WO2016089814A1 - Deuterated analogues of daclatasvir - Google Patents

Abstract

This invention relates to novel 4,4'-di(1H-imidazol-5-yl)-1,1'-biphenyl compounds, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering an NS5A inhibitor.

Description

DEUTERATED ANALOGUES OF DACLATASVIR

CLAIM OF PRIORITY

[1] This application claims the benefit of U.S. Provisional Application number

62/086,373, filed December 2, 2014. 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, nonradioactive 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 AD ME 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 novel 4, 4'-di(lH-imidazol-5-yl)-1 , 1'-biphenyl compounds, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by

administering an NS5A inhibitor.

[10] Daclatasvir also known as BMS-790052, methyl [(25)-1-{(25)-2-[4-(4'-{2-[(25)-1- {(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-pyrrolidinyl]-1H-imidazol-4- yl} -4-biphenylyl)-1H-imidazol-2-yl]- 1 -pyrrolidinyl} -3-methyl- 1 -oxo-2- butanyl]carbamate, or methyl ((lS)-1-(((2S)-2-(5-(4'-(2-((2S)-1-((2S) -2- ((methoxycarbonyl)amino)-3 -methylbutanoyl)-2-pyrrolidinyl)- 1 H-imidazol-5 -yl)-4- biphenylyl)- 1 H-imidazol-2-yl)- 1 -pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate, modulates the expression and/or activity of NS5A viral replication complex.

[11] Daclatasvir in combination with sofosbuvir has been given a positive opinion by the Committee for Medicinal Products of Human Use of the European Medicines Agency for treatment of chronic hepatitis C, and is currently in phase III clinical trials in the United States in combination with other antiviral medications to treat hepatitis C. [12] In a placebo-controlled, single dose study of daclatasvir in combination with pegylated interferon alpha-2a and ribavirin, asthenia, irritability and vomiting were observed more frequently in subjects receiving daclatasvir compared with placebo. In a phase II dual-therapy combination trial of daclatasvir and asunaprevir, adverse reactions such as diarrhea, headache and elevation of liver transaminase enzymes were observed.

[13] Despite the beneficial activities of daclatasvir, there is a continuing need for new compounds to treat the aforementioned diseases and conditions.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[14] 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.

[15] "Disease" means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.

[16] The term "alkyl" refers to a monovalent saturated hydrocarbon group. C₁-C ₆ alkyl is an alkyl having from 1 to 6 carbon atoms. An alkyl may be linear or

branched. Examples of alkyl groups include methyl; ethyl; propyl, including n-propyl and isopropyl; butyl, including n-butyl, isobutyl, sec-butyl, and t-butyl; pentyl, including, for example, n-pentyl, isopentyl, and neopentyl; and hexyl, including, for example, n- hexyl and 2-methylpentyl.

[17] Unless otherwise specified, "alkylene" by itself or as part of another substituent refers to a saturated straight-chain or branched divalent group having the stated number of carbon atoms and derived from the removal of two hydrogen atoms from the corresponding alkane. Examples of straight chained and branched alkylene groups include -CH₂- (methylene), -CH₂-CH₂- (ethylene), -CH₂-CH₂-CH₂-

(propylene), -C(CH₃)₂-, -CH₂-CH(CH₃)-, -CH₂-CH₂-CH₂-CH₂-, -CH₂-CH₂-CH₂-CH₂-

CH₂- (pentylene), -CH₂-CH(CH₃)-CH₂-, and -CH₂-C(CH₃)₂-CH₂-.

[18] The term "alkenyl" refers to a monovalent unsaturated hydrocarbon group where the unsaturation is represented by a double bond. C₂-C₆ alkenyl is an alkenyl having from 2 to 6 carbon atoms. An alkenyl may be linear or branched. Examples of alkenyl groups include CH₂=CH-, CH₂=C(CH₃)-, CH₂=CH-CH₂-, CH₃-CH=CH-CH₂-, CH₃- CH=C(CH₃)- and CH₃-CH=CH-CH(CH₃)-CH₂-. Where double bond stereoisomerism is possible, the stereochemistry of an alkenyl may be (E), (Z), or a mixture thereof.

[19] The term "alkynyl" refers to a monovalent unsaturated hydrocarbon group where the unsaturation is represented by a triple bond. C₂-C₆ alkynyl is an alkynyl having from 2 to 6 carbon atoms. An alkynyl may be linear or branched. Examples of alkynyl groups include CH_≡C-, -C_≡C(CH₃), CH₃-C_≡C-CH₂-, CH₃-C_≡C-CH₂-CH₂ and CH₃-C_≡C- CH(CH₃)-CH₂-.

[20] The term "cycloalkyl" refers to a monocyclic or bicyclic monovalent saturated or non-aromatic unsaturated hydrocarbon ring system. The term "C₃-Cio cycloalkyl" refers to a cycloalkyl wherein the number of ring carbon atoms is from 3 to 10. Examples of C₃-Cio cycloalkyl include C₃-C₆ cycloalkyl. Bicyclic ring systems include fused, bridged, and spirocyclic ring systems. More particular examples of cycloalkyl groups include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cis- and trans- decalinyl, norbornyl, and spiro[4.5]decanyl.

