Derivatives of substituted morpholines and uses thereof

Abstract

To provide derivatives of substituted morpholine, and their use in pharmaceutical compositions, and their use for the treatment of central nervous system (CNS) disorders.SOLUTION: The present invention provides a compound of a formula (I), a stereoisomer thereof, or a salt thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Application No. 63 / 162,671, filed on March 18, 2021, the entire content of which is incorporated herein by reference.

[0002] The present technology generally relates to derivatives of substituted morpholines, as well as their use in pharmaceutical compositions and their use for the treatment of central nervous system (CNS) disorders.

Background Art

[0003] (R,S)-2-[(2 - Ethoxyphenoxy)methyl]morpholine:

Chemical

[0004] 2 - ((2 - Ethoxyphenoxy)methyl)morpholine is known to have several desirable pharmacological uses, including the treatment of depression, enuresis, narcolepsy, sleep disorders, and alcohol dependence. 2 - ((2 - Ethoxyphenoxy)methyl)morpholine was previously sold 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 can also promote the release of serotonin from neuronal stores.

[0005] However, treatment with 2-((2-ethoxyphenoxy)methyl)morpholine has been associated with many side effects, including nausea, vomiting, anorexia, increased erythrocyte sedimentation, EKG and EEG abnormalities, epigastric pain, diarrhea, constipation, dizziness, orthostatic hypotension, lower extremity edema, dysarthria, tremors, psychomotor agitation, confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, and seizures.

[0006] 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 been previously disclosed in the art, for example, in British Patent No. 1243391 and British Patent No. 1260886. In another approach, the inventors synthesize novel derivatives of substituted morpholines. Prodrugs are a class of derivatives that often have little or no pharmacological activity and are converted in vivo to therapeutically active compounds. In some cases, the prodrug itself may have biological activity. Activation of the prodrug can occur by enzymatic or non-enzymatic cleavage of a temporary bond between the carrier and the drug molecule, or by sequential or simultaneous combinations of both.

[0007] Newly synthesized derivatives of substituted morpholines, involving derivatization of the amine group of morpholine in the structure of 2-((2-ethoxyphenoxy)methyl)morpholine, produce chemically stable compounds that function 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

[0008] In one aspect, derivatives of substituted morpholines are provided, including compounds of formula I, their stereoisomers, or their salts.

CHEM

[0009] In some embodiments, the technology relates to derivatives of substituted morpholine by a compound of formula II, its stereoisomers, and / or its salts.

Chemical formula

[0010] In some embodiments, the technology relates to derivatives of substituted morpholine by a compound of formula III, its stereoisomers, and / or its salts.

Chemical formula

[0011] In some embodiments, derivatives of substituted morpholine are provided by Formula IV, its stereoisomers, and / or its salts.

Chemical formula

[0012] In any of the above embodiments, R 2 can be CH2CH3. In any of the above embodiments, R 3 ~R 14 can each be H.

[0013] In some aspects, a composition is provided that includes a derivative of substituted morpholine of Formula I, II, III, or IV, their stereoisomers and / or their salts, and at least one pharmaceutically acceptable excipient or carrier.

[0014] In some aspects, treatment of a central nervous system (“CNS”) disorder is provided, the treatment including administering to a subject in need thereof a pharmaceutical composition comprising a derivative of substituted morpholine (including a compound of Formula I, II, III, or IV).

[0015] In some embodiments, provided is a method for preparing a derivative of a substituted morpholine (including a compound of formula I, II, III, or IV, their stereoisomers and / or salts thereof), 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.

BEST MODE FOR CARRYING OUT THE INVENTION

[0016] Definitions. The following terms are used throughout according to the following definitions.

[0017] As used herein, the term "biroxidine" or 2-((2-ethoxyphenoxy)methyl)morpholine means (R,S)-2-[(2-ethoxyphenoxy)methyl]morpholine (including its pharmaceutically acceptable salts or esters), and includes either a single (-) enantiomer or a single (+) enantiomer, or is in the form of a racemic or non-racemic mixture of enantiomers containing varying amounts of the (-) enantiomer and the (+) enantiomer.

[0018] As used in this specification and the appended claims, the singular forms of items in the context of element descriptions (particularly in the context of the following claims), such as "a," "an," "the," and similar references, are to be considered to include both the singular and plural unless specifically stated otherwise in this specification or clearly contradicted by the context. The recitation of a range of values in this specification is intended, unless otherwise indicated herein, merely as a shorthand way of referring individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by the context. The use of any example, or exemplary language (e.g., "such as") presented herein is intended merely to make the embodiments more readily understood and does not limit the claims in any way. No language in this specification should be construed as indicating any non-claimed element as essential.

[0019] As used herein, "about" is as understood by one of ordinary skill in the art and will vary to some extent depending on the context in which the term is used. Where the use of the term is not clear to one of ordinary skill in the art, considering the context in which the term is used, "about" shall mean plus or minus 10% of the particular term.

[0020] Generally, references to a particular element such as hydrogen or H mean that all isotopes of that element are included. For example, if an R group is defined to include hydrogen or H, it includes deuterium and tritium. Thus, compounds containing radioactive isotopes such as tritium, C 14 , P 32 , and S 35 are included within the scope of this technology. Procedures for inserting such labels into the compounds of this technology will be readily apparent to one of ordinary skill in the art based on the disclosure herein.

[0021] Generally, "substituted" refers to an organic group (e.g., an alkyl group) as defined below in which one or more bonds to a hydrogen atom contained therein are replaced by bonds to non-hydrogen or non-carbon atoms. Substituents also include groups in which one or more bonds to a carbon atom(s) or hydrogen atom(s) are replaced by one or more bonds (including double or triple bonds) to a heteroatom. Thus, unless otherwise specified, a substituent is substituted with one or more substituents. In some embodiments, a substituent is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituents include halogen (i.e., F, Cl, Br, I); hydroxyl; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyl (oxo); carboxylate; ester; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; thiol; sulfide; sulfoxide; sulfone; sulfonyl; pentafluorosulfanyl (i.e., SF5), sulfonamide; amine; N-oxide; hydrazine; hydrazide; hydrazone; azide; amide; urea; amidine; guanidine; enamine; imide; isocyanate; isothiocyanate; cyanate; thiocyanate; imine; nitro group; nitrile (i.e., CN), etc.

[0022] As used herein, the term "carboxylate" refers to the conjugate base of a carboxylic acid having the chemical formula -COO.

