AU2016257892A1 - Deuterated filgotinib - Google Patents

Abstract

This invention relates to deuterated forms of filgotinib, 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 a JAK inhibitor.

Description

DEUTERATED FILGOTINIB

RELATED APPLICATION

[1] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62/157,035, filed May 5, 2015, the contents of which are incorporated herein by reference in its entirety.

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 codosed 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 filgotinib, and pharmaceutically acceptable salts thereof. Certain aspects of the present invention are directed to a compound represented by Formula I:

or a pharmaceutically acceptable salt thereof, wherein each R1 is independently hydrogen or deuterium; Q is

wherein each R2a is independently hydrogen or deuterium, each R2b is independently hydrogen or deuterium, each R3a is independently hydrogen or deuterium, and each R3b is independently hydrogen or deuterium; Z is

wherein R4 is hydrogen or deuterium, each R5 is independently hydrogen or deuterium, and each R6 is independently hydrogen or deuterium; provided that at least one of R1, R2, R3, R4, R5, and R6 is deuterium.

[10] This invention also provides compositions comprising a compound of thisinvention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a Janus kinase (JAK) inhibitor such as filotinib. Certain aspects of the invention are directed to a pharmaceutical composition, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[11] Certain aspects of the present invention are directed to a method of inhibiting JAK1 or JAK2 activity in a cell, comprising contacting the cell with a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I.

[12] Certain aspects of the present invention are directed to a method of treating rheumatoid arthritis or Crohn’s disease, the method comprising administering to a subject in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

[13] Filgotinib (also known as N-[5-[4-[(l,l-dioxo-l,4-thiazinan-4-yl)methyl]phenyl]-[l,2,4]triazolo[l,5-a]pyridin-2-yl]cyclopropanecarboxamide and GLPG0634) is a Janus kinase (JAK) inhibitor with selectivity for subtype JAK1 of this enzyme. JAK inhibitors function by inhibiting the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2), thereby interfering with the JAK-STAT signaling pathway. These inhibitors have therapeutic application in the treatment of inflammatory diseases such as rheumatoid arthritis or Crohn’s disease.

[14] Filgotinib is currently in phase II human clinical trials for the treatment of rheumatoid arthritis or Crohn’s disease. Despite the beneficial activities of filgotinib, safety concerns, which include three incidents of serious infection, prompted 1.7% of patients to discontinue the rheumatoid arthritis trial. Thus, there is a continuing need for new (JAK) inhibitors to treat the aforementioned diseases and conditions. Definitions [15] 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.

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

[17] 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 filgotinib 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.

[18] 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).

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

[20] 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).

[21] 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.

[22] 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.

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

[24] 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.

[25] 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.

[26] 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-l,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, 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.

[27] The pharmaceutically acceptable salt may also be a salt of a compound of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base. Exemplary bases include, but are not limited to, hydroxide of alkali metals including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Ci-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.

[28] The compounds of the present invention (e.g., compounds of Formula I or A), 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.

[29] 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.

[30] 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).

[31] “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.

[32] “Substituted with deuterium” refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.

[33] Throughout this specification, a variable may be referred to generally (e.g., "each R") or may be referred to specifically (e.g., R , R , R , 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 [34] The present invention provides a compound of Formula A:

(A), or a pharmaceutically acceptable salt thereof, wherein each R1 is independently hydrogen or deuterium; each R2a is independently hydrogen or deuterium; each R2b is independently hydrogen or deuterium; each R3a is independently hydrogen or deuterium; each R3b is independently hydrogen or deuterium; R4 is hydrogen or deuterium, each R5 is independently hydrogen or deuterium; each R6 is independently hydrogen or deuterium; and each Yla, Ylb, Y2a, Y2b, Y3, Y4, and Y5 is H or D; provided that at least one R or Y is deuterium.

[35] In one embodiment of Formula A, each Yla, Ylb, Y2a, Y2b, Y3, Y4, and Y5 is H.

[36] In certain embodiments of Formula A, at least one of Yla, Ylb, Y2a, Y2b, Y3, Y4, Y5, R1, R2a, R2b, R3a, R3b, R4, R5, or R6 is H. In certain embodiments of Formula A, at least one of Yla, Ylb, Y2a, Y2b, Y3, Y4, and Y5 is H. In certain embodiments of Formula A, at least one of R1, R2a, R2b, R3a, R3b, R4, R5, or R6 is H.