[21] The term "carbocyclyl" refers to a monocyclic or bicyclic monovalent saturated or non-aromatic unsaturated hydrocarbon ring system. The term "C₃-Cio carbocyclyl" refers to a carbocyclyl wherein the number of ring carbon atoms is from 3 to 10. Examples of C₃-Cio carbocyclyl include C₃-C₆ carbocyclyl. Bicyclic ring systems include fused, bridged, and spirocyclic ring systems. More particular examples of carbocyclyl groups include, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cis- and trans-decalinyl, norbornyl, norbornenyl, and spiro[4.5]decanyl.

[22] The term "heterocycloalkyl" refers to a monocyclic or bicyclic monovalent saturated or non-aromatic unsaturated ring system wherein from 1 to 4 ring atoms are heteroatoms independently selected from the group consisting of O, N and S. The term "3 to 10-membered heterocycloalkyl" refers to a heterocycloalkyl wherein the number of ring atoms is from 3 to 10. Examples of 3 to 10-membered heterocycloalkyl include 3 to 6-membered heterocycloalkyl. Bicyclic ring systems include fused, bridged, and spirocyclic ring systems. More particular examples of heterocycloalkyl groups include azepanyl, azetidinyl, aziridinyl, imidazolidinyl, morpholinyl, oxazolidinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrrolidinyl, quinuclidinyl, and thiomorpholinyl. [23] In the above heterocycloalkyl substituents, the nitrogen, phosphorus, carbon or sulfur atoms can be optionally oxidized to various oxidation states. In a specific example, the group -S(O)_0-2-, refers to -S- (sulfide), -S(O)- (sulfoxide), and -SO2- (sulfone), respectively. For convenience, nitrogens, particularly but not exclusively, are meant to include their corresponding N-oxide form, although not explicitly defined as such in a particular example. Thus, for a compound of the invention having, for example, a pyridyl ring; the corresponding pyridyl-N-oxide is meant to be included as another compound of the invention. In addition, annular nitrogen atoms can be optionally quatemized; and the ring substituent can be partially or fully saturated or aromatic.

[24] "Aryl" by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon group having the stated number of carbon atoms (i.e., C₅-C₁₄ means from 5 to 14 carbon atoms). Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene, 5-indacene, indane, indene, naphthalene, octacene, octophene, octalene, ovalene, penta- 2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthylene, and the like. In a specific embodiment, the aryl group is cyclopentadienyl, phenyl or naphthyl. In a more specific embodiment, the aryl group is phenyl or naphthyl.

[25] "Arylalkyl" by itself or as part of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp₃ carbon atom, is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2- naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. In one embodiment, the alkyl moiety of the arylalkyl group is (C₁-C₆) and the aryl moiety is ( C₅-C₁₄). In a more specific embodiment the alkyl group is (C₁-C₃) and the aryl moiety is (C₅-C₁₀), such as (C₆-C₁₀).

[26] The term "heteroaryl" refers to a monovalent aromatic monocyclic

ring system wherein at least one ring atoms is a heteroatom independently selected from the group consisting of O, N and S. The term 5-membered heteroaryl refers to a heteroaryl wherein the number of ring atoms is 5. Examples of 5-membered heteroaryl groups include pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, furazanyl, imidazolinyl, and triazolyl.

[27] "Heteroarylalkyl" by itself or as part of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³ carbon atom, is replaced with a heteroaryl group. In one embodiment, the alkyl moiety of the heteroarylalkyl is (C₁-C₆) alkyl and the heteroaryl moiety is a 5-14- membered heteroaryl. In a more specific embodiment, the alkyl moiety is (C₁-C₃) alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

[28] "Halogen" or "Halo" by themselves or as part of another substituent refers to fluorine, chlorine, bromine and iodine, or fluoro, chloro, bromo and iodo.

[29] 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 daclatasvir 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, 1 19:725.

[30] 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. 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).

[31] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[32] 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).

[33] 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.

[34] 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. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[35] The invention also provides salts of the compounds of the invention.

[36] 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 another

embodiment, the compound is a pharmaceutically acceptable acid addition salt.

[37] 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.

[38] 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-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, 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.

[39] The compounds of the present invention (e.g., compounds of Formula I and/or Formula la), 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. 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.

[40] 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.

[41] 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).

[42] "D" and "d" both refer to deuterium. "Stereoisomer" refers to both enantiomers and diastereomers. "Tert" and "t-" each refer to tertiary. "US" refers to the United States of America.

[43] "Substituted with deuterium" refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.

[44] Throughout this specification, a variable may be referred to generally (e.g., "each R") or may be referred to specifically (e.g., R^la, R^lb, R^2a, 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

[45] The present invention provides a compound of Formula I:

wherein each of R^la, R^lb, R^2a and R^2b is independently selected from CH₃ and CD₃; and yla ylb ylc y2a y2b y3a y3b y4a y4b y5a y5b y6 y7 y8a y8b y9a y9b ylOa I , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , ylOb ylla yllb γ12 γ13 yl4a yl4b yl5a yl5b yl6a yl6b yl7a yl7b yl8a yl8b _an(j

Y^18c are independently selected from hydrogen and deuterium;

provided that when each of R^la, R^lb, R^2a and R^2b is CH₃, at least one of Y^la, Y^lb, Y^lc, Y^2a, y2b y3a y3b y4a y4b y5a y5b y6 y7 y8a y8b y9a y9b ylOa ylOb ylla yllb yl2 I , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 ,

Y¹³, Y^14a, Y^14b, Y^15a, Y^15b, Y^16a, Y^16b, Y^17a, Y^17b, Y^18a, Y^18b, and Y^18c is deuterium.

