Topical phosphoinositide 3-kinase inhibitors

Abstract

To provide a compound represented by formula (I), in which subscripts m, L1, R1, and L1-R1 are as described in the present specification.SOLUTION: The present invention also provides a topical formulation including a compound for curing blood vessel abnormalities.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 802,093, filed February 6, 2019, and U.S. Provisional Patent Application No. 62 / 958,049, filed January 7, 2020. Each of these provisional applications is incorporated herein in its entirety for all purposes.

[0002] STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT Not applicable

[0003] Reference to a "Sequence Listing," table, or computer program listing appendix submitted on a compact disc Not applicable [Background technology]

[0004] Vascular anomalies are broadly classified as vascular tumors and vascular malformations. These lesions consist of various types of abnormal vascular elements and primarily occur in infants, children, and young adults, worsening and persisting into adulthood. Vascular anomalies can be painful and may be complicated by bleeding, infection, or organ damage, potentially resulting in secondary effects on other tissues. Current treatments include surgical resection, pulsed laser, and sclerotherapy, which are invasive and carry the risk of recurrence. While pharmacological options for these vascular anomalies are increasingly available, no specific targeted therapies have yet been developed.

[0005] Vascular malformations present a clinical challenge because current classifications only consider patient outcomes and histologic features. Indeed, much effort has been devoted to distinguishing these lesions from vascular tumors. While benign vascular tumors, such as infantile hemangiomas, regress spontaneously and can be treated with propranolol, vascular malformations continue to progress for years. Venous malformations have attracted intense interest due to the current lack of treatment and prognosis. Furthermore, the pathogenesis of these lesions remains unclear.

[0006] The phosphoinositide 3-kinase (PI3K) pathway has been extensively studied in tumors due to its role in promoting cell growth and proliferation. The most common mutations in PI3K are in the PIK3CA gene, which encodes the p110α catalytic subunit, and include the "hotspot" activating mutations E545K and H1047R, which can result in constitutive signaling of this pathway. Consequently, activation of the serine / threonine kinase Akt can promote proliferation and cell growth pathways through regulation of mTOR and other intermediates. In addition to promoting tumorigenesis, hotspot PIK3CA mutations have also been shown to cause a wide range of nonmalignant overgrowth disorders, collectively referred to as the PIK3CA-associated aberrant overgrowth spectrum. Recently, PIK3CA mutations have been identified in venous malformations (VMs), the most common type of vascular malformation, occurring in approximately 1 in 5,000 people in the general population (Limaye N, et al. Am J Hum Genet. 2015;97:914-921). These painful and often disfiguring lesions are characterized by endothelial cell hyperproliferation, loss of supporting vascular wall cells, and disorganized extracellular matrix, resulting in dilated and distended blood vessels in various tissues, most commonly in the cutaneous layer of the skin (Uebelhoer M, et al. Cold Spring Harb Perspect Med. 2012;2).

[0007] U.S. Patent No. 6,838,457 discloses that 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol has excellent PI3K inhibitory activity and cancer cell proliferation suppression activity. However, local delivery of compounds through the skin to treat vascular malformations by inhibiting the phosphoinositide 3-kinase (PI3K) pathway is unknown. In light of this, there is an urgent need to develop PI3K inhibitors and formulations thereof that can be delivered locally to treat vascular malformations. Summary of the Invention

[0008] In a first aspect, the present invention provides a compound of formula (I): [ka] or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof, During the ceremony, The subscript m is an integer between 0 and 2, and i)L 1 is a bond, —C(O)—, —C(O)O—, —C(O)S—, or —C(O)NH—, and R 1 But C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 6-10 Aryl, C 6-10 Aryl-C 1-6 Alkyl or C 6-10 Aryl-C 2-6 is alkenyl, ii)L 1 -R 1 is the expression: [ka] and During the ceremony, The wavy lines indicate the connections to adjacent oxygen atoms in formula (I); The subscript t is an integer between 0 and 1, The subscripts p and q are independently integers from 0 to 2; R 3 is hydrogen or the side chain of a natural or unnatural amino acid, and R 4 is hydrogen, or R 3 and R 4 are combined to form the side chain of a cyclic amino acid, R 5 is hydrogen or the side chain of a natural or unnatural amino acid, and R 6 is hydrogen, C 1-6 Alkyl or C 2-6 alkenyl, or R 5 and R 6are combined to form the side chain of a cyclic amino acid, and R 7 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkyl-C(O)- or C 2-6 alkenyl-C(O)-; or R 5 is hydrogen or the side chain of a natural or unnatural amino acid, and R 6 and R 7 combine to form a 3- to 6-membered heterocyclic ring optionally having 1-2 additional heteroatoms selected from O, S, and N as ring vertices; or iii) L 1 is -C(O)-, and R 1 is an aliphatic chain of a saturated fatty acid having 8 to 18 carbon atoms or an unsaturated fatty acid having 10 to 18 carbon atoms The present invention provides a compound, or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof.

[0009] In a second aspect, the present invention provides a topical formulation for treating vascular malformations, the topical formulation comprising: a) Formula (I): [ka] or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof, During the ceremony, The subscript m is an integer between 0 and 2, and i)L 1 is a bond, —C(O)—, —C(O)O—, —C(O)S—, or —C(O)NH—, and R 1 But C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 6-10 Aryl, C 6-10 Aryl-C 1-6Alkyl or C 6-10 Aryl-C 2-6 is alkenyl, ii)L 1 -R 1 is the expression: [ka] and During the ceremony, The wavy lines indicate the connections to adjacent oxygen atoms in formula (I); The subscript t is an integer between 0 and 1, The subscripts p and q are independently integers from 0 to 2; R 3 is hydrogen or the side chain of a natural or unnatural amino acid, and R 4 is hydrogen, or R 3 and R 4 are combined to form the side chain of a cyclic amino acid, R 5 is hydrogen or the side chain of a natural or unnatural amino acid, and R 6 is hydrogen, C 1-6 Alkyl or C 2-6 alkenyl, or R 5 and R 6 are combined to form the side chain of a cyclic amino acid, and R 7 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkyl-C(O)- or C 2-6 alkenyl-C(O)-; or R 5 is hydrogen or the side chain of a natural or unnatural amino acid, and R 6 and R 7 combine to form a 3- to 6-membered heterocyclic ring optionally having 1-2 additional heteroatoms selected from O, S, and N as ring vertices; or iii) L 1 is -C(O)-, and R 1is an aliphatic chain of a saturated fatty acid having 8 to 18 carbon atoms or an unsaturated fatty acid having 10 to 18 carbon atoms a compound, or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof, and b) one or more topical excipients Includes:

[0010] In a third aspect, the present invention provides a method for treating vascular malformations through the inhibition of phosphoinositide-3-kinase (PI3K), comprising administering to a subject in need thereof a topical formulation comprising an effective amount of a compound of formula (I) and one or more topical excipients. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 shows a synthetic scheme 1 for preparing compounds of formula (IIa) or (IIb). [Figure 2] FIG. 2 shows synthetic scheme 2 for preparing compounds of formula (IIIa) or (IIIb). [Figure 3] FIG. 3 shows a plot of the cumulative permeation of compound 1.002 in a topical gel formulation through human skin as a function of time. [Figure 4] FIG. 4 shows a comparison of the cumulative permeation of 3-(4-morpholinothieno(3,2-d)pyrimidin-2-yl)phenol (MTPP) and compound 1.002 in gel formulations through human skin. [Figure 5] Figure 5 compares the cumulative permeation of compound 1.002 in a topical gel formulation through human and mouse skin. [Figure 6] FIG. 6 shows a liquid reservoir transdermal patch system. [Figure 7] FIG. 7 depicts a flow diagram of the manufacturing process for preparing a transdermal liquid reservoir patch. [Figure 8] FIG. 8 shows a plot of the cumulative permeation of 3-(4-morpholinothieno(3,2-d)pyrimidin-2-yl)phenol through a transdermal reservoir patch into human skin over a 7-day period. [Figure 9] FIG. 9 shows a plot of the cumulative permeation of compound 1.002 through a transdermal reservoir patch into human skin over a 7 day period. [Figure 10] FIG. 10 shows a comparison of the cumulative permeation of 3-(4-morpholinothieno(3,2-d)pyrimidin-2-yl)phenol and compound 1.002 into human skin via a transdermal reservoir patch over a 7-day period. [Figure 11] FIG. 11 shows the effect of glycerol monooleate, oleyl oleate, or isostearic acid compared to oleic acid in a gel formulation on the skin flux of compound 1.002 across human skin. [Figure 12] FIG. 12 shows the effect of neodecanoic acid or isostearic acid compared to oleic acid in a gel formulation on the skin permeation rate of compound 1.002 through human skin. [Figure 13] FIG. 13 shows the effect of oleic acid in a gel formulation on the skin permeation rate of compound 1.002 through human skin. [Figure 14] Figure 14 shows the effect of oleic acid and oleyl alcohol in a gel formulation on the skin permeation rate of compound 1.002 through human skin. [Figure 15] FIG. 15 shows a comparison of the cumulative permeation of compound 1.002 in gel formulations with glycol combinations. DETAILED DESCRIPTION OF THE INVENTION

[0012] I. Overview The present invention provides compounds of formula (I) and topical formulations containing the compounds of formula (I) for the treatment of vascular malformations. After topical delivery, the compounds of the present invention are substantially converted to the corresponding compounds of formula (IV) that can inhibit one or more phosphoinositide 3-kinase enzymes that are part of the PI3K / AKT pathway, thereby providing a beneficial therapeutic effect for the treatment of vascular malformations. The present invention also provides methods for treating vascular malformations by inhibiting the PI3K / AKT pathway using the topical formulations of the present invention.

[0013] II. Definition The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0014] "Alkyl" has the indicated number of carbon atoms (i.e., C 1-6 refers to a straight-chain or branched saturated aliphatic radical (meaning 1 to 6 carbons). Alkyl refers to a C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 and the like. For example, C alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 24 carbons, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc.

[0015] "Alkenyl" refers to an alkyl group having at least two carbon atoms and at least one double bond, and having the number of carbon atoms indicated (i.e., C 2-6 refers to straight or branched chain carbon atoms (2 to 6 carbon atoms). Alkenyl refers to C2, C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C4-5 , C 4-5 , C5, C 5-6 Alkenyl groups can include any number of carbons, such as C, C, and C. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5, or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl.

[0016] "Alkoxy" refers to an alkyl group with an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. The alkoxy group can have any suitable number of carbon atoms, such as C1-C6. Examples of alkoxy groups include methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0017] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which at least one hydrogen atom has been replaced with a hydroxy group. As with the alkyl group, the hydroxyalkyl or alkylhydroxy group can have any suitable number of carbon atoms, such as C1-C6. Exemplary hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (hydroxy in the 1- or 2-position), hydroxypropyl (hydroxy in the 1-, 2-, or 3-position), hydroxybutyl (hydroxy in the 1-, 2-, 3-, or 4-position), hydroxypentyl (hydroxy in the 1-, 2-, 3-, 4-, or 5-position), hydroxyhexyl (hydroxy in the 1-, 2-, 3-, 4-, 5-, or 6-position), 1,2-dihydroxyethyl, and the like.

[0018] "Halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

[0019] "Haloalkyl" refers to an alkyl, as defined above, in which some or all of the hydrogen atoms have been replaced with halogen atoms. As an alkyl group, the haloalkyl group can have any suitable number of carbon atoms, such as C1-C6. For example, haloalkyl includes trifluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, and the like. In some instances, the term "perfluoro" can be used to define a compound or radical in which all hydrogen atoms have been replaced with fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0020] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic, fused bicyclic, or bridged polycyclic ring assembly containing 3 to 12 ring atoms, or the number of atoms indicated. 3-6 Or, C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , C 3-12Cycloalkyl groups can contain any number of carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated monocyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds within the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. When cycloalkyl is a saturated monocyclic C3-C8 cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When cycloalkyl is a saturated monocyclic C3-6 cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0021] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can contain any suitable number of ring atoms and 6 to 10, 6 to 12, or 6 to 14 ring members, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Some aryl groups have 6 to 12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl.

[0022] "Aryl-alkyl" refers to a radical having an alkyl component and an aryl component, where the alkyl component connects the aryl component to the attachment point. The alkyl component is as defined above, except that it is at least a divalent alkylene to connect the aryl component to the attachment point. The alkyl component is as defined above, except that it is at least a divalent alkylene to connect the aryl component to the attachment point. 1-2 Or, C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 The aryl group may contain any number of carbons, such as aryl, aryl- ...

[0023] "Aryl-alkenyl" refers to a radical having both an alkenyl and an aryl component, where the alkenyl component connects the aryl component to the point of attachment. The alkenyl component is as defined above, except that it is at least a divalent alkenylene to connect the aryl component to the point of attachment. The alkenyl component can be any alkylene, such as C2 or C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-8 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-5 , C5, C 5-6The alkenyl component can have any number of carbons, such as C, ...

[0024] "Heterocycle" or "heterocycloalkyl" refers to a saturated ring system having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. The heteroatoms can also be oxidized, including, but not limited to, S(O) and S(O). Heterocycloalkyl groups can contain any number of ring atoms, including 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Heterocycloalkyl groups can contain any suitable number of heteroatoms, including 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. Heterocycloalkyl groups can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups include, among many others, C 1-6 It can be substituted with alkyl or oxo (=O).

[0025] The heterocycloalkyl group can be linked through any position on the ring. For example, aziridine can be 1- or 2-aziridine, azetidine can be 1- or 2-azetidine, pyrrolidine can be 1-, 2-, or 3-pyrrolidine, piperidine can be 1-, 2-, 3-, or 4-piperidine, pyrazolidine can be 1-, 2-, 3-, or 4-pyrazolidine, imidazolidine can be 1-, 2-, 3-, or 4-imidazolidine, and piperazine can be 1-, 2-, 3-, or 4-piperazine. wherein tetrahydrofuran can be 1- or 2-tetrahydrofuran, oxazolidine can be 2-, 3-, 4- or 5-oxazolidine, isoxazolidine can be 2-, 3-, 4- or 5-isoxazolidine, thiazolidine can be 2-, 3-, 4- or 5-thiazolidine, isothiazolidine can be 2-, 3-, 4- or 5-isothiazolidine, and morpholine can be 2-, 3- or 4-morpholine.

[0026] "N-linked heterocycloalkyl" or "nitrogen-linked heterocycloalkyl" refers to a heterocycloalkyl group linked through the N-position on the ring. For example, N-linked aziridinyl is aziridin-1-yl, N-linked azetidinyl is azetidin-1-yl, N-linked pyrrolidinyl is pyrrolidin-1-yl, N-linked piperidinyl is piperidin-1-yl, N-linked pyrazolidinyl can be pyrazolidin-1-yl or pyrazolidin-2-yl, N-linked imidazolidinyl can be imidazolidin-1-yl or imidazolidin-3-yl, N-linked piperazinyl is piperazin-1-yl or piperazin-4-yl, N-linked oxazolidinyl is oxazolidin-3-yl, N-linked isoxazolidinyl is isoxazolidin-2-yl, N-linked thiazolidinyl is thiazolidin-3-yl, N-linked isothiazolidinyl is isothiazolidin-2-yl, and N-linked morpholinyl is 4-morpholinyl.

[0027] When a heterocycloalkyl contains 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. Heterocycloalkyls can also form rings having 5 to 6 ring members and 1 to 2 heteroatoms, representative ring members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0028] "Amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Amino acids contain an amine functional group (-NH or -NH) and a carboxyl functional group (-COOH), along with a side chain (R group) that is unique to each amino acid. Amino acids with the amine group attached to the first (α-) carbon adjacent to the carboxylic acid group are called α-amino acids.

[0029] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Examples of naturally occurring amino acids include 20 amino acids selected from the group consisting of alanine (Ala / A), glycine (Gly / G), isoleucine (Ile / I), leucine (Leu / L), proline (Pro / P), valine (Val / V), phenylalanine (Phe / F), tryptophan (Trp / W), tyrosine (Tyr / Y), aspartic acid (Asp / D), glutamic acid (Glu / E), arginine (Arg / R), histidine (His / H), lysine (Lys / K), serine (Ser), threonine (Thr / T), asparagine (Asn / N), glutamine (Gln / Q), methionine (Met / M), and cysteine ​​(Cys / C).

[0030] "Unnatural amino acid" refers to a compound that can, but does not necessarily, have the same basic structure as a naturally occurring amino acid. In some embodiments, unnatural amino acids have modified side chains (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Unnatural amino acids include homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium, azetidine carboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, tert-butylglycine, 2,4-diaminoisobutyric acid, desmosine, 2,2'-diaminopimelic acid, 2,4'-diaminoisobutyric acid, 2,2'-diaminopimelic acid, 2,2'-diaminoisobutyric ... , 3-diaminopropionic acid, N-ethylglycine, N-ethylsparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalanine, norvaline, ornithine, pentylglycine, pipecolic acid, and thioproline.

[0031] "Alkylene glycol" refers to a compound having the formula HO-[alkylene-O]-H, where the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, alkylene glycol is C 2-6 In some embodiments, C is an alkylene glycol. 2-6 The alkylene glycol is propylene glycol (1,2-propanediol).

[0032] "Di-alkylene glycol" refers to a compound having the formula HO-(alkylene-O)-H, where the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, di-alkylene glycol is a di-(C 2-6In some embodiments, di-(C alkylene) glycol. 2-6 The alkylene glycol is dipropylene glycol. Dipropylene glycol can include one or more isomers, such as 4-oxa-2,6-heptanediol, 2-(2-hydroxy-propoxy)-propan-1-ol, 2-(2-hydroxy-1-methyl-ethoxy)-propan-1-ol, and 3,3'-oxybis(propan-1-ol).

[0033] "Polyethylene glycol" is a compound with a wide variety of subscripts, such as HO-(CH2CH2O). n "PEG" refers to a polymer having the formula -OH. Suitable polyethylene glycols may have a free hydroxyl group at each end of the polymer molecule, or one or more hydroxyl groups etherified with a lower alkyl, e.g., methyl, group. Also suitable are polyethylene glycol derivatives having esterifiable carboxy groups. Polyethylene glycols useful in the present invention can be polymers of any chain length or molecular weight and can include branching. In some embodiments, the average molecular weight of the polyethylene glycol is about 200 to about 9000. In some embodiments, the average molecular weight of the polyethylene glycol is about 200 to about 5000. In some embodiments, the average molecular weight of the polyethylene glycol is about 200 to about 900. In some embodiments, the average molecular weight of the polyethylene glycol is about 400. Suitable polyethylene glycols include, but are not limited to, PEG 200, PEG 300, PEG 400, PEG 600, and PEG 900. The number following "PEG" in the name refers to the average molecular weight of the polymer.

[0034] "Fatty acid" refers to a carboxylic acid with a long aliphatic chain that may be straight or branched, saturated or unsaturated. Most naturally occurring fatty acids have unbranched chains of an even number of carbon atoms, between 8 and 24.

[0035] "Saturated fatty acid" refers to a fatty acid having an alkyl chain, where the alkyl component is as defined above. Saturated fatty acids having 8 to 24 carbon atoms include caprylic acid, pelargonic acid, capric acid, neodecanoic acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, isostearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, behenic acid, tricosylic acid, and lignoceric acid. In some embodiments, the saturated fatty acid having 8 to 18 carbon atoms is caprylic acid, pelargonic acid, capric acid, neodecanoic acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, or isostearic acid.

[0036] The term "aliphatic chain of a saturated fatty acid" refers to the alkyl chain of the corresponding saturated fatty acid defined above. The aliphatic chain has one less carbon atom than the corresponding saturated fatty acid. For example, the aliphatic chain of a saturated fatty acid having 8 to 18 carbon atoms has 7 to 17 carbon atoms.