[37] In some embodiments of Formula A, the compound is a compound of Formula F

or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently hydrogen or deuterium; Q is

wherein each R2a is independently hydrogen or deuterium, each R2b is independently hydrogen or deuterium, each R3a is independently hydrogen or deuterium, and each R3b is independently hydrogen or deuterium; Z is

wherein R4 is hydrogen or deuterium, each R5 is independently hydrogen or deuterium, and each R6 is independently hydrogen or deuterium; provided that at least one of R1, R2, R3, R4, R5, and R6 is deuterium.

[38] In certain embodiments of Formula I, at least one of R1, R2a, R2b, R3a, R3b, R4, R5, or R6 is H.

[39] In some embodiments of Formula A or I, each R1 is the same. In one aspect of these embodiments, each R1 is hydrogen. In an alternative aspect of these embodiments, each R1 is deuterium.

[40] In some embodiments of Formula A or I, when each R1 is the same, each R2a is the same, each R2b is the same, each R3a is the same, each R3b is the same, each R5 is the same, and each R6 is the same.

[41] In some embodiments of Formula A or I, when each R1 is the same, each R2a is hydrogen when each R2b is hydrogen, each R2a is deuterium when each R2b is deuterium, each R3a is hydrogen when each R3b is hydrogen, each R3a is deuterium when each R3b is deuterium, each R5 is hydrogen when each R6 is hydrogen, and each R5 is deuterium when each R6 is deuterium.

[42] In some embodiments of Formula A or I, each R1 is hydrogen. In one aspect of these embodiments, each R1 is hydrogen, each R2a is the same, each R2b is the same, each R3a is the same, each R3b is the same, each R5 is the same, and each R6 is the same. In another aspect of these embodiments, each R1 is hydrogen, each R2a is hydrogen when each R2b is hydrogen, each R2a is deuterium when each R2b is deuterium, each R3a is hydrogen when each R3b is hydrogen, each R3a is deuterium when each R3b is deuterium, each R5 is hydrogen when each R6 is hydrogen, and each R5 is deuterium when each R6 is deuterium.

[43] In some embodiments of Formula A or I, each R1 is deuterium. In one aspect of these embodiments, each R1 is deuterium, each R2a is the same, each R2b is the same, each R3a is the same, each R3b is the same, each R5 is the same, and each R6 is the same. In another aspect of these embodiments, each R1 is deuterium, each R2a is hydrogen when each R2b is hydrogen, each R2a is deuterium when each R2b is deuterium, each R3a is hydrogen when each R3b is hydrogen, each R3a is deuterium when each R3b is deuterium, each R5 is hydrogen when each R6 is hydrogen, and each R5 is deuterium when each R6 is deuterium.

[44] In some embodiments of Formula A or I, R4 is deuterium, each R5 is deuterium, and each R6 is deuterium. In one aspect of these embodiments, R4 is deuterium, each R5 is deuterium, each R6 is deuterium, and each R1 is the same. In one aspect of these embodiments, R4 is deuterium, each R5 is deuterium, each R6 is deuterium, and each R1 is hydrogen. In an alternate aspect of these embodiments, R4 is deuterium, each R5 is deuterium, each R6 is deuterium, and each R1 is deuterium.

[45] In some embodiments of Formula A or I, R4 is deuterium, each R5 is deuterium, each R6 is deuterium, each R1 is the same, each R2a is the same, each R2b is the same, each R3a is the same, and each R3b is the same. In one aspect of these embodiments, R4 is deuterium, each R5 is deuterium, each R6 is deuterium, each R1 is hydrogen, each R2a is the same, each R2b is the same, each R3a is the same, and each R3b is the same. In an alternative aspect of these embodiments, R4 is deuterium, each R5 is deuterium, each R6 is deuterium, each R1 is deuterium, each R2a is the same, each R2b is the same, each R3a is the same, and each R3b is the same.