[46] In some embodiments, Y^la, Y^lb, and Y^lc are all the same. In some aspects of these embodiments, Y^la, Y^lb, and Y^lc are all deuterium.

[47] In some embodiments, Y^2a and Y^2b are each deuterium.

[48] In some embodiments, Y^3a and Y^3b are the same. In some aspects of these embodiments, Y^3a and Y^3b are each deuterium.

[49] In some embodiments, Y^4a and Y^4b are the same. In some aspects of these embodiments, Y^4a and Y^4b are each deuterium.

[50] In some embodiments, Y^5a and Y^5b are the same. In some aspects of these embodiments, Y^5a and Y^5b are each deuterium.

[51] In some embodiments, Y⁶ is deuterium.

[52] In some embodiments, Y^3a, Y^3b, Y^4a, Y^4b, Y^5a, Y^5b, and Y⁶ are the same. In some aspects of these embodiments, Y^3a, Y^3b, Y^4a, Y^4b, Y^5a, Y^5b, and Y⁶ are all deuterium.

[53] In some embodiments, Y⁷ is deuterium.

[54] In some embodiments, Y^8a and Y^8b are the same. In some aspects of these embodiments, Y^8a and Y^8b are each deuterium.

[55] In some embodiments, Y^9a and Y^9b are the same. In some aspects of these embodiments, Y^9a and Y^9b are each deuterium.

[56] In some embodiments, Y^10a and Y^10b are the same. In some aspects of these embodiments, Y^10a and Y^10b are each deuterium.

[57] In some embodiments, Y^lla and Y^llb are the same. In some aspects of these embodiments, Y^lla and Y^llb are each deuterium.

[58] In some embodiments, Y^8a, Y^8b, Y^9a, Y^9b, Y^10a, Y^10b, Y^lla and Y^llb are the same. In some aspects of these embodiments, Y^8a, Y^8b, Y^9a, Y^9b, Y^10a, Y^10b, Y^llaand Y^llb are all deuterium.

[59] In some embodiments, Y¹² is deuterium. [60] In some embodiments, Y is deuterium.

[61] In some embodiments, Y^14a and Y^14b are the same. In some aspects of these embodiments, Y^14a and Y^14b are each deuterium.

[62] In some embodiments, Y^15a and Y^15b are the same. In some aspects of these embodiments, Y^15a and Y^15b are each deuterium.

[63] In some embodiments, Y^16a and Y^16b are the same. In some aspects of these embodiments, Y^16a and Y^16b are each deuterium.

[64] In some embodiments, Y¹³, Y^14a, Y^14b, Y^15a, Y^15b, Y^16a, and Y^16b are the same. In some aspects of these embodiments, Y¹³, Y^14a, Y^14b, Y^15a, Y^15b, Y^16a, and Y^16b are all deuterium.

[65] In some aspects of these embodiments, Y^3a, Y^3b, Y^4a, Y^4b, Y^5a, Y^5b, and Y⁶ are all hydrogen; and Y¹³, Y^14a, Y^14b, Y^15a, Y^15b, Y^16a, and Y^16b are all deuterium. In some aspects of these embodiments, Y^3a, Y^3b, Y^4a, Y^4b, Y^5a, Y^5b, and Y⁶ are all deuterium; and

Y¹³, Y^14a, Y^14b, Y^15a, Y^15b, Y^16a, and Y^16b are all hydrogen.

[66] In some embodiments, Y^17a and Y^17b are each deuterium.

[67] In some embodiments, Y^18a, Y^18b, and Y^18c are all the same. In some aspects of these embodiments, Y^18a, Y^18b, and Y^18c are all deuterium.

[68] In some embodiments, Y^la, Y^lb, and Y^lc are all hydrogen; and Y^18a, Y^18b, and Y¹⁸' are all deuterium. In other embodiments, Y^la, Y^lb, and Y^lc are all deuterium; and Y^18a, Y^18b, and Y^18c are all hydrogen.

[69] In some embodiments, R^la and R^lb are the same. In some aspects of these embodiments, R^la and R^lb are each CD₃.

[70] In some embodiments, R^2a and R^2b are the same. In some aspects of these embodiments, R^2a and R^2b are each CD₃.

[71] In some embodiments, R^la and R^lb are each CD₃; R^2a and R^2b are each CH₃; Y^2a and Y^2b are each deuterium; and Y^17a and Y^17b are each hydrogen. In some embodiments, R^la and R^lb are each CH₃; R^2a and R^2b are each CD₃; Y^2a and Y^2b are each hydrogen; and Y^17a and Y^17b are each deuterium.

