Deuterated forms and derivatives of flibanserin

Abstract

Describes deuterated forms of flibanserin of structural formula (I) and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing these compounds, and methods of treatment or prophylaxis using these compounds or pharmaceutical compositions. The compounds can be used for the treatment or prophylaxis of diseases or conditions selected from psychosis, schizophrenia, schizoaffective disorder, Parkinson's disease, dementia with Lewy bodies, sleep disorders (including insomnia), agitation, mood disorders (including depression), thromboembolic disorders, autism and attention deficit hyperactivity disorder. #imgabs0#

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 784,056, filed Dec. 21, 2018. The entire teachings of that application are incorporated herein by reference. Background of the Invention

[0003] Many existing drugs have poor absorption, distribution, metabolism, and / or excretion (ADME) properties, which hinders their wider use or limits their use in certain indications. Poor ADME properties are also a major reason for the failure of candidate drugs in clinical trials. Although in some cases formulation techniques and prodrug strategies can be employed to improve certain ADME properties, these methods generally cannot address the underlying ADME problems present in many drugs and candidate drugs. One such problem is rapid metabolism, which results in the overly rapid clearance of many drugs from the body that could otherwise be highly effective in treating a disease. A possible solution to rapid drug clearance is to administer the drug frequently or at high doses to achieve a plasma drug concentration that is high enough. However, this introduces many potential therapeutic problems, such as poor patient compliance with the dosing regimen, more severe side effects as the dose increases, and increased treatment costs. Drugs that are rapidly metabolized may also expose the patient to adverse toxic or reactive metabolites.

[0004] Another ADME limitation that affects many drugs is the formation of toxic or bioreactive metabolites. As a result, some patients who receive the drug may experience toxicity, or the safe dose of such a drug may be limited such that the patient receives an insufficient active dose. In some cases, modifying the dosing interval or formulation method can help reduce clinical adverse reactions, but the formation of such adverse metabolites is generally inherent to the metabolism of the compound.

[0005] In certain selected cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. This is the case with protease inhibitor drugs used to treat HIV infection. The FDA recommends co-administration of these drugs with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), which is normally responsible for drug metabolism (see Kempf, D. J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3):654-60). However, ritonavir causes adverse effects and increases the drug burden in HIV patients who already have to use different drugs in combination. Similarly, the CYP2D6 inhibitor quinidine has been added to dextromethorphan to reduce the rapid CYP2D6 metabolism of dextromethorphan when treating pseudobulbar affect. However, quinidine has unwanted side effects, which greatly limit its use in potential combination therapies (see Wang, L. et al., Clinical Pharmacology and Therapeutics, 1994, 56(6Pt1):659-67; and FDA quinidine label, available at www.accessdata.fda.gov).

[0006] Generally speaking, co-administering a drug with a cytochrome P450 inhibitor is not a satisfactory strategy for reducing drug clearance. Inhibition of CYP enzyme activity affects the metabolism and clearance of other drugs metabolized by that enzyme. CYP inhibition can lead to the accumulation of other drugs in the body to toxic levels.

[0007] A potentially attractive strategy for improving drug metabolic properties is deuterium modification. In this approach, one attempts to slow CYP-mediated drug metabolism or reduce the formation of adverse metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared with hydrogen, deuterium forms stronger bonds with carbon. In selected cases, the increased bond strength conferred by deuterium can have a positive impact on the ADME properties of a drug, thereby creating the potential to improve drug efficacy, safety, and / or tolerability. At the same time, since the size and shape of deuterium are essentially the same as those of hydrogen, replacing hydrogen with deuterium is not expected to affect the biochemical potency and selectivity of the drug compared to the original chemical entity containing only hydrogen.

[0008] In the past 35 years, the effects of deuterium substitution on metabolic rates have been reported for a very small number of approved drugs (see, e.g., Blake, MI et al., J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner, DJ et al., Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al., Curr Opin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results have been variable and unpredictable. For some compounds, deuteration results in a decrease in in vivo metabolic clearance. For other compounds, there is no change in metabolism. Still other compounds show an increase in metabolic clearance. The variability of the deuterium effect has also led experts to question or reject deuterium modification as a viable drug design strategy for suppressing unwanted metabolism (see page 35 of Foster and page 101 of Fisher). SUMMARY OF THE INVENTION

[0009] The present invention relates to deuterated forms and derivatives (including prodrugs) of flibanserin, and pharmaceutically acceptable salts thereof. In one aspect, the present invention provides a compound of structural formula (I) or a pharmaceutically acceptable salt thereof,

[0010]

[0011] wherein R 1 and R 2 are independently selected from -CH3, -CH2D, -CHD2, and -CD3; X is -OH or -F; and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 and Y 11 are each independently selected from hydrogen and deuterium;

[0012] provided that Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , R 1 and R 2 at least one of which contains deuterium; provided that when Y 1a , Y 1b , Y 2a and Y 2b are each deuterium, then Y 3a , Y 3b , Y 4a , Y 4b , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , R 1 and R 2 at least one of which contains deuterium; and provided that when Y 3a , Y 3b , Y 4a and Y 4b are each deuterium, then Y 1a , Y 1b , Y 2a , Y 2b , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , R 1 and R 2 at least one of which contains deuterium.

[0013] The present invention also provides a composition comprising a compound of the present invention, including a pharmaceutical composition, said pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The present invention also provides the use of such compounds, salts and compositions in methods for treating diseases and conditions, said diseases and conditions being mediated by the administration of flibanserin or the primary action of 5-hydroxytryptamine 2A (5-HT 2A) Beneficial treatment is obtained by inverse agonism or antagonism of other drugs mediated by the receptor. Some exemplary embodiments include a method of treating or preventing a disease or condition selected from psychosis, schizophrenia (including chronic schizophrenia), schizoaffective disorder, Parkinson's disease (including Parkinson's disease psychosis), dementia with Lewy bodies, sleep disorders (including insomnia), agitation, mood disorders (including depression), thromboembolic disorders, autism, attention deficit hyperactivity disorder, and any combination thereof, the method comprising the step of administering to a subject in need thereof a pharmaceutically acceptable compound, salt, or composition of the present invention. Detailed Description

[0014] Flisoxetine, also known as (R)-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, is a highly selective 5-HT 2A receptor antagonist. It is widely used in scientific research to explore the function of the 5-HT 2A receptor.

[0015] Flisoxetine is being studied in clinical trials as a potential treatment for antipsychotics, antidepressants, and insomnia, and is also active in animal models involving blockade of NMDA glutamatergic channel receptors, an effect known to resemble some behavioral symptoms of human schizophrenia. De Paulis T, Curr Opin Investig Drugs. 2001 Jan;2(1):123-32.

[0016] Despite the beneficial activity of flisoxetine, there is still a need for new compounds to treat the above diseases and conditions.

[0017] Definitions

[0018] The term "treatment" refers to reducing, inhibiting, attenuating, alleviating, preventing, or stabilizing the development or progression of a disease (such as the diseases described herein), reducing the severity of the disease, or improving the symptoms associated with the disease.

[0019] "Disease" refers to any condition or disorder that impairs or interferes with the normal function of cells, tissues, or organs.

[0020] As used herein, the term "subject" includes human or non-human mammals. Non-limiting examples of non-human mammals include mice, rats, guinea pigs, rabbits, dogs, cats, monkeys, apes, pigs, cows, sheep, horses, etc.

[0021] The term "alkyl" refers to a monovalent saturated hydrocarbon group. C a -C bThe alkyl group is an alkyl group having a to b carbon atoms. For example, a C1-C6 alkyl group is an alkyl group having 1 to 6 carbon atoms. In some embodiments, the alkyl group can be straight-chain or branched-chain. In some embodiments, the alkyl group can be a primary, secondary, or tertiary alkyl group. Non-limiting examples of the alkyl group include methyl; ethyl; propyl, including n-propyl and isopropyl; butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl; pentyl, including, for example, n-pentyl, isopentyl, and neopentyl; and hexyl, including, for example, n-hexyl and 2-methylpentyl. Non-limiting examples of the primary alkyl group include methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Non-limiting examples of the secondary alkyl group include isopropyl, sec-butyl, and 2-methylpentyl. Non-limiting examples of the tertiary alkyl group include tert-butyl.

[0022] The term "alkenyl" refers to a monovalent unsaturated hydrocarbon group in which the unsaturation is represented by a double bond. A C2-C6 alkenyl group is an alkenyl group having 2 to 6 carbon atoms. The alkenyl group can be straight-chain or branched-chain. Examples of the alkenyl group include CH2=CH-(vinyl), CH2=C(CH3)-, CH2=CH-CH2-(allyl), CH3-CH=CH-CH2-(crotyl), CH3-CH=C(CH3)-, and CH3-CH=CH-CH(CH3)-CH2-. In cases where double bond stereoisomers may exist, the stereochemical structure of the alkenyl group can be (E), (Z), or a mixture thereof.

[0023] The term "alkynyl" refers to a monovalent unsaturated hydrocarbon group in which the unsaturation is represented by a triple bond. A C2-C6 alkynyl group is an alkynyl group having 2 to 6 carbon atoms. The alkynyl group can be straight-chain or branched-chain. Examples of the alkynyl group include HC≡C-, CH3-C≡C-, CH3-C≡C-CH2-, CH3-C≡C-CH2-CH2-, and CH3-C≡C-CH(CH3)-CH2-.

[0024] The compounds described herein can be PEGylated. A "PEGylated" compound refers to a compound having at least one poly(ethylene glycol) chain covalently bonded thereto. For example, R in the following structural formula (II) 3 can be a poly(ethylene glycol) (PEG) group. Generally, the poly(ethylene glycol) can have a plurality of (e.g., n) repeating units (e.g., -O(CH2CH2O) nH, where n ranges from 5 to 350). Polyethylene glycol is not limited to any specific number of repeating units n or any specific molecular weight, provided that the resulting PEGylated compound (e.g., a compound of structural formula (II) described herein) is suitable as a prodrug. For example, the molecular weight of the PEG group can reach 25 kDa. For example, the PEG group can be a low molecular weight PEG (i.e., ≤12 kDa), such as a molecular weight of 300 Da to 12 kDa, 1 kDa to 12 kDa, 3 kDa to 12 kDa, or 3 kDa to 8 kDa. In another example, the PEG group can be a high molecular weight PEG (i.e., >12 kDa), such as a molecular weight of 12 kDa to 25 kDa or 18 kDa to 22 kDa.

[0025] "Amino acid ester" refers to those amino acid derivatives that convert a carboxylic acid group to an ester. For example, amino acid esters include valine ester, leucine ester, isoleucine ester, α-tert-butylglycine ester, and dimethylglycine ester, etc.

[0026] Suitable amino acids include but are not limited to histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), threonine (Thr), tryptophan (Trp), valine (Val), arginine (Arg), cysteine (Cys), glutamine (Gln), glycine (Gly), proline (Pro), serine (Ser), tyrosine (Tyr), alanine (Ala), asparagine (Asn), aspartic acid (Asp), glutamic acid (Glu), and selenocysteine (Sec).

[0027] It will be appreciated that there will be some variation in the natural isotope abundances in synthetic compounds, depending on the source of the chemical materials used in the synthesis. Thus, formulations of fluselazine will inherently contain small amounts of deuterated isotopologues. Despite this variation, the concentration of naturally abundant stable hydrogen and carbon isotopes is small and insignificant compared to the degree of stable isotope substitution in the compounds of the present invention. See, e.g., Wada, E. et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0028] In the compounds of the present invention, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen in its natural isotope composition. However, in certain specified embodiments, when a position is specifically designated as "H" or "hydrogen", that position has at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% hydrogen. In some specified embodiments, when a position is specifically designated as "H" or "hydrogen", ≤20%, ≤10%, ≤5%, ≤4%, ≤3%, ≤2% or ≤1% deuterium is introduced at that position. Additionally, unless otherwise indicated, when a position is specifically designated as "D" or "deuterium", it is understood that the abundance of deuterium at that position is at least 3340 times the natural abundance of deuterium (which is 0.015%) (i.e., at least 50.1% deuterium is introduced).

[0029] As used herein, the term "isotope enrichment factor" refers to the ratio of the isotope abundance of a particular isotope to its natural abundance.

[0030] In other embodiments, the isotope enrichment factor of each designated deuterium atom in the compounds of the present invention is at least 3500 (52.5% deuterium introduced at each designated deuterium atom), at least 4000 (60% deuterium introduced), at least 4500 (67.5% deuterium introduced), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium introduced), at least 6000 (90% deuterium introduced), at least 6333.3 (95% deuterium introduced), at least 6466.7 (97% deuterium introduced), at least 6600 (99% deuterium introduced) or at least 6633.3 (99.5% deuterium introduced).

[0031] In some embodiments, in the compounds of the present invention, at least 52.5% deuterium is introduced at each designated deuterium atom.

[0032] In some embodiments, in the compounds of the present invention, at least 60% deuterium is introduced at each designated deuterium atom.

[0033] In some embodiments, in the compounds of the present invention, at least 67.5% deuterium is introduced at each designated deuterium atom.

[0034] In some embodiments, in the compounds of the present invention, at least 75% deuterium is introduced at each designated deuterium atom.

[0035] In some embodiments, in the compounds of the present invention, at least 82.5% deuterium is introduced at each designated deuterium atom.

[0036] In some embodiments, in the compounds of the present invention, each designated deuterium atom introduces at least 90% deuterium.

[0037] In some embodiments, in the compounds of the present invention, each designated deuterium atom introduces at least 95% deuterium.

[0038] In some embodiments, in the compounds of the present invention, each designated deuterium atom introduces at least 97.5% deuterium.

[0039] In some embodiments, in the compounds of the present invention, each designated deuterium atom introduces at least 99% deuterium.

[0040] In some embodiments, in the compounds of the present invention, each designated deuterium atom introduces at least 99.5% deuterium.

[0041] The term "isotopologue" refers to a molecule whose chemical structure differs from that of the substance of the present invention only in its isotopic composition.

[0042] When referring to the compounds of the present invention, the term "compound" refers to a collection of molecules having the same chemical structure, except that there may be isotopic variations between the constituent atoms of the molecules. Thus, it will be clear to those skilled in the art that a compound represented by a specific chemical structure will include molecules having deuterium at each position designated as deuterium in the chemical structure, and may also include isotopologues having hydrogen atoms at one or more designated deuterium positions in the structure. The relative amounts of such isotopologues in the compounds of the present invention will depend on many factors, including the isotopic purity of the deuteration reagents used to prepare the compounds and the efficiency of introducing deuterium in the various synthetic steps used to prepare the compounds. In certain embodiments, the relative amounts of such isotopologues will generally be less than 49.9% of the compound. In other embodiments, the relative amounts of such isotopologues will generally be less than 47.5% of the compound, less than 40% of the compound, less than 32.5% of the compound, less than 25% of the compound, less than 17.5% of the compound, less than 10% of the compound, less than 5% of the compound, less than 3% of the compound, less than 1% of the compound or less than 0.5% of the compound.

[0043] The present invention also provides salts of the compounds of the present invention (e.g., pharmaceutically acceptable salts). Unless otherwise stated, even without explicit statement, in any of the embodiments or aspects described herein, the compounds described herein (e.g., the compounds of structural formulas (I), (II)) can be replaced with salts of the compounds described herein (e.g., pharmaceutically acceptable salts).

[0044] The salts of the compounds of the present invention are formed between an acid and a basic group (e.g., an amino functional group) of the compound or between a base and an acidic group (e.g., a carboxyl functional group) of the compound. According to one embodiment, the compound is a pharmaceutically acceptable acid addition salt. In one embodiment, the acid addition salt may be a deuterated acid addition salt.

[0045] As used herein, the term "pharmaceutically acceptable" means that a component is suitable for contact with the tissues of humans and other mammals within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salts" means any non-toxic salts that, upon administration to a recipient, can directly or indirectly provide the compounds of the present invention. "Pharmaceutically acceptable counterions" are the ionic portions of salts that are non-toxic when released from the salt upon administration to a recipient.

[0046] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen sulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, caprates, octanoates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In one embodiment, the pharmaceutically acceptable acid addition salts include acid addition salts formed with mineral acids such as hydrochloric acid and hydrobromic acid, especially acid addition salts formed with organic acids such as maleic acid. In one embodiment, the acids commonly used to form pharmaceutically acceptable salts include the inorganic acids listed above, wherein at least one hydrogen is replaced by deuterium.