[46] In some embodiments of Formula A or I, R4 is deuterium, each R5 is deuterium, each R6 is deuterium, each R1 is the same, each R2a is hydrogen when each R2b is hydrogen, each R2a is deuterium when each R2b is deuterium, each R3a is hydrogen when each R3b is hydrogen, and each R3a is deuterium when each R3b is deuterium. In one aspect of these embodiments, R4 is deuterium, each R5 is deuterium, each R6 is deuterium, each R1 is hydrogen, each R2a is hydrogen when each R2b is hydrogen, each R2a is deuterium when each R2b is deuterium, each R3a is hydrogen when each R3b is hydrogen, and each R3a is deuterium when each R3b is deuterium. In an alternative aspect of these embodiments, R4 is deuterium, each R5 is deuterium, each R6 is deuterium, each R1 is deuterium, each R2a is hydrogen when each R2b is hydrogen, each R2a is deuterium when each R2b is deuterium, each R3a is hydrogen when each R3b is hydrogen, and each R3a is deuterium when each R3b is deuterium. 2 3 [47] In some embodiments of Formula A or I, each R is deuterium and each R is 2 3 deuterium. In one aspect of these embodiments, each R is deuterium, each R is 1 2 deuterium, and each R is the same. In one aspect of these embodiments, each R is 3 1 deuterium, each R is deuterium, and each R is hydrogen. In an alternative aspect of 2 3 1 these embodiments, each R is deuterium, each R is deuterium, and each R is deuterium. 2 3 [48] In some embodiments of Formula A or I, each R is deuterium, each R is deuterium, each R1 is the same, each R5 is the same, and each R6 is the same. In one aspect of these embodiments, each R is deuterium, each R is deuterium, each R is hydrogen, each R5 is the same, and each R6 is the same. In an alternative aspect of these embodiments, each R is deuterium, each R is deuterium, each R is deuterium, each R5 is the same, and each R6 is the same. 2 3 [49] In some embodiments of Formula A or I, each R is deuterium, each R is deuterium, each R1 is the same, each R5 is hydrogen when each R6 is hydrogen, and each R5 is deuterium when each R6 is deuterium. In one aspect of these embodiments, each R is deuterium, each R is deuterium, each R is hydrogen, each R is hydrogen when each R6 is hydrogen, and each R5 is deuterium when each R6 is deuterium. In an alternative embodiment of Formula I or A, each R is deuterium, each R is deuterium, each R1 is deuterium, each R5 is hydrogen when each R6 is hydrogen, and each R5 is deuterium when each R6 is deuterium.

[50] In some embodiments of Formula A or I, wherein each R1 is the same, each R2a is the same, each R2b is the same, each R3a is the same, each R3b is the same, each R5 is the same, and each R6 is the same; and the compound is selected from any one of the compounds set forth in the table below:

Table 1: Exemplary Embodiments of Formula I or A

or a pharmaceutically acceptable salt of the foregoing, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

[51] In some embodiments of Formula I or A, any atom not designated as deuterium is present at its natural isotopic abundance.

[52] In some embodiments of a compound of this invention, when R1 is deuterium, the level of deuterium incorporation at each R1 is at least 52.5%. In one aspect, the level of deuterium incorporation is at least 75%. In one aspect, the level of deuterium incorporation is at least 82.5%. In one aspect, the level of deuterium incorporation is at least 90%. In one aspect, the level of deuterium incorporation is at least 95%. In one aspect the level of deuterium incorporation is at least 97%. In one aspect the level of deuterium incorporation is at least 99%.

[53] In some embodiments of a compound of this invention, when R2a or R2b is deuterium the level of deuterium incorporation at each R2a or R2b is at least 52.5%. In one aspect, the level of deuterium incorporation is at least 75%. In one aspect, the level of deuterium incorporation is at least 82.5%. In one aspect, the level of deuterium incorporation is at least 90%. In one aspect, the level of deuterium incorporation is at least 95%. In one aspect the level of deuterium incorporation is at least 97%. In one aspect the level of deuterium incorporation is at least 99%.

[54] In some embodiments of a compound of this invention, when R3a or R3b is deuterium the level of deuterium incorporation at each R3a or R3b is at least 52.5%. In one aspect, the level of deuterium incorporation is at least 75%. In one aspect, the level of deuterium incorporation is at least 82.5%. In one aspect, the level of deuterium incorporation is at least 90%. In one aspect, the level of deuterium incorporation is at least 95%. In one aspect the level of deuterium incorporation is at least 97%. In one aspect the level of deuterium incorporation is at least 99%.

[55] In some embodiments of a compound of this invention, when R4 is deuterium, the level of deuterium incorporation at R4 is at least 52.5%. In one aspect, the level of deuterium incorporation is at least 75%. In one aspect, the level of deuterium incorporation is at least 82.5%. In one aspect, the level of deuterium incorporation is at least 90%. In one aspect, the level of deuterium incorporation is at least 95%. In one aspect the level of deuterium incorporation is at least 97%. In one aspect the level of deuterium incorporation is at least 99%.

[56] In some embodiments of a compound of this invention, when R5 is deuterium, the level of deuterium incorporation at each R5 is at least 52.5%. In one aspect, the level of deuterium incorporation is at least 75%. In one aspect, the level of deuterium incorporation is at least 82.5%. In one aspect, the level of deuterium incorporation is at least 90%. In one aspect, the level of deuterium incorporation is at least 95%. In one aspect the level of deuterium incorporation is at least 97%. In one aspect the level of deuterium incorporation is at least 99%.

