MLL1-WDR5 protein-protein interaction inhibitor compounds that cross the blood-brain barrier and their uses

Abstract

Described herein are phenyltriazole and aniline compounds that are MLL1-WDR5 protein-protein interaction inhibitors. Also disclosed herein are pharmaceutical compositions and methods of use of the phenyltriazole and aniline compounds.

Description

[Technical field]

[0001] cross reference This application claims the benefit of priority to U.S. Provisional Application No. 63 / 319,589, filed March 14, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the field of medicinal chemistry, more specifically to phenyltriazole and aniline compounds that inhibit MLL1-WDR5 protein-protein interaction, and their preparation and medical use. [Background technology]

[0003] Translocations and rearrangements of the histone H3K4 methyltransferase mixed lineage leukemia 1 (MLL1) gene can lead to mixed lineage leukemia (including acute myeloid leukemia and acute lymphoblastic leukemia). After rearrangement, the MLL1 gene fuses with other chaperone genes to form fusion genes, leading to the expression of oncogenic MLL fusion proteins. MLL fusion proteins can interact with RNA polymerase II (Pol II)-associated elongation factors to form super elongation complexes (SECs). The SEC complex can lead to the abnormal expression of Hox genes regulated by the MLL1 gene, which causes a series of serious consequences, including the development of MLL1 leukemia.

[0004] The C-terminal WIN motif portion of MLL protein can bind to WDR5, RbBP5, Ash2L, and DPY30 to form a complex. MLL1 directly interacts with WDR5 through the C-terminal WIN motif portion and mediates the interaction between the catalytic domain of MLL1 and other protein complexes. When WDR5 is knocked out, the level of H3K4me2 / 3 is reduced, the expression of Hox genes is downregulated, and the apoptosis of leukemia cells is induced. Therefore, the effect of treating leukemia can be achieved by specifically inhibiting the enzymatic activity of wild-type MLL1.

[0005] Therefore, using small molecule inhibitors to disrupt MLL1-WDR5 protein-protein interaction is an effective way to inhibit MLL1 enzyme activity and downregulate the expression of Hox and Meis-1 genes to block leukemia progression. MLL1-WDR5 protein-protein interaction inhibitors are described in WO2019205687A1 and WO2020172932A1, each of which is incorporated herein by reference in its entirety. Additional MLL1-WDR5 protein-protein interaction inhibitors with additional and / or additional improved properties are needed. Summary of the Invention

[0006] The above and additional needs are met by the embodiments described herein. Provided herein are small molecule compounds and compositions that can modulate MLL1-WDR5 protein-protein interaction, as well as methods of using the compounds and compositions. Inhibition of MLL1-WDR5 protein-protein interaction inhibits the enzymatic catalytic activity of MLL1, downregulating the methylation level of H3K4 and the gene expression level of Hox and Meis-1 genes to induce apoptosis of leukemia cells. Thus, the compounds and compositions described herein can be used to treat cancer, including, but not limited to, leukemia.

[0007] Some embodiments described herein are phenyltriazole and aniline compounds, or pharma- ceutically acceptable salts or solvates thereof. In some embodiments, the compounds are those described in Table 1 hereinbelow.

[0008] In some embodiments, described herein are pharmaceutical compositions comprising a compound described herein or a pharma- ceutically acceptable salt or solvate thereof and one or more pharma- ceutically acceptable carriers, diluents, and excipients. In some embodiments provided herein, described are pharmaceutical compositions comprising a compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb), or a pharma- ceutically acceptable salt thereof, and optionally one or more pharma- ceutically acceptable ingredients. Some embodiments described herein provide a process for making a pharmaceutical composition comprising a compound or a pharma- ceutically acceptable salt, and mixing the compound with one or more pharma- ceutically acceptable ingredients. Thus, some embodiments described herein provide the use of a compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb), or a pharma- ceutically acceptable salt thereof, and optionally one or more pharma- ceutically acceptable ingredients, for the preparation of a pharmaceutical composition. In some embodiments, a pharmaceutical composition comprises one or more pharma- ceutically acceptable ingredients.

[0009] Some embodiments provided herein are methods of treating or preventing cancer in a patient in need of such treatment or prevention, comprising administering to the patient a therapeutically acceptable dose of a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof.Some embodiments provided herein are methods of treating or preventing acute leukemia in a patient in need of such treatment or prevention, comprising administering to the patient a therapeutically acceptable dose of a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof.Some embodiments provided herein are methods of treating or preventing acute leukemia in a patient in need of such treatment or prevention, comprising administering to the patient a pharmaceutical composition described herein.In some embodiments, the acute leukemia being treated is acute leukemia with MLL1 gene rearrangement.

[0010] In some embodiments, provided herein is a method for treating cancer, the method comprising administering to a patient in need of cancer treatment an effective amount of a composition comprising a compound having a structure of Formula (I) or Formula (III): [ka] (In the formula, X1 is N or CH; X2 is N, CR2; X3 is N or CH; R2 is selected from N-morpholino, wherein the morpholino group is optionally substituted with one or two methyl groups; Each of R4 and R5 is hydrogen or alkyl, where one or both of R4 and R5 may be alkyl; R 10 and R 11 each is C1-C4 alkyl or R 10 and R 11 together form a 4-alkylpiperazinyl group).

[0011] In some embodiments of the methods for treating cancer disclosed herein, the compound has a structure selected from the group consisting of Formula (Ia), Formula (Ib), Formula (IIIa), and Formula (IIIb), or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof: [ka]

[0012] In some embodiments of the method of treating cancer, the compound has the structure of Formula (Ia) or is a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof. In some embodiments, the compound has the structure of Formula (Ib) or is a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof. In some embodiments, the compound has the structure of Formula (IIIa) or is a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof. In some embodiments, the compound has the structure of Formula (IIIb) or is a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof. In some embodiments, the compound has the structure of Formula (II) or is a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof: [ka] (In the formula, Each of R4 and R5 is hydrogen or methyl, at least one of R5 and R6 is methyl, and each of R6 and R7 is hydrogen or methyl).

[0013] In some embodiments of the methods of treating cancer herein, the methods include oral administration of an effective amount of the compound to a patient. In some embodiments, the effective amount is about 0.1 to about 1000 mg / kg of patient body weight (mpk). In some embodiments, the effective amount is about 1 to about 100 mg / kg of patient body weight (mpk). In some embodiments, the effective amount is about 1 to about 20 mg / kg of patient body weight (mpk). In some embodiments, the patient is a human and the compound is administered at a dose of about 1 to about 20 mg / kg of patient body weight. In some embodiments, the compound is administered to a human at a dose of about 1 to about 20 mg / kg of patient body weight, with a brain concentration Cmax of about 10 to about 310 ng / gram of estimated brain weight of the patient. In some embodiments, the methods of treating cancer include administering the compound once a day (QD), once every other day (QOD), once a week (QW), twice a week (BIW), or three times a week (TIW). In some embodiments, the method of treating cancer includes administering a compound on a dosing schedule, the dosing schedule includes: (1) a first dosing period consisting of about one cycle of administering an effective dose of the compound at a frequency of about once per week (QW); (2) a first rest period; (3) a second dosing period consisting of about one cycle of administering an effective dose of the compound at a frequency of about once per week (QW). In some embodiments, each cycle is about 7 days to about 12 days long. In some embodiments, the rest period is from about the same duration as each cycle. In some embodiments, the method of treating cancer includes administering a compound on a dosing schedule, the dosing schedule includes: (1) a first dosing period consisting of about one cycle of administering an effective dose of the compound at a frequency of about once per week (QW); (2) a first rest period. In some embodiments, the rest period is from about the same duration as about one cycle. The rest period is about 1 month, 1 to 6 months, or 1 to 12 months.

[0014] In some embodiments of the method of treating cancer with a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb), the compound, when administered orally to a dog in an amount of 1.5 mg per kilogram of the dog's body weight (mpk), provides a maximum plasma concentration (Cmax) in the dog of about 150 to about 235 nM. In some embodiments, the compound, when administered orally to a dog in an amount of 1.5 mg per kilogram of the dog's body weight (mpk), provides an area under the plasma concentration curve (AUC0-last) of about 4225 nM.h to about 6603 nM.h. In some embodiments, the compound, when administered orally to a dog in an amount of 4.5 mg per kilogram of the dog's body weight (mpk), provides a maximum plasma concentration (Cmax) in the dog of about 356 nM to about 556 nM. In some embodiments, the compound, when administered orally to a dog in an amount of 4.5 mg per kilogram of dog body weight (mpk), provides an area under the plasma concentration curve (AUC0-last) of about 10734 nM.h to about 16772 nM.h. In some embodiments, the compound, when administered orally to a mouse in an amount of 10 mg per kilogram of mouse body weight (mpk), provides a maximum plasma concentration (Cmax) in the mouse of about 1056 nM to about 1651 nM. In some embodiments, the compound, when administered orally to a mouse in an amount of 10 mg per kilogram of mouse body weight (mpk), provides an area under the plasma concentration curve (AUC0-last) of about 13132 nM.h to about 20519 nM.h. In some embodiments, the compound, when administered orally to a mouse in an amount of 30 mg per kilogram of mouse body weight (mpk), provides a maximum plasma concentration (Cmax) in the mouse of about 2744 nM to about 4288 nM. In some embodiments, the compound has an area under the plasma concentration curve (AUC0-last) of about 44791 nM.h to about 69986 nM.h when orally administered to mice at 30 mg per kilogram of mouse body weight (mpk). In some embodiments, the compound has the structure of Formula (Ib), or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof.In some embodiments, the compound provides a maximum plasma concentration (Cmax) in mice of about 1338 nM to about 2091 nM when orally administered to mice at 10 mg per kilogram of mouse body weight (mpk). In some embodiments, the compound provides an area under the plasma concentration curve (AUC0-last) of about 5681 nM.h to about 8876 nM.h when orally administered to mice at 10 mg per kilogram of mouse body weight (mpk). In some embodiments, the compound provides a maximum plasma concentration (Cmax) in mice of about 4374 nM to about 6834 nM when orally administered to mice at 30 mg per kilogram of mouse body weight (mpk). In some embodiments, the compound provides an area under the plasma concentration curve (AUC0-last) of about 29637 nM.h to about 46309 nM.h when orally administered to mice at 30 mg per kilogram of mouse body weight (mpk). In some embodiments, the compound has the structure of Formula (Ia) or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof. In some embodiments, the compound, when orally administered to dogs in an amount of 1.5 mg per kilogram of dog body weight (mpk), provides a maximum plasma concentration (Cmax) in dogs of about 6.7 nM to about 11 nM. In some embodiments, the compound, when orally administered to dogs in an amount of 1.5 mg per kilogram of dog body weight (mpk), provides an area under the plasma concentration curve (AUC0-last) of about 37 nM.h to about 59 nM.h. In some embodiments, the compound, when orally administered to dogs in an amount of 4.5 mg per kilogram of dog body weight (mpk), provides a maximum plasma concentration (Cmax) in dogs of about 38 nM to about 60 nM. In some embodiments, the compound provides an area under the plasma concentration curve (AUC0-last) of about 367 nM.h to about 574 nM.h when orally administered to dogs at 4.5 mg per kilogram of dog body weight (mpk). In some embodiments, the compound provides a maximum plasma concentration (Cmax) in mice of about 287 nM to about 449 nM when orally administered to mice at 10 mg per kilogram of mouse body weight (mpk).In some embodiments, the compound, when administered orally to mice at 10 mg per kilogram of mouse body weight (mpk), provides an area under the plasma concentration curve (AUC0-last) of about 1050 nM.h to about 1641 nM.h. In some embodiments, the compound, when administered orally to mice at 30 mg per kilogram of mouse body weight (mpk), provides a maximum plasma concentration (Cmax) in mice of about 1020 nM to about 1595 nM. In some embodiments, the compound, when administered orally to mice at 30 mg per kilogram of mouse body weight (mpk), provides an area under the plasma concentration curve (AUC0-last) of about 4515 nM.h to about 7055 nM.h. In some embodiments, the compound has the structure of Formula (IIIb), or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof. In some embodiments, the compound provides a maximum plasma concentration (Cmax) in mice of about 1337 nM to about 2090 nM when orally administered to mice at 10 mg per kilogram of mouse body weight (mpk). In some embodiments, the compound provides an area under the plasma concentration curve (AUC0-last) of about 1779 nM.h to about 2780 nM.h when orally administered to mice at 10 mg per kilogram of mouse body weight (mpk). In some embodiments, the compound provides a maximum plasma concentration (Cmax) in mice of about 3627 nM to about 5668 nM when orally administered to mice at 30 mg per kilogram of mouse body weight (mpk). In some embodiments, the compound provides an area under the plasma concentration curve (AUC0-last) of about 6084 nM.h to about 9506 nM.h when orally administered to mice at 30 mg per kilogram of mouse body weight (mpk). In some embodiments, the compound has the structure of formula (IIIa) or is a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof. In some embodiments, the compound crosses the blood-brain barrier. In some embodiments, the patient has a brain tumor. In some embodiments, the brain tumor is a metastatic brain tumor, a meningioma, a neuroblastoma, a glioblastoma, or an astrocytoma.

[0015] Some embodiments disclosed herein provide a method for treating cancer, the method comprising administering to a patient in need of cancer treatment a composition comprising an effective amount of a compound having a structure of Formula (IIIb): [ka]

[0016] In some embodiments of the method of treating cancer with a compound of formula (IIIb) (also referred to herein as HBI-2375 or HYBI-084), the compound crosses the blood-brain barrier. In some embodiments, the cancer is a solid cancer, a hematological cancer, or a brain tumor. In some embodiments, the effective amount is about 0.5 to about 20 mg per kg of patient body weight (mpk). In some embodiments, the patient is a human and the compound is administered at a dose of about 1 to about 20 mg per kg of patient body weight. In some embodiments, the compound is administered to a human at a dose of about 1 to about 20 mg per kg of patient body weight, with a brain concentration Cmax of about 10 to about 310 ng per gram of estimated brain weight of the patient. In some embodiments, the compound, when orally administered to a mouse in an amount of 40 mg per kilogram of mouse body weight (mpk), results in a maximum plasma concentration (Cmax) in the mouse of about 770 ng / mL to about 1505 ng / mL within about 30 minutes. In some embodiments, the compound, when administered orally to mice in an amount of 40 mg per kilogram of mouse body weight (mpk), provides an average concentration in the mouse brain of about 58 ng / mL to about 156 ng / mL within about 30 minutes. In some embodiments, the compound, when administered orally to mice in an amount of 80 mg per kilogram of mouse body weight (mpk), provides a maximum plasma concentration (Cmax) in the mouse of about 2700 ng / mL to about 5200 ng / mL within about 30 minutes. In some embodiments, the compound, when administered orally to mice in an amount of 80 mg per kilogram of mouse body weight (mpk), provides an average concentration in the mouse brain of about 191 ng / mL to about 540 ng / mL within about 30 minutes. In some embodiments, the compound, when administered orally to mice in an amount of 40 mg per kilogram of mouse body weight (mpk), provides a maximum concentration (Cmax) in the mouse brain of about 126 ng / mL to about 234 ng / mL within about 4 hours. In some embodiments, the compound, when orally administered to a mouse at an amount of 80 mg per kilogram of mouse body weight (mpk), provides a maximum concentration (Cmax) of about 360 ng / mL to about 700 ng / mL in the mouse brain within about 4 hours.In some embodiments, the compound, when administered orally to mice at an amount of 40 mg per kilogram of mouse body weight (mpk), exhibited a plasma concentration area under the curve (AUC. last In some embodiments, the area under the brain concentration curve (AUC) of the compound when administered orally to mice at an amount of 40 mg per kilogram of mouse body weight (mpk) is about 4600 hr·ng / mL to about 8600 hr·ng / mL. last In some embodiments, the area under the plasma concentration curve (AUC) of the compound when administered orally to mice at an amount of 80 mg per kilogram of mouse body weight (mpk) is about 1400 hr·ng / mL to about 2640 hr·ng / mL. last In some embodiments, the area under the brain concentration curve (AUC) of the compound when administered orally to mice at 80 mg per kilogram of mouse body weight (mpk) is about 10,900 hr·ng / mL to about 20,200 hr·ng / mL. last In some embodiments, the compound provides a maximum plasma concentration (Cmax) in dogs of about 150 nM to about 235 nM when orally administered to dogs in an amount of 1.5 mg per kilogram of dog body weight (mpk). In some embodiments, the compound provides an area under the plasma concentration curve (AUC) of about 150 nM to about 235 nM when orally administered to dogs in an amount of 1.5 mg per kilogram of dog body weight (mpk). 0-last ) is approximately 4225 nM·h to approximately 6603 nM·h.

