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WO2018023009A1 - Deuterated lurasidone - Google Patents

Deuterated lurasidone 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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WO
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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French (fr)
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/en
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

This invention relates to deuterated forms of hexahydro-4,7-methano-1H-isoindole-1,3(2H)-diones, and pharmaceutically acceptable salts thereof. In one aspect, the invention provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof. This invention also provides compositions comprising a compound of this invention, including pharmaceutical compositions comprising the compound 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 compounds 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. 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.

Description

DEUTERATED LURASIDONE CROSS REFERENCE TO RELATED APPLICATIONS
[1] This application claims the benefit of U.S. Provisional Application No.
62/368,630, filed July 29, 2016. The entire contents of the foregoing are hereby incorporated by reference. BACKGROUND OF THE INVENTION
[2] Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose patients to undesirable toxic or reactive metabolites.
[3] Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites. As a result, 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. In certain cases, 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.
[4] In some select cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. 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). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, 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, however, 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).
[5] In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme’s activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.
[6] A potentially attractive strategy for improving a drug’s metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. 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. At the same time, because 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.
[7] Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p.35 and Fisher at p.101).
[8] The effects of deuterium modification on a drug’s metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem.1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug. SUMMARY OF THE INVENTION
[9] This invention relates to deuterated forms of hexahydro-4,7-methano-1H- isoindole-1,3(2H)-diones, and pharmaceutically acceptable salts thereof.
[10] In one aspect, the invention provides a compound of Formula I:
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof,
wherein Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 are independently selected from hydrogen and deuterium;
provided that at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 is deuterium.
[11] In one aspect, the invention provides a compound of Formula II:
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof,
wherein Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, and Y19 are independently selected from hydrogen and deuterium;
provided that at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18 and Y19 comprises deuterium. [12] This invention also provides 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. 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. DETAILED DESCRIPTION OF THE INVENTION
[13] 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.
[14] 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) for treatment of bipolar I disorder, phase 3 clinical trials for treatment of major depressive with mixed features, phase 3 clinical trials to assess effectiveness in the long term maintenance treatment of schizophrenia, phase 3 clinical trials for the treatment of chronic schizophrenia, phase 3 clinical trials for the treatment of children and adolescents with bipolar I disorder, phase 4 clinical trials treatment for mania in children and adolescents with bipolar I, bipolar II, and bipolar spectrum disorders, phase 3 clinical trials for the treatment of major depressive disorder with mixed features, and is currently being tested for safety and efficacy in patients with an acute exacerbation of these diseases.
[15] Commonly observed adverse reactions (incidence≥ 5% and at least twice the rate for placebo) in patients diagnosed with schizophrenia and treated with lurasidone at daily doses ranging from 20 to 160 mg are somnolence, akathisia, extrapyramidal symptoms, and nausea; in patients diagnosed with bipolar depression and treated with lurasidone at daily doses ranging from 20 to 120 mg (monotherapy) are akathisia, extrapyramidal symptoms, somnolence, nausea, vomiting, diarrhea, and anxiety; and in patients diagnosed with bipolar depression and treated with lurasidone at daily doses ranging from 20 to 120 mg as adjunctive therapy with lithium or valproate are akathisia and
somnolence.
[16] Despite the beneficial activities of lurasidone, there is a continuing need for new compounds to treat the aforementioned diseases and conditions. Definitions
[17] The term“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.
[18] “Disease” means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
[19] As used herein, the term“subject” includes humans and non-human
mammals. Non-limiting examples of non-human mammals include mice, rats, guinea pigs, rabbits, dogs, cats, monkeys, apes, pigs, cows, sheep, horses, etc.
[20] It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of lurasidone will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen and carbon isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention. See, for instance, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.
[21] In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as“H” or“hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. In some embodiments, when a position is designated specifically as“H” or“hydrogen”, 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. In some embodiments, 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).
[22] The term“isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
[23] In other embodiments, 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).
[24] In some embodiments, in a compound of this invention, 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
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%. In some embodiments, in a compound of this invention, 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%.
[25] The term“isotopologue” refers to a species in which the chemical structure differs from a specific compound of this invention only in the isotopic composition thereof.
[26] The term“compound,” when referring to a compound of this invention, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that 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.
[27] The invention also provides salts of the compounds of the invention.
[28] 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. According to one embodiment, the compound is a pharmaceutically acceptable acid addition salt. In one embodiment the acid addition salt may be a deuterated acid addition salt.
[29] The term“pharmaceutically acceptable,” as used herein, 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. A “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. A“pharmaceutically acceptable counterion” is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
[30] 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. Such
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, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesu1fonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In one embodiment, 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. In one embodiment, the acids commonly employed to form pharmaceutically acceptable salts include the above-listed inorganic acids, wherein at least one hydrogen is replaced with deuterium.
[31] The compounds of the present invention (e.g., compounds of Formula I), may contain an asymmetric carbon atom, for example, as the result of deuterium substitution or otherwise. As such, compounds of this invention can exist as either individual enantiomers, or mixtures of the two enantiomers. Accordingly, 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. The term “substantially free of other stereoisomers” as used herein 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. Methods of obtaining or synthesizing an individual enantiomer for a given compound are known in the art and may be applied as practicable to final compounds or to starting material or intermediates.
[32] Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.
[33] The term“stable compounds,” as used herein, 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).
[34] “D” and“d” both refer to deuterium.“Tert” and“t-” each refer to tertiary.“US” refers to the United States of America.
[35] “Substituted with deuterium” refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.
[36] Throughout this specification, a variable may be referred to generally (e.g.,"each R") or may be referred to specifically (e.g., R1, R2, R3, etc.). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable. Therapeutic Compounds
[37] Certain aspects of the present invention provide a compound of Formula I:
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof,
wherein Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 are independently selected from hydrogen and deuterium;
provided that at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b,
Figure imgf000013_0002
Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 is deuterium. [38] In some embodiments, at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18 and Y19 is deuterium.
[39] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b together comprise zero deuterium atoms.
[40] In some embodiments, Y1a and Y1b are the same, Y4a and Y4b are the same, Y2a and Y2b are the same, Y3a and Y3b are the same, Y6a and Y6b are the same, Y9a and Y9b are the same, Y7a and Y7b are the same, Y8a and Y8b are the same, Y11 and Y12 are the same, Y13 and Y14 are the same, and Y15a, Y15b, Y16a and Y16b are the same. [41] In some embodiments, Y1a, Y1b, Y4a and Y4b are the same, Y2a, Y2b, Y3a and Y3b are the same, Y6a, Y6b, Y9a and Y9b are the same, Y7a, Y7b, Y8a and Y8b are the same, Y11 and Y12 are the same, Y13 and Y14 are the same, and Y15a, Y15b, Y16a and Y16b are the same.
[42] In some embodiments, Y1a and Y1b are the same. In some aspects of these embodiments, Y1a and Y1b are each hydrogen. In other aspects of these embodiments, Y1a and Y1b are each deuterium.
[43] In some embodiments, Y2a and Y2b are the same. In some aspects of these embodiments, Y2a and Y2b are each hydrogen. In other aspects of these embodiments, Y2a and Y2b are each deuterium.
[44] In some embodiments, Y1a, Y1b, Y2a and Y2b are the same. In some aspects of these embodiments, Y1a, Y1b, Y2a and Y2b are each hydrogen. In other aspects of these embodiments, Y1a, Y1b, Y2a and Y2b are each deuterium.
[45] In some embodiments, Y1a, Y1b, Y4a and Y4b are the same. In some aspects of these embodiments, Y1a, Y1b, Y4a and Y4b are each hydrogen. In other aspects of these embodiments, Y1a, Y1b, Y4a and Y4b are each deuterium.
[46] In some embodiments, Y3a and Y3b are the same. In some aspects of these embodiments, Y3a and Y3b are each hydrogen. In other aspects of these embodiments, Y3a and Y3b are each deuterium.
[47] In some embodiments, Y4a and Y4b are the same. In some aspects of these embodiments, Y4a and Y4b are each hydrogen. In other aspects of these embodiments, Y4a and Y4b are each deuterium.
[48] In some embodiments, Y3a, Y3b, Y4a and Y4b are the same. In some aspects of these embodiments, Y3a, Y3b, Y4a and Y4b are each hydrogen. In other aspects of these embodiments, Y3a, Y3b, Y4a and Y4b are each deuterium.
[49] In some embodiments, Y3a, Y3b, Y2a and Y2b are the same. In some aspects of these embodiments, Y3a, Y3b, Y2a and Y2b are each hydrogen. In other aspects of these embodiments, Y3a, Y3b, Y2a and Y2b are each deuterium.
[50] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are the same. In some aspects of these embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each hydrogen. In other aspects of these embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium.
[51] In some embodiments, Y1a, Y1b, Y2a and Y2b are each hydrogen and Y3a, Y3b, Y4a and Y4b are each deuterium.
[52] In some embodiments, Y1a, Y1b, Y2a and Y2b are each deuterium and Y3a, Y3b, Y4a and Y4b are each hydrogen.
[53] In some embodiments, Y5a and Y5b are the same. In some aspects of these embodiments, Y5a and Y5b are each hydrogen. In other aspects of these embodiments, Y5a and Y5b are each deuterium.
[54] In some embodiments, Y6a and Y6b are the same. In some aspects of these embodiments, Y6a and Y6b are each hydrogen. In other aspects of these embodiments, Y6a and Y6b are each deuterium.
[55] In some embodiments, Y7a and Y7b are the same. In some aspects of these embodiments, Y7a and Y7b are each hydrogen. In other aspects of these embodiments, Y7a and Y7b are each deuterium.
[56] In some embodiments, Y8a and Y8b are the same. In some aspects of these embodiments, Y8a and Y8b are each hydrogen. In other aspects of these embodiments, Y8a and Y8b are each deuterium.
[57] In some embodiments, Y9a and Y9b are the same. In some aspects of these embodiments, Y9a and Y9b are each hydrogen. In other aspects of these embodiments, Y9a and Y9b are each deuterium.
[58] In some embodiments, Y10a and Y10b are the same. In some aspects of these embodiments, Y10a and Y10b are each hydrogen. In other aspects of these embodiments, Y10a and Y10b are each deuterium.
[59] In some embodiments, Y18 is hydrogen.
[60] In some embodiments, Y18 is deuterium.
[61] In some embodiments, Y19 is hydrogen.
[62] In some embodiments, Y19 is deuterium.
[63] In some embodiments, Y18 and Y19 are the same. In some aspects of these embodiments, Y18 and Y19 are each hydrogen. In other aspects of these embodiments, Y18 and Y19 are each deuterium. [64] In some embodiments, Y18 is hydrogen and Y19 is deuterium.
