3-palmitoyl-amido-1,2-propanediol and 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane crystals, their preparation and use

Abstract

This disclosure includes crystalline solids of 3-palmitoyl-amido-1,2-propanediol and 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Methods for preparing crystalline solids of 3-palmitoyl-amido-1,2-propanediol and single crystals of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane are also provided. A method for preparing 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane from crystalline solids of 3-palmitoyl-amido-1,2-propanediol is also described.

Description

[0001] This application is a divisional application of Chinese patent application No. 202080090889.0 (application date: October 23, 2020, invention title: Crystalline solids of 3-palmitoyl-amido-1,2-propanediol and 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane and their preparation and use methods).

[0002] Cross-reference to related applications

[0003] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 926,810, filed October 28, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0004] This invention relates to crystalline solids of 3-palmitoyl-amido-1,2-propanediol and 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane, as well as methods for their preparation and use. Background Technology

[0005] Imetelstat is a telomerase inhibitor that binds to the template region of telomerase RNA components with high affinity. Studies have shown that imetelstat inhibits telomerase activity and effectively suppresses cell proliferation in various cancer cell lines and human tumors. Imetelstat has been used in clinical trials for patients with hematologic malignancies. A clinical trial in patients with myelofibrosis showed that imetelstat can achieve complete clinical remission in some patients. In these patients, imetelstat led to the reversal of myelofibrosis and resulted in morphological and molecular remission.

[0006] The structure of imestral comprises an N3'→P5' thiophosphoramide oligonucleotide. The synthesis of imestral is carried out via solid-phase oligonucleotide synthesis, in which the first phosphoramide nucleotide is coupled to a carrier and then sulfidated. Chain elongation of the oligonucleotide component is achieved through repeated reactions of the 3'-amino group of the oligonucleotide bound to the solid-phase carrier with other phosphoramide monomers of the nucleotide. The imestral oligonucleotide is coupled to the solid-phase carrier via a palmitoyl-amide linker. Therefore, this fatty acid-amide linker is a component in the synthesis of imestral. Summary of the Invention

[0007] This disclosure includes a crystalline solid of 3-palmitoyl-amido-1,2-propanediol (Formula I):

[0008] (I).

[0009] In the embodiments, the crystalline solid of 3-palmitoyl-amido-1,2-propanediol has an X-ray powder diffraction (XRPD) pattern containing a peak at a 2ơ value of approximately 8.25°. In some embodiments, the crystalline solid of 3-palmitoyl-amido-1,2-propanediol has an XRPD pattern containing one or more peaks at 2ơ values ​​of approximately 2.75°, approximately 6°, approximately 3.8°, approximately 15°, approximately 26.3°, approximately 30.5°, and approximately 33.1°. In some cases, the thermogravimetric analysis (TGA) of the crystalline solid of 3-palmitoyl-amido-1,2-propanediol is characterized by a single weight loss step. In some cases, the weight loss step begins at approximately 200.5°C. In some embodiments, by differential scanning calorimetry (DSC), the crystalline solid of 3-palmitoyl-amido-1,2-propanediol exhibits a first endothermic reaction at 79.3°C and a second endothermic reaction at approximately 102.5°C. In these embodiments, the second endothermic reaction is a unimodal endothermic reaction.

[0010] A method for preparing a crystalline solid of 3-palmitoyl-amido-1,2-propanediol is also provided. In implementing the method according to certain embodiments, 3-palmitoyl-amido-1,2-propanediol is contacted with one or more solvents to generate a 3-palmitoyl-amido-1,2-propanediol composition and precipitated to generate a crystalline solid of 3-palmitoyl-amido-1,2-propanediol. In some embodiments, 3-palmitoyl-amido-1,2-propanediol is contacted with a polar solvent. In other embodiments, 3-palmitoyl-amido-1,2-propanediol is contacted with a nonpolar solvent. In still other embodiments, 3-palmitoyl-amido-1,2-propanediol is contacted with a mixture of polar and nonpolar solvents. The solvent may further comprise an organic base, such as triethylamine. In some embodiments, the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP), or combinations thereof. In some cases, the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, and dichloromethane. In some cases, the solvent is tetrahydrofuran. In some embodiments, precipitating crystalline solids of 3-palmitoyl-amido-1,2-propanediol comprises heating a 3-palmitoyl-amido-1,2-propanediol composition to produce a heated composition (e.g., wherein 3-palmitoyl-amido-1,2-propanediol is dissolved in a solvent); and cooling the heated 3-palmitoyl-amido-1,2-propanediol composition to produce crystalline solids of 3-palmitoyl-amido-1,2-propanediol.

[0011] A method for preparing 3-palmitoyl-amido-1,2-propanediol from 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is also described. In implementing the subject method according to certain embodiments, a solvent is contacted with a crystalline solid of 3-palmitoyl-amido-1,2-propanediol to produce a precursor composition; and the precursor composition is contacted with a composition comprising dimethoxytriphenylmethyl chloride to produce a composition having 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. In some embodiments, the solvent is tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate (iPrOAc), ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP), or combinations thereof. In some cases, the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP). In other cases, the solvent is selected from methyltetrahydrofuran, tetrahydrofuran, and dichloromethane.

[0012] In some embodiments, the precursor composition comprises a base, such as an organic base. For example, the base may be 1,8-bis(dimethylamino)naphthalene (proton sponge), imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2,4,6-trimethylpyridine (trimethylpyridine), triethylamine (TEA), potassium carbonate, sodium methoxide, tetramethylethylenediamine (TMEDA), or dimethylaminoethanol. In some cases, the base is selected from 1,8-bis(dimethylamino)naphthalene (proton sponge), tetramethylethylenediamine (TMEDA), and triethylamine (TEA). In some cases, the base is triethylamine.

[0013] In other embodiments, the precursor composition includes an additive. For example, the additive may be calcium oxide, magnesium oxide, boric acid, tetrabutylammonium fluoride (TBAF), 4-dimethylaminopyridine (DMAP), copper chloride (CuCl2), ytterbium(III) chloride (YbCl3), or 1,4-diazabicyclo[2.2.2]octane (DABCO). In some cases, the additive is selected from tetrabutylammonium fluoride (TBAF), magnesium oxide, and boric acid. In some cases, the additive is magnesium oxide.

[0014] In some cases, the crystalline solid of 3-palmitoyl-amido-1,2-propanediol has an XRPD plot containing one or more peaks at 2Ɵ values ​​of approximately 2.75°, 2Ɵ values ​​of approximately 6°, 2Ɵ values ​​of approximately 3.8°, 2Ɵ values ​​of approximately 8.25°, 2Ɵ values ​​of approximately 15°, 2Ɵ values ​​of approximately 26.3°, 2Ɵ values ​​of approximately 30.5°, and 2Ɵ values ​​of approximately 33.1°. In some cases, the thermogravimetric analysis (TGA) of the crystalline solid of 3-palmitoyl-amido-1,2-propanediol is characterized by a single weight reduction step. In some cases, the weight reduction step begins at approximately 200.5°C. In some embodiments, by differential scanning calorimetry (DSC), the crystalline solid of 3-palmitoyl-amido-1,2-propanediol exhibits a first endothermic reaction at 79.3°C and a second endothermic reaction at approximately 102.5°C.

[0015] In some cases, the method further includes forming (e.g., by recrystallization) one or more single crystals of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. In these embodiments, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is contacted with a solvent, and a crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane precipitates from the solvent. In some cases, the solvent is a polar solvent. In other cases, the solvent is a nonpolar solvent. In still other cases, the solvent is a mixture of polar and nonpolar solvents. In some embodiments, forming a crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane comprises heating the 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane composition to produce a heated composition; and cooling the heated composition to produce a crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane, such as one or more single crystals of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane.

[0016] This disclosure also includes crystalline solids of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (Formula II):

[0017] (II).

[0018] In some cases, the crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is a single crystal of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. According to examples, the crystalline solid is in monoclinic form. Each unit cell in the crystalline solid comprises two different conformations of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane, such as a bent conformation and a linear conformation. In examples, each conformation (bent and linear) of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is present in the unit cell in a 1:1 ratio. Each unit cell in the crystalline solid comprises 4 molecules of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. In some embodiments, the cell size is about 8.44 μm × about 26.56 μm × about 10.06 μm, wherein the cell volume is about 2254.8 μm. 3 The density of the palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane crystalline solid is approximately 1.2 g / cm³. 3 Approximately 1.3 g / cm 3 Furthermore, the purity of the polymorph is 95% or higher.

[0019] A method for preparing a crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is also provided. In implementing the method according to certain embodiments, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is contacted with one or more solvents to produce a 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane composition and precipitated to produce a crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane, such as one or more single crystals of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. In some embodiments, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is contacted with a polar solvent. In other embodiments, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is contacted with a nonpolar solvent. In some embodiments, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is contacted with a mixture of polar and nonpolar solvents. In some cases, the polar solvent is dichloromethane and the nonpolar solvent is pentane. In some embodiments, precipitating a crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane comprises heating the 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane composition to produce a heated composition (e.g., wherein 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is dissolved in a solvent); and cooling the heated 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane composition to produce a crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Attached Figure Description

[0020] Figure 1 X-ray powder diffraction patterns of polycrystalline solids of 3-palmitoyl-amido-1,2-propanediol formed from solutions of (b) THF, (c) 2-methyl THF and (d) DCM are shown, and their comparison with the starting material of (a) 3-palmitoyl-amido-1,2-propanediol is presented.

[0021] Figure 2 Thermogravimetric analysis (TGA) spectra of the polycrystalline solid of 3-palmitoyl-amido-1,2-propanediol formed from THF solution according to certain embodiments are shown. Figure 2 The figure also depicts a differential scanning calorimetry (DSC) plot of the polycrystalline solid of 3-palmitoyl-amido-1,2-propanediol formed from THF according to certain embodiments.

[0022] Figure 3A comparison of the DSC plots of the polycrystalline solid of 3-palmitoyl-amido-1,2-propanediol formed from THF with those of the 3-palmitoyl-amido-1,2-propanediol starting material is presented.

[0023] Figure 4A Oak Ridge Thermal Ellipsoid (ORTEP) plots depicting two different conformations of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane as determined by X-ray crystallography. Figure 4B The unit cell of crystalline 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was depicted. Figure 4C A crystal packing view of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane along the first axis is depicted. Figure 4D A crystal packing view of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane along the second axis is depicted. Figure 4E The intermolecular hydrogen bonding along the second crystallization axis between conformational isomer A and conformational isomer B is described. Detailed Implementation

[0024] Choose the definition of chemical terminology

[0025] Unless otherwise stated, the following terms have the following meanings. Any undefined term has its generally accepted meaning in the art.

[0026] As used herein, the terms “phosphate” and “phosphate group” are intended to encompass both thiophosphate groups and oxophosphate groups.

