KR102070361B1 - Deuterated cftr potentiators - Google Patents

Abstract

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본 발명은 또한 본 발명의 화합물을 포함하는 조성물 및 CFTR 강화제(potentiator)를 투여함으로써 유익하게 치료되는 질병 및 질환의 치료 방법에 있어서 상기 조성물의 용도를 제공한다.The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof:

.
The invention also provides the use of the composition in a method of treating a disease and disorder that is beneficially treated by administering a composition comprising a compound of the invention and a CFTR potentiator.

Description

Deuterated CFC Enhancer {DEUTERATED CFTR POTENTIATORS}

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof:

.

.

In addition, the present invention also provides the use of the composition in a method comprising the composition comprising the compound of the invention and a method of treating diseases and disorders which are beneficially treated by administering a CFTR potentiator.

Background of the Invention

Many current medicines suffer from low absorption, distribution, metabolic and / or excretion (ADME) properties that prevent their widespread use or limit their use in certain applications. Low ADME properties are also a major contributor to drug candidate failure in clinical trials. Although formulation techniques and prodrug strategies can be used in some cases to enhance certain ADME properties, these methods often fail to address the underlying ADME problems present in many drugs and drug candidates. One such problem is the rapid metabolism that causes too many drugs to be removed from the body too rapidly, which would otherwise be very effective in treating the disease. A possible solution to rapid drug clearance is frequent or high doses to reach plasma levels of sufficiently high drugs. However, this creates a number of potential treatment problems, such as low patient compliance with the dosing regimen, side effects exacerbated by higher dosages, and increased treatment costs. Rapidly metabolized drugs can also expose the patient to unwanted toxic or reactive metabolites.

Another ADME limit that affects many medications is the formation of toxic or biologically reactive metabolites. As a result, some patients receiving drugs may experience toxicities, or the safe administration of these drugs may be limited so that patients receive a suboptimal amount of active agent. In certain cases, modifying the interval of administration or formulation method may help to reduce clinical side effects, but the formation of such unwanted metabolites is usually inherent in the metabolism of the compound.

In some selected cases, the metabolic inhibitor will be coadministered with the drug being removed too rapidly. This is the case for the protease inhibitor class of drugs used to treat HIV infection. The FDA recommends taking these drugs in common with ritonavir, an inhibitor of the cytochrome P450 enzyme 3A4 (CYP3A4), an enzyme responsible for their metabolism (see Kempf, DJ et al., Antimicrobial agents and chemotherapy, 1997, 41 (3): 654-60). However, ritonavir causes side effects and increases the pill burden in HIV patients who already need to take different combinations of drugs. Likewise, the CYP2D6 inhibitor quinidine has been added to dextrometophan for the purpose of reducing the rapid CYP2D6 metabolism of dextrometophan in the treatment of pseudobulbar affect. Quinidine, however, has unwanted side effects that greatly limit its use in potential multidrug combination therapies (Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56 (6 Pt 1): 659-67; and www.accessdata. see FDA labeling for quinidine at fda.gov).

In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy to reduce drug clearance. Inhibition of the activity of the CYP enzyme may affect the rate of metabolism and clearance of other drugs metabolized by the same enzyme. CYP inhibition can cause other drugs to accumulate in the body at toxic levels.

A potentially attractive strategy for improving the metabolic properties of drugs is the deuterium modification. In this method, attempts are made to reduce the formation of unwanted metabolites by slowing the CYP-mediated metabolism of the drug or by substituting one or more hydrogen atoms for deuterium atoms. Deuterium is a safe and stable nonradioactive isotope of hydrogen. Compared with hydrogen, deuterium forms stronger bonds with carbon. In certain cases, the increased binding strength given by deuterium positively affects the ADME properties of the drug, creating the possibility for improved drug efficacy, stability and / or tolerance. At the same time, since the size and shape of deuterium are essentially the same as the size and shape of hydrogen, the substitution of hydrogen by deuterium does not affect the biochemical efficacy and selectivity of the drug compared to the original species containing only hydrogen. It is not expected.

Over the past 35 years, the effect of deuterium substitution on metabolic rate has been reported for very low rates of approved drugs (eg, 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 (See “Fisher”)). The results were varied and unpredictable. For some compounds, deuteration is in vivo ( in in vivo ) resulting in reduced metabolic clearance. For other compounds, there was no change in metabolism. While other compounds showed increased metabolic clearance. The diversity of deuterium effects has also led experts to question or dismiss deuterium modifications as viable drug design strategies to suppress adverse metabolism (see Foster's page 35 and Fisher's page 101).

The effect of deuterium modification on the metabolic properties of the drug is unpredictable even when deuterium atoms are incorporated at known positions of metabolism. Only by actually preparing and testing deuterated drugs can one find out how and if the metabolic rate of deuterated drug differs from that of its non-deuterated counterparts. See, for example, Fukuto et al. (J. Med. Chem., 1991, 34, 2871-76). Many drugs have several positions that can be metabolized. The degree of deuteration needed to see the location (s) required for deuterium substitution and the effect on metabolism will be different for each drug, if any.

The present invention relates to novel derivatives of ivacaftor and pharmaceutically acceptable salts thereof. The invention also provides the use of a composition comprising a compound of the invention and a method of treating a disease and disorder that is beneficially treated by administering a CFTR (cystic fibrosis transmembrane conductance regulator) enhancer. do.

Iva, also known as VX-770, also known as the chemical name N- (2,4-di-tert-butyl-5-hydroxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxamide Kafter acts as a CFTR enhancer. Phase 3 clinical trial results of VX-770 in cystic fibrosis patients with more than one copy of the G551D-CFTR mutations are associated with lung function, sweat-induced chloride levels, potential for lung exacerbation and body weight. In other key indicators of the disease, including, a marked level of improvement was shown. VX-770 is also in phase 2 clinical trial with VX-809 (CFTR corrector) for oral treatment of cystic fibrosis patients with the more common ΔF508-CFTR mutation. VX-770 was approved by the FDA in 2006 and 2007 for fast track and rare drug designation, respectively.

Despite the beneficial activity of VX-770, there is a continuing need for new compounds to treat the aforementioned diseases and disorders.

Justice

The term “treat” reduces, inhibits, attenuates, lowers, arrests or stabilizes the development or progression of a disease (eg, a disease or disorder described herein), alleviates the severity of a disease, or a symptom associated with a disease. It means to improve.

"Disease" means any condition or disorder that impairs or interferes with the normal functioning of a cell, tissue or organ.

It will be appreciated that some variation in natural isotopic abundance occurs depending on the origin of the chemical used in the synthesis in the synthesized compound. Thus, the preparation of VX-770 will inherently contain a small amount of deuterated isomers. Despite these variations, naturally rich concentrations of stable hydrogen and carbon isotopes are small and immaterial relative to the level of stable isotope substitution of the compounds of the present invention. See, for example, Wada, E et al., Seikagaku, 1994, 66:15; See Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119: 725.

Any atom not specifically designated as a particular isotope in the compounds of the present invention is considered to represent any stable isotope of that atom. Unless stated otherwise, when a position is specifically designated as “H” or “hydrogen”, it is understood that the position has hydrogen in its isotope composition in its natural abundance. Also, unless specifically stated otherwise, if a position is specifically designated “D” or “deuterium”, it is understood that the position has deuterium at an abundance of 3000 times more than the natural abundance of deuterium, which is 0.015% (ie, 45%). Deuterium incorporation).

As used herein, the term “isotopic enrichment factor” refers to the ratio between the natural and isotope abundance of a particular isotope.

In another embodiment, the compounds of the present invention comprise 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), for each designated deuterium atom, 5000 or more (75% deuterium), 5500 or more (82.5% deuterium), 6000 or more (90% deuterium), 6333.3 or more (95% deuterium), 6466.7 or more (97% deuterium), 6600 or more (99% deuterium) Incorporation) or at least 6633.3 (incorporation of 99.5% deuterium).

The term “isotopologue” refers to a species whose chemical structure differs only in certain compounds of the invention from their isotopic composition.

The term “compound” when referring to a compound of the present invention refers to a collection of molecules having the same chemical structure except that there may be isotopic variations among the constituent atoms of the molecules. Thus, it will be apparent to those skilled in the art that a compound represented by a particular chemical structure containing the indicated deuterium atoms will also contain a smaller amount of isotopes with hydrogen atoms at one or more designated deuterium positions in the structure. The relative amount of such isomers in the compounds of the present invention will depend on several factors including the isotope purity of the deuteration reagents used to make the compounds and the efficiency of incorporation of deuterium in the various synthetic steps used to prepare the compounds. . However, as mentioned above, the relative amounts of all such isomers will be less than 49.9% of the compound. In other embodiments, the relative amounts of all such isomers are 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 Will be less than 0.5%.