[0037] "Unsaturated fatty acid" refers to a carboxylic acid with a long aliphatic chain containing one or more C=C double bonds. The C=C double bonds can result in either cis or trans isomers. The cis configuration means that the two hydrogen atoms adjacent to the double bond are on the same side of the chain. In contrast, the trans configuration means that the two adjacent hydrogen atoms are on opposite sides of the chain. Unsaturated fatty acids can contain 10 to 24 carbons. Unsaturated fatty acids include mono-unsaturated fatty acids, di-unsaturated fatty acids, and poly-unsaturated fatty acids.

[0038] Mono-unsaturated fatty acids include, but are not limited to, caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccinic acid, gadoleic acid, eicosenoic acid, erucic acid, brassidic acid, and nervonic acid. In some embodiments, the unsaturated fatty acid having 10 to 18 carbon atoms is caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccinic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, columbic acid, pinolenic acid, or stearidonic acid.

[0039] Di-unsaturated fatty acids include, but are not limited to, linoleic acid, eicosadienoic acid, and docosadienoic acid. A di-unsaturated fatty acid with 18 carbon atoms is linoleic acid.

[0040] Polyunsaturated fatty acids include, but are not limited to, α-linolenic acid, γ-linolenic acid, columbic acid, pinolenic acid, eleostearic acid, β-eleostearic acid, mead acid, dihomo-γ-linolenic acid, eicosatrienoic acid, stearidonic acid, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid.In some embodiments, the polyunsaturated fatty acid having 18 carbon atoms is α-linolenic acid, γ-linolenic acid, columbic acid, pinolenic acid, or stearidonic acid.

[0041] The term "aliphatic chain of an unsaturated fatty acid" refers to the aliphatic chain of the corresponding unsaturated fatty acid defined above. The aliphatic chain has one less carbon atom than the corresponding unsaturated fatty acid. For example, the aliphatic chain of an unsaturated fatty acid having 10 to 18 carbon atoms has 9 to 17 carbon atoms.

[0042] "Fatty alcohol" refers to a primary alcohol with a long aliphatic chain, either saturated or unsaturated. Fatty alcohols can range from as few as 4-6 carbons to as many as 22-26 carbons. Fatty alcohols include, but are not limited to, capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleic alcohol (unsaturated), heptadecyl alcohol, stearyl alcohol, oleyl alcohol (unsaturated), nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol (unsaturated), and lignoceryl alcohol.

[0043] A "fatty ester" or "fatty acid ester" is a type of ester formed by combining a fatty acid with an alcohol.

[0044] "Glyceride" refers to a fatty ester where the alcohol component is glycerol. The glyceryl fatty ester (or glyceride) produced can be a monoglyceride, diglyceride, or triglyceride. A "monoglyceride" is a glyceride consisting of one fatty acid chain covalently attached to a glycerol molecule through an ester bond. A "diglyceride" is a glyceride consisting of two fatty acid chains covalently attached to a glycerol molecule through ester bonds. A "triglyceride" is a glyceride consisting of three fatty acid chains covalently attached to a glycerol molecule through ester bonds.

[0045] "Sorbitan ester" refers to a compound or mixture of compounds resulting from the esterification of sorbitol with at least one fatty acid. Fatty acids useful for obtaining sorbitan esters include, but are not limited to, those described herein. Suitable sorbitan esters include, but are not limited to, the Span™ series (available from Uniqema), including Span 20 (sorbitan monolaurate), 40 (sorbitan monopalmitate), 60 (sorbitan monostearate), 65 (sorbitan tristearate), 80 (sorbitan monooleate), and 85 (sorbitan trioleate). Other suitable sorbitan esters include those listed in R.C. Rowe and P.J. Shesky, Handbook of Pharmaceutical Excipients, (2006), 5th ed., which is incorporated herein by reference in its entirety.

[0046] "Adipate" refers to a diester of adipic acid, "sebacate" refers to a diester of sebacic acid, "laurate" refers to an ester of lauric acid, "myristate" refers to an ester of myristic acid, "palmitate" refers to an ester of palmitic acid, and "stearate" refers to an ester of stearic acid. In some embodiments, adipate, sebacate, laurate, myristate, palmitate, or stearate is each a di-C diester of adipic acid. 1-6 Alkyl esters of sebacic acid, di-C 1-6 Alkyl esters of palmitic acid, C 1-6 It is an alkyl ester or glycol monoester of stearic acid.

[0047] "Solvate" refers to a compound provided herein, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. As used herein, solvent refers to a non-aqueous solvent.

[0048] "Hydrate" refers to a compound complexed with at least one water molecule. The compounds of the invention can be complexed with 1 to 10 water molecules.

[0049] As used herein, "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, and any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not have an adverse effect on the recipient thereof.

[0050] A "pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to and absorption by a subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, and coloring agents. Pharmaceutical excipients useful for transdermal / topical delivery in the present invention include, but are not limited to, enhancers, solubilizers, antioxidants, plasticizers, thickeners, polymers, and pressure-sensitive adhesives. One of ordinary skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0051] "Weight of base formulation" refers to the total weight of the formulation excluding the compound of formula (I) or 3-(4-morpholinothieno(3,2-d)pyrimidin-2-yl)phenol (abbreviated as MTPP) and the gelling agent.

[0052] "The fatty acid is present in an amount of about x% to about y% by weight of the base formulation" refers to the fatty acid being present in an amount of about x% to about y% by weight relative to the total weight of the base formulation excluding the compound of formula (I) or MTPP and gelling agent.

[0053] "The compound of formula (I) is present in an amount of about x% by weight of the base formulation" refers to the weight percent of the compound of formula (I) compared to the total weight of the formulation, excluding the compound of formula (I) and the gelling agent.

[0054] "One or more gelling agents are present in an amount of about x% to about y% by weight of the base formulation" refers to the weight percent of the gelling agent compared to the total weight of the formulation without the compound of Formula (I) or MTPP and the gelling agent. For example, "hydroxypropyl cellulose is present in an amount of about x% to about y% by weight of the base formulation" refers to the weight percent of hydroxypropyl cellulose compared to the total weight of the base formulation without the compound of Formula (I) or MTPP and hydroxypropyl cellulose.

[0055] "Relative purity of the compound of formula (I) in a topical formulation" refers to the purity of the compound of formula (I) at a certain time point (e.g., day 10) stored under stress conditions (e.g., 80°C) or normal storage conditions (e.g., room temperature) compared to the initial purity of the compound of formula (I) at time zero (i.e., day 0). Conventionally, the relative purity of the compound of formula (I) at time zero (i.e., day 0) is taken as 100%.

[0056] "I C 50 " refers to the amount, concentration, or dosage of a particular test compound in an assay measuring such response that achieves a 50% inhibition of a maximal response.

[0057] "Inhibition," "inhibit," and "inhibitor" refer to a compound or method that prevents a particular action or function.

[0058] "Administering" refers to topical administration, for example, as a lotion, spray, ointment, cream, gel, paste, or patch.

[0059] "Topical" refers to the application of a suitable compound (e.g., an active agent) or a composition comprising a compound (e.g., an active agent) to the skin to treat a disease or condition, such as a vascular malformation. In some embodiments, "topical" refers to the application of a suitable compound (e.g., an active agent) or a composition comprising a compound (e.g., an active agent) to the skin with sufficient penetration into the epidermis or dermis to treat a vascular malformation. In some embodiments of topical application, the compound or composition penetrates the epidermis or dermis without significant systemic exposure or with the intent to treat or prevent disease of other organ systems. In some embodiments of topical application, the compound or composition is delivered transdermally across the skin for systemic distribution. Examples include transdermal patches used for drug delivery.

[0060] "Treate," "treating," and "treatment" refer to any measure of successful treatment or amelioration of an injury, condition, or pathology, including objective or subjective parameters such as palliation, remission, reduction of symptoms, or making the injury, condition, or pathology more tolerable to the patient, slowing the rate of degeneration or decline, making the debilitating end point of degeneration less severe, improving the patient's physical or mental well-being, etc. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0061] "Patient" or "subject" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition described herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammalian animals. In some embodiments, the patient is a human.

[0062] A "therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition useful for treating or ameliorating a specified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. The precise amount will depend on the purpose of the treatment and can be ascertained by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0063] "About" refers to a range of values ​​that includes the specified value and that one of ordinary skill in the art would consider to be reasonably similar to the specified value. In some embodiments, the term "about" refers to within a standard deviation using measurements generally accepted in the art. In some embodiments, about refers to a range that extends + / - 10% of the specified value. In some embodiments, about refers to the specified value.

[0064] "A," "an," or "a(n)," when used herein with respect to a group of substituents or "substituents," means at least one. For example, if a compound is substituted with "an" alkyl or aryl, the compound is optionally substituted with at least one alkyl and / or at least one aryl, and each alkyl and / or aryl is optionally different. In another example, if a compound is substituted with "a" substituent group, the compound is substituted with at least one substituent, and each substituent is optionally different.

[0065] III.Compound In one aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: Formula (I): [ka] or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof, During the ceremony, The subscript m is an integer between 0 and 2, and i)L 1 is a bond, —C(O)—, —C(O)O—, —C(O)S—, or —C(O)NH—, and R 1 But C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 6-10 Aryl, C 6-10 Aryl-C 1-6 Alkyl or C 6-10 Aryl-C 2-6 is alkenyl, ii)L 1 -R 1 is the expression: [ka] and During the ceremony, The wavy lines indicate the connections to adjacent oxygen atoms in formula (I); The subscript t is an integer between 0 and 1, The subscripts p and q are independently integers from 0 to 2; R 3 is hydrogen or the side chain of a natural or unnatural amino acid, and R 4 is hydrogen, or R 3 and R 4 are combined to form the side chain of a cyclic amino acid, R 5 is hydrogen or the side chain of a natural or unnatural amino acid, and R 6 is hydrogen, C 1-6 Alkyl or C 2-6 alkenyl, or R 5 and R 6are combined to form the side chain of a cyclic amino acid, and R 7 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkyl-C(O)- or C 2-6 alkenyl-C(O)-; or R 5 is hydrogen or the side chain of a natural or unnatural amino acid, and R 6 and R 7 combine to form a 3- to 6-membered heterocyclic ring optionally having 1-2 additional heteroatoms selected from O, S, and N as ring vertices; or iii) L 1 is -C(O)-, and R 1 is an aliphatic chain of a saturated fatty acid having 8 to 18 carbon atoms or an unsaturated fatty acid having 10 to 18 carbon atoms The present invention provides a compound, or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the subscript m is 0 or 1. In some embodiments, the subscript m is 1. In some embodiments, the subscript m is 0.

[0067] In some embodiments, the subscript m is 0 and the compound has formula (II): [ka] is expressed as In the formula, L 1 , R 1 , and L 1 -R 1 is as defined herein in any aspect or embodiment described herein.

[0068] In some embodiments, the subscript m is 1 and the compound has formula (III): [ka] is expressed as In the formula, L 1 , R 1 , and L 1 -R 1 is as defined herein in any aspect or embodiment described herein.

[0069] In some embodiments of any one of Formulas (I), (II), and (III), L 1 is a bond. In some embodiments, L 1 is —C(O)—. In some embodiments, L 1 is —C(O)O—. In some embodiments, L 1 is —C(O)NH—. In some embodiments, L 1 is -C(O)S-.

[0070] In some embodiments of Formula (II), L 1 is —C(O)— and the compound has formula (IIa): [ka] is expressed as In the formula, R 1 or L 1 -R 1 -C(O)-R as 1 is as defined herein in any aspect or embodiment described herein.

[0071] In some embodiments of Formula (II), the compound has the formula (IIb), (IIc), and (IId): [ka] It is represented by one of In the formula, R 1 is C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 6-10 Aryl, C 6-10 Aryl-C1-6 Alkyl or C 6-10 Aryl-C 2-6 It is alkenyl.

[0072] In some embodiments of Formula (III), L 1 is —C(O)— and the compound has formula (IIIa): [ka] is expressed as In the formula, R 1 or L 1 -R 1 -C(O)-R as 1 is as defined herein in any aspect or embodiment described herein.

[0073] In some embodiments of Formula (III), the compound has the formula (IIIb), (IIIc), and (IIId): [ka] It is represented by one of In the formula, R 1 is C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 6-10 Aryl, C 6-10 Aryl-C 1-6 Alkyl or C 6-10 Aryl-C 2-6 It is alkenyl.

[0074] With respect to any one of Formulas (I)-(III), (IIa)-(IId), and (IIIa)-(IIId), in some embodiments, R 1 is C 1-6 Alkyl, C 2-6 Alkenyl, C 6-10 Aryl, C 6-10 Aryl-C 1-6 Alkyl or C 6-10 Aryl-C 2-6 It is alkenyl.

[0075] In some embodiments of any one of Formulas (I)-(III), (IIa)-(IId), and (IIIa)-(IIId), R 1 is C 1-6 In some embodiments, R 1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. 1 is methyl. In some embodiments, R 1 is ethyl.

[0076] In some embodiments of any one of Formulas (I)-(III), (IIa)-(IId), and (IIIa)-(IIId), R 1 is C 2-6 In some embodiments, R is alkenyl. 1 is vinyl(ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. 1 is propenyl.

[0077] In some embodiments of any one of Formulas (I)-(III), (IIa)-(IId), and (IIIa)-(IIId), R 1 is C 6-10 Aryl-C 2-6 In some embodiments, R is alkenyl. 1 is phenyl-C 2-6 In some embodiments, R is alkenyl. 1 is phenyl -CH=CH-.

[0078] With respect to any one of formulas (I), (II), (IIa), (III), and (IIIa), L 1 -R 1 or -C(O)R 1 is the expression: [ka] and During the ceremony, the wavy line indicates a connection to an adjacent oxygen atom of any one of formulas (I), (II), (IIa), (III), and (IIIa); The subscript t is an integer between 0 and 1, The subscripts p and q are independently integers from 0 to 2; R 3 is hydrogen or the side chain of a natural or unnatural amino acid, and R 4 is hydrogen, or R 3 and R 4 are combined to form the side chain of a cyclic amino acid, R 5 is hydrogen or the side chain of a natural or unnatural amino acid, and R 6 is hydrogen, C 1-6 Alkyl or C 2-6 alkenyl, or R 5 and R 6 are combined to form the side chain of a cyclic amino acid, and R 7 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkyl-C(O)- or C 2-6 alkenyl-C(O)-; or R 5 is hydrogen or the side chain of a natural or unnatural amino acid, and R 6 and R 7 combine to form a 3- to 6-membered heterocycle optionally having 1-2 additional heteroatoms selected from O, S, and N as ring vertices.

[0079] In some embodiments of any one of Formulas (I), (II), (IIa), (III), and (IIIa), the subscript t is 1. In some embodiments, the subscript t is 0.

[0080] In some embodiments of any one of Formulas (I), (II), (IIa), (III), and (IIIa), the subscript t is 1 and the subscripts p and q are independently integers from 0 to 2. In some embodiments, the subscript t is 1 and the subscripts p and q are independently 0 or 1. In some embodiments, the subscript t is 1 and the subscripts p and q are each 0.

[0081] In some embodiments of any one of formulas (I), (II), (IIa), (III), and (IIIa), when the subscript t is 1 and the subscripts p and q are each 0, R 4 is hydrogen and R 3 is the side chain of an amino acid selected from the group consisting of alanine (Ala / A), glycine (Gly / G), isoleucine (Ile / I), leucine (Leu / L), valine (Val / V), phenylalanine (Phe / F), tryptophan (Trp / W), tyrosine (Tyr / Y), aspartic acid (Asp / D), glutamic acid (Glu / E), arginine (Arg / R), histidine (His / H), lysine (Lys / K), serine (Ser / S), threonine (Thr / T), asparagine (Asn / N), glutamine (Gln / Q), methionine (Met / M), and cysteine ​​(Cys / C). In some embodiments, R 4 is hydrogen and R 3 is the side chain of an amino acid selected from the group consisting of alanine (Ala / A), glycine (Gly / G), isoleucine (Ile / I), leucine (Leu / L), valine (Val / V), phenylalanine (Phe / F), serine (Ser), threonine (Thr / T), asparagine (Asn / N), and glutamine (Gln / Q). In some embodiments, R 4 is hydrogen and R 3is the side chain of an amino acid selected from the group consisting of alanine (Ala / A), glycine (Gly / G), isoleucine (Ile / I), leucine (Leu / L), valine (Val / V), and phenylalanine (Phe / F). 3 and R 4 together to form proline (Pro / P).

[0082] In some embodiments of any one of Formulas (I), (II), (IIa), (III), and (IIIa), R 5 is the side chain of an amino acid selected from the group consisting of alanine (Ala / A), glycine (Gly / G), isoleucine (Ile / I), leucine (Leu / L), valine (Val / V), phenylalanine (Phe / F), tryptophan (Trp / W), tyrosine (Tyr / Y), aspartic acid (Asp / D), glutamic acid (Glu / E), arginine (Arg / R), histidine (His / H), lysine (Lys / K), serine (Ser / S), threonine (Thr / T), asparagine (Asn / N), glutamine (Gln / Q), methionine (Met / M), and cysteine ​​(Cys / C). In some embodiments, R 5 is the side chain of an amino acid selected from the group consisting of alanine (Ala / A), glycine (Gly / G), isoleucine (Ile / I), leucine (Leu / L), valine (Val / V), phenylalanine (Phe / F), serine (Ser), threonine (Thr / T), asparagine (Asn / N), and glutamine (Gln / Q). In some embodiments, R 5 is the side chain of an amino acid selected from the group consisting of alanine (Ala / A), glycine (Gly / G), isoleucine (Ile / I), leucine (Leu / L), valine (Val / V), and phenylalanine (Phe / F).

[0083] In some embodiments of any one of Formulas (I), (II), (IIa), (III), and (IIIa), R 6 and R 7 are independently hydrogen, C 1-6Alkyl or C 2-6 In some embodiments, R is alkenyl. 6 and R 7 are each hydrogen. In some embodiments, R 6 and R 7 One of them is hydrogen and the other is C 1-6 Alkyl or C 2-6 In some embodiments, R is alkenyl. 6 and R 7 One of them is hydrogen and the other is C 1-6 In some embodiments, R 6 and R 7 is hydrogen and the other is methyl, ethyl, propyl, isopropyl, butyl, pentyl, or hexyl. 6 and R 7 are independent of each other, C 1-6 In some embodiments, R 6 and R 7 are each independently methyl, ethyl, propyl, isopropyl, butyl, pentyl, or hexyl. 6 and R 7 Each is methyl. In some embodiments, R 6 and R 7 are independent of each other, C 2-6 In some embodiments, R is alkenyl. 6 and R 7 are -CH2CH=CH2, respectively.

[0084] In some embodiments of any one of Formulas (I), (II), (IIa), (III), and (IIIa), R 6 is hydrogen, C 1-6 Alkyl or C 2-6 alkenyl, and R 7 is C 1-6 Alkyl-C(O)- or C 2-6 alkenyl-C(O)-. In some embodiments, R 7is methyl-C(O)-, ethyl-C(O)-, propyl-C(O)-, isopropyl-C(O)-, butyl-C(O)-, pentyl-C(O)-, or hexyl-C(O)-. In some embodiments, R 6 is hydrogen and R 7 is -C(O)CH3.

