Methods and compositions for treating cancer

Abstract

RAS proteins are often mutated in human cancer. Disclosed herein are compounds that interfere with RAS effectors and inhibit Ras / RafrMEK / ERK pathway signaling. Disclosed herein further is a method of using the compounds in combination with checkpoint inhibitors to treat cancer. The disclosure provides a combination of the compounds disclosed herein, such as rigosertib, with checkpoint inhibitors. The checkpoint inhibitors disclosed herein can be, for example, nivolumab, which blocks PD-1.

Description

[Technical field]

[0001] cross reference This application is a continuation of U.S. Provisional Patent Application No. 63 / 211,070, filed June 16, 2021, and U.S. Provisional Patent Application No. 63 / 211,071, filed June 16, 2021, each of which is incorporated by reference in its entirety herein. [Background technology]

[0002] background The majority of lung adenocarcinomas harbor KRAS mutations as the primary genetic driver. Tumors with mutations in KRAS may have a worse prognosis than KRAS wild-type tumors. Therefore, treatments that can target the KRAS pathway may be beneficial for patients with cancers that harbor 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] Summary of the Invention Provided herein is a method of treating a condition, comprising administering to a subject in need of treatment for the condition a) a therapeutically effective amount of a compound of the formula: [ka] or a pharma- ceutically acceptable salt or zwitterion thereof [In the formula, - Each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R9 , 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 , -SR x , -NR x R y , -NR x C(O)R y , -OC(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; and b) a therapeutically effective amount of a checkpoint inhibitor A method is disclosed comprising administering [Brief description of the drawings]

[0005] [Figure 1] FIG. 1 is a schematic diagram of a dose escalation study of the compounds disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] Detailed Description of the Invention Ras is the most commonly mutated gene that causes cancer. Approximately 40% of patients with non-small cell lung cancer (NSCLC) have mutations in RAS, most commonly KRAS. 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.

[0007] 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.

[0008] The present disclosure provides a combination of a compound disclosed herein, such as rigosertib, with a checkpoint inhibitor. The checkpoint inhibitor disclosed herein can be, for example, nivolumab, which blocks PD-1.

[0009] In some embodiments, rigosertib can cause genitourinary toxicity, including dysuria and hematuria, hi some embodiments, risk mitigation strategies can minimize these effects.

[0010] In some embodiments, the dose of the checkpoint inhibitor combination partner is in accordance with the FDA label. In some embodiments, patient safety requires deviation from the labeled dose.

[0011] Compounds of the Disclosure In some embodiments, the present disclosure provides a compound of the formula [ka] [In the formula, - 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 , -SR x , -NR x R y , -NR x C(O)R y , -OC(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 pharma- ceutically acceptable salt or zwitterion thereof is disclosed.

[0012] 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 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 x is independently substituted C 1~6 In some embodiments, each R x is independently substituted C 1~3 In some embodiments, each R xis 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.

[0013] 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.

[0014] In some embodiments, R 7 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.

[0015] In some embodiments, each R 11a and R 11bis 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 C 1~6 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.

[0016] In some embodiments, the present disclosure provides a compound of the formula [ka] is disclosed.

[0017] In some embodiments, the compound has the formula: [ka] has.

[0018] In some embodiments, each R 1 , R 3 , R 5 , and R 8are, 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 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 independently substituted methyl.

[0019] 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.

[0020] In some embodiments, the compound has the formula: [ka] has.

[0021] 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.

[0022] In some embodiments, each R 14 and R 15is 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.

[0023] In some embodiments, the compound has the formula: [ka] has.

[0024] 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 5ais methyl. In some embodiments, R 8a is methyl.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C67, C68, C69, C70, C71, C72, C73, C74, C75, C76, C77, C78, ​​C79, C80, C81, C82, C83, C84, C85, C85, C86, C87, C88, C89, C90, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C101, C102, C103, C104, C105, C106, C107, C108, C109, C111, C112, C113, C114, C115, C115, C11 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 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 1~3It is alkylene.

[0029] Non-limiting examples of straight chain alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0030] 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.

[0031] Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, and 3-carboxypropyl.

[0032] 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.

[0033] 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, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C77, C81, C92, C93, C94, C95, C96, C97, C98, C99, C109, C111, C122, C133, C143, C154, C165, C176, C187, C198, C199, C191, C192, C193, C194, C195, C196, C197, C198, C199, C199, C200, C201, C202, C203, C204, C205, C206, 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C18 , 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.

[0034] 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, 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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).

[0041] 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).

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] Pharmaceutical Compositions of the Present Disclosure The pharmaceutical composition of the compound disclosed herein may be any pharmaceutical compound described herein in combination with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, or excipients.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 routes and forms, 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.

[0050] The pharmaceutical composition can be administered in a local or systemic manner, for example, by injecting the compound directly into an organ, optionally in a depot or sustained release formulation.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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] For buccal or sublingual administration, the compositions may be tablets, lozenges, or gels.

[0055] 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.

[0056] The active compounds may be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, ointments, etc. Such pharmaceutical compositions may contain solubilizers, stabilizers, isotonicity enhancing agents, buffers, and preservatives.

[0057] Suitable formulations for transdermal administration of active compounds can use transdermal delivery devices and transdermal delivery patches, and can be lipophilic emulsions or buffered aqueous solutions dissolved or dispersed in polymers or adhesives. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical compounds. Transdermal delivery can be achieved by iontophoretic patches. In addition, transdermal patches can provide controlled delivery. Absorption rate can be slowed down by using a rate-limiting membrane or by trapping the compound in a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption. Absorption enhancers or carriers can include pharma-ceutically acceptable absorbent solvents that aid in passage through the skin. For example, transdermal devices can be in the form of a dressing, including a backing member, a reservoir containing the compound and carrier, a rate-limiting barrier for delivering the compound to the subject's skin at a controlled, predetermined rate over an extended period of time, and an adhesive for fixing the device to the skin or eye.

[0058] For administration by inhalation, active compound can be in the form of aerosol, vapor, mist or powder.Inhalation can be performed by nasal delivery, oral delivery, or both.Nasal or intranasal administration involves insufflation of compound through the nose, for example, nasal drops and nasal sprays.This administration route can produce local and / or systemic effects.Inhaler or insufflator device can be used for nose-to-lung delivery of the compound described herein.

[0059] The compound 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.Suppository forms of the composition may use a mixture of fatty acid glycerides or a low melting wax, such as cocoa butter.In some embodiments, the pharmaceutical composition of the present disclosure comprises PEG.In some embodiments, the pharmaceutical composition of the present disclosure comprises PEG-400.In some embodiments, the pharmaceutical composition of the present disclosure comprises PEG-4000.

[0060] 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.

[0061] 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.

[0062] The 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. The methods and pharmaceutical compositions described herein include the use of crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity.

[0063] 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, cachets, and suppositories. 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.

[0064] 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, geltabs, 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.

[0065] Non-limiting examples of pharma- ceutically acceptable excipients suitable for use in the methods disclosed herein include granulating agents, binders, lubricants, disintegrants, sweeteners, glidants, antiadhesives, 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.

[0066] The composition of the compounds disclosed herein may be, for example, in immediate release form or in controlled release formulation. Immediate release formulations may be formulated to make the compound act quickly. Non-limiting examples of immediate release formulations include readily soluble formulations. Controlled release formulations may be pharmaceutical formulations in which drug release rate and drug release profile are adapted to meet physiological and chronotherapeutic requirements, or are formulated to provide drug release at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations that include polymeric materials in which at least one active ingredient is dispersed), granules in a matrix, polymer mixtures, and granular agglomerates.

[0067] The disclosed compositions can optionally contain from about 0.001% to about 0.005% by weight by volume of a pharma- ceutically acceptable preservative.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] The methods disclosed herein include, for example, administering a compound disclosed herein or a pharma- ceutically acceptable salt thereof in combination with a pharma- ceutically acceptable carrier. The carrier can be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject.

[0072] The compounds disclosed herein or their pharmaceutically acceptable salts disclosed herein can be conveniently formulated into pharmaceutical compositions composed of one or more pharmaceutically acceptable carriers. For example, see Remington's Pharmaceutical Sciences, latest edition, by EW Martin Mack Pub. Co., Easton, PA, which discloses carriers and methods for preparing pharmaceutical compositions that can be used in conjunction with the preparation of formulations of the compounds described herein and is incorporated herein by reference. Such pharmaceuticals can be standard carriers for administering compositions to humans and non-humans, including solutions such as sterile water, saline, and buffer solutions at physiological pH. Other compositions can be administered according to standard procedures. For example, pharmaceutical compositions can also include one or more additional active ingredients, such as antimicrobial agents, anti-inflammatory agents, and anesthetic agents.

[0073] Non-limiting examples of pharmaceutically acceptable carriers include saline solution, Ringer's solution and dextrose solution.Further carriers include sustained release preparations such as semitransparent matrices of solid hydrophobic polymers containing the compound disclosed herein or a pharmaceutically acceptable salt thereof, where the matrices are in the form of shaped articles, such as films, liposomes, microparticles and microcapsules.

[0074] The method disclosed herein relates to administering the compound disclosed herein or a pharma- ceutically acceptable salt thereof as part of a pharmaceutical composition. In various embodiments, the composition of the compound disclosed herein can include a liquid that includes the active agent in a solution, suspension, or both. The liquid composition can include a gel. In one embodiment, the liquid composition is aqueous. Alternatively, the composition can be in the form of an ointment. In another embodiment, the composition is an aqueous composition that can gel in situ. In some embodiments, the composition is an aqueous solution that can gel in situ.

[0075] In addition to the compounds disclosed herein, the pharmaceutical formulations can include additional carriers, as well as thickeners, diluents, buffers, preservatives, and surface active agents. The pharmaceutical formulations can also include one or more additional active ingredients, such as antimicrobial agents, anti-inflammatory agents, and anesthetic agents.

[0076] Excipients can serve simply and directly as inert fillers, or excipients, as used herein, can be part of a pH stabilizing system or coating to ensure delivery of ingredients that are safe for the stomach.

[0077] The compounds disclosed herein, or pharma- ceutically acceptable salts thereof, may also be present in a liquid, emulsion, or suspension for delivery of the active therapeutic agent in aerosol form to body cavities such as the nose, throat, or bronchial passages.

[0078] Depending on the intended mode of administration, pharmaceutical compositions administered as part of the methods disclosed herein may be in the form of solid, semi-solid, or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, gels, etc., in unit dosage forms suitable for single administration of precise dosage amounts. The compositions can contain an effective amount of a compound disclosed herein or a pharma- ceutically acceptable salt thereof in combination with a pharma- ceutically acceptable carrier, as described above, and can, in addition, include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc.

