Derivatives of substituted morpholines and uses thereof

Abstract

The present invention relates to derivatives of substituted morpholines and uses thereof. A compound of formula I includes a stereoisomer and / or a salt thereof; wherein R1 is a substituted alkane group, heterocyclic group or pyridine group; x is hydrogen, halogen, amino acid residue, substituted amino acid residue, alkyl or ester. Such compounds are useful in pharmaceutical compositions and for the treatment of central nervous system (CNS) disorders;

Description

[0001] This application is a divisional application of the Chinese national phase patent application No. 202280015922.2, which was filed on August 18, 2023, after the international application No. PCT / US2022 / 020976, international application date March 18, 2022, entitled "Substituted Morpholine Derivatives and Their Uses".

[0002] Cross-references to related applications

[0003] This application claims priority to U.S. Provisional Application No. 63 / 162,671, filed March 18, 2021, the entire contents of which are incorporated herein by reference. Technical Field

[0004] This technology generally relates to substituted morpholine derivatives and their use in pharmaceutical compositions and for the treatment of central nervous system (CNS) disorders. Background Technology

[0005] (R,S)-2-[(2-ethoxyphenoxy)methyl]morpholine:

[0006]

[0007] It is a bicyclic morpholine derivative, designated CAS number 46817-91-8 (CAS number 35604-67-2 for the HCl salt). Its characteristic is formula C 13 H 19 NO3 has a molecular weight of 237.295 g / mol.

[0008] 2-((2-ethoxyphenoxy)methyl)morpholine is known to have several promising pharmacological uses, including the treatment of depression, nocturnal enuresis, narcolepsy, sleep disorders, and alcoholism. 2-((2-ethoxyphenoxy)methyl)morpholine was previously marketed in several European countries for the treatment of major depressive disorder (MDD). 2-((2-ethoxyphenoxy)methyl)morpholine is an inhibitor of norepinephrine (“NRI”) reuptake, but it can also enhance the release of serotonin from neuronal stores.

[0009] However, treatment with 2-((2-ethoxyphenoxy)methyl)morpholine has been associated with a number of side effects, including nausea, vomiting, loss of appetite, increased erythrocyte sedimentation rate, abnormal EKG and EEG, upper abdominal pain, diarrhea, constipation, dizziness, orthostatic hypotension, lower extremity edema, dysarthria, tremor, psychomotor agitation, confusion, inappropriate secretion of antidiuretic hormone, increased transaminase levels, and seizures.

[0010] To minimize the side effects associated with 2-((2-ethoxyphenoxy)methyl)morpholine, chemists have synthesized derivatives and analogs that retain the pharmacological properties of 2-((2-ethoxyphenoxy)methyl)morpholine. Derivatives of substituted morpholines have previously been disclosed in the art, for example in British Patent 1,243,391 and British Patent 1,260,886. The inventors have synthesized novel derivatives of substituted morpholines using various methods. Prodrugs are a class of derivatives that, in many cases, have little or no pharmacological activity and are converted into therapeutically active compounds in vivo. In some cases, prodrugs themselves may be biologically active. Prodrug activation can occur via enzymatic or non-enzymatic cleavage of the temporary bond between the carrier and the drug molecule, or both sequentially or simultaneously.

[0011] Newly synthesized substituted morpholine derivatives (derivatively modifying the amino group of morpholine in the structure of 2-((2-ethoxyphenoxy)methyl)morpholine) produce chemically stable compounds that can serve as novel compounds. These derivatives of 2-((2-ethoxyphenoxy)methyl)morpholine can be used in pharmaceutical compositions and for the treatment of central nervous system (CNS) disorders. Summary of the Invention

[0012] In one aspect, substituted morpholine derivatives are provided, including compounds of formula I, their stereoisomers, or salts thereof:

[0013]

[0014] In equation I, R 1 It can be alkyl, heterocyclic, or pyridinyl, R 2 It can be alkyl, aryl, heteroaryl, or heterocyclic, R 3 -R 14 Each can be independently H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl, or heterocyclic; and X can be H, F, Cl, Br, I, amino acid residue, substituted amino acid residue, alkyl, or ester.

[0015] In some embodiments, this technology relates to substituted morpholine derivatives of compounds according to formula II, their stereoisomers, and / or salts thereof:

[0016]

[0017] In formula II, L can be an alkyl group, a substituted pyridine carboxylic acid, or a substituted alkyl acetate diester; R 2 It can be alkyl, aryl, heteroaryl, or heterocyclic; and R 3 -R 14Each can be independently H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl, or heterocyclic.

[0018] In some embodiments, this technology relates to substituted morpholine derivatives of compounds according to formula III, their stereoisomers, and / or salts thereof:

[0019]

[0020] In Formula III, Y can be F, Cl, Br, I, an amino acid residue, a substituted amino acid residue, an alkyl group, or an ester; R 2 It can be alkyl, aryl, heteroaryl, or heterocyclic; and R 3 -R 14 Each can be independently H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl, or heterocyclic.

[0021] In some embodiments, substituted morpholine derivatives according to formula IV, their stereoisomers, and / or salts thereof are provided:

[0022]

[0023] In formula IV, Z can be H, F, Cl, Br, I, an amino acid residue, a substituted amino acid residue, or a nitrogen-containing group; R 2 It can be alkyl, aryl, heteroaryl, or heterocyclic; and R 3 -R 14 Each can be independently H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl, or heterocyclic.

[0024] In any of the above implementation schemes, R 2 It can be CH2CH3. In any of the above embodiments, R 3 -R 14 Each can be H.

[0025] In some aspects, a composition is provided comprising a substituted morpholine derivative of formula I, II, III or IV, its stereoisomers and / or salts thereof, and at least one pharmaceutically acceptable excipient or carrier.

[0026] In some respects, treatments for central nervous system (“CNS”) disorders are provided, the treatment comprising administering a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising a substituted morpholine derivative, including compounds of formula I, II, III or IV.

[0027] In some aspects, a method is provided for preparing substituted morpholine derivatives, including compounds of formula I, II, III or IV, their stereoisomers and / or salts thereof, said method comprising contacting 2-((2-ethoxyphenoxy)methyl)morpholine or a salt thereof, intermediate 1, intermediate 2 or intermediate 3 with a reactive compound suitable for forming compounds of formula I, II, III or IV. Detailed Implementation

[0028] Definitions. The following terms, as defined below, are used throughout this document.

[0029] As used herein, the term “viloxazine” or 2-((2-ethoxyphenoxy)methyl)morpholine means (R,S)-2-[(2-ethoxyphenoxy)methyl]morpholine], including its pharmaceutically acceptable salts or esters, including a single (-) enantiomer or a single (+) enantiomer, or in the form of a racemic mixture or non-racemic mixture of enantiomers with different amounts of (-) and (+) enantiomers.

[0030] As used herein and in the appended claims, in the context of describing elements (especially in the context of the following claims), singular articles such as “a / an” and “the”, and similar pronouns, should be interpreted to cover both the singular and plural, unless otherwise specified herein or clearly contradicted by the context. Unless otherwise indicated herein, descriptions of ranges of values ​​herein are intended only as a shorthand method for individually referring to each individual value belonging to the range, and each individual value is incorporated into this specification as if individually described herein. Unless otherwise specified herein or clearly contradicted by the context, all methods described herein may be performed in any suitable order. Unless otherwise stated, any and all instances of language used, or exemplary language provided herein (e.g., “such as”), are intended only to better illustrate the embodiments and do not limit the scope of the claims. No language in this specification should be construed as indicating any unclaimed element necessary for its designation.

[0031] As used herein, “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. If the use of the term is unclear to those skilled in the art, then given the context in which it is used, “about” will mean an addition or subtraction of 10% to a particular term.

[0032] Generally, mentioning an element such as hydrogen or H means including all isotopes of that element. For example, if the R group is defined as including hydrogen or H, it also includes deuterium and tritium. Therefore, it includes radioactive isotopes such as tritium, C, etc. 14 P 32and S 35 The compounds are within the scope of this technology. Based on the disclosure herein, the procedure for inserting such markings into compounds of this technology will be apparent to those skilled in the art.