The invention also provides salts of the compounds of the invention. Salts of the compounds of the invention are formed between the acidic and basic groups of the compound, such as amino functional groups, or are formed between the basic and acidic groups of the compound, such as carboxyl functional groups. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

As used herein, the term “pharmaceutically acceptable” refers to ingredients that are suitable for use in contact with human or other mammalian tissue without undue toxicity, irritation, allergic reactions, etc., within the scope of reasonable medical judgment, Proportional to the profit / risk ratio. “Pharmaceutically acceptable salt” means any non-toxic salt that can provide a compound of the invention, directly or indirectly when administered to a recipient. A “pharmaceutically acceptable counterion” is an ionic portion of a salt that is not toxic when released from salt upon administration to a recipient.

Acids commonly used to prepare pharmaceutically acceptable salts include, but are not limited to, inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, iodine hydrochloric acid, sulfuric acid and phosphoric acid, as well as para-toluenesulfonic acid, salicylic acid, tartaric acid, Byartaric 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, carbonate Organic acids such as succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts are therefore sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromide, iodides, Acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, subberate, sebacate, puma Latex, maleate, butyne-1,4-dioate, hexyn-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 salts made with mineral acids such as hydrochloric acid and hydrobromic acid, and salts made with organic acids, especially maleic acid.

As used herein, the term “stable compound” refers to compounds that have sufficient stability to allow their preparation, and they are intended for the purposes described herein (eg, formulation to therapeutics, intermediates used in the production of therapeutic compounds, isolation The integrity of the compound is maintained for a sufficient period of time to be useful for possible or storage intermediate compounds, the treatment of a disease or condition in response to a therapeutic agent).

“D” and “d” both refer to deuterium. "Stereoisomer" refers to both enantiomers and diastereomers. “Tut” and “t” refer to tertiary, respectively. “US” refers to the United States.

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

Throughout the specification, variables may be referred to generally (eg, "each R") or may be specifically referred to (eg, R ¹ , R ² , R ^3, etc.). Unless otherwise indicated, when a variable is referred to generally, it is considered to include all specific embodiments of that particular variable.

Therapeutic compound

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Wherein each X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ is independently hydrogen or deuterium;

Each Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ and Y ⁶ is independently CH ₃ or CD ₃ ;

If each Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ and Y ⁶ is CH ₃ , then X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ At least one of is deuterium.

In one embodiment, X ¹ , X ² , X ³ and X ⁴ are the same. In one aspect of this embodiment, X ⁶ and X ⁷ are the same. In one aspect of this embodiment, Y ¹ , Y ² and Y ³ are the same. In one aspect of this embodiment, Y ⁴ , Y ⁵ and Y ⁶ are the same. In one embodiment of this aspect, Y ¹ , Y ² and Y ³ are the same. In a more particular embodiment, X ⁶ and X ⁷ are the same.

In one embodiment, each of Y ¹ , Y ² and Y ³ is the same. In one aspect of this embodiment, each Y ⁴ , Y ⁵ and Y ⁶ is the same. In one embodiment of this aspect, X ⁶ and X ⁷ are the same.

In one embodiment, at least one of C (Y ¹ ) (Y ² ) (Y ³ ) and C (Y ⁴ ) (Y ⁵ ) (Y ⁶ ) is C (CD ₃ ) ₃ .

In one embodiment, Y ¹ , Y ² and Y ³ are CD ₃ . In one aspect of this embodiment, Y ⁴ , Y ⁵ and Y ⁶ are CH ₃ . In another embodiment, Y ⁴ , Y ⁵ and Y ⁶ are CD ₃ . In one aspect of this embodiment, Y ¹ , Y ² and Y ³ are CH ₃ . In yet another embodiment, Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are CD ₃ . In yet another embodiment, Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are CH ₃ . In one aspect of any embodiment where Y ¹ , Y ² and Y ³ are CD ₃ , X ⁶ is hydrogen. In one embodiment of this aspect, X ⁷ is hydrogen. In another embodiment of this aspect, X ⁷ is deuterium. In one aspect of any embodiment where Y ¹ , Y ² and Y ³ are CD ₃ , X ⁶ is deuterium. In one embodiment of this aspect, X ⁷ is hydrogen. In another embodiment of this aspect, X ⁷ is deuterium. In one embodiment of embodiments where Y ¹ , Y ² and Y ³ are CD ₃ and X ⁶ is deuterium, the isotope enrichment factor of X ⁶ is at least 4000 (in 60% deuterium incorporation), such as at least 4500 (in 67.5% deuterium incorporation), For example 5000 or more (75% deuterium) but not to more than 5500 (82.5% deuterium incorporation).

In one aspect of any embodiment where Y ¹ , Y ² and Y ³ are CH ₃ , Y ⁴ , Y ⁵ and Y ⁶ are CD ₃ and X ⁶ is hydrogen. In one embodiment of this aspect, X ⁷ is hydrogen. In another embodiment of this aspect, X ⁷ is deuterium. In one aspect of any embodiment where Y ¹ , Y ² and Y ³ are CH ₃ , Y ⁴ , Y ⁵ and Y ⁶ are CD ₃ and X ⁶ is deuterium. In one embodiment of this aspect, X ⁷ is hydrogen. In another embodiment of this aspect, X ⁷ is deuterium. In one aspect of any embodiment where Y ¹ , Y ² and Y ³ are CD ₃ , Y ⁴ , Y ⁵ and Y ⁶ are CD ₃ and X ⁶ is deuterium. In one embodiment of this aspect, X ⁷ is hydrogen. In another embodiment of this aspect, X ⁷ is deuterium. In one embodiment of the embodiment where Y ¹ , Y ² and Y ³ are CH ₃ , Y ⁴ , Y ⁵ and Y ⁶ are CD ₃ , and X ⁶ is deuterium, the isotope concentration factor of X ⁶ is at least 4000 (60% Deuterium incorporation), such as at least 4500 (67.5% deuterium incorporation), such as at least 5000 (75% deuterium), but not to exceed 5500 (82.5% deuterium incorporation).

In one aspect of the embodiment wherein Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are CH ₃ , X ⁶ is deuterium. In ^one embodiment of this embodiment wherein Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are CH ₃ and X ⁶ is deuterium, the isotope concentration factor of X ⁶ is at least 4000 (incorporating 60% deuterium) Such as at least 4500 (67.5% deuterium incorporation), such as at least 5000 (75% deuterium) but does not exceed 5500 (82.5% deuterium incorporation).

In one embodiment, each of Y ⁴ , Y ⁵ and Y ⁶ is the same. In one aspect of this embodiment, X ⁶ and X ⁷ are the same.

In any one of the foregoing embodiments, aspects, or embodiments, X ⁵ is hydrogen. In another embodiment, X ⁵ is deuterium.

In one embodiment, the compound of formula I is a compound of one of the compounds of Table 1 or a pharmaceutically acceptable salt thereof:

Compound # X ^One X ² X ³ X ⁴ X ⁵ X ⁶ X ⁷ Y ^One Y ² Y ³ Y ⁴ Y ⁵ Y ⁶ 100 D D D D D D D CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ 101 H H H H D H H CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ 102 H H H H D H H CD ₃ CD ₃ CD ₃ CH ₃ CH ₃ CH ₃ 103 H H H H D H H CH ₃ CH ₃ CH ₃ CD ₃ CD ₃ CD ₃ 104 H H H H D H H CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ 105 H H H H H H H CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ 106 H H H H H H H CD ₃ CD ₃ CD ₃ CH ₃ CH ₃ CH ₃ 107 H H H H H H H CH ₃ CH ₃ CH ₃ CD ₃ CD ₃ CD ₃

Any atom not designated as deuterium in the above formula is present in the natural isotope abundance.

