Substituted morpholine derivatives and uses thereof

Abstract

A compound of formula I includes its stereoisomers and / or salts thereof; wherein R 1 is a substituted alkane group, a heterocyclic group or a pyridine group; X is hydrogen, a halogen, an amino acid residue, a substituted amino acid residue, an alkyl group or an ester. Such compounds can be used in pharmaceutical compositions and for the treatment of central nervous system (CNS) disorders:

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 162,671, filed on March 18, 2021, the entire contents of which are incorporated herein. Technical Field

[0003] The present technology generally relates to derivatives of substituted morpholines and their use in pharmaceutical compositions and for treating central nervous system (CNS) disorders. Background Art

[0004] (R,S)-2-[(2-ethoxyphenoxy)methyl]morpholine:

[0005]

[0006] It is a bicyclic morpholine derivative, designated CAS No. 46817-91-8 (for the HCl salt, CAS No. 35604-67-2). It is characterized by formula C 13 H 19 NO3, molecular weight is 237.295g / mol.

[0007] 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 also enhances the release of serotonin from neuronal stores.

[0008] However, treatment with 2-((2-ethoxyphenoxy)methyl)morpholine has been associated with numerous side effects, including nausea, vomiting, loss of appetite, increased erythrocyte sedimentation, EKG and EEG abnormalities, epigastric pain, diarrhea, constipation, vertigo, orthostatic hypotension, lower extremity edema, dysarthria, tremor, psychomotor agitation, confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, and seizures.

[0009] In order 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 morpholine have previously been disclosed in the art, for example in British Patent 1 243 391 and British Patent 1 260 886. In a different approach, the present inventors have synthesized novel derivatives of substituted morpholine. Prodrugs are a class of derivatives that, in many cases, have little or no pharmacological activity, which are converted into therapeutically active compounds in vivo. In some cases, the prodrug itself can have biological activity. Prodrug activation can occur by enzymatic or non-enzymatic cleavage of the temporary bond between the carrier and the drug molecule, or a combination of both in sequence or simultaneously.

[0010] Newly synthesized substituted morpholine derivatives (in which the morpholine amine group is derivatized in the structure of 2-((2-ethoxyphenoxy)methyl)morpholine) produce chemically stable compounds that serve as novel compounds. These derivatives of 2-((2-ethoxyphenoxy)methyl)morpholine can be used in pharmaceutical compositions and for treating central nervous system (CNS) disorders. Summary of the Invention

[0011] In one aspect, provided are derivatives of substituted morpholines, including compounds of Formula I, stereoisomers thereof, or salts thereof:

[0012]

[0013] In Formula I, R 1 It can be an alkyl group, a heterocyclic group or a pyridyl group, R 2 It can be an alkyl, aryl, heteroaryl or heterocyclic group, R 3 -R 14 R and R are each independently H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl or heterocyclyl; and X can be H, F, Cl, Br, I, an amino acid residue, a substituted amino acid residue, an alkyl group, or an ester.

[0014] In some embodiments, the present technology relates to substituted morpholine derivatives, stereoisomers thereof, and / or salts thereof according to the compound of Formula II:

[0015]

[0016] In Formula II, L can be an alkyl group, a substituted pyridine carboxylic acid, or a substituted azanediyl acetate; R 2 can be alkyl, aryl, heteroaryl or heterocyclic; and R 3 -R 14Each of them can independently be H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl or heterocyclic.

[0017] In some embodiments, the present technology relates to substituted morpholine derivatives, stereoisomers thereof, and / or salts thereof according to the compound of formula III:

[0018]

[0019] 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 can be alkyl, aryl, heteroaryl or heterocyclic; and R 3 -R 14 Each of them can independently be H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl or heterocyclic.

[0020] In some embodiments, provided are derivatives of substituted morpholines, stereoisomers thereof, and / or salts thereof according to Formula IV:

[0021]

[0022] 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 can be alkyl, aryl, heteroaryl or heterocyclic; and R 3 -R 14 Each of them can independently be H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl or heterocyclic.

[0023] In any of the above embodiments, R 2 Can be CH2CH3. In any of the above embodiments, R 3 -R 14 Each can be H.

[0024] In some aspects, a composition is provided comprising a substituted morpholine derivative of Formula I, II, III, or IV, a stereoisomer thereof, and / or a salt thereof, and at least one pharmaceutically acceptable excipient or carrier.

[0025] In some aspects, treatments for central nervous system ("CNS") disorders are provided, comprising administering to a subject in need thereof a pharmaceutical composition comprising a derivative of a substituted morpholine, including a compound of Formula I, II, III, or IV.

[0026] In some aspects, a method for preparing a derivative of a substituted morpholine, including a compound of Formula I, II, III, or IV, a stereoisomer thereof, and / or a salt thereof, is provided, the 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 a compound of Formula I, II, III, or IV. DETAILED DESCRIPTION

[0027] Definitions. The following terms are used throughout as defined below.