[0079] In some embodiments, the pharmaceutical composition may have a pH of about 7 to about 12, about 9 to about 13, about 3 to about 4, about 4 to about 5, about 5 to about 6, about 6 to about 7, about 7 to about 8, about 8 to about 9, about 9 to about 10, about 10 to about 11, about 11 to about 12, about 12 to about 13, or about 13 to about 14. In some embodiments, the pharmaceutical composition may have a pH of at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, or at least about 13. In some embodiments, the pharmaceutical composition may have a pH of about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, or about 13. In some embodiments, the pharmaceutical composition may have a pH of at most about 4, at most about 5, at most about 6, at most about 7, at most about 8, at most about 9, at most about 10, at most about 11, at most about 12, or at most about 13.

[0080] 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 to about 80 mg, about 80 mg to about 90 mg, about 90 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 150 mg to about 250 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 to about 100 mg, about 150 mg to about 200 mg, about 150 mg to about 250 mg, about 150 mg to about 300 mg, about 150 mg to about 350 mg, about 150 mg to about 400 mg, about 150 mg to about 400 mg, about 150 mg to about 500 mg, about 150 mg to about 500 mg, about 150 mg to about 500 mg, about 150 mg to about The amount of the active ingredient may be present in the composition in the range of about 100 mg to 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.

[0081] 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.

[0082] In some embodiments, the pharmaceutical composition of the present disclosure may contain a compound in an amount of about 25 mg / mL to about 3000 mg / mL. In some embodiments, the pharmaceutical composition of the present disclosure may contain a compound in an amount of about 25 mg / mL to about 50 mg / mL, about 50 mg / mL to about 100 mg / mL, about 100 mg / mL to about 250 mg / mL, about 250 mg / mL to about 500 mg / mL, about 500 mg / mL to about 750 mg / mL, about 750 mg / mL to about 1000 mg / mL, about 1000 mg / mL to about 1500 mg / mL, about 1500 mg / mL to about 2000 mg / mL, about 2000 mg / mL to about 2500 mg / mL, or about 2500 mg / mL to about 3000 mg / mL. In some embodiments, pharmaceutical compositions of the present disclosure may contain a compound in an amount of at least about 25 mg / mL, at least about 50 mg / mL, at least about 100 mg / mL, at least about 250 mg / mL, at least about 500 mg / mL, at least about 750 mg / mL, at least about 1000 mg / mL, at least about 1250 mg / mL, at least about 1500 mg / mL, at least about 1750 mg / mL, at least about 2000 mg / mL, at least about 2250 mg / mL, at least about 2500 mg / mL, at least about 2750 mg / mL, or at least about 3000 mg / mL. In some embodiments, pharmaceutical compositions of the disclosure may contain a compound in an amount of about 25 mg / mL, about 50 mg / mL, about 100 mg / mL, about 250 mg / mL, about 500 mg / mL, about 750 mg / mL, about 1000 mg / mL, about 1250 mg / mL, about 1500 mg / mL, about 1750 mg / mL, about 2000 mg / mL, about 2250 mg / mL, about 2500 mg / mL, about 2750 mg / mL, or about 3000 mg / mL. In some embodiments, pharmaceutical compositions of the present disclosure may contain a compound in an amount of up to about 25 mg / mL, up to about 50 mg / mL, up to about 100 mg / mL, up to about 250 mg / mL, up to about 500 mg / mL, up to about 750 mg / mL, up to about 1000 mg / mL, up to about 1250 mg / mL, up to about 1500 mg / mL, up to about 1750 mg / mL, up to about 2000 mg / mL, up to about 2250 mg / mL, up to about 2500 mg / mL, up to about 2750 mg / mL, or up to about 3000 mg / mL.

[0083] In some embodiments, the pharmaceutical composition of the present disclosure may comprise a compound in an amount of about 35 mg / mL. In some embodiments, the pharmaceutical composition of the present disclosure may comprise a compound in an amount of about 70 mg / mL. In some embodiments, the pharmaceutical composition of the present disclosure may comprise a compound in an amount of about 75 mg / mL. In some embodiments, the pharmaceutical composition of the present disclosure may comprise a compound in an amount of about 140 mg / mL. In some embodiments, the pharmaceutical composition of the present disclosure may comprise a compound in an amount of about 280 mg / mL.

[0084] 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 parenteral injection may be provided in unit dosage form, for example, in ampoules, and in multi-dose containers with preservatives.

[0085] Intravenous (IV) formulations: In some embodiments, the compounds or pharmaceutical compositions of the present disclosure may be administered intravenously. In some embodiments, the formulations disclosed herein may be parenteral formulations of a solution of the active pharmaceutical ingredient (API) 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 the parenteral formulation. If the parenteral formulation is administered IV, dilution with IV saline may be required.

[0086] Oral Capsule Formulation: In some embodiments, the compound or pharmaceutical composition of the present disclosure can be administered orally. In some embodiments, the compound or pharmaceutical composition of the present disclosure can be formulated as a soft gelatin capsule in two strengths: 1) about 70 mg / mL compound solution in PEG400, or 2) about 280 mg / mL compound suspension in PEG400 and PEG4000. A 70 mg capsule contains 1 mL of 70 mg / mL compound or pharmaceutical composition solution and can be, for example, clear and transparent oval. A 280 mg capsule contains 1 mL of 280 mg / mL compound or pharmaceutical composition solution and can be, for example, opaque yellow to orange.

[0087] dosage The present disclosure provides a maximum tolerated dose (MTD) of a compound disclosed herein in combination with a checkpoint inhibitor.

[0088] In some embodiments, the individual dose administered to the subject may be in an amount of about 1 mg to about 3000 mg. In some embodiments, the individual dose administered to the subject may be in an amount of about 1 mg to about 250 mg, about 250 mg to about 500 mg, about 500 mg to about 750 mg, about 750 mg to about 1000 mg, about 1000 mg to about 1250 mg, about 1250 mg to about 1500 mg, about 1500 mg to about 1750 mg, about 1750 mg to about 2000 mg, about 2000 mg to about 2250 mg, about 2250 mg to about 2500 mg, about 2500 mg to about 2750 mg, or about 2750 mg to about 3000 mg.

[0089] In some embodiments, the individual doses administered to a subject are at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, mg, at least about 90 mg, at least about 95 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg, at least about 200 mg, at least about 250 mg, at least about 280 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, 50 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, at least about 1050 mg, at least about 1100 mg, at least about 1150 mg, at least about 1200 mg, at least about 1250 mg, at least about 1300 mg, at least about 1350 mg, at least about 1400 mg, at least about 1450 mg, at least about 1500 mg, at least about 1550 mg, at least about 1600 mg, at least about 1650 mg, at least about 1700 mg, at least about 1750 mg, at least about 1800 mg g, at least about 1850 mg, at least about 1900 mg, at least about 1950 mg, at least about 2000 mg, at least about 2050 mg, at least about 2100 mg, at least about 2150 mg, at least about 2200 mg, at least about 2250 mg, at least about 2300 mg, at least about 2350 mg, at least about 2400 mg, at least about 2450 mg, at least about 2500 mg, at least about 2550 mg, at least about 2600 mg, at least about 2650 mg, at least about 2700 mg, at least about 2750 mg,The amount may be at least about 2800 mg, at least about 2850 mg, at least about 2900 mg, at least about 2950 mg, or at least about 3000 mg. In some embodiments, the individual doses administered to a subject may be 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 15 ... 00mg, about 125mg, about 150mg, about 175mg, about 200mg, about 250mg, about 280mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500m g, about 550mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800mg, about 850mg, about 900mg, about 950mg, about 1000mg, about 1050mg, About 1100mg, about 1150mg, about 1200mg, about 1250mg, about 1300mg, about 1350mg, about 1400mg, about 1450mg, about 1500mg, about 1550mg, About 1600mg, about 1650mg, about 1700mg, about 1750mg, about 1800mg, about 1850mg, about 1900mg, about 1950mg, about 2000mg, about 2050mg, about The amount may be about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, or about 3000 mg. In some embodiments, the individual doses administered to a subject are up to about 1 mg, up to about 2 mg, up to about 3 mg, up to about 4 mg, up to about 5 mg, up to about 10 mg, up to about 15 mg, up to about 20 mg, up to about 25 mg, up to about 30 mg, up to about 35 mg, up to about 40 mg, up to about 45 mg, up to about 50 mg, up to about 55 mg, up to about 60 mg, up to about 65 mg, up to about 70 mg, up to about 75 mg, up to about 80 mg, up to about 85 mg, up to about 90 mg, up to about 95 mg, up to about 100 mg, up to about 125 mg, up to about 150 mg, up to about 175 mg, up to about 200 mg, up to about 250 mg, up to about 280 mg, up to about 300 mg,Max 350mg, Max 400mg, Max 450mg, Max 500mg, Max 550mg, Max 600mg, Max 650mg, Max 700mg, Max 750mg, Max 800mg, Max 850mg, Max 900mg, Max 950mg, Max 1000mg, Max 1050 mg, maximum approximately 1100mg, maximum approximately 1150mg, maximum approximately 1200mg, maximum approximately 1250mg, maximum approximately 1300mg, maximum approximately 1350mg, maximum approximately 1400mg, maximum approximately 1450mg, maximum approximately 1500mg, maximum approximately 1550mg, maximum approximately 1600mg, maximum approximately 1650mg, maximum approximately 1700mg, maximum The amount may be greater than about 1750 mg, up to about 1800 mg, up to about 1850 mg, up to about 1900 mg, up to about 1950 mg, up to about 2000 mg, up to about 2050 mg, up to about 2100 mg, up to about 2150 mg, up to about 2200 mg, up to about 2250 mg, up to about 2300 mg, up to about 2350 mg, up to about 2400 mg, up to about 2450 mg, up to about 2500 mg, up to about 2550 mg, up to about 2600 mg, up to about 2650 mg, up to about 2700 mg, up to about 2750 mg, up to about 2800 mg, up to about 2850 mg, up to about 2900 mg, up to about 2950 mg, or up to about 3000 mg.