[0047] The compounds of the present invention (such as compounds of formula I) may contain asymmetric carbon atoms, for example due to deuterium substitution or other reasons. Thus, the compounds of the present invention may exist as individual enantiomers or as a mixture of two enantiomers. Accordingly, the compounds of the present invention may exist as a racemic mixture or a scalemic mixture, or as individual stereoisomers substantially free of the other possible stereoisomers. As used herein, the term "substantially free of other stereoisomers" means that less than 25% of the other stereoisomers are present, preferably less than 10% of the other stereoisomers, more preferably less than 5% of the other stereoisomers, and most preferably less than 2% of the other stereoisomers. Methods for obtaining or synthesizing the individual enantiomers of a given compound are known in the art and can be applied, where feasible, to the final compound or starting materials or intermediates.

[0048] Unless otherwise indicated, when a disclosed compound is named or depicted by structure without specifying the stereochemical structure and has one or more chiral centers, it is to be understood as representing all possible stereoisomers of the compound.

[0049] As used herein, the term "stable compound" refers to a compound having sufficient stability to permit its preparation and maintaining the integrity of the compound for a sufficient period of time for the purposes detailed herein (e.g., formulated into a therapeutic product, an intermediate for the production of a therapeutic compound, an isolable or storable intermediate compound, treating a disease or condition responsive to a therapeutic agent).

[0050] Both "D" and "d" refer to deuterium. "Stereoisomer" refers to enantiomers and diastereomers. Both "Tert" and "t-" refer to "tert". Both "Sec" or "s-" refer to "sec". "n-" refers to "n". "i-" refers to "iso". "US" refers to the United States.

[0051] "Substituted with deuterium" means replacing one or more hydrogen atoms with the corresponding number of deuterium atoms.

[0052] Throughout the specification, variables may be referred to generically (e.g., "each R") or may be referred to specifically (e.g., R 1 、R 2 、R 3 etc.). Unless otherwise indicated, when a variable is referred to generically, it is meant to include all specific embodiments of that particular variable.

[0053] Therapeutic compound

[0054] In certain embodiments, the present invention provides a compound of structural formula (I):

[0055]

[0056] Wherein:

[0057] R 1 and R 2 are independently selected from -CH3, -CH2D, -CHD2, and -CD3;

[0058] X is -OH or -F; and

[0059] Y 1a 、Y 1b 、Y 2a 、Y 2b 、Y 3a 、Y 3b 、Y 4a 、Y 4b 、Y 5 、Y 6 、Y 7 、Y 8 、Y 9 、Y 10 and Y 11 each independently selected from hydrogen and deuterium;

[0060] Provided that at least one of Y 1a 、Y 1b 、Y 2a 、Y 2b 、Y 3a 、Y 3b 、Y 4a 、Y 4b 、Y 5 、Y 6 、Y 7 、Y 8 、Y 9 、Y 10 、Y 11 、R 1 and R 2 contains deuterium;

[0061] Provided that when Y 1a 、Y 1b 、Y 2a and Y 2b are each deuterium, then at least one of Y 3a 、Y 3b 、Y 4a 、Y 4b 、Y 5 、Y 6 、Y 7 、Y 8 、Y 9 、Y 10 、Y 11 、R 1 and R 2 contains deuterium; and

[0062] The condition is that when Y 3a 、Y 3b 、Y 4a and Y 4b are each deuterium, then Y 1a 、Y 1b 、Y 2a 、Y 2b 、Y 5 、Y 6 、Y 7 、Y 8 、Y 9 、Y 10 、Y 11 、R 1 and R 2 contain deuterium in at least one of them.

[0063] In other embodiments, the present invention provides a compound of structural formula (I), wherein: R 1 and R 2 are independently selected from -CH3, -CH2D, -CHD2 and -CD3; X is -OH or -F; and Y 1a 、Y 1b 、Y 2a 、Y 2b 、Y 3a 、Y 3b 、Y 4a 、Y 4b 、Y 5 、Y 6 、Y 7 、Y 8 、Y 9 、Y 10 and Y 11 are each independently selected from hydrogen and deuterium; provided that Y 1a 、Y 1b 、Y 2a 、Y 2b 、Y 3a 、Y 3b y 4a 、Y 4b 、Y 5 、Y 6 、Y 7 、Y 8 、Y 9 、Y 10 、Y 11 、R 1 and R 2 contain deuterium in at least one of them.

[0064] In other embodiments, the present invention provides a compound of structural formula (II) (i.e., a prodrug of the compound of structural formula (I)) or a pharmaceutically acceptable salt thereof,

[0065]

[0066] Wherein:

[0067] R 1 and R 2 are independently selected from -CH3, -CH2D, -CHD2, and -CD3;

[0068] R 3 is -C(O)-C 1-21 alkyl (such as -C(O)-C 1-6 alkyl, -C(O)-C 5-19 alkyl, -C(O)-C 9-17 alkyl, or -C(O)-C 15 alkyl (i.e., palmitoyl)), -C(O)-C 2-8 alkenyl, C(O)-C 2-8 alkynyl, polyethylene glycol (PEG), or an amino acid, where the amino acid is attached through its carboxylic acid group to the oxygen bonded to the R 3 group to form an amino acid ester; and

[0069] Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 and Y 11 are each independently selected from hydrogen and deuterium;

[0070] Provided that Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , R 1 and R 2At least one of them contains deuterium. In one aspect of this embodiment of the compound of structural formula (II), a further condition is that when Y 1a 、Y 1b 、Y 2a and Y 2b are each deuterium, then Y 3a 、Y 3b 、Y 4a 、Y 4b 、Y 5 、Y 6 、Y 7 、Y 8 、Y 9 、Y 10 、Y 11 、R 1 and R 2 at least one of them contains deuterium; and

[0071] the condition is that when Y 3a 、Y 3b 、Y 4a and Y 4b are each deuterium, then Y 1a 、Y 1b 、Y 2a 、Y 2b 、Y 5 、Y 6 、Y 7 、Y 8 、Y 9 、Y 10 、Y 11 、R 1 and R 2 at least one of them contains deuterium.

[0072] In certain embodiments of the compound of structural formula (I) or the compound of structural formula (II), R 1 and R 2 are independently selected from -CH3 and -CD3. In one aspect of this embodiment, when X is present, it is -OH. In another aspect of this embodiment or any of the foregoing aspects of this embodiment, Y 7 、Y 8 、Y 9 、Y 10 and Y 11 are each hydrogen. In another aspect of this embodiment or any of the foregoing aspects of this embodiment, Y 4a 、Y 4b 、Y 5 、Y 7 、Y 8 、Y 9 、Y 10 and Y 11Each is hydrogen. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, Y 1a and Y 1b are the same. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, Y 2a and Y 2b are the same. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, Y 3a and Y 3b are the same. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, Y 4a and Y 4b are the same.

[0073] In yet another aspect of this embodiment, R 1 and R 2 are independently selected from -CH3 and -CD3; when X is present, it is -OH; Y 1a and Y 1b are the same; Y 2a and Y 2b are the same; Y 3a and Y 3b are the same; Y 4a and Y 4b are the same; and Y 7 、Y 8 、Y 9 、Y 10 and Y 11 are each hydrogen.

[0074] In yet another aspect of this embodiment, R 1 and R 2 are independently selected from -CH3 and -CD3; when X is present, it is -OH; Y 4a 、Y 4b 、Y 5 、Y 7 、Y 8 、Y 9 、Y 10 and Y 11 are each hydrogen; Y 1a 、Y 1b 、Y 2a and Y 2b are the same; and Y 3a and Y 3b are the same. In yet another aspect of this embodiment, R 1 and R 2 are independently selected from -CH3 and -CD3; when X is present, it is -OH; Y 4a 、Y 4b 、Y 5 、Y 7 、Y 8 、Y9 and Y 10 and Y 11 are each hydrogen; Y 1a and Y 1b are the same; and Y 2a and Y 2b and Y 3a and Y 3b are the same. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, Y 2a and Y 2b are deuterium. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, any atoms not specified as deuterium are present in their natural isotopic abundances.

[0075] In another embodiment of the compound of structural formula (I) or the compound of structural formula (II), Y 4a and Y 4b and Y 5 and Y 7 and Y 8 and Y 9 and Y 10 and Y 11 are each hydrogen. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, Y 1a and Y 1b are the same. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, Y 2a and Y 2b are the same. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, Y 3a and Y 3b are the same. In yet another aspect of this embodiment, R 1 and R 2 are independently selected from -CH3 and -CD3; when X is present, it is -OH; Y 4a and Y 4b and Y 5 and Y 7 and Y 8 and Y 9 and Y 10 and Y 11 are each hydrogen; Y 1a and Y 1b and Y 2a and Y 2b are the same; and Y 3a and Y 3b are the same. In yet another aspect of this embodiment, R 1 and R 2 are independently selected from -CH3 and -CD3; when X is present, it is -OH; Y 4a and Y 4b and Y 5, Y 7 , Y 8 , Y 9 , Y 10 and Y 11 are each hydrogen; Y 1a and Y 1b are the same; and Y 2a , Y 2b , Y 3a and Y 3b are the same. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, Y 2a and Y 2b are deuterium. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, any atom not specified as deuterium is present in its natural isotopic abundance.

[0076] In another embodiment of the compound of formula (I) or the compound of formula (II), Y 1a and Y 1b are the same. In yet another aspect of this embodiment, Y 2a and Y 2b are the same. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, Y 3a and Y 3b are the same. In yet another aspect of this embodiment, R 1 and R 2 are independently selected from -CH3 and -CD3; when X is present, it is -OH; Y 4a , Y 4b , Y 5 , Y 7 , Y 8 , Y 9 , Y 10 and Y 11 are each hydrogen; Y 1a , Y 1b , Y 2a and Y 2b are the same; and Y 3a and Y 3b are the same. In yet another aspect of this embodiment, R 1 and R 2 are independently selected from -CH3 and -CD3; when X is present, it is -OH; Y 4a , Y 4b , Y 5 , Y 7 , Y 8 , Y 9 , Y 10 and Y 11 are each hydrogen; Y 1a and Y 1b are the same; and Y 2a、Y 2b 、Y 3a and Y 3b In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, Y 2a and Y 2b In a further aspect of this embodiment or any preceding aspect of this embodiment, any atom not designated as deuterium is present at its natural isotopic abundance.

[0077] In another embodiment of the compound of formula (I) or the compound of formula (II), Y 2a and Y 2b In another aspect of this embodiment, Y 3a and Y 3b In another aspect of this embodiment, R 1 and R 2 are independently selected from -CH3 and -CD3; when X is present, it is -OH; Y 4a 、Y 4b 、Y 5 、Y 7 、Y 8 、Y 9 、Y 10 and Y 11 Each is hydrogen; Y 1a 、Y 1b 、Y 2a and Y 2b the same; and Y 3a and Y 3b In another aspect of this embodiment, R 1 and R 2 are independently selected from -CH3 and -CD3; when X is present, it is -OH; Y 4a 、Y 4b 、Y 5 、Y 7 、Y 8 、Y 9 、Y 10 and Y 11 Each is hydrogen; Y 1a and Y 1b the same; and Y 2a 、Y 2b 、Y 3a and Y 3b In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, Y 2a and Y 2b In a further aspect of this embodiment or any preceding aspect of this embodiment, any atom not designated as deuterium is present at its natural isotopic abundance.

[0078] In another embodiment of the compound of structural formula (I) or the compound of structural formula (II), Y 3a and Y 3b are the same. In yet another aspect of this embodiment, R 1 and R 2 are independently selected from -CH3 and -CD3; when X is present, it is -OH; Y 4a , Y 4b , Y 5 , Y 7 , Y 8 , Y 9 , Y 10 and Y 11 are each hydrogen; Y 1a , Y 1b , Y 2a and Y 2b are the same; and Y 3a and Y 3b are the same. In yet another aspect of this embodiment, R 1 and R 2 are independently selected from -CH3 and -CD3; when X is present, it is -OH; Y 4a , Y 4b , Y 5 , Y 7 , Y 8 , Y 9 , Y 10 and Y 11 are each hydrogen; Y 1a and Y 1b are the same; and Y 2a , Y 2b , Y 3a and Y 3b are the same. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, Y 2a and Y 2b are deuterium. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, any atom not specified as deuterium is present in its natural isotopic abundance.

[0079] In another embodiment of the compound of structural formula (I) or the compound of structural formula (II), R 1 and R 2 are independently selected from -CH3 and -CD3; when X is present, it is -OH; Y 4a , Y 4b , Y 5 , Y 7 , Y 8 , Y 9 , Y 10 and Y 11 are each hydrogen; Y 1a , Y1b and Y 2a and Y 2b are the same; and Y 3a and Y 3b are the same. In yet another aspect of this embodiment, Y 2a and Y 2b are deuterium. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, any atoms not specified as deuterium are present in their natural isotopic abundances.

[0080] In another embodiment of the compound of formula (I) or the compound of formula (II), R 1 and R 2 are independently selected from -CH3 and -CD3; when X is present, it is -OH; Y 4a , Y 4b , Y 5 , Y 7 , Y 8 , Y 9 , Y 10 and Y 11 are each hydrogen; Y 1a and Y 1b are the same; and Y 2a , Y 2b , Y 3a and Y 3b are the same. In yet another aspect of this embodiment, Y 2a and Y 2b are deuterium. In yet another aspect of this embodiment or any of the foregoing aspects of this embodiment, any atoms not specified as deuterium are present in their natural isotopic abundances.

[0081] In another embodiment of the compound of formula (I) or the compound of formula (II), Y 2a and Y 2b are deuterium. In yet another aspect of this embodiment, any atoms not specified as deuterium are present in their natural isotopic abundances.

[0082] In another embodiment of the compound of formula (I) or the compound of formula (II), any atoms not specified as deuterium are present in their natural isotopic abundances.

[0083] In some embodiments, the compound of formula (I) or the compound of formula (II) is selected from any of the compounds described in Table 1 (below), wherein when X is present, it is -OH; Y 1a and Y 1b are the same; Y 2a and Y 2b are the same; Y 3a and Y 3b are the same; and Y4a and Y 4b and Y 5 and Y 7 and Y 8 and Y 9 and Y 10 and Y 11 each is hydrogen:

[0084] Table 1: Exemplary Embodiments of Structural Formula (I)

[0085]

[0086]

[0087] In some embodiments, the compound is selected from any of the compounds described in Table 1 (above), wherein any atom not specified as deuterium is present in its natural isotopic abundance.

[0088] In some embodiments, the compound of structural formula (I) or structural formula (II) is selected from any of the compounds described in Table 2 (below), wherein when X is present, it is -OH; Y 1a and Y 1b are the same; Y 2a and Y 2b are the same; Y 3a and Y 3b are the same; and Y 4a and Y 4b and Y 5 and Y 7 and Y 8 and Y 9 and Y 10 and Y 11 each is hydrogen:

[0089] Table 2: Exemplary Embodiments of Structural Formula (I)

[0090]

[0091]

[0092] In some embodiments, the compound is selected from any of the compounds described in Table 2 (above), wherein any atom not specified as deuterium is present in its natural isotopic abundance.

[0093] In some embodiments, the compound of structural formula (I) or structural formula (II) is selected from any of the compounds described in Table 3 (below), wherein X is -OH; Y 1a and Y 1b are the same; Y 2a and Y 2b are the same; Y 3aand Y 3b is the same; Y 4a and Y 4b is the same; and Y 7 、Y 8 、Y 9 、Y 10 and Y 11 are each hydrogen:

[0094] Table 3: Exemplary Embodiments of Structural Formula (I)

[0095]

[0096]

[0097]

[0098]

[0099]

[0100] In some embodiments, the compound is selected from any of the compounds described in Table 3 (above), wherein any atom not specified as deuterium is present in its natural isotopic abundance.

