Compositions and methods for generating deuterated compounds

Abstract

This invention is in the field of medicinal chemistry. In particular, the invention relates to methods for generating deuterated compounds. In particular, methods are provided involving formation of D4-formamides via a modified Leuckart-Wallach reaction and subsequently D2-isonitriles, used in conjunction with D1-aldehydes in MCRs to afford products in high yield with no deuterium scrambling.

Description

[0001] COMPOSITIONS AND METHODS FOR GENERATING DEUTERATED COMPOUNDS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] The present application claims priority to U.S. Provisional Application No. 63 / 521,131, filed June 15, 2023, which is incorporated herein by reference in its entirety.

[0004] STATEMENT OF GOVERNMENT SUPPORT

[0005] This invention was made with government support under Grant Nos. MH090878, AG067926, and GM 125920 awarded by National Institutes of Health. The government has certain rights in the invention.

[0006] FIELD OF THE INVENTION

[0007] This invention is in the field of medicinal chemistry. In particular, the invention relates to methods for generating deuterated compounds. In particular, methods are provided involving formation of D4- formamides via a modified Leuckart- Wallach reaction and subsequently D2- isonitriles, used in conjunction with Di -aldehydes in MCRs to afford products in high yield with no deuterium scrambling.

[0008] INTRODUCTION

[0009] Multi-component reactions (MCRs) are one -pot reactions that utilize three or more readily available starting materials.1Typically, MCRs use reactive functional groups such as ketones or aldehydes, carboxylic acids, amines, and isocyanides where these simple building blocks can be utilized to form large libraries of drug-like compounds with synthetic ease.2In recent years use of deuterium in drug discovery has expanded beyond mechanistic and tracer studies to deuterium incorporation in small molecules in attempts to hijack the deuterium kinetic isotope effect to induce longer drug Tl / 2 and greater systemic exposure.3Improved techniques pertaining to the merging of site specific deuterium labeling with the operational friendliness of MCRs through use of deuterated aldehydes and deuterated isocyanides are needed.

[0010] The present invention addresses these needs.

[0011] SUMMARY OF THE INVENTION

[0012] The utility of bio-isosteres is broad in drug discovery and methodology described herein enables Hydrogen-Deuterium exchange design strategies in the most conservative of known bio- isosteric replacements. Thus, D1-aldehydes are employed in 8 multi-component reactions (MCRs) to give diverse arrays of deuterated products. Experiments described herein demonstrate the formation of D4-formamides via a modified Leuckart- Wallach reaction and subsequently D2- isonitriles, used in conjunction with D1-aldehydes in MCRs to afford products in high yield with no deuterium scrambling. Through this technology often metabolically labile benzylic positions are indirectly selectively deuterated through D -isonitrile use and the metabolic soft-spot of several FDA approved drugs via use of D1-aldehydes.

[0013] Accordingly, the invention relates to methods for generating deuterated compounds. In particular, methods are provided involving formation of D4-formamides via a modified Leuckart-Wallach reaction and subsequently D2-isonitriles, used in conjunction with D1- aldehydes in MCRs to afford products in high yield with no deuterium scrambling.

[0014] In certain embodiments, a method for D4-formamide formation via modified Leuckart- Wallach reaction with D2-formic acid via implementation of the reaction described in Scheme 2 is provided.

[0015] In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 3 is provided.

[0016] In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 4 is provided.

[0017] In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 5 is provided.

[0018] In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 6 is provided.

[0019] In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 7 is provided.

[0020] In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 8 is provided.

[0021] In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 9 is provided.

[0022] In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 10 is provided. In a particular embodiment, compounds encompassed within Formula I are provided: (Formula I); including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0023] In some embodiments, R 1 is selected from hydrogen,

[0024] In some embodiments, R2 is selected from hydrogen,

[0025] In some embodiments, R3 is selected from hydrogen, and deuterated hydrogen. In some embodiments, R4 is selected from hydrogen, In a particular embodiment, compounds encompassed within Formula are provided; including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0026] In some embodiments, R5 is selected from hydrogen, deuterated hydrogen,

[0027] In some embodiments, R6 is selected from hydrogen, deuterated hydrogen,

[0028] In some embodiments, R7 is selected from hydrogen, deuterated hydrogen,

[0029] In some embodiments, R6 and R7 combine to form the following chemical moiety: he resulting compound is encompassed within the following formula:

[0030]

[0031] In some embodiments, R9 is hydrogen or deuterated hydrogen.