[0090] In some embodiments, the individual doses administered to the subject may be in 280 mg increments. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 280 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 560 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 840 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 1120 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 1200 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 1400 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 1500 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 1680 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 1800 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 1960 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 2000 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 2200 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 2240 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 2500 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 2520 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 2800 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 3000 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 3080 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 280 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 560 mg. In some embodiments, the individual doses administered to the subject may be in an amount of at least about 840 mg.In some embodiments, the individual doses administered to the subject may be in an amount of about 1120 mg. In some embodiments, the individual doses administered to the subject may be in an amount of about 1200 mg. In some embodiments, the individual doses administered to the subject may be in an amount of about 1500 mg. In some embodiments, the individual doses administered to the subject may be in an amount of about 1800 mg. In some embodiments, the individual doses administered to the subject may be in an amount of about 2000 mg. In some embodiments, the individual doses administered to the subject may be in an amount of about 2200 mg. In some embodiments, the individual doses administered to the subject may be in an amount of about 2500 mg. In some embodiments, the individual doses administered to the subject may be in an amount of about 2800 mg. In some embodiments, the individual doses administered to the subject may be in an amount of about 3000 mg. In some embodiments, the individual doses administered to the subject may be in an amount of up to about 280 mg. In some embodiments, the individual doses administered to the subject may be in an amount of up to about 560 mg. In some embodiments, the individual doses administered to the subject may be in an amount of up to about 840 mg. In some embodiments, the individual doses administered to the subject may be in an amount of up to about 1120 mg. In some embodiments, the individual doses administered to the subject may be in an amount of up to about 1200 mg. In some embodiments, the individual doses administered to the subject may be in an amount of up to about 1500 mg. In some embodiments, the individual doses administered to the subject may be in an amount of up to about 1800 mg. In some embodiments, the individual doses administered to the subject may be in an amount of up to about 2000 mg. In some embodiments, the individual doses administered to the subject may be in an amount of up to about 2200 mg. In some embodiments, the individual doses administered to the subject may be in an amount of up to about 2500 mg. In some embodiments, the individual doses administered to the subject may be in an amount of up to about 2800 mg. In some embodiments, the individual doses administered to the subject may be in an amount of up to about 3000 mg.

[0091] 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.

[0092] In some embodiments, dose escalation can be performed in increments of 70 mg to reach an effective dose for treating the conditions disclosed herein. In some embodiments, the dose disclosed herein having the maximum biological effect can be administered to a subject in need thereof.

[0093] In some embodiments, the compound of the present disclosure is administered intravenously. In some embodiments, the compound of the present disclosure can be administered continuously for 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, 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, or about 40 days. In some embodiments, the compound of the present disclosure can be administered continuously for about 7 days. In some embodiments, the compound of the present disclosure can be administered continuously for about 14 days. In some embodiments, the compounds of the present disclosure may be administered for about 21 consecutive days. In some embodiments, the compounds of the present disclosure may be administered for about 28 consecutive days.

[0094] In some embodiments, the compounds of the present disclosure can be administered for about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, or about 28 consecutive days of a 28-day cycle. In some embodiments, the compounds of the present disclosure can be administered for about 7 consecutive days of a 28-day cycle. In some embodiments, the compounds of the present disclosure can be administered for about 14 consecutive days of a 28-day cycle. In some embodiments, the compounds of the present disclosure can be administered for about 21 consecutive days of a 28-day cycle. In some embodiments, the compounds of the present disclosure can be administered for about 28 consecutive days of a 28-day cycle.

[0095] 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.

[0096] In some embodiments, the compounds of the present disclosure may be administered at a dose of 560 mg twice a day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 840 mg twice a day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 1120 mg twice a day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 1400 mg twice a day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 1680 mg twice a day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 1960 mg twice a day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 2240 mg twice a day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 2520 mg twice a day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 2800 mg twice a day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 3080 mg twice a day.

[0097] In some embodiments, the compounds of the present disclosure may be administered at a dose of 560 mg divided into two doses throughout the day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 840 mg divided into two doses throughout the day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 1120 mg divided into two doses throughout the day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 1400 mg divided into two doses throughout the day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 1680 mg divided into two doses throughout the day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 1960 mg divided into two doses throughout the day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 2240 mg divided into two doses throughout the day. In some embodiments, the compounds of the present disclosure may be administered at a dose of 2520 mg divided into two doses throughout the day. In some embodiments, the disclosed compounds may be administered in a dose of 2800 mg divided into two doses throughout the day. In some embodiments, the disclosed compounds may be administered in a dose of 3080 mg divided into two doses throughout the day.

[0098] In some embodiments, the compound of the present disclosure can be administered in the morning or early afternoon in a first dose, and in the afternoon or evening in a second dose.In some embodiments, the first dose is about 280mg, about 560mg, about 840mg, about 1120mg, about 1400mg, about 1680mg, about 1960mg, about 2240mg, about 2520mg, about 2800mg, or about 3080mg.In some embodiments, the second dose is about 280mg, about 560mg, about 840mg, about 1120mg, about 1400mg, about 1680mg, about 1960mg, about 2240mg, about 2520mg, about 2800mg, or about 3080mg.

[0099] In some embodiments, the compounds of the present disclosure can be administered at a dose of about 800 mg for 2-5 days every other week. In some embodiments, the compounds of the present disclosure can be administered at a dose of about 650 mg to about 1700 mg for 3-6 days every other week. In some embodiments, the compounds of the present disclosure can be administered at a dose of about 800 mg to about 1500 mg for 2 days per week for 3 weeks, followed by 1 week of no treatment. In some embodiments, the compounds of the present disclosure can be administered at a dose of about 1800 mg per day for 3 days per other week. In some embodiments, the compounds of the present disclosure can be administered at a dose of about 70 mg, about 140 mg, about 280 mg, about 560 mg, or about 700 mg once per day for 1 week. In some embodiments, the compounds of the disclosure can be administered twice daily at a dose of about 70 mg, about 140 mg, about 280 mg, about 560 mg, about 700 mg, or about 1120 mg per day for the first 14 days of a 21 day cycle.

[0100] In some embodiments, the compounds of the present disclosure can be administered at a dose of about 560 mg once in the morning and about 280 mg once in the evening for two weeks, followed by a one week rest period. In some embodiments, the compounds are administered in the fasted state, about 1-2 hours before or about 1-2 hours after a meal.

[0101] The dosing regimen for intravenous administration of the compound can be, for example, 1,800 mg / day given on days 1-3 of a 14-day cycle for 8 cycles, then every day 1-3 of a 28-day cycle thereafter. In combination with the dose of nivolumab, a 3+3 dose escalation can be incorporated to find the RP2D (recommended phase 2 dose). The dose escalation cohort can receive the full dose of nivolumab, and first receive a reduced dose of rigosertib, for example, 1,200 mg / day, then 1500 mg / day, then 1800 mg / day given on days 1-3 of a 14-day cycle for 8 cycles, then every day 1-3 of a 28-day cycle thereafter. In solid tumor studies with less risk of bone marrow toxicity, the dose can be gradually further increased to 2,100 mg / day, 2,400 mg / day until the MTD and RP2D are established according to the 3+3 dose escalation.

[0102] In some embodiments, the disclosed compounds can be administered in a first dose of about 840 mg administered about 1-2 hours before breakfast, followed by a second dose of about 280 mg administered about 2 hours after lunch or about 6-8 hours after the first dose. In some embodiments, the disclosed compounds can be administered in a first dose of about 560 mg administered about 1-2 hours before breakfast, followed by a second dose of about 280-560 mg administered about 2 hours after lunch or about 6-8 hours after the first dose.

[0103] The dosing regimen disclosed herein can be, for example, one dose of oral rigosertib 840mg in the morning and 560mg in the afternoon. Dose escalation can continue depending on the number of dose-limiting toxicities (DLTs) observed. The dosing regimen disclosed herein can be, for example, 840mg twice a day, then 1,120mg in the morning, then 840mg in the afternoon. Dose escalation can continue, for example, by increments of 280mg. For example, the morning dose can be increased by 280mg, and then the afternoon dose can be increased by 280mg.

[0104] Dose escalation may continue until two or more DLTs are observed in a single cohort, at which point the previous dose cohort may be expanded to six patients, and if fewer than two DLTs occur in those six patients, that dose may be considered the MTD.

[0105] Alternatively, dose escalation can be done in 70 mg increments. Furthermore, a much larger percentage of the total daily dose can be administered in the morning dose and a smaller percentage in the afternoon dose (i.e., 1,400 mg in the morning and 560 mg in the afternoon).

[0106] In some embodiments, the subject is encouraged to drink at least 2 L of fluids per day. In some embodiments, the subject is advised to take 650 mg of sodium bicarbonate three times per day, especially if the urinary pH is less than about 7.5.

[0107] Method of administration 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.

[0108] 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.

[0109] In some embodiments, the compounds of the present disclosure can be administered once a day. In some embodiments, the compounds of the present disclosure can be administered twice a day. In some embodiments, the compounds of the present disclosure can be administered three times a day. In some embodiments, the absorption of the compound can be hindered by food. In some embodiments, the dosing is spaced at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 1 hour, at least about 1.5 hours, at least about 2 hours, at least about 2.5 hours, at least about 3 hours, at least about 3.5 hours, at least about 4 hours, at least about 4.5 hours, at least about 5 hours, at least about 5.5 hours, or at least about 6 hours from a meal. In some embodiments, the dosing is spaced at least about 30 minutes from a meal. In some embodiments, the dosing is spaced at least about 1 hour from a meal. In some embodiments, the dosing is spaced at least about 2 hours from a meal. In some embodiments, the compound is administered before the subject consumes food. In some embodiments, the compound is administered after the subject consumes food. In some embodiments, the compound is administered before the subject consumes the drink, hi some embodiments, the compound is administered after the subject consumes the drink.

[0110] In some embodiments, the morning dose of the compound is taken one hour before breakfast after an overnight fast. In some embodiments, the afternoon dose of the compound is taken two hours after lunch and one hour before dinner or other food. In some embodiments, a first therapeutically effective amount of the compound is administered to the subject in the morning of the day, and a second therapeutically effective amount of the compound is administered to the subject in the afternoon of the day. In some embodiments, a first therapeutically effective amount of the compound is administered to the subject in the morning of the day, and a second therapeutically effective amount of the compound is administered to the subject in the evening of the day. In some embodiments, the first therapeutically effective amount and the second therapeutically effective amount are the same. In some embodiments, the first therapeutically effective amount and the second therapeutically effective amount are different. In some embodiments, the first therapeutically effective amount is greater than the second therapeutically effective amount. In some embodiments, the first therapeutically effective amount is less than the second therapeutically effective amount.

[0111] Intravenous rigosertib can be given via a large bore intravenous catheter to avoid the risk of extravasation. IV infusion can be continuous (CIV) over 72 hours, delivered by a standard infusion pump in three separate infusion bags for 24 hours each.