[0101] In some embodiments, the compound of Structural Formula (I) or Structural Formula (II) is selected from any of the compounds described in Table 4 (below), wherein X is -OH; Y 1a and Y 1b is the same; Y 2a and Y 2b is the same; Y 3a and Y 3b is the same; Y 4a and Y 4b is the same; and Y 7 、Y 8 、Y 9 、Y 10 and Y 11 are each hydrogen:

[0102] Table 4

[0103] Representative examples of the compound# <![CDATA[R 1 > <![CDATA[R 2 > <![CDATA[Y 1a / Y 1b > <![CDATA[Y 2a / Y 2b > <![CDATA[Y 3a / Y 3b > <![CDATA[Y 4a / Y 4b > <![CDATA[Y 5 > <![CDATA[Y 6 > 100 <![CDATA[CH3]]> <![CDATA[CH3]]> H H H H H D 107 <![CDATA[CH3]]> <![CDATA[CH3]]> D H H H H H 155 <![CDATA[CD3]]> <![CDATA[CD3]]> D H H H H H 115 <![CDATA[CH3]]> <![CDATA[CD3]]> H H H H H H 131 <![CDATA[CD3]]> <![CDATA[CH3]]> H H H H H H 147 <![CDATA[CD3]]> <![CDATA[CD3]]> H H H H H H 148 <![CDATA[CD3]]> <![CDATA[CD3]]> H H H H H D 151 <![CDATA[CD3]]> <![CDATA[CD3]]> H D H H H H 159 <![CDATA[CD3]]> <![CDATA[CD3]]> D D H H H H 203 <![CDATA[CH3]]> <![CDATA[CH3]]> H H D D D H 215 <![CDATA[CH3]]> <![CDATA[CH3]]> H D D D D H 347 <![CDATA[CD3]]> <![CDATA[CD3]]> H H D D D H 359 <![CDATA[CD3]]> <![CDATA[CD3]]> H D D D D H 383 <![CDATA[CD3]]> <![CDATA[CD3]]> D D D D D H

[0104] In some embodiments, the compound is selected from any of the compounds described in Table 4 (above), wherein any atom not specified as deuterium is present in its natural isotopic abundance.

[0105] In some embodiments of the compounds of the present invention, when Y 1a or Y 1b is deuterium, at each Y 1a or Y1b The level of deuterium introduced at this position is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97% or at least 99%.

[0106] In some embodiments of the compounds of the present invention, when Y 2a or Y 2b is deuterium, the level of deuterium introduced at each Y 2a or Y 2b designated as deuterium is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97% or at least 99%.

[0107] In some embodiments of the compounds of the present invention, when Y 3a or Y 3b is deuterium, the level of deuterium introduced at each Y 3a or Y 3b designated as deuterium is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97% or at least 99%.

[0108] In some embodiments of the compounds of the present invention, when Y 4a or Y 4b is deuterium, the level of deuterium introduced at each Y 4a or Y 4b designated as deuterium is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97% or at least 99%.

[0109] In some embodiments of the compounds of the present invention, when Y 5 is deuterium, the level of deuterium introduced at each Y 5 designated as deuterium is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97% or at least 99%.

[0110] In some embodiments of the compounds of the present invention, when Y 6 is deuterium, the level of deuterium introduced at each Y 6 designated as deuterium is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97% or at least 99%.

[0111] In some embodiments of the compounds of the present invention, when Y 7 is deuterium, the level of deuterium introduced at each Y 7 designated as deuterium is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97% or at least 99%.

[0112] In some embodiments of the compounds of the present invention, when Y 8 is deuterium, the level of deuterium introduced at each Y 8 designated as deuterium is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97% or at least 99%.

[0113] In some embodiments of the compounds of the present invention, when Y 9 is deuterium, the level of deuterium introduced at each Y 9 designated as deuterium is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97% or at least 99%.

[0114] In some embodiments of the compounds of the present invention, when Y 10 is deuterium, the level of deuterium introduced at each Y 10 designated as deuterium is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97% or at least 99%.

[0115] In some embodiments of the compounds of the present invention, when Y 11 is deuterium, the level of deuterium introduced at each Y 11 designated as deuterium is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97% or at least 99%.

[0116] In some embodiments of the compounds of the present invention, when R 1 is -CH2D, -CHD2 or -CD3, the level of deuterium introduced at each designated deuterium of R 1 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97% or at least 99%.

[0117] In some embodiments of the compounds of the present invention, when R 2 is -CH2D, -CHD2 or -CD3, the level of deuterium introduced at each designated deuterium of R 2 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97% or at least 99%.

[0118] In another set of embodiments, any atom not designated as deuterium in any of the embodiments described herein is present at its natural isotopic abundance.

[0119] In some embodiments of the compounds of the present invention, the deuterium introduced at each specified deuterium atom is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97% or at least 99%.

[0120] In some embodiments of the compounds of the present invention, Y 1a 、Y 1b 、Y 2a 、Y 2b 、Y 3a 、Y 3b 、Y 4a 、Y 4b 、Y 5 、Y 6 、Y 7 、Y 8 、Y 9 、Y 10 and Y 11 in at least one is hydrogen, R 1 is -CH3, -CH2D or -CHD2, or R 2 is -CH3, -CH2D or -CHD2.

[0121] By referring to the exemplary syntheses and examples disclosed herein, a synthetic chemist of ordinary skill can readily effect the synthesis of the compounds of structural formula (I). Related procedures similar to those for preparing the compounds of structural formula (I) and their intermediates are disclosed in the following documents: for example, U.S. Patent Publication No. 2005 / 0,261,341; Huck, L. et al., Org. Lett., 2017, 19, 3747 - 3750; Reddy, B.P. et al., WO 2017017630 A1; Winkler, M. et al., Adv. Synth. Cat., 2007, 8 + 9, 1475 - 1480; Barker, O. et al., WO 2012035023A1; Ratton, S. et al., EP0037353A1; Huet, L. et al., Synlett, 2012, 23, 1230 - 1234; Senaweera, S. et al., Chem. Comm., 2017, 53, 7545 - 7548; Shaik, S. et al., Eur. J. Med. Chem., 2017, 126, 36 - 51; Mahtab, R. et al., J. Chem. Pharm. Sci., 2014, 7, 34 - 38; Sakamuri, S. et al., Bioorg. Med. Chem. Lett., 2001, 11, 495 - 500.

[0122] Such methods can utilize the corresponding deuterated and optionally other isotope-containing reagents and / or intermediates to synthesize the compounds described herein, or can call upon standard synthetic protocols known in the art for introducing isotope atoms into chemical structures.

[0123] [1] Exemplary Synthesis

[0124] A facile method for synthesizing a compound of structural formula (I) is described in Scheme 1.

[0125] Scheme 1.

[0126]

[0127] Laux et al. described the synthesis of flibanserin (7a) in U.S. Patent Publication No. 2005 / 0261341, which first converts carboxylic acid 1 to the corresponding Weinreb amide 2 by treatment with methoxymethylamine and CDI (carbonyldiimidazole). 2 reacts with a Grignard reagent generated from aryl bromide 3 to then afford ketone 4. This is a modification of the route described by Laux et al. to allow for the preparation of flibanserin analogs having an asymmetric deuteration pattern at the R 1 、R 2 、Y 7 、Y 8 and Y 9 positions. Shown below is an all-protio example that describes the proposed reaction between an aryl Grignard and a Weinreb amide as described in Huck, L. et al., Org. Lett., 2017, 19, 3747 - 3750.

[0128]

[0129] The Boc protecting group is removed and then reacted with alkyl bromide 9 (prepared in one step from primary alcohol 8) to form ketone 6, which is converted to flibanserin by asymmetric reduction using borane - dimethyl sulfide in the presence of a chiral catalyst ((R)-methyl - CBS).

[0130] The final exchange process of intermediate 6 can be used (using K2CO3 / D2O or DCl) to obtain a high level of %D at the Y 5 position prior to the final asymmetric reduction. Alternatively, if a high level of %H is desired at this stage, intermediate 6 is placed in K2CO3 / H2O or HCl and can be used to completely de-enrich position Y 5 .

[0131] As shown above, obtaining the deuterated analogs presented in Scheme 1 requires the following synthetic intermediates and reagents: 1, 3, 8, and BD3·SMe2. While the reagent BD3·SMe2 is purchased from Cambridge Isotope Laboratories, obtaining the deuterated analogs of intermediates 1, 3, and 8 requires separate synthesis from commercially available deuterated precursors and reagents, as shown in Schemes 2-4 below.

[0132] The synthesis of the all-proton analog of carboxylic acid 1 (1a, Y 3a =Y 3b =Y 4a =Y 4b =Y 5 =H) is shown in Scheme 2a below. According to the procedure described by Reddy et al. in WO 2017 / 017630A1, the first step in this procedure involves reducing ketone 10a (purchased from Sigma Aldrich) by treatment with sodium borohydride (NaBH4). The resulting alcohol 11a is then converted to nitrile 12a via a two-step procedure reported by Winkler et al., Adv. Synth. Cat., 2007, 8 + 9, 1475-1480. The nitrile 12a is then hydrolyzed to carboxylic acid 1a by treatment with aqueous potassium hydroxide according to the hydrolysis procedure for structurally similar compounds described by Barker et al. in WO 2012 / 035023A1. Replacing the sodium borohydride in Scheme 2a with sodium borodeuteride (NaBD4 (99% D), purchased from Cambridge Isotope Laboratories) provides 1b (Y 3a =Y 3b =Y 4a =Y 4b =H, Y 5 =D) (Scheme 2b).

[0133] The remaining analogs (1c-1h) can be prepared in a similar manner starting from appropriately labeled commercially available starting materials (10b (99% D), obtained from CDN Isotopes; 10c (95-98% D), obtained from APIChemical; and 10d (98% D), obtained from CombiPhos), as described in Schemes 2c-2h below.

[0134] The use of appropriately deuterated reagents allows for the introduction of deuterium at the Y 3a 、Y 3b 、Y 4a 、Y 4b and Y 5 positions of the compounds of structural formula (I) (e.g., compound 7) or any appropriate intermediate herein, e.g., at any Y 3a 、Y 3b 、Y4a , Y 4b and Y 5 About 90%, about 95%, about 97%, about 98% or about 99% of deuterium is introduced at

[0135] Scheme 2. Synthesis of intermediates 1a - 1h

[0136]

[0137]

[0138]

[0139] Although the fully protonated analogue of aryl bromide 3 (3a, Y 7 = Y 8 = Y 9 = H; R 1 = R 2 = CH3) is purchased from Alfa Aesar, its preparation according to the literature procedure is shown in Scheme 3a. As described by Ratton, S. et al. in European Patent No. 0037353A1, the first step in this procedure involves the reaction of catechol (13a, purchased from Alfa Aesar) with methanol in the presence of sodium acetate and acetic acid to form the monomethyl ether 14a. As described by Huet, L. et al., Synlett, 2012, 23, 1230 - 1234, the resulting phenol can then be converted to 3a by a two - step method involving bromination and then alkylation with methyl iodide.

[0140] The remaining analogues (3b - 3h) can be prepared according to the general route shown in Scheme 3a, starting from catechol (13a) or d4 - catechol (13b (96% D), purchased from Aldrich) and optionally substituting methanol with d4 - methanol (99.8% D, purchased from Aldrich) and / or methyl iodide with d3 - methyl iodide (99.5% D, purchased from Aldrich) (Scheme 3b - 3h).

[0141] Using appropriately deuterated reagents enables the introduction of deuterium at the Y 7 , Y 8 , Y 9 , R 1 and R 2 positions of the compounds of structural formula (I) (such as compound 7) or any suitable intermediate herein, for example, introducing about 90%, about 95%, about 97%, about 98% or about 99% of deuterium at any Y 7 , Y 8 , Y 9 , R 1 and R 2 positions.

[0142] Scheme 3. Synthesis of Intermediates 3a - 3h

[0143]

[0144]

[0145] Although the fully protonated analogue of primary alcohol 8 (8a, Y 1a = Y 1b = Y 2a = Y 2b = Y 10 = Y 11 = H) was purchased from Aldrich, its preparation according to the literature procedure is shown in Scheme 4a. According to the method described by Senaweera et al., Chem.Comm., 2017, 53, 7545 - 7548, the first step in this procedure involves reducing 4 - fluorobenzoic acid (16a, purchased from Aldrich) with lithium aluminium hydride to give benzyl alcohol 17a. This was subsequently treated with phosphorus tribromide as described by Shaik et al., Eur.J.Med.Chem., 2017, 126, 36 - 51, thereby providing alkyl bromide 18a, which was then converted to carboxylic acid 19a by the two - step procedure reported by Mahtab et al., J.Chem.Pharm.Sci., 2014, 7, 34 - 38. Finally, according to the procedure of Sakamuri et al., Bioorg.Med.Chem.Lett., 2001, 11, 495 - 500, carboxylic acid 19a was reduced with borane to obtain primary alcohol 8a.

[0146] The remaining analogues (8b - 8h) can be prepared according to the general route shown in Scheme 4a, starting from 4 - fluorobenzoic acid (16a) or d4 - 4 - fluorobenzoic acid (16b (99% D), purchased from CDN Isotopes) and replacing LiAlH4 with LiAlD4 (98% D, purchased from Cambridge Isotope Laboratories) and / or BH3 with BD3 (98% D, purchased from Cambridge Isotope Laboratories) as appropriate (Scheme 8b - 8h).

[0147] The use of appropriately deuterated reagents allows for the introduction of deuterium at the Y 1a 、Y 1b 、Y 2a 、Y 2b 、Y 10 and Y 11 positions of the compounds of formula I (e.g., compound 7) or any suitable intermediate herein, e.g., at any Y 1a 、Y 1b 、Y 2a 、Y2b , Y 10 and Y 11 about 90%, about 95%, about 97%, about 98% or about 99% deuterium is introduced at

[0148] Scheme 4. Synthesis of Intermediates 8a - 8h

[0149]

[0150]

[0151]

[0152] Proposed d 27 -The synthesis of flibanserin (7h) is described in Scheme 5 below as using the deuterated intermediates described herein are described.

[0153] Scheme 5.d 27 - Representative synthesis of flibanserin (7h)

[0154]

[0155]

[0156] Use of appropriately deuterated reagents allows for the introduction of deuterium at Y of the compound of structural formula (I) or any suitable intermediate herein 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , R 1 and R 2 positions, for example at any Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , R 1 and / or R 2About 90%, about 95%, about 97% or about 99% deuterium is introduced therein.

[0157] The specific methods and compounds shown above are not intended to be limiting. Whether designated by the same variable names (i.e., R 1 , R 2 , R 3 etc.), the variables depicted in the chemical structures in the present schemes are hereby defined to correspond to the definitions of the chemical groups (moieties, atoms, etc.) at the corresponding positions in the chemical formulas of the compounds of the present disclosure. The suitability of the chemical groups in the compound structures for synthesizing another compound is within the knowledge of those of ordinary skill in the art.

[0158] Other methods for synthesizing the compounds of formula (I) and their synthetic precursors (including those within pathways not explicitly shown in the present schemes) are within the means of those of ordinary skill in the art of chemistry. The methods described herein may additionally include steps before or after the steps specifically described herein for adding or removing suitable protecting groups to ultimately allow the synthesis of the compounds of the present disclosure. Additionally, the various synthetic steps may be carried out in an alternate sequence or order to obtain the desired compounds. Synthetic chemical transformations and protecting group methods (protection and deprotection) useful for synthesizing applicable compounds are known in the art and include, for example, those described in the following: Larock R, Comprehensive Organic Transformations, VCH Publishers (1989); Greene, TW et al., Protective Groups in Organic Synthesis, 3 rd th Ed., John Wiley and Sons (1999); Fieser, L. et al., Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and Paquette, L ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

[0159] Only those combinations of substituents and variables contemplated by the present invention are those that result in the formation of stable compounds.

[0160] Composition

[0161] The present invention also provides a pharmaceutical composition, which comprises an effective amount of a compound of structural formula (I) (such as the first or second embodiment or any of the foregoing embodiments or aspects of the embodiments thereof), or a compound of structural formula (II), or a pharmaceutically acceptable salt of the compound; and a pharmaceutically acceptable carrier. The carrier is "acceptable" in the sense that it is compatible with the other ingredients of the formulation, and in the case of a pharmaceutically acceptable carrier, the amount used thereof in the drug is harmless to its recipient.

[0162] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polypropylene block polymers, polyethylene glycol and lanolin.