[0023] As used herein, the term "ester" refers to -COOR 2 - and -C(O)O-G groups. R 2is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. G is a carboxylic acid protecting group. Carboxylic acid protecting groups are well known to those skilled in the art. A comprehensive list of protecting groups for carboxylic acid group functionality can be found in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P.G.M., John Wiley & Sons, New York, NY, (3rd Edition, 1999), and can be added or removed using the procedures described therein, and the entirety thereof is hereby incorporated by reference for all purposes as if fully set forth herein.

[0024] The term "amide" (or "amido") includes C- and N-amide groups, i.e., C(O)NR 3 R 4 and -NRC(O)-R groups. R 3 and R 4 are independently hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Thus, amide groups include, but are not limited to, carbamoyl groups (-C(O)NH2) and formamide groups (NHC(O)H). In some embodiments, the amide is -NRC(O)-(C 1~5 alkyl), and the group is referred to as "carbonylamino", and in other embodiments, the amide is -NHC(O)-alkyl, and the group is referred to as "alkanoylamino".

[0025] The term "amine" (or "amino") as used herein refers to an -NR 5 R 6 group, wherein R 5 and R 6is either hydrogen independently or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. In some embodiments, the amine is alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[0026] As used herein, the terms "halogen" or "halo" refer to bromine (Br), chlorine (Cl), fluorine (F), or iodine (I). In some embodiments, the halogen is chlorine (Cl).

[0027] As used herein, the terms "polypeptide" or "peptide" refer to two or more amino acids linked by peptide (i.e., amide) bonds 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, e.g., "pentapeptide" is a peptide consisting of five amino acids.

[0028] The term "amino acid" is recognized in the art and generally refers to natural or unnatural alpha or beta amino acids. The term "amino acid" includes, but is not limited to, any of the 21 standard L-amino acids commonly found in natural peptides.

[0029] 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).

[0030] As used herein, the term "acetyl" refers to a methyl group bonded to a carbonyl group (CH3CO-).

[0031] As used herein, the term "pyridine" group refers to a group having a heterocyclic organic compound having the chemical formula C5H5N.

[0032] As used herein, the term "pyridinecarboxylic acid" refers to a compound having a pyridine ring and a carboxyl group.

[0033] As used herein, the term "azanediyl" refers to a functional group having the formula -NH, which group is bonded to the remainder of the compound by two single bonds.

[0034] Pharmaceutically acceptable salts of the compounds described herein are within the scope of the present technology, retain the desired pharmacological activity, and are not biologically undesirable (e.g., the salts are not overly toxic, allergenic, or irritating and are bioavailable). Such salts include acid or base addition salts. When the compounds of the present technology have a basic group such as an amino group, pharmaceutically acceptable salts can be formed using inorganic acids (such as hydrochloric acid, boric acid, nitric acid, sulfuric acid, phosphoric acid, etc.), organic acids (e.g., alginic acid, 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, glutamic acid, etc.). When the compounds of the present technology have an acidic group such as a carboxylic acid group, salts can be formed with metals such as alkali metals and alkaline earth metals (e.g., Na + 、Li + 、K + 、Ca 2+ 、Mg 2+ 、or Zn 2+ ), ammonia, or organic amines (e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, or triethanolamine) or basic amino acids (e.g., arginine, lysine, or ornithine). These salts can be prepared in situ during the isolation and purification of the compound or by separately reacting the purified compound in the form of the free salt or free acid with the appropriate acid or base and isolating the formed salt.

[0035] The stereoisomers of a compound (also known as optical isomers) include all chiral, diastereoisomers, and racemic forms of the structure unless a specific stereochemistry is specified. That is, the compounds used in the present technology include those in which the optical isomers are enriched or resolved at any or all of the asymmetric atoms when clear from the description. Both racemic mixtures and mixtures of diastereomers, as well as individual optical isomers, can be isolated or synthesized so as to substantially exclude their enantiomeric partners or diastereomeric partners, and all of these stereoisomers are within the scope of the present technology.

[0036] The term "pharmaceutically acceptable excipient" refers to substances widely recognized by the industry and regulatory authorities, such as those listed in the USP-NF, Food Chemicals Codex, Code of Federal Regulations (CFR), FDA Inactive Ingredients Guide, etc., and monographs listed in the compendium of 21 CFR Parts 182 and 184, which list substances that are generally regarded as safe (GRAS) food ingredients.

[0037] In one aspect, there is provided a compound represented by formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [Chemical formula] In the compound of formula I, R 1 can be alkyl, heterocylyl, or pyridyl, R 2 can be alkyl, aryl, heteroaryl, or heterocylyl, R 3 ~R 14 can each independently be H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl, or heterocylyl, and X can be H, halogen, amino acid residue, substituted amino acid residue, alkyl, or ester. In some preferred embodiments, R 2 is ethyl. In any of the above embodiments, R1 can be CH2, CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, (CH3)2C, (CH3)2CHCH2, or (CH3)3CCH2. In any of the above embodiments, X can be an amino acid residue. In such embodiments, the amino acid residue can further 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 can independently be H, F, Cl, Br, I, or alkyl. In some such embodiments, R 3 ~R 14 each can independently be H or C1-C6 alkyl. In some embodiments, R 3 ~R 14 are all H. In any of the above embodiments, R 1 can be CH2CH2 or CH2CH2CH2CH2. In various embodiments above, R1 can be CH2 or C2H5, and / or X can be an ester. In various embodiments above, R 1 can be a pyridyl group and X can be F, Cl, Br, or I.

[0038] In various embodiments, the compound represented by formula I is one or more of the following compounds. When a chiral center exists, it is understood that each representation also includes any R, S, or racemic structure:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0039] In some embodiments, the compound represented by Formula I is: [Chemical formula] as follows. 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 alkyl, 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 are methyl. In some embodiments, R 15 is -C(O)OR 17 ; R 16 is H; and R 17 is methyl.

[0040] In another aspect, there is provided a compound represented by Formula II, or a stereoisomer thereof, and / or a salt thereof. [Chemical formula] In Formula II, L is alkyl, substituted pyridinecarboxylic acid, or substituted azandiylacetate; R 2 is alkyl, aryl, heteroaryl, or heterocyclyl; and R 3 to R 14 are each independently H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl, or heterocyclyl. In some embodiments, R 2 is ethyl.

[0041] In some embodiments, the compound represented by Formula II is [Chem.] is.

[0042] In various embodiments, the compound of Formula II is one or more of the following: [Chem.]