[0112] To reduce the risk of genitourinary adverse events, a second dose of a compound disclosed herein can be administered in the afternoon, a subject disclosed herein can be instructed to orally ingest fluids before sleep, a subject disclosed herein can be instructed to urinate before sleep, or a combination thereof.

[0113] The urine pH of the subject disclosed herein can be monitored.If the urine pH is acidic, the subject can be administered oral bicarbonate.The urine dipstick obtained from the subject disclosed herein can be further monitored for evidence of microscopic hematuria.

[0114] Dosage schedules for administration of the compounds described herein include, but are not limited to, once a day (QD), twice a day (BID), three times a day (TID), four times a day (QID), once a week, twice a week, three times a week, once a month, twice a month, and once every two months. In some embodiments, the compounds of the present disclosure are administered once a day. In some embodiments, the compounds of the present disclosure are administered twice a day. In some embodiments, the compounds of the present disclosure are administered three times a day. In some embodiments, the compounds of the present disclosure are administered four times a day.

[0115] Approximate doses can be predicted or determined based on data available in other species. In some embodiments, allometric scaling can be used to exchange drug doses based on normalization of dose to body surface area. Allometric scaling takes into account the size of an individual species based on body surface area, which is related to the metabolic rate of the animal, established by the evolutionary adaptation of the animal to its size. First, a no observed adverse effect level (NOAEL) is determined in the animal species, the NOAEL is converted to a human equivalent dose (HED), the appropriate animal species is selected, a safety factor is applied, and a pharmacologically active dose is determined.

[0116] The NOAEL, the highest dose level not causing significant adverse effects, is a typical index of safety derived from animal studies to determine a safe starting dose. The NOAEL value can be converted to a HED using the appropriate conversion factor from the animal species based on the body surface area correction factor. Table 1 lists the HED calculation guidelines based on body surface area. The HED is calculated using the equation: HED (mg / kg) = NOAEL (mg / kg) x (body weight) 動物 [kg] / weight ヒト [kg]) (1~0.67) is determined using

[0117] To increase the safety of the first dose in humans, the HED is divided by a factor value of 10. The safety factor can account for differences in physiological and biological processes between humans and animal species.

[0118] Correction factor (K m ) is the ratio of the average body weight (kg) of a species to the body surface area (m 2 ) for various animal species. m The coefficient values ​​are used to estimate the HED as follows: HED (mg / kg) = Animal dose (mg / kg) × (Animal K m / Human K m ),or HED(mg / kg)=Animal dose(mg / kg)×K m ratio [Table 1]

[0119] Table 2 provides guidelines for calculating the Animal Equivalent Dose (AED) based on body surface area. The Animal Equivalent Dose (AED) is calculated based on body surface area by converting the human dose (mg / kg) to the K values ​​provided in Table 2. m Divide by ratio or K m The AED can also be calculated by either multiplying the ratio. The AED can be calculated using the following equation: AED(mg / kg) = Human dose(mg / kg) × K m ratio [Table 2]

[0120] For parenteral administration, HED conversion (mg / kg) is also based on body surface area normalization. Conversion can be performed by dividing the NOAEL for the appropriate species by the conversion factor. Table 3 provides guidance for maximum injection volumes by species, site location, and gauge size. Injection volumes for parenteral formulations are calculated by the following equation: Injection volume (mL) = [animal weight (kg) x animal dose (mg / kg)] / concentration (mg / kg) [Table 3]

[0121] Checkpoint inhibitors In some embodiments, disclosed herein are methods of treating cancer by administering immunomodulators. In some embodiments, disclosed herein are methods of treating cancer by administering compounds and cancer immunotherapies of the present disclosure. In some embodiments, the cancer immunotherapies target immune checkpoints. In some embodiments, the cancer immunotherapies can block inhibitory checkpoints and restore immune system function. In some embodiments, disclosed herein are methods of treating cancer by administering compounds and antibodies of the present disclosure. In some embodiments, disclosed herein are methods of treating cancer by administering compounds and biologics of the present disclosure.

[0122] Immune checkpoints are costimulatory and inhibitory elements inherent to the immune system. They help maintain self-tolerance and modulate the duration and magnitude of physiological immune responses to reduce damage to tissues when the immune system responds to pathogenic infections. Immune responses can also be initiated when T cells recognize antigens unique to tumor cells (e.g., non-self antigens or tumor neo-antigens) or characteristic of tumor cells (e.g., tumor-associated antigens (TAA)). The balance of costimulatory and inhibitory signals used to control immune responses from T cells can be modulated by immune checkpoint proteins. After T cells mature and are activated in the thymus, they can migrate to sites of inflammation and injury to perform repair functions. T cell function can occur by direct action or by recruitment of cytokines and membrane ligands involved in the immune system. The steps involved in T cell maturation, activation, proliferation, and function can be regulated by costimulatory and inhibitory signals, i.e., by immune checkpoint proteins. Tumors can dysregulate checkpoint protein function as an immune tolerance mechanism. Therefore, the development of modulators of checkpoint proteins can have therapeutic value.Non-limiting examples of immune checkpoint molecules include LAG3, BTLA, KIR, CTLA4, ICOS, TIM3, A2aR, PD-1, PD-L1, PD-L2, CD40L, OX40L, CD137L, CD47, B7-H3 and B7-H4.These checkpoint molecules can manipulate IL-2 upstream of the pathway.

[0123] Checkpoint molecules defend against unwanted and harmful immune system activation directed against the self (autoimmunity). These molecules are necessary to help suppress autoimmunity, but can hinder immunotherapies aimed at targeting malignant self-cells that primarily display the same set of surface molecules as the parent cells. Therapies aimed at overcoming these peripheral immune tolerance mechanisms, specifically by blocking inhibitory checkpoints, offer the potential to produce antitumor activity, either as monotherapy or in combination with other therapies that directly or indirectly enhance the presentation of tumor epitopes to the immune system.

[0124] Immune checkpoints can be molecules that regulate inhibitory signaling pathways (e.g., LAG3, CTLA4, PD-1, and TIM3) or molecules that regulate stimulatory signaling pathways (e.g., by ICOS). Some proteins in the broad immunoglobulin superfamily can be ligands for immune checkpoints. Non-limiting examples of immune checkpoint ligand proteins include B7-H4, ICOSL, PD-L1, PD-L2, CD40L, OX40L, CD86, and CD137L.

[0125] In some embodiments, the checkpoint inhibitor is a cell surface checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In some embodiments, the checkpoint inhibitor is an intracellular checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is a cytokine-inducible SH2-containing protein (CISH).

[0126] PD-1 is an inhibitory receptor of the CD28 / CTLA4 family that mediates the activation of activated T lymphocytes, B cells, monocytes, DCs, NK cells, and T regsIt is expressed on the surface of the immune system. The main role of PD-1, in contrast to CTLA4, is to limit T cell activation in peripheral tissues at the time of inflammatory response to infection and to limit autoimmunity. Chronic antigen exposure can result in persistently high levels of PD-1 expression. This expression can induce exhaustion or an anergic state of antigen-specific T cells. This state can be at least partially reversed by blockade of PD-1.

[0127] Two ligands of PD-1, PD-L1 and PD-L2, are expressed on T cells, APCs, and malignant cells. Their ligands function to suppress autoreactive lymphocytes and inhibit the effector function of TAA-specific cytotoxic T lymphocytes (CTLs). Thus, therapies targeting PD-1, PD-L1, or PD-L2 have the potential to restore the cytotoxic activity of TAA-specific T cells.

[0128] Upon ligand engagement, PD-1, through the phosphatase SHP2, can inhibit kinases involved in T cell activation. PD-1 can limit T cell activation in peripheral tissues at the time of inflammatory response to infection and limit autoimmunity. Reduced T cell proliferation can result in reduced IL-2 secretion. PD-1 also inhibits T regs It can be highly expressed on the T regs The tumor can increase the proliferation of T regs can be highly invasive, therefore, blockade of PD-1 may reduce the intratumoral T regs It can reduce the immunosuppressive function of

[0129] PD-1 can also enhance NK activity in tumors or tissues due to its widespread expression pattern. +It can increase antibody production via B cells. Chronic antigen exposure, as observed in viral infections and cancer, can lead to persistent PD-1 activation and T cell anergy among cognate antigen-specific T cells. This anergic state can be reversed by blocking PD-1.

[0130] PD-1 can also be expressed on tumor-infiltrating lymphocytes (TILs) in many tumor types. + Enhanced cellular PD-1 expression may reflect high expression of PD-1 on regulatory T cells within the tumor. PD-1 is a CD8 + It can also be highly expressed on lymphocytes from many tumors, and may reflect an anergic state. Consistent with the increased expression of PD-1 on lymphocytes from many tumors, the ligands of PD-1 can also be highly expressed on tumor cell surfaces. PD-L1 can be highly expressed, for example, on melanoma, ovarian cancer, lung cancer, and kidney cancer cells. PD-L2 can be highly expressed, for example, on primary mediastinal B-cell lymphoma, follicular cell B-cell lymphoma, and Hodgkin's lymphoma. Anti-PD-1 antibodies can induce regression of several tumor types, including colon, kidney, lung, and melanoma. Treatments that directly target PD-1 or target the interaction of PD-1 with its ligand include nivolumab, pembrolizumab, pidilizumab, and AMP-224.

[0131] In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is pidilizumab. Non-limiting examples of anti-PD-1 antibodies include AGEN-2034, AMP-224, BCD-100, BGBA-317, BI-754091, CBT-501, CC-90006, cemiplimab, durvalumab + MEDI-0680, GLS-010, IBI-308, JNJ-3283, JS-001, MEDI-0680, MGA-012, MGD-013, pazopanib hydrochloride + pembrolizumab, PDR-001, PF-06801591, REGN-2810, SHR-1210, TSR-042, LZM-009, and ABBV-181.

[0132] In some embodiments, the anti-PD-Ll antibody is, for example, durvalumab, atezolizumab, avelumab, CX-072, BMS-936559, SHR-1316, M-7824, LY-3300054, FAZ-053, KN-035, CA-170, CK-301, CS-1001, HLX-10, MCLA-145, MSB-2311, or MEDI-4736.

[0133] LAG3 (lymphocyte activation gene 3) is expressed on activated antigen-specific cytotoxic T cells and can enhance regulatory T cell function and independently inhibit CD8+ effector T cell activity. LAG3 is a CD-4-like negative regulatory protein that has a high affinity binding site for MHC class II that is upregulated on some epithelial cancers and confers resistance to T cell proliferation and homeostasis. Blocking LAG-3 / class II interaction using LAG-3-IG fusion protein enhances antitumor immune responses. Therapeutic agents targeting LAG3 include IMP321 and other monoclonal antibodies.