[0163] If desired, the solubility and bioavailability of the compounds of the present invention in the pharmaceutical composition can be enhanced by methods well known in the art. One method includes using lipid excipients in the formulation. See "Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences)," edited by David J. Hauss, Informa Healthcare, 2007; and "Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples," edited by Kishor M. Wasan, Wiley-Interscience, 2006.

[0164] Another known method for enhancing bioavailability is to use the amorphous form of the compounds of the present invention optionally in combination with poloxamer (such as LUTROL TM and PLURONIC TM(BASF Corporation)) or a block copolymer formulation of ethylene oxide and propylene oxide. See U.S. Patent 7,014,866; and U.S. Patent Publications 20060094744 and 20060079502.

[0165] The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compounds of formula herein are administered transdermally (e.g., using a transdermal patch or iontophoresis techniques). Other formulations can be conveniently provided as unit dosage forms, such as tablets, sustained release capsules and in liposomes, and can be prepared by any method known in the pharmaceutical art. See, e.g., Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th Edition, 2000).

[0166] Such preparation methods include the step of combining the molecule to be administered with components (such as carriers) that constitute one or more auxiliary components. Generally, the composition is prepared by uniformly and tightly combining the active ingredient with a liquid carrier, liposome or a divided solid carrier or both, and then, if necessary, shaping the product.

[0167] Another embodiment is a controlled release pharmaceutical composition comprising a compound of formula (I) (such as any of the embodiments or aspects of the embodiments described herein).

[0168] In one aspect of the controlled release pharmaceutical composition, the controlled release pharmaceutical composition further comprises a release control agent and optionally a pharmaceutically acceptable excipient.

[0169] The release control agent is optionally selected from hydrophilic release control agents, hydrophobic release control agents or mixtures thereof.

[0170] The hydrophilic release control agents are selected from, but not limited to: hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyethylene oxide, polyvinyl alcohol, polyvinylpyrrolidone, xanthan gum, guar gum, chitosan and its derivatives, carbomer, carrageenan, carboxymethyl cellulose, sodium alginate, polyethylene glycolated glycerides, polyethylene glycol or mixtures thereof.

[0171] The hydrophobic release control agent is selected from, but not limited to: polyvinyl acetate dispersions, ethylcellulose, cellulose acetate, cellulose propionate (low, medium or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate) and poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), waxes such as beeswax, palm wax, paraffin wax, microcrystalline wax and ozokerite; fatty alcohols such as cetearyl alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol; fatty acid esters such as glyceryl monostearate; glyceryl monooleate, acetylated glyceryl monoesters, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate or hydrogenated vegetable oil.

[0172] The amount of the release control agent can be from about 5% to about 95% by weight of the composition, more typically from about 25% to about 75% by weight of the composition, and more preferably from about 35% to about 65% by weight of the composition.

[0173] Pharmaceutically acceptable excipients include, but are not limited to: diluents, binders, solubilizers, solubilization promoters, pore formers, permeants, gas formers, lubricants and glidants known to those skilled in the art.

[0174] Another embodiment is a controlled release pharmaceutical composition comprising: a compound of structural formula (I) (or any embodiment or aspect of the compound of structural formula (I)); a release control agent selected from hydrophilic release control agents, hydrophobic release control agents and mixtures thereof; and optionally a pharmaceutically acceptable excipient.

[0175] Another embodiment is a controlled release pharmaceutical composition comprising: a compound of structural formula (I) (or any embodiment or aspect of the compound of structural formula (I)); a release control agent selected from hydrophilic release control agents, hydrophobic release control agents and mixtures thereof; and optionally a pharmaceutically acceptable excipient, wherein the hydrophilic release control agent is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyethylene oxide, polyvinyl alcohol, polyvinylpyrrolidone, xanthan gum, guar gum, chitosan and its derivatives, carbomer, carrageenan, carboxymethyl cellulose, sodium alginate, polyethylene glycolated glycerides, polyethylene glycol and mixtures thereof.

[0176] Another embodiment is a controlled-release pharmaceutical composition comprising: a compound of structural formula (I) (or any embodiment or aspect of the compound of structural formula (I)); a release control agent selected from hydrophilic release control agents, hydrophobic release control agents, and mixtures thereof; and optionally a pharmaceutically acceptable excipient, wherein the hydrophobic release control agent is selected from polyvinyl acetate dispersions, ethylcellulose, cellulose acetate, cellulose propionate (low, medium, or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), and poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), waxes such as beeswax, palm wax, paraffin wax, microcrystalline wax, and ozokerite; fatty alcohols such as cetearyl alcohol, stearyl alcohol, cetyl alcohol, and myristyl alcohol; fatty acid esters such as glyceryl monostearate; glyceryl monooleate, acetylated glyceryl monostearate, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, and hydrogenated vegetable oils.

[0177] U.S. Patent Application Publication No. 2013 / 0143897, published on June 6, 2013, describes a controlled-release pharmaceutical composition comprising blonanserin. In the described composition, blonanserin can be replaced with a compound of structural formula (I) (or any embodiment or aspect of the compound of structural formula (I)) to form a controlled-release pharmaceutical composition of the compound of the present invention.

[0178] In certain embodiments, the compound is administered orally. The compositions of the present invention suitable for oral administration can be provided as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil liquid emulsions; oil-in-water liquid emulsions; encapsulated in liposomes; or as a bolus, etc. Soft gelatin capsules can be used to contain such suspensions, which can advantageously increase the absorption rate of the compound.

[0179] In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, available diluents include lactose and dry corn starch. When an aqueous suspension is administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents can be added.

[0180] Compositions suitable for oral administration include: troches containing the ingredients in a flavored matrix, usually sucrose and gum arabic or tragacanth; and lozenges containing the active ingredients in an inert matrix such as gelatin and glycerin or sucrose and gum arabic.

[0181] Compositions suitable for parenteral administration include: aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostatic agents, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Immediate injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0182] Such injection solutions may be in the form of sterile injectable aqueous or oily suspensions. Such suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents, such as Tween 80, and suspending agents. Sterile injectable formulations may also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil may be used, including synthetic mono- or di-glycerides of fatty acids. Fatty acids such as oleic acid and its glyceride derivatives may be used in the preparation of injectables, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersing agents.

[0183] The pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal administration. These compositions may be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and will thus melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0184] The pharmaceutical composition of the present invention can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulations and can be prepared as a saline solution using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. See, for example, Rabinowitz JD and Zaffaroni AC, U.S. Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.

[0185] Local administration of the pharmaceutical composition of the present invention is particularly useful when the desired treatment involves a region or organ that is readily accessible by topical application. For topical application to the skin, the pharmaceutical composition is formulated as a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present invention include, but are not limited to: mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene - polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated as a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to: mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 - octyldodecanol, benzyl alcohol, and water. The pharmaceutical composition of the present invention can also be applied locally to the lower intestine by rectal suppository formulation or in a suitable enema formulation. The present invention also includes topical transdermal patches and iontophoretic administration.

[0186] The application of the therapeutic agent can be local to administer at the site of interest. Various techniques can be used to deliver the composition to the site of interest, such as injection, using a catheter, trocar, projectile, pluronic gel, stent, sustained - release drug polymer, or other devices that provide internal access.

[0187] Thus, according to yet another embodiment, the compounds of the invention can be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents or catheters. The general preparation of suitable coatings and coated implantable devices is known in the art and is illustrated in U.S. Pat. Nos. 6,099,562; 5,886,026 and 5,304,121. The coating is generally a biocompatible polymeric material such as a hydrogel polymer, polydimethylsiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene-vinyl acetate and mixtures thereof. The coating can optionally be further covered with a suitable outer coating of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid or combinations thereof to impart controlled release characteristics to the composition. As used herein, coatings for invasive devices should be included within the definition of a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0188] According to another embodiment, the invention provides a method of coating an implantable medical device, which comprises the step of contacting the device with the coating composition described above. It will be apparent to those skilled in the art that the coating of the device will be carried out prior to implantation into a mammal.

[0189] According to another embodiment, the invention provides a method of impregnating an implantable drug delivery device, which comprises the step of contacting the drug delivery device with a compound or composition of the invention. Implantable drug delivery devices include, but are not limited to, biodegradable polymer capsules or pellets, non-degradable diffusible polymer capsules and biodegradable polymer wafers.

[0190] According to another embodiment, the invention provides an implantable medical device coated with a compound of the invention or a composition comprising a compound of the invention such that the compound has therapeutic activity.

[0191] According to another embodiment, the invention provides an implantable drug delivery device impregnated with or containing a compound of the invention or a composition comprising a compound of the invention such that the compound is released from the device and has therapeutic activity.

[0192] When an organ or tissue is accessible due to removal from a subject, such organ or tissue can be bathed in a medium containing a composition of the invention, the composition of the invention can be applied to the organ or the composition of the invention can be applied in any other convenient manner.

[0193] In another embodiment, the composition of the present invention further comprises one or more other therapeutic agents. The other therapeutic agent can be selected from any compound or therapeutic agent known to have or exhibit favorable properties when administered with a compound having the same mechanism of action as flunicroceed. Such agents include those shown to be useful in combination with flunicroceed, including but not limited to escitalopram.

[0194] Preferably, the additional therapeutic agent is an agent useful for treating a disease or condition selected from the group consisting of psychosis, schizophrenia (including chronic schizophrenia), schizoaffective disorder, Parkinson's disease (including Parkinson's disease psychosis), dementia with Lewy bodies, sleep disorders (including insomnia), agitation, mood disorders (including depression), thromboembolic disorders, autism, and attention deficit hyperactivity disorder.

[0195] In one embodiment, the additional therapeutic agent is escitalopram.

[0196] In another embodiment, the present invention provides separate dosage forms of a compound of the invention and one or more of any of the above-mentioned additional therapeutic agents, wherein the compound and the other therapeutic agents are associated with each other. As used herein, the term "associated with each other" means that the separate dosage forms are packaged together or otherwise attached to each other so that it is readily understood that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of each other, sequentially or simultaneously).

[0197] In the pharmaceutical composition of the present invention, the compound of the present invention is present in an effective amount. As used herein, the term "effective amount" refers to an amount sufficient to treat the target disease when administered in an appropriate dosage regimen.

[0198] The term "subject in need thereof" refers to a subject who has or has been diagnosed with a disease or condition selected from psychosis, schizophrenia (including chronic schizophrenia), schizoaffective disorder, Parkinson's disease (including Parkinson's disease psychosis), dementia with Lewy bodies, sleep disorders (including insomnia), agitation, mood disorders (including depression), thromboembolic disorders, autism and attention deficit hyperactivity disorder, or is at risk of persisting or developing such a disease or disorder.

[0199] The relationship between dosages for animals and humans (based on milligrams per square meter of body surface) is described in Freireich et al., Cancer Chemother. Rep., 1966, 50:219. Body surface area can be roughly determined based on the height and weight of the subject. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY, 1970, 537.

[0200] In one embodiment, the effective amount of the compound of the present invention can be from 0.4 mg to 4 mg, from 0.2 mg to 10 mg, or from 0.02 mg to 20 mg. In a preferred embodiment, the effective amount is 2 mg.

[0201] In one embodiment, the effective amount of the compound of the present invention can be from 0.4 mg / day to 4 mg / day, from 0.2 mg / day to 10 mg / day, or from 0.02 mg / day to 20 mg / day. In a preferred embodiment, the effective amount is 2 mg / day.

[0202] In one embodiment, the effective amount of the compound of the present invention can be from 0.008 mg / kg to 0.08 mg / kg, from 0.004 mg / kg to 0.2 mg / kg, from 0.0004 mg / kg to 0.4 mg / kg. In a preferred embodiment, the effective amount is 0.04 mg / kg.

[0203] In one embodiment, the effective amount of the compound of the present invention can be from 0.008 mg / kg / day to 0.08 mg / kg / day, from 0.004 mg / kg / day to 0.2 mg / kg / day, from 0.0004 mg / kg / day to 0.4 mg / kg / day. In a preferred embodiment, the effective amount is 0.04 mg / kg / day.

[0204] The effective amount can be administered once or twice daily, every other day, weekly, or bi - weekly. In a preferred embodiment, the effective amount is administered once daily. As will be appreciated by those skilled in the art, the effective dose will also vary depending on the disease being treated, the severity of the disease, the route of administration, the sex, age, and general health of the subject, the use of excipients, the likelihood of co - administration with other therapeutic treatments (e.g., use of other agents), and the judgment of the attending physician. For example, guidance for selecting an effective dose can be determined by referring to the prescribing information for flibanserin.

[0205] For a pharmaceutical composition comprising one or more other therapeutic agents, the effective amount of the other therapeutic agent is from about 20% to 100% of the dose typically used in a single therapy regimen using only that agent. Preferably, the effective amount is from about 70% to 100% of the normal single therapy dose. The normal single therapy doses of these other therapeutic agents are well known in the art. See, e.g., Wells et al., Pharmacotherapy Handbook, 2nd ed., Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), which references are hereby incorporated by reference in their entirety.

[0206] Some of the other therapeutic agents mentioned above may act synergistically with the compounds of the invention. When this occurs, it will permit a reduction in the effective dose of the other therapeutic agent and / or the compounds of the invention relative to the dose required for single therapy. This has the advantage of minimizing the toxic side effects of the other therapeutic agent or the compounds of the invention, synergistically enhancing efficacy, improving the convenience of administration or use, and / or reducing the overall cost of compound preparation or formulation.

[0207] Method of treatment

[0208] In other embodiments, the invention provides a method of antagonizing or inverse agonizing 5-hydroxytryptamine 5-HT 2A receptor activity in a cell, which comprises contacting the cell with one or more compounds of formula (I) (e.g., any embodiment or aspect of an embodiment thereof) or formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is contacted in vitro. In some embodiments, the cell is contacted in vivo. In some embodiments, the cell is contacted ex vivo.

[0209] In certain embodiments, the invention provides a method of treating a disease beneficially treatable by a compound of formula (I) in a subject in need thereof, which comprises the step of administering to the subject an effective amount of the compound or a pharmaceutically acceptable salt thereof or a composition of the invention (including the pharmaceutical compositions and controlled release pharmaceutical compositions described herein). In certain embodiments, the subject is a patient in need of such treatment. In certain embodiments, the subject is a human.

[0210] In other embodiments, the present invention provides a pharmaceutical composition for treating or preventing a disease or condition selected from psychosis, chronic schizophrenia (including chronic schizophrenia), schizoaffective disorder, Parkinson's disease (including Parkinson's disease psychosis), Lewy body dementia, sleep disorders (including insomnia), agitation, mood disorders (including depression), thromboembolic disorders, autism, attention deficit hyperactivity disorder, and any combination thereof, comprising a compound of structural formula (I) (such as an embodiment described herein or an aspect of an embodiment thereof) or structural formula (II) or a pharmaceutically acceptable salt thereof.

[0211] In other embodiments, the present invention provides the use of a compound of structural formula (I) (such as an embodiment described herein or an aspect of an embodiment thereof) or structural formula (II) or a pharmaceutically acceptable salt thereof for treating or preventing a disease or condition selected from psychosis, schizophrenia (including chronic schizophrenia), schizoaffective disorder, Parkinson's disease (including Parkinson's disease psychosis), Lewy body dementia, sleep disorders (including insomnia), agitation, mood disorders (including depression), thromboembolic disorders, autism, attention deficit hyperactivity disorder, and any combination thereof.

[0212] In other embodiments, the present invention provides the use of a compound of structural formula (I) (such as an embodiment described herein or an aspect of an embodiment thereof) or structural formula (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or condition selected from psychosis, schizophrenia (including chronic schizophrenia), schizoaffective disorder, Parkinson's disease (including Parkinson's disease psychosis), Lewy body dementia, sleep disorders (including insomnia), agitation, mood disorders (including depression), thromboembolic disorders, autism, attention deficit hyperactivity disorder, and any combination thereof.

[0213] Diseases suitable for the treatment methods disclosed herein are well known in the art and include, but are not limited to: psychosis, schizophrenia (including chronic schizophrenia), schizoaffective disorder, Parkinson's disease (including Parkinson's disease psychosis), Lewy body dementia, sleep disorders (including insomnia), agitation, mood disorders (including depression), thromboembolic disorders, autism, and attention deficit hyperactivity disorder.

