Methods and compositions for treating cancer

Abstract

Disclosed herein is a method for treating squamous cell carcinoma (SCC), a disease, such as SCC associated with recessive dystrophic epidermolysis bullosa (RDEB). The disclosed method describes administering a therapeutically effective amount of (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetic acid, or its pharma- ceutically acceptable salt or zwitterion, and its derivatives. Disclosed herein is a method for treating a condition in a subject in need of treatment of the condition.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 232,409, filed Aug. 12, 2021, the entirety of which is incorporated by reference herein. [Background technology]

[0002] background Some lung adenocarcinomas have KRAS mutations as their primary genetic driver. Tumors with mutations in KRAS may have a worse prognosis than KRAS wild-type tumors. Treatments that can target the KRAS pathway may benefit patients with cancers that have KRAS mutations.

[0003] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Summary of the Invention [Means for solving the problem]

[0004] Disclosed herein is a method of treating a condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of formula: [ka] or a pharma- ceutically acceptable salt or zwitterion thereof, During the ceremony, - Each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R12 , and R 13 are independently alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, C(O)R x , C(O)OR x , C(O)NR x R y , OR x , S.R. x , N.R. x R y , N.R. x C(O)R y , O.C.(O)R x , or SiR x R y R z (each of which is independently substituted or unsubstituted), or hydrogen or halogen; - Each R x , R y , and R z is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; administering a compound or a pharma- ceutically acceptable salt or zwitterion thereof, The condition is recessive dystrophic epidermolysis bullosa, Lesions in skin areas associated with recessive dystrophic epidermolysis bullosa resolve within about 12 weeks of treatment as determined by magnetic resonance imaging of the skin areas. [Brief description of the drawings]

[0005] [Figure 1] Rigosertib induces cell death in RDEB SCC keratinocytes without affecting normal primary keratinocytes. Panel A. Cells were seeded at high density and exposed to rigosertib or vehicle control for 48 hours, after which the cells were fixed and stained with crystal violet. Panel B. Phase contrast images of unfixed cells in culture after receiving either control (left) or rigosertib (1 μM, right) treatment.

[0006] [Diagram 2] Rigosertib inhibits RDEB SCC keratinocytes growing in vivo. SCC RDEB16 keratinocytes were inoculated subcutaneously into Balb / c SCID mice. After tumors reached 100 mm3, vehicle control, rigosertib or compound 1 (ATP-competitive inhibitor) were administered six times and tumor volumes were measured with calipers. Tumors were harvested and photographed on day 35.

[0007] [Diagram 3] Figure 3 shows clinical photographic images of the target legions on the left hand (panels 3A, 3C, 3E, 3G, and 3I) and right elbow (panels 3B, 3D, 3F, 3H, and 3J) in V1 (day 1), V13 (days 85-95), V25 (days 169-175), V41 (days 281-283), and V52 (days 358-364). Both lesions in V25 were biopsied, but there was no histological evidence of malignancy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Detailed Description Ras is a gene that often mutates and causes cancer. A significant number of patients with non-small cell lung cancer (NSCLC) have mutations in RAS, most commonly KRAS. In some embodiments, the mechanism of action of the compounds disclosed herein, such as rigosertib, is to downregulate the mutated RAS pathway. This modulation of the RAS pathway can lead to less production of ERK, a protein involved in cell proliferation. When ERK is overexpressed, it can provide a growth advantage to cells, thus leading to cancer. KRAS-mutated NSCLC can be managed, for example, with checkpoint inhibitors.

[0009] Rigosertib ((E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetic acid, or a pharma- ceutically acceptable salt or zwitterion thereof) can block the RAS cascade and promote the expression of novel antigens on the tumor surface. This process can change a cold tumor, not surrounded by host lymphocytes, into a hot tumor, surrounded by host lymphocytes. This modulation of the tumor microenvironment (TME) combined with checkpoint blockade can promote the host immune system to contribute to tumor control. Host lymphocytes can contribute to tumor control when exposed to checkpoint inhibitors.

[0010] The present disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula: [ka] or a pharma- ceutically acceptable salt or zwitterion thereof, During the ceremony, - Each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 12 , and R 13 are independently alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, C(O)R x , C(O)OR x , C(O)NR x R y , OR x , S.R. x , N.R. x R y , N.R. x C(O)R y , O.C.(O)R x , or SiR xR y R z (each of which is independently substituted or unsubstituted), or hydrogen or halogen; - Each R x , R y , and R z is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; administering a compound or a pharma- ceutically acceptable salt or zwitterion thereof, The condition is recessive dystrophic epidermolysis bullosa, Lesions in skin areas associated with recessive dystrophic epidermolysis bullosa resolve within about 12 weeks of treatment as determined by magnetic resonance imaging of the skin areas.

[0011] The present disclosure also provides a method of treating squamous cell carcinoma, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of the present disclosure, such as (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetic acid, or a pharma- ceutically acceptable salt or zwitterion thereof, in a unit dosage form.

[0012] The disclosure further provides a method of treating a subject having locally advanced / metastatic squamous cell carcinoma (SCC) associated with recessive dystrophic epidermolysis bullosa (RDEB), comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of the disclosure, e.g., (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetic acid, or a pharma- ceutically acceptable salt or zwitterion thereof, in a unit dosage form.

[0013] Compounds of the Disclosure In some embodiments, the formula: [ka] A compound of the formula: During the ceremony, - Each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 12 , and R 13 are independently alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, C(O)R x , C(O)NR x R y , OR x , S.R. x , N.R. x R y , N.R. x C(O)R y , O.C.(O)R x , or SiR x R y R z (each of which is independently substituted or unsubstituted), or hydrogen or halogen; - Each R x , R y , and R z Disclosed herein is a compound, or a pharma- ceutically acceptable salt or zwitterion thereof, wherein: is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl (each of which is independently substituted or unsubstituted), or hydrogen or halogen.

[0014] In some embodiments, R 1 , R 3 , and R 5 is the same. In some embodiments, R 1 , R 3 , R 5 , and R 8 In some embodiments, each R 1 , R 3, and R 5 are, independently, OR x In some embodiments, each R 1 , R 3 , R 5 , and R 8 are, independently, OR x In some embodiments, each R x is independently alkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, each R x is hydrogen. In some embodiments, each R x is independently an unsubstituted C 1~6 In some embodiments, each R x is independently an unsubstituted C 1~3 In some embodiments, each R x is methyl. In some embodiments, each R x is ethyl. In some embodiments, each R x is independently substituted C 1~6 In some embodiments, each R x is independently substituted C 1~3 In some embodiments, each R x is a C alkyl substituted with hydroxy, sulfhydryl, halogen, amino, nitro, cyano, sulfoxide, sulfone, sulfonamide, carboxyl, carboxylic acid, carboxaldehyde, alkoxy, aryl, heterocyclyl, acyl, amide, or ester.

[0015] In some embodiments, R 2 is hydrogen. In some embodiments, R 4 is hydrogen. In some embodiments, R 6 is hydrogen. In some embodiments, R 9 is hydrogen. In some embodiments, R 10 is hydrogen.

[0016] In some embodiments, R7 is alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, OR x , or N.R. x R y In some embodiments, R 7 is NR x R y In some embodiments, R x is hydrogen. In some embodiments, R y is hydrogen. In some embodiments, R y is substituted alkyl. In some embodiments, R y is replaced by C 1~6 In some embodiments, R y is a C alkyl substituted with hydroxy, sulfhydryl, halogen, amino, nitro, cyano, sulfoxide, sulfone, sulfonamide, carboxyl, carboxylic acid, carboxaldehyde, alkoxy, aryl, heterocyclyl, acyl, amide, or ester. y is CH2COOH.

[0017] In some embodiments, each R 11a and R 11b is independently alkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, each R 11a and R 11b is independently substituted C 1~6 In some embodiments, each R 11a and R 11b is independently an unsubstituted C 1~6 In some embodiments, each R 12 and R 13 is independently alkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, each R 12 and R 13 is independently substituted C1~6 In some embodiments, each R 12 and R 13 is independently an unsubstituted C 1~6 In some embodiments, R 11a is hydrogen. In some embodiments, R 11b is hydrogen. In some embodiments, R 12 is hydrogen. In some embodiments, R 13 is hydrogen.

[0018] In some embodiments, the present disclosure provides a compound of the formula [ka] is disclosed.

[0019] In some embodiments, the compound has the formula: [ka] has.

[0020] In some embodiments, each R 1 , R 3 , R 5 , and R 8 are, independently, OR x In some embodiments, each R x is independently alkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, each R x is independently hydrogen. In some embodiments, each R x is independently an unsubstituted C 1~6 In some embodiments, each R x is independently an unsubstituted C 1~3 In some embodiments, each R x is independently methyl. In some embodiments, each R x is independently ethyl. In some embodiments, each R xis independently substituted C 1~6 In some embodiments, each R x is independently substituted C 1~3 In some embodiments, each R x is independently substituted methyl.

[0021] In some embodiments, each R 14 and R 15 is independently alkyl, alkoxy, aryl, heteroaryl, heterocyclyl (each of which is independently substituted or unsubstituted), or hydrogen. In some embodiments, R 14 is H. In some embodiments, R 15 is H. In some embodiments, R 15 is substituted alkyl. In some embodiments, R 15 is replaced by C 1~6 In some embodiments, R 15 is a substituted C alkyl. In some embodiments, R 15 is CH2COOH.

[0022] In some embodiments, the compound has the formula: [ka] has.

[0023] In some embodiments, each R 1a , R 3a , R 5a , and R 8a In some embodiments, each R 1a , R 3a , R 5a , and R 8a In some embodiments, each R 1a , R 3a , R 5a , and R 8a is independently substituted or unsubstituted alkyl. In some embodiments, each R 1a, R 3a , R 5a , and R 8a are independently substituted or unsubstituted C 1~8 In some embodiments, each R 1a , R 3a , R 5a , and R 8a are independently substituted or unsubstituted C 1~3 In some embodiments, each R 1a , R 3a , R 5a , and R 8a is independently a substituted or unsubstituted C alkyl. In some embodiments, each R 1a , R 3a , R 5a , and R 8a is independently methyl. In some embodiments, each R 1a , R 3a , R 5a , and R 8a is independently ethyl.

[0024] In some embodiments, each R 14 and R 15 is independently alkyl, alkoxy, aryl, heteroaryl, heterocyclyl (each of which is independently substituted or unsubstituted), or hydrogen. In some embodiments, R 14 is H. In some embodiments, R 15 is H. In some embodiments, R 15 is substituted alkyl. In some embodiments, R 15 is replaced by C 1~6 In some embodiments, R 15 is a substituted C alkyl. In some embodiments, R 15 is CH2COOH.