[0028] As used herein, the term "viloxazine" or 2-((2-ethoxyphenoxy)methyl)morpholine means (R,S)-2-[(2-ethoxyphenoxy)methyl]morpholine], including pharmaceutically acceptable salts or esters thereof, including a single (-) enantiomer or a single (+) enantiomer, or in the form of a racemic mixture or non-racemic mixture of enantiomers having varying amounts of the (-) and (+) enantiomers.

[0029] As used herein and in the appended claims, in the context of describing an element (especially in the context of the following claims), singular articles such as "a / an" and "the" and similar references should be interpreted as covering both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. Unless otherwise indicated herein, the recitation of a range of values ​​herein is intended only to serve as a shorthand method of individually referring to each individual value belonging to the range, and each individual value is incorporated into this specification as if individually recited herein. Unless otherwise indicated herein or the context clearly contradicts, all methods described herein can be performed in any suitable order. Unless otherwise stated, any and all examples 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. Any language in this specification should not be interpreted as indicating any unclaimed elements that are necessary.

[0030] As used herein, "about" will be understood by one of ordinary skill 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 one of ordinary skill in the art, "about" will mean up to plus or minus 10% of the particular term given the context in which it is used.

[0031] In general, reference to an element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Thus, radioactive isotopes such as tritium, C 14 、P 32and S 35 The procedures for inserting such labels into the compounds of the present technology will be apparent to those skilled in the art based on the disclosure herein.

[0032] In general, "substituted" refers to an organic group (e.g., an alkyl group) as defined below, wherein one or more bonds to hydrogen atoms contained therein are replaced by bonds to non-hydrogen atoms or non-carbon atoms. Substituted groups also include groups in which one or more bonds to carbon or hydrogen atoms are replaced by one or more bonds to heteroatoms (including double or triple bonds). Therefore, unless otherwise indicated, a substituted group is substituted by one or more substituents. In some embodiments, a substituted group is substituted by 1, 2, 3, 4, 5, or 6 substituents. Examples of substituents include: halogen (i.e., F, Cl, Br, and I); hydroxyl; alkoxy, alkenyloxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy; carbonyl (oxo); carboxylates; esters; polyurethanes; oximes; hydroxylamines; alkoxyamines; aralkyloxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyl; pentafluorosulfanyl (i.e., SF5), sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro; nitriles (i.e., CN); and the like.

[0033] As used herein, the term "carboxylate" refers to the conjugate base of a carboxylic acid having the chemical formula -COO.

[0034] As used herein, the term "ester" refers to -COOR 2 - and –C(O)OG groups. R 2 G is a carboxylate protecting group. Carboxylate protecting groups are well known to those of ordinary skill in the art. A detailed list of protecting groups for carboxylate 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 the protecting groups can be added or removed using the procedures specified therein, and the document is hereby incorporated by reference in its entirety and for any and all purposes, as fully set forth herein.

[0035] The term "amide" (or "amido") includes both C- and N-amide groups, namely C(O)NR 3 R 4and -NRC(O)-R groups. 3 and R 4 is independently hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. Amide groups thus include, but are not limited to, carbamoyl (-C(O)NH2) and carboxamide groups (NHC(O)H). In some embodiments, an amide is -NRC(O)-(C 1-5 In some embodiments, the amide is -NHC(O)-alkyl and the group is referred to as a "carbonylamino" group, and in other embodiments, the amide is -NHC(O)-alkyl and the group is referred to as an "alkanoylamino" group.

[0036] As used herein, the term "amine" (or "amino") refers to a -NR 5 R 6 Group, where R 5 and R 6 is independently hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl 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.

[0037] As used herein, the term "halogen" or "halo" refers to bromine (Br), chlorine (Cl), fluorine (F), or iodine (I). In some embodiments, the halogen is chlorine (Cl).

[0038] 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" can be combined with a prefix indicating the number of amino acids in the peptide, for example, a "pentapeptide" is a peptide having five amino acids.

[0039] The term "amino acid" is art-recognized and generally refers to a natural or unnatural alpha or beta amino acid. 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.

[0040] 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), 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).

[0041] The term "acetyl" as used herein refers to a methyl group bonded to a carbonyl group (CH3CO-).

[0042] As used herein, the term "pyridine" group refers to a group of a heterocyclic organic compound having the chemical formula C5H5N.

[0043] The term "pyridinecarboxylic acid" as used herein refers to a compound having a pyridine ring and a carboxyl group.

[0044] As used herein, the term "azanediyl" refers to a functional group having the formula -NH; the group is bonded to the rest of the compound through two single bonds.

[0045] Pharmaceutically acceptable salts of the compounds described herein are within the scope of the present 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 overly toxic, allergic, or irritating and are bioavailable). When the compound of the present technology has a basic group (such as, for example, an amino group), it can be formed with inorganic acids (such as hydrochloric acid, boric 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 compound of the present technology has an acidic group (such as, for example, a carboxylic acid group), it can be formed with metals, such as alkali metals and alkaline earth metals (such as Na + 、Li + , K + , Ca 2+ Mg 2+ or Zn 2+ ), ammonia or an organic amine (for example, dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine or triethanolamine) or a basic amino acid (for example, arginine, lysine or ornithine) to form a salt. Such salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base or free acid form with a suitable acid or base, respectively, and isolating the salt thus formed.