[0043] In another aspect, there is provided a compound represented by Formula III, or a stereoisomer thereof, and / or a salt thereof. [Chem.] In Formula III, Y can be F, Cl, Br, I, an amino acid residue, a substituted amino acid residue, alkyl, or an ester, and R 2 can be alkyl, aryl, heteroaryl, or heterocyclyl, and R 3 ~R 14 can each independently be H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl, or heterocyclyl. In some embodiments, R 2 is ethyl.

[0044] In some embodiments, the compound represented by Formula III is [Chem.] is.

[0045] In some embodiments, the compound represented by Formula III is: [Chem.] is.

[0046] In another aspect, there is provided a compound represented by Formula IV, or a stereoisomer thereof, and / or a salt thereof. [Chemistry] 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, and R 2 can be alkyl, aryl, heteroaryl, or heterocyclyl, and R 3 ~R 14 can each independently be H, F, Cl, Br, I, CN, NO2, alkyl, aryl, heteroaryl, or heterocyclyl. In some embodiments, R 2 is ethyl.

[0047] In some embodiments, the compound represented by formula IV is [Chemistry] as follows.

[0048] In some embodiments, the compound represented by formula IV is [Chemistry] as follows.

[0049] In some embodiments, the composition comprises a derivative of a substituted morpholine of formula I, II, III, or IV, its stereoisomers, and / or its salts, and at least one pharmaceutically acceptable excipient or carrier.

[0050] In some embodiments, the pharmaceutical composition comprises a derivative of a substituted morpholine of formula I, II, III, or IV, its stereoisomers, and / or its salts, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical formulation can be in a suitable dosage form. Exemplary dosage forms include, but are not limited to, injections, oral preparations, suppositories, cachets, pouches, transdermal preparations, etc.

[0051] In another aspect, there is provided a method for treating a CNS disorder by administering to a subject in need thereof a composition comprising a derivative of a substituted morpholine of formula I, II, III, or IV as described herein, or a salt thereof.

[0052] In another aspect, there is provided a method 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 a further embodiment, the mammalian subject is a human. In a particular embodiment, the mammalian subject is a human adult or a human child.

[0053] 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 a further embodiment, the at least one additional agent is 2-((2-ethoxyphenoxy)methyl)morpholine or a salt thereof.

[0054] In one embodiment, the derivative of the substituted morpholine can be prepared from 2-((2-ethoxyphenoxy)methyl)morpholine or a salt thereof.

[0055] In one embodiment, the derivative of the substituted morpholine 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:

Chemical formula

[0056] In one embodiment, the derivative of the 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:

Chemical formula

[0057] In one embodiment, the derivative of substituted morpholine can be prepared by reacting 2-((2-ethoxyphenoxy)methyl)morpholine or a salt thereof with 1-chloroethyl chloroformate to form Intermediate 3 having the following structure:

Chemical formula

[0058] In one embodiment, the derivative of 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.

[0059] In another embodiment, a method for producing a derivative of substituted morpholine of Formula I, II, III, or IV is provided.

[0060] The derivative of substituted morpholine can be analyzed by liquid chromatography-mass spectrometry (LCMS) and nuclear magnetic resonance (NMR) spectroscopy.

[0061] The present invention is generally described herein, but will be more readily understood by reference to the following examples, which are provided for purposes of illustration and are not intended to limit the present invention.

Examples

[0062] Procedure for preparing intermediates. In some structures, the chiral centers are shown in the R or S configuration, but it is understood that other configurations are also disclosed herein.

[0063] Intermediate 1: Synthesis of 2-((2-ethoxyphenoxy)methyl)morpholine-4-carbonyl chloride.

Chemical formula

[0064] A solution of 2-((2-ethoxyphenoxy)methyl)-morpholine hydrochloride (500 mg, 1.83 mmol) in dichloromethane (50 ml) was added dropwise to a slurry of sodium bicarbonate (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 mass 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%).

[0065] 1 H NMR(CDCl3,400MHz):δ ppm 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).

[0066] Intermediate 2: Chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate.

Chemical Structure

[0067] To a stirred ice-cooled mixture of 2-((2-ethoxyphenoxy)methyl)morpholine hydrochloride (1.3 g, 4.52 mmol), trimethylamine (1.01 g, 9.95 mmol) in dichloromethane, 1-chloromethyl chloroformate was added dropwise. The reaction mixture was stirred at 10 - 15 °C, returned to 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 g (80%) of a white solid.

[0068] 11H NMR (CDCl3, 400 MHz): δ ppm 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).

[0069] Intermediate 3: 1-chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate.

Chemical Structure

[0070] To a stirred ice-cooled mixture of 2-((2-ethoxyphenoxy)-methyl)morpholine hydrochloride (2 g, 6.96 mmol), trimethylamine (1.01 g, 9.95 mmol) in dichloromethane, 1-chloroethyl chloroformate (1.19 g, 83.5 mmol) was added dropwise. The reaction mixture was stirred at 10 - 15 °C, returned to room temperature and stirred for 5 h. The precipitated solid was filtered and the filtrate was concentrated. The crude product was purified by column chromatography (hexane:EtOAc 7:3) to afford 1.42 g (59.3%) of a white solid.

[0071] 1 1H NMR (400 MHz, CDCl3): δ ppm 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).

[0072] Procedure for synthesizing a compound of formula I, II, III or IV:

[0073] SP-16: ((D-valyl)oxy)methyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate. Step 1.

Chemical Structure

[0074] A reaction mixture of N-Boc-D-valine (175 mg, 0.80 mmol) and cesium carbonate (130 mg, 0.4 mmol) in methanol (3.3 ml) was stirred at room temperature for 3 hours, then the methanol was evaporated and the residue was redissolved in DMF (1 ml). To the reaction mixture was added chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (Intermediate 2) (177 mg, 0.52 mmol). The resulting mixture was stirred at 80 °C for 20 hours. The DMF was evaporated under vacuum, 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. Step 2:

Chemical Structure

[0075] 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 semi-solid. LCMS: Purity: 96.27% by ELS detector. MS: M+H = 411.14. 1 1H NMR (CDCl3, 400 MHz): δ ppm 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 - 4.20 (m, 10H), 5.83 (br.s, 1H), 5.95 (d, 1H), 6.85 - 6.96 (m, 4H), 8.24 (br.s, 2H).

[0076] SP-17: 1-((L-valyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate. Step 1.

