrumentation; Mass spectra of acidic, aqueous solutions of the compounds were obtained on a Hewlett Packard quadrupole mass spectrometer model 1100 LC-MSD. Liquid chromatography was performed on an Agilent 1100 HPLC-system coupled to the mass spectrometer.

Experimental: Solutions of the samples were made by dissolving approx. 2 mg substance in 2 mL methanol + 18 mL 10 mM ammonium formate pH 3.0. Subsequently the solutions were diluted 10O-fold prior to analysis. In order to get a “clean peak, the samples were chromatographed using a Waters X-bridge C18, 3.5 microm (150x2.1mm) column, and 0.1% trifluoroacetic acid / acetonitrile 50/50 as mobile phase. This procedure gave one peak of

-4216797 the compound of interest eluting at ca. 3.6 min, containing both the deuterated compounds of the invension as well as small quantities of deuterium-deficient species. The mass spectra obtained from these peaks were used to evaluate the spéciation of the target molécules. The results were analyzed in percent of the total amount of substance, adding up to 100%. The actual potency of the compounds were not analyzed, merely the relative content of the deuterium déficient species.

As a représentative example, the mass spectrum of Compound (IV) is shown in Figure 4. The isotopic pattern of the protonated Compound (V) [M+H ]⁺ with mass 363.1u (362.1 u + 1.0u) and the isotope ions 363.1u, 364.1u, 365.1u and 366.1u was in the ratio 100: 25.3 : 34.9 : 7.9; calculation for C₂qH₂₂N₂CID₈ gives the ratio 100: 25.2: 34.9: 8.3. Furthemnore, D₇-analogs and the D₃-analogs were observed at masses 362.1 u and 358.1 u, respectively. The signais at 364u, 365u and 366u are primarily due to protonated molécules containing ¹³C and/or ³⁷CI isotopes instead of ¹²C and ³⁵CI (due to the natural distribution). This data shows that the incorporation of eight deuterium atoms was greater than 94 %.

Example 7: Experimental Binding Assays

Description of human D? bindinq assay

The assay was performed as a SPA-based competition-binding in a 50 mM Tris pH 7.4 assay buffer containing 120 mM NaCI, 5 mM KCI, 4 mM MgCI₂, 1.5 mM CaCI₂, 1 mM EDTA.

1.5 nM ³H-raclopride (Perkin Elmer, NET 975) was mixed with test compound before addition of 20 microg of a homogenised human D₂ receptor membrane-preparation and 0,25 mg SPA beads (WGA RPNQ 0001, Amersham) in a total volume of 90 microL. The assay plates were under agitation incubated for 60 minutes at room température and subsequently counted in a scintillation counter (TriLux, Wallac). The total binding, which comprised approximately 15 % of added radioligand, was defined using assay buffer, whereas the nonspecific binding was defined in the presence of 10 microM haloperidol. The non-specific binding constituted approximately 10% of the total binding.

Data points were expressed in percent of the spécifie binding of ³H-Raclopride and the IC50 values (concentration causing 50 percent inhibition of ³H-raclopride spécifie binding) were determined by non-linear régression analysis using a sigmoidal variable slope curve fitting. The dissociation constant (Kf) was calculated from the Cheng Prusoff équation (Kj = ICso/(1 +(I_/KD)), where the concentration of free radioligand L is approximated to the concentration of added ³Hraclopride in the assay. The K_D of ³H-raclopride was determined to 1.5 nM from two independent saturation assays each performed with triplicate déterminations.

Description of human Di bindinq assay

-43 16797

The assay was performed as a SPA-based competition-binding in a 50 mM Tris pH 7.4 assay buffer containing 120 mM NaCI, 5 mM KCI, 4 mM MgCI₂, 1,5 mM CaCI₂, 1 mM EDTA. Approximately 1 nM ³H-SCH23390 (Perkin Elmer, NET 930) was mixed with test compound before addition of 2,5 microg of a homogenized human D, receptor membrane-preparation and 0,25 mg SPA beads (WGA RPNQ 0001, Amersham) in a total volume of 60 microL.

The assay plates were under agitation incubated for 60 minutes at room température before the plates were centrifuged and subsequently counted in a scintillation counter(TriLux, Wallac). The total binding, which comprised approximately 15 % of added radioligand, was defined using assay buffer whereas the non-specific binding was defined in the presence of 10 microM haloperidol.

Data points were expressed in percent of the spécifie binding and the IC50 values (concentration causing 50 percent inhibition of spécifie binding) and were determined by nonlinear régression analysis using a sïgmoidal variable slope curve fitting. The dissociation constant (K) was calculated from the Cheng Prusoff équation (K| = IC5q/(1 +(L/K₀)), where the concentration of free radioligand L is approximated to the concentration of added radio-ligand in the assay.

Description of human 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 demonstrating central effects of the compound. By in vivo binding, the compound’s in vivo affinity for D₂ receptors was assessed and occupancy of 60 % of the target was observed. Occupancy of D₂ receptors is closely linked to antipsychotic effects in animal models and in patients.