[0017] Some embodiments described herein provide compounds that inhibit MLL1-WDR5 protein-protein interaction and cross the blood-brain barrier. In some embodiments, the compound has the structure of Formula (I) or Formula (III): [ka] (In the formula, X1 is N or CH; X2 is N, CR2; X3 is N or CH; R2 is selected from N-morpholino, wherein the morpholino group is optionally substituted with one or two methyl groups; Each of R4 and R5 is hydrogen or alkyl, where one or both of R4 and R5 may be alkyl; R 10 and R 11 each is C1-C4 alkyl or R 10 and R 11 together form a 4-alkylpiperazinyl group).

[0018] In some embodiments, the compound has a structure selected from the group consisting of Formula (Ia), Formula (Ib), Formula (IIIa), and Formula (IIIb), or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof: [ka]

[0019] In some embodiments, the compound has the structure of formula (IIIb). In some embodiments, the compound is suitable for use in the treatment of cancer. In some embodiments, the cancer to be treated is a brain tumor. In some embodiments, the cancer to be treated is a primary brain tumor or a secondary brain tumor. In some embodiments, the cancer to be treated is a metastatic tumor. In some embodiments, the cancer to be treated is a glioblastoma, a neuroblastoma, or an astrocytoma.

[0020] Other objects, features, and advantages of the methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

[0021] 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 herein. [Brief description of the drawings]

[0022] [Figure 1A] In vitro cell viability of test compounds of the present disclosure in MV411 cells. [Figure 1B] In vitro cell viability of test compounds of the present disclosure in MV411 cells. [Diagram 2] In vitro binding affinity of the compounds of the present disclosure to WDR5 protein, i.e., MLL1-WDR5 PPI inhibitory activity of representative compounds disclosed herein. [Figure 3A] Tolerance studies of representative compounds disclosed herein. [Figure 3B] Tolerance studies of representative compounds disclosed herein. [Figure 3C] Tolerance studies of representative compounds disclosed herein. [Figure 3D] Tolerance studies of representative compounds disclosed herein. [Figure 4A] Efficacy studies of representative compounds disclosed herein in the MV411 model. [Figure 4B] Efficacy studies of representative compounds disclosed herein in the MV411 model. [Figure 4C] Efficacy studies of representative compounds disclosed herein in the MV411 model. [Figure 4D] Efficacy studies of representative compounds disclosed herein in the MV411 model. [Figure 5A] Tolerance study of representative compounds disclosed herein in the MV411 model. [Figure 5B] Tolerance study of representative compounds disclosed herein in the MV411 model. [Figure 6A]Pharmacokinetic studies of representative compounds disclosed herein in an in vivo mouse model. [Figure 6B] Pharmacokinetic studies of representative compounds disclosed herein in an in vivo mouse model. [Figure 6C] Pharmacokinetic studies of representative compounds disclosed herein in an in vivo mouse model. [Figure 6D] Pharmacokinetic studies of representative compounds disclosed herein in an in vivo mouse model. [Figure 7] Pharmacokinetic studies of representative compounds disclosed herein in the MV411 model. [Figure 8] Pharmacokinetic studies of representative compounds disclosed herein in the MV411 model. [Figure 9A] Pharmacokinetic studies of representative compounds disclosed herein in an in vivo model. [Figure 9B] Pharmacokinetic studies of representative compounds disclosed herein in an in vivo model. [Figure 9C] Pharmacokinetic studies of representative compounds disclosed herein in an in vivo model. [Figure 10A] Pharmacokinetic studies of representative compounds disclosed herein in an in vivo model. [Figure 10B] Pharmacokinetics of representative compounds disclosed in the present disclosure in an in vivo model. [Figure 10C] Pharmacokinetics of representative compounds disclosed herein in an in vivo model. [Figure 10D] Pharmacokinetics of representative compounds disclosed herein in an in vivo model. [Figure 11A] Inhibition of HMT2&3 activity by representative compounds disclosed herein. [Figure 11B] Inhibition of HMT2&3 activity by representative compounds disclosed herein. [Figure 11C] Inhibition of HMT2&3 activity by representative compounds disclosed herein. [Figure 12A] Mean concentrations of HBI-2375 in plasma, CSF, and brain tissue from male rats. [Figure 12B] Mean concentrations of HBI-2375 in plasma, CSF, and brain tissue from female rats. [Figure 13A] Pharmacokinetic profile of HBI-2375 measured in an in vivo mouse model (matrix: plasma). [Figure 13B] Pharmacokinetic profile of HBI-2375 measured in an in vivo mouse model (matrix: brain).

[0023] Various embodiments of the present disclosure are set forth in detail in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative implementations, in which the principles of the present disclosure are utilized, and the accompanying drawings, in which: DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The phenyltriazole and aniline compounds described herein have potent inhibitory activity against MLL1-WDR5 protein-protein interaction. These compounds can reduce the MLL1 catalytic activity of MLL1 at the cellular level, downregulate the expression of Hox and Meis-1 genes, and induce apoptosis of leukemia cells. Furthermore, the compounds described herein exhibit good aqueous solubility, blood-brain barrier (BBB) ​​permeability, and pharmaceutical safety, and can be used to treat cancer, including, but not limited to, leukemia. Compounds with blood-brain barrier permeability, such as those described herein, are useful for treating brain tumors, particularly tumors expressing oncogenic MLL fusion protein phenotypes. Thus, in addition to having excellent bioavailability, the compounds described herein can further be used to treat brain tumors expressing MLL fusion protein phenotypes, whether they arise in the brain or metastasize from a primary tumor expressing MLL fusion protein.

[0025] compound Some embodiments described herein provide compounds having potent inhibitory activity against MLL1-WDR5 protein-protein interaction. Some such embodiments cross the blood-brain barrier. Some embodiments described herein provide compounds of formula (I), or a pharma- ceutically acceptable salt or solvate thereof: [ka] (In the formula, X1 is N or CH; X2 is N or CR2; X3 is N or CH; R2 is selected from N-morpholino, wherein the morpholino group is optionally substituted with one or two methyl groups; Each of R4 and R5 is hydrogen or alkyl, and one or both of R4 and R5 may be alkyl. In some preferred embodiments, one or both of R4 and R5 are alkyl. In some embodiments of the compound of formula (I), such compounds cross the blood-brain barrier.

[0026] In some embodiments, the compound has the structure of Formula (III) or a pharma- ceutically acceptable salt or solvate thereof: [ka] (In the formula, R 10 and R 11 Each of is hydrogen or C1-C4 alkyl, or R 10 and R 11 together form a 4-alkylpiperazinyl group. In some embodiments of the compounds of formula III, some of the embodiments described herein cross the blood-brain barrier.

[0027] In some embodiments, the compound has the structure of Formula (II) or a pharma- ceutically acceptable salt or solvate thereof: [ka] (In the formula, Each of R4 and R5 is hydrogen or methyl, one or both of R5 and R6 is methyl, and each of R6 and R7 is hydrogen or methyl.) In some embodiments of the compounds of formula II, some of the embodiments described herein cross the blood-brain barrier.

[0028] In some embodiments, the compound of Formula (I) or Formula (II) is represented by Formula (Ia) (DDO-2213-20), or a pharma- ceutically acceptable salt or solvate thereof: [ka]

[0029] In some embodiments, the compound of Formula (I) is represented by formula (Ib) (DDO-2213-23), or a pharma- ceutically acceptable salt or solvate thereof: [ka]

[0030] In some embodiments, the compound of formula (III) is represented by formula (IIIa) (HYBI-082), or a pharma- ceutically acceptable salt or solvate thereof: [ka]

[0031] In some embodiments, the compound of formula (III) is represented by formula (IIIb) (HYBI-084), or a pharma- ceutically acceptable salt or solvate thereof: [ka]

[0032] Surprisingly, the compound of formula (IIIb) (HYBI-084) can cross the blood-brain barrier, thereby allowing the compound to inhibit MLL1-WDR5 protein-protein interaction in brain tissue and tissues associated with brain tissue, such as the meninges. Such MLL1-WDR5 protein-protein interaction inhibitory activity exposes cancers in the brain and associated tissues to the anti-cancer activity of the compounds described herein. Some embodiments of the compounds of formula III, particularly compounds of formula (IIIb), cross the blood-brain barrier, thereby allowing the treatment of one or more brain tumors, including primary and secondary brain tumors.

[0033] In some embodiments, the compositions described herein include a compound of Formula (I), Formula (II), or Formula (III), or a pharma- ceutically acceptable salt thereof, or a solvate thereof, together with one or more pharma- ceutically acceptable carriers, diluents, and excipients. In some embodiments, the compound is a compound of Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb), or a pharma- ceutically acceptable salt thereof, or a solvate thereof.

[0034] In some embodiments, compounds described herein include, but are not limited to, compounds of formula (Ia), formula (Ib), or a pharma- ceutically acceptable salt or solvate thereof.

[0035] In some embodiments, compounds described herein include, but are not limited to, compounds of Formula (IIIa) or Formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof.

[0036] In some embodiments, compounds described herein include, but are not limited to, compounds of formula (II): or a pharma- ceutically acceptable salt or solvate thereof.

[0037] In some embodiments, the present disclosure provides a compound of formula (I), formula (II), or formula (III) that crosses the BBB. In some embodiments, the compound of formula (I), formula (II), or formula (III) crosses the BBB by transmembrane diffusion, saturable transporter, adsorptive endocytosis, or extracellular pathway. In some embodiments, the compound of formula (IIIb) crosses the BBB.

[0038] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), formula (II), or formula (III), or a pharma- ceutically acceptable salt, or a solvate thereof, and one or more pharma- ceutically acceptable carriers, diluents, and excipients. In some embodiments, the compound of formula (I), formula (II), or formula (III) can cross the blood-brain barrier. In some embodiments, after administration to a subject or patient, the compound of formula (I), formula (II), or formula (III) can be detected in the cerebrospinal fluid (CSF) of the subject or patient. In some embodiments, after administration to a subject or patient, the compound of formula (I), formula (II), or formula (III) can be detected in the brain tissue of the subject or patient. In some embodiments, the compound of formula (I), formula (II), or formula (III) can be detected in the CSF or brain tissue of the subject or patient by one of the methods described herein or art-recognized methodologies. In some embodiments, the compound of Formula (I), Formula (II), or Formula (III) is a compound of Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb).

[0039] A compound of formula (I), formula (II), or formula (III) is a compound of formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb), which has superior properties, such as improved bioavailability, superior pharmacokinetics, and the ability to cross the blood-brain barrier (BBB), as compared to other members of the same drug class. In some embodiments, the compound has superior pharmacokinetics (PK) as shown in animal models, such as mice, rats, or dogs. In some embodiments, the compounds of the invention, such as the compound of formula (IIIb) (also referred to herein as HBI-2375 or HYBI-084), cross the blood-brain barrier. In some embodiments, when the compound is administered to a human at a dose of about 1 to about 20 mg per kg of patient body weight, a brain concentration Cmax of about 10 to about 310 ng per gram of estimated patient brain weight is achieved. Brain weight may be estimated by measuring or estimating brain volume, for example, by one or more standard cranial measurements, such as extracranial measurements (e.g., using calipers), computed tomography (CT) scans, magnetic resonance (MR) scans, or similar methods of measuring or estimating brain volume and multiplying the estimated or measured brain volume by standard or population average brain density. In some embodiments, the compound, when administered orally to mice in an amount of 40 mg per kilogram of mouse body weight (mpk), provides a maximum plasma concentration (Cmax) of about 770 ng / mL to about 1505 ng / mL in mice within about 30 minutes. In some embodiments, the compound, when administered orally to mice in an amount of 40 mg per kilogram of mouse body weight (mpk), provides an average concentration of about 58 ng / mL to about 156 ng / mL in mouse brain within about 30 minutes. In some embodiments, the compound provides a maximum plasma concentration (Cmax) of about 2700 ng / mL to about 5200 ng / mL in mice within about 30 minutes when administered orally to mice at an amount of 80 mg per kilogram of mouse body weight (mpk). In some embodiments, the compound provides a mean concentration of about 191 ng / mL to about 540 ng / mL in the mouse brain within about 30 minutes when administered orally to mice at an amount of 80 mg per kilogram of mouse body weight (mpk).In some embodiments, the compound, when administered orally to mice at 40 mg per kilogram of mouse body weight (mpk), provides a maximum concentration (Cmax) in the mouse brain of about 126 ng / mL to about 234 ng / mL within about 4 hours. In some embodiments, the compound, when administered orally to mice at 80 mg per kilogram of mouse body weight (mpk), provides a maximum concentration (Cmax) in the mouse brain of about 360 ng / mL to about 700 ng / mL within about 4 hours. In some embodiments, the compound, when administered orally to mice at 40 mg per kilogram of mouse body weight (mpk), provides an area under the plasma concentration curve (AUC last In some embodiments, the area under the brain concentration curve (AUC) of the compound when administered orally to mice at an amount of 40 mg per kilogram of mouse body weight (mpk) is about 4600 hr·ng / mL to about 8600 hr·ng / mL. last In some embodiments, the area under the plasma concentration curve (AUC) of the compound when administered orally to mice at an amount of 80 mg per kilogram of mouse body weight (mpk) is about 1400 hr·ng / mL to about 2640 hr·ng / mL. last In some embodiments, the area under the brain concentration curve (AUC) of the compound when administered orally to mice at 80 mg per kilogram of mouse body weight (mpk) is about 10,900 hr·ng / mL to about 20,200 hr·ng / mL. last In some embodiments, the compound provides a maximum plasma concentration (Cmax) in dogs of about 150 nM to about 235 nM when orally administered to dogs in an amount of 1.5 mg per kilogram of dog body weight (mpk). In some embodiments, the compound provides an area under the plasma concentration curve (AUC) of about 150 nM to about 235 nM when orally administered to dogs in an amount of 1.5 mg per kilogram of dog body weight (mpk). 0-last ) is approximately 4225 nM·h to approximately 6603 nM·h.

[0040] In some embodiments, the compounds and pharmaceutical compositions described herein are useful for treating diseases, disorders, or alleviating or eliminating symptoms of diseases and disorders, such as cancer. In some embodiments, the cancer is a brain tumor. In some embodiments, the brain tumor may be a primary tumor or a metastasis secondary to another tumor.