Chemical Structure

[0077] A reaction mixture of N-Boc-L-valine (175 mg, 0.80 mmol) and cesium carbonate (130 mg, 0.4 mmol) in methanol (3.3 ml) was stirred at room temperature for 3 hours. Then, the methanol was evaporated and the residue was redissolved in DMF (1 ml). To the reaction mixture was added chloromethyl 2 1-chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (Intermediate 3) (184 mg, 0.52 mmol). The resulting mixture was stirred at 80 °C for 20 hours. The DMF was evaporated under vacuum, 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. Step 2:

Chemical formula

[0078] A solution of SP-17A (65 mg, 0.11 mmol) and 2M HCl in dioxane was stirred at room temperature overnight. Then, the solvent was 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 by ELS detector: 100%. MS: M+H = 425.17. 1 H NMR (CDCl3, 400 MHz): δ ppm 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 - 4.20 (m, 10H), 5.83 (br.s., 1H), 5.95 (d, 1H), 6.85 - 6.96 (m, 4H), 8.24 (br.s, 2H).

[0079] SP-18: (2R)-2-Amino-N-((2-((2-ethoxyphenoxy)methyl)morpholino)methyl)-3-methylbutanamide bis hydrochloride. Step 1:

Chemical formula

[0080] A slurry of sodium bicarbonate (92 mg, 1.1 mmol) was added to a solution of 2-((2-ethoxyphenoxy)methyl)-morpholine hydrochloride (108 mg, 0.4 mmol) and paraformaldehyde (50 mg) in THF (2 ml). The reaction mixture was stirred for 48 hours. The reaction product was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in chloroform and purified by column chromatography (hexane:EtOAc 8:1) to afford 80 mg (43%) of a semi-solid oil. Step 2:

Chemical formula

[0081] SP-18A (70 mg, 0.15 mmol) and a dioxane solution of 2M HCl were stirred at room temperature overnight. The solvent was evaporated and dried under vacuum to afford 50 mg (76%) of the pure desired product (SP-18) as a brown solid. LCMS: M+H = 366.20. Purity by ELS detector 98.73%. 1 H NMR (CDCl3, 400 MHz): δ ppm 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).

[0082] SP-19: Pyridin-2-yl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate

Chemical formula

[0083] A solution of triphosgene (163 mg, 0.55 mmol) in dichloromethane (DCM; 1 ml) was stirred at a temperature of 0 - 5 °C for 15 minutes in an ice bath, 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 returned to room temperature. The completion of the reaction was observed by TLC. After the reaction was completed, the reaction mixture was evaporated, redissolved in DCM, and evaporated (×3) to remove excess triphosgene. The residue was redissolved in 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 obtain 56 mg (12.3%) of the target compound (SP-19) as a semi-solid. LCMS: M+H = 359.08. Purity 100% by ELS detector. 1 H NMR(400MHz,CDCL3):δ 1.25 - 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).

[0084] SP-20: 2-Chloropyridin-4-yl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate.

Chemical Structure

[0085] To a stirred, 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 the dropwise addition of NaH (60% in oil, 35 mg, 0.146 mmol). The reaction mixture was stirred at room temperature under argon for 14 h. After evaporation of the solvent in vacuo, water (5 mL) was added and the mixture was 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 a semi-solid (SP-20). LCMS: purity 100% by ELS detector. MS: M+H = 393.08. 1 H NMR(CDCl3,400MHz):δ ppm 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).

[0086] SP-21: Methylenebis(2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate).

Chemical Structure

[0087] A solution of 2-((2-ethoxyphenoxy)methyl)morpholine hydrochloride (108 mg, 0.4 mmol) and methylene dibromide (50 mg) in DMF (2 ml) was added to a slurry of cesium carbonate (100 mg, 1.2 mmol). Carbon dioxide gas was passed through the reactants for 30 minutes and the mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in chloroform and purified by column chromatography (hexane:EtOAc 4:1) to give 52 mg (22.6%) of a solid. Purity 100% by ELS detector. MS: M+H = 575.15. 1 H NMR (CDCl3, 400 MHz): δ ppm 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).

[0088] SP-22: 1-((L-phenylalanyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate. Step 1.

Chemical formula

[0089] A reaction mixture of N-Boc-phenylalanine (175 mg, 0.66 mmol) and cesium carbonate (107 mg, 0.33 mmol) in methanol (1.3 ml) was stirred at room temperature for 3 hours, then methanol was evaporated and the residue was redissolved in DMF (1 ml). To the reaction mixture was added 1-chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (Intermediate 3) (150 mg, 0.42 mmol). The resulting mixture was stirred at 80 °C for 20 hours. Then DMF was evaporated under vacuum and the residue was dissolved in chloroform and then purified by column chromatography (hexane:EtOAc 8:2) to give 232 mg (61%) of a semi-solid oil. Step 2:

Chemical formula

[0090] A solution of SP-22A (140 mg, 0.238 mmol) and 2 M 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 by ELS detector: 100%. MS: M+H = 495.24. 1 1H NMR (CDCl3, 400 MHz): δ ppm 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).

[0091] SP-23 1-((Dimethyl-L-valyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate, hydrochloride.

Chemical formula

[0092] The reaction mixture of L-Val-N,N-dimethyl (100 mg, 0.68 mmol) and cesium carbonate (110 mg, 0.34 mmol) in methanol (0.75 ml) was stirred at room temperature for 3 hours, then methanol was evaporated and the residue was redissolved in DMF (1 ml). To the reaction mixture was added 1-chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (Intermediate 3) (160 mg, 0.44 mmol). 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 91 mg (45.7%) of a semi-solid.

[0093] 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. Then the solvent was evaporated under argon and then under vacuum to give 81 mg of an oil. LCMS: Purity by ELS detector: 99.61%. MS: M+H = 453.30 M+Na = 475.28. 1 H NMR (CDCl3, 400 MHz): δ ppm 0.89 (dd, 3H), 0.97 (d, 3H), 1.45 (t, 3H), 1.53 (d, 3H), 1.63 (s, 1H), 2.01 (dt, 6.54 Hz, 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).

[0094] SP-24: 1-((acetyl-L-valyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate.

Chemical Structure

[0095] A reaction mixture of N-acetylvaline (120 mg, 0.69 mmol) and 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 redissolved in DMF (1 ml). To the reaction mixture was added 1-chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (Intermediate 3) (160 mg, 0.44 mmol). The resulting mixture was stirred at 80 °C for 20 hours. The 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 an oil. LCMS: Purity by ELS detector: 100%. MS: M+H = 473.26 M+Na = 495.24. 11H NMR (CDCl3, 400 MHz): δ ppm 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).

[0096] SP - 25: 1 - ((Methyl - D - valyl)oxy)ethyl 2 - ((2 - ethoxyphenoxy)methyl)morpholine - 4 - carboxylate, trifluoroacetate salt. Step 1.