[0027] As used herein, the term "phosphamide amino" refers to the amino group—NR—attached to the phosphorus atom of the phosphoramide group. 4 R 5 Furthermore, the term "phosphoramide nitrogen" refers to the nitrogen atom in the amino group of phosphoramide.

[0028] "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, such as 1 to 6 carbon atoms (e.g., "alkyl of 1 to 6 carbon atoms"), or 1 to 5 carbon atoms (e.g., "alkyl of 1 to 5 carbon atoms"), or 1 to 4 carbon atoms (e.g., "alkyl of 1 to 4 carbon atoms"), or 1 to 3 carbon atoms (e.g., "alkyl of 1 to 3 carbon atoms"). For example, the term includes straight-chain and branched hydrocarbon groups, such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), tert-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0029] The term "substituted alkyl" refers to an alkyl group as defined herein, wherein one or more carbon atoms in the alkyl chain are optionally replaced by heteroatoms, such as -O-, -N-, -S-, -S(O). n - (where n is 0 to 2), -NR- (where R is hydrogen or alkyl) substituted and having 1 to 5 substituents selected from the group consisting of: alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acyl amine alkyl, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thionyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclicoxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, hydroxylamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl and -NR a R b ;where R a and R b They may be the same or different and are selected from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclic. In some cases, "substituted alkyl" means an alkyl group having 1 to 5 substituents as defined herein, said substituents being selected from the group consisting of: alkoxy, cycloalkyl, cycloalkenyl, acyl, acyl... amine Acyl, amino, aminoacyl, aminoacyl, oxyaminoacyl, azide, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, sulfonyl amine base and -NRa R b ;where R a and R b They can be the same or different and are selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.

[0030] "Alkylene" refers to a divalent aliphatic hydrocarbon group, preferably having 1 to 6, more preferably 1 to 3, carbon atoms, which is straight-chain or branched, and optionally selected from -O-, -NR. 10 -、-NR 10 C(O)-、-C(O)NR 10 - One or more groups are interrupted. For example, the term includes methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-), (-C(CH3)2CH2C(O)-), (-C(CH3)2CH2C(O)NH-), (-CH(CH3)CH2-), etc.

[0031] "Substituted alkylene" refers to an alkylene group having 1 to 3 hydrogen atoms that is substituted by a substituent as described in the definition of "substituted" below for the carbon atom.

[0032] The term "alkane" refers to alkyl groups and alkylene groups as defined herein.

[0033] The terms “alkylaminoalkyl”, “alkylaminoolefin” and “alkylaminoynyl” refer to the group R'NHR” - where R' is an alkyl group as defined herein and R” is an alkylene, olefin or ynylene as defined herein.

[0034] The terms “alkylaryl” or “aryl” refer to the groups -alkylene-aryl and -substituted alkylene-aryl, wherein the alkylene, substituted alkylene and aryl are as defined herein.

[0035] "Alkoxy" refers to the group -O-alkyl, where alkyl is as defined herein. Alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, etc. The term "alkoxy" also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and ynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and ynyl are as defined herein.

[0036] The term “substituted alkoxy” refers to a substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- group, wherein the substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl, and substituted alkynyl are as defined herein.

[0037] The term "alkoxyamino" refers to the group -NH-alkoxy, where the alkoxy group is as defined herein.

[0038] The term "haloalkoxy" refers to an alkyl-O- group in which one or more hydrogen atoms on the alkyl group have been replaced by a halogen group, and includes groups such as trifluoromethoxy.

[0039] The term "haloalkyl" refers to a substituted alkyl group as described above, wherein one or more hydrogen atoms on the alkyl group have been replaced by a halogroup. Examples of such groups include, but are not limited to, fluoroalkyl groups, such as trifluoromethyl, difluoromethyl, trifluoroethyl, etc.

[0040] The term “alkylalkoxy” refers to the group -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl, wherein the alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0041] The term “alkylthioalkoxy” refers to the group -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl, and substituted alkylene-S-substituted alkyl, wherein the alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0042] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and having at least 1, preferably 1 to 2, double-bonded unsaturated sites. For example, the term includes divinyl, allyl, and but-3-en-1-yl. The term includes cis and trans isomers or mixtures of these isomers.

[0043] The term "substituted alkenyl" refers to an alkenyl group having 1 to 5 substituents or 1 to 3 substituents as defined herein, wherein the substituents are selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acyl amine alkyl, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thionyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclicoxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0044] "Alynyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, and having at least 1, preferably 1 to 2, triple bond unsaturation sites. Examples of such alkynyl groups include ethynyl (-C≡CH) and propynyl (-CH2C≡CH).

[0045] The term "substituted alkynyl" refers to an alkynyl group having 1 to 5 substituents or 1 to 3 substituents as defined herein, wherein the substituents are selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acyl amine alkyl, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thionyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclicoxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0046] "Alkyneoxy group" refers to the -O-alkynyl group, where the alkynyl group is as defined herein. Alkyneoxy groups include, for example, acetylenoxy and propynylenoxy.

[0047] "Acyl" refers to the following groups: HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl- -C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl groups include the "acetyl" group CH3C(O)-.

[0048] "Acylamino" refers to the group -NR 20 C(O)alkyl, -NR 20 C(O) substituted alkyl groups, NR 20 C(O)cycloalkyl, -NR 20 C(O) substituted cycloalkyl groups, -NR 20 C(O)cycloalkenyl, -NR 20C(O)-substituted cycloalkenyl, -NR 20 C(O) alkenyl, -NR 20 C(O)-substituted alkenyl groups, -NR 20 C(O) ynyl group, -NR 20 C(O)-substituted alkynyl groups, -NR 20 C(O) aryl, -NR 20 C(O)-substituted aryl, -NR 20 C(O) heteroaryl, -NR 20 C(O)-substituted heteroaryl, -NR 20 C(O) heterocycle and -NR 20 C(O)-substituted heterocycles, where R 20 It is hydrogen or alkyl; and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0049] "Amino carbonyl" or the term "amino acyl" refers to the group -C(O)NR. 21 R 22 , where R 21 and R 22 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; and wherein R 21 and R 22 Optionally linked to a nitrogen atom thereto to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0050] "Aminocarbonylamino" refers to the group -NR 21 C(O)NR 22 R 23 , where R 21 R 22 and R 23 It is independently selected from hydrogen, alkyl, aryl or cycloalkyl, or two of the R groups are linked to form a heterocyclic group.

[0051] The term “alkoxycarbonylamino” refers to the group -NRC(O)OR, wherein each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic, wherein the alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic groups are as defined herein.

[0052] The term “acyloxy” refers to the group alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclic-C(O)O-, wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.

[0053] "Aminosulfonyl" refers to the group –SO2NR 21 R 22 , where R 21 and R 22 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle; and wherein R 21 and R 22 Optionally linked to a nitrogen atom thereto to form a heterocyclic group or a substituted heterocyclic group, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle as defined herein.

[0054] sulfonyl amine "Base" refers to the group -NR 21 SO2R 22 , where R 21 and R 22 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle; and wherein R 21 and R 22 Optionally linked to atoms thereto to form a heterocyclic group or a substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0055] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group with 6 to 18 carbon atoms, having a monocyclic ring (e.g., present in phenyl) or a ring system having multiple fused rings (examples of such aromatic ring systems include naphthyl, anthracene, and indanyl), wherein the fused rings may or may not be aromatic, as long as the bonding point passes through an atom of the aromatic ring. This term includes, for example, phenyl and naphthyl. Unless otherwise defined, such aryl groups may optionally be substituted with 1 to 5 or 1 to 3 substituents selected from acyloxy, hydroxyl, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acyl amine aryl, alkylaryl, aryl, aryloxy, azide, carboxyl, carboxyalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, aminoacyloxy, oxyamide, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and trihalomethyl. In these cases, an aryl group substituted with 1 to 5 substituents (e.g., as described herein) is called a "substituted aryl".

[0056] "Aryloxy group" refers to the group -O-aryl, where, as defined herein, aryl groups include, for example, phenoxy, naphthoxy, etc., including optionally substituted aryl groups as also defined herein.

[0057] "Amino" refers to the group -NH2.

[0058] The term “substituted amino” refers to a group -NRR, wherein each R is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, provided that at least one R is not hydrogen.

[0059] The term "azido" refers to the group -N3.

[0060] "Carboxyl" or "carboxylate" refers to -CO2H or its salt.

[0061] "Carboxyl ester" or the term "carboxyalkyl" refers to the group -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-ynyl, -C(O)O-substituted ynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, or -C(O)O-substituted cycloalkyl. Alkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic and -C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0062] "(Carboxyester)oxy" or "carbonate" refers to the following groups: -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-ynyl, -OC(O)O-substituted ynyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O- ... Alkenyl, -OC(O)O-substituted cycloalkenyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclic and -OC(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0063] "Cyano" or "nitrile" refers to the -CN group.

[0064] "Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms, possessing one or more rings, including fused rings, bridged rings, and spirocyclic systems. Suitable examples of cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl, or polycyclic structures such as adamantyl.

[0065] The term "substituted cycloalkyl" refers to a cycloalkyl group having 1 to 5 substituents or 1 to 3 substituents as defined herein, wherein the substituents are selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, amide, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxy, oxo, thionyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclic, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0066] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group having 3 to 10 carbon atoms, having a monocyclic or polycyclic structure and having at least one double bond, preferably 1 to 2 double bonds.

[0067] The term "substituted cycloalkenyl" refers to a cycloalkenyl group having 1 to 5 substituents or 1 to 3 substituents selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, amide, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxy, ketone, thionyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclic, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0068] "Cycloalkynyl" refers to a non-aromatic cycloalkyl group with 5 to 10 carbon atoms that has a monocyclic or polycyclic structure and at least one triple bond.

[0069] “Cycloalkoxy” refers to -O-cycloalkyl.

[0070] "Cycloalkenyl group" refers to -O-cycloalkenyl group.

[0071] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0072] "Hydroxyl (hydroxy or hydroxyl)" refers to the -OH group.

[0073] "Heteroaryl" refers to an aromatic group having 1 to 15 carbon atoms within a ring, for example, 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Such heteroaryl groups may have a monocyclic ring (e.g., pyridinyl, imidazolyl, or furanyl) or multiple fused rings in a ring system (e.g., in groups such as indenyl, quinolinyl, benzofuran, benzimidazolyl, or benzothiophene), wherein at least one ring in the ring system is aromatic, provided that the connecting point passes through an atom of the aromatic ring. In some embodiments, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. The term includes, for example, pyridinyl, pyrroleyl, indoleyl, thiophene, and furanyl. Unless otherwise defined, such heteroaryl substituents may optionally be substituted with 1 to 5 or 1 to 3 substituents selected from acyloxy, hydroxyl, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, amide, alkylaryl, aryl, aromatic Oxygen, azide, carboxyl, carboxyalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, aminoacyloxy, oxyamide, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and trihalomethyl. In these cases, a heteroaryl group substituted with 1 to 5 substituents (e.g., as described herein) is called a "substituted heteroaryl".