[72] 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. [73] In one embodiment of a compound of Formula I, Y^3a, Y^3b, Y^4a, Y^4b, Y^5a, Y^5b, Y⁶, Y⁷, Y¹², Y¹³, Y^14a, Y^14b, Y^15a, Y^15b, Y^16a andY^16b are each deuterium; Y^2a, Y^2b, Y^17a and Y^17b are each hydrogen; R^la, R^lb, R^2a, and R^2b are each CH₃; Y^8a and Y^8b are the same; Y^9a and Y^9b are the same; Y^10a and Y^10b are the same; Y^{l la} and Y^{l lb} are the same; Y^la, Y^lb, and Y^lc are the same; and Y^18a, Y^18b, and Y^18c are the same, and the compound is any one of the compounds (Cmpd) set forth in Table la (below):

Table la: Exemplary Embodiments of Formula I

or a p armaceut ca y accepta e sa t t ereo , w ere n, or eac compoun set ort above, any atom not designated as deuterium is present at its natural isotopic abundance. [74] In one embodiment of a compound of Formula I, Y^2a, Y^2b, Y^3a, Y^3b, Y^4a, Y^4b, Y^5a, Y^5b, Y⁶, Y⁷, Y¹², Y¹³, Y^14a, Y^14b, Y^15a, Y^15b, Y^16a,Y^16b, Y^17a and Y^17b are each deuterium; R^la, R^lb, R^2a, and R^2b are each CD₃; Y^8a and Y^8b are the same; Y^9a and Y^9b are the same; Y^10a and Y^10b are the same; Y^{l la} and Y^{l lb} are the same; Y^la, Y^lb, and Y^lc are the same; and Y^18a, Y^18b, and Y^18c are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in Table lb (below):

Table lb: Exemplary Embodiments of Formula I

or a p armaceut ca y accepta e sa t t ereo , w ere n, or eac compoun set ort above, any atom not designated as deuterium is present at its natural isotopic abundance. [75] In one embodiment of a compound of Formula I, Y^2a, Y^2b, Y^3a, Y^3b, Y^4a, Y^4b, Y^5a, Y^5b and Y⁶ are each hydrogen; Y⁷, Y¹², Y¹³, Y^14a, Y^14b, Y^15a, Y^15b, Y^16a,Y^16b, Y^17a and Y^17b are each deuterium; R^la and R^lb are each CH₃; R^2a and R^2b are each CD₃; Y^8a and Y⁸' are the same; Y^9a and Y^9b are the same; Y^10a and Y^10b are the same; Y^{l la} and Y^{l lb} are the same; Y^la, Y^lb, and Y^lc are the same; and Y^18a, Y^18b, and Y^18c are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in Table lc (below):

Table lc: Exemplary Embodiments of Formula I

or a p armaceut ca y accepta e sa t t ereo , w ere n, or eac compoun set ort above, any atom not designated as deuterium is present at its natural isotopic abundance. [76] In one embodiment of a compound of Formula I, Y^2a, Y^2b, Y^3a, Y^3b, Y^4a, Y^4b, Y^5a, Y^5b, Y⁶, Y⁷ and Y¹² are each deuterium; Y¹³, Y^14a, Y^14b, Y^15a, Y^15b, Y^16a, Y^16b, Y^17a and Y^17b are each hydrogen; R^la and R^lb are each CD₃; R^2a and R^2b are each CH₃; Y^8a and Y⁸¹ are the same; Y^9a and Y^9b are the same; Y^10a and Y^10b are the same; Y^{l la} and Y^{l lb} are the same; Y^la, Y^lb, and Y^lc are the same; and Y^18a, Y^18b, and Y^18c are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in Table Id (below):

Table Id: Exemplary Embodiments of Formula I

above, any atom not designated as deuterium is present at its natural isotopic abundance.

[77] In one embodiment of a compound of Formula I, Y^3a, Y^3b, Y^4a, Y^4b, Y^5a, Y^5b, Y⁶, Y¹³, Y^14a, Y^14b, Y^15a, Y^15b, Y^16a andY^16b are each hydrogen; Y^2a, Y^2b, Y⁷, Y¹², Y^17a and Y^17b are each deuterium; R^la, R^lb, R^2a, and R^2b are each CD₃; Y^8a and Y^8b are the same; Y^9a and Y^9b are the same; Y^10a and Y^10b are the same; Y^{l la} and Y^{l lb} are the same; Y^la, Y^lb, and Y^lc are the same; and Y^18a, Y^18b, and Y^18c are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in Table le (below): Table le: Exemplary Embodiments of Formula I

or a pharmaceutically acceptable salt thereof, wherein, for each compound set forth above, any atom not designated as deuterium is present at its natural isotopic abundance.

[78] In one aspect of any of the above embodiments or tables of compounds of Formula I, when each of Y^la, Y^lb, Y^lc, Y^18a, Y^18b, and Y^18c is deuterium, at least one of y2a y2b y3a Y3b y4a γ-tb y5a Y5b γ6 γ7 y8a - y8b - y9a -y9b y10a

Y^10b, Y^lla, Y^{l lb}, Y¹², Y¹³, Y^14a, Y^14b, Y^15a, Y^15b, Y^16a, Y^16b, Y^17a, and Y^17b comprises deuterium.

[79] In some embodiments, the compound of Formula I has the structure of Formula la:

wherein Y^la, Y^lb, Y^lc, Y⁷, Y^8a, Y^8b, Y^9a, Y^9b, Y^10a, Y^10b, Y^{l la}, Y^{l lb}, Y¹², Y^18a, Y^18b, and

Y are independently selected from hydrogen and deuterium;

Provided that at least one of Y^la, Y^lb, Y^lc, Y⁷, Y^8a, Y^8b, Y^9a, Y^9b, Y^10a, Y^10b, Y^{l la}, Y^llb, Y¹², Y^18a, Y^18b, and Y^18c is deuterium.