[0032] In some embodiments, the compound of Formula IIA and IIB is selected from:

[0033]

[0034] In a particular embodiment, compounds encompassed within Formula IIIA IIIB (Formula IIIB); including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0035]

[0036] In some embodiments, Rl l is selected from hydrogen or deuterated hydrogen.

[0037] In some embodiments, the compound of Formula III is selected from: In a particular embodiment, compounds encompassed within Formula IV are provided: (Formula IV); including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0038] In some embodiments, R12 is selected from hydrogen and deuterated hydrogen.

[0039] In some embodiments, R13 is selected from hydrogen , and

[0040] In some embodiments, the compound of Formula IV is selected from:

[0041] In a particular embodiment, compounds encompassed within Formula V are provided: solvates, and / or prodrugs thereof.

[0042] In some embodiments, R14 is selected from hydrogen and deuterated hydrogen.

[0043] In some embodiments, R15 is selected from hydrogen, deuterated hydrogen, In some embodiments, R 16 is selected from hydrogen, deuterated hydrogen,

[0044] 5 In some embodiments, the compound of Formula V is selected from: The compounds of the invention are useful for the treatment, amelioration, or prevention of any type of disorder (e.g., any type of disorder that may be treated, ameliorated, or prevented through administration of a compound of the invention).

[0045] The invention also provides pharmaceutical compositions comprising the compounds of the invention in a pharmaceutically acceptable carrier.

[0046] The invention also provides kits comprising a compound of the invention and instructions for administering the compound to an animal. The kits may optionally contain other therapeutic agents.

[0047] DETAILED DESCRIPTION OF THE INVENTION

[0048] This invention is in the field of medicinal chemistry. In particular, the invention relates to methods for generating deuterated compounds. In particular, methods are provided involving formation of Dr-f rm amides via a modified Leuckart- Wallach reaction and subsequently D2- isonitriles, used in conjunction with D1-aldehydes in MCRs to afford products in high yield with no deuterium scrambling.

[0049] In certain embodiments, a method for Dr-form amide formation via modified Leuckart- Wallach reaction with D2-formic acid via implementation of the reaction described in Scheme 2 is provided.

[0050] In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 3 is provided.

[0051] In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 4 is provided.

[0052] In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 5 is provided.

[0053] In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 6 is provided.

[0054] In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 7 is provided.

[0055] In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 8 is provided.

[0056] In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 9 is provided. In certain embodiments, a method for generating deuterated compounds via implementation of the reaction described in Scheme 10 is provided.

[0057] In a particular embodiment, compounds encompassed within Formula I are provided: (Formula I); including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0058] In some embodiments, R1 is selected from hydrogen,

[0059] In some embodiments, R2 is selected from hydrogen, In some embodiments, R3 is selected from hydrogen, and deuterated hydrogen.

[0060] In some embodiments, R4 is selected from hydrogen,

[0061] In some embodiments, the compound of Formula I is selected from: In a particular embodiment, compounds encompassed within Formula

[0062] IIB) are provided; including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0063] In some embodiments, R5 is selected from hydrogen, deuterated hydrogen,

[0064] In some embodiments, R6 is selected from hydrogen, deuterated hydrogen,

[0065] In some embodiments, R7 is selected from hydrogen, deuterated hydrogen,

[0066] In some embodiments, R6 and R7 combine to form the following chemical moiety: resulting compound is encompassed within the following formula:

[0067]

[0068] In some embodiments, R9 is hydrogen or deuterated hydrogen.

[0069] In some embodiments, the compound of Formula IIA and IIB is selected from:

[0070]

[0071] In a particular embodiment, compounds encompassed within Formula IIIA IIIB (Formula IIIB); including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0072] In some embodiments, RIO is selected from hydrogen,

[0073] In some embodiments, R 11 is selected from hydrogen or deuterated hydrogen.

[0074] In some embodiments, the compound of Formula III is selected In a particular embodiment, compounds encompassed within Formula IV are provided: (Formula IV); including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0075] In some embodiments, R12 is selected from hydrogen and deuterated hydrogen.

[0076] In some embodiments, R 13 is selected from hydrogen,

[0077] In some embodiments, the compound of Formula IV is selected from:

[0078] In a particular embodiment, compounds encompassed within Formula V are provided: solvates, and / or prodrugs thereof.

[0079] In some embodiments, R14 is selected from hydrogen and deuterated hydrogen.

