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WO2018023009A1 - Lurasidone deutérée - Google Patents

Lurasidone deutérée Download PDF

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Publication number
WO2018023009A1
WO2018023009A1 PCT/US2017/044400 US2017044400W WO2018023009A1 WO 2018023009 A1 WO2018023009 A1 WO 2018023009A1 US 2017044400 W US2017044400 W US 2017044400W WO 2018023009 A1 WO2018023009 A1 WO 2018023009A1
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WIPO (PCT)
Prior art keywords
deuterium
same
compound
hydrogen
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2017/044400
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English (en)
Inventor
Ian Robert Silverman
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Concert Pharmaceuticals Inc
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Concert Pharmaceuticals Inc
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Filing date
Publication date
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Publication of WO2018023009A1 publication Critical patent/WO2018023009A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • ADME absorption, distribution, metabolism and/or excretion
  • ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites.
  • some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent.
  • modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.
  • a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly.
  • a drug that is cleared too rapidly.
  • the FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60).
  • CYP3A4 cytochrome P450 enzyme 3A4
  • Ritonavir causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs.
  • the CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect.
  • Quinidine has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at www.accessdata.fda.gov).
  • a potentially attractive strategy for improving a drug’s metabolic properties is deuterium modification.
  • Deuterium is a safe, stable, non- radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability.
  • the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.
  • This invention relates to deuterated forms of hexahydro-4,7-methano-1H- isoindole-1,3(2H)-diones, and pharmaceutically acceptable salts thereof.
  • the invention provides a compound of Formula I:
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 are independently selected from hydrogen and deuterium;
  • the invention provides a compound of Formula II:
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , and Y 19 are independently selected from hydrogen and deuterium;
  • compositions comprising a compound of this invention, including pharmaceutical compositions comprising a compound of this invention and a pharmaceutically acceptable carrier.
  • This invention also provides the use of such compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering a compound that modulates the activity of a receptor selected from the group consisting of central dopamine Type 2 (D2) receptor and serotonin Type 2 (5HT2A) receptor.
  • D2 central dopamine Type 2
  • 5HT2A serotonin Type 2
  • Some exemplary embodiments include a method of treating a disease or condition selected from schizophrenia and depressive episodes associated with bipolar I disorder, the method comprising the step of administering to a subject in need thereof a pharmaceutically acceptable composition of the present invention.
  • Lurasidone (CAS Registry Number 367514-87-2), also known as SM-13496 and (3aR,4S,7R,7aS)-2-[[(1R,2R)-2-[[4-(1,2-benzisothiazol-3-yl)-1- piperazinyl]methyl]cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)- dione, modulates the activity of central dopamine Type 2 (D2) receptor and/or serotonin Type 2 (5HT2A) receptor.
  • D2 central dopamine Type 2
  • 5HT2A serotonin Type 2
  • Lurasidone is currently approved by FDA as an atypical antipsychotic for the treatment of schizophrenia and depressive episodes associated with bipolar I disorder (bipolar depression), as monotherapy and as adjunctive therapy with lithium and valproate. Lurasidone is also in phase 4 clinical trials for the treatment of schizoaffective disorder, phase 3 clinical trials for the treatment of irritability associated with autistic disorder (e.g., pediatric autism), phase 1 clinical trials for the treatment of autism, phase 3 clinical trials for the treatment of pediatric schizophrenia, phase 3 clinical trials for improving cognition in bipolar patients, phase 3 clinical trials to assess the cognitive effects of lurasidone in bipolar I and II patients (manic depression) who are in remission from an episode, phase 3 clinical trials the treatment of schizophrenia or schizoaffective disorder in subjects switched from other antipsychotic agents, phase 3 clinical trials for the treatment of acute schizophrenia, phase 4 clinical trials for treating the treatment- resistant schizophrenia or schizoaffective disorder, phase 3 clinical trials in combination with either lithium or divalproex (valproate)
  • treat means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.
  • a disease e.g., a disease or disorder delineated herein
  • Disease means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • the term“subject” includes humans and non-human
  • Non-limiting examples of non-human mammals include mice, rats, guinea pigs, rabbits, dogs, cats, monkeys, apes, pigs, cows, sheep, horses, etc.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • the position is understood to have hydrogen at its natural abundance isotopic composition.
  • the 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.
  • a position when a position is designated specifically as“H” or“hydrogen”, the position incorporates ⁇ 20% deuterium, ⁇ 10% deuterium, ⁇ 5% deuterium, ⁇ 4% deuterium, ⁇ 3% deuterium, ⁇ 2% deuterium, or ⁇ 1% deuterium. Also unless otherwise stated, when a position is designated specifically as “D” or“deuterium”, the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium).
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium
  • incorporation at each designated deuterium atom at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • each designated deuterium atom has deuterium incorporation of at least 52.5%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium
  • each designated deuterium atom has deuterium incorporation of at least 60%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 67.5%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 75%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 82.5%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 90%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 95%.
  • each designated deuterium atom has deuterium incorporation of at least 97.5%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 99%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 99.5%.
  • isotopologue refers to a species in which the chemical structure differs from a specific compound of this invention only in the isotopic composition thereof.
  • a compound represented by a particular chemical structure containing indicated deuterium atoms will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure.
  • the relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound.
  • the invention also provides salts of the compounds of the invention.
  • a salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • the acid addition salt may be a deuterated acid addition salt.
  • pharmaceutically acceptable refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
  • pharmaceutically acceptable counterion is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para- toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids.
  • organic acids such as para- toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid
  • pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate
  • pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.
  • the acids commonly employed to form pharmaceutically acceptable salts include the above-listed inorganic acids, wherein at least one hydrogen is replaced with deuterium.
  • the compounds of the present invention may contain an asymmetric carbon atom, for example, as the result of deuterium substitution or otherwise.
  • compounds of this invention can exist as either individual enantiomers, or mixtures of the two enantiomers.
  • a compound of the present invention may exist as either a racemic mixture or a scalemic mixture, or as individual respective stereoisomers that are substantially free from another possible stereoisomer.“Stereoisomer” refers to both enantiomers and diastereomers.
  • substantially free of other stereoisomers means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and most preferably less than 2% of other stereoisomers are present.
  • stable compounds refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).
  • Substituted with deuterium refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.
  • variable may be referred to generally (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 generally, it is meant to include all specific embodiments of that particular variable.
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 are independently selected from hydrogen and deuterium;
  • At least one of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 and Y 19 is deuterium.
  • Y 1a and Y 1b are the same, Y 4a and Y 4b are the same, Y 2a and Y 2b are the same, Y 3a and Y 3b are the same, Y 6a and Y 6b are the same, Y 9a and Y 9b are the same, Y 7a and Y 7b are the same, Y 8a and Y 8b are the same, Y 11 and Y 12 are the same, Y 13 and Y 14 are the same, and Y 15a , Y 15b , Y 16a and Y 16b are the same.
  • Y 1a , Y 1b , Y 4a and Y 4b are the same, Y 2a , Y 2b , Y 3a and Y 3b are the same, Y 6a , Y 6b , Y 9a and Y 9b are the same, Y 7a , Y 7b , Y 8a and Y 8b are the same, Y 11 and Y 12 are the same, Y 13 and Y 14 are the same, and Y 15a , Y 15b , Y 16a and Y 16b are the same.
  • Y 1a and Y 1b are the same. In some aspects of these embodiments, Y 1a and Y 1b are each hydrogen. In other aspects of these embodiments, Y 1a and Y 1b are each deuterium.
  • Y 2a and Y 2b are the same. In some aspects of these embodiments, Y 2a and Y 2b are each hydrogen. In other aspects of these embodiments, Y 2a and Y 2b are each deuterium.
  • Y 1a , Y 1b , Y 2a and Y 2b are the same. In some aspects of these embodiments, Y 1a , Y 1b , Y 2a and Y 2b are each hydrogen. In other aspects of these embodiments, Y 1a , Y 1b , Y 2a and Y 2b are each deuterium.
  • Y 1a , Y 1b , Y 4a and Y 4b are the same. In some aspects of these embodiments, Y 1a , Y 1b , Y 4a and Y 4b are each hydrogen. In other aspects of these embodiments, Y 1a , Y 1b , Y 4a and Y 4b are each deuterium.