[65] In some embodiments, Y18 is deuterium and Y19 is hydrogen.
[66] In some embodiments, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18 and Y19 are the same. In some aspects of these embodiments, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18 and Y19 are each hydrogen. In other aspects of these embodiments, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18 and Y19 are each deuterium.
[67] In some embodiments, Y5a and Y5b are each hydrogen, and Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18 and Y19 are each deuterium.
[68] In some embodiments, Y5a and Y5b are each deuterium, and Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18 and Y19 are each hydrogen.
[69] In some embodiments, Y10a and Y10b are each hydrogen, and Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each deuterium.
[70] In some embodiments, Y10a, Y10b are each deuterium, and Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each hydrogen.
[71] In some embodiments, Y5a, Y5b, Y10a and Y10b are each hydrogen, and Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each deuterium.
[72] In some embodiments, Y5a, Y5b, Y10a and Y10b are each deuterium, and Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each hydrogen.
[73] In some embodiments, Y11 is hydrogen.
[74] In some embodiments, Y11 is deuterium.
[75] In some embodiments, Y12 is hydrogen.
[76] In some embodiments, Y12 is deuterium.
[77] In some embodiments, Y11 and Y12 are the same. In some aspects of these embodiments, Y11 and Y12 are each hydrogen. In other aspects of these embodiments, Y11 and Y12 are each deuterium. In some embodiments, Y11 is hydrogen and Y12 is deuterium. In some embodiments, Y11 is deuterium and Y12 is hydrogen.
[78] In some embodiments, Y13 is hydrogen.
[79] In some embodiments, Y13 is deuterium.
[80] In some embodiments, Y14 is hydrogen.
[81] In some embodiments, Y14 is deuterium. [82] In some embodiments, Y13 and Y14 are the same. In some aspects of these embodiments, Y13 and Y14 are each hydrogen. In other aspects of these embodiments, Y13 and Y14 are each deuterium. In some embodiments, Y13 is hydrogen and Y14 is deuterium. In some embodiments, Y13 is deuterium and Y14 is hydrogen.
[83] In some embodiments, Y15a and Y15b are the same. In some aspects of these embodiments, Y15a and Y15b are each hydrogen. In other aspects of these embodiments, Y15a and Y15b are each deuterium.
[84] In some embodiments, Y16a and Y16b are the same. In some aspects of these embodiments, Y16a and Y16b are each hydrogen. In other aspects of these embodiments, Y16a and Y16b are each deuterium.
[85] In some embodiments, Y17a and Y17b are the same. In some aspects of these embodiments, Y17a and Y17b are each hydrogen. In other aspects of these embodiments, Y17a and Y17b are each deuterium.
[86] In some embodiments, Y15a and Y15b are each hydrogen and Y16a and Y16b are each deuterium. In some embodiments, Y15a and Y15bare each deuterium and Y16a and Y16b are each hydrogen.
[87] In some embodiments, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are the same. In some aspects of these embodiments, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are each hydrogen. In other aspects of these embodiments, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are each deuterium.
[88] In some embodiments, Y11 and Y12 are each hydrogen, and Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are each deuterium.
[89] In some embodiments, Y11 and Y12 are each deuterium, and Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are each hydrogen.
[90] In some embodiments, Y15a, Y15b, Y16a and Y16b are the same. In some aspects of these embodiments, Y15a, Y15b, Y16a and Y16b are each hydrogen. In other aspects of these embodiments, Y15a, Y15b, Y16a and Y16b are each deuterium.
[91] In some embodiments, Y15a, Y15b, Y16a and Y16b are each deuterium and Y11, Y12, Y13, Y14, Y17a and Y17b are each hydrogen.
[92] In some embodiments, Y15a, Y15b, Y16a, Y16b, Y11, and Y12 are each deuterium and Y13, Y14, Y17a and Y17b are each hydrogen.
Figure imgf000018_0001
[94] In some embodiments, Y , Y , Y , Y , Y , and Y are each deuterium and Y11, Y12, Y13 and Y14 are each hydrogen.
[95] In some embodiments, Y15a, Y15b are each deuterium and Y11, Y12, Y13, Y14, Y16a, Y16b, Y17a and Y17b are each hydrogen.
[96] In some embodiments, Y16a, Y16b are each deuterium and Y11, Y12, Y13, Y14, Y15a, Y15b, Y17a and Y17b are each hydrogen.
[97] In some embodiments, Y5a, Y5b, Y15a, Y15b, Y16a and Y16b are each deuterium.
[98] In some embodiments, Y5a, Y5b, Y15a, Y15b, Y16a and Y16b are each deuterium and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 are each hydrogen.
[99] In some embodiments, Y5a and Y5b are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium.
[100] In some embodiments, Y5a and Y5b are each deuterium, Y15a, Y15b, Y16a and Y16b are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium.
[101] In some embodiments, Y20, Y21, Y22 and Y23 are the same. In some aspects of these embodiments, Y20, Y21, Y22 and Y23 are each hydrogen. In other aspects of these embodiments, Y20, Y21, Y22 and Y23 are each deuterium.
[102] In some embodiments, when Y20, Y21, Y22 and Y23 are each hydrogen, at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18 and Y19 is deuterium.
[103] In some embodiments, the absolute configuration of the carbon atom to which Y18 is attached is (R) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y19 is attached is (R) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y11 is attached is (S) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y12 is attached is (R) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y13 is attached is (R) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y14 is attached is (S) according to Cahn- Ingold-Prelog nomenclature.
[104] In some embodiments, the absolute configuration of the carbon atom to which Y18 is attached is (R), the carbon atom to which Y19 is attached is (R), the carbon atom to which Y11 is attached is (S), the carbon atom to which Y12 is attached is (R), the carbon atom to which Y13 is attached is (R), and the carbon atom to which Y14 is attached is (S) according to Cahn-Ingold-Prelog nomenclature.
[105] In some embodiments, at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 is hydrogen.
[106] In some embodiments, at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18 and Y19 is hydrogen.
[107] In some embodiments, Y11 is deuterium, Y12 is deuterium, and at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 is deuterium.
[108] In some embodiments, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are each deuterium, and at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18, Y19, Y20, Y21, Y22, and Y23 is deuterium.
[109] In some embodiments, Y10a and Y10b are each deuterium, and at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 is deuterium.
[110] In some embodiments, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each deuterium, and at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y20, Y21, Y22, and Y23 is deuterium.
[111] In some embodiments, Y5a and Y5b are each deuterium, and at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 is deuterium.
[112] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium, and at least one of Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a,
Figure imgf000020_0001
deuterium.
[113] In some embodiments, Y20, Y21, Y22 and Y23 are each deuterium, and at least one
Figure imgf000020_0002
, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18 and Y19 is deuterium.
[114] In some embodiments, the compound of Formula I is not a compound where Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b,
Figure imgf000020_0003
each deuterium.
[115] In some embodiments, the compound of Formula I is not a compound where Y11 is deuterium, Y12 is deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 are independently selected from hydrogen and deuterium.
[116] In some embodiments, the compound of Formula I is not a compound where Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18, Y19, Y20, Y21, Y22, and Y23 are independently selected from hydrogen and deuterium.
[117] In some embodiments, the compound of Formula I is not a compound where Y10a and Y10b are each deuterium and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 are independently selected from hydrogen and deuterium.
[118] In some embodiments, the compound of Formula I is not a compound where Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y20, Y21, Y22, and Y23 are independently selected from hydrogen and deuterium.
[119] In some embodiments, the compound of Formula I is not a compound where Y5a and Y5b are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 are independently selected from hydrogen and deuterium.
[120] In some embodiments, the compound of Formula I is not a compound where Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium, and Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 are independently selected from hydrogen and deuterium.
[121] In some embodiments, the compound of Formula I is not a compound where Y20, Y21, Y22 and Y23 are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18 and Y19 are independently selected from hydrogen and deuterium.
[122] In some embodiments, the compound of Formula I is not a compound where Y11 is deuterium, Y12 is deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 are each hydrogen.
[123] In some embodiments, the compound of Formula I is not a compound where Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18, Y19, Y20, Y21, Y22, and Y23 are each hydrogen.
[124] In some embodiments, the compound of Formula I is not a compound where Y10a and Y10b are each deuterium and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 are each hydrogen.
[125] In some embodiments, the compound of Formula I is not a compound where Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y20, Y21, Y22, and Y23 are each hydrogen.
[126] In some embodiments, the compound of Formula I is not a compound where Y5a and Y5b are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 are each hydrogen.
[127] In some embodiments, the compound of Formula I is not a compound where Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium, and Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 are each hydrogen.