[0080] In some embodiments, R15 is selected from hydrogen, deuterated hydrogen, In some embodiments, R 16 is selected from hydrogen, deuterated hydrogen,

[0081] 5 In some embodiments, the compound of Formula V is selected from: The compounds of the invention are useful for the treatment, amelioration, or prevention of any type of disorder (e.g., any type of disorder that may be treated, ameliorated, or prevented through administration of a compound of the invention).

[0082] The invention also provides pharmaceutical compositions comprising the compounds of the invention in a pharmaceutically acceptable carrier.

[0083] The invention also provides kits comprising a compound of the invention and instructions for administering the compound to an animal. The kits may optionally contain other therapeutic agents.

[0084] In some embodiments, the compositions and methods of the present invention are used to treat diseased cells, tissues, organs, or pathological conditions and / or disease states in an animal e.g., a mammalian patient including, but not limited to, humans and veterinary animals). In this regard, various diseases and pathologies are amenable to treatment or prophylaxis using the present methods and compositions.

[0085] Some embodiments of the present invention provide methods for administering an effective amount of a compound of the invention and at least one additional therapeutic agent.

[0086] Compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, the compounds may be administered to mammals, e.g. humans, orally at a dose of 0.0025 to 50 mg / kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for disorders responsive to induction of apoptosis. In one embodiment, about 0.01 to about 25 mg / kg is orally administered to treat, ameliorate, or prevent such disorders. For intramuscular injection, the dose is generally about one-half of the oral dose. For example, a suitable intramuscular dose would be about 0.0025 to about 25 mg / kg, or from about 0.01 to about 5 mg / kg.

[0087] The unit oral dose may comprise from about 0.01 to about 1000 mg, for example, about 0.1 to about 100 mg of the compound. The unit dose may be administered one or more times daily as one or more tablets or capsules each containing from about 0.1 to about 10 mg, conveniently about 0.25 to 50 mg of the compound or its solvates.

[0088] In a topical formulation, the compound may be present at a concentration of about 0.01 to 100 mg per gram of carrier. In a one embodiment, the compound is present at a concentration of about 0.07-1 .0 mg / ml, for example, about 0.1 -0.5 mg / ml, and in one embodiment, about 0.4 mg / ml.

[0089] In addition to administering the compound as a raw chemical, the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically. The preparations, particularly those preparations which can be administered orally or topically and which can be used for one type of administration, such as tablets, slow release lozenges and capsules, mouth rinses and mouth washes, gels, liquid suspensions, hair rinses, hair gels, shampoos and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by intravenous infusion, injection, topically or orally, contain from about 0.01 to 99 percent, in one embodiment from about 0.25 to 75 percent of active compound(s), together with the excipient.

[0090] The pharmaceutical compositions of the invention may be administered to any patient which may experience the beneficial effects of the compounds of the invention. Foremost among such patients are mammals, e.g. , humans, although the invention is not intended to be so limited. Other patients include veterinary animals (cows, sheep, pigs, horses, dogs, cats and the like).

[0091] The compounds and pharmaceutical compositions thereof may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

[0092] The pharmaceutical preparations of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, drageemaking, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets.

[0093] Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinyl pyrrolidone. If desired, disintegrating agents may be added such as the above- mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.

[0094] Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are in one embodiment dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.

[0095] Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

[0096] Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and / or dextran. Optionally, the suspension may also contain stabilizers.

[0097] The topical compositions of this invention are formulated in one embodiment as oils, creams, lotions, ointments and the like by choice of appropriate carriers. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C12). The carriers may be those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers can be employed in these topical formulations. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762; each herein incorporated by reference in its entirety.

[0098] Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment is one which includes about 30% almond oil and about 70% white soft paraffin by weight. Lotions may be conveniently prepared by dissolving the active ingredient, in a suitable high molecular weight alcohol such as propylene glycol or polyethylene glycol.

[0099] One of ordinary skill in the art will readily recognize that the foregoing represents merely a detailed description of certain preferred embodiments of the present invention. Various modifications and alterations of the compositions and methods described above can readily be achieved using expertise available in the art and are within the scope of the invention.

[0100] EXAMPLES

[0101] The following examples are illustrative, but not limiting, of the compounds, compositions, and methods of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention. Use of pronouns such as, “we”, “our,” and “I” refer to the inventive entity.

[0102] Example I.

