Crystalline solids of 3-palmitoyl-amido-1,2-propanediol and 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethylether-propane and methods of making and using the same

Abstract

To provide crystalline solids of 3-palmitoyl-amido-1,2-propanediol.SOLUTION: Aspects of the disclosure include crystalline solids of 3-palmitoyl-amido-1,2-propanediol and 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethylether-propane. Methods for preparing the crystalline solids of 3-palmitoyl-amido-1,2-propanediol and single crystals of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethylether-propane are also provided. Methods for preparing 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethylether-propane from a crystalline solid of 3-palmitoyl-amido-1,2-propanediol are also described.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 926,810, filed October 28, 2019, the disclosure of which is incorporated herein by reference.

[0002] Introduction Imeterstat is a telomerase inhibitor that binds with high affinity to the template region of the RNA component of telomerase. Studies have shown that imeterstat inhibits telomerase activity and is effective against cell proliferation in many different cancer cell lines and human tumors. Imeterstat is being used in clinical trials in patients with hematological malignancies. Clinical trials in patients with myelofibrosis have shown that imeterstat is capable of achieving a complete clinical remission in certain patients. In these patients, imeterstat resulted in an antagonism to myelofibrosis and produced morphological and molecular remissions.

[0003] The structure of imeterstat contains an N3’→P5’ thiophosphoramidate oligonucleotide. The synthesis of imeterstat is carried out by solid - phase oligonucleotide synthesis in which the first phosphoramidite nucleotide is attached to a support and subsequently sulfurized. Chain extension of the oligonucleotide components is achieved by repeated reactions of the 3’ - amino group of the solid - support - bound oligonucleotide with additional nucleotide phosphoramidite monomers. The oligonucleotide of imeterstat is attached to the solid support through a palmitoyl - amide linker. Thus, this fatty acid - amide linker is a component in the synthesis of imeterstat.

Summary of the Invention

Means for Solving the Problems

[0004] Aspects of the disclosure include a crystalline solid of 3 - palmitoyl - amido - 1,2 - propanediol (Formula I): [Chemical formula]

[0005] In an embodiment, the crystalline solid of 3-palmitoyl-amido-1,2-propanediol has an X-ray powder diffraction (XRPD) pattern that includes a peak at approximately 8.25° 2θ. In certain embodiments, the crystalline solid of 3-palmitoyl-amido-1,2-propanediol has an X-ray powder diffraction (XRPD) pattern that includes one or more peaks at approximately 2.75° 2θ, approximately 6° 2θ, approximately 3.8° 2θ, approximately 15° 2θ, approximately 26.3° 2θ, approximately 30.5° 2θ, and approximately 33.1° 2θ. The crystalline solid of 3-palmitoyl-amido-1,2-propanediol is, in some cases, characterized by a single weight loss step by thermogravimetric analysis (TGA). In certain cases, the weight loss step begins at approximately 200.5°C. In some embodiments, the crystalline solid of 3-palmitoyl-amido-1,2-propanediol exhibits a first endotherm at approximately 79.3°C and a second endotherm at approximately 102.5°C by differential scanning calorimetry (DSC). In these embodiments, the second endotherm is a single peak endotherm.

[0006] Also provided is a method for preparing a crystalline solid of 3-palmitoyl-amido-1,2-propanediol. In the method according to certain embodiments, 3-palmitoyl-amido-1,2-propanediol is contacted with one or more solvents to produce a 3-palmitoyl-amido-1,2-propanediol composition, which is then precipitated to produce 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 a polar solvent and a nonpolar solvent. 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-methylbutan-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 certain cases, the solvent is tetrahydrofuran. In certain embodiments, precipitating the crystalline solid of 3-palmitoyl-amido-1,2-propanediol comprises heating the 3-palmitoyl-amido-1,2-propanediol composition to produce a heated composition (e.g., solubilizing 3-palmitoyl-amido-1,2-propanediol in a solvent) and cooling the heated 3-palmitoyl-amido-1,2-propanediol composition to produce a crystalline solid of 3-palmitoyl-amido-1,2-propanediol.

[0007] A method for preparing 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane from 3-palmitoyl-amido-1,2-propanediol is also described. In carrying out the method of the subject according to certain embodiments, a solvent is contacted with the crystalline solid of 3-palmitoyl-amido-1,2-propanediol to produce a precursor composition, and the precursor composition is contacted with a composition containing dimethoxytrityl chloride to produce a composition having 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl 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-methylbutan-2-ol (tAmOH), N-methyl-2-pyrrolidone (NMP), or a combination thereof. In some cases, the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, acetonitrile, toluene, 2-methylbutan-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP). In certain cases, the solvent is selected from methyltetrahydrofuran, tetrahydrofuran, and dichloromethane.

[0008] In some embodiments, the precursor composition includes a base such as an organic base. For example, the base can be 1,8-bis(dimethylamino)naphthalene (proton sponge), imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2,4,6-trimethylpyridine (collidine), 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 certain cases, the base is triethylamine.

[0009] In other embodiments, the precursor composition includes an additive. For example, the additive can be calcium oxide, magnesium oxide, boric acid, tetra-n-butylammonium fluoride (TBAF), 4-dimethylaminopyridine (DMAP), copper(II) chloride (CuCl2), ytterbium(III) chloride (YbCl3), or 1,4-diazabicyclo[2.2.2]octane (DABCO). In some cases, the additive is selected from tetra-n-butylammonium fluoride (TBAF), magnesium oxide, and boric acid. In certain cases, the additive is magnesium oxide.

[0010] In certain cases, the crystalline solid of 3-palmitoyl-amido-1,2-propanediol has an X-ray powder diffraction (XRPD) pattern that includes one or more peaks at about 2.75° 2θ, about 6° 2θ, about 3.8° 2θ, about 8.25° 2θ, about 15° 2θ, about 26.3° 2θ, about 30.5° 2θ, and about 33.1° 2θ. The crystalline solid of 3-palmitoyl-amido-1,2-propanediol is, in some cases, characterized by a single weight loss step by thermogravimetric analysis (TGA). In certain cases, the weight loss step begins at about 200.5 °C. In some embodiments, the crystalline solid of 3-palmitoyl-amido-1,2-propanediol exhibits a first endotherm at about 79.3 °C and a second endotherm at about 102.5 °C by differential scanning calorimetry (DSC).

[0011] In some cases, the method further includes forming one or more single crystals of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl-ether-propane (e.g., by recrystallization). In these embodiments, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl-ether-propane is contacted with a solvent and a crystalline solid of 3-palmitoyl-2-hydroxy-1-dimethoxytrityl-ether-propane is precipitated from the solvent. In some cases, the solvent is a polar solvent. In other cases, the solvent is a non-polar solvent. In still other cases, the solvent is a mixture of a polar solvent and a non-polar solvent. In certain embodiments, forming a crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl-ether-propane includes heating a 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl-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-dimethoxytrityl-ether-propane, such as one or more single crystals of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl-ether-propane.

[0012] The disclosed embodiments also include a crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (Formula II).

Chemical formula

[0013] In certain 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 crystalline solid according to the embodiments is in the monoclinic form. Each unit cell in the crystalline solid contains 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 contains four molecules of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. In some embodiments, the unit cell has dimensions of approximately 8.44 Å × approximately 26.56 Å × approximately 10.06 Å, and the volume of the unit cell is approximately 2254.8 Å 3 ³. The subject 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenyl ether-propane crystalline solid has a density of about 1.2 g / cm 3 ³ to about 1.3 g / cm 3 ³ and has a polymorph purity of 95% or more.