[0033] Generally, "substituted" means an organic group (e.g., alkyl) as defined below, wherein one or more bonds to a hydrogen atom are replaced by bonds to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbon or hydrogen atom are replaced by one or more bonds to a heteroatom (including double or triple bonds). Therefore, unless otherwise stated, a substituted group is substituted by one or more substituents. In some embodiments, the substituted group is substituted by 1, 2, 3, 4, 5, or 6 substituents. Examples of substituents include: halogens (i.e., F, Cl, Br, and I); hydroxyl groups; alkoxy, alkenoxy, aryloxy, arylalkoxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, and heterocyclic alkoxy groups; carbonyl (oxo); carboxylic esters; esters; polyurethanes; oximes; hydroxylamines; alkoxyamines; arylalkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyl groups; pentafluorothioalkyl (i.e., SF5); sulfonamides; amines; N-oxides; hydrazides; acylhydrazides; hydrazones; azides; amides; urea; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; nitriles (i.e., CN); and so on.

[0034] As used in this article, the term "carboxylic acid ester" refers to the conjugate base of a carboxylic acid having the chemical formula -COO.

[0035] As used in this article, the term "ester" refers to –COOR 2 - and –C(O)OG groups. R 2 It is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclic alkyl, or heterocyclic group as defined herein. G is a carboxylic acid ester protecting group. Carboxylic acid ester protecting groups are well known to those skilled in the art. A detailed list of protecting groups for carboxylic acid ester functional groups can be found in Protective Groups in Organic Synthesis, Greene, TW; Wuts, PGM, John Wiley & Sons, New York, NY, (3rd edition, 1999), and these protecting groups can be added or removed using the procedures specified therein, and the literature is hereby incorporated by reference in its entirety and for any and all purposes, as fully set forth herein.

[0036] The term "amide" (or "amide group") includes C- and N-amide groups, namely C(O)NR, respectively. 3 R 4And -NRC(O)-R group. R 3 and R 4 Independently hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclic alkyl, or heterocyclic group as defined herein. The amide group therefore includes, but is not limited to, carbamoyl (-C(O)NH2) and formamide (NHC(O)H). In some embodiments, the amide is –NRC(O)-(C 1-5 The amide is an alkyl group and the group is referred to as "carbonylamino". In other embodiments, the amide is -NHC(O)-alkyl and the group is referred to as "alkanoylamino".

[0037] As used in this article, the term "amine" (or "amino group") refers to –NR 5 R 6 Group, wherein R 5 and R 6 The amine is independently hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclic alkyl, or heterocyclic group as defined herein. In some embodiments, the amine is an alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[0038] As used herein, the term "halogen" or "halogen group" refers to bromine (Br), chlorine (Cl), fluorine (F), or iodine (I). In some embodiments, the halogen is chlorine (Cl).

[0039] As used herein, the term "polypeptide" or "peptide" refers to two or more amino acids linked by a peptide (i.e., amide) bond between the carboxyl terminus of one amino acid and the amino terminus of another amino acid. The term "peptide" may be combined with a prefix indicating the number of amino acids in the peptide; for example, "pentapeptide" is a peptide having five amino acids.

[0040] The term "amino acid" is recognized in the art and generally refers to natural or non-natural α- or β-amino acids. The term "amino acid" includes, but is not limited to, any of the twenty-one standard L-amino acids commonly found in naturally occurring peptides.

[0041] As used herein, the term "amino acid residue having a hydrophobic side chain" refers to the following amino acids: alanine (Ala), valine (Val), isoleucine (Ile), leucine (Leu), methionine (Met), phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp). In some embodiments, the amino acid residue having a hydrophobic side chain is valine (Val). In other embodiments, the amino acid residue having a hydrophobic side chain is phenylalanine (Phe).

[0042] As used in this article, the term "acetyl" refers to a methyl group bonded to a carbonyl group (CH3CO-).

[0043] As used herein, the term "pyridine" refers to a group in a heterocyclic organic compound having the chemical formula C5H5N.

[0044] As used in this article, the term "pyridine carboxylic acid" refers to a compound having a pyridine ring and a carboxyl group.

[0045] As used herein, the term "azinediyl" refers to a functional group having the formula -NH; said group is bonded to the rest of the compound by two single bonds.

[0046] Pharmaceutically acceptable salts of the compounds described herein are within the scope of this technology and include acid or base addition salts that retain the desired pharmacological activity and are not biologically undesirable (e.g., the salts are not excessively toxic, allergenic, or irritating, and are bioavailable). When the compounds of this technology have a basic group (such as, for example, an amino group), they can form pharmaceutically acceptable salts with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (such as alginate, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and p-toluenesulfonic acid), or acidic amino acids (such as aspartic acid and glutamic acid). When the compounds of this technology have an acidic group (such as, for example, a carboxylic acid group), they can form pharmaceutically acceptable salts with metals, such as alkali metals and alkaline earth metals (e.g., Na). + Li + K + Ca 2+ Mg 2+ or Zn 2+ Salts can be formed from ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine, methylpyridine, ethanolamine, diethanolamine, or triethanolamine) or basic amino acids (e.g., arginine, lysine, or ornithine). These salts can be prepared in situ during the final separation and purification of the compound, or by reacting the purified compound, in its free base or free acid form, separately with a suitable acid or base and separating the resulting salt.

[0047] Unless otherwise specified in the stereochemistry, stereoisomers (also known as optical isomers) of a compound include all chiral, diastereomeric, and racemic forms of the structure. Therefore, as is apparent from the description, compounds used in this technique include optical isomers enriched or resolved at any or all asymmetric atoms. Racemic mixtures and diastereomeric mixtures, as well as individual optical isomers, can be isolated or synthesized, thus substantially free of their enantiomers or diastereomeric counterparts, and these stereoisomers are all within the scope of this technique.

[0048] The term “pharmaceuticalally acceptable excipient” refers to substances that are widely accepted by industry and regulatory bodies, such as those listed in monographs such as the USP-NF, the Food Chemicals Codex, the Federal Regulations (CFR), the FDA Guidelines for Inactive Ingredients, and the summaries of Parts 182 and 184 of 21 CFR that list substances generally considered safe (GRAS) food ingredients.

[0049] In one aspect, a compound represented by Formula I or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is provided:

[0050]

[0051] In compound I, R 1 It can be alkyl, heterocyclic, or pyridinyl; R 2 It can be alkyl, aryl, heteroaryl, or heterocyclic; R 3 -R 14 Each of these can be independently H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl, or heterocyclic; and X can be H, halogen, amino acid residue, substituted amino acid residue, alkyl, or ester. In some preferred embodiments, R 2 It is ethyl. In any of the above embodiments, R 1 It can be CH2, CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, (CH3)2C, (CH3)2CHCH, or (CH3)3CCH. In any of the above embodiments, X can be an amino acid residue. In such embodiments, the amino acid residue may also include a hydrophobic side chain. In any of the above embodiments, the amino acid residue can be valine or phenylalanine. In any of the above embodiments, R 3 -R 14 Each of these can independently be H, F, Cl, Br, I, or an alkyl group. In some such embodiments, R 3 -R 14 Each of these can be independently H or C1-C6 alkyl. In some embodiments, R 3 -R 14All are H. In any of the above implementations, R 1 It can be CH2CH2 or CH2CH2CH2CH2. In the various embodiments above, R1 can be CH2 or C2H5, and / or X can be an ester. In the various embodiments above, R... 1 It can be pyridinyl and X can be F, Cl, Br or I.

[0052] In various embodiments, the compound represented by Formula I is one or more of the following compounds, and it should be understood that each representation also includes any R, S, or racemic structure when a chiral center is present:

[0053]

[0054]

[0055]

[0056]

[0057]

[0058] In some embodiments, the compound represented by Formula I is:

[0059]

[0060] In the above formula, R 15 It can be H, alkyl, or -C(O)OR 17 ;R 16 It can be H, alkyl, or -C(O)OR 17 And R 17 It can be H or alkyl. In some embodiments, R 15 It can be an alkyl group, and R 16 It can be H or alkyl. In such embodiments, R 15 It can be methyl, and R 16 It can be H or methyl. In some embodiments, R 15 and R 16 It is methyl. In some embodiments, R 15 It is -C(O)OR 17 R 16 It is H, and R 17 It is a methyl group.