In one embodiment, the compound of Formula I is a compound of one of the compounds of Table 2 below or a pharmaceutically acceptable salt thereof:

Compound # X ¹ X ² X ³ X ⁴ X ⁵ X ⁶ X ⁷ Y ¹ Y ² Y ³ Y ⁴ Y ⁵ Y ⁶ 110 H H H H H D D CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ 111 H H H H D D D CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ 112 H H H H D D D CD ₃ CD ₃ CD ₃ CH ₃ CH ₃ CH ₃ 113 H H H H D D D CH ₃ CH ₃ CH ₃ CD ₃ CD ₃ CD ₃ 114 H H H H D D D CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ 115 H H H H H D D CD ₃ CD ₃ CD ₃ CH ₃ CH ₃ CH ₃ 116 H H H H H D D CH ₃ CH ₃ CH ₃ CD ₃ CD ₃ CD ₃ 117 D D D D D D D CD ₃ CD ₃ CD ₃ CH ₃ CH ₃ CH ₃ 118 D D D D D D D CH ₃ CH ₃ CH ₃ CD ₃ CD ₃ CD ₃ 119 D D D D D H H CD ₃ CD ₃ CD ₃ CH ₃ CH ₃ CH ₃ 120 D D D D D H H CH ₃ CH ₃ CH ₃ CD ₃ CD ₃ CD ₃ 121 H H H H H H D CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ 122 H H H H H H D CD ₃ CD ₃ CD ₃ CH ₃ CH ₃ CH ₃ 123 H H H H H H D CH ₃ CH ₃ CH ₃ CD ₃ CD ₃ CD ₃ 124 H H H H H D H CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ 125 H H H H H D H CD ₃ CD ₃ CD ₃ CH ₃ CH ₃ CH ₃ 126 H H H H H D H CH ₃ CH ₃ CH ₃ CD ₃ CD ₃ CD ₃

Any atom not designated as deuterium in the above formula is present in the natural isotope abundance.

In one embodiment, the compound of formula I is a compound of one of the compounds of the following Table 3 or a pharmaceutically acceptable salt thereof:

Compound # X ^One X ² X ³ X ⁴ X ⁵ X ⁶ X ⁷ Y ^One Y ² Y ³ Y ⁴ Y ⁵ Y ⁶ 301 D D D D D H H CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ 302 D D D D D D D CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ 303 D D D D D H H CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ 304 D D D D H D D CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ 305 D D D D H H H CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ CD ₃ 306 D D D D H D D CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ 307 D D D D H H H CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ 308 H H H H H D D CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃

Any atom not designated as deuterium in the above formula is present in the natural isotope abundance.

In yet another set of embodiments, any atom not designated as deuterium in any of the embodiments, embodiments or embodiments set forth above is present in a natural isotope abundance.

Synthesis of the compounds of formula (I) can be readily accomplished by synthetic chemists of ordinary skill with reference to the exemplary synthesis and examples described herein. Similar useful suitable methods for the preparation of compounds of formula (I) and intermediates thereof are disclosed, for example, in WO 2007075946, WO 2011019413, WO 2010019239, WO 2007134279, WO 2007079139 and WO # 2006002421, the disclosures of which are disclosed herein Is incorporated by reference.

Such methods are known in the art using the corresponding deuteration and other isotope-containing reagents and / or intermediates to optionally synthesize the compounds described herein, or to introduce isotope atoms into the chemical structure. It can be implemented by applying standard synthesis protocols.

Exemplary Synthesis

A convenient method of synthesizing the compound of formula I is shown in Scheme 1 below.

Scheme 1:

The compound of formula (I ) is formulated as HATU ( N, N, N ' , N' -tetramethyl- O- (7-azabenzo) in the presence of DIEA ( N, N'-diisopropylethylamine), as shown in Scheme 1. Triazol-1-yl) uronium hexafluorophosphate) can be prepared via the coupling of A and B.

The deuterated intermediates of type A (Scheme 1) include Singh, A .; Van Goor, F .; Worley, FJ III; Knapp, T. Compounds Useful in CFTR Assays and Methods Therewith, similar to WO 2007075946 A1 July 5, 2007, the entire disclosures of which are incorporated herein by reference.

Scheme 2:

As shown in Scheme 2, heating the mixture of aniline 1 in the presence of malonate derivative 2 provides a suitably deuterated ((phenylamino) methylene) malonate and its polyphosphoric acid in the presence of POCl ₃ . Subsequent exposure following ester hydrolysis provides carboxylic acid A. In Scheme 2, X is hydrogen or deuterium. In one embodiment, X, X ¹ , X ² , X ³ and X ⁴ are the same.

Exemplary compounds for use in Scheme 2 include embodiments of compound (1) wherein X, X ¹ , X ² , X ³ and X ⁴ , each commercially available from Aldrich, are deuterium; And the method described in Scheme 2a when X ⁵ is hydrogen by using an embodiment of 3 wherein X ⁵ is deuterium (Parham, WE; Reed, LJ Org. Syn., 1948, 28, 60, the disclosures herein Embodiments of Compound (2) wherein X ⁵ is deuterium (available from CDDN isotops), prepared analogously). As shown in Scheme 2a, an appropriately deuterated type 2 (ethoxymethylene) malonate in the presence of acetic anhydride is obtained by reaction of diethylmalonate with an appropriately deuterated type 3 triethylorthoformate. Can be prepared and promoted by ZnCl ₂ .

Deuterated intermediates of type B (Scheme 1) can be prepared analogously to Singh, A., et al., As described above in Scheme 3.

Scheme 3:

As shown in Scheme 3, exposure to nitric acid following the protection of type 4 di-tertbutylphenol with methyl chloroformate results in the formation of nitro-methylcarbonate intermediates. Palladium catalytic reduction of the nitro group followed by subsequent carbonate hydrolysis eventually yields type B aminophenols. In Scheme 3, X 'is hydrogen or deuterium. In one embodiment, X ', X ⁶ and X ⁷ are the same.

In Scheme 3, the compound of formula B can be treated with DCl or HCl to obtain compounds of formula B 'or B', respectively, having a high incorporation ratio of deuterium or hydrogen at the X ⁶ position, respectively. This method is effective regardless of whether B to X ⁶ is hydrogen or deuterium. Thus, if X ⁶ in B is hydrogen or deuterium at a lower level of isotope purity than desired, treatment of DCl provides B '; If X ⁶ in B is deuterium, treatment with HCl provides B ”. Both treatments are shown in the following two equations:

The method can be used to exchange H for D or D for H and to enrich the compound of Formula B having a low level of isotope purity (0-85%) at X ⁶ . This method facilitates the preparation of compounds of formula B 'or B "containing> 95% D or> 95% H at the position corresponding to X ⁶ , respectively. B ′ or B ″ may then be treated with A according to Scheme 1 to provide compounds of formula I wherein X ⁶ is deuterium or hydrogen, respectively.

The deuterated intermediates of type 4 (Scheme 3) are shown in Sun, Y., as shown in Schemes 4a-4d; Tang, N. Huaxue Shiji 2004, 26, 266-268, which is incorporated herein by reference in its entirety.

Scheme 4a:

Scheme 4b:

Scheme 4c:

Scheme 4d:

As shown in Schemes 4a-4d, type 4 ditertbutylphenol is suitably deuterated phenol (phenol, 4-tert-butyl phenol or 2-tert butylphenol) and Friedel-Craft alkylation of d9-tert butylchloride. It can be prepared through. Embodiments of compound (4) that can be obtained as shown in Scheme 4 are exemplary compounds for use in Scheme 3. In embodiments 4a, 4b, 4c and 4d of Scheme 4, any atom not designated as deuterium is present in its natural isotopic abundance. In Scheme 4, both compound 5 and compound 6 are commercially available (CDN isotops).

The specific methods and compounds shown above are not intended to be limiting. Chemical structures in the schemes herein are represented by the same variable name (ie, R ¹ , R ² , R ^3, etc.) in the chemical group definition (moiety, atom, etc.) of the corresponding position in the formula of the compound of the present application. Represents properly defined variables. The suitability of chemical groups in the structure of compounds for use in the synthesis of other compounds is within the knowledge of those skilled in the art.

Additional methods of synthesizing the compounds of Formula I and their synthetic precursors, including methods in routes not explicitly shown in the schemes herein, are within the methods of chemists of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful for the synthesis of suitable compounds are known in the art, for example Larock R, Comprehensive Organic Transformations, VCH Publishers (1989); Greene, TW et al., Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); Fieser, L et al., Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); And those described in Paquette, L, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

Combinations of substituents and variables contemplated by the present invention are only combinations that result in the formation of stable compounds.

Composition

The present invention also provides an effective amount of a compound of Formula I (eg, including any formula herein) or a pharmaceutically acceptable salt of said compound; And it provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier. The carrier (s) is “acceptable” in the sense of being compatible with the other ingredients of the formulation, and in the case of pharmaceutically acceptable carriers it is not harmful to its recipient in the amounts used in medicine.

Pharmaceutically acceptable carriers, adjuvants and carriers that can be used in the pharmaceutical compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, Buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated plant fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colo Silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycols and wool fats this month.