[0025] In some embodiments, the compound has the formula: [ka] has.

[0026] In some embodiments, each R 1a , R 3a , R 5a , and R 8a is independently substituted or unsubstituted alkyl. In some embodiments, each R 1a , R 3a , R 5a , and R 8a are independently substituted or unsubstituted C 1~8 In some embodiments, R 1a is C 1~6 In some embodiments, R 3a is C 1~6 In some embodiments, R 5a is C 1~6 In some embodiments, R 8a is C 1~6 In some embodiments, R 1a is methyl. In some embodiments, R 3a is methyl. In some embodiments, R 5a is methyl. In some embodiments, R 8a is methyl.

[0027] In some embodiments, R 15 is substituted alkyl. In some embodiments, R 15 is replaced by C 1~6 In some embodiments, R 15 is a substituted C alkyl. In some embodiments, R 15 is CH2COOH.

[0028] In some embodiments, the present disclosure provides a compound of the formula [ka] Disclosed is (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetic acid, or a pharma- ceutically acceptable salt or zwitterion thereof. In some embodiments, the compound is [ka] (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetic acid sodium. In some embodiments, the compounds disclosed herein are sodium salts.

[0029] Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azide groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, acyloxy groups, carbamate groups, amide groups, ureido groups, epoxy groups, and ester groups.

[0030] Non-limiting examples of alkyl and alkylene groups include linear, branched, and cyclic alkyl and alkylene groups. The alkyl or alkylene group can be, for example, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C5 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 In some embodiments, the alkyl or alkylene may be a substituted or unsubstituted C 1~8 Alkyl or C 1~8 In some embodiments, the alkyl or alkylene is a substituted or unsubstituted C 1~6 Alkyl or C 1~6 In some embodiments, the alkyl or alkylene is a substituted or unsubstituted C 1~3 Alkyl or C 1~3 It is alkylene.

[0031] Non-limiting examples of straight chain alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0032] Branched alkyl groups include any straight chain alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, and t-butyl.

[0033] Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, and 3-carboxypropyl.

[0034] Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also include fused, bridged, and spiro bicycles, as well as higher fused, bridged, and spiro systems. Cyclic alkyl groups may be substituted with any number of linear, branched, or cyclic alkyl groups. Non-limiting examples of cyclic alkyl groups include cyclopropyl, 2-methyl-cycloprop-1-yl, cycloprop-2-en-1-yl, cyclobutyl, 2,3-dihydroxycyclobut-1-yl, cyclobut-2-en-1-yl, cyclopentyl, cyclopent-2-en-1-yl, cyclopenta-2,4-dien-1-yl, cyclohexyl, cyclohex-2-en-1-yl, cycloheptyl, cyclooctanyl, 2,5-dimethylcyclopent-1-yl, 3,5-dichlorocyclohex-1-yl, 4- Examples include hydroxycyclohex-1-yl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

[0035] Non-limiting examples of alkenyl and alkenylene groups include linear, branched, and cyclic alkenyl groups. The olefin(s) of the alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene. The alkenyl or alkenylene group can be, for example, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 Non-limiting examples of alkenyl and alkenylene groups include ethenyl, prop-1-en-1-yl, isopropenyl, but-1-en-4-yl, 2-chloroethenyl, 4-hydroxybuten-1-yl, 7-hydroxy-7-methyloct-4-en-2-yl, and 7-hydroxy-7-methylocta-3,5-dien-2-yl.

[0036] Non-limiting examples of alkynyl or alkynylene groups include linear, branched, and cyclic alkynyl groups. The triple bond of the alkynyl or alkynylene group can be internal or terminal. The alkynyl or alkynylene group can be, for example, a substituted or unsubstituted C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C67, C68, C69, C70, C71, C72, C73, C74, C75, C76, C77, C78, ​​C79, C82, C83, C84, C85, C86, C87, C88, C89, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C101, C102, C103, C104, 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 Non-limiting examples of alkynyl or alkynylene groups include ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, and 2-methyl-hex-4-yn-1-yl; 5-hydroxy-5-methylhex-3-yn-1-yl, 6-hydroxy-6-methylhept-3-yn-2-yl, and 5-hydroxy-5-ethylhept-3-yn-1-yl.

[0037] A halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, such as fluorine, chlorine, bromine, and iodine atoms. A halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms. A halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms.

[0038] An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group. An ether or ether group comprises an alkoxy group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.

[0039] The aryl group may be heterocyclic or non-heterocyclic. The aryl group may be monocyclic or polycyclic. The aryl group may be substituted with any number of substituents described herein, such as hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms. Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl. Non-limiting examples of substituted aryl groups include 3,4-dimethylphenyl, 4-tert-butylphenyl, 4-cyclopropylphenyl, 4-diethylaminophenyl, 4-(trifluoromethyl)phenyl, 4-(difluoromethoxy)-phenyl, 4-(trifluoromethoxy)phenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 2-chlorophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-fluorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydro ... methoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 3,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,Examples of the phenyl group include 6-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, 2,4,6-triethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, and 4-isopropylphenyl.

[0040] Non-limiting examples of substituted aryl groups include 2-aminophenyl, 2-(N-methylamino)phenyl, 2-(N,N-dimethylamino)phenyl, 2-(N-ethylamino)phenyl, 2-(N,N-diethylamino)phenyl, 3-aminophenyl, 3-(N-methylamino)phenyl, 3-(N,N-dimethylamino)phenyl, 3-(N-ethylamino)phenyl, 3-(N,N-diethylamino)phenyl, 4-aminophenyl, 4-(N-methylamino)phenyl, 4-(N,N-dimethylamino)phenyl, 4-(N-ethylamino)phenyl, and 4-(N,N-diethylamino)phenyl.

[0041] Heterocycles can be any ring containing non-carbon ring atoms, such as N, O, S, P, Si, B, or any other heteroatom. Heterocycles can be substituted with any number of substituents, such as alkyl groups and halogen atoms. Heterocycles can be aromatic (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.

[0042] Non-limiting examples of heterocyclic rings include heterocyclic units having a single ring containing one or more heteroatoms, non-limiting examples of which include diazirinyl, aziridinyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl, 2,3,4,5-tetrahydro-1H-azepicyclyl, and the like. ii) heterocyclic units having two or more rings, one of which is a heterocyclic ring (non-limiting examples of which include hexahydro-1H-pyrrolidinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, and decahydro-1H-cycloocta[b]pyrrolyl).

[0043] Non-limiting examples of heteroaryls include i) heteroaryl rings containing a single ring, non-limiting examples of which include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl; and ii) heteroaryl rings containing two or more rings, non-limiting examples of which include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Included are heteroaryl rings that contain multiple fused rings, one of which is a heteroaryl ring (non-limiting examples of which include 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinolinyl).

[0044] Any of the compounds herein may be purified. The compounds herein may be at least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure , at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure,It may be at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure.

[0045] In some embodiments, the compound is at least about 85% pure. In some embodiments, the compound is at least about 90% pure. In some embodiments, the compound is at least about 95% pure. In some embodiments, the compound is at least about 98% pure. In some embodiments, the compound is at least about 99% pure. In some embodiments, the compound is at least about 99.5% pure.

[0046] Pharmaceutically acceptable salts The method disclosed herein provides for the use of any compound described herein with pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts. The acid that is added to the compound to generate an acid addition salt can be an organic acid or an inorganic acid. The base that is added to the compound to generate a base addition salt can be an organic base or an inorganic base. In some embodiments, the pharmaceutically acceptable salt is a metal salt. In some embodiments, the pharmaceutically acceptable salt is a sodium salt.

[0047] Metal salts can result from the addition of inorganic bases to the compounds disclosed herein. Inorganic bases consist of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, an alkaline earth metal, a transition metal, or a main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0048] In some embodiments, the metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.

[0049] Acid addition salts may result from the addition of an acid to a compound disclosed herein. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

[0050] In some embodiments, the salt is a hydrochloride, hydrobromide, hydroiodide, nitrate, nitrite, sulfate, sulfite, phosphate, isonicotinate, lactate, salicylate, tartrate, ascorbate, gentisinate salt, gluconate, glucaronate salt, saccarate salt, formate, benzoate, glutamate, pantothenate, acetate, propionate, butyrate, fumarate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate, oxalate, or maleate salt.

[0051] Pharmaceutical Compositions A pharmaceutical composition of the invention may be used, eg, before, during, or after treatment of a subject with another pharmaceutical agent.

[0052] The subject can be, for example, an older adult, an adult, an adolescent, a pre-adolescent, a child, a toddler, an infant, a newborn, and a non-human animal. In some embodiments, the subject is a patient.

[0053] The pharmaceutical composition of the present invention may be a combination of any pharmaceutical compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. The pharmaceutical composition may be administered in a therapeutically effective amount as a pharmaceutical composition by various forms and routes, including, for example, intravenous, subcutaneous, intramuscular, oral, parenteral, ophthalmic, subcutaneous, transdermal, nasal, vaginal, and topical administration. The pharmaceutical composition facilitates the administration of the compound to an organism. The pharmaceutical composition may be administered in a therapeutically effective amount as a pharmaceutical composition by various forms and routes, including, for example, intravenous, intravitreal, intranasal, inhalation, nasal inhalation, oral inhalation, intratracheal, intrapulmonary, transmucosal, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, aural, nasal, and topical administration.

[0054] The pharmaceutical composition can be administered in a localized manner, for example, by injecting the compound directly into an organ, optionally in a depot or sustained release formulation or implant.The pharmaceutical composition can be provided in the form of a fast release formulation, a sustained release formulation, or an intermediate release formulation.The fast release form can provide immediate release.The sustained release formulation can provide controlled release or sustained delayed release.

[0055] For oral administration, pharmaceutical compositions can be formulated by combining active compounds with pharma- ceutical acceptable carriers or excipients.Such carriers can be used to formulate tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, or suspensions for oral ingestion by subjects.Non-limiting examples of solvents used in oral dissolving formulations can include water, ethanol, isopropanol, saline, saline, DMSO, dimethylformamide, potassium phosphate buffer, phosphate buffered saline (PBS), sodium phosphate buffer, 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N'-bis(2-ethanesulfonic acid) buffer (PIPES), and saline sodium citrate buffer (SSC). Non-limiting examples of co-solvents used in orally soluble formulations can include sucrose, urea, cremaphor, DMSO, and potassium phosphate buffer.