  • Y 3a and Y 3b are the same. In some aspects of these embodiments, Y 3a and Y 3b are each hydrogen. In other aspects of these embodiments, Y 3a and Y 3b are each deuterium.
  • Y 4a and Y 4b are the same. In some aspects of these embodiments, Y 4a and Y 4b are each hydrogen. In other aspects of these embodiments, Y 4a and Y 4b are each deuterium.
  • Y 3a , Y 3b , Y 4a and Y 4b are the same. In some aspects of these embodiments, Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen. In other aspects of these embodiments, Y 3a , Y 3b , Y 4a and Y 4b are each deuterium.
  • Y 3a , Y 3b , Y 2a and Y 2b are the same. In some aspects of these embodiments, Y 3a , Y 3b , Y 2a and Y 2b are each hydrogen. In other aspects of these embodiments, Y 3a , Y 3b , Y 2a and Y 2b are each deuterium.
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are the same.
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen.
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each deuterium.
  • Y 1a , Y 1b , Y 2a and Y 2b are each hydrogen and Y 3a , Y 3b , Y 4a and Y 4b are each deuterium.
  • Y 1a , Y 1b , Y 2a and Y 2b are each deuterium and Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen.
  • Y 5a and Y 5b are the same. In some aspects of these embodiments, Y 5a and Y 5b are each hydrogen. In other aspects of these embodiments, Y 5a and Y 5b are each deuterium.
  • Y 6a and Y 6b are the same. In some aspects of these embodiments, Y 6a and Y 6b are each hydrogen. In other aspects of these embodiments, Y 6a and Y 6b are each deuterium.
  • Y 7a and Y 7b are the same. In some aspects of these embodiments, Y 7a and Y 7b are each hydrogen. In other aspects of these embodiments, Y 7a and Y 7b are each deuterium.
  • Y 8a and Y 8b are the same. In some aspects of these embodiments, Y 8a and Y 8b are each hydrogen. In other aspects of these embodiments, Y 8a and Y 8b are each deuterium.
  • Y 9a and Y 9b are the same. In some aspects of these embodiments, Y 9a and Y 9b are each hydrogen. In other aspects of these embodiments, Y 9a and Y 9b are each deuterium.
  • Y 10a and Y 10b are the same. In some aspects of these embodiments, Y 10a and Y 10b are each hydrogen. In other aspects of these embodiments, Y 10a and Y 10b are each deuterium.
  • Y 18 is hydrogen
  • Y 18 is deuterium
  • Y 19 is hydrogen
  • Y 19 is deuterium
  • Y 18 and Y 19 are the same. In some aspects of these embodiments, Y 18 and Y 19 are each hydrogen. In other aspects of these embodiments, Y 18 and Y 19 are each deuterium. [64] In some embodiments, Y 18 is hydrogen and Y 19 is deuterium.
  • Y 18 is deuterium and Y 19 is hydrogen.
  • Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 18 and Y 19 are the same.
  • Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 18 and Y 19 are each hydrogen.
  • Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 18 and Y 19 are each deuterium.
  • Y 5a and Y 5b are each hydrogen, and Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 18 and Y 19 are each deuterium.
  • Y 5a and Y 5b are each deuterium, and Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 18 and Y 19 are each hydrogen.
  • Y 10a and Y 10b are each hydrogen, and Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each deuterium.
  • Y 10a , Y 10b are each deuterium, and Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each hydrogen.
  • Y 5a , Y 5b , Y 10a and Y 10b are each hydrogen, and Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each deuterium.
  • Y 5a , Y 5b , Y 10a and Y 10b are each deuterium, and Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each hydrogen.
  • Y 11 is hydrogen
  • Y 11 is deuterium
  • Y 12 is hydrogen
  • Y 12 is deuterium
  • Y 11 and Y 12 are the same. In some aspects of these embodiments, Y 11 and Y 12 are each hydrogen. In other aspects of these embodiments, Y 11 and Y 12 are each deuterium. In some embodiments, Y 11 is hydrogen and Y 12 is deuterium. In some embodiments, Y 11 is deuterium and Y 12 is hydrogen.
  • Y 13 is hydrogen
  • Y 13 is deuterium
  • Y 14 is hydrogen
  • Y 14 is deuterium.
  • Y 13 and Y 14 are the same. In some aspects of these embodiments, Y 13 and Y 14 are each hydrogen. In other aspects of these embodiments, Y 13 and Y 14 are each deuterium. In some embodiments, Y 13 is hydrogen and Y 14 is deuterium. In some embodiments, Y 13 is deuterium and Y 14 is hydrogen.
  • Y 15a and Y 15b are the same. In some aspects of these embodiments, Y 15a and Y 15b are each hydrogen. In other aspects of these embodiments, Y 15a and Y 15b are each deuterium.
  • Y 16a and Y 16b are the same. In some aspects of these embodiments, Y 16a and Y 16b are each hydrogen. In other aspects of these embodiments, Y 16a and Y 16b are each deuterium.
  • Y 17a and Y 17b are the same. In some aspects of these embodiments, Y 17a and Y 17b are each hydrogen. In other aspects of these embodiments, Y 17a and Y 17b are each deuterium.
  • Y 15a and Y 15b are each hydrogen and Y 16a and Y 16b are each deuterium. In some embodiments, Y 15a and Y 15b are each deuterium and Y 16a and Y 16b are each hydrogen.
  • Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are the same. In some aspects of these embodiments, Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are each hydrogen.
  • Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are each deuterium.
  • Y 11 and Y 12 are each hydrogen, and Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are each deuterium.
  • Y 11 and Y 12 are each deuterium, and Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are each hydrogen.
  • Y 15a , Y 15b , Y 16a and Y 16b are the same. In some aspects of these embodiments, Y 15a , Y 15b , Y 16a and Y 16b are each hydrogen. In other aspects of these embodiments, Y 15a , Y 15b , Y 16a and Y 16b are each deuterium.
  • Y 15a , Y 15b , Y 16a and Y 16b are each deuterium and Y 11 , Y 12 , Y 13 , Y 14 , Y 17a and Y 17b are each hydrogen.
  • Y 15a , Y 15b , Y 16a , Y 16b , Y 11 , and Y 12 are each deuterium and Y 13 , Y 14 , Y 17a and Y 17b are each hydrogen.
  • Y , Y , Y , Y , Y , and Y are each deuterium and Y 11 , Y 12 , Y 13 and Y 14 are each hydrogen.
  • Y 15a , Y 15b are each deuterium and Y 11 , Y 12 , Y 13 , Y 14 , Y 16a , Y 16b , Y 17a and Y 17b are each hydrogen.
  • Y 16a , Y 16b are each deuterium and Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 17a and Y 17b are each hydrogen.
  • Y 5a , Y 5b , Y 15a , Y 15b , Y 16a and Y 16b are each deuterium.
  • Y 5a , Y 5b , Y 15a , Y 15b , Y 16a and Y 16b are each deuterium and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 17a , Y 17b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 are each hydrogen.
  • Y 5a and Y 5b are each deuterium
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each deuterium.
  • Y 5a and Y 5b are each deuterium
  • Y 15a , Y 15b , Y 16a and Y 16b are each deuterium
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each deuterium.
  • Y 20 , Y 21 , Y 22 and Y 23 are the same. In some aspects of these embodiments, Y 20 , Y 21 , Y 22 and Y 23 are each hydrogen. In other aspects of these embodiments, Y 20 , Y 21 , Y 22 and Y 23 are each deuterium.
  • the absolute configuration of the carbon atom to which Y 18 is attached is (R) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y 19 is attached is (R) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y 11 is attached is (S) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y 12 is attached is (R) according to Cahn-Ingold-Prelog nomenclature.
  • the absolute configuration of the carbon atom to which Y 13 is attached is (R) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y 14 is attached is (S) according to Cahn- Ingold-Prelog nomenclature.
  • the absolute configuration of the carbon atom to which Y 18 is attached is (R), the carbon atom to which Y 19 is attached is (R), the carbon atom to which Y 11 is attached is (S), the carbon atom to which Y 12 is attached is (R), the carbon atom to which Y 13 is attached is (R), and the carbon atom to which Y 14 is attached is (S) according to Cahn-Ingold-Prelog nomenclature.