If desired, the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions can be increased by methods well known in the art. One method involves the use of lipid excipients in the formulation. “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. See Wiley-Interscience, 2006.

Another known method of increasing bioavailability is optionally formulated with poloxamers such as LUTROL ^™ and PLURONIC ^™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. The use of amorphous forms of the compounds of the present invention. U.S. Patent 7,014,866; And US published patents 20060094744 and 20060079502.

The pharmaceutical compositions of the present invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and dermal) administration. In certain embodiments, compounds of formulas herein are administered transdermally (eg, using transdermal patches or iontophoretic techniques). Other formulations may conveniently be presented in unit dose form, such as in tablets, sustained release capsules and liposomes, and may be prepared by any method 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).

The method of preparation includes the step of bringing into association the molecule to be administered with a component such as a carrier which constitutes one or more accessory ingredients. Generally, the compositions are prepared by associating the active ingredient uniformly and closely with the liquid carrier, liposomes or finely divided solid carriers, or both, and if necessary, shaping the product.

In certain embodiments, the compound is administered orally. Compositions of the 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; Powder or granules; Suspensions or solutions in aqueous or non-aqueous liquids; Oil-in-water liquid emulsions; Water-in-oil liquid emulsions; Packaging in liposomes; Or as bolus or the like. Soft gelatin capsules may be useful to contain such suspensions and will beneficially increase the rate of compound absorption.

For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also generally added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is administered orally, the active ingredient is mixed with emulsifiers and suspending agents. If desired, any sweetening and / or flavoring and / or coloring agents may be added.

Compositions suitable for oral administration include lozenges comprising the active ingredient in a flavor based, usually sucrose and acacia or tragacanth; And pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, bacteriostats and solutes that make the formulation isotonic with the blood of the subject recipient; And aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be contained in disposable or multi-use containers such as sealed ampoules and vials and stored in a lyophilized state requiring only the addition of a sterile liquid carrier such as water for injection immediately before use. have. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

Such injection solutions may be, for example, in the form of sterile injectable aqueous or oily suspensions. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable carriers and solvents that may be used are mannitol, water, Ringer's solution and isotonic saline solution. Sterile, nonvolatile oils are also commonly used as solvents or dispersion media. For this purpose any bland fixed oil can be used including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for the preparation of injectables as pharmaceutically-acceptable natural oils such as olive oil or castor oil, especially in their polyoxyethylated versions. Such oil solutions or suspensions may also contain long chain alcohol diluents or dispersants.

The pharmaceutical composition of the present invention may be administered in the form of suppositories for rectal administration. Such compositions may be prepared by mixing the compounds of the present invention with suitable non-irritating excipients which are solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical composition of the present invention may be administered by nasal aerosol or inhalant. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art and using benzyl alcohol or other suitable preservatives, absorption promoters that increase bioavailability, fluorocarbons and / or other solubilizers or dispersants known in the art. It can be prepared as a solution in saline. See, eg, Rabinowitz JD and Zaffaroni AC, US Pat. No. 6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of the invention is particularly useful when the desired treatment involves a site or organ that is readily accessible by topical application. When applied topically to the skin, the pharmaceutical composition should be formulated in a suitable ointment containing the active ingredient suspended or dissolved in the carrier. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oils, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying waxes and water. Alternatively, the pharmaceutical composition may be formulated into a suitable lotion or cream containing the active compound suspended or dissolved in the carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of the invention may also be applied locally to the lower intestine by rectal suppository formulation or in a suitable enema formulation. Topical-transdermal patches and iontophoretic administration are also included in the present invention.

Application of the subject therapy will be topical for administration to the site of interest. Various techniques, such as injection, catheter use, trocars, projectiles, pluronic gels, stents, sustained release drug release polymers or other devices that provide in vivo access to provide compositions to a subject at a site of interest Can be used for

In another embodiment, the composition of the present invention further comprises a second therapeutic agent. The second therapeutic agent can be selected from any compound or therapeutic agent known to demonstrate or demonstrate beneficial properties when administered with a compound having the same activity mechanism as VX-770.

Preferably, the second therapeutic agent is cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolytic deficiency, such as protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, such as familial hypercholesterolemia, type 1 Chylomicronemia, mubetalipoproteinemia, lysosomal accumulation diseases such as I-cell disease / Pseudo-Hurler, mucopolysaccharide, Sandhof / Tey-Sachs disease, Krigler-Nazar type II, Multiple endocrine / hyperinsulinemia, diabetes mellitus, laron dwarfism, myeloperoxidase deficiency, primary hypothyroidism, melanoma, glycanosis CDG type 1, hereditary emphysema, neonatal hyperthyroidism, osteopenia, hereditary Hypofibrosis, ACT deficiency, diabetes insipidus (DI), neurofissil DI, neprogenic DI, Shaco-Marithus syndrome, Perijaeus-Mertzvacher disease, neurodegenerative diseases, for example Major Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive nuclear palsy, peak disease, several polyglutamine neurological disorders such as Huntington, ataxia type I, spinal cord atrophy, hypotrophic nucleus cholangiotrophic atrophy And muscular dystrophy atrophy, as well as cavernous encephalopathy, such as hereditary Creutzfeldt-Jakob disease, Fabry's disease, Stroy'sler-Scheinker's disease, COPD, dry eye syndrome, and Sjogren's syndrome.

In one embodiment, the second therapeutic agent is an agent useful for the treatment of cystic fibrosis.

In one embodiment, the second therapeutic agent is VX-809 (Lumacaptor) or VX-661.

In another embodiment, the present invention provides separate formulations of a compound of the invention with one or more of the foregoing second therapeutic agents, wherein the compound and the second therapeutic agent are associated with each other. As used herein, the term “associated with each other” is readily apparent that separate formulations are packaged together or otherwise attached to one another so that separate formulations are sold and administered together (within less than 24 hours, continuously or simultaneously). It means load.

In the pharmaceutical composition of the present invention, the compound of the present invention is present in an effective amount. As used herein, the term “effective amount” means an amount sufficient to treat a target disorder when administered in an appropriate dosage form.

Dose correlations in animals and humans (mg / m ² ) Body surface based) Freireich et al., Cancer Chemother. Rep. 1966, 50: 219. Body surface area can be approximately determined from the height and weight of the subject. See, eg, Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY, 1970, 537.

In one embodiment, an effective amount of a compound of the invention may range from about 0.02 to 2500 mg per therapeutic agent. In more specific embodiments, the range is about 0.2 to 1250 mg or about 0.4 to 500 mg, or most specifically 2 to 250 mg per therapeutic agent. Therapeutic agents are usually administered 1-2 times daily. In one embodiment, the compound of the present invention is administered twice daily in an amount of 50 to 300 mg each time. In one embodiment, the compound of the present invention is administered once daily in an amount of 100-500 mg. In the above embodiments, the compound is optionally administered with a second agent. Examples of second agents include CFTR correctors such as lumacaptor or VX-661. In some embodiments in which the compound is optionally administered with the second agent, the amount of the compound is administered twice daily at 100 mg to 300 mg each time, such as 150 mg to 250 mg each time. In another embodiment in which the compound is optionally administered with the second agent, the amount of the compound is administered three times daily at 100 mg to 300 mg each time, such as 150 mg to 250 mg each time.

An effective amount, as will be appreciated by those skilled in the art, is co-existing with other therapeutic treatments, such as the diseases to be treated, the severity of the disease, the route of administration, the sex, age and general health of the subject, excipients used, the use of other agents It will also depend on the availability and the judgment of the treating physician.

For pharmaceutical compositions comprising a second therapeutic agent, the effective amount of the second therapeutic agent is about 20% to 100% of the dose normally used in a monotherapy regime using only that agent. Preferably, the effective amount is about 70% to 100% of the usual monotherapy dose. Common monotherapy doses of the second therapeutic agent are well known in the art. See, for example, 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 reference is incorporated herein by reference in its entirety.

Some of the aforementioned second therapeutic agents are expected to work synergistically with the compounds of the present invention. If this action occurs, it will allow to reduce the effective amount of the second therapeutic agent and / or the compound of the present invention to the amount necessary for monotherapy. This has the advantage of minimizing the toxic side effects of both the second treatment and the compounds of the present invention, synergistic improvements in efficacy, increased convenience of administration or use and / or reduced total cost of compound preparation or formulation.