[57] In some embodiments of a compound of this invention, when R6 is deuterium, the level of deuterium incorporation at each R6 is at least 52.5%. In one aspect, the level of deuterium incorporation is at least 75%. In one aspect, the level of deuterium incorporation is at least 82.5%. In one aspect, the level of deuterium incorporation is at least 90%. In one aspect, the level of deuterium incorporation is at least 95%. In one aspect the level of deuterium incorporation is at least 97%. In one aspect the level of deuterium incorporation is at least 99%.

[58] In some embodiments of a compound of this invention, when any Y is deuterium, the level of deuterium incorporation at each Y is at least 52.5%. In one aspect, the level of deuterium incorporation is at least 75%. In one aspect, the level of deuterium incorporation is at least 82.5%. In one aspect, the level of deuterium incorporation is at least 90%. In one aspect, the level of deuterium incorporation is at least 95%. In one aspect the level of deuterium incorporation is at least 97%. In one aspect the level of deuterium incorporation is at least 99%.

[59] The present invention also provides deuterated intermediates useful, e.g., in the preparation of the compounds of Formula I or A, and as provided in the Exemplary Schemes.

[60] 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.

[61] 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 [62] A convenient method for synthesizing compounds of Formula I or A is depicted in Scheme 1 below.

[63] Using commercially available reagents and deuterated reagents that can be readily prepared by known methods, compounds of Formula I or A can be prepared with greater than 90% or greater than 95% or greater than 97% or greater than 99% deuterium incorporation at each position designated as D (for example, at positions Yla, Ylb, Y2a, Y2b, Y3, Y4, Y5, R1, R2a, R2b, R3a, R3b, R4, R5, or R6) in Formula I or A, or any appropriate intermediate herein, see below for details).

[64] The synthesis of compounds of Formula I or A may be readily achieved by synthetic chemists of ordinary skill by reference to the Exemplary Synthesis. Relevant procedures analogous to those of use for the preparation of compounds of Formula I or A, and intermediates thereof are disclosed using well known methods in the art disclosed, for instance in U.S. Patent No. 8,088,764 and Menet, C. et al., Journal of Medicinal Chemistry, 57(22), 9323-9342; 2014. 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.

[65] Scheme 1: General Synthesis of Compounds of Formula I or A

Formula A

Reagents and conditions: (a) Et3N; (b) Pd(dppf)Cl2, K2CO3 [66] In a manner analogous to a procedure described in U.S. Patent No. 8,088,764, and by Menet, C. et al., Journal of Medicinal Chemistry, 57(22), 9323-9342; 2014, appropriately deuterated amino- triazolopyridine intermediate (1) is acylated with appropriately deuterated acid chloride intermediate (2) to furnish appropriately deuterated amide intermediate (3). Subsequent Suzuki coupling reaction with appropriately deuterated boron reagent, such as boronate ester intermediate (4) produces appropriately deuterated compounds of Formula A or I.

[67] Use of appropriately deuterated reagents (for example, commercially available reagents or deuterated reagents that can be readily prepared by known methods) allows deuterium incorporation at the Yla, Ylb, Y2a, Y2b, Y3, Y4, Y5, R1, R2a, R2b, R3a, R3b, R4, R5, or R6 positions of intermediates (1), (2), (3) or (4) and Formula I or A , e.g., 90, 95, 97, or 99% deuterium incorporation at any of these positions.

[68] General Synthesis of Compounds of Formula IF

Formula II

Compounds of Formula II are prepared using intermediates depicted in Scheme I, by Suzuki coupling reaction of intermediate (1) and intermediate (4), or by acid hydrolysis of compounds of Formula I or A using HC1, followed by basification with sodium hydroxide in a manner analogous to a procedure described in PCT Publication No. WO2013189771.

[69] Use of appropriately deuterated reagents (for example, commercially available reagents or deuterated reagents that can be readily prepared by known methods) allows deuterium incorporation at the Yla, Ylb, Y2a, Y2b, Y3, Y4, Y5, R2a, R2b, R3a, and R3b positions of intermediates (1) or (4) or Formula II, e.g., 90, 95, 97, or 99% deuterium incorporation at any of these positions.

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

[71] Scheme 2: Preparation of Intermediate (11

Reagents and conditions: (a) Ethyl isothiocyanatoformate; (b) EtN(Pr-i)2, Hydroxylamine hydrochloride.

[72] In a manner analogous to a procedure described in U.S. Patent No. 8,088,764, and by Menet, C. et al., Journal of Medicinal Chemistry, 57(22), 9323-9342; 2014, appropriately deuterated aminopyridine intermediate (5) is treated with ethyl isothiocyanatoformate to furnish corresponding and deuterated thiourea intermediate (6), which is subsequently treated with hydroxylamine in the presence of a base such as diisopropylethylamine at elevated temperature to produce appropriate deuterated triazolo-pyridine intermediate (1). Appropriately deuterated intermediate (5) for use in the preparation of intermediate (1) is prepared as described in Scheme 5 below.