[0134] BTLA (B- and T-lymphocyte attenuator) can inhibit T cells when associated with HVEM (herpes virus entry mediator) as a ligand. HVEM can be expressed on melanoma and endothelial cancer cells. BTLA levels can be high on TILs of subjects with melanoma, and BTLA-expressing T cells can be inhibited in the presence of HVEM.

[0135] KIRs (Killer Immunoglobulin-Like Receptors) are expressed by natural killer (NK) cells and a subset of T lymphocytes. KIRs are cell surface inhibitory receptors that are mostly specific for allelic forms of human leukocyte antigen (HLA) class I molecules. Upon engagement with HLA class I molecules, KIRs block NK cell activation and function. When KIRs are blocked, NK cell activation and function can be blocked.

[0136] CTLA4 (Cytotoxic T-Lymphocyte Antigen 4) is also known as CD152 (Cluster of Differentiation 152). CTLA4 shares sequence homology and ligands (CD80 / B7-1 and CD86 / B7-2) with the costimulatory molecule CD28, but differs in that it delivers an inhibitory signal to T cells that express CTLA4 as a receptor. CTLA4 has a fairly high overall affinity for both ligands and can compete and outcompete CD28 for binding when ligand density is limiting.

[0137] CTLA4 is expressed on the surface of CD8+ effector T cells and plays a functional role in the early activation stages of both naive and memory T cells. CTLA4 opposes the activity of CD28 by increasing its affinity for CD80 and CD86 during the early stages of T cell activation. The main functions of CTLA4 include down-modulation of helper T cells and enhancing the immunosuppressive activity of regulatory T cells. Evidence for the importance of CTLA4 can be demonstrated by the lethal systemic immune hyperactivation phenotype in Ctla4- / - mice.

[0138] CTLA4 can also downregulate immune system function by inhibiting IL-2 production and IL-2 receptor expression.CTLA4 can inhibit the CD28-dependent upregulation of IL-2, and inhibiting IL-2 production can lead to cell cycle arrest.The reduction of IL-2 and subsequent cell cycle arrest can be the cause of the reduced T cell proliferation observed in the presence of CTLA4.

[0139] CTLA4 contains an extracellular domain, a transmembrane domain, and a cytoplasmic tail. There are alternative transcriptional splice variants that code for various isoforms. The membrane-bound isoforms can function as homodimers interconnected by disulfide bonds, and the soluble isoforms can function as monomers. Mutations in CTLA4 can be associated with, for example, insulin-dependent diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, and other autoimmune diseases.

[0140] Therapies that target CTLA4 can be developed to circumvent tumor resistance mechanisms. Inhibition of CTLA4 can result in a broad enhancement of immune responses that depend on helper T cells. Thus, therapeutic agents aimed at blocking CTLA4 can help evade tumor cell resistance mechanisms. Examples of therapies that target CTLA4 include ipilimumab and tremelimumab, which are monoclonal antibodies that can target CTLA4 and can be used, for example, to treat melanoma. Therapies can also be directed to increasing the activity of CTLA4 for the treatment of autoimmune diseases. Fusion proteins of CTLA4 and antibodies can increase the immune response, for example, in patients with rheumatoid arthritis or in patients undergoing kidney transplants who are sensitized to Epstein-Barr virus (EPV).

[0141] ICOS (inducible T cell costimulatory molecule), also known as CD278, is a CD28-superfamily costimulatory molecule expressed on activated T cells. CD40 and CD134 are further examples of costimulatory molecules.

[0142] TIM3 (T cell immunoglobulin and mucin domain-containing protein 3), also known as Hepatitis A virus cellular receptor 2 (HAVCR2), is a Th1-specific cell surface protein that regulates macrophage activation. TIM3 can inhibit helper T cell responses through association with the TIM3 ligand, galectin 9. Galectin 9 can be upregulated in various types of cancer, including breast cancer. TIM3 can be co-expressed with PD-1 on tumor-specific CD8+ T cells, and inhibition of both molecules can significantly enhance T cell proliferation and cytokine production.

[0143] Four types of adenosine receptors, namely A1, A2A, A2B, and A3 receptors, are expressed on the surface of immune cells. The main subtype expressed on T cells is the A2A adenosine receptor (A2aR). Immunosuppressive signaling by the A2aR receptor can function to control the cytokine secretion pattern of NK cells and protect inflamed tissues from excessive damage by immune cells. The A2aR receptor inhibits T cell responses by driving CD4+ T cells to express FOXP3 (forkhead box P3). In turn, FOXP3 can drive CD4+ T cells to develop into regulatory T cells. Deletion of A2aR can result in pathological inflammatory responses to infection.

[0144] B7-H3 can costimulate the proliferation of both CD4+ and CD8+ T cells, enhance the induction of cytotoxic T cells, and selectively stimulate interferon-gamma (IFN-γ) production in the presence of T cell receptor signaling. The B7-H3 receptor can be expressed on dendritic cells and monocytes.

[0145] B7-H4, also known as B7S1 or B7x, is a co-inhibitory member of the B7 family that negatively regulates neutrophil-mediated innate immune responses. B7-H4 receptors can be expressed on B cells and antigen-presenting cells. B7-H4 receptors can also be overexpressed in breast, ovarian, lung cancer, and other solid tumors.

[0146] Immunotherapies disclosed herein include those that modulate checkpoint molecules or checkpoint proteins. Non-limiting examples of agents that modulate checkpoint molecules or checkpoint proteins include cytokines, immunotoxins, recombinant proteins, antibodies, monoclonal antibodies, tumor-specific monoclonal antibodies, antibody-drug conjugates, immunotoxins, and any agent that modulates, upregulates, downregulates, stimulates, antagonizes, inhibits, or induces one or more of LAG3, BTLA, KIR, CTLA4, ICOS, TIM3, A2aR, PD-1, B7-H3, B7-H4, ICOSL, PD-L1, PD-L2, CD40L, OX40L, CD47, CD86, and CD137L. In some embodiments, the immunotoxin treatment is a treatment for one or more of CD5, CD7, CD19, CD22, CD25 (T-NHL), CD30, and CD38 (B-NHL). In some embodiments, the immunotherapy is ipilimumab, nivolumab, tremelimumab, pembrolizumab, pidilizumab, AMP-224 or Resimmune™ (also called A-dmDT390-bisFv(UCHT1)). The agents can be administered in the same unit dosage form as the compounds described herein or in separate dosage forms in any order or simultaneously.

[0147] Non-limiting examples of cells whose activity may be modulated by combination therapy include endothelial cells; B cells; CD4; CD8; blood cells, including red and white blood cells; dendritic cells, including dendritic antigen presenting cells; leukocytes; macrophages; memory B cells; memory T cells; monocytes; NK cells; neutrophil granulocytes; helper T cells; and cytotoxic T cells.

[0148] In some embodiments, the checkpoint inhibitor is ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, or cemiplimab. In some embodiments, the checkpoint inhibitor is nivolumab. In some embodiments, the checkpoint inhibitor is pembrolizumab. In some embodiments, the checkpoint inhibitor is avelumab. In some embodiments, the checkpoint inhibitor is durvalumab.

[0149] In some embodiments, the checkpoint inhibitor may be administered at a dose of about 0.1 mg / kg to about 10 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1 mg / kg, about 1 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2 mg / kg, about 2 mg / kg to about 2.5 mg / kg, about 2.5 mg / kg to about 3 mg / kg, about 3 mg / kg to about 3.5 mg / kg, about 3.5 mg / kg to about 4 mg / kg, about 4 mg / kg to about 4.5 mg / kg, about 4.5 mg / kg to about 5 mg / kg, or about 5 mg / kg to about 6 mg / kg. The checkpoint inhibitor may be administered at a dose of about 0.1 mg / kg to about 0.5 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 0.5 mg / kg to about 1 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 0.5 mg / kg to about 1 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 1 mg / kg to about 1.5 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 1.5 mg / kg to about 3 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 3 mg / kg to about 5 mg / kg.

[0150] In some embodiments, the checkpoint inhibitor may be administered at a dose of at least about 0.1 mg / kg, at least about 0.5 mg / kg, at least about 1 mg / kg, at least about 1.5 mg / kg, at least about 2 mg / kg, at least about 2.5 mg / kg, at least about 3 mg / kg, at least about 3.5 mg / kg, at least about 4 mg / kg, at least about 4.5 mg / kg, at least about 5 mg / kg, at least about 5.5 mg / kg, at least about 6 mg / kg, at least about 6.5 mg / kg, at least about 7 mg / kg, at least about 7.5 mg / kg, at least about 8 mg / kg, at least about 8.5 mg / kg, at least about 9 mg / kg, at least about 9.5 mg / kg, or at least about 10 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 8.5 mg / kg, about 9 mg / kg, about 9.5 mg / kg, or about 10 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 1 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 2.5 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 3 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 3.5 mg / kg.

[0151] In some embodiments, the checkpoint inhibitor may be administered at a dose of up to about 0.1 mg / kg, up to about 0.5 mg / kg, up to about 1 mg / kg, up to about 1.5 mg / kg, up to about 2 mg / kg, up to about 2.5 mg / kg, up to about 3 mg / kg, up to about 3.5 mg / kg, up to about 4 mg / kg, up to about 4.5 mg / kg, up to about 5 mg / kg, up to about 5.5 mg / kg, up to about 6 mg / kg, up to about 6.5 mg / kg, up to about 7 mg / kg, up to about 7.5 mg / kg, up to about 8 mg / kg, up to about 8.5 mg / kg, up to about 9 mg / kg, up to about 9.5 mg / kg, or up to about 10 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of up to about 1 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of up to about 2 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of up to about 3 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of up to about 4 mg / kg. In some embodiments, the checkpoint inhibitor may be administered at a dose of up to about 5 mg / kg.

[0152] In some embodiments, the checkpoint inhibitor is administered in a dose of about 25 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 300 mg to about 350 mg, about 350 mg to about 400 mg, about 400 mg to about 450 mg, or about 450 mg The checkpoint inhibitor may be administered at a dose of about 50 mg to about 250 mg per dose administered. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 250 mg to about 500 mg per dose administered. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 500 mg to about 750 mg per dose administered. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 500 mg to about 750 mg per dose administered. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 500 mg to about 750 mg per dose administered.