[0214] The identification of subjects in need of such treatment can be made by the judgment of the subject or a health care professional and can be subjective (e.g., an opinion) or objective (e.g., measurable by a test or diagnostic method).

[0215] In another embodiment, any of the above-described treatment methods includes a further step of co-administering to a subject in need thereof one or more other therapeutic agents. The other therapeutic agents can be selected from any other therapeutic agents known to be useful for co-administration with flibanserin. The selection of the other therapeutic agents also depends on the particular disease or condition to be treated. Examples of other therapeutic agents that can be employed in the methods of the present invention are those described above for combination compositions comprising a compound of the present invention and other therapeutic agents.

[0216] In particular, the combination therapy of the present invention includes co-administering to a subject in need thereof a compound of formula (I) (e.g., an embodiment described herein or an aspect of an embodiment thereof) or formula (II) or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents to treat the following conditions (specific other therapeutic agents are shown in parentheses following the indication): depression (escitalopram).

[0217] As used herein, the term "co-administer" means that the other therapeutic agent can be administered with the compound of the present invention as part of a single dosage form (e.g., a composition of the present invention containing the compound of the present invention and the other therapeutic agent described above) or as separate multiple dosage forms. Alternatively, the other agent can be administered before, sequentially, or after the compound of the present invention is administered. In such combination therapy treatment, both the compound of the present invention and the other therapeutic agent are administered by conventional methods. Administration to a subject of a composition of the present invention containing the compound of the present invention and the other therapeutic agent does not exclude administration of the same therapeutic agent, any other other therapeutic agent, or any compound of the present invention alone to the subject at another time during the course of treatment.

[0218] The effective amounts of these other therapeutic agents are well known to those of skill in the art, and dosing guidance can be found in the patents and published patent applications referred to herein as well as Wells et al., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000) and other medical articles. However, determining the optimal effective amount range of the other therapeutic agents is well within the ability of those of skill in the art.

[0219] In one embodiment of the present invention, when other therapeutic agents are administered to a subject, the effective amount of the compounds of the present invention is less than the effective amount when no other therapeutic agents are administered. In another embodiment, the effective amount of the other therapeutic agent is less than the effective amount when no compounds of the present invention are administered. In this way, the undesirable side effects associated with high doses of either agent can be minimized. Other potential advantages, including but not limited to improved dosing regimens and / or reduced drug costs, will be apparent to those skilled in the art.

[0220] In yet another aspect, the present invention provides the use of a compound of structural formula (I) (such as an embodiment described herein or an aspect of an embodiment thereof) or structural formula (II) or a pharmaceutically acceptable salt thereof alone or in combination with one or more of the above other therapeutic agents in the manufacture of a medicament for treating a disease, disorder or symptom as described above in a subject, either as a single composition or in separate dosage forms. Another aspect of the present invention is a compound of structural formula (I) (such as an embodiment described herein or an aspect of an embodiment thereof) or structural formula (II) or a pharmaceutically acceptable salt thereof for use in treating a disease, disorder or symptom described herein in a subject.

[0221] Examples

[0222] Example 1. Synthesis of (R)-(2,3-bis(methoxy-d3)phenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanol (Compound 147).

[0223] Scheme 6. Preparation of (R)-(2,3-bis(methoxy-d3)phenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanol (Compound 147).

[0224]

[0225] Step 1. 1,2-Bis(methoxy-d3)benzene (21b). To a solution of 1,2-dihydroxybenzene (20a) (30 g, 272.5 mmol) in anhydrous DMSO (250 mL) at room temperature was added KOH (61.2 g, 1090 mmol), followed by methyl iodide-d3 (42.4 mL, 681.1 mmol, Sigma Aldrich, >99.5% atom D). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (800 mL) and extracted with CH2Cl2 (4 × 600 mL). The combined organic layers were washed with water (3 × 1 L), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dried (vacuum oven) to give 21b as a yellow oil (36.4 g, 92%).

[0226] Step 2.4 - tert-Butyl (2,3-bis(methoxy-d3)benzoyl)piperidine-1-carboxylate (4b) . To a solution of 21b (18 g, 125 mmol) in THF (230 mL) at 0 °C was slowly added a solution of 2.5 M n-butyllithium in hexane (50 mL, 125 mmol). The reaction mixture was heated to room temperature, stirred for 2 h, and then cooled back to 0 °C. A solution of 2a (34.0 g, 125 mmol) in THF (400 mL) was pre-cooled to 0 °C and slowly added to the reaction mixture. The reaction mixture was heated to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous NH4Cl (400 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 600 mL). The combined organic layers were washed with saturated brine (1 × 600 mL), dried (Na2SO4), filtered, and concentrated to a yellow oil. The crude material was purified in three portions by chromatography (Interchim automated chromatography system, SorbTech 330 g silica gel column, eluted with a gradient of 5 - 20% EtOAc in hexane) to afford 4b (26.6 g, 60%) as a clear oil.

[0227] Step 3. (2,3-Bis(methoxy-d3)phenyl)(piperidin-4-yl)methanone (5b). A mixture of 4b (26.6 g, 75 mmol) and trifluoroacetic acid (172 mL, 2240 mmol) was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure to afford a clear oil. Et2O (800 mL) was added to the mixture to give a white precipitate, which was filtered to afford 5b (26.5 g, 95%) as a white solid.

[0228] Step 4. (2,3-Bis(methoxy-d3)phenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanone (6b). To a solution of 5b (5.0 g, 14.2 mmol) in anhydrous DMF (66 mL) at room temperature was added sodium bicarbonate (3.0 g, 35.5 mmol), followed by 9a (2.88 g, 14.2 mmol). The reaction mixture was heated at 90 °C for 3 h and then concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and then washed with water (3 × 100 mL) and saturated brine (100 mL). The organic layer was concentrated under reduced pressure and the residue was purified by chromatography (Interchim automated chromatography system, Biotage 60 g silica gel column, eluted with a gradient of 0 - 5% MeOH in CH2Cl2) to afford 6b (2.96 g, 55%) as a brown oil.

[0229] Step 5. (2,3-Bis(methoxy-d3)phenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanol (7b). To a solution of 6b (0.80 g, 2.12 mmol) in MeOH (30 mL) at 0 °C was added sodium borohydride (0.24 g, 6.37 mmol). The reaction mixture was heated to room temperature and stirred for 16 h. The reaction mixture was cooled to 0 °C and sodium borohydride (0.16 g, 4.24 mmol) was added. The reaction mixture was heated to room temperature and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water (50 mL) and EtOAc (50 mL). The layers were separated and the organic layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were concentrated under reduced pressure and purified by chromatography (Interchim automated chromatography system, Interchim 25 g HP silica gel column, eluted with a gradient of 0 - 10% MeOH in CH2Cl2) to afford racemic 7b as a white solid (0.51 g, 64%).

[0230] Chiral separation of (R)-(2,3-Bis(methoxy-d3)phenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanol (Compound 147). 7b (0.44 g) was purified by chiral SFC (Chiralpak AD-H, 250 × 20 mm, 5 mm; 25% EtOH (0.1% diethylamine / CO2, 100 bar; flow rate 65 mL / min; wavelength 220 nm) to afford the early eluting (R)-enantiomer as a clear oil (220 mg).

[0231] The resulting clear oil was triturated with CH2Cl2 and hexanes to afford Compound 147 as a white solid (212 mg, 96%).

[0232] 1 H NMR (400 MHz, CDCl3) δ 1.26 - 1.53 (m, 3H), 1.68 (td, J = 3.9, 7.8, 11.6 Hz, 1H), 1.81 - 2.02 (m, 2H), 2.04 - 2.11 (m, 1H), 2.39 (br s, 1H), 2.46 - 2.58 (m, 2H), 2.70 - 2.82 (m, 2H), 2.92 (br d, J = 12.0 Hz, 1H), 3.07 (br d, J = 11.2 Hz, 1H), 4.63 (d, J = 8.1 Hz, 1H), 6.81 - 7.00 (m, 4H), 7.01 - 7.07 (m, 1H), 7.13 (t, J = 6.1 Hz, 2H). LCMS (method: SorbTech C 18AQ, 2.1×50 mm, 3 μm; 5 - 95% acetonitrile / water containing 0.1% formic acid for 14 minutes, hold for 4 minutes; flow rate: 0.7 mL / min; wavelength: 210 nm): retention time: 4.7 minutes; purity: 99.3%; (EI-MS): m / z = 380.2 ([M + H] + )。

[0233] Chiral HPLC (Chiralpak IG column, 150 mm × 4.6 mm, 3 μm, method: 100% EtOH; flow rate: 0.8 mL / min; wavelength: 230 nm): retention time: (R)-isomer: 4.1 minutes, (S)-isomer: 5.3 minutes; 99.9% ee.

[0234] Optical rotation [α] D 20 (2.14 g / 100 mL MeOH) = +19.1°.

[0235] Example 2. Synthesis of (R)-(1-(4-fluorophenethyl)piperidin-4-yl)(2-methoxy-3-(methoxy-d3)phenyl)methanol (Compound 115).

[0236] Scheme 7. Preparation of (R)-(1-(4-fluorophenethyl)piperidin-4-yl)(2-methoxy-3-(methoxy-d3)phenyl)methanol (Compound 115).

[0237]

[0238] Step 1. 2-((1-(4-fluorophenethyl)piperidin-4-yl)(hydroxy)methyl)-6-(methoxy-d3)phenol (30b). To a solution of 6b (2.5 g, 7 mmol) in anhydrous THF (100 mL) at 0 °C was added a solution of 1.0 M lithium tri-sec-butylborohydride in THF (27 mL, 27 mmol). The reaction mixture was stirred at 0 °C for 2 hours and then heated at 70 °C overnight. The reaction mixture was cooled to 0 °C and quenched with water (150 mL). The layers were separated and the aqueous layer was extracted with Et2O (2 × 150 mL). The combined organic layers were washed with saturated brine solution, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography (Interchim automated chromatography system, Biotage 100 g silica gel column, eluting with a gradient of 0 - 10% 0.3 M ammonia / MeOH in CH2Cl2) to afford 30b as a white solid (0.8 g, 33%).

[0239] Step 2. (1-(4-Fluorophenethyl)piperidin-4-yl)(3-(methoxy-d3)-2-methoxyphenyl)-methanol (7c). Cesium carbonate (1.2 g, 3.8 mmol) was added to a solution of 30b (680 mg, 1.9 mmol) in acetone (60 mL) at room temperature. Methyl 4-methylbenzenesulfonate (321 mg, 1.7 mmol) was added in four portions over 4 hours at room temperature. The reaction mixture was stirred at room temperature for 1 hour, filtered through Celite (10 g), and the filter cake was washed with CH2Cl2 (2 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (Interchim automated chromatography system, Biotage 55 g KP-NH column, eluting with a gradient of 0-10% MeOH in CH2Cl2). The resulting material was purified again as described above to afford the racemic 7c as a clear oil (458 mg, 65%).

[0240] Chiral separation of (R)-(1-(4-fluorophenethyl)piperidin-4-yl)(2-methoxy-3-(methoxy-d3)phenyl)methanol (Compound 115). 7c (0.45 g) was purified by chiral SFC (AD-H, 250 × 20 mm, 5 mm; 25% EtOH (0.1% diethylamine / CO2, 100 bar; flow rate 60 mL / min; wavelength 220 nm) to afford the early eluting (R)-enantiomer as a clear oil (230 mg). The resulting clear oil was triturated with CH2Cl2 and hexanes to afford Compound 115 as a white solid (184 mg).

[0241] 1 H NMR (400 MHz, CDCl3) δ 1.24 - 1.33 (m, 1H), 1.33 - 1.43 (m, 1H), 1.44 - 1.54 (m, 1H), 1.68 (tdt, J = 3.9, 7.8, 11.6 Hz, 1H), 1.91 (dt, J = 2.8, 11.5 Hz, 1H), 1.99 (dt, J = 2.4, 11.6 Hz, 1H), 2.05 - 2.11 (m, 1H), 2.37 (br s, 1H), 2.49 - 2.56 (m, 2H), 2.73 - 2.81 (m, 2H), 2.93 (br d, J = 10.9 Hz, 1H), 3.07 (br d, J = 11.2 Hz, 1H), 3.87 (s, 3H), 4.63 (d, J = 8.1 Hz, 1H), 6.84 (dd, J = 1.5, 8.1 Hz, 1H), 6.89 (dd, J = 1.5, 7.8 Hz, 1H), 6.91 - 6.98 (m, 2H), 7.02 - 7.08 (m, 1H), 7.10 - 7.16 (m, 2H).

[0242] LCMS (Method: Atlantis T3 column, 2.1×50 mm, 3 μm; 5 - 95% acetonitrile / water containing 0.1% formic acid for 14 minutes, hold for 4 minutes; flow rate: 0.7 mL / min; wavelength: 210 nm): retention time: 4.5 minutes; purity: 98.8%; (EI-MS): m / z = 377.2 ([M+H] + ).

[0243] Chiral HPLC (Chiralpak IG column, 250 mm × 4.6 mm, 5 μm, Method: 100% EtOH; flow rate: 1.0 mL / min; wavelength: 230 nm): retention time: (R) isomer: 4.8 minutes, (S) isomer: 5.8 minutes; 98.9% ee.

[0244] Example 3. Synthesis of (R)-(2,3-bis(methoxy-d3)phenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanol-d (Compound 148).

[0245] Scheme 8. Preparation of (R)-(2,3-bis(methoxy-d3)phenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanol-d (Compound 148).

[0246]

[0247] Step 1. (2,3-Bis(methoxy-d3)phenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanol-d (7d). Sodium borodeuteride (0.64 g, 15.12 mmol, CIL, 99% D4) was added to a solution of 6b (1.90 g, 5.04 mmol) in MeOD (70 mL, Aldrich, 99.5 atom % D) at 0 °C. The reaction mixture was heated to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water (50 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were concentrated under reduced pressure to afford 7d (2.4 g, quantitative) as a yellow oil.

[0248] Chiral separation of (R)-(2,3-bis(methoxy-d3)phenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanol-d (Compound 148). 7d (830 mg) was purified by chiral SFC (AD-H, 250 × 20 mm, 5 mm; 25% EtOH (0.1% diethylamine / CO2, 100 bar; flow rate 65 mL / min; wavelength 220 nm) to afford the early eluting (R) enantiomer as a clear oil (398 mg).

[0249] The obtained clear oily substance was triturated with CH2Cl2 and hexane to afford the white solid compound 148 (286 mg).

[0250] 1 1H NMR (400 MHz, CDCl3) δ 1.21 - 1.32 (m, 1H), 1.32 - 1.42 (m, 1H), 1.43 - 1.52 (m, 1H), 1.57 (s, 4H), 1.67 (tt, J = 3.8, 7.8, 11.6 Hz, 1H), 1.89 (dt, J = 2.9, 11.5 Hz, 1H), 1.97 (dt, J = 2.4, 11.7 Hz, 1H), 2.08 (br d, J = 13.1 Hz, 1H), 2.31 (br s, 1H), 2.49 - 2.54 (m, 2H), 2.73 - 2.78 (m, 2H), 2.92 (br d, J = 10.8 Hz, 1H), 3.07 (br d, J = 11.5 Hz, 1H), 3.81 - 3.85 (m, 1H), 4.60 - 4.65 (m, 1H), 6.84 (dd, J = 1.4, 8.1 Hz, 1H), 6.89 (dd, j = 1.5, 7.8 Hz, 1H), 6.95 (t, J = 8.7 Hz, 2H), 7.04 (t, J = 7.9 Hz, 1H), 7.13 (dd, J = 5.5, 8.5 Hz, 2H).

[0251] LCMS (Method: SorbTech C18AQ column, 2.1×50 mm, 3 μm; 5 - 95% acetonitrile / water containing 0.1% formic acid for 14 minutes, hold for 4 minutes; flow rate: 0.7 mL / min; wavelength: 210 nm): retention time: 4.6 minutes; purity: 99.6%; (EI-MS): m / z = 381.3 ([M+H] + )

[0252] Chiral HPLC (Chiralpak IG column, 150 mm×4.6 mm, 3 μm, Method: 100% EtOH; flow rate: 0.8 mL / min; wavelength: 230 nm): retention time: (R)-isomer: 4.1 minutes, (S)-isomer: 5.3 minutes; 99.7% ee.