[0061] In another aspect, a compound represented by formula II or its stereoisomer and / or its salt is provided:

[0062]

[0063] In formula II, L is an alkyl group, a substituted pyridine carboxylic acid, or a substituted alkyl acetate diester; R 2 It is an alkyl, aryl, heteroaryl, or heterocyclic group; and R 3 -R 14 Each can be independently H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl, or heterocyclic. In some embodiments, R 2 It is an ethyl group.

[0064] In some embodiments, the compound represented by Formula II is:

[0065]

[0066] In various embodiments, the compound of formula II is one or more of the following:

[0067]

[0068]

[0069] In another aspect, a compound represented by formula III or its stereoisomer and / or its salt is provided:

[0070]

[0071] In Formula III, Y can be F, Cl, Br, I, an amino acid residue, a substituted amino acid residue, an alkyl group, or an ester; R 2 It can be alkyl, aryl, heteroaryl, or heterocyclic; and R 3 -R 14 Each of these groups can be independently H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl, or heterocyclic. In some embodiments, R... 2 It is an ethyl group.

[0072] In some embodiments, the compound represented by Formula III is:

[0073]

[0074] In some embodiments, the compound represented by Formula III is:

[0075]

[0076] In another aspect, compounds represented by formula IV or their stereoisomers and / or salts thereof are provided:

[0077]

[0078] In Formula III, Z can be H, F, Cl, Br, I, an amino acid residue, a substituted amino acid residue, or a nitrogen-containing group; R 2 It can be alkyl, aryl, heteroaryl, or heterocyclic; and R 3 -R 14 Each of these groups can be independently H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl, or heterocyclic. In some embodiments, R... 2 It is an ethyl group.

[0079] In some embodiments, the compound represented by formula IV is:

[0080]

[0081] In some embodiments, the compound represented by formula IV is:

[0082]

[0083] In some embodiments, the composition comprises a substituted morpholine derivative of formula I, II, III or IV, its stereoisomers and / or salts thereof, and at least one pharmaceutically acceptable excipient or carrier.

[0084] In some embodiments, the pharmaceutical composition comprises a substituted morpholine derivative of formula I, II, III, or IV, its stereoisomers, and / or salts thereof, along with a pharmaceutically acceptable carrier or excipient. The pharmaceutical formulation may be in a suitable dosage form. Illustrative dosage forms include, but are not limited to, injections, oral dosage forms, suppositories, capsules, sachets, transdermal formulations, etc.

[0085] In another respect, treatment of CNS symptoms is provided by administering to a subject in need a composition comprising a substituted morpholine derivative or a salt thereof as described herein, such as formula I, II, III or IV.

[0086] In another aspect, a method is provided for administering to a subject a composition comprising a compound of formula I, II, III, or IV, or a salt thereof. In one aspect, the subject is a mammal. In other embodiments, the mammalian subject is a human. In a particular embodiment, the mammalian subject is an adult or a human child.

[0087] In some embodiments, the method described herein includes administering a substituted morpholine derivative of formula I, II, III, or IV, its stereoisomers, and / or salts thereof together with at least one additional agent. In some embodiments, the at least one additional agent is another agent for CNS conditions. In other embodiments, the at least one additional agent is 2-((2-ethoxyphenoxy)methyl)morpholine or a salt thereof.

[0088] In one embodiment, the substituted morpholine derivative may be prepared from 2-((2-ethoxyphenoxy)methyl)morpholine or a salt thereof.

[0089] In one embodiment, the substituted morpholine derivative can be prepared by reacting 2-((2-ethoxyphenoxy)methyl)morpholine or a salt thereof with sodium bicarbonate to form intermediate 1 having the following structure:

[0090]

[0091] In one embodiment, the substituted morpholine derivative can be prepared by reacting 2-((2-ethoxyphenoxy)methyl)morpholine or a salt thereof with 1-chloromethyl chloroformate to form intermediate 2 having the following structure:

[0092]

[0093] In one embodiment, the substituted morpholine derivative can be prepared by reacting 2-((2-ethoxyphenoxy)methyl)morpholine or a salt thereof with chloroethyl 1-chloroformate to form intermediate 3 having the following structure:

[0094]

[0095] In one embodiment, a substituted morpholine derivative of formula I, II, III or IV is prepared by reacting 2-((2-ethoxyphenoxy)methyl)morpholine or a salt thereof with intermediate 1, intermediate 2 or intermediate 3.

[0096] In another embodiment, a method for preparing substituted morpholine derivatives of formula I, II, III or IV is provided.

[0097] Substituted morpholine derivatives can be analyzed by liquid chromatography-mass spectrometry (LCMS) and nuclear magnetic resonance (NMR) spectroscopy.

[0098] The invention, which is thus generally described, will be more readily understood by referring to the following embodiments, which are provided by way of illustration and are not intended to limit the invention.

[0099] Example

[0100] Procedures for preparing intermediates. It should be understood that, although the chiral center is represented by the R or S configuration in some structures, other configurations are also disclosed herein.

[0101] Intermediate 1: Synthesis of 2-((2-ethoxyphenoxy)methyl)morpholine-4-carbonyl chloride.

[0102]

[0103] A solution of 2-((2-ethoxyphenoxy)methyl)-morpholine hydrochloride (500 mg, 1.83 mmol) in dichloromethane (50 mL) was added dropwise to a sodium bicarbonate slurry (460 mg, 5.48 mmol). The reaction mixture was stirred for 30 minutes. A solution of triphosgene (358 mg, 1.21 mmol) in dichloromethane (25 mL) was added over 15 minutes at 10-15 °C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered to remove sodium chloride, and the filtrate was concentrated under vacuum to give 438 mg of ethylmethylcarbamoyl chloride as a pale yellow oil (yield: 80%).

[0104] 1 H NMR (CDCl3, 400MHz): δppm 6.88-6.91(m,4H),4.39-4.47(br t,1H),3.96-4.25(m,6H),3.83-3.87(br t,1H),3.61-3.71(br t,1H),3.03-3.38(m,2H),1.44(t,3H).

[0105] Intermediate 2: 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid methyl ester.

[0106]

[0107] 1-Chloromethyl chloroformate was added dropwise to a stirred, ice-cold mixture of 2-((2-ethoxyphenoxy)methyl)morpholine hydrochloride (1.3 gm, 4.52 mmol), trimethylamine (1.01 gm, 9.95 mmol), and dichloromethane. The reaction mixture was stirred at 10-15 °C until it reached room temperature and then stirred for 5 hours. The precipitated solid was filtered off and the filtrate was concentrated. The crude product was purified by column chromatography (hexane:EtOAc 7:3) to give 1.2 gm (80%) of white solid.

[0108] 1 H NMR (CDCl3, 400MHz): δppm 1.46(t,3H),1.59(s,4H),3.05(d,2H),3.63(d,1H),3.92-4.02(m,2H),4 .04-4.15(m,4H),4.23(br.s.,1H),5.76-5.86(m,2H),6.84-7.00(m,4H).

[0109] Intermediate 3: 1-chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid.

[0110]

[0111] 1-Chloroethyl chloroformate (1.19 g, 83.5 mmol) was added dropwise to a stirred, ice-cold mixture of 2-((2-ethoxyphenoxy)-methyl)morpholine hydrochloride (2 gm, 6.96 mmol), trimethylamine (1.01 g, 9.95 mmol), and dichloromethane. The reaction mixture was stirred at 10-15 °C and allowed to reach room temperature for 5 hours. The precipitated solid was filtered off and the filtrate was concentrated. The crude product was purified by column chromatography (hexane:EtOAc 7:3) to give 1.42 gm (59.3%) of white solid.