[0046] Unless specific stereochemistry is explicitly indicated, stereoisomers (also referred to as optical isomers) of a compound include all chiral, diastereomeric, and racemic forms of the structure. Thus, as will be apparent from the description, the compounds used in the present technology include enriched or resolved optical isomers at any or all asymmetric atoms. Racemic and diastereomeric mixtures, as well as individual optical isomers, can be separated or synthesized to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are within the scope of the present technology.

[0047] The term "pharmaceutically acceptable excipient" refers to those substances that are widely accepted by industry and regulatory agencies, such as those listed in monographs published in, for example, the USP-NF, the Food Chemicals Codex, the Code of Federal Regulations (CFR), the FDA Inactive Ingredient Guide, and in the compendium of 21 CFR parts 182 and 184 that lists substances that are generally regarded as safe (GRAS) food ingredients.

[0048] In one aspect, provided is a compound represented by Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0049]

[0050] In the compound of formula I, R 1 It can be an alkyl group, a heterocyclic group or a pyridyl group; R 2 It can be an alkyl, aryl, heteroaryl or heterocyclic group; R 3 -R 14 can each independently be 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, ester. In some preferred embodiments, R 2 In any of the above embodiments, R 1 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 can 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 R can independently be H, F, Cl, Br, I or alkyl. In some such embodiments, R 3 -R 14 Each of R is independently H or C1-C6 alkyl. 3 -R 14are all H. In any of the above embodiments, R 1 In the above embodiments, R1 may be CH2 or C2H5, and / or X may be an ester. In the above embodiments, R 1 may be pyridyl and X may be F, Cl, Br or I.

[0051] In various embodiments, the compound represented by Formula I is one or more of the following compounds, it being understood that each representation also includes any R, S, or racemic structure when a chiral center is present:

[0052]

[0053]

[0054]

[0055]

[0056]

[0057] In some embodiments, the compound represented by Formula I is:

[0058]

[0059] In the above formula, R 15 Can be H, alkyl or -C(O)OR 17 ; R 16 Can be H, alkyl or -C(O)OR 17 ; and R 17 Can be H or alkyl. In some embodiments, R 15 can be an alkyl group, and R 16 Can be H or alkyl. In such embodiments, R 15 can be methyl, and R 16 Can be H or methyl. In some embodiments, R 15 and R 16 In some embodiments, R 15 Yes-C(O)OR 17 , R 16 is H, and R 17 It's methyl.

[0060] In another aspect, provided is a compound represented by Formula II or a stereoisomer and / or a salt thereof:

[0061]

[0062] In Formula II, L is an alkyl group, a substituted pyridinecarboxylic acid, or a substituted azanediyl acetate; R 2 is alkyl, aryl, heteroaryl or heterocyclyl; and R 3 -R 14 Each is independently H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl or heterocyclyl. In some embodiments, R 2 It's ethyl.

[0063] In some embodiments, the compound represented by Formula II is:

[0064]

[0065] In various embodiments, the compound of Formula II is one or more of:

[0066]

[0067]

[0068] In another aspect, provided is a compound represented by Formula III or a stereoisomer and / or a salt thereof:

[0069]

[0070] 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 can be alkyl, aryl, heteroaryl or heterocyclic; and R 3 -R 14 Each of R is independently H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl or heterocyclyl. 2 It's ethyl.

[0071] In some embodiments, the compound represented by Formula III is:

[0072]

[0073] In some embodiments, the compound represented by Formula III is:

[0074]

[0075] In another aspect, there is provided a compound represented by Formula IV, or a stereoisomer thereof, and / or a salt thereof:

[0076]

[0077] 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 can be alkyl, aryl, heteroaryl or heterocyclic; and R 3 -R 14 Each of R is independently H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl or heterocyclyl. 2 It's ethyl.

[0078] In some embodiments, the compound represented by Formula IV is:

[0079]

[0080] In some embodiments, the compound represented by Formula IV is:

[0081]

[0082] In some embodiments, the composition comprises a substituted morpholine derivative of Formula I, II, III, or IV, a stereoisomer thereof, and / or a salt thereof and at least one pharmaceutically acceptable excipient or carrier.

[0083] In some embodiments, the pharmaceutical composition comprises a substituted morpholine derivative comprising Formula I, II, III or IV, its stereoisomers and / or salts thereof and a pharmaceutically acceptable carrier or excipient. The pharmaceutical preparation can be in an appropriate dosage form. Illustrative dosage forms include, but are not limited to, injections, oral dosage forms, suppositories, cachets, sachets, transdermal formulations, and the like.

[0084] In another aspect, treatment of a CNS disorder is provided by administering to a subject in need thereof a composition comprising a derivative of a substituted morpholine of Formula I, II, III, or IV, or a salt thereof, as described herein.