[0074] The term "heteroaryl" refers to the group -alkylene-heteroaryl, wherein the alkylene and heteroaryl groups are as defined herein. This term includes, for example, pyridylmethyl, pyridylethyl, indolylmethyl, etc.

[0075] "Heteroaryl group" refers to -O-heteroaryl group.

[0076] "Heterocycle," "heterocyclic," and "heterocyclic group" refer to a saturated or unsaturated group having a monocyclic or multiple fused rings, including fused bridged rings and spirocyclic systems, and having 3 to 20 ring atoms, including 1 to 10 heteroatoms. These ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, provided that the connection point is through a non-aromatic ring. In some embodiments, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide an N-oxide, -S(O)-, or -SO2- moiety.

[0077] Examples of heterocyclic and heteroaryl compounds include, but are not limited to, aza-butane, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indene, isoindole, indole, dihydroindole, indazole, purine, quinazine, isoquinazine, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cyclophosphine, pteridine, carbazole, caroline, phenanthridine, acridine, phenanthroxaline, isothiazole, phenazine, isoxazole, phenoxazine, phenanthridine Thiazide, imidazoline, imidazoline, piperidine, piperazine, dihydroindole, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazoline, thiophene, benzo[b]thiophene, morpholino, thiomorpholino (also known as thiomorpholino), 1,1-dioxothiomorpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, etc.

[0078] Unless otherwise defined, such heterocyclic substituents may optionally be substituted with 1 to 5 or 1 to 3 substituents selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, amide, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxy, oxo, thionyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclicoxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl and fused heterocycles.

[0079] "Heterocyclic group" refers to the -O-heterocyclic group.

[0080] The term "heterocyclic thio group" refers to the heterocyclic group -S-.

[0081] The term "heterocyclic alkene" refers to a biradical group formed from a heterocycle as defined herein.

[0082] The term "hydroxyamino" refers to the group -NHOH.

[0083] "Nitro" refers to the group –NO2.

[0084] "O" refers to the atom (=O).

[0085] "Sulfonyl" refers to the group SO2-alkyl, SO2-substituted alkyl, SO2-alkenyl, SO2-substituted alkenyl, SO2-cycloalkyl, SO2-substituted cycloalkyl, SO2-cycloalkenyl, SO2-substituted cycloalkenyl, SO2-aryl, SO2-substituted aryl, SO2-heteroaryl, SO2-substituted heteroaryl, SO2-heterocyclic, and SO2-substituted heterocyclic, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, sulfonyl groups include methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.

[0086] "Sulfoyloxy" refers to the group -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-cycloalkenyl, -OSO2-substituted cycloalkenyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, and -OSO2-substituted heterocyclic, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0087] The term “aminocarbonyloxy” refers to the group -OC(O)NRR, wherein each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic, wherein the alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.

[0088] "Thiol" refers to the -SH group.

[0089] The term "thio" or "thion" refers to the atom (=S).

[0090] "Alkylthio" or the term "thioalkoxy" refers to the group -S-alkyl, wherein the alkyl group is as defined herein. In some embodiments, sulfur may be oxidized to -S(O)-. Sulfoxides may exist as one or more stereoisomers.

[0091] The term "substituted thioalkoxy" refers to an alkyl group that is -S-substituted.

[0092] The term “thioaryloxy” refers to the aryl-S- group, wherein the aryl group is as defined herein, including optionally substituted aryl groups as defined herein.

[0093] The term “thioheteroaryloxy” refers to the heteroaryl-S- group, wherein the heteroaryl group, as defined herein, includes optionally substituted aryl groups, as defined herein.

[0094] The term “thioheterocyclic group” refers to a heterocyclic group -S-, wherein the heterocyclic group is as defined herein, including optionally substituted heterocyclic groups as defined herein.

[0095] In addition to the contents disclosed herein, the term “substituted” when used to modify a particular group or radical can also mean that one or more hydrogen atoms of the particular group or radical are each independently substituted by the same or different substituents as defined below.

[0096] Except for the groups disclosed herein for specific terms, unless otherwise stated, the groups used to replace one or more hydrogen atoms on a saturated carbon atom in a specified group or radical (any two hydrogen atoms on a single carbon atom can be replaced with =O, =NR) 70 =N-OR 70 The substituents of (=N2 or =S) are -R 60 Halogenated, =O, -OR 70 -SR 70 -NR 80 R 80 Trihalomethyl, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -SO2R 70 -SO2O – M + -SO2OR 70 -OSO2R 70 -OSO2O – M + -OSO2OR 70 -P(O)(O) – )2(M + )2、-P(O)(OR 70 )O – M + -P(O)(OR) 70 )2、-C(O)R 70 -C(S)R 70 -C(NR) 70 )R 70 -C(O)O – M + -C(O)OR 70 -C(S)OR 70 -C(O)NR 80 R 80 -C(NR) 70 )NR 80 R80 -OC(O)R 70 -OC(S)R 70 -OC(O)O - M + -OC(O)OR 70 -OC(S)OR 70 -NR 70 C(O)R 70 -NR 70 C(S)R 70 -NR 70 CO2 – M + -NR 70 CO2R 70 -NR 70 C(S)OR 70 -NR 70 C(O)NR 80 R 80 -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 , where R 60 Choose from the group consisting of: optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; each R 70 Independently hydrogen or R 60 ; Each R 80 R is independent 70 Or, two Rs 80 Together with the nitrogen atoms they are bonded to, they form 5, 6, or 7-membered heterocyclic alkyl groups, which may optionally include 1 to 4 identical or different additional heteroatoms selected from the group consisting of O, N, and S, wherein N may have -H or C1-C3 alkyl substituents; and each M + It is a counterion carrying a net positive charge. Each M + It can be independently, for example, an alkali metal ion, such as K+. + Na + Li + Ammonium ions, for example + N(R 60 )4; or alkaline earth ions, such as [Ca 2+ ] 0.5 、[Mg 2+ ] 0.5 or[Ba 2+ ] 0.5(The subscript 0.5 indicates that one of the counter ions of this type of divalent alkaline earth ion can be the ionized form of the compound of the present invention, while the other counter ion is, for example, a chloride ion, or the two ionized compounds disclosed herein can be used as counter ions of this type of divalent alkaline earth ion, or the double ionized compound of the present invention can be used as a counter ion of this type of divalent alkaline earth ion.) As a specific example, -NR 80 R 80 This means it includes -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl, and N-morpholinyl.

[0097] Except as otherwise stated herein, the substituent for hydrogen on the unsaturated carbon atom in “substituted” alkenes, alkynes, aryls, and heteroaryls is -R. 60 Halogenated, -O - M + -OR 70 -SR 70 -S – M + -NR 80 R 80 Trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R 70 -SO3 – M + -SO3R 70 -OSO2R 70 -OSO3 – M + -OSO3R 70 -PO3 -2 (M + )2、-P(O)(OR 70 )O – M + -P(O)(OR) 70 )2、-C(O)R 70 -C(S)R 70 -C(NR) 70 )R 70 -CO2 – M + -CO2R 70 -C(S)OR 70 -C(O)NR 80 R 80 -C(NR) 70 )NR 80 R 80 -OC(O)R 70 -OC(S)R 70 -OCO2 –M + -OCO2R 70 -OC(S)OR 70 -NR 70 C(O)R 70 -NR 70 C(S)R 70 -NR 70 CO2 – M + -NR 70 CO2R 70 -NR 70 C(S)OR 70 -NR 70 C(O)NR 80 R 80 -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 , where R 60 R 70 R 80 and M + The definition is as stated above, provided that in the case of substituted alkenes or alkynes, the substituent is not -OM. + -OR 70 -SR 70 or -S - M + .

[0098] Except for the groups disclosed herein for specific terms, unless otherwise stated, the substituents of hydrogen atom on nitrogen atom in “substituted” heteroalkyl and cyclohexaalkyl groups are -R. 60 -O - M + -OR 70 -SR 70 -S - M + -NR 80 R 80 Trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R 70 -S(O)2O - M + -S(O)2OR 70 -OS(O)2R 70 -OS(O)2O - M + -OS(O)2OR 70 -P(O)(O) -)2(M + )2、-P(O)(OR 70 )O - M + -P(O)(OR) 70 (OR) 70 -C(O)R 70 -C(S)R 70 -C(NR) 70 )R 70 -C(O)OR 70 -C(S)OR 70 -C(O)NR 80 R 80 -C(NR) 70 )NR 80 R 80 -OC(O)R 70 -OC(S)R 70 -OC(O)OR 70 -OC(S)OR 70 -NR 70 C(O)R 70 -NR 70 C(S)R 70 -NR 70 C(O)OR 70 -NR 70 C(S)OR 70 -NR 70 C(O)NR 80 R 80 -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 , where R 60 R 70 R 80 and M + As mentioned above.

[0099] In addition to the disclosure herein, in one embodiment, the substituted group has 1, 2, 3 or 4 substituents, 1, 2 or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0100] Unless otherwise stated, the naming of substituents not explicitly defined herein is obtained by naming the terminal portion of the functional group, followed by the adjacent functional group near the junction. For example, the substituent “arylalkoxycarbonyl” refers to the group (aryl)-(alkyl)-OC(O)-.

[0101] With respect to any group comprising one or more substituents disclosed herein, it should be understood that such group does not include any sterically impractical and / or synthetically infeasible substitutes or substitution patterns. Furthermore, the subject compounds include all stereochemical isomers derived from the substitutes of these compounds.

[0102] "Stereoisomers" are compounds that have the same atomic connectivity but different atomic arrangements in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers.

[0103] It should be understood that the term "or its salt or solvate or stereoisomer" is intended to include all permutations of salts, solvates, and stereoisomers, such as solvates of pharmaceutically acceptable salts of stereoisomers of the subject compound. It should be understood that the term "or its salt" is intended to include all permutations of salts. It should be understood that the term "or its solvate" is intended to include all permutations of solvates. It should be understood that the term "or its stereoisomer" is intended to include all permutations of stereoisomers. It should be understood that the term "or its tautomer" is intended to include all permutations of tautomers. Therefore, for example, it is intended to include solvates of pharmaceutically acceptable salts of tautomers of stereoisomers of the subject compound.

[0104] As used herein, the term "isolated" is intended to describe a target compound in an environment different from the environment in which the compound naturally occurs. "Isolated" is intended to include compounds in a sample that are substantially enriched with the target compound and / or in which the target compound has been partially or substantially purified.

[0105] Before describing the invention in more detail, it should be understood that the invention is not limited to the specific embodiments described, and variations are certainly possible. 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 restrictive, as the scope of the invention will be limited only by the appended claims.