[0112] 1 H NMR (400MHz, CDCl3): δppm 1.39-1.51(m,3H),1.83(d,3H),2.92-3.12(m,2H),3.54-3.72(m,1H),3.85( br.s.,1H),3.89-4.13(m,7H),4.20(d,1H),6.61(m,1H),6.84-7.01(m,4H).

[0113] Procedures for synthesizing compounds of formula I, II, III, or IV:

[0114] SP-16: 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid ((D-valine)oxy)methyl ester.

[0115] Step 1.

[0116]

[0117] The reaction mixture of N-Boc-D-valine (175 mg, 0.80 mmol), cesium carbonate (130 mg, 0.4 mmol), and methanol (3.3 mL) was stirred at room temperature for 3 hours. The methanol was then evaporated, and the residue was reconstituted with DMF (1 mL). Chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (intermediate 2) (177 mg, 0.52 mmol) was added to the reaction mixture. The resulting mixture was stirred at 80 °C for 20 hours. The DMF was evaporated under vacuum, and the residue was dissolved in chloroform and purified by column chromatography (hexane:EtOAc 1:1) to give 112 mg (39.4%) of a semi-solid oil.

[0118] Step 2:

[0119]

[0120] A solution of SP-16A (65 mg, 0.12 mmol) and 2 M HCl in dioxane was stirred overnight at room temperature. The solvent was evaporated and dried under vacuum to give 50 mg (95.6%) of the desired product (SP-16) as a brown semi-solid. LCMS: Purity: 96.27% according to ELS detector. MS: M+H = 411.14. 1 H NMR (CDCl3, 400MHz): δppm 1.12(t,6H),1.44(t,3H),2.46(br.s,1H),2.90-3.10(m,2H),3.52-3.66(m,1H),3 .85-420(m,10H),5.83(br.s,1H),5.95(d,1H),6.85-6.96(m,4H),8.24(br.s,2H).

[0121] SP-17: 1-((L-valine)oxy)ethyl ester of 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid.

[0122] Step 1.

[0123]

[0124] The reaction mixture of N-Boc-L-valine (175 mg, 0.80 mmol), cesium carbonate (130 mg, 0.4 mmol), and methanol (3.3 mL) was stirred at room temperature for 3 hours. The methanol was then evaporated, and the residue was reconstituted with DMF (1 mL). 1-Chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (intermediate 3) (184 mg, 0.52 mmol) was added to the reaction mixture. The resulting mixture was stirred at 80 °C for 20 hours. The DMF was evaporated under vacuum, and the residue was dissolved in chloroform and purified by column chromatography (hexane:EtOAc 8:2) to give 141 mg (48.3%) of a semi-solid oil.

[0125] Step 2:

[0126]

[0127] A solution of SP-17A (65 mg, 0.11 mmol) and 2 M HCl in dioxane was stirred overnight at room temperature. The solvent was then evaporated and the product was dried under vacuum to give 51 mg (92.4%) of the pure desired product (SP-17) as a brown solid. LCMS: Purity: 100% according to ELS detector. MS: M+H = 425.17. 1H NMR (CDCl3, 400MHz): δppm 1.12(t,6H),1.44(t,3H),2.46(br.s.,1H),2.90-3.10(m,2H),3.52-3.66(m,1H),3 .85-420(m,10H),5.83(br.s.,1H),5.95(d,1H),6.85-6.96(m,4H),8.24(br.s.2H).

[0128] SP-18: (2R)-2-amino-N-((2-((2-ethoxyphenoxy)methyl)morpholino)methyl)-3-methylbutyramide dihydrochloride.

[0129] Step 1:

[0130]

[0131] Sodium bicarbonate slurry (92 mg, 1.1 mmol) was added to a solution of 2-((2-ethoxyphenoxy)methyl)morpholine hydrochloride (108 mg, 0.4 mmol) and polyoxymethylene (50 mg) in THF (2 ml). The reaction mixture was stirred for 48 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was dissolved in chloroform and purified by column chromatography (hexane:EtOAc 8:1) to give 80 mg (43%) of a semi-solid oil.

[0132] Step 2:

[0133]

[0134] A solution of SP-18A (70 mg, 0.15 mmol) and 2 M HCl in dioxane was stirred overnight at room temperature. The solvent was evaporated and dried under vacuum to give 50 mg (76%) of the desired product (SP-18) as a brown solid. LCMS: M + H = 366.20. Purity 98.73% according to ELS detector. 1 H NMR (CDCl3, 400MHz): δppm 9.8-10.5 (br m, 1H), 8.2-8.5 (br s,2H),6.75-7.1(m,4H),4.2-5.0(m,4H),3.9-4.2(m,6H),3.70-3.87(m,2H),3.0-3.5(br s,1H),1.75-2.25(m,4H),1.3-1.5(m,3H),1.1(br s,6H).

[0135] SP-19: 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid pyridin-2-yl ester

[0136] A solution of triphosgene (163 mg, 0.55 mmol) in dichloromethane (DCM; 1 ml) was stirred in an ice bath at 0-5 °C for 15 min, and a solution of 2-hydroxypyridine (150 mg, 1.58 mmol) and N,N-diisopropylethylamine (DIPEA; 208 mg, 1.61 mmol) in DCM (1 ml) was added dropwise. The reaction mixture was allowed to reach room temperature. The reaction was monitored for completion by TLC. After the reaction was complete, the reaction mixture was evaporated, reconstituted with DCM, and evaporated (X3) to remove excess triphosgene. The residue was reconstituted with DCM, and a solution of 2-((2-ethoxyphenoxy)methyl)morpholine hydrochloride (363 mg, 1.26 mmol) and TEA (13.6 mg, 1.34 mmol) in DCM was added, and the mixture was stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified by column chromatography using hexane-ethyl acetate (2:1) to give 56 mg (12.3%) of the target compound (SP-19) as a semi-solid. LCMS: M+H = 359.08. Purity 100% according to ELS detector. 1 H NMR (400MHz, CDCL3): δ1.25-1.46(m,3H), 3.02-3.34(m,2H), 3.69-3.76(m,1H), 3.95–4.16(m,7H), 4.28–4.42(d,1H),6.85-6.99(m,4H),7.11(dd,1H),7.21(dd,1H),7.75-7.83(m,1H),8.39(dd,1H).

[0137] SP-20: 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid 2-chloropyridin-4-yl ester.

[0138]

[0139] 2-((2-ethoxyphenoxy)methyl)morpholine-4-carbonyl chloride (intermediate 1) (273 mg, 0.33 mmol) was added to a stirred and ice-cooled solution of 2-chloro-4-hydroxypyridine (95 mg, 0.73 mmol) in anhydrous THF (10 mL), followed by dropwise addition of NaH (60% in oil, 35 mg, 0.146 mmol). The reaction mixture was stirred at room temperature under argon for 14 hours. After evaporation of the solvent under vacuum, water (5 mL) was added and extracted with diethyl ether (3 × 10 mL). The organic phase was washed with dilute NaOH (pH 10–11), dried, and evaporated to dryness under vacuum. Purification by column chromatography (hexane:EtOAc 2:1) yielded 83 mg (29%) of semi-solid (SP-20). LCMS: 100% purity according to ELS detector. MS: M+H = 393.08. 1 H NMR (CDCl3, 400MHz): δppm 1.38-1.47(m,3H),3.04-3.32(m,2H),3.70(t,1H)3.9-3.93(m,1H),4.03-4.08(m,5H),4.15-4 .18(m,1H),4.30-4.35(m,1H),6.87-6.99(m,4H),7.11-7.12(m,1H),7.23(d,1H),8.37(d,1H).

[0140] SP-21: Bis(2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid)methylene ester.