Figure imgf000022_0001
Figure imgf000023_0001
, or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance. [130] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are the same, Y5a and Y5b are the same, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are the same, Y10a and Y10b are the same, Y15a, Y15b, Y16a, Y16b are the same, Y11, Y12, Y13, Y14, Y17a and Y17b are the same, Y20 is hydrogen, and Y21, Y22 and Y23 are each deuterium, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 1b (below):
Table 1b: Exemplary Embodiments of Formula I
Figure imgf000024_0001
Figure imgf000025_0001
, or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance. [131] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are the same, Y5a and Y5b are the same, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are the same, Y10a and Y10b are the same, Y15a, Y15b, Y16a, Y16b are the same, Y11, Y12, Y13, Y14, Y17a and Y17b are the same, Y21 is hydrogen, and Y20, Y22 and Y23 are each deuterium, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 1c (below):
Figure imgf000026_0001
Figure imgf000027_0001
, or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance. [132] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are the same, Y5a and Y5b are the same, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are the same, Y10a and Y10b are the same, Y15a, Y15b, Y16a, Y16b are the same, Y11, Y12, Y13, Y14, Y17a and Y17b are the same, Y22 is hydrogen, and Y20, Y21 and Y23 are each deuterium, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 1d (below):
Figure imgf000028_0001
Figure imgf000029_0001
, or a p armaceu ca y accepa e sa ereo, weren any aom no esgnae as deuterium is present at its natural isotopic abundance. [133] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are the same, Y5a and Y5b are the same, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are the same, Y10a and Y10b are the same, Y15a, Y15b, Y16a, Y16b are the same, Y11, Y12, Y13, Y14, Y17a and Y17b are the same, Y23 is hydrogen, and Y20, Y21 and Y22 are each deuterium, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 1e (below):
Table 1e: Exemplary Embodiments of Formula I
Figure imgf000030_0001
Figure imgf000031_0001
[134] In some embodiments, Yla, Ylb, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium, Y5a and Y5b are each hydrogen, Y6a, Y6b, Y7a, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each hydrogen, Y10a and Y10b are each hydrogen, Y11 and Y12 are the same, Y13 and Y14 are the same, Y15a and Y15b are the same, Y16a and Y16b are the same, Y17a and Y17b are the same, and Y20, Y21, Y22 and Y23 are each deuterium, and the compound is selected from any one of the compounds (Cmpd) set forth in Table If (below): Table 1f: Exemplary Embodiments of Formula I
Figure imgf000032_0001
, or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance. [135] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each hydrogen, Y5a and Y5b are each deuterium, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each hydrogen, Y10a and Y10b are each hydrogen, Y11 and Y12 are the same, Y13 and Y14 are the same, Y15a and Y15b are the same, Y16a and Y16b are the same, Y17a and Y17b are the same, and Y20, Y21, Y22 and Y23 are each deuterium, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 1g (below):
Figure imgf000033_0002
Figure imgf000033_0001
[136] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each hydrogen, Y5a and Y5b are each hydrogen, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each deuterium, Y10a and Y10b are each hydrogen, Y11 and Y12 are the same, Y13 and Y14 are the same, Y15a and Y15b are the same, Y16a and Y16b are the same, Y17a and Y17b are the same, and Y20, Y21, Y22 and Y23 are each deuterium, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 1h (below):
Figure imgf000034_0001
, or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance. [137] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each hydrogen, Y5a and Y5b are each hydrogen, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each hydrogen, Y10a and Y10b are each deuterium, Y11 and Y12 are the same, Y13 and Y14 are the same, Y15a and Y15b are the same, Y16a and Y16b are the same, Y17a and Y17b are the same, and Y20, Y21, Y22 and Y23 are each deuterium, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 1i (below):
Figure imgf000035_0001
deuterium is present at its natural isotopic abundance. [138] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each hydrogen, Y5a and Y5b are each hydrogen, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each hydrogen, Y10a and Y10b are each hydrogen, Y11 and Y12 are the same, Y13 and Y14 are the same, Y15a and Y15b are the same, Y16a and Y16b are the same, Y17a and Y17b are the same, and Y20, Y21, Y22 and Y23 are each deuterium, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 1j (below):
Figure imgf000036_0001
deuterium is present at its natural isotopic abundance. [139] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each hydrogen, Y5a and Y5b are each deuterium, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each hydrogen, Y10a and Y10b are each deuterium, Y11 and Y12 are the same, Y13 and Y14 are the same, Y15a and Y15b are the same, Y16a and Y16b are the same, Y17a and Y17b are the same, and Y20, Y21, Y22 and Y23 are each deuterium, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 1k (below): Table 1k: Exemplary Embodiments of Formula I
Figure imgf000037_0001
d p p b d [140] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are the same, Y5a and Y5b are the same, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are the same, Y10a and Y10b are the same, Y11 and Y12 are the same, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are the same, Y20, Y21, Y22 and Y23 are each deuterium, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 1l (below):
Figure imgf000038_0001
[141] In some embodiments, the compound of Formula (I) has Formula (II):
Figure imgf000039_0001
or a pharmaceutically acceptable salt thereof,
wherein Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a,
Figure imgf000039_0002
, and Y19 are independently selected from hydrogen and deuterium;
provided that at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18 and Y19 is deuterium. [142] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b together comprise zero deuterium atoms.
[143] In some embodiments, Y1a and Y1b are the same, Y4a and Y4b are the same, Y2a and Y2b are the same, Y3a and Y3b are the same, Y6a and Y6b are the same, Y9a and Y9b are the same, Y7a and Y7b are the same, Y8a and Y8b are the same, Y11 and Y12 are the same, Y13 and Y14 are the same, and Y15a, Y15b, Y16a and Y16b are the same.
[144] In some embodiments, Y1a, Y1b, Y4a and Y4b are the same, Y2a, Y2b, Y3a and Y3b are the same, Y6a, Y6b, Y9a and Y9b are the same, Y7a, Y7b, Y8a and Y8b are the same, Y11 and Y12 are the same, Y13 and Y14 are the same, and Y15a, Y15b, Y16a and Y16b are the same. [145] In some embodiments, Y1a and Y1b are the same. In some aspects of these embodiments, Y1a and Y1b are each hydrogen. In other aspects of these embodiments, Y1a and Y1b are each deuterium.
[146] In some embodiments, Y2a and Y2b are the same. In some aspects of these embodiments, Y2a and Y2b are each hydrogen. In other aspects of these embodiments, Y2a and Y2b are each deuterium.
[147] In some embodiments, Y1a, Y1b, Y2a and Y2b are the same. In some aspects of these embodiments, Y1a, Y1b, Y2a and Y2b are each hydrogen. In other aspects of these embodiments, Y1a, Y1b, Y2a and Y2b are each deuterium.
[148] In some embodiments, Y1a, Y1b, Y4a and Y4b are the same. In some aspects of these embodiments, Y1a, Y1b, Y4a and Y4b are each hydrogen. In other aspects of these embodiments, Y1a, Y1b, Y4a and Y4b are each deuterium.
[149] In some embodiments, Y3a, Y3b, Y2a and Y2b are the same. In some aspects of these embodiments, Y3a, Y3b, Y2a and Y2b are each hydrogen. In other aspects of these embodiments, Y3a, Y3b, Y2a and Y2b are each deuterium.
[150] In some embodiments, Y3a and Y3b are the same. In some aspects of these embodiments, Y3a and Y3b are each hydrogen. In other aspects of these embodiments, Y3a and Y3b are each deuterium.
[151] In some embodiments, Y4a and Y4b are the same. In some aspects of these embodiments, Y4a and Y4b are each hydrogen. In other aspects of these embodiments, Y4a and Y4b are each deuterium.
[152] In some embodiments, Y3a, Y3b, Y4a and Y4b are the same. In some aspects of these embodiments, Y3a, Y3b, Y4a and Y4b are each hydrogen. In other aspects of these embodiments, Y3a, Y3b, Y4a and Y4b are each deuterium.
[153] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are the same. In some aspects of these embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each hydrogen. In other aspects of these embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium.
[154] In some embodiments, Y1a, Y1b, Y2a and Y2b are each hydrogen and Y3a, Y3b, Y4a and Y4b are each deuterium. [155] In some embodiments, Y1a, Y1b, Y2a and Y2b are each deuterium and Y3a, Y3b, Y4a and Y4b are each hydrogen.
[156] In some embodiments, Y5a and Y5b are the same. In some aspects of these embodiments, Y5a and Y5b are each hydrogen. In other aspects of these embodiments, Y5a and Y5b are each deuterium.
[157] In some embodiments, Y5a and Y5b are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each hydrogen. In some embodiments, Y5a and Y5b are each hydrogen, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium.
[158] In some embodiments, Y5a and Y5b are each deuterium, Y15a, Y15b, Y16a and Y16b are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium.
[159] In some embodiments, Y6a and Y6b are the same. In some aspects of these embodiments, Y6a and Y6b are each hydrogen. In other aspects of these embodiments, Y6a and Y6b are each deuterium.
[160] In some embodiments, Y7a and Y7b are the same. In some aspects of these embodiments, Y7a and Y7b are each hydrogen. In other aspects of these embodiments, Y7a and Y7b are each deuterium.
[161] In some embodiments, Y8a and Y8b are the same. In some aspects of these embodiments, Y8a and Y8b are each hydrogen. In other aspects of these embodiments, Y8a and Y8b are each deuterium.
[162] In some embodiments, Y9a and Y9b are the same. In some aspects of these embodiments, Y9a and Y9b are each hydrogen. In other aspects of these embodiments, Y9a and Y9b are each deuterium.
[163] In some embodiments, Y10a and Y10b are the same. In some aspects of these embodiments, Y10a and Y10b are each hydrogen. In other aspects of these embodiments, Y10a and Y10b are each deuterium.
[164] In some embodiments, Y18 is hydrogen.
[165] In some embodiments, Y18 is deuterium.
[166] In some embodiments, Y19 is hydrogen.
[167] In some embodiments, Y19 is deuterium. [168] In some embodiments, Y18 and Y19 are the same. In some aspects of these embodiments, Y18 and Y19 are each hydrogen. In other aspects of these embodiments, Y18 and Y19 are each deuterium.
[169] In some embodiments, Y18 is hydrogen and Y19 is deuterium.
[170] In some embodiments, Y18 is deuterium and Y19 is hydrogen.
[171] In some embodiments, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18 and Y19 are the same. In some aspects of these embodiments, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18 and Y19 are each hydrogen. In other aspects of these embodiments, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18 and Y19 are each deuterium.
[172] In some embodiments, Y5a and Y5b are each hydrogen, and Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18 and Y19 are each deuterium.
[173] In some embodiments, Y5a and Y5b are each deuterium, and Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18 and Y19 are each hydrogen.
[174] In some embodiments, Y10a and Y10b are each hydrogen, and Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each deuterium.
[175] In some embodiments, Y10a, Y10b are each deuterium, and Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each hydrogen.
[176] In some embodiments, Y5a, Y5b, Y10a and Y10b are each hydrogen, and Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each deuterium.
[177] In some embodiments, Y5a, Y5b, Y10a and Y10b are each deuterium, and Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each hydrogen.
[178] In some embodiments, Y11 is hydrogen.
[179] In some embodiments, Y11 is deuterium.
[180] In some embodiments, Y12 is hydrogen.
[181] In some embodiments, Y12 is deuterium.
[182] In some embodiments, Y11 and Y12 are the same. In some aspects of these embodiments, Y11 and Y12 are each hydrogen. In other aspects of these embodiments, Y11 and Y12 are each deuterium. In some embodiments, Y11 is hydrogen and Y12 is deuterium. In some embodiments, Y11 is deuterium and Y12 is hydrogen.
[183] In some embodiments, Y13 is hydrogen. [184] In some embodiments, Y13 is deuterium.
[185] In some embodiments, Y14 is hydrogen.
[186] In some embodiments, Y14 is deuterium.
[187] In some embodiments, Y13 and Y14 are the same. In some aspects of these embodiments, Y13 and Y14 are each hydrogen. In other aspects of these embodiments, Y13 and Y14 are each deuterium. In some embodiments, Y13 is hydrogen and Y14 is deuterium. In some embodiments, Y13 is deuterium and Y14 is hydrogen.
[188] In some embodiments, Y15a and Y15b are the same. In some aspects of these embodiments, Y15a and Y15b are each hydrogen. In other aspects of these embodiments, Y15a and Y15b are each deuterium.
[189] In some embodiments, Y16a and Y16b are the same. In some aspects of these embodiments, Y16a and Y16b are each hydrogen. In other aspects of these embodiments, Y16a and Y16b are each deuterium.
[190] In some embodiments, Y17a and Y17b are the same. In some aspects of these embodiments, Y17a and Y17b are each hydrogen. In other aspects of these embodiments, Y17a and Y17b are each deuterium.