Description of in vivo binding to D? receptors in rat brain

In vivo binding was carried out according to Andersen et al (Eur J Pharmacol, (1987) 144:1-6; herein incorporated by référencé in its entirety) with a few modifications (Kapur S. et al, J Pharm Exp Ther, 2003, 305, 625 - 631; herein incorporated by référencé in its entirety). Briefly, 6 rats (male Wistar, 180-200 g) were treated with 20 mg/kg test compound subeutaneous 30 minutes before receiving 9.4 micro Ci [³H]-raclopride intravenously via the tail vein.

minutes after the injection of the radio ligand the animais were killed by cervical dislocation, the brain quickly removed and striatum and cerebellum dissected out and homogenized in 5 mL (cerebellum in 20 mL) ice-cold buffer (50 mM K3PO4, pH 7.4). 1.0 mL of the homogenate was filtered through 0.1% PEI - soaked Whatman GF/C filters. This was completed within 60 seconds subséquent to the décapitation. Filters were washed 2 times with -4416797 mL ice-cold buffer and counted in a scintillation counter. A group of vehicle treated animais was used to détermine [³H]-raclopride total binding in striatum and non-specific binding in cerebellum. The homogenate was measured for protein content by the BCA protein détermination assay (Smith P.K. et al (1985) Anal. Biochem., 150: 6-85; herein incorporated by référencé in its entirety).

Example 8: Investigation of the metabolism of 4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-

1,2,2-trimethyl-piperazine (Compound (X)) and 4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1methyl-cG-2,2-dimethyl-piperazine (Compound (I))

Cryopreserved dog (male Beagle dog) hépatocytes (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 concentration 0.1 or 1 microM of 4-((1R,3S)-6-chloro-3-pheny1-indan-1-yl)-

1.2.2- trimethyl-piperazine (Compound (X)) or4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1methyl-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 samples were then removed for LC-MS analysis of the desmethyl métabolite (Compound (XI)). Data were expressed as MS area relative to an internai standard.

The results (Figure 5 and Figure 6) show that the amount of the desmethyl métabolite (Compound (XI)) produced in cryopreserved dog hépatocytes 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 of Compounds.

4-((1 R,3S)-6-chloro-3-phenyl-indan-1 -yl)-1 -d₃-methyl-2,2-dimethyl-piperazine (Compound (I)):

4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-d₃-methyl-2,2-dimethyl-piperazine (Compound (I)) was tested in three in vitro assays for dopamine D,, dopamine D₂ and serotonin 5-HT_2A affinity.

The experiments were carried out as in the section Binding assays. The experimental results showed the following affinities for 4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-

2.2- dimethyl-piperazine:

D_t: Kt log mean = 7.5 nM (pKi 0.88 +/- 0.15)

D₂ : Ki log mean = 34 nM (pKi 1.54 +/- 0.11)

5HT_2A: IC50 = 1.14 nM

-4516797

These binding affinities indicate that Compound (I) has biological activity likely to exert a nti psychotic effect

Pharmacological testing of Compound (II) and Compound (IV)

The experiments were carried out as described in the section “Binding assays. The experimental results for the two compounds are provided below,

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

Compound (IV):

D,: 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):

D,: 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 affinities indicate that Compound (II) and (IV) hâve biological activity likely 15 to exert antipsychotic effect.

Compound (II) and (IV) were also tested in an in vivo set up demonstrating central effects of the compound. By in vivo binding, the compound’s in vivo affinity for D₂ receptors was assessed and occupancy of 70% (Compound (IV)) and 75% (Compound (II)) of the target was observed. Occupancy of D₂ receptors is closely linked to antipsychotic effects in animal models 20 and in patients.

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

Table 4. Binding of Compounds to D1, D2 and 5-HT2a.

Cmpd.	alternative human Di receptor binding (K|)	alternative human D2
receptor binding (Ki)	human 5-HT^ (IC50)
O)	0.10 nM	7.6 nM	0.37 nM; 1.14 nM*
(II)	0.20 nM	6.8 nM	1.1 nM
(III)	0.36 nM	7.6 nM	1.1 nM
(IV)	0.05 nM	10 nM	0.25 nM
(V)	0.10 nM	4.8 nM	0.61 nM

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(VI)	0.10 nM	3.7 nM	0.24 nM
(VII)	0.14 nM	5.2 nM	0.33 nM
(X)	0.22 nM	7 nM	0.79 nM
* Compound (I) was tested twice in this assay.