  • At least one of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 and Y 19 is hydrogen.
  • Y 11 is deuterium
  • Y 12 is deuterium
  • Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are each deuterium, and at least one of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 is deuterium.
  • Y 10a and Y 10b are each deuterium, and at least one of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 is deuterium.
  • Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each deuterium, and at least one of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 20 , Y 21 , Y 22 , and Y 23 is deuterium.
  • Y 5a and Y 5b are each deuterium, and at least one of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 is deuterium.
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each deuterium, and at least one of Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a ,
  • Y 20 , Y 21 , Y 22 and Y 23 are each deuterium, and at least one , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 and Y 19 is deuterium.
  • the compound of Formula I is not a compound where Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b ,
  • the compound of Formula I is not a compound where Y 11 is deuterium, Y 12 is deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 are independently selected from hydrogen and deuterium.
  • the compound of Formula I is not a compound where Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are each deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 are independently selected from hydrogen and deuterium.
  • the compound of Formula I is not a compound where Y 10a and Y 10b are each deuterium and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 are independently selected from hydrogen and deuterium.
  • the compound of Formula I is not a compound where Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 20 , Y 21 , Y 22 , and Y 23 are independently selected from hydrogen and deuterium.
  • the compound of Formula I is not a compound where Y 5a and Y 5b are each deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 are independently selected from hydrogen and deuterium.
  • the compound of Formula I is not a compound where Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each deuterium, and Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 are independently selected from hydrogen and deuterium.
  • the compound of Formula I is not a compound where Y 20 , Y 21 , Y 22 and Y 23 are each deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 and Y 19 are independently selected from hydrogen and deuterium.
  • the compound of Formula I is not a compound where Y 11 is deuterium, Y 12 is deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 are each hydrogen.
  • the compound of Formula I is not a compound where Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are each deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 are each hydrogen.
  • the compound of Formula I is not a compound where Y 10a and Y 10b are each deuterium and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 are each hydrogen.
  • the compound of Formula I is not a compound where Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 20 , Y 21 , Y 22 , and Y 23 are each hydrogen.
  • the compound of Formula I is not a compound where Y 5a and Y 5b are each deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 are each hydrogen.
  • the compound of Formula I is not a compound where Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each deuterium, and Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , Y 19 , Y 20 , Y 21 , Y 22 , and Y 23 are each hydrogen.
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are the same, Y 5a and Y 5b are the same, Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are the same, Y 10a and Y 10b are the same, Y 15a , Y 15b , Y 16a , Y 16b are the same, Y 11 , Y 12 , Y 13 , Y 14 , Y 17a and Y 17b are the same, Y 20 is hydrogen, and Y 21 , Y 22 and Y 23 are each de
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are the same, Y 5a and Y 5b are the same, Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are the same, Y 10a and Y 10b are the same, Y 15a , Y 15b , Y 16a , Y 16b are the same, Y 11 , Y 12 , Y 13 , Y 14 , Y 17a and Y 17b are the same, Y 21 is hydrogen, and Y 20 , Y 22 and Y 23 are each de
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are the same, Y 5a and Y 5b are the same, Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are the same, Y 10a and Y 10b are the same, Y 15a , Y 15b , Y 16a , Y 16b are the same, Y 11 , Y 12 , Y 13 , Y 14 , Y 17a and Y 17b are the same, Y 22 is hydrogen, and Y 20 , Y 21 and Y 23 are each de
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are the same, Y 5a and Y 5b are the same, Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are the same, Y 10a and Y 10b are the same, Y 15a , Y 15b , Y 16a , Y 16b are the same, Y 11 , Y 12 , Y 13 , Y 14 , Y 17a and Y 17b are the same,
  • Y la , Y lb , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each deuterium
  • Y 5a and Y 5b are each hydrogen
  • Y 6a , Y 6b , Y 7a , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each hydrogen
  • Y 10a and Y 10b are each hydrogen
  • Y 11 and Y 12 are the same
  • Y 13 and Y 14 are the same
  • Y 15a and Y 15b are the same
  • Y 16a and Y 16b are the same
  • Y 17a and Y 17b are the same
  • Y 20 , Y 21 , Y 22 and Y 23 are each deuterium
  • the compound is selected from any one of the compounds (Cmpd) set forth in Table If (below): Table 1f: Exemplar
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen, Y 5a and Y 5b are each deuterium, Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each hydrogen, Y 10a and Y 10b are each hydrogen, Y 11 and Y 12 are the same, Y 13 and Y 14 are the same, Y 15a and Y 15b are the same, Y 16a and Y 16b are the same, Y 17a and Y 17b are the same, and Y 20 , Y 21 , Y 22 and Y
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen
  • Y 5a and Y 5b are each hydrogen
  • Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each deuterium
  • Y 10a and Y 10b are each hydrogen
  • Y 11 and Y 12 are the same
  • Y 13 and Y 14 are the same
  • Y 15a and Y 15b are the same
  • Y 16a and Y 16b are the same
  • Y 17a and Y 17b are the same
  • Y 20 , Y 21 , Y 22 and Y 23 are each deuterium
  • the compound is selected from any one of the compounds (Cmpd) set forth in Table 1h (below
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen
  • Y 5a and Y 5b are each hydrogen
  • Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each hydrogen
  • Y 10a and Y 10b are each deuterium
  • Y 11 and Y 12 are the same
  • Y 13 and Y 14 are the same
  • Y 15a and Y 15b are the same
  • Y 16a and Y 16b are the same
  • Y 17a and Y 17b are the same
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen
  • Y 5a and Y 5b are each hydrogen
  • Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each hydrogen
  • Y 10a and Y 10b are each hydrogen
  • Y 11 and Y 12 are the same
  • Y 13 and Y 14 are the same
  • Y 15a and Y 15b are the same
  • Y 16a and Y 16b are the same
  • Y 17a and Y 17b are the same
  • Y 20 , Y 21 , Y 22 and Y 23 are each deuterium, and the compound is selected from any one of the compounds (Cmpd
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen, Y 5a and Y 5b are each deuterium, Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each hydrogen, Y 10a and Y 10b are each deuterium, Y 11 and Y 12 are the same, Y 13 and Y 14 are the same, Y 15a and Y 15b are the same, Y 16a and Y 16b are the same, Y 17a and Y 17b are the same, and Y 20 , Y 21 , Y 22 and Y 23 are each deuterium, and the compound is selected from any one of the compounds
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are the same, Y 5a and Y 5b are the same, Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are the same, Y 10a and Y 10b are the same, Y 11 and Y 12 are the same, Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are the same, Y 20 , Y 21 , Y 22 and Y 23 are each deuterium, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 1l
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , , and Y 19 are independently selected from hydrogen and deuterium;
  • Y 1a and Y 1b are the same, Y 4a and Y 4b are the same, Y 2a and Y 2b are the same, Y 3a and Y 3b are the same, Y 6a and Y 6b are the same, Y 9a and Y 9b are the same, Y 7a and Y 7b are the same, Y 8a and Y 8b are the same, Y 11 and Y 12 are the same, Y 13 and Y 14 are the same, and Y 15a , Y 15b , Y 16a and Y 16b are the same.
  • Y 1a , Y 1b , Y 4a and Y 4b are the same, Y 2a , Y 2b , Y 3a and Y 3b are the same, Y 6a , Y 6b , Y 9a and Y 9b are the same, Y 7a , Y 7b , Y 8a and Y 8b are the same, Y 11 and Y 12 are the same, Y 13 and Y 14 are the same, and Y 15a , Y 15b , Y 16a and Y 16b are the same. [145] In some embodiments, Y 1a and Y 1b are the same. In some aspects of these embodiments, Y 1a and Y 1b are each hydrogen. In other aspects of these embodiments, Y 1a and Y 1b are each deuterium.
  • Y 2a and Y 2b are the same. In some aspects of these embodiments, Y 2a and Y 2b are each hydrogen. In other aspects of these embodiments, Y 2a and Y 2b are each deuterium.
  • Y 1a , Y 1b , Y 2a and Y 2b are the same. In some aspects of these embodiments, Y 1a , Y 1b , Y 2a and Y 2b are each hydrogen. In other aspects of these embodiments, Y 1a , Y 1b , Y 2a and Y 2b are each deuterium.