[191] In some embodiments, Y15a and Y15b are each hydrogen and Y16a and Y16b are each deuterium. In some embodiments, Y15a and Y15b are each deuterium and Y16a and Y16b are each hydrogen.
[192] In some embodiments, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are the same. In some aspects of these embodiments, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are each hydrogen. In other aspects of these embodiments, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are each deuterium.
[193] In some embodiments, Y11 and Y12 are each hydrogen, and Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are each deuterium.
[194] In some embodiments, Y11 and Y12 are each deuterium, and Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are each hydrogen.
[195] In some embodiments, Y15a, Y15b, Y16a and Y16b are the same. In some aspects of these embodiments, Y15a, Y15b, Y16a and Y16b are each hydrogen. In other aspects of these embodiments, Y15a, Y15b, Y16a and Y16b are each deuterium. [196] In some embodiments, Y15a, Y15b, Y16a and Y16b are each deuterium and Y11, Y12, Y13, Y14, Y17a and Y17b are each hydrogen.
[197] In some embodiments, Y15a, Y15b, Y16a, Y16b, Y11, and Y12 are each deuterium and Y13, Y14, Y17a and Y17b are each hydrogen.
[198] In some embodiments, Y15a, Y15b, Y16a, Y16b, Y13, and Y14 are each deuterium and Y11, Y12, Y17a and Y17b are each hydrogen.
[199] In some embodiments, Y15a, Y15b, Y16a, Y16b, Y17a, and Y17b are each deuterium and Y11, Y12, Y13 and Y14 are each hydrogen.
[200] In some embodiments, Y15a, Y15b are each deuterium and Y11, Y12, Y13, Y14, Y16a, Y16b, Y17a and Y17b are each hydrogen.
[201] In some embodiments, Y16a, Y16b are each deuterium and Y11, Y12, Y13, Y14, Y15a, Y15b, Y17a and Y17b are each hydrogen.
[202] In some embodiments, Y5a, Y5b, Y15a, Y15b, Y16a and Y16b are each deuterium.
[203] In some embodiments, the absolute configuration of the carbon atom to which Y18 is attached is (R) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y19 is attached is (R) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y11 is attached is (S) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y12 is attached is (R) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y13 is attached is (R) according to Cahn-Ingold-Prelog nomenclature. In some embodiments, the absolute configuration of the carbon atom to which Y14 is attached is (S) according to Cahn- Ingold-Prelog nomenclature.
[204] In some embodiments, the absolute configuration of the carbon atom to which Y18 is attached is (R), the carbon atom to which Y19 is attached is (R), the carbon atom to which Y11 is attached is (S), the carbon atom to which Y12 is attached is (R), the carbon atom to which Y13 is attached is (R), and the carbon atom to which Y14 is attached is (S) according to Cahn-Ingold-Prelog nomenclature. [205] In some embodiments, at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, and Y19 is hydrogen.
[206] In some embodiments, Y11 is deuterium, Y12 is deuterium, and at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18 and Y19 comprises deuterium.
[207] In some embodiments, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are each deuterium, and at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18, and Y19 comprises deuterium.
[208] In some embodiments, Y10a and Y10b are each deuterium, and at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18 and Y19 comprises deuterium.
[209] In some embodiments, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each deuterium, and at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, and Y17b comprises deuterium.
[210] In some embodiments, Y5a and Y5b are each deuterium, and at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, and Y19 comprises deuterium.
[211] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium, and at least one of Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, and Y19 comprises deuterium.
[212] In some embodiments, the compound of Formula II is not a compound where Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, and Y19 are each deuterium.
[213] In some embodiments, the compound of Formula II is not a compound where Y11 is deuterium, Y12 is deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y13, Y14,
Figure imgf000045_0001
, Y18, and Y19 are independently selected from hydrogen and deuterium.
[214] In some embodiments, the compound of Formula II is not a compound where Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18, and Y19 are independently selected from hydrogen and deuterium.
[215] In some embodiments, the compound of Formula II is not a compound where Y10a and Y10b are each deuterium and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, and Y19 are independently selected from hydrogen and deuterium.
[216] In some embodiments, the compound of Formula II is not a compound where Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, and Y17b are independently selected from hydrogen and deuterium.
[217] In some embodiments, the compound of Formula II is not a compound where Y5a and Y5b are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, and Y19 are independently selected from hydrogen and deuterium.
[218] In some embodiments, the compound of Formula II is not a compound where Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium, and Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, and Y19 are independently selected from hydrogen and deuterium.
[219] In some embodiments, the compound of Formula II is not a compound where Y11 is deuterium, Y12 is deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, and Y19 are each hydrogen.
[220] In some embodiments, the compound of Formula II is not a compound where Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y18, and Y19 are each hydrogen.
[221] In some embodiments, the compound of Formula II is not a compound where Y10a and Y10b are each deuterium and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, and Y19 are each hydrogen. [222] In some embodiments, the compound of Formula II is not a compound where Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, and Y17b are each hydrogen.
[223] In some embodiments, the compound of Formula II is not a compound where Y5a and Y5b are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, and Y19 are each hydrogen.
[224] In some embodiments, the compound of Formula II is not a compound where Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium, and Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, and Y19 are each hydrogen.
[225] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are the same, Y5a and Y5b are the same, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are the same, Y10a and Y10b are the same, Y15a, Y15b, Y16a, Y16b are the same, Y11, Y12, Y13, Y14, Y17a and Y17b are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 2a (below):
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0002
, or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
[227] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each hydrogen, Y5a and Y5b are each deuterium, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each hydrogen, Y10a and Y10b are each hydrogen, Y11 and Y12 are the same, Y13 and Y14 are the same, Y15a and Y15b are the same, Y16a and Y16b are the same, Y17a and Y17b are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 2c (below):
Figure imgf000050_0001
Figure imgf000051_0002
[228] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each hydrogen, Y5a and Y5b are each hydrogen, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each deuterium, Y10a and Y10b are each hydrogen, Y11 and Y12 are the same, Y13 and Y14 are the same, Y15a and Y15b are the same, Y16a and Y16b are the same, Y17a and Y17b are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 2d (below):
Table 2d: Exemplary Embodiments of Formula II
Figure imgf000051_0001
Figure imgf000052_0002
[229] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each hydrogen, Y5a and Y5b are each hydrogen, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each hydrogen, Y10a and Y10b are each deuterium, Y11 and Y12 are the same, Y13 and Y14 are the same, Y15a and Y15b are the same, Y16a and Y16b are the same, Y17a and Y17b are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 2e (below):
Figure imgf000052_0001
Figure imgf000053_0001
, or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
[230] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each hydrogen, Y5a and Y5b are each hydrogen, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each hydrogen, Y10a and Y10b are each hydrogen, Y11 and Y12 are the same, Y13 and Y14 are the same, Y15a and Y15b are the same, Y16a and Y16b are the same, Y17a and Y17b are the same and the compound is selected from any one of the compounds (Cmpd) set forth in Table 2f (below):
Figure imgf000053_0002
Figure imgf000054_0001
[231] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each hydrogen, Y5a and Y5b are each deuterium, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are each hydrogen, Y10a and Y10b are each deuterium, Y11 and Y12 are the same, Y13 and Y14 are the same, Y15a and Y15b are the same, Y16a and Y16b are the same, Y17a and Y17b are the same and the compound is selected from any one of the compounds (Cmpd) set forth in Table 2g (below):
Table 2g: Exemplary Embodiments of Formula II
Figure imgf000054_0002
Figure imgf000055_0001
[232] In some embodiments, Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are the same, Y5a and Y5b are the same, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are the same, Y10a and Y10b are the same, Y11 and Y12 are the same, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 2h (below):
Table 2h: Exemplary Embodiments of Formula II
Figure imgf000055_0002
Figure imgf000056_0001
, or a p armaceu ca y accepa e sa ereo, weren any aom no esgnae as deuterium is present at its natural isotopic abundance.
Figure imgf000057_0001
[234] Referring to any one of the Formulae disclosed herein:
[235] In some embodiments, when Y1a or Y1b is deuterium, the level of deuterium incorporation at each Y1a or Y1b 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%.
[236] In some embodiments, when Y2a or Y2b is deuterium, the level of deuterium incorporation at each Y2a or Y2b 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%. [237] In some embodiments, when Y3a or Y3b is deuterium, the level of deuterium incorporation at each Y3a or Y3b 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%.
[238] In some embodiments, when Y4a or Y4b is deuterium, the level of deuterium incorporation at each Y4a or Y4b 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%.
[239] In some embodiments, when Y5a or Y5b is deuterium, the level of deuterium incorporation at each Y5a or Y5b 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%.
[240] In some embodiments, when Y6a or Y6b is deuterium, the level of deuterium incorporation at each Y6a or Y6b 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%.
[241] In some embodiments, when Y7a or Y7b is deuterium, the level of deuterium incorporation at each Y7a or Y7b 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%.
[242] In some embodiments, when Y8a or Y8b is deuterium, the level of deuterium incorporation at each Y8a or Y8b 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%.
[243] In some embodiments, when Y9a or Y9b is deuterium, the level of deuterium incorporation at each Y9a or Y9b 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%.
[244] In some embodiments, when Y18 is deuterium, the level of deuterium
incorporation at Y18 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%.
[245] In some embodiments, when Y19 is deuterium, the level of deuterium
incorporation at Y19 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%.
[246] In some embodiments, when Y10a or Y10b is deuterium, the level of deuterium incorporation at each Y10a or Y10b 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%. [247] In some embodiments, when Y11 is deuterium, the level of deuterium
incorporation at Y11 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%.
[248] In some embodiments, when Y12 is deuterium, the level of deuterium
incorporation at Y12 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%.
[249] In some embodiments, when Y13 is deuterium, the level of deuterium
incorporation at Y13 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%.
[250] In some embodiments, when Y14 is deuterium, the level of deuterium
incorporation at Y14 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%.
[251] In some embodiments, when Y15a or Y15b is deuterium, the level of deuterium incorporation at each Y15a or Y15b 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%.
[252] In some embodiments, when Y16a or Y16b is deuterium, the level of deuterium incorporation at each Y16a or Y16b 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%.
[253] In some embodiments, when Y17a or Y17b is deuterium, the level of deuterium incorporation at each Y17a or Y17b 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%.
[254] In some embodiments, when Y20 is deuterium, the level of deuterium
incorporation at Y20 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%.
[255] In some embodiments, when Y21 is deuterium, the level of deuterium
incorporation at Y21 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%.
[256] In some embodiments, when Y22 is deuterium, the level of deuterium
incorporation at Y22 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%. [257] In some embodiments, when Y23 is deuterium, the level of deuterium incorporation at Y23 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%.
[258] In another set of embodiments, any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance.