Example 10: Metabolism Investigations in pooled human liver microsomes (HLM)

Pooled human liver microsomes (50 donors, from Xenotech) were incubated with 1 microM or 10 microM of compound at 37 °C. The incubation mixture contained 50 mM Tris-HCI,

154 mM KCI, 5 mM MgCI₂ and a NADPH regenerating system (1 mM NADP⁺, 5 mM isocitric acid, 1 unit/mL isocitric dehydrogenase, from Sigma-Aldrich). The protein concentration was 0.2 mg/mL and the final volume was 0.5 mL. Following a 10 minute pre-incubation, the reaction was initiated by adding Compound. After 0,15, 30, 60, 90,120 and 180 minutes, the reactions were terminated by transferring the subcellular fraction to 0.5 mL of stopping reagent containing 10 internai standard. The incubations were carried out in triplicate. The samples were centrifuged at 4000 g (4 °C, 15 min) and the supernatants were analysed by HPLC-MS/MS. Data were expressed as MS area relative to an internai standard.

The results are shown as the mean of triplicate déterminations ± SD. Figure 7 and Figure 8 show that the amount of the desmethyl métabolite 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 concentration 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 métabolites of compounds (II), (IV) and (X) are compounds (XX) and (XI), respectively (see

Figure 13).

Investigations usina 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 Tris-HCI, 154 mM KCI, 5 mM MgCI₂ and a 25 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. Following 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 terminated by transferring the subcellular fraction to 0.5 mL of

-4716797 stopping reagent containing internai standard. The incubations were carried out in triplicate. The samples were centrifuged at 4000 g (4 °C, 15 minutes) and the supematants were analyzed by HPLC-MS/MS. Data were expressed as MS area relative to an internai standard.

The results (Figure 14 and Figure 15) show that the amount of the desmethyl métabolite produced following incubation with recombinant human liver CYP2C19 enzymes is lower from the deuterated forms (Compound (II) and Compound (IV)) than from the non-deuterated 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 of the desmethyl métabolite 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 Hvperactivitv

Compound (IV) dose-dependently reverses PCP-induced hyperactivity in mice, indicative of antipsychotic 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. Locomotor activity was measured for 60 minutes as number of beam breaks (counts). Eîght to 16 male mice were used in each group. ## indicates P <0.01 versus Vehicle-PCP (One-way analysis of variance [ANOVA] followed by Bonferroni post-hoc test). PCP is blocking NMDA receptors and as such is used to model the hypoglutamatergic state related to schizophrenia. PCP produces behavioural effects in animais reminiscent of positive, négative, and cognitive symptoms of schizophrenia patients (Jentsch, J.D. and Roth, R. H. Neuropsychopharmacology 1999; 20: 201-225; herein incorporated by reference in its entirety). PCP-induced hyperactivity is commonly used as an assay for évaluation of antipsychotic compounds (Jackson, D.M. et al„ Pharmacol Biochem Behav. 1994; 48: 465-471; herein incorporated by reference in its entirety).

Catalepsv

Catalepsy is thought to reflect drug-induced suppression of the ability to initiate a behavioral response. The catalepsy test in rats is a common and widely used preclinical screening test for the EPS liability of potentially antipsychotic drugs. Although catalepsy is usually assessed following acute drug administration, the test has proven to be a reliable

-4816797 predictor for the propensity of an antipsychotic drug to induce EPS (that is, pseudo parkinsonism, dystonia) in humans (Elliott, P.J. et al, J. Neural. Transm. Park. Dîs.Dement. Sect. 1990; 2: 79-89; herein incorporated by reference in its entirety).

Compound (IV) dose-dependently induced catalepsy in rats suggestive of EPS liability. The minimal effective dose inducing catalepsy was 10 mg/kg (Figure 17). Compound (IV) tartrate was administered s.c. 30 minutes before the test. Eight male Sprague 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 participants received daily doses of 3 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 measure the exposure of both compounds and their demethylated métabolites, 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 métabolites 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 enantioselective synthesis of ketone intermediate.

This example discloses the synthesis of (S)-6-chloro-3-phenyl(d_s)-indan-1-one, Compound (XV), and (S)-6-chloro-3-phenyl-indan-1-one, Compound (XVIII).

(S)-6-chloro-3-phenyl(d_s)-indan-1-one, Compound (XV), has proven to be a valuable building block in the synthesis of deuterated variants of Compound (X) where the free phenyl group is deuterated.

General 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 % solution of phosphomolybdenic acid (PMA) in éthanol or basic aqueous potassium permanganate (KMnO₄) and then heating. Column chromatography was carried out using Merck C60 (40-63 pm, 230-240 mesh) silica gel.

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NMR spectra were recorded at 500 or 600 MHz (¹H NMR), and calibrated to the residual solvent peak. The following abbreviations are used for NMR data: s, singlet; d, doublet; t, triplet; m, multiplet. Coupling constants are rounded to nearest 0.5 Hz. Enantiomeric excess was determined by chiral HPLC.

LC-MS method:

Acquity UPLC BEH C18 1.7 pm column; 2.1 x 50 mm operating at 60°C with flow 1.2 mL/min of a binary gradient consisting of water + 0.1 % fomnic acid (A) and acetonitrile + 5% water + 0.1 % fomnic acid (B).