How to treat

In another embodiment, the present invention provides a method of enhancing the activity of CFTR in an infected cell comprising contacting the infected cell with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

According to another embodiment, the present invention provides a method of treating a disease beneficially treated by VX-770 in a subject in need thereof comprising administering to the subject an effective amount of a compound or composition of the invention. do. In one embodiment, the subject is a patient in need of such treatment. Such diseases include cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, hemocoagulation-fibrinolytic deficiency, such as protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, such as familial hypercholesterolemia, type 1 kilomicronemia, no Beta-lipoproteinemia, lysosomal accumulation diseases such as I-cell disease / caustic, mucopolysaccharide, sandhof / Tey-Sachs disease, Krigler-Nazar type II, multiple endocrine disease / hyperinsulinemia, diabetes mellitus , Laron dwarfism, myeloperoxidase deficiency, primary hypothyroidism, melanoma, glycanosis CDG type 1, hereditary emphysema, neonatal hyperthyroidism, osteopenia, hereditary hypofibrosis, ACT deficiency, diabetes insipidus (DI ), Neuropisil DI, nephrogenic DI, shaco-maritus syndrome, perizaeus-merzvacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's Disease, amyotrophic lateral sclerosis, progressive nuclear palsy, peak disease, some polyglutamine neurological disorders, such as Huntington, ataxia type I, myelomyelodystrophic atrophy, alveolar nucleus cholangiotrophic atrophy and dystonia, as well as cavernous Cerebroencephalopathy, such as hereditary Creutzfeldt-Jakob disease, Fabry's disease, Stroy'sler-Scheinker's disease, COPD, dry eye syndrome and Shogran syndrome.

In one embodiment, the compounds of the present invention are used to treat cystic fibrosis in a subject, such as a subject in need thereof. In one embodiment, the compounds of the invention are used to treat COPD in a subject, such as a subject in need thereof. In embodiments of the foregoing embodiments, the compound is administered by nasal aerosol or inhalation. In another embodiment of the foregoing embodiments, the compound is administered orally.

In another embodiment, any of the above methods of treatment further comprise co-administering one or more second therapeutic agents to the subject in need thereof. The selection of the second therapeutic agent can be made from any second therapeutic agent known to be useful for co-administration with VX-770. The choice of second therapeutic agent also depends on the particular disease or condition to be treated. Examples of second therapeutic agents that may be used in the methods of the present invention are those previously disclosed for use in combination compositions comprising a compound of the present invention and a second therapeutic agent.

In particular, the combination therapies of the present invention comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof and a second compound in a subject in need thereof (with a specific second therapeutic agent indicated in the inset phrase after Co-administering a therapeutic agent.

As used herein, the term “co-administered” means that the second therapeutic agent is part of a single dosage form (eg, a composition of the invention comprising a compound of the invention and a second therapeutic agent as described above), or isolated, multiple dosage forms. As used in conjunction with a compound of the present invention. Alternatively, additional agents may be administered before, continuously or after administration of the compounds of the present invention. In such a multi-drug combination therapy, both the compounds of the invention and the second therapeutic agent (s) can be administered by conventional methods. Administration of a composition of the invention comprising both a compound of the invention and a second therapeutic agent to a subject separates the same therapeutic agent, any other second therapeutic agent, or any compound of the invention into the subject at different times during the course of treatment. It does not make it impossible to administer.

Effective amounts of these second therapeutic agents are well known in the art, and guidance for administration is given in the 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 books. However, it is within the scope of those skilled in the art to determine the optimum effective amount range of the second therapeutic agent.

In one embodiment of the invention when the second therapeutic agent is administered to a subject, the effective amount of a compound of the invention is less than the effective amount when the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than the effective amount when no compound of the invention is administered. In this way, unwanted side effects associated with high dosages of each agent will be minimized. Other potential benefits will be apparent to those skilled in the art (improved dosing without limitation and / or reduced drug price).

In yet another aspect, the invention provides, alone or in combination with one or more of the aforementioned second therapeutic agents, in the manufacture of a medicament as a single composition or as a separate formulation for the treatment or prevention of the aforementioned diseases, disorders or symptoms in a subject. , Compounds of formula (I) or pharmaceutically acceptable salts thereof. Another aspect of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease, disorder or condition of a subject described herein.

Example

Example  One.  N- (2,4-di- ( Tert Butyl d ₉ ) -3,6- d ₂ -5- Hydroxyphenyl ) -4-oxo-1,4-dihydroquinoline-3- Carboxamide  Synthesis of (Compound 110).

Compound 110 was prepared as shown in Scheme 5 below.

Scheme 5. Preparation of Compound 110

Step 1. 2,4-Di- ( tert -butyl- d ₉ ) -3,5,6- d ₃ -phenol (4a). Intermediate 4a was prepared using tert-butyl chloride-d ₉ instead of tert-butylchloride according to the procedure described for the synthesis of 2,4-di-tert-butyl-3,5-d ₂ -phenol (Kurahashi , T .; Hada, M .; Fujii, HJ Am. Chem. Soc. 2009, 131, 12394-12405): Phenol-d ₆ (459 mg, 4.59 mmol, 99 in 1,2-dichloroethane (10.0 mL) ReBr (CO) ₅ (19.0 mg) in a solution of atomic% D, Sigma Aldrich) and tert-butyl chloride-d ₉ (2.50 mL, 23.0 mmol, 98 atomic% D, Cambridge Isotop Laboratories, Inc.) , 0.0459 mmol) was added. The reaction mixture was stirred at 85 ° C. for 15 h, at which time additional tert-butyl chloride-d ₉ (2.50 mL, 23.0 mmol, 98 atomic% D, Cambridge Isotop Laboratories, Inc.) and ReBr ( CO) ₅ (19.0 mg, 0.0459 mmol) was added. Stirring was continued at 85 ° C. for 2 hours, the mixture was cooled to room temperature, concentrated in vacuo and purified by column chromatography (SiO ₂ , 30% CH ₂ Cl ₂ / heptane) 4a (0.789 g, 76% yield). ) As a light yellow oil. MS (ESI) 228.1 [(M + H) ⁺ ].

Step 2. Preparation of 2,4-di- (tert-butyl-d ₉₎ -3,5,6- d _3-phenyl methyl Carbonate (20). To a solution of 4a (2.72 g, 12.0 mmol), triethylamine (3.33 mL, 23.9 mmol) and N, N-dimethylaminopyridine (73.0 mg, 0.598 mmol) in CH ₂ Cl ₂ (30.0 mL) was methyl at 0 ° C. Chloroformate (1.38 mL, 17.9 mmol) was added. The reaction mixture was stirred at rt for 15 h and then diluted with 10% ethyl acetate / heptane and filtered through a silica plug. The silica plug was then washed with additional 10% ethyl acetate / heptane. The filtrates were combined and concentrated in vacuo to afford 20 (2.40 g, 70% yield) without purification as light yellow oil.

Step 3. 2,4-Di- ( tert -butyl- d ₉ ) -3,6- d ₂ -5-nitrophenol (21). To a solution of 20 (2.40 g, 8.41 mmol) in sulfuric acid (1.00 mL) was added dropwise a 1: 1 mixture of sulfuric acid and nitric acid (2.00 mL) at 0 ° C. The reaction mixture was then stirred for 2 hours at room temperature and then slowly added to ice water with vigorous stirring. The resulting slurry was extracted with ethyl acetate (3 × 100 mL), the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to amber oil containing a mixture of regio-isomers. oil). This crude oil was then added to MeOH (50 mL) and KOH (1.54 g, 27.5 mmol) was added. The reaction mixture was stirred at rt for 2 h and then acidified to pH = 2 with concentrated HCl. The resulting solution was extracted with diethyl ether (3 × 100 mL), dried (MgSO ₄ ), filtered and concentrated. The residue was then purified by column chromatography (SiO ₂ , 0-5% ethyl acetate / heptane) to give 21 (526 mg, 23%) as a light yellow solid. MS (ESI) 270.3 [(M ⁻ H) ⁻ ].

Step 4. 5-Amino-2,4-di- ( tert -butyl- d ₉ ) -3,6- d ₂ -phenol (22) . A solution of 21 (526 mg, 1.94 mmol) and ammonium formate (489 mg, 7.75 mmol) in ethanol (25.0 mL) was heated to the point of reflux. At this time, a small amount of 10% Pd / C (250 mg, 50% humidity) was added and the reaction mixture was stirred at reflux for 2 hours. The mixture was cooled to rt, diluted with THF, filtered through Celite® and concentrated in vacuo to give 22 (473 mg, 100%) as a tan solid. MS (ESI) 242.4 [(M + H) ⁺ ].