[0106] When numerical ranges are provided, it should be understood that every intermediate value between the upper and lower limits of the range (accurate to one-tenth of the lower limit unit, unless the context explicitly indicates otherwise) and any other indicated or intermediate value within the range are included in this invention. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges and are also included in this invention, except for any specifically excluded limits within the range. When the range includes one or both limits, the range excluding any one or both of these included limits is also included in this invention.

[0107] It should be understood that certain features of the invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention described in the context of a single embodiment may also be provided individually or in any suitable sub-combination. All combinations of embodiments relating to the invention are specifically included in the invention and disclosed herein as if each combination were disclosed individually and explicitly, provided that such combinations contain a target, for example, a compound that is a stable compound (i.e., a compound that can be prepared, isolated, characterized, and tested for biological activity). Furthermore, all sub-combinations of the various embodiments and their elements (e.g., elements of chemical groups listed in the embodiments describing these variables) are also specifically included in the invention and disclosed herein as if each such sub-combination were disclosed individually and explicitly herein.

[0108] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The target methods and materials are now described; however, any methods and materials similar to or equivalent to those described herein may also be used in the practice or testing of this invention. All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials relating to the cited publications.

[0109] It must be noted that, as used herein and in the appended claims, the singular forms “a / an” and “the” include plural referents unless the context clearly indicates otherwise. It should be further noted that claims may be drafted to exclude any optional elements. Therefore, this statement is intended as a prior basis for the use of exclusive terms such as “only,” “merely,” etc., or the use of negative limiting terms, together with elements of the cited claims.

[0110] It should be understood that certain features of the invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention described in the context of a single embodiment may also be provided individually or in any suitable sub-combination.

[0111] The publications discussed herein refer only to their public disclosure prior to the filing date of this application. Nothing herein should be construed as an admission that this invention is not entitled to precedence over these publications due to prior inventions. Furthermore, the publication dates provided may differ from the actual publication dates, which may require independent verification.

[0112] Unless otherwise stated, the methods and techniques of this embodiment are generally performed according to conventional methods known in the art and as described in the various general and more specific references cited and discussed throughout this specification. See, for example, Loudon, *Organic Chemistry*, 4th ed., New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, *March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure*, 5th ed., Wiley-Interscience, 2001.

[0113] The nomenclature used to name the subject compounds in this article is illustrated in the examples presented herein. Where possible, this nomenclature is typically derived using commercially available AutoNom software (MDL, San Leandro, Calif.).

[0114] Numerous general references providing known chemical synthetic schemes and conditions for synthesizing the disclosed compounds are available (see, for example, Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structures, 5th ed., Wiley Electronic Journal, 2001; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, 4th ed., New York: Longman, 1978).

[0115] The compounds described herein can be purified by any method known in the art, including chromatographic methods such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, rapid column chromatography, and ion-exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases, as well as ion exchange resins. See, for example, *Introduction to Modern Liquid Chromatography*, 2nd ed., by L.R. Snyder and J.J. Kirkland, John Wiley and Sons, 1979; and *Thin Layer Chromatography*, by E. Stahl, Springer-Verlag, New York, 1969.

[0116] In any method of preparing the compounds disclosed herein, it may be necessary and / or desirable to protect any sensitive or reactive groups on the relevant molecules. This can be achieved using conventional protecting groups as described in standard literature, such as TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, New York, 2006. Protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0117] The compounds described herein may contain one or more chiral centers and / or double bonds, and thus may exist as stereoisomers, such as double-bonded isomers (i.e., geometric isomers), enantiomers, or diastereomers. Therefore, all possible enantiomers and stereoisomers of the compounds, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and mixtures of enantiomers and stereoisomers, are included in the description of the compounds herein. Mixtures of enantiomers and stereoisomers can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art. The compounds may also exist in several tautomeric forms, including enol forms, ketone forms, and mixtures thereof. Therefore, the chemical structures described herein include all possible tautomeric forms of the compounds shown. The described compounds also include isotopically labeled compounds, wherein one or more atoms have atomic masses different from those conventionally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, those shown. 2 H, 3 H, 11 C 13 C 14C 15 N、 18 O、 17 O, etc. The compound can exist in both non-solventized and solvated forms, including hydrated forms. Generally, the compound can be in a hydrated or solvated form. Some compounds can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent to the uses contemplated herein and are intended to fall within the scope of this disclosure.

[0118] Specific embodiments of the present invention

[0119] This disclosure includes a crystalline solid of 3-palmitoyl-amido-1,2-propanediol (Formula I):

[0120] (I).

[0121] The term "crystallization" is used herein in its conventional sense to refer to a solid material, i.e., a solid material in which the molecules forming the solid are arranged in a highly ordered microscopic geometry (e.g., forming an ordered lattice structure) and extend in three dimensions. In the embodiments described herein, the crystalline solid is not amorphous, characterized by an undefined structural order and a microscopic structure lacking a regular geometric arrangement in the three dimensions.

[0122] In the embodiments, the polymorph of crystalline solid 3-palmitoyl-amido-1,2-propanediol has a purity of 90% or higher, for example 95% or higher, for example 97% or higher, for example 99% or higher, and including 99.9% or higher, as demonstrated by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) analysis, as described in more detail below. In some embodiments, the polymorph of 3-palmitoyl-amido-1,2-propanediol described herein exists in a crystalline solid with 100% purity. In some embodiments, the polymorph of crystalline solid 3-palmitoyl-amido-1,2-propanediol provided herein exhibits improved solubility and reactivity compared to other polymorphs of crystalline and amorphous 3-palmitoyl-amido-1,2-propanediol.

[0123] In embodiments, polymorphs of crystalline solids of 3-palmitoyl-amido-1,2-propanediol are shown in X-ray powder diffraction (XRPD) patterns containing peaks at 2Ɵ values ​​of approximately 8.25°. For a given crystal form, the relative intensities of the diffraction peaks may vary depending on the orientation of the crystal relative to X-rays (e.g., from the crystal morphology). In embodiments, the intensities of the X-ray powder diffraction peaks at 2Ɵ may vary from crystal to crystal, but the characteristic peak positions of the polymorph remain constant. In some embodiments, polymorphs of crystalline solids of 3-palmitoyl-amido-1,2-propanediol have X-ray powder diffraction (XRPD) patterns with one or more peaks at 2Ɵ values ​​of approximately 2.75°, 2Ɵ values ​​of approximately 6°, 2Ɵ values ​​of approximately 3.8°, 2Ɵ values ​​of approximately 15°, 2Ɵ values ​​of approximately 26.3°, 2Ɵ values ​​of approximately 30.5°, and 2Ɵ values ​​of approximately 33.1°. In some cases, the thermogravimetric analysis (TGA) of the polymorphs of the crystalline solids of 3-palmitoyl-amido-1,2-propanediol presented herein is characterized by a single weight reduction step. In some cases, the weight reduction step begins at approximately 200.5 °C.

[0124] Differential scanning calorimetry (DSC) is used to measure the transition temperatures of crystalline solids as they absorb or release heat due to structural changes or melting. DSC is used to distinguish different crystalline forms (e.g., different polymorphs). Different polymorphs can be identified based on their distinct characteristic transition temperatures. In some embodiments, by differential scanning calorimetry (DSC), the polymorph of the crystalline solid of 3-palmitoyl-amido-1,2-propanediol exhibits a first endothermic reaction at 79.3°C and a second endothermic reaction at approximately 102.5°C. In these embodiments, the second endothermic reaction is a unimodal endothermic reaction.

[0125] A method for preparing polymorphs of crystalline solids of 3-palmitoyl-amido-1,2-propanediol is also provided. In implementing the method according to certain embodiments, 3-palmitoyl-amido-1,2-propanediol is contacted with one or more solvents to generate a 3-palmitoyl-amido-1,2-propanediol composition and precipitated to generate crystalline solids of 3-palmitoyl-amido-1,2-propanediol. In some embodiments, the solvent is a polar solvent. In other embodiments, the solvent is a nonpolar solvent. In still other embodiments, the solvent is a mixture of polar and nonpolar solvents. Target solvents may include, but are not limited to, tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP) and combinations thereof. In some cases, the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, and dichloromethane. In other cases, the solvent is tetrahydrofuran.

[0126] In some embodiments, 3-palmitoyl-amido-1,2-propanediol is contacted with a solvent in the presence of a base. In some cases, the base is an organic base. The organic base used may include, but is not limited to, triethylamine, triethanolamine, amines, arginine, benzylamine, ethylenediamine, meglumine, procaine, N-methylglucosamine, piperazine, aminobutanetriol, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, ethanolamine, diisopropylamine, diisopropylethylamine, 1,8-bis(dimethylamino)naphthalene (proton sponge), imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2,4,6-trimethylpyridine (trimethylpyridine), potassium carbonate, sodium methoxide, tetramethylethylenediamine (TMEDA), and dimethylaminoethanol, as well as other organic bases. In some cases, the base is selected from tetramethylethylenediamine (TMEDA), 1,8-bis(dimethylamino)naphthalene (proton sponge), and triethylamine. In some cases, the base is triethylamine. The amount of base in contact with 3-palmitoylamido-1,2-propanediol can vary, ranging from 1 equivalent to 4 equivalents relative to 3-palmitoylamido-1,2-propanediol, for example, from 1.5 equivalents to 3.5 equivalents and including about 3 equivalents relative to 3-palmitoylamido-1,2-propanediol.

[0127] To precipitate crystalline solid 3-palmitoyl-amido-1,2-propanediol, the 3-palmitoyl-amido-1,2-propanediol solvent composition can be first heated (with or without a base) to produce a heated 3-palmitoyl-amido-1,2-propanediol solvent composition, which is then cooled to form crystalline solid 3-palmitoyl-amido-1,2-propanediol. The 3-palmitoyl-amido-1,2-propanediol solvent composition can be heated to temperatures ranging from 10°C to 60°C, for example from 15°C to 55°C, for example from 25°C to 55°C, and including temperatures of 50°C. The duration for which the heated composition is maintained at the elevated temperature can vary, for example, 1 minute or longer, for example, 2 minutes or longer, for example, 5 minutes or longer, for example, 10 minutes or longer, for example, 15 minutes or longer, for example, 30 minutes or longer, and including 60 minutes or longer. In some embodiments, the 3-palmitoyl-amido-1,2-propanediol solvent is heated to a temperature sufficient to dissolve the 3-palmitoyl-amido-1,2-propanediol in the solvent. All or part of the 3-palmitoyl-amido-1,2-propanediol may be soluble in the solvent (e.g., the 3-palmitoyl-amido-1,2-propanediol solvent composition may change from a clear solution to a slurry composition when examined visually), for example, 25% or more by weight, such as 50% or more, such as 75% or more, such as 90% or more, such as 95% or more, such as 97% or more, and including 99% or more of the 3-palmitoyl-amido-1,2-propanediol may be soluble in the solvent.