[0041] In some embodiments, the present invention provides the use of a compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of cancer. In some embodiments, methods are provided herein for the use of a compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of cancer. The compounds described herein have superior bioavailability and pharmacokinetic properties compared to other compounds in the same class. In some embodiments of the method of treating cancer with a compound of formula (IIIb) (also referred to herein as HBI-2375 or HYBI-084), the compound crosses the blood-brain barrier. In some embodiments, the cancer is a solid cancer, a hematological cancer, or a brain tumor. In some embodiments, the effective amount is about 0.5 to about 20 mg per kg of patient body weight (mpk). In some embodiments, the patient is a human and the compound is administered at a dose of about 1 to about 20 mg per kg of patient body weight. In some embodiments, the compound is administered to a human at a dose of about 1 to about 20 mg per kg of patient body weight, with a brain concentration Cmax of about 10 to about 310 ng per gram of estimated patient brain weight. In some embodiments, the compound, when administered orally to a mouse in an amount of 40 mg per kilogram of mouse body weight (mpk), provides a maximum plasma concentration (Cmax) in the mouse of about 770 ng / mL to about 1505 ng / mL within about 30 minutes. In some embodiments, the compound, when administered orally to a mouse in an amount of 40 mg per kilogram of mouse body weight (mpk), provides an average concentration in the mouse brain of about 58 ng / mL to about 156 ng / mL within about 30 minutes. In some embodiments, the compound, when orally administered to mice in an amount of 80 mg per kilogram of mouse body weight (mpk), provides a maximum plasma concentration (Cmax) of about 2700 ng / mL to about 5200 ng / mL within about 30 minutes in mice.In some embodiments, the compound, when administered orally to mice in an amount of 80 mg per kilogram of mouse body weight (mpk), provides an average concentration in the mouse brain of about 191 ng / mL to about 540 ng / mL within about 30 minutes. In some embodiments, the compound, when administered orally to mice in an amount of 40 mg per kilogram of mouse body weight (mpk), provides a maximum concentration (Cmax) in the mouse brain of about 126 ng / mL to about 234 ng / mL within about 4 hours. In some embodiments, the compound, when administered orally to mice in an amount of 80 mg per kilogram of mouse body weight (mpk), provides a maximum concentration (Cmax) in the mouse brain of about 360 ng / mL to about 700 ng / mL within about 4 hours. In some embodiments, the compound, when administered orally to mice in an amount of 40 mg per kilogram of mouse body weight (mpk), provides an area under the plasma concentration curve (AUC last In some embodiments, the area under the brain concentration curve (AUC) of the compound when administered orally to mice at an amount of 40 mg per kilogram of mouse body weight (mpk) is about 4600 hr·ng / mL to about 8600 hr·ng / mL. last In some embodiments, the area under the plasma concentration curve (AUC) of the compound when administered orally to mice at an amount of 80 mg per kilogram of mouse body weight (mpk) is about 1400 hr·ng / mL to about 2640 hr·ng / mL. last In some embodiments, the area under the brain concentration curve (AUC) of the compound when administered orally to mice at 80 mg per kilogram of mouse body weight (mpk) is about 10,900 hr·ng / mL to about 20,200 hr·ng / mL. last In some embodiments, the compound provides a maximum plasma concentration (Cmax) in dogs of about 150 nM to about 235 nM when orally administered to dogs in an amount of 1.5 mg per kilogram of dog body weight (mpk). In some embodiments, the compound provides an area under the plasma concentration curve (AUC) of about 150 nM to about 235 nM when orally administered to dogs in an amount of 1.5 mg per kilogram of dog body weight (mpk). 0-last ) is approximately 4225 nM·h to approximately 6603 nM·h.

[0042] In some embodiments, the present invention provides the use of a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a disease mediated by inhibiting MLL1-WDR5 protein-protein interaction.

[0043] In some embodiments, the present invention provides the use of a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of MLL gene fusion leukemia.

[0044] In some embodiments, the invention provides a method for the treatment of MLL gene fusion leukemia, comprising administering a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb), or a pharma- ceutical acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of MLL gene fusion leukemia.

[0045] In some embodiments, the compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, is administered in an effective amount of about 0.1 to about 1000 mg (mpk) of the compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb) per kg of patient body weight. Preferably, the effective amount is about 0.5 to about 500 mg (mpk) of the compound per kg of patient body weight. More preferably, the effective amount is about 1 to about 100 mg (mpk) of the compound per kg of patient body weight.

[0046] In some embodiments, the compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, is administered in an effective amount of about 1.62 to about 6.48 mg (mpk) of the compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb) per kg of patient body weight. Preferably, the effective amount is about 1.30 to about 8.1 mg (mpk) per kg of patient body weight. More preferably, the effective amount is about 2.59 to about 4.05 mg (mpk) per kg of patient body weight.

[0047] In some embodiments, a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, is administered to a patient on a 1 ml basis over the body surface of the patient. 2 The effective amount of the compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is administered per m of the patient's body surface. 2 More preferably, the effective amount is about 48 to about 300 mg per square meter of the patient's body surface. 2 Approximately 96 to 150 mg per serving.

[0048] In some embodiments, the compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, is administered at an effective amount of greater than about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, or any range of amounts between any two of these amounts.

[0049] In some embodiments, the compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, is administered at an effective amount of at least about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, or any range of amounts from one to the other of any two of these amounts.

[0050] In some embodiments, the compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, is administered in an effective amount of about 1 to about 80 mg (mpk) of the compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb) per kg of patient body weight. Preferably, the effective amount is about 1 to about 60 mg (mpk) per kg of patient body weight. More preferably, the effective amount is about 1 to about 40 mg (mpk) per kg of patient body weight.

[0051] In some embodiments, the compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, is administered in an effective amount of about 1.5 to about 45 mg (mpk) of the compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb) per kg of patient body weight. Preferably, the effective amount is about 1.5 to about 40 mg (mpk) per kg of patient body weight. More preferably, the effective amount is about 1.5 to about 35 mg (mpk) per kg of patient body weight. Most preferably, the effective amount is about 1.5 to about 30 mg (mpk) per kg of patient body weight.

[0052] In some embodiments, the compound of formula (Ia), formula (Ib), or a pharma- ceutically acceptable salt or solvate of either thereof is administered in an effective amount of about 1.5 to about 45 mg (mpk) of the compound of formula (Ia) or formula (Ib) per kg of the patient's body weight. Preferably, the effective amount is about 1.5 to about 40 mg (mpk) per kg of the patient's body weight. More preferably, the effective amount is about 1.5 to about 35 mg (mpk) per kg of the patient's body weight. Most preferably, the effective amount is about 1.5 to about 30 mg (mpk) per kg of the patient's body weight.

[0053] In some embodiments, the compound of Formula (IIIa) or Formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, is administered in an effective amount of about 1.5 to about 45 mg (mpk) of the compound of Formula (IIIa) or Formula (IIIb) per kg of patient body weight. Preferably, the effective amount is about 1.5 to about 40 mg (mpk) per kg of patient body weight. More preferably, the effective amount is about 1.5 to about 35 mg (mpk) per kg of patient body weight. Most preferably, the effective amount is about 1.5 to about 30 mg (mpk) per kg of patient body weight.

[0054] In some embodiments, an effective dose of a compound of Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, is from about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 1.5 mg to about 5 mg, about 1.5 mg to about 4.5 mg, or about 15 mg to about 50 mg, about 15 mg to about 40 mg, about 10 mg to about 35 mg, or about 10 mg to about 30 mg (mpk) of the compound of Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb).

[0055] In some embodiments, the compound of formula (IIIb) or a pharma- ceutically acceptable salt or solvate thereof is administered in an effective amount of about 0.5 to about 20 mg of the compound of formula (IIIb) per kg of patient body weight (mpk). Preferably, the effective amount is about 1 to about 10 mg per kg of patient body weight (mpk). More preferably, the effective amount is about 1.5 to about 7 mg per kg of patient body weight (mpk). In some embodiments, the compound, or a pharma- ceutically acceptable salt or solvate thereof, may be administered in a clinical dose of about 1.62 mg to 6.48 mg / kg per day, and may deviate from this range depending on the severity of the condition or the dosage form.

[0056] In some embodiments, the peak concentration achieved by the compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is 287 to about 450 nM, preferably about 300 to about 370 nM, more preferably about 330 to about 360 nM, or about 1020 to 1600 nM, preferably about 1150 to 1350, more preferably 1250 to 1290 nM.

[0057] In some embodiments, the peak concentration achieved by the compounds of the present disclosure is from 1056 to about 1651 nM, preferably from about 1200 to about 1400 nM, more preferably from about 1310 to about 1350 nM, or from about 2744 to 4288 nM, preferably from about 3000 to 4000, more preferably from 3200 to 3600 nM.

[0058] In some embodiments, the peak concentration achieved by the compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is 6.7 to about 11 nM, preferably about 7.5 to about 9.5 nM, more preferably about 8.0 to about 9 nM, or about 38 to 60 nM, preferably about 40 to 55 nM, more preferably 45 to 50 nM.

[0059] In some embodiments, the peak concentration achieved by the compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is about 150 to about 235 nM, preferably about 160 to about 220 nM, more preferably about 180 to 195 nM, or 356 to about 556 nM, preferably about 400 to about 500 nM, more preferably about 420 to about 460 nM.

[0060] In some embodiments, the area under the curve (AUC) achieved by a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is 0-last ) is about 1050 to 1641 nM·h, preferably about 1200 to 1500 nMh, more preferably about 1300 to about 1350 nMh, or about 4515 to 7055 nMh, preferably about 5000 to 6500 nMh, more preferably about 5300 to 5800 nMh.

[0061] In some embodiments, the area under the curve (AUC) achieved by a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is 0-last ) is about 13132 to 20519 nM·h, preferably about 15500 to 17000 nM·h, more preferably about 16000 to about 16700 nM·h, or about 44791 to 69886 nM·h, preferably about 50000 to 60000 nM·h, more preferably about 53000 to 58000 nM·h.

[0062] In some embodiments, the area under the curve (AUC) achieved by a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is 0-last ) is about 37 to 59 nM·h, preferably about 40 to 55 nM·h, more preferably about 43 to about 48 nM·h, or about 367 to 574 nM·h, preferably about 400 to 500 nM·h, more preferably about 430 to 480 nM·h.

[0063] In some embodiments, the area under the curve (AUC) achieved by a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is 0-last ) is about 4225 to 6603 nM·h, preferably about 4800 to 5800 nM·h, more preferably about 5000 to about 5400 nM·h, or about 10734 to 16772 nM·h, preferably about 12000 to 15000 nMh, more preferably about 13200 to 13800 nM·h.

[0064] In some embodiments, the peak plasma concentration achieved by a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is from 770 ng / mL to about 1505 ng / mL, or from about 2750 to about 5200 ng / mL, or from about 1700 to about 3300.

[0065] In some embodiments, the peak concentration in the brain achieved by a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is from 120 ng / mL to about 240 ng / mL, or from about 360 to about 700 ng / mL, or from about 560 to about 1100 ng / mL.

[0066] In some embodiments, the area under the curve (AUC) achieved by a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) in plasma is last ) is approximately 4600-8600 h·ng / mL, or approximately 10900-20300 h·ng / mL, or approximately 12300-23500 h·ng / mL.

[0067] In some embodiments, the area under the curve (AUC) achieved by a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) in the brain is last) is approximately 1400-2700 h·ng / mL, or approximately 4000-7600 h·ng / mL, or approximately 6999-13100 h·ng / mL.

[0068] In some embodiments, the peak plasma concentration achieved by a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is from 730 ng / mL to about 1110 ng / mL, or from about 1240 to about 3100 ng / mL, or from about 2050 to about 3000 ng / mL within 1 hour.

[0069] In some embodiments, the peak plasma concentration achieved by a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is 580 ng / mL to about 900 ng / mL, or about 1360 to about 1740 ng / mL, or about 1040 to about 2070 ng / mL within 4 hours.

[0070] In some embodiments, the peak concentration in the brain achieved by a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is from 110 ng / mL to about 200 ng / mL, or from about 290 to about 500 ng / mL, or from about 440 to about 765 ng / mL within 1 hour.

[0071] In some embodiments, the peak concentration in the brain achieved by a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is from 150 ng / mL to about 210 ng / mL, or from about 460 to about 600 ng / mL, or from about 410 to about 1210 ng / mL within 4 hours.

[0072] In some embodiments, the method of treating cancer comprises administering a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, once daily (QD), twice daily (BID), once every other day (QOD), once weekly (QW), twice weekly (BIW), three times weekly (TIW), or once monthly (QM), in any of the dosages provided herein.

[0073] In some embodiments, a method of treating cancer includes administering a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, according to a dosing schedule, the dosing schedule comprising a first dosing period consisting of about one cycle of administering an effective dose of the compound, or a pharma- ceutically acceptable salt or solvate thereof, about once per week (QW); a first rest period; and a second dosing period consisting of about 1 to 10 cycles of administering an effective dose of the compound about once per week (QW) to about three times per day (TID).

[0074] In certain embodiments, the administered dose of a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, may be temporarily reduced or temporarily interrupted for a period of time (i.e., a "drug holiday") to alleviate unacceptable toxicity.

[0075] In some embodiments, the method of treating cancer is such that each treatment cycle is from about 7 days or about 12 days long. In some embodiments, the drug holiday is from about the same period as each cycle. In some embodiments, the drug holiday is from about 1 month, 1-6 months, or 1-12 months.

[0076] In some embodiments, the methods of treating cancer include administering a compound in a dosing schedule that includes a first dosing period consisting of about one cycle of administering an effective dose of the compound about once per week (QW) to about three times per week (TIW), followed by a first rest period, which may be followed by one or more additional cycles of treatment and rest periods.

[0077] In some embodiments, a typical daily dose of a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof, will vary within a wide range and will depend on a variety of factors, such as the indication involved, the severity of the disease being treated, the route of administration, the age, weight, and sex of the patient, and the particular compound used, and can be determined by a physician.

[0078] In some embodiments, the compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb), or a pharma- ceutically acceptable salt or solvate, may be administered in a regimen. The regimen may be configured to provide a therapeutically effective amount of the compound over a predefined period (e.g., administration time). The regimen may be configured to limit or prevent side effects or undesirable complications of the compounds disclosed herein. A regimen useful for treating cancer may include any number of days of administration, which may be repeated as needed. The administration period may be separated by a rest period that does not include administration of at least one treatment. For example, the regimen may include an administration period that includes 2, 3, 5, 7, 10, 15, 21, 28, or more days. These periods may be repeated. For example, the regimen may include a number of days set forth above, which may be repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or more times.

[0079] The regimen may include at least 1, 2, 3, 5, 7, 10 or more drug holidays.Drug holidays can be determined, for example, by monitoring the patient's response to the drug or by measuring the effectiveness of the treatment.Drug holidays apply to all of the treatments administered to the subject, so that the subject does not receive treatment for a set period of time during the drug holidays.

[0080] The regimen described herein for the treatment of cancer using the disclosed compound or its pharmacologic acceptable salt or solvate can be continued until disease progression or unacceptable toxicity.In some embodiments, treatment is continued until disease progression is reduced or reversed (i.e., disease progression from stage I to stage II cancer is slowed or reversed).In some embodiments, treatment is continued until unacceptable toxicity in the patient being treated.

[0081] In some embodiments, the compounds described herein are formulated in a pharmaceutical composition.

[0082] In some embodiments, the pharmaceutical formulation of the compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is orally administered in the form of a tablet. In some embodiments, the pharmaceutical formulation may be in the form of a capsule, gel capsule, caplet, oral suspension, oral formulation, or intravenous (IV) solution, etc.

[0083] In some embodiments, compounds described herein include, but are not limited to, compounds in Table 1, or a pharma- ceutically acceptable salt or solvate thereof. [Table 1]

[0084] In some embodiments, the compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) is a compound selected from Table 1, or a pharma- ceutically acceptable salt, solvate, polymorph, or prodrug thereof.

[0085] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof can be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0086] Further forms of the compound In some embodiments, the compounds described herein have one or more stereocenters, each of which independently exists in either the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric, and epimeric forms, as well as appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entogen (E), and zusanmen (Z) isomers, as well as appropriate mixtures thereof. In certain embodiments, the compounds described herein are prepared as stereoisomeric mixtures enriched in one of the individual stereoisomers. In some embodiments, enriched stereoisomers may be prepared by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure enantiomer-enriched portion. In some embodiments, resolution of the enantiomers is performed using covalent diastereomeric derivatives of the compounds described herein. In other embodiments, the diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is accomplished by chromatography or by formation of diastereomeric salts, separation is accomplished by recrystallization, or chromatography, or any combination thereof. See, e.g., Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers may be obtained by stereoselective synthesis.

[0087] In one embodiment, the compounds described herein may be prepared as prodrugs. A "prodrug" refers to an agent that is converted to the parent drug in vivo. Prodrugs are often useful because they may be easier to administer than the parent drug in some situations. For example, a prodrug may be bioavailable by oral administration even when the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective aqueous solubility. A non-limiting example of a prodrug is a compound described herein that is administered as an ester ("prodrug") that crosses cell membranes where aqueous solubility adversely affects motility, but when injected inside a cell where aqueous solubility is beneficial, is metabolically hydrolyzed to the carboxylic acid, the active entity. A further example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group, which is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to a form of the compound that is more biologically, pharma- ceutical, or therapeutically active. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to a biologically, pharma- ceutical, or therapeutically active compound form.