Chiral HPLC method:

Phenomenex Lux 5p Cellulose-2 column; 250 x 4.6 mm operating at 30°C with flow 0.6 mL/min of n-hexane:isopropanol:diethylamine, 90:10:0.1.

Synthesis of (S)-6-chloro-3-phenyl(d₅)-indan-1-one (Compound (XV)) (Scheme 14)

Scheme 14. Synthesis of Compound (XV)

Tf₂O DIPEA

DCM, rt

Step A: 82%

(XII)

Acetone,

Step C 96% 96% ee (98:

mol

(xv)

1-phenyl(d₅)-vinyl trifluoromethanesulfonate (XII):

To a solution of acetophenone-d₅ (1.56 g, 12.5 mmol) in CH₂CI₂ (25.0 mL) was added trifluoromethanesulfonic anhydride (2.52 mL, 15.0 mmol) at room température. Then N,Ndiisopropylethylamine (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 température, and it was stirred for 1.5 h. Trifluoromethanesulfonic anhydride (0.63 mL, 3.74

-5016797 mmol) was added followed by N,/V-diisopropylethylamine (1.09 mL, 6.24 mmol). The reaction mixture was stirred for 2 hours at room température. Toluene (25 mL) and silica gel (5 g) was added. The mixture was concentrated in vacuo, and the resulting 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 without further purification.

¹H NMR (600 MHz, CDCI₃) δ_Η 5.38 (d, 1H, J = 4.0 Hz), 5.62 (d, 1H, J = 4.0 Hz).

5-chloro-2-(1-phenyl(d₅)-vinyl)benzaldehyde (XIV) (Takagi, J.; Takahashi, K.; Ishîyama, T.; Miyaura, N. J. Am. Chem. Soc. 2002, 124, 8001-8006; Simeone, J. P.; Sowa, J. R. Jr. Tetrahedron 2007, 63,12646-12654; each herein incorporated by référencé in its entirety).

To a solution of Compound (XII) (3.11 g, 10.3 mmol, purity (NMR): approx. 85%) in toluene was added triphenylphosphine (108 mg, 0.685 mmol), bis(pinacolato)diboron (2.61 g, 10.3 mmol), bis(triphenylphosphine)palladium(ll) 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 température, and éthanol (10 mL) and water (5 mL) was added, followed by tetrakis(triphenylphosphine)palladïum(0) (495 mg, 0.428 mmol), potassium carbonate (4.73 g, 34.2 mmol) and 2-bromo-5-chlorobenzaldehyde (1.88 g, 8.56 mmol). The reaction mixture was stirred at 80°C for 16 hours. The mixture was cooled to room température, and partitioned between 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 MgSOi, filtered and evaporated to dryness in vacuo. The residue was subjected to purification by column chromatography eluting with 80:1 n-heptane:EtOAc mixture to afford Compound (XIV) (1.66 g, 74%) as an orange oil.

¹H NMR (600 MHz, CDCI3) δΗ 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, CDCI3) 5_C 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 cale, for C₁₅H₇D₅CIO [M+H]* 248.1, found 248.1.

(S)-6-Chloro-3-phenyl(£fs)-indan-1-one (XV) (Kundu, K.; McCullagh, J. V.; Morehead, A. T. Jr. J. Am. Chem. Soc. 2005, 127,16042-16043; herein incorporated by référencé in its entirety).

Hydrogen was bubbled through a N₂-flushed solution of ((R)-2,2'bis(diphenylphosphino)-1,T-binaphthyl)(norbomadiene)rhodium(l) tetrafluoroborate (37 mg,

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0.0404 mmol) in acetone (7.5 mL) for 10 min at room température, 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 température. The reaction mixture was stirred for 24 hours at room température. The reaction mixture was mixed with silica gel and evaporated to dryness in vacuo. The obtained material 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, CDCI3) δΗ 2.72 (dd, 1H,7 = 4.0, 19.5 Hz), 3.27 (dd, 1 H, 7 = 8.0, 19.5 Hz), 4.55 (dd, 1 H, 7 = 4.0, 8.0 Hz), 7.21 (d, 1H ; 7 = 8.0 Hz), 7.52 (dd, 1 H, 7= 2.0, 8.0 Hz), 7.77 (d, 1 H, 7 = 2.0 Hz); ¹³C NMR (125 MHz, CDCI3) 5_C 44.0, 47.2,123.2, 126.8 (t, 7 = 24.0 Hz), 127.3 (t, 7= 24.0 Hz), 128.7 (t, 7= 24.0 Hz), 134.4, 135.1, 138.2, 142.9, 156.0, 206.4; LCMS (APPI): m/e cale, for C₁₅H₇D₅CIO [M+H]* 248.1, found 247.6.