[0253] Example 4. Synthesis of (R)-(1-(4-fluorophenethyl)piperidin-4-yl)(3-methoxy-2-(methoxy-d3)phenyl)methanol (Compound 131)

[0254] Scheme 9. Preparation of (R)-(1-(4-fluorophenethyl)piperidin-4-yl)(3-methoxy-2-(methoxy-d3)phenyl)methanol (Compound 131).

[0255]

[0256] Step 1. tert-Butyl 4-(2,3-dimethoxybenzoyl)piperidine-1-carboxylate (4a). To a solution of 21a (2.7 g, 19.5 mmol) in anhydrous THF (30 mL) at 0 °C was added a solution of 2.5 M n-butyllithium in hexane (7.8 mL, 19.5 mmol). The reaction mixture was heated to room temperature for 2 h and then cooled back to 0 °C. A pre-cooled solution of 2a (5.3 g, 19.5 mmol) in anhydrous THF (50 mL) was slowly added at 0 °C. The reaction mixture was heated to room temperature and stirred overnight. The reaction mixture was quenched with saturated NH4Cl solution (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 120 mL). The combined organic layers were washed with saturated brine solution, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography (Interchim automatic chromatography system, SorbTech 220 g silica gel column, eluted with a gradient of 5 - 20% EtOAc in hexane) to afford 4a as a clear oil (4.05 g, 60%).

[0257] Step 2. (2,3-Dimethoxyphenyl)(piperidin-4-yl)methanone trifluoroacetate (5a). To 4a (6.7 g, 19 mmol) at 0 °C was added trifluoroacetic acid (44 mL, 576 mmol). The reaction mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure to afford a clear oil. Et2O (100 mL) was added and the mixture was stirred at room temperature for 2 h. The solid was filtered and washed with Et2O (50 mL) to afford 5a as a white solid (5.9 g, 90%).

[0258] Step 3. (2,3-Dimethoxyphenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanone (6a). To a solution of 5a (5.9 g, 17 mmol) in DMF (80 mL) at room temperature was added NaHCO3 (3.6 g, 43 mmol) and 9a (3.5 g, 17 mmol). The reaction mixture was heated at 90 °C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was adsorbed onto silica gel (25 g) and then purified by chromatography (Interchim automatic chromatography system, Biotage 100 g silica gel column, eluted with a gradient of 0 - 10% MeOH in CH2Cl2) to afford 6a as a dark brown oil (4.3 g, 68%).

[0259] Step 4. 2-((1-(4-Fluorophenethyl)piperidin-4-yl)(hydroxy)methyl)-6-methoxyphenol (30a). To a solution of 6a (4.3 g, 12 mmol) in anhydrous THF (200 mL) at 0 °C was added a solution of 1.0 M lithium tri-sec-butylborohydride in THF (46 mL, 46 mmol). The reaction mixture was stirred at 0 °C for 2 h and then heated at 70 °C overnight. The reaction mixture was cooled to 0 °C and diluted with water (150 mL). The layers were separated and the aqueous layer was extracted with Et2O (2 × 150 mL). The combined organic layers were washed with saturated brine solution and concentrated under reduced pressure. The residue was purified by chromatography (Interchim automated chromatography system, Biotage 100 g silica gel column, eluting with a gradient of 0-10% 0.3 M ammonia / MeOH in CH2Cl2) to afford 30a as a yellow solid (2.9 g, 70%).

[0260] Step 5. (1-(4-Fluorophenethyl)piperidin-4-yl)(3-methoxy-2-(methoxy-d3)phenyl)-methanol (7e). To a solution of 30a (310 mg, 0.86 mmol) in acetone (50 mL) at room temperature was added cesium carbonate (564 mg, 1.7 mmol). Methyl d3-4-methylbenzenesulfonate (151 mg, 0.8 mmol, CDN, 99.5 atom % D) was added to the reaction mixture in four equal portions at room temperature over 4 h. The reaction mixture was stirred at room temperature for 1 h and then filtered through Celite (10 g) and the cake was washed with CH2Cl2 (2 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (Interchim automated chromatography system, Biotage 110 g KP-NH column, eluting with a gradient of 0-10% MeOH in CH2Cl2) to afford 7e as a clear oil (0.2 g, 62%).

[0261] Chiral separation of (R)-(1-(4-Fluorophenethyl)piperidin-4-yl)(3-methoxy-2-(methoxy-d3)phenyl)methanol (Compound 131). 7e (390 mg) was purified by chiral SFC (AD-H, 250 × 20 mm, 5 mm; 25% EtOH (0.1% diethylamine / CO2, 100 bar; flow rate 60 mL / min; wavelength 220 nm) to afford the early eluting (R)-enantiomer as a clear oil (180 mg).

[0262] The resulting clear oil was triturated with CH2Cl2 and hexanes to afford Compound 131 as a white solid (148 mg, 82% recovery).

[0263] 11H NMR (400 MHz, CDCl3) δ 1.24 - 1.33 (m, 1H), 1.34 - 1.43 (m, 1H), 1.44 - 1.54 (m, 1H), 1.68 (tdt, J = 3.9, 7.8, 11.6 Hz, 1H), 1.79 (br s, 1H), 1.90 (dt, J = 2.9, 11.4 Hz, 1H), 1.98 (dt, J = 2.4, 11.7 Hz, 1H), 2.08 (quint, J = 2.8, 13.1 Hz, 1H), 2.37 (br s, 1H), 2.48 - 2.56 (m, 2H), 2.71 - 2.81 (m, 2H), 2.93 (br d, J = 11.1 Hz, 1H), 3.07 (br d, J = 11.4 Hz, 1H), 3.87 (s, 3H), 4.63 (d, J = 8.1 Hz, 1H), 6.84 (dd, J = 1.5, 8.2 Hz, 1H), 6.89 (dd, J = 1.5, 7.8 Hz, 1H), 6.91 - 6.98 (m, 2H), 7.01 - 7.07 (m, 1H), 7.10 - 7.17 (m, 2H).

[0264] LCMS (Method: Atlantis T3 column, 2.1×50 mm, 3 μm; 5 - 95% acetonitrile / water with 0.1% formic acid for 14 minutes, hold for 4 minutes; Flow rate: 0.7 mL / min; Wavelength: 210 nm): Retention time: 4.6 minutes; Purity: 99.9%; (EI - MS): m / z = 377.2 ([M + H] + )。

[0265] Chiral HPLC (Chiralpak IG column, 250 mm×4.6 mm, 5 μm, Method: 100% EtOH; Flow rate: 1.0 mL / min; Wavelength: 230 nm): Retention time: (R) isomer: 4.8 minutes, (S) isomer: 5.8 minutes; 99.9% ee.

[0266] Example 5. Synthesis of (R)-(2,3 - bis(methoxy - d3)phenyl)(1-(2-(4 - fluorophenyl)ethyl - 1,1 - d2)piperidin - 4 - yl)methanol (Compound 151)

[0267] Scheme 10. Preparation of 1-(2 - bromoethyl - 2,2 - d2)-4 - fluorobenzene (9b)

[0268]

[0269] Step 1. 2-(4-Fluorophenyl)ethane-1,1-d2-1-ol (8b). 19a (5.0 g, 32.45 mmol) was dissolved in MeOD (8 mL, Cambridge Isotope, 99.8 atom % D) and concentrated under reduced pressure, and then repeated twice. The residue was dissolved in anhydrous THF (20 mL), and a suspension of lithium aluminum deuteride (1.36 g, 32.45 mmol, Boc Sciences, 98 atom % D) in anhydrous THF (50 mL) was added at 0 °C. The reaction mixture was heated to room temperature, stirred for 1 h, and then heated under reflux for 4 h. The reaction mixture was cooled to room temperature and quenched with water (1.5 mL), 15% sodium hydroxide solution (2 mL), and then water (3 mL). The mixture was filtered through a Celite pad (20 g), and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (Interchim automatic chromatography system, RediSep 80 g silica gel column, eluted with a hexane gradient of 0 - 25% acetone) to give 8b as a yellow oil (4.0 g, 87%).

[0270] Step 2. 1-(2-Bromoethyl-2,2-d2)-4-fluorobenzene (9b). Carbon tetrabromide (5.08 g, 15.32 mmol) was added to a solution of 8b (1.74 g, 12.26 mmol) in CH2Cl2 (25 mL) at 0 °C, and then triphenylphosphine (4.82 g, 18.39 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h, then diluted with diethyl ether (100 mL) and hexane (40 mL), and stirred for 40 min to form a white precipitate. The suspension was filtered through a Celite pad (20 g) to obtain a clear filtrate, which was concentrated under reduced pressure. The crude product was purified by chromatography (Interchim automatic chromatography system, Biotage 100 g silica gel column, eluted with a hexane gradient of 0 - 10% EtOAc) to give 9b as a clear oil (1.57 g, 63%).

[0271] Scheme 11. Preparation of (R)-(2,3-Bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1-d2)piperidin-4-yl)methanol (Compound 151).

[0272]

[0273] Step 3. (2,3-Bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1-d2)piperidin-4-yl)-methanone (6c). At room temperature, sodium bicarbonate powder (0.89 g, 10.61 mmol) was added to a solution of 5b (1.5 g, 4.24 mmol) in anhydrous DMF (21 mL), and then a solution of 9b (0.87 g, 4.24 mmol) in anhydrous DMF (1 mL) was added. The reaction mixture was heated at 90 °C for 3 hours and then concentrated under reduced pressure. Water (30 mL) was added, and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (30 mL) and saturated brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (Interchim automatic chromatography system, SorbTech 80 g silica gel column, eluted with a gradient of 0 - 5% MeOH in CH2Cl2), affording 6c (0.58 g, 36%) as a yellow oil.

[0274] Step 4. (2,3-Bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1-d2)piperidin-4-yl)-methanol (7f). Sodium borohydride (0.173 g, 4.59 mmol) was added portionwise to a solution of 6c (0.58 g, 1.53 mmol) in MeOH (20 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water (20 mL) and EtOAc (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure, affording 7f (0.46 g, 80%) as a white solid.

[0275] Chiral separation of (R)-(2,3-Bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1-d2)piperidin-4-yl)methanol (Compound 151). 7f (437 mg) was purified by chiral SFC (AD-H, 250 × 20 mm, 5 mm; 25% EtOH (0.1% diethylamine / CO2, 100 bar; flow rate 60 mL / min; wavelength 220 nm), affording the early eluting (R)-enantiomer as a clear oil (230 mg).

[0276] The resulting clear oil was triturated with CH2Cl2 and hexanes, affording Compound 151 (220 mg) as a white solid.

[0277] 11H NMR (400 MHz, CDCl3) δ 1.22 - 1.34 (m, 2H), 1.38 (s, 1H), 1.48 (d, J = 24.5 Hz, 1H), 1.68 (d, J = 8.0 Hz, 1H), 1.89 (d, J = 20.3 Hz, 1H), 1.98 (d, J = 23.3 Hz, 1H), 2.08 (d, J = 18.5 Hz, 1H), 2.31 (s, 1H), 2.74 (s, 2H), 2.92 (d, J = 11.6 Hz, 1H), 3.06 (d, J = 11.9 Hz, 1H), 4.59 - 4.67 (m, 1H), 6.84 (d, J = 9.5 Hz, 1H), 6.89 (d, J = 8.9 Hz, 1H), 6.95 (t, J = 8.7 Hz, 2H), 7.04 (t, J = 7.9 Hz, 1H), 7.10 - 7.16 (m, 2H).

[0278] LCMS (Method: SorbTech C18AQ column, 2.1×50 mm, 3 μm; 5 - 95% acetonitrile / water with 0.1% formic acid for 14 minutes, hold for 4 minutes; flow rate: 0.7 mL / min; wavelength: 210 nm): retention time: 4.6 minutes; purity: 98.6%; (EI-MS): m / z = 382.2 ([M+H] + )

[0279] Chiral HPLC (Chiralpak IG column, 150 mm×4.6 mm, 3 μm, Method: 100% EtOH; flow rate: 0.3 mL / min; wavelength: 230 nm): retention time: (R)-isomer: 10.9 minutes, (S)-isomer: 14.2 minutes; 99.7% ee.

[0280] Example 6. Synthesis of (R)-(2,3-Bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1,2,2-d4)piperidin-4-yl)methanol (Compound 159)

[0281] Scheme 12. Preparation of 1-(2-Bromoethyl-1,1,2,2-d4)-4-fluorobenzene (9c)

[0282]

[0283] Step 1. Methyl (4-fluorophenyl)acetate-d2 (20b). A freshly prepared 2.11 M solution of sodium methoxide in MeOD (2.82 mL, 5.9 mmol) was added to a solution of 20a (10 g, 59.5 mmol) in MeOD (100 mL) at room temperature. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure to give a white semi-solid. Additional MeOD (110 mL) and a freshly prepared 2.11 M solution of sodium methoxide in MeOD (2.82 mL, 5.9 mmol) were added at room temperature, and then the reaction mixture was stirred overnight. This process was repeated for a total of 4 cycles. The reaction mixture was concentrated under reduced pressure to give 20b (11.50 g, quantitative yield).

[0284] Step 2. 2-(4-Fluorophenyl)ethane-1,1,2,2-d4-1-ol (8c). A suspension of 20b (10 g, 58.7 mmol) in anhydrous THF (50 mL) was slowly added to a suspension of lithium aluminum deuteride (3.69 g, 88.0 mmol, Boc Sciences, 98 atom % D) in anhydrous THF (100 mL) at 0 °C. The reaction mixture was heated to room temperature, stirred for 1 h, and then heated at reflux for 4 h. The reaction mixture was cooled to room temperature and then quenched with water (3 mL), 15% NaOH solution (4 mL), and then water (6 mL). THF was added as needed when the mixture became very viscous during quenching. The mixture was then filtered through a pad of diatomaceous earth (20 g), and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (Interchim automated chromatography system, Biotage 350 g silica gel column, eluting with a hexane gradient of 0 - 25% acetone) to give 8c as a clear oil (7.06 g, 83%).

[0285] Step 3.1-(2-Bromoethyl-1,1,2,2-d4)-4-fluorobenzene (9c). To a solution of 8c (8.33 g, 58.0 mmol) in CH2Cl2 (140 mL) at 0 °C was added carbon tetrabromide (23.95 g, 72.0 mmol), and then triphenylphosphine (22.73 g, 86.6 mmol). The reaction mixture was stirred at 0 °C for 2 h and then concentrated under reduced pressure to a yellow oil. The oil was diluted with Et2O (400 mL) and stirred for 40 min to give a white suspension. The suspension was filtered through a pad of Celite (20 g) to give a clear filtrate, which was concentrated under reduced pressure. Hexane (300 mL) was added, and the mixture was stirred for 15 min to give more white precipitate. The precipitate was filtered through a fine-porosity funnel, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (Biotage automated chromatography system, Biotage 350 g silica gel column, eluting with a hexane gradient of 0 - 25% EtOAc) to give 9c as a clear oil (7.7 g, 64%).

[0286] Scheme 13. Preparation of (R)-(2,3-Bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1,2,2-d4)piperidin-4-yl)methanol (Compound 159)

[0287]

[0288] Step 4. (2,3-Bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1,2,2-d4)piperidin-4-yl)methanone (6d). To a solution of 5b (1.2 g, 3.35 mmol) in DMF (15 mL) at room temperature was added sodium bicarbonate powder (0.71 g, 8.4 mmol), and then a solution of 9c (0.70 g, 3.35 mmol, 1 equiv) in DMF (3 mL). The reaction mixture was heated at 90 °C for 2 h, then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (35 mL) and extracted with EtOAc (3 × 35 mL). The combined organic layers were washed with saturated brine (50 mL) and water (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (Biotage automated chromatography system, Biotage 50 g silica gel column, eluting with a CH2Cl2 gradient of 0 - 5% MeOH) to give 6d as a yellow oil (0.86 g, 68%).

[0289] Step 5. (2,3-Bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1,2,2-d4)piperidin-4-yl)methanol (7 g). Sodium borohydride (0.26 g, 6.80 mmol, 3 eq) was added in one portion to a solution of 6d (0.86 g, 2.27 mmol, 1 eq) in MeOH (30 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred for 38 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water (30 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 7 g (0.77 g, 89%) of a white solid.