[0088] In some embodiments, prodrugs may be designed to alter the metabolic stability or transport properties of a drug, to mask side effects or toxicity, to improve the taste of a drug, or to alter other characteristics or properties of a drug. Knowledge of in vivo pharmacokinetics, pharmacodynamic processes, and drug metabolism allows for the design of prodrugs of a pharmacoactive compound once that compound is known. (See, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392;Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004;Aesop Cho, "Recent Advances in Oral Prodrug Discovery," Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006;T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series).

[0089] In some embodiments, some of the compounds described herein may be a prodrug of another derivative or active compound.

[0090] In some embodiments, the aromatic ring moiety on the compound disclosed herein is susceptible to various metabolic reactions.The incorporation of suitable substituents on the aromatic ring structure can reduce, minimize or eliminate this metabolic pathway.In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of aromatic ring to metabolic reactions are, for example, halogen, deuterium, or alkyl groups.

[0091] In some embodiments, the compounds described herein may be labeled by other means, including but not limited to, isotopic labels (e.g., radioisotopes) or the use of chromophores or fluorophores, bioluminescent labels, or chemiluminescent labels.

[0092] The compounds described herein include isotopically labeled compounds that are identical to those recited in the various formulas and structures presented herein, but in fact have one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl, and 125 In some embodiments, the isotopically labeled compounds described herein, e.g., 3 H and 14 Incorporation of a radioactive isotope such as C is useful for drug and / or substrate tissue distribution assays. In some embodiments, substitution with deuterium confers certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0093] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need of producing a metabolic product, which is then used to provide a desired effect, including a desired therapeutic effect.

[0094] As used herein, the term "pharmaceutical acceptable" refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and that is relatively non-toxic, i.e., the substance may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0095] The term "pharmaceutical acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not neutralize the biological activity and properties of the compound. In some embodiments, a pharmaceutical acceptable salt is obtained by reacting a compound disclosed herein with an acid. A pharmaceutical acceptable salt can also be obtained by reacting a compound disclosed herein with a base to form a salt.

[0096] Compounds of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) can be formed and / or used as pharma- ceutically acceptable salts. Types of pharma- ceutically acceptable salts include: (1) salts of the free base form of the compound with pharma- ceutically acceptable acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and inorganic acids; or salts of, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-capric acid, and the like. (1) acid addition salts formed by reacting with organic acids such as carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, etc.; (2) salts formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium or calcium), or an aluminum ion. In some cases, the compounds described herein may be coordinated with organic bases such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, etc. In other cases, the compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine.Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0097] It is to be understood that reference to pharmaceutically acceptable salts includes solvent addition forms, particularly solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. When the solvent is water, they form hydrates, or when the solvent is alcohol, they form alcohol acid salts. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein exist in unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein. Pharmaceutically acceptable salts and solvates may form one or more pharmaceutically acceptable polymorphs, which are also intended to be encompassed by the broader class of pharmaceutically acceptable salts or solvates.

[0098] Pharmaceutical Compositions In some embodiments, the compounds of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb) are generally formulated into pharmaceutical compositions for administration to subjects or patients. Thus, described herein are pharmaceutical compositions comprising any one or more of the aforementioned compounds, or pharma- ceutically acceptable salts thereof, and optionally one or more additional pharma- ceutically acceptable ingredients. Also described herein are methods for producing such pharma-ceutically acceptable compositions, and the use of the compositions in the manufacture of medicaments for the treatment of humans. Pharmaceutical compositions comprising the compounds of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb), or pharma-ceutically acceptable salts thereof, may be formulated in a conventional manner using one or more pharma-ceutically acceptable inactive ingredients that facilitate processing of the active compounds into pharma- ceutically usable preparations. Appropriate formulations depend on the selected route of administration. Summary summaries of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0099] As used herein, a pharmaceutical composition refers to a mixture of a compound disclosed herein, such as a compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb), or a pharma- ceutically acceptable salt thereof, with one or more other chemical components (i.e., pharma- ceutically acceptable inactive components), such as a carrier, excipient, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersant, surfactant, lubricant, colorant, diluent, solubilizer, wetting agent, plasticizer, stabilizer, permeation enhancer, wetting agent, antifoaming agent, antioxidant, preservative, or one or more combinations thereof. A pharmaceutical composition facilitates administration of a compound to an organism.

[0100] The pharmaceutical formulations described herein may be administered to a subject in a variety of ways by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intracerebroventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, buccal, topical, or transdermal routes of administration. Pharmaceutical formulations described herein include, but are not limited to, aqueous dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0101] In some embodiments, the compounds disclosed herein are administered orally.

[0102] In some embodiments, the compounds disclosed herein are administered topically.In such embodiments, the compounds disclosed herein can be formulated into various compositions that can be administered topically, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated dressings, balms, creams, or ointments.In some embodiments, the compounds disclosed herein are administered topically to skin.

[0103] In some embodiments, the compounds disclosed herein are administered by inhalation.

[0104] In some embodiments, the compounds disclosed herein are formulated for intranasal administration. Such formulations include nasal sprays, nasal mists, and the like.

[0105] In some embodiments, the compounds disclosed herein are formulated as eye drops.

[0106] In any of the foregoing aspects, there are further embodiments in which an effective amount of a compound disclosed herein is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by inhalation to a mammal, and / or (e) administered by nasal administration to a mammal, and / or (f) administered by injection to a mammal, and / or (g) administered topically to a mammal, and / or (h) administered by ophthalmic administration, and / or (i) administered rectally to a mammal, and / or (j) administered non-systemically or topically to a mammal.

[0107] In any of the foregoing aspects, further embodiments include a single administration of an effective amount of a compound disclosed herein, including further embodiments in which (i) the compound is administered once, (ii) the compound is administered to the mammal multiple times during the day, (iii) the compound is administered continuously, or (iv) the compound is administered continuously.

[0108] In any of the above aspects, further embodiments include multiple administration of an effective amount of a compound disclosed herein, including further embodiments in which (i) the compound is administered continuously or intermittently as a single dose, (ii) the multiple administrations are spaced apart by 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the mammal every 12 hours, or (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday, during which administration of the compound disclosed herein is temporarily suspended or the dose of the compound administered is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In some embodiments, the length of the drug holiday varies from 2 days to up to 1 year.

[0109] In certain embodiments, the compounds disclosed herein are administered locally rather than systemically.

[0110] In some embodiments, the compounds disclosed herein are administered locally, hi some embodiments, the compounds disclosed herein are administered systemically.

[0111] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, the pharmaceutical formulation of the compounds disclosed herein is in the form of a capsule.

[0112] In some embodiments, the dosage form of the liquid formulation for oral administration is in the form of an aqueous suspension or solution, including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.

[0113] For administration by inhalation, the compounds disclosed herein will be formulated for use as an aerosol, mist, or powder.

[0114] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner.

[0115] In some embodiments, the compounds disclosed herein are formulated as transdermal dosage forms.

[0116] In some embodiments, the compounds disclosed herein are formulated into pharmaceutical compositions suitable for intramuscular, subcutaneous, or intravenous injection.

[0117] In some embodiments, the compounds disclosed herein are to 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, or ointments.

[0118] In some embodiments, the compounds disclosed herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas. Dosage and Treatment Regimens

[0119] In some embodiments, the compounds of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) are used in the manufacture of a medicament for the treatment of a disease or condition described herein. Additionally, a method of treating any of the diseases or conditions described herein comprises administering to a subject in need of such treatment a pharmaceutical composition comprising at least one compound disclosed herein, or a pharma- ceutically acceptable salt, active metabolite, prodrug, or solvate thereof, in a therapeutically effective amount.

[0120] In some embodiments of the method of treating cancer with a compound of formula (IIIb) (also referred to herein as HBI-2375 or HYBI-084), the compound crosses the blood-brain barrier. In some embodiments, the cancer is a solid cancer, a hematological cancer, or a brain tumor. In some embodiments, the effective amount is about 0.5 to about 20 mg per kg of patient body weight (mpk). In some embodiments, the patient is a human and the compound is administered at a dose of about 1 to about 20 mg per kg of patient body weight. In some embodiments, the compound is administered to a human at a dose of about 1 to about 20 mg per kg of patient body weight, with a brain concentration Cmax of about 10 to about 310 ng per gram of estimated brain weight of the patient. In some embodiments, the compound, when orally administered to a mouse in an amount of 40 mg per kilogram of mouse body weight (mpk), results in a maximum plasma concentration (Cmax) in the mouse of about 770 ng / mL to about 1505 ng / mL within about 30 minutes. In some embodiments, the compound, when administered orally to mice in an amount of 40 mg per kilogram of mouse body weight (mpk), provides an average concentration in the mouse brain of about 58 ng / mL to about 156 ng / mL within about 30 minutes. In some embodiments, the compound, when administered orally to mice in an amount of 80 mg per kilogram of mouse body weight (mpk), provides a maximum plasma concentration (Cmax) in the mouse of about 2700 ng / mL to about 5200 ng / mL within about 30 minutes. In some embodiments, the compound, when administered orally to mice in an amount of 80 mg per kilogram of mouse body weight (mpk), provides an average concentration in the mouse brain of about 191 ng / mL to about 540 ng / mL within about 30 minutes. In some embodiments, the compound, when administered orally to mice in an amount of 40 mg per kilogram of mouse body weight (mpk), provides a maximum concentration (Cmax) in the mouse brain of about 126 ng / mL to about 234 ng / mL within about 4 hours. In some embodiments, the compound, when orally administered to a mouse at an amount of 80 mg per kilogram of mouse body weight (mpk), provides a maximum concentration (Cmax) of about 360 ng / mL to about 700 ng / mL in the mouse brain within about 4 hours.In some embodiments, the compound, when administered orally to mice at an amount of 40 mg per kilogram of mouse body weight (mpk), exhibited a plasma concentration area under the curve (AUC. last In some embodiments, the area under the brain concentration curve (AUC) of the compound when administered orally to mice at an amount of 40 mg per kilogram of mouse body weight (mpk) is about 4600 hr·ng / mL to about 8600 hr·ng / mL. last In some embodiments, the area under the plasma concentration curve (AUC) of the compound when administered orally to mice at an amount of 80 mg per kilogram of mouse body weight (mpk) is about 1400 hr·ng / mL to about 2640 hr·ng / mL. last In some embodiments, the area under the brain concentration curve (AUC) of the compound when administered orally to mice at 80 mg per kilogram of mouse body weight (mpk) is about 10,900 hr·ng / mL to about 20,200 hr·ng / mL. last In some embodiments, the compound provides a maximum plasma concentration (Cmax) in dogs of about 150 nM to about 235 nM when orally administered to dogs in an amount of 1.5 mg per kilogram of dog body weight (mpk). In some embodiments, the compound provides an area under the plasma concentration curve (AUC) of about 150 nM to about 235 nM when orally administered to dogs in an amount of 1.5 mg per kilogram of dog body weight (mpk). 0-last ) is approximately 4225 nM·h to approximately 6603 nM·h.

[0121] In some embodiments, compositions comprising a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest at least one symptom of the disease or condition. Amounts effective for this use will vary depending on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, response to the drug, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation clinical trials.

[0122] In prophylactic applications, compositions containing the compounds disclosed herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition.

[0123] In certain embodiments, the dose of the administered drug may be temporarily reduced or temporarily suspended for a period of time (ie, a "drug holiday").

[0124] Doses used in adult human treatment typically range from 97.2 mg to 388.8 mg, or from about 78 mg to about 486 mg, of a compound of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) per day. In one embodiment, the desired dose is conveniently presented in single or divided doses.

[0125] Treatment method Described herein are methods for treating diseases mediated by MLL1 through inhibition of MLL1-WDR5 protein-protein interaction, such as MLL gene fusion leukemia or brain tumors, which can be treated through inhibition of the enzymatic activity of MLL1. In some embodiments, described herein are methods for treating a disease or condition, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof. Thus, also described herein are compounds and pharmaceutical compositions for use in treating diseases mediated by MLL1 through inhibition of MLL1-WDR5 protein-protein interaction, such as MLL gene fusion leukemia or brain tumors, which can be treated through inhibition of the enzymatic activity of MLL1.

[0126] In some embodiments, the disease or condition being or being treated is cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a brain tumor. In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, the brain tumor is a secondary tumor, e.g., a metastatic brain tumor. In some embodiments, the tumor is a metastatic brain tumor, meningioma, neuroblastoma, glioblastoma, oligodendroma, or astrocytoma. In some embodiments, the cancer is a glioblastoma or neuroblastoma. In some embodiments, the cancer is a brain metastasis, e.g., a metastasis derived from one or more of the cancers in the immediately following paragraph.

[0127] In some aspects, the cancer being treated or to be treated is one or more of prostate cancer, skin cancer, ovarian cancer, cancer of non-lymphoid parenchymal organs including heart, placenta, skeletal muscle and lung, breast cancer, head and neck cancer including various lymphomas such as mantle cell lymphoma, non-Hodgkin's B-cell lymphoma, PTCL, adenoma, squamous cell carcinoma, laryngeal carcinoma, salivary gland carcinoma, thymoma and thymic carcinoma, leukemia, retinal cancer, esophageal cancer, multiple myeloma, melanoma, colorectal cancer, lung cancer, cervical cancer, endometrial cancer, gallbladder cancer, liver cancer, thyroid follicular cancer, gastric cancer, non-small cell lung cancer, glioma, urothelial carcinoma, bladder cancer, prostate cancer, renal cell carcinoma, invasive ductal carcinoma, and glioblastoma multiforme. In some embodiments, the cancer is a blood cancer or brain cancer.

[0128] In some embodiments, the cancer is a hematological cancer selected from lymphoma, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, Reed-Stemberg disease, multiple myeloma (MM), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), or chronic lymphocytic leukemia (CLL). In certain embodiments, the cancer is Hodgkin's lymphoma or Reed-Stemberg disease.

[0129] leukemia Leukemia is characterized by an abnormal increase in white blood cells in the blood or bone marrow. Among all types of cancer, the incidence of leukemia is highest in patients under the age of 35. More than 70% of childhood leukemia patients have a translocation involving chromosome 11 in which the MLL1 gene is fused with another gene (Nat. Rev. Cancer., 2007, 7(11):823-833). MLL1 translocations are also found in approximately 10% of adult acute myeloid leukemia (AML) patients who have been previously treated with topoisomerase II inhibitors for other types of cancer.

[0130] MLL1 enzyme activity is determined by the protein-protein interaction between MLL1 and WDR5. MLL1 enzyme activity affects the methylation level of H3K4. The methylation level of H3K4 is abnormally elevated in MLL fusion leukemia, and the expression levels of downstream Hox and Meis-1 genes are abnormally upregulated. When MLL1-WDR5 protein-protein interaction is inhibited by, for example, a compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa) or formula (IIIb), MLL1 catalytic activity is decreased, H3K4 methylation level is decreased, Hox and Meis-1 gene expression level is downregulated, and leukemia cell proliferation is inhibited.

[0131] In some embodiments, the cancer to be treated is leukemia. In some embodiments, the leukemia is acute leukemia. In some embodiments, the acute leukemia is acute leukemia with MLL1 gene rearrangement.

[0132] Acute myeloid leukemia (AML) The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of the short (30 kDa) CCAAT enhancer-binding protein a (C / EBPa) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. However, studies have shown that C / EBPa p30 preferentially interacts with WDR5, a key component of the SET / MLL (SET domain / mixed lineage leukemia) histone-methyltransferase complex, rather than the canonical p42 isoform. Thus, p30-bound genomic regions are enriched for MLL-dependent H3K4me3 marks. WDR5 is required for p30-dependent increased self-renewal and inhibition of myeloid differentiation, and downregulation of the latter inhibited proliferation and restored differentiation in a p30-dependent AML model. Small molecule inhibitors of WDR5-MLL binding selectively inhibit proliferation and induce differentiation in human AML cells expressing p30, revealing a mechanism of p30-dependent transformation and establishing the p30 cofactor WDR5 as a therapeutic target in CEBPA-mutated AML (Nat.Chem. Biol. 2015;11(8):571-8). Inhibition of WDR5-MLL binding by compounds of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb) provides a basis for the treatment of AML with one or more of these compounds, or pharma- ceutically acceptable salts or solvates thereof. Thus, in some embodiments, the leukemia to be treated is AML leukemia.