[259] The synthesis of compounds of Formula I and/or Formula II may be readily achieved by synthetic chemists of ordinary skill by reference to the Exemplary Synthesis and Examples disclosed herein. Relevant procedures analogous to those of use for the preparation of compounds of Formula I and/or Formula II and intermediates thereof are disclosed, for instance, in US patent No.5,532,372; US patent No.8,853,395; US patent No.8,981,095; PCT publication No.2013/190455; PCT publication No.2014/064714; PCT publication No.2015/056205; PCT publication No.2015/081920; PCT publication No.2016/059649; US patent No.6,111,105; and J. Med. Chem., 1989, 32, 1024-1033.
[260] 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. Exemplary Synthesis
[261] The compounds of Formula I and/or Formula II may be prepared in a manner analogous to that described in US patent No.5,532,372; US patent No.8,853,395; US patent No.8,981,095; PCT publication No.2013/190455; PCT publication No.
2014/064714; PCT publication No.2015/056205; PCT publication No.2015/081920 (as shown below); and PCT publication No.2016/059649 using appropriately deuterated starting materials which are commercially available or which synthesis is readily apparent to one of skill in the art.
[262] A convenient method for synthesizing compounds of Formula I and/or Formula II is depicted in Scheme 1, below.
Scheme 1: General Synthesis of Compounds of Formula I and / or Formula II
Figure imgf000061_0001
Reagents and conditions: (a) rt, Chiral resolution; (b) NaOH, H2, Raney-Ni; (c) heat, then D- tartaric acid; (d) Na2CO3, then HCl
[263] In a manner analogous to a procedure described in WO2015081920 reductive amination of appropriately deuterated chiral aldehyde intermediate (1) with appropriately deuterated piperazinyl intermediate (2) using appropriately deuterated boron reducing agent (3) followed by treatment with an optically active acid such as (+)-O, O’-Di-p- toluoyl-D-tartaric acid results in diastereisomeric purification to furnish a salt of appropriately deuterated alkyl amine intermediate (4). Subsequent reduction of the nitro moiety in (4) by hydrogenation using a nickel catalyst furnishes appropriately deuterated primary amine intermediate (5). 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. Finally, 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.
[264] Reagent (3a), borate(1-), tris(acetato-κO)hydro-d-, sodium may be prepared according to a procedure described in WO2015189413 from sodium borodeuteride (98 atom %D).
[265] Use of appropriately deuterated reagents allows deuterium incorporation at the Y5 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 Y5.
[266] Using commercially available reagents and deuterated reagents that can be readily prepared by known methods, compounds of Formula I and / or Formula II can be prepared with greater than 90% or greater than 95% deuterium incorporation at each position designated as D (see below for details).
[267] Appropriately 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.
Scheme 2: Preparation of Intermediate (1)
Figure imgf000062_0001
Reagents and conditions: (a) H2NCH2CH2NH2, CH3NO2; (b) NaOCH3, SiO2; (c) Jorgensen- Hayashi catalyst, s-Collidine
[268] By analogy to a procedure described by Li, Z. et al., Tetrahedron, 67(51), 9844- 9852; 2011, condensation of appropriately deuterated ketone intermediate (7) with nitromethane using ethylenediamine as base and at elevated temperature, affords appropriately deuterated nitroalkene intermediate (8). In a manner analogous to a procedure described by Hogg, J. et al., Organic Preparations and Procedures
International, 10(1), 9-11; 1978, or Pinnick H. W.2004, Organic Reactions.38:3:655– 792, Nef reaction of (8) using sodium methoxide activated silica gel furnishes
appropriately deuterated alkene aldehyde intermediate (9). Finally, by analogy to a procedure described in WO2015081920, asymmetric Michael addition of (9) with appropriately deuterated nitromethane intermediate (10), catalyzed by (2S)-2- [diphenyl[(trimethylsilyl)oxy]-methyl]pyrrolidine (Jorgensen- Hayashi catalyst) in the presence of a base such as s-Collidine and appropriately deuterated co-catalyst acid such as benzoic acid intermediate (11), produces correspondingly and appropriately deuterated chiral aldehyde intermediate (1).
[269] 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). The following intermediates (7) may be prepared according to published methods: 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. et al., Journal of Labelled Compounds (1973), 9(2), 331-8; 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.
Intermediate (10a) is commercially available: Nitromethane-d3 (99 atom %D) (10a). Intermediate (11a) is commercially available: Benzoic acid-d (98 atom % D) (11a).
[270] Use of appropriately deuterated reagents allows deuterium incorporation at the Y6a, 6b, Y7a, 7b, Y8a, 8b, Y9a, 9b, Y10a, 10b, Y18, Y19 positions of a compound of Formula I and Formula II or any appropriate intermediate herein, e.g., 90, 95, 97, or 99% deuterium incorporation at any Y6a, 6b, Y7a, 7b, Y8a, 8b, Y9a, 9b, Y10a, 10b, Y18, and/or Y19position.
[271] Appropriately 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.
Scheme 3: Preparation of Intermediate (2)
Figure imgf000064_0001
Reagents and conditions: (a) HCl, H2O2, SDS; (b) SOCl2, NH4OH; (c) Na2S, HCl, pH 4, H2O2, pH 9, then HCl, pH 5; (d) SO2Cl, Heat; (e) Heat; (f) HBr [272] In a manner analogous to a procedure described by Samant, B. Journal of Dispersion Science and Technology, 33(7), 1030-1037; 2012, regioselective oxy- chlorination of appropriately deuterated benzoic acid intermediate (12) in the presence of a surfactant such as sodium dodecylsulfate (SDS) affords appropriately deuterated ortho- chloro intermediate (13), and subsequent amidation of the carboxylic acid in (13) using thionyl chloride and ammonia by analogy to a procedure described in CN102532016, or common methods known in the art, furnishes appropriately deuterated halobenzamide intermediate (14).By analogy to a procedure described in WO2013060766, (14) is treated with sodium sulfide at elevated temperature to afford a mercaptobenzamide and its salt, which is not isolated but oxidatively cyclized in the presence of an oxidant such as hydrogen peroxide, followed by treatment with hydrochloric acid to furnish appropriately deuterated benzisothiazolone intermediate (15). Halogenation of (15) using thionyl chloride, and at elevated temperature affords appropriately deuterated
chlorobenzisothiazole intermediate (16) by analogy to a procedure described in EP 2554543. In a manner analogous to a procedure described in US4957916, 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).
[273] Certain intermediates (12) are commercially available: benzoic-d5 acid (99 atom %D) (12a), benzoic-3,5-d2 acid (98 atom %D) (12b), benzoic-2,6-d2 acid (95 atom %D) (12c). The following intermediates (12) may be prepared according to published procedures: benzoic-3,4,5-d3 acid (12d) may be prepared from commercially available benzoic-d5 acid (99 atom %D) (12a) according to a method described by Qin, X. et al., Organic Letters, 17(7), 1762-1765; 2015; 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.
[274] Use of appropriately deuterated reagents allows deuterium incorporation at the Y1a, 1b, Y2a, 2b, R Y3a, 3b, Y4a, 4b, Y20, Y21, Y22, Y23 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 Y1a, 1b, Y2a, 2b, R Y3a, 3b, Y4a, 4b, Y20, Y21, Y22 and/or Y23 position.
[275] Appropriately deuterated intermediate (17), for use in the preparation of intermediate (2) according to Scheme 3, which is used to prepare compounds of Formula I and / or Formula II according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 4.
Scheme 4: Preparation of Intermediate (17)
Figure imgf000066_0001
Reagents and conditions: (a) Et3N, EtOC(O)Cl; (b) HBr
[276] By analogy to a procedure described by Zulli, A. et al Bioorganic & Medicinal Chemistry Letters, 22(8), 2807-2810; 2012, acylation of appropriately deuterated Boc protected piperazine intermediate (19) with a chloroformate such as ethylchloroformate in the presence of a base such as triethylamine, furnishes unsymmetrical bis-carbamate protected and appropriately deuterated piperazine intermediate (20), and subsequent acid treatment results in Boc deprotection to produce mono carbamate protected and appropriately deuterated piperazine intermediate (17).
[277] Certain intermediate (19) are commercially available: piperazine-d8-N-t-BOC (98 atom % D) (19a), piperazine-3,3,5,5-d4-N-t-BOC (98 atom %D) (19b).1-Piperazine-2,2, 6,6-d4-carboxylic acid, 1,1-dimethylethyl ester (19c) may be prepared according to a procedure described by Dischino, D. et al., Journal of Labelled Compounds and
Radiopharmaceuticals 25(4), 359-67; 1988. [278] Use of appropriately deuterated reagents allows deuterium incorporation at the Y1a, 1b, Y2a, 2b, Y3a, 3b, Y4a, 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 Y1a, 1b, Y2a, 2b, Y3a, 3b, and or/ Y4a, 4b position.
[279] Appropriately 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.
Figure imgf000067_0001
Reagents and conditions: (a) 0º C; (b) reflux, 1,2-dicholorobenzene; (c) D2, Pd-C or H2, Pd-C [280] In a manner analogous to a procedure described by Kiriazis, A. et al.,
Tetrahedron, 67(45), 8665-8670; 2011, Diels-Alder reaction of appropriately deuterated anhydride intermediate (21) appropriately deuterated diene intermediate (22) with at low temperature affords cis-, endo- adduct of appropriately deuterated alkene anhydride intermediate (23), which is subsequently heated at elevated temperature in a suitable high boiling halobenzene solvent such as 1,2-dicholorobenzene to furnish cis-, exo- adduct of appropriately deuterated alkene anhydride intermediate (24) by analogy to a procedure described by Matson, J. et al., J. Am. Chem. Soc., 2008, 130, 6731 - 6733. Finally, reduction of olefin in (24) under the atmosphere of deuterium gas in the presence of palladium on carbon, or hydrogen gas in the presence of palladium on carbon by analogy to a procedure described in WO2012016569 or WO2013121440 furnishes
correspondingly and appropriately deuterated anhydride intermediate (6). [281] Intermediate (21) is commercially available: maleic-2,3-d2 anhydride (98 atom %D) (21a).
[282] Intermediate (22), 1,3-cyclopentadiene-1,2,3,4,5,5-d6 (22a), may be prepared according to a procedure described by Cangoenuel, A. et al., Inorganic Chemistry, 52(20), 11859-11866; 2013.
[283] Use of appropriately deuterated reagents allows deuterium incorporation at the Y11, Y12, Y13, Y14 Y15a, 15b, Y16a, 16b, Y17a, 17b 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 Y11, Y12, Y13, Y14 Y15a, 15b, Y16a, 16b and / or Y17a, 17b position.
[284] In some embodiments, 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.