[0085] In some embodiments of any one of Formulas (I), (II), (IIa), (III), and (IIIa), R 5 and R 6 together to form proline (Pro / P), and R 7 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkyl-C(O)- or C 2-6 alkenyl-C(O)-. In some embodiments, R 5 and R 6 together to form proline (Pro / P), and R 7 is hydrogen. In some embodiments, R 5 and R 6 together to form proline (Pro / P), and R 7 is C 1-6 In some embodiments, R 5 and R 6 together to form proline (Pro / P), and R 7 is methyl. In some embodiments, R 5 and R 6 together to form proline (Pro / P), and R 7 is C 1-6 In some embodiments, R 5 and R 6 together to form proline (Pro / P), and R 7 is -C(O)CH3.

[0086] In some embodiments of any one of Formulas (I), (II), (IIa), (III), and (IIIa), R 6 and R 7are taken together to form a 3-6 membered heterocyclic ring optionally having 1-2 additional heteroatoms selected from O, S, and N as ring vertices. In some embodiments, R 6 and R 7 taken together form a 3- to 6-membered heterocycle selected from N-linked aziridinyl, N-linked azetidinyl, N-linked pyrrolidinyl, N-linked piperidinyl, N-linked piperazinyl, and N-linked morpholinyl.

[0087] In some embodiments of any one of Formulas (I), (II), (IIa), (III), and (IIIa), the subscript p is 1 and R 3 is hydrogen. In some embodiments, the subscript q is 1 and R 5 is hydrogen. In some embodiments, the index p is 2 and R 3 is hydrogen. In some embodiments, the subscript q is 2 and R 5 is hydrogen.

[0088] In some embodiments of any one of formulas (I), (II), and (IIa), the subscripts t and q are each 0, and the compound has the formula (IIa-1): [ka] where R 5 , R 6 , and R 7 is as defined herein in any aspect or embodiment described herein.

[0089] In some embodiments of any one of formulas (I), (III), and (IIIa), the subscripts t and q are each 0, and the compound has the formula (IIIa-1): [ka] where R 5 , R 6 , and R 7 is as defined herein in any aspect or embodiment described herein.

[0090] With respect to formula (IIa-1) or (IIIa-1), in some embodiments, R 5 is the side chain of an amino acid selected from the group consisting of alanine (Ala / A), glycine (Gly / G), isoleucine (Ile / I), leucine (Leu / L), valine (Val / V), and phenylalanine (Phe / F).

[0091] In some embodiments of formula (IIa-1) or (IIIa-1), R 6 and R 7 are independently hydrogen, C 1-6 Alkyl or C 2-6 In some embodiments, R is alkenyl. 6 and R 7 are each independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pentyl, or hexyl. 6 and R 7 are each hydrogen. In some embodiments, R 6 and R 7 are each methyl.

[0092] In some embodiments of formula (IIa-1) or (IIIa-1), R 6 is hydrogen, C 1-6 Alkyl or C 2-6 alkenyl, and R 7 is C 1-6 Alkyl-C(O)- or C 2-6 alkenyl-C(O)-. In some embodiments, R 7 is methyl-C(O)-, ethyl-C(O)-, propyl-C(O)-, isopropyl-C(O)-, butyl-C(O)-, pentyl-C(O)-, or hexyl-C(O)-. In some embodiments, R 6 is hydrogen and R 7 is —C(O)CH. In some embodiments, R 6 is methyl and R 7 is -C(O)CH3.

[0093] With respect to any one of formulas (I), (II), (IIa), (III), and (IIIa), L 1 is -C(O)- and R 1 is an aliphatic chain of a saturated fatty acid having 8 to 18 carbon atoms or an unsaturated fatty acid having 10 to 18 carbon atoms.

[0094] In some embodiments of any one of Formulas (I), (II), (IIa), (III), and (IIIa), L 1 is -C(O)- and R 1 is an aliphatic chain of a saturated fatty acid having 8 to 18 carbon atoms. In some embodiments, the saturated fatty acid having 8 to 18 carbon atoms is selected from the group consisting of caprylic acid, pelargonic acid, capric acid, neodecanoic acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, and isostearic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of caprylic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of pelargonic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of capric acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of neodecanoic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of undecylic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of lauric acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of tridecylic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of myristic acid. In some embodiments, L1 is -C(O)- and R 1 is the aliphatic chain of pentadecylic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of palmitic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of margaric acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of stearic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of isostearic acid.

[0095] In some embodiments of any one of Formulas (I), (II), (IIa), (III), and (IIIa), L 1 is -C(O)- and R 1 is an aliphatic chain of an unsaturated fatty acid having 10 to 18 carbon atoms. In some embodiments, the unsaturated fatty acid having 10 to 18 carbon atoms is a mono-unsaturated fatty acid having 10 to 18 carbon atoms, a di-unsaturated fatty acid having 18 carbon atoms, or a poly-unsaturated fatty acid having 18 carbon atoms.

[0096] In some embodiments of any one of Formulas (I), (II), (IIa), (III), and (IIIa), L 1 is -C(O)- and R 1 is an aliphatic chain of a mono-unsaturated fatty acid having 10 to 18 carbon atoms. In some embodiments, the mono-unsaturated fatty acid having 10 to 18 carbon atoms is selected from the group consisting of caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, and vaccinal acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of caproleic acid. In some embodiments, L 1 is -C(O)- and R 1is the aliphatic chain of lauroleic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of myristoleic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of palmitoleic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of sapienic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of oleic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of elaidic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of the vaccinal acid.

[0097] In some embodiments of any one of Formulas (I), (II), (IIa), (III), and (IIIa), L 1 is -C(O)- and R 1 is an aliphatic chain of a di-unsaturated fatty acid having 18 carbon atoms. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of linoleic acid.

[0098] In some embodiments of any one of Formulas (I), (II), (IIa), (III), and (IIIa), L 1 is -C(O)- and R 1 is the aliphatic chain of a poly-unsaturated fatty acid having 18 carbon atoms. In some embodiments, the poly-unsaturated fatty acid having 18 carbon atoms is selected from the group consisting of α-linolenic acid, γ-linolenic acid, columbic acid, pinolenic acid, and stearidonic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of α-linolenic acid. In some embodiments, L 1 is -C(O)- and R1 is the aliphatic chain of gamma-linolenic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of columbic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of pinolenic acid. In some embodiments, L 1 is -C(O)- and R 1 is the aliphatic chain of stearidonic acid.

[0099] Exemplary compounds of formula (I) are listed in Table 1. [Table 1-1] [Table 1-2]

[0100] In some embodiments, the compound of any one of Formulas (I), (II), and (IIa) has the formula: [ka] It has.

[0101] In some embodiments, the compound of any one of Formulas (I), (III), and (IIIa) has the formula: [ka] It has.

[0102] The compounds of the present invention can exist as salts. The present invention includes such salts. Examples of applicable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate or mixtures thereof, including racemic mixtures), succinate, benzoate, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art. Also included are base addition salts, such as sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of acceptable acid addition salts include hydrochloride, hydrobromide, nitric acid, carbonate, monohydrogen carbonate (monohydrogen carbonate), and the like. Included are salts derived from inorganic acids such as monohydrogencarbonic, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydriodic acid, or phosphorous acid, and from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as alginate, and salts of organic acids such as glucuronic acid or galacturonic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, which allow the compounds to be converted into either base or acid addition salts.

[0103] Other salts include acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of pharmaceutically acceptable salts are salts of mineral acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammonium salts (such as methyl iodide, ethyl iodide, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Further information about suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0104] Pharmaceutically acceptable salts include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, magnesium salts, or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as alginate, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0105] Preferably, the neutral forms of the compounds are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0106] Certain compounds of the present invention can exist in solvated forms, including hydrated forms, as well as non-solvated forms. Generally, solvated forms are equivalent to non-solvated forms and are included within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0107] Certain compounds of the present invention contain double bonds, and tautomers, geometric isomers, and individual isomers are encompassed within the scope of the present invention. Compounds of the present invention do not include those known in the art to be too unstable to synthesize and / or isolate.

[0108] Isomers include compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ in terms of the structural or steric arrangement of the atoms.

[0109] It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms. All tautomeric forms of such compounds are within the scope of the present invention. A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0110] Unless otherwise specified, the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds of the present invention may contain isotopes such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), fluorine-18( 18 F), nitrogen-15( 15 N), oxygen-17( 17 O), oxygen-18( 18 O), carbon-13( 13 C), or carbon-14 ( 14The compounds may be labeled with radioactive or stable isotopes, such as C. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0111] IV. Topical Preparations In another aspect, the present invention provides a topical formulation for treating vascular malformations, the topical formulation comprising: a) a compound having formula (I), and b) one or more topical excipients, wherein the compound having formula (I) is as defined and described herein.

[0112] In some embodiments, the one or more topical excipients are selected from the group consisting of one or more solvents, one or more penetration enhancers, one or more gelling agents, and combinations thereof.

[0113] As will be appreciated, some excipients in the topical formulations described herein may have multiple functions. For example, a given substance may act as both a solvent and a penetration enhancer. In some such cases, the function of a given substance can be considered to be single, even if the properties of the substance allow for multiple functions.

[0114] In some embodiments, the one or more solvents or penetration enhancers are C 2-6 Alcohol, C 2-6 Alkylene glycol, di-(C 2-6 Alkylene) glycol, polyethylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, DMSO, fatty alcohols, fatty acids, and fatty esters.

[0115] In some embodiments, the one or more solvents or penetration enhancers are C 2-6 In some embodiments, C 2-6The alcohol is selected from the group consisting of ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol, and combinations thereof. 2-6 The alcohol is ethanol or isopropanol. 2-6 The alcohol is ethanol. In some embodiments, the one or more solvents or penetration enhancers include ethanol. In some embodiments, the one or more solvents or penetration enhancers do not include ethanol.

[0116] In some embodiments, C 2-6 The alcohol is present in an amount of from 0% to about 80% by weight of the formulation. 2-6 No alcohol is present. In some embodiments, no ethanol is present.

[0117] In some embodiments, the one or more solvents or penetration enhancers are C 2-6 Alkylene glycol, di-(C 2-6 In some embodiments, the C 2-6 The alkylene glycol is propylene glycol. In some embodiments, the one or more solvents or penetration enhancers are di-(C 2-6 In some embodiments, the one or more solvents or penetration enhancers comprise glycols selected from di-(C alkylene) glycols, polyethylene glycols, or combinations thereof. 2-6 In some embodiments, C 2-6 The alkylene glycol is propylene glycol. In some embodiments, the di-(C 2-6In some embodiments, the polyethylene glycol is PEG 200, PEG 300, PEG 400, PEG 600, or PEG 900. In some embodiments, the one or more solvents or penetration enhancers include propylene glycol, dipropylene glycol, PEG 200, PEG 300, PEG 400, PEG 600, PEG 900, or a combination thereof. In some embodiments, the one or more solvents or penetration enhancers include dipropylene glycol, PEG 200, PEG 300, PEG 400, PEG 600, PEG 900, or a combination thereof. In some embodiments, the one or more solvents or penetration enhancers include dipropylene glycol. In some embodiments, the one or more solvents or penetration enhancers include dipropylene glycol and PEG 400.

[0118] In some embodiments, the glycol is present in an amount of about 5% to about 60% by weight of the base formulation. In some embodiments, the glycol is present in an amount of 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 20% to 60%, 20% to 50%, 20% to 40%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 60%, 40% to 50%, or 50% to 60% by weight of the base formulation. In some embodiments, the glycol is present in an amount of about 5% by weight of the base formulation. In some embodiments, the glycol is present in an amount of about 10% by weight of the base formulation. In some embodiments, the glycol is present in an amount of about 20% by weight of the base formulation. In some embodiments, the glycol is present in an amount of about 30% by weight of the base formulation. In some embodiments, the glycol is present in an amount of about 35% by weight of the base formulation. In some embodiments, the glycol is present in an amount of about 40% by weight of the base formulation. In some embodiments, the glycol is dipropylene glycol, PEG 400, or a combination thereof. In some embodiments, the glycol is dipropylene glycol. In some embodiments, the glycol is PEG 400. In some embodiments, the glycol is dipropylene glycol and PEG 400. In some embodiments, dipropylene glycol and / or PEG 400 are present in an amount of about 10% by weight of the base formulation. In some embodiments, dipropylene glycol and / or PEG 400 are present in an amount of about 20% by weight of the base formulation. In some embodiments, dipropylene glycol and / or PEG 400 are present in an amount of about 30% by weight of the base formulation. In some embodiments, dipropylene glycol and / or PEG 400 are present in an amount of about 35% by weight of the base formulation. In some embodiments, dipropylene glycol and / or PEG 400 is present in an amount of about 40% by weight of the base formulation, hi some embodiments, dipropylene glycol is present in an amount of about 5% by weight of the base formulation and PEG 400 is present in an amount of about 30% by weight of the base formulation.In some embodiments, dipropylene glycol is present in an amount of about 5% by weight of the base formulation and PEG 400 is present in an amount of about 35% by weight of the base formulation, hi some embodiments, dipropylene glycol is present in an amount of about 5% by weight of the base formulation and PEG 400 is present in an amount of about 40% by weight of the base formulation.

[0119] In some embodiments, the one or more solvents or penetration enhancers are C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol (i.e., transcutol). In some embodiments, the one or more solvents or penetration enhancers include 2-(2-ethoxyethoxy)ethanol.

[0120] In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in an amount of about 1% to about 50% by weight of the base formulation. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in an amount of 5% to 50%, 10% to 50%, 10% to 40%, or 10% to 30% by weight of the base formulation. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in an amount of about 20% by weight of the base formulation. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in an amount of about 25% by weight of the base formulation.

[0121] In some embodiments, the one or more solvents or penetration enhancers comprise a fatty alcohol. As used herein, the term "fatty alcohol" refers to a fatty alcohol that is saturated or unsaturated. In some embodiments, the fatty alcohol is a mixture of different fatty alcohols. In some embodiments, the fatty alcohol has an average of about 12-20, 14-20, 12-18, 14-18, or 16-18 carbon atoms. Suitable fatty alcohols include, but are not limited to, capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleic alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, or mixtures thereof. In some embodiments, the solvent or penetration enhancer comprises one or more fatty alcohols selected from capric alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, palmitoleic alcohol, stearyl alcohol, oleyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, and lignoceryl alcohol, hi some embodiments, the one or more solvent or penetration enhancer comprises oleyl alcohol.

[0122] In some embodiments, the fatty alcohol is present in an amount of about 0.5% to about 20% by weight of the base formulation. In some embodiments, the fatty alcohol is present in an amount of 1% to 20%, 1% to 15%, 1% to 10%, 5% to 20%, 5% to 15%, or 5% to 10% by weight of the base formulation. In some embodiments, the fatty alcohol is present in an amount of about 10% by weight of the base formulation. In some embodiments, oleyl alcohol is present in an amount of 0.5% to 20%, 1% to 20%, 1% to 15%, 1% to 10%, 5% to 20%, 5% to 15%, or 5% to 10% by weight of the base formulation. In some embodiments, oleyl alcohol is present in an amount of about 10% by weight of the base formulation.

[0123] In some embodiments, the one or more solvents or penetration enhancers comprise a fatty acid. As used herein, the term "fatty acid" refers to an aliphatic acid that is straight-chain or branched, saturated or unsaturated. In some embodiments, the fatty acid is a mixture of different fatty acids. In some embodiments, the fatty acid has an average of about 8 to about 30 carbon atoms. In some embodiments, the fatty acid has an average of about 12-20, 14-20, 12-18, 14-18, or 16-18 carbon atoms. Suitable fatty acids include capric acid, neodecanoic acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, isostearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, behenic acid, tricosylic acid, lignoceric acid, caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccinic acid, gadoleic acid, and einic acid. These include, but are not limited to, cosenoic acid, erucic acid, brassidic acid, nervonic acid, linoleic acid, eicosadienoic acid, docosadienoic acid, α-linolenic acid, γ-linolenic acid, columbic acid, pinolenic acid, α-eleostearic acid, β-eleostearic acid, mead acid, dihomo-γ-linolenic acid, eicosatrienoic acid, stearidonic acid, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, or mixtures thereof. In some embodiments, the fatty acid is selected from capric acid, neodecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, oleic acid, erucic acid, linoleic acid, linolenic acid, hydroxystearic acid, 12-hydroxystearic acid, cetostearic acid, isostearic acid, sesquioleic acid, sesqui-9-octadecanoic acid, sesquiisooctadecanoic acid, behenic acid, isobehenic acid, arachidonic acid, and combinations thereof.In some embodiments, the one or more solvents or penetration enhancers comprise one or more fatty acids selected from neodecanoic acid, isostearic acid, caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, and linolenic acid. In some embodiments, the one or more solvents or penetration enhancers comprise one or more fatty acids selected from neodecanoic acid, isostearic acid, and oleic acid. In some embodiments, the one or more solvents or penetration enhancers comprise neodecanoic acid. In some embodiments, the one or more solvents or penetration enhancers comprise isostearic acid. In some embodiments, the one or more solvents or penetration enhancers comprise oleic acid. In some embodiments, the one or more solvents or penetration enhancers comprise linoleic acid. In some embodiments, the one or more solvents or penetration enhancers comprise linoleic acid.

[0124] In some embodiments, the fatty acid is present in an amount of about 0.5% to about 15% by weight of the base formulation. In some embodiments, the fatty acid is present in an amount of 1% to 15%, 2% to 15%, 3% to 15%, 2% to 15%, 2% to 10%, or 5% to 15% by weight of the base formulation. In some embodiments, the oleic acid is present in an amount of about 0.5% to about 15% by weight of the base formulation. In some embodiments, the oleic acid is present in an amount of about 2% by weight of the base formulation. In some embodiments, the oleic acid is present in an amount of about 5% by weight of the base formulation. In some embodiments, the oleic acid is present in an amount of about 10% by weight of the base formulation.

[0125] In some embodiments, the one or more solvents or penetration enhancers comprise fatty esters, such as glyceryl fatty esters, ethylene glycol monoesters and diesters of fatty acids, propylene glycol monoesters and diesters of fatty acids, sorbitan esters, C6 fatty acids, and the like. 1-6 alkyl esters, adipic acid, sebacic acid, or a combination thereof di-(C 1-6 alkyl) esters.

[0126] In some embodiments, the fatty ester is a glyceride. In some embodiments, the glyceride is a monoglyceride, diglyceride, or triglyceride. The glyceride may optionally be substituted with a sulfonic acid group or a pharmaceutically acceptable salt thereof. Suitable fatty acids from which to derive the fatty acid glyceride include, but are not limited to, those described herein. In some embodiments, the glyceride is a monoglyceride of a fatty acid having 12 to 18 carbon atoms. In some embodiments, the glyceride is glyceryl stearate. In some embodiments, the glyceride is glycerol monolaurate, glycerol monocaprate, glycerol monocaprylate, glycerol monostearate, or glycerol monooleate. In some embodiments, the glyceride is glycerol monooleate. In some embodiments, the glyceride is a triglyceride of a fatty acid having 12 to 18 carbon atoms.

[0127] In some embodiments, one or more solvents or penetration enhancers comprise a glyceride. In some embodiments, one or more solvents or penetration enhancers comprise a monoglyceride. In some embodiments, one or more solvents or penetration enhancers comprise glycerol monooleate.

[0128] In some embodiments, the fatty ester is an ethylene glycol monoester of a fatty acid, a propylene glycol monoester of a fatty acid, or a C 1-6 In some embodiments, the fatty ester is an ethylene glycol monoester, a propylene glycol monoester, or a C alkyl ester of a fatty acid. 1-4 Alkyl esters. Ethylene glycol monoesters, propylene glycol monoesters, and C fatty acids 1-4Suitable fatty acids for obtaining any one of the alkyl esters include, but are not limited to, those described herein. In some embodiments, the fatty ester is an ethylene glycol monoester, a propylene glycol monoester, or a C6 fatty acid having 12 to 18 carbon atoms. 1-4 It is an alkyl ester. Non-limiting examples of esters of fatty acids include laurate, myristate, palmitate, stearate, or oleate. In some embodiments, the fatty ester is methyl laurate. In some embodiments, the fatty ester is isopropyl myristate. In some embodiments, the fatty ester is isopropyl palmitate. In some embodiments, the fatty ester is ethylene glycol monostearate. In some embodiments, the fatty ester is propylene glycol monostearate. In some embodiments, the fatty ester is ethylene glycol monooleate. In some embodiments, the fatty ester is propylene glycol monooleate.