[0014] A method for preparing a crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane is also provided. In a method according to certain embodiments, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane is contacted with one or more solvents to produce a 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane composition, which is precipitated to produce a crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane, such as one or more single crystals of 3-palmitoyl-2-hydroxy-1-dimethoxytrityl ether-propane. In some embodiments, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane is contacted with a polar solvent. In other embodiments, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane is contacted with a nonpolar solvent. In still other embodiments, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane is contacted with a mixture of a polar solvent and a nonpolar solvent. In certain cases, the polar solvent is dichloromethane and the nonpolar solvent is pentane. In certain embodiments, precipitating the crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane comprises heating the 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane composition to produce a heated composition (e.g., solubilizing 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane in the solvent) and cooling the heated 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane composition to produce a crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane. BRIEF DESCRIPTION OF THE DRAWINGS

[0015]

Figure 1

Figure 2

Figure 3

Figure 4A

Figure 4B

Figure 4C

Figure 4D

Figure 4E

DETAILED DESCRIPTION OF THE INVENTION

[0016] Select the definition of chemical terms Unless otherwise indicated, the following terms have the following meanings. Any term that is not defined has the meaning recognized in the relevant technical field.

[0017] As used herein, the terms "phosphate" and "phosphate group" are meant to include thiophosphate groups and oxophosphate groups.

[0018] As used herein, the term "phosphoramidite amino group" refers to an amino group --NR 4 R 5 bonded to the phosphorus atom of the phosphoramidite group, and the term "phosphoramidite nitrogen" refers to the nitrogen atom of the phosphoramidite amino group.

[0019] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl 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 (e.g., "alkyl of 1 to 4 carbon atoms"), or 1 to 3 carbon atoms (e.g., "alkyl of 1 to 3 carbon atoms"). Examples of this term include linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0020] The term "substituted alkyl" means that one or more carbon atoms of the alkyl chain are optionally -O-, -N-, -S-, -S(O) n-(where n is from 0 to 2), -NR- (where R is hydrogen or alkyl), etc., are replaced by heteroatoms, and alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketone, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, and -NR a R b (R a and R b may be the same or different and are selected from the group consisting of hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclic, and refers to an alkyl group having 1 to 5 substituents as defined herein. In some cases, "substituted alkyl" is alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, sulfonamide, and -NR a R b (R a and R b may be the same or different and are selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclic, and refers to an alkyl group having 1 to 5 substituents as defined herein.

[0021] "Alkylene" is either straight-chain or branched-chain, preferably having 1 to 6, more preferably 1 to 3 carbon atoms, and optionally interrupted by one or more groups selected from -O-, -NR 10 -, -NR 10 C(O)-, -C(O)NR 10 -, etc., and refers to a divalent aliphatic hydrocarbyl group. Examples of this term include methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-), (-C(CH3)2CH2C(O)-), (-C(CH3)2CH2C(O)NH-), (-CH(CH3)CH2-), and the like.

[0022] "Substituted alkylene" refers to an alkylene group having 1 to 3 hydrogens replaced by substituents as described for carbon in the following definition of "substitution".

[0023] The term "alkane" refers to the alkyl and alkylene groups defined herein.

[0024] The terms "alkylaminoalkyl", "alkylaminoalkenyl", and "alkylaminoalkynyl" refer to an R ’ that is an alkyl group as defined herein, an R ” that is an alkylene, alkenylene, or alkynylene group as defined herein, and an R ’ NHR ” - group.

[0025] The term "alkaryl" or "aralkyl" refers to -alkylene-aryl and -substituted alkylene-aryl groups in which alkylene, substituted alkylene, and aryl are as defined herein.

[0026] "Alkoxy" refers to an -O-alkyl group where the alkyl is as defined herein. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like. The term "alkoxy" also refers to alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O- groups where the alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.

[0027] The term "substituted alkoxy" refers to substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- groups where the substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl, and substituted alkynyl are as defined herein.

[0028] The term "alkoxyamino" refers to an -NH-alkoxy group where the alkoxy is as defined herein.

[0029] The term "haloalkoxy" refers to an alkyl-O- group in which one or more hydrogen atoms on the alkyl group are replaced by halo groups, examples of such groups including, but not limited to, trifluoromethoxy.

[0030] The term "haloalkyl" refers to the above-defined substituted alkyl group in which one or more hydrogen atoms on the alkyl group are replaced by halo groups. Examples of such groups include, but are not limited to, fluoroalkyl groups such as trifluoromethyl, difluoromethyl, trifluoroethyl, and the like.

[0031] The term "alkylalkoxy" refers to -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl groups where the alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0032] The term "alkylthioalkoxy" refers to groups of -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl, and substituted alkylene-S-substituted alkyl, where alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0033] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbyl group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and having at least 1, preferably 1 to 2 double bond unsaturated sites. Examples of this term include, by way of example, bi-vinyl, allyl, and but-3-en-1-yl. Included in this term are cis and trans isomers, or mixtures of these isomers.

[0034] The term "substituted alkenyl" refers to an alkenyl group as defined herein having 1 to 5 substituents, or 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0035] "Alkynyl" refers to a monovalent straight-chain or branched-chain hydrocarbyl group having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, and having at least 1, preferably 1 to 2 triple-bond unsaturated sites. Examples of such alkynyl groups include ethynyl (-C≡CH) and propargyl (-CH2C≡CH).

[0036] The term "substituted alkynyl" refers to an alkynyl group as defined herein having 1 to 5 substituents, or 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketone, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2 substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0037] "Alkynyloxy" refers to an -O-alkynyl group where alkynyl is as defined herein. Examples of alkynyloxy include ethynyloxy, propynyloxy, etc.

[0038] "Acyl" refers to a group of H-C(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, and substituted heterocyclic, where 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, as an acyl, the "acetyl" group CH3C(O)- can be mentioned.

[0039] "Acylamino" is R 20 is hydrogen or alkyl, and 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, -NR 20 C(O)alkyl, -NR 20 C(O)substituted alkyl, NR 20 C(O)cycloalkyl, -NR 20 C(O)substituted cycloalkyl, -NR 20 C(O)cycloalkenyl, -NR 20 C(O)substituted cycloalkenyl, -NR 20 C(O)alkenyl, -NR 20 C(O)substituted alkenyl, -NR 20 C(O)alkynyl, -NR 20 C(O)substituted alkynyl, -NR 20 C(O)aryl, -NR 20 C(O)substituted aryl, -NR 20C(O) heteroaryl, -NR 20 C(O)-substituted heteroaryl, -NR 20 C(O) heterocyclic, and -NR 20 refer to a C(O)-substituted heterocyclic group.

[0040] The term "aminocarbonyl" or "aminoacyl" means that R 21 and R 22 are 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 R 21 and R 22 optionally combine with the nitrogen to which they are attached to form a heterocyclic or 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, heterocyclic, and substituted heterocyclic are as defined herein, -C(O)NR 21 R 22 refers to a group.

[0041] "Aminocarbonylamino" means that R 21 , R 22 , and R 23 are independently selected from hydrogen, alkyl, aryl, or cycloalkyl, and two R groups combine to form a heterosilyl group, -NR 21 C(O)NR 22 R 23 refers to a group.

[0042] The term "alkoxycarbonylamino" refers to an -NRC(O)OR group where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl, and alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0043] The term "acyloxy" refers to an 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 heterocyclyl-C(O)O- group where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0044] "Aminosulfonyl" is R 21 and R 22 are each 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, substituted heterocyclic, and R 21 and R 22 optionally combine together with the nitrogen to which they are attached to form a heterocyclic or 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, heterocyclic and substituted heterocyclic are as defined herein, and refers to a -SO2NR 21 R 22 group.

[0045] "Sulfonylamino" is R 21 and R 22is 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, R 21 and R 22 optionally combine together with the nitrogen to which they are attached to form a heterocyclic or 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, heterocyclic, and substituted heterocyclic are as defined herein, -NR 21 SO2R 22 refers to.

[0046] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group having 6 to 18 carbon atoms with a single ring (such as those present in a phenyl group), or a ring system having a plurality of fused rings, where the fused rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring (examples of such aromatic ring systems include naphthyl, anthryl, and indanyl). As examples of this term, phenyl and naphthyl are included. Unless otherwise restricted by the definition of the aryl substituent, such an aryl group may optionally be substituted with 1 to 5 substituents selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azide, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, 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, or may be substituted with 1 to 3 substituents. In such a case, an aryl group substituted with 1 to 5 substituents (e.g., as described herein) is referred to as a "substituted aryl".