[80] In some embodiments, Y^la, Y^lb, and Y^lc are all the same. In some aspects of these embodiments, Y^la, Y^lb, and Y^lc are all deuterium.

[81] In some embodiments, Y⁷ is deuterium.

[82] In some embodiments, Y^8a and Y^8b are the same. In some aspects of these embodiments, Y^8a and Y^8b are each deuterium.

[83] In some embodiments, Y^9a and Y^9b are the same. In some aspects of these embodiments, Y^9a and Y^9b are each deuterium.

[84] In some embodiments, Y^10a and Y^10b are the same. In some aspects of these embodiments, Y^10a and Y^10b are each deuterium.

[85] In some embodiments, Y^{l la} and Y^{l lb} are the same. In some aspects of these embodiments, Y^{l la} and Y^{l lb} are each deuterium.

[86] In some embodiments, Y^8a, Y^8b, Y^9a, Y^9b, Y^10a, Y^10b, Y^{l la} and Y^llb are the same. In some aspects of these embodiments, Y^8a, Y^8b, Y^9a, Y^9b, Y^10a, Y^10b, Y^{l la} and Y^{l lb} are all deuterium.

[87] In some embodiments, Y¹² is deuterium.

[88] In some embodiments, Y^18a, Y^18b, and Y^18c are all the same. In some aspects of these embodiments, Y^18a, Y^18b, and Y^18c are all deuterium.

[89] In some embodiments, Y^la, Y^lb, and Y^lc are all hydrogen; and Y^18a, Y^18b, and Y^18c are all deuterium. In other embodiments, Y^la, Y^lb, and Y^lc are all deuterium; and Y^18a, Y^18b, and Y^18c are all hydrogen.

[90] 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.

18 [91] In one embodiment of a compound of Formula la, Y⁷ and Y¹² are each hydrogen; Y^8a and Y^8b are the same; Y^9a and Y^9b are the same; Y^10a and Y^10b are the same; Y^{l la} and Y^{l lb} are the same; Y^la, Y^lb, and Y^lc are the same; and Y^18a, Y^18b, and Y^18c are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 2a (below):

Table 2a: Exemplary Embodiments of Formula la

above, any atom not designated as deuterium is present at its natural isotopic abundance.

[92] In one embodiment of a compound of Formula la, Y⁷ and Y¹² are each deuterium; Y^8a and Y^8b are the same; Y^9a and Y^9b are the same; Y^10a and Y^10b are the same; Y^{l la} and Y^{l lb} are the same; Y^la, Y^lb, and Y^lc are the same; and Y^18a, Y^18b, and Y^18c are the same, and the compound is selected from any one of the compounds (Cmpd) set forth in Table 2b (below): Table 2b: Exemplary Embodiments of Formula la

above, any atom not designated as deuterium is present at its natural isotopic abundance.

[93] In one aspect of any of the above embodiments or tables of compounds of Formula la, when each of Y^la, Y^lb, Y^lc, Y^18a, Y^18b, and Y^18c is deuterium, at least one of Y⁷, Y^8a, Y^8b, Y^9a, Y^9b, Y^10a, Y^10b, Y^lla, Y^{l lb} and Y¹² is deuterium.

[94] The synthesis of compounds of Formula I and/or Formula la 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 la and intermediates thereof are disclosed, for instance in US patent 8,329,159, US patent publication 20090043107 and references cited therein. [95] 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

[96] A convenient method for synthesizing compounds of Formula I is depicted in Scheme 1, below.

Scheme 1 : General Synthesis of Compounds of Formula I

22

Reagents and conditions: (a) Pd(Ph₃P)₄, NaHC0₃; (b) HC1; (c) HOBt, EDC, EtN(Pr-z)₂; (d) H₂/Pd-C; (e) 1) HOBt, EDC, EtN(Pr-z)₂, 2) HC1

[97] In a manner analogous to the procedure described in WO2008021927, suitably protected and appropriately deuterated boronate ester (1) is coupled with suitably protected and appropriately deuterated aryl halide (2), resulting in correspondingly deuterated and suitably protected biphenyl intermediate (3) using standard Suzuki- Miyaura coupling conditions described in Chemler S. et al. Angew. Chem. Int. Ed. Engl., 40 (24), 4544-4568, (2001). When R³ and R¹⁷ are different, mono-deprotection of the pyrrolidine moiety may be achieved. For example, when R³ = t-butyl and R¹⁷ = benzyl, treatment with strong acid such as HC1 or TFA to remove Boc protection produces deuterated pyrrolidine intermediate (4). Acylation of (4) with appropriately deuterated starting material (5) may be accomplished under standard amidation conditions known in the art, and a coupling reagent such as EDC, HOBt with amine base such as Hunig's base is used to produce correspondingly deuterated intermediate (6). Further deprotection of intermediate (6) to remove the exemplary Cbz protection is accomplished by

hydrogenolysis employing, e.g., Pd/C catalyst to produce intermediate (7). Subsequent treatment of intermediate (7) with starting material (5') under standard amidation conditions analogous to those employed to convert (4) to (6) affords correspondingly deuterated compounds of Formula I. It will be appreciated by one skilled in the art that selective deprotection steps may be reversed using synthetic protocols that successfully accomplishes the synthesis of compounds of Formula I.