[0129] In some embodiments, the fatty ester is a sorbitan ester. Suitable fatty acids for deriving sorbitan esters include, but are not limited to, those described herein. Suitable sorbitan esters include, but are not limited to, the Span™ series (available from Uniqema), including Span 20 (sorbitan monolaurate), 40 (sorbitan monopalmitate), 60 (sorbitan monostearate), 65 (sorbitan tristearate), 80 (sorbitan monooleate), and 85 (sorbitan trioleate).

[0130] In some embodiments, the fatty ester is a di-(C 1-4 alkyl) esters (i.e., adipates) or di-(C 1-4In some embodiments, the fatty ester is diisopropyl adipate. In some embodiments, the fatty ester is diethyl sebacate.

[0131] In some embodiments, the one or more solvents or penetration enhancers are di-(C 2-6 Alkylene) glycol, polyethylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the one or more solvents or penetration enhancers are selected from the group consisting of DMSO, oleic acid, oleyl alcohol, 2-(2-ethoxyethoxy)ethanol, dipropylene glycol, and PEG 400. In some embodiments, the one or more solvents or penetration enhancers are selected from the group consisting of DMSO, oleic acid, 2-(2-ethoxyethoxy)ethanol, dipropylene glycol, and PEG 400. In some embodiments, the one or more solvents or penetration enhancers are selected from the group consisting of DMSO, oleic acid, 2-(2-ethoxyethoxy)ethanol, dipropylene glycol, and PEG 400. In some embodiments, the one or more solvents or penetration enhancers are selected from the group consisting of DMSO, oleic acid, 2-(2-ethoxyethoxy)ethanol, dipropylene glycol, and PEG 400.

[0132] In some embodiments, the one or more solvents or penetration enhancers do not include DMSO. In some embodiments, the one or more solvents or penetration enhancers include DMSO. In some embodiments, DMSO is present in an amount less than 50%, less than 40%, less than 30%, or less than 20% by weight of the base formulation. In some embodiments, DMSO is present in an amount between 30% and 50%, 20% and 50%, 10% and 50%, 30% and 40%, 20% and 40%, 10% and 40%, 20% and 30%, 10% and 30%, or 10% and 20% by weight of the base formulation. In some embodiments, DMSO is present in an amount between 30% and 50%, 20% and 50%, 30% and 40%, 20% and 40%, or 20% and 30% by weight of the base formulation. In some embodiments, DMSO is present in an amount of 20% to 40% or 20% to 30% by weight of the base formulation, hi some embodiments, DMSO is present in an amount of about 30% by weight of the base formulation.

[0133] Polymer thickeners (gelling agents) that can be used in the present invention include those known to those skilled in the art, such as hydrophilic and hydroalcoholic gelling agents frequently used in the cosmetics and pharmaceutical industries. In some embodiments, the one or more gelling agents are carbopol (now known as carbomer), carboxymethylcellulose, ethylcellulose, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, magnesium aluminum silicate (Veegum), methylcellulose, poloxamer (Pluronics), polyvinyl alcohol, sodium alginate, tragacanth, xanthan gum, or combinations thereof. In some embodiments, the one or more gelling agents include hydroxypropylcellulose. In some embodiments, the hydroxypropyl cellulose has a molecular weight selected from the group consisting of 40,000 Da, 80,000 Da, 100,000 Da, 140,000 Da, 180,000 Da, 280,000 Da, 370,000 Da, 700,000 Da, 850,000 Da, 1,000,000 Da, 1,150,000 Da, and 2,500,000 Da. In some embodiments, the hydroxypropyl cellulose has a molecular weight selected from the group consisting of 140,000 Da, 180,000 Da, 280,000 Da, 370,000 Da, 700,000 Da, 850,000 Da, 1,000,000 Da, and 1,150,000 Da. In some embodiments, the hydroxypropyl cellulose has a molecular weight selected from the group consisting of 700,000 Da, 850,000 Da, 1,000,000 Da, and 1,150,000 Da.

[0134] Hydroxypropyl cellulose (HPC) as described herein includes Nisso SSL, Nisso SL, Nisso L, Nisso LM, Nisso LMM, Nisso M, Nisso H, Nisso VH, Klucel ELF, Klucel EF, Klucel LF, Klucel JF, Klucel GF, Klucel MF, and Klucel HF. Nisso SSL has an average molecular weight of 40,000 Da, Nisso SL has an average molecular weight of 100,000 Da, Nisso L has an average molecular weight of 140,000 Da, Nisso LM has an average molecular weight of 180,000 Da, Nisso LMM has an average molecular weight of 280,000 Da, Nisso M has an average molecular weight of 700,000 Da, Nisso H has an average molecular weight of 1,000,000 Da, and Nisso VH has an average molecular weight of 2,500,000 Da. Suitable particle sizes for Nisso HPC (i.e., Nisso SSL, Nisso SL, Nisso L, Nisso LM, Nisso LMM, Nisso M, Nisso H, and Nisso VH) in topical formulations include regular powder (40 mesh), fine powder (100 mesh), and ultrafine powder (300 mesh). See the Technical Data Sheet for Nisso HPC, which is incorporated herein by reference in its entirety for all purposes. In some embodiments, the hydroxypropyl cellulose is Nisso H. Klucel ELF has an average molecular weight of 40,000 Da, Klucel EF has an average molecular weight of 80,000 Da, Klucel LF has an average molecular weight of 95,000 Da, Klucel JF has an average molecular weight of 140,000 Da, Klucel GF has an average molecular weight of 370,000 Da, Klucel MF has an average molecular weight of 850,000 Da, and Klucel HF has an average molecular weight of 1,150,000 Da. Suitable particle sizes of Klucel HPC in topical formulations include regular grade and fine grade. See the Klucel HPC product technical data sheet, which is incorporated herein by reference in its entirety for all purposes. In some embodiments, the hydroxypropyl cellulose is Klucel HF.

[0135] When one or more gelling agents are present, in some embodiments, the topical formulation has a viscosity of 5,000-100,000 cP. When one or more gelling agents are present, in some embodiments, the topical formulation has a viscosity of 5,000-50,000 cP. When one or more gelling agents are present, in some embodiments, the topical formulation has a viscosity of 5,000-15,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the topical formulation has a viscosity of 5,000-100,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the topical formulation has a viscosity of 5,000-50,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the topical formulation has a viscosity of 5,000-15,000 cP.

[0136] In some embodiments, the one or more gelling agents are present in an amount of about 0.5% to about 30% by weight of the base formulation, while the topical formulation has a viscosity of 5,000 to 100,000 cP. In some embodiments, the one or more gelling agents are present in an amount of about 0.5% to about 30% by weight of the base formulation, while the topical formulation has a viscosity of 5,000 to 50,000 cP. In some embodiments, the one or more gelling agents are present in an amount of about 0.5% to about 30% by weight of the base formulation, while the topical formulation has a viscosity of 5,000 to 15,000 cP. In some embodiments, the hydroxypropyl cellulose is present in an amount of about 0.5% to about 5%, about 5% to about 10%, about 10% to about 20%, or about 20% to about 30% by weight of the base formulation, while the topical formulation has a viscosity of 5,000 to 100,000 cP. When hydroxypropyl cellulose having an average molecular weight of less than 700,000 Da is used, in some embodiments, the hydroxypropyl cellulose is present in an amount of about 5% to about 30% by weight of the base formulation, while the topical formulation has a viscosity of 5,000 to 100,000 cP. In some embodiments, the hydroxypropyl cellulose is present in an amount of 0.5% to 4%, 0.5% to 3%, 0.5% to 2%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, or 2% to 5% by weight of the base formulation, while the topical formulation has a viscosity of 5000 to 15000 cP. In some embodiments, the hydroxypropyl cellulose having an average molecular weight selected from 700,000 Da to 1,150,000 Da is present in an amount of about 2% by weight of the base formulation. In some embodiments, the hydroxypropyl cellulose having an average molecular weight selected from 700,000 Da to 1,150,000 Da is present in an amount of about 1% by weight of the base formulation.

[0137] In some embodiments, the topical formulation includes a stabilizer. The stabilizers described herein include agents or buffers that stabilize the formulation. Suitable buffers for use in the present invention include, but are not limited to, acetate buffer, citrate buffer, phosphate buffer, lactate buffer, and borate buffer. Suitable agents for stabilizing the formulation include antioxidants. Suitable antioxidants for use in the present invention include, but are not limited to, citric acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, coenzyme Q10 (CoQ10), idebenone, lycopene, ascorbic acid, epigallocatechin-3-gallate (EGCG), and silymarin.

[0138] In some embodiments, the topical formulation is substantially free of oxygen.

[0139] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is in anhydrous form. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is in hydrated form. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a mixture of anhydrous and hydrate forms.

[0140] In some embodiments, the compound of formula (I) used to prepare the topical formulations of the present invention is in a salt-free form.

[0141] In some embodiments, the compound of Formula (I) is present in an amount of 0.05% to 15%, 0.5% to 12%, 0.5% to 10%, 1% to 10%, 2% to 10%, 5% to 10%, or 2% to 5% by weight of the base formulation on an anhydrous basis. In some embodiments, the compound of Formula (I) is present in an amount of about 1% by weight of the base formulation on an anhydrous basis. In some embodiments, the compound of Formula (I) is present in an amount of about 5% by weight of the base formulation on an anhydrous basis. In some embodiments, the compound of Formula (I) is present in an amount of about 10% by weight of the base formulation on an anhydrous basis. In some embodiments, the compound of Formula (I) is present in a saturation concentration in the topical formulation.

[0142] In some embodiments, ethanol is not present in the topical formulation. In some embodiments, DMSO is not present in the topical formulation.

[0143] In some embodiments, the topical formulation (FI) comprises: a) 0.5% to 10% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 50% to 90% by weight of C 2-6 alcohol, c) 1% to 15% by weight of a fatty acid, a fatty alcohol, a fatty ester, or a combination thereof; d) 5% to 15% by weight of C 2-6 Alkylene glycol, di-(C 2-6 alkylene) glycol, polyethylene glycol, or a combination thereof, and e) 0% to 5% by weight of hydroxypropyl cellulose; Here, the total weight of one or more topical excipients b) to d) is taken as 100%.

[0144] In some embodiments, the topical formulation (FI-1) comprises: a) 0.5% to 10% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 60% to 90% by weight of C 2-6 alcohol, c) 1% to 15% by weight of a fatty acid, and d) 5 wt% to 15 wt% of di-(C 2-6 alkylene) glycol, where the total weight of one or more topical excipients b) through d) is 100%.

[0145] In some embodiments, the topical formulation (FI-2) comprises: a) 0.5% to 10% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 60% to 90% by weight of C 2-6 alcohol, c) 1% to 15% by weight of a fatty acid; d) 5 wt% to 15 wt% of di-(C 2-6 alkylene) glycols, and e) 1% to 3% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) to d) is 100%.

[0146] In some embodiments, the topical formulation (FI-3) comprises: a) 0.5% to 10% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 60% to 90% by weight of C 2-6 alcohol, c) 1% to 15% by weight of a fatty alcohol; d) 5 wt% to 15 wt% of di-(C 2-6 alkylene) glycols, and e) 1% to 3% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) to d) is 100%.

[0147] In some embodiments, the topical formulation (FI-4) comprises: a) 0.5% to 10% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 60% to 90% by weight of C 2-6 alcohol, c) 1% to 15% by weight of a fatty ester; d) 5 wt% to 15 wt% of di-(C 2-6 alkylene) glycols, and e) 1% to 3% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) to d) is 100%.

[0148] In some embodiments of any one of the above formulations (FI), (FI-1), (FI-2), (FI-3), and (FI-4), C 2-6 The alcohol is ethanol, the fatty acid is oleic acid, the fatty alcohol is oleyl alcohol, the fatty ester is glycerol monooleate, and the di-(C 2-6 The alkylene glycol is dipropylene glycol, and the hydroxypropyl cellulose is Klucel HF.

[0149] In some embodiments, the topical formulation (FII) comprises: a) 0.5% to 15% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 20% to 30% by weight of DMSO; c) 2% to 15% by weight of a fatty acid, a fatty alcohol, a fatty ester, or a combination thereof; d) 10% to 30% by weight of C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, e) 30% to 50% by weight of C 2-6 Alkylene glycol, di-(C 2-6 alkylene) glycol, polyethylene glycol, or a combination thereof, and f) 0.5% to 5% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) to e) is 100%.

[0150] In some embodiments, the topical formulation (FII-1) comprises: a) 0.5% to 15% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 20% to 30% by weight of DMSO; c) 5% to 15% by weight of a fatty acid, a fatty alcohol, a fatty ester, or a combination thereof; d) 10% to 30% by weight of C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, e) 30% to 50% by weight of C 2-6 Alkylene glycol, di-(C 2-6 alkylene) glycol, polyethylene glycol, or a combination thereof, and f) 0.5% to 5% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) to e) is 100%.

[0151] In some embodiments, the topical formulation (FII-2) comprises: a) 0.5% to 15% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 20% to 30% by weight of DMSO; c) 5% to 15% by weight of a fatty acid; d) 10% to 30% by weight of C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, e) 30 wt% to 50 wt% of di-(C 2-6 alkylene glycols, and f) 0.5% to 5% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) to e) is 100%.

[0152] In some embodiments, the topical formulation (FII-3) comprises: a) 0.5% to 15% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 20% to 30% by weight of DMSO; c) 5% to 15% by weight of a fatty alcohol; d) 10% to 30% by weight of C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, e) 30 wt% to 50 wt% of di-(C 2-6 alkylene) glycols, and f) 0.5% to 5% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) to e) is 100%.

[0153] In some embodiments, the topical formulation (FII-4) comprises: a) 0.5% to 15% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 20% to 30% by weight of DMSO; c) 2% to 15% by weight of a fatty acid or a fatty alcohol; d) 10% to 30% by weight of C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, e) 30 wt% to 50 wt% of di-(C 2-6 alkylene) glycols and polyethylene glycols, and f) 0.5% to 5% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) to e) is 100%.

[0154] In some embodiments, the topical formulation (FII-5) comprises: a) 0.5% to 15% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 20% to 30% by weight of DMSO; c) 2% to 15% by weight of a fatty acid or a fatty alcohol; d) 10% to 30% by weight of C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, e) 3 wt% to 10 wt% of di-(C 2-6 alkylene) glycols, f) 25% to 45% by weight of polyethylene glycol, and g) 0.5% to 5% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) to f) is 100%.

[0155] In some embodiments, the topical formulation (FII-6) comprises: a) 0.5% to 15% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 20% to 30% by weight of DMSO; c) 2% to 15% by weight of a fatty acid or a fatty alcohol; d) 10% to 30% by weight of C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, e) 3 wt% to 5 wt% of di-(C 2-6 alkylene) glycols, f) 25% to 45% by weight of polyethylene glycol, and g) 0.5% to 5% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) to f) is 100%.

[0156] In some embodiments of any one of Formulations (FII) through (FII-6), the fatty acid is oleic acid, the fatty alcohol is oleyl alcohol, and the fatty ester is glycerol monooleate; 1-3 Alkyl-(OCH2CH2) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol (Transcutol), and di-(C 2-6The alkylene glycol is dipropylene glycol, the polyethylene glycol is PEG400, and the hydroxypropyl cellulose is Klucel HF.

[0157] In some embodiments, the topical formulation (FII-7) comprises: a) 0.5% to 15% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 20% to 30% by weight of DMSO; c) 5% to 15% by weight of oleic acid; d) 10% to 30% by weight of 2-(2-ethoxyethoxy)ethanol; e) 30% to 50% by weight of dipropylene glycol, and f) 0.5% to 5% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) to e) is 100%.

[0158] In some embodiments, the topical formulation (FII-8) comprises: a) about 10% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) about 30% by weight of DMSO; c) about 10% by weight of oleic acid; d) about 20% by weight of 2-(2-ethoxyethoxy)ethanol; e) about 40% by weight of dipropylene glycol, and f) about 2% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) through e) is 100%.

[0159] In some embodiments, the topical formulation (FII-9) comprises: a) about 10% by weight, on a salt-free and anhydrous basis, of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenylacetate or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) about 30% by weight of DMSO; c) about 10% by weight of oleic acid; d) about 20% by weight of 2-(2-ethoxyethoxy)ethanol; e) about 40% by weight of dipropylene glycol, and f) about 2% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) through e) is 100%.

[0160] In some embodiments, the topical formulation (FII-10) comprises: a) about 10% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) about 30% by weight of DMSO; c) about 10% by weight of oleic acid; d) about 20% by weight of 2-(2-ethoxyethoxy)ethanol; e) about 40% by weight of dipropylene glycol, and f) about 1% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) through e) is 100%.

[0161] In some embodiments, the topical formulation (FII-11) comprises: a) about 10% by weight, on a salt-free and anhydrous basis, of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenylacetate or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) about 30% by weight of DMSO; c) about 10% by weight of oleic acid; d) about 20% by weight of 2-(2-ethoxyethoxy)ethanol; e) about 40% by weight of dipropylene glycol, and f) about 1% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) through e) is 100%.

[0162] In some embodiments, the topical formulation (FII-12) comprises: a) 0.5% to 15% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 20% to 30% by weight of DMSO; c) 2% to 15% by weight of oleic acid or oleyl alcohol; d) 10% to 30% by weight of 2-(2-ethoxyethoxy)ethanol; e) 3% to 5% by weight of dipropylene glycol; f) 25% to 45% by weight of PEG 400, and g) 0.5% to 5% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) to f) is 100%.

[0163] In some embodiments, the topical formulation (FII-13) comprises: a) about 10% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) about 30% by weight of DMSO; c) about 10% by weight of oleyl alcohol; d) about 20% by weight of 2-(2-ethoxyethoxy)ethanol; e) about 5% by weight of dipropylene glycol; f) about 35% by weight of PEG 400, and g) about 2% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) through f) is 100%.

[0164] In some embodiments, the topical formulation (FII-14) comprises: a) about 10% by weight, on a salt-free and anhydrous basis, of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenylacetate or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) about 30% by weight of DMSO; c) about 10% by weight of oleyl alcohol; d) about 20% by weight of 2-(2-ethoxyethoxy)ethanol; e) about 5% by weight of dipropylene glycol; f) about 35% by weight of PEG 400, and g) about 2% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) through f) is 100%.

[0165] In some embodiments, the topical formulation (FII-15) comprises: a) about 10% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) about 33% by weight of DMSO; c) about 2% by weight of oleic acid; d) about 22% by weight of 2-(2-ethoxyethoxy)ethanol; e) about 5% by weight of dipropylene glycol; f) about 38% by weight of PEG 400, and g) about 2% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) through f) is 100%.

[0166] In some embodiments, the topical formulation (FII-16) comprises: a) about 10% by weight, on a salt-free and anhydrous basis, of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenylacetate or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) about 30% by weight of DMSO; c) about 10% by weight of oleyl alcohol; d) about 20% by weight of 2-(2-ethoxyethoxy)ethanol; e) about 5% by weight of dipropylene glycol; f) 35% by weight of PEG 400, and g) about 2% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) through f) is 100%.