[0290] Chiral separation of (R)-(2,3-Bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1,2,2-d4)piperidin-4-yl)methanol (Compound 159). 7 g (700 mg) was purified by chiral SFC (AD-H, 250 × 20 mm, 5 mm; 25% EtOH (0.1% diethylamine / CO2, 100 bar; flow rate 65 mL / min; wavelength 220 nm) to afford the early eluting (R)-enantiomer as a clear oil (385 mg).

[0291] The resulting clear oil was triturated with CH2Cl2 and hexanes to afford Compound 159 (270 mg) as a white solid.

[0292] 1 H NMR (400 MHz, CDCl3) δ 1.21 - 1.42 (m, 2H), 1.42 - 1.55 (m, 1H), 1.68 (dtd, J = 4.0, 7.8, 11.6 Hz) (s, 2H), 1.91 (br t, J = 11.0 Hz, 1H), 1.99 (br t, J = 11.4 Hz, 1H), 2.08 (d, J = 2.7, 13.1 Hz, 1H), 2.35 (br s, 1H), 2.93 (d, J = 10.9 Hz, 1H), 3.07 (d, J = 10.8 Hz, 1H), 4.63 (d, J = 8.1 Hz, 1H), 6.84 (dd, J = 1.6, 8.1 Hz, 1H), 6.89 (dd, J = 1.4, 7.8 Hz, 1H), 6.91 - 6.98 (m, 2H), 7.02 - 7.07 (m, 1H), 7.10 - 7.17 (m, 2H).

[0293] LCMS (Method: Atlantis T3 column, 2.1×50 mm, 3 μm; 5-95% acetonitrile / water containing 0.1% formic acid for 14 minutes, hold for 4 minutes; flow rate: 0.7 mL / min; wavelength: 210 nm): retention time: 4.5 minutes; purity: 99.9%; (EI-MS): m / z = 384.3 ([M+H] + ).

[0294] Chiral HPLC (Chiralpak IG column, 250 mm×4.6 mm, 3 μm, Method: 100% EtOH; flow rate: 0.3 mL / min; wavelength: 230 nm): retention time: (R) isomer: 16.9 minutes, (S) isomer: 21.5 minutes; 99.7% ee.

[0295] Example 7. Synthesis of (R)-(2,3-dimethoxyphenyl)(1-(4-fluorophenethyl)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (Compound 203)

[0296] Scheme 14. Preparation of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate-2,2,3,3,4,5,5,6,6-d9 (2b).

[0297]

[0298] Step 1. 1-(tert-Butoxycarbonyl)piperidine-4-carboxylic-2,2,3,3,4,5,5,6,6-d9 acid (1h). MeOD (12 mL, Sigma Aldrich, 99.5 atom % D) was added to piperidine-4-carboxylic-2,2,3,3,4,5,5,6,6-d9 acid (3 g, CDN Isotope, 98.6 atom % D). The mixture was concentrated under reduced pressure. This process was repeated more than twice. Then triethylamine (6.6 g, 65.0 mmol) was added to a solution of piperidine-4-carboxylic-2,2,3,3,4,5,5,6,6-d9 acid (3 g, 22.0 mmol) in anhydrous CH2Cl2 (30 mL) at room temperature, and then Boc anhydride (5.7 g, 26 mmol) was added. The reaction mixture was stirred overnight at this temperature. The reaction mixture was concentrated under reduced pressure. THF (40 mL) was added to the residue, and the mixture was acidified with 1N deuterium chloride (aq.) (30 mL, Sigma, ≥99 atom % D). The mixture was stirred for 15 minutes, and then EtOAc (70 mL) was added. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 70 mL). The organic layers were combined, washed with saturated brine in deuterium oxide (1 × 70 mL), dried (Na2SO4), filtered, concentrated under reduced pressure and dried (vacuum oven) to give 1h (4.81 g, 93%).

[0299] Step 2. tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate-2,2,3,3,4,5,5,6,6-d9 (2b). Triethylamine (3.1 mL, 22.0 mmol) was added to solid N,O-dimethylhydroxylamine hydrochloride (2.14 g, 22.0 mmol) at room temperature, and the mixture was stirred for 1 hour to give the free base N,O-dimethylhydroxylamine as an oil. DBU (3.38 g, 22.0 mmol) was added to a solution of 1h (4.81 g, 20.16 mmol) in anhydrous acetonitrile (60 mL) at 0 °C, and then propanephosphonic acid anhydride (1.07 g, 64.5 mmol) was added. After stirring for 15 minutes, the free base N,O-dimethylhydroxylamine was added to the above reaction mixture at 0 °C, and the mixture was stirred at this temperature for 3 hours. Then the reaction mixture was concentrated under reduced pressure. EtOAc (400 mL) was added to the residue, and the mixture was washed with 25% citric acid (aq.) (2 × 200 mL) and saturated sodium bicarbonate (2 × 200 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to give 2b as a yellow oil (3.31 g, 58%).

[0300] Scheme 15. Preparation of (R)-(2,3-dimethoxyphenyl)(1-(4-fluorophenethyl)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (Compound 203).

[0301]

[0302] Step 1. tert-Butyl 4-(2,3-dimethoxybenzoyl)piperidine-1-carboxylate-2,2,3,3,4,5,5,6,6-d9 (4c). A solution of 2.5 M n-butyllithium in hexanes (1.95 mL, 4.86 mmol) was added dropwise to a solution of 21a (0.64 g, 4.6 mmol, 1 equiv) in anhydrous THF (11 mL) at 0 °C. After addition, the mixture was heated to room temperature, stirred for 2 h, and then cooled back to 0 °C. A pre-cooled (0 °C) solution of 2b (1.30 g, 4.6 mmol) in anhydrous THF (9 mL) was added slowly to the reaction mixture. The reaction mixture was heated to room temperature and stirred overnight. Another portion of 21a (0.64 g, 4.6 mmol) in anhydrous THF (11 mL) was treated with 2.5 M n-BuLi in hexanes (1.95 mL, 4.86 mmol) at 0 °C and then added to the reaction mixture at 0 °C. The reaction mixture was heated to room temperature and stirred overnight. The reaction mixture was quenched with a saturated ND4Cl solution in deuterium oxide (25 mL, CIL, 99.9 atom % D) and stirred for 15 min. The layers were separated and the aqueous layer was extracted with Et2O (3 × 30 mL). The combined organic layers were washed with saturated brine in deuterium oxide (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to afford crude 4c (2.9 g) as a yellow oil. The crude material was purified by chromatography (Biotage automated chromatography system, Biotage 100 g silica gel column, eluting with a gradient of 10 - 15% EtOAc in hexanes) and subsequent reverse phase chromatography (Biotage automated chromatography system, Teledyne 100 g C 18Column, eluting with water containing 0 - 85% acetonitrile) purification to obtain 4c with 22% α - proton incorporated into acetone (0.51 g, 31%). At room temperature, potassium carbonate (0.3 g, 2.15 mmol) was added to a solution of the obtained 4c (0.51 g, 1.43 mmol) in a 1:1 mixture of deuterium oxide (50 mL, CIL, 99.9 atom % D) and anhydrous THF (50 mL). The reaction mixture was stirred for 3 days. The reaction mixture was diluted with saturated brine in deuterium oxide (20 mL, CIL, 99.9 atom % D), and then extracted with CH2Cl2 (150 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were washed with saturated brine in deuterium oxide (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to obtain 4c (0.51 g).

[0303] Step 2. (2,3 - Dimethoxyphenyl)(piperidin - 4 - yl - 2,2,3,3,4,5,5,6,6 - d9)methanone trifluoroacetate (5c). Trifluoroacetic acid - d (7.54 g, 66.11 mmol, Sigma Aldrich, 99.5 atom % D) was added to 4c (0.79 g, 2.20 mmol) at 0 °C. The reaction mixture was heated to room temperature and stirred for 1.5 h. The reaction mixture was concentrated under reduced pressure to obtain a yellow oil. Et2O (150 mL) was added, and the mixture was stirred for 10 min to obtain a white precipitate. The solid was filtered to obtain 5c as a white solid (0.66 g, 85%).

[0304] Step 3. (2,3 - Dimethoxyphenyl)(piperidin - 4 - yl - 2,2,3,3,4,5,5,6,6 - d9)methanol (30b). Sodium borohydride (0.28 g, 7.45 mmol) was added in one portion to a solution of 5c (0.66 g, 1.86 mmol) in MeOD (35 mL, Sigma Aldrich, 99.5 atom % D) at 0 °C. The reaction mixture was heated to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and then the residue was partitioned between deuterium oxide (60 mL, CIL, 99.9 atom % D) saturated with sodium bicarbonate and CH2Cl2 (100 mL) containing 10% MeOH. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×100 mL) containing 10% MeOH. The combined organic layers were washed with deuterium oxide (50 mL, CIL, 99.9 atom % D), dried (Na2SO4), filtered and concentrated under reduced pressure to obtain 30b (0.17 g). The combined aqueous layers obtained above were concentrated under reduced pressure, and the residue was extracted with CH2Cl2 (3×100 mL). The combined organic layers were concentrated under reduced pressure to obtain a total of 30b (0.40 g, 83%).

[0305] Step 4. (2,3-Dimethoxyphenyl)(1-(4-fluorophenethyl)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (7j). To a solution of 30b (0.2 g, 0.77 mmol) in anhydrous DMF (7 mL) at room temperature was added sodium bicarbonate powder (0.13 g, 1.54 mmol), and then a solution of 9a (0.15 g, 0.77 mmol) in anhydrous DMF (3 mL) was added. The reaction mixture was heated at 90 °C for 2 h and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with saturated brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give 7j (0.26 g, 88%) as a yellow oil, which solidified upon standing.

[0306] Chiral separation of (R)-(2,3-Dimethoxyphenyl)(1-(4-fluorophenethyl)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (Compound 203). 7j (260 mg) was purified by chiral SFC (AD-H, 250 × 20 mm, 5 mm; 20% EtOH (0.1% diethylamine / CO2, 100 bar; flow rate 60 mL / min; wavelength 220 nm) to give the early eluting (R)-enantiomer as a clear oil (130 mg).

[0307] The resulting clear oil was triturated with CH2Cl2 and hexane to give Compound 203 (86 mg) as a white solid.

[0308] 1 H NMR (400 MHz, CDCl3) δ 2.35 (bs, 1H), 2.49 - 2.55 (m, 2H), 2.72 - 2.83 (m, 2H), 3.87 (s, 6H), 4.63 (s, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.96 (m, 2H), 7.05 (t, J = 7.9 Hz, 1H), 7.10 - 7.17 (m, 2H).

[0309] LCMS (method: Atlantis T3 column, 2.1 × 50 mm, 3 μm; 5 - 95% acetonitrile / water containing 0.1% formic acid for 14 min, hold for 4 min; flow rate: 0.7 mL / min; wavelength: 210 nm): retention time: 4.5 min; purity 99.9%; (EI-MS): m / z = 383.3 ([M+H] + )

[0310] Chiral HPLC (Chiralpak IG column, 250 mm × 4.6 mm, 5 μm, method: 100% EtOH; flow rate: 0.3 mL / min; wavelength: 230 nm): retention time: (R) isomer: 16.6 minutes, (S) isomer: 21.2 minutes; 99.9% ee.

[0311] Example 8. Synthesis of (R)-(2,3-dimethoxyphenyl)(1-(2-(4-fluorophenyl)ethyl-1,1-d2)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (Compound 215)

[0312] Scheme 16. Preparation of (R)-(2,3-dimethoxyphenyl)(1-(2-(4-fluorophenyl)ethyl-1,1-d2)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (Compound 215).

[0313]

[0314] Step 1. (2,3-Dimethoxyphenyl)(1-(2-(4-fluorophenyl)ethyl-1,1-d2)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (7i). Sodium bicarbonate (0.13 g, 1.6 mmol) was added to a solution of 30b (0.21 g, 0.80 mmol) in DMF (7 mL) at room temperature, and then a solution of 9b (0.16 g, 0.80 mmol) in DMF (3 mL) was added. The reaction mixture was heated at 90 °C for 2.5 h, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with saturated brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give crude 7i (0.26 g, 87% yield) as a clear oil, which solidified upon standing.

[0315] Chiral separation of (R)-(2,3-dimethoxyphenyl)(1-(2-(4-fluorophenyl)ethyl-1,1-d2)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (Compound 215). 7i (266 mg) was purified by chiral SFC (AD-H, 250 × 20 mm, 5 mm; 20% EtOH (0.1% diethylamine / CO2, 100 bar; flow rate 60 mL / min; wavelength 220 nm) to give the early eluting (R)-enantiomer as a clear oil (134 mg).

[0316] The resulting clear oil was triturated with CH2Cl2 and hexane to give Compound 215 (105 mg) as a white solid.

[0317] 1 1H NMR (400 MHz, CDCl3) δ 2.29 (br s, 1H), 2.74 (s, 2H), 3.87 (s, 6H), 4.63 (s, 1H), 6.85 (dd, J = 1.5, 8.1 Hz, 1H), 6.89 (dd, J = 1.2, 7.8 Hz, 1H), 6.95 (t, J = 8.7 Hz, 2H), 7.05 (t, J = 7.9 Hz, 1H), 7.10 - 7.18 (m, 2H).

[0318] LCMS (Method: Atlantis T3 column, 2.1×50 mm, 3 μm; 5 - 95% acetonitrile / water with 0.1% formic acid in 14 minutes, hold for 4 minutes; flow rate: 0.7 mL / min; wavelength: 210 nm): retention time: 4.6 minutes; purity: 99.8%; (EI-MS): m / z = 385.3 ([M+H] + )

[0319] Chiral HPLC (Chiralpak IG column, 250 mm×4.6 mm, 5 μm, Method: 100% EtOH; flow rate: 0.3 mL / min; wavelength: 230 nm): retention time: (R) isomer: 16.8 minutes, (S) isomer: 21.3 minutes; 99.2% ee.

[0320] Example 9. Synthesis of (R)-(2,3-bis(methoxy-d3)phenyl)(1-(4-fluorophenethyl)piperidin-4-yl)-,2,2,3,3,4,5,5,6,6-d9)methanol (Compound 347)

[0321] Scheme 17. Preparation of (R)-(2,3-bis(methoxy-d3)phenyl)(1-(4-fluorophenethyl)piperidin-4-yl)-,2,2,3,3,4,5,5,6,6-d9)methanol (Compound 347).

[0322]

[0323] Step 1.4 - tert-Butyl (2,3-bis(methoxy-d3)benzoyl)piperidine-1-carboxylate-2,2,3,3,4,5,5,6,6-d9 (4d). A solution of 2.5 M n-butyllithium in hexanes (2.89 mL, 7.23 mmol) was added dropwise to a solution of 21b (0.99 g, 6.90 mmol) in anhydrous THF (16 mL) at 0 °C. After addition, the reaction mixture was heated to room temperature, stirred for 2 h, and then cooled back to 0 °C. A pre-cooled (0 °C) solution of 2b (1.94 g, 6.90 mmol) in THF (14 mL) was slowly added to the reaction mixture. The reaction mixture was heated to room temperature and then stirred overnight. Another portion of 21b (0.99 g, 6.9 mmol) in anhydrous THF (16 mL) was treated with 2.5 M n-BuLi in hexanes (2.89 mL, 7.23 mmol) at 0 °C and then added to the reaction mixture at 0 °C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution in deuterium oxide (35 mL, CIL, 99.9 atom % D) and stirred for 15 min. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated brine in deuterium oxide (60 mL, CIL, 99.9 atom % D), dried (Na2SO4), filtered and concentrated under reduced pressure to give crude 4d (3.9 g) as a yellow oil. The crude material was purified by chromatography (Biotage automated chromatography system, Biotage 100 g silica gel column, eluting with a gradient of 10 - 15% EtOAc in hexanes) and then further purified by reverse phase chromatography (Biotage automated chromatography system, Teledyne 100 g C 18 column, eluting with a gradient of 0 - 85% acetonitrile in water) to give 4d with 19% α-proton incorporation into the ketone group (1.16 g, 46% yield).