[0047] "Aryloxy" refers to an -O-aryl group, where aryl is as defined herein and includes an optionally substituted aryl group as defined herein, and includes, for example, phenoxy, naphthoxy, and the like.

[0048] "Amino" refers to an -NH2 group.

[0049] The term "substituted amino" refers to an -NRR group, where 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 heterocyclyl, provided that at least one R is not hydrogen.

[0050] The term "azide" refers to an -N3 group.

[0051] "Carboxyl", "carboxy", or "carboxylate" refers to -CO2H or a salt thereof.

[0052] The term "carboxyl ester" or "carboxy ester", or "carboxyalkyl" or "carboxylalkyl" refers to an 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 as defined herein, -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -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 groups.

[0053] "(Carboxylester)oxy" or "carbonate" refers to -O-C(O)O-alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-alkynyl, -O-C(O)O-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O-cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl, -O-C(O)O-heteroaryl, -O-C(O)O-substituted heteroaryl, -O-C(O)O-heterocyclic, and -O-C(O)O-substituted heterocyclic groups, where 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.

[0054] "Cyano" or "nitrile" refers to the -CN group.

[0055] "Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms, including a monocyclic ring, or a polycyclic ring including a fused ring system, a bridged ring system, and a spiro ring system. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. Such cycloalkyl groups include, by way of example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and polycyclic structures such as adamantanyl.

[0056] The term "substituted cycloalkyl" refers to a cycloalkyl group having from 1 to 5 substituents selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl, or having from 1 to 3 substituents.

[0057] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group having from 3 to 10 carbon atoms, having a single ring or multiple rings, and having at least 1 double bond, preferably 1 to 2 double bonds.

[0058] The term "substituted cycloalkenyl" refers to a cycloalkenyl group having from 1 to 5 substituents selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl, or a cycloalkenyl group having from 1 to 3 substituents.

[0059] "Cycloalkynyl" refers to a non-aromatic cycloalkyl group of 5 to 10 carbon atoms having a single ring or multiple rings and having at least one triple bond.

[0060] "Cycloalkoxy" refers to -O-cycloalkyl.

[0061] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0062] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0063] "Hydroxy" or "hydroxyl" refers to the -OH group.

[0064] "Heteroaryl" refers to an aromatic group having 1 to 15 carbon atoms such as 1 to 10 carbon atoms in the ring, and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Such a heteroaryl group is a single ring (such as pyridinyl, imidazolyl, or furyl), or a plurality of fused rings of a ring system (such as groups of indolizinyl, quinolinyl, benzofuran, benzimidazolyl, or benzothienyl), provided that at least one ring in the ring system is aromatic and at least one ring in the ring system is aromatic, but the point of attachment is through an atom of the aromatic ring. In certain 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. Examples of this term include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless otherwise restricted by the definition of the heteroaryl substituent, such a heteroaryl group may be acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azide, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl, and trihalomethyl, selected from 1 to 5 substituents, or may be optionally substituted with 1 to 3 substituents. In such cases, a heteroaryl group substituted with 1 to 5 substituents (such as described herein) is referred to as a "substituted heteroaryl".

[0065] The term "heteroalkyl" refers to an -alkylene-heteroaryl group, where alkylene and heteroaryl are as defined herein. Examples of this term include pyridylmethyl, pyridylethyl, indolylmethyl, etc.

[0066] "Heteroaryloxy" refers to -O-heteroaryl.

[0067] "Heterocycle", "heterocyclic", "heterocycloalkyl", and "heterocyclyl" refer to a saturated or unsaturated group having a single ring or multiple fused rings, including fused bridged ring systems and spiro ring systems, and having 3 to 20 ring atoms containing 1 to 10 heteroatoms. These ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen, and in a fused ring system, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through a non-aromatic ring. In certain embodiments, the nitrogen and / or sulfur ring atoms of the heterocyclic group are optionally oxidized to provide an N-oxide, -S(O)-, or -SO2- moiety.

[0068] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4 - tetrahydroisoquinoline, 4,5,6,7 - tetrahydrobenzothiophene, thiazole, thiazolidine, thiophene, benzothiophenol, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1 - dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.

[0069] Unless otherwise restricted by the definition of the heterocyclic substituent, such heterocyclic groups can optionally be substituted with 1 to 5, or 1 to 3 substituents selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketone, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and fused heterocycles.

[0070] "Heterocyclyloxy" refers to an -O-heterocyclyl group.

[0071] The term "heterocyclylthio" refers to a heterocyclic -S-group.

[0072] The term "heterocylene" refers to a diradical group formed from a heterocycle as defined herein.

[0073] The term "hydroxyamino" refers to an -NHOH group.

[0074] "Nitro" refers to an -NO2 group.

[0075] "Oxo" refers to an atom (=O).

[0076] "Sulfonyl" refers to an SO2-alkyl, SO2-substituted alkyl, SO2-alkenyl, SO2-substituted alkenyl, SO2-alkynyl, SO2-substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic group as defined herein. Examples of sulfonyl include methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.

[0077] "Sulfonyloxy" refers to an -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 group in which 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.

[0078] The term "aminocarbonyloxy" refers to an -OC(O)NRR group in which each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic, and alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.

[0079] "Thiol" refers to an -SH group.

[0080] The term "thioxo" or "thioketo" refers to the atom (=S).

[0081] The term "alkylthio" or "thioalkoxy" refers to an -S-alkyl group in which alkyl is as defined herein. In certain embodiments, sulfur may be oxidized to -S(O)-. Sulfoxides may exist as one or more stereoisomers.

[0082] The term "substituted thioalkoxy" refers to an -S-substituted alkyl group.

[0083] The term "thioaryloxy" refers to an aryl-S-group in which the aryl group optionally includes a substituted aryl group as defined herein and is as defined herein.

[0084] The term "thioheteroaryloxy" refers to a heteroaryl-S-group as defined herein, where the heteroaryl group optionally includes a substituted heteroaryl group as defined herein and as defined herein.

[0085] The term "thioheterocyclooxy" refers to a heterocyclyl-S-group as defined herein, where the heterocyclyl group optionally includes a substituted heterocyclyl group as defined herein and as defined herein.

[0086] In addition to the disclosure herein, the term "substituted", when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each independently replaced with the same or different substituents as defined below.

[0087] In addition to the disclosed groups for the individual terms herein, substituents for replacing one or more hydrogens (any two hydrogens on a single carbon can be replaced by =O, =NR 70 , =N-OR 70 , =N2 or =S) on the saturated carbon atoms of the specified group or radical are, unless otherwise specified, R 60 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each R 70 is independently hydrogen or R 60 and each R 80 is independently R 70 or alternatively, two Rs 80’may optionally form a 5-, 6-, or 7-membered heterocycloalkyl optionally containing the same or different additional 1 to 4 heteroatoms selected from the group consisting of O, N, and S, with the nitrogen to which they are attached, and their N may have -H or a C1-C3 alkyl substituent, each M + is a counterion having a net single positive charge, -R 60 , halo, =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 + ), -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 R 80 , -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 70CO2 - 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 Each M + are independently, e.g., K + , Na + , Li + Alkaline ions such as + N(R 60 )4, or [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 (The "subscript 0.5" means that one of the counterions of such divalent alkaline earth ion may be an ionized form of an inventive compound and the other counterion may be an ionized form such as chloride, or a two ionized compound disclosed herein may serve as a counterion of such divalent alkaline earth ion, or a doubly ionized compound of the inventive compound may serve as a counterion of such divalent alkaline earth ion. A specific example is -NR 80 R 80 is meant to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl, and N-morpholinyl.

[0088] Further to the disclosure herein, the substitution of hydrogen on an unsaturated carbon atom of a “substituted” alkene, alkyne, aryl, and heteroaryl group is, unless otherwise specified, R 60 , R 70 , R 80 , and M. +is as previously defined, provided that in the case of a substituted alkene or alkyne, the substituent is not -O - M + 、 -OR 70 、 -SR 70 、 or -S - M + and is -R 60 、 halo, -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 is.