[0167] In some embodiments, the topical formulation (FII-17) comprises: a) about 10% by weight, on a salt-free and anhydrous basis, of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenylacetate or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) about 33% by weight of DMSO; c) about 2% by weight of oleic acid; d) about 22% by weight of 2-(2-ethoxyethoxy)ethanol; e) about 5% by weight of dipropylene glycol; f) 38% by weight of PEG 400, and g) about 2% by weight of hydroxypropylcellulose, where the total weight of one or more topical excipients b) through f) is 100%.

[0168] In some embodiments of any one of the above formulations (FII-7) through (FII-17), the hydroxypropyl cellulose is Klucel HF.

[0169] In some embodiments, hydroxypropyl cellulose is absent from any one of the above formulations (FII), (FII-1) through (FII-17).

[0170] In some embodiments, the topical formulation (FIII) comprises: a) 0.5% to 15% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 20% to 30% by weight of DMSO; c) 5% to 15% by weight of a fatty acid, a fatty alcohol, a fatty ester, or a combination thereof; d) 10% to 30% by weight of C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, and e) 30% to 50% by weight of C 2-6 Alkylene glycol, di-(C 2-6 alkylene) glycol, polyethylene glycol, or a combination thereof, where the total weight of one or more topical excipients b) through e) is 100%.

[0171] In some embodiments, the topical formulation (FIII-1) comprises: a) 0.5% to 15% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 20% to 30% by weight of DMSO; c) 5% to 15% by weight of a fatty acid; d) 10% to 30% by weight of C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, and e) 30 wt% to 50 wt% of di-(C 2-6 alkylene) glycol, where the total weight of one or more topical excipients b) through e) is 100%.

[0172] In some embodiments of any one of formulations (FIII) and (FIII-1), the fatty acid is oleic acid, the fatty alcohol is oleyl alcohol, and the fatty ester is glycerol monooleate; 1-3 Alkyl-(OCH2CH2) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol (Transcutol), and di-(C 2-6 The alkylene glycol is dipropylene glycol.

[0173] In some embodiments, the topical formulation (FIII-2) comprises: a) 0.5% to 15% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) 20% to 30% by weight of DMSO; c) 5% to 15% by weight of oleic acid; d) 10% to 30% by weight of 2-(2-ethoxyethoxy)ethanol, and e) 30% to 50% by weight of dipropylene glycol, where the total weight of one or more topical excipients b) through e) is 100%.

[0174] In some embodiments, the topical formulation (FIII-3) comprises: a) about 3% by weight, on a salt-free and anhydrous basis, of a compound of formula (I) or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) about 30% by weight of DMSO; c) about 10% by weight of oleic acid; d) about 20% by weight of 2-(2-ethoxyethoxy)ethanol, and e) about 40% by weight of dipropylene glycol, where the total weight of one or more topical excipients b) through e) is 100%.

[0175] In some embodiments, the topical formulation (FIII-4) comprises: a) about 10% by weight, on a salt-free and anhydrous basis, of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenylacetate or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof; b) about 30% by weight of DMSO; c) about 10% by weight of oleic acid; d) about 20% by weight of 2-(2-ethoxyethoxy)ethanol, and e) about 40% by weight of dipropylene glycol, where the total weight of one or more topical excipients b) through e) is 100%.

[0176] In some embodiments of any one of the above formulations (FIII-2) through (FIII-4), the topical formulation further comprises tocopherol.

[0177] In some embodiments, the topical formulations described herein have a clear, transparent, or monophasic visual appearance. In some embodiments, the visual appearance of the topical formulation is maintained for 10 days at a temperature of 80° C. In some embodiments, the visual appearance of the topical formulation is maintained for 6 months at a temperature of 40° C. and 75% relative humidity.

[0178] When one or more gelling agents are present, the topical gel formulations described herein have a stable viscosity at a temperature of 80° C. for 10 days or at a temperature of 40° C. and 75% relative humidity for 6 months. In some embodiments, the viscosity of the topical gel formulation remains between 5,000 and 100,000 cps for 10 days at a temperature of 80° C. or for 6 months at a temperature of 40° C. and 75% relative humidity. In some embodiments, the viscosity of the topical gel formulation remains between 5,000 and 50,000 cps for 10 days at a temperature of 80° C. or for 6 months at a temperature of 40° C. and 75% relative humidity. In some embodiments, the viscosity of the topical gel formulation remains between 5,000 and 15,000 cps for 10 days at a temperature of 80° C. or for 6 months at a temperature of 40° C. and 75% relative humidity.

[0179] The purity of the compound of Formula (I) in the formulation can be determined by analytical methods, such as HPLC. In some embodiments, the compound of Formula (I) has a purity of 95% to 105% of that present in the topical formulation at time zero (i.e., day 0).

[0180] The topical formulations described herein provide suitable physical stability of the compound of Formula (I) over 10 days at 80°C or over 6 months at 40°C and 75% relative humidity. In some embodiments, the relative purity of the compound of Formula (I) in the formulation decreases by less than 10% over 10 days at 80°C or over 6 months at 40°C and 75% relative humidity. In some embodiments, the relative purity of the compound of Formula (I) in the formulation decreases by less than 5% over 10 days at 80°C or over 6 months at 40°C and 75% relative humidity. In some embodiments, the relative purity of the compound of Formula (I) in the formulation decreases by less than 2% over 10 days at 80°C or over 6 months at 40°C and 75% relative humidity. In some embodiments, the relative purity of the compound of Formula (I) in the formulation decreases by less than 1% over 10 days at 80°C or over 6 months at 40°C and 75% relative humidity.

[0181] It is believed that compounds of formula (I) can be hydrolyzed to the corresponding compounds of formula (IV) under certain conditions, as shown below. [ka] In the formula, the subscripts m and L 1 , and R 1 is as defined and described herein.

[0182] In some embodiments, the hydrolysis of the compound having formula (I) in a formulation to the corresponding compound having formula (IV) is less than 10% over a period of 10 days at 80° C. or over a period of 6 months at 40° C. and 75% relative humidity. In some embodiments, the hydrolysis of the compound having formula (I) in a formulation to the corresponding compound having formula (IV) is less than 5% over a period of 10 days at 80° C. or over a period of 6 months at 40° C. and 75% relative humidity. In some embodiments, the hydrolysis of the compound having formula (I) in a formulation to the corresponding compound having formula (IV) is less than 2% over a period of 10 days at 80° C. or over a period of 6 months at 40° C. and 75% relative humidity. In some embodiments, the hydrolysis of the compound having formula (I) in a formulation to the corresponding compound having formula (IV) is less than 1% over a period of 10 days at 80° C. or over a period of 6 months at 40° C. and 75% relative humidity.

[0183] The topical formulations described herein provide enhanced skin permeability compared to a compound of Formula (IV) in a formulation with the same composition (i.e., the same one or more topical excipients). Skin permeability can be assessed by skin permeation rate experiments in various animal skin models. In some embodiments, the skin permeation rate of a compound of Formula (I) is increased by 2-5 times compared to the skin permeation rate of a corresponding compound of Formula (IV) in the same topical formulation. In some embodiments, the skin permeation rate of a compound of Formula (I) is increased by about 2-fold compared to the skin permeation rate of a corresponding compound of Formula (IV) in the same topical formulation.

[0184] In some embodiments, the compound of Formula (I) in the formulation has Formula (IIa): [ka] In the formula, R 1 or L 1 -R 1 -C(O)R as 1 is as defined and described herein.

[0185] In some embodiments, the compound of Formula (I) in the formulation is represented by any one of Formulas (IIb), (IIc), and (IId). [ka] In the formula, R 1 is as defined herein in any aspect or embodiment described herein.

[0186] In some embodiments, the compound of Formula (I) in the formulation has the formula: [ka]

[0187] In some embodiments, the compound of Formula (I) in the formulation has Formula (IIIa): [ka] In the formula, R 1 or L 1 -R 1 -C(O)-R as 1 is as defined herein in any aspect or embodiment described herein.

[0188] In some embodiments, the compound of Formula (I) in the formulation is represented by any one of Formulas (IIIb), (IIIc), and (IIId). [ka] In the formula, R 1 is as defined herein in any aspect or embodiment described herein.

[0189] In some embodiments, the compound of Formula (I) in the formulation has the formula: [ka]

[0190] In some embodiments, the hydrolysis of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl acetate to 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol in the formulation is less than 10% over a period of 10 days at 80° C. or over a period of 6 months at 40° C. and 75% relative humidity. In some embodiments, the hydrolysis of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl acetate to 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol in the formulation is less than 5% over a period of 10 days at 80° C. or over a period of 6 months at 40° C. and 75% relative humidity. In some embodiments, the hydrolysis of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl acetate to 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol in the formulation is less than 2% over a period of 10 days at 80° C. or over a period of 6 months at 40° C. and 75% relative humidity. In some embodiments, the hydrolysis of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl acetate to 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol in the formulation is less than 1% over a period of 10 days at 80° C. or over a period of 6 months at 40° C. and 75% relative humidity.

[0191] In some embodiments, the hydrolysis of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)benzyl acetate to (3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl)methanol in the formulation is less than 10% over a period of 10 days at a temperature of 80° C. or over a period of 6 months at a temperature of 40° C. and 75% relative humidity. In some embodiments, the hydrolysis of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)benzyl acetate to (3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl)methanol in the formulation is less than 5% over a period of 10 days at a temperature of 80° C. or over a period of 6 months at a temperature of 40° C. and 75% relative humidity. In some embodiments, the hydrolysis of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)benzyl acetate to (3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl)methanol in the formulation is less than 2% over a period of 10 days at 80° C. or over a period of 6 months at 40° C. and 75% relative humidity. In some embodiments, the hydrolysis of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)benzyl acetate to (3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl)methanol in the formulation is less than 1% over a period of 10 days at 80° C. or over a period of 6 months at 40° C. and 75% relative humidity.

[0192] The topical formulation used to deliver the compounds of formula (I) may be a lotion, spray, ointment, cream, gel, paste, or patch.

[0193] In some embodiments, the topical formulation used to deliver the compound of Formula (I) is a lotion or cream. Topical formulations and the creams and lotions that can be used to prepare them are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 282-291 (Alfonso R. Gennaro ed. 19th ed. 1995), which is incorporated herein by reference.

[0194] In some embodiments, the topical formulation used to deliver the compound of Formula (I) is a gel, such as a two-phase gel or a single-phase gel. A gel is a semi-solid system consisting of a suspension of small inorganic particles or large organic molecules interpenetrated by a liquid. If the gel mass contains a network of small, discrete inorganic particles, it is classified as a two-phase gel. A single-phase gel consists of organic macromolecules uniformly dispersed throughout a liquid, with no clear boundary between the dispersed macromolecules and the liquid. Gels suitable for use in the present invention are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1517-1518 (Alfonso R. Gennaro ed. 19th ed. 1995), which is incorporated herein by reference. Other suitable gels for use in the present invention are disclosed in U.S. Patent No. 6,387,383, issued May 14, 2002, U.S. Patent No. 6,517,847, issued February 11, 2003, and U.S. Patent No. 6,468,989, issued October 22, 2002, each of which is incorporated herein by reference.

[0195] In some embodiments, the topical formulation used to deliver the compound of Formula (I) is an ointment. An ointment is an oily semi-solid that contains little, if any, water. In some examples, the ointment is based on a hydrocarbon, such as wax, petrolatum, or gelled mineral oil. Ointments suitable for use in the present invention are well known in the art and are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1585-1591 (Alfonso R. Gennaro ed. 19th ed. 1995), which is incorporated herein by reference.

[0196] In some embodiments, topical administration can be achieved in the form of a patch containing the topical formulations described herein. In some embodiments, the patch is applied to the affected area of ​​the skin. In some embodiments, the patch is applied to an area of ​​the skin adjacent to the affected area.

[0197] V. Method In a third aspect, the present invention provides a method for treating vascular malformations through the inhibition of phosphoinositide-3-kinase (PI3K), comprising administering to a subject in need thereof a topical formulation comprising an effective amount of a compound of formula (I) and one or more topical excipients.

[0198] As used herein, the term "vascular malformation" refers to a non-malignant congenital abnormality of blood and / or lymphatic vessels that may be apparent at birth or that may not be apparent at birth and may appear weeks, months, or years later. In some embodiments, the vascular malformation is not a hemangioma. In certain non-limiting embodiments, the vascular malformation is characterized by the presence of a single endothelial layer forming dilated blood vessels of various diameters, surrounded by a disorganized mural cell layer containing both smooth muscle cells and pericytes.

[0199] In some embodiments, the vascular malformation can be a venous malformation, an arterial malformation, an arteriovenous malformation, or a lymphatic malformation. In certain non-limiting embodiments, the subject is suffering from a vascular malformation.

[0200] Vascular malformations can be present in or adjacent to a variety of parts of the body, including but not limited to organs such as the central nervous system (brain, spinal cord), skin, eyes (including but not limited to the retina), ears, (facial) sinuses, lungs, heart, liver, gallbladder, spleen, digestive system (esophagus, stomach, duodenum, intestines, colon, rectum), pancreas, kidneys, bladder, ovaries, testes, joints, nose, lips, etc.

[0201] In some embodiments, the subject is suffering from a malignancy.

[0202] In some embodiments, the subject is not known to be afflicted with a malignancy.

[0203] In some embodiments, the subject is afflicted with a multisystem genetic disorder.

[0204] In some embodiments, the subject is not known to be afflicted with a multisystem genetic disorder.

[0205] In some embodiments, the subject suffers from at least one vascular malformation for which surgical treatment is deemed to be high-risk. These would include vascular malformations in areas that, due to their location, are difficult to access without substantial risk of morbidity or mortality (e.g., but not limited to, malformations within the brain, e.g., the brainstem), and malformations in debilitated subjects for which surgery is contraindicated. Furthermore, in the presence of multiple lesions, medical treatment may be preferable to surgical options due to overall risk, efficacy, or risk of recurrence.

[0206] In some embodiments, the subject is at risk for the development or recurrence of a vascular malformation, for example, due to genetics and / or a pre-existing lesion.

[0207] In some embodiments, the topical formulation is administered locally to the site of the vascular malformation, hi some embodiments, the topical formulation is administered locally as a lotion, spray, ointment, cream, gel, paste, or patch.

[0208] After topical delivery, the compound of formula (I) is believed to be converted to the corresponding compound of formula (IV), as shown below. [ka] In the formula, the subscripts m and L 1 , and R 1 is as defined and described herein.

[0209] In some embodiments, the methods of the present invention involve the local administration of a topical formulation comprising a compound of formula (I) capable of inhibiting one or more of the phosphoinositide 3-kinase enzymes that are part of the PI3K / AKT pathway, thereby providing a beneficial therapeutic effect for the treatment of vascular malformations.

[0210] In some embodiments, the methods of the present invention comprise topical administration of a topical formulation comprising a compound of formula (I), wherein the compound of formula (I) is substantially converted to the corresponding compound of formula (IV), which is capable of inhibiting one or more of the phosphoinositide 3-kinase enzymes that are part of the PI3K / AKT pathway, thereby providing a beneficial therapeutic effect for the treatment of vascular malformations.

[0211] In some embodiments, after passing through the skin, the conversion of the compound having Formula (I) to the corresponding compound having Formula (IV) is at least 50% over 24 hours. In some embodiments, after passing through the skin, the conversion of the compound having Formula (I) to the corresponding compound having Formula (IV) is 50% to 99%, 60% to 90%, or 70% to 90% over 24 hours. In some embodiments, after passing through the skin, the conversion of the compound having Formula (I) to the corresponding compound having Formula (IV) is about 85% over 24 hours.

[0212] When the compound having Formula (I) is delivered via a non-topical route, in some embodiments, the conversion of the compound having Formula (I) to the corresponding compound having Formula (IV) in the subject is at least 50% over a 24-hour period. In some embodiments, the conversion of the compound having Formula (I) to the corresponding compound having Formula (IV) in the subject is 50% to 99%, 60% to 90%, or 70% to 90% over a 24-hour period. In some embodiments, the conversion of the compound having Formula (I) to the corresponding compound having Formula (IV) in the subject is about 85% over a 24-hour period.

[0213] In some embodiments, the compound of Formula (I) in the formulation used in the methods of the invention is any one of Formulas (II), (IIa), (IIb), (IIc), (IId), (IIa-1), (IIIa), (IIIb), (IIIc), (IIId), and (IIIa-1). In some embodiments, the compound of Formula (I) in the formulation used in the methods of the invention is 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenylacetate. In some embodiments, the compound of Formula (I) in the formulation used in the methods of the invention is 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)benzylacetate.

[0214] In some embodiments, the methods of the present invention involve locally administering a topical formulation comprising 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenylacetate, which is converted to 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol, which inhibits the PI3K / AKT pathway, thereby treating a vascular malformation.

[0215] In some embodiments, the methods of the present invention involve locally administering a topical formulation comprising 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)benzyl acetate, which is converted to (3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl)methanol, which inhibits the PI3K / AKT pathway, thereby treating the vascular malformation.

[0216] The therapeutic methods of the present invention may be administered alone or in combination with other forms of medical and / or surgical treatment. Non-limiting examples of medical treatments and / or drugs include, but are not limited to, treatment with one or more of antiangiogenic agents, steroids, mTOR inhibitors, beta-blockers (e.g., propranolol), and / or blood pressure-lowering drugs. In certain embodiments, "in combination" means that a PI3K / Akt pathway inhibitor and another pharmaceutical agent, such as an mTOR inhibitor, are administered to a subject as part of a treatment regimen or plan. In certain embodiments, when used in combination, the PI3K / Akt pathway inhibitor and the pharmaceutical agent do not need to be physically combined prior to administration, nor do they need to be administered over the same time frame. [Example]

[0217] VI. Working Examples General synthesis method The compounds described herein can be prepared, isolated, or obtained by any method apparent to one skilled in the art. The compounds described herein can be prepared according to the exemplary preparation schemes shown below. Reaction conditions, steps, and reactants not shown in the exemplary preparation schemes will be apparent and known to those skilled in the art. As used herein, the symbols and conventions used in these processes, schemes, and examples are consistent with those used in modern scientific literature, e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry, regardless of whether a particular abbreviation is specifically defined. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout this specification: g (gram), mg (milligram), mL (milliliter), μL (microliter), mM (millimole), μM (micromole), Hz (hertz), MHz (megahertz), mol (mole), mmol (millimole), h, hr, or hrs (hours), min (minute), rt or RT (room temperature), MS (mass spectrometry), ESI (electrospray ionization), TLC (thin layer chromatography), HPLC (high pressure liquid chromatography), THF (tetrahydrofuran), CDCl3 (deuterated chloroform), AcOH (acetic acid), AcO (acetic anhydride), DCM (dichloromethane), DMSO (dimethyl sulfoxide), DMSO-d6 (deuterated dimethyl sulfoxide), EtOAc (ethyl acetate), MeOH (methanol), and BOC (t-butyloxycarbonyl).

[0218] In all of the following examples, standard workup and purification methods known to those skilled in the art can be utilized. Unless otherwise noted, all temperatures are in °C (Celsius). All reactions are conducted at room temperature unless otherwise indicated. The synthetic methodologies described herein are intended to illustrate applicable chemistry through the use of specific examples and are not indicative of the scope of the present disclosure.

[0219] Compounds of formula (IIa) or (IIb) are prepared via key intermediate 6 according to synthetic scheme 1, as shown in FIG.

[0220] Compounds of formula (IIIa) or (IIIb) are prepared via key intermediate 15 according to synthetic scheme 2, as shown in FIG.