  • Y 1a , Y 1b , Y 4a and Y 4b are the same. In some aspects of these embodiments, Y 1a , Y 1b , Y 4a and Y 4b are each hydrogen. In other aspects of these embodiments, Y 1a , Y 1b , Y 4a and Y 4b are each deuterium.
  • Y 3a , Y 3b , Y 2a and Y 2b are the same. In some aspects of these embodiments, Y 3a , Y 3b , Y 2a and Y 2b are each hydrogen. In other aspects of these embodiments, Y 3a , Y 3b , Y 2a and Y 2b are each deuterium.
  • Y 3a and Y 3b are the same. In some aspects of these embodiments, Y 3a and Y 3b are each hydrogen. In other aspects of these embodiments, Y 3a and Y 3b are each deuterium.
  • Y 4a and Y 4b are the same. In some aspects of these embodiments, Y 4a and Y 4b are each hydrogen. In other aspects of these embodiments, Y 4a and Y 4b are each deuterium.
  • Y 3a , Y 3b , Y 4a and Y 4b are the same. In some aspects of these embodiments, Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen. In other aspects of these embodiments, Y 3a , Y 3b , Y 4a and Y 4b are each deuterium.
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are the same. In some aspects of these embodiments, Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen. In other aspects of these embodiments, Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each deuterium.
  • Y 1a , Y 1b , Y 2a and Y 2b are each hydrogen and Y 3a , Y 3b , Y 4a and Y 4b are each deuterium.
  • Y 1a , Y 1b , Y 2a and Y 2b are each deuterium and Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen.
  • Y 5a and Y 5b are the same. In some aspects of these embodiments, Y 5a and Y 5b are each hydrogen. In other aspects of these embodiments, Y 5a and Y 5b are each deuterium.
  • Y 5a and Y 5b are each deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen. In some embodiments, Y 5a and Y 5b are each hydrogen, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each deuterium.
  • Y 5a and Y 5b are each deuterium
  • Y 15a , Y 15b , Y 16a and Y 16b are each deuterium
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each deuterium.
  • Y 6a and Y 6b are the same. In some aspects of these embodiments, Y 6a and Y 6b are each hydrogen. In other aspects of these embodiments, Y 6a and Y 6b are each deuterium.
  • Y 7a and Y 7b are the same. In some aspects of these embodiments, Y 7a and Y 7b are each hydrogen. In other aspects of these embodiments, Y 7a and Y 7b are each deuterium.
  • Y 8a and Y 8b are the same. In some aspects of these embodiments, Y 8a and Y 8b are each hydrogen. In other aspects of these embodiments, Y 8a and Y 8b are each deuterium.
  • Y 9a and Y 9b are the same. In some aspects of these embodiments, Y 9a and Y 9b are each hydrogen. In other aspects of these embodiments, Y 9a and Y 9b are each deuterium.
  • Y 10a and Y 10b are the same. In some aspects of these embodiments, Y 10a and Y 10b are each hydrogen. In other aspects of these embodiments, Y 10a and Y 10b are each deuterium.
  • Y 18 is hydrogen
  • Y 18 is deuterium
  • Y 19 is hydrogen
  • Y 19 is deuterium.
  • Y 18 and Y 19 are the same. In some aspects of these embodiments, Y 18 and Y 19 are each hydrogen. In other aspects of these embodiments, Y 18 and Y 19 are each deuterium.
  • Y 18 is hydrogen and Y 19 is deuterium.
  • Y 18 is deuterium and Y 19 is hydrogen.
  • Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 18 and Y 19 are the same.
  • Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 18 and Y 19 are each hydrogen.
  • Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 18 and Y 19 are each deuterium.
  • Y 5a and Y 5b are each hydrogen, and Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 18 and Y 19 are each deuterium.
  • Y 5a and Y 5b are each deuterium, and Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 18 and Y 19 are each hydrogen.
  • Y 10a and Y 10b are each hydrogen, and Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each deuterium.
  • Y 10a , Y 10b are each deuterium, and Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each hydrogen.
  • Y 5a , Y 5b , Y 10a and Y 10b are each hydrogen, and Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each deuterium.
  • Y 5a , Y 5b , Y 10a and Y 10b are each deuterium, and Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each hydrogen.
  • Y 11 is hydrogen
  • Y 11 is deuterium
  • Y 12 is hydrogen
  • Y 12 is deuterium
  • Y 11 and Y 12 are the same. In some aspects of these embodiments, Y 11 and Y 12 are each hydrogen. In other aspects of these embodiments, Y 11 and Y 12 are each deuterium. In some embodiments, Y 11 is hydrogen and Y 12 is deuterium. In some embodiments, Y 11 is deuterium and Y 12 is hydrogen.
  • Y 13 is hydrogen. [184] In some embodiments, Y 13 is deuterium.
  • Y 14 is hydrogen
  • Y 14 is deuterium
  • Y 13 and Y 14 are the same. In some aspects of these embodiments, Y 13 and Y 14 are each hydrogen. In other aspects of these embodiments, Y 13 and Y 14 are each deuterium. In some embodiments, Y 13 is hydrogen and Y 14 is deuterium. In some embodiments, Y 13 is deuterium and Y 14 is hydrogen.
  • Y 15a and Y 15b are the same. In some aspects of these embodiments, Y 15a and Y 15b are each hydrogen. In other aspects of these embodiments, Y 15a and Y 15b are each deuterium.
  • Y 16a and Y 16b are the same. In some aspects of these embodiments, Y 16a and Y 16b are each hydrogen. In other aspects of these embodiments, Y 16a and Y 16b are each deuterium.
  • Y 17a and Y 17b are the same. In some aspects of these embodiments, Y 17a and Y 17b are each hydrogen. In other aspects of these embodiments, Y 17a and Y 17b are each deuterium.
  • Y 15a and Y 15b are each hydrogen and Y 16a and Y 16b are each deuterium. In some embodiments, Y 15a and Y 15b are each deuterium and Y 16a and Y 16b are each hydrogen.
  • Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are the same. In some aspects of these embodiments, Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are each hydrogen.
  • Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are each deuterium.
  • Y 11 and Y 12 are each hydrogen, and Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are each deuterium.
  • Y 11 and Y 12 are each deuterium, and Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are each hydrogen.
  • Y 15a , Y 15b , Y 16a and Y 16b are the same. In some aspects of these embodiments, Y 15a , Y 15b , Y 16a and Y 16b are each hydrogen. In other aspects of these embodiments, Y 15a , Y 15b , Y 16a and Y 16b are each deuterium. [196] In some embodiments, Y 15a , Y 15b , Y 16a and Y 16b are each deuterium and Y 11 , Y 12 , Y 13 , Y 14 , Y 17a and Y 17b are each hydrogen.
  • Y 15a , Y 15b , Y 16a , Y 16b , Y 11 , and Y 12 are each deuterium and Y 13 , Y 14 , Y 17a and Y 17b are each hydrogen.
  • Y 15a , Y 15b , Y 16a , Y 16b , Y 13 , and Y 14 are each deuterium and Y 11 , Y 12 , Y 17a and Y 17b are each hydrogen.
  • Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , and Y 17b are each deuterium and Y 11 , Y 12 , Y 13 and Y 14 are each hydrogen.
  • Y 15a , Y 15b are each deuterium and Y 11 , Y 12 , Y 13 , Y 14 , Y 16a , Y 16b , Y 17a and Y 17b are each hydrogen.
  • Y 16a , Y 16b are each deuterium and Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 17a and Y 17b are each hydrogen.
  • Y 5a , Y 5b , Y 15a , Y 15b , Y 16a and Y 16b are each deuterium.
  • the absolute configuration of the carbon atom to which Y 18 is attached is (R) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y 19 is attached is (R) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y 11 is attached is (S) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y 12 is attached is (R) according to Cahn-Ingold-Prelog nomenclature.
  • the absolute configuration of the carbon atom to which Y 13 is attached is (R) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y 14 is attached is (S) according to Cahn- Ingold-Prelog nomenclature.