[0103] Improved techniques pertaining to the merging of site specific deuterium labeling with the operational friendliness of MCRs through use of deuterated aldehydes and deuterated isocyanides are needed. Previous work by Srivastava obtained a 65% deuterated Passerini product starting from a 65% deuterated aldehyde.4The use of deuterated benzylic isocyanides is even less known. Yamamoto utilized a 90% deuterated D2-isocyanide in a copper catalyzed [3+2] cycloaddition to afford a 60% deuterated Di-pyrrole.5Use of such reagents in MCRs and determination of discrepancies in deuterium retention with MCRs has yet to be explored. To address this, experiments were conducted that began by gathering highly deuterated aldehydes (>95% D) prepared via NHC catalysis.6However, the aldehyde is just one possible component in an MCR and the deuteration scope would be limited. Therefore, a route was developed to site specific deuterated D1-isocyanides with the goal of applying these reagents to the burgeoning field IMCR chemistry which has enabled concise access to a vast array of biologically relevant chemotypes via one step IMCRs or secondary reactions thereafter.7Many of these decorated chemotypes have found their way into corporate collections through in-house production or external purchase and have progressed along the value chain to the clinic and full approval.2The only established common method to prepare deuterated benzylic isonitriles is to reduce a nitrile in the presence of a deuterium source (Scheme I).8

[0104] Scheme 1. Competitive examples of D2-benzylamine formation via phenylnitriles.

[0105] In this work, we hypothesized that deuterated aldehydes could be converted to D - benzylic isocyanides using D2- formic acid via Leuckart- Wallach reaction followed by dehydration. Surprisingly, the Leuckart- Wallach reaction gave D4-formamides which are scarce in the primary literature. The common method to prepare D1-formamides (D-C=O) is through a Leuckart- Wallach reaction with an amine and D1-methyl / ethyl formate or D1- dimethylformamide.9Stockmann and coworkers produced D2-formamides (N-D, D-C=O) via acid catalyzed nitrile hydrolysis with HC1 and D2O.10A tentative mechanism to D4-formamides is shown, Scheme 2. Thus, formamide adds to the D1-aldehyde A to form hemiaminal B which eliminates D2O to give imine D. Deuterium exchange, which may occur with several of the proposed intermediates, is followed by deprotonation to form the resonance and zwiterrion stabilized isocyanate F.11We then hypothesize that zwitterion F rearranges with loss of CO2 to form D4-formamide. Mechanistic studies are underway as alternate pathways may be feasible.

[0106] Scheme 2. Proposed tentative mechanism of D4-formamide formation via modified Leuckart-

[0107] Wallach reaction with D2-formic acid.

[0108] Thus, using the methodology developed herein, a >99% deuterated aldehyde can give a -88% D2 isocyanide. The optimized conditions for this reaction are presented in general reaction procedure 8 in the SI. The ability to deuterate at benzylic positions is particularly relevant as benzylic C-H bonds are common in biologically relevant chemotypes and moreover appear in approximately 25% of the top selling 200 pharmaceuticals.12Benzyl cation stability is a driver of metabolism at these sites which readily react with cytochrome P450 oxidases via singleelectron oxidation.13This metabolic lability may be tempered by hydrogen-deuterium exchange, an almost perfect bio-isosteric replacement (C-H to C-D) which maintains 3D surface, shape and flexibility.3bIndeed, early incorporation of deuterium in the early hit generation phase may avoid the need for late-stage C-H functionalization which often requires strong external oxidants or affords products that significantly negates biological activity.14Thus, eight MCRs were evaluated for D-reagent scope of reactivity and determination of deuterium retention using a combination of deuterated aldehydes, D1-, and / or D2-isocyanides. We began with the venerable Ugi 4-component reaction (Ugi-4CR), first reported by Ivar Ugi in 1959.15The Ugi-4CR utilizes an amine, carbonyl, carboxylic acid, and isocyanide component to afford a-aminoacyl amide derivatives 1a - 1g in good isolated yield (Scheme 3). A D / -aldehyde and D1-isocyanide were independently used in conjunction with supporting reagents to afford 1b - 1d and le and If resepectively with no observation of deuterium scrambling. A post-condensation modification of 1d, representative of the large swath of chemical space accessible by Ugi-Deprotect-Cyclize (UDC) methodology, gave the dihydroquinoxaline 1g in good yield with high deuterium retention.16 Scheme 3. Ugi-4CR products: no deuterium scrambling observed.