[0141]

[0142] Cesium carbonate slurry (100 mg, 1.2 mmol) was added to a solution of 2-((2-ethoxyphenoxy)methyl)morpholine hydrochloride (108 mg, 0.4 mmol) and dibromomethane (50 mg) in DMF (2 mL). Carbon dioxide gas was passed into the reaction mixture for 30 min, and the mixture was stirred at room temperature for 48 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was dissolved in chloroform and purified by column chromatography (hexane:EtOAc 4:1) to give 52 mg (22.6%) of solid. Purity was 100% according to an ELS detector. MS: M+H = 575.15. 1 H NMR (CDCl3, 400MHz): δppm 6.7-7.00 (m, 8H), 5.83 (s, 2H), 3.8-4.2 (m, 16H), 3.5-3.6 (m, 2H), 2.8-3.0 (m, 4H), 1.43-1.47 (t, 6H).

[0143] SP-22: 1-((L-phenylalanyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid.

[0144] Step 1.

[0145]

[0146] The reaction mixture of N-Boc-phenylalanine (175 mg, 0.66 mmol), cesium carbonate (107 mg, 0.33 mmol), and methanol (1.3 mL) was stirred at room temperature for 3 hours. The methanol was then evaporated, and the residue was reconstituted with DMF (1 mL). 1-Chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (intermediate 3) (150 mg, 0.42 mmol) was added to the reaction mixture. The resulting mixture was stirred at 80 °C for 20 hours. The DMF was then evaporated under vacuum, and the residue was dissolved in chloroform and purified by column chromatography (hexane:EtOAc 8:2) to give 232 mg (61%) of a semi-solid oil.

[0147] Step 2:

[0148]

[0149] A solution of SP-22A (140 mg, 0.238 mmol) and 2 M HCl in dioxane was stirred overnight at room temperature. The solvent was evaporated and dried under vacuum to give 58 mg (52%) of the desired product as a light brown solid. LCMS: Purity: 100% according to ELS detector. MS: M+H = 495.24. 1 H NMR (CDCl3, 400MHz): δppm 1.25-1.50(m,6H),2.95-3.06(m,2H),3.35–3.71(m,4H)3.76-4.13(m,8H)4.34–4. 40(m,2H)6.85-6.92(m,5H),7.25-7.36(m,5H),8.70(br.s.,1H),8.79(br.s.,1H).

[0150] SP-23 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid 1-((dimethyl-L-valine)oxy)ethyl ester, hydrochloride.

[0151]

[0152] The reaction mixture of L-Val-N,N-dimethyl (100 mg, 0.68 mmol), cesium carbonate (110 mg, 0.34 mmol), and methanol (0.75 mL) was stirred at room temperature for 3 hours. The methanol was then evaporated, and the residue was reconstituted with DMF (1 mL). 1-Chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (intermediate 3) (160 mg, 0.44 mmol) was added to the reaction mixture. The resulting mixture was stirred at 80 °C for 20 hours. The DMF was evaporated under vacuum, and the residue was dissolved in chloroform and purified by column chromatography (hexane:EtOAc 3:2) to give 91 mg (45.7%) of a semi-solid.

[0153] 77 mg of the parent compound was dissolved in 2 ml of chloroform, and 0.17 ml of 2 M HCl in dioxane was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was then evaporated under argon and then under vacuum to give 81 mg of an oil. LCMS: Purity: 99.61% according to ELS detector. MS: M+H = 453.30 M+Na = 475.28. 1 H NMR (CDCl3, 400MHz): δppm 0.89(dd,3H),0.97(d,3H),1.45(t,3H),1.53(d,3H),1.63(s,1H),2.01(dt,6.54Hz,1H),2. 31(s,6H),2.72(m,1H),3.04(br.s.,2H),3.59(d,1H),3.81–4.18(m,8H),6.88-6.91(m,5H).

[0154] SP-24: 1-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid ethyl ester (acetyl-L-valine)oxy)

[0155]

[0156] The reaction mixture of N-acetylvaline (120 mg, 0.69 mmol), cesium carbonate (110 mg, 0.34 mmol), and methanol (0.9 mL) was stirred at room temperature for 3 hours. The methanol was then evaporated, and the residue was reconstituted with DMF (1 mL). 1-Chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (intermediate 3) (160 mg, 0.44 mmol) was added to the reaction mixture. The resulting mixture was stirred at 80 °C for 20 hours. The DMF was evaporated under vacuum, and the residue was dissolved in chloroform and purified by column chromatography (hexane:EtOAc 3:2) to give 75 mg (37%) of oil. LCMS: Purity: 100% according to ELS detector. MS: M+H = 473.26, M+Na = 495.24. 1 H NMR (CDCl3, 400MHz): δppm 0.82-1.03(m,3H),0.93(d,3H),1.45(br.s.,3H),1.52-1.53(m,3H),2.04(d,3H),2.17(m,1H),2.94-3. 10(m,2H),3.57-3.60(m,1H),3.84-4.17(m,8H),4.55-4.62(m,1H),5.97(br.s.,1H),6.89-6.95(m,5H).

[0157] SP-25: 1-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid ethyl ester, trifluoroacetate.

[0158] Step 1.

[0159]

[0160] The reaction mixture of N-Boc-D-valine (160 mg, 0.69 mmol), cesium carbonate (110 mg, 0.35 mmol), and methanol (1.2 mL) was stirred at room temperature for 3 hours. The methanol was then evaporated, and the residue was reconstituted with DMF (1 mL). 1-Chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (intermediate 3) (160 mg, 0.44 mmol) was added to the reaction mixture. The resulting mixture was stirred at 80 °C for 20 hours. The DMF was evaporated under vacuum, and the residue was dissolved in chloroform and purified by column chromatography (hexane:EtOAc 2:1) to give 90 mg (36.1%) of a semi-solid oil.

[0161] Step 2:

[0162]

[0163] A solution of SP-25A (50 mg, 0.09 mmol) in DCM (1 ml) and TFA (0.1 ml) was stirred overnight (18 hours) at room temperature. The solvent was then evaporated and dried under vacuum to give 35.8 mg (85.3%) of the desired product as a pure yellow oil. LCMS: Purity: 100% according to ELS detector. MS: M+H = 439.24. 1 H NMR (CDCl3, 400MHz): δ0.98-1.15(m,6H),1.36-1.49(m,3H),1.57(d,3H),2.37(br.s.,1H),2.78(s,3H),2.88-3.10(m,2H),3.14(d,1H),3. 49-3.64(m,1H),3.67(br.s.,1H),3.84(br.s.,1H),3.89(br.s.,1H),3.97(br.s.,2H),4.00-4.11(m,3H),4.16(d,2H),6.84-7.00(m,5H).

[0164] SP-26: HCl salt of 1-((D-valine)oxy)-2-methylpropyl 2-((2-ethoxyphenoxy)methyl)-morpholine-4-carboxylic acid.

[0165] Step 1:

[0166]

[0167] 1-Chloro-2-methylpropyl chloroformate (210 mg, 1.46 mmol) was added dropwise to a stirred, ice-cold mixture of 2-((2-ethoxyphenoxy)-methyl)morpholine hydrochloride (350 mg, 1.22 mmol), trimethylamine (271 mg, 2.68 mmol), and dichloromethane. The reaction mixture was stirred at 10-15 °C and allowed to reach room temperature for 2 hours. The precipitated solid was filtered off and the filtrate was concentrated. The crude product was purified by column chromatography (hexane:EtOAc 4:1) to give 0.55 gm (59.3%) of oil. 1 H NMR (CDCl3, 400MHz): δppm 1.06-1.09(m,6H),1.43–1.46(t,3H),2.18–2.22(m,1H),2.95-3.20(m,2H), 3.55-3.69(m,1H),3.86-4.27(m,8H),6.36-6.37(d,1H),6.86-6.97(m,4H).

[0168] Step 2.

[0169]

[0170] The reaction mixture of N-Boc-D-valine (200 mg, 0.92 mmol), cesium carbonate (150 mg, 0.46 mmol), and methanol (1.5 mL) was stirred at room temperature for 2 hours. The methanol was then evaporated, and the residue was reconstituted with DMF (1 mL). 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid 1-chloro-2-methylpropyl ester (SP-26A) (230 mg, 0.59 mmol) was added to the reaction mixture. The resulting mixture was stirred at 80 °C for 20 hours. The DMF was evaporated under vacuum, and the residue was dissolved in chloroform and purified by column chromatography (hexane:EtOAc 4:1) to give 170 mg (52.1%) of a semi-solid oil.