[0089] In addition to the disclosure basis for the individual terms of this specification, the substituents of hydrogen on the nitrogen atom of the "substituted" heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, R 60 , R 70 , R 80 , and M + are as previously defined, -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 )R70 、 -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 are as follows.

[0090] In addition to the disclosure of this specification, in certain embodiments, the substituted group has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0091] Unless otherwise indicated, the nomenclature of substituents not explicitly defined in this specification is arrived at by naming from the adjacent functional group towards the point of attachment following the terminal portion of the functional group. For example, the substituent "arylalkyloxycarbonyl" refers to the (aryl)-(alkyl)-O-C(O)- group.

[0092] With respect to any of the groups disclosed herein that contain one or more substituents, it is understood that such groups do not, of course, contain any substitution or substitution pattern that is sterically unfeasible and / or synthetically unrealizable. In addition, the subject compounds include all stereochemical isomers resulting from the substitution of these compounds.

[0093] The terms "stereoisomer" and "stereoisomers" refer to 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.

[0094] It will be understood that the term "or a salt or solvate or stereoisomer thereof" is intended to include all permutations of salts, solvates, and stereoisomers, such as solvates of pharmaceutically acceptable salts of stereoisomers of the subject compounds. It is understood that the term "or a salt thereof" is intended to include all permutations of salts. It is understood that the term "or a pharmaceutically acceptable salt thereof" is intended to include all permutations of salts. It is understood that the term "or a solvate thereof" is intended to include all permutations of solvates. It is understood that the term "or a stereoisomer thereof" is intended to include all permutations of stereoisomers. It is understood that the term "or a tautomer thereof" is intended to include all permutations of tautomers. Thus, for example, it is intended to include solvates of pharmaceutically acceptable salts of tautomers of stereoisomers of the subject compounds.

[0095] As used herein, the term "isolated" means that the compound is in an environment different from its natural environment. "Isolated" means that the compound of interest is included in a sample that is substantially concentrated and / or in which the compound of interest is partially or substantially purified.

[0096] Before further describing the present invention, it should be understood that, as such things can of course vary, the present invention is not limited to the specific embodiments described. Since the scope of the present invention is limited only by the appended claims, it should also be understood that the terms used herein are for the purpose of describing only specific embodiments and are not intended to be limiting.

[0097] Where a range of values is provided, each intervening value between the upper and lower limits, and also any other value or intervening value in the described range to one tenth of the unit of the lower limit, is understood to be included within the present invention, unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and also be included within the invention, subject to any specifically excluded limitations of the described range. Where the described range includes one or both of the limits, ranges excluding one or both of those included limits are also included in the invention.

[0098] For clarity, it is understood that certain features of the invention described in the context of separate embodiments 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 separately or in any suitable partial combination. All combinations of embodiments relevant to the invention are specifically included by the present invention, to the extent that such combinations, for example, include a subject matter that is a compound (i.e., a compound that can be made, isolated, characterized, and tested for biological activity) that is a stable compound, as if each and every such combination were individually and explicitly disclosed herein. In addition, all partial combinations of the various embodiments and their elements (e.g., elements of chemical groups listed in embodiments that describe such variables) are also specifically included by the present invention, as if each and every such partial combination were individually and explicitly disclosed herein, as disclosed herein.

[0099] 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 belongs. Any methods and materials similar to or equivalent to those described herein can also be used in the practice or testing of the present invention, but the preferred methods and materials are described below. All publications mentioned herein are incorporated herein by reference for the purpose of disclosing and describing the methods and / or materials related to the cited publications.

[0100] It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Further note that the claims may be drafted to exclude any optional element. Thus, this description is intended to function as a precedent for the use of exclusive terms such as "solely", "only", etc. or the use of "negative" limitations in connection with the recitation of elements of the claims.

[0101] It is understood that, for clarity, certain features of the invention that are described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, the various features of the invention that are described in the context of a single embodiment may also be provided separately or in any suitable partial combination.

[0102] The publications discussed herein are provided only for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention has no right to antedate such disclosure by virtue of prior invention. Further, the dates of the publications provided may be different from the actual dates of publication and may need to be individually verified.

[0103] Unless otherwise noted, the methods and techniques of this embodiment are generally carried out according to conventional methods well known in the art and are carried out as described in various general and more specific reference documents cited and discussed throughout this specification. For example, see Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360 - 361, 1084 - 1085, and Smith and March, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley - Interscience, 2001.

[0104] The nomenclature used herein to name the compounds of the subject matter is illustrated in the examples of this specification. Where possible, this nomenclature is generally derived using commercially available AutoNom software (MDL, San Leandro, Calif.).

[0105] Many general references are available that provide generally known chemical synthesis schemes and conditions useful for synthesizing the disclosed compounds (e.g., Smith and March, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley - Interscience, 2001, or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978).

[0106] The compounds described herein can be purified by any of the means known in the art, including chromatographic means such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phases, as well as ion exchange resins. See, for example, Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L.R. Snyder and J.J. Kirkland, John Wiley and Sons, 1979, and Thin Layer Chromatography, ed E. Stahl, Springer-Verlag, New York, 1969.

[0107] During any of the processes for preparing the compounds of the present disclosure, it may be necessary and / or desirable to protect any sensitive or reactive groups of any of the related molecules. This can be achieved by conventional protecting group means described in standard treatises such as T.W. Greene and P.G.M. Wuts, “Protective Groups in Organic Synthesis”, Fourth edition, Wiley, New York 2006. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0108] The compounds described herein may contain one or more chiral centers and / or double bonds and, accordingly, may exist as stereoisomers such as double bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Accordingly, all possible enantiomers and stereoisomers of the compounds, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure), as well as mixtures of enantiomers and mixtures of stereoisomers, are included in the description of the compounds herein. Mixtures of enantiomers and mixtures of 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. Compounds may also exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Accordingly, the chemical structures shown herein encompass all possible tautomeric forms of the exemplified compounds. The described compounds also include isotopically labeled compounds in which one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include, but are not limited to 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, and the like. Compounds may exist in unsolvated forms as well as solvated forms including hydrated forms. In general, compounds may be hydrated or solvated. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the intended uses herein and are intended to be within the scope of the present disclosure.

[0109] The disclosed embodiments include crystalline solids of 3-palmitoyl-amido-1,2-propanediol (Formula I).

Chemical Structure

[0110] As used herein, the term "crystalline" is used in its conventional sense to refer to a solid material in which the molecules forming the solid are arranged in a highly ordered microscopic geometrical configuration that extends in three dimensions (e.g., forms an ordered lattice-type structure). In embodiments, the crystalline solids described herein are not amorphous and are characterized by an undefined structural order and microscopic configuration lacking a regular geometrical arrangement in three dimensions.

[0111] In embodiments, the crystalline solid of 3-palmitoyl-amido-1,2-propanediol is at least 90%, such as at least 95%, at least 97%, at least 99%, and at least 99.9%, polymorphic purity (i.e., present as a polymorph as evidenced by X-ray powder diffraction (XRPD) analysis, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) analysis, detailed below). In some embodiments, the polymorphs of 3-palmitoyl-amido-1,2-propanediol described herein are present in the crystalline solid at 100% purity. In some embodiments, the polymorphs of the crystalline solid of 3-palmitoyl-amido-1,2-propanediol provided herein exhibit improved solubility and reactivity compared to other polymorphs of crystalline 3-palmitoyl-amido-1,2-propanediol and amorphous 3-palmitoyl-amido-1,2-propanediol.

[0112] In an embodiment, the polymorph of the crystalline solid 3-palmitoyl-amido-1,2-propanediol exhibits an X-ray powder diffraction (XRPD) pattern that includes a peak at approximately 8.25° 2θ. The relative intensities of the diffraction peaks in a given crystal form can vary due to the orientation of the crystals with respect to the X-rays, such as from crystallography. In an embodiment, the intensity of the X-ray powder diffraction peaks at 2θ can vary from crystal to crystal, but the characteristic peak positions of the polymorphs will remain the same. In certain embodiments, the polymorph of the crystalline solid 3-palmitoyl-amido-1,2-propanediol has an X-ray powder diffraction (XRPD) pattern that includes one or more peaks at approximately 2.75° 2θ, approximately 6° 2θ, approximately 3.8° 2θ, approximately 15° 2θ, approximately 26.3° 2θ, approximately 30.5° 2θ, and approximately 33.1° 2θ. In some cases, the polymorphs of the crystalline solid 3-palmitoyl-amido-1,2-propanediol provided herein are characterized by a single weight loss step by thermogravimetric analysis (TGA). In certain cases, the weight loss step begins at approximately 200.5 °C.