[0221] Example 1: 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl acetate (compound 1.002) Step-1: Methyl 3-(3-methoxybenzamido)thiophene-2-carboxylate (3) [ka] To a solution of methyl 3-amino-2-thiophenecarboxylate (2) (90 g, 0.57 mol, 1.0 equiv.) in acetonitrile (1075 mL), potassium carbonate (87.0 g, 0.63 mol) was added, followed by 3-methoxybenzoyl chloride (1) (96.8 g, 0.57 mol), and the mixture was heated at reflux for 1 h. Most of the acetonitrile was evaporated under reduced pressure to give a pale yellowish solid residue. Water (2.0 L) was added, and the reaction mixture was stirred for 1 h. The solid was collected by filtration, washed with water (200 mL), and dried to give methyl 3-(3-methoxybenzamido)thiophene-2-carboxylate (3) (156.2 g, 93.65% yield).

[0222] Step-2: 2-(3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (4) [ka] A solution of ammonia in methanol (14%, 2.0 L) was added to methyl 3-(3-methoxybenzamido)thiophene-2-carboxylate (3) (100.0 g, 0.343 mol), and the mixture was heated at 70 °C for 36 hours in a steel bomb at 50 psi. The solvent was removed under reduced pressure. Isopropanol (1.66 L) was added, followed by aqueous sodium hydroxide (2 M, 2.0 L). The solution was heated under reflux for 15 hours and then cooled in an ice-water bath. The reaction mixture was acidified to pH 1 with aqueous hydrochloric acid (4 M, 1.1 L), and the precipitated white solid was collected by filtration, washed with water (2.0 L), and dried in a vacuum oven at 50 °C to give 2-(3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (4) (75.1 g, 84.7% yield).

[0223] Step-3: 4-chloro-2-(3-methoxyphenyl)thieno[3,2-d]pyrimidine (5) [ka] To 2-(3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one 4 (150.0 g, 0.58 mol) was added phosphorus oxychloride (750 mL), and the dark mixture was heated at reflux for 5 hours. Most of the excess phosphorus oxychloride was removed by distillation under reduced pressure. The remaining oily residue was added to saturated aqueous sodium bicarbonate solution (4.0 L) at below 20°C. The reaction mixture was stirred at 20°C for 2 hours. The resulting solid was collected by filtration, washed thoroughly with water (0.5 L), and then dried in a vacuum oven at 50°C for 24 hours to give 4-chloro-2-(3-methoxyphenyl)thieno[3,2-d]pyrimidine 5 (122.5 g, 76.3%). The remaining viscous material (in the flask) was dissolved in dichloromethane (1.5 L), and the solution was stirred with saturated aqueous sodium bicarbonate solution (1.5 L) at below 20°C. The dichloromethane layer was separated, dried over NaSO, and concentrated to give a second crop (29.4 g, 18.3%) of compound 5. The overall yield was 151.9 g (94.6%).

[0224] Step-4: 4-(2-(3-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl)morpholine (Compound 1.001) [ka] Morpholine (165.27 g, 1.897 mol) was added to a stirred suspension of 4-chloro-2-(3-methoxyphenyl)thieno[3,2-d]pyrimidine (5) (150.0 g, 0.542 mol) in methanol (3.75 L). The reaction mixture was heated at reflux for 2 hours. Most of the methanol (85–90% of the original volume) was evaporated under reduced pressure. The resulting solid was collected by filtration, then suspended in water (2.0 L) and stirred for 1 hour. The solid was collected by filtration, washed with water (100 mL), and dried in a vacuum oven at 60 °C to give 4-(2-(3-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl)morpholine (1.001) (151.0 g, 85%).

[0225] Step-5: 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol (6) [ka] To a suspension of 4-(2-(3-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl)morpholine (1.001) (150.0 g, 0.458 mol) in acetic acid (900 mL) was added aqueous HBr (48%, 900 mL), and the reaction mixture was heated at reflux for 24 h. The reaction mixture was cooled to 20 °C. The precipitated solid was collected by filtration and washed with demineralized water (1.0 L). The solid was mixed with a saturated aqueous solution of sodium bicarbonate (0.75 L) and stirred at room temperature for 1.0 h. The solid was collected by filtration, washed thoroughly with water (0.75 L), and dried in a vacuum oven at 50 °C to give crude 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol (6) (103.1 g, 71.8% yield).

[0226] DMSO (388 mL) was added to crude 6 (77.7 g) at room temperature. The mixture was stirred at 50° C. for 30 minutes to completely dissolve the solid. The solution was cooled to 35° C. and filtered through a 0.45 micron filter. Demineralized water (1.3 L) was added to the filtrate and stirred for 2 hours. The precipitated white solid was filtered, washed with water (0.5 L), and then dried in a vacuum oven at 60° C. to give pure material 6 (75.2 g, 96.7%).

[0227] Step-6: 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenylacetate (Compound 1.002) [ka] A mixture of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol (6) (10.0 g, 31.9 mmol), sodium acetate (0.65 g, 0.25 equiv., 3.86 mol), and acetic anhydride (6.52 g, 2.0 equiv., 63.82 mmol) in ethyl acetate (250 mL) was heated to 80°C for 2.5 h. The reaction mixture was cooled to 40°C. Activated carbon (2.5 g) was added and stirred at 40°C for 1 h. The reaction mixture was filtered through a hyflow bed and the solid was washed with ethyl acetate (50 mL). The filtrate was washed with saturated aqueous sodium bicarbonate (100 mL), then with demineralized water (100 mL), dried over NaSO, filtered through a 0.45 micron filter, and the solid was washed with ethyl acetate (50 mL). The filtrate was concentrated to remove approximately 70-80% of the original volume. n-Heptane (20 mL) was added, and the solvent was completely evaporated under reduced pressure to give 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenylacetate (1.002) (9.1 g, 80.2%) as an off-white solid.

[0228] Example 2: 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenylhexanoate (Compound 1.006) [ka] Hexanoyl chloride (12.88 g, 95.73 mmol) was added dropwise to a solution of 6 (10.0 g, 31.9 mmol) in pyridine (410.0 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. Analysis indicated that the reaction mixture contained approximately 95% unreacted starting material. Hexanoyl chloride (4.0 g) was added at 0 °C, and the reaction mixture was stirred at room temperature for 24 h. TLC analysis indicated that approximately 50% to 60% unreacted 6 still remained. The reaction mixture was concentrated in vacuo. Methylene chloride (2 × 500 mL) was added to the residue, followed by saturated aqueous NaHCO3 (1.0 L). After stirring the mixture for 15 min, stirring was stopped, and the organic layer was separated and dried over anhydrous sodium sulfate. The solution was filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel using 0-30% EtOAc in n-heptane as the eluent to give 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenylhexanoate (1.006) (2.4 g, yield: 18.3%) as a yellow viscous semi-solid.

[0229] Example 3: 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyldecanoate (compound 1.008) [ka] Decanoyl chloride (18.2 g, 95.73 mmol) was added dropwise to a solution of 6 (10.0 g, 31.91 mmol) in pyridine (410.0 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated in vacuo. The crude product (9.0 g) was dissolved in ethyl acetate (250 mL). Saturated NaHCO3 solution (2 × 500 mL) was added to the solution and stirred at room temperature for 30 min. The organic layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel using 15% ethyl acetate in n-heptane to give 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyldecanoate (1.008) (10.0 g, 67.0%) as a yellowish liquid.

[0230] The product (9.0 g) was dissolved in EtOAc (250 mL), and the solution was mixed with saturated aqueous NaHCO3 (500 mL) and stirred for 30 min. The organic layer was separated, dried (Na2SO4), and the solvent was evaporated under reduced pressure. The resulting product was further purified by column chromatography on silica gel using 15% EtOAc in n-heptane to give pure compound 1.008 (8.0 g, 88.9%) as a colorless viscous compound (overall yield: 59.6%).

[0231] Example 4: 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl oleate (compound 1.011) [ka] Oleic acid (10.63 g, 37.65 mmol), EDC HCl (6.72 g, 35.10 mmol), and DMAP (0.97 g, 7.98 mmol) were added to a solution of 6 (10.0 g, 31.91 mmol) in DCM (310 mL). The reaction mixture was stirred at room temperature for 15 h. Saturated NaHCO solution (1.0 L) was added to the reaction mixture and stirred for 15 min. The layers were separated. The aqueous layer was extracted with methylene chloride (2 × 500 mL) and the extracts were combined with the organic layer. The combined CHCl was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel using 0-30% ethyl acetate in n-heptane as the eluent to give 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl oleate (1.011) (8.7 g, 47.18%) as a colorless liquid.

[0232] Example 5: Ethyl (3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl)carbonate (Compound 1.012) [ka] Ethyl chloroformate (10.38 g, 95.73 mmol) was added to a stirred solution of 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol (6) (10.0 g, 31.91 mmol) in pyridine (410 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 48 hours. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution (1.0 L) was added to the residue, and the product was extracted with DCM (2×500.0 mL). The combined organic extracts were washed with water (2×500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel using 0-30% EtOAc in n-heptane as the eluent to give ethyl (3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl)carbonate (1.012) (8.0 g, 65.0%) as a white solid.

[0233] Example 6: 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl cinnamate (compound 1.014) [ka] Cinnamoyl chloride (15.94 g, 95.73 mmol) was added dropwise to a solution of 6 (10.0 g, 31.9 mmol) in pyridine (410 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated under reduced pressure. Methylene chloride (2 × 500 mL) was added to dissolve the residue. The methylene chloride solution was washed with saturated aqueous NaHCO3 (1.0 L). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel using 0–30% ethyl acetate in n-heptane as the eluent to give ethyl 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenylcinnamate (1.014) as a white solid in two crops (1st crop: 1.2 g, 2nd crop: 11.0 g, total 12.2 g, overall yield: 86.2%).

[0234] Example 7: 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)benzyl acetate (compound 1.015) Step 1: 3-Cyanobenzoyl chloride (8) [ka] DMF (9 mL) and thionyl chloride (500 mL) were added to a stirred solution of 3-cyanobenzoic acid (7) (1hg e 300 g, 679.8 mmol, 1.0 equiv) in toluene (1.0 L) at room temperature. The resulting mixture was stirred at 80 °C for 1.5 h. The progress of the reaction was monitored by TLC (mobile phase: 40% EtOAc in n-heptane). The solvent was evaporated under reduced pressure to give 3-cyanobenzoyl chloride (8) as a yellow liquid (105.35 g, 93.6%).

[0235] Step 2: Methyl 3-(3-cyanobenzamido)thiophene-2-carboxylate (10) [ka] To a solution of methyl 3-amino-2-thiophenecarboxylate (9) (100 g, 636.17 mmol, 1.0 equiv.) in acetonitrile (1.0 L), potassium carbonate (96.71 g, 699.79 mmol, 1.1 equiv.) was added, followed by 3-cyanobenzoyl chloride (8) (105.34 g, 636.17 mmol, 1.0 equiv.), and the mixture was heated under reflux for 2 h. The reaction progress was monitored by TLC (mobile phase: 35% EtOAc in n-heptane). A pale yellow precipitate appeared. Most of the acetonitrile was evaporated under reduced pressure to give a pale yellow solid. The mixture was diluted with water (1.2 L) and stirred for 0.5 h. The solid was collected by filtration, washed with water (0.4 L), and dried at 50° C. to give methyl 3-(3-cyanobenzamido)thiophene-2-carboxylate (10) (172.0 g, 94.2%).

[0236] Step 3: 3-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)benzoic acid (11) [ka] A stirred solution of methyl 3-(3-cyanobenzamido)thiophene-2-carboxylate (10) (229.0 g, 799.83 mmol, 1.0 equiv.) in methanol (4.5 L) was cooled to 10°C. Ammonia was purged into the solution to make an 11% ammoniacal solution, and the mixture was then heated at 100°C for 16 hours in a steel bomb at 200 psi. The reaction progress was monitored by TLC (mobile phase: 5% MeOH in DCM). The solvent was then removed under vacuum, and 2 M aqueous sodium hydroxide (4.5 L) was added. The solution was heated at 80°C for 1 hour. The reaction progress was monitored by TLC (mobile phase: 5% MeOH in DCM). The mixture was cooled to 10°C. The reaction mixture was acidified to pH 1 with 4 M hydrochloric acid (4.5 L), and the white precipitate was collected by filtration and washed with water (2.2 L). The wet cake was stirred in isopropyl alcohol (572.5 mL) at room temperature for 1 hour, and the resulting solid was collected by filtration and dried at 60° C. to give compound 3-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)benzoic acid (11) (206.0 g, 94.6%).

[0237] Step 4: Methyl 3-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)benzoate (12) [ka] To a solution of 3-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)benzoic acid (11) (205.0 g, 752.9 mmol, 1.0 equiv.) in methanol (4.1 L), sulfuric acid (920 g, 9.38 mol, 12.46 equiv.) was added at room temperature, and the mixture was heated under reflux for 2 h. The progress of the reaction was monitored by TLC (mobile phase: 5% MeOH in DCM). Most of the methanol was evaporated under reduced pressure. The residue was added to chilled saturated aqueous sodium bicarbonate solution (2.5 L) to pH 7. The solid was collected by filtration, washed thoroughly with water (1.7 L), and dried at 50° C. to give 3-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)benzoate (12) as a light brown solid (161.10 g, 74.69%).

[0238] Step 5: Methyl 3-(4-chloro-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)benzoate (13) [ka] To methyl 3-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)benzoate (12) (161.0 g, 562.33 mmol, 1.0 equiv.) was added POCl (805.0 mL), and the dark mixture was heated at reflux for 2 h. The reaction progress was monitored by TLC (mobile phase: 5% MeOH in DCM). Most of the phosphorus oxychloride was removed by distillation under reduced pressure. The oily residue was added to saturated aqueous sodium bicarbonate (3.5 L) at <20 °C and diluted with CHCl (8.0 L). The organic layer was separated, washed with water (3.5 L), dried over NaSO, and concentrated to give methyl 3-(4-chloro-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)benzoate (13) (115.0 g, 66.7%) as a light brown solid.

[0239] Step 6: Methyl 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)benzoate (14) [ka] Morpholine (99.38 g, 1140.96 mmol, 3.5 equiv.) was added to a stirred suspension of methyl 3-(4-chloro-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)benzoate (13) (100.0 g, 325.99 mmol, 1.0 equiv.) in methanol (2.5 L). The reaction mixture was heated at reflux for 2 h. The progress of the reaction was monitored by TLC (mobile phase: 50% ethyl acetate in n-heptane). Most of the methanol was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (230-400 mesh size) using 20-50% EtOAc in n-heptane followed by 0-3% MeOH in DCM to give 4-(2-(3-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl)morpholine (14) as an off-white solid (93.0 g, 80.26%).

[0240] Step 7: (3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl)methanol (15) [ka] DIBAL (99.56 g, 700.08 mmol, 4.29 equiv.) was added to a solution of 4-(2-(3-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl)morpholine (14) (58.0 g, 163.19 mmol, 1.0 equiv.) in toluene (1.16 L) at −78° C. under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 2 h. The progress of the reaction was monitored by TLC (mobile phase: 60% EtOAc in n-heptane). The reaction mixture was quenched with methanol (100 mL) at <20° C. Then, it was diluted with water (3.5 L) and extracted with ethyl acetate (3×2.0 L). The combined extracts were washed with brine (3.5 L), dried over NaSO, and concentrated to give (3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl)methanol (15) as an off-white solid (50.0 g, 93.6%).

[0241] Step 8: 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)benzyl acetate (compound 1.015) [ka] To a stirred solution of (3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl)methanol (15) (27.0 g, 82.47 mmol, 1.0 equiv.) in ethyl acetate (0.54 L) was added acetic anhydride (59.43 g, 582.24 mmol, 7.06 equiv.) and sodium acetate (33.83 g, 412.35 mmol, 5.0 equiv.) at room temperature. The reaction mixture was heated at reflux for 2 h. The progress of the reaction was monitored by TLC (mobile phase: 60% EtOAc in n-heptane). The reaction mixture was cooled to room temperature and then diluted with water (0.9 L). The aqueous layer was extracted twice with ethyl acetate (1.25 L × 2). The combined extracts were washed with saturated aqueous NaHCO (0.8 L) and brine (0.8 L), then dried over NaSO and concentrated under reduced pressure to give crude 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)benzyl acetate (1.015) (27.9 g, yield: 91.57%, HPLC area: 97.67%). Crude 1.015 (27.9 g, HPLC: 97.67%) was suspended in ethyl acetate (83.7 mL, 3 equivalent volumes) and stirred at room temperature for 2 hours. The resulting solid was collected by filtration, washed with ethyl acetate (14.0 mL), and dried at room temperature to give 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)benzyl acetate (1.015) (25.0 g, 82%, HPLC area: 99.25%).

[0242] Example 8: Preparation of a topical gel formulation The topical gel formulations of the present invention can be prepared according to the procedures set forth below: Reaction conditions and steps not set forth in the procedures below will be apparent and known to those skilled in the art.

[0243] Topical gel formulations were prepared using the excipients listed in Table 2. The liquid excipients, i.e., DMSO, oleic acid, Transcutol P, and dipropylene glycol, were mixed in a 20 mL vial by vortexing. The active ingredient, a compound of Formula (I), e.g., Compound 1.002, was then added, and the vial contents were sonicated for 10 minutes to dissolve the compound. The solution reached a saturation concentration of approximately 105 mg / mL. Hydroxypropyl cellulose (HPC) was added, and the vial was vortexed for an additional 10 minutes to obtain the gel formulation. The viscosity of the clear gel was measured to be in the range of approximately 7,000 to 10,000 centipoise (cp). [Table 2]

[0244] Example 9: In vitro human skin permeation study Test-1: Topical gel formulation of Compound 1.002 The gel formulation of Example 8 was used as the donor phase to study the permeation of Compound 1.002 into human skin and its efficacy as a topical application. Three skin donors and three diffusion cells (per donor) were used for each formulation in the in vitro skin permeation experiments. Split-thickness dermatomed (approximately 375 μm thick) human cadaver skin provided by the New York Firefighters Skin Bank, New York, was used to measure the permeation rate of the test compound (i.e., drug) in vitro. All in vitro skin permeation studies were performed using a Vertical Diffusion Cells assembly with a console (Model FDC-6) and a heating controller (Logan Instruments, Somerset, NJ). Each assembly contained a magnetic stirrer and a 1.767 cm 2 The device consisted of six vertical jacketed (37°C ± 0.5°C) 12 mL Franz diffusion cells with a diffusion area of ​​100 μm.

[0245] The skin permeation rate test was conducted over a 48-hour period. At predetermined intervals (2, 4, 8, 24, and 48 hours) after the start of the experiment, the entire contents of the receiver compartment were sampled for drug concentration measurement by HPLC. The receiver compartment was refilled with fresh receiver medium. The receiver medium was a pH 7.4 phosphate buffer containing 0.5 mg / ml Oleath 20, and the saturation concentration of the drug in the receiver medium was 0.152 mg / ml. The drug solubility in the receiver medium was sufficient to ensure sink conditions throughout each sampling interval.

[0246] Receptor phase samples were taken at 2, 4, 8, 12, 24, and 48 hours and the concentrations of compound 1.002 and 3-(4-morpholinothieno(3,2-d)pyrimidin-2-yl)phenol (a metabolite of compound 1.002, abbreviated as MTPP) were measured using a validated HPLC method. Metabolism of compound 1.002 to MTPP occurs in human skin by esterolytic enzymes.

[0247] HPLC method: Column - Gemini C-18 4.6 x 150 mm, particle size 5 μm, mobile phase - water:acetonitrile 25:75 (containing 0.1% TFA), flow rate - 1 mL / min, detection - 274 nm, column temperature - 40°C, and run time - 10 min. The retention times of MTPP and compound 1.002 were 3.9 minutes and 7.2 minutes, respectively.