[0056] In some embodiments, the compositions of the present disclosure may be formulated for oral administration. In some embodiments, the compounds of the present disclosure may be formulated as capsules. In some embodiments, the compounds of the present disclosure may be formulated as soft gelatin capsules. In some embodiments, the compounds of the present disclosure may be formulated as soft gelatin capsules. In some embodiments, the compounds of the present disclosure may be formulated as soft gelatin capsules. In some embodiments, the compounds of the present disclosure may be formulated as soft gelatin capsules. In some embodiments, the compounds of the present disclosure may be formulated as soft gelatin capsules. In some embodiments, the compounds of the present disclosure may be formulated as soft gelatin capsules. In some embodiments, the compounds of the present disclosure may be formulated as soft gelatin capsules. In some embodiments, the compounds of the present disclosure may be formulated as soft gelatin capsules. In some embodiments, the compounds of the present disclosure may be formulated as soft gelatin capsules. In some embodiments, the compounds of the present disclosure may be formulated as soft gelatin capsules. The composition may be formulated to contain a compound of the disclosure at a concentration of at least about 0 mg / mL, at least about 260 mg / mL, at least about 280 mg / mL, at least about 300 mg / mL, at least about 320 mg / mL, at least about 340 mg / mL, at least about 360 mg / mL, at least about 380 mg / mL, at least about 400 mg / mL, at least about 420 mg / mL, at least about 440 mg / mL, at least about 460 mg / mL, at least about 480 mg / mL, or at least about 500 mg / mL. In some embodiments, the compounds of the disclosure may be formulated to contain a compound of the disclosure at a concentration of about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 120 mg / mL, about 140 mg / mL, about 160 mg / mL, about 180 mg / mL, about 200 mg / mL, about 220 mg / mL, about 240 mg / mL, about 260 mg / mL, about 280 mg / mL, about 300 mg / mL, about 320 mg / mL, about 340 mg / mL, about 360 mg / mL, about 380 mg / mL, about 400 mg / mL, about 420 mg / mL, about 440 mg / mL, about 460 mg / mL, about 480 mg / mL, or about 500 mg / mL.In some embodiments, the compounds of the disclosure have a concentration of up to about 20 mg / mL, up to about 30 mg / mL, up to about 40 mg / mL, up to about 50 mg / mL, up to about 60 mg / mL, up to about 70 mg / mL, up to about 80 mg / mL, up to about 90 mg / mL, up to about 100 mg / mL, up to about 120 mg / mL, up to about 140 mg / mL, up to about 160 mg / mL, up to about 180 mg / mL, up to about 200 mg / mL, up to about 220 mg / mL, up to about 240 mg / mL, up to about 260 mg / mL, up to about 280 mg / mL, up to about 300 mg / mL, up to about 320 mg / mL, up to about 360 mg / mL, up to about 380 mg / mL, up to about 390 mg / mL, up to about 400 mg / mL, up to about 420 mg / mL, up to about 440 mg / mL, up to about 460 mg / mL, up to about 480 mg / mL, up to about 490 mg / mL, up to about 500 mg / mL, up to about 520 mg / mL, up to about 540 mg / mL, up to about 560 mg / mL, up to about 580 mg / mL, up to about 590 mg / mL, up to about 600 mg / mL, up to about 620 mg / mL, up to about 640 mg / mL, up to about 650 mg / mL, up to about 660 mg / mL, up to about 670 mg / mL, up to about 680 mg / mL, up to about 690 mg / mL, up to about 700 mg / mL, up to about 720 mg / mL, up to about 740 mg / mL, The compound of the present disclosure may be formulated to contain a compound of the present disclosure at a concentration of about 0 mg / mL, up to about 260 mg / mL, up to about 280 mg / mL, up to about 300 mg / mL, up to about 320 mg / mL, up to about 340 mg / mL, up to about 360 mg / mL, up to about 380 mg / mL, up to about 400 mg / mL, up to about 420 mg / mL, up to about 440 mg / mL, up to about 460 mg / mL, up to about 480 mg / mL, or up to about 500 mg / mL. In some embodiments, the compound of the present disclosure may be formulated to contain a compound of the present disclosure at a concentration of about 70 mg / mL. In some embodiments, the compound of the present disclosure may be formulated to contain a compound of the present disclosure at a concentration of about 100 mg / mL. In some embodiments, the compound of the present disclosure may be formulated to contain a compound of the present disclosure at a concentration of about 150 mg / mL. In some embodiments, the compounds of the present disclosure may be formulated to contain the compounds of the present disclosure at a concentration of about 200mg / mL.In some embodiments, the compounds of the present disclosure may be formulated to contain the compounds of the present disclosure at a concentration of about 250mg / mL.In some embodiments, the compounds of the present disclosure may be formulated to contain the compounds of the present disclosure at a concentration of about 280mg / mL.

[0057] In some embodiments, the compounds of the present disclosure can be formulated in a suspension of polyethylene glycol (PEG) for oral administration.In some embodiments, the compounds of the present disclosure can be formulated in a suspension of PEG400 for oral administration.In some embodiments, the compounds of the present disclosure can be formulated in a suspension of PEG4000 for oral administration.In some embodiments, the compounds of the present disclosure can be formulated in a suspension of PEG400 and PEG4000 for oral administration.

[0058] In some embodiments, a capsule formulated for oral administration may contain at least about 0.1 mL, at least about 0.2 mL, at least about 0.3 mL, at least about 0.4 mL, at least about 0.5 mL, at least about 0.6 mL, at least about 0.7 mL, at least about 0.8 mL, at least about 0.9 mL, at least about 1 mL, at least about 1.1 mL, at least about 1.2 mL, at least about 1.3 mL, at least about 1.4 mL, or at least about 1.5 mL of a solution comprising a compound of the present disclosure. In some embodiments, a capsule formulated for oral administration may contain at least about 0.1 mL, at least about 0.2 mL, at least about 0.3 mL, at least about 0.4 mL, at least about 0.5 mL, at least about 0.6 mL, at least about 0.7 mL, at least about 0.8 mL, at least about 0.9 mL, at least about 1 mL, at least about 1.1 mL, at least about 1.2 mL, at least about 1.3 mL, at least about 1.4 mL, or at least about 1.5 mL of a solution comprising a compound of the present disclosure. In some embodiments, a capsule formulated for oral administration may contain up to about 0.1 mL, up to about 0.2 mL, up to about 0.3 mL, up to about 0.4 mL, up to about 0.5 mL, up to about 0.6 mL, up to about 0.7 mL, up to about 0.8 mL, up to about 0.9 mL, up to about 1 mL, up to about 1.1 mL, up to about 1.2 mL, up to about 1.3 mL, up to about 1.4 mL, or up to about 1.5 mL of a solution comprising a compound of the present disclosure. In some embodiments, a capsule formulated for oral administration may contain up to about 0.5 mL of a solution comprising a compound of the present disclosure. In some embodiments, a capsule formulated for oral administration may contain up to about 0.8 mL of a solution comprising a compound of the present disclosure. In some embodiments, a capsule formulated for oral administration may contain up to about 1 mL of a solution comprising a compound of the present disclosure. In some embodiments, a capsule formulated for oral administration may contain up to about 1.2 mL of a solution comprising a compound of the present disclosure. In some embodiments, a capsule formulated for oral administration may contain up to about 1.5 mL of a solution comprising a compound of the present disclosure.

[0059] In some embodiments, the capsules for oral administration may be clear or transparent. In some embodiments, the capsules for oral administration may be opaque. In some embodiments, the capsules for oral administration may be opaque yellow or orange.

[0060] For oral administration, pharmaceutical compositions can be formulated by combining the active compounds with pharma- ceutically acceptable carriers or excipients.Such carriers can be used to formulate tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, or suspensions for oral ingestion by a subject.

[0061] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, grinding the resulting mixture as necessary, and processing the mixture of granules after adding suitable auxiliaries as required to obtain tablets or dragee cores. The cores can be provided with suitable coatings. For this purpose, excipients such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide, lacquer solutions, and concentrated sugar solutions that can contain suitable organic solvents or solvent mixtures can be used. For example, dyes or pigments can be added to tablets or dragee coatings to identify or characterize different combinations of doses of active compounds.

[0062] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers such as glycerol or sorbitol. In some embodiments, the capsules include hard gelatin capsules that contain one or more of pharmaceutical beef gelatin and vegetable gelatin. The gelatin can be treated with alkali. The push-fit capsules can contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, or a lubricant such as talc or magnesium stearate, and a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Stabilizers can be added. All preparations for oral administration are provided in dosages suitable for such administration.

[0063] For buccal or sublingual administration, the compositions may be tablets, lozenges, or gels.

[0064] The pharmaceutical preparation may be formulated for intravenous administration. The pharmaceutical composition may be in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain a formulatory agent such as a suspending agent, a stabilizing agent, and / or a dispersing agent. Pharmaceutical preparations for parenteral administration include aqueous solutions of the active compound in water-soluble form. Suspensions of the active compound may be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. The suspension may also contain suitable stabilizers, or agents that increase the solubility of the compound, to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0065] The pharmaceutical formulations disclosed herein may be, for example, parenteral formulations of solutions of active pharmaceutical ingredients (APIs). In some embodiments, the compounds of the present disclosure may be prepared for intravenous administration at a concentration of about 25 mg / mL to about 50 mg / mL, about 50 mg / mL to about 75 mg / mL, about 75 mg / mL to about 100 mg / mL, about 100 mg / mL to about 125 mg / mL, about 125 mg / mL to about 150 mg / mL, about 150 mg / mL to about 175 mg / mL, about 175 mg / mL to about 200 mg / mL, about 200 mg / mL to about 225 mg / mL, or about 225 mg / mL to about 250 mg / mL in a liquid vehicle. In some embodiments, the compounds of the present disclosure may be prepared for intravenous administration at a concentration of at least about 25 mg / mL, at least about 50 mg / mL, at least about 75 mg / mL, at least about 100 mg / mL, at least about 125 mg / mL, at least about 150 mg / mL, at least about 175 mg / mL, at least about 200 mg / mL, at least about 225 mg / mL, or at least about 250 mg / mL in a liquid vehicle. In some embodiments, the compounds of the present disclosure may be prepared for intravenous administration at a concentration of at least about 25 mg / mL, at least about 50 mg / mL, at least about 75 mg / mL, at least about 100 mg / mL, at least about 125 mg / mL, at least about 150 mg / mL, at least about 175 mg / mL, at least about 200 mg / mL, at least about 225 mg / mL, or at least about 250 mg / mL in a liquid vehicle. In some embodiments, the compounds of the present disclosure may be prepared for intravenous administration at a concentration of up to about 25 mg / mL, up to about 50 mg / mL, up to about 75 mg / mL, up to about 100 mg / mL, up to about 125 mg / mL, up to about 150 mg / mL, up to about 175 mg / mL, up to about 200 mg / mL, up to about 225 mg / mL, or up to about 250 mg / mL in the liquid vehicle. In some embodiments, the liquid vehicle is an organic solvent. In some embodiments, the liquid vehicle is polyethylene glycol (PEG). In some embodiments, the liquid vehicle is PEG400. In some embodiments, the liquid vehicle is adjusted to pH 7-13 or pH 12-13 using sodium hydroxide (NaOH) solution.In some embodiments, a pharmaceutical composition for intravenous administration may include a compound of the present disclosure at a concentration of about 75 mg / mL in a liquid vehicle of polyethylene glycol (PEG) 400, adjusted to pH 7-13 or pH 12-13 by the use of sodium hydroxide (NaOH) solution. The solution may be a clear, colorless to light yellow, sterile, preservative-free solution packaged in a clear glass vial sealed with a Teflon-coated rubber stopper. The vial disclosed herein may be, for example, a 30 mL clear glass vial containing 24 mL of parenteral formulation. If the parenteral formulation is administered IV, dilution with IV saline may be required.