Chem.

[0097] A reaction mixture of N - Boc - D - valine (160 mg, 0.69 mmol) and cesium carbonate (110 mg, 0.35 mmol) in methanol (1.2 ml) was stirred at room temperature for 3 hours, then methanol was evaporated and the residue was redissolved in DMF (1 ml). To the reaction mixture was added 1 - chloroethyl 2 - ((2 - ethoxyphenoxy)methyl)morpholine - 4 - carboxylate (Intermediate 3) (160 mg, 0.44 mmol). 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 90 mg (36.1%) of a semi - solid oil. Step 2:

Chem.

[0098] 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 h). 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 by ELS detector: 100%. MS: M+H = 439.24 .1 H NMR (CDCl3, 400 MHz): δ 0.98 - 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).

[0099] SP-26: 1-((D-Valyl)oxy)-2-methylpropyl 2-((2-ethoxyphenoxy)methyl)-morpholine-4-carboxylate HCl salt. Step 1: [Chemical formula]

[0100] To a stirred ice-cooled mixture of 2-((2-ethoxyphenoxy)-methyl)morpholine hydrochloride (350 mg, 1.22 mmol), trimethylamine (271 mg, 2.68 mmol) in dichloromethane, 1-chloro-2-methylpropyl chloroformate (210 mg, 1.46 mmol) was added dropwise. The reaction mixture was stirred at 10 - 15 °C and then returned to room temperature and stirred for 2 h. 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 an oil. 11H NMR (CDCl3, 400 MHz): δ ppm 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). Step 2.

Chem.

[0101] A reaction mixture of N-Boc-D-valine (200 mg, 0.92 mmol) and cesium carbonate (150 mg, 0.46 mmol) in methanol (1.5 ml) was stirred at room temperature for 2 hours. Then, methanol was evaporated and the residue was redissolved in DMF (1 ml). To the reaction mixture, 1-chloro-2-methylpropyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (SP-26A) (230 mg, 0.59 mmol) was added. 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 obtain 170 mg (52.1%) of a semi-solid oil. Step 3:

Chem.

[0102] SP-26B (110 mg, 0.2 mmol) in dioxane (1 ml) and a solution of 2M HCl in dioxane (0.4 ml) were stirred at room temperature overnight (18 hours). Then, the solvent was evaporated and dried under vacuum to obtain 80 mg (88%) of the pure desired product as an oil. LCMS: Purity by ELS detector: 100%. MS: M+H = 453.22. 11H NMR (CDCl3, 400 MHz): δ ppm 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).

[0103] SP-27: 1-(((R)-2-(Aminomethyl)-3-methylbutanoyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate trifluoroacetate. Step 1.

Chemical formula

[0104] The reaction mixture of N-Boc-3-amino-2-isopropionic acid (100 mg, 0.43 mmol) and cesium carbonate (70 mg, 0.22 mmol) in methanol (0.75 ml) was stirred at room temperature for 2 hours ("h"), then methanol was evaporated and the residue was redissolved in DMF (0.75 ml). To the reaction mixture was added chloromethyl 2 1-chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (Intermediate 3) (99 mg, 0.28 mmol). 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 a semi-solid. Step 2:

Chemical formula

[0105] 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 h. The solvent was then evaporated and dried under vacuum to give 52 mg (90%) of the pure desired product as an oil. LCMS: Purity by ELS detector: 100%. MS: M+H = 439.21. 1 H NMR (CDCl3, 400 MHz): δ ppm 0.86 - 1.04 (m, 6H), 1.35 - 1.49 (m, 3H), 1.53 (br.s., 3H), 2.96 - 3.09 (m, 1H), 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).

[0106] SP-28: 1-(((R)-2-(Aminomethyl)-3-methylbutanoyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate trifluoroacetate. Step 1.

Chem.

[0107] A reaction mixture of Boc-Val-Val (150 mg, 0.47 mmol) and cesium carbonate (80 mg, 0.24 mmol) in methanol (1.13 ml) was stirred at room temperature for 2 h. Methanol was then evaporated and the residue was redissolved in DMF (1 ml). To the reaction mixture was added 1-chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (Intermediate 3) (110 mg, 0.3 mmol). The resulting mixture was stirred at 80 °C for 18 h. 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. Step 2:

Chem.

[0108] 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. Then, the solvent was evaporated and dried under vacuum to give 33 mg (98%) of the pure desired product as a yellow semi-solid. LCMS: Purity by ELS detector: 100%. MS: M+H = 524.27. 1 H NMR (CDCl3, 400 MHz): δ ppm 0.87 - 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).

[0109] SP-29: (((R)-3-Amino-4-methylpentanoyl)oxy)methyl 2-((2-ethoxyphenoxy)-methyl)morpholine-4-carboxylate, trifluoroacetate Step 1.

Chemical formula

[0110] A reaction mixture of Boc-L-β-leucine (150 mg, 0.65 mmol) and cesium carbonate (110 mg, 0.146 mmol) in methanol (1.13 ml) was stirred at room temperature for 2 hours. Then, methanol was evaporated and the residue was redissolved in DMF (1 ml). To the reaction mixture, chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (Intermediate 2) (140 mg, 0.42 mmol) was added. The resulting mixture was stirred at 80 °C for 18 hours. 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. Step 2:

Chemical formula

[0111] 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 h. The solvent was then evaporated and dried under vacuum to give 50 mg (90%) of the pure desired product as an oil. LCMS: Purity by ELS detector: 100%. MS: M+H = 425.19. 1 H NMR (CDCl3, 400 MHz): δ ppm 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).

[0112] SP-30: Bis(((2-((2-ethoxyphenoxy)methyl)morpholine-4-carbonyl)oxy)methyl)pyridine-3,5-dicarboxylate

Chemical formula

[0113] A reaction mixture of 3,5-pyridinedicarboxylic acid (75 mg, 0.4 mmol) and cesium carbonate (190 mg, 0.6 mmol) in methanol (0.6 ml) was stirred at room temperature for 2 h. Methanol was then evaporated and the residue was redissolved in DMF (1 ml). To the reaction mixture was added chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (Intermediate 2) (370 mg, 1.1 mmol). The resulting mixture was stirred at 80 °C for 18 h. 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 by ELS detector: 100%. MS: M+H = 754.21. 11H NMR (CDCl3, 400 MHz): δ ppm 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).

[0114] SP-31: ((2,2'-(methylazanediyl)bis(acetyl))bis(oxy))bis(methylene)bis(2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate).