[0248] The skin permeation rate of the drug and the cumulative amount of the drug permeated (the sum of MTPP and Compound 1.002) over a 48-hour period were calculated and are shown in Table 3. A plot of the cumulative amount permeated against time is shown in Figure 3. [Table 3]

[0249] Test-2: Topical gel formulation of Compound 1.002 The skin permeation rate experiment of Test-1 was repeated using the same gel formulation, except that the saturation concentration of Compound 1.002 was 120 mg / mL. The cumulative amount of MTPP or Compound 1.002 that permeated the skin over a 48-hour period is shown in Table 4. [Table 4]

[0250] The above studies 1 and 2 showed that a significant amount (e.g., 82% to 100%) of compound 1.002 that permeated the skin in the first 24 hours was metabolized to the parent compound, 3-(4-morpholinothieno(3,2-d)pyrimidin-2-yl)phenol (abbreviated as MTPP). The first 24 hours represent the actual in vivo application time.

[0251] Study-3: Topical gel formulation of MTPP and Compound 1.002 Saturated gel formulations were prepared according to the composition and procedure used in Example 8, except that compound 1.002 in one of the formulations was replaced with 3-(4-morpholinothieno(3,2-d)pyrimidin-2-yl)phenol (abbreviated as MTPP). Skin permeation rate experiments were performed according to the procedure described in Test-1 of Example 9. The cumulative amount of MTPP or compound 1.002 permeated through the skin over a 48-hour period is shown in Figure 4. From this figure, it is clear that the permeation of compound 1.002 into human skin is approximately six times higher than that of MTPP.

[0252] Study-4: Topical gel formulation of MTPP and Compound 1.001 Saturated gel formulations were prepared according to the composition and procedure used in Example 8, except that compound 1.002 was replaced with 3-(4-morpholinothieno(3,2-d)pyrimidin-2-yl)phenol (abbreviated as MTPP) and compound 1.001, respectively. Skin permeation rate experiments were performed according to the procedure described in Test-1 of Example 9.

[0253] 3-(4-morpholinothieno(3,2-d)pyrimidin-2-yl)phenol (MTPP) permeated as its intact compound. Compound 1.001, a methyl ether derivative of MTPP, was found to permeate as its intact compound in skin permeation rate experiments, indicating that this compound does not appear to be metabolized to MTPP in human skin. Skin permeation rate data for MTPP and compound 1.001 are shown in Table 5. [Table 5]

[0254] Test-5: Topical gel formulation of compound 1.006 A saturated gel formulation was prepared according to the composition and procedure used in Example 8, except that compound 1.002 was replaced with compound 1.006. Skin permeation rate experiments were performed according to the procedure described in Test-1 of Example 9.

[0255] Compound 1.006 was found to penetrate human skin and be metabolized to MTPP by esterases in the skin. Tables 6A and 6B show skin permeation data from two separate experiments. The saturation concentration of compound 1.006 in the formulation for the results shown in Table 6B was 215 mg / mL. [Table 6] [Table 7]

[0256] The sum of the drugs (ie, MTPP and compound 1.006) showed that the total amount of compound 1.006 that permeated was significantly less than the total amount of compound 1.002.

[0257] Test-6: Topical gel formulation of compound 1.012 A saturated gel formulation was prepared according to the composition and procedure used in Example 8, except that compound 1.002 was replaced with compound 1.012. The saturated concentration of compound 1.012 in the formulation was 58 mg / mL. Skin permeation rate experiments were performed according to the procedure described in Test-1 of Example 9.

[0258] Compound 1.012 was found to penetrate human skin and be completely metabolized to MTPP by esterases in the skin. Skin permeation data are shown in Table 7. [Table 8]

[0259] Stability studies of gel formulations containing compound 1.012 were performed at 80° C. Compound 1.012 in the formulation was found to be very stable, with HPLC analysis showing a relative purity of 99% after 5 days and 96% after 10 days at 80° C.

[0260] The sum of the drugs (ie, MTPP and compound 1.012) showed that the total amount of compound 1.012 that permeated was significantly less than the total amount of compound 1.002.

[0261] Test-7: Topical gel formulations of compounds 1.008, 1.011, and 1.014 Using the same procedure as in Example 8, saturated gel formulations of compounds 1.008, 1.011, or 1.014 were prepared, respectively. The saturated solubility was determined by observing miscibility. The skin permeation rate experiment was carried out according to the procedure described in Test-1 of Example 9.

[0262] The skin permeation of compounds 1.008, 1.011, and 1.014 in gel formulations was found to be less than 10% compared to that of compound 1.002.

[0263] Stability studies of gel formulations containing compounds 1.008, 1.011, or 1.014 were performed at 80° C. All three compounds were found to be very stable at 80° C. for 10 days.

[0264] Example 10: In vitro skin permeation studies - human skin vs. mouse skin The gel formulations of Example 8 were used to measure skin permeation through human and mouse skin. Because mouse skin is widely used for toxicology studies and early in vivo testing, it is important to understand the differences in permeation through the two types of skin. Skin permeation studies were performed according to the method described in Example 9.

[0265] Figure 5 shows a comparison of the skin permeation of compound 1.002 through human and mouse skin over a 48 hour period. As shown in Figure 5, the permeation of compound 1.002 through mouse skin was approximately three times higher than through human skin. Metabolism of compound 1.002 to MTPP proceeded equally well in both skin types.

[0266] Example 11: Ethanol-based topical gel formulation A topical gel formulation containing compound 1.002 and primarily ethanol was prepared according to the procedure described in Example 8 using the following composition: [Table 9]

[0267] The skin permeation experiment was carried out according to the procedure shown in Example 9, and the results are shown in Table 8. [Table 10]

[0268] Example 12: Preparation of liquid formulations A solution formulation was prepared similar to the gel formulation described in Example 8, without the thickener. The formulation composition is shown in Table 9. The viscosity of the solution was 13.4 cp. The solution can be used as a topical spray or lotion. [Table 11]

[0269] Example 13: Reservoir transdermal patch for compound delivery A liquid reservoir transdermal patch system, as shown in Figure 6, can be constructed and used to deliver 3-(4-morpholinothieno(3,2-d)pyrimidin-2-yl)phenol (abbreviated as MTPP) or a compound of Formula (I). Using a transdermal patch, up to 3.5 or 7 days of drug can be delivered with a single patch application, compared to topical applications useful for one-day delivery.

[0270] Test-1: 3-(4-morpholinothieno(3,2-d)pyrimidin-2-yl)phenol The following gel formulations having the compositions shown in Table 10 were prepared according to Example 8 and incorporated into the reservoir patch system. [Table 12]

[0271] Patches using gel formulations with the compositions in Table 10 were prepared according to the process shown in Figure 7. In summary, the process includes: a) preparation of the gel formulation; b) preparation of the backing film, including patch formation, filling, and heat sealing; c) preparation of the pressure-sensitive adhesive layer; and d) lamination of the separate layers and die-cutting of individual patches.

[0272] FIG. 8 shows MTPP skin permeation data through a liquid transdermal reservoir patch containing the gel formulations of Table 10 obtained over a 7-day period.

[0273] Test-2: Compound 1.002 A liquid reservoir transdermal patch as in Figure 6 was prepared and used to study the delivery of Compound 1.002. The transdermal patch was used to deliver Compound 1.002 through human skin in vitro for 7 days following a single patch application. The following gel formulations, having the compositions shown in Table 11, were prepared according to Example 8 and incorporated into the reservoir patch system. [Table 13]

[0274] Patches using gel formulations having the compositions in Table 11 were prepared according to the method shown in Figure 7. The patches were 1.8 cm in size. 2 The patches contained 0.3 mL of gel formulation. The backing layer of the patch was Scotchpak 9723, a polyester and polyethylene laminate commonly used in transdermal patches. The control membrane was SOLUPOR® 10P05A, a porous (up to 90%) ultra-high molecular weight polyethylene membrane with controlled pore size. The pressure-sensitive adhesive that contacts human skin was Scotchpak 9723, a non-crosslinked acrylate copolymer with no functional groups.

[0275] Figure 9 shows skin permeation data for compound 1.002 through a liquid transdermal reservoir patch containing the gel formulation of Table 11 obtained over a 7-day period. Compound 1.002 was confirmed to be metabolized to MTPP by esterases as it permeates human skin. In this study, approximately 85% of compound 1.002 was found to be metabolized to MTPP after permeating human skin.

[0276] FIG. 10 shows a comparison of human skin permeation of MTPP and compound 1.002 from a transdermal reservoir patch.

[0277] Example 14: Effect of human skin permeation enhancers in vitro Test-1: Glycerol Monooleate, Oleyl Oleate, and Isostearic Acid vs. Oleic Acid The 10% oleic acid (OA) in the gel formulation of Example 8 was replaced with other skin permeation enhancers, such as 10% glycerol monooleate, 10% oleyl oleate, and 10% isostearic acid, and skin permeation was obtained using the procedure described in Example 9. The results of the study are shown in Figure 11.

[0278] Test-2: Neodecanoic or Isostearic Acid vs. Oleic Acid The 10% oleic acid (OA) in the gel formulation of Example 8 was replaced with other skin permeation enhancers, such as 10% neodecanoic acid (NA), 10% neodecanoic acid (NA + 1% citric acid, 2% oleic acid, and 2% oleic acid + 5% isostearic acid, and skin permeation was obtained using the procedure described in Example 9. The results of the study are summarized in Table 12 and Figure 12. [Table 14]

[0279] Example 15: In vitro human skin permeation - effect of oleic acid Four topical gel formulations of Compound 1.002 using 1%, 2%, 5%, and 10% oleic acid, respectively, were prepared according to Example 8. The formulation using 10% oleic acid had the same composition as shown in Table 2. The other formulations were modifications of the 10% formulation, with all ingredients proportionally reduced to account for the lower amount of oleic acid. The solubility of Compound 1.002 in all formulations was measured, and all formulations prepared thereafter were considered saturated gel formulations. As with the example shown above, the majority of Compound 1.002 was metabolized to MTPP. Permeation data for Compound 1.002 in the above four formulations are shown in Figure 13. It is clear that the observed permeation rate of Compound 1.002 through human skin increases with increasing amounts of oleic acid in the gel formulation.

[0280] Example 16: In vitro human skin permeation - effect of oleic acid and oleyl alcohol Topical gel formulations 16A, 16B, and 16C containing compound 1.002 were prepared according to Example 8. The composition of each formulation and the amount of compound 1.002 in each formulation are shown in Table 13. The solubility of compound 1.002 in all three formulations reached saturation. [Table 15]

[0281] Using the procedure described in Example 9, skin permeation from each of the three formulations as a function of time was obtained. The permeation data, expressed as the total amount of permeated (MTPP + Compound 1.002), are shown in Figure 14. At 24 hours, Compound 1.002 represented approximately 10% of the total amount of permeated (MTPP + Compound 1.002) for the three formulations. It is clear from the graph that Formulation 16B, containing 10% oleic acid, performed better than the other two formulations. At 24 hours, the cumulative permeation of Compound 1.002 in Formulation 16B was approximately 20% higher than the permeation of Formulation 16C, containing 10% oleyl alcohol.

[0282] Example 17: Topical gel formulations with glycol combinations Topical gel formulations containing a combination of DPG and PEG400 were prepared using the excipients shown in Table 14 according to the procedure of Example 8, except that PEG400 was also mixed with the other excipients. [Table 16]

[0283] The skin permeation test was carried out according to the method described in Example 9.

[0284] Figure 15 shows a comparison of skin permeation between the gel formulations of Example 16 (2% oleic acid) and 16A (2% oleic acid). It is clear from the graph that both formulations 17A and 17B, which contain PEG 400, performed better than formulation 16A, which contains only DPG. At 24 hours, formulation 17A, which has 2% oleic acid, performed comparable to formulation 17B, which has 10% oleyl alcohol.

[0285] Example 18: Accelerated stability testing of topical gel formulations Test-1: Gel formulations of compounds 1.002, 1.012, or 1.006 Topical gel formulations using compounds 1.002, 1.012, and 1.006 as the active ingredient were prepared according to Example 8 with the excipients shown in Table 2. These gel formulations were subjected to stability testing at 80°C for 10 days. Stability at 80°C for 10 days is considered to be approximately equivalent to stability at room temperature for 3 years. The relative purity of the test compounds after 5 and 10 days of exposure at 80°C was measured by HPLC compared to their initial purity (day 0). The stability data for the test compounds in each formulation are shown in Table 15. [Table 17]

[0286] Test-2: Gel formulations of compounds 1.008, 1.011, or 1.014 Topical gel formulations using compounds 1.008, 1.011, and 1.014, respectively, as the active ingredient were prepared according to Example 8 using the excipients shown in Table 2. Saturation solubility was determined by miscibility observations.

[0287] Accelerated stability testing at 80°C was performed on each formulation. All three compounds were found to be very stable at 80°C for 10 days, as shown in Table 16 below. The values ​​shown in the table are the % hydrolysis of each compound relative to the parent compound MTPP. [Table 18]

[0288] Test-3: Effect of oleic acid Topical gel formulations of Compound 1.002 with varying oleic acid contents of 1%, 2%, 5%, and 10% were prepared according to Example 8 using the excipients listed in Table 2. These gel formulations were subjected to a 10-day stability study at 80°C, which is believed to be approximately equivalent to a 3-year stability at room temperature. The purity of the test compound was measured by HPLC on days 0, 5, 7, and 10 at 80°C. The impurity detected in the test compound appears to be the hydrolysate MTPP. The stability data for Compound 1.002 in topical formulations with varying oleic acid contents are shown in Table 17. [Table 19]

[0289] It was also found that all the above formulations remained clear without any discolouration even after exposure to 80°C for 10 days.

[0290] Study 4: Gel formulations containing 2% oleic acid or 10% oleyl alcohol, DPG, and PEG 400 The gel formulation of Example 17 was subjected to a 10-day stability study at 80°C. Stability at 80°C for 10 days is believed to be approximately equivalent to stability at room temperature for 3 years. The relative purity of compound 1.002 after 5 and 10 days of exposure at 80°C was measured by HPLC compared to its initial purity (day 0). The stability data for compound 1.002 in each formulation are shown in Table 18. [Table 20]

[0291] The gel formulations of Example 17, which were formulated with Compound 1.002 at 80% saturation, were subjected to a freeze / thaw test (-20°C / 25°C, 24 hours / 24 hours; 3 cycles). The appearance of Compound 1.002 in each formulation is shown in Table 19. [Table 21]

[0292] Example 19: Topical gel formulation containing compound 1.002 Six-month stability study of topical gel formulation Unless otherwise indicated, HPLC methods were used to measure the content of compound 1.002 and impurities, ASTM D1544 was used as the standard test method for color of gel formulations, gas chromatography methods were used to measure the content of oleic acid, and a Brookfield viscometer was used to measure the viscosity (cP) of the gel formulations.

[0293] A: Stability of Compound 1.002 Gel Formulation in Glass Containers Test-1: Gel formulation containing 10% oleic acid and DPG in HPLC glass vials A topical gel formulation was prepared according to the procedure of Example 8 using the excipients shown in Table 20. [Table 22]

[0294] The gel formulations in HPLC glass vials were subjected to a 6-month stability study at 40°C / 75% relative humidity. The purity of Compound 1.002 was determined by HPLC at 0, 1, 3, and 6 months at 40°C / 75% relative humidity. The detected impurity in Compound 1.002 appears to be the hydrolysate MTPP. The stability data for Compound 1.002 in a topical formulation with 10% oleic acid are shown in Table 21. [Table 23]

[0295] Test-2: Gel formulation containing 10% oleyl alcohol, DPG, and PEG 400 A topical gel formulation containing 10% oleyl alcohol, DPG, and PEG400 was prepared using the excipients shown in Table 22 according to the procedure of Example 8, except that the PEG400 was also mixed with the other excipients. [Table 24]

[0296] The gel formulation in the vial was subjected to a 6-month stability study at 25°C / 60% relative humidity. The purity of compound 1.002 was determined by HPLC at 0, 1, 3, and 6 months at 25°C / 60% relative humidity. The detected impurity in compound 1.002 appears to be the hydrolysate MTPP. The stability data for compound 1.002 in a topical formulation with 10% oleyl alcohol, 5% DPG, and 35% PEG400 are shown in Table 23. [Table 25]

[0297] B: Stability of Compound 1.002 Gel Formulation in Lablabo Containers Study-3: Gel formulation containing 10% oleyl alcohol and DPG in Lablabo Amcor foil 18 mL containers A topical gel formulation containing 10% oleyl alcohol and DPG was prepared according to the procedure of Example 8 using the excipients shown in Table 24. [Table 26]

[0298] The gel formulation in Lablabo Amcor Foil 18 mL containers was subjected to a 6-month stability study at 40°C / 75% relative humidity. The purity of Compound 1.002 was determined by HPLC at 0, 1, 3, 4, 5, and 6 months at 40°C / 75% relative humidity. The detected impurity in Compound 1.002 appears to be the hydrolysate MTPP. The stability data for Compound 1.002 in a topical formulation with 10% oleyl alcohol and 40% DPG are shown in Table 25. [Table 27]

[0299] Study-4: Gel formulation containing 10% oleyl alcohol, DPG, and PEG 400 in a Lablabo Amcor Foil 18 mL container A topical gel formulation containing 10% oleyl alcohol, DPG, and PEG400 was prepared using the excipients shown in Table 26 according to the procedure of Example 8, except that the PEG400 was also mixed with the other excipients. [Table 28]

[0300] The gel formulation in Lablabo Amcor Foil 18 mL containers was subjected to a 6-month stability study at 40°C / 75% relative humidity. The purity of compound 1.002 was determined by HPLC at 0, 1, 2, 3, and 6 months at 40°C / 75% relative humidity. The detected impurity in compound 1.002 appears to be the hydrolysate MTPP. The stability data for compound 1.002 in a topical formulation with 10% oleyl alcohol, 5% DPG, and 35% PEG400 are shown in Table 27. [Table 29]

[0301] Study-5: Gel formulation containing 10% oleyl alcohol, DPG, and PEG 400 in a Lablabo Eliopack foil 33 mL container A topical gel formulation containing 10% oleyl alcohol, DPG, and PEG400 was prepared using the excipients shown in Table 26 of Study 4 according to the procedure of Example 8, except that the PEG400 was also mixed with the other excipients.

[0302] The gel formulation in Lablabo Eliopack foil 33 mL containers was subjected to a 6-month stability study at 40°C / 75% relative humidity. The purity of compound 1.002 was determined by HPLC at 0, 1, 2, 3, and 6 months at 40°C / 75% relative humidity. The detected impurity in compound 1.002 appears to be the hydrolysate MTPP. The stability data for compound 1.002 in a topical formulation with 10% oleyl alcohol, 5% DPG, and 35% PEG400 are shown in Table 28. [Table 30]

[0303] Study-6: Gel formulation containing 10% oleyl alcohol, DPG, and PEG 400 in a Lablabo ACS foil 55 mL container A topical gel formulation containing 10% oleyl alcohol, DPG, and PEG400 was prepared using the excipients shown in Table 22 of Study 2 according to the procedure of Example 8, except that the PEG400 was also mixed with the other excipients.

[0304] The gel formulation in Lablabo ACS foil 55 mL containers was subjected to a 6-month stability study at 40°C / 75% relative humidity. The purity of compound 1.002 was determined by HPLC at 0, 1, 3, and 6 months at 40°C / 75% relative humidity. The detected impurity in compound 1.002 appears to be the hydrolysate MTPP. The stability data for compound 1.002 in a topical formulation with 10% oleyl alcohol, 5% DPG, and 35% PEG400 are shown in Table 29. [Table 31]

[0305] Example 20: Stability study of compound 1.002 The stability of three lots of compound 1.002 as an active pharmaceutical ingredient (API) was studied over a 12 month period. Table 30 below shows the HPLC assay results of the stability study. [Table 32]

[0306] Example 21: Lipid kinase inhibitory activity The lipid kinase inhibitory activity of compounds 1.002 and 1.015 was evaluated in comparison with their corresponding parent compounds, namely, 3-(4-morpholinothieno(3,2-d)pyrimidin-2-yl)phenol (MTPP) and (3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenyl)methanol (abbreviated as MTPPM).