[0133] MYCN-amplified neuroblastoma MYCN gene amplification in neuroblastoma drives a gene expression program that strongly correlates with aggressive disease. Mechanistically, trimethylation of histone H3 lysine 4 (H3K4) at target gene promoters is a prerequisite for the transcriptional program to take hold. WDR5 is a donor of histone H3K4 that has been found to play an essential role in H3K4 trimethylation. We investigated the relationship between WDR5-mediated H3K4 trimethylation and the N-Myc transcriptional program in neuroblastoma cells. N-Myc upregulated WDR5 expression in neuroblastoma cells. Gene expression analysis revealed that WDR5 target genes include those with MYC-binding elements in their promoters, such as MDM2. WDR5 has been shown to form a protein complex with N-Myc, but not with p53, at the MDM2 promoter, leading to trimethylation of histone H3K4 and activation of MDM2 transcription (Cancer Res 2015;75(23);5143-54). RNAi-mediated attenuation of WDR5 upregulated the expression of wild-type, but not mutant, p53, an effect associated with growth inhibition and apoptosis. Similarly, small molecule antagonists of WDR5 reduced the formation of N-Myc / WDR5 complexes, expression of N-Myc target genes, and cell proliferation in neuroblastoma cells. In MYCN transgenic mice, WDR5 was overexpressed in precancerous ganglion and neuroblastoma cells compared with normal ganglion cells. Clinically, elevated levels of WDR5 in neuroblastoma specimens are an independent predictor of poor overall survival. WDR5 has been identified as a cofactor associated with N-Myc-regulated transcriptional activation and tumorigenesis, and as a novel therapeutic target for MYCN-amplified neuroblastoma (Cancer Res. 2015;75(23);5143-54, Mol. Cell. 2015;58(3):440-52). Inhibition of WDR5-MLL binding by compounds of Formula (I), Formula (II), Formula (III), Formula (Ia), Formula (Ib), Formula (IIIa), or Formula (IIIb) provides the basis for treatment of MYCN-amplified neuroblastoma with one or more of those compounds, or pharma- ceutically acceptable salts or solvates thereof.Thus, in some embodiments, the cancer to be treated is a solid tumor, e.g., a brain tumor, e.g., a neuroblastoma, which may be a MYCN-amplified neuroblastoma.

[0134] definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise. Moreover, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0135] As used herein, the following terms have the following meanings, unless otherwise indicated:

[0136] "Oxo" refers to the =O substituent.

[0137] "Alkyl" refers to a straight or branched hydrocarbon chain radical having from 1 to 20 carbon atoms and attached to the remainder of the molecule by a single bond. Alkyl containing up to 10 carbon atoms is any of the groups C1-C 10 It is referred to as alkyl, and similarly, for example, an alkyl containing up to 6 carbon atoms is C1-C6 alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, the alkyl is methyl or ethyl. Unless otherwise specified herein, the alkyl group can be optionally substituted as described below.

[0138] "Alkylene" refers to a straight or branched, divalent hydrocarbon chain that connects the rest of the molecule to a radical group. In some embodiments, alkylene is -CH-, -CHCH-, -CHCHCH-, or -CHCHCHCHCH-.

[0139] "Alkoxy" refers to a radical of formula -OR, where R is an alkyl radical as defined. Unless stated otherwise in the specification, an alkoxy group can be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In some embodiments, an alkoxy is methoxy. In some embodiments, an alkoxy is ethoxy.

[0140] "Heteroalkyl" refers to an alkyl radical as described above in which one or more carbon atoms of the alkyl are replaced with an O, N (i.e., NH, N-alkyl), or S atom. "Heteroalkylene" refers to a straight or branched, divalent heteroalkyl chain linking the remainder of the molecule to a radical group. Unless otherwise stated in the specification, a heteroalkyl or heteroalkylene group can be optionally substituted as described below. Representative heteroalkyl groups include, but are not limited to, -OCHOMe, -OCHCHOMe, or -OCHCHOCHCHNH. Representative heteroalkylene groups include, but are not limited to, -OCHCHO-, -OCHCHOCHCHO-, or -OCHCHOCHCHOCHCHO-.

[0141] "Alkylamino" refers to a radical of the formula -NHR or -NRR, where each R is independently an alkyl radical as defined above. Unless stated otherwise in the specification, an alkylamino group can be optionally substituted as described below.

[0142] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. Aromatic compounds can be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0143] "Aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. An aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, an aryl is a phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless otherwise stated in this specification, the term "aryl" or the prefix "ar-" (e.g., "aralkyl") is meant to include an optionally substituted aryl radical.

[0144] "Carboxy" refers to -CO2H. In some embodiments, the carboxy moiety may be replaced with a "carboxylic acid bioisostere," which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as the carboxylic acid moiety. A carboxylic acid bioisostere has biological properties similar to those of the carboxylic acid group.

[0145] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. Cycloalkyls may be saturated or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is attached through a carbon atom of the non-aromatic ring). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, bicyclic, or polycyclic. In some embodiments, the cycloalkyl is monocyclic. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl is bicyclic. In some embodiments, the cycloalkyl is polycyclic. Unless stated otherwise in the specification, a cycloalkyl group can be optionally substituted.

[0146] "Fused" refers to any ring structure described herein that is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or fused heteroaryl ring may be replaced with a nitrogen atom.

[0147] "Halo" or "halogen" refers to fluoro, chloro, bromo, or iodo.

[0148] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise in the specification, a haloalkyl group may be optionally substituted.

[0149] "Haloalkoxy" refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, such as trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, etc. Unless otherwise stated in the specification, a haloalkoxy group can be optionally substituted.

[0150] "Heterocycloalkyl" or "heterocyclyl" or "heterocyclic ring" refers to a 3- to 14-membered non-aromatic ring radical containing 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless otherwise stated in the specification, a heterocycloalkyl radical may be a monocyclic, bicyclic ring (which may include a fused bicyclic heterocycloalkyl (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom), a bridged heterocycloalkyl, or a spiroheterocycloalkyl), or polycyclic. A heterocycloalkyl radical is partially or fully saturated. Examples of heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise noted, heterocycloalkyls have 2-10 carbons in the ring. In some embodiments, heterocycloalkyls have 2-8 carbons in the ring. In some embodiments, heterocycloalkyls have 2-8 carbons and 1 or 2 N atoms in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons, 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons, 1-2 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.When referring to the number of carbon atoms of a heterocycloalkyl, it is understood that the number of carbon atoms of the heterocycloalkyl is not the same as the total number of atoms (i.e., skeletal atoms of the heterocycloalkyl ring) (including heteroatoms) that make up the heterocycloalkyl. Unless otherwise specified in the specification, a heterocycloalkyl group may be optionally substituted.

[0151] "Heteroaryl" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl is monocyclic or bicyclic. Specific examples of monocyclic heteroaryl include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Specific examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, the heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, the heteroaryl contains 0-4 N atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl has 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl has 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In one embodiment, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl.In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0152] The term “optionally substituted” or “substituted” means that the referenced group is substituted with one or more additional group(s) individually and independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne, C1-C6 alkylalkyne, halogen, acyl, acyloxy, —CO2H, —CO2alkyl, nitro, and amino (mono- and di-substituted amino groups (e.g., —NH2, —NHR, —NR2), and protected derivatives thereof). In some embodiments, the optional substituents are independently selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, -CN-NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, and -CO2alkyl. In some embodiments, the optional substituents are independently selected from fluoro, chloro, bromo, iodo, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituents are substituted with one or two of the aforementioned groups. In some embodiments, the optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0153] "Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by the migration of a hydrogen atom with the switching of a single bond and an adjacent double bond. In bond configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms disclosed herein are contemplated.

[0154] "Co-administration" and the like terms, as used herein, are meant to encompass the administration of selected therapeutic agents to a single patient and are intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0155] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of an agent or compound administered that is sufficient to alleviate to some extent one or more of the symptoms of the disease or condition being treated. The result may be a reduction and / or alleviation of the signs, symptoms, or pathogenesis of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound as disclosed herein that is required to produce a clinically significant reduction in a symptom of the disease. The appropriate "effective" amount in any individual case may be determined using techniques such as a dose escalation study. An "effective amount" is an amount sufficient to achieve the stated purpose (e.g., achieve the effect for which it is administered, treat the disease, reduce enzyme activity, increase enzyme activity, reduce one or more symptoms of the disease or condition) compared to the absence of the compound. An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom(s) of a disease, which may also be referred to as a "therapeutically effective amount." "Relief" of a symptom(s) (and grammatical equivalents of this phrase) refers to a decrease in the severity or frequency of the symptom(s), or the elimination of the symptom(s). A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, has an intended prophylactic effect, such as, for example, prevention or delay of onset (or recurrence) of an injury, disease, pathology, or condition, or a reduction in the likelihood of onset (or recurrence) of an injury, disease, pathology, or condition, or a symptom thereof. A complete prophylactic effect does not necessarily occur by administration of one dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount can be administered in one or more administrations. "Activity-reducing amount" as used herein refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of the antagonist. "Function-disrupting amount" as used herein refers to the amount of antagonist required to disrupt the function of an enzyme or protein compared to the absence of the antagonist.The exact amount will depend on the purpose of the treatment, and can be ascertained by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0156] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combination of two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb), and the co-agent are both administered to a patient at the same time in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb), and the co-agent are administered to a patient as separate entities, either simultaneously, in parallel, or sequentially, without any specific intervening time limit, such administration resulting in effective levels of the two agents in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients. Thus, combination therapy differs from individual therapy in that individual therapy involves stopping administration of one agent followed by a suitable drug holiday before initiating administration of the other agent.

[0157] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human. Unless otherwise specified, the terms "subject" and "patient" are intended to be synonymous, whether treated as part of a preclinical or clinical trial, or in a post-approval clinical setting.

[0158] The terms "treat," "treating," or "treatment" as used herein include alleviating, attenuating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., preventing the onset of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, alleviating symptoms caused by the disease or condition, or prophylactically and / or therapeutically halting the symptoms of the disease or condition. Synthesis method

[0159] In some embodiments, synthesis of the compounds described herein is accomplished using methods described herein, means described in the chemical literature (e.g., WO2019205687A1, WO2020172932A1, US11,479,545B2, and US2022 / 0152027A1, all of which are incorporated herein by reference in their entirety), or a combination thereof. In addition, solvents, temperatures, and other reaction conditions presented herein may be varied.

[0160] In other embodiments, the starting materials and reagents used in the synthesis of the compounds described herein are synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and AcrosOrganics.

[0161] In further embodiments, the compounds described herein, and other related compounds having different substituents, can be synthesized using the techniques and materials described herein and in, for example, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (the disclosures of which are incorporated by reference in their entirety) using art recognized methods. General methods for the preparation of the compounds disclosed herein may be obtained from reactions which may be modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formulae as provided herein. As a guide, the following synthetic methods may be utilized.

[0162] In the reactions described, it may be necessary to protect reactive functional groups, such as hydroxy, amino, imino, thio, or carboxy groups, which may be desirable in the final product to avoid undesired participation in the reaction. Detailed descriptions of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, the disclosures of which are incorporated herein by reference.

[0163] It is understood that other similar procedures and reagents may be used and that these schemes are intended as non-limiting examples only. EXAMPLES

[0164] Pharmaceutical Compositions Example A-1: ​​Parenteral Pharmaceutical Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-1000 mg of a water-soluble salt of a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. An appropriate buffer, and an optional acid or base, are optionally added to adjust the pH. The mixture is incorporated into a dosage unit form suitable for administration by injection.

[0165] Example A-2: Oral Solution To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, is added to water (along with optional solubilizer(s), optional buffer(s), and flavor excipients) to obtain a 20 mg / mL solution.

[0166] Example A-3: Oral Tablet Tablets are formulated by mixing 20-50% by weight of a compound described herein, or a pharma- ceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropylcellulose, 1-10% by weight of magnesium stearate, or other suitable excipients. Tablets are formulated by direct compression. The total weight of the compressed tablets is maintained at 100-500 mg.

[0167] Example A-4: Oral Capsules To prepare a pharmaceutical composition for oral delivery, 1-1000 mg of a compound described herein, or a pharma- ceutically acceptable salt thereof, is mixed with starch or other suitable powder blend, and the mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, suitable for oral administration.

[0168] In another embodiment, 1-1000 mg of a compound described herein, or a pharma- ceutically acceptable salt thereof, is placed into a No. 4 capsule, or a No. 1 capsule (hypromellose or hard gelatin), and the capsule is closed.

[0169] Example A-5: Topical gel composition To prepare a pharmaceutical topical gel composition, a compound as described herein, or a pharma- ceutically acceptable salt thereof, is mixed with hydroxypropylcellulose, propylene glycol, isopropyl myristate, and purified alcohol USP. The resulting gel mixture is then incorporated into a container, such as a tube, suitable for topical administration.

[0170] Compound synthesis The compounds in Table 2 may be synthesized as described in the following paragraphs.

[0171] [Table 2]

[0172] Synthesis of HYBI-084 (Formula (IIIb)): 5-amino-2-chloro-4-fluoro-N-(4-fluoro-5-(4-(4-methylpiperazine-1-carbonyl)-1H-1,2,3-triazol-1-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-3-methylbenzamide

[0173] To a solution of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 187.28 μmol, 1 eq.) and 1-methylpiperazine (38 mg, 374.56 μmol, 41.55 μL, 2 eq.) in DMF (5 mL) was added HATU (107 mg, 280.92 μmol, 1.5 eq.) and DIEA (73 mg, 561.84 μmol, 97.86 μL, 3 eq.). The mixture was stirred at 25° C. for 12 h. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm, mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3), mobile phase B: acetonitrile, gradient: 26 to 66% B in 11 min). HYBI-084 (13.2 mg, 20.57 μmol, 10.98% yield, 96.02% purity) was obtained as a yellow solid.

[0174] 1H NMR:(DMSO-d6, 400MHz) δH = 9.62 (s, 1H), 8.96 (d, J = 1.2 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 12.4 Hz, 1H), 6.81 (d, J = 9.2 Hz, 1H), 5.49 (s, 2H), 3.98 (s, 2H), 3.66 (s, 2H), 3.08 (d, J = 10.8 Hz, 2H), 2.58 - 2.52 (m, 2H), 2.38 (t, J = 4.8 Hz, 4H), 2.35 - 2.29 (m, 2H), 2.26 - 2.17 (m, 9H), 1.02 (d, J = 6.0 Hz, 6H).

[0175] HPLC: Rt = 8 min chromatography 3.439 min, XBridge Shield RP18, 5 μm, 2.1 × 50 mm, purity 96.02%.

[0176] LCMS: Rt = 4 min chromatography 2.636 min, XBridge Shield RP18, 5 μm, 2.1 × 50 mm, purity 97.89%, MS ESI calculated 615.26 [M+H] + 616.26, found 616.3.

[0177] Synthesis of HYBI-082: 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-N,N-diethyl-1H-1,2,3-triazole-4-carboxamide

[0178] To a solution of 1-(5-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 187.28 μmol, 1 eq.) and N-ethylethanamide (27 mg, 374.56 μmol, 38.58 μL, 2 eq.) in DMF (5 mL) was added HATU (107 mg, 280.92 μmol, 1.5 eq.) and DIEA (73 mg, 561.84 μmol, 97.86 μL, 3 eq.). The mixture was stirred at 25° C. for 12 h. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm, mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3), mobile phase B: acetonitrile, gradient: 29 to 69% B in 11 min). HYBI-082 (10 mg, 16.82 μmol, yield 8.98%, purity 99.101%) was obtained as a red solid.

[0179] 1H NMR:(DMSO-d6, 400MHz) δH = 9.61 (s, 1H), 8.93 (d, J = 1.6 Hz, 1H), 8.23 ​​(d, J = 8.0 Hz, 1H), 7.33 (d, J = 12.4 Hz, 1H), 6.81 (d, J = 9.2 Hz, 1H), 5.49 (s, 2H), 3.75 (q, J = 6.8 Hz, 2H), 3.47 (q, J = 7.2 Hz, 2H), 3.08 (d, J = 10.8 Hz, 2H), 2.58 - 2.51 (m, 2H), 2.39 - 2.28 (m, 2H), 2.24 (d, J = 2.4 Hz, 3H), 2.19 (s, 3H), 1.24 (t, J = 6.8 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H), 1.02 (d, J = 6.0 Hz, 6H).