  • the absolute configuration of the carbon atom to which Y 18 is attached is (R), the carbon atom to which Y 19 is attached is (R), the carbon atom to which Y 11 is attached is (S), the carbon atom to which Y 12 is attached is (R), the carbon atom to which Y 13 is attached is (R), and the carbon atom to which Y 14 is attached is (S) according to Cahn-Ingold-Prelog nomenclature.
  • At least one of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , and Y 19 is hydrogen.
  • Y 11 is deuterium
  • Y 12 is deuterium
  • at least one of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 and Y 19 comprises deuterium.
  • Y 10a and Y 10b are each deuterium, and at least one of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 and Y 19 comprises deuterium.
  • Y 5a and Y 5b are each deuterium, and at least one of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , and Y 19 comprises deuterium.
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each deuterium, and at least one of Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , and Y 19 comprises deuterium.
  • the compound of Formula II is not a compound where Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , and Y 19 are each deuterium.
  • the compound of Formula II is not a compound where Y 11 is deuterium, Y 12 is deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 13 , Y 14 , , Y 18 , and Y 19 are independently selected from hydrogen and deuterium.
  • the compound of Formula II is not a compound where Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are each deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 18 , and Y 19 are independently selected from hydrogen and deuterium.
  • the compound of Formula II is not a compound where Y 10a and Y 10b are each deuterium and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , and Y 19 are independently selected from hydrogen and deuterium.
  • the compound of Formula II is not a compound where Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , and Y 17b are independently selected from hydrogen and deuterium.
  • the compound of Formula II is not a compound where Y 5a and Y 5b are each deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , and Y 19 are independently selected from hydrogen and deuterium.
  • the compound of Formula II is not a compound where Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each deuterium, and Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , and Y 19 are independently selected from hydrogen and deuterium.
  • the compound of Formula II is not a compound where Y 11 is deuterium, Y 12 is deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , and Y 19 are each hydrogen.
  • the compound of Formula II is not a compound where Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are each deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 18 , and Y 19 are each hydrogen.
  • the compound of Formula II is not a compound where Y 10a and Y 10b are each deuterium and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , and Y 19 are each hydrogen.
  • the compound of Formula II is not a compound where Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , and Y 17b are each hydrogen.
  • the compound of Formula II is not a compound where Y 5a and Y 5b are each deuterium, and Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , and Y 19 are each hydrogen.
  • the compound of Formula II is not a compound where Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each deuterium, and Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11 , Y 12 , Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18 , and Y 19 are each hydrogen.
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are the same, Y 5a and Y 5b are the same, Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are the same, Y 10a and Y 10b are the same, Y 15a , Y 15b , Y 16a , Y 16b are the same, Y 11 , Y 12 , Y 13 , Y 14 , Y 17a and Y 17b are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 2a (below):
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen, Y 5a and Y 5b are each deuterium, Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each hydrogen, Y 10a and Y 10b are each hydrogen, Y 11 and Y 12 are the same, Y 13 and Y 14 are the same, Y 15a and Y 15b are the same, Y 16a and Y 16b are the same, Y 17a and Y 17b are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 2c (below):
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen
  • Y 5a and Y 5b are each hydrogen
  • Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each deuterium
  • Y 10a and Y 10b are each hydrogen
  • Y 11 and Y 12 are the same
  • Y 13 and Y 14 are the same
  • Y 15a and Y 15b are the same
  • Y 16a and Y 16b are the same
  • Y 17a and Y 17b are the same
  • the compound is selected from any one of the compounds (Cmpd) set forth in Table 2d (below):
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen
  • Y 5a and Y 5b are each hydrogen
  • Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each hydrogen
  • Y 10a and Y 10b are each deuterium
  • Y 11 and Y 12 are the same
  • Y 13 and Y 14 are the same
  • Y 15a and Y 15b are the same
  • Y 16a and Y 16b are the same
  • Y 17a and Y 17b are the same
  • the compound is selected from any one of the compounds (Cmpd) set forth in Table 2e (below):
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen
  • Y 5a and Y 5b are each hydrogen
  • Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each hydrogen
  • Y 10a and Y 10b are each hydrogen
  • Y 11 and Y 12 are the same
  • Y 13 and Y 14 are the same
  • Y 15a and Y 15b are the same
  • Y 16a and Y 16b are the same
  • Y 17a and Y 17b are the same and the compound is selected from any one of the compounds (Cmpd) set forth in Table 2f (below):
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are each hydrogen, Y 5a and Y 5b are each deuterium, Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are each hydrogen, Y 10a and Y 10b are each deuterium, Y 11 and Y 12 are the same, Y 13 and Y 14 are the same, Y 15a and Y 15b are the same, Y 16a and Y 16b are the same, Y 17a and Y 17b are the same and the compound is selected from any one of the compounds (Cmpd) set forth in Table 2g (below):
  • Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a and Y 4b are the same, Y 5a and Y 5b are the same, Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 18 and Y 19 are the same, Y 10a and Y 10b are the same, Y 11 and Y 12 are the same, Y 13 , Y 14 , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a and Y 17b are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 2h (below):
  • the level of deuterium incorporation at each Y 1a or Y 1b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 2a or Y 2b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 3a or Y 3b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 4a or Y 4b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 5a or Y 5b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 6a or Y 6b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 7a or Y 7b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 8a or Y 8b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 9a or Y 9b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • incorporation at Y 18 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • incorporation at Y 19 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 10a or Y 10b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 10a or Y 10b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • incorporation at Y 11 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • incorporation at Y 12 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • incorporation at Y 13 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • incorporation at Y 14 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 15a or Y 15b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 16a or Y 16b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 17a or Y 17b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • incorporation at Y 20 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • incorporation at Y 21 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • incorporation at Y 22 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at Y 23 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance.
  • Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.
  • Reagents and conditions (a) rt, Chiral resolution; (b) NaOH, H2, Raney-Ni; (c) heat, then D- tartaric acid; (d) Na 2 CO 3 , then HCl
  • Treatment of (5) with appropriately deuterated anhydride intermediate (6) in the presence of an inorganic base such as potassium carbonate at elevated temperature furnishes crude material of appropriately deuterated compounds of Formula I and Formula II.
  • an inorganic base such as potassium carbonate
  • treatment of the crude material with D-tartaric acid affords a tartrate salt which is treated with sodium carbonate and then hydrochloric acid or any pharmaceutically acceptable acid to produce the hydrochloride salt or any pharmaceutically acceptable salt of appropriately deuterated compounds of Formula I and/or Formula II in high optical purity.
  • Reagent (3a), borate(1-), tris(acetato- ⁇ O)hydro-d-, sodium may be prepared according to a procedure described in WO2015189413 from sodium borodeuteride (98 atom %D).
  • deuterated intermediate (1) for use in the preparation of compounds of Formula I and / or Formula II according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 2.
  • Certain intermediates (7) are commercially available: cyclohexanone-2,2,3,3,4,4, 5,5,6,6-d10 (98 atom %D) (7a), cyclohexanone-2,2,6,6-d4 (98 atom %D) (7b); and cyclohexanone-3,3,4,4,5,5-d6 (98 atom %D) (7c).
  • cyclohexanone-2,2,4,4,6,6-d6 (7d) and cyclohexanone-4,4-d2 (7e) may be prepared according to a procedure described in WO 2012151343;
  • cyclohexanone-2,2,3,3,5,5,6,6-d8 (7f) and cyclohexanone-3,3,5,5-d4 (7g) may be prepared according to a procedure described by Lompa-Krzywien, L.
  • cyclohexanone-2,2,3,3,4,4-d6 (7h) may be prepared according to a procedure described in EP2566869
  • cyclohexanone-2,2,3, 3,6,6-d6 (7i) may be prepared according to a procedure described by Stibbe, W. et al., Journal of Labelled Compounds and Radiopharmaceuticals (1979), 16(4), 567-77.
  • deuterated intermediate (2) for use in the preparation of compounds of Formula I and /or Formula II according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 3.
  • Reagents and conditions (a) HCl, H 2 O 2 , SDS; (b) SOCl 2 , NH 4 OH; (c) Na 2 S, HCl, pH 4, H 2 O 2 , pH 9, then HCl, pH 5; (d) SO 2 Cl, Heat; (e) Heat; (f) HBr [272] In a manner analogous to a procedure described by Samant, B.
  • chlorobenzisothiazole intermediate (16) by analogy to a procedure described in EP 2554543.