[0153] In some embodiments, the checkpoint inhibitor may be administered at a dose of at least about 25 mg, at least about 50 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, at least about 900 mg, at least about 950 mg, or at least about 1,000 mg. In some embodiments, the checkpoint inhibitor may be administered at a dose of at least about 240 mg. In some embodiments, the checkpoint inhibitor may be administered at a dose of at least about 250 mg. In some embodiments, the checkpoint inhibitor may be administered at a dose of at least about 300 mg. In some embodiments, the checkpoint inhibitor may be administered at a dose of at least about 450 mg. In some embodiments, the checkpoint inhibitor may be administered in a dose of at least about 480 mg. In some embodiments, the checkpoint inhibitor may be administered in a dose of at least about 500 mg.

[0154] In some embodiments, the checkpoint inhibitor may be administered at a dose of about 25 mg, about 50 mg, about 100 mg, about 150 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 mg, or about 1,000 mg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 240 mg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 250 mg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 300 mg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 450 mg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 480 mg. In some embodiments, the checkpoint inhibitor may be administered at a dose of about 500 mg.

[0155] In some embodiments, the checkpoint inhibitor is administered at a concentration of about 1 mg / mL to about 2 mg / mL, about 2 mg / mL to about 3 mg / mL, about 3 mg / mL to about 4 mg / mL, about 4 mg / mL to about 5 mg / mL, about 5 mg / mL to about 6 mg / mL, about 6 mg / mL to about 7 mg / mL, about 7 mg / mL to about 8 mg / mL, about 8 mg / mL to about 9 mg / mL, or about 9 mg / mL to about 10 mg / mL. In some embodiments, the checkpoint inhibitor is administered at a concentration of about 9 mg / mL to about 10 mg / mL. In some embodiments, the checkpoint inhibitor is administered at a concentration of at least about 1 mg / mL, at least about 1.5 mg / mL, at least about 2 mg / mL, at least about 2.5 mg / mL, at least about 3 mg / mL, at least about 3.5 mg / mL, at least about 4 mg / mL, at least about 4.5 mg / mL, at least about 5 mg / mL, at least about 5.5 mg / mL, at least about 6 mg / mL, at least about 6.5 mg / mL, at least about 7 mg / mL, at least about 7.5 mg / mL, at least about 8 mg / mL, at least about 8.5 mg / mL, at least about 9 mg / mL, at least about 9.5 mg / mL, or at least about 10 mg / mL. In some embodiments, the checkpoint inhibitor is administered at a concentration of about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, or about 10 mg / mL. In some embodiments, the checkpoint inhibitor is administered at a concentration of about 10 mg / mL.

[0156] In some embodiments, the injection volume is up to about 5 mL, up to about 4.5 mL, up to about 4 mL, up to about 3.5 mL, up to about 3 mL, up to about 2.5 mL, up to about 2 mL, up to about 1.5 mL, up to about 1 mL, or up to about 0.5 mL per kg of body weight. In some embodiments, the injection volume is up to about 4 mL per kg of body weight. In some embodiments, the injection volume is up to about 3 mL per kg of body weight.

[0157] In some embodiments, the total injection volume is up to about 200 mL, up to about 175 mL, up to about 150 mL, up to about 125 mL, up to about 100 mL, up to about 75 mL, up to about 50 mL, or up to about 25 mL. In some embodiments, the total injection volume is up to about 160 mL. In some embodiments, the total injection volume is up to about 125 mL. In some embodiments, the total injection volume is up to about 100 mL.

[0158] In some embodiments, the checkpoint inhibitor can be administered in a dose of at least about 240 mg. In some embodiments, the checkpoint inhibitor can be administered in a dose of at least about 480 mg.

[0159] In some embodiments, the checkpoint inhibitor is administered intravenously. In some embodiments, the checkpoint inhibitor is administered orally.

[0160] In some embodiments, the checkpoint inhibitor is administered once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, or once every 12 weeks. In some embodiments, the checkpoint inhibitor is administered once a week. In some embodiments, the checkpoint inhibitor is administered once a week. In some embodiments, the checkpoint inhibitor is administered once every 2 weeks. In some embodiments, nivolumab is administered once every 4 weeks. In some embodiments, the checkpoint inhibitor is administered once every 6 weeks. In some embodiments, the checkpoint inhibitor is administered once every 8 weeks. In some embodiments, the checkpoint inhibitor is administered once every 12 weeks.

[0161] In some embodiments, the checkpoint inhibitor is administered once, about twice, about three times, about four times, about five times, about six times, about seven times, about eight times, about nine times, about ten times, about eleven times, about twelve times, about thirteen times, about fourteen times, about fifteen times, about sixteen times, about seventeen times, about eighteen times, about nineteen times, about twenty times, about twenty-one times, about twenty-two times, about twenty-three times, about twenty-four times, about twenty-five times, about twenty-six times, about twenty-seven times, or about twenty-eight times over a twenty-eight day cycle. In some embodiments, the checkpoint inhibitor is administered once over a twenty-eight day cycle. In some embodiments, the checkpoint inhibitor is administered twice over a twenty-eight day cycle. In some embodiments, the checkpoint inhibitor is administered three times over a twenty-eight day cycle. In some embodiments, the checkpoint inhibitor is administered four times over a twenty-eight day cycle. In some embodiments, the checkpoint inhibitor is administered on day 1 of a twenty-eight day cycle. In some embodiments, the checkpoint inhibitor is administered on day 15 of a 28 day cycle. In some embodiments, the checkpoint inhibitor is administered on day 22 of a 28 day cycle. In some embodiments, the checkpoint inhibitor is administered on days 1 and 15 of a 28 day cycle.

[0162] In some embodiments, the checkpoint inhibitor is administered over about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, or about 120 minutes. In some embodiments, the checkpoint inhibitor is administered over 30 minutes. In some embodiments, the checkpoint inhibitor is administered over 60 minutes. In some embodiments, the checkpoint inhibitor is administered over 90 minutes. In some embodiments, the checkpoint inhibitor is administered over 120 minutes.

[0163] In some embodiments, nivolumab is administered over 30 minutes. In some embodiments, nivolumab is administered over 60 minutes. In some embodiments, nivolumab is administered over 30 minutes at a dose of about 240 mg every 2 weeks. In some embodiments, nivolumab is administered over 60 minutes at a dose of about 480 mg every 2 weeks. In some embodiments, nivolumab is administered over 30 minutes at a dose of about 480 mg every 4 weeks for the first 16 weeks, followed by 480 mg every 4 weeks at a dose of 30 minutes.

[0164] disease The methods disclosed herein can be used to treat, for example, infectious diseases, proliferative diseases, cancer, solid tumors, liquid tumors, non-small cell lung cancer, melanoma, colorectal cancer, head and neck cancer, bladder cancer, or pancreatic cancer. In some embodiments, the compounds of the present invention can be used to treat cancer in a subject.

[0165] The subject can be, for example, an older adult, an adult, an adolescent, a pre-adolescent, a child, a toddler, an infant, a neonate, and a non-human animal. In some embodiments, the subject is a patient.

[0166] The compounds of the present invention can, for example, slow down the growth of cancer cell lines or kill cancer cells. In some embodiments, the cancer comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mutations. In some embodiments, the cancer comprises 1 mutation. In some embodiments, the cancer comprises 2 mutations. In some embodiments, the cancer comprises 3 mutations. In some embodiments, the cancer comprises 4 mutations. In some embodiments, the cancer comprises 5 mutations.

[0167] In some embodiments, the cancer comprises a KRAS mutation. In some embodiments, the cancer comprises a G12V mutation. In some embodiments, the cancer comprises a G12D mutation. In some embodiments, the cancer comprises a G12C mutation. In some embodiments, the cancer comprises an I46T mutation.

[0168] 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.

[0169] Tumor response according to the methods disclosed herein can be measured based on RECIST response classification. EXAMPLES

[0170] Example 1 Studies to evaluate the oral pharmaceutical compositions disclosed herein for treating a disease of interest Approximately 30 patients will be enrolled in the Rigosertib Dose Escalation Study in Non-Small Cell Lung Cancer to investigate the dose of Rigosertib in combination with Nivolumab. The Nivolumab dose is 240mg every 2 weeks or 480mg every 4 weeks. The next Rigosertib dose cohort will be 840mg in the morning and 560mg in the afternoon, given at least 2 hours after the previous meal and 1 hour before each subsequent meal. The dose increments in the dose escalation 3+3 study will be 280mg each, with the morning dose being increased first in the next cohort, followed by the afternoon dose being increased, e.g., 840mg / 560mg, then 840mg / 840mg, then 1,120mg / 840mg (morning and afternoon, respectively). For each 3+3 dose escalation study, the MTD and RP2D will be determined based on DLT, and an expansion cohort of up to 12 patients will be enrolled after the determination of the RP2D. In addition to evaluating safety and tolerability, efficacy will be measured by overall response rate as assessed by iRECIST.

[0171] After determination of the RP2D, a randomized controlled Phase 2 study will be conducted combining rigosertib with nivolumab. Approximately 200 patients will be enrolled in a 1:1 ratio to receive either nivolumab + placebo or nivolumab + rigosertib. The primary outcome will be a statistical comparison between progression-free survival (PFS) rates, with overall survival (OS) as a secondary endpoint.

[0172] Example 2 Studies to evaluate the intravenous pharmaceutical compositions disclosed herein for treating diseases in subjects Approximately 30 patients will be enrolled in an IV rigosertib dose escalation study in colorectal cancer to determine the MTD in combination with nivolumab. The study will be conducted in combination with standard dose checkpoint inhibition, per label. The initial dose of IV rigosertib given in combination will be 1,200 mg / 24 hours, given as a continuous infusion (CIV) on days 1-3 of a 14-day cycle. The next rigosertib dose cohort will be 1,500 mg / 24 hours, given as a continuous infusion (CIV) on days 1-3 of a 14-day cycle. Dose increments for the dose escalation 3+3 study will be 300 mg / 24 hours each (1,800 mg, 2,100 mg, 2,400 mg, etc.). For each 3+3 dose escalation study, the MTD and RP2D will be determined based on DLTs, and an expansion cohort of up to 12 patients will be enrolled at the RP2D following determination of the RP2D. In addition to evaluating safety and tolerability, efficacy will be measured by overall response rate as assessed by iRECIST.

[0173] After the RP2D is determined, a randomized controlled Phase 2 study will be conducted in combination with nivolumab. Approximately 200 patients will be enrolled in a 1:1 ratio to receive either nivolumab + placebo or nivolumab + rigosertib. The primary outcome will be a statistical comparison between progression-free survival (PFS) rates, with overall survival (OS) as a secondary endpoint.