[0128] In embodiments, crystalline solids of 3-palmitoyl-amido-1,2-propanediol are precipitated by cooling the heated 3-palmitoyl-amido-1,2-propanediol solvent composition. The composition can be cooled to 20°C to 40°C, for example, 15°C to 35°C and including temperatures of about 30°C. In some embodiments, the method includes precipitating crystalline solids of 3-palmitoyl-amido-1,2-propanediol by removing a portion of the solvent from the composition, for example, by rotary evaporation or under an inert gas (N2 or argon).

[0129] In some embodiments, the crystalline solids of 3-palmitoyl-amido-1,2-propanediol are separated by filtration (e.g., vacuum filtration) or the solvent can be removed by heating or rotary evaporation. In some embodiments, the crystalline solids of 3-palmitoyl-amido-1,2-propanediol are separated by drying at room temperature in a nitrogen atmosphere or under vacuum.

[0130] This disclosure also includes crystalline solids of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (Formula III):

[0131] (III)

[0132] Wherein DMTr stands for dimethoxytriphenylmethyl. In some cases, the crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is a single crystal of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. The term "single crystal" is used herein in its conventional sense, referring to a single-crystal solid in which the crystal lattice is continuous throughout the sample and uninterrupted with the edges of the sample, without grain boundaries. In some embodiments, the target single crystal is a single-crystal solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane of sufficient size and mass for X-ray crystallography (XRC) and X-ray crystal structure determination.

[0133] In the embodiments, the purity of the crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (e.g., a single crystal of 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane) is 90% or higher, for example 95% or higher, for example 97% or higher, for example 99% or higher, and includes 99.9% or higher. In some embodiments, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is present in the crystalline solid with 100% purity. In some embodiments, the crystalline solids of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane provided herein (e.g., single crystals of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane) exhibit improved solubility and reactivity compared to other crystalline forms (e.g., powder) or amorphous solids of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane.

[0134] According to an embodiment, the crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is in monoclinic form. Each unit cell in the crystalline solid comprises two different conformations of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane, such as a bent conformation and a linear conformation. In an embodiment, each conformation (bent and linear) of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is present in the unit cell in a 1:1 ratio. Each unit cell in the crystalline solid comprises 4 molecules of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. In some embodiments, the unit cell size is about 8.44 μm × about 26.56 μm × about 10.06 μm, wherein the volume of the unit cell is about 2254.8 μm. 3The density of the palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane crystalline solid is approximately 1.2 g / cm³. 3 Approximately 1.3 g / cm 3 And the purity is 95% or higher.

[0135] A method for preparing crystalline solids (e.g., single crystals) of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is also provided. In implementing the method according to certain embodiments, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is contacted with one or more solvents to produce a 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane composition and precipitated to produce crystalline solids of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane, such as one or more single crystals of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane.

[0136] In some embodiments, the solvent is a polar solvent. In other embodiments, the solvent is a nonpolar solvent. In still other embodiments, the solvent is a mixture of polar and nonpolar solvents. The target solvent may include, but is not limited to, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, dichloromethane, trichloromethane, carbon tetrachloride, 1,4-dioxane, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, 2-methylbut-2-ol (tAmOH), dimethyl sulfoxide, pentane, hexane, heptane, octane, etc. In some embodiments, the solvent is a mixture of dichloromethane and pentane.

[0137] To precipitate 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane crystalline solid, the 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane solvent composition can be first heated to produce a heated 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane solvent composition, followed by cooling to form a crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. The 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane solvent composition can be heated to temperatures ranging from 10°C to 60°C, for example from 15°C to 55°C, for example from 25°C to 55°C, and including temperatures of 50°C. The duration for which the heated composition is maintained at the elevated temperature can vary, for example, 1 minute or longer, for example, 2 minutes or longer, for example, 5 minutes or longer, for example, 10 minutes or longer, for example, 15 minutes or longer, for example, 30 minutes or longer, and including 60 minutes or longer. In some embodiments, the 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane solvent is heated to a temperature sufficient to dissolve the 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane in the solvent.

[0138] In other embodiments, crystalline solids of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane are precipitated by cooling the heated solvent composition. The composition can be cooled to -20°C to 20°C, for example -19°C to 19°C, for example -18°C to 18°C, for example -17°C to 17°C, for example -16°C to 16°C, for example -15°C to 15°C, for example -14°C to 14°C, for example -13°C to 13°C, for example -12°C to 12°C, for example -11°C to 11°C, and temperatures including -10°C to 10°C. In some embodiments, the method includes precipitating crystalline solids of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane by removing the solvent from the composition, for example by rotary evaporation or under an inert gas (N2 or argon).

[0139] The crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is separated by filtration (e.g., vacuum filtration) or the solvent can be removed by heating or rotary evaporation. In some embodiments, the crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is separated by drying at room temperature under a nitrogen atmosphere or under vacuum.

[0140] A method for preparing 3-palmitoyl-amido-1,2-propanediol from 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is also described. In carrying out the subject method according to certain embodiments, a solvent is contacted with a crystalline solid of 3-palmitoyl-amido-1,2-propanediol to produce a precursor composition; and the precursor composition is contacted with a composition containing dimethoxytriphenylmethyl chloride to produce a composition having 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane.

[0141] In the embodiments, the target solvent may include, but is not limited to, tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate (iPrOAc), ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP) or combinations thereof. In some cases, the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP). In other cases, the solvent is selected from methyltetrahydrofuran, tetrahydrofuran, and dichloromethane.

[0142] In some embodiments, the precursor composition includes an additive. For example, the additive may be calcium oxide, magnesium oxide, boric acid, tetrabutylammonium fluoride (TBAF), 4-dimethylaminopyridine (DMAP), copper chloride (CuCl2), ytterbium(III) chloride (YbCl3), or 1,4-diazabicyclo[2.2.2]octane (DABCO). In some cases, the additive is selected from tetrabutylammonium fluoride (TBAF), magnesium oxide, and boric acid. In some cases, the additive is magnesium oxide. The amount of the additive in the precursor composition can vary, ranging from 0.05 equivalents to 1 equivalent relative to 3-palmitoyl-amido-1,2-propanediol, for example, from 0.1 equivalents to 0.5 equivalents relative to 3-palmitoyl-amido-1,2-propanediol, and including about 0.3 equivalents.

[0143] In some embodiments, the precursor composition is further contacted with a base. In some cases, the base is an organic base. In some embodiments, the precursor composition is contacted with a protecting group in the presence of a base, wherein the base is selected from 1,8-bis(dimethylamino)naphthalene (proton sponge), imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2,4,6-trimethylpyridine (trimethylpyridine), triethylamine (TEA), potassium carbonate, sodium methoxide, tetramethylethylenediamine (TMEDA), dimethylaminoethanol, and combinations thereof. In some cases, the base is selected from 1,8-bis(dimethylamino)naphthalene (proton sponge), tetramethylethylenediamine (TMEDA), and triethylamine (TEA). In some cases, the base is triethylamine.

[0144] The amount of base contacted with the 3-palmitoyl-amido-1,2-propanediol precursor composition can vary, ranging from 0.5 equivalents to 3.5 equivalents, for example 0.75 equivalents to 1.95 equivalents, for example 1 equivalent to 1.9 equivalents, for example 1.1 equivalents to 1.85 equivalents, for example 1.15 equivalents to 1.80 equivalents, for example 1.25 equivalents to 1.75 equivalents, relative to 3-palmitoyl-amido-1,2-propanediol; and includes contacting 3-palmitoyl-amido-1,2-propanediol with 1.5 equivalents of base.

[0145] In some embodiments, the precursor composition is formed and maintained at ambient temperature. In other embodiments, the precursor composition is formed and maintained at elevated temperatures, such as 25°C to 40°C, such as 27.5°C to 45°C, and including 30°C to 35°C, such as about 30°C. In some embodiments, the precursor composition is formed at a first temperature and transitions to a second temperature. In one example, the precursor composition is formed at ambient temperature and transitions to an elevated temperature, such as 25°C to 40°C, such as 27.5°C to 45°C, and including 30°C to 35°C, such as about 30°C. In another example, the precursor composition is formed at an elevated temperature, such as about 50°C or higher, and is cooled to a lower temperature (e.g., about 30°C) before the precursor composition comes into contact with a protecting group.

[0146] In the examples, the precursor composition is contacted with a hydroxyl protecting group to generate 3-palmitoyl-amido)-2-hydroxy-1-(protected hydroxy)-propane. The hydroxyl protecting group can vary, and in some cases, the hydroxyl protecting group includes, but is not limited to: 1) alkyl ether type protecting groups, such as alkyl ethers, allyl ethers, triphenylmethyl ethers, dimethoxy-triphenylmethyl ethers, benzyl ethers, or p-methoxybenzyl ether protecting groups; 2) ester and carbonate type protecting groups, such as acetates, chloroacetic acids, dichloroacetic acids, trichloroacetic acids, trifluoroacetic acids, neopentanoates, benzoates, p-methoxybenzoates, p-bromobenzoates, methyl carbonate, 9-(fluorenylmethyl)carbonate (Fmoc), allyl carbonate (Alloc), 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (Teoc), benzyl carbonate (Cbz), tert-butyl carbonate (Boc), or dimethyl thiocarbamate (DMTC) protecting groups; 3) acetal type protecting groups. For example, protecting groups include methoxymethyl ether (MOM), benzyloxymethyl ether (BOM), 2,2,2-trichloroethoxymethyl ether, 2-methoxymethyl ether (MEM), methylthiomethyl ether (MTM), p-methoxybenzyloxymethyl ether (PMBM), 2-(trimethylsilyl)ethoxymethyl ether (SEM), and tetrahydropyran ether (THP); and 2) silyl ether type protecting groups, such as trimethylsilyl (TMS), triethylsilyl (TES), isopropyl dimethylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), tert-butyl dimethylsilyl (TBS), tert-butyl diphenylsilyl (TBDPS), triisopropylsilyl (TIPS), tetraisopropyldisiloxanediol (TIPDS), or di-tert-butylsilyl (DTBS). In some embodiments, the hydroxyl protecting group is a dimethoxy-triphenylmethyl protecting group.

[0147] The amount of hydroxyl protecting group in contact with the precursor composition can vary, ranging from 0.5 equivalents to 2 equivalents relative to 3-palmitoyl-amido-1,2-propanediol, for example from 0.75 equivalents to 1.5 equivalents relative to 3-palmitoyl-amido-1,2-propanediol, and including about 1.4 equivalents.