[0066] Parenteral injections may be formulated for bolus injection or continuous infusion. Pharmaceutical compositions may be in a form suitable for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. Suspensions of the active compound may be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Suspensions may also contain suitable stabilizers, or agents that increase the solubility of the compound, to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0067] The active compound may be administered topically and may be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments. Such pharmaceutical compositions may contain solubilizers, stabilizers, isotonicity enhancers, buffers, and preservatives. The pharmaceutical composition of the compounds disclosed herein may be a combination of any pharmaceutical compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, or excipients. The pharmaceutical composition facilitates administration of the compound to an organism.

[0068] The compounds of the invention may be applied topically to the skin or to a body cavity of a subject, such as the oral, vaginal, bladder, cranial, spinal, thoracic or pelvic cavity. The compounds of the invention may be applied to any accessible body cavity.

[0069] The compounds can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone and PEG. In the suppository form of the composition, a low melting wax such as a mixture of fatty acid glycerides, optionally combined with cocoa butter, may be melted.

[0070] When practicing the method or use of treatment provided herein, a therapeutically effective amount of the compound described herein is administered in a pharmaceutical composition to a subject having a disease or condition to be treated.In some embodiments, the subject is a mammal, such as a human.The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors.The compound can be used alone or in combination with one or more therapeutic agents as a component of a mixture.

[0071] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers, including excipients and auxiliary agents, which facilitate the processing of active compounds into medicament-usable preparations.Formulations may be modified according to the route of administration selected.The pharmaceutical compositions comprising the compounds described herein may be prepared, for example, by mixing, dissolving, emulsifying, encapsulating, entrapping or compressing process.

[0072] Pharmaceutical compositions can include at least one pharma- ceutically acceptable carrier, diluent, or excipient, and the compounds described herein as free base or pharma- ceutically acceptable salt form. Pharmaceutical compositions may also contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives. The methods and pharmaceutical compositions described herein include the use of crystalline forms (also known as polymorphs) and active metabolites of these compounds that have the same type of activity.

[0073] The method of preparing a composition comprising the compound described herein includes formulating the compound with one or more inert pharma- ceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets. Liquid compositions include, for example, solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compound described herein. Semi-solid compositions include, for example, gels, suspensions, and creams. The composition may be a liquid solution or suspension, a solid form suitable for dissolving or suspending in liquid before use, or an emulsion. These compositions may also contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharma- ceutical acceptable additives.

[0074] Non-limiting examples of dosage forms suitable for use in the present invention include liquids, powders, gels, nanosuspensions, nanoparticles, microgels, aqueous or oily suspensions, emulsions, and any combination thereof.Non-limiting examples of dosage forms suitable for use in the methods disclosed herein include feed, food, pellets, lozenges, liquids, elixirs, aerosols, inhalants, sprays, powders, tablets, pills, capsules, gels, gel tabs, nanosuspensions, nanoparticles, microgels, suppositories, troches, aqueous or oily suspensions, ointments, patches, lotions, dentifrices, emulsions, creams, drops, dispersible powders or granules, emulsions in hard or soft gel capsules, syrups, phytoceuticals, nutraceuticals, and any combination thereof.

[0075] Non-limiting examples of dosage forms suitable for use in the present invention include liquids, powders, gels, nanosuspensions, nanoparticles, microgels, aqueous or oily suspensions, emulsions, and any combination thereof.Non-limiting examples of pharma- ceutically acceptable excipients suitable for use in the methods disclosed herein include granulating agents, binders, lubricants, disintegrants, sweeteners, glidants, anti-adhesive agents, antistatic agents, surfactants, antioxidants, gums, coating agents, colorants, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifiers, antimicrobial agents, plant cellulosic materials, and spheronization agents, and any combination thereof.

[0076] The composition of the present invention can be, for example, an immediate release form or a controlled release formulation.The immediate release formulation can be formulated to make the compound act quickly.Non-limiting examples of immediate release formulation include formulations that are easily soluble.The controlled release formulation can be a pharmaceutical formulation that is adapted so that the release rate and release profile of active agent can meet the requirements of physiology and chronotherapeutics, or is formulated to produce the release of active agent at a programmed rate.

[0077] In some cases, the controlled release formulation is a delayed release form.The delayed release form may be formulated to delay the action of compound for a long period of time.The delayed release form may be formulated to delay the release of the effective dose of one or more compounds for, for example, about 4, about 8, about 12, about 16 or about 24 hours.

[0078] The controlled release formulation may be a sustained release form.The sustained release form may be formulated, for example, to sustain the action of the compound for a long period of time.The sustained release form may be formulated to provide an effective dose of any compound described herein (for example, provide a physiologically effective blood profile) for about 4, about 8, about 12, about 16, or about 24 hours.

[0079] Non-limiting examples of pharma- ceutically acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. (Lippincott Williams & Wilkins, 1999), each of which is incorporated herein by reference in its entirety.

[0080] The therapeutic agent described herein may be administered before, during, or after the onset of a disease or condition, and the timing of administration of the composition containing the therapeutic agent may vary. For example, the composition may be used as a prophylactic agent, and may be administered continuously to a subject with a condition or tendency to a disease to reduce the likelihood of the onset of the disease or condition. The compound may be administered to a subject during the onset of symptoms, or as soon as possible after onset. Administration of the therapeutic agent may be initiated within the first 48 hours of the onset of symptoms, within the first 24 hours of the onset of symptoms, within the first 6 hours of the onset of symptoms, or within 3 hours of the onset of symptoms. Initial administration may be by any practical route, for example, by any route described herein, using any formulation described herein.

[0081] The compounds may be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for the length of time necessary to treat the disease, such as, for example, from about one month to about three months. In some embodiments, the length of time over which the compound may be administered is about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months It can be about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years. The length of treatment can vary from subject to subject.

[0082] The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of precise dosage. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dosage may be in the form of a package containing separate amounts of the formulation. Non-limiting examples are packaged injections, vials, or ampoules. Aqueous suspension compositions may be packaged in single-dose non-reclosable containers. Multi-dose reclosable containers may be used, for example, with or without preservatives. Preparations for injection may be provided in unit dosage form, for example, in ampoules, and in multi-dose containers with preservatives.

[0083] The pharmaceutical compositions provided herein can be administered in conjunction with other treatments, such as chemotherapy, radiation, surgery, anti-inflammatory agents, and selected vitamins. The other agents can be administered before, after, or simultaneously with the pharmaceutical composition.

[0084] Depending on the intended mode of administration, the pharmaceutical composition may be in the form of a solid, semi-solid, or liquid dosage form, such as, for example, a tablet, suppository, pill, capsule, powder, liquid, suspension, lotion, cream, or gel, in a unit dosage form suitable for single administration of a precise dosage amount.

[0085] For solid compositions, non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate.

[0086] Compounds can be delivered by liposome technology. The use of liposomes as drug carriers can increase the therapeutic index of compounds. Liposomes are composed of natural phospholipids and may contain mixed lipid chains (e.g., egg phosphatidylethanolamine) with surface active properties. Liposome designs may use surface ligands to bind to unhealthy tissues. Non-limiting examples of liposomes include multilamellar vesicles (MLVs), small unilamellar vesicles (SUVs), and large unilamellar vesicles (LUVs). The physicochemical properties of liposomes can be modulated to optimize penetration of biological barriers and retention at the site of administration, reducing the likelihood of premature degradation and toxicity to non-target tissues. Optimal liposome properties depend on the route of administration, i.e., larger sized liposomes show better retention upon local injection, while smaller sized liposomes are better suited to achieve passive targeting. PEGylation reduces the uptake of liposomes by liver and spleen, increases circulation time, and leads to increased localization at inflammation sites due to enhanced permeability and retention (EPR) effect.In addition, the surface of liposomes can be modified to achieve selective delivery of encapsulated drugs to specific target cells.Non-limiting examples of targeting ligands include monoclonal antibodies, vitamins, peptides, and polysaccharides that are specific for receptors concentrated on the surface of disease-related cells.

[0087] Non-limiting examples of dosage forms suitable for use in the present disclosure include liquids, elixirs, nanosuspensions, aqueous or oily suspensions, drops, syrups, and any combination thereof.Non-limiting examples of pharma- ceutically acceptable excipients suitable for use in the present disclosure include granulating agents, binders, lubricants, disintegrants, sweeteners, glidants, anti-adhesive agents, antistatic agents, surfactants, antioxidants, gums, coating agents, colorants, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifiers, plant cellulosic materials, and spheronization agents, and any combination thereof.

[0088] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers, including excipients and auxiliary agents, which facilitate the processing of active compounds into medicament-usable preparations.Formulations may be modified according to the route of administration selected.The pharmaceutical compositions comprising the compounds described herein may be prepared, for example, by mixing, dissolving, granulating, dragee-making, wet milling, emulsifying, encapsulating, entrapping or compressing process.

[0089] The composition of the present invention may be packaged as a kit. In some embodiments, the kit includes written instructions for administration / use of the composition. The written material may be, for example, a label. The written material may suggest the conditions and methods of administration. The instructions provide the subject and the attending physician with the best guidance to achieve optimal clinical outcomes from the administration of the treatment. The written material may be a label. In some embodiments, the label may be approved by a regulatory agency, for example, the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agency. dosage

[0090] The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of precise dosage. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dosage may be in the form of a package containing separate amounts of the formulation. Non-limiting examples are liquids in vials, or ampoules. Aqueous suspension compositions may be packaged in single-dose non-reclosable containers. Multi-dose reclosable containers may be used, for example, in combination with a preservative. Preparations for parenteral injection may be provided in unit dosage form, for example, in ampoules, and in multi-dose containers with a preservative.