[0174] Example 3 Studies to evaluate the PK / PD results for the pharmaceutical compositions disclosed herein for treating a disease of interest Biomarker or protein levels are measured in cancer cell samples collected before the start of treatment and at the end of treatment. The effect of rigosertib on RAS mutations in tumors and circulating tumor cells is studied along with the immunological environment of responding patients compared to those not responding to treatment. Specific time points for blood and tissue collection for pharmacodynamic evaluation are determined by protocol. Pharmacodynamic data are tabulated and summarized by individual patient and by dose level. Graphical displays are provided when useful for interpretation of results.

[0175] Results available from previous genetic and biomarker testing, as well as further testing of blood and liquid cancer cell samples for biomarkers related to the safety and efficacy of the pharmaceutical compositions described herein, can be examined for possible correlations with patient outcomes.

[0176] Example 4 An animal model to test the activity of rigosertib with immune checkpoint inhibitors in RAS-mutated cancers KRAS has been identified to be mutated in several tumor types, including lung, gastrointestinal (colon), pancreatic, skin, breast, hematopoietic tissue, gynecological, testicular, and urological tumors. In addition to mutations, other perturbations of the KRAS pathway can occur, leading to activation of the pathway, such as the amplification of wild-type KRAS. Identification of specific KRAS shows that the majority of mutations occur primarily at G12 and G13 amino acids, with mutations that change G to C (G12C and G13C, respectively). In addition, G12D, G12V, G12R, and G12A mutations are also considered clinically relevant and cancer-specific.

[0177] Multiple mouse models are used to test the efficacy of rigosertib in combination with immune checkpoint inhibitors in RAS-mutated cancers. Patient-derived xenograft (PDX) models, including samples obtained from NSCLC, colorectal, and pancreatic cancer patients, are used for the experiments. The specific PDX model used is determined based on the KRAS mutation status of the patient's sample. Tumors are analyzed by genome sequencing to determine KRAS mutations and any other driver mutations or amplifications in other known cell cycle or survival signaling pathways.

[0178] Patient-derived samples are studied in humanized mice. As optimal activity of checkpoint inhibitors requires an intact immune system, studies are performed in specific immunocompetent mouse models. For humanized mouse models, mice with severe combined immunodeficiency that are transplanted with hematopoietic stem cells or human peripheral blood cells are routinely used. After transplantation, mice are engrafted with KRAS-driven PDX lines and treated as described below.

[0179] In addition to humanized models using PDX models, the combination of rigosertib with checkpoint inhibitors will be studied in mouse syngeneic models that utilize allografts of KRAS-driven tumor cells derived from the very mouse strain in which the tumor is engrafted, protecting it from rejection. A third model uses mouse models that are genetically engineered to express human immune components (GEMMS) that also carry genetically defined KRAS mutation-driven cancers.

[0180] Animal assays will establish the ability of rigosertib to synergize or act additively with the activity of checkpoint inhibitors. This study will also address different dosing and scheduling of rigosertib, and how dosing affects the efficacy of rigosertib-checkpoint inhibitor combination treatment.

[0181] Humanized mice are implanted subcutaneously or orthotopically with patient-derived tumor tissue. Syngeneic mice are implanted subcutaneously with KRAS-activated cells with the same genetic background as the mouse strain receiving the implant. Tumors are grown to tumor volumes of 50 mm 3 Once enough animals have tumors of similar tumor volume, the mice are treated with rigosertib and a checkpoint inhibitor.

[0182] Rigosertib is administered at various doses and schedules. Rigosertib is administered by oral gavage at 50mg / kg (HED=243.9), 100mg / kg (HED:487.8mg), 150mg / kg (HED 731.7mg), 200mg / kg (HED=975mg), 250mg / kg (HED=1219.8mg), or 300mg / kg (HED=1463.4mg). The schedule is each dose BID. The schedule is further modified to mimic the schedule in humans and reduce potential toxicity, resulting in the following schedule: 150mg / kg, 200mg / kg, 250mg / kg, and 300mg / kg in the morning, followed by a higher dose in the afternoon (Table 4). [Table 4]

[0183] Animals receiving checkpoint inhibitors are dosed on a clinically relevant schedule. For example, nivolumab is tested at a dose range between 5-30 mg / kg, administered 1-2 times per week via intraperitoneal injection. Pembrolizumab is administered at 5-10 mg / kg every 3-5 days via intraperitoneal injection. For the syngeneic model, murine anti-PD-1, PD-L1 and CTLA-4 clones are used for optimal antigen-specific recognition. In addition to the combination groups, control groups consist of rigosertib alone, checkpoint inhibitors alone, and appropriate vehicle controls.

[0184] The evaluation of the growth inhibitory activity of each drug is determined by two criteria: tumor growth and life expectancy extension (ILS). Tumor growth is monitored by determining the tumor volume. Tumor size is calculated according to the formula W 2 The ILS is calculated according to the following formula: (mean survival of the treatment group) / (mean survival of the vehicle control)-1×100. The second criterion (used for the leukemia model) measures the extension of the ILS. The ILS is calculated using the following formula: (mean survival of the treatment group) / (mean survival of the vehicle control)-1×100.

[0185] Embodiment The following non-limiting embodiments provide illustrative examples of the present invention, but do not limit the scope of the invention.

[0186] 1. A method of treating a condition, the method comprising administering to a subject in need of treatment for said condition: a) The therapeutically effective amount is given by: [ka] or a pharma- ceutically acceptable salt or zwitterion thereof, wherein - 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 , -SR x , -NR x R y , -NR x C(O)R y , -OC(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 zis independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; a compound or a pharma- ceutically acceptable salt or zwitterion thereof, and b) a therapeutically effective amount of a checkpoint inhibitor The method of claim 1, further comprising administering

[0187] Embodiment 2. The method of embodiment 1, wherein the condition is cancer.

[0188] Embodiment 3. The method of embodiment 2, wherein the cancer comprises a KRAS mutation.

[0189] Embodiment 4. The method of embodiment 3, wherein the KRAS mutation is G12V.

[0190] Embodiment 5. The method of embodiment 3, wherein the KRAS mutation is G12D.

[0191] Embodiment 6. The method of embodiment 3, wherein the KRAS mutation is G12C.

[0192] Embodiment 7. The method of embodiment 3, wherein the KRAS mutation is I46T.

[0193] Embodiment 8. The method of embodiment 2, wherein said cancer does not comprise a G12C KRAS mutation.

[0194] Embodiment 9. The method of any one of embodiments 1 to 8, wherein the condition is non-small cell lung cancer.

[0195] Embodiment 10. The method of any one of embodiments 1 to 8, wherein the condition is lung adenocarcinoma.

[0196] Embodiment 11. The method of any one of embodiments 1-10, wherein said administering said compound is intravenous.

[0197] Embodiment 12. The method of any one of embodiments 1-10, wherein said administering said compound is oral.

[0198] Embodiment 13. The method of any one of embodiments 1 to 12, wherein said therapeutically effective amount of said compound is from about 100 mg to about 3,000 mg.

[0199] Embodiment 14. The method of any one of embodiments 1-12, wherein said therapeutically effective amount of said compound is at least about 560 mg.

[0200] Embodiment 15. The method of any one of embodiments 1-12, wherein said therapeutically effective amount of said compound is at least about 840 mg.

[0201] Embodiment 16. The method of any one of embodiments 1-12, wherein said therapeutically effective amount of said compound is at least about 1,120 mg.

[0202] Embodiment 17. The method of any one of embodiments 1-12, wherein said therapeutically effective amount of said compound is at least about 1,200 mg.

[0203] Embodiment 18. The method of any one of embodiments 1-12, wherein said therapeutically effective amount of said compound is at least about 1,500 mg.

[0204] Embodiment 19. The method of any one of embodiments 1-12, wherein said therapeutically effective amount of said compound is at least about 1,800 mg.

[0205] Embodiment 20. The method of any one of embodiments 1-19, wherein the compound is administered once a day.

[0206] Embodiment 21 The method of any one of embodiments 1-19, wherein the compound is administered twice daily.

[0207] Embodiment 22. The method of any one of embodiments 1-19 or 21, wherein a first therapeutically effective amount of the compound is administered to the subject in the morning of a day and a second therapeutically effective amount of the compound is administered to the subject in the afternoon of a day.

[0208] Embodiment 23. The method of any one of embodiments 1-19 or 21, wherein a first therapeutically effective amount of the compound is administered to the subject in the morning of a day and a second therapeutically effective amount of the compound is administered to the subject in the evening of a day.

[0209] Embodiment 24. The method of embodiment 22 or 23, wherein the first therapeutically effective amount and the second therapeutically effective amount are the same.

[0210] Embodiment 25 The method of embodiment 22 or 23, wherein the first therapeutically effective amount and the second therapeutically effective amount are different.

[0211] Embodiment 26 The method of embodiment 22 or 23, wherein the first therapeutically effective amount is greater than the second therapeutically effective amount.

[0212] Embodiment 27 The method of embodiment 22 or 23, wherein the first therapeutically effective amount is less than the second therapeutically effective amount.

[0213] Embodiment 28. The method of any one of embodiments 1-19, wherein said administering of said compound occurs three times a day.

[0214] Embodiment 29. The method of any one of embodiments 1 to 28, wherein said administering of said compound occurs at least 1 hour before said subject consumes food.

[0215] Embodiment 30 The method of any one of embodiments 1-28, wherein said administering of said compound occurs at least 1 hour after said subject has consumed food.

[0216] Embodiment 31 The method of any one of embodiments 1 to 30, wherein said administering of said compound occurs at least 1 hour before said subject consumes a drink.

[0217] Embodiment 32. The method of any one of embodiments 1 to 30, wherein said administering of said compound occurs at least 1 hour after said subject consumes a drink.

[0218] Embodiment 33. Each R 1 , R 3 , and R 5 But independently, OR x 33. The method of any one of embodiments 1 to 32, wherein

[0219] Embodiment 34. Each R x The method of any one of embodiments 1-33, wherein is independently alkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted.

[0220] Embodiment 35. Each R x is independently substituted or unsubstituted C 1~6 The method of any one of embodiments 1-33, wherein the alkyl group is alkyl.

[0221] Embodiment 36. Each R x is 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.

[0222] Embodiment 37. Each R x The method of any one of the preceding embodiments, wherein is independently methyl.

[0223] Embodiment 38. Each R 2 , R4 , R 6 , R 9 , and R 10 The method of any one of the preceding embodiments, wherein is independently hydrogen.

[0224] Embodiment 39. Each R 11a and R 11b The method of any one of the preceding embodiments, wherein is independently hydrogen.