[73] Use of appropriately deuterated reagents (for example, commercially available reagents or deuterated reagents that can be readily prepared by known methods) allows deuterium incorporation at the R4, R5, or R6 positions of intermediates (2), (7), (8) or (9), e.g., 90, 95, 97, or 99% deuterium incorporation at any of these positions.

[74] Appropriately deuterated intermediate (2), for use in the preparation of compounds of Formula I or A according to Scheme 1 may be prepared from corresponding deuterated reagents exemplified in Scheme 3.

[75] Scheme 3: Preparation of Intermediate (2)

Reagents and conditions: (a) SOCI2, Isopropyl alcohol; (b) NaOH, H+; (c) Oxalyl chloride, DMF

[76] In a manner analogous to a procedure described by Yi, J. Et al., Journal of Central South University of Technology (English Edition), 7(2), 81-83; 2000, ringopening of appropriately deuterated γ-butyrolactone intermediate (7) with SOCI2 in the presence of suitable alcohol such as isopropyl alcohol produces appropriately deuterated γ-chlorobutyrate intermediate (8) which after base hydrolysis followed by neutralization with acid, is cyclized to produce appropriately deuterated cyclopropane carboxylic acid intermediate (9). Using a procedure known to anyone skilled in the art, or by analogy to a procedure described by Sugikubo, K. et al., Angewandte Chemie, International Edition, 52(43), 11369-11372; 2013, appropriately deuterated intermediate (9) is treated with halogenation agent such as, oxalyl chloride in the presence of catalytic amounts of DMF to produce appropriately deuterated acid chloride intermediate (2). The following intermediates (7) are commercially available: y-Butyrolactone-d6 (98 atom %D) (7a), y-Butyrolactone-5,5,-d2 (99 atom %D) (7b). Appropriately deuterated intermediates (7c), (7d), (7e), and (7f) are prepared in accordance with a method described in PCT Publication No. WO 2014031840. Intermediate (7g) is prepared according to a procedure described in U.S. Patent

Publication No. 20110257111. Additionally, the following intermediates (9) are commercially available: cyclopropane-ds-carboxylic Acid (98 atom %D) (9a), cyclopropane-1-di-carboxylic Acid (98 atom %D) (9f), and cyclopropane-2,2,3,3-d4-carboxylic Acid (99 atom %D) (9g). Furthermore, cyclopropane-ds-carbonyl chloride (98 atom %D) (2a) is commercially available.

[77] Use of appropriately deuterated reagents (for example, commercially available reagents or deuterated reagents that can be readily prepared by known methods) allows deuterium incorporation at the Yla, Ylb, Y2a, Y2b, R1, R2a, R2b, R3a, or R3b positions of intermediates (10), (11), (12) or (4), e.g., 90, 95, 97, or 99% deuterium incorporation at any of these positions.

[78] Appropriately deuterated intermediate (4), for use in the preparation of compounds of Formula I or A according to Scheme 1 may be prepared from corresponding deuterated reagents exemplified in Scheme 4.

[79] Scheme 4: Preparation of Intermediate (4)

Reagents and conditions: (a) EpN; (b) Bis(pinacolato)diboron, PdCWdppf). CH2CI2, KOAc.

[80] In a manner analogous to a procedure described in U.S. Patent No. 8,193,189, appropriately deuterated amino hydrochloride salt intermediate (11) is alkylated with appropriately deuterated benzyl bromide intermediate (10) in the presence of a base such as EtsN, to furnish appropriately deuterated alkylated arylbromide intermediate (12). Subsequent treatment of intermediate (12) with a boron reagent such as

Bis(pinacolato)diboron under modified procedure of Miyaura, N. et al., J. Org. Chem. 1995,60, 7508-7510, produces appropriately deuterated boronic ester intermediate (4).

[81] Appropriately deuterated intermediate (10) and intermediate (11) for use in the preparation of intermediate (4) are prepared as described in Scheme 6 and Scheme 7 below.

[82] Use of appropriately deuterated reagents (for example, commercially available reagents or deuterated reagents that can be readily prepared by known methods) allows deuterium incorporation at the Y , Y , or Y positions of intermediates (5) or (13), e.g., 90, 95, 97, or 99% deuterium incorporation at any of these positions.

[83] Appropriately deuterated intermediate (5), for use in the preparation of compounds of Formula I or A according to Scheme 1 may be prepared from corresponding deuterated reagents exemplified in Scheme 5.