[98] In embodiments where protecting groups R³ and R¹⁷ are equivalent, direct acylation to produce compounds of Formula I may be accomplished in a manner analogous to the methods described herein or those well known in the art, utilizing intermediate (3a), wherein R³ = R¹⁷ = H. Intermediate (3a) may be obtained by acid hydrolysis of intermediate (3) when protected with R³ = R¹⁷ = t-butyl, or by

hydrogenolysis of intermediate (3) when protected with R³= R¹⁷ = benzyl.

[99] Using commercially available reagents and deuterated reagents that can be readily prepared by known methods, compounds of Formula I can be prepared with greater than 90% or greater than 95% deuterium incorporation at each position designated as D (see below for details).

[100] Appropriately deuterated intermediate (1), for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 2.

Scheme 2: Pre aration of Intermediate (1)

(1) Reagents and conditions: (a) Br2, ACOH; (b) EtN(Pr-z^')2; c) NH4OAC; (d) Bis(pinacolato)diboron, KOAc, Pd(Ph₃P)₄

[101] Appropriately deuterated intermediate (9) is prepared from commercially available 4'-Bromoacetophenone-d₇ (99 atom %D) (8), by treatment with bromine as described in WO2010099527. Alternative sources of bromonium ion such as N- bromosuccinimide or CBr₄ may be utilized. Reaction of intermediate (9) with

appropriately deuterated proline starting material (10) in the presence of base such as Hunig's base, gives correspondingly deuterated ketoester intermediate (11). Intermediate (11), upon heating with NH₄OAc at elevated temperature affords appropriately deuterated imidazole intermediate (12). Bromide (12) is treated with bis-pinacolatodiboron under palladium catalysis in a manner analogous to that described in WO 2009102318 to afford appropriately deuterated boronate ester intermediate (1).

[102] Starting material (10), for use in the preparation of intermediate (1) according to Scheme 2 are available as follows. Proline (10a), wherein each Y is hydrogen and R³ is t-butyl, is commercially available. Deuterated proline starting material (10b), may be prepared from corresponding deuterated reagents exemplified in Scheme 3.

Scheme 3: Pre aration of Starting Material (10b)

Reactions and conditions: (a) Bis(2-methylallyl)(l,5-cyclooctadiene)ruthenium (II), (S,S)-(R,R)- PhTRAP, Et₃N, D₂; (b) LiOH

[103] Appropriately deuterated intermediate (14) is prepared by asymmetric reduction of commercially available methyl N-Boc-2-pyrrolecarboxylate (13) using ruthenium catalyst in the presence of D₂, in a manner analogous to that described by Kuwano, R. et al, J. Am. Chem. Soc. (2008), 130(3), 808-809. Subsequent hydrolysis of the methyl ester utilizing a base such as LiOH, affords appropriately deuterated starting material (10b). [104] Appropriately deuterated starting material (2), for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared as described herein. When R¹⁷ = t-butyl, intermediate (2) is equivalent to intermediate (12) and is produced as described herein in scheme 2. Likewise, when R¹⁷ = benzyl, intermediate (2) is prepared as described in scheme 2 using Cbz- protected (10), thereby affording access to the synthesis of unsymmetrical deuterated and protonated compounds of Formula I.

[105] Appropriately deuterated starting material (5), for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as shown in Scheme 5.

Scheme 5: Preparation of Starting Material (5)

Reagents and conditions: (a) NaOH, Na2CO₃, HQ

[106] Appropriately deuterated starting material (5a) is prepared from commercially available L-valine-d8 (15) (98 atom %D) and appropriately deuterated reagent (16) under Schotten Baumann reaction conditions known in the art, and basic conditions such as NaOH, Na₂CO₃ affords correspondingly deuterated starting material (5a). Appropriately deuterated reagent (16) utilized for this preparation is readily produced from methanol-d₃ (99.8 atom %D) and phosgene, according to a procedure delineated in WO 2007120621.

[107] Appropriately deuterated starting material (5b) is prepared from commercially available L-valine and appropriately deuterated reagent (16) under Schotten Baumann reaction conditions known in the art, and basic conditions such as NaOH, Na₂CO₃.

[108] Appropriately deuterated starting material (5c) may be prepared as shown above or from corresponding deuterated reagents as shown in Scheme 6. Scheme 6: Preparation of Starting Material (5c)

Reagents and conditions: (a) (±)-Benzyloxycarbonyl-a-phosphonoglycine trimethyl ester, N,N, Ν',Ν'-Tetramethylguanidine; (b) l,2-Bis[(2S,5S)-2,5-dimethylphospholano]ethane(cyclooctadien e)rhodium(I) tetrafluoroborate, H₂ or D₂; (c) 1) H₂, Pd-C, 2) (16), NaOH, Na₂C0₃, HCl; (d) LiOH

[109] In a manner analogous to prodecures described in WO 2012039878, (also in Schmidt, U. et al, Synthesis 5, 487-90, 1992; Hamada M, et al. Org. Lett. 11(20) 4664,2009), appropriately deuterated dehydro-amino acid intermediate (18) is prepared by Wittig reaction of commercially available acetone-d6 (99.9 atom %D) (17). Selective asymmetric reduction of (18) with chiral phospholane, in the presence of H₂ or D₂ produces appropriately deuterated intermediate (19). Hydrogenolysis of (19) and subsequent treatment with (16), wherein each Y¹ is deuterium, produces ester (20), which upon hydrolysis affords correspondingly deuterated starting material (5c).