[0085] In another aspect, a method for administering a composition comprising a compound of Formula I, II, III or IV, or a salt thereof, to a subject is provided. In one aspect, the subject is a mammal. In other embodiments, the mammalian subject is a human. In specific embodiments, the mammalian subject is an adult or a human child.

[0086] In some embodiments, the methods described herein comprise administering a derivative of a substituted morpholine of Formula I, II, III, or IV, a stereoisomer thereof, and / or a salt thereof, together with at least one additional agent. In some embodiments, the at least one additional agent is another agent for a CNS disorder. In other embodiments, the at least one additional agent is 2-((2-ethoxyphenoxy)methyl)morpholine or a salt thereof.

[0087] In one embodiment, derivatives of substituted morpholines can be prepared from 2-((2-ethoxyphenoxy)methyl)morpholine or a salt thereof.

[0088] In one embodiment, derivatives of substituted morpholines 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:

[0089]

[0090] In one embodiment, a derivative of a substituted morpholine 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:

[0091]

[0092] In one embodiment, a derivative of a substituted morpholine 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:

[0093]

[0094] In one embodiment, the derivative of a substituted morpholine 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.

[0095] In another embodiment, a method of preparing a derivative of a substituted morpholine of Formula I, II, III, or IV is provided.

[0096] The substituted morpholine derivatives can be analyzed by liquid chromatography-mass spectrometry (LCMS) and nuclear magnetic resonance (NMR) spectroscopy.

[0097] The invention thus generally described will be understood more readily by reference to the following examples which are provided by way of illustration and are not intended to be limiting of the invention.

[0098] Example

[0099] Procedures for Preparing Intermediates It is understood that while in some structures, chiral centers are depicted in the R or S configuration, other configurations are disclosed herein.

[0100] Intermediate 1: Synthesis of 2-((2-ethoxyphenoxy)methyl)morpholine-4-carbonyl chloride.

[0101]

[0102] 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 at 10-15° C. over 15 minutes. The reaction mixture was stirred at room temperature for 3 hours. The reaction mass was filtered to remove sodium chloride, and the filtrate was concentrated in vacuo to give 438 mg of ethylmethylcarbamoyl chloride as a light yellow oil (yield: 80%).

[0103] 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).

[0104] Intermediate 2: Chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate.

[0105]

[0106] 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 was added 1-chloromethyl chloroformate dropwise. The reaction mixture was stirred at 10-15°C, allowed to reach room temperature and stirred for 5 hours. The precipitated solid was filtered and the filtrate was concentrated. The crude product was purified by column chromatography (hexane:EtOAc 7:3) to give 1.2 gm (80%) of a white solid.

[0107] 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).

[0108] Intermediate 3: 1-chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate.

[0109]

[0110] 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 was added 1-chloroethyl chloroformate (1.19 g, 83.5 mmol) dropwise. The reaction mixture was stirred at 10-15° C. and allowed to reach room temperature and stirred for 5 hours. The precipitated solid was filtered 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 a white solid.

[0111] 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).

[0112] Procedure for the synthesis of compounds of formula I, II, III or IV:

[0113] SP-16: ((D-valyl)oxy)methyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate.

[0114] Step 1.

[0115]

[0116] The reaction mixture of N-Boc-D-valine (175mg, 0.80mmol), cesium carbonate (130mg, 0.4mmol) in methanol (3.3ml) was stirred at room temperature for 3 hours, then methanol was evaporated and the residue was reconstructed with DMF (1ml). 2-((2-ethoxyphenoxy) methyl) morpholine-4-chloromethyl formate (intermediate 2) (177mg, 0.52mmol) 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 1: 1) to give 112mg (39.4%) of semi-solid oil.

[0117] Step 2:

[0118]

[0119] A solution of SP-16A (65 mg, 0.12 mmol) and 2M HCl in dioxane was stirred at room temperature overnight. The solvent was evaporated and dried under vacuum to give 50 mg (95.6%) of the pure desired product (SP-16) as a brown semisolid. LCMS: Purity: 96.27% by 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).

[0120] SP-17: 1-((L-valyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate.

[0121] Step 1.

[0122]

[0123] The reaction mixture of N-Boc-L-valine (175mg, 0.80mmol), cesium carbonate (130mg, 0.4mmol) in methanol (3.3ml) was stirred at room temperature for 3 hours, then methanol was evaporated and the residue was reconstructed with DMF (1ml). 2-((2-ethoxyphenoxy) methyl) morpholine-4-carboxylic acid 1-chloroethyl ester (intermediate 3) (184mg, 0.52mmol) 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 8:2) to give 141mg (48.3%) of semi-solid oil.

[0124] Step 2:

[0125]

[0126] A solution of SP-17A (65 mg, 0.11 mmol) and 2M HCl in dioxane was stirred at room temperature overnight. The solvent was then evaporated and the product dried under vacuum to give 51 mg (92.4%) of the pure desired product (SP-17) as a brown solid. LCMS: Purity: 100% by 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).