[84] Scheme 5: Preparation of Intermediate (5)

Reagents and conditions: (a) NH3, H2O

[85] Appropriately deuterated intermediate (5) is prepared in a manner analogous to a procedure described by Zhang, E. et al., Journal of Organic Chemistry, 74(22), 85958603; 2009, by treating dibromopyridine intermediate (13) with aqueous ammonia solution at elevated temperature. 2,6-Dibromopyridine-d3 (98 atom % D) (13a) is commercially available.

[86] Use of appropriately deuterated reagents (for example, commercially available reagents or deuterated reagents that can be readily prepared by known methods) allows deuterium incorporation at the Yla, Ylb, Y2a, Y2b, or R1 positions of intermediates (14a-g), (15), or (10), e.g., 90, 95, 97, or 99% deuterium incorporation at any of these positions.

[87] Appropriately deuterated intermediate (10), for use in the preparation of compounds of Formula I or A according to Scheme 1 may be prepared from corresponding deuterated reagents exemplified in Scheme 6.

[88] Scheme 6: Preparation of Intermediate (10)

Reagents and conditions: (a) 13¾ NaY Zeolite; (b) NBS, 40W Lamp.

[89] In a manner analogous to a procedure described by Wacker, S. et al., Journal of the American Chemical Society, 133(32), 12386-12389; 2011, appropriately deuterated toluene intermediate (14) is treated with bromine in the presence of zeolite catalyst, furnishing aryl bromide intermediate (15), which is subsequently treated with NBS to produce appropriately deuterated benzyl bromide intermediate (10).

[90] The following intermediates (14) are commercially available: Toluene-dg (99.96 atom % D) (14a), Toluene-α, a, a-d3 (99 atom % D) (14b), Toluene-2,3,4,5,6-ds (98 atom % D) (14c), Toluene-3,5-d2 (98 atom % D) (14d). Intermediate (14e) is prepared in accordance with a prodecure described by Bialecki, J. et al., Journal of Mass Spectrometry, 41(9), 1195-1204; 2006, and, (14f) & (14g) are prepared according to a procedure described by Webster-Gardiner, M. et al., Catalysis Science & Technology, 5(1), 96-100; 2015.

[91] Additionally, 4-Bromobenzyl-d6 bromide (99 atom%D) (10a), and 1-bromo-4-(bromo di-deuteromethyl)benzene (10b) are commercially available.

[92] Use of appropriately deuterated reagents (for example, commercially available reagents or deuterated reagents that can be readily prepared by known methods) allows deuterium incorporation at the R2a, R2b, R3a, or R3b positions of intermediates (16), (17), (18a-c), (19), (20), or (11), e.g., 90, 95, 97, or 99% deuterium incorporation at any of these positions.

[93] Appropriately deuterated intermediate (11), for use in the preparation of compounds of Formula I or A according to Scheme 1 may be prepared from corresponding deuterated reagents exemplified in Scheme 7.

[94] Scheme 7: Preparation of Intermediate (11)

Reagents and conditions: (a) DiO-Dioxane, K2CO3, DC1, D2O; (b) L1AID4, NaOH, D2O or L1AIH4, NaOH, H2O; (c) (Boc)20, EtsN; (d) Na2C03, mCPBA, or Oxone; (e) HC1 [95] In a manner analogous to a procedure described in PCT Publication WO 2008070619, commercially available 3,5-Thiomorpholinedione intermediate (16) (or prepared from thiodiglycolic acid, according to a procedure described by Barkenbus, C. et al., Journal of the American Chemical Society, 70, 684-5; 1948) is treated with D2O in dioxane in the presence of a base such as potassium carbonate, followed by neutralization with DC1 in D2O to furnish appropriately deuterated thiomorpholinedione intermediate (17). Subsequent reduction of intermediate (17) using reducing agent such as L1AID4 followed by standard work up using sodium hydroxide in D2O produces appropriately deuterated thiomorpholine intermediate (18). In a manner analogous to procedure described in US 8022059, protection of appropriately deuterated intermediate (18) using protecting group such as di-t-butyl dicarbonate in the presence of triethylamine affords appropriately deuterated Boc protected thio morpholine intermediate (19), which is subsequently oxidized by treating with m-chloroperbenzoic acid or with Oxone (US6362188) to furnish appropriately deuterated Boc protected dioxothiomorpholine intermediate (20). Finally deprotected under standard conditions known in the art or as described in W09850420, produces appropriately deuterated amino hydrochloride salt intermediate (11). By omitting step (a), intermediate (18c) for use in the preparation of corresponding intermediate (11c) is produced directly from intermediate (16).

[96] 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 , R , R , 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.

[97] Additional methods of synthesizing compounds of Formula I or A 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 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.