  • nucleophilic displacement of chloride in (16) with mono carbamate protected and appropriately deuterated piperazine intermediate (17) at elevated temperature furnishes protected and appropriately deuterated arylpiperazine intermediate (18), and final treatment of (18) with acid such as hydrobromic acid results in removal of protecting group to produce appropriately deuterated arylpiperazine intermediate (2).
  • benzoic-2,4,6-d3 acid (12e) may prepared from commercially available bromobenzene-2,4,6-d3 (98 atom %D) according to a procedure described by Raftery, M. et al., Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), (4), 563-9; 1988; benzoic-3,4-d2 acid (12f) and benzoic-3-d acid (12g) may be prepared according to a procedure described by Tashiro, M. et al., Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), (2), 179-81; 1988.
  • Use of appropriately deuterated reagents allows deuterium incorporation at the Y 1a, 1b , Y 2a, 2b , Y 3a, 3b , Y 4a, 4b positions of a compound of Formula I and/or Formula II, or any appropriate intermediate herein, e.g., 90, 95, 97, or 99% deuterium incorporation at any Y 1a, 1b , Y 2a, 2b , Y 3a, 3b , and or/ Y 4a, 4b position.
  • deuterated intermediate (6) for use in the preparation of compounds of Formula I and / or Formula II according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 5.
  • the synthetic intermediates useful in the preparation of the compounds of Formula I and/or Formula II may be prepared in a manner analogous to that described in US patent No.6,111,105; and J. Med. Chem., 1989, 32, 1024-1033 using appropriately deuterated starting materials which are commercially available or which synthesis is readily apparent to one of skill in the art.
  • the invention also provides pharmaceutical compositions comprising an effective amount of a compound of Formula I (e.g., including any of the formulae herein), or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier e.g., including any of the formulae herein
  • the carrier(s) are“acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.
  • Pharmaceutically acceptable carriers, adjuvants, excipients and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates (e.g., phosphate-buffered saline, etc.), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers e.g., phosphat
  • solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions may be enhanced by methods well-known in the art.
  • One method includes the use of lipid excipients in the formulation. See“Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare, 2007; and“Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples,” Kishor M. Wasan, ed. Wiley-Interscience, 2006.
  • Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROL TM and PLURONIC TM (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See United States patent 7,014,866; and United States patent publications 20060094744 and 20060079502.
  • 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.
  • the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques).
  • Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed.2000).
  • Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients.
  • ingredients such as the carrier that constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc.
  • Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • compositions suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit- dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long- chain alcohol diluent or dispersant.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g.: Rabinowitz JD and Zaffaroni AC, US Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.
  • Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutical composition can be formulated with 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 compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.
  • Application of the subject therapeutics may be local, so as to be administered at the site of interest.
  • Various techniques can be used for providing the subject
  • compositions at the site of interest such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.
  • the compounds of this invention may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • an implantable medical device such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in US Patents 6,099,562; 5,886,026; and 5,304,121.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer,
  • Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.
  • the invention provides a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal.
  • the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention.
  • Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.
  • the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active.
  • the invention provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this invention, such that said compound is released from said device and is therapeutically active.
  • composition of this invention may be painted onto the organ, or a composition of this invention may be applied in any other convenient way.
  • composition of this invention further comprises one or more additional therapeutic agents.
  • the additional therapeutic agent may be selected from any compound or therapeutic agent known to have or that demonstrates
  • Such agents include those indicated as being useful in combination with lurasidone, including but not limited to, those described in US patent No.9,259,423 and PCT publication No.2012/002583.
  • the additional therapeutic agent is an antipsychotic (e.g., chlorpromazine fluphenazine, haloperidol, loxapine, perphenazine, thioridazin, thiothixene, clozapine, lithium (e.g., as lithium citrate or lithium carbonate) or atypical antipsychotic (e.g., aripiprazole, aripiprazole lauroxil, asenapine, brexpiprazole, cariprazine, paliperidone, paliperidone palmitate, quetiapine, risperidone, olanzapine, ziprasidone and iloperidone)).
  • an antipsychotic e.g., chlorpromazine fluphenazine, haloperidol, loxapine, perphenazine, thioridazin, thiothixene, clozapine
  • lithium e.g., as lithium citrate or
  • the additional therapeutic agent is an anticonvulsant such as valproate (e.g., valproic acid or valproic acid sodium salt).
  • valproate e.g., valproic acid or valproic acid sodium salt.
  • the additional therapeutic agent is a serotonin receptor ligand selected from the group consisting of 5-HT1A agonist, a 5-HT7 antagonist, a 5-HT6 antagonist, a 5-HT2C agonist, a 5-HT2A antagonist or a 5-HT2A inverse agonist.
  • the additional therapeutic agent is a serotonin receptor ligand selected from the group consisting of tandospirone, buspirone, gepirone, flibanserin, osemozotan, befiradol, piclozotan, F-15599, naluzotan, flesionoxan, isapirone, eptapirone, repinotan, Org-13011, alnespirone, lesopitron, adatanserin, zalospirone, ebalzotan, U-93385, EMD- 56551, binospirone, CGS-19480A, Ru-24969, R-137696, amisulpride, SB-269970-A, SB-656104-A, DR-4446, DR-4365, DR-4485, SB-258741, DR-4004, SB-258719, LY- 215840, eplivanserin, pimavanserin, ritanserin, LY- 2158
  • the additional therapeutic agent is a D4 receptor agonist (e.g., PD-168077, ABT-724, ABT-670, F-15063, A-412997, FAUC-327, Ro-10-5824, CP-226269, PIP-3EA, FAUC-299, FAUC-316, FAUC-179, FAUC-356, FAUC-312, or A-369508).
  • D4 receptor agonist e.g., PD-168077, ABT-724, ABT-670, F-15063, A-412997, FAUC-327, Ro-10-5824, CP-226269, PIP-3EA, FAUC-299, FAUC-316, FAUC-179, FAUC-356, FAUC-312, or A-369508.
  • the additional therapeutic agent is an antidepressant.
  • the antidepressant is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a noradrenergic and specific serotonergic antidepressant, a norepinephrine (noradrenaline) reuptake inhibitor, a norepinephrine- dopamine reuptake inhibitor, tricyclic antidepressant, or a monoamine oxidase inhibitor.
  • the selective serotonin reuptake inhibitor can be citalopram, dapoxetine, escitalopram, fluvoxamine, norfluoxetine, fluoxetine, paroxetine, sertraline, or zimelidine, or pharmaceutically acceptable salts thereof.
  • the serotonin-norepinephrine reuptake inhibitor can be venlafaxine, desvenlafaxine, sibutramine, nefazodone, milnacipran, duloxetine, or bicifadine, or pharmaceutically acceptable salts thereof.
  • the noradrenergic and specific serotonergic antidepressant can be mirtazapine, or pharmaceutically acceptable salts thereof.
  • the norepinephrine (noradrenaline) reuptake inhibitor can be atomoxetine, reboxetine, viloxazine, maprotiline, bupropion, or radafaxine, or pharmaceutically acceptable salts thereof.
  • the norepinephrine-dopamine reuptake inhibitor is bupropion or methylphenidate, or pharmaceutically acceptable salts thereof.
  • antidepressant can be amitriptyline, butriptyline, amoxapine, clomipramine, desipramine, dosulepin, doxepin, imipramine, dibenzepin, iprindole, lofepramine, nortriptyline, opipramol, protriptyline or trimipramine, or pharmaceutically acceptable salts thereof.
  • the monoamine oxidase inhibitor can be isocarboxazid,
  • moclobemide phenelzine, tranylcypromine, selegiline, rasagiline, nialamide, iproniazid, iproclozide, or toloxatone, or pharmaceutically acceptable salts thereof.
  • the additional therapeutic agent is selected from lithium and/or valproate.
  • the invention provides separate dosage forms of a compound of this invention and one or more of any of the above-described additional therapeutic agents, wherein the compound and additional therapeutic agent are associated with one another.
  • the term“associated with one another” as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).
  • the compound of the present invention is present in an effective amount.
  • the term“effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat the target disorder.
  • body surface area may be approximately determined from height and weight of the subject. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970, 537.