[0307] Lipid kinase: Lipid kinase from Reaction Biology Corporation (RBC) in the ADP-Glo ​​format was used.

[0308] Assay Description: The kinase reaction used ATP to generate ADP as a by-product. The amount of ADP produced was quantified by luminescent detection with ADP-Glo. The assay involved three steps: first, a kinase reaction with a lipid substrate in the presence of ATP; then, the reaction was quenched with ADP-Glo™ Reagent to remove residual ATP; and finally, ADP was converted to ATP, which was measured using a luciferase / luciferin reaction.

[0309] Assay procedure: The assay was performed according to the following steps. 1. Prepare the substrate in freshly prepared reaction buffer. 2. Add the kinase to the substrate solution and mix gently. 3. Compounds in 100% DMSO are delivered to the kinase reaction mixture using Acoustic technology (Echo 550, nanoliter range) and incubated at room temperature for 20 minutes. 4. ATP is added to the reaction mixture to initiate the reaction. 5. Incubate at 30°C for 30 minutes. 6. Quench the reaction with ADP-Glo ​​reagent and incubate for 40 minutes. 7. Add Detection Mixture and incubate for 30 minutes. 8. Measure the luminescence.

[0310] Data analysis: Luminescence was converted to μM ADP production based on an ADP standard curve. Standard curve and IC 50 Nonlinear regression to obtain values ​​was performed using Graphpad Prism software.

[0311] Table 31 shows the IC values ​​of compounds 1.002 and 1.015. 50 Values ​​are listed relative to the corresponding parent compounds MTPP and MTPPM, respectively. [Table 33]

[0312] Although the foregoing invention has been described in some detail by way of illustration and example for clarity of understanding, those skilled in the art will recognize that certain changes and modifications may be practiced within the scope of the appended claims. Additionally, each reference cited herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of a conflict between this application and a reference cited herein, the present application shall control. The present invention can be summarized as follows. 1. Formula (I): [ka] or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof, During the ceremony, The subscript m is an integer between 0 and 2, and i)L 1 is a bond, —C(O)—, —C(O)O—, —C(O)S—, or —C(O)NH—, and R 1 But C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 6-10 Aryl, C 6-10 Aryl-C 1-6 Alkyl or C6-10 Aryl-C 2-6 is alkenyl, ii)L 1 -R 1 is the expression: [ka] and During the ceremony, The wavy lines indicate the connections to adjacent oxygen atoms in formula (I); The subscript t is an integer between 0 and 1, The subscripts p and q are independently integers from 0 to 2; R 3 is hydrogen or the side chain of a natural or unnatural amino acid, and R 4 is hydrogen, or R 3 and R 4 are combined to form the side chain of a cyclic amino acid, R 5 is hydrogen or the side chain of a natural or unnatural amino acid, and R 6 is hydrogen, C 1-6 Alkyl or C 2-6 alkenyl, or R 5 and R 6 are combined to form the side chain of a cyclic amino acid, and R 7 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkyl-C(O)- or C 2-6 alkenyl-C(O)-; or R 5 is hydrogen or the side chain of a natural or unnatural amino acid, and R 6 and R 7 combine to form a 3- to 6-membered heterocyclic ring optionally having 1-2 additional heteroatoms selected from O, S, and N as ring vertices; or iii) L 1 is -C(O)-, and R 1 is an aliphatic chain of a saturated fatty acid having 8 to 18 carbon atoms or an unsaturated fatty acid having 10 to 18 carbon atoms, The compound, or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof. 2. 2. The compound according to claim 1, wherein the subscript m is 0 or 1. 3. Formula (II) or (III): [ka] The compound according to any one of 1 to 2 above, having the following structure: 4. Formula (IIa): [ka] The compound according to any one of the above 1 to 3, having the following structure: 5. The following formula: [ka] The compound according to any one of the above 1 to 3, having a formula selected from the group consisting of: 6. R 1 6. The compound according to any one of the above 1 to 5, wherein is methyl or ethyl. 7. R 1 6. The compound according to any one of the above 1 to 5, wherein is phenyl-CH═CH—. 8. 5. The compound according to any one of the above 1 to 4, wherein the subscripts p and q are each 0. 9. 9. The compound according to claim 8, having the formula (IIa-1) or (IIIa-1). [ka] 10. 5. The compound according to any one of 1 to 4 above, wherein the saturated fatty acid having 8 to 18 carbon atoms is selected from the group consisting of caprylic acid, pelargonic acid, capric acid, neodecanoic acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, and isostearic acid. 11. 5. The compound according to any one of 1 to 4 above, wherein the unsaturated fatty acid having 10 to 18 carbon atoms is selected from the group consisting of caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccinic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, columbic acid, pinolenic acid, and stearidonic acid. 12. The following formula: [ka] 2. The compound according to claim 1, selected from the group consisting of: 13. 1. A topical formulation for treating vascular malformations, comprising: a) Formula (I): [ka] or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof, During the ceremony, The subscript m is an integer between 0 and 2, and i)L 1 is a bond, —C(O)—, —C(O)O—, —C(O)S—, or —C(O)NH—, and R 1 But C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 6-10 Aryl, C 6-10 Aryl-C 1-6 Alkyl or C 6-10 Aryl-C 2-6 is alkenyl, ii)L 1 -R 1 is the expression: [ka] and During the ceremony, The wavy lines indicate the connections to adjacent oxygen atoms in formula (I); The subscript t is an integer between 0 and 1, The subscripts p and q are independently integers from 0 to 2; R 3 is hydrogen or the side chain of a natural or unnatural amino acid, and R 4 is hydrogen, or R 3 and R 4 are combined to form the side chain of a cyclic amino acid, R 5 is hydrogen or the side chain of a natural or unnatural amino acid, and R 6 is hydrogen, C 1-6 Alkyl or C 2-6 alkenyl, or R 5 and R 6 are combined to form the side chain of a cyclic amino acid, and R 7 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkyl-C(O)- or C 2-6 alkenyl-C(O)-; or R 5 is hydrogen or the side chain of a natural or unnatural amino acid, and R 6 and R 7 combine to form a 3- to 6-membered heterocyclic ring optionally having 1-2 additional heteroatoms selected from O, S, and N as ring vertices; or iii) L 1 is -C(O)-, and R 1 is an aliphatic chain of a saturated fatty acid having 8 to 18 carbon atoms or an unsaturated fatty acid having 10 to 18 carbon atoms a compound, or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof, and b) one or more topical excipients 1. A topical formulation comprising: 14. 14. The topical formulation of claim 13, selected from the group consisting of lotions, sprays, ointments, creams, gels, pastes, and patches. 15. 14. The topical formulation of claim 13, wherein the one or more topical excipients are selected from the group consisting of one or more solvents, one or more penetration enhancers, one or more gelling agents, and combinations thereof. 16. The one or more solvents or penetration enhancers are 2-6 Alcohol, C 2-6 Alkylene glycol, di-(C 2-6 Alkylene) glycol, polyethylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 16. The topical formulation of claim 15, wherein the hydroxybenzoate is selected from the group consisting of —OH, DMSO, fatty alcohols, fatty acids, and fatty esters. 17. The one or more solvents or penetration enhancers are di-(C 2-6 Alkylene) glycol, polyethylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 17. The topical formulation of claim 16, wherein the hydroxybenzoate is selected from the group consisting of —OH, DMSO, fatty alcohols, and fatty acids. 18. 16. The topical formulation of claim 15, wherein the one or more gelling agents are selected from the group consisting of hydroxypropyl cellulose, carbopol, carboxymethyl cellulose, ethyl cellulose, gelatin, hydroxyethyl cellulose, magnesium aluminum silicate (Veegum), methyl cellulose, poloxamer (Pluronics), polyvinyl alcohol, sodium alginate, tragacanth, xanthan gum, and combinations thereof. 19. Said C 2-6 17. The topical formulation of claim 16, wherein the alcohol is selected from the group consisting of ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol, and combinations thereof. 20. Said C 2-6 20. A topical formulation according to claim 16 or 19, wherein the alcohol is ethanol or isopropanol. twenty one. The di-(C2-6 17. The topical formulation of claim 16, wherein the alkylene glycol is dipropylene glycol. twenty two. 17. The topical formulation of claim 16, wherein the polyethylene glycol is PEG400. twenty three. Said C 1-3 Alkyl-(OCH2CH2) 1-5 17. The topical formulation of claim 16, wherein -OH is 2-(2-ethoxyethoxy)ethanol. twenty four. 17. The topical formulation of claim 16, wherein the fatty alcohol is selected from capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleic alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, and combinations thereof. twenty five. The fatty acids include capric acid, neodecanoic acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, isostearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, behenic acid, tricosylic acid, lignoceric acid, caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccinic acid, gadoleic acid, eicosenoic acid, elicacid ... 17. The topical formulation of claim 16, wherein the hydroxybenzoate is selected from the group consisting of carboxylic acid, brassidic acid, nervonic acid, linoleic acid, eicosadienoic acid, docosadienoic acid, α-linolenic acid, γ-linolenic acid, columbic acid, pinolenic acid, α-eleostearic acid, β-eleostearic acid, mead acid, dihomo-γ-linolenic acid, eicosatrienoic acid, stearidonic acid, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, and combinations thereof. 26. 17. The topical formulation of claim 16, wherein the fatty acid is selected from the group consisting of neodecanoic acid, isostearic acid, caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, and combinations thereof. 27. The fatty esters include glycerides, ethylene glycol monoesters and diesters of fatty acids, propylene glycol monoesters and diesters of fatty acids, sorbitan esters, C 1-6 Alkyl esters and di-(C 1-6 17. The topical formulation of claim 16, wherein the compound is selected from the group consisting of alkyl) esters. 28. 18. The topical formulation of claim 17, wherein the one or more solvents or penetration enhancers are selected from the group consisting of DMSO, oleic acid, oleyl alcohol, 2-(2-ethoxyethoxy)ethanol, dipropylene glycol, and PEG400. 29. 17. The topical formulation of claim 16, wherein DMSO, if present, is present in an amount of 30% to 50%, 20% to 50%, 30% to 40%, 20% to 40%, or 20% to 30% by weight of the base formulation. 30. Said C 2-6 17. A topical formulation according to claim 16, wherein alcohol is absent. 31. 14. The topical formulation according to claim 13, wherein said compound of formula (I) is in a salt-free form. 32. 32. The topical preparation according to any one of the above 13 to 31, further comprising a stabilizer. 33. 33. A topical formulation according to any of the above 13 to 32, wherein the compound of formula (I) is present in an amount of 0.05% to 15%, 0.5% to 10%, 1% to 10%, 2% to 10%, 5% to 10%, or 2% to 5% by weight of the base formulation on a salt-free and anhydrous basis. 34. 34. A topical formulation according to any one of claims 13 to 33, wherein the relative purity of the compound having formula (I) decreases by less than 10% over a period of 10 days at a temperature of 80°C or over a period of 6 months at a temperature of 40°C and 75% relative humidity. 35. from the compound having formula (I) to the compound having formula (IV): [ka] 35. A topical formulation according to any of claims 13 to 34, wherein hydrolysis to the corresponding compound having the formula: 36. 36. A topical formulation according to any one of claims 13 to 35, wherein the skin permeation rate of the compound having formula (I) is increased by more than two-fold compared to the skin permeation rate of the corresponding compound having formula (IV) in the same topical formulation. 37. 37. A topical formulation according to any one of claims 13 to 36, wherein the skin permeation rate of the compound having formula (I) is increased by 2 to 5 times compared to the skin permeation rate of the corresponding compound having formula (IV) in the same topical formulation. 38. The compound of formula (I) has formula (IIa): [ka] 38. The topical preparation according to any one of the above 13 to 37, represented by the formula: 39. wherein said compound of formula (I) [ka] 38. The topical preparation according to any one of the above 13 to 37, represented by a formula selected from the group consisting of: 40. The compound of formula (I) has the formula: [ka] 39. The topical preparation according to any one of the above items 13 to 38, represented by the formula: 41. The compound of formula (I) has the formula: [ka] 40. The topical preparation according to any one of the above items 13 to 37 and 39, represented by the formula: 42. A method for treating vascular malformations through inhibition of phosphoinositide-3-kinase (PI3K), comprising administering to a subject in need of such treatment an effective amount of the local preparation described in any one of 13 to 41 above. 43. 43. The method according to claim 42, wherein the vascular malformation is a venous malformation, an arterial malformation, an arteriovenous malformation, or a lymphatic malformation. 44. 44. The method of claim 42 or 43, wherein the topical formulation is administered topically. 45. 45. The method according to any one of claims 42 to 44, wherein the topical formulation is administered as a lotion, spray, ointment, cream, gel, paste, or patch. 46. 46. ​​The method according to any one of claims 42 to 45, wherein the conversion of said compound having formula (I) to the corresponding compound having formula (IV) after passing through the skin is at least 50% over 24 hours.

Claims

1. Formula (II): 【Chemistry 1】 or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof, During the ceremony, L 1 is —C(O)— or —C(O)O—, R 1 But C 1-6 Alkyl, or C 2-6 is alkenyl, The compound, or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof.

2. Formula (IIa): 【Chemistry 2】 2. The compound of claim 1 having the formula:

3. Formula (IIb): 【Transformation 3】 2. The compound of claim 1 having the formula:

4. R 1 is C 1-6 The compound according to any one of claims 1 to 3, which is alkyl.

5. R 1 The compound according to any one of claims 1 to 4, wherein is methyl or ethyl.

6. R 1 The compound of claim 5 , wherein is methyl.

7. The following formula: 【Chemistry 4】 2. The compound of claim 1 selected from the group consisting of:

8. The following formula 【Transformation 5】 2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

9. The following formula 【Transformation 6】 2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

10. The following formula 【Transformation 7】 2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

11. 1. A topical formulation comprising: a) Formula (II): 【Transformation 8】 or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof, During the ceremony, L 1 is —C(O)— or —C(O)O—, and R 1 But C 1-6 Alkyl, or C 2-6 Alkenyl a compound, or a hydrate, solvate, and / or pharmaceutically acceptable salt thereof, and b) one or more topical excipients 1. A topical formulation comprising:

12. 12. The topical formulation of claim 11, selected from the group consisting of a lotion, a spray, an ointment, a cream, a gel, a paste, and a patch.

13. the one or more topical excipients are selected from the group consisting of one or more solvents, one or more penetration enhancers, one or more gelling agents, and combinations thereof; Optionally, the one or more solvents or penetration enhancers are selected from the group consisting of C 2-6 Alcohol, C 2-6 Alkylene glycol, di-(C 2-6 alkylene) glycol, polyethylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH, DMSO, fatty alcohols, fatty acids, and fatty esters; and / or 12. The topical formulation of claim 11, wherein the one or more gelling agents are selected from the group consisting of hydroxypropyl cellulose, carbopol, carboxymethyl cellulose, ethyl cellulose, gelatin, hydroxyethyl cellulose, magnesium aluminum silicate, methyl cellulose, poloxamer, polyvinyl alcohol, sodium alginate, tragacanth, xanthan gum, and combinations thereof.

14. The one or more solvents or penetration enhancers are di-(C 2-6 alkylene) glycol, polyethylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 14. The topical formulation of claim 13, wherein the hydroxyl group is selected from the group consisting of -OH, DMSO, fatty alcohols, and fatty acids.

15. The di-(C 2-6 The C alkylene glycol is dipropylene glycol, the polyethylene glycol is PEG 400, and / or 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 15. The topical formulation of claim 13 or 14, wherein -OH is 2-(2-ethoxyethoxy)ethanol.

16. the fatty alcohol is selected from capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleic alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, and combinations thereof; The fatty acids include capric acid, neodecanoic acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, isostearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, behenic acid, tricosylic acid, lignoceric acid, caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccinal acid, gadoleic acid, and eicose. and / or selected from the group consisting of carboxylic acid, erucic acid, brassidic acid, nervonic acid, linoleic acid, eicosadienoic acid, docosadienoic acid, α-linolenic acid, γ-linolenic acid, columbic acid, pinolenic acid, α-eleostearic acid, β-eleostearic acid, mead acid, dihomo-γ-linolenic acid, eicosatrienoic acid, stearidonic acid, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, and combinations thereof; The fatty esters include glycerides, ethylene glycol monoesters and diesters of fatty acids, propylene glycol monoesters and diesters of fatty acids, sorbitan esters, C esters of fatty acids, and the like. 1-6 Alkyl esters and di-(C 1-6 14. The topical formulation of claim 13, wherein the hydroxybenzoate is selected from the group consisting of hydroxybenzoates (alkyl).

17. 15. The topical formulation of claim 13 or 14, wherein the fatty acid is selected from the group consisting of neodecanoic acid, isostearic acid, caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, and combinations thereof.

18. 15. The topical formulation of claim 13 or 14, wherein the one or more solvents or penetration enhancers are selected from the group consisting of DMSO, oleic acid, oleyl alcohol, 2-(2-ethoxyethoxy)ethanol, dipropylene glycol, and PEG 400.

19. 19. The topical formulation of claim 13, 14, or 18, wherein DMSO, if present, is present in an amount of 30% to 50%, 20% to 50%, 30% to 40%, 20% to 40%, or 20% to 30% by weight of the base formulation.

20. 12. The topical formulation of claim 11, wherein said compound of formula (II) is in a salt-free form.

21. 21. The topical formulation of any one of claims 11 to 20, wherein the compound of formula (II) is present in an amount of 0.05% to 15%, 0.5% to 10%, 1% to 10%, 2% to 10%, 5% to 10%, or 2% to 5% by weight of the base formulation on a salt-free and anhydrous basis.

22. from the compound having formula (II) to the compound having formula (IV): 【Chemistry 9】 22. A topical formulation according to any one of claims 11 to 21, wherein the formulation undergoes less than 10% hydrolysis at a temperature of 80°C over a period of 10 days or at a temperature of 40°C and 75% humidity over a period of 6 months to the corresponding compound having the formula:

23. In the same topical formulation, the skin permeation rate of the compound having formula (II) is determined by the compound having formula (IV): 【Chemistry 10】 23. The topical formulation of any one of claims 11 to 22, wherein the skin permeation rate is 2 to 5 times that of the corresponding compound having the formula:

24. The compound of formula (II) has the formula: 【Chemistry 11】 The topical formulation according to any one of claims 11 to 23, wherein the compound is represented by the formula:

25. 25. A topical formulation comprising a compound of any one of claims 1 to 10 and one or more topical excipients, or a topical formulation of any one of claims 11 to 24, for the treatment of a vascular malformation in a subject in need thereof.

26. 26. The topical formulation of claim 25, wherein the vascular malformation is a venous malformation, an arterial malformation, an arteriovenous malformation, or a lymphatic malformation.

27. 27. The topical formulation of any one of claims 25 to 26, wherein the topical formulation is administered as a lotion, spray, ointment, cream, gel, paste, or patch.

28. After passing through the skin, the compound having formula (II) is converted to a compound having formula (IV): 【Chemistry 12】 28. A topical formulation according to any one of claims 25 to 27, wherein the conversion to the corresponding compound having the formula:

29. The compound of formula (II) is 【Chemistry 13】 The topical formulation according to any one of claims 25 to 28, wherein the compound is represented by the formula:

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