Chemical formula

[0115] A reaction mixture of methyliminodiacetic acid (50 mg, 0.3 mmol) and cesium carbonate (144 mg, 0.4 mmol) in methanol (0.4 ml) was stirred at room temperature for 2 hours. Then, the methanol was evaporated and the residue was redissolved in DMF (1 ml). To the reaction mixture, chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (Intermediate 2) (280 mg, 0.8 mmol) was added. The resulting mixture was stirred at 80 °C for 18 hours. The DMF was evaporated under vacuum, the residue was dissolved in DCM, and purified by column chromatography (hexane:EtOAc 1:1). The obtained product was re-purified by a reverse-phase C18 column using a gradient mixture of acetonitrile and water to give 30.5 mg (13.8%) of a pure semi-solid oil product. LCMS: Purity by ELS detector: 100%. MS: M+H = 734.23. 1 1H NMR (CDCl3, 400 MHz): δ ppm 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).

[0116] SP-32: (((R)-2-(Aminomethyl)-3-methylbutanoyl)oxy)methyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate, trifluoroacetate salt. Step 1. [Chemical formula]

[0117] A reaction mixture of N-Boc-3-amino-2-isopropylpropionic acid (10 mg, 0.4 mmol) and cesium carbonate (78 mg, 0.2 mmol) in methanol (0.85 ml) was stirred at room temperature for 2 hours. Then, methanol was evaporated and the residue was redissolved in DMF (1 ml). To the reaction mixture, chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (Intermediate 2) (95 mg, 0.3 mmol) was added. 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 obtain 80 mg (50.8%) of a semi-solid. Step 2: [Chemical formula]

[0118] 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 obtain 49 mg (93%) of the pure desired product as a semi-solid oil. LCMS: Purity by ELS detector: 100%. MS: M+H = 425.18. 11H NMR (CDCl3, 400 MHz): δ ppm 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), 3.20 - 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).

[0119] Although specific embodiments have been illustrated and described, it should be understood that changes and modifications can be made by those skilled in the art without departing from the broad aspects of the technology as defined in the claims.

[0120] The embodiments described herein as examples are suitably practicable without any element(s) or limitation(s) not specifically disclosed herein. That is, for example, terms such as "comprising", "including", "containing", etc. should be read expansively and non - restrictively. Further, the terms and expressions used herein have been used as terms for explanation rather than limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the features shown and described or a part thereof, but rather it is recognized that various modifications are possible within the scope of the claimed technology. Further, it is understood that the phrase "consisting essentially of" includes additional components that do not substantially affect the basic and novel features of the specifically described components and the claimed technology. The phrase "consisting of" excludes any component not specified.

[0121] This disclosure is not limited to the specific embodiments described in this application. Many modifications and variations can be made without departing from the spirit and scope, as will be apparent to those skilled in the art. Not only the ones listed herein, but also functionally equivalent methods and compositions within the scope of this disclosure will be apparent to those skilled in the art from the above description. Such modifications and variations are intended to be included within the scope of the appended claims. This disclosure is limited only to the terms of the appended claims and the scope of equivalents of those claims given by the rights. It should be understood that this disclosure is not limited to a particular method, reagent, compound, composition or biological system and may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0122] Also, when features or aspects of this disclosure are described in Markush groups, those skilled in the art will understand that this disclosure thereby describes any individual element or subgroup of elements of that Markush group as well.

[0123] It will be understood by those skilled in the art that, for any purpose, particularly in terms of providing a written description, all ranges disclosed herein include any and all possible subranges and combinations of subranges thereof. Each of the listed ranges is fully described and can be readily recognized as being capable of being divided at least into equal halves, thirds, quarters, fifths, tenths, etc. of the same range. By way of non-limiting example, each range described herein can be readily divided into lower thirds, middle thirds, upper thirds, etc. Also, as will be understood by those skilled in the art, all terms such as "maximum", "at least", "greater than", "less than", etc. include the recited numerical values and ranges that can then be divided into subranges as described above. Finally, as will be understood by those skilled in the art, ranges include each individual member thereof.

[0124] All publications, patent applications, issued patents, and other documents referred to in this specification are hereby incorporated by reference as if each individual publication, patent application, issued patent, or other document were specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in incorporated documents are excluded to the extent they conflict with the definitions of the present disclosure.

[0125] In one embodiment, a process for preparing 2-((2-ethoxyphenoxy)methyl)morpholine-4-carbonyl chloride (Intermediate 1) is provided, the process comprising reacting 2-((2-ethoxyphenoxy)methyl)-morpholine with a reaction mixture comprising triphosgene

Chemical formula

[0126] In a further embodiment, the reaction mixture comprises dichloromethane. In other embodiments, the reaction mixture comprises sodium bicarbonate.

[0127] In some embodiments, Intermediate 1 is used to prepare 2-chloropyridin-4-yl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (SP-20), comprising reacting 2-((2-ethoxyphenoxy)methyl)morpholine-4-carbonyl chloride (Intermediate 1) with a reaction mixture comprising 2-chloro-4-hydroxypyridine

Chemical formula

[0128] In a further embodiment, the reaction mixture further comprises anhydrous tetrahydrofuran.

[0129] In some embodiments, a process for preparing chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (Intermediate 2) is provided, the process comprising reacting 2-((2-ethoxyphenoxy)methyl)-morpholine with a reaction mixture comprising 1-chloromethyl chloroformate

Chemical formula

[0130] In further embodiments, the reaction mixture comprises trimethylamine. In other embodiments, the reaction mixture comprises dichloromethane.

[0131] In some embodiments, Intermediate 2 is used to prepare ((D-valyl)oxy)methyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (SP-16), forming (SP-16A) by reacting Intermediate 2 with a reaction mixture comprising N-Boc-D-valine, and

Chemical formula

Chemical formula

[0132] In further embodiments, the reaction mixture comprises cesium carbonate. In other embodiments, the reaction mixture comprises methanol. In some embodiments, the organic acid is hydrochloric acid.

[0133] 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), (a) Forming SP-29A by reacting intermediate 2 with a reaction mixture containing Boc-L-β-leucine, and

Chem.

Chem.

[0134] In further embodiments, this reaction mixture contains cesium carbonate. In other embodiments, the reaction mixture contains methanol.

[0135] 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), including reacting intermediate 2 with a reaction mixture containing 3,5-pyridinedicarboxylic acid

Chem.

[0136] In further embodiments, this reaction mixture contains cesium carbonate. In other embodiments, the reaction mixture contains methanol.