Synthesis of (S)-6-chloro-3-phenyl-indan-1-one (XVIII) (Scheme 15)

Scheme 15. Synthesis of Compound (XVIII)

NaQH _]

MeOH-H_zO. rt

Stop A: 46%

CK
		'‘OH (xvi)

Overall yield: 34%

Tf₂0

D1PEA ----►

DCM, 0’C

Stop B: 97% (E)-1-(5-chloro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (XVI):

To an ice-cooled solution of sodium hydroxide (2.34 g, 58.6 mmol) in water (17.0 mL) was added benzaldehyde (0.746g, 7.03 mmol) and then a solution of 5-chloro-2hydroxyacetophenone (1.00 g, 5.86 mmol) in methanol (17.0 mL). The reaction mixture was allowed to warm to room température, and it was stirred for 24 hours. The bulk of the organic solvent was removed by évaporation in vacuo. The aqueous residue was extracted with EtOAc (3 x 30 mL). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over MgSO₄, filtered and evaporated to dryness in vacuo. The residue was dissolved in a minimum volume of CH₂CI₂, and n-pentane was added which resulted in précipitation. The

-5216797 obtained suspension was filtered and the precipitate was washed with little cold pentane, and dried in vacuo to afford Compound (XVI) (695 mg, 46%) as an orange solid.

¹H NMR (500 MHz, CDCI3) δΗ 6.22 (d, 1 H, J = 9.0 Hz), 6.80 (dd, 1 H, 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, CDCI3) 5_C 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-2-((E)-(3-phenyl-acryloyl))-phenyl ester (XVII):

To a solution of Compound (XVI) (517 mg, 2.00 mmol) in CH₂CI₂ (10.0 mL) was added N,N-diisopropylethylamine (697 pL, 4.00 mmol). Trifluoromethanesulfonic anhydride (437 pL, 2.60 mmol) was added dropwise at 0°C. The reaction mixture was stirred for 45 min at 0°C. Sat. aq. NH4CI (5 mL) and water (10 mL) was added, and the mixture was stirred for 5 minutes. The organic phase was separated, and the aqueous phase was extracted with CH₂CI₂ (10 mL). The combined extracts were dried over MgSO₄, filtered and evaporated to dryness in vacuo. The residue was purified by column chromatography eluting with 4:1 n-heptane:EtOAc to yield (XVII) (757 mg, 97%) as an oil.

¹H NMR (500 MHz, CDCI3) δΗ 7.16 (d, 1H, J = 16.0 Hz), 7.34 (d, 1H, J = 9.0 Hz), 7.407.47 (m, 3H), 7.57 (dd, 1H, J= 2.5, 9.0 Hz), 7.60-7.62 (m, 2H), 7.69 (d, 1H, 16.0 Hz), 7.72 (d, 1H, J = 2.5 Hz); ¹³C NMR (125 MHz, CDCI3) 5_C 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)-6-Chloro-3-phenyl-indan-1-one (XVIII) (Minatti, A.; Zheng, X.; Buchwald, S. L. J. Org. Chem. 2007, 72, 9253-9258; herein incorporated by reference in its entirety).

To a solution of Compound (XVII) (195 mg, 0.500 mmol) in DMF (2.0 mL) was added proton-sponge (214 mg, 1.00 mmol), palladium acetate (6 mg, 0.025 mmol) and (R)-3,5XylMeOBIPHEP (35 mg, 0.05 mmol) at rt. The reaction mixture was stirred at 85°C for 45 h. The mixture was cooled to rt, and diluted with TBME (15 mL). The mixture was washed three times with water (3 x 20 mL), and the organic phase was dried over MgSO₄, 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).

¹H NMR (600 MHz, CDCI3) δΗ 2.71 (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 Hz), 7.25 (t, 1H, J - 7.5 Hz), 7.31 (t, 2H, J - 7.5 Hz), 7.50 (dd, 1 H, J = 2.0, 8.0 Hz), 7.75 (d, 2H, J = 2.0 Hz); ¹³C NMR (150 MHz, CDCI3) 5_C 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 of Compound (XVIII) by Reprecipitation

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Compound (XVII) (940 mg, 3.87 mmol, 96% ee) was dissolved in a minimum volume of boiling éthanol (99% v/v). The resulting solution was allowed to cool slowly to rt 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 of Compound (XVIII) could be obtained by cooling the filtrate in the freezer (-8°C) to yield Compound (XVIII) (80 mg, 98.6% ee, 9%).

Analytical data (NMR and LC-MS) for Compound (XVIII) were the same as those reported above.