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

Pharmaceutical Compositions [99] The invention also provides pharmaceutical compositions comprising an effective amount of a compound of Formula I or A (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.

[100] 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.

[101] If required, the solubility and bio availability 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 Bio availability 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.

[102] 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™ 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.

[103] 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).

[104] 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.

[105] 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.

[106] 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.

[107] 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.

[108] 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.

[109] 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.

[110] 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.

[111] 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 bio availability, 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.

[112] 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.

[113] 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.

[114] 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 in the treatment of any of inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL-6.

[115] In one embodiment, the second therapeutic agent is an agent useful in the treatment of rheumatoid arthritis, for example, but not limited to, abatacept, adalimumab, azathioprine, chloroquine, hydroxychloroquine, ciclosporin (Cyclosporin A), D-penicillamine, etanercept, golimumab, infliximab, lefhmomide, methotrexate (MTX), minocycline, rituximab, and sulfasalazine (SSZ). In one embodiment, the second therapeutic agent is methotrexate.

[116] In one embodiment, the second therapeutic agent is an agent useful in the treatment of Crohn’s disease, for example, but not limited to, 5-aminosalicylic acid (5-ASA) formulations, prednisone, immunomodulators such as azathioprine (given as the prodrug for 6-mercaptopurine), methotrexate, infliximab, adalimumab, certolizumab, natalizumab, hydrocortisone.

[117] 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).

[118] 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.

[119] 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.

[120] In one embodiment, an effective amount of a compound of this invention can range from about 0.1 mg to about 500 mg/day. In more specific aspects of this embodiments, an effective amount of a compound of this invention ranges from about 1.0 mg - 400 mg/day, from about 5 mg - 300 mg/day, from about 10 mg - 250 mg/day, from about 20 mg - 200 mg/day, from about 50 mg - 200 mg/day and from about 100 mg - 200 mg/day. Effective dosage amounts may be administered as a single dose once a day, or as split doses administered two, three or four times a day, e.g., 50 mg once per day, or 25 mg twice per day; 100 mg once per day, or 50 mg twice per day; or 200 mg once per day, or 100 mg twice per day.

[121] 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.

[122] 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.

[123] 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 [124] The deuterated compounds are useful for treating any disease or condition beneficially treated by administering a JAK inhibitor, such as a JAK1 or JAK2 inhibitor, such as filgotinib. Examples of such diseases or conditions are treating inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL-6.

[125] As used herein the term ‘inflammatory condition(s)’ refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, allergic airway disease (e.g. asthma, rhinitis), inflammatory bowel diseases (e.g. Crohn's disease, colitis), endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the joints. In one embodiment, the disease is rheumatoid arthritis.

[126] As used herein the term ‘autoimmune disease(s)’ refers to the group of diseases including obstructive airways disease, including conditions such as COPD, asthma (e.g intrinsic asthma, extrinsic asthma, dust asthma, infantily asthma) particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), multiple sclerosis, type I diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. In one embodiment, the disease is Crohn’s disease.

[127] As used herein the term ‘proliferative disease(s)’ refers to conditions such as cancer (e.g. uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g. polycythemia vera, essential thrombocytosis and myelofibrosis), leukemia (e.g. acute myeloid leukaemia and acute lymphoblastic leukemia), multiple myeloma, psoriasis, restenosis, sclerodermitis or fibrosis.

[128] As used herein, the term ‘cancer’ refers to a malignant or benign growth of cells in skin or in body organs, for example but without limitation, breast, prostate, lung, kidney, pancreas, stomach or bowel. A cancer tends to infiltrate into adjacent tissue and spread (metastasise) to distant organs, for example to bone, liver, lung or the brain. As used herein the term cancer includes both metastatic tumor cell types, such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma and types of tissue carcinoma, such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer and uterine leiomyosarcoma.

[129] As used herein the term ‘leukemia’ refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding.

[130] As used herein the term ‘transplantation rejection’ refers to the acute or chronic rejection of cells, tissue or solid organ alio- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases.

[131] As used herein the term ‘diseases involving impairment of cartilage turnover’ includes conditions such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.

[132] As used herein the term ‘congenital cartilage malformation(s)’ includes conditions such as hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, in particular, but without limitation, microtia, anotia, metaphyseal chondrodysplasia, and related disorders.

[133] As used herein the term ‘disease(s) associated with hypersecretion of IL6’ includes conditions such as Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and/or mesangial proliferative glomerulonephritis.

[134] In another embodiment, the invention provides a method of inhibiting JAK1 or JAK2 activity in a cell, comprising contacting a cell with one or more compounds of Formula I or A herein, or a pharmaceutically acceptable salt thereof.