[0109] The catalytic three-component Ugi reaction was first reported by List in 200817and is comprised of reaction of an isonitrile, amine, and aldehyde / ketone, in the presence of phenylphosphinic acid (PPA), to give a-amino amides. Examples of deuterated Ugi-3CR products are represented in Scheme 3. Like the Ugi 4-CR reaction, there was no deuterium scrambling in the Ugi 3-CR. Using a >95% deuterated aldehyde gave a >95% deuterated product. The low yield in 2c is explained by the difficulty to produce aliphatic deuterated aldehydes which led us to believe that the starting material was partially decomposed.

[0110] Nonetheless, both aliphatic and aromatic deuterated aldehydes have been demonstrated to work without loss of deuterium in the Ugi-3CR.

[0111] Scheme 4. Ugi-3CR products. No deuterium scrambling observed.

[0112] First reported in 1961, the Ugi-azide reaction differs from the classical Ugi 4-CR in that an azide anion traps out the intermediate nitrilium ion, leading to formation of a- aminotetrazoles.18Thus, it comprises reaction of an isocyanide, carbonyl, amine and TMSN3 to give tetrazole containing products. Isolated yields for eight analogs are reported with excellent retention of the deuterium label (Scheme 5). Of note, 3i was prepared from combination of a D2- isocyanide and a Di -aldehyde.

[0113]

[0114] Scheme 5. Ugi-azide reaction products, no deuterium scrambling observed. Another versatile IMCR is the Passerini reaction19discovered 60 years prior to the Ugi reaction. It uses the reactivity of isocyanides, aldehydes, and carboxylic acids to yield a-acyloxy amides (Scheme 6). Six deuterated analogs are reported in good yield with no observation of deuterium scrambling. For the preparation of 4d, a deuterated isocyanide was solely employed and for 4a-b and 4e-4f, water was used as solvent. For the latter, product precipitates from the aqueous solution which deters undesirable side-reactions whilst also aiding rate of the reaction.

[0115]

[0116] Scheme 6. Passerini products, no deuterium scrambling observed.aWater was used as solvent.

[0117] The fifth MCR employed herein is the ubiquitous Strecker reaction20where cyanide, aldehyde, and carboxylic acid react to afford a-aminonitriles. These products may be treated with acid to afford amino acids in a further step, enticingly opening up the possibility of scaleproduction of deuterium-labled a-amino acids. Deuterated Strecker products are presented in Scheme 7 in good yield with no observed deuterium scrambling.

[0118]

[0119] Scheme 7. Strecker reaction products (precursors to D1-a-amino acids), no deuterium scrambling was observed. The 19th centrury Biginelli reaction utilizes an aryl aldehyde, urea, and acetoacetate component to give 3,4-dihydropyrimidin-2(lH)-ones.21Such molecules are widely used as calcium channel blockers and antihypertensive agents.22

[0120]

[0121] Scheme 8. Biginelli reaction products, no deuterium scrambling was observed.

[0122] Six site-specific deuterated Biginelli products are revealed in good yield with no deuterium scrambling, Scheme 8.

[0123] The Groebke-Blackbum-Bienayme (GBB) reaction is an intramolecular variant of the Ugi reaction where the intermediate nitrilium ion is intercepted by heteroatoms from the aminoheterocyclic input. Discovered in 1998, and reported independently by three different research groups, it is a three component reaction of a-amino-heterocycles, aldehydes, and isocyanides which affords various aza-bicyclic molecules.23The methodology has been widely used for file enhancement purposes. Three deuterated GBB products are presented, Scheme 9. Unlike the previous MCRs, labeling via a deuterated aldehyde is not feasible as deuterium is removed in favor of the aromatic bicyclic product. Both D - and D1- isocyanides are exemplified in 7a-7c.

[0124]

[0125] Scheme 9. GBB reaction products, no deuterium scrambling was observed. *A 70% Di isocyanide was used in 7a and 7b.

[0126] Finally, we studied the compatibility of the Hantzsch dihydropyridine synthesis with D1- aldehydes. The reaction is a condensation of ethyl acetoacetate with acetaldehyde and ammonia to give 1,4-dihydropyridine.24Such scaffolds are seen in several FDA approved calcium channel blockers including nifedipine, nicardipine and nimodipine and three site-specific deuterated analogs of approved 1 ,4-dihydropyridines (DHPs) are presented, Scheme 10. In line with all prior MCRs, good yields were observed with no deuterium scrambling. Scheme 10. Modified Hantzsch pyridine synthesis to afford 1 ,4-dihydropyridines. No deuterium scrambling was observed.