[0113] Differential scanning calorimetry (DSC) measures the transition temperature of a crystalline solid when the crystal absorbs or releases heat due to a change in its structure or due to melting. DSC is provided to distinguish between different crystalline forms (e.g., different polymorphs). Different crystalline forms can be identified according to their different characteristic transition temperatures. In some embodiments, the polymorphs of the crystalline solid 3-palmitoyl-amido-1,2-propanediol provided herein exhibit a first endotherm at approximately 79.3 °C and a second endotherm at approximately 102.5 °C by differential scanning calorimetry (DSC). In these embodiments, the second endotherm is a single peak endotherm.

[0114] Also provided is a method for preparing polymorphs of the crystalline solid of 3-palmitoyl-amido-1,2-propanediol. In the method according to certain embodiments, 3-palmitoyl-amido-1,2-propanediol is contacted with one or more solvents to produce a 3-palmitoyl-amido-1,2-propanediol composition, which is then precipitated to produce a 3-palmitoyl-amido-1,2-propanediol crystalline solid. In some embodiments, the solvent is a polar solvent. In other embodiments, the solvent is a non-polar solvent. In still other embodiments, the solvent is a mixture of a polar solvent and a non-polar solvent. Examples of suitable solvents 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-methylbutan-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP), and combinations thereof. In some cases, the solvent is selected from tetrahydrofuran, methyl-tetrahydrofuran, and dichloromethane. In certain cases, the solvent is tetrahydrofuran.

[0115] In certain 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. Examples of organic bases that can be used include, but are not limited to, triethylamine, triethanolamine, ammonia, arginine, benzathine, ethylenediamine, meglumine, procaine, N-methylglucamine, piperazine, tromethamine, 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 (collidine), potassium carbonate, sodium methoxide, tetramethylethylenediamine (TMEDA), and dimethylaminoethanol. In some cases, the base is selected from tetramethylethylenediamine (TMEDA), 1,8-bis(dimethylamino)naphthalene (proton sponge), and triethylamine. In certain cases, the base is triethylamine. The amount of base contacted with 3-palmitoyl-amido-1,2-propanediol can vary in the range of 1 equivalent to 4 equivalents of base, such as 1.5 equivalents to 3.5 equivalents, and including about 3 equivalents of base relative to 3-palmitoyl-amido-1,2-propanediol.

[0116] To precipitate the crystalline solid of 3-palmitoyl-amido-1,2-propanediol, the 3-palmitoyl-amido-1,2-propanediol solvent composition (with or without a base) is first heated to produce a heated 3-palmitoyl-amido-1,2-propanediol solvent composition, and then cooled to form the crystalline solid 3-palmitoyl-amido-1,2-propanediol. The 3-palmitoyl-amido-1,2-propanediol solvent composition can be heated to a temperature in the range of 10°C to 60°C, such as 15°C to 55°C, such as 25°C to 55°C, and up to 50°C. The heated composition can be maintained at a high temperature for a varying duration, including for 1 minute or more, such as 2 minutes or more, such as 5 minutes or more, such as 10 minutes or more, such as 15 minutes or more, such as 30 minutes or more, and 60 minutes or more. In certain embodiments, the 3-palmitoyl-amido-1,2-propanediol solvent is heated to a temperature sufficient to solubilize 3-palmitoyl-amido-1,2-propanediol in the solvent. All or a portion of the amount of 3-palmitoyl-amido-1,2-propanediol can be solubilized in the solvent, such as 25 wt% or more, such as 50 wt% or more, such as 75 wt% or more, such as 90 wt% or more, such as 95 wt% or more, such as 97 wt% or more, and 99 wt% or more (e.g., the 3-palmitoyl-amido-1,2-propanediol solvent composition can range from a clear solution to a slurry composition when examined visually).

[0117] In embodiments, the crystalline solid of 3-palmitoyl-amido-1,2-propanediol precipitates by cooling the heated 3-palmitoyl-amido-1,2-propanediol solvent composition. The composition can be cooled to a temperature in the range of 20°C to 40°C, such as 15°C to 35°C, and including about 30°C. In certain embodiments, the method includes precipitating the crystalline solid of 3-palmitoyl-amido-1,2-propanediol by removing a certain amount of the solvent from the composition, such as by rotary evaporation or under an inert gas (N2 or argon).

[0118] In certain embodiments, the crystalline solid of 3-palmitoyl-amido-1,2-propanediol is isolated by filtration (e.g., vacuum filtration), or the solvent can be removed by heating or rotary evaporation. In certain embodiments, the crystalline solid of 3-palmitoyl-amido-1,2-propanediol is isolated by drying under a nitrogen atmosphere at room temperature or under vacuum.

[0119] The disclosed embodiments also include a crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl-ether-propane (Formula III).

Chemical Formula

[0120] (wherein DMTr is dimethoxytrityl). In certain cases, the crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl-ether-propane is a single crystal of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl-ether-propane. The term "single crystal" as used herein refers to a single crystalline solid in its conventional meaning, where the crystal lattice of the entire sample has no grain boundaries, is continuous at the edges of the sample, and is not broken. In certain embodiments, the desired single crystal is a single crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl-ether-propane of a size and quality sufficient for X-ray crystal structure analysis (XRC) and X-ray crystal structure determination.

[0121] In embodiments, the crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane is at least 90% pure, including at least 95%, such as at least 97%, at least 99%, and at least 99.9% (e.g., single crystals of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane). In some embodiments, the 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane is present in the crystalline solid at 100% purity. In some embodiments, the crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane provided herein (e.g., single crystals of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane) exhibits improved solubility and reactivity compared to other crystalline forms (e.g., powder) or amorphous solids of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane.

[0122] The crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane according to embodiments is in a monoclinic form. Each unit cell in the crystalline solid contains two different conformations of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane, such as a bent conformation and a linear conformation. In embodiments, each conformation (bent and linear) of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane is present in the unit cell in a 1:1 ratio. Each unit cell in the crystalline solid contains four molecules of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane. In some embodiments, the unit cell has dimensions of about 8.44 Å × about 26.56 Å × about 10.06 Å, and the volume of the unit cell is about 2254.8 Å 3 ³. The subject 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenyl ether-propane crystalline solid has a density of about 1.2 g / cm 3 ³ to about 1.3 g / cm3 has a density and has a purity of 95% or more.

[0123] Also provided is a method for preparing a crystalline solid (e.g., a single crystal) of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane. In a method according to certain embodiments, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane is contacted with one or more solvents to produce a 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane composition, which is then precipitated to produce a crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane, such as one or more single crystals of 3-palmitoyl-2-hydroxy-1-dimethoxytrityl ether-propane.

[0124] 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 a polar solvent and a nonpolar solvent. Suitable solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, t-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-methylbutan-2-ol (tAmOH), dimethyl sulfoxide, pentane, hexane, heptane, octanane. In certain embodiments, the solvent is a mixture of dichloromethane and pentane.

[0125] To precipitate the 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane crystalline solid, first, heat the 3-palmitoyl-2-hydroxy-1-dimethoxytrityl ether-propane solvent composition to produce a heated 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane solvent composition, and then cool it to form the crystalline solid 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane. The 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane solvent composition can be heated to a temperature in the range of 10°C to 60°C, including, for example, 15°C to 55°C, 25°C to 55°C, and up to 50°C. The heated composition can be maintained at a high temperature for a varying duration, including, for example, 1 minute or more, 2 minutes or more, 5 minutes or more, 10 minutes or more, 15 minutes or more, 30 minutes or more, and 60 minutes or more. In certain embodiments, the 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane solvent is heated to a temperature sufficient to solubilize 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane in the solvent.