[0225] Embodiment 40. Each R 12 and R 13 The method of any one of the preceding embodiments, wherein is independently hydrogen.

[0226] 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 15 is independently alkyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen; The method of claim 1.

[0227] Embodiment 42. Each R 1a , R 3a , R 5a , and R 8a is independently methyl.

[0228] Embodiment 43.R 14 42. The method of embodiment 41, wherein is hydrogen.

[0229] Embodiment 44.R 15The method of embodiment 41, 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.

[0230] Embodiment 45.R 15 42. The method of embodiment 41, wherein is CH2COOH.

[0231] Embodiment 46. The method of any one of embodiments 1 to 45, 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.

[0232] Embodiment 47. The method of any one of embodiments 1 to 45, wherein the compound is sodium (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetate.

[0233] Embodiment 48. The method of any one of embodiments 1 to 47, wherein said administering of said checkpoint inhibitor is intravenous.

[0234] Embodiment 49. The method of any one of embodiments 1 to 47, wherein said administering of said checkpoint inhibitor is oral.

[0235] Embodiment 50. The method of any one of embodiments 1 to 49, wherein the checkpoint inhibitor is a cell surface checkpoint inhibitor.

[0236] Embodiment 51. The method of any one of embodiments 1 to 49, wherein the checkpoint inhibitor is a CTLA-4 inhibitor.

[0237] Embodiment 52. The method of any one of embodiments 1 to 49, wherein the checkpoint inhibitor is a PD-1 inhibitor.

[0238] Embodiment 53. The method of any one of embodiments 1 to 49, wherein the checkpoint inhibitor is a PD-L1 inhibitor.

[0239] Embodiment 54 The method of any one of embodiments 1 to 49, wherein the checkpoint inhibitor is an intracellular checkpoint inhibitor.

[0240] Embodiment 55. The method of any one of embodiments 1 to 49, wherein the checkpoint inhibitor is a cytokine-inducible SH2-containing protein (CISH).

[0241] Embodiment 56. The method of any one of embodiments 1 to 49, wherein the checkpoint inhibitor is nivolumab.

[0242] Embodiment 57. The method of any one of embodiments 1 to 49, wherein the checkpoint inhibitor is pembrolizumab.

[0243] Embodiment 58. The method of any one of embodiments 1 to 49, wherein the checkpoint inhibitor is ipilimumab.

[0244] Embodiment 59. The method of any one of embodiments 1 to 49, wherein the checkpoint inhibitor is atezolizumab.

[0245] Embodiment 60. The method of any one of embodiments 1 to 59, wherein the therapeutically effective amount of the checkpoint inhibitor is from about 100 mg to about 1,000 mg.

[0246] Embodiment 61. The method of any one of embodiments 1 to 59, wherein the therapeutically effective amount of the checkpoint inhibitor is about 240 mg.

[0247] Embodiment 62. The method of any one of embodiments 1 to 59, wherein the therapeutically effective amount of the checkpoint inhibitor is about 480 mg.

[0248] Embodiment 63. The method of any one of embodiments 1 to 59, wherein the therapeutically effective amount of the checkpoint inhibitor is from about 2 mg / kg to about 12 mg / kg.

[0249] Embodiment 64. The method of any one of embodiments 1 to 59, wherein the therapeutically effective amount of the checkpoint inhibitor is about 2 mg / kg.

[0250] Embodiment 65. The method of any one of embodiments 1 to 59, wherein the therapeutically effective amount of the checkpoint inhibitor is about 3 mg / kg.

[0251] Embodiment 66. The method of any one of embodiments 1 to 59, wherein the therapeutically effective amount of the checkpoint inhibitor is about 10 mg / kg.

[0252] Embodiment 67. The method of any one of embodiments 1 to 66, wherein the checkpoint inhibitor is administered over a 30 minute period.

[0253] Embodiment 68. The method of any one of embodiments 1 to 66, wherein the checkpoint inhibitor is administered over a period of 60 minutes.

[0254] Embodiment 69. The method of any one of embodiments 1 to 68, wherein the checkpoint inhibitor is administered once every two weeks.

[0255] Embodiment 70. The method of any one of embodiments 1 to 68, wherein said administering of said checkpoint inhibitor occurs once every four weeks.

[0256] Embodiment 71 The method of any one of embodiments 1-68, wherein said administering of said compound occurs for 21 consecutive days in a 28 day cycle.

[0257] Embodiment 72. The method of any one of embodiments 1 to 68, wherein said administering of said checkpoint inhibitor occurs on days 1 and 15 of a 28 day cycle.

Claims

A combination for the treatment of cancer, said combination comprising: a) A therapeutically effective amount of a compound of the formula: 【Chemical 11】 or a pharmaceutically acceptable salt or zwitterion thereof, wherein: - 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 is independently alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, -C(O)R ｘ , -C(O)OR ｘ , -C(O)NR ｘ R ｙ , -OR ｘ , -SR ｘ , -NR ｘ R ｙ , -NR ｘ C(O)R ｙ , -OC(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, a compound or a pharmaceutically acceptable salt or zwitterion thereof, and b) A therapeutically effective amount of a checkpoint inhibitor A combination comprising.

2. The combination according to claim 1, wherein the cancer comprises a KRAS mutation.

3. The combination according to claim 2, wherein the KRAS mutation is G12V, G12D, G12C or I46T.

4. The combination according to claim 1, wherein the cancer does not comprise a G12C KRAS mutation.

5. The combination according to claim 1, wherein the condition is non-small cell lung cancer or lung adenocarcinoma.

6. The combination according to claim 1, wherein the compound is configured for intravenous or oral administration.

7. The combination according to any one of the preceding claims, wherein the therapeutically effective amount of the compound is from about 100 mg to about 3,000 mg.

8. The combination according to claim 7, wherein the therapeutically effective amount of the compound is at least about 560 mg, at least about 840 mg, at least about 1,120 mg, at least about 1,200 mg, at least about 1,500 mg or at least about 1,800 mg.

9. The combination according to claim 1, wherein the compound is administered once a day.

10. The combination according to claim 1, wherein the compound is administered twice a day.

11. The combination according to claim 1, wherein the compound is configured for a first administration to the subject in the morning of the day and a second administration to the subject in the afternoon or evening of the day.

12. The combination according to claim 11, wherein the first therapeutically effective amount and the second therapeutically effective amount are the same.

13. The combination according to claim 11, wherein the first therapeutically effective amount and the second therapeutically effective amount are different.

14. The combination according to claim 11, wherein the first therapeutically effective amount is more than the second therapeutically effective amount.

15. The combination according to claim 11, wherein the first therapeutically effective amount is less than the second therapeutically effective amount.

16. The combination according to claim 11, wherein the compound is configured for administration to the subject three times a day.

17. Each R １ , R ３ , and R ５ is, independently, OR ｘ The combination according to claim 1.

18. Each R ｘ is, independently, alkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. The combination according to claim 17.

19. Each R ｘ is, independently, substituted or unsubstituted C １～６ alkyl. The combination according to claim 17.

20. Each R ｘ is, independently, C １ alkyl substituted with hydroxy, sulfhydryl, halogen, amino group, nitro group, cyano, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxylic acid, carboxyaldehyde group, alkoxy, aryl, heterocyclyl group, acyl group, amide, or ester. The combination according to claim 19.

21. Each R ｘ is, independently, methyl. The combination according to claim 17.

22. Each R ２ , R ４ , R ６ , R ９ , and R １０ is, independently, hydrogen, the combination according to claim 1.

23. The compound has the formula: 【Chemical Formula 12】 wherein - each R １ａ , R ３ａ , R ５ａ , and R ８ａ is, independently, substituted or unsubstituted C １～８ 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 combination according to claim 1.

24. Each R １ａ , R ３ａ , R ５ａ , and R ８ａ is, independently, methyl, R 14 is hydrogen, R 15 is C 1 alkyl substituted with hydroxy, sulfhydryl, halogen, amino group, nitro group, cyano, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxylic acid, carboxyaldehyde group, alkoxy, aryl, heterocyclyl group, acyl group, amide, or ester, the combination according to claim 23.

25. R １５ is CH ２ COOH, the combination according to claim 23.

26. The combination according to 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, or wherein the compound is sodium (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetate.

27. The combination according to claim 26, wherein the checkpoint inhibitor is formulated for intravenous or oral administration.

28. The combination according to claim 26, wherein the checkpoint inhibitor is a cell surface checkpoint inhibitor, the checkpoint inhibitor is a CTLA-4 inhibitor, the checkpoint inhibitor is a PD-1 inhibitor, the checkpoint inhibitor is a PD-L1 inhibitor, the checkpoint inhibitor is an intracellular checkpoint inhibitor, the checkpoint inhibitor is nivolumab, the checkpoint inhibitor is pembrolizumab, the checkpoint inhibitor is ipilimumab, or the checkpoint inhibitor is atezolizumab.

29. The combination according to claim 26, wherein the therapeutically effective amount of the checkpoint inhibitor is from about 100 mg to about 1,000 mg.

30. A composition for the treatment of cancer, the composition comprising a compound of the formula: 【Chemical 13】 or a pharmaceutically acceptable salt or zwitterion thereof, wherein, in the formula, - Each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11a, R11b, R12, and R13 is independently alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, -C(O)Rx, -C(O)ORx, -C(O)NRxRy, -ORx, -SRx, -NRxRy, -NRxC(O)Ry, -OC(O)Rx, or -SiRxRyRz (each of which is independently optionally substituted), or hydrogen or halogen, - Each of Rx, Ry, and Rz is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl (each of which is independently optionally substituted), or hydrogen or halogen, comprising a compound or a pharmaceutically acceptable salt or zwitterion thereof, wherein the composition is administered in combination with a checkpoint inhibitor, Composition. **Claim 31** A composition for the treatment of cancer, comprising a checkpoint inhibitor, wherein the composition has the formula: **Chemical Formula 14** a compound or a pharmaceutically acceptable salt or zwitterion thereof, wherein in the formula, - Each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11a, R11b, R12, and R13 is independently alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, -C(O)Rx, -C(O)ORx, -C(O)NRxRy, -ORx, -SRx, -NRxRy, -NRxC(O)Ry, -OC(O)Rx, or -SiRxRyRz (each of which is independently substituted or unsubstituted), or hydrogen or halogen, - Each of Rx, Ry, and Rz is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl (each of which is independently substituted or unsubstituted), or hydrogen or halogen, A composition, characterized by being administered in combination with a compound or a pharmaceutically acceptable salt or zwitterion thereof. Composition.

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