[0180] HPLC: Rt = 8 min chromatography 2.973 min, XBridge Shield RP18, 5 μm, 2.1 × 50 mm, purity 99.10%.

[0181] LCMS: Rt = 4 min chromatography 2.368 min, XBridge Shield RP18, 5 μm, 2.1 × 50 mm, purity 98.77%, MS ESI calculated 588.25 [M+H] + + 589.25, found 589.3.

[0182] DDO-2213_023: (S)-6-chloro-N4-(2-(3,4-dimethylpiperazin-1-yl)-4-fluoro-5-(2-morpholinopyrimidin-5-yl)phenyl)pyrimidine-4,5-diamine

[0183] Step 1: (S)-6-chloro-N4-(2-(3,4-dimethylpiperazin-1-yl)-4-fluoro-5-(2-morpholinopyrimidin-5-yl)phenyl)pyrimidine-4,5-diamine (DDO-2213_020)

[0184] A mixture of DDO-2213_001_5 (150 mg, 349.07 μmol, 1 equiv.), 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine (122 mg, 418.88 μmol, 1.2 equiv.), Pd(dppf)Cl2.CH2Cl2 (28 mg, 34.91 μmol, 0.1 equiv.), and Cs2CO3 (227 mg, 698.13 μmol, 2 equiv.) in dioxane (4 mL) and HO (0.8 mL) was degassed and purged with N2 three times, then the mixture was stirred at 100° C. under N2 atmosphere for 12 h. The reaction mixture was diluted with DCM (100 mL) and washed with brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 μm, mobile phase A: purified water (0.05% NH3H2O+10 mM NH4HCO3), mobile phase B: acetonitrile, gradient: 30-60% B in 11 min). DDO-2213_020 (69.3 mg, 133.60 μmol, 38.27% yield, 99.09% purity) was obtained as a white solid.

[0185] 1H NMR (DMSO-d6, 400MHz) δH = 8.55 (s, 2H), 8.11 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.81 (s, 1H), 7.11 - 7.01 (m, 1H), 5.35 (s, 2H), 3.77 - 3.63 (m, 8H), 2.99 - 2.86 (m, 2H), 2.80 - 2.69 (m, 2H), 2.47 - 2.39 (m, 1H), 2.31 - 2.23 (m, 1H), 2.18 (s, 4H), 0.95 (d, J = 6.0Hz, 3H).

[0186] HPLC: Rt = 8 min chromatography 3.487 min, XBridge Shield RP18, 5 μm, 2.1 × 50 mm, purity 99.09%.

[0187] LCMS: Rt=4 min chromatography 2.674 min, XBridge Shield RP18, 5 μm, 2.1×50 mm, purity 99.49%, MS ESI calculated 513.22 [M+H]+ 514.22, found 514.3.

[0188] DDO-2213_023: Chloro-N4-(5-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-2-((S)-3,4-dimethylpiperazin-1-yl)-4-fluorophenyl)pyrimidine-4,5-diamine

[0189] Step 1: (2S,6R)-4-(5-bromopyrimidin-2-yl)-2,6-dimethylmorpholine (compound 2A)

[0190] To a solution of compound 1A (1 g, 5.17 mmol, 1 equiv.) and (2S,6R)-2,6-dimethylmorpholine (595 mg, 5.17 mmol, 1 equiv.) in MeCN (15 mL) was added DIEA (1.34 g, 10.34 mmol, 1.80 mL, 2 equiv.). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (20 mL), extracted with DCM (100 mL), and washed with brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0-2% methanol / dichloromethane at 40 mL / min). Compound 2A (1.4 g, 5.02 mmol, 97.02% yield) was obtained as a white solid.

[0191] 1H NMR (DMSO-d6, 400MHz) δH = 8.46 (s, 2H), 4.41 (dd, J = 1.6, 13.2 Hz, 2H), 3.54 (dd, J = 2.4, 4.4 Hz, 2H), 2.58 - 2.51 (m, 2H), 1.14 (d, J = 6.4 Hz, 6H).

[0192] Step 2: (2S,6R)-2,6-Dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine (compound 3A)

[0193] To a mixture of compound 2A (1 g, 3.67 mmol, 1 equiv.) in dioxane (17 mL), AcOK (721 mg, 7.35 mmol, 2 equiv.), Pin2B2 (1.12 g, 4.41 mmol, 1.2 equiv.), and Pd(dppf)Cl2 (269 mg, 367.46 μmol, 0.1 equiv.) were added under N2. The reaction mixture was stirred at 100 °C for 2 h. The mixture was diluted with H2O (20 mL) and extracted with DCM (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution of 0-5% ethyl acetate / DCM at 30 mL / min). Compound 3A (1.1 g, 3.10 mmol, 84.40% yield) was obtained as a brown oil.

[0194] 1H NMR (DMSO-d6, 400MHz) δH = 8.51 - 8.48 (m, 1H), 8.49 (s, 1H), 4.61 - 4.54 (m, 2H), 3.56 - 3.49 (m, 2H), 3.56 - 3.49 (m, 1H), 2.60 - 2.53 (m, 2H), 1.16 (s, 12H), 1.07 (s, 6H).

[0195] Step 3: 6-chloro-N4-(5-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-2-((S)-3,4-dimethylpiperazin-1-yl)-4-fluorophenyl)pyrimidine-4,5-diamine (DDO-2213_023)

[0196] A mixture of compound 5 (70 mg, 162.90 μmol, 1 equiv.), compound 3A (63 mg, 195.48 μmol, 1.2 equiv.), Pd(dppf)Cl2.CH2Cl2 (13 mg, 16.29 μmol, 0.1 equiv.), and Cs2CO3 (106 mg, 325.80 μmol, 2 equiv.) in dioxane (4 mL) and H2O (0.8 mL) was degassed and purged with N2 three times, then the mixture was stirred at 100° C. under N2 atmosphere for 12 h. The reaction mixture was diluted with H2O (10 mL), extracted with DCM (50 mL), and washed with brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm, mobile phase A: purified water (0.04% NH3H2O ​​+ 10 mM NH4HCO3), mobile phase B: acetonitrile, gradient: 40 to 70% B in 11 min). Compound DDO-2213_023 (15.1 mg, 27.77 μmol, yield 17.05%, purity 99.7%) was obtained as a white solid.

[0197] 1H NMR (DMSO-d6, 400MHz) δH = 8.53 (s, 2H), 8.10 (s, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.81 (s, 1H), 7.06 (d, J = 12.4 Hz, 1H), 5.35 (s, 2H), 4.60 - 4.48 (m, 2H), 3.63 - 3.50 (m, 2H), 2.98 - 2.86 (m, 2H), 2.81 - 2.70 (m, 2H), 2.62 - 2.52 (m, 2H), 2.43 (s, 1H), 2.31 - 2.22 (m, 1H), 2.18 (s, 3H), 2.16 - 2.11 (m, 1H), 1.16 (d, J = 6.0 Hz, 6H), 0.95 (d, J = 6.0 Hz, 3H).

[0198] HPLC: Rt = 8 min chromatography 2.997 min, XBridge Shield RP18, 5 μm, 2.1 × 50 mm, purity 99.78%.

[0199] LCMS: 2.406 min chromatographed at Rt=4 min, XBridge Shield RP18, 5 μm, 2.1×50 mm, purity 99.78%, MS ESI calculated 541.25 [M+H] + 542.25, found 542.4.

[0200] Biological Examples Cell lines and maintenance: All cell lines (MV411) used for in vitro and in vivo testing were provided as part of the Wuxi AppTech cell bank. Cell lines were maintained in medium supplemented with 10% heat-inactivated fetal bovine serum at 37°C in a 5% CO2 atmosphere in air. Tumor cells were routinely passaged twice weekly. Exponentially growing cells were used for in vitro cell potency and in vivo efficacy studies.

[0201] Example 1: Cell viability assay: For cytotoxicity assays, 2000 cells / well were seeded in 384-well plates. 24 hours after seeding, cells were treated with inhibitors at the indicated compound concentrations. On day 3 (72 hours), cells were lysed with CellTiter-Glo® Luminescent Cell Viability Assay Reagent (Promega) and luminescence was read using an EnVision multiplate reader. IC 50 The dose-response curves were fitted to a sigmoidal dose-response curve using a nonlinear regression model in order to calculate the survival rate. The equation for survival rate is given below: IC 50 Values ​​were automatically generated by GraphPad Prism 8.0. See Figures 1A and 1B and Tables 3 and 4.

number

[0202] [Table 3]

[0203] [Table 4]

[0204] WDR5 TR-FRET assay procedure: Stock compounds were transferred to the assay plate with an Echo Liquid Handler. Reactions were performed in 384-well white plates (PerkinElmer) in a final volume of 20 μl with 5 nM WDR5 protein, 10 nM peptide (Ac-ARTEVHLRKS-[Ahx-Ahx][C]-Alexa Fluor 488- NH2), and 0.25 nM Tb-anti-His antibody (Tb-Ab) in assay buffer (1X PBS, 300 mM NaCl, 0.5 mM TCEP, 0.1% CHAPS). Compounds were incubated with WDR5 protein for 30 min at room temperature. After addition of peptide and Tb-Ab, the plate was covered, protected from light, and incubated for 60 min at room temperature. An EnVision Multimode Plate reader (PerkinElmer) was used for the TR-FRET assay with an excitation wavelength of 340 nm and emission wavelengths of 495 and 520 nm. The ratio of 520 / 495 nm wavelength was used to assess the extent of FRET signal. IC was calculated by fitting the inhibition data to a sigmoidal dose-response model using XLFIT software. 50 was calculated. See FIG. 2.

[0205] [Table 5]

[0206] Compound formulation stability assay: Test samples were formulated in 10% DMSO / 10% HS 15 / 80% water and stored at 4°C. The formulated compounds were analyzed by HPLC-UV method for actual concentration and % remaining at 1, 4, and 7 days after formulation to determine the stability of the formulated test samples. The HPLC system was equipped with a Shimadzu LC-20 high performance liquid chromatograph, SIL-20AC autosampler, LC-20AB pump, and SPD-M20A detector. A Waters XBridge C18 (4.6 x 100 mm) column was applied for separation. The formulated compounds were analyzed at 1, 4, and 7 days after formulation to determine the stability of the formulated test samples. The results are summarized in Table 6. [Table 6]

[0207] Example 2: Animal Model and In Vivo Treatment: The procedures for the care and use of animals in this study were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Wuxi AppTech prior to the execution of the in-life portion of the study. The care and use of animals during the study was in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Animals (6-8 weeks old) were obtained from Beiji Vital River Laboratory Animal Co.,LTD and were acclimated prior to inoculation with tumor cells for efficacy studies and prior to dosing for tolerability studies.

[0208] In vivo safety (tolerability) study: The safety (tolerability) of the test articles was evaluated in naive BALB / c nude mice (n=3 / group). All animals were weighed and assigned to groups using a randomized block design based on body weight to ensure that all groups were comparable at baseline. The test articles were formulated in 10% DMSO / 10% solute HS 15 / 80% water and administered at 10 mL / kg. Animals were treated with each dose of the test article for 7 days and weighed daily. Any animals that showed a 20% weight loss on any one day were humanely euthanized and the corresponding dose was considered not tolerated. After 7 days, the low dose (20 mg / kg group) was increased to 80 mg / kg for the remainder of the study to determine if this dose was tolerated. Animals were terminated on day 12. See Figures 3A, 3B, 3C, and 3D. Also see Figures 5A and 5B.

[0209] Tumor Efficacy Test: MV411 cells were maintained in culture, and exponentially growing cells were harvested and quantified by cell counter prior to tumor inoculation. To generate tumors, each mouse was inoculated with MV411 tumor cells (10 × 10 in 50% Matrigel) into the right flank. 6 ) was inoculated subcutaneously. Animals were randomized and the mean tumor volume was 136 + / - 15 mm 3 Treatment was initiated when the tumor volume reached 10 mm. The day of randomization and treatment initiation was designated as day 0. Compounds were formulated in 10% DMSO / 10% solute HS15 / 80% water and administered at 10 mL / kg. Each test article was administered orally at each dose daily for 21 days. Body weight and tumor volume were measured twice weekly. Tumor volume was calculated in mm using the formula: V=(L×W×W) / 2. 3 where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L). At termination, tumors were harvested for further analysis. See Figures 4A, 4B, 4C, and 4D.

[0210] Mouse PK: Naïve C57 / Bl6 mice (Beijing Vital River Laboratory Animal Co., LTD) were administered a single intravenous bolus or oral gavage. Blood samples were collected at each sampling time point. Quantification of compound concentrations in mouse or rat plasma was quantified using an LC-MS / MS method. Plasma concentration data versus time were analyzed by a non-compartmental mode approach using the WinNonlin software program (version 6.3 or higher, Pharsight). C0 (initial concentration after drug administration), CL (serum drug concentration at steady state), V dss (distribution volume), C max (maximum peak concentration of drug), T max ( Cmax Time required to reach T 1 / 2 (time required for drug concentration to decrease by 50% after administration), AUC 0-last (area under the concentration-time curve from administration time t=0 to the time of the last measured concentration), AUC 0-inf (total drug exposure over time), MRT 0-last (mean residence time from administration time t=0 to the time of last measured concentration), MRT 0-inf Pharmacokinetic parameters were calculated, including (mean residence time of total drug exposure), % bioavailability (percentage (or fraction F) of the administered drug dose that reaches the systemic circulation) in the IV and PO groups. See Table 7 and Figures 6A, 6B, 6C, and 6D. [Table 7]

[0211] PK from tumor-bearing animals: After 22 days of continuous administration, blood was collected from tumor-bearing animals at each time point after the last dose administration, and plasma was isolated. Tumors were harvested 4 hours after the last dose administration. Samples were analyzed by LC-MS / MS analysis using PhoenixWinNonlin6.3 to determine the compound concentration in plasma or tumor samples. Concentrations were calculated using the linear / logarithmic trapezoidal rule. See Figure 7 and Figure 8.

[0212] Canine PK: Fasted or fed non-naive beagle dogs (Marshall Bioresources, Beijing, China) were administered a single intravenous bolus or oral gavage of the test compounds at the respective doses. Blood samples for plasma isolation were collected from peripheral blood vessels from restrained, unsedated animals at each sampling time point. Quantification of compound concentrations in dog plasma was quantified using an LC-MS / MS method. Plasma concentration data versus time were analyzed by a non-compartmental mode approach using the WinNonlin software program (version 6.3 or higher, Pharsight). C0, CL, V dss , C max , T max T 1 / 2 , AUC 0-last , AUC 0-inf , MRT 0-last , MRT 0-inf Pharmacokinetic parameters (%) including bioavailability (%) for the IV and PO groups were calculated. The results are summarized in Table 8. See Figures 9A, 9B, 9C and Figures 10A, 10B, 10C, and 10D. [Table 8]

[0213] Liver S9 stability assay: Test compounds (1 μM) and positive controls were incubated in duplicate with 5 mM GSH and liver S9 (1 mg protein / ml) from multiple species (including human, monkey, dog, rat, and mouse) for 0, 10, 30, and 60 minutes at 37° C. After addition of stop solution, 100 μL of supernatant was analyzed by LC-MS / MS. % remaining test compound, T 1 / 2 (min), and CLint (μL / min / mg) were calculated and reported. Liver stability data are summarized in Tables 9A, 9B, and 10.

[0214] [Table 9A]

[0215] [Table 9B]

[0216] [Table 10] TIFF2025509830000027.tif132159

[0217] WBS (whole blood stability) assay: Blood samples were freshly collected from multiple species including human, monkey, dog, rat, and mouse. 2 μM test compound and positive control were incubated with whole blood in duplicate at 0, 10, 30, 60, and 120 min at 37° C. After addition of stop solution, 200 μL of supernatant was analyzed by LC-MS / MS. % remaining test compound and T 1 / 2 The results (min) were calculated and reported. These results are summarized in Table 11.