[0126] In other embodiments, the crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane precipitates by cooling a heated 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane solvent composition. The composition can be cooled to a temperature of -20°C to 20°C, including, for example, -19°C to 19°C, -18°C to 18°C, -17°C to 17°C, -16°C to 16°C, -15°C to 15°C, -14°C to 14°C, -13°C to 13°C, -12°C to 12°C, -11°C to 11°C, and -10°C to 10°C. In certain embodiments, the method includes precipitating the crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane by removing the solvent from the composition, such as by rotary evaporation or under an inert gas (N2 or argon).

[0127] The crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane can be isolated by filtration (e.g., vacuum filtration), or the solvent can be removed by heating or rotary evaporation. In certain embodiments, the crystalline solid of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane is isolated by drying under a nitrogen atmosphere at room temperature or under vacuum.

[0128] A method for preparing 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane from 3-palmitoyl-amido-1,2-propanediol is also described. In the practice of the method of the subject matter according to certain embodiments, a solvent is contacted with the crystalline solid of 3-palmitoyl-amido-1,2-propanediol to produce a precursor composition, and the precursor composition is contacted with a composition containing dimethoxytrityl chloride to produce a composition having 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane.

[0129] In embodiments, the solvent of interest is not limited, but may include tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate (iPrOAc), ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbutan-2-ol (tAmOH), N-methyl-2-pyrrolidone (NMP), or combinations thereof. In some cases, the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, acetonitrile, toluene, 2-methylbutan-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP). In certain cases, the solvent is selected from methyltetrahydrofuran, tetrahydrofuran, and dichloromethane.

[0130] In some embodiments, the precursor composition includes an additive. For example, the additive can be calcium oxide, magnesium oxide, boric acid, tetra-n-butylammonium 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 tetra-n-butylammonium fluoride (TBAF), magnesium oxide, and boric acid. In certain cases, the additive is magnesium oxide. The amount of the additive in the precursor composition can vary in the range of 0.05 equivalent to 1 equivalent, such as 0.1 equivalent to 0.5 equivalent, of the additive per equivalent of 3-palmitoyl-amide-1,2-propanediol, and can include about 0.3 equivalent of the additive per equivalent of 3-palmitoyl-amide-1,2-propanediol.

[0131] In some embodiments, the precursor composition is further contacted with a base. In certain 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 selected from 1,8-bis(dimethylamino)naphthalene (proton sponge), imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2,4,6-trimethylpyridine (collidine), 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 certain cases, the base is triethylamine.

[0132] The amount of base contacted with the 3-palmitoyl-amido-1,2-propanediol precursor composition can vary in the range of 0.5 equivalents to 3.5 equivalents of base, such as 0.75 equivalents to 1.95 equivalents relative to 3-palmitoyl-amido-1,2-propanediol, such as 1 equivalent to 1.9 equivalents, such as 1.1 equivalents to 1.85 equivalents, such as 1.15 equivalents to 1.80 equivalents, such as 1.25 equivalents to 1.75 equivalents, and including contacting 3-palmitoyl-amido-1,2-propanediol with 1.5 equivalents of base.

[0133] In some embodiments, the precursor composition is formed and maintained at ambient temperature. In other embodiments, the precursor composition is formed and maintained at an elevated temperature, such as about 30°C, including 25°C to 40°C, such as 27.5°C to 45°C, and 30°C to 35°C. In certain embodiments, the precursor composition is formed at a first temperature and changed to a second temperature. In one example, the precursor composition is formed at ambient temperature and then changed to an elevated temperature of 25°C to 40°C, such as about 30°C, including 27.5°C to 45°C, and 30°C to 35°C. In another example, the precursor composition is formed at an elevated temperature (e.g., about 50°C or higher) and cooled to a lower temperature (e.g., about 30°C), and then the precursor composition is contacted with a protecting group.

[0134] In an embodiment, the precursor composition is contacted with a hydroxyl protecting group to produce 3-palmitoyl-amide)-2-hydroxy-1-(protected hydroxy)-propane. The hydroxyl protecting group can vary and, in certain cases, examples of the hydroxyl protecting group include, but are not limited to, 1) alkyl ether type protecting groups such as alkyl ether, allyl ether, triphenylmethyl ether, dimethoxy-triphenylmethyl ether, benzyl ether, or p-methoxybenzyl ether protecting groups, 2) ester and carbonate type protecting groups such as acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, pivaloate, benzoate, p-methoxybenzoate, p-bromobenzoate, methyl carbonate, 9-(fluorenylmethyl) carbonate (Fmoc), allyl carbonate (Alloc), 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (Teoc), benzyl carbonate (Cbz), t-butyl carbonate (Boc), or dimethylthiocarbmate (DMTC) protecting groups, 3) acetal type protecting groups such as 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), tetrahydropyranyl ether (THP) protecting groups, and 2) silyl ether type protecting groups such as trimethylsilyl (TMS), triethylsilyl (TES), isopropyldimethylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), tetraisopropyldisiloxanylidene (TIPDS), or di-t-butylsilylene (DTBS) protecting groups. In some embodiments, the hydroxyl protecting group is a dimethoxy-triphenylmethyl protecting group.

[0135] The amount of the hydroxyl protecting group to be contacted with the precursor composition can vary in the range of 0.5 equivalents to 2 equivalents of an additive, such as 0.75 equivalents to 1.5 equivalents, and including about 1.4 equivalents of the hydroxyl protecting group relative to 3-palmitoyl-amido-1,2-propanediol.

[0136] In some embodiments, the 3-palmitoyl-amido-1,2-propanediol used in the method for preparing 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane is a crystalline solid of 3-palmitoyl-amido-1,2-propanediol. In certain embodiments, the 3-palmitoyl-amido-1,2-propanediol is a polymorph of crystalline solid 3-palmitoyl-amido-1,2-propanediol that exhibits an X-ray powder diffraction (XRPD) pattern having one or more peaks at about 2.75° 2θ, about 6° 2θ, about 3.8° 2θ, about 8.25° 2θ, about 15° 2θ, about 26.3° 2θ, about 30.5° 2θ, and about 33.1° 2θ.

[0137] The components used in each step of the subject method can be a purified composition or a crude composition, as desired. The term "purified" is used in its conventional meaning, referring to a composition in which at least some isolation or purification process, such as filtration of the reaction mixture or an aqueous workup, has been performed. In certain cases, purification can include 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 methods described herein without purification or other workup of the reaction mixture. In certain cases, the crude composition reaction mixture is such that the crude composition is analyzed by high performance liquid chromatography (HPLC), proton nuclear magnetic resonance spectroscopy ( 1Determined by 1H NMR, or a combination thereof, the target compound is included with a sufficient purity, such as a purity of 90% or more, including 95% or more, 97% or more, and 99% or more.

[0138] Aspects of the disclosure Aspects, including embodiments, of the subject matter described herein may be useful alone or in combination with one or more other aspects or embodiments. Without limitation, certain non-limiting aspects of the disclosure numbered 1 to 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 all such combinations of aspects and is not limited to the combinations of aspects explicitly provided below.

[0139] 1. A crystalline solid of a compound of formula I.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Examples

[0140] The following examples are presented to provide a complete disclosure and description of the methods of making and using the invention to those skilled in the art and are not intended to limit the scope that the inventors regard as their invention, nor are they intended to represent that the following experiments are all or the only experiments performed. Efforts have been made to ensure the accuracy of the numerical values used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations need to be taken into account. Unless otherwise indicated, parts are parts by weight, molecular weight is weight-average molecular weight, temperature is in degrees Celsius, and pressure is at approximately atmospheric pressure. "Average" means arithmetic mean. Standard abbreviations 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; i.m, intramuscular; intraperitoneal; s.c., subcutaneous, etc. may be used.

[0141] General Synthetic Procedure Numerous general reference works are available that provide generally known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds (e.g., Smith and March, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001, or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978).

[0142] The compounds described herein can be purified by any purification protocol known in the art, including chromatography such as HPLC, preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phases, as well as ion-exchange resins. In certain embodiments, the disclosed compounds are purified via silica gel and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979, and Thin Layer Chromatography, ed E. Stahl, Springer-Verlag, New York, 1969.