[0148] In some embodiments, the 3-palmitoyl-amido-1,2-propanediol used in the method for preparing 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is a crystalline solid of 3-palmitoyl-amido-1,2-propanediol. In some embodiments, 3-palmitoyl-amido-1,2-propanediol is a polymorph of the crystalline solid 3-palmitoyl-amido-1,2-propanediol, shown in XRPD plots containing one or more peaks at 2ơ values ​​of approximately 2.75°, 2ơ values ​​of approximately 6°, 2ơ values ​​of approximately 3.8°, 2ơ values ​​of approximately 8.25°, 2ơ values ​​of approximately 15°, 2ơ values ​​of approximately 26.3°, 2ơ values ​​of approximately 30.5°, and 2ơ values ​​of approximately 33.1°.

[0149] As needed, the components used in each step of the method may be purified compositions or crude compositions. The term "purified" is used in its conventional sense to refer to a composition in which at least some separation or purification process has been performed, such as, for example, filtration or aqueous post-treatment of the reaction mixture. In some cases, purification includes liquid chromatography, recrystallization, distillation (e.g., azeotropic distillation), or other types of compound purification. In some embodiments, the reaction mixture is used as a crude mixture in subsequent steps of the method described herein, wherein the reaction mixture has not been purified or otherwise post-treated. In some cases, the crude composition reaction mixture comprises the target compound of sufficient purity, for example, obtained by high-performance liquid chromatography (HPLC), proton nuclear magnetic resonance spectroscopy (PRISMR), etc. 1 The crude composition, determined by ¹H NMR or a combination thereof, comprises a purity of 90% or higher, such as 95% or higher, such as 97% or higher, and includes 99% or higher of the target compound.

[0150] This disclosure

[0151] The aspects of the subject matter described herein, including embodiments, may be advantageous, either alone or in combination with one or more other aspects or embodiments. Without limiting the description, certain non-limiting aspects of this disclosure, numbered 1-66, are provided below. As will be apparent to those skilled in the art upon reading this disclosure, each of the individually numbered aspects can be used or combined with any of the preceding or following individually numbered aspects. This is intended to support combinations of all such aspects, and is not limited to combinations of the aspects explicitly provided below:

[0152] 1. A crystalline solid of a compound of formula I:

[0153] (I).

[0154] 2. The crystalline solid according to aspect 1, having an X-ray powder diffraction (XRPD) pattern containing a peak at a 2θ value of approximately 8.25°.

[0155] 3. The crystalline solid according to any one of aspects 1 to 2, having an XRPD plot containing one or more peaks at 2Ɵ values ​​of approximately 2.75°, 2Ɵ values ​​of approximately 6°, 2Ɵ values ​​of approximately 3.8°, 2Ɵ values ​​of approximately 15°, 2Ɵ values ​​of approximately 26.3°, 2Ɵ values ​​of approximately 30.5°, and 2Ɵ values ​​of approximately 33.1°.

[0156] 4. A crystalline solid according to any one of aspects 1 to 3, wherein the thermogravimetric analysis (TGA) of the crystalline solid is characterized by a single weight reduction step change.

[0157] 5. The crystalline solid according to aspect 4, wherein the weight reduction transition begins at about 200.5°C.

[0158] 6. The crystalline solid according to any one of aspects 1 to 5, by differential scanning calorimetry (DSC), the crystalline solid has a first endothermic reaction at 79.3°C and a second endothermic reaction at about 102.5°C.

[0159] 7. The crystalline solid according to aspect 6, wherein the second endothermic reaction is a unimodal endothermic reaction.

[0160] 8. A method comprising:

[0161] Contact the solvent with the compound of formula I:

[0162] (I)

[0163] To generate a precursor composition; and

[0164] The precursor composition is used to generate a crystalline solid of the compound of formula I.

[0165] 9. The method according to aspect 8, wherein the solvent is selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP) and combinations thereof.

[0166] 10. The method according to aspect 9, wherein the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, and dichloromethane.

[0167] 11. The method according to aspect 10, wherein the solvent is tetrahydrofuran.

[0168] 12. The method according to any one of aspects 8 to 11, wherein generating the crystalline solid of the compound of formula I comprises:

[0169] The precursor composition is heated to a temperature of approximately 45°C to approximately 65°C; and

[0170] The heated precursor composition is cooled to a temperature of about 25°C to about 35°C to produce the crystalline solid of the compound of formula I.

[0171] 13. The method according to aspect 12, wherein generating the crystalline solid of the compound of formula I comprises heating the precursor composition to a temperature of about 50°C; and cooling the heated precursor composition to a temperature of about 30°C to generate the crystalline solid of the compound of formula I.

[0172] 14. The method according to any one of aspects 8 to 13, wherein the compound of formula I is contacted with the solvent in the presence of a base.

[0173] 15. The method according to aspect 14, wherein the base is triethylamine (TEA).

[0174] 16. The method according to any one of aspects 8 to 15, wherein the crystalline solid of the compound of formula I has an X-ray powder diffraction (XRPD) pattern containing a peak at a 2 Å value of about 8.25°.

[0175] 17. The method according to any one of aspects 8 to 16, wherein the crystalline solid of the compound of formula I has an XRPD plot having one or more peaks at 2α values ​​of approximately 2.75°, approximately 6°, approximately 3.8°, approximately 15°, approximately 26.3°, approximately 30.5°, and approximately 33.1°.

[0176] 18. The method according to any one of aspects 8 to 17, wherein the thermogravimetric analysis (TGA) of the crystalline solid of the compound of formula I is characterized by a single weight reduction step change.

[0177] 19. The method according to aspect 18, wherein the weight reduction step begins at approximately 200.48°C.

[0178] 20. The method according to any one of aspects 8 to 19, wherein the crystalline solid of the compound of formula I has a first endothermic reaction at 79.3°C and a second endothermic reaction at about 102.5°C by differential scanning calorimetry (DSC).

[0179] 21. The method according to aspect 20, wherein the second heat absorption is unimodal heat absorption.

[0180] 22. A method comprising:

[0181] Contact the solvent with the crystalline solid of compound I:

[0182] (I)

[0183] To generate a precursor composition; and

[0184] The precursor composition is contacted with a composition containing dimethoxytriphenylmethyl chloride to generate a composition containing compound II:

[0185] (II)

[0186] DMTr stands for dimethoxytriphenylmethyl.

[0187] 23. The method according to aspect 22, wherein the precursor composition is contacted with dimethoxytriphenylmethyl chloride in the presence of a base.

[0188] 24. The method according to aspect 23, wherein the base is an organic base.

[0189] 25. The method according to aspect 23, wherein the base is selected from the group consisting of 1,8-bis(dimethylamino)naphthalene (proton sponge), imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2,4,6-trimethylpyridine (trimethylpyridine), triethylamine (TEA), potassium carbonate, sodium methoxide, tetramethylethylenediamine (TMEDA), and dimethylaminoethanol.

[0190] 26. The method according to aspect 23, wherein the base is selected from 1,8-bis(dimethylamino)naphthalene (proton sponge), tetramethylethylenediamine (TMEDA), and triethylamine (TEA).

[0191] 27. The method according to aspect 23, wherein the base is triethylamine (TEA).

[0192] 28. The method according to any one of aspects 22 to 27, wherein the precursor composition is contacted with dimethoxytriphenylmethyl chloride in the presence of an additive.

[0193] 29. The method according to aspect 28, wherein the additive is selected from the group consisting of calcium oxide, magnesium oxide, boric acid, tetrabutylammonium fluoride (TBAF), 4-dimethylaminopyridine (DMAP), copper chloride (CuCl2), ytterbium(III) chloride (YbCl3) and 1,4-diazabicyclo[2.2.2]octane (DABCO).

[0194] 30. The method according to aspect 29, wherein the additive is selected from tetrabutylammonium fluoride (TBAF), magnesium oxide and boric acid.

[0195] 31. The method according to aspect 29, wherein the additive is magnesium oxide.

[0196] 32. The method according to any one of aspects 22 to 31, wherein the solvent is selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP) and combinations thereof.

[0197] 33. The method according to aspect 32, wherein the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, acetonitrile, toluene, 2-methylbut-2-ol (tAmOH) and N-methyl-2-pyrrolidone (NMP).

[0198] 34. The method according to aspect 32, wherein the solvent is selected from methyltetrahydrofuran, tetrahydrofuran, and dichloromethane.

[0199] 35. The method according to any one of aspects 22 to 34, wherein the crystalline solid of the compound of formula I has an X-ray powder diffraction (XRPD) pattern containing a peak at a 2 Å value of about 8.25°.

[0200] 36. The method according to any one of aspects 22 to 35, wherein the crystalline solid of the compound of formula I has an XRPD plot containing one or more peaks at 2α values ​​of approximately 2.75°, approximately 6°, approximately 3.8°, approximately 15°, approximately 26.3°, approximately 30.5°, and approximately 33.1°.

[0201] 37. The method according to any one of aspects 22 to 36, wherein the thermogravimetric analysis (TGA) of the crystalline solid of the compound of formula I is characterized by a single weight reduction step change.

[0202] 38. The method according to aspect 37, wherein the weight reduction step begins at approximately 200.48°C.

[0203] 39. The method according to any one of aspects 22 to 38, wherein the crystalline solid of the compound of formula I has a first endothermic reaction at 79.3°C and a second endothermic reaction at about 102.5°C by differential scanning calorimetry (DSC).

[0204] 40. The method according to aspect 39, wherein the second heat absorption is a unimodal heat absorption.

[0205] 41. A crystalline solid of a compound of formula II:

[0206] (II)

[0207] DMTr stands for dimethoxytriphenylmethyl.

[0208] 42. The crystalline solid according to aspect 41, wherein the crystalline solid of formula II is in monoclinic form.

[0209] 43. A crystalline solid according to any one of aspects 40 to 42, wherein each unit cell of the crystalline solid comprises two different conformations of the compound of formula II.

[0210] 44. The crystalline solid according to aspect 43, wherein each unit cell comprises an extended conformation and a bent conformation of the compound of formula II.

[0211] 45. A crystalline solid according to any one of aspects 43 to 44, wherein each conformation of the compound of formula II is present in a 1:1 ratio.

[0212] 46. ​​A crystalline solid according to any one of aspects 41 to 45, wherein each unit cell of the crystalline solid comprises 4 molecules of the compound of formula II.

[0213] 47. The crystalline solid according to aspect 46, wherein the size of the unit cell is about 8.44 μm × about 26.56 μm × about 10.06 μm.

[0214] 48. The crystalline solid according to aspect 47, wherein the volume of said unit cell is about 2254.8 ppm. 3 .

[0215] 49. The crystalline solid according to aspect 48, having a density of about 1.2 g / cm³. 3 Approximately 1.3 g / cm 3 .

[0216] 50. A crystalline solid according to any one of aspects 41 to 49, wherein the polymorph of the compound of formula II has a purity of 95% or higher.

[0217] 51. A method comprising:

[0218] Contact a composition containing one or more solvents with a compound of formula III:

[0219] (II); and

[0220] One or more single crystals of the compound of formula II are formed.

[0221] 52. The method according to aspect 51, wherein the composition comprises two different solvents.