[0218] [Table 11]

[0219] Inhibition of HMT2&3 in MV411 tumors: Histone methylation analysis by MesoScale Discovery (MSD) ELISA in MV4-11 tumors: Capture antibody, anti-histone antibody clone H11-4 (MAB3422), was purchased from EMD-Millipore. Detection antibody, H3(D1H2)XP® rabbit mAb (4499), was purchased from CST. Methyl-Histone H3(Lys4) recombinant polyclonal antibody (710795), di-methyl-Histone H3(Lys4) recombinant polyclonal antibody (710796), and tri-methyl-Histone H3(Lys4) polyclonal antibody (PA5-27029) were purchased from Threlmo Scientific. Anti-rabbit antibody goat SULFO-TAG labeled (R32AB-1) was purchased from MSD. MV4-11 tumor cell lysates were extracted with RIPA buffer containing protease inhibitors and PMSF according to MSD's instructions. Plates were coated and tumor lysates were incubated with antibodies for ELISA according to MSD's instructions. Signals from each well were read on a MESO SECTOR S600 and the ratio of mono-, di-, or trimethyl histone H3 to total H3 was analyzed. See Figure 11A-C.

[0220] Example 3: PK profile of HBI-2375 (compound of formula (IIIb) (HYBI-084)) in plasma, brain, and cerebrospinal fluid (CSF) in SD rats: This study was conducted in accordance with all regulatory protocols and in accordance with the study protocol and standard operating procedures (SOPs) of Pharmaron (Ningbo) TSP. This study was conducted under non-GLP environment.

[0221] After a single oral gavage dose of 40 mg / kg HBI-2375 / HYBI-084 in SD rats, the maximum plasma concentration of HBI-2375 in males and females was observed at 15 min after dosing. The maximum concentration of HBI-2375 in CSF in males and females was observed at 1 h after dosing. The maximum concentration of HBI-2375 in the brain was observed at 15 min after dosing in males and 1 h after dosing in females. The AUC of HBI-2375 lastThe mean values, from highest to lowest, were brain > plasma > CSF in males and plasma > brain > CSF in females. See Figures 12A-B.

[0222] AUC of HBI-2375 last The tissue to plasma ratios of HBI-2375 are summarized below in Table 12. Exposure of HBI-2375 in CSF was lower than that in plasma, with ratios of 0.011 in males and 0.0338 in females. Exposure in the brain was closer to that in plasma, with ratios of 1.31 in males and 0.928 in females.

[0223] [Table 12]

[0224] As shown in Table 13, after a single oral gavage dose of HBI-2375 at 40 mg / kg, T max The maximum concentration of HBI-2375 in SD rat plasma (C max The mean CSF HBI-2375 concentrations were 544 ng / mL in males and 934 ng / mL in females. The maximum HBI-2375 concentrations in the CSF of males and females were 1 hour after dosing. The maximum HBI-2375 concentrations in the brain were 15 minutes after dosing in males and 1 hour after dosing in females. The CSF HBI-2375 concentrations were 544 ng / mL in males and 934 ng / mL in females. max The mean C of HBI-2375 in the brain was 7.48 ng / mL in males and 24.0 ng / mL in females. max The mean values ​​for were 413 ng / g in males and 833 ng / g in females, respectively.

[0225] As shown in Table 13, the MRT of HBI-2375 in the plasma of SD rats was measured after a single oral gavage of HBI-2375 at 40 mg / kg. last The MRT for males was 4.50 hours and for females was 5.11 hours. last The CSF time was 2.00 hours in males and 8.41 hours in females. last The mean values ​​were 7.00 hours in males and 5.81 hours in females.

[0226] As shown in Table 13, the mean exposure (AUC last ) was 1679hr*ng / mL in males and 3659hr*ng / mL in females. last The mean AUC in the brain was 18.6 hr*ng / mL in males and 124 hr*ng / mL in females. last The mean AUC of HBI-2375 was 2199 hr*ng / mL in males and 3394 hr*ng / mL in females. last The values, from highest to lowest, were brain > plasma > CSF in males and plasma > brain > CSF in females.

[0227] [Table 13]

[0228] AUC last The tissue to plasma ratios of HBI-2375 are summarized below in Table 13. Exposure of HBI-2375 in CSF was lower than that in plasma, with ratios of 0.011 in males and 0.0338 in females. Exposure in the brain was closer to that in plasma, with ratios of 1.31 in males and 0.928 in females.

[0229] AUC last The female to male ratios for each group are summarized below in Table 14. HBI-2375 exposure in CSF, plasma, and brain was higher in females than in males with ratios of 6.66, 2.18, and 1.54, respectively.

[0230] [Table 14]

[0231] After a single oral gavage of 40 mg / kg HBI-2375 to SD rats, the concentrations of HBI-2375 in plasma, brain, and CSF were determined by LC-MS / MS. No abnormalities were observed in any animals during the in-life period. The maximum concentration of HBI-2375 in plasma of males and females was observed 15 min after administration. The maximum concentration of HBI-2375 in CSF of males and females was observed 1 h after administration. The maximum concentration of HBI-2375 in the brain was observed 15 min after administration in males and 1 h after administration in females.

[0232] The exposure of HBI-2375 in CSF was lower than that in plasma, with ratios of 0.011 in males and 0.0338 in females. The exposure in brain was close to that in plasma, with ratios of 1.31 in males and 0.928 in females. The exposure of HBI-2375 in CSF, plasma, and brain was higher in females than in males, with ratios of 6.66, 2.18, and 1.54, respectively. The AUClast values ​​of HBI-2375, from highest to lowest, were brain > plasma > CSF in male SD rats and plasma > brain > CSF in female SD rats.

[0233] In conclusion, after a single oral dose of 40 mg / kg HBI-2375 was administered to SD rats, HBI-2375 was distributed in the CSF and brain, and exposure continued for 24 h. Exposure in the brain was close to that in plasma, but exposure in the CSF was lower than that in plasma.

[0234] Example 4: PK profile of compound of formula (IIIb) (HBI-2375, HYBI-84) in plasma and brain in C57BL / 6J mice: This study was conducted in accordance with all regulatory protocols and in accordance with the research protocol and standard operating procedures (SOPs) of Pharmaron (Ningbo) TSP. This study was conducted under non-GLP environment.

[0235] After a single oral gavage of 40 mg / kg HBI-2375 to C57BL / 6J mice, the T max is 30 minutes, C maxwas 1139 ng / mL, and AUC last was 6598hr*ng / mL, and MRT last The T max 4 hours, C max is 180ng / g, and AUC last is 2029hr*ng / g, and MRT last The time to recovery was 8.15 hours. Details are shown in Table 15. See also Figures 16A-B.

[0236] After a single oral gavage of 80 mg / kg HBI-2375 to C57BL / 6J mice, the T max is 30 minutes, C max was 3973ng / mL, and AUC last was 15604hr*ng / mL, and MRT last The T max 4 hours, C max was 528ng / g, and AUC last is 5844hr*ng / g, and MRT last The time to recovery was 8.21 hours. Details are shown in Table 15. See also Figures 16A-B.

[0237] After repeated oral gavage of 80 mg / kg HBI-2375 for 7 days in C57BL / 6J mice, the T max is 1 hour, and C max was 2533ng / mL, and AUC last The mean plasma concentration was 17709hr*ng / mL. In the brain, T max 4 hours, C max is 807ng / g, AUC last The average mean concentration was 10001 hr*ng / g. Details are shown in Table 15. See also Figures 13A-B.

[0238] [Table 15]

[0239] After single oral gavage of 40 mg / kg or 80 mg / kg HBI-2375 and repeated oral administration of 80 mg / kg for 7 days in C57BL / 6J mice, the mean plasma concentration of HBI-2375 at 24 hours after administration was C max The mean brain concentrations of HBI-2375 at 24 hours after administration were 0.748-1.10%, 0.671-0.757%, and 2.68-3.94%, respectively. max The rates were 10.4-11.1%, 9.71-11.2%, and 14.4-18.9%. Details are shown in Table 16.

[0240] After single oral gavage of 40 mg / kg and 80 mg / kg HBI-2375 and repeated oral administration of 80 mg / kg for 7 days in C57BL / 6J mice, the exposure of HBI-2375 in the brain was lower than that in the plasma, with the ratios being 0.283, 0.361, and 0.536 in males and 0.332, 0.388, and 0.588 in females, respectively. Details are shown in Table 16.

[0241] [Table 16]

[0242] As shown in Table 17, after single oral gavage of 40 mg / kg and 80 mg / kg HBI-2375 and repeated oral dosing at 80 mg / kg for 7 days in C57BL / 6J mice, the plasma exposure of HBI-2375 in females was close to that in males (C max The ratio is 0.967 to 1.27, AUC last The ratios ranged from 0.989 to 1.22), indicating that there was no sex difference in plasma HBI-2375 exposure in C57BL / 6J mice.

[0243] As shown in Table 17, the AUC of HBI-2375 in plasma was significantly higher after single oral doses of 40 mg / kg and 80 mg / kg of HBI-2375 were administered to C57BL / 6J mice. last The increases were nearly dose-proportional, with ratios ranging from 2.32 to 2.41.

[0244] As shown in Table 17, after repeated oral administration of 80 mg / kg of HBI-2375 to C57BL / 6J mice for 7 days, the AUC last The ratios were close to those from a single dose at 80 mg / kg, ranging from 1.04 to 1.23. This result indicates that there was no obvious drug accumulation in the plasma of C57BL / 6J mice after 7 consecutive days of HBI-2375 administration at 80 mg / kg.

[0245] [Table 17]

[0246] As shown in Table 18, after single oral gavage administration of 40 mg / kg and 80 mg / kg HBI-2375 and repeated oral administration of 80 mg / kg for 7 days in C57BL / 6J mice, the exposure of HBI-2375 in the female brain was close to that of the male (C max The ratio is 1.11 to 1.24, AUC last The ratios ranged from 1.10 to 1.34), indicating that there was no sex difference in the brain exposure of HBI-2375 in C57BL / 6J mice.

[0247] As shown in Table 18, the AUC of HBI-2375 in the brain was significantly increased after single oral doses of 40 mg / kg and 80 mg / kg of HBI-2375 were administered to C57BL / 6J mice. last The increases were nearly dose-proportional, with ratios ranging from 2.81 to 2.96.

[0248] As shown in Table 18, after repeated oral administration of 80 mg / kg HBI-2375 to C57BL / 6J mice for 7 days, the exposure of HBI-2375 in the brain was close to that of a single dose of 80 mg / kg, and max The ratio was 1.44–1.60, and the AUC last The ratios were 1.54–1.87. The results indicate that there was no obvious drug accumulation in the brains of C57BL / 6J mice after 7 consecutive days of HBI-2375 administration at 80 mg / kg.

[0249] [Table 18]

[0250] After single oral gavage of 40 mg / kg and 80 mg / kg HBI-2375 and repeated oral administration of 80 mg / kg for 7 days in C57BL / 6J mice, the concentrations of HBI-2375 in plasma and brain were determined by LC-MS / MS. No abnormalities were observed in any animals during the in-life period. No gender differences in the exposure of HBI-2375 in plasma and brain were observed. The maximum concentrations of HBI-2375 in plasma were observed at 30 minutes, 30 minutes, and 1 hour, respectively, after administration. The maximum concentrations of HBI-2375 in brain were all observed at 4 hours after administration. The mean plasma HBI-2375 concentrations at 24 hours after administration were C max The mean brain concentration of HBI-2375 at 24 hours after administration was 0.671% to 3.94% of that of the control group. max The AUC exposure of HBI-2375 in the brain was lower than that in the plasma, being calculated to be 28.3-33.2% and 36.1-38.8% of that in the plasma at single doses of 40 and 80 mg / kg, and 53.6-58.8% at repeated doses of 80 mg / kg / day. The exposure of HBI-2375 in the plasma and brain of females was closer to that of males, with ratios of 0.989-1.22 in plasma and 1.10-1.34 in brain.

[0251] After single-dose oral administration of 40 mg / kg and 80 mg / kg HBI-2375 in C57BL / 6J mice, plasma and brain HBI-2375 concentrations were approximately 100%. last and C. max showed a proportional increase in exposure to

[0252] After repeated oral administration of 80 mg / kg of HBI-2375 for 7 days to C57BL / 6J mice, the AUC of HBI-2375 in the plasma and brain was last and C maxwas close to that from a single dose at 80 mg / kg. This result indicates that there was no obvious drug accumulation in the plasma and brain of C57BL / 6J mice after 7 consecutive days of HBI-2375 administration at 80 mg / kg.

[0253] In conclusion, after single oral doses of HBI-2375 at 40 mg / kg and 80 mg / kg, and repeated oral doses at 80 mg / kg for 7 days in C57BL / 6J mice, HBI-2375 was distributed to the brain with a Tmax of 4 hours, and brain exposure continued for 24 hours, accounting for 28.3-58.8% of the AUC in plasma. HBI-2375 in plasma and brain showed proportional increases in exposure, no gender differences, and no obvious drug accumulation was observed.

[0254] Example 5: Pharmacokinetics in humans

[0255] The pharmacokinetic profile for pharmaceutical compositions containing a compound of formula (I), formula (II), formula (III), formula (Ia), formula (Ib), formula (IIIa), or formula (IIIb) is determined by means similar to those described in the preceding examples. A compound, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable ingredients, are provided. The pharmaceutical composition may be administered intravenously (IV), or orally (PO), or both. The pharmaceutical composition is administered to one or more human subjects at one or more doses of about 1 to about 100 mg per kg of subject body weight, for example, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100 mg per kg of subject body weight, or any subweight within any range formed by two of the aforementioned doses. Subjects are bled immediately prior to drug administration and at designated intervals for 12, 24, 36, or 48 hours after administration. Compound concentration may be quantified, for example, by quantification using LC-MS / MS methods, as described above for mouse or rat plasma. Plasma concentration data versus time may be analyzed by similar methods. C0 (initial concentration after drug administration), CL (serum drug concentration at steady state), V dss (distribution volume), C max (maximum peak concentration of drug), T max ( Cmax Time required to reach T 1 / 2 (time required for drug concentration to decrease by 50% after administration), AUC 0-last (area under the concentration-time curve from administration time t=0 to the time of the last measured concentration), AUC 0-inf (total drug exposure over time), MRT 0-last (mean residence time from administration time t=0 to the time of last measured concentration), MRT 0-inf Pharmacokinetic parameters including (mean residence time of total drug exposure), % bioavailability (percentage (or fraction F) of an administered drug dose that reaches the systemic circulation) in one or more groups of subjects can be calculated in a similar manner.

[0256] Example 6: Crossing the Blood-Brain Barrier in Humans

[0257] The ability of the compound of formula (IIIb) (HBI_084 (HBI-2375)) to cross the BBB is determined in a population including one or more human subjects by orally (PO) or intravenously (IV) administering a pharmaceutical composition including the compound of formula (IIIb) to individual members of the population of human subjects at one or more doses as described in Example 5. Blood samples and CSF are drawn from the subjects and compound concentrations are determined in the subjects' plasma and CSF as described in Example 4. Pharmacokinetic parameters are determined by means similar to those described in Examples 1-4. The dose of HBI-2375 may be based on the target concentration in the subject's brain predicted using the following table.

[0258] [Table 19]

[0259] The compounds disclosed herein have strong inhibitory activity against MLL1-WDR5 protein-protein interaction, can reduce the MLL1 catalytic activity of MLL1 at the cellular level, downregulate the expression of Hox and Meis-1 genes, and induce apoptosis of leukemia cells.The compounds of the present invention also exhibit good water solubility, excellent bioavailability, blood-brain barrier permeability, and pharmaceutical safety, and can be used to treat various cancers, including leukemia and brain tumors.

[0260] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes in light thereof will be suggested to one skilled in the art, which are within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A method for treating cancer, the method comprising administering to a patient in need of cancer treatment a composition comprising an effective amount of a compound having a structure of Formula (I) or Formula (III): 【Chemistry 1】 (In the formula, X １ is N or CH; X ２ N, CR ２ and X ３ is N or CH; R ２ is selected from N-morpholino, wherein said morpholino group is optionally substituted with one or two methyl groups; R ４ and R ５ is hydrogen or alkyl, where R ４ and R ５ One or both of may be alkyl; R １０ and R １１ Each of the １ -C ４ alkyl or R １０ and R １１ together form a 4-alkylpiperazinyl group).