[0143] During any of the processes for preparing the subject compounds, it may be necessary and / or desirable to protect any sensitive or reactive groups of any of the related molecules. This is described in J.F.W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, T.W. Greene, and P.G.M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999, “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, “Methoden der organischen Chemie”, Houben-Weyl, 4 thIt can be achieved by the means of conventional protecting groups described in reference books such as the 15th edition, Vol. 15 / l, Georg Thieme Verlag, Stuttgart 1974, H.-D. Jakubke and H. Jescheit, “Aminosauren, Peptide, Proteine”, Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and / or Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide and Derivate”, Georg Thieme Verlag, Stuttgart 1974. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0144] The compounds of the subject can be synthesized via a variety of different synthetic routes using commercially available starting materials and / or starting materials prepared by conventional synthetic methods. Various examples of synthetic routes that can be used to synthesize the compounds disclosed herein are described below.

[0145] Example 1 - Preparation and Analysis of the Crystalline Polymorph of 3 - Palmitoyl - amido - 1,2 - propanediol The solubility of 3-palmitoyl-amido-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-methylbutan-2-ol (tAmOH), isopropyl acetate (iPrOAc), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF) were identified as solvents for use in the study. The effect of triethylamine on solubility was also evaluated. Triethylamine was shown to have little effect on the solubility of 3-palmitoyl-amido-1,2-propanediol in these solvents. Dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF) were determined to have moderate solubility of 3-palmitoyl-amido-1,2-propanediol.

[0146] The crystalline solid was identified as a new polymorph of 3-palmitoyl-amido-1,2-propanediol using triethylamine and THF, 2-methyl-THF, or DCM during crystallization induced by heating / cooling. Heating / cooling crystallization includes solubilizing 3-palmitoyl-amido-1,2-propanediol in a THF solution and heating and maintaining the composition at 50 °C overnight. In 2-methyl-THF or DCM, the solution with palmitoyl-amido-1,2-propanediol was heated overnight to 60 °C to form a solution. After cooling the sample to 30 °C, a crystalline solid was formed as a slurry in solutions of THF, 2-methyl-THF, and DCM.

[0147] When the polymorph of 3-palmitoyl-amido-1,2-propanediol formed was used as a substrate in the preparation of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane, it exhibited faster solubility and higher reaction selectivity.

[0148] The crystalline solid was analyzed by X-ray powder diffraction (as a slurry drop), thermogravimetric analysis, differential scanning calorimetry, and nuclear magnetic resonance spectroscopy. Figure 1 shows a comparison of the peaks of the X-ray powder diffraction patterns (XRPD) of the crystalline solids formed from solutions of (b) THF, (c) 2-methyl THF, and (d) DCM with the starting material 3-palmitoyl-amido-1,2-propanediol (a). As shown in Figure 1, the crystalline solids formed from THF, 2-methyl THF, and DCM exhibit peaks (e.g., at approximately 2.75° 2θ, approximately 6° 2θ, approximately 3.8° 2θ, approximately 8.25° 2θ, approximately 15° 2θ, approximately 26.3° 2θ, approximately 30.5° 2θ, and approximately 33.1° 2θ) that are different from those of the 3-palmitoyl-amido-1,2-propanediol starting material.

[0149] Figure 2 shows the thermogravimetric analysis of the crystalline solid formed from a solution of THF. The TGA of the polymorph of 3-palmitoyl-amido-1,2-propanediol formed from THF was characterized by a single weight loss step starting at approximately 200.5 °C. The graph in Figure 2 also shows the differential scanning calorimetry of the crystalline solid formed from a solution of THF. Figure 2 shows the DSC plot of the polymorph of 3-palmitoyl-amido-1,2-propanediol formed from THF, which exhibited two endotherms, a first endotherm at approximately 79.9 °C and a second endotherm at approximately 102.5 °C. The second endotherm peak at approximately 102.5 °C was a single peak endotherm. Figure 3 shows a comparison of the DSC plots of the polymorph of 3-palmitoyl-amido-1,2-propanediol formed from THF with the starting material 3-palmitoyl-amido-1,2-propanediol. The 3-palmitoyl-amido-1,2-propanediol starting material exhibits a first endotherm at approximately 79.3 °C and a second endotherm at approximately 105.8 °C.

[0150] Example 2 - Preparation of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane (Compound B) from 3-palmitoyl-amido-1,2-propanediol (Compound A) The reaction of 3-palmitoyl-amido-1,2-propanediol (CMPD-A) with 4,4'-dimethoxytrityl chloride was 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-dimethoxytrityl ether-propane (CMPD-B), 3-palmitoyl-amido-1-hydroxy-2-dimethoxytrityl ether-propane (CMPD-B-Reg), 3-palmitoyl-amido-1,2-dimethoxytrityl ether-propane (Bis-DMTr). For each reaction, 3-palmitoyl-amido-1,2-propanediol was charged into a three-necked round-bottom flask containing a solvent at 30 °C and stirred for 1 hour. 3.0 equivalents of base were added to the 3-palmitoyl-amido-1,2-propanediol solvent composition and stirred at 30 °C. When an additive was used, 0.3 equivalent of the additive was contacted with the reaction mixture. 1.4 equivalents of 4,4'-dimethoxytrityl chloride were added and the resulting suspension was stirred at 30 °C for a duration of about 17.3 hours. Samples from the reaction mixture were taken periodically (every 2 hours, every 4 hours, etc.) and the reaction products were characterized by HPLC.

Table 1-1

Table 1-2

[0151] Example Preparation of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane (Compound B) from 3-palmitoyl-amido-1,2-propanediol (Compound A) using 3-methyl THF and TEA 3-Palmitoyl-amido-1,2-propanediol was charged into a three-necked round-bottom flask containing methyl THF at 30 °C to form a white suspension, which was stirred at 30 °C for 1 hour. The flask was equipped with an overhead stirrer, a thermocouple, a nitrogen inlet, and a glass stopper. 3.0 equivalents of triethylamine were added and stirred at 30 °C for 0.5 hour. To the white suspension, 1.4 equivalents of 4,4'-dimethoxytrityl chloride were added all at once. The resulting yellow suspension was stirred at 30 °C for 23 hours. Samples were analyzed at 2 hours, 4 hours, 20 hours, and 23 hours to confirm the progress of the tritylation reaction and the formation of any impurities (e.g., unwanted positional isomers and bis-tritylated compounds). After 2 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane was formed in 63.2% yield. The positional isomer impurity, 3-palmitoyl-amido-2-dimethoxytrityl ether-1-hydroxy-propane, was formed in 0.4% yield, and the bis-tritylated compound exhibited a yield of 7.8%. After 4 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane was formed in 65.8% yield. The positional isomer impurity, 3-palmitoyl-amido-2-dimethoxytrityl ether-1-hydroxy-propane, was formed in 0.2% yield, and the bis-tritylated compound increased to a yield of 11.2%. After 20 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane was formed in 62.4% yield. The positional isomer impurity, 3-palmitoyl-amido-2-dimethoxytrityl ether-1-hydroxy-propane, was formed in 0.1% yield, and the bis-tritylated compound increased to a yield of 16.6%. After 23 hours, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane was formed in 62.6% yield. The positional isomer impurity, 3-palmitoyl-amido-2-dimethoxytrityl ether-1-hydroxy-propane, was formed in 0.1% yield, and the bis-tritylated compound was maintained at a yield of 16.6%.