[110] The specific approaches and compounds shown above are not intended to be limiting. The chemical structures in the schemes herein depict variables that are hereby defined commensurately with chemical group definitions (moieties, atoms, etc.) of the corresponding position in the compound formulae herein, whether identified by the same variable name (i.e., R^la, R^lb, R^2a, etc.) or not. The suitability of a chemical group in a compound structure for use in the synthesis of another compound is within

the knowledge of one of ordinary skill in the art. [111] Additional methods of synthesizing compounds of Formula I and/or Formula la and their synthetic precursors, including those within routes not explicitly shown in schemes herein, 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, 3^rd 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.

[112] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.

Compositions

[113] The invention also provides pharmaceutical compositions comprising an effective amount of a compound of Formula I and/or Formula la (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.

[114] Pharmaceutically acceptable carriers, adjuvants 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, 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.

[115] 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.

[116] 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 LUTPvOL™ and PLURONIC™ (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.

[117] 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).

[118] 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.

[119] 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.

[120] 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.

[121] 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.

[122] Compositions suitable for parenteral administration include aqueous and nonaqueous 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.

[123] 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.

[124] 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.

[125] 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.

[126] 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.

[127] 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.

[128] 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.

[129] 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.

[130] 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. [131] 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.

[132] 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.

[133] 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.

[134] In another embodiment, a composition of this invention further comprises a second therapeutic agent. The second 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 daclatasvir. Such agents include those indicated as being useful in combination with daclatasvir, including but not limited to, those described in PCT WO 2013/024155; WO 2013/059638; WO 2012/118712; US patent 8,329,159; and US application

2009/0041716.

[135] Preferably, the second therapeutic agent is an agent useful in the treatment of hepatitis C infection (e.g., HCV-1, HCV-2, or HCV-3, including chronic hepatitis C infection, e.g., infection with genotype 1, 2, 3, or 4), alone or co-infection with other viruses, such as human immunodeficiency virus (HIV).

[136] In one embodiment, the second therapeutic agent is selected from darunavir, ritonavir, lopinavir, simeprevir, ribavirin, pegylated interferon alpha-2a, pegylated interferon alpha-2b, pegylated interferon lambda, VX-135, BMS-650032, BMS-791325, sofosbuvir and asunaprevir.

[137] 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 second therapeutic agents, wherein the compound and second 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).

[138] 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.

[139] 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.

[140] In one embodiment, an effective amount of a compound of this invention can range from about 30 mg to about 90 mg per day. In some embodiments, an effective amount of a compound of this invention can range from about 6 mg per day to about 180 mg per day. In some embodiments, an effective amount of a compound of this invention can range from about 0.6 mg per day to about 900 mg per day. In some embodiments, an effective amount of a compound of this invention can range from about 0.006 mg per day to about 9 grams per day.

[141] 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 daclatasvir.

[142] For pharmaceutical compositions that comprise a second therapeutic agent, an effective amount of the second 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 second 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.

[143] It is expected that some of the second therapeutic agents referenced above will act synergistically with the compounds of this invention. When this occurs, it will allow the effective dosage of the second 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 second therapeutic agent of a compound of this invention, synergistic improvements in efficacy, improved ease of administration or use and/or reduced overall expense of compound preparation or formulation.

Methods of Treatment

[144] In another embodiment, the invention provides a method of modulating the activity of NS5A in a cell, comprising contacting a cell with one or more compounds of Formula I and/or Formula la herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of modulating the activity of NS5A in a cell is a method of inhibiting the activity of the NS5A.

[145] According to another embodiment, the invention provides a method of treating a disease that is beneficially treated by daclatasvir 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. Such diseases are well known in the art and are disclosed in, but not limited to the following patents and published applications: WO 2013/024155; WO

2013/059638; WO 2012/118712; US 8,329,159 and US 2009/0041716. Such diseases include, but are not limited to, hepatitis C infection (e.g., HCV-1, HCV-2, or HCV-3, including chronic hepatitis C infection, e.g., infection with genotype 1, 2, 3, or 4), alone or co-infection with other viruses, such as human immunodeficiency virus (HIV).

[146] In one particular embodiment, the method of this invention is used to treat hepatitis C infection (including chronic hepatitis C infection), alone or co-infection with other viruses, such as human immunodeficiency virus (HIV) in a subject in need thereof. [147] In another particular embodiment, the method of this invention is used to treat hepatitis C infection in a subject in need thereof.

[148] 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).

[149] 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 second therapeutic agents. The choice of second therapeutic agent may be made from any second therapeutic agent known to be useful for co-administration with daclatasvir. The choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of second 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 a second therapeutic agent.