Example 14: Large scale production of Compound (IV)

The following process was developed for the large scale production of the tartrate sait of Compound (IV)

Scheme 16: Synthesis of rac-trans-1-(6-Chloro-3-phenyl(d_s)-indan-1-yl)-3,3-dimethylpîperazine maleate

Mw 249.75 C,_sH_êCIOD_s

cls racemate (+15% trans) Mw 268.20

C,_SH,CI,D_S

KaCO₃, MIBK

2. malelc acid

(XXV) maleate

Mw 462.00(345.93+116.07) trans racemate (+6% cls)

Procedure:

2.01 kg (16.9 mol) thionylchloride and 7.2 kg tetrahydrofuran are mixed and the reaction is cooled to 10-15 °C a solution of 2.76 kg (11.1 mol) (XXII) in 7.2 kg THF is slowly added and after completion 5.9 kg tetrahydrofuran is added the reaction is stirred at 15 °C for approximately 90 hours

16.7 kg water is cooled to 11 °C and added slowly to the reaction, afterwards 7.8 kg 27.7% aqueous sodium hydroxide is added slowly, followed by 10 kg ethylacetate the mixture is stirred for 20-40 minutes the phases are separated and the organic phase is reduced to a volume of approximately 6L kg methyl isobutylketone is added and the volume is reduced to approximately 8 L

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1.58 kg (11.4 mol) potassium carbonate, 1.69 kg (14.8 mol) 2,2-dimethylpiperazin and 13.6 kg methyl isobutyl ketone are added the reaction is stirred 35 hours at 90-95 °C after cooling to room température 11 kg water is added and the mixture is stirred for 30 - 60 minutes the phases are separated. 13.7 kg water is added to the organic phase and the mixture is stirred slowly for 30 - 60 minutes the phases are separated and the organic phase is blank filtered kg methyl isobutyl ketone, 7.8 kg water and 5.9 kg 36% aqueous hydrogen chloride are added and the mixture is stirred at 50 °C for 30 - 60 minutes the phases are separated. 8 kg methyl isobutyl ketone is added to the water phase and the mixture is cooled to 10-15 °C a mixture of 3.5 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 °C for 60 - 90 minutes the phases are separated and the organic phase is washed with 10.5 kg water the organic phase is reduced to 8 L

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 °C after cooling to 10-15 °C the precipitate is filtered off and washed with 10 kg methyl isobutyl ketone the solid is dried in a vacuum oven at 50 °C for approximately 20 hours to give 3.47 kg (68% yield) of (XXV) maleate.

NMR data for (XXV) maleate:

H-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).

Scheme 17: Synthesis of rac-trans-1-(6-chloro-3-phenyi(d₅)-indan-1-yl)-1(d₃), 2,2trimethyl-piperazine succinate

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1. NHjaq., MTBE

2. CDjI, KOH, H₃O, MTBE

3. NH_a aq.

4. AcCI, MTBE

5. NHj aq.

6. succlnlc acid, acetone (XXV) Maleate

Mw 462.00(345.93+116.07) trans racemate (+8% cis)

(XXVII)Succlnate

Mw481.07 (362.98+118.09) trans racemal

Procedure:

kg (2.38 mol) (XXV) maleate, 11 L methyl tertbutyl ether, 1.8 L water and 1 L 25% aqueous ammonia are stirred for 1 - 2 hours the phases are separated and the organic phase is washed with two times 2 L water a solution of 254 g (3.85 mol) 85% aqueous potassium hydroxide and 1.5 L water is added to the organic phase, followed by addition of 450 g (3.11 mol) methyl(d3)iodide (CD₃I) the reaction is stirred at 20-25 °C for 16 - 24 hours

L water are added and the precipitating by-product is filtered off

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 the phases are separated and the organic phase is washed with 2 L water the phases are separated and 38 g (0.48 mol) acetylchlorîde is added to the organic phase which is stirred for 20 - 40 minutes

0.8 L water and 0.2 L 25% aqueous ammonia are added and the mixture is stirred for 20 - 40 minutes the phases are separated and the organic phase is washed with 2 L water the organic phase is reduced to dryness and acetone is added

225 g (1.91 mol) succinîc acid and acetone are added so that the reaction volume is approximately 6 - 6.5 L

The reaction is warmed to reflux and afterwards cooled to 5-10 °C

The precipitate is filtered off and washed with 1 L acetone the solid is dried in a vacuum oven at 50 °C for more than 16 hours to give 630 g (55% yield) of (XXVII) succinate

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NMR data for (XXVII) succinate:

H-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, 1 H, J=8.8 Hz,

J=5.8 Hz), 2.65-2.56 (m, 4H), 2.46-2.41 (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 of 4-((1R,3S)-6-chloro-3-phenyl(d₅)-indan-1-yl)-1(c/3),2,2trimethyl-piperazine L(+)-tartrate

1. NH₃ aq.. EtOAc

2. L(+) tartarlc acid, acetone

3. EtOH (recrystalllsatlon)

Yietd Irom Lu AF3B107:

-15« (1*g SM ÿves ~300g API)

XXVII Succinate

Mw 481.07 (362.98+118.09)

L(+) (IV) tartrate

Mw 513.07 (362.98+150.09) C^HjCIODj,

Procedure:

kg (2.08 mol) (XXVII) succinate, 8 L ethyl acetate, 2L water and 1L 25% aqueous ammonia are stirred for 0.5 -1 hours the phases are separated and the organic phase is washed with 2 L water the organic phase is reduced to approximately 1.5 L