  • an effective amount of a compound of this invention can range from about 5 mg to about 200 mg, from about 5 mg to about 180 mg, from about 10 mg to about 160 mg, from about 20 mg to about 160 mg, from about 20 mg to about 120 mg, from about 40 mg to about 160 mg, from about 40 mg to about 120 mg, from about 4 mg to about 320 mg, from about 2 mg to about 800 mg, or from about 0.2 mg to about 1600 mg.
  • an effective amount of a compound of this invention is about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg.
  • an effective amount of a compound of this invention can range from about 0.01 mg.kg to about 100 mg/kg, from about 0.05 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.15 mg/kg to about 30 mg/kg, from about 0.2 mg/kg to about 20 mg/kg, from about 0.25 mg/kg to about 15 mg/kg, from about 0.5 mg/kg to about 10 mg/kg.
  • an effective amount of a compound of this invention is about 0.05 mg/kg, about 0.1 mg/kg, about 0.15 mg/kg, about 0.2 mg/kg, about 0.25 mg/kg, about 0.3 mg/kg, about 0.35 mg/kg, about 0.4 mg/kg, about 0.45 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.1 mg/kg, about 1.15 mg/kg, about 1.2 mg/kg, about 1.25 mg/kg, about 1.3 mg/kg, about 1.35 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.75 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, or about 10 mg/kg.
  • the effective amount of a compound of this invention is administered to the subject once daily. In some embodiments, the effective amount of a compound of this invention is administered to the subject twice daily.
  • Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co- usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. For example, guidance for selecting an effective dose can be determined by reference to the prescribing information for lurasidone.
  • an effective amount of the additional therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent.
  • an effective amount is between about 70% and 100% of the normal monotherapeutic dose.
  • the normal monotherapeutic dosages of these additional therapeutic agents are well known in the art. See, e.g., Wells et al., eds.,
  • the invention provides a method of modulating the activity of a receptor selected from the group consisting of central dopamine Type 2 (D2) receptor and serotonin Type 2 (5HT2A) receptor in a cell, comprising contacting the cell with one or more compounds of Formula I or Formula II herein, or a pharmaceutically acceptable salt thereof.
  • the method of modulating the activity of the receptor is a method of antagonizing the activity of the receptor.
  • the invention provides a method of modulating the activity of a receptor selected from the group consisting of 5-HT7 receptor and ⁇ 2A adrenergic receptor in a cell, comprising contacting the cell with one or more compounds of Formula I or Formula II herein, or a pharmaceutically acceptable salt thereof.
  • the method of modulating the activity of the receptor is a method of antagonizing the activity of the receptor.
  • the invention provides a method of modulating the activity of 5-HT1A receptor in a cell comprising contacting the cell with one or more compounds of Formula I or Formula II herein, or a pharmaceutically acceptable salt thereof.
  • the method of modulating the activity of the receptor is a method of partially agonizing the activity of the receptor.
  • the invention provides a method of modulating the activity of ⁇ 2C-adrenergic receptor in a cell, comprising contacting the cell with one or more compounds of Formula I or Formula II herein, or a pharmaceutically acceptable salt thereof.
  • the method of modulating the activity of the receptor is a method of antagonizing the activity of the receptor.
  • the invention provides a method of modulating the activity of a receptor selected from the group consisting of ⁇ 1-adrenergic receptor, D1 receptor and 5-HT2C receptor in a cell, comprising contacting the cell with one or more compounds of Formula I or Formula II herein, or a pharmaceutically acceptable salt thereof.
  • the cell is contacted in vitro. In some embodiments, the cell is contacted in vivo. In some embodiments, the cell is contacted ex vivo.
  • the invention provides a method of treating a disease that is beneficially treated by lurasidone in a subject in need thereof, comprising the step of administering to the subject an effective amount of a compound or a composition of this invention.
  • the subject is a patient in need of such treatment.
  • the subject is a human.
  • diseases are well known in the art and are disclosed in, but not limited to the following patents and published applications: US patent No.5,532,372 and US patent publication No.2014/0350029.
  • Such diseases include, but are not limited to, schizophrenia, childhood
  • schizophrenia (pediatric schizophrenia), senile insanity, manic-depressive psychosis, neurosis, bipolar I disorder, bipolar II disorder, senile dementia, mixed depression, impairment in learning and memory associated with schizophrenia, impaired cognitive function, adjunctive therapy in bipolar disorder, adjunctive therapy in depression, adolescent bipolar disorder, adolescent depression, alcohol dependence, Alzheimer's disease, anorexia nervosa, attention deficit disorder (ADD), attention deficit/hyperactivity disorder (ADHD), aggression in ADHD, severe impulsiveness, attention deficit in schizophrenia, attention deficit in bipolar disorder (bipolar I or II disorder), an anxiety disorder including generalized anxiety disorder and social anxiety disorder, bipolar maintenance, borderline personality disorder, circadian rhythm sleep disorder, cognitive function impairment, cognitive impairment associated with schizophrenia, cognitive remediation therapy, conduct disorder, delirium, depression maintenance, first episode psychosis, Fragile-X Syndrome, mixed depression, monotherapy in bipolar disorder, monotherapy in depression, neuropathic pain, obsessive compulsive disorder
  • mixed depression is depression and at least one symptom chosen from manic symptoms and hypomanic symptoms.
  • mixed depression is a major depressive disorder with mixed features, such as a major depressive episode with mixed features, such as with a limited number of manic symptoms.
  • a major depressive episode is diagnosed according to the proposed Diagnostic and
  • the at least one CNS disorder is negative symptoms associated with schizophrenia.
  • negative symptoms associated with schizophrenia include, but are not limited to, extrapyramidal symptoms, tardive dyskinesia, sedation, and metabolic side effects such as, for example, weight gain, hyperglycemia, hyperlipidemia, hypotension, cardiac disease, and diabetes.
  • the at least one CNS disorder is chosen from learning and memory impairment and cognitive impairment associated with schizophrenia. Examples of learning and memory impairment include, but are not limited to, decline in cognitive functions or cognitive domains, e.g., working memory, attention and vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving, e.g., executive function and/or speed of processing.
  • the method of this invention is used to treat a disease or condition selected from schizophrenia, depressive episodes associated with bipolar I disorder (bipolar depression), schizoaffective disorder, irritability associated with autistic disorder (e.g., pediatric autism), autism, pediatric schizophrenia, improving cognition in bipolar patients, schizophrenia or schizoaffective disorder in subjects switched from other antipsychotic agents, acute schizophrenia, chronic schizophrenia, treatment-resistant schizophrenia or schizoaffective disorder, major depressive disorder, maintenance treatment of schizophrenia, bipolar I disorder in children and adolescents, mania in children and adolescents with bipolar I or bipolar II disorder, mania in patients with bipolar spectrum disorders, and major depressive disorder with mixed features in a subject in need thereof.
  • a disease or condition selected from schizophrenia, depressive episodes associated with bipolar I disorder (bipolar depression), schizoaffective disorder, irritability associated with autistic disorder (e.g., pediatric autism), autism, pediatric schizophrenia, improving cognition in bipolar patients, schizophrenia or schizoaffective disorder in subjects switched from other antipsych
  • the method of this invention is used to treat a disease or condition selected from schizophrenia and depressive episodes associated with bipolar I disorder (bipolar depression), as monotherapy and as adjunctive therapy with lithium and valproate in a subject in need thereof.
  • a disease or condition selected from schizophrenia and depressive episodes associated with bipolar I disorder (bipolar depression), as monotherapy and as adjunctive therapy with lithium and valproate in a subject in need thereof.
  • Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g.
  • any of the above methods of treatment comprises the further step of co-administering to the subject in need thereof one or more additional therapeutic agents.
  • additional therapeutic agent may be made from any additional therapeutic agent known to be useful for co-administration with lurasidone.
  • the choice of additional therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of additional therapeutic agents that may be employed in the methods of this invention are those set forth above for use in
  • combination compositions comprising a compound of this invention and an additional therapeutic agent.
  • the combination therapies of this invention include co-administering a compound of Formula I or Formula II and one or more additional therapeutic agents to a subject in need thereof for treatment of the following conditions (with the particular additional therapeutic agent indicated in parentheses following the indication): depressive episodes associated with bipolar I disorder (lithium and/or valproate).