[0091] The compounds described herein may be administered in an amount of from about 1 mg to about 2000 mg; from about 100 mg to about 2000 mg; from about 10 mg to about 2000 mg; from about 5 mg to about 1000 mg, from about 10 mg to about 500 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg , about 350 mg to about 400 mg, about 400 mg to about 450 mg, about 450 mg to about 500 mg, about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1000 mg.

[0092] The compounds described herein may be administered in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 ... In some embodiments, the compound may be present in the composition in an amount of about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, or about 2500 mg.

[0093] In some embodiments, the dose can be expressed as the amount of drug divided by the mass of the subject, e.g., milligrams of drug per kilogram of subject body weight. In some embodiments, the compound is administered in an amount ranging from about 5 mg / kg to about 50 mg / kg, 250 mg / kg to about 2000 mg / kg, about 10 mg / kg to about 800 mg / kg, about 50 mg / kg to about 400 mg / kg, about 100 mg / kg to about 300 mg / kg, or about 150 mg / kg to about 200 mg / kg. Treatment

[0094] In some embodiments, the compounds of the invention can be used to treat cancer in a subject, for example, by slowing the growth of cancer cell lines or by killing cancer cells.Non-limiting examples of cancers that may be treated by the compounds of the invention include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumors, e.g., cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, optic tract and hypothalamic glioma, breast cancer, bronchial adenoma, Burkitt's lymphoma, cancer of unknown primary, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, colon cancer, cutaneous T-cell Lymphoma, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, germ cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, glioma, hairy cell leukemia, head and neck cancer, cardiac cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell carcinoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liposarcoma, liver cancer, lung cancer, e.g. non-small cell and small cell lung cancer, lymphoma, leukemia, macroglobulinemia, malignant fibrous histiocytoma / osteosarcoma of bone, medulloblastoma, melanoma, mesothelioma, metastatic squamous neck cancer with occult primary primary), cancer of the mouth, multiple endocrine neoplasia syndrome, myelodysplastic syndrome, myeloid leukemia, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cavity cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, pancreatic islet cell cancer, paranasal and paranasal sinus cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germinoma, pituitary adenoma, pleuropulmonary blastoma, plasma cell neoplasm , primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureteral transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, Merkel cell skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, T-cell lymphoma, throat cancer, thymoma, thymic carcinoma, thyroid cancer, trophoblastic neoplasm (gestational), cancer of unknown primary site, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's hypergammaglobulinemia, and Wilms' tumor.

[0095] The methods disclosed herein can be used to treat, for example, a proliferative disease, cancer, cancer metastasis, a solid tumor, a liquid tumor, a carcinoma, squamous cell carcinoma (SCC), SCC associated with a disease, such as recessive dystrophic epidermolysis bullosa (RDEB), or any metastasis thereof.

[0096] Tumor response according to the methods disclosed herein can be measured based on RECIST response classification.

[0097] Recessive dystrophic epidermolysis bullosa (RDEB or EB) is a severe genodermatosis caused by mutations in COL7A1, characterized by generalized skin blistering and mucosal involvement. Invasive metastatic squamous cell carcinoma (SCC), which typically arises in areas of chronic skin wounds, is a common complication that can significantly contribute to the short life expectancy of patients under the age of 40. Individuals can develop high-grade, early-onset tumors, often occurring in multiples, at different sites in individuals between the ages of 20 and 40. These neoplasms can show limited response rates, mostly of short duration, to conventional chemotherapy and radiotherapy. Furthermore, invasive cytotoxic chemotherapy is poorly tolerated (e.g., in terms of skin, mucosa, kidney, as well as bone marrow toxicity and sepsis risk with neutropenia) along with the burden of EB-associated disease and systemic morbidity.

[0098] Squamous cell carcinoma is a carcinoma that occurs in many different organs, including the skin, mouth, esophagus, lungs, and cervix. This cancer is a malignant tumor of epithelium that shows squamous cell differentiation. Squamous cell carcinoma usually occurs in the epithelial layer of the skin and occasionally in various mucous membranes of the body. This type of cancer can be found in the skin, lips, inside the mouth, throat, or esophagus.

[0099] RDEB is a hereditary blistering skin disorder associated with significant esophageal stenosis, resulting in dysphagia and nutritional deficiency.Esophageal dysphagia refers to the sensation of food sticking or getting stuck in the throat or chest after the subject begins to swallow food or drink.Esophageal stenosis refers to a narrowed esophagus that can trap large chunks of food.Scar tissue can cause the narrowing of the esophagus.In some embodiments, the subject who is administered a therapeutically effective amount of the compound of the present disclosure has esophageal obstruction.

[0100] Provided herein is a method for treating squamous cell carcinoma (SCC) by administering the compounds of the present disclosure. Provided herein is a method for treating metastatic SCC by administering the compounds of the present disclosure. Provided herein is a method for treating invasive metastatic SCC by administering the compounds of the present disclosure.

[0101] As demonstrated herein, RDEB SCC keratinocytes are sensitive to compounds of the present disclosure at concentrations lower than those required for an equivalent response in normal keratinocytes or fibroblasts isolated from RDEB patients (Figure 1). The efficacy of compounds of the present disclosure for treating RDEB SCC in tumor xenograft experiments is shown in Figure 2.

[0102] In some embodiments, disclosed herein are methods of assaying for a biomarker indicative of the presence of a condition and administering a compound of the disclosed pharmaceutical composition. In some embodiments, the biomarker is a genetic biomarker. In some embodiments, the biomarker is a protein biomarker. In some embodiments, the assays, biological samples, methods.

[0103] In some embodiments, disclosed herein is a method for assaying a subject for a phosphatidylinositol-3-kinase (PI3K) pathway biomarker before administering the disclosed compound.In some embodiments, the PI3K pathway biomarker is a mutation in the PIK3CA gene.In some embodiments, the PI3K pathway biomarker is a PTEN loss mutation.In some embodiments, the PI3K pathway biomarker is p4E-BP1 or pAkt.In some embodiments, the PI3K pathway biomarker is p21-activated kinase 1 (PAK1) protein.

[0104] In some embodiments, disclosed herein is a method of assaying a subject for a biomarker of protein kinase B (Akt) pathway before administering a compound of the present disclosure. In some embodiments, the Akt pathway biomarker is PIKCA gene. In some embodiments, the Akt pathway biomarker is PTEN loss. In some embodiments, the Akt pathway biomarker is Bcl2-associated death protein (BAD). In some embodiments, the Akt pathway biomarker is phosphatidylinositol 3,4,5-triphosphate (PIP3).

[0105] In some embodiments, disclosed herein is a method for assaying a subject for a biomarker of serine / threonine-protein kinase 1 (PLK1) pathway before administering a compound of the present disclosure. In some embodiments, the PLK1 pathway biomarker is a mutation of splicing factor (SF). In some embodiments, the PLK1 pathway biomarker is SRSF2. In some embodiments, the PLK1 pathway biomarker is SF3B1. In some embodiments, the PLK1 pathway biomarker is centrosomal protein 55 kDa (CEP55).

[0106] dosage The dosing regimen disclosed herein may be, for example, one oral dose of the disclosed compound in the morning and a second dose of the compound in the afternoon or evening.In some embodiments, the morning dose and the afternoon or evening dose may be the same.In some embodiments, the morning dose and the afternoon or evening dose may be different.In some embodiments, one oral dose of 840mg of rigosertib may be administered in the morning, and one oral dose of 560mg of rigosertib may be administered in the afternoon.

[0107] In some embodiments, the dose can be titrated depending on the number of dose-limiting toxicities (DLTs) observed. In some embodiments, the dose escalation can continue in increments of about 70 mg, about 140 mg, about 280 mg, about 560 mg, or about 1120 mg. In some embodiments, the dose escalation can continue in increments of 280 mg. In some embodiments, the dose escalation can continue in increments of 560 mg. In some embodiments, the morning dose can be increased in increments of 280 mg and the afternoon dose can be increased in increments of 280 mg. In some embodiments, the morning dose can be increased in increments of 560 mg and the afternoon dose can be increased in increments of 560 mg.

[0108] Dose escalation can continue until two or more DLTs are observed in a single cohort. At that point, the previous dose cohort can be expanded to six patients, and if less than two DLTs occur in those six patients, the dose can be considered the MTD. In addition, a much larger percentage of the total daily dose can be administered in the morning dose and a lower percentage in the afternoon dose (i.e., 1,400 mg in the morning and 560 mg in the afternoon).

[0109] The dosage regimen for intravenous rigosertib can be, for example, at least about 300 mg / day, at least about 600 mg / day, at least about 900 mg / day, at least about 1200 mg / day, at least about 1500 mg / day, at least about 1800 mg / day, at least about 2100 mg / day, at least about 2400 mg / day, at least about 2700 mg / day, or at least about 3000 mg / day. In some embodiments, the dosage regimen for intravenous rigosertib can be, for example, about 300 mg / day, about 600 mg / day, about 900 mg / day, about 1200 mg / day, about 1500 mg / day, about 1800 mg / day, about 2100 mg / day, about 2400 mg / day, about 2700 mg / day, or about 3000 mg / day. In some embodiments, the dosage regimen for intravenous rigosertib can be, for example, up to about 300 mg / day, up to about 600 mg / day, up to about 900 mg / day, up to about 1200 mg / day, up to about 1500 mg / day, up to about 1800 mg / day, up to about 2100 mg / day, up to about 2400 mg / day, up to about 2700 mg / day, or up to about 3000 mg / day. In some embodiments, the dosage regimen for intravenous rigosertib can be about 1800 mg / day. In some embodiments, the dosage regimen for intravenous rigosertib can be about 2100 mg / day. In some embodiments, the dosage regimen for intravenous rigosertib can be about 2400 mg / day.

[0110] In some embodiments, the dosing regimen for intravenous rigosertib can include administration on days 1-3 of a 14-day cycle. In some embodiments, the dosing regimen for intravenous rigosertib can include administration on days 1-3 of a 28-day cycle. In some embodiments, the dosing regimen for intravenous rigosertib can include administration on days 1-3 of a 14-day cycle, followed by administration on days 1-3 of a subsequent 28-day cycle. In some embodiments, the dosing regimen for intravenous rigosertib can include escalating the dose on days 1-3 of a 14-day cycle. In some embodiments, the dosing regimen for intravenous rigosertib can include escalating the dose on days 1-3 of a 28-day cycle.