[0171] Step 3:

[0172]

[0173] A solution of SP-26B (110 mg, 0.2 mmol) in dioxane (1 mL) and 2 M HCl in dioxane (0.4 mL) was stirred overnight (18 h) at room temperature. The solvent was then evaporated and dried under vacuum to give 80 mg (88%) of the desired product as an oily substance. LCMS: Purity: 100% according to ELS detector. MS: M+H = 453.22. 1 H NMR (CDCl3, 400MHz): δppm 0.92-1.04(m,6H),1.04-1.23(m,6H),1.42(t,3H),2.09(br,1H),2.48(br,1H),2.89-3. 17(m,1H),3.49-4.25(m,13H),6.81-6.73(m,1H),6.88–6.92(m,4H),8.70–8.76(d,2H).

[0174] SP-27: 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid 1-(((R)-2-(aminomethyl)-3-methylbutyryl)oxy)ethyl ester trifluoroacetate.

[0175] Step 1.

[0176]

[0177] The reaction mixture of N-Boc-3-amino-2-isopropionic acid (100 mg, 0.43 mmol), cesium carbonate (70 mg, 0.22 mmol), and methanol (0.75 mL) was stirred at room temperature for 2 hours ("h"), followed by evaporation of methanol and reconstruction of the residue with DMF (0.75 mL). 1-Chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (intermediate 3) (99 mg, 0.28 mmol) was added to the reaction mixture. The resulting mixture was stirred at 80 °C for 20 hours. DMF was evaporated under vacuum, the residue was dissolved in chloroform, and purified by column chromatography (hexane:EtOAc 4:1) to give 117 mg (77.6%) of semi-solid.

[0178] Step 2:

[0179]

[0180] A solution of SP-27A (58 mg, 0.012 mmol) in chloroform (1 ml) and TFA (0.2 ml) was stirred at room temperature for 24 hours. The solvent was then evaporated and dried under vacuum to give 52 mg (90%) of the desired product as a pure oil. LCMS: Purity: 100% according to ELS detector. MS: M+H = 439.21. 1 H NMR (CDCl3, 400MHz): δppm0.86-1.04(m,6H),1.35-1.49(m,3H),1.53(br.s.,3H),2.96-3.09(m,1 H),3.10-3.31(m,2H),3.79-3.91(m,2H),3.92-4.16(m,6H),6.85-7.01(m,4H),7.65(br.s.,3H).

[0181] SP-28: 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid 1-(((R)-2-(aminomethyl)-3-methylbutyryl)oxy)ethyl ester trifluoroacetate.

[0182] Step 1.

[0183]

[0184] The reaction mixture of Boc-Val-Val (150 mg, 0.47 mmol), cesium carbonate (80 mg, 0.24 mmol), and methanol (1.13 mL) was stirred at room temperature for 2 hours. The methanol was then evaporated, and the residue was reconstituted with DMF (1 mL). 1-Chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (intermediate 3) (110 mg, 0.3 mmol) was added to the reaction mixture. The resulting mixture was stirred at 80 °C for 18 hours. The DMF was evaporated under vacuum, and the residue was dissolved in DCM and purified by column chromatography (hexane:EtOAc 1:1) to give 35 mg (11.9%) of a semi-solid.

[0185] Step 2:

[0186]

[0187] The solution of SP-28A (32 mg, 0.005 mmol) in chloroform (1 ml) and TFA (0.085 ml) was stirred at room temperature for 6 hours. The solvent was then evaporated and dried under vacuum to give 33 mg (98%) of the desired product as a yellow semi-solid. LCMS: Purity: 100% according to ELS detector. MS: M+H = 524.27. 1 H NMR (CDCl3, 400MHz): δppm0.87-1.16(m,11H),1.36-1.56(m,6H),2.18(br.s.,2H),2.99-3.05(m, 2H),3.59-4.24(m,11H),6.18(br.s.,2H),6.84-7.05(m,5H),7.34-7.53(m,1H),8.10(br.s.,2H).

[0188] SP-29: 2-((2-ethoxyphenoxy)-methyl)morpholine-4-carboxylic acid (((R)-3-amino-4-methylpentanoyl)oxy)methyl ester, trifluoroacetate

[0189] Step 1.

[0190]

[0191] The reaction mixture of Boc-L-β-leucine (150 mg, 0.65 mmol), cesium carbonate (110 mg, 0.146 mmol), and methanol (1.13 mL) was stirred at room temperature for 2 hours. The methanol was then evaporated, and the residue was reconstituted with DMF (1 mL). Chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (intermediate 2) (140 mg, 0.42 mmol) was added to the reaction mixture. The resulting mixture was stirred at 80 °C for 18 hours. The DMF was evaporated under vacuum, and the residue was dissolved in DCM and purified by column chromatography (hexane:EtOAc 4:1) to give 120 mg (54.5%) of a semi-solid.

[0192] Step 2:

[0193]

[0194] The solution of SP-29A (58 mg, 0.11 mmol) in chloroform (1 ml) and TFA (0.55 ml) was stirred at room temperature for 24 hours. The solvent was then evaporated and dried under vacuum to give 50 mg (90%) of the desired product as a pure oil. LCMS: Purity: 100% according to ELS detector. MS: M+H = 425.19. 1 H NMR (CDCl3, 400MHz): δppm 1.03(dd,6H),1.36-1.48(m,3H),2.04(m,1H),2.79(d,2H),2.93-3.22(m,2H),3.46(br.s.1H),3.57–3. 65(m,1H),3.90-4.18(m,6H),5.72-5.91(m,2H),6.86-7.02(m,3H),7.43-7.73(m,3H),8.35(br.s.,3H).

[0195] SP-30: Pyridine-3,5-dicarboxylic acid bis(((2-((2-ethoxyphenoxy)methyl)morpholine-4-carbonyl)oxy)methyl) ester

[0196]

[0197] The reaction mixture of 3,5-pyridinedicarboxylic acid (75 mg, 0.4 mmol), cesium carbonate (190 mg, 0.6 mmol), and methanol (0.6 mL) was stirred at room temperature for 2 hours. The methanol was then evaporated, and the residue was reconstituted with DMF (1 mL). Chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (intermediate 2) (370 mg, 1.1 mmol) was added to the reaction mixture. The resulting mixture was stirred at 80 °C for 18 hours. The DMF was evaporated under vacuum, and the residue was dissolved in DCM and purified by column chromatography (hexane:EtOAc 1:1) to give 56 mg (18.5%) of a semi-solid oil. LCMS: Purity: 100% according to ELS detector. MS: M+H = 754.21. 1 H NMR (CDCl3, 400MHz): δppm 1.44(t,6H),2.92-3.21(m,4H),3.57-3.67(m,2H),3.84(br.s,2H)3.93-4.12(m,12H ),4.18-4.27(m,2H),6.07-6.11(m,4H),6.82-7.04(m,8H),8.93(s,1H),9.43(s,2H).

[0198] SP-31: Bis(2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid)((2,2'-(methylazinediyl)bis(acetyl))bis(oxy))bis(methylene) ester.

[0199]

[0200] The reaction mixture of methyliminodiacetic acid (50 mg, 0.3 mmol), cesium carbonate (144 mg, 0.4 mmol), and methanol (0.4 mL) was stirred at room temperature for 2 hours. The methanol was then evaporated, and the residue was reconstituted with DMF (1 mL). Chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (intermediate 2) (280 mg, 0.8 mmol) was added to the reaction mixture. The resulting mixture was stirred at 80 °C for 18 hours. The DMF was evaporated under vacuum, and the residue was dissolved in DCM and purified by column chromatography (hexane:EtOAc 1:1). The product was repurified by a reversed-phase C18 column using a gradient mixture of acetonitrile and water to give 30.5 mg (13.8%) of a pure semi-solid oil. LCMS: Purity: 100% according to ELS detector. MS: M+H = 734.23. 1H NMR (CDCl3, 400MHz): δppm 1.43–1.48(t,6H),2.55(s,3H),2.89-3.18(m,4H),3.51-3.69(m,6H),3.82-4.24(m,16H),5.82(s,4H),6.83-7.00(m,8H).