[0222] 53. The method according to aspect 52, wherein the composition comprises a polar solvent and a nonpolar solvent.

[0223] 54. The method according to aspect 53, wherein the polar solvent is dichloromethane.

[0224] 55. The method according to any one of aspects 53 to 54, wherein the nonpolar solvent is pentane.

[0225] 56. The method according to any one of aspects 51 to 55, wherein the composition is contacted with the compound of formula II at a temperature of about 10°C to about 75°C.

[0226] 57. The method according to aspect 56, wherein the method comprises heating the composition to a temperature sufficient to dissolve the compound of formula II, and cooling the heated composition after the compound of formula II has dissolved.

[0227] 58. The method according to any one of aspects 51 to 57, wherein one or more of the single crystals formed are in monoclinic form.

[0228] 59. The method according to any one of aspects 51 to 58, wherein each single crystal comprises two different conformations of the compound of formula II.

[0229] 60. The method according to aspect 59, wherein each unit cell of the single crystal comprises an extended conformation and a bent conformation of the compound of formula II.

[0230] 61. The method according to any one of aspects 59 to 60, wherein each conformation of the compound of formula II is present in a 1:1 ratio.

[0231] 62. The method according to any one of aspects 51 to 61, wherein the unit cell in each single crystal comprises 4 molecules of the compound of formula II.

[0232] 63. The method according to aspect 62, wherein the size of the unit cell is about 8.44 μm × about 26.56 μm × about 10.06 μm.

[0233] 64. The method according to aspect 63, wherein the volume of the unit cell is approximately 2254.8 oz. 3 .

[0234] 65. The method according to any one of aspects 51 to 64, wherein the density of each formed single crystal is about 1.2 g / cm³. 3 Approximately 1.3 g / cm 3 .

[0235] 66. The method according to any one of aspects 51 to 65, wherein the polymorph of each formed single crystal of the formula II compound has a purity of 95% or higher.

[0236] Example

[0237] The following examples are provided to provide a complete disclosure and description of how to make and use the invention to those skilled in the art, and are not intended to limit the scope of the inventors' ideas, nor to represent that the following experiments are all or only those conducted. Efforts have been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but some errors and deviations should be accounted for. Unless otherwise stated, parts are parts by weight, molecular weight is the weight-average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure. "Average" refers to the arithmetic mean. Standard abbreviations may be used, such as bp, base pair; kb, kilobase; pl, picoliter; s or sec, second; min, minute; h or hr, hour; aa, amino acid; kb, kilobase; bp, base pair; nt, nucleotide; im, intramuscular injection; ip, intraperitoneal injection; sc, subcutaneous injection; etc.

[0238] General synthesis procedure

[0239] Numerous general references providing known chemical synthesis schemes and conditions for synthesizing the disclosed compounds are available (see, for example, Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structures, 5th ed., Wiley Electronic Journal, 2001; or Vogel, Practical Organic Chemistry Textbook, Including Qualitative Organic Analysis, 4th ed., New York: Longman, 1978).

[0240] The compounds described herein can be purified using any purification method known in the art, including chromatographic methods such as HPLC, preparative thin-layer chromatography, rapid column chromatography, and ion-exchange chromatography. Any suitable stationary phase can be used, including normal and reversed-phase, as well as ion exchange resins. In some embodiments, the disclosed compounds are purified by silica gel and / or alumina chromatography. See, for example, *Introduction to Modern Liquid Chromatography*, 2nd ed., by L.R. Snyder and J.J. Kirkland, John Wiley & Son Publishing, 1979; and *Thin-Layer Chromatography*, by E. Stahl, Springer Publishers, New York, 1969.

[0241] In any process of preparing the subject compound, it may be necessary and / or desirable to protect any sensitive or reactive groups on any related molecules. This can be achieved using conventional protecting groups described in standard literature, such as JFW McOmie, *Protective Groups in Organic Chemistry*, Plenum Press, London and New York, 1973; TW Greene and PGM Uts, *Protective Groups in Organic Chemistry*, 3rd edition, Wiley Press, New York, 1999; *The Peptides*, Volume 3 (edited by E. Gross and J. Meienhofer), Academic Press, London and New York, 1981; *Methoden der organischen Chemie*, Houben-Weyl, 4th edition, Volume 15 / 1, Georg Thieme Verlag, Stuttgart, 1974; H.-D. Jakubke and H. Jescheit, *Amino Acids, Peptides, Proteins*, Chemical Press (Verlag) Chemie), Weinheim, Deerfield Beach and Basel, 1982; and / or Jochen Lehmann, Chemie der Kohlenhydrate: Monosaccharide and Derivate, Georg Thieme Verlag, Stuttgart, 1974. Protecting groups can be removed at convenient subsequent stages using methods known in the art.

[0242] The compounds of this subject matter can be synthesized via a variety of different synthetic routes using commercially available starting materials and / or starting materials prepared by conventional synthetic methods. Examples of various synthetic routes that can be used to synthesize the compounds disclosed herein are described below.

[0243] Example 1—Preparation and Analysis of Crystalline Polymorphs of 3-Palmitoyl-Amamido-1,2-Propanediol

[0244] The solubility of 3-palmitoylamido-1,2-propanediol was screened using various solvents and solvent mixtures. Tetrahydrofuran (THF), 2-methyl-THF, dichloromethane (DCM), N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMAc), toluene, 2-methylbut-2-ol (tAmOH), isopropyl acetate (iPrOAc), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF) were identified as solvents for the study. The effect of triethylamine on solubility was also evaluated. It was shown that triethylamine had little effect on the solubility of 3-palmitoylamido-1,2-propanediol in these solvents. 3-palmitoylamido-1,2-propanediol was determined to have moderate solubility in dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF).

[0245] During the heat / cooling induced crystallization process, crystalline solids obtained using THF, 2-methyl-THF, or DCM with triethylamine were identified as novel polymorphs of 3-palmitoyl-amido-1,2-propanediol. Heat / cooling crystallization involved dissolving 3-palmitoyl-amido-1,2-propanediol in a THF solution and heating the composition at 50°C overnight. For 2-methyl-THF or DCM, the solution containing palmitoyl-amido-1,2-propanediol was heated to 60°C overnight to produce a solution. After cooling the sample to 30°C, the crystalline solids formed a slurry in THF, 2-methyl-THF, and DCM solutions.

[0246] The resulting 3-palmitoyl-amido-1,2-propanediol polymorph exhibits faster solubility and greater reaction selectivity when used as a substrate for the preparation of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane.

[0247] The crystalline solid was analyzed by X-ray powder diffraction (as a drop of slurry), thermogravimetric analysis, differential scanning calorimetry, and nuclear magnetic resonance spectroscopy. Figure 1 X-ray powder diffraction (XRPD) patterns of the crystalline solid formed from solutions of (b) THF, (c) 2-methyl THF, and (d) DCM are shown, along with a peak comparison with that of the starting material (a) 3-palmitoyl-amido-1,2-propanediol. Figure 1 As shown, the crystalline solid formed from THF, 2-methylTHF, and DCM exhibits peaks different from those of the 3-palmitoyl-amido-1,2-propanediol starting material (e.g., at 2Ɵ values ​​of approximately 2.75°, 2Ɵ values ​​of approximately 6°, 2Ɵ values ​​of approximately 3.8°, 2Ɵ values ​​of approximately 8.25°, 2Ɵ values ​​of approximately 15°, 2Ɵ values ​​of approximately 26.3°, 2Ɵ values ​​of approximately 30.5°, and 2Ɵ values ​​of approximately 33.1°).

[0248] Figure 2 Thermogravimetric analysis was performed on the crystalline solids formed from THF solution. The TGA of the 3-palmitoyl-amido-1,2-propanediol polymorph formed from THF is characterized by a single weight reduction step beginning at about 200.5 °C. Figure 2 The charts also depict differential scanning calorimetry of crystalline solids formed from THF solutions. Figure 2 DSC plots were drawn for the polymorph of 3-palmitoyl-amido-1,2-propanediol formed from THF, showing two endothermic events: a first endothermic peak at 79.9 °C and a second endothermic peak at approximately 102.5 °C. The second endothermic peak at approximately 102.5 °C is a single-peak endothermic peak. Figure 3 DSC diagrams of the polymorphs of 3-palmitoyl-amido-1,2-propanediol formed from THF were plotted and compared with those of the 3-palmitoyl-amido-1,2-propanediol starting material. The 3-palmitoyl-amido-1,2-propanediol starting material exhibited a first endothermic reaction at approximately 79.3 °C and a second endothermic reaction at approximately 105.8 °C.

[0249] Example 2—Preparation of 3-palmitoyl-amido-1,2-propanediol from 3-palmitoyl-amido-1,2-propanediol (Compound A) 2-Hydroxy-1-dimethoxytriphenylmethyl ether-propane (Compound B)

[0250] The reactions of 3-palmitoyl-amido-1,2-propanediol (CMPD-A) with 4,4'-dimethoxytriphenylmethyl chloride were tested in different bases and solvents. Different additives to the reaction mixture were also tested. Table 1 summarizes the reaction products formed: 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (CMPD-B), 3-palmitoyl-amido-1-hydroxy-2-dimethoxytriphenylmethyl ether-propane (CMPD-B-Reg), and 3-palmitoyl-amido-1,2-dimethoxytriphenylmethyl ether-propane (Bis-DMTr). For each reaction, 3-palmitoyl-amido-1,2-propanediol was placed in a three-necked round-bottom flask, and the solvent was heated to 30°C with stirring for 1 hour. 3.0 equivalents of base were added to the 3-palmitoyl-amido-1,2-propanediol solvent composition, and the mixture was stirred at 30°C. When using an additive, 0.3 equivalents of the additive are contacted with the reaction mixture. 1.4 equivalents of 4,4'-dimethoxytriphenylmethyl chloride are added, and the resulting suspension is stirred at 30°C for approximately 17.3 hours. Samples are taken from the reaction mixture periodically (every 2 hours, 4 hours, etc.), and the reaction products are characterized by HPLC.