[0152] Preparation of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane (Compound B) from 3-palmitoyl-amido-1,2-propanediol (Compound A) using 4-methyl-THF and TEA, and magnesium oxide 3-Palmitoyl-amido-1,2-propanediol and 0.3 equivalents of magnesium oxide were charged into a three-necked round-bottom flask containing methyl THF at 30 °C. The flask was equipped with an overhead stirrer, a thermocouple, a nitrogen inlet, and a glass stopper. The white suspension was stirred at 30 °C for 1 hour. 3.0 equivalents of triethylamine were added and stirred at 30 °C for 0.5 hour. 1.4 equivalents of 4,4’-dimethoxytrityl chloride were added all at once. The resulting yellow-green suspension was stirred at 30 °C for 23 hours. Samples were analyzed at 2 hours, 4 hours, 20 hours, and 23 hours to confirm the progress of the tritylation reaction and the formation of any impurities (e.g., unwanted positional isomers and bis-tritylated compounds). After 2 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane was formed in a 63.2% yield. The positional isomer impurity 3-palmitoyl-amido-2-dimethoxytrityl ether-1-hydroxy-propane was formed in a 0.4% yield, and the bis-tritylated compound exhibited a 7.7% yield. After 4 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane was formed in a 65.7% yield. The positional isomer impurity 3-palmitoyl-amido-2-dimethoxytrityl ether-1-hydroxy-propane was formed in a 0.3% yield, and the bis-tritylated compound increased to an 11.0% yield. After 20 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane was formed in a 63.2% yield. The positional isomer impurity 3-palmitoyl-amido-2-dimethoxytrityl ether-1-hydroxy-propane was no longer present, and the bis-tritylated compound increased to a 16.7% yield. After 23 hours, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane was formed in a 62.6% yield.The positional isomer impurity, 3-palmitoyl-amido-2-dimethoxytrityl ether-1-hydroxy-propane, was formed in a 0.1% yield, and the bis-tritylated compound increased slightly to a 16.9% yield.

[0153] Preparation of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane (Compound B) from 3-palmitoyl-amido-1,2-propanediol (Compound A) using Example 5-methyl-THF and TEA, as well as magnesium oxide and heating 3-Palmitoyl-amido-1,2-propanediol, 0.3 equivalents of magnesium oxide, and 3.0 equivalents of triethylamine were charged into a three-necked round-bottom flask containing methyl THF at ambient temperature. The flask was equipped with an overhead stirrer, a thermocouple, a nitrogen inlet, and a glass stopper. The composition was heated to 48 °C to form a white suspension and stirred at 48 °C for 1 hour. The composition was further heated to 55 °C and stirred for an additional 1 hour. The reaction mixture was heated again to 60 °C and stirred for an additional 30 minutes. The reaction mixture was cooled to 30 °C over 70 minutes, and 1.4 equivalents of 4,4'-dimethoxytrityl chloride were added all at once to the resulting white suspension. The resulting pale green suspension was stirred at 30 °C for 23 hours. Samples were analyzed at 2 hours, 4 hours, 20 hours, and 23 hours to confirm the progress of the tritylation reaction and the formation of any impurities (e.g., unwanted positional isomers and bis-tritylated compounds). After 2 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane was formed in 67.0% yield. The positional isomer impurity 3-palmitoyl-amido-2-dimethoxytrityl ether-1-hydroxy-propane was formed in 0.2% yield, and the bis-tritylated compound exhibited a yield of 8.3%. After 4 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane was formed in 66.2% yield. The positional isomer impurity 3-palmitoyl-amido-2-dimethoxytrityl ether-1-hydroxy-propane was formed in 0.1% yield, and the bis-tritylated compound increased to a yield of 11.6%. After 20 hours of reaction, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane was formed in 63.2% yield. The positional isomer impurity 3-palmitoyl-amido-2-dimethoxytrityl ether-1-hydroxy-propane was no longer present, and the bis-tritylated compound increased to a yield of 18.1%. After 23 hours, 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane was formed in 63.0% yield.The positional isomer impurity, 3-palmitoyl-amido-2-dimethoxytrityl ether-1-hydroxy-propane, is no longer present, and the bis-tritylated compound increased slightly to a yield of 18.2%.

[0154] Example 6 - X-ray Crystal Structure Analysis of 3-Palmitoyl-Amido-2-Hydroxy-1-Dimethoxytrityl Ether-Propane Single crystals of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane were produced by recrystallization of compositions of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane in various solvents and solvent mixtures. Single crystals formed from dichloromethane / pentane were used for X-ray diffraction studies.

[0155] X-ray diffraction was collected on single crystals in their as-grown form at -100 °C. For X-ray crystal structure analysis, a monoclinic plate-shaped specimen with dimensions of approximately 0.080 mm × 0.130 mm × 0.130 mm was used. A Bruker D8 QUEST single-crystal X-ray diffractometer equipped with high-intensity IμS 3.0 microfocus (50 kV × 1 mA) for Cu radiation (λ = 1.54178 Å) was used to study the X-ray structure, and a PHOTON II charge-integrating pixel array detector with excellent speed, sensitivity, and accuracy was used for crystal screening / evaluation and diffraction data collection. A Cryostream 800 low-temperature device provided a sample temperature of 80 K to 500 K and was used to cool the crystals at 173 K (-100 °C). The Bruker APEX3 software suite including SHELXTL was used for diffraction experiments for data collection and integration, as well as for elucidation, refinement, and display of the structural results.

[0156] A total of 1346 frames were collected. The total exposure time was 12.76 hours. The frames were integrated using the Bruker SAINT software package with a narrow-frame algorithm. Integration of the data using a triclinic unit cell yielded a total of 30535 reflections up to a maximum θ angle of 65.20° (0.85 Å resolution), of which 12077 were independent (average redundancy 2.528, completeness = 96.7%, Rint = 3.33%, Rsig = 3.88%), and of these 10927 (90.48%) were greater than 2σ(F2). The final unit cell constants of 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)°, volume = 3644.9(4) Å3 are based on the precision of the XYZ centroid of 9845 reflections above 20σ(I) in the range 6.873° < 2θ < 130.4°. Absorption effect data were corrected using the Multi-Scan method (SADABS). The minimum to maximum ratio of apparent transmittance was 0.853. The calculated minimum and maximum transmission coefficients (based on crystal size) were 0.9280 and 0.9550. Using the Bruker SHELXTL software package with the formula unit C40H57NO5 and space group P-1 with Z = 4, the structure was solved and refined. The final anisotropic full-matrix least-squares refinement of F2 using 838 variables converged to R1 = 11.45% for the observed data and wR2 = 26.68% for all data. The goodness of fit was 1.106. The maximum peak in the final difference in the electron density synthesis at an RMS deviation of 0.073 e− / Å3 was 0.692 e− / Å3, and the maximum hole was −0.510 e− / Å3. Based on the final model, the calculated density was 1.151 g / cm3. Table 2 shows the atomic coordinates and equivalent isotropic atomic displacement parameters (Å 2) provides. Table 3 provides the measured bond lengths (Å) determined from the crystal structure of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane. Table 4 provides the measured bond angles (°) determined from the crystal structure of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane. Table 5 provides the measured torsion angles (°) determined from the crystal structure of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane. Table 6 provides the anisotropic atomic displacement parameters (Å 2 ) provided. Table 7 provides the hydrogen atom coordinates and isotropic atomic displacement parameters (Å 2 ) provided.

[0157] Figure 4A shows the Oak Ridge Thermal Ellipsoid Plot (ORTEP) diagrams of two different conformations of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane determined by X-ray crystallographic analysis. Conformer A exhibits a linear conformation of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane. Conformer B exhibits a bent conformation of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane. Figure 4B shows the unit cell of the crystal of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane, with each unit cell containing 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane of four molecules (two molecules of conformer A and two molecules of conformer B). Figure 4C shows a diagram of the crystal packing of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane along the first axis, and Figure 4D shows the crystal packing of 3-palmitoyl-amido-2-hydroxy-1-dimethoxytrityl ether-propane along the second axis. Figure 4E shows the intermolecular hydrogen bonds between conformer A and conformer B along the second crystal structure analysis axis.

Table 2-1

Table 2-2

Table 2-3

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 4-1

Table 4-2

Table 4-3

Table 4-4

Table 4-5

Table 5-1

Table 5-2

Table 5-3

Table 5-4

Table 5-5

Table 6-1

Table 6-2

Table 6-3

Table 6-4

Table 7-1

Table 7-2

Table 7-3

Table 7-4

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Claims

【Claim 1】 The article, method or system described in this specification and the drawings.

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