[0127] SP-18: (2R)-2-amino-N-((2-((2-ethoxyphenoxy)methyl)morpholino)methyl)-3-methylbutanamide dihydrochloride.

[0128] Step 1:

[0129]

[0130] To a solution of 2-((2-ethoxyphenoxy)methyl)-morpholine hydrochloride (108mg, 0.4mmol) and polyoxymethylene (50mg) in THF (2ml) was added sodium bicarbonate slurry (92mg, 1.1mmol). The reaction mixture was stirred for 48 hours. The reaction mass 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 80mg (43%) of semi-solid oil.

[0131] Step 2:

[0132]

[0133] A solution of SP-18A (70 mg, 0.15 mmol) and 2M HCl in dioxane was stirred at room temperature overnight. The solvent was evaporated and dried under vacuum to give 50 mg (76%) of the pure desired product (SP-18) as a brown solid. LCMS: M+H = 366.20. Purity 98.73% according to ELS detection. 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).

[0134] SP-19: 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid pyridin-2-yl ester

[0135]

[0136] By triphosgene (163mg, 0.55mmol) in dichloromethane (DCM; 1ml) solution in was stirred at 0 DEG C-5 DEG C temperature in an ice bath for 15 minutes, and 2-hydroxypyridine (150mg, 1.58mmol), N, N-diisopropylethylamine (DIPEA; 208mg, 1.61mmol) in DCM (1ml) were added dropwise. The reaction mixture was allowed to reach room temperature. The completion of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was evaporated, reconstructed with DCM and evaporated (X3) to remove excess triphosgene. The residue was reconstructed with DCM, and a solution of 2- ((2- ethoxyphenoxy) methyl) morpholine hydrochloride (363mg, 1.26mmol) and TEA (13.6mg, 1.34mmol) in DCM was added, and stirred at room temperature overnight. The reaction mixture was adsorbed onto silica and purified by column chromatography using hexane-ethyl acetate (2:1) to obtain 56 mg (12.3%) of the target compound (SP-19) as a semisolid. LCMS: M+H = 359.08. ELS detector: 100% purity. 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-chloropyridin-4-yl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate.

[0138]

[0139] To a stirred and ice-cooled solution of 2-chloro-4-hydroxypyridine (95 mg, 0.73 mmol) in anhydrous THF (10 mL) was added 2-((2-ethoxyphenoxy)methyl)morpholine-4-carbonyl chloride (intermediate 1) (273 mg, 0.33 mmol), 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 evaporating the solvent in vacuo, water (5 mL) was added and extracted with ether (3 × 10 mL). The organic phase was washed with dilute NaOH (pH 10-11), dried, and evaporated to dryness in vacuo. Purification by column chromatography (hexane: EtOAc 2: 1) gave 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] To a solution of 2-((2-ethoxyphenoxy)methyl)morpholine hydrochloride (108 mg, 0.4 mmol) and dibromomethane (50 mg) in DMF (2 ml) was added cesium carbonate slurry (100 mg, 1.2 mmol). Carbon dioxide gas was passed through the reaction for 30 minutes and the mixture was stirred at room temperature for 48 hours. The reaction mass 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. According to the ELS detector, the purity was 100%. 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-carboxylate.

[0144] Step 1.

[0145]

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

[0147] Step 2:

[0148]

[0149] A solution of SP-22A (140 mg, 0.238 mmol) and 2M HCl in dioxane was stirred at room temperature overnight. The solvent was evaporated and dried under vacuum to give 58 mg (52%) of the pure desired product as a light brown solid. LCMS: Purity: 100% by 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 1-((dimethyl-L-valyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate, hydrochloride.

[0151]

[0152] The reaction mixture of L-Val-N, N- dimethyl (100mg, 0.68mmol), cesium carbonate (110mg, 0.34mmol) in methanol (0.75ml) was stirred at room temperature for 3 hours, then methanol was evaporated and the residue was reconstructed with DMF (1ml). 2- ((2- ethoxyphenoxy) methyl) morpholine-4-carboxylic acid 1- chloroethyl ester (intermediate 3) (160mg, 0.44mmol) 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 3: 2) to give 91mg (45.7%) semi-solid.

[0153] 77 mg of the parent compound was dissolved in 2 ml of chloroform and 0.17 ml of 2M 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 yield 81 mg of an oil. LCMS: Purity: 99.61% by 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-((acetyl-L-valyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate.

[0155]

[0156] The reaction mixture of N-acetyl valine (120 mg, 0.69 mmol), cesium carbonate (110 mg, 0.34 mmol) in methanol (0.9 ml) was stirred at room temperature for 3 hours, then the methanol was evaporated and the residue was reconstructed with DMF (1 ml). 1-Chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (intermediate 3) (160 mg, 0.44 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 3: 2) to give 75 mg (37%) of oil. LCMS: Purity: 100% according to ELS detector. MS: M+H=473.26M+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-((methyl-D-valyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate, trifluoroacetate.