[0127] Calcium channel blockers derived from this methodology are heavily metabolized by CYP3A4 via dehydrogenation to afford inactive pyrdines, Scheme ll.25As such, bio-isosteric deuterium-hydrogen exchange at this position was thought a reasonable approach to extend drug Tl / 2 through exploitation of the kinetic isotope effect underpinned by the C-D bond being slightly shorter and stronger than a C-H bond. Such site specific labeling was hypothesized to slow CYP3A4 metabolism.

[0128] Scheme 11. CYP3A4 mediated dehydrogenation of dihydropyridines.

[0129] To evaluate the hypothesis, surrogate studies were conducted in mouse liver microsomes to compare deuterated DHPs with their non-deuterated counterparts (Table 1).

[0130] Table 1. Microsomal stability package of deuterated and non-deuterated dihydropyridines. aMouse liver microsomes clearance (MLM Cl), units :mL / min / kg

[0131] D-Nicardipine saw a marginal increase in stability when compared to its non-deuterated counterpart H-Nicardipine (3.0 vs 2.8 mins) with both molecules being rapidly metabolized. D- nimodipine witnessed a 23% improvement in Tl / 2 over its non-deuterated counterpart although both molecules were metabolized quickly. The most significant improvement was seen with D- z'Pr-nicardipine - a 77% increase in MLM stability compared to H-iPr-nicardipine. Note that baseline stability of H-iPr-Nicardipine was higher (8 mins) related to enhanced ester stabilty with an iso-propyl group versus a methyl ester. Collectively these results point to high potential for translation in vivo where novel deuterated analogs exhibit longer Tl / 2 and by extension oral biolavailability.

[0132] In summary we have presented the first method to prepare highly deuterated D4- formamides and Ds-isocyanides from deuterated aldehydes. Furthermore, we have demonstrated that large libraries of deuterated drug-like molecules can be produced rapidly with MCR technology, with particular value for site selective deuteration of often metabolically soft benzylic C-H sites. Lastly, preliminary surrogate metabolic stability studies on site selective D1- DHPs suggest these novel deuterated analogs may afford increased exposure in an in vivo setting. The methodology is likely to have wide utility for the drug-hunting community at large.

[0133] INCORPORATION BY REFERENCE

[0134] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. The following references are herein incorporated by reference in their entireties:

[0135] (1) (a) Domling, A.; Kang, K.; Wang, W.; Chem. Rev., 2012, 112, 3083-3135. (b) Zhu, J.; Wang, Q.; Wang, M.; Multicomponent Reactions in Organic Synthesis, 2014, John Wiley & Sons, (b) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Chem. Rev., 2014, 114, 8323-8359.

[0136] (c) Brauch, S.; van Berkel, S.S.; Westermann, B.; Chem. Soc. Rev., 2013, 42, 4948-4962.

[0137] (2) (a) Hulme, C.; Ayaz, M.; Martinez- Ariza, G.; Medda, F.; Shaw, A.; 2015, Small Molecule Medicinal Chemistry: Strategies and Technologies, ed. W. Czechtizky, P. Hamley, Wiley, Weinheim, ch. 6, 145-187. (b) Hulme, C.; Bienayme, H.; Nixey, T.; Chenera, B.; Jones, W.; Tempest, P.; Smith A. L.; Methods in Enzymology, 2003, 369, 469-496.

[0138] (3) (a) Gant, T.G.; J. Med. Chem., 2014, 57, 3595-3611. (b) Pirali, T.; Serafini, M.; Cargnin, S.; Genazzani, A. A.; J. Med. Chem., 2019, 62, 5276-5297. (c) Meanwell, N.A.; J. Med. Chem., 2011, 54, 2529-2591.

[0139] (4) Ghoshal, A.; Ambule, M. D.; Sravanthi, R.; Taneja, M.; Srivastava, A. K. New J. Chem., 2019, 43, 14459-14474.

[0140] (5) Kamijo, S.; Kanazawa, C.; Yamamoto, Y.; J. Am. Chem. Soc., 2005, 127, 9260-9266.

[0141] (6) Geng, H.; Chen, X.; Gui, J.; Zhang, Y.; Shen, Z.; Qian, P.; Chen, J.; Zhang, S.; Wang, W.; Nat. Catal., 2019, 2, 1071-1077.