Step 5. N- (2,4-Di- ( tert -butyl- d ₉ ) -3,6- d ₂ -5 -hydroxyphenyl ) -4-oxo-1,4 -dihydroquinoline- 3- car Voxamide (Compound 110). 22 (250 mg, 1.04 mmol), 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (23, purchased from Matrix Scientific, 98.0 mg, 0.518 mmol) and N, N in DMF (5.00 mL) To a solution of diisopropylethylamine (181 μL, 1.04 mmol) was added HATU (197 mg, 0.518 mmol). The reaction mixture was stirred at rt for 3 h and then diluted with saturated NaHCO ₃ and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with water (3 × 20 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue obtained was purified by column chromatography (SiO ₂ , 0-70% ethyl acetate / heptane) to give compound 110 (77.0 mg, 36% yield) as a white solid. ¹ H NMR (d ₆ -DMSO, 400 MHz): δ 12.87 (br s, 1H), 11.80 (s, 1H), 9.18 (s, 1H), 8.86 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.76 (t, J = 8.2 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.10 (s, 0.2H) ^* ; MS (ESI) 413.5 [(M + H) ⁺ ]. ^* 7.10 ¹ H NMR signals at ppm is 2 refers to deuterium incorporation of about 80% in one of the two deuterated aryl position. Absence of signal at 7.20 ppm and 1.37 ppm means high levels of incorporation (> 95%) at remaining deuterated sites.

Example  2.  N- (2- ( Tert -Butyl) -4- ( Tert Butyl d ₉ ) -6-d-5- Hydroxyphenyl ) -4-oxo-1,4- Dihydroquinoline -3- Carboxamide  Synthesis of (Compound 125).

Compound 125 was prepared as shown in Scheme 6 below.

Scheme 6. Preparation of Compound 125

Step 1. 2- ( tert -butyl- d ₉ ) -4- ( tert -butyl) -6-d-phenol (7). 4-tert-butyl phenol (3.43 g, 22.7 mmol) and tert-butyl alcohol-d10 (3.00 mL, 31.8 mmol, 98 atomic% D, Cambridge Isotop Laboratories, Inc.) in dichloromethane (40.0 mL) ) Was added D ₂ SO ₄ (1.50 mL, 99.5 atomic% D, Sigma-Aldrich). The reaction was stirred at rt for 15 h before diluted with water and extracted with dichloromethane (3 x 100 mL). The organic layers were mixed, washed with saturated NaHCO ₃ , dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The oil obtained was purified by column chromatography (SiO ₂ , 0-15% ethyl acetate / heptane) to give 7 (4.04 g, 83% yield) as a clear oil. ¹ H NMR (d ₆ -DMSO, 400 MHz) δ 9.04 (s, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.98 (dd, J = 3.8, 2.5 Hz, 1H), 6.67 (d, J = 8.3 Hz, 0.3H), 1.22 (s, 10H).

Step 2. 2- ( tert -butyl- d ₉ ) -4- ( tert -butyl) -6-d- phenyl methyl Carbonate (8). To a solution of 7 (4.04 g, 18.8 mmol), triethylamine (5.24 mL, 37.6 mmol) and N, N-dimethylaminopyridine (115 mg, 0.940 mmol) in CH ₂ Cl ₂ (40.0 mL) was methyl at 0 ° C. Chloroformate (2.17 mL, 28.2 mmol) was added. The reaction was stirred at rt for 15 h, and further triethylamine (1.30 mL, 9.33 mmol) and methyl chloroformate (0.550 mL, 7.15 mmol) were added. After stirring for an additional 1 hour, the reaction was diluted with 10% ethyl acetate / heptane and filtered through a silica plug. The silica plug was then washed with additional 10% ethyl acetate / heptane. The filtrate was mixed and concentrated in vacuo to give 8 (4.69 g, 91% yield) that was passed over without purification as a pale yellow oil. ¹ H NMR (d ₆ -DMSO, 400 MHz) δ 7.33 (d, J = 2.4 Hz, 1H), 7.30-7.20 (m, 1H), 7.06 (d, J = 8.5 Hz, 0.3H), 3.84 (d , J = 0.7 Hz, 3H), 1.28 (s, 9H).

Step 3. 2- ( tert -butyl- d ₉ ) -4- ( tert -butyl) -6-d-5-nitro-phenol (9). To a solution of 8 (4.69 g, 17.2 mmol) in sulfuric acid (2.00 mL) was added dropwise a 1: 1 mixture of sulfuric acid and nitric acid (4.00 mL) at 0 ° C. The reaction was then stirred at room temperature for 2 hours and then slowly added to ice water with vigorous stirring. The resulting slurry was extracted with ethyl acetate (3 × 100 mL) and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give amber oil containing a mixture of regioisomers. This crude oil was then added to MeOH (100 mL) and KOH (3.50 g) was added. The reaction was stirred at rt for 2 h and then acidified to pH = 2 with concentrated HCl. The resulting solution was extracted with diethyl ether (3 × 100 mL), dried (MgSO ₄ ), filtered and concentrated. The residue was then purified by column chromatography (SiO ₂ , 0-5% ethyl acetate / heptane) to give 9 (1.33 g, 30%) as a pale yellow solid. MS (ESI) 260.2 [(M ⁻ H) ⁻ ].

Step 4. 5-Amino-2- ( tert -butyl- d ₉ ) -4- ( tert -butyl) -6-d-phenol (10). A solution of 9 (1.33 g, 5.11 mmol) and ammonium formate (1.29 g, 20.4 mmol) in ethanol (60.0 mL) was heated to reflux. At this time, a small amount of 10% Pd / C (650 mg, 50% wet) was added and the reaction was continued stirring at reflux for 2 hours. The reaction was then cooled to rt, diluted with THF, filtered through Celite® and concentrated in vacuo to give 10 (1.19 g, 100%) as a pink solid. MS (ESI) 232.3 [(M + H) ⁺ ].

Step 5. N- (2- ( tert -butyl) -4- ( tert -butyl- d ₉ ) -6-d-5 -hydroxyphenyl ) -4-oxo-1,4-di hydroquinolin- 3 -carboxamide 125. 10 (892 mg, 3.87 mmol), 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (11, purchased from Matrix Scientific, 366 mg, 1.93 mmol) and N, N- in DMF (20.0 mL) To a solution of diisopropylethylamine (674 μL, 3.87 mmol) was added HATU (734 mg, 1.93 mmol). The reaction was stirred at rt for 3 h and then diluted with saturated NaHCO ₃ and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with water (3 × 20 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue obtained was purified by column chromatography (SiO ₂ , 0-70% ethyl acetate / heptane) to give 125 (277 mg, 36% yield) as a white solid. ¹ H NMR (d ₆ -DMSO, 400 MHz) δ 12.88 (s, 1H), 11.81 (s, 1H), 9.19 (s, 1H), 8.86 (s, 1H), 8.32 (dd, J = 8.1, 1.4 Hz, 1H), 7.86-7.77 (m, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.51 (s, 1H), 7.15 (s, 1H), 7.09 (s, 0.3H) ^* , 1.37 (s, 9H); MS (ESI) 403.3 [(M + H) ⁺ ]. ^* The ¹ H NMR at 7.09 ppm signal indicates an approximate 70% deuterium incorporation at one of the two aryl position.

Example  3.   N- (2- ( Tert -Butyl) -4- ( Tert Butyl d ₉ ) -5- Hydroxyphenyl ) -4-oxo-1,4-di Hydroquine Nolin-3- Carboxamide  Synthesis of (Compound 106).

Compound 106 was prepared as shown in Scheme 7 below.

Scheme 7. Preparation of Compound 106

Step 1. 5-Amino-2- ( tert -butyl- d ₉ ) -4- ( tert -butyl) -phenol (12). Compound 10 (298 mg, 1.29 mmol), prepared as described in Example 2, was dissolved in 5M HCl in 2-propanol (20 mL) and the reaction stirred at room temperature for 15 hours. The reaction was then concentrated in vacuo and put back in 5M HCl in 2-propanol (20 mL). After stirring for an additional 15 hours at room temperature, the reaction was concentrated in vacuo and diluted with saturated aqueous sodium bicarbonate (100 mL). The obtained aqueous solution was extracted with dichloromethane (3 x 50 mL). The organic layers were mixed, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give 12 (240 mg, 81%) as a pink solid. ¹ H NMR (d6-DMSO, 400 MHz) δ 8.62 (s, 1H), 6.83 (s, 1H), 6.08 (s, 1H), 1.27 (s, 9H).