[285] Additional methods of synthesizing compounds of Formula I and/or Formula II and their synthetic precursors are within the means of chemists of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the applicable compounds are known in the art and include, for example, those described in Larock R, Comprehensive Organic
Transformations, VCH Publishers (1989); Greene, TW et al., Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); Fieser, L et al., Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and Paquette, L, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
[286] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. Compositions
[287] 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. 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.
[288] 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.
[289] If required, the 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.
[290] 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 LUTROLTM and PLURONICTM (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.
[291] The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the 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).
[292] 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. In general, 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.
[293] In certain embodiments, the compound is administered orally. 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.
[294] In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When 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.
[295] 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.
[296] 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.
[297] 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. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, 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.
[298] The pharmaceutical 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. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
[299] The pharmaceutical 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. [300] 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. For topical application topically to the skin, 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. Alternatively, 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.
[301] 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.
[302] Thus, according to yet another embodiment, 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. 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,
polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.
[303] According to another embodiment, 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.
[304] According to another embodiment, 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.
[305] According to another embodiment, 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.
[306] According to another embodiment, 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.
[307] Where an organ or tissue is accessible because of removal from the subject, such organ or tissue may be bathed in a medium containing a composition of this invention, a composition of this invention may be painted onto the organ, or a composition of this invention may be applied in any other convenient way.
[308] In another embodiment, a 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
advantageous properties when administered with a compound having the same mechanism of action as lurasidone. 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.
[309] In some embodiments, 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)).
[310] In some embodiments, the additional therapeutic agent is an anticonvulsant such as valproate (e.g., valproic acid or valproic acid sodium salt).
[311] In some embodiments, 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. In some embodiments, 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, pruvanserin, irindalone tartate, ICI- 170809, seganserin, M100907, lorcaserin hydrochloride, PRX-00933, ATHX-105, mCPP, vabicaserin hydrochloride, CP-809101, MK-212, latrepirdine hydrochloride, SB- 258585, AVN-211, SA -531, GSK-742457, Lu-AE-58054, SYN-120, AVN-322, SYN- 114, SUVN-502, and AVN-458, or a pharmaceutically acceptable salt thereof.
[312] In some embodiments, 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).
[313] In some embodiments, the additional therapeutic agent is an antidepressant. In certain instances 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.
[314] In some embodiments, the selective serotonin reuptake inhibitor can be citalopram, dapoxetine, escitalopram, fluvoxamine, norfluoxetine, fluoxetine, paroxetine, sertraline, or zimelidine, or pharmaceutically acceptable salts thereof. In some embodiments, the serotonin-norepinephrine reuptake inhibitor can be venlafaxine, desvenlafaxine, sibutramine, nefazodone, milnacipran, duloxetine, or bicifadine, or pharmaceutically acceptable salts thereof. In some embodiments, the noradrenergic and specific serotonergic antidepressant can be mirtazapine, or pharmaceutically acceptable salts thereof. In some embodiments, the norepinephrine (noradrenaline) reuptake inhibitor can be atomoxetine, reboxetine, viloxazine, maprotiline, bupropion, or radafaxine, or pharmaceutically acceptable salts thereof. In some embodiments, the norepinephrine-dopamine reuptake inhibitor is bupropion or methylphenidate, or pharmaceutically acceptable salts thereof. In some embodiments, the tricyclic
antidepressant can be amitriptyline, butriptyline, amoxapine, clomipramine, desipramine, dosulepin, doxepin, imipramine, dibenzepin, iprindole, lofepramine, nortriptyline, opipramol, protriptyline or trimipramine, or pharmaceutically acceptable salts thereof. In some embodiments, the monoamine oxidase inhibitor can be isocarboxazid,
moclobemide, phenelzine, tranylcypromine, selegiline, rasagiline, nialamide, iproniazid, iproclozide, or toloxatone, or pharmaceutically acceptable salts thereof.
[315] In one embodiment, the additional therapeutic agent is selected from lithium and/or valproate.
[316] In another embodiment, 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).
[317] In the pharmaceutical compositions of the invention, the compound of the present invention is present in an effective amount. As used herein, the term“effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat the target disorder. [318] The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in Freireich et al., Cancer Chemother. Rep, 1966, 50: 219. 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.
[319] In one embodiment, 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. In one embodiment, 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.
[320] In one embodiment, 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. In one embodiment, 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.
[321] In some embodiments, 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. [322] 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.
[323] For pharmaceutical compositions that comprise one or more additional therapeutic agents, 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. Preferably, 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.,
Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are incorporated herein by reference in their entirety.
[324] Some of the additional therapeutic agents referenced above may act
synergistically with the compounds of this invention. When this occurs, it will allow the effective dosage of the additional therapeutic agent and/or the compound of this invention to be reduced from that required in a monotherapy. This has the advantage of minimizing toxic side effects of either the additional therapeutic agent of a compound of this invention, synergistically improving efficacy, improving ease of administration or use and/or reduced overall expense of compound preparation or formulation. Methods of Treatment
[325] In another embodiment, 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. In some embodiments, the method of modulating the activity of the receptor is a method of antagonizing the activity of the receptor.
[326] In some embodiments, the invention provides a method of modulating the activity of a receptor selected from the group consisting of 5-HT7 receptor and α2A 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. In some aspects of these embodiments, the method of modulating the activity of the receptor is a method of antagonizing the activity of the receptor.
[327] In some embodiments, 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. In some aspects of these embodiments, the method of modulating the activity of the receptor is a method of partially agonizing the activity of the receptor.
[328] In some embodiments, the invention provides a method of modulating the activity of α2C-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. In some aspects of these embodiments, the method of modulating the activity of the receptor is a method of antagonizing the activity of the receptor.
[329] In some embodiments, the invention provides a method of modulating the activity of a receptor selected from the group consisting of α1-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.
[330] In some embodiments, the cell is contacted in vitro. In some embodiments, the cell is contacted in vivo. In some embodiments, the cell is contacted ex vivo.
[331] According to another embodiment, 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. In one embodiment the subject is a patient in need of such treatment. In certain embodiments the subject is a human. Such 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.
[332] 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, panic disorder, pathological gambling, post-traumatic stress disorder, prodromal risk syndrome, psychosocial function impairment, psychotic depression, decreased quality of life in schizophrenia, negative symptoms associated with schizophrenia, schizophrenia maintenance, schizoaffective disorder, sleep disorder, social functioning impairment, substance abuse, treatment resistant depression, treatment resistant schizophrenia, cyclothymic disorder, central nervous system (CNS) disorder responsive to modulation of glutamate levels, depressive episodes associated with bipolar I disorder, depressive episodes associated with bipolar II disorder, manic episodes associated with bipolar I disorder, manic episodes associated with bipolar II disorder, and Tourette's Disorder. In some embodiments, the at least one CNS disorder is mixed depression. In one
embodiment, mixed depression is depression and at least one symptom chosen from manic symptoms and hypomanic symptoms. In another embodiment, 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. In an embodiment, a major depressive episode is diagnosed according to the proposed Diagnostic and
Statistical Manual of Mental Disorders (DSM-5). In another embodiment, the at least one CNS disorder is negative symptoms associated with schizophrenia. Examples of 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. In an embodiment, 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.
[333] In one particular embodiment, 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.
[334] In another particular embodiment, 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.
[335] 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.
measurable by a test or diagnostic method).
[336] In another embodiment, 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. The choice of 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.
[337] In particular, 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).
[338] 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. The administration of a 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.
[339] Effective amounts of these additional therapeutic agents are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications referenced herein, as well as in Wells et al., eds., Pharmacotherapy
Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR
Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical texts. However, it is well within the skilled artisan’s purview to determine the additional therapeutic agent’s optimal effective-amount range. [340] In one embodiment of the invention, where an additional therapeutic agent is administered to a subject, the effective amount of the compound of this invention is less than its effective amount would be where the additional therapeutic agent is not administered. In another embodiment, the effective amount of the additional therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.
[341] In yet another aspect, 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
[342] 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.
[343] Determination of Metabolic Stability: 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). 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 MgCl2. 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. Supernatants are transferred to another 96-well plate and analyzed for amounts of parent remaining by LC-MS/MS using an Applied Bio-systems API 4000 mass spectrometer. The same procedure is followed for the non-deuterated counterpart of the compound of Formula I and the positive control, 7-ethoxycoumarin (1 µM). Testing is done in triplicate.
[344] Data analysis: The in vitro t1/2s for test compounds are calculated from the slopes of the linear regression of % parent remaining (ln) vs incubation time relationship.
in vitro t ½ = 0.693/k
k = -[slope of linear regression of % parent remaining (ln) vs incubation time]
[345] Data analysis is performed using Microsoft Excel Software.
Figure imgf000084_0001
[346] Methyl 1-cyclohexene-1-carboxylate 25 (1 equiv) is reduced with DIBAL-D (1 equiv) to give cyclohex-1-ene-1-carbaldehyde-d 26.
[347] Carbaldehyde 26 (1 equiv) is treated with (S)-(–)-α,α-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).
[348] A mixture of carbaldehyde 27 (major) and carbaldehyde 28 (minor) (1 equiv total) is treated with 3-(1-piperazinyl)-1,2-benzisothiazole 29 (1 equiv), followed by sodium borodeuteride (2.5 equiv) to give crude 3-(4-(((1R,2R)-2- (Nitromethyl)cyclohexyl)methyl-d2)piperazin-1-yl)benzo[d]-isothiazole 30 and the corresponding diastereomer.
[349] Crude isothiazole 30 and the corresponding diastereomer (1 equiv total) in acetone is treated with a solution of (+)-O,O’-di-p-toluoyl-D-tartaric acid (1.03 equiv) in methanol to give 3-(4-(((1R,2R)-2-(Nitromethyl)cyclohexyl)methyl-d2)piperazin-1- yl)benzo[d]-isothiazole (+)-O,O’-di-p-toluoyl-D-tartaric salt 31 as a single diastereomer.
[350] 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.
[351] Methanamine 32 (1 equiv) is refluxed with (3aR,4S,7R,-7aS)-4,7-methano-1H- isoindole-1,3(2H)-dione 33 (1.28 equiv), potassium carbonate (1.5 equiv) and dibenzo- 18-crown-6 (0.01 equiv) in xylene to give (3aR,4S,7R,7aS)-2-(((1R,2R)-2-((4- (Benzo[d]isothiazol-3-yl)piperazin-1-yl)-methyl-d2)cyclohexyl)methyl)hexahydro-1H- 4,7-methanoisoindole-1,3(2H)-dione (Compound 217a).