2. 2. The method of claim 1, wherein the compound has a structure selected from the group consisting of Formula (Ia), Formula (Ib), Formula (IIIa), and Formula (IIIb), or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof: 【Chemistry 2】

3. 3. The method of claim 1 or claim 2, wherein the compound has the structure of Formula (Ia), or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof.

4. 3. The method of claim 1 or claim 2, wherein the compound has the structure of formula (Ib), or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof.

5. 3. The method of claim 1 or claim 2, wherein the compound has the structure of Formula (IIIa), or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof.

6. 3. The method of claim 1 or claim 2, wherein the compound has the structure of formula (IIIb), or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof.

7. 2. The method of claim 1 , wherein the compound has the structure of formula (II) or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof: 【Chemistry 3】 (In the formula, R ４ and R ５ Each of R is hydrogen or methyl; ５ and R ６ At least one of R ６ and R ７ is hydrogen or methyl).

8. The method of any one of claims 1 to 7, comprising oral administration of an effective amount of said compound to said patient.

9. 9. The method of any one of claims 1 to 8, wherein said effective amount of said compound is from about 0.1 to about 1000 mg / kg (mpk) of said patient's body weight.

10. 10. The method of claim 9, wherein said effective amount of said compound is from about 1 to about 100 mg / kg (mpk) of said patient's body weight.

11. 11. The method of claim 10, wherein said effective amount of said compound is from about 1 to about 20 mg / kg (mpk) of said patient's body weight.

12. The compound of any one of claims 1 to 11, wherein the patient is a human and the compound is administered at a dose of about 1 to about 20 mg / kg of the patient's body weight.

13. 13. The compound of claim 12, wherein the compound is administered to a human at a dose of about 1 to about 20 mg per kg of the patient's body weight, and a brain concentration Cmax of about 10 to about 310 ng per gram of estimated brain weight of the patient.

14. 14. The method of any one of claims 1-13, comprising administering the compound once a day (Q.D.), once every other day (Q.O.D.), once a week (Q.W.), twice a week (BIW), or three times a week (TIW).

15. administering the compound in a dosing schedule, the dosing schedule comprising: a. a first administration period comprising from about one cycle of administration of an effective dose of the compound at a frequency of from about once per week (Q.W.); b. a first drug holiday; c. a second administration period comprising from about one cycle of administration of an effective dose of said compound at a frequency of from about once per week (Q.W.); The method according to any one of claims 1 to 14, comprising:

16. 16. The method of claim 15, wherein each cycle is from about 7 days or from about 12 days in length.

17. 17. The method of claim 15 or 16, wherein the drug holiday is from about the same length as each cycle.

18. administering the compound in a dosing schedule, the dosing schedule comprising: a. a first administration period comprising from about one cycle of administration of an effective dose of the compound at a frequency of from about once per week (Q.W.); b. a first drug holiday; The method according to any one of claims 1 to 14, comprising:

19. 20. The method of claim 18, wherein the drug holiday is from about as long as about one cycle.

20. 20. The method of claim 19, wherein the drug holiday is about 1 month, 1 to 6 months, or 1 to 12 months.

21. 21. The method of any one of claims 1, 2, 4, or 7-20, wherein the compound provides a maximum plasma concentration (Cmax) of about 150 to about 235 nM in the dog when orally administered to the dog in an amount of 1.5 mg per kilogram of dog body weight (mpk).

22. When the compound was orally administered to dogs at a dose of 1.5 mg per kilogram of dog body weight (mpk), the area under the plasma concentration curve (AUC ０－ｌａｓｔ 22. The method of any one of claims 1, 2, 4, or 7-21, wherein the .times. ...

23. 21. The method of any one of claims 1, 2, 4, or 7-20, wherein the compound provides a maximum plasma concentration (Cmax) of about 356 nM to about 556 nM in the dog when orally administered to the dog in an amount of 4.5 mg per kilogram of dog body weight (mpk).

24. When the compound was orally administered to dogs at a dose of 4.5 mg per kilogram of dog body weight (mpk), the area under the plasma concentration curve (AUC ０－ｌａｓｔ 24. The method of any one of claims 1, 2, 4, 7-20, or 23, wherein the .times. ...

25. 21. The method of any one of claims 1, 2, 4, or 7-20, wherein the compound provides a maximum plasma concentration (Cmax) in the mouse of about 1056 to about 1651 nM when orally administered to the mouse in an amount of 10 mg per kilogram of mouse body weight (mpk).

26. When the compound was orally administered to mice at an amount of 10 mg per kilogram of mouse body weight (mpk), the area under the plasma concentration curve (AUC ０－ｌａｓｔ 26. The method of any one of claims 1, 2, 4, 7-20, or 25, wherein the .times. ...

27. 21. The method of any one of claims 1, 2, 4, or 7-20, wherein the compound provides a maximum plasma concentration (Cmax) in the mouse of about 2744 to about 4288 nM when orally administered to the mouse in an amount of 30 mg per kilogram (mpk) of mouse body weight.

28. When the compound was orally administered to mice at an amount of 30 mg per kilogram of mouse body weight (mpk), the area under the plasma concentration curve (AUC ０－ｌａｓｔ 28. The method of any one of claims 1, 2, 4, 7-20, or 27, wherein the .times. ...

29. 29. The method of any one of claims 21-28, wherein the compound has the structure of Formula (Ib), or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof.

30. 21. The method of any one of claims 1-3, or 7-20, wherein the compound provides a maximum plasma concentration (Cmax) in the mouse of about 1338 to about 2091 nM when orally administered to the mouse in an amount of 10 mg per kilogram (mpk) of mouse body weight.

31. When the compound was orally administered to mice at an amount of 10 mg per kilogram of mouse body weight (mpk), the area under the plasma concentration curve (AUC ０－ｌａｓｔ 31. The method of any one of claims 1 to 3, 7 to 20, or 30, wherein the .times. ...

32. 21. The method of any one of claims 1-3, or 7-20, wherein the compound provides a maximum plasma concentration (Cmax) of about 4374 to about 6834 nM in the mouse when orally administered to the mouse in an amount of 30 mg per kilogram (mpk) of mouse body weight.

33. When the compound was orally administered to mice at an amount of 30 mg per kilogram of mouse body weight (mpk), the area under the plasma concentration curve (AUC ０－ｌａｓｔ 33. The method of any one of claims 1-3, 7-20, or 32, wherein the .times. ...

34. 34. The method of any one of claims 30-33, wherein the compound has the structure of Formula (Ia), or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof.

35. 21. The method of any one of claims 1, 2, 6, or 8-20, wherein the compound provides a maximum plasma concentration (Cmax) of about 6.7 nM to about 11 nM in the dog when orally administered to the dog in an amount of 1.5 mg per kilogram (mpk) of the dog's body weight.

36. When the compound was orally administered to dogs at a dose of 1.5 mg per kilogram of dog body weight (mpk), the area under the plasma concentration curve (AUC ０－ｌａｓｔ 36. The method of any one of claims 1, 2, 6, 8-20, or 35, wherein the mAb is from about 37 nM·h to about 59 nM·h.

37. 21. The method of any one of claims 1, 2, 6, or 8-20, wherein the compound provides a maximum plasma concentration (Cmax) of about 38 nM to about 60 nM in the dog when orally administered to the dog in an amount of 4.5 mg per kilogram of dog body weight (mpk).

38. When the compound was orally administered to dogs at a dose of 4.5 mg per kilogram of dog body weight (mpk), the area under the plasma concentration curve (AUC ０－ｌａｓｔ 38. The method of any one of claims 1, 2, 6, 8-20, or 37, wherein the .times. ...

39. 21. The method of any one of claims 1, 2, 6, or 8-20, wherein the compound provides a maximum plasma concentration (Cmax) in the mouse of about 287 to about 449 nM when orally administered to the mouse in an amount of 10 mg per kilogram (mpk) of mouse body weight.

40. When the compound was orally administered to mice at an amount of 10 mg per kilogram of mouse body weight (mpk), the area under the plasma concentration curve (AUC ０－ｌａｓｔ 40. The method of any one of claims 1, 2, 6, 8-20, or 39, wherein the .times. ...

41. 21. The method of any one of claims 1, 2, 6, or 8-20, wherein the compound provides a maximum plasma concentration (Cmax) in the mouse of about 1020 to about 1595 nM when orally administered to the mouse in an amount of 30 mg per kilogram (mpk) of mouse body weight.

42. When the compound was orally administered to mice at an amount of 30 mg per kilogram of mouse body weight (mpk), the area under the plasma concentration curve (AUC ０－ｌａｓｔ 42. The method of any one of claims 1, 2, 6, 8-20, or 41, wherein the .times. ...

43. 43. The method of any one of claims 35-42, wherein the compound has the structure of Formula (IIIb), or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof.

44. 21. The method of any one of claims 1, 2, 5, or 8-20, wherein the compound provides a maximum plasma concentration (Cmax) in the mouse of about 1337 to about 2090 nM when orally administered to the mouse in an amount of 10 mg per kilogram (mpk) of mouse body weight.

45. When the compound was orally administered to mice at an amount of 10 mg per kilogram of mouse body weight (mpk), the area under the plasma concentration curve (AUC ０－ｌａｓｔ 45. The method of any one of claims 1, 2, 5, 8-20, or 44, wherein the .times. ...

46. 21. The method of any one of claims 1, 2, 5, or 8-20, wherein the compound provides a maximum plasma concentration (Cmax) of about 3627 to about 5668 nM in the mouse when orally administered to the mouse in an amount of 30 mg per kilogram (mpk) of mouse body weight.

47. When the compound was orally administered to mice at an amount of 30 mg per kilogram of mouse body weight (mpk), the area under the plasma concentration curve (AUC ０－ｌａｓｔ 46. ​​The method of any one of claims 1, 2, 5, 8-20, or 45, wherein the .times. ...

48. 48. The method of any one of claims 44-47, wherein the compound has the structure of Formula (IIIa), or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof.

49. 10. The method of any one of claims 1, 2 or 7, wherein the compound crosses the blood-brain barrier.

50. The method of any one of claims 1 to 49, wherein the patient has a brain tumor.

51. 51. The method of claim 50, wherein the brain tumor is a metastatic brain tumor, meningioma, neuroblastoma, glioblastoma, or astrocytoma.

52. A method for treating cancer, the method comprising administering to a patient in need of cancer treatment a composition comprising an effective amount of a compound having a structure of formula (IIIb): 【Chemistry 4】

53. 53. The method of claim 52, wherein the compound crosses the blood-brain barrier.

54. 53. The method of claim 52, wherein the cancer is a solid cancer, a blood cancer, or a brain cancer.

55. 53. The method of claim 52, wherein said effective amount of said compound is from about 0.5 to about 20 mg / kg (mpk) of said patient's body weight.

56. The compound of any one of claims 1 to 11, wherein the patient is a human and the compound is administered at a dose of about 1 to about 20 mg / kg of the patient's body weight.

57. 57. The compound of claim 56, wherein the compound is administered to a human at a dose of about 1 to about 20 mg per kg of the patient's body weight, and a brain concentration Cmax of about 10 to about 310 ng per gram of estimated brain weight of the patient.

58. 58. The method of any one of claims 52-57, wherein the compound, when orally administered to the mouse in an amount of 40 mg per kilogram of mouse body weight (mpk), provides a maximum plasma concentration (Cmax) of about 770 ng / mL to about 1505 ng / mL within about 30 minutes in the mouse.

59. 58. The method of any one of claims 52-57, wherein the compound, when orally administered to the mouse in an amount of 40 mg per kilogram of mouse body weight (mpk), results in an average concentration of about 58 ng / mL to about 156 ng / mL in the brain of the mouse within about 30 minutes.

60. 58. The method of any one of claims 52-57, wherein the compound, when orally administered to the mouse in an amount of 80 mg per kilogram of mouse body weight (mpk), provides a maximum plasma concentration (Cmax) of about 2700 ng / mL to about 5200 ng / mL within about 30 minutes in the mouse.

61. 58. The method of any one of claims 52-57, wherein the compound, when orally administered to a mouse in an amount of 80 mg per kilogram of mouse body weight (mpk), results in an average concentration of about 191 ng / mL to about 540 ng / mL in the brain of the mouse within about 30 minutes.

62. 58. The method of any one of claims 52-57, wherein the compound, when orally administered to the mouse in an amount of 40 mg per kilogram of mouse body weight (mpk), results in a maximum concentration (Cmax) of about 126 ng / mL to about 234 ng / mL in the brain of the mouse within about 4 hours.

63. 58. The method of any one of claims 52-57, wherein the compound, when orally administered to the mouse in an amount of 80 mg per kilogram of mouse body weight (mpk), results in a maximum concentration (Cmax) of about 360 ng / mL to about 700 ng / mL in the brain of the mouse within about 4 hours.

64. When the compound was orally administered to mice at an amount of 40 mg per kilogram of mouse body weight (mpk), the area under the plasma concentration curve (AUC ｌａｓｔ 58. The method of any one of claims 52 to 57, wherein the IL-10 concentration is from about 4600 hr.ng / mL to about 8600 hr.ng / mL.

65. When the compound was orally administered to mice at a dose of 40 mg per kilogram of mouse body weight (mpk), the area under the brain concentration curve (AUC ｌａｓｔ 58. The method of any one of claims 52 to 57, wherein the .times. ...

66. When the compound was orally administered to mice at an amount of 80 mg per kilogram of mouse body weight (mpk), the area under the plasma concentration curve (AUC ｌａｓｔ 58. The method of any one of claims 52 to 57, wherein the HR ng / mL is from about 10900 hr ng / mL to about 20200 hr ng / mL.

67. When the compound was orally administered to mice at a dose of 80 mg per kilogram of mouse body weight (mpk), the area under the brain concentration curve (AUC ｌａｓｔ 58. The method of any one of claims 52 to 57, wherein the HR ng / mL is from about 4090 hr ng / mL to about 7600 hr ng / mL.

68. 58. The method of any one of claims 52-57, wherein the compound provides a maximum plasma concentration (Cmax) of about 150 to about 235 nM in the dog when orally administered to the dog in an amount of 1.5 mg per kilogram (mpk) of the dog's body weight.

69. When the compound was orally administered to dogs at a dose of 1.5 mg per kilogram of dog body weight (mpk), the area under the plasma concentration curve (AUC ０－ｌａｓｔ 58. The method of any one of claims 52 to 57, wherein the .times. ...

70. A compound that inhibits MLL1-WDR5 protein-protein interaction and crosses the blood-brain barrier.

71. 71. The compound of claim 70, wherein the structure of the compound is Formula (I) or Formula (III): 【Chemistry 5】 (In the formula, X １ is N or CH; X ２ N, CR ２ and X ３ is N or CH; R ２ is selected from N-morpholino, wherein said morpholino group is optionally substituted with one or two methyl groups; R ４ and R ５ is hydrogen or alkyl, where R ４ and R ５ One or both of may be alkyl; R １０ and R １１ Each of the １ -C ４ alkyl or R １０ and R １１ together form a 4-alkylpiperazinyl group).

72. 71. The compound of claim 70, wherein the compound has a structure selected from the group consisting of Formula (Ia), Formula (Ib), Formula (IIIa), and Formula (IIIb), or a pharma- ceutically acceptable salt, polymorph, solvate, enantiomer, stereoisomer, or prodrug thereof: 【Chemistry 6】

73. 73. The compound of claim 72 having the structure of formula (IIIb):

74. 74. A compound according to any one of claims 70 to 73 for use in the treatment of cancer.

75. 75. The compound of claim 74, wherein the cancer being treated is a brain tumor.

76. 76. The compound of claim 75, wherein the cancer being treated is a primary or secondary brain tumor.

77. 77. The compound of claim 76, wherein the cancer being treated is a metastatic tumor.

78. 78. The compound of claim 77, wherein the cancer being treated is glioblastoma, neuroblastoma, or astrocytoma.

79. A pharmaceutical composition comprising a compound according to any one of claims 70 to 78, and optionally one or more pharma- ceutically acceptable ingredients.

80. Use of a compound according to any of claims 70 to 78 for the preparation of a pharmaceutical composition.

81. 81. The use of claim 80, wherein the pharmaceutical composition comprises one or more pharma- ceutically acceptable ingredients.

82. 82. A process for making the pharmaceutical composition of claim 81, comprising mixing the compound with one or more pharma- ceutically acceptable ingredients.

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