Step 2. N- (2- ( tert -butyl) -4- ( tert -butyl- d ₉ ) -5 -hydroxyphenyl ) -4-oxo-1,4-di hydroquinolin- 3 -carboxamide (106). 12 (240 mg, 1.04 mmol), 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (11, purchased from Matrix Scientific, 99 mg, 0.521 mmol) and N, N- in DMF (6.00 mL) To a solution of diisopropylethylamine (181 μL, 1.04 mmol) was added HATU (198 mg, 0.521 mmol). The reaction was stirred at rt for 3 h and then diluted with saturated NaHCO ₃ and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with water (3 × 20 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue obtained was purified by column chromatography (SiO ₂ , 0-70% ethyl acetate / heptane) to give 106 (80 mg, 38% yield) as a white solid. ¹ H NMR (d ₆ -DMSO, 400 MHz) δ 12.88 (s, 1H), 11.81 (s, 1H), 9.19 (s, 1H), 8.86 (s, 1H), 8.32 (dd, J = 8.1, 1.4 Hz, 1H), 7.86-7.77 (m, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.51 (s, 1H), 7.15 (s, 1H), 7.09 (s, 1H), 1.37 (s , 9H) .; MS (ESI) 402.3 [(M + H) ⁺ ].

Example  4.  N- (2,4-di- ( Tert Butyl d ₉ ) -5- Hydroxyphenyl ) -4-oxo-1,4- Dihydroquinoline -3- Carboxamide  Synthesis of (Compound 105).

Compound 105 was prepared as shown in Scheme 5 below.

Scheme 8. Preparation of Compound 105

Step 1. 2,4,6- d ₃ - phenol - OD (32). Phenol (20.0 g, 212 mmol) was added to a 3.5M solution of DCl in D ₂ O (200 mL) in a sealed tube. The mixture was then stirred at 140 ° C. for 72 hours, then cooled to room temperature and extracted with CH ₂ Cl ₂ (3 × 100 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give a pale pink solid (19.2 g, 93% yield). ¹ H NMR (d ₆ -DMSO, 400 MHz) δ 9.34 (s, 0.22H, OH), 7.15 (s, 2H), 6.76 (m, 0.14H). (The peak at 6.72 ppm represents hydrogen atoms at the 2,4 and 6 positions, thus an integration of 0.14 means that the material obtained has a deuterium incorporation of ˜95% at these positions. )

Step 2. 2-d-4,6- bis (1,1,1,3,3,3- d ₆ 2- (methyl - d ₃₎ propan-2-yl) phenol (33). D in a solution of 32 (2.08 g, 21.2 mmol) and tert-butyl alcohol-d10 (5.00 mL, 53.0 mmol, 98 atomic% D, Cambridge Isotop Laboratories, Inc.) in dichloromethane (40.0 mL) ₂ SO ₄ (1.71 mL, 99.5 atomic% D, Sigma-Aldrich) was added. The reaction was stirred at rt for 15 h before diluted with water and extracted with dichloromethane (3 x 100 mL). The organic layers were mixed, washed with saturated NaHCO ₃ , dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The oil obtained was purified by column chromatography (SiO ₂ , 0-15% ethyl acetate / heptane) to give 33 (1.45 g, 30% yield) as a clear oil. ¹ H NMR (d ₆ -DMSO, 400 MHz) δ 9.03 (s, 1H), 7.11 (d, J = 2.5 Hz, 1H), 6.98 (td, J = 4.1, 2.5 Hz, 1H), 6.67 (d, J = 8.3 Hz, 0.5H), 1.28 (s, 0.18H), 1.17 (s, 0.21H). (The peak at 6.67 ppm, integrating 0.5 H, means isotope erosion to approximately 50% D in the 2-position during the reaction process. Peaks at 1.28 and 1.17 ppm represent the hydrogen content of the t-butyl group, thus Integration of 0.18 and 0.21 means approximately 98% D incorporation in both cases.)

Step 3. methyl (2-d-4,6- bis ( 1,1,1,3,3,3- d 6 -2- ( methyl - d ₃₎ - propan-2-yl) phenyl) carbonate (34 ). To a solution of 33 (1.45 g, 6.43 mmol), triethylamine (2.24 mL, 16.1 mmol) and N, N-dimethylaminopyridine (40.0 mg, 0.322 mmol) in CH ₂ Cl ₂ (15.0 mL) at 0 ° C. Methyl chloroformate (0.990 mL, 12.9 mmol) was added. The reaction was stirred at rt for 15 h, then diluted with 10% ethyl acetate / heptane and filtered over a plug of silica. The silica plug was then washed with additional 10% ethyl acetate / heptane. The filtrates were mixed and concentrated in vacuo to give 34 (1.78 g, 98% yield) that was passed over without purification as a pale yellow oil.

Step 4. 2-d-4,6- bis (1,1,1,3,3,3- d ₆ 2- (methyl - d ₃₎ propan-2-yl) -3-nitro-phenol (35) . To a solution of 34 (1.78 g, 6.28 mmol) in sulfuric acid (1.00 mL) was added dropwise a 1: 1 mixture of sulfuric acid and nitric acid (2.00 mL) at 0 ° C. The reaction was then stirred at room temperature for 2 hours and then slowly added to ice water with vigorous stirring. The resulting slurry was extracted with ethyl acetate (3 × 100 mL) and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give amber oil containing a mixture of regioisomers. This crude oil was then added to MeOH (20 mL) and KOH (664 mg, 11.8 mmol) was added. The reaction was stirred at rt for 2 h and then acidified to pH = 2 with concentrated HCl. The resulting solution was extracted with diethyl ether (3 × 100 mL), dried (MgSO ₄ ), filtered and concentrated. The residue was then purified by column chromatography (SiO ₂ , 0-5% ethyl acetate / heptane) to give 35 (319 mg, 19%) as a light yellow solid. MS (ESI) 269.3 [(M ⁻ H) ⁻ ].

Step 5. 3-Amino -2-d-4,6- bis (1,1,1,3,3,3- d ₆ 2- (methyl - d ₃₎ propan-2-yl) phenol (36) . A solution of 35 (319 mg, 1.18 mmol) and ammonium formate (298 mg, 4.72 mmol) in ethanol (20.0 mL) was heated to reflux. At this time, a small amount of 10% Pd / C (160 mg, 50% humidity) was added and the reaction was continued stirring at reflux for 2 hours. The reaction was cooled to rt, diluted with THF, filtered through Celite® and concentrated in vacuo to give 36 (279 mg, 98%) as a tan solid. MS (ESI) 241.3 [(M + H) ⁺ ].

Step 6. 3-Amino-4, 6-bis (1,1,1,3,3,3- d ₆ 2- (methyl - d ₃₎ propan-2-yl) phenol (37). Compound 36 (279 mg, 1.16 mmol) was dissolved in 5M HCl in 2-propanol (20 mL) and the reaction was stirred at rt for 15 h. The reaction was then concentrated in vacuo and put back in 5M HCl in 2-propanol (20 mL). After stirring for an additional 15 hours at room temperature, the reaction was concentrated in vacuo and diluted with saturated aqueous sodium bicarbonate (100 mL). The obtained aqueous solution was extracted with dichloromethane (3 x 50 mL). The organic layers were mixed, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give 37 (255 mg, 91%) as a pink solid. MS (ESI) 240.3 [(MH-H) ⁺ ].

Step 7. N- (2,4- bis (1,1,1,3,3,3- d ₆ -2- (methyl - d ₃₎ propan-2-yl) -5-hydroxyphenyl) -4 -Oxo - 1,4 -dihydroquinoline- 3 -carboxamide (105). 37 (255 mg, 1.06 mmol), 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (purchased from Matrix Scientific, 100 mg, 0.532 mmol) and N, N-diiso in DMF (6.00 mL) To a solution of propylethylamine (185 μL, 1.06 mmol) was added HATU (202 mg, 0.532 mmol). The reaction was stirred at rt for 3 h and then diluted with saturated NaHCO ₃ and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with water (3 × 20 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue obtained was purified by column chromatography (SiO ₂ , 0-70% ethyl acetate / heptane) to give 105 (92 mg, 42% yield) as a white solid. ¹ H NMR (d ₆ -DMSO, 400 MHz) δ 12.88 (s, 1H), 11.81 (s, 1H), 9.19 (s, 1H), 8.86 (s, 1H), 8.32 (dd, J = 8.1, 1.5 Hz, 1H), 7.86-7.69 (m, 2H), 7.51 (ddd, J = 8.2, 6.7, 1.4 Hz, 1H), 7.14 (s, 1H), 7.10 (s, 1H), 1.32 (s, 0.2H ), 1.30 (s, 0.18 H). (The peaks at 1.32 and 1.30 ppm represent the hydrogen content of the t-butyl group, so integration of 0.20 and 0.18 means approximately 98% D incorporation for both.) MS (ESI) 411.4 [(M + H ) ⁺ ].