[0137] In some embodiments, intermediate 2 is used to prepare ((2,2'-(methylazanediyl)bis(acetyl))bis(oxy))bis(methylene)bis(2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate) (SP-31), including reacting chloromethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (intermediate 2) with a reaction mixture containing methyliminodiacetic acid

Chem.

[0138] In further embodiments, the reaction mixture comprises cesium carbonate. In other embodiments, the reaction mixture comprises methanol.

[0139] 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), (a) forming SP-32A by reacting Intermediate 2 with a reaction mixture comprising N-Boc-3-amino-2-isopropylpropionic acid;

Chemical formula

Chemical formula

[0140] In further embodiments, the reaction mixture comprises cesium carbonate. In other embodiments, the reaction mixture comprises methanol.

[0141] In another embodiment, a process for preparing 1-chloroethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (Intermediate 3) is provided, the process comprising reacting 2-((2-ethoxyphenoxy)methyl)-morpholine with a reaction mixture comprising 1-chloroethyl chloroformate

Chemical formula

[0142] In further embodiments, the reaction mixture comprises trimethylamine. In other embodiments, the reaction mixture comprises dichloromethane.

[0143] In some embodiments, intermediate 3 is used to prepare 1 - ((L-valyl)oxy)ethyl 2 - ((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (SP-17), (a) forming SP-17A by reacting intermediate 3 with a reaction mixture comprising N-Boc-L-valine,

Chemical formula

Chemical formula

[0144] In further embodiments, the reaction mixture includes methanol. In other embodiments, the reaction mixture includes cesium carbonate. In some further embodiments, the organic acid is hydrochloric acid.

[0145] In some embodiments, intermediate 3 is used to prepare 1 - ((1-phenylalanyl)oxy)ethyl 2 - ((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (SP-22), (a) forming SP-22A by reacting intermediate 3 with a reaction mixture comprising N-Boc-phenylalanine,

Chemical formula

Chemical formula

[0146] In further embodiments, the reaction mixture further includes cesium carbonate. In other embodiments, the reaction mixture further includes methanol. In alternative embodiments, the organic acid is hydrochloric acid.

[0147] In some embodiments, intermediate 3 is used to prepare 1-((dimethyl-L-valyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (SP-23), including reacting intermediate 3 with a reaction mixture containing L-Val-N,N-dimethyl

Chem.

[0148] In further embodiments, this reaction mixture contains cesium carbonate. In some embodiments, the reaction mixture contains methanol.

[0149] In some embodiments, intermediate 3 is used to prepare 1-((acetyl-L-valyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (SP-24), including reacting intermediate 3 with a reaction mixture containing N-acetylvaline

Chem.

[0150] In further embodiments, this reaction mixture contains cesium carbonate. In some embodiments, the reaction mixture contains methanol.

[0151] In some embodiments, intermediate 3 is used to prepare 1-((methyl-D-valyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (SP-25), (a) forming SP-25A by reacting intermediate 3 with a reaction mixture containing N-Boc-D-valine;

Chem.

Chem.

[0152] In a further embodiment, the reaction mixture includes methanol. In some embodiments, the reaction mixture includes cesium carbonate.

[0153] 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), (a) forming SP-27A by reacting Intermediate 3 with a reaction mixture comprising N-Boc-3-amino-2-isopropionic acid, [Chemical formula] (b) stirring a solution of SP-27A in chloroform and trifluoroacetic acid, [Chemical formula] including

[0154] In a further embodiment, the reaction mixture further includes cesium carbonate. In other embodiments, the reaction mixture further includes methanol.

[0155] 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), (a) forming SP-28A by reacting Intermediate 3 with a reaction mixture comprising Boc-Val-Val, [Chemical formula] (b) stirring a solution of SP-28A in chloroform and trifluoroacetic acid, [Chemical formula] including.

[0156] In a further embodiment, the reaction mixture further comprises cesium carbonate. In some embodiments, the reaction mixture further comprises methanol.

[0157] In one embodiment, a process for preparing (2R)-2-amino-N-((2-((2-ethoxyphenoxy)methyl)morpholino)methyl)-3-methylbutanamide (SP-18) is provided, the process comprising (a) forming SP-18A by reacting 2-((2-ethoxyphenoxy)methyl)morpholine with a reaction mixture comprising paraformaldehyde; [Chemical formula] (b) reacting SP-18A in dioxane and an organic acid; [Chemical formula] including.

[0158] In a further embodiment, the reaction mixture further comprises tetrahydrofuran. In some embodiments, the organic acid is hydrochloric acid.

[0159] In another embodiment, a process for preparing pyridin-2-yl 2((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (SP-19) is provided, the process comprising (a) forming pyridin-2-yl carbonochloridate by reacting 2-hydroxypyridine with a reaction mixture comprising N,N-diisopropylethylamine; [Chemical formula] (b) reacting pyridin-2-yl carbonochloridate with a second reaction mixture comprising 2-((2-ethoxyphenoxy)methyl)morpholine; [Chemistry] comprises.

[0160] In further embodiments, the reaction mixture comprises triphosgene. In some embodiments, the reaction mixture comprises dichloromethane. In other embodiments, the second reaction mixture comprises dichloromethane. In still further embodiments, the second reaction mixture comprises triethylamine.

[0161] In one embodiment, a process for preparing methylenebis(2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (SP-21) is provided, the process comprising reacting (2-((2-ethoxyphenoxy)methyl)morpholine with a reaction mixture comprising methylene dibromide [Chemistry]

[0162] In further embodiments, the reaction mixture comprises dimethylformamide. In some embodiments, carbon dioxide gas is passed through the reaction mixture.

[0163] In another embodiment, a process for preparing 1-((D-valyl)oxy)-2-methylpropyl 2-((2-ethoxyphenoxy)methyl)-morpholine-4-carboxylate (SP-26) is provided, the process comprising (a) forming SP-26A by reacting (2-((2-ethoxyphenoxy)-methyl)morpholine with a first reaction mixture comprising 1-chloro-2-methylpropyl chloroformate, and [Chemistry] (b) forming SP-26B by reacting SP-26A with a second reaction mixture comprising N-Boc-D-valine, and [Chemistry] (b) Reacting SP-26B in dioxane and an organic acid, and [Chemistry] includes.

[0164] In a further embodiment, the first reaction mixture includes trimethylamine. In some embodiments, the first reaction mixture includes dichloromethane. In other embodiments, the second reaction mixture includes cesium carbonate. In some embodiments, the second reaction mixture includes methanol. In other embodiments, the organic acid is hydrochloric acid.