Example 3
Scheme 7: Synthesis of Compound 219a
Figure imgf000086_0001
[352] A solution of cyclohex-1-ene-1-carbaldehyde 34 (2.00 g, 18.18 mmol, 1 equiv), (S)-(–)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether (0.54 mL, 1.73 mmol, 0.095 equiv) and benzoic acid (0.21 g, 1.73 mmol, 0.095 equiv) in ethanol (10 mL) was stirred at room temperature for 5 minutes. 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). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a mixture of (1R,2R)-2-(Nitromethyl-d2)cyclohexane-1-carbaldehydes 35 and 36 (3.9 g, quantitative yield) as an orange oil, which was used without further purification.1H-NMR analysis indicated 50% H incorporation at the CD2 position.
[353] Benzisothiazole 29 (2.86 g, 13.1 mmol, 0.86 equiv) was added at room
temperature to a solution of crude carbaldehydes 35 and 36 (3.9 g, 15.2 mmol,1 equiv) in dichloromethane (36 mL). The reaction mixture was cooled to 0 °C and sodium triacetoxyborohydride (8.06 g, 38 mmol, 2.5 equiv) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by the drop- wise addition of ice water (4 mL) and 1N aqueous NaOH (9 mL) and was stirred at room temperature for 10 minutes. The layers were separated and the organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a mixture of 3-(4-(((1R,2R)-2- (Nitromethyl)cyclohexyl)methyl)piperazin-1-yl)benzo[d]-isothiazole 37 and the corresponding diastereomer (7.9 g, quantitative yield) as an orange oil which was used directly without further purification.1H-NMR analysis indicated 100% H incorporation.
[354] A solution of (+)-O,O’-di-p-toluoyl-D-tartaric acid (5.2 g, 13.4 mmol, 1.03 equiv) in methanol (11 mL) was added at 50 °C to a suspension of crude isothiazole 37 and the corresponding diastereomer (7.9 g, 13.1 mmol, 1 equiv) in acetone (16 mL). The mixture was slowly cooled to room temperature and stirred for 4 hours, at which time white precipitate formed. The solid was filtered, washed with methanol and dried in a vacuum oven at 50 °C for 1 hour to give 3-(4-(((1R,2R)-2- (Nitromethyl)cyclohexyl)methyl)piperazin-1-yl)benzo[d]-isothiazole (+)-O,O’-di-p- toluoyl-D-tartaric salt 38 (4.76 g, 48% yield) as a white foam.1H-NMR analysis indicated less than 3% of the undesired diastereomer.
[355] A 0.5N aqueous solution of NaOH (7 mL) was added at room temperature to a suspension of isothiazole salt 38 (1.00 g, 1.31 mmol, 1 equiv) in dichloromethane (8 mL). The reaction mixture was stirred vigorously for 10 minutes. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a thick, beige oil. To the free base was added at room
temperature 1,5,7-tri-azabicyclo[4.4.0]dec-5-ene (0.018 g, 0.13 mmol, 0.1 equiv) and chloroform-D (10 mL,99.8 atom% D, Aldrich). The reaction mixture was stirred at room temperature for 16 hours and was then concentrated under reduced pressure, at which time 1H-NMR analysis indicated 10-15% H incorporation at the CD2 position. The crude product was subjected to two additional H/D exchange cycles, at which time 1H-NMR analysis indicated no H incorporation at the CD2 position. The reaction mixture was washed with 1N DCl (99.5 atom% D, 35% w/w in D2O, Cambridge Isotopes) in D2O (99 atom% D, Cambridge Isotopes) (5 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure and dried in a vacuum oven at 40 °C for 2 days to give 3-(4- (((1R,2R)-2-(Nitromethyl-d2)cyclohexyl)methyl)piperazin-1-yl)benzo[d]-isothiazole 39 (0.53 g, quantitative yield) a white foam.
[356] 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.
[357] Amine 40 (1 equiv) is heated at reflux with dione 33 (1.28 equiv), potassium carbonate (1.5 equiv) and dibenzo-18-crown-6 (0.01 equiv) in xylene to give
(3aR,4S,7R,7aS)-2-(((1R,2R)-2-((4-(Benzo[d]isothiazol-3-yl)piperazin-1- yl)methyl)cyclohexyl)methyl-d2)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione (Compound 219a).
Example 4
Scheme 8: Synthesis of Compound 224a
Figure imgf000089_0001
[358] 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
deuteroxide in deuterium oxide (0.42 mL, Cambridge Isotopes, 99.5 atom% D) and deuterium oxide (1.24 mL). The mixture was stirred overnight and filtered through a pad of Celite (washing with THF). The filtrate was concentrated under reduced pressure to give ((1R,2R)-cyclohexane-1,2-diyl)bis(methan-d2-ol) 42 (820 mg) as a colorless oil which formed a solid on standing. The solid was used without purification in the next step.
[359] Methanesulfonyl chloride (0.85 mL, 11 mmol, 2.2 equiv) was added drop-wise to a solution of bis(methan-d2-ol) 42 (820 mg, 5 mmol, assumed 100% yield in previous step, 1 equiv), and triethylamine (1.7 mL, 12.5 mmol, 2.5 equiv) in dichloromethane (10 mL) at 0 °C. The reaction was warmed to room temperature and was stirred for 3 hours. Dichloromethane (50 mL) was added and the mixture was washed with water (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to provide a pale yellow oil. The crude product was dissolved in a minimum volume of dichloromethane and was diluted with heptanes (25 mL). The solution was partially concentrated at room temperature to afford a white solid. The solid was filtered, washed with heptanes and dried in a vacuum oven to give ((1R,2R)-Cyclohexane-1,2- diyl)bis(methylene-d2) dimethanesulfonate 43 (1.3 g, 86% yield over 2 steps) as a white solid. Optical Rotation = -26.9 (c=3.495 g/ 100 mL benzene)
[360] A mixture of dimethanesulfonate 43 (1.0 g, 3.3 mmol, 1 equiv), benzisothiazole 29 (720 mg, 3.3 mmol, 1 equiv) and sodium carbonate (370 mg, 3.5 mmol, 1.05 equiv) in acetonitrile (10 mL) was heated at 70 °C for 3 days. The reaction mixture was filtered while hot, washing the solids with acetonitrile, and the filtrate was concentrated under reduced pressure. The yellow oil was dissolved in a minimum volume of acetone (10 mL) and was stirred at room temperature for 1 hour to afford a white solid. The solid was filtered, washed with heptanes and dried to give (3aR,7aR)-4'-(benzo[d]isothiazol-3- yl)octahydrospiro[isoindole-2,1'-piper-azin]-2-ium-1,1,3,3-d4 methanesulfonate 44 (1.1 g, 78 % yield) as a white solid.
[361] A suspension of methanesulfonate 44 (400 mg, 0.94 mmol, 1 equiv) in xylenes (8 mL) was sparged with nitrogen for 10 minutes. Dione 33 (200 mg, 1.2 mmol, 1.3 equiv), dibenzo-18-crown-6 (spatula tip, 0.01 equiv) and potassium carbonate (195 mg, 1.4 mmol, 1.5 equiv) were added and the reaction mixture was heated at 130 °C for 24 hours. The reaction mixture was cooled to room temperature, and the solids were filtered and washed with toluene. The filtrate was concentrated under reduced pressure. The crude product was dissolved in a minimum volume of dichloromethane, adsorbed onto Celite and purified using an Interchim automated chromatography system (30 g, C18 RP column), eluting with 15 to 98% acetonitrile in water, to give (3aR,4S,7R,7aS)-2- (((1R,2R)-2-((4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)-methyl-d2)cyclohexyl)methyl- d2)hexahydro-1H-4,7-methanoisoindole-1,3-(2H)-dione (Compound 224a) (370 mg, 79% yield) as an off-white foam after drying in a vacuum oven at 40 °C overnight. 1H-NMR (CDCl3, 400 MHz): δ 7.91 (d, 1H), 7.80 (d, 1H), 7.46 (t, 1H), 7.35 (t, 1H), 3.52 (t, 4H), 2.70 (s, 2H), 2.64 (q, 4H), 2.60 (d, 2H), 1.88 (d, 1H), 1.00-1.68 (m, 15H); 2H-NMR (CHCl3, 61.4 MHz): δ 3.88 (s, 1D), 3.27 (s, 1D), 2.58 (s, 1D), 2.18 (s, 1D); MS (m/z): 497.3 [M+H]+; m.p.: 146.6-146.7 °C; optical rotation: -20 (0.102 g / 100 mL CH2Cl2), wavelength 589 nm. Example 5
Scheme 9: Synthesis of Compound 262h
Figure imgf000091_0001
[362] A solution of freshly cracked cyclopentadiene 45 (42 g, 636 mmol, 1 equiv) in DMSO-d6 (60 mL, Aldrich, 99.5 atom% D) was cooled to 0 °C. A 40% solution of sodium deuteroxide in deuterium oxide (20 g, 488 mmol, 0.75 equiv, Cambridge Isotopes, 99.5 atom% D) diluted with deuterium oxide (100 mL, Cambridge Isotopes, 99.5 atom% D) was added and the mixture was stirred at 0 °C for 2 hours. The crude mixture was transferred to a separatory funnel and the layers were separated. 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.
[363] Deuterated cyclopentadiene 46 (11.0 g, 153 mmol, 1.5 equiv) was added drop- wise over 10 minutes to a solution of furan-2,5-dione 47 (10.0 g, 102 mmol, 1 equiv) in MTBE (100 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours with formation of a white precipitate. The solid was filtered, washed with MTBE (200 mL) and dried on the filter to give (3aR,4S,7R,7aS)-3a,4,7,7a-tetrahydro-4,7- methanoisobenzofuran-1,3-dione-4,5,6,7,8,8-d648 (13.1 g, 76% yield) as a white solid.
[364] A solution of d6-dione 48 (3.0 g, 17.6 mmol) in 1,2-dichlorobenzene (6 mL) was sparged with nitrogen for 15 minutes, then was heated at 120 °C overnight to give a 55% conversion to product by GC/MS analysis. Additional heating did not increase the conversion. The crude reaction mixture was concentrated on a Kugelrohr distillation apparatus. The residue was dissolved in a minimum volume of dichloromethane and adsorbed on silica gel. 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.
[365] A 500-mL Parr shaker bottle was charged with 10% Pd/C (80 mg, dry), ethyl acetate (10 mL), d6-dione 49 (620 mg, 3.64 mmol, 1 equiv) and additional ethyl acetate (40 mL). The reaction mixture was placed under 45 psi deuterium (Cambridge Isotopes, 99.6 atom% D) and shaken for 4 hours, at which time GC/MS analysis indicated the reaction was complete. The reaction mixture was filtered through a pad of Celite, washing with ethyl acetate. The filtrate was concentrated under reduced pressure to give (3aR,4S,7R,7aS)-hexahydro-4,7-methanoisobenzofuran-1,3-dione-4,5,5,6,6,7,8,8-d850 (660 mg, >99% yield) as a light green oil which formed a solid on standing.