[0324] Potassium carbonate (0.66 g, 4.77 mmol) was added to a solution of the thus obtained 4d (1.16 g, 3.18 mmol) in a 1:1 mixture of deuterium oxide (100 mL, CIL, 99.9 atom % D) and anhydrous THF (100 mL) at room temperature. The reaction mixture was stirred for 3 days. The reaction mixture was partitioned between saturated brine in deuterium oxide (60 mL, CIL, 99.9 atom % D) and CH2Cl2 (300 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (200 mL). The combined organic layers were washed with saturated brine in deuterium oxide (100 mL, CIL, 99.9 atom % D), dried (Na2SO4), filtered and concentrated under reduced pressure to give 4d (1.18 g) as a clear oil.

[0325] Step 2. (2,3-Bis(methoxy-d3)phenyl)(piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanone trifluoroacetate (5d). Trifluoroacetic acid-d (10.88 g, 95.5 mmol, Sigma Aldrich, 99.5 atom % D) was added to 4d (1.16 g, 3.2 mmol) at 0 °C. The reaction mixture was heated to room temperature and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to give a yellow oil. Et2O (100 mL) was added to the residue. The mixture was stirred for 10 min to give a heavy white precipitate. The solid was filtered to give 5d as a white solid (1.17 g, quantitative yield).

[0326] Step 3. (2,3-Bis(methoxy-d3)phenyl)(piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (30c). Sodium borohydride (0.49 g, 12.9 mmol) was added in one portion to a solution of 5d (1.17 g, 3.22 mmol) in MeOD (60 mL, Sigma Aldrich, 99.5 atom % D) at 0 °C. The reaction mixture was heated to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between saturated sodium bicarbonate in deuterium oxide (50 mL, CIL, 99.9 atom % D) solution and CH2Cl2 (100 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 × 100 mL). The combined organic layers were washed with deuterium oxide (50 mL, CIL, 99.9 atom % D), dried (Na2SO4), filtered and concentrated under reduced pressure to give 30c (0.26 g). The combined aqueous layers were concentrated under reduced pressure and the residue was extracted with CH2Cl2 (3 × 100 mL). The combined organic extracts were concentrated under reduced pressure to give 30c (0.74 g, 87 %).

[0327] Step 4. (2,3-Bis(methoxy-d3)phenyl)(1-(4-fluorophenethyl)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (7k). Sodium bicarbonate powder (0.15 g, 1.8 mmol) was added to a solution of 30c (0.24 g, 0.90 mmol) in DMF (7 mL) at room temperature, followed by a solution of 9a (0.18 g, 0.90 mmol) in DMF (3 mL). The reaction mixture was heated at 90 °C for 2.5 h, cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with saturated brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give crude 7k as a clear oil (0.31 g, 88 %), which solidified upon standing.

[0328] Chiral separation of (R)-(2,3-bis(methoxy-d3)phenyl)(1-(4-fluorophenethyl)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (Compound 347). Purify 7k (290 mg) by chiral SFC (AD-H, 250×20 mm, 5 mm; 20% EtOH (0.1% diethylamine / CO2, 100 bar; flow rate 60 mL / min; wavelength 220 nm) to obtain the early-eluting (R)-enantiomer as a clear oil (154 mg).

[0329] Grind the resulting clear oil with CH2Cl2 and hexane to obtain Compound 347 as a white solid (102 mg).

[0330] 1 H NMR (400 MHz, CDCL3) δ 2.32 (br s, 1H), 2.51 (d, J = 16.5 Hz, 2H), 2.75 (d, J = 16.5 Hz, 2H), 4.63 (s, 1H), 6.84 (d, J = 6.9 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.95 (t, J = 8.7 Hz, 2H), 7.04 (t, J = 7.9 Hz, 1H), 7.10 - 7.18 (m, 2H).

[0331] LCMS (Method: Atlantis T3 column, 2.1×50 mm, 3 μm; 5 - 95% acetonitrile / water containing 0.1% formic acid for 14 minutes, hold for 4 minutes; flow rate: 0.7 mL / min; wavelength: 210 nm): retention time: 4.6 minutes; purity 99.8%; (EI-MS): m / z = 389.3 ([M+H] + )

[0332] Chiral HPLC (Chiralpak IG column, 250 mm×4.6 mm, 5 μm, Method: 100% EtOH; flow rate: 0.3 mL / min; wavelength: 230 nm): retention time: (R)-isomer: 16.9 minutes, (S)-isomer: 21.4 minutes; 99.3% ee

[0333] Example 10. Synthesis of (R)-(2,3-bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1-d2)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (Compound 359)

[0334] Scheme 18. Preparation of (R)-(2,3-bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1-d2)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (Compound 359).

[0335]

[0336] Step 1. (2,3-bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1-d2)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (7m). Sodium bicarbonate powder (0.15 g, 1.8 mmol) was added to a solution of 30c (0.24 g, 0.90 mmol) in DMF (7 mL) at room temperature, and then a solution of 9b (0.19 g, 0.90 mmol) in DMF (3 mL) was added. The reaction mixture was heated at 90 °C for 2.5 h, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with saturated brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 7m (0.30 g, 83%) as a clear oil, which solidified upon standing.

[0337] Chiral separation of (R)-(2,3-bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1-d2)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (Compound 359). 7m (289 mg) was purified by chiral SFC (AD-H, 250 × 20 mm, 5 mm; 20% EtOH (0.1% diethylamine / CO2, 100 bar; flow rate 60 mL / min; wavelength 220 nm) to give the early eluting (R)-enantiomer as a clear oil (148 mg). The resulting clear oil was triturated with CH2Cl2 and hexane to give Compound 359 (113 mg) as a white solid.

[0338] 1 H NMR (400 MHz, CDCl3) δ 2.32 (br s, 1H), 2.74 (s, 2H), 4.63 (s, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.95 (t, J = 8.7 Hz, 2H), 7.04 (t, J = 7.9 Hz, 1H), 7.13 (d, J = 13.9 Hz, 2H).

[0339] LCMS (Method: Atlantis T3 column, 2.1×50 mm, 3 μm; 5-95% acetonitrile / water containing 0.1% formic acid for 14 minutes, hold for 4 minutes; Flow rate: 0.7 mL / min; Wavelength: 210 nm): Retention time: 4.5 minutes; Purity: 99.8%; (EI-MS): m / z = 391.3 ([M+H] + ).

[0340] Chiral HPLC (Chiralpak IG column, 250 mm×4.6 mm, 3 μm, Method: 100% EtOH; Flow rate: 0.3 mL / min; Wavelength: 230 nm): Retention time: (R)-isomer: 16.8 minutes, (S)-isomer: 21.4 minutes; 99.2% ee.

[0341] Example 11. Synthesis of (R)-(2,3-bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1,2,2-d4)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (Compound 383)

[0342] Scheme 19. Preparation of (R)-(2,3-bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1,2,2-d4)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (Compound 383)

[0343]

[0344] Step 1. (2,3-bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1,2,2-d4)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (7n). To a solution of 30c (for 0.27 g, 1.0 mmol) in DMF (7 mL) was added NaHCO3 (0.17 g, 2.0 mmol), and then a solution of 9c (0.21 g, 1.0 mmol) in DMF (3 mL) was added. The reaction mixture was heated at 90 °C for 2.5 h, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with saturated brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 7n (0.35 g, 90%) as a clear oil, which solidified upon standing.

[0345] Chiral separation of (R)-(2,3-bis(methoxy-d3)phenyl)(1-(2-(4-fluorophenyl)ethyl-1,1,2,2-d4)piperidin-4-yl-2,2,3,3,4,5,5,6,6-d9)methanol (Compound 383). Purification of 7n (350 mg) by chiral SFC (AD-H, 250×20 mm, 5 mm; 20% EtOH (0.1% diethylamine / CO2, 100 bar; flow rate 60 mL / min; wavelength 220 nm) afforded the early-eluting (R)-enantiomer as a clear oil (150 mg).

[0346] The resulting clear oil was triturated with CH2Cl2 and hexanes to afford Compound 359 as a white solid (142 mg).

[0347] 1 1H NMR (400 MHz, CDCl3) δ 2.32 (s, 1H), 4.63 (s, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.95 (t, J = 8.8 Hz, 2H), 7.04 (t, J = 7.9 Hz, 1H), 7.13 (d, J = 14.1 Hz,2H).

[0348] LCMS (Method: Atlantis T3 column, 2.1×50 mm, 3 μm; 5-95% acetonitrile / water with 0.1% formic acid over 14 minutes, hold for 4 minutes; flow rate: 0.7 mL / min; wavelength: 210 nm): retention time: 4.5 minutes; purity: 99.9%; (EI-MS): m / z = 393.3 ([M+H] + )

[0349] Chiral HPLC (Chiralpak IG column, 250 mm×4.6 mm, 5 μm, Method: 100% EtOH; flow rate: 0.3 mL / min; wavelength: 230 nm): retention time: (R)-isomer: 16.8 minutes, (S)-isomer: 21.4 minutes; 99.3% ee

[0350] Example 12. Evaluation of metabolic stability in human liver microsomes

[0351] Microsomal assay: Human liver microsomes (20 mg / mL) were obtained from Xenotech, LLC (Lenexa, KS). Reduced β-nicotinamide adenine dinucleotide phosphate (NADPH), magnesium chloride (MgCl2), and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich.

[0352] Determination of metabolic stability: Prepare a 7.5 mM stock solution of the test compound of formula (I) (e.g., an embodiment described herein or an aspect of an embodiment thereof) or formula (II) or a pharmaceutically acceptable salt thereof in DMSO. Dilute the 7.5 mM stock solution in acetonitrile (ACN) to 12.5 - 50 μM. Dilute 20 mg / mL human liver microsomes in 0.1 M potassium phosphate buffer (pH 7.4, containing 3 mM MgCl2) to 0.625 mg / mL. Add the diluted microsomes in triplicate to the wells of a 96-well deep-well polypropylene plate. Add a 10 μL aliquot of the 12.5 - 50 μM test compound to the microsomes and preheat the mixture for 10 minutes. Initiate the reaction by adding the preheated NADPH solution. The final reaction volume is 0.5 mL and contains 4.0 mg / mL human liver microsomes, 0.25 μM test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer (pH 7.4, 3 mM MgCl2). Incubate the reaction mixture at 37 °C and remove 50 μL aliquots at 0, 5, 10, 20, and 30 minutes and add them to a shallow-well 96-well plate containing 50 μL ice-cold ACN (acetonitrile) and an internal standard to stop the reaction. Store the plate at 4 °C for 20 minutes, then add 100 μL of water to the wells of the plate and centrifuge to pellet the precipitated protein. Transfer the supernatant to another 96-well plate and analyze the remaining amount of the parent by LC-MS / MS using an Applied Bio-systems API 4000 mass spectrometer. Follow the same procedure for the non-deuterated counterpart of the compound of formula I and the positive control 7-ethoxycoumarin (1 μM). Perform the tests in triplicate.

[0353] Data analysis: Calculate the in vitro t of the test compound from the slope of the linear regression of the percent parent remaining (ln) versus incubation time. 1 / 2 .

[0354] In vitro t 1 / 2 = 0.693 / k

[0355] k = -[slope of the linear regression of percent parent remaining (ln) versus incubation time]

[0356] Calculate the apparent intrinsic clearance using the following formula:

[0357] CL int (mL / min / kg) = (0.693 / in vitro t 1 / 2 )(incubation volume / mg of microsomes)(45 mg microsomes / g of liver)(20 g of liver / kg b.w.)

[0358] Perform data analysis using Microsoft Excel software. The results are shown in Tables 5 and 6 below.

[0359] Table 5

[0360]

[0361]

[0362] Table 6

[0363]

[0364] In these experiments, values where the half-life increase was equal to or exceeded 15% were considered to be significantly different. If the apparent intrinsic clearance (deuterated compound / fluoxetine) > 1.15 or < 0.85, a significant difference was considered to exist.

[0365] The results showed that compared with non-deuterated fluoxetine, deuterated compounds 147, 115, 148, 131, 151, 159, 359, and 383 showed a significant increase in the half-life (t 1 / 2 ) in human liver microsomes, while deuterated compounds 203, 215, and 347 did not.

[0366] Example 13. Evaluation of Metabolic Stability in CYP3A4 Supersomes

[0367] Materials and Methods:

[0368] Materials: CYP3A4 supersomes TM Obtained from Corning Gentest. Reduced β-nicotinamide adenine dinucleotide phosphate (NADPH), magnesium chloride (MgCl2), and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich. The D-crizotinib compound was provided by Concert Pharmaceuticals.

[0369] Determination of metabolic stability: Prepare a 10 mM stock solution of the test compound in DMSO. Dilute the 7.5 mM stock solution to 12.75 μM in acetonitrile (ACN). Dilute CYP3A4 supersomes to 50 pmol / mL in 0.1 M potassium phosphate buffer (pH 7.4, containing 3 mM MgCl2). Add the diluted supersomes in triplicate to the wells of a 96-well deep-well polypropylene plate. Add 10 μL of the 12.75 μM test compound to the supersomes and preheat the mixture for 10 minutes. Initiate the reaction by adding the preheated NADPH solution. The final reaction volume is 0.5 mL and contains 50 pmol / mL CYP3A4 supersomes, 0.25 μM test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer (pH 7.4, 3 mM MgCl2). Incubate the reaction mixture at 37 °C and remove 50 μL aliquots at 0, 5, 10, 20, and 30 minutes and add them to a shallow-well 96-well plate containing 50 μL of ice-cold ACN and internal standard to stop the reaction. Store the plate at 4 °C for 20 minutes, then add 100 μL of water to the wells of the plate and centrifuge to pellet the precipitated protein. Transfer the supernatant to another 96-well plate and analyze the remaining amount of the parent by LC-MS / MS using an Applied Bio-systems API 4000 mass spectrometer.

[0370] Data analysis: Calculate the in vitro t of the test compound from the slope of the linear regression of the relationship between the percentage of parent remaining (ln) and the incubation time. 1 / 2 .

[0371] In vitro t 1 / 2 = 0.693 / k

[0372] k = - [the slope of the linear regression of the percentage of parent remaining (ln) against the incubation time]

[0373] Perform data analysis using Microsoft Excel software. The results are shown in Tables 7 and 8 below.

[0374] Table 7

[0375]

[0376] Table 8

[0377]

[0378] In these experiments, values of the half-life increase equal to or exceeding 15% were considered to be significant differences. The results showed that, compared with undehydrogenated flisolidine, the dehydrogenated compounds 147, 115, 148, 131, 151, 159, 347, 359 and 383 showed a significant increase in the half-life (t 1 / 2 ) in CYP3A4 supersomes, while the dehydrogenated compounds 203 and 215 did not.

[0379] The relevant teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

[0380] Without further description, it is believed that one of ordinary skill in the art can use the foregoing description and illustrative embodiments to prepare and utilize the compounds of the present invention and to practice the claimed methods. It should be understood that the foregoing discussion and embodiments merely present a detailed description of certain preferred embodiments. Various modifications and equivalent forms will be obvious to one of ordinary skill in the art without departing from the spirit and scope of the present invention.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein X is -OH; Y 1a and Y 1b are the same; Y 2a and Y 2b are the same; Y 3a and Y 3b are the same; Y 4a and Y 4b are the same; and Y 7 , Y 8 , Y 9 , Y 10 and Y 11 are each hydrogen; and the compound is selected from any one of the compounds shown in Table 4 below: Table 4 wherein any atom not specifically designated as deuterium is present in its natural isotopic abundance, and wherein at least 90% deuterium is introduced at each position specifically designated as deuterium.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is compound 147, 151 or 159.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is compound 147.

4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is compound 151.

5. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is compound 159.

6. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is compound 115, 131, 147, 151 or 159.

7. The compound or pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein at least 95% deuterium, or at least 97% deuterium, is introduced at each position specifically designated as deuterium.

8. A pharmaceutical composition comprising: the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7; and a pharmaceutically acceptable carrier.

9. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment or prevention of a disease or condition selected from psychosis, schizophrenia, schizoaffective disorder, Parkinson's disease, dementia with Lewy bodies, sleep disorder, agitation, mood disorder, thromboembolic disorder, autism, attention deficit hyperactivity disorder and any combination thereof.

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