L acetone and 312 g (2.08 mol) L(+)-tartaric acid are added the reaction is warmed to reflux and afterwards cooled to 5-10 °C the precipitate is filtered off, washed with 1.2 L acetone the wet filtercake is recharged and 11 L absolute éthanol are added the reaction is warmed to reflux and afterwards cooled to 5-10 °C the precipitate is filtered off and washed with 1.2 L absolute éthanol the solid is dried in a vacuum oven at 50 °C for more than 16 hours to give 395 g (37% yield) of (IV) L(+)-tartrate

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NMR data for (IV) L(+)-tartrate:

H-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), 2.61-2.50 (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: Physico-Chemical characterization of salts of Compound (IV) pKa and log P/D of Compound (IV) pK_a was determined by potentiometric titration of the base at ion strength 0.16 using MeOH as co-solvent. Three sériés of three repeated titrations on the same solution of the sample was performed in a conventional way from low to high pH and a différence curve was created from each of these titrations by blank subtraction. The apparent pK_a-value at each MeOH:water ratio is calculated from the différence curves, and the pK_a value is determined by extrapolation to zéro MeOH content.

The lower pK_a value is too low to be determined by potentiometric titration as data only were found reliable down to ~3. The high pK_a was determined to be 8.9 + 0.1

The lower pK_a was determined by Dip Probe Absorption Spectroscopy détection during titration of the 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 pK_a-value. Two sériés of three repeated titrations on the same solution of the sample was performed from low to high pH, with a photo diode array as additional détection. The apparent pK_a-value 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 zéro MeOH content.

Resuit : The lower pK_a was determined to be 2.5+ 0.1

The logD profile was determined by titration at 27°C and ion strength of approx. 0.16. A sériés of three repeated titrations on the same sample in solution was performed, from low to high pH. The first titration was performed with a small amount of n-octanol présent in the solution, the second and thîrd with increasing amounts.

A différence curve was created from each of these titrations by blank subtraction, and from these différence curves, the apparent pK_a values (p₀K_a) were calculated. From the change in the apparent pK_a values (ApK_a) with the n-octanol:water ratio combined with the real pK_a 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

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Melting point determined by PSC

The melting point of the (R.R)-hydrogen tartrate sait of Compound (IV) was determined using différentiel scanning calorimetry (DSC), using a TA instruments DSC Q1000 heating the sample 5°/minute. The sample was placed in a covered pan with a punched pinhole.

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

Solubility

Solubility of the (R.R)-hydrogen tartrate sait 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 sait of Compound (IV).

Solvent	Meas. conc. (mg base/ml)	PH
Hydrogen tartrate in water, 5 °C	3.1	3.25
Hydrogen tartrate in water, RT	4.0	3.15
Hydrogen tartrate in water, 37 °C	6.6	3.08
Solvent	Meas. conc. (mg base/ml)	pH
10%HPpCD	25.2	3.59
5%ΗΡβΟΡ, at RT	15.5	3.61
5%ΗΡβΟΡ, at 5°C	12

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 prepared by précipitation of Compound (IV) from 99% EtOH.

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Analytical data are given in the table below (Table 6),

Table 6. Data for salts of Compound (IV)

Sait	DSC (Tonset C)	Solubility (mg/ml)	pH
Dihydrogen phosphate	Dégradation at 250°C	1.4	4.67
Hydrogen fumarate	202.7°C	1.2	4.10
Hydrogen maleate	150.4°C	1.2	4.94
Hydrogen malonate	145.0°C followed by dégradation	9.5	4.08
Hydrogen tartrate	187°C	4.0	3.15
Base	59.9	0.1	7.6

Although the invention has been described and illustrated in the foregoing illustrative embodiments, it is understood that the présent disclosure has been made only by way of example, and that numerous changes in the details of implémentation of the invention can be made without departing from the spirit and scope of the invention, which is limited only by the daims that follow. Features of the disclosed embodiments can be combined and/or reamanged in various ways within 10 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 expérimentation, numerous équivalents to the spécifie embodiments described specifically in this disclosure. Such équivalents are intended to be encompassed in the scope of the following daims.

Claims (33)

1. What is Claimed:

   l. A compound of formula Y :

   wherein,

   R¹ - R¹⁰ are independently hydrogen or deuterium, wherein at least one of R'-R¹⁰ comprises at least about 50% deuterium, or a pharmaceutically acceptable acid addition sali thereof.
2. 2, The compound of claim I, wherein R⁶-R¹⁰ are each deuterium.
3. 3. The compound of claim 2, wherein R³-R⁵ are each hydrogen.
4. 4. The compound of claim 2, wherein R³-R⁵ arc each deuterium.

   (VU).

   (IV).