[150] In particular, the combination therapies of this invention include co-administering a compound of Formula I and/or Formula la and a second therapeutic agent to a subject in need thereof for treatment of the following conditions (with the particular second therapeutic agent indicated in parentheses following the indication): hepatitis C infection (darunavir, ritonavir, lopinavir, simeprevir, ribavirin, pegylated interferon alpha-2a, pegylated interferon alpha-2b, pegylated interferon lambda, VX-135, BMS-650032, BMS-791325, sofosbuvir, and/or asunaprevir).

[151] The term "co-administered" as used herein means that the second 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 second 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 second therapeutic agent(s) are administered by conventional methods. The administration of a composition of this invention, comprising both a compound of the invention and a second therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said subject at another time during a course of treatment.

[152] Effective amounts of these second 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 second therapeutic agent's optimal effective-amount range.

[153] In one embodiment of the invention, where a second 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 second therapeutic agent is not

administered. In another embodiment, the effective amount of the second 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.

[154] In yet another aspect, the invention provides the use of a compound of Formula I and/or Formula la alone or together with one or more of the above-described second 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 and/or Formula la for use in the treatment in a subject of a disease, disorder or symptom thereof delineated herein.

Example X. Evaluation of Metabolic Stability

[155] Microsomal Assay: Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, KS). β -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCb), and dimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich. [156] 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 μΜ 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 aliquot of the 12.5-50 μΜ 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 μΜ 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 μL aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow- well 96-well plates which contain 50 μL of ice-cold ACN with internal standard to stop the reactions. The plates are stored at 4 °C for 20 minutes after which 100μL 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/or Formula la and the positive control, 7-ethoxycoumarin (1 μΜ). Testing is done in triplicate.

[157] Data analysis: The in vitro ti/₂s for test compounds are calculated from the slopes of the linear regression of % parent remaining (In) vs incubation time relationship,

in vitro t ½ = 0.693/k

k = -[slope of linear regression of % parent remaining (In) vs incubation time] [158] Data analysis is performed using Microsoft Excel Software.

[159] 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.

Claims

We claim:

1. A compound of Formula la:

or pharmaceutically acceptable salt thereof,

wherein Y^la, Y^lb, Y^lc, Y⁷, Y^8a, Y^8b, Y^9a, Y^9b, Y^10a, Y^10b, Y^{l la}, Y^{l lb}, Y¹², Y^18a, Y^18b, and Y^18c are independently selected from hydrogen and deuterium;

provided that at least one of Y^la, Y^lb, Y^lc, Y⁷, Y^8a, Y^8b, Y^9a, Y^9b, Y^10a, Y^10b, Y^{l la}, Y^llb, Y¹², Y^18a, Y^18b, and Y^18c is deuterium.

2. The compound of claim 1, wherein Y^la, Y^lb, and Y^lc are all the same.

3. The compound of claim 2, wherein Y^la, Y^lb, and Y^lc are all deuterium.

4. The compound of claim 1, wherein Y⁷ is deuterium.

5. The compound of claim 1, wherein Y^8a and Y^8b are the same.

6. The compound of claim 5, wherein Y^8a and Y^8b are each deuterium.

7. The compound of claim 1, wherein Y^9a and Y^9b are the same.

8. The compound of claim 7, wherein Y^9a and Y^9b are each deuterium.

9. The compound of claim 1, wherein Y^10a and Y^10b are the same.

10. The compound of claim 9, wherein Y^10a and Y^10b are each deuterium.

11. The compound of claim 1 , wherein Y^{1 la} and Y^{1 lb} are the same.

12. The compound of claim 11, wherein Y^{l la} and Y^{l lb} are each deuterium.

39

13. The compound of claim 1, wherein Y is deuterium.

14. The compound of claim 1, wherein Y^18a, Y^18b, and Y^18c are all the same.

15. The compound of claim 14, wherein Y^18a, Y^18b, and Y^18c are all deuterium.

16. The compound of claim 1, wherein Y⁷ and Y¹² are each hydrogen; Y^8a and Y^8b are the same; Y^9a and Y^9b are the same; Y^10a and Y^10b are the same; Y^{l la} and Y^{l lb} are the same; Y^la, Y^lb, and Y^lc are the same; and Y^18a, Y^18b, and Y^18c are the same, and the compound is selected from any one of the compounds in the table below:

any atom not designated as deuterium is present at its natural isotopic abundance.

17. The compound of claim 1, wherein Y⁷ and Y¹² are each deuterium; Y^8a and Y^8b are the same; Y^9a and Y^9b are the same; Y^10a and Y^10b are the same; Y^{l la} and Y^{l lb} are the same; Y^la, Y^lb, and Y^lc are the same; and Y^18a, Y^18b, and Y^18c are the same, and the compound is selected from any one of the compounds in the table below:

any atom not designated as deuterium is present at its natural isotopic abundance.

18. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. A method of inhibiting the activity of NS5A in a cell, comprising contacting the cell with a composition of claim 18.

20. A method of treating hepatitis C infection, comprising the step of administering to the subject in need thereof a composition of claim 18.

21. The method of claim 20, wherein the composition of claim 18 is administered with a second therapeutic agent.

22. The method of claim 21, wherein the second therapeutic agent is selected from the group consisting of: darunavir, ritonavir, lopinavir, simeprevir, ribavirin, pegylated interferon alpha-2a, pegylated interferon alpha-2b, pegylated interferon lambda, VX-135, BMS-650032, BMS-791325, sofosbuvir, and asunaprevir.