[0111] In some embodiments, the dosing regimen for intravenous rigosertib can include dosing on days 1-3 of a 14 day cycle, followed by no dosing on days 4-14 of the 14 day cycle. In some embodiments, the dosing regimen for intravenous rigosertib can include dosing on days 1-3 of a 28 day cycle, followed by no dosing on days 4-28 of the 28 day cycle. In some embodiments, the dosing regimen for intravenous rigosertib can include dosing on days 1-3 of a 14 day cycle, followed by no dosing on days 4-14 of the 14 day cycle, then dosing on days 1-3 of a 28 day cycle, followed by no dosing on days 4-28 of the 28 day cycle, repeated any number of times as needed for the 28 day cycle. In some embodiments, the dosing regimen for intravenous rigosertib can include escalating the dose on days 1-3 of a 14 day cycle. In some embodiments, a dosing regimen for intravenous rigosertib can include escalating the dose on days 1-3 of a 28-day cycle.

[0112] In some embodiments, the dosing regimen can be dose escalated to 2100 mg / day. In some embodiments, the dosing regimen can be dose escalated to 2400 mg / day. In some embodiments, the dosing regimen can be dose escalated until the MTD and RP2D are established according to 3+3 dose escalation.

[0113] The compounds disclosed herein can be administered by subcutaneous or intravenous injection.The volume of injection can be about 0.1mL, about 0.2mL, about 0.3mL, about 0.4mL, about 0.5mL, about 0.6mL, about 0.7mL, about 0.8mL, about 0.9mL, about 1mL, about 1.1mL, about 1.2mL, about 1.3mL, about 1.4mL, about 1.5mL, about 1.6mL, about 1.7mL, about 1.8mL, about 1.9mL, about 2mL, about 2.1mL, about 2.2mL, about 2.3mL, about 2.4mL, about 2.5mL, about 2.6mL, about 2.7mL, about 2.8mL, about 2.9mL, or about 3mL. The individual doses administered to a subject may be about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 75 mg, about 76 mg, about 7 , about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, or about 50 mg.

[0114] The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of precise dosage. In unit dosage form, the formulation may be divided into unit doses containing appropriate amounts of one or more compounds. The unit dosage may be in the form of a package containing separate amounts of the formulation. Non-limiting examples are packaged injections, vials, or ampoules. Aqueous suspension compositions may be packaged in single-dose non-reclosable containers. Multi-dose reclosable containers may be used, for example, with or without preservatives. Preparations for parenteral injection may be provided in unit dosage form, for example, in ampoules, or in multi-dose containers with preservatives.

[0115] The compounds described herein may be administered in an amount of about 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 125 mg, about 125 mg to about 150 mg, about 150 mg to about 175 mg, about 175 mg to about 200 mg, about 200 mg to about 225 mg, about 225 mg to about 250 mg, or about 250 mg to about 300 mg.

[0116] The compounds described herein may be present in the composition in an amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or about 300 mg.

[0117] In some embodiments, the compounds described herein may be administered to a subject in an amount of about 0.1 mg / kg to about 500 mg / kg, about 1 mg / kg to about 500 mg / kg, about 0.1 mg / kg to about 300 mg / kg, about 1 mg / kg to about 300 mg / kg, or about 0.1 mg / kg to about 30 mg / kg. In some embodiments, a compound described herein is administered to about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg of a subject. In some embodiments, the subject is administered an amount of about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 120 mg / kg, about 150 mg / kg, about 160 mg / kg, about 180 mg / kg, about 200 mg / kg, about 240 mg / kg, about 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 360 mg / kg, about 400 mg / kg, about 450 mg / kg, about 500 mg / kg, or about 600 mg / kg.

[0118] The compounds described herein may be administered before, during, or after the onset of a disease or condition, and the timing of administration of the composition containing the compound may vary. For example, the compounds may be used as prophylactics, and may be administered continuously to subjects with a condition or tendency to a disease to reduce or decrease the likelihood of the onset of the disease or condition. The compounds and compositions may be administered to a subject during the onset of symptoms, or as soon as possible after onset. Administration of the compounds may be initiated within the first 48 hours of the onset of symptoms, within the first 24 hours of the onset of symptoms, within the first 6 hours of the onset of symptoms, or within 3 hours of the onset of symptoms. Initial administration may be by any practical route, for example, by any route described herein, using any formulation described herein.

[0119] The compounds may be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for the length of time necessary to treat the disease, such as, for example, from about one month to about three months. In some embodiments, the length of time over which the compound may be administered is about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months It can be about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, about 20 years, about 21 years, about 22 years, about 23 years, about 24 years, or about 25 years. The length of treatment can vary from subject to subject.

[0120] In some embodiments, the dosing regimen can include administration of the compound of the present disclosure for a first period of time, followed by a period of time during which the compound of the present disclosure is not administered. In some embodiments, the first period during which the compound of the present disclosure is administered is at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, at least about 14 days, at least about 15 days, at least about 16 days, at least about 17 days, at least about 18 days, at least about 19 days, at least about 20 days, at least about 21 days, at least about 22 days, at least about 23 days, at least about 24 days, at least about 25 days, at least about 26 days, at least about 27 days, at least about 28 days, at least about 29 days, or at least about 30 days. In some embodiments, the first period during which the compound of the present disclosure is administered is about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, or about 30 days. In some embodiments, the first period during which the compound of the present disclosure is administered is about 1 day. In some embodiments, the first period during which the compound of the present disclosure is administered is about 3 days. In some embodiments, the first period during which the compound of the present disclosure is administered is about 5 days. In some embodiments, the first period during which the compound of the present disclosure is administered is about 7 days. In some embodiments, the first period during which the compound of the present disclosure is administered is about 10 days.In some embodiments, the first period during which the compound of the present disclosure is administered is about 14 days.In some embodiments, the first period during which the compound of the present disclosure is administered is about 21 days.In some embodiments, the first period during which the compound of the present disclosure is administered is about 28 days.

[0121] In some embodiments, the second period during which a compound of the present disclosure is not administered (i.e., the break during the treatment period) is at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, at least about 14 days, at least about 15 days, at least about 16 days, at least about 17 days, at least about 18 days, at least about 19 days, at least about 20 days, at least about 21 days, at least about 22 days, at least about 23 days, at least about 24 days, at least about 25 days, at least about 26 days, at least about 27 days, at least about 28 days, at least about 29 days, or at least about 30 days. In some embodiments, the second period during which the compound of the present disclosure is not administered (i.e., the break during the treatment period) is about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, or about 30 days. In some embodiments, the second period during which the compound of the present disclosure is not administered (i.e., the break during the treatment period) is about 1 day. In some embodiments, the second period during which the compound of the present disclosure is not administered (i.e., the break during the treatment period) is about 5 days. In some embodiments, the second period during which the compound of the present disclosure is not administered (i.e., the break between treatment periods) is about 7 days. In some embodiments, the second period during which the compound of the present disclosure is not administered (i.e., the break between treatment periods) is about 11 days. In some embodiments, the second period during which the compound of the present disclosure is not administered (i.e., the break between treatment periods) is about 14 days. In some embodiments, the second period during which the compound of the present disclosure is not administered (i.e., the break between treatment periods) is about 21 days. In some embodiments, the second period during which the compound of the present disclosure is not administered (i.e., the break between treatment periods) is about 25 days.

[0122] In some embodiments, a treatment cycle includes a first period during which a compound of the present disclosure is administered and a second period during which the compound is not administered. In some embodiments, a treatment cycle includes at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, at least about 14 days, at least about 15 days, at least about 16 days, at least about 17 days, at least about 18 days, at least about 19 days, at least about 20 days, at least about 21 days, at least about 22 days, at least about 23 days, at least about 24 days, at least about 25 days, at least about 26 days, The period may be at least about 27 days, at least about 28 days, at least about 29 days, at least about 30 days, at least about 31 days, at least about 32 days, at least about 33 days, at least about 34 days, at least about 35 days, at least about 36 days, at least about 37 days, at least about 38 days, at least about 39 days, at least about 40 days, at least about 41 days, at least about 42 days, at least about 43 days, at least about 44 days, at least about 45 days, at least about 46 days, at least about 47 days, at least about 48 days, at least about 49 days, or at least about 50 days. In some embodiments, a treatment cycle can be about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, about 44 days, about 45 days, about 46 days, about 47 days, about 48 days, about 49 days, or about 50 days. In some embodiments, the treatment cycle may be about 14 days or 2 weeks. In some embodiments, the treatment cycle may be about 21 days or 3 weeks.In some embodiments, a treatment cycle may be about 28 days, or 4 weeks.

[0123] In some embodiments, the dosing regimen cycle can be administered for more than one cycle.In some embodiments, the dosing regimen of the present disclosure can be administered for at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, or more cycles.In some embodiments, the dosing regimen of the present disclosure can be administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more cycles. In some embodiments, the dosage regimen of the present disclosure may be administered for one cycle. In some embodiments, the dosage regimen of the present disclosure may be administered for three cycles. In some embodiments, the dosage regimen of the present disclosure may be administered for five cycles. In some embodiments, the dosage regimen of the present disclosure may be administered for eight cycles. In some embodiments, the dosage regimen of the present disclosure may be administered for ten cycles. In some embodiments, the dosage regimen of the present disclosure may be administered for twelve cycles. In some embodiments, the dosage regimen of the present disclosure may be administered for fifteen cycles.

[0124] In some embodiments, a dosing regimen for a compound of the present disclosure can include administration on days 1-3 of a 14-day cycle. In some embodiments, a dosing regimen for a compound of the present disclosure can include administration on days 1-3 of a 28-day cycle. In some embodiments, a dosing regimen for a compound of the present disclosure can include administration on days 1-3 of a 14-day cycle, followed by administration on days 1-3 of a subsequent 28-day cycle. In some embodiments, a dosing regimen for a compound of the present disclosure can include escalating the dose on days 1-3 of a 14-day cycle. In some embodiments, a dosing regimen for a compound of the present disclosure can include escalating the dose on days 1-3 of a 28-day cycle.

[0125] In some embodiments, the method of the present disclosure can include a drug holiday between treatment cycles.In some embodiments, the drug holiday can be at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, or at least about 20 weeks.In some embodiments, the drug holiday can be about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, or about 20 weeks.

[0126] In some embodiments, the administering is once a day. In some embodiments, the administering is twice a day. In some embodiments, the administering is three times a day. In some embodiments, the administering is four times a day. In some embodiments, the administering is in the morning. In some embodiments, the administering is in the afternoon. In some embodiments, the administering is in the evening. In some embodiments, the administering is in the morning and in the afternoon. In some embodiments, the administering is in the morning and in the evening. In some embodiments, the administering is in the afternoon and in the evening.