Example  5a. Compound 110-Human CYP3A4 Supersomes ( Supersomes ) ^TM Metabolic stability assessment.

Supersomes ^TM Assay . 7.5 mM standard solutions of test compounds, compound 110 and ibacaptor were prepared in DMSO. The 7.5 mM standard solution was diluted to 50 mM in acetonitrile (ACN). Human CYP3A4 super jomseu ^TM 0.1 (pH 7.4) containing MgCl ₂ in 3 mM to [1000 pmol / mL, BD Zen test ^TM Products and Services's (BD Gentest ^TM Products and Services) purchased from] M potassium phosphate buffer in 62.5 pmol Dilute to / mL. Diluted supersomes were added three times to the wells of a 96-well polypropylene plate. A 10 mL aliquot of 50 mM test compound was added to the supersomes and the mixture was pre-heated for 10 minutes. The reaction was started by the addition of pre-heated NADPH solution. The final reaction volume was 0.5 mL and contained 50 pmol / mL CYP3A4 Supersomes ^™ , 1.0 mM test compound, and 2 mM NADPH, and 3 mM MgCl ₂ in 0.1 M potassium phosphate buffer at pH 7.4. The reaction mixtures were incubated at 37 ° C. and 50 mL aliquots were removed at 0, 5, 10, 20 and 30 minutes and added to a 96-well plate containing 50 mL of ice cold ACN and internal standards. The reaction was stopped. The plates were stored at 4 ° C. for 20 minutes, after which 100 mL of water was added to the wells of the plate before centrifugation to pellet precipitated proteins. The supernatants were transferred to another 96-well plate and many remaining parent samples were analyzed by LC-MS / MS using the Applied Bio-systems API 4000 mass spectrometer.

Data analysis: in vitro of test compounds vitro) half-life (t _1/2 values) were calculated from the slope of the linear regression for the incubation time between LN (% parent remaining samples):

In vitro t _½ = 0.693 / k, where k = [slope of linear regression of remaining mother sample (ln) versus incubation time]

FIG. 1 shows a graph of the ratio of parent compounds remaining over time for Compound 110 and ibacaptor in human cytochrome P450-specific Supersomes ™. to increase the ratio (% Δ) in the t _1/2 and the average value t _1/2 is shown in Table 4.

Table 4 shows that Compound 110 had a 55% longer half-life than ibacaptor in the analysis.

Example  5b. Compound 105 and 106-human CYP3A4 Supersomes ^TM Metabolic stability assessment.

Supersomes ^TM Assay. 7.5 mM standard solutions of test compounds, compounds 105, 106 and ibacaptor were prepared in DMSO. The 7.5 mM standard solution was diluted to 50 mM in acetonitrile (ACN). Human CYP3A4 super jomseu ^TM was diluted [1000 pmol / mL, BD Zen test ^TM's Products and services purchased from a] to 62.5 pmol / mL in 0.1 M potassium phosphate buffer of pH 7.4 containing 3 mM of MgCl _2. Diluted supersomes were added three times to the wells of a 96-well polypropylene plate. A 10 mL aliquot of 50 mM test compound was added to the supersomes and the mixture was pre-heated for 10 minutes. The reaction was started by the addition of pre-heated NADPH solution. The final reaction volume was 0.5 mL and contained 50 pmol / mL CYP3A4 Supersomes ^™ , 1.0 mM test compound, and 2 mM NADPH, and 3 mM MgCl ₂ in 0.1 M potassium phosphate buffer at pH 7.4. The reaction mixtures were incubated at 37 ° C. and 50 mL aliquots were removed at 0, 5, 10, 20 and 30 minutes and added to a 96-well plate containing 50 mL of ice cold ACN and internal standards. The reaction was stopped. The plates were stored at 4 ° C. for 20 minutes, after which 100 mL of water was added to the wells of the plate before centrifugation to pellet precipitated proteins. The supernatants were transferred to another 96-well plate and many remaining parent samples were analyzed by LC-MS / MS using the Applied Bio-systems API 4000 mass spectrometer.

Data analysis: was calculated from the slope of the linear regression of a test in vitro half-life of the compounds (t _1/2 value) for LN (% parent remaining samples) versus incubation time relationship:

In vitro t _½ = 0.693 / k, where k = [slope of linear regression of remaining mother sample (ln) versus incubation time]

To increase the rate (Δ%) in the human cytochrome P450- specific super jomseu ™ in compounds 105, 106 and Ibanez t _1/2 values for the CAP site, and the mean t _1/2 is shown in Table 5.

Table 5 shows that in the analysis, Compound 106 has 41% longer half-life than ibacaptor and Compound 105 has 49% longer half-life than ibacaptor.

Example  6. In rats  For compounds 105 and 106 Pharmacokinetics  evaluation.

Ibarcaptor, Compound 105 and Compound 106 were administered to rats separately by gavage (PO). Each compound was administered to 3 rats at a dose of 10 mg / kg (N = 3 rats / compound; 9 rats in total in this study). Each compound was formulated with 100% PEG400 at a concentration of 2 mg / mL. Blood samples were collected from each rat at 15 and 30 minutes and post-dose for 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 48 hours and 72 hours. Blood samples were centrifuged to obtain plasma. Plasma samples were analyzed for the concentration of compound administered at each time point using LC-MS / MS. The limit of quantitation for each compound was 1 ng / mL.

Rats of the t _1/2 values for each compound is (as measured by non-compartment analysis using the WinNonlin software) are set forth in Table 6:

Administered compound animal ID t _{One /2}  (time) Iba Captor 1.1 9.03 1.2 12.43 1.3 10.01 Average 10.49 SD 1.75 SE 1.01 CV% 16.70 106 2.1 13.50 2.2 14.28 2.3 11.92 Average 13.24 (+ 26% ^a ) SD 1.20 SE 0.69 CV% 9.10 105 3.1 13.80 3.2 16.33 3.3 14.39 Average 14.84 (+ 42% ^a ) SD 1.32 SE 0.76 CV% 8.90

% relative change in the t _1/2 value of ^a CAP site Ceiba

Table 6 shows that Compound 106 has an average half-life of 26% longer than ibacapter, and Compound 105 has an average half-life of 42% longer than ibacaptor.

Without further description, it is believed that using the foregoing description and exemplary embodiments, those skilled in the art can make and use the compounds of the invention and practice the claimed methods. It is to be understood that the foregoing discussion and examples merely represent a detailed description of any preferred embodiments. It will be apparent to those skilled in the art that various modifications and equivalents may be made without departing from the spirit and scope of the invention.

FIG. 1 shows the proportion of compounds remaining over time for Compound 110 and Ivacaptor of the present invention in human cytochrome P450-specific Supersomes ™.

Claims (16)

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

Formula I
Each of X ¹ , X ² , X ³ , X ⁴ , and X ⁵ is hydrogen;
Each X ⁶ and X ⁷ is hydrogen or deuterium and X ⁶ and X ⁷ are the same;
Each of Y ¹ , Y ² , and Y ³ is CD ₃ ;
Each of Y ⁴ , Y ⁵ , and Y ⁶ is CH ₃ or CD ₃ and Y ⁴ , Y ⁵ , and Y ⁶ are the same;
An isotope enrichment factor (ratio of isotope abundance to natural abundance of a particular isotope) for each designated deuterium is at least 3500. The compound of claim 1, wherein C (Y ⁴ ) (Y ⁵ ) (Y ⁶ ) is C (CD ₃ ) ₃ . The compound of claim 1, wherein any hydrogen atom not designated as deuterium is present in natural isotopic abundance. The compound of claim 1, wherein the compound of formula I is any one of the compounds of the table below or a pharmaceutically acceptable salt thereof:

Any hydrogen atom not designated as deuterium in the above formula is present in the natural isotope abundance. The compound of claim 1, wherein the compound of formula I is a compound of the table below or a pharmaceutically acceptable salt thereof:

Any hydrogen atom not designated as deuterium in the above formula is present in the natural isotope abundance. A compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof; And a pharmaceutically acceptable carrier. 17. A pharmaceutical composition for treating cystic fibrosis. The compound of claim 1, wherein the isotope concentration factor for each designated deuterium is 6000 or greater. The compound of claim 1, wherein the isotope concentration factor for each designated deuterium is at least 6333.3. The compound of claim 1, wherein the isotope concentration factor for each designated deuterium is at least 6466.7.
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