[0201] SP-32: 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (((R)-2-(aminomethyl)-3-methylbutyryl)oxy)methyl ester, trifluoroacetate.

[0202] Step 1.

[0203]

[0204] The reaction mixture of N-Boc-3-amino-2-isopropylpropionic acid (10 mg, 0.4 mmol), cesium carbonate (78 mg, 0.2 mmol), and methanol (0.85 mL) was stirred at room temperature for 2 hours. The methanol was then evaporated, and the residue was reconstituted with DMF (1 mL). Chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (intermediate 2) (95 mg, 0.3 mmol) was added to the reaction mixture. The resulting mixture was stirred at 80 °C for 18 hours. The DMF was evaporated under vacuum, and the residue was dissolved in DCM and purified by column chromatography (hexane:EtOAc 4:1) to give 80 mg (50.8%) of a semi-solid.

[0205] Step 2:

[0206]

[0207] A solution of SP-32A (65 mg, 0.124 mmol) in chloroform (1 ml) and TFA (0.23 ml) was stirred at room temperature for 24 hours. The solvent was evaporated and dried under vacuum to give 49 mg (93%) of the desired product as a semi-solid oil. LCMS: Purity: 100% according to ELS detector. MS: M+H = 425.18. 1 H NMR (CDCl3, 400MHz): δppm 0.95(d,3H),0.93(d,3H),1.40-1.48(m,3H),2.13(br.s.,1H),2.72-2.83(m,1H),2.90-3.16(m,3H),3.2 0-3.32(m,1H),3.51-3.67(m,1H),3.84(d,1H),3.91-4.20(m,7H),5.74-5.86(m,2H),6.83-7.01(m,4H).

[0208] While certain embodiments have been described and illustrated, it should be understood that changes and modifications may be made to them in accordance with general art without departing from the broader aspects of the art as defined in the following claims.

[0209] The embodiments described herein may be suitably practiced in the absence of any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising / including,” “including,” and “containing” should be interpreted expansively and without limitation. Furthermore, the terms and expressions used herein have been used as descriptive rather than restrictive terms, and their use is not intended to exclude any equivalents of the features shown and described or portions thereof; however, it should be recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consistently composed of” will be understood to include those specifically listed elements as well as any additional elements that do not materially affect the essential and novel features of the claimed technology. The phrase “consisting of” excludes any unspecified elements.

[0210] This disclosure is not limited to the specific embodiments described herein. Many modifications and variations are possible without departing from the spirit and scope of this disclosure, and such modifications and variations will be apparent to those skilled in the art. Based on the foregoing description, functionally equivalent methods and compositions within the scope of this disclosure, other than those listed herein, will be apparent to those skilled in the art. Such modifications and variations are intended to fall within the scope of the appended claims. This disclosure is limited only by the terms of the appended claims and the full scope of their equivalents. It should be understood that this disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems, which can, of course, be varied. It will also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be restrictive.

[0211] Furthermore, in the context of describing features or aspects of this disclosure in accordance with the Markush group, those skilled in the art will recognize that this disclosure is also described in accordance with any individual member or subgroup of the Markush group.

[0212] As those skilled in the art will understand, for any and all purposes, particularly in providing a written description, all scopes disclosed herein also encompass any and all possible subscopes and combinations thereof. Any listed scope can be readily identified as adequately describing the same scope and enabling the same scope to be decomposed into at least two, three, four, five, ten, etc., equal parts. As a non-limiting example, each scope discussed herein can be readily decomposed into a lower third, a middle third, and an upper third, etc. As those skilled in the art will also understand, all language such as “at most,” “at least,” “greater than,” “less than,” etc., includes the enumerated numbers and refers to a scope that can subsequently be decomposed into subscopes as discussed above. Finally, as those skilled in the art will understand, a scope includes each individual member.

[0213] All publications, patent applications, granted patents and other documents mentioned in this specification are incorporated herein by reference as if each individual publication, patent application, granted patent or other document were expressly and individually incorporated by reference in its entirety. Definitions contained in the text incorporated by reference are excluded to the extent that they contradict the definitions in this disclosure.

[0214] In one embodiment, a method for preparing 2-((2-ethoxyphenoxy)methyl)morpholine-4-carbonyl chloride (intermediate 1) is provided, the method comprising:

[0215] The reaction of 2-((2-ethoxyphenoxy)methyl)-morpholine with a reaction mixture containing triphosgene is carried out.

[0216]

[0217] In other embodiments, the reaction mixture comprises dichloromethane. In other embodiments, the reaction mixture comprises sodium bicarbonate.

[0218] In some embodiments, intermediate 1 is used to prepare 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid 2-chloropyridin-4-yl ester (SP-20), comprising:

[0219] The reaction mixture of 2-((2-ethoxyphenoxy)methyl)morpholine-4-carbonyl chloride (intermediate 1) and 2-chloro-4-hydroxypyridine is reacted.

[0220]

[0221] In other embodiments, this reaction mixture also contains anhydrous tetrahydrofuran.

[0222] In some embodiments, a method is provided for preparing chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (intermediate 2), the method comprising:

[0223] The reaction mixture of 2-((2-ethoxyphenoxy)methyl)-morpholine and 1-chloromethyl chloroformate is reacted.

[0224]

[0225] In other embodiments, this reaction mixture contains trimethylamine. In other embodiments, this reaction mixture contains dichloromethane.

[0226] In some embodiments, intermediate 2 is used to prepare 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid ((D-valine)oxy)methyl ester (SP-16), comprising:

[0227] (a) Formed by reacting intermediate 2 with a reaction mixture containing N-Boc-D-valine (SP-16A); and

[0228]

[0229] (b) React SP-16A with dioxane in an organic acid.

[0230]

[0231] In other embodiments, the reaction mixture contains cesium carbonate. In other embodiments, the reaction mixture contains methanol. In some embodiments, the organic acid is hydrochloric acid.

[0232] In some embodiments, intermediate 2 is used to prepare 2-((2-ethoxyphenoxy)-methyl)morpholine-4-carboxylic acid (((R)-3-amino-4-methylpentanoyl)oxy)methyl ester (SP-29), comprising:

[0233] (a) SP-29A is formed by reacting intermediate 2 with a reaction mixture containing Boc-L-β-leucine; and

[0234]

[0235] (b) Stir SP-29A in chloroform and trifluoroacetic acid.

[0236]

[0237] In other embodiments, the reaction mixture contains cesium carbonate. In other embodiments, the reaction mixture contains methanol.

[0238] In other embodiments, intermediate 2 is used to prepare bis(((2-((2-ethoxyphenoxy)methyl)morpholine-4-carbonyl)oxy)methyl) pyridine-3,5-dicarboxylic acid ester (SP-30), comprising:

[0239] Intermediate 2 is reacted with a reaction mixture containing 3,5-pyridinedicarboxylic acid.

[0240]

[0241] In other embodiments, the reaction mixture contains cesium carbonate. In other embodiments, the reaction mixture contains methanol.

[0242] In some embodiments, intermediate 2 is used to prepare bis(2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid)((2-2'-(methylazanediyl)bis(acetyl))bis(oxy))bis(methylene) ester (SP-31), comprising:

[0243] Chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (intermediate 2) is reacted with a reaction mixture containing methyliminodiacetic acid.

[0244]

[0245] In other embodiments, the reaction mixture contains cesium carbonate. In other embodiments, the reaction mixture contains methanol.

[0246] In other embodiments, intermediate 2 is used to prepare 2-((2-ethoxyphenoxy)-methyl)morpholine-4-carboxylic acid (((R)-2-(aminomethyl)-3-methylbutyryl)oxy)methyl ester, trifluoroacetate (SP-32), comprising:

[0247] (a) SP-32A is formed by reacting intermediate 2 with a reaction mixture containing N-Boc-3-amino-2-isopropylpropionic acid; and

[0248]

[0249] (b) Stir SP-32A in chloroform and trifluoroacetic acid.