[0127] In some embodiments, the subject is fasted in the morning when the compound of the present disclosure is administered to the subject. In some embodiments, the subject is fed in the afternoon when the compound of the present disclosure is administered to the subject. In some embodiments, the subject is fed in the evening when the compound of the present disclosure is administered to the subject. In some embodiments, the administering is performed in the morning and in the afternoon, and the subject is fasted in the morning and fed in the afternoon. In some embodiments, the administering is performed in the morning and in the evening, and the subject is fasted in the morning and fed in the evening. In some embodiments, the administering is performed in the afternoon and in the evening, and the subject is fed in the afternoon and fed in the evening.

[0128] Non-limiting examples of dosing schedules for administration of the compounds described herein include once daily (QD), twice daily (BID), three times daily (TID), four times daily (QID), once weekly, twice weekly, three times weekly, once monthly, twice monthly, and once every two months. EXAMPLES

[0129] Example 1 Clinical studies to evaluate the oral and intravenous pharmaceutical compositions disclosed herein for treating a disease in a subject We conducted a phase 2, open-label, single-arm study designed to evaluate the efficacy and safety of rigosertib in patients with locally advanced / metastatic squamous cell carcinoma (SCC) associated with recessive dystrophic epidermolysis bullosa (RDEB).

[0130] In addition to evaluating safety and tolerability, efficacy was measured by overall response rate as assessed by RECIST. Patients were treated for 12 consecutive months until RECIST progression criteria were met (i.e., a 20% increase in tumor diameter or the appearance of new malignant lesions), or until unacceptable toxicity or intolerance occurred, or until remission.

[0131] Study Design: Rigosertib was administered in two different formulations: oral capsules and an IV solution for intravenous infusion. Rigosertib was provided as 280 mg capsules and as a liquid solution.

[0132] The study had two primary endpoints. The first primary endpoint was to determine the antitumor activity of rigosertib in RDEB patients with advanced SCC who had failed previous standard of care, by overall response rate (ORR), defined as the proportion of patients who achieved either a complete response (CR) or partial response (PR). The second primary endpoint was to evaluate the safety and tolerability of rigosertib in the population. Secondary study endpoints included quality of life and biomarker analyses performed on archival tissue from all patients. Patients were treated for up to one year, with the trial duration expected to be approximately two and a half years.

[0133] Oral dosing: Study subjects received oral rigosertib continuously for a total of 3 weeks every 4-week cycle (3 weeks on, 1 week off). Study subjects received oral rigosertib 560 mg (i.e., two 280 mg capsules) in the morning and oral rigosertib 560 mg (i.e., two 280 mg capsules) in the afternoon for a total of 1120 mg / day.

[0134] Intravenous Administration: For IV continuous infusion as rigosertib, sodium salt concentrate, 75 mg / mL, was formulated to contain 75 mg of rigosertib sodium salt per mL (equivalent to 75 mg of rigosertib sodium per mL) as a sterile solution in polyethylene glycol 400 (PEG400) containing a small amount of sodium hydroxide for pH adjustment. Rigosertib.Na 75 mg / mL was packaged in a single-use glass vial with a Teflon®-covered rubber stopper containing 24 mL of drug product (1800 mg). Immediately prior to administration, the rigosertib concentrate (i.e., one glass vial, 24 mL) was diluted with 0.9% sodium chloride to a final volume of 500 mL for injection.

[0135] Efficacy Assessment: Overall response rate (ORR) was defined as the proportion of patients who achieved either CR or PR. Responses of complete response (CR), partial response (PR), mCR, SD, failure, and PD were determined by RECIST criteria. The number and percentage of patients with CR, PR, mCR, SD, failure, or PD were summarized.

[0136] Response by RECIST criteria: Efficacy assessments included an initial tumor evaluation at 12 weeks (± 3 days) after the first dose. Further tumor evaluations were completed every 12 weeks (± 3 days). Study evaluations were performed according to RECIST 1.1 criteria. High-resolution CT with oral or IV contrast or contrast-enhanced MRI was used as the imaging modality to radiographically evaluate tumor response. Screening / baseline evaluations were performed within 4 weeks of the first dose of study drug. Brain MRI was used as the imaging method to assess CNS metastases and evaluations were required during screening / baseline and at the end of treatment or when clinically indicated.

[0137] Target Lesions: If more than one measurable lesion was present at baseline, all lesions up to a total of five lesions representing all involved sites (and a maximum of two lesions per site) were examined as target lesions and recorded and measured at baseline. Target lesions were selected based on size (lesions with the longest diameter) to represent all involved sites. The sum of the diameters of all target lesions (longest for non-nodal lesions, short axis for nodal lesions) was calculated and reported as the baseline total diameter. If lymph nodes were included in the total, only the short axis was added to the total. The baseline total diameter was used as a reference to characterize any objective tumor regression of the measurable dimensions of disease.

[0138] Quality of Life: Quality of life was measured by the QOLEB questionnaire administered at baseline and weekly thereafter. Baseline and change from baseline results by visit were summarized using descriptive statistics for this global measure.

[0139] RESULTS: Clinical and imaging studies showed complete resolution of two of the three squamous cell target lesions and a reduction in the third target lesion after treatment of a patient with REDB with intravenous rigosertib. The two target lesions on the left hand were completely resolved both visually and by MRI. The third target lesion on the right elbow, although not resolved, was clearly reduced in size. These data were obtained from MRI and clinic visits at week 12.

[0140] Example 2 Rigosertib for locally advanced / metastatic EB-associated SCC RDEB is a severe genodermatosis characterized by generalized skin blistering and mucosal involvement caused by mutations in COL7A1. Aggressive metastatic squamous cell carcinoma (SCC), which typically arises in chronic skin wounds and areas of inflammation, is the leading cause of death in this cohort. These SCCs show limited response rates, often of short duration, to conventional chemotherapy and radiation therapy, as well as targeted treatment with anti-epidermal growth factor antibodies (cetuximab, panitumumab) and tyrosine kinase inhibitors (gefitinib, erlotinib). In preclinical models, (1) RDEB SCC keratinocytes were demonstrated to be specifically sensitive to PLK1 reduction by siRNA treatment compared to normal primary RDEB keratinocytes, and (2) the PI3K / PLK1 inhibitor rigosertib was identified as having the best specificity by further demonstrating the largest therapeutic window separating tumor and normal cells.

[0141] Eligible patients presented with histologically confirmed locally advanced / metastatic SCC that had failed previous standard of care including immune checkpoint inhibitors. Treatment regimen was initially 1800mg / 24h 72h CIV infusion on days 1-3 of 2-week cycles for 8 cycles, then days 1-3 of 4-week cycles for 9 cycles. Patients were treated as previously described in Example 1.

[0142] The patient was a 24-year-old RDEB patient with histologically confirmed, unresectable multiple cutaneous SCC. The disease had continued to progress under previous treatment with cemiplimab. Application of rigosertib resulted in sustained clinical and histological remission of all target lesions without evidence of metastatic disease, as assessed after study completion (17 treatment cycles).

[0143] The safety and tolerability of rigosertib was favorable. Adverse effects observed included CTCAE grade II irritative cystitis, alopecia, recurrent episodes of bacteremia, mainly S. aureus and P. aeruginosa (most likely due to chronic skin wounds and indwelling catheters for CIV rigosertib infusions, but without cardiovascular-systemic disorders), nausea, increased lesional pain, and amenorrhea. All side effects were expected based on safety data from other non-EB trials and characteristic of a cytotoxic treatment approach. Early single-patient studies demonstrated the antitumor activity and acceptable safety profile of rigosertib in the setting of EB-associated SCC, usually with a fatal prognosis.

[0144] Figure 3 shows clinical photographic images of target lesions on the left hand (panels 3A, 3C, 3E, 3G, and 3I) and right elbow (panels 3B, 3D, 3F, 3H, and 3J) at V1 (day 1), V13 (days 85–95), V25 (days 169–175), V41 (days 281–283), and V52 (days 358–364). At V25, both lesions were biopsied but showed no histologic signs of malignancy. At V41, a wound was noted at the right elbow. The wound showed a process typical of EB and healed completely within a few weeks.

[0145] Embodiment The following non-limiting embodiments provide illustrative examples of the present invention, but do not limit the scope of the invention.

[0146] Embodiment 1. A method of treating a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the formula: [ka] or a pharma- ceutically acceptable salt or zwitterion thereof, During the ceremony, a.Each R 1 , R 2 , R 3 , R 4 , R 5, R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 12 , and R 13 are independently alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, C(O)R x , C(O)OR x , C(O)NR x R y , OR x , S.R. x , N.R. x R y , N.R. x C(O)R y , O.C.(O)R x , or SiR x R y R z (each of which is independently substituted or unsubstituted), or hydrogen or halogen; b.Each R x , R y , and R z is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; administering a compound or a pharma- ceutically acceptable salt or zwitterion thereof, c. the condition is recessive dystrophic epidermolysis bullosa; d. lesions on said skin area associated with recessive dystrophic epidermolysis bullosa resolve within about 12 weeks of said administering as determined by magnetic resonance imaging of said skin area. method.

[0147] Embodiment 2. The method of embodiment 1, wherein said lesions of said skin area associated with recessive dystrophic epidermolysis bullosa resolve within about 8 weeks of administration as determined by magnetic resonance imaging of said skin area.

[0148] Embodiment 3. The method of embodiment 1, wherein said lesions of said skin area associated with recessive dystrophic epidermolysis bullosa resolve within about 4 weeks of treatment as determined by magnetic resonance imaging of said skin area.

[0149] Embodiment 4. The method of embodiment 1, wherein said lesions of said skin area associated with recessive dystrophic epidermolysis bullosa resolve within about two weeks of treatment as determined by magnetic resonance imaging of said skin area.

[0150] Embodiment 5. The method of any one of embodiments 1-4, wherein the recessive dystrophic epidermolysis bullosa is associated with squamous cell carcinoma.

[0151] Embodiment 6. The method of any one of embodiments 1 to 5, wherein the lesion is squamous cell carcinoma.

[0152] Embodiment 7. The method of any one of embodiments 1-6, wherein the subject is refractory to standard of care treatments for recessive dystrophic epidermolysis bullosa.

[0153] Embodiment 8. The method of any one of embodiments 1-7, wherein the subject is refractory to standard of care treatment for squamous cell carcinoma.

[0154] Embodiment 9. The method of any one of embodiments 1-8, wherein the administering is oral.

[0155] Embodiment 10 The method of any one of embodiments 1-9, wherein the compound is formulated as a capsule.

[0156] Embodiment 11 The method of any one of embodiments 1-10, wherein the compound is formulated as a soft gel capsule.