   -216797 (VI).
5. 9. The compound of claim l, wherein R¹ and R² are each deuterium.
6. 10. The compound of claim 9, wherein R³-R⁵ are each deuterium.
7. 11. The compound of claim 9, wherein R³-R⁵ are each hydrogen

   -316797
8. 14. The compound ofany of daims I-13, wherein al least about 85% of the compound has a deuterium atom at each position designated as deuterium, and any atom not designated as deuterium is présent al about its naturel isotopic abundance.
9. 15. The compound of any of daims 1-14, 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 présent at about its naturel isotopic abundance.
10. 16. The compound of claim I, wherein the compound is the hydrogen tartrate sait of (1Â,3S)-(IV).
11. 17. The compound of claim 16, whereîn the compound exists in polymorphie form A, and having an XRPD diffraction pattern as indicatcd in Figure 18.
12. 18. The compound of claim 16, wherein at least about 85% of the compound lias a deuterium atom at each position designated as deuterium, and any atom not designated as deuterium is présent at about its naturel isotopic abundance.
13. 19. A pharmaceutical composition comprising the compound of any of daims l to 18 and one or more pharmaceutically acceptable carriers, diluents, or excipients.
14. 20. The pharmaceutical composition of claim I9, wherein the compound is the hydrogen
15. 21. The composition of daims 19 or 20, wherein the carrier comprises hydroxypropyl-βcyclodextrin in water, and wherein at least about 85% of the compound has a deuterium atom at each position designated as deuterium, and any atom not designated as deuterium is présent at about îts naturel isotopic abundance.
16. 22. Use of the compound of any of daims I-I8, or the composition ofany of daims I9-2I for the manufacture of a médicament for treatment of psychosis, olhcr discases involving psychotic symptoms, psychotic disorders or diseases that présent with psychotîc symptoms.

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17. 23. Use according to daims 22, wherein the psychosis or disease involving psycliotic symptoms is schizophrenia, schizophrcniforin disorder, scliizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, bipolar disorder, or mania in bipolar disorder.
18. 24. Use according to daims 22 or 23, further comprising a compound selected from the group consisting of sertindole, olanzapine, rispéridone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.
19. 25. Use according to daims 22 or 23, wherein the psychosis or disease involving psychotic symptoms is schizophrenia.
20. 26. Use according to any of daims 22-25, wherein the psycbosis or disease involving psychotic symptoms is schizophrenia, wherein the pharmaceutical composition comprises an effective amount of hydrogen tartrate sait of (1Â,3S)-(IV) and hydroxypropyl-p-cyclodextrin in water, and wherein al leasl about 85% of (IV) has a deuterium atom at each position designated as deuterium, and any atom not designated as deuterium is présent at about ils natural isotopîc abundance.

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21. 27. A compound of daims l -18, or the composition of any of daims 19-21 for use in treating psychosis, other diseases involvïng psychotic symptoms, psychotic disorders or dîseases that présent with psychotic symptoms.
22. 28. The compound or composition of daim 27, wherein the psychosis or disease involvïng psychotic symptoms is schizophrenia.
23. 29. The compound or composition of daim 27 or 28, further comprising one or more neuroleptic agents.
24. 30. The compound or composition of daim 29, wherein the neuroleptic agent is selected from sertindole, olanzapine, rispéridone, quetiapine, aripiprazole, halopcridol, clozapine, ziprasidone and osanetant.
25. 31. The compound or composition of any of daims 27-30, wherein the compound or composition comprises the hydrogen tarlrate sait of (IV).

    (In-
26. 32. The compound or composition of any of daims 27-3 I, wherein at least about 85% of the compound has a deuterium atom at each position designated as deuterium, and any atom not designated as deuterium is présent at about its nalural isotopic abundance.

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27. 33. The compound or composition of any of daims 27-32, wherein the composition comprises hydroxypropyl-p-cyclodextrin in water.
28. 34. A pharmaceutical composition comprising a hydrogen tartrate sait of (1^,35)-( IV) and hydroxypropyl-p-cyclodextrin in water, wherein at least about 85% of (IV) lias a deuterium atom at each position designatcd as deuterium, and any atom not designated as deuterium is présent at about its nalural isotopic abundance for use in treating schizophrenia in a subject.
29. 35. A compound of formula (S)-(XV).

    -816797 comprising treating compound (XIV) with [(S)-BlNAP]Rh(I)BF4.
30. 37. The process of claim 36, wherein [(5)-BINAP]Rh(l)BF4 is used in a catalylic amount.

    b) treatment with 2-bromo-5-chlorobenzaldehyde.

    -916797 bis(pinacolato) diboron further comprises addition of Pd(II).
31. 40. The process of claim 39, wherein treatment with 2-bromo-5-chlorobenzaldehyde further comprises addition of Pd(0).
32. 41. A process ofthe préparation ofcompound (IÆ,3S)-(IV) tartrate comprising, treatment of racemic /ranô’-l-(6-chloro-3-phenyl(i/5)-indan-l-yl)-l(i/₃), 2, 2-lrimelhyl-piperazine with L-(+)-tartaric acid.
33. 42. The process of claim 41, wherein racemic /ram-l-(6-chloro-3-phenyl(i/5)-indan-l-yl)1(î/3), 2, 2-lrimcthyl-piperazine is gcnerated from the corresponding succinate sait thereof.