  • the term“co-administered” as used herein means that the additional therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an additional therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the additional therapeutic agent(s) are administered by conventional methods.
  • composition of this invention comprising both a compound of the invention and an additional therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other additional therapeutic agent or any compound of this invention to said subject at another time during a course of treatment.
  • the invention provides the use of a compound of Formula I alone or together with one or more of the above-described additional therapeutic agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment in a subject of a disease, disorder or symptom set forth above.
  • Another aspect of the invention is a compound of Formula I for use in the treatment in a subject of a disease, disorder or symptom thereof delineated herein.
  • Example 1 Evaluation of Metabolic Stability
  • Microsomal Assay Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, KS). ⁇ -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl2), and dimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich.
  • 7.5 mM stock solutions of test compounds are prepared in DMSO.
  • the 7.5 mM stock solutions are diluted to 12.5-50 ⁇ M in acetonitrile (ACN).
  • ACN acetonitrile
  • the 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl2.
  • the diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate.
  • a 10 ⁇ L aliquot of the 12.5-50 ⁇ M test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. Reactions are initiated by addition of pre-warmed NADPH solution.
  • the final reaction volume is 0.5 mL and contains 0.5 mg/mL human liver microsomes, 0.25-1.0 ⁇ M test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl 2 .
  • the reaction mixtures are incubated at 37 °C, and 50 ⁇ L aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 ⁇ L of ice-cold ACN with internal standard to stop the reactions.
  • the plates are stored at 4 °C for 20 minutes after which 100 ⁇ L of water is added to the wells of the plate before centrifugation to pellet precipitated proteins.
  • Carbaldehyde 26 (1 equiv) is treated with (S)-(–)- ⁇ , ⁇ -diphenyl-2- pyrrolidinemethanol trimethylsilyl ether (0.1 equiv) and benzoic acid (0.1 equiv) in ethanol, followed by nitromethane (3 equiv) to give a mixture of (1R,2R)-2- (nitromethyl)cyclohexane-1-carbaldehyde-d 27 (major) and (1S,2R)-2- (nitromethyl)cyclohexane-1-carbaldehyde-d 28 (minor).
  • Isothiazole salt 31 (1 equiv) is treated with 0.5M aqueous sodium hydroxide and then is hydrogenated at 130 psi in methanol in the presence of Raney-Nickel and acetic acid to give ((1R,2R)-2-((4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl- d2)cyclohexyl)-methanamine 32.
  • Nitromethane-d3 (3.37 g, 52.73 mmol, 2.9 equiv, 99.2 atom% D, CDN) was added and the reaction mixture was stirred at room temperature for 16 hours, then was concentrated under reduced pressure and partitioned between ethyl acetate (10 mL) and 0.1 N HCl (aq.) (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 10 mL).
  • Isothiazole 39 (1 equiv) is treated with 0.5M aqueous sodium hydroxide then hydrogenated at 130 psi in methanol in the presence of Raney-Nickel in D2O and acetic acid-D to give ((1R,2R)-2-((4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl)cyclo- hexyl)methan-d2-amine 40.
  • Lithium aluminum deuteride (420 mg, 10 mmol, 2 equiv, BOC Science, 98 atom % D) was suspended in THF (10 mL) and cooled to 0 °C.
  • a solution of dimethyl (1R,2R)-cyclohexane-1,2-dicarboxylate 41 (1.0 g, 5 mmol, 1 equiv) in THF (2 mL) was added drop-wise at a rate to maintain the temperature under 15 °C.
  • the reaction mixture was stirred at room temperature overnight, cooled to 0 °C, quenched by the addition of deuterium oxide (0.42 mL, Cambridge Isotopes, 99.9 atom% D), 15% sodium
  • the top light yellow layer (containing product) was resubjected to the exchange conditions for 2 more cycles to give Cyclopenta-1,3-diene-d646 (28 g, 67% yield, 1-2% H incorporation by quantitative NMR analysis) as a light yellow liquid which was used as is.
  • the crude product was purified using an Interchim automated chromatography system (40 g column), eluting with a gradient of 0 to 40% ethyl acetate in heptanes over 40 minutes, to afford (3aR,4R,7S,7aS)-3a,4,7,7a-tetrahydro-4,7- methanoisobenzofuran-1,3-dione-4,5,6,7,8,8-d649 (0.62 g, 21% yield, >99% GCMS purity) as a white solid. Unreacted d6-dione 48 (690 mg) was also recovered.
  • Dimethanesulfonate 53 (0.73 g, 3.33 mmol, 1 equiv) and sodium carbonate (0.36 g, 3.40 mmol, 1.02 equiv) were added.
  • the reaction mixture was heated at reflux for 16 hours, filtered and concentrated under reduced pressure.
  • Acetone 2.5 mL was added to the residue and the solution was stirred until a white precipitate formed.

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Abstract

L'invention concerne des formes deutérées de hexahydro -4,7-méthano -1 H-isoindole -1,3 (2H)-diones et leurs sels pharmaceutiquement acceptables. Dans un premier aspect, l'invention concerne un composé de formule (I): ou un sel pharmaceutiquement accepté de celui-ci. L'invention concerne également des compositions comprenant un composé de cette invention, y compris des compositions pharmaceutiques comprenant le composé et un support pharmaceutiquement acceptable. L'invention concerne en outre l'utilisation de ces composés et compositions dans des méthodes de traitement de maladies et d'états pathologiques qui sont avantageusement traités par l'administration d'un composé qui module l'activité d'un récepteur choisi dans le groupe constitué par les récepteurs de la dopamine centrale de Type 2 (D2) et de la sérotonine de Type 2 (5 HT2A). Certains modes de réalisation donnés à titre d'exemple comprennent un procédé de traitement d'une maladie ou d'un état choisi parmi la schizophrénie et les épisodes dépressifs associés à un trouble bipolaire I, le procédé comprenant l'étape consistant à administrer à un sujet en ayant besoin une composition pharmaceutiquement acceptable de la présente invention.
PCT/US2017/044400 2016-07-29 2017-07-28 Lurasidone deutérée Ceased WO2018023009A1 (fr)

Applications Claiming Priority (2)

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US201662368630P 2016-07-29 2016-07-29
US62/368,630 2016-07-29

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WO2018023009A1 true WO2018023009A1 (fr) 2018-02-01

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113747870A (zh) * 2018-12-21 2021-12-03 泰兰生物科技有限公司 氟利色林的氘化形式和衍生物

Citations (3)

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Publication number Priority date Publication date Assignee Title
US20090076027A1 (en) * 2007-09-17 2009-03-19 Protia, Llc Deuterium-enriched lurasidone
US20140348909A1 (en) * 2011-05-13 2014-11-27 Cadila Healthcare Limited Pharmaceutical compositions of lurasidone
US20150168431A1 (en) * 2013-12-12 2015-06-18 Ameritox, Ltd. Methods of monitoring adherence to lurasidone therapy

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090076027A1 (en) * 2007-09-17 2009-03-19 Protia, Llc Deuterium-enriched lurasidone
US20140348909A1 (en) * 2011-05-13 2014-11-27 Cadila Healthcare Limited Pharmaceutical compositions of lurasidone
US20150168431A1 (en) * 2013-12-12 2015-06-18 Ameritox, Ltd. Methods of monitoring adherence to lurasidone therapy

Non-Patent Citations (2)

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Title
DATABASE Pubmed [O] U.S. National Library of Medicine; 1 November 2013 (2013-11-01), "Compound Summary for CID 71749857", XP055459709, Database accession no. 71749857 *
DATABASE Pubmed [O] U.S. National Library of Medicine; 25 August 2014 (2014-08-25), XP055459706, retrieved from NCBI Database accession no. 76974229 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113747870A (zh) * 2018-12-21 2021-12-03 泰兰生物科技有限公司 氟利色林的氘化形式和衍生物
EP3897507A4 (fr) * 2018-12-21 2022-09-14 Terran Biosciences, Inc. Formes deutérées et dérivés de volinansérine
CN113747870B (zh) * 2018-12-21 2025-08-01 泰兰生物科技有限公司 氟利色林的氘化形式和衍生物

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