[0157] Embodiment 12. The method of any one of embodiments 1-8, wherein the administering is intravenous.

[0158] Embodiment 13 The method of embodiment 1 or 12, wherein the administering is an intravenous infusion for 72 hours.

[0159] Embodiment 14 The method of any one of embodiments 1-8, wherein the administering is intratumoral.

[0160] Embodiment 15. The method of any one of embodiments 1-14, wherein the administering occurs on each of days 1, 2, and 3 of a two-week cycle.

[0161] Embodiment 16. The method of any one of embodiments 1-14, wherein the administering occurs on each of days 1, 2, and 3 of a two-week cycle, then on each of days 1, 2, and 3 of a four-week cycle, for eight cycles.

[0162] Embodiment 17. The method of any one of embodiments 1-14, wherein the administering is performed in a four week cycle of three weeks of daily administration followed by one week of no administration.

[0163] Embodiment 18. Each R 1 , R 3 , and R 5 But independently, OR x The method according to any one of embodiments 1 to 17, wherein

[0164] Embodiment 19. Each R x is independently alkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted.

[0165] Embodiment 20. Each R x is independently substituted or unsubstituted C 1~6 19. The method of embodiment 18, wherein said alkyl is alkyl.

[0166] Embodiment 21. Each R xis independently a C alkyl substituted with hydroxy, sulfhydryl, halogen, amino, nitro, cyano, sulfoxide, sulfone, sulfonamide, carboxyl, carboxylic acid, carboxaldehyde, alkoxy, aryl, heterocyclyl, acyl, amide, or ester.

[0167] Embodiment 22. Each R x is independently methyl.

[0168] Embodiment 23. Each R 2 , R 4 , R 6 , R 9 , and R 10 23. The method of any one of the preceding embodiments, wherein is independently hydrogen.

[0169] Embodiment 24. Each R 11a and R 11b The method of any one of the preceding embodiments, wherein is independently hydrogen.

[0170] Embodiment 25. Each R 12 and R 13 The method of any one of the preceding embodiments, wherein is independently hydrogen.

[0171] Embodiment 26. The compound has the formula: [ka] wherein - Each R 1a , R 3a , R 5a , and R 8a are independently substituted or unsubstituted C 1~8 is alkyl, - Each R 14 and R 15is independently alkyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen; The method according to any one of embodiments 1 to 25.

[0172] Embodiment 27. Each R 1a , R 3a , R 5a , and R 8a is independently methyl.

[0173] Embodiment 28. R 14 27. The method of embodiment 26, wherein is hydrogen.

[0174] Embodiment 29. R 15 27. The method of embodiment 26, wherein is a C alkyl substituted with hydroxy, sulfhydryl, halogen, amino group, nitro group, cyano, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxylic acid, carboxaldehyde group, alkoxy, aryl, heterocyclyl group, acyl group, amide, or ester.

[0175] Embodiment 30. R 15 27. The method of embodiment 26, wherein is CH2COOH.

[0176] Embodiment 31. The method of any one of embodiments 1-17, wherein the compound is (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetic acid or a pharma- ceutically acceptable salt or zwitterion thereof.

[0177] Embodiment 32. The method of any one of embodiments 1-17, wherein the compound is sodium (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetate.

[0178] Embodiment 33. The method of any one of embodiments 1 to 32, wherein the therapeutically effective amount is from about 280 mg to about 2400 mg.

[0179] Embodiment 34. The method of any one of embodiments 1-32, wherein the therapeutically effective amount is about 280 mg.

[0180] Embodiment 35 The method of any one of embodiments 1 to 32, wherein the therapeutically effective amount is about 560 mg.

[0181] Embodiment 36 The method of any one of embodiments 1-32, wherein the therapeutically effective amount is about 840 mg.

[0182] Embodiment 37. The method of any one of embodiments 1 to 32, wherein the therapeutically effective amount is about 1120 mg.

[0183] Embodiment 38. The method of any one of embodiments 1 to 32, wherein the therapeutically effective amount is about 1800 mg.

[0184] Embodiment 39. The method of any one of embodiments 1-32, wherein the therapeutically effective amount is about 2100 mg.

[0185] Embodiment 40. The method of any one of embodiments 1-32, wherein the therapeutically effective amount is about 2400 mg.

[0186] Embodiment 41 The method of any one of embodiments 1-40, wherein the administering is once daily.

[0187] Embodiment 42 The method of any one of embodiments 1-40, wherein the administering is twice daily.

[0188] Embodiment 43 The method of any one of embodiments 1-40, wherein the administering is three times a day.

[0189] Embodiment 44. The method of any one of embodiments 1-40, wherein the administering is oral for 4 week cycles of i) about 560 mg in the morning and 560 mg in the evening for 3 weeks, and ii) 1 week of no administration.

[0190] Embodiment 45. The method of any one of embodiments 1-40, wherein the administering occurs during a morning time and an evening time, and the subject is in a fasted state during the morning time and the subject is in a fed state during the evening time.

[0191] Embodiment 46 The method of any one of embodiments 1-8, 12-45, wherein the therapeutically effective amount is about 1,800 mg and the compound is diluted in 0.9% saline.

[0192] Embodiment 47. The method of any one of embodiments 1 to 46, further comprising assaying the subject for a biomarker of the P13K pathway prior to said administering.

[0193] Embodiment 48 The method of any one of embodiments 1 to 47, further comprising assaying the subject for a biomarker of the Akt pathway prior to said administering.

[0194] Embodiment 49. The method of any one of embodiments 1 to 48, further comprising assaying the subject for a biomarker of the PLK1 pathway prior to said administering.

[0195] Embodiment 50 The method of any one of embodiments 1-49, wherein the subject has an esophageal obstruction.

Claims

1. A pharmaceutical composition for use in the treatment of recessive dystrophic epidermolysis bullosa, said pharmaceutical composition comprising a compound of the formula: 【Chemistry 12】 or a pharmaceutically acceptable salt or zwitterion thereof, During the ceremony, - Each R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ａ , R １１ｂ , R １２ , and R １３ are independently alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, C(O)R ｘ , C(O)OR ｘ , C(O)NR ｘ R ｙ , OR ｘ , S.R. ｘ , N.R. ｘ R ｙ , N.R. ｘ C(O)R ｙ , O.C.(O.)R ｘ , or SiR ｘ R ｙ R ｚ (each of which is independently substituted or unsubstituted), or hydrogen or halogen; - Each R ｘ , R ｙ , and R ｚ is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; or a pharmaceutically acceptable salt or zwitterion thereof, wherein the lesions on the skin area associated with recessive dystrophic epidermolysis bullosa resolve within about 12 weeks of administration of the composition as determined by magnetic resonance imaging of the skin area. Pharmaceutical compositions.

2. 2. The pharmaceutical composition of claim 1, wherein the recessive dystrophic epidermolysis bullosa is associated with squamous cell carcinoma.

3. The pharmaceutical composition of claim 1 , wherein the lesion is squamous cell carcinoma.

4. 10. The pharmaceutical composition of claim 1, wherein the subject is refractory to standard care treatment for recessive dystrophic epidermolysis bullosa or the subject is refractory to standard care treatment for squamous cell carcinoma.

5. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is adapted for oral administration and the pharmaceutical composition is formulated as a capsule or a soft gel capsule.

6. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured for intravenous administration as an intravenous infusion over a period of 72 hours, if necessary.

7. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is configured for intratumoral administration.

8. The pharmaceutical composition comprises: (a) administration on each of days 1, 2, and 3 of a two-week cycle; (b) administration on each of days 1, 2, and 3 of two-week cycles followed by administration on each of days 1, 2, and 3 of four-week cycles for eight cycles; or (c) Dosing in a 4-week cycle with 3 weeks of daily dosing followed by 1 week of no dosing. The pharmaceutical composition according to claim 1, which is adapted for use.

9. Each R １ , R ３ , and R ５ But independently, OR ｘ The pharmaceutical composition of claim 1, wherein

10. Each R ｘ but, independently alkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; independently substituted or unsubstituted C 1-6 alkyl; C 1 alkyl substituted independently with hydroxy, sulfhydryl, halogen, amino, nitro, cyano, sulfoxide, sulfone, sulfonamide, carboxyl, carboxylic acid, carboxaldehyde, alkoxy, aryl, heterocyclyl, acyl, amide, or ester; are independently methyl; The pharmaceutical composition of claim 9.

11. Each R ２ , R ４ , R ６ , R ９ , and R １０ 2. The pharmaceutical composition of claim 1, wherein R<11a> and R<11b> are independently hydrogen, each R<11a> and R<11b> are independently hydrogen, and each R<12> and R<13> are independently hydrogen.

12. The compound has the formula: 【Chemistry 13】 wherein - Each R １ａ , R ３ａ , R ５ａ , and R ８ａ are independently substituted or unsubstituted C １～８ is alkyl, - Each R １４ and R １５ is independently alkyl, alkoxy, aryl, heteroaryl, or heterocyclyl (each of which is independently substituted or unsubstituted), or hydrogen; The pharmaceutical composition of claim 1.

13. Each R １ａ , R ３ａ , R ５ａ , and R ８ａ is independently methyl, R14 is hydrogen, and R15 is C1 alkyl substituted with hydroxy, sulfhydryl, halogen, amino group, nitro group, cyano, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxylic acid, carboxaldehyde group, alkoxy, aryl, heterocyclyl group, acyl group, amide, ester, or CH2COOH.

14. 2. The pharmaceutical composition of claim 1, wherein the compound is (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetic acid or a pharmaceutically acceptable salt or zwitterion thereof.

15. 2. The pharmaceutical composition of claim 1, wherein the compound is sodium (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetate.

16. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured for administration in a therapeutically effective amount ranging from 280 mg to 2400 mg.

17. 17. The pharmaceutical composition of claim 16, wherein the therapeutically effective amount is 280 mg, 560 mg, 840 mg, 1120 mg, 1800 mg, 2100 mg, or 2400 mg.

18. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured for administration once daily, twice daily, or three times daily.

19. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured for oral administration in a 4-week cycle of i) about 560 mg in the morning and 560 mg in the evening for 3 weeks, and ii) one week without administration.

20. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured for administration in the morning and evening, wherein the subject is fasted during the morning hours and the subject is fed during the evening hours.

21. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured for administration in a therapeutically effective amount of 1,800 mg, and the pharmaceutical composition further comprises 0.9% saline.

22. The pharmaceutical composition of claim 1, characterized in that prior to administration, the subject has been evaluated for biomarkers of the P13K pathway, the Akt pathway or the PLK1 pathway.

23. The pharmaceutical composition of claim 1, wherein the subject has esophageal obstruction.

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