[0158] Step 1.

[0159]

[0160] The reaction mixture of N-Boc-D-valine (160mg, 0.69mmol), cesium carbonate (110mg, 0.35mmol) in methanol (1.2ml) was stirred at room temperature for 3 hours, then methanol was evaporated and the residue was reconstructed with DMF (1ml). 2-((2-ethoxyphenoxy) methyl) morpholine-4-carboxylic acid 1-chloroethyl ester (intermediate 3) (160mg, 0.44mmol) 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 2: 1) to give 90mg (36.1%) of 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 at room temperature overnight (18 hours). The solvent was then evaporated and dried under vacuum to give 35.8 mg (85.3%) of the pure desired product as a yellow oil. LCMS: Purity: 100% by 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: 2-((2-Ethoxyphenoxy)methyl)-morpholine-4-carboxylic acid 1-((D-valyl)oxy)-2-methylpropyl ester HCl salt.

[0165] Step 1:

[0166]

[0167] 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 was added dropwise 1-chloro-2-methylpropyl chloroformate (210 mg, 1.46 mmol). The reaction mixture was stirred at 10-15° C. and allowed to reach room temperature and stirred for 2 hours. The precipitated solid was filtered 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 an oil. 1 HNMR (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 (200mg, 0.92mmol), cesium carbonate (150mg, 0.46mmol) in methanol (1.5ml) was stirred at room temperature for 2 hours, then methanol was evaporated and the residue was reconstructed with DMF (1ml). 2-((2-ethoxyphenoxy) methyl) morpholine-4-carboxylic acid 1-chloro-2-methylpropyl esters (SP-26A) (230mg, 0.59mmol) were 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 170mg (52.1%) of semi-solid oil.

[0171] Step 3:

[0172]

[0173] A solution of SP-26B (110 mg, 0.2 mmol) in dioxane (1 ml) and 2M HCl in dioxane (0.4 ml) was stirred at room temperature overnight (18 hours). The solvent was then evaporated and dried under vacuum to give 80 mg (88%) of the pure desired product as an oil. LCMS: Purity: 100% by 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: 1-(((R)-2-(aminomethyl)-3-methylbutanoyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate 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) in methanol (0.75 ml) was stirred at room temperature for 2 hours ("h"), then the methanol was evaporated and the residue was reconstructed with DMF (0.75 ml). 1-Chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (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 pure desired product as an oil. LCMS: Purity: 100% by 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: 1-(((R)-2-(aminomethyl)-3-methylbutanoyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate trifluoroacetate.

[0182] Step 1.

[0183]

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

[0185] Step 2:

[0186]

[0187] A 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 pure desired product as a yellow semisolid. LCMS: Purity: 100% by 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: ((R)-3-amino-4-methylpentanoyl)oxy)methyl 2-((2-ethoxyphenoxy)-methyl)morpholine-4-carboxylate, trifluoroacetate

[0189] Step 1.

[0190]

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

[0192] Step 2:

[0193]

[0194] A 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 pure desired product as an oil. LCMS: Purity: 100% by 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: Bis(((2-((2-ethoxyphenoxy)methyl)morpholine-4-carbonyl)oxy)methyl)pyridine-3,5-dicarboxylate

[0196]

[0197] The reaction mixture of 3,5-pyridinedicarboxylic acid (75 mg, 0.4 mmol), cesium carbonate (190 mg, 0.6 mmol) in methanol (0.6 ml) was stirred at room temperature for 2 hours, then the methanol was evaporated and the residue was reconstructed with DMF (1 ml). 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid chloromethyl ester (intermediate 2) (370 mg, 1.1 mmol) was added to the reaction mixture. The resulting mixture was stirred at 80 ° C for 18 hours. DMF was evaporated under vacuum, the residue was dissolved in DCM and purified by column chromatography (hexane: EtOAc 1: 1) to give 56 mg (18.5%) of 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′-(methylazanediyl)bis(acetyl))bis(oxy))bis(methylene) ester.

[0199]

[0200] The reaction mixture of methyliminodiacetic acid (50mg, 0.3mmol), cesium carbonate (144mg, 0.4mmol) in methanol (0.4ml) was stirred at room temperature for 2 hours, then the methanol was evaporated and the residue was reconstructed with DMF (1ml). 2-((2-ethoxyphenoxy)methyl)morpholine-4-chloromethyl formate (intermediate 2) (280mg, 0.8mmol) was added to the reaction mixture. The resulting mixture was stirred at 80°C for 18 hours. DMF was evaporated under vacuum, the residue was dissolved in DCM and purified by column chromatography (hexane: EtOAc 1: 1). The resulting product was re-purified using an acetonitrile and water gradient mixture by a reversed-phase C18 column to obtain 30.5mg (13.8%) of pure semi-solid oily product. 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: (((R)-2-(aminomethyl)-3-methylbutanoyl)oxy)methyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate, trifluoroacetate.