[0142] (7) (a) Ayaz, M.; De Moliner, F.; Dietrich, J.; Hulme, C.; Isocyanide Chemistry: Applications in Synthesis and Material Science, 2012, 335-384. (b) Bedard, N.; Fistrovich, A.; Schofield, K.; Shaw, A.; Hulme, C.; Multicomponent Reactions towards Heterocycles: Concepts and Applications. 2022, Wiley-VCH GmbH, 339-409.

[0143] (8) (a) Ding, Y.; Luo, S.; Weng, C.; An, J.; J. Org. Chem., 2019, 84, 15098-15105. (b) Kurita, T.; Aoki, F.; Mizumoto, T.; Maejima, T.; Esaki, H.; Maegawa, T.; Monguchi, Y.; Sajiki, H.; Chem. Eur. J., 2008, 14, 3371-3379. (c) Kim, S. S.; Yang, K. W.; Lee, C. S.; J. Org. Chem., 1996, 67, 4827-4829.

[0144] (9) a) Kesharwani, T.; Verma, A. K.; Emrich, D.; Ward, J. A.; Larock, R. C.; Org. Lett., 2009, 77, 2591-2593; b) Suchy, M.; Elmehriki, A. A. H.; Hudson, R. H. E.; Org. Lett., 2011, 13, 3952-3955.

[0145] (10) Stockmann, V.; Bakke, J. M.; Bruheim, P.; Fiksdahl. A.; Tetrahedron, 2009, 65, 3668- 3672.

[0146] (11) Kende, A. S.; Brands, K. M. J.; Blass, B.; Tetrahedron Lett., 1993, 34, 579-582.

[0147] (12) McGrath, N. A.; Brichacek, M.; Njardarson, J. T.; J. Chem. Educ., 2010, 87, 1348-1349.

[0148] (13) Engst, W.; Landsiedel, R.; Hermersdorfer, H.; Doehmer, J.; Glatt, H.; Carcinogenesis, 1999, 20, 1777-1785.

[0149] (14) (a) Xu, W.; Wang, W.; Liu, T.; Xie, J.; Zhu, C. Nature Comm., 2019, 10, 4867. Abu Salim, D. I.; Cook, S. P.; J. Am. Chem.

[0150] Soc., 2018, 140, 12378-12382. (c) Qin, Y.; Zhu, L.; Luo, S.; Chem. Rev., 2017, 777, 9433- 9520.

[0151] (15) Ugi, I.; Angew. Chem., 1959, 77, 373-388.

[0152] (16) (a) Tempest, P.; Ma, V.; Thomas, S.; Hua, Z.; Kelly, M. G.; Hulme, C.; Tetrahedron Lett., 2001, 42, 4959-4962. (b) Dietrich, J.; Kaiser, C.; Meurice, N.; Hulme, C.; Tetrahedron Lett., 2010, 57, 3951-3955 (c) Hulme, C.; Gore, V.; Curr. Med. Chem., 2003, 10, 51-80. (d) Xu, Z.; De Moliner, F.; Cappelli, A.P.; Ayaz, M.; Hulme, C.; Synlett., 2014, 25, 225-228

[0153] (17) (a) Pan, S. C.; List, B.; Angew. Chem. Int. Ed Engl., 2008, 47, 3622-3625. (b) Ayaz, M.; Martinez-Ariza, G.; Hulme, C.; Synlett., 2014 25, 1680-1684.

[0154] (18) (a) Ugi, I.; Steinbriickner, C.; Angew. Chem., 1960, 72 (7-8), 267-268; (b) Ugi, I.; Steinbriickner, C.; Chem. Ber., 1961, 94, 734-742. (c) Gunawan, S.; Petit, J.; Hulme, C.; ACS Comb. Sci., 2012, 14, 160-163. (d) Gunawan, S.; Hulme, C.; Org. Biomol. Chem., 2013, 77, 6036-6046.

[0155] (19) (a) Passerini, M.; Gazz, S.; Chim. Ital., 1921, 57, 126-129. (b) Banfi, L.; Basso, A.; Lambruschini, C.; Moni, L.; Riva, R.; Chem. Sci., 2021, 72, 15445-15472. (c) Banfi, L.; Basso, A.; Guanti, G.; Riva, R.; Mol. Divers., 2003, 6, 227-235. (d) Shaw, A.Y.; Medda, F.; Hulme, C. Tetrahedron Lett., 2012, 53, 1313-1315

[0156] (20) (a) Strecker, A.; Ann. Chem. Pharm., 1850, 75, 27. (b) Ayaz, M.; De Moliner, F.; Morales, G.A.; Hulme, C.; Science of Synthesis, 2014, 99-122.

[0157] (21) Biginelli, P.; Chem. Ges., 1891, 24, 1317-1319.

[0158] (22) Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland, S.; Gougoutas, J. Z.; O’Reilly, B. C.; Schwartz, J.; Malley, M. F.; J. Med. Chem., 1992, 35, 3254-3263.

[0159] (23) (a) Groebke, K.; Weber, L.; Mehlin, F. Synlett, 1998, 6, 661-663; (b) Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S.; Tetrahedron Lett., 1998, 39, 3635-3638; (c) Bienayme, H.; Bouzid, K.; Angew. Chem. Int. Ed Engl., 1998, 37, 2234-2237. (d) Hulme, C.; Lee, YS. Mol. Divers., 2008 12, 1-15. (e) Umkehrer, M.; Ross, G.; Jager, N.; Burdack, C.; Kolb, J.; Hu, H.; Alvim-Gaston, M.; Hulme, C.; Tetrahedron Lett., 2007, 48, 2213-2216.

[0160] (24) Hantzsch, A. Berichte der deutschen chemischen Gesellschaft 1881, 14, 1637-1638.

[0161] (25) Zhu, Y.; Wang, F.; Li, Q.; Zhu, M.; Du, A.; Tang, W.; Chen, W.; Drug Metab. Dispos., 2014, 42, 245-249.

[0162] EQUIVALENTS

[0163] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

What Is Claimed Is:

1. A method for D4-formamide formation via modified Leuckart- Wallach reaction with D2- formic acid via implementation of the reaction described in Scheme 22. A method for generating deuterated compounds via implementation of the reaction described in Scheme 3.

3. A method for generating deuterated compounds via implementation of the reaction described in Scheme 4.

4. A method for generating deuterated compounds via implementation of the reaction described in Scheme 5.

5. A method for generating deuterated compounds via implementation of the reaction described in Scheme 6.

6. A method for generating deuterated compounds via implementation of the reaction described in Scheme 7.

7. A method for generating deuterated compounds via implementation of the reaction described in Scheme 8.

8. A method for generating deuterated compounds via implementation of the reaction described in Scheme 9.

9. A method for generating deuterated compounds via implementation of the reaction described in Scheme 10.

10. A composition comprising a compound encompassed within Formula T:(Formula I); including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof; wherein R1 is selected from hydrogen,wherein R2 is selected from hydrogen,wherein R3 is selected from hydrogen, and deuterated hydrogen;wherein R4 is selected from hydrogen,11. The composition of Claim 10, wherein the compound is selected from:

12. A composition comprising a compound encompassed within FormulaIIB); including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof; wherein R5 is selected from hydrogen, deuterated hydrogen,wherein R8 is selected from hydrogen,wherein R9 is hydrogen or deuterated hydrogen; andwherein R6 and R7 combine to form the following chemical moiety:that the resulting compound is encompassed within the following formula:wherein R7 is selected from hydrogen, deuterated hydrogen,13. The composition of Claim 12, wherein the compound is selected from:

14. A composition comprising a compound encompassed within Formula IIIAIIIB (Formula IIIB); including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof;wherein RIO is selected from hydrogen,and wherein R11 is selected from hydrogen or deuterated hydrogen.

15. The composition of Claim 14, wherein the compound is selected from:

16. A composition comprising a compound encompassed within Formula IV :(Formula IV); including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof;wherein R12 is selected from hydrogen and deuterated hydrogen; wherein R13 is selected from hydrogen,17. The composition of Claim 16, wherein the compound is selected from:

18. A composition comprising a compound encompassed within Formula V :solvates, and / or prodrugs thereof wherein R14 is selected from hydrogen and deuterated hydrogen;wherein R15 is selected from hydrogen, deuterated hydrogen,wherein R16 is selected from hydrogen, deuterated hydrogen, andwherein R17 is selected from19. The composition of Claim 18, wherein the compound is selected from:

20. A pharmaceutical composition comprising a compound recited in Claims 1-19.

21. A method of treating, ameliorating, or preventing a disorder in a patient comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of Claim 20.

22. A kit comprising a compound of Claims 1-19 and instructions for administering said compound to a patient.

Images