[366] A 35-mL microwave vial was charged with d8-dione 50 (550 mg, 3.16 mmol, 1 equiv) as a solution in THF (6 mL), and 30% ammonium hydroxide (2 mL). The vial was sealed and heated under microwave irradiation (CEM) to 65 °C. Once the temperature reached 60 °C, an exotherm to 100 °C occurred in less than 1 minute, at which point GC/MS analysis indicated 35% conversion. The reaction was reheated, ramping up the temperature to 120 °C and maintaining this temperature for 40 minutes. The crude reaction mixture was combined with a 100 mg scale front-run, diluted with ethyl acetate (50 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give (3aR,4S,7R,7aS)-hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione- 4,5,5,6,6,7,8,8-d851 (330 mg, 51% yield) as a white solid.
[367] A suspension of (3aR,7aR)-4'-(Benzo[d]isothiazol-3-yl)octahydrospiro[isoindole- 2,1'-piperazin]-2-ium methanesulfonate 52 (300 mg, 0.71 mmol, 1 equiv), d8-dione 51 (160 mg, 0.92 mmol, 1.3 equiv), dibenzo-18-crown-6 (spatula tip, 0.01 equiv) and potassium carbonate (150 mg, 1.1 mmol, 1.5 equiv) in xylenes (8 mL) was heated at 130 °C overnight. The reaction mixture was cooled to room temperature and the solids were filtered, washing with toluene. The filtrate was concentrated under reduced pressure and the crude product was purified using an Interchim automated chromatography system (40 g column), eluting with 0 to 6% methanol in dichloromethane, to give (3aR,4S,7R,7aS)-2- (((1R,2R)-2-((4-(benzo[d]isothiazol-3-yl)piperazin-1- yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione- 4,5,5,6,6,7,8,8-d8 (Compound 262h) (200 mg, 94% purity and 90 mg, 90% purity, representing 82% combined yield). The less pure material was repurified using an Interchim automated chromatography system (6 g, C18 RP column, eluting with 10 to 100% acetonitrile in water, to give Compound 262h (45 mg, >98% purity). The remaining 200 mg (94% purity) material was repurified as above and the batches were combined to give a total of 130 mg (>98% purity) of Compound 262h as a white foam after drying in a vacuum oven at 40 °C overnight. 1H-NMR (CDCl3, 400 MHz): δ 7.91 (d, 1H), 7.80 (d, 1H), 7.46 (t, 1H), 7.35 (t, 1H), 3.93 (dd, 1H), 3.52 (t, 4H), 3.32 (dd, 1H), 2.64 (m, 5H), 2.59 (s, 2H), 2.23 (dd, 1H), 1.89 (d, 1H), 1.66 (m, 2H), 1.52 (m, 2H), 1.38 (m, 1H), 1.12-1.25 (m, 2H), 0.97-1.05 (m, 2H); MS (m/z): 501.3 [M+H]+; optical rotation: -23 (0.101 g / 100 mL CH2Cl2), wavelength 589 nm. Scheme 10: Synthesis of Intermediate 52
Figure imgf000094_0001
[368] Benzisothiazole 29 (0.73 g, 3.33 mmol, 1 equiv) and sodium carbonate (0.36 g, 3.40 mmol, 1.02 equiv) were added at room temperature to a solution of ((1R,2R)- cyclohexane-1,2-diyl)bis(methylene)dimethanesulfonate 53 (1.00 g, 3.33 mmol, 1 equiv) in acetonitrile (10 mL). The reaction mixture was heated at reflux for 30 hours, at which time LC/MS analysis indicated 50% conversion. 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. Heptanes (3 mL) were added and the solids were filtered to give (3aR,7aR)-4'-(Benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'- piperazin]-2-ium methanesulfonate 52 (1.31 g, 93% yield) as a white solid. Example 6
Scheme 11: Synthesis of Compound 255h
Figure imgf000094_0002
[369] A suspension of methanesulfonate 44 (400 mg, 0.94 mmol, 1 equiv) in xylenes (8 mL) was sparged with nitrogen for 10 minutes. d8-Dione 51 (210 mg, 1.2 mmol, 1.3 equiv), dibenzo-18-crown-6 (spatula tip, 0.01 equiv), and potassium carbonate (195 mg, 1.4 mmol, 1.5 equiv) were added and the reaction mixture was heated at 130 °C for 24 hours. The reaction mixture was cooled to room temperature and the solids were filtered, washing with toluene. The filtrate was concentrated under reduced pressure. The crude product was dissolved in a minimum volume of dichloromethane, adsorbed onto Celite and purified using an Interchim automated chromatography system (50 g, C18 RP column), eluting with 15 to 98% acetonitrile in water, to give (3aR,4S,7R,7aS)-2- (((1R,2R)-2-((4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl-d2)cyclohexyl)methyl- d2)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione-4,5,5,6,6,7,8,8-d8 (Compound 255h) (350 mg, 74% yield) as a white foam after drying in a vacuum oven at 40 °C overnight. 1H-NMR (CDCl3, 400 MHz): δ 7.91 (d, 1H), 7.80 (d, 1H), 7.46 (t, 1H), 7.35 (t, 1H), 3.52 (t, 4H), 2.64 (m, 4H), 2.59 (s, 2H), 1.89 (d, 1H), 1.66 (m, 2H), 1.52 (m, 2H), 1.37 (m, 1H), 1.12-1.25 (m, 2H), 0.97-1.05 (m, 2H); MS (m/z): 505.3 [M+H]+; m.p.: 147.0-150.7 °C; optical rotation: -23 (0.100 g / 100 mL CH2Cl2), wavelength 589 nm. [370] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples merely present a detailed description of certain preferred embodiments. It will be apparent to those of ordinary skill in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention. The relevant teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

Claims

CLAIMS What is claimed is: 1. A compound of Formula I:
Figure imgf000096_0001
or a pharmaceutically acceptable salt thereof,
wherein Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 are independently selected from hydrogen and deuterium;
provided that at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, Y19, Y20, Y21, Y22, and Y23 is deuterium.
2. The compound of claim 1, wherein the compound is a compound of Formula II:
Figure imgf000097_0001
or a pharmaceutically acceptable salt thereof,
wherein Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18, and Y19 are independently selected from hydrogen and deuterium;
provided that at least one of Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y10a, Y10b, Y11, Y12, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a, Y17b, Y18 and Y19 comprises deuterium.
3. The compound of claim 1 or claim 2 wherein Y1a and Y1b are the same, Y4a and Y4b are the same, Y2a and Y2b are the same, Y3a and Y3b are the same, Y6a and Y6b are the same, Y9a and Y9b are the same, Y7a and Y7b are the same, Y8a and Y8b are the same, Y11 and Y12 are the same, Y13 and Y14 are the same, and Y15a, Y15b, Y16a and Y16b are the same.
4. The compound of any one of claims 1-3, wherein Y1a, Y1b, Y4a and Y4b are the same, Y2a, Y2b, Y3a and Y3b are the same, Y6a, Y6b, Y9a and Y9b are the same, Y7a, Y7b, Y8a and Y8b are the same, Y11 and Y12 are the same, Y13 and Y14 are the same, and Y15a, Y15b, Y16a and Y16b are the same.
5. The compound of any one of claims 1-4, wherein Y5a and Y5b are each deuterium.
6. The compound of any one of claims 1-5, wherein Y15a, Y15b, Y16a and Y16b are each deuterium.
7. The compound of any one of claims 1-6, wherein Y5a, Y5b, Y15a, Y15b, Y16a and Y16b are each deuterium.
8. The compound of any one of claims 1-7, wherein Y1a, Y1b, Y4a and Y4b are each deuterium.
9. The compound of any one of claims 1-8, wherein Y2a, Y2b, Y3a and Y3b are each deuterium.
10. The compound of any one of claims 1-9, wherein Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium.
11. The compound of any one of claims 1-10, wherein Y5a and Y5b are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium.
12. The compounds of any one of claims 1-11, wherein Y5a and Y5b are each deuterium, Y15a, Y15b, Y16a and Y16b are each deuterium, and Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are each deuterium.
13. The compound of any of the claims 1-12, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
14. The compound of claim 1, wherein Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are the same, Y5a and Y5b are the same, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are the same, Y10a and Y10b are the same, Y15a, Y15b, Y16a, Y16b are the same, Y11, Y12, Y13, Y14, Y17a and Y17b are the same, Y20, Y21, Y22 and Y23 are each deuterium, and the compound is selected from any one of the compounds (Cmpd) set forth in the table below:
Figure imgf000099_0001
Figure imgf000100_0001
deuterium is present at its natural isotopic abundance.
15. The compound of claim 1 , wherein Yla, Ylb, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are the same, Y5a and Y5b are the same, Y6a, Y6b, Y7a, Y7b Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are the same, Y10a and Y10b are the same, Y11 and Y12 are the same, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are the same, Y20, Y21, Y22 and Y23 are each deuterium, and the compound is selected from any one of the compounds (Cmpd) set forth in the table below:
Figure imgf000100_0002
Figure imgf000101_0001
deuterium is present at its natural isotopic abundance.
16. The compound of claim 2, wherein Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are the same, Y5a and Y5b are the same, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are the same, Y10a and Y10b are the same, Y15a, Y15b, Y16a, Y16b are the same, Y11, Y12, Y13, Y14, Y17a and Y17b are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in the table below:
Figure imgf000102_0001
Figure imgf000103_0001
deuterium is present at its natural isotopic abundance.
17. The compound of claim 2, wherein Y1a, Y1b, Y2a, Y2b, Y3a, Y3b, Y4a and Y4b are the same, Y5a and Y5b are the same, Y6a, Y6b, Y7a, Y7b, Y8a, Y8b, Y9a, Y9b, Y18 and Y19 are the same, Y10a and Y10b are the same, Y11 and Y12 are the same, Y13, Y14, Y15a, Y15b, Y16a, Y16b, Y17a and Y17b are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in the table below:
Figure imgf000104_0001
deuterium is present at its natural isotopic abundance.
18. The compound of claim 2, selected from:
Figure imgf000105_0001
19. A pharmaceutical composition comprising a compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20. 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 the compound of any one of claims 1-18, or a composition of claim 19.
21. A method of treating schizophrenia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19.
22. A method of treating depressive episodes associated with bipolar I disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19.
23. The method of claim 22, further comprising administering to the subject an additional therapeutic agent selected from lithium and valproic acid or a pharmaceutically acceptable salt thereof.
24. A method for treating major depressive disorder with mixed features in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19.
PCT/US2017/044400 2016-07-29 2017-07-28 Deuterated lurasidone Ceased WO2018023009A1 (en)

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