[0251] Table 1

[0252]

[0253]

[0254] Example 3—Preparation of 3-palmitoyl-amido-1,2-propanediol (compound A) with methyl THF and TEA Palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (Compound B)

[0255] 3-Palmitoyl-amido-1,2-propanediol was added to a three-necked round-bottom flask containing methyl THF at 30 °C to produce a white suspension, which was then stirred at 30 °C for 1 hour. The flask was equipped with a top stirrer, thermocouple, nitrogen inlet, and glass stopper. 3.0 equivalents of triethylamine were added, and the mixture was stirred at 30 °C for 0.5 hours. 1.4 equivalents of 4,4'-dimethoxytriphenylmethyl chloride were added to the white suspension in a single addition. The resulting yellow suspension was stirred at 30 °C for 23 hours. The sample was analyzed at 2 hours, 4 hours, 20 hours, and 23 hours to confirm the progress of the triphenylmethylation reaction and the formation of any impurities (e.g., unwanted regioisomers and bistriphenylmethylated compounds). After 2 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 63.2% yield. The regioisomer 3-palmitoyl-amido-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane was formed in 0.4% yield, and the yield of the bis(triphenylmethylated) compound was 7.8%. After 4 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 65.8% yield. The regioisomer 3-palmitoyl-amido-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane was formed in 0.2% yield, and the yield of the bis(triphenylmethylated) compound increased to 11.2%. After 20 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 62.4% yield. The regioisomer 3-palmitoyl-amido-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane was formed in 0.1% yield, and the yield of the bis(triphenylmethylated) compound increased to 16.6%. After 23 hours, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 62.6% yield. A regiomeric impurity, 3-palmitoyl-amido-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane, was formed in 0.1% yield, and the yield of the bis(triphenylmethylated) compound remained at 16.6%.

[0256] Example 4—Combined with 3-palmitoyl-amido-1,2-propanediol (compound A) and methyl-THF and TEA, as well as oxidation Preparation of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (compound B) from magnesium.

[0257] 3-Palmyl-amido-1,2-propanediol and 0.3 equivalents of magnesium oxide were added to a three-necked round-bottom flask containing methyl THF at 30 °C. The flask was equipped with a top stirrer, thermocouple, nitrogen inlet, and glass stopper. The white suspension was stirred at 30 °C for 1 hour. 3.0 equivalents of triethylamine were added and the mixture was stirred at 30 °C for 0.5 hours. 1.4 equivalents of 4,4'-dimethoxytriphenylmethyl chloride were added in a single batch. The resulting yellow-green suspension was stirred at 30 °C for 23 hours. The sample was analyzed at 2 hours, 4 hours, 20 hours, and 23 hours to confirm the progress of the triphenylmethylation reaction and the formation of any impurities (e.g., unwanted regioisomers and bistriphenylmethylated compounds). After 2 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 63.2% yield. The regioisomer 3-palmitoyl-amido-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane is formed in 0.4% yield, and the yield of the bis(triphenylmethylated) compound is 7.7%. After 4 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is formed in 65.7% yield. The regioisomer 3-palmitoyl-amido-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane is formed in 0.3% yield, and the yield of the bis(triphenylmethylated) compound increases to 11.0%. After 20 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is formed in 63.2% yield. The regioisomer 3-palmitoyl-amido-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane is no longer present, and the yield of the bis(triphenylmethylated) compound increases to 16.7%. After 23 hours, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 62.6% yield. A regiomeric impurity, 3-palmitoyl-amido-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane, was formed in 0.1% yield, and the yield of the bis(triphenylmethylated) compound increased slightly to 16.9%.

[0258] Example 5—Combined with 3-palmitoyl-amido-1,2-propanediol (compound A) and methyl-THF and TEA, as well as oxidation Magnesium was heated to prepare 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (compound B).

[0259] At ambient temperature, 3-palmitoyl-amido-1,2-propanediol, 0.3 equivalents of magnesium oxide, and 3.0 equivalents of triethylamine were added to a three-necked round-bottom flask containing methyl THF. The flask was equipped with a top stirrer, thermocouple, nitrogen inlet, and glass stopper. The composition was heated to 48°C to produce a white suspension and stirred at 48°C for 1 hour. The composition was further heated to 55°C and stirred for another hour. The reaction was then heated again to 60°C and stirred for another 30 minutes. The reaction was cooled to 30°C over 70 minutes, and 1.4 equivalents of 4,4'-dimethoxytriphenylmethyl chloride were added to the resulting white suspension in a single batch. The resulting pale green suspension was stirred at 30°C for 23 hours. The sample was analyzed at 2 hours, 4 hours, 20 hours, and 23 hours to confirm the progress of the triphenylmethylation reaction and the formation of any impurities (e.g., unwanted regioisomers and bistriphenylmethylated compounds). After 2 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is formed in 67.0% yield. A regiomeric impurity, 3-palmitoyl-amido-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane, is formed in 0.2% yield, and the yield of the bis(triphenylmethylated) compound is 8.3%. After 4 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is formed in 66.2% yield. A regiomeric impurity, 3-palmitoyl-amido-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane, is formed in 0.1% yield, and the yield of the bis(triphenylmethylated) compound increases to 11.6%. After 20 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is formed in 63.2% yield. The regioisomer impurity 3-palmitoyl-amido-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane was no longer present, and the yield of the bis(triphenylmethylated) compound increased to 18.1%. After 23 hours, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed with a yield of 63.0%. The regioisomer impurity 3-palmitoyl-amido-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane was no longer present, and the yield of the bis(triphenylmethylated) compound increased to 18.2%.

[0260] Example 6—X-ray structure of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane Crystallography

[0261] Single crystals of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane were prepared by recrystallizing compositions of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane in various solvents and solvent mixtures. Single crystals formed from dichloromethane / pentane were used for X-ray diffraction studies.

[0262] X-ray diffraction was collected in pure form on a single crystal at -100 °C. X-ray crystallography analysis was performed using monoclinic slab samples with dimensions of approximately 0.080 mm × 0.130 mm × 0.130 mm. A Bruker D8 QUEST single-crystal X-ray diffractometer was used to investigate X-ray structures. This diffractometer is equipped with a high-brightness 1µS 3.0 microfocus (50 kV × 1 mA) for copper radiation (λ = 1.54178 Å) and a PHOTON II charge-integrated pixel array detector with excellent speed, sensitivity, and accuracy for screening / evaluating crystals and collecting diffraction data. A Cryostream 800 cryogenic device, providing sample temperatures between 80 K and 500 K, was used to cool the crystal to 173 K (-100 °C). The Bruker APEX3 software package, including SHELXTL, was used for data collection and integrated diffraction experiments, as well as for solving, refining, and displaying structural results.

[0263] A total of 1346 frames were collected. The total exposure time was 12.76 hours. The frames were integrated with the Bruker SAINT software package using a narrow frame algorithm. The integration of the data using a triclinic cell yielded a total of 30535 reflections with a maximum θ angle of 65.20° (0.85 Å resolution), of which 12077 were independent (average redundancy 2.528, integrity = 96.7%, Rint = 3.33%, Rsig = 3.88%) and 10927 (90.48%) were greater than 2σ(F2). The final cell constants are a = 8.6815(6) Å, b = 12.9371(9) Å, c = 32.676(2) Å, α = 83.787(3)°, β = 87.487(3)°, γ = 89.930(3)°, and volume = 3644.9(4) ų. The XYZ centroids are refined based on 9845 reflections above 20 σ(I), where 6.873° < 2θ < 130.4°. The data were corrected for absorption effects using the multi-scan method (SADABS). The ratio of minimum to maximum apparent transmittance is 0.853. The calculated minimum and maximum transmittance coefficients (based on crystal size) are 0.9280 and 0.9550, respectively. The structure was analyzed and refined using the BrukerSHELXTL software package with space group P-1, where Z=4 represents the molecular formula unit C40H57NO5. The final anisotropic full-matrix least-squares refinement of F2 had 838 variables, with observed data converging to R1 = 11.45% and all data converging to wR2 = 26.68%. The goodness of fit was 1.106. The final differential electron density synthesis showed a maximum peak of 0.692 e- / Å3 and a maximum hole of -0.510 e- / Å3, with an RMS bias of 0.073 e- / Å3. Based on the final model, the calculated density was 1.151 g / cm3. Table 2 provides the atomic coordinates and equivalent isotropic atomic displacement parameters (Å) determined from the crystal structure of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. 2 Table 3 provides the bond lengths (Å) determined based on the crystal structure of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Table 4 provides the bond angles (°) determined based on the crystal structure of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Table 5 provides the measured torsion angles (°) determined based on the crystal structure of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Table 6 provides the anisotropic atomic displacement parameters (Å) determined based on the crystal structure of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. 2Table 7 provides the hydrogen atom coordinates and isotropic atomic displacement parameters (Å) determined based on the crystal structure of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. 2 ).

[0264] Figure 4A Oak Ridge Thermal Ellipsoids (ORTEPs) depicting two different conformations of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane determined by X-ray crystallography are shown. Conformal isomer A exhibits a linear conformation of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Conformal isomer B exhibits a bent conformation of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Figure 4B A unit cell depicting a crystal of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is shown, wherein each unit cell comprises 4 molecules (2 conformational isomers A and B) of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Figure 4C A crystal packing view of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane along the first axis is depicted. Figure 4D A crystal packing view of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane along the second axis is depicted. Figure 4E The intermolecular hydrogen bonding along the second crystallization axis between conformational isomer A and conformational isomer B is described.

[0265] Table 2 - Atomic coordinates and equivalent isotropic atomic displacement parameters

[0266]

[0267]

[0268]

[0269] Table 3 - Bond Lengths

[0270]

[0271]

[0272]

[0273] Table 4 - Bond Angles

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280] Table 5 – Angle of Twist

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287] Table 6 – Anisotropic Atomic Displacement Parameters

[0288]

[0289]

[0290]

[0291]

[0292] Table 7 - Hydrogen atom coordinates and isotropic atom displacement parameters

[0293]

[0294]

[0295]

[0296]

Claims

1. A crystalline solid of a compound of formula I: （I）。 2. The crystalline solid according to claim 1, having an X-ray powder diffraction (XRPD) pattern containing a peak at a 2θ value of approximately 8.25°.

3. The crystalline solid according to any one of claims 1 to 2, having an XRPD plot containing one or more peaks at 2α values ​​of approximately 2.75°, approximately 6°, approximately 3.8°, approximately 15°, approximately 26.3°, approximately 30.5°, and approximately 33.1°.

4. The crystalline solid according to any one of claims 1 to 3, wherein the thermogravimetric analysis (TGA) of the crystalline solid is characterized by a single weight reduction step change.

5. The crystalline solid according to claim 4, wherein the weight reduction step begins at about 200.5°C.

6. The crystalline solid according to any one of claims 1 to 5, wherein, by differential scanning calorimetry (DSC), the crystalline solid has a first endothermic reaction at 79.3°C and a second endothermic reaction at about 102.5°C.

7. The crystalline solid according to claim 6, wherein the second endothermic reaction is a unimodal endothermic reaction.

8. A method comprising: Contact the solvent with the compound of formula I: （I） To generate a precursor composition; as well as The precursor composition is used to generate a crystalline solid of the compound of formula I.

9. A method comprising: Contact the solvent with the crystalline solid of compound I: （I） To generate a precursor composition; and The precursor composition is contacted with a composition containing dimethoxytriphenylmethyl chloride to generate a composition containing compound II: (II), DMTr stands for dimethoxytriphenylmethyl.

10. A method comprising: Contact a composition containing one or more solvents with a compound of formula III: (II); and One or more single crystals of the compound of formula II are formed.

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