[0202] Step 1.

[0203]

[0204] The reaction mixture of N-Boc-3-amino-2-isopropylpropionic acid (10mg, 0.4mmol), cesium carbonate (78mg, 0.2mmol) in methanol (0.85ml) was stirred at room temperature for 2 hours, then methanol was evaporated and the residue was reconstructed with DMF (1ml). 2-((2-ethoxyphenoxy) methyl) morpholine-4-chloromethyl formate (intermediate 2) (95mg, 0.3mmol) was added to the reaction mixture. The resulting mixture was stirred at 80°C for 18 hours. DMF was evaporated under vacuum, the residue was dissolved in DCM and purified by column chromatography (hexane: EtOAc 4: 1) to give 80mg (50.8%) 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 pure desired product as a semisolid oil. LCMS: Purity: 100% by 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 illustrated and described, it will be understood that changes and modifications may be made thereto in accordance with ordinary skill in the art without departing from the broader aspects of the technology as defined in the following claims.

[0209] The embodiments illustratively described herein can be appropriately practiced in the absence of any one or more elements, one or more limitations not specifically disclosed herein. Thus, for example, the terms "comprise / include", "include", "contain" etc. should be understood expansively and without restriction. In addition, the terms and expressions adopted herein have been used as descriptive terms rather than restrictive terms, and when using such terms and expressions, it is not intended to exclude any equivalents of the features shown and described or parts thereof, but it should be recognized that various modifications are possible within the scope of the claimed technology. In addition, the phrase "essentially consisting of..." will be understood to include those elements specifically enumerated and those additional elements that will not substantially affect the basic and novel features of the claimed technology. The phrase "consisting of..." excludes any unspecified elements.

[0210] The present disclosure is not limited to the specific embodiments described in this application. Without departing from the spirit and scope of the present disclosure, many modifications and variations can be made, and the 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 the present disclosure other than those methods and compositions 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. The present disclosure is limited only by the terms of the appended claims and the full scope of the equivalents granted by these claims. It should be understood that the present disclosure is not limited to specific methods, reagents, compounds, compositions or biological systems, which can certainly vary. It will also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to be restrictive.

[0211] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0212] As will be understood by those skilled in the art, for any and all purposes, particularly in providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily identified as fully describing the same range and enabling the same range to be decomposed into at least equal halves, thirds, quarters, fifths, tenths, etc. As non-limiting examples, each range discussed herein can be easily decomposed into a lower third, a middle third, and an upper third, etc. As will be understood by those skilled in the art, all languages ​​such as "at most," "at least," "greater than," "less than," etc. include the enumerated numbers and refer to ranges that can subsequently be decomposed into subranges as discussed above. Finally, as will be understood by those skilled in the art, a range includes each individual member.

[0213] All publications, patent applications, issued patents, and other documents mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in text incorporated by reference are excluded to the extent they conflict with definitions in this disclosure.

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

[0215] Reacting 2-((2-ethoxyphenoxy)methyl)-morpholine with a reaction mixture containing triphosgene

[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-chloropyridin-4-yl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (SP-20), comprising:

[0219] 2-((2-ethoxyphenoxy)methyl)morpholine-4-carbonyl chloride (Intermediate 1) is reacted with a reaction mixture containing 2-chloro-4-hydroxypyridine

[0220]

[0221] In other embodiments, the reaction mixture further comprises anhydrous tetrahydrofuran.

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

[0223] 2-((2-ethoxyphenoxy)methyl)-morpholine is reacted with a reaction mixture containing 1-chloromethyl chloroformate

[0224]

[0225] In other embodiments, the reaction mixture comprises trimethylamine. In other embodiments, the reaction mixture comprises dichloromethane.

[0226] In some embodiments, Intermediate 2 is used to prepare ((D-valyl)oxy)methyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (SP-16) comprising:

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

[0228]

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

[0230]

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

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

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

[0234]

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

[0236]

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

[0238] In other embodiments, Intermediate 2 is used to prepare bis(((2-((2-ethoxyphenoxy)methyl)morpholine-4-carbonyl)oxy)methyl)pyridine-3,5-dicarboxylate (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 comprises cesium carbonate. In other embodiments, the reaction mixture comprises 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) was reacted with a reaction mixture containing methyliminodiacetic acid

[0244]

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

[0246] In other embodiments, Intermediate 2 is used to prepare (((R)-2-(aminomethyl)-3-methylbutanoyl)oxy)methyl 2-((2-ethoxyphenoxy)-methyl)morpholine-4-carboxylate, trifluoroacetate (SP-32) comprising:

[0247] (a) forming SP-32A by reacting intermediate 2 with a reaction mixture comprising 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 comprises cesium carbonate. In other embodiments, the reaction mixture comprises methanol.