[135] According to another embodiment, the invention provides a method of treating a disease or condition selected from rheumatoid arthritis or Crohn’s disease, 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.

[136] In one particular embodiment, the method of this invention is used to treat rheumatoid arthritis in a subject in need thereof.

[137] In another particular embodiment, the method of this invention is used to treat Crohn’s disease in a subject in need thereof.

[138] 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).

[139] 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 the treatment of any of rheumatoid arthritis or Crohn’s disease. The choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated.

[140] In some embodiments, the combination therapies of this invention include coadministering a compound of Formula I or A and methotrexate to a subject in need thereof. In one aspect of these embodiments, the invention provides a method of treating rheumatoid arthritis, wherein the second therapeutic agent is methotrexate.

[141] 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.

[142] 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.

[143] 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.

[144] In yet another aspect, the invention provides the use of a compound of Formula I or A 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 or A for use in the treatment in a subject of a disease, disorder or symptom thereof delineated herein.

Example 1. Evaluation of Metabolic Stability [145] 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 (MgCh), and dimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich.

[146] 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 MgCF. The diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate. A 10 μι 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 μι aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 μι of ice-cold ACN with internal standard to stop the reactions. The plates are stored at 4 °C for 20 minutes after which 100 μι 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 or A and the positive control, 7-ethoxycoumarin (1 μΜ). Testing is done in triplicate.

[147] Data analysis: The in vitro Lqs for test compounds are calculated from the slopes of the linear regression of % parent remaining (In) vs incubation time relationship. in vitro t y2 = 0.693/k k = -[slope of linear regression of % parent remaining (In) vs incubation time] [148] Data analysis is performed using Microsoft Excel Software.

[149] 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 (14)

1. What is claimed is:

   1. A compound represented by Formula I:

   or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently hydrogen or deuterium; Q is

   wherein each R2a is independently hydrogen or deuterium, each R2b is independently hydrogen or deuterium, each R3a is independently hydrogen or deuterium, and each R3b is independently hydrogen or deuterium; Z is

   wherein R4 is hydrogen or deuterium, each R5 is independently hydrogen or deuterium, and each R6 is independently hydrogen or deuterium; provided that at least one of R1, R2, R3, R4, R5, and R6 is deuterium.
2. 2. The compound of claim 1, wherein each R1 is the same.
3. 3. The compound of claim 1, wherein each R1 is the same, each R2a is the same, each R2b is the same, each R3a is the same, each R3b is the same, each R5 is the same, and each R6 is the same.
4. 4. The compound of claim 3, wherein each R1 is the same, each R2a is hydrogen when each R2b is hydrogen, each R2a is deuterium when each R2b is deuterium, each R3a is hydrogen when each R3b is hydrogen, each R3a is deuterium when each R3b is deuterium, each R5 is hydrogen when each R6 is hydrogen, and each R5 is deuterium when each R6 is deuterium.
5. 5. The compound of any one of claims 1-4, wherein each R1 is hydrogen.
6. 6. The compound of any one of claims 1-4, wherein each R1 is deuterium.
7. 7. The compound of any one of claims 1-6, wherein R4 is deuterium, each R5 is deuterium, and each R6 is deuterium.
8. 8. The compound of any one of claims 1-7, wherein each R is deuterium and each R is deuterium.
9. 9. The compound of any of the preceding claims, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
10. 10. The compound of claim 1, wherein each R1 is the same, each R2a is the same, each R2b is the same, each R3a is the same, each R3b is the same, each R5 is the same, and each R6 is the same; and the compound is selected from any one of the compounds set forth in the table below:

    or a pharmaceutically acceptable salt of the foregoing, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
11. 11. A pharmaceutical composition, comprising a compound of any of claims 1-10, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
12. 12. A method of inhibiting JAK1 or JAK2 activity in a cell, comprising contacting the cell with a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 11.
13. 13. A method of treating rheumatoid arthritis or Crohn’s disease, the method comprising administering to a subject in need of such treatment an effective amount of a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 11.
14. 14. A compound of Formula A:

    or a pharmaceutically acceptable salt thereof, wherein each R1 is independently hydrogen or deuterium; each R2a is independently hydrogen or deuterium; each R2b is independently hydrogen or deuterium; each R3a is independently hydrogen or deuterium; each R3b is independently hydrogen or deuterium; R4 is hydrogen or deuterium; each R5 is independently hydrogen or deuterium; each R6 is independently hydrogen or deuterium; and each of Yla, Ylb, Y2a, Y2b, Y3, Y4, and Y5 is independently hydrogen or deuterium; provided that at least one R or Y is deuterium.