[0165] Other embodiments are described in the following claims.

Claims

1. A compound of formula I, a stereoisomer thereof, or a salt thereof, 【Chemistry 1】 During the ceremony, R １ is alkyl, heterocyclyl, or pyridyl; R ２ is alkyl, aryl, heteroaryl, or heterocyclyl; R ３ ~R １４ are each independently H, F, Cl, Br, I, CN, or NO ２ , alkyl, aryl, heteroaryl, or heterocyclyl; The compound, wherein X is H, halogen, an amino acid residue, a substituted amino acid residue, an alkyl, or an ester.

2. R １ But, CH ２ , C.H. ２ CH ２ , C.H. ３ C.H., C.H. ２ CH ２ CH ２ , C.H. ２ CH ２ CH ２ CH ２ , (CH ３ ) ２ C, (CH ３ ) ２ CHCH, or (CH ３ ) ３ 2. The compound of claim 1, wherein the compound is CCH.

3. 3. The compound of claim 2, wherein X is an amino acid residue.

4. The compound of claim 3 , wherein the amino acid residue comprises a hydrophobic side chain.

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

6. R １ But, CH ２ , C.H. ３ CH, or (CH ３ ) ２ 6. The compound of claim 5, wherein: 【Request 7】 【Chemical 2】 7. The compound of claim 6,

8. The compound of claim 4 , wherein the amino acid residue containing a hydrophobic side chain is phenylalanine.

9. R １ But, CH ３ 9. The compound of claim 8, wherein:

10. 【Chemical 3】 10. The compound of claim 9 having the structure:

11. R ３ ~R １４ 4. The compound of claim 3, wherein each of is independently H, F, Cl, Br, I, or alkyl.

12. R ３ ~R １４ each independently is H or C １ ~C ６ The compound of claim 11 , which is alkyl.

13. R ３ ~R １４ The compound of claim 12, wherein all of

14. R １ But, CH ２ , C.H. ２ CH ２ , C.H. ３ C.H., C.H. ２ CH ２ CH ２ CH ２ , or C.H. ３ CH ２ CH ２ CH, or (CH ３ ) ３ 14. The compound of claim 13, which is CCH.

15. 【Chemical 4】 and During the ceremony, R １５ is H, alkyl, -C(O)OR １７ or -C(O)R １７ and R １６ is H, alkyl, -C(O)OR １７ or -C(O)R １７ and R １７ is H or alkyl.

16. R １５ is alkyl, R １６ The compound of claim 15 , wherein is H or alkyl.

17. R １５ is methyl, R １６ is H or methyl.

18. 【Chemical 5】 20. The compound of claim 17 having the structure:

19. R １５ and R １６ The compound of claim 17, wherein is methyl.

20. 【Chemical 6】 20. The compound of claim 19 having the structure:

21. R １５ -C(O)R １７ and R １６ is H, and R １７ The compound of claim 15 , wherein is methyl.

22. 【Chemical 7】 22. The compound of claim 21 having the structure:

23. R １ But, CH ２ or CH ３ 2. The compound of claim 1 , wherein R is CH.

24. 24. The compound of claim 23, wherein X is an ester. 【Request 25】 【Chemical 8-1】 【Chemistry 8-2】 25. The compound of claim 24, wherein

26. 【Chemical 9】 2. The compound of claim 1 ,

27. R １ 2. The compound of claim 1, wherein is a pyridyl group and X is H.

28. [Chemical 10] 28. The compound of claim 27,

29. R １ 2. The compound of claim 1, wherein: is a pyridyl group; and X is F, Cl, Br, or I.

30. 【Catalog 11】 30. The compound of claim 29,

31. Compounds of formula II, their stereoisomers, and / or salts thereof, 【Chemistry 12】 During the ceremony, L is an alkyl, a substituted pyridine carboxylic acid, or a substituted azanediyl acetate; R ２ is alkyl, aryl, heteroaryl, or heterocyclyl; R ３ ~R １４ are each independently H, F, Cl, Br, I, CN, or NO ２ , alkyl, aryl, heteroaryl, or heterocyclyl.

32. L is CH ２ 32. The compound of claim 31 ,

33. 【Chemical 13】 33. The compound of claim 31 or 32,

34. 32. The compound of claim 31, wherein L is a substituted pyridine carboxylic acid group.

35. The compound of claim 34, wherein the substituted pyridine carboxylic acid group is dimethylpyridine-dicarboxylate.

36. 【Catalog 14】 36. The compound of claim 31 or 35,

37. 32. The compound of claim 31 , wherein the substituted azanediyl acetate group is methyl azanediyl acetate.

38. 【Chemical 15】 38. The compound of claim 31 or 37,

39. Compounds of formula III, their stereoisomers, and / or salts thereof, 【Chemistry 16】 During the ceremony, Y is F, Cl, Br, I, an amino acid residue, a substituted amino acid residue, an alkyl, or an ester; R ２ is alkyl, aryl, heteroaryl, or heterocyclyl; R ３ ~R １４ are each independently H, F, Cl, Br, I, CN, or NO ２ , alkyl, aryl, heteroaryl, or heterocyclyl.

40. 40. The compound of claim 39, wherein Y is Cl.

41. 【Catalogue 17】 41. The compound of claim 39 or 40,

42. Compounds of formula IV, their stereoisomers, and / or salts thereof, 【Chemistry 18】 During the ceremony, Z is H, F, Cl, Br, I, an amino acid residue, a substituted amino acid residue, or a nitrogen-containing group; R ２ is alkyl, aryl, heteroaryl, or heterocyclyl; R ３ ~R １４ are each independently H, F, Cl, Br, I, CN, or NO ２ , alkyl, aryl, heteroaryl, or heterocyclyl.

43. 43. The compound of claim 42, wherein Z is a nitrogen-containing group.

44. 44. The compound of claim 43, wherein the nitrogen-containing group is an amide.

45. 【Chemical 19】 45. The compound of claim 42 or 44,

46. 47. A composition comprising a compound according to any one of claims 1, 31, 39 or 42, and a pharma- ceutically acceptable excipient.

47. 47. A method for treating a central nervous system disorder, the method comprising administering to a subject a composition according to claim 46.

48. A method for producing a compound of formula I, II, III, or IV by contacting 2-((2-ethoxyphenoxy)methyl)morpholine or a salt thereof, intermediate 1, intermediate 2, or intermediate 3 with a reactive compound suitable to form said compound of formula I, II, III, or IV.

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