[0252] In another embodiment, there is provided a process for preparing 1-chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (Intermediate 3), comprising:

[0253] Reacting 2-((2-ethoxyphenoxy)methyl)morpholine with a reaction mixture containing 1-chloroethyl chloroformate

[0254]

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

[0256] In some embodiments, Intermediate 3 is used to prepare 1-((L-valyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (SP-17) comprising:

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

[0258]

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

[0260]

[0261] In other embodiments, the reaction mixture comprises methanol. In other embodiments, the reaction mixture comprises 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-carboxylate (SP-22), comprising:

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

[0264]

[0265] (b) Reaction of 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 alternative embodiments, the organic acid is hydrochloric acid.

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

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

[0270]

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

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

[0273] Intermediate 3 is reacted with a reaction mixture containing N-acetyl valine

[0274]

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

[0276] In some embodiments, Intermediate 3 is used to prepare 1-((methyl-D-valyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (SP-25) comprising:

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

[0278]

[0279] (b) Reaction of SP-25A with dichloromethane and trifluoroacetic acid

[0280]

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

[0282] In some embodiments, Intermediate 3 is used to prepare 1-(((R)-2-(aminomethyl)-3-methylbutanoyl)oxy)ethyl 2-((2-ethoxyphenoxy)-methyl)morpholine-4-carboxylate (SP-27), comprising:

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

[0284]

[0285] (b) Stirring a solution of SP-27A 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-methylbutanoyl)oxy)ethyl 2-((2-ethoxyphenoxy)-methyl)morpholine-4-carboxylate (SP-28), comprising:

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

[0290]

[0291] (b) Stirring a solution of SP-28A in chloroform and trifluoroacetic acid

[0292]

[0293] In other embodiments, the reaction mixture further comprises cesium carbonate. In some embodiments, the reaction mixture further comprises methanol.

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

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

[0296]

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

[0298]

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

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

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

[0302]

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

[0304]

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

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

[0307] Reacting 2-((2-ethoxyphenoxy)methyl)-morpholine with a reaction mixture containing dibromomethane

[0308]

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

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

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

[0312]

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

[0314]

[0315] (c) Reaction of 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 accompanying claims.

Claims

1. A compound of formula I, a stereoisomer thereof or a salt thereof: in: R 1 is CH2, CH2CH2, CH3CH, CH2CH2CH2, CH2CH2CH2CH2, CH3CH2CH2CH, (CH3)2C, (CH3)2CHCH, (CH3)3CCH or pyridyl; R 2 It is ethyl; R 3 -R 14 are each independently H, F, Cl, Br, I, CN, NO2 or C1-C6 alkyl; and X, when R 1 When it is pyridyl, it is H or halogen; or X, when R 1 when it is CH2, CH2CH2, CH3CH, CH2CH2CH2, CH2CH2CH2CH2, CH3CH2CH2CH, (CH3)2C, (CH3)2CHCH or (CH3)3CCH, it is a halogen, an amino acid residue having a hydrophobic side chain or an ester; wherein the amino acid residue having a hydrophobic side chain is selected from alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine and tryptophan, and When X is an ester, the compound of formula I is:

2. The compound of claim 1, wherein the amino acid residue having a hydrophobic side chain is unsubstituted.

3. The compound of claim 2, wherein the amino acid residue having a hydrophobic side chain is valine.

4. The compound of claim 3, wherein R1 is CH2, CH3CH or (CH3)2CHCH.

5. The compound of claim 4, which is: The compound of claim 2 , wherein the amino acid residue having a hydrophobic side chain is phenylalanine.

7. The compound of claim 6, wherein R1 is CH3CH.

8. The compound of claim 7, having the following structure:

9. The compound of claim 2, wherein R 3 -R 14 Each of the groups is independently H, F, Cl, Br, I or C1-C6 alkyl.

10. The compound of claim 9, wherein R 3 -R 14 Each of the groups is independently H or C1-C6 alkyl.

11. The compound of claim 10, wherein R 3 -R 14 All are H.

12. The compound of claim 11, wherein R 1 It is CH2, CH2CH2, CH3CH, CH2CH2CH2CH2 or CH3CH2CH2CH or (CH3)3CCH.

13. A compound of the formula: in: R 15 is H, methyl or -C(O)R 17 , where R 17 is H or methyl; and R 16 is H, methyl or -C(O)R 17 , where R 17 It is H or methyl.

14. The compound of claim 13, wherein R 15 is a methyl group, and R 16 It is H or methyl.

15. The compound of claim 14, having the following structure:

16. The compound of claim 14, wherein R 15 and R 16 It's methyl.

17. The compound of claim 16, having the following structure:

18. The compound of claim 13, wherein R 15 Yes-C(O)R 17 , where R 17 is methyl; and R 16 It’s H.

19. The compound of claim 18, having the following structure:

20. The compound of claim 1, wherein R1 is CH2 or CH3CH.

21. The compound of claim 1, which is:

22. The compound of claim 1, wherein R 1 is pyridyl, and X is H.

23. The compound of claim 22, which is:

24. The compound of claim 1, wherein R 1 is pyridyl, and X is F, Cl, Br or I.

25. The compound of claim 24, which is:

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