[0250]

[0251] In other embodiments, the reaction mixture contains cesium carbonate. In other embodiments, the reaction mixture contains methanol.

[0252] In another embodiment, a method for preparing 1-chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (intermediate 3) is provided, the method comprising:

[0253] The reaction mixture of 2-((2-ethoxyphenoxy)methyl)morpholine with a reaction mixture containing 1-chloroethyl chloroformate is then reacted.

[0254]

[0255] In other embodiments, the reaction mixture contains trimethylamine. In other embodiments, the reaction mixture contains dichloromethane.

[0256] In some embodiments, intermediate 3 is used to prepare 1-((L-valinel)oxy)ethyl ester of 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (SP-17), comprising:

[0257] (a) SP-17A is formed by reacting intermediate 3 with a reaction mixture containing N-Boc-L-valine; and

[0258]

[0259] (b) React SP-17A with dioxane in an organic acid.

[0260]

[0261] In other embodiments, the reaction mixture contains methanol. In other embodiments, the reaction mixture contains cesium carbonate. In some other embodiments, the organic acid is hydrochloric acid.

[0262] In some embodiments, intermediate 3 is used to prepare 1-((l-phenylalanyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (SP-22), comprising:

[0263] (a) SP-22A is formed by reacting intermediate 3 with a reaction mixture containing N-Boc-phenylalanine; and

[0264]

[0265] (b) React SP-22A with dioxane in an organic acid.

[0266]

[0267] In other embodiments, the reaction mixture further comprises cesium carbonate. In other embodiments, the reaction mixture further comprises methanol. In an alternative embodiment, the organic acid is hydrochloric acid.

[0268] In some embodiments, intermediate 3 is used to prepare 1-((dimethyl-L-valine)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (SP-23), comprising:

[0269] Intermediate 3 is reacted with a reaction mixture containing L-Val-N,N-dimethyl.

[0270]

[0271] In other embodiments, this reaction mixture contains cesium carbonate. In some embodiments, the reaction mixture contains methanol.

[0272] In some embodiments, intermediate 3 is used to prepare 1-((acetyl-L-valinel)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (SP-24), comprising:

[0273] Intermediate 3 is reacted with a reaction mixture containing N-acetylvaline.

[0274]

[0275] In other embodiments, this reaction mixture contains cesium carbonate. In some embodiments, the reaction mixture contains methanol.

[0276] In some embodiments, intermediate 3 is used to prepare 1-((methyl-D-valine)oxy)ethyl ester of 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (SP-25), comprising:

[0277] (a) SP-25A is formed by reacting intermediate 3 with a reaction mixture containing N-Boc-D-valine; and

[0278]

[0279] (b) React SP-25A with dichloromethane and trifluoroacetic acid.

[0280]

[0281] In other embodiments, the reaction mixture contains methanol. In some embodiments, the reaction mixture contains cesium carbonate.

[0282] In some embodiments, intermediate 3 is used to prepare 1-(((R)-2-(aminomethyl)-3-methylbutyryl)oxyethyl 2-((2-ethoxyphenoxy)-methyl)morpholine-4-carboxylic acid (SP-27), comprising:

[0283] (a) SP-27A is formed by reacting intermediate 3 with a reaction mixture containing N-Boc-3-amino-2-isopropionic acid; and

[0284]

[0285] (b) Stir the SP-27A solution in chloroform and trifluoroacetic acid.

[0286]

[0287] In other embodiments, the reaction mixture further comprises cesium carbonate. In other embodiments, the reaction mixture further comprises methanol.

[0288] In some embodiments, intermediate 3 is used to prepare 1-(((R)-2-(aminomethyl)-3-methylbutyryl)oxyethyl 2-((2-ethoxyphenoxy)-methyl)morpholine-4-carboxylic acid (SP-28), comprising:

[0289] (a) SP-28A is formed by reacting intermediate 3 with a reaction mixture containing Boc-Val-Val; and

[0290]

[0291] (b) Stir the SP-28A solution in chloroform and trifluoroacetic acid.

[0292]

[0293] In other embodiments, the reaction mixture also contains cesium carbonate. In some embodiments, the reaction mixture also contains methanol.

[0294] In one embodiment, a method for preparing (2R)-2-amino-N-((2-((2-ethoxyphenoxy)methyl)morpholino)methyl)-3-methylbutyramide (SP-18) is provided, the method comprising:

[0295] (a) SP-18A is formed by reacting 2-((2-ethoxyphenoxy)methyl)morpholine with a reaction mixture containing polyoxymethylene; and

[0296]

[0297] (b) React SP-18A with dioxane in an organic acid.

[0298]

[0299] In other embodiments, the reaction mixture also contains tetrahydrofuran. In some embodiments, the organic acid is hydrochloric acid.

[0300] In another embodiment, a method for preparing pyridin-2-yl ester of 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (SP-19) is provided, the method comprising:

[0301] (a) Formation of pyridin-2-yl chloroformate by reacting 2-hydroxypyridine with a reaction mixture containing N,N-diisopropylethylamine; and

[0302]

[0303] (b) Reacting pyridin-2-yl chloroformate with a second reaction mixture containing 2-((2-ethoxyphenoxy)methyl)morpholine

[0304]

[0305] In other embodiments, this reaction mixture contains triphosgene. In some embodiments, the reaction mixture contains dichloromethane. In other embodiments, the second reaction mixture contains dichloromethane. In other embodiments, the second reaction mixture contains triethylamine.

[0306] In one embodiment, a method for preparing bis(2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid methylene ester (SP-21) is provided, the method comprising:

[0307] The reaction mixture of 2-((2-ethoxyphenoxy)methyl)-morpholine and dibromomethane is reacted.

[0308]

[0309] In other embodiments, the reaction mixture contains dimethylformamide. In some embodiments, carbon dioxide gas is passed through the reaction mixture.

[0310] In another embodiment, a method is provided for preparing 1-((D-valinel)oxy)-2-methylpropyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid (SP-26), the method comprising:

[0311] (a) SP-26A is formed by reacting (2-((2-ethoxyphenoxy)-methyl)morpholine with a first reaction mixture containing 1-chloro-2-methylpropyl chloroformate;

[0312]

[0313] (b) SP-26B is formed by reacting SP-26A with a second reaction mixture containing N-Boc-D-valine; and

[0314]

[0315] (c) React SP-26B with dioxane in an organic acid.

[0316]

[0317] In other embodiments, the first reaction mixture comprises trimethylamine. In some embodiments, the first reaction mixture comprises dichloromethane. In other embodiments, the second reaction mixture comprises cesium carbonate. In some embodiments, the second reaction mixture comprises methanol. In other embodiments, the organic acid is hydrochloric acid.

[0318] Other embodiments are set forth in the appended claims.

Claims

1. A compound of Formula I, a stereoisomer thereof, or a salt thereof: ###0001### wherein: X is H, halogen, an amino acid residue, a substituted amino acid residue, alkyl, ester.

3. The compound of claim 2, wherein X is an amino acid residue. R 1 is alkyl, heterocyclyl or pyridyl; R 2 is alkyl, aryl, heteroaryl or heterocyclyl; R 3 -R 14 each independently H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl, or heterocyclyl; and 4. The compound of claim 3, wherein the amino acid residue comprises a hydrophobic side chain.

2. The compound of claim 1, wherein R 1 is CH2, CH2CH2, CH3CH, CH2CH2CH2, CH2CH2CH2CH2, (CH3)2C, (CH3)2CHCH, or (CH3)3CCH.

5. The compound of claim 4, wherein the amino acid residue having a hydrophobic side chain is valine.

6. The compound of claim 5, wherein R1 is CH2, CH3CH, or (CH3)2CHCH.

7. The compound of claim 6, which is: ###0002### 8. The compound of claim 4, wherein the amino acid residue having a hydrophobic side chain is phenylalanine.

9. The compound of claim 8, wherein R1 is CH3CH.

10. The compound of claim 9, which has the